Officers of the Society: President: Mary M. Reilly, President‐Elect: Steven S. Scherer,
Secretary/Treasurer: David R. Cornblath, Assistant Secretary/Treasurer: Michael Polydefkis
Board Members: David Adams, Alessandra Bolino, Chiara Briani, Christopher Klein, Michael
P.T. Lunn, Davide Pareyson
Inflammatory Neuropathy Consortium Representative: Richard Lewis
Charcot Marie Tooth and Related Neuropathies Consortium Representative: Davide Pareyson
Scientific Program Committee: Lawrence Wrabetz, Co‐chair, David Bennett, Co‐chair
Scientific Review Committee: Jose Berciano, Wendy Campana, David R. Cornblath, Susumu
Kusunoki, Isabel Illa, Alison Lloyd, Xavier Navarro, Francesc Palau, Davide Pareyson,
Michael Polydefkis, Luis Querol, Mary M. Reilly, Ricardo Rojas Garcia, Steven S. Scherer,
Jordi Serra, Teresa Sevilla, Charlotte Sumner, Carla Taveggia, Pieter van Doorn
Local Organizing Committee: Isabel Illa, Chair, Jose Berciano, Xavier Navarro, Francesc
Palau, Luis Querol, Ricardo Rojas Garcia, Jordi Serra
PNS Executive Office
Executive Director: Janel Fick (janelfick@PNSociety.com)
Communications & Project Coordinator: Tanya Baker (info@PNSociety.com; http://www.pnsociety.com)
Organizing Secretariat
The office: (pns2017@theoffice.it; http://www.theoffice.it/pns2017)
Platinum sponsorship for the Meeting was provided by: Alnylam Pharmaceuticals, Inc.,
CSL Behring, Grifols, S.A., Kedrion S.p.A., Pfizer, Inc. ‐ Rare Disease, Terumo BCT,
Inc.
Gold sponsorship for the Meeting was provided by: Shire, Plc
Silver sponsorship for the Meeting was provided by: GBS/CIDP Foundation International,
Octapharma AG
Bronze sponsorship for the Meeting was provided by: Acceleron Pharma, Inc., Ionis
Pharmaceuticals, Inc., LFB Biomedicaments, Mayo Medical Laboratories, Pharnext, SA
Sponsors: Hereditary Neuropathy Foundation, Syntimmune, Inc., UCB Biosciences, Inc.
This support is gratefully acknowledged.
The Peripheral Nerve Society
The Peripheral Nerve Society was founded in 1994 from two groups of academic investigators,
Peripheral Nerve Study Group and Peripheral Neuropathy Association of America, interested
in the basic biology and function of the peripheral nervous system and its application
to the clinic. Their invite only biennial meetings involved 80–125 attendees in cloistered
settings organized by shoestring and local initiative. From this, we have grown remarkably.
We now have an annual meeting of over 600 people including meetings within the meeting
for the special interest groups in inflammatory, diabetic and hereditary neuropathy.
With this substantial growth and the success of JPNS, the Journal of the Peripheral
Nervous System the Society continues to flourish.
2017 has proven to be a year full of exciting changes for the Society. PNS has transitioned
from a biannual, to an annual meeting. Next year, the meeting will be taking place
at the Renaissance Baltimore Harborplace Hotel from 22–25 July in Baltimore, Maryland.
The development of a new website has been completed, please visit http://www.pnsociety.com
to see the new face of the Society. Finally, PNS has adopted new Executive Staff.
With their guidance and the leadership of an active and diverse Board of prominent
professionals in the field the Peripheral Nerve Society continues to grow and anticipates
more exciting changes in the year to come.
The Peripheral Nerve Society provides Annual Meetings, Teaching Courses, Guidelines,
and other resources to aid in the education of members. Becoming a member of PNS means
collaborating with prominent global professionals in the field to develop and provide
the best treatments for people with peripheral nerve diseases and setting standards
of care within the field. Please participate in our future by joining the PNS, volunteering
for a project aligned with your interests and sending your ideas for the future to
the Executive Office, or Board member.
RP Bunge Lecture
MOLECULAR ASPECTS OF THE FORMATION/MAINTENANCE OF THE NODE OF RANVIER
Peles E
1.
1Department of Molecular Cell Biology, Rehovot, Israel.
Two Schwann cell‐dependent mechanisms control the presence of Na+ channels at the
nodes of Ranvier:
i.
clustering of the nodal complex by glia‐derived proteins and
ii.
restriction of nodal proteins within the nodal gap by the paranodal junctions. These
mechanisms depend on specific cell adhesion molecules that mediate the contact between
myelinating glia and their underlying axons at the forming nodes and the paranodal
junction. During myelination, Na+ channels initially clustered at heminodes that border
each myelin segment. This process requires gliomedin, NrCAM and neurofascin 186 (NF186),
three cell adhesion molecules (CAMs) that mediate the interaction between Schwann
cell microvilli and the axon. Na+ channels clustering activity of gliomedin is tightly
regulated by two distinct and functionally opposing proteolytic events. While the
clustering activity of gliomedin is enhanced by its shedding from the surface of Schwann
cells by a furin protease, its activity is negatively regulated by bone morphogenetic
protein 1/Tolloid‐like (BMP1/TLD), and Tolloid‐like 1 (Tll1) metalloproteinase. Cleavage
by these enzymes restricts the activity of gliomedin to the nodal area and prevents
the formation of ectopic clusters along axons that are devoid of myelin segments,
as well as below the myelin internodes. Hence, proteolytic processing of gliomedin
facilitates, yet limits, the clustering of Na+ channels to specific sites along the
axon in a timely manner. Furthermore, axon‐glial contact mediated by gliomedin and
NF186 at the nodes, not only plays a role in Na+ channel clustering during development,
but also contributes to the long‐term maintenance of Na+ channels at nodes of Ranvier.
In addition to clustering by gliomedin, the distribution of Na+ channels is restricted
between two growing myelin segments by the flanking paranodal junction. At this site,
axon‐glia contact is mediated by a distinct set of cell adhesion molecules (i.e.,
Caspr, NF155 and contactin) that also delineate the underlying axonal and glial cytoskeleton.
This paranodal junction‐dependent restriction of Na+ channels to the nodes is mediated
by the spectrin‐based paranodal axonal cytoskeleton.
AK Asbury Lecture
CLINICAL ASPECTS AND NEW ANIMAL MODELS OF AUTO‐IMMUNITY TO NODAL COMPONENTS
Illa I
1.
1Neuromuscular Unit, Neurology Department, Hospital Santa Creu i Sant Pau, Universitat
Autònoma de Barcelona, Barcelona, Spain.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune
disorder of the peripheral nerves with clinical and immunological heterogeneity. Currently,
the diagnosis of CIDP is based on clinical and electrophysiological criteria and does
not take into consideration the presence of immune biomarkers. Several autoantibodies
against proteins of the node of Ranvier in patients with CIDP have now been described.
These antibodies define specific CIDP subtypes sometimes referred to as nodopathies
and can have diagnostic and prognostic implications.
Anti‐Contactin 1 (CNTN1) antibodies
. We have described the presence of antibodies to CNTN1 in a small subset of patients
with CIDP. These patients shared a phenotype and have poor response to IVIg. The anti‐CNTN1
antibodies are predominantly IgG4. Pathological studies from skin and sural nerve
biopsies of patients show morphological changes in the paranodes. Experimental data
supporting the pathogenicity of anti‐CNTN1 IgG4 antibodies include: A) demonstration
in vitro that the antibodies disrupt the binding of the CNTN1–CASPR1 complex to neurofascin‐155
(NF155); B) intraneural injections of antibodies progressively and specifically disrupt
the paranodal axo‐glial junction; and C) chronic infusion of antibodies induced clinical
and electrophysiological worsening in animals with experimental autoimmune neuritis
(EAN).
Anti‐NF155 antibodies
. Antibodies to neurofascins were first reported in patients with Guillain‐Barré (GBS)
and CIDP and subsequently, antibodies specific to the NF155 isoform were found in
a small group (<3%) of patients with CIDP. Studies by us and confirmed by others have
demonstrated that patients with CIDP and anti‐NF155 antibodies have a distinct phenotype
that often includes a low‐frequency tremor and poor responses to IVIg. The autoantibodies
are predominantly of the IgG4 subtype. The passive transfer of monoclonal anti‐neurofascin
antibodies (which recognize all neurofascin isoforms) to mice with EAN strongly exacerbated
the severity of the pathology, but no studies have yet demonstrated that patient‐derived
anti‐NF155 IgG4 antibodies are pathogenic. A pathogenic role of the antibodies is
however supported by sural nerve biopsies from patients with CIDP and anti‐NF155 antibodies
that showed paranodal demyelination in the absence of inflammation, the loss of septate‐like
junctions and, the interposition of cellular processes between the paranodal loops
and the axolemma. These alterations are reminiscent of those found in Nfasc‐null mice
suggesting that anti‐NF155 antibodies may specifically disrupt the NF155–CNTN1–CASPR1
complex at the paranodes.
Antibodies to other nodal proteins
. Recently neurofascin‐186 and neurofascin‐140 were reported as the main targets of
autoantibodies in five patients with IgG reactivity against the nodes of Ranvier;
the antibodies were predominantly IgG4. These patients presented with clinical features
distinct from those in patients with anti‐NF155 IgG4 antibodies. Four of these patients
had subacute onset of sensory ataxia without tremor. The presence of anti‐CASPR1 antibodies
has been reported in two patients with inflammatory neuropathies, one classified as
CIDP, the other as GBS. Both patients had intense neuropathic pain. The skin biopsy
from both patients showed paranodal disruption. Some patients whose sera show nodal
or paranodal reactivity in teased nerve fiber preparations have antibodies against
other nodal proteins, such as gliomedin or neuronal cell adhesion molecule (NrCAM).
Treatment of nodopathies
. Corticosteroids are reported effective in approximately 40‐60% of cases. Clinical
remission has been noted following rituximab, and was associated with autoantibody
depletion and neurophysiological improvement.
Conclusions.
The clinical and immunological heterogeneity of CIDP is being unraveled with the description
of specific autoantibodies and their association with disease phenotypes. For some
of these autoantibodies, such as CNTN1 and NF155, we have shown their clinical value
and association with treatment response, as well as a pathogenic role in these immune
neuropathies that are now recognized as nodopathies. On‐going research will determine
if there are additional clinically valuable immune associations in other subgroups
of CIDP patients.
JW Griffin Lecture
METABOLIC SUPPORT OF AXONS BY SCHWANN CELLS
Milbrandt J
1.
1Washington University School of Medicine, Washington, USA.
Axon degeneration is a form of programmed subcellular death that is a central, perhaps
initiating event, in many neurological disorders. NAD metabolism plays a central role
in this self‐destructive process, which also requires the Toll‐like receptor adaptor,
SARM1, and MAP kinases, including DLK. The dismantling of damaged axons can be prevented
by NAD biosynthetic enzymes. This was first observed in studies of the Wlds mutant
mouse, with later work showing that the short‐lived NMNAT2 isoform located in the
axon helps block activation of this degeneration pathway. SARM1 is the central executioner
of the axonal degeneration pathway and its activation culminates in depletion of axonal
NAD+, yet the identity of the underlying NAD+‐ depleting enzyme(s) was unknown. We
have now discovered that the SARM1‐TIR domain itself, which is commonly appreciated
as a scaffolding domain, has intrinsic NADase activity—cleaving NAD+ into ADP‐ribose
(ADPR), cyclic ADPR, and nicotinamide. Mutation analysis of SRM1 showed that its NADase
activity is necessary for axon degeneration after injury, suggesting that SARM1 represents
a novel therapeutic target for peripheral neuropathy and other neurodegenerative conditions.
PJ Dyck Lecture
MECHANOTRANSDUCTION AND PAIN
Lewin G
1.
1Max Delbrück Center for Molecular Medicine, Berlin, Germany.
The skin is equipped with specialized mechanoreceptors that allow the perception of
the slightest brush. Indeed some mechanoreceptors can detect even nanometer‐scale
movements. Movement is transformed into electrical signals via the gating of mechanically‐activated
ion channels at sensory endings in the skin. The sensitivity of PIEZO mechanically‐gated
ion channels are controlled by stomatin‐like protein‐3 (STOML3), which is required
for normal mechanoreceptor function. Under pathophysiological conditions following
nerve injury or diabetic neuropathy the slightest touch can produce pain. It is at
present unclear whether peripheral changes in sensory mechanotransduction may underlie
hypersensitivity associated with neuropathic pain. Here we have examined the role
of the STOML3 modulation of PIEZO2 channels in mechanoreceptors and nociceptors to
under pathophysiological conditions. We recently developed small molecules that act
as inhibitors of STOML3 function. Peripheral application of STOML3 inhibitors can
alleviate hypersensitivity in models of neuropathic pain. Our data strongly suggest
that tactile evoked pain in models of peripheral neuropathy may be at least partly
driven by sensitization of sensory mechanotransduction driven by STOML3.
PK Thomas Lecture
THE CONTROL OF WALLERIAN DEGENERATION AND ITS RELEVANCE TO PERIPHERAL NEUROPATHY
Coleman M
1.
1John van Geest Centre for Brain Repair, Cambridge, UK.
Axons are lost early in many neurodegenerative disorders of peripheral and central
nervous system. The degeneration of transected axons (Wallerian degeneration) can
be slowed tenfold by overexpression of a variety of NAD‐synthesizing enzymes, such
as isoforms of NMNAT or the related mutant fusion protein, WLDS. Wallerian degeneration
is also delayed by deletion of TLR adapter protein SARM1, a protein recently reported
to promote NAD degradation. It is important to understand fully the mechanism of Wallerian
degeneration because related mechanisms contribute to axon loss in a number of disease
models, including models of peripheral neuropathies, Parkinson's disease, multiple
sclerosis and glaucoma. New data also suggest a role in hereditary spastic paraplegia.
While depletion of NAD is an attractive hypothesis for the mechanism of Wallerian
degeneration, especially as NAD can be increased by dietary methods, it cannot explain
a number of key observations. FK866, an inhibitor of NAMPT, blocks the NAD salvage
pathway and strongly depletes NAD, including within axons. However, instead of killing
axons as the NAD hypothesis would predict, it does precisely the opposite: it phenocopies
the protective effect of WLDS. Moreover, ectopic expression of the bacterial enzyme
NMN deamidase, a protein absent in mammals, protects injured axons both in transgenic
mice and in primary neuronal cultures, but it has no effect on NAD levels either under
basal conditions or in degenerating nerves. These observations fit better with a proposed
toxic role for the NAD synthesis intermediate NMN, a model that can also explain the
protective effect of WLDS. A full understanding of the pathway should identify a number
of points where intervention could be a treatment for multiple axonopathies.
Plenary Lecture
NEURO‐EPIDEMIOLOGY AND ITS RELEVANCE TO PHERIPHERAL NEUROPATHY
Sejvar J
1.
1National Center for Emerging and Zoonotic Diseases, U.S. Centers for Disease Control
and Prevention, Atlanta, GA, USA.
As with any medical discipline, expansoin of knowledge about the fundamental science
behing a disorder of the human nervous system comes part and parcel with a change
in our understanding of the epidemiology of any given disorder or groups of disorders.
Recent advances in our fundamental understanding of inflammatory neuropathies of the
peripheral nervous system have been accompanied by drastic changes in our understanding
of the neuroepidemiology of these disorders – the specific populationss affected by
peripheral neuropathies, as well as the varying importance / contributions of select
peripheral neuropathies to the overall burden of peripheral nervous system (PNS) disease,
and how this shift in epidemiological understanding influences the clinical approach
to diagnosis and management of patients with PNS disease. The past few decades have
witnessed a paradigm shift in many aspects of PNS disease diagnosis and treatment;
from the association of human immunodeficiency virus (HIV)‐associated neuropathies;
to the increassing recognition of hereditary / familial peripheral neuropathies; to
the increased recognition of specific neuropathies such as multifocal motor neuropathy
with conduction block. In addition, timely events such as the recent, and increasingly
irrefutalbe evidence for a link between Zika virus and a Guillain‐Barré syndrome,
and the rather unexpected resurgence of peripheral neuropathies due to previously
‘exotic’ etiologies such as lepromatous neuropathy require prompt clinical attention.
This plenary session aims to describe the evolving neuroepidemiology of peripheral
nervous system disorders, and how these changes may influnece the clinical approach
to the diagnosis, prognostication, and treatment of otherwise ‘unusual’ periphal nerve
diseases.
PNS Meeting Abstracts
LECITHIN THERAPY AMELIORATES DISEASE PROGRESSION IN A RAT MODEL OF CHARCOT MARIE TOOTH
DISEASE 1A
Abdelaal T
1,2, Fledrich R1, Rasch L1, Stenzel J1, Prukop T1, Stassart RM1,2, Nave KA1, Sereda
MW1,3.
1Department of Neurogenetics, Max‐Planck‐Institute of Experimental Medicine, Göttingen,
Germany; 2Department of Clinical Neuropathology, University Medical Center Göttingen,
Göttingen, Germany; 3Department of Clinical Neurophysiology, University Medical Center
Göttingen, Göttingen, Germany.
Charcot–Marie–Tooth disease is the most common inherited neuropathy and a duplication
of the peripheral myelin protein 22 gene (PMP22) causes the most frequent sub‐form
Charcot–Marie–Tooth 1A (CMT1A). In contrary to the notion that CMT1A manifests in
the second decade of life, moderate walking disability and electrophysiological abnormalities
are usually already present during childhood. The early onset and developmental nature
of the disease is also supported by findings derived from a Pmp22 transgenic rat model
for CMT1A (CMT rat), which displays a reduced number of myelinated fibers per peripheral
nerve already early postnatally and never reaches a wildtype level throughout development.
In line, CMT rat Schwann cells show a strongly impaired lipid biogenesis required
for myelination as assessed by RNA expression and lipid profiling of peripheral nerve
transcriptomes and myelin composition, respectively. Importantly, Pmp22 overexpressing
Schwann cells also reflect an impaired myelination competence in vitro, when co‐cultured
with dorsal root ganglia neurons. A remarkable improvement of Schwann cell myelination
upon supplementation with phosphatidylcholine in vitro has led to the hypothesis that
exogenous supplementation with lipids in vivo may improve disease progression. Indeed,
we observed improved disease progression on the histological, electrophysiological
and behavioral levels in CMT rats which were fed with a chow enriched in lecithin
from P2 to adulthood. Moreover, disease amelioration is also visible after late long‐term
(P21‐P112) and early short‐term treatment (P2 to P21), but the effect is fading after
treatment cessation. Therefore, continuously supplying patients with exogenous lipids
may be considered as a promising therapeutic approach for CMT1A disease.
AN IN VIVO AND IN VITRO NEUROPHYSIOLOGICAL APPROACH TO ACUTE AND CHRONIC OXALIPLATIN‐INDUCED
PERIPHERAL NEUROTOXICITY
Alberti P
1, Lecchi M2, Monza L1,2,3, Pastori V2, Fumgalli F1, Pozzi E1, Becchetti A2, Bostock
H4, Cavaletti G1.
1PhD Program in Neuroscience, School of Medicine and Surgery, University of Milano‐Bicocca,
Monza, Italy; 2Department of Biotechnology and Bioscience, University of Milano‐Bicocca,
Milan, Italy; 3PhD Program in Translational and Molecular Medicine (DIMET), University
of Milano‐Bicocca, Milan, Italy; 4University College London, London, UK.
Oxaliplatin chemotherapy for colorectal cancer is seriously limited by neurotoxic
side effects which are not fully understood. Oxaliplatin‐induced peripheral neurotoxicity
(OIPN) comprises an acute syndrome and a chronic sensory neuropathy. The acute symptoms,
notably cold hyperalgesia, have been attributed to transient ion channel dysfunction,
and the worse they are the more severe the chronic neuropathy that ensues. We designed
a combined in vitro and in vivo project, using neurophysiology to better understand
the pathogenesis of OIPN. In the in vitro study, differentiated F11 cells (rat DRG
neurons x mouse neuroblastoma N18TG‐2 cell line) were incubated for 24 and 48 hours
in 7.5 μM oxaliplatin, and their electrophysiological properties studied by patch‐clamp.
The treated F11 cells showed relatively depolarized resting membrane potentials, significantly
decreased firing frequencies, and increased sodium current densities. Moreover, a
decrease in ERG (ether‐à‐go‐go‐related gene) potassium current was also evident. In
the in vivo study, we applied Nerve Excitability Testing (NET) to a Wistar rat model
of OIPN. To investigate the acute syndrome, we compared behavioural and neurophysiological
data of 2 animal cohorts (controls and OIPN rats, n=9 each) before and after Oxaliplatin
administration (5mg/Kg, iv). Twenty‐four hours after the injection we observed differences
between the 2 groups in behaviour (cold plate test, P=0.008) and in superxcitability
of motor axons (P=0.002). To investigate the chronic neuropathy, we compare a control
group (n=10) with a treated group (n=10, oxaliplatin 3 mg/Kg twice weekly x 4 weeks,
iv). Both groups are studied with behavioural, neurophysiological (sensory and motor
nerve conduction studies, NET), and pathological (caudal and sciatic nerve, skin biopsy,
DRGs) methods. Data are collected at baseline, end of treatment and 6 weeks after
treatment; to obtain a full NET profile of all significant changes. In this highly
translational approach to OIPN, the in vivo NET changes in the acute and chronic rat
models can be matched on the one hand to findings from in vitro experiments, and on
the other to clinical data, since NET is also easily applied in humans.
EPIDEMIOLOGY OF GUILLAIN‐BARRÉ SYNDROME IN DENMARK – THE INTERNATIONAL GBS OUTCOME
STUDY IN A POPULATION‐BASED PERSPECTIVE
Al‐Hakem H
1, Sindrup SH2, Dornonville de la Cour C3, van den Berg B4, Jacobs BC4, Andersen H1,
Harbo T1.
1Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; 2Department
of Neurology, Odense University Hospital, Odense, Denmark; 3Department of Clinical
Neurophysiology, Danish National Hospital, Copenhagen, Denmark; 4Department of Neurology
and Immunology, Erasmus Medical Centre, Rotterdam, The Netherlands.
The International GBS Outcome Study (IGOS) is a prospective observational international
study aiming to identify clinical and biological determinants of disease progression
and outcome in a large cohort of GBS patients. Demographic and clinical characteristics
of the first 1000 included patients will be analysed and presented. However, within
IGOS there is no population based control group, and therefore it is important to
assess the generalizability of these results. In Denmark there is a unique situation
to conduct epidemiological studies facilitated by The Danish Civil Registration and
The Danish National Hospital Registry (DNHR). This enables us to identify all GBS
patients in Denmark in a given period. From the same period as the IGOS 1000 cohort
was included we have identified all GBS patients admitted to or seen in outpatient's
clinics of hospitals in Denmark (September 1st 2012 to December 31st 2015). Records
from the population based Danish cohort will be reviewed for demographic and clinical
data and compared to the patients included in IGOS from Denmark, as well as with the
IGOS 1000 Europe/America cohort. During this period 93 patients from Denmark have
been included in IGOS. The Danish group is comparable to the Europe/America group
not counting the Danish patients (n=640) of the IGOS1000 cohort in regard to sex and
age at entry, GBS disability score at nadir, and percentage of patients needing mechanical
ventilation. In the Danish IGOS group 57% are males, the median age is 58(39–67) years,
the mean(SD) GBS disability score at nadir 3.6 (1.0), and 18 % of the Danish group
needed mechanical ventilation. In the Europe/America group 59% are males, the median
age is 54(37–66), mean(SD) GBS disability score at nadir 3.5(1.0) and 17 % of the
group needed mechanical ventilation. At the meeting we will compare and present data
from the Danish population based cohort as well as epidemiological data.
ITG2A‐EXPRESSING SCHWANN CELLS UPREGULATE A MACROPHAGE RECRUITMENT FACTOR PERIOSTIN
DURING SPONTANEOUS AUTOIMMUNE PERIPHERAL NEUROPATHY
Allard D
1, Zeng XL2, Wang Y3, Kimpston C4, Notini R5, Li J6, Sailer D7, Conley B8, Howard
J9, Scherer S10, Su M11.
1Department of Pediatrics, University of North Carolina, Chapel Hill, USA; 2Department
of Neurology, University of North Carolina, Chapel Hill, USA; 3Department of Neurology,
University of Pennsylvania, Philadelphia, PA, USA.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a common autoimmune disease
of the peripheral nervous system (PNS) that causes sensorimotor impairment. Mice with
a dominant Autoimmune Regulator gene (Aire) G228W mutation on the non‐obese diabetic
(NOD) background (NOD.AireGW/+ mice) develop spontaneous autoimmune peripheral polyneuropathy
(SAPP) resembling CIDP. In SAPP, demyelination is caused primarily by Th1 T cells;
however, the contributions of nerve‐resident cells such as Schwann cells are poorly
understood. We identified a population of non‐hematopoietic, integrin alpha 2+ (Itga2+)
cells in the PNS that increases in frequency and number during SAPP. These Itga2+
cells coexpress numerous Schwann cell markers including Sox10, P75, S100b, myelin
protein zero, and peripheral myelin protein 22, suggesting that Itga2+ cells are Schwann
cell‐like. Additionally, during SAPP, these Itga2+ cells upregulate the extracellular
matrix protein periostin (Postn), which has recently been shown to promote macrophage
recruitment and activation in inflammatory disease and cancer. Our data indicate that
macrophages are pathogenic during SAPP. Therefore, we hypothesized that Itg2a+ cells
promote macrophage recruitment during SAPP via Postn production. To test this hypothesis,
we performed in vitro chemotaxis assays. Conditioned media from NOD.AireGW/+ nerve
promoted significantly more macrophage chemotaxis than conditioned media from Postn−/−
nerve. Furthermore, Postn recombinant protein was sufficient to induce macrophage
chemotaxis in vitro. Our findings show that Itg2a+ Schwann cell‐like cells mediate
macrophage chemotaxis by upregulating Postn during SAPP and suggests Postn as a novel
target for the treatment of CIDP.
INTRAVENOUS IMMUNOGLOBULIN (IVIG) TREATMENT‐RELATED FLUCTUATIONS IN CHRONIC INFLAMMATORY
DEMYELINATING POLYNEUROPATHY (CIDP) PATIENTS USING DAILY GRIP STRENGTH MEASUREMENTS
(GRIPPER): STUDY DESIGN AND PROGRESS UPDATE
Allen JA
1, Pasnoor M2, Burns T3, Ajroud‐Driss S4, Ney JP5, Cook AA6, Brannagan III TH7, Lawson
VH8, Kissel JT9, Gorson KC10, Lewis RA11, Jensen S12, Walton TP13.
1Department of Neurology, University of Minnesota, Minneapolis, MN, USA and Department
of Neurology, Northwestern University, Chicago, IL, USA; 2Department of Neurology,
Kansas University Medical Center, Kansas City, KS, USA; 3Department of Neurology,
University of Virginia, Charlottesville, VA, USA; 4Department of Neurology, Northwestern
University, Chicago, IL, USA; 5Department of Neurology, Boston University Medical
Center, Boston, MA, USA; 6Neurology and Johns Creek, Johns Creek, GA, USA; 7Department
of Neurology, Columbia University Medical Center, New York, NY, USA; 8Department of
Neurology, Dartmouth Geisel School of Medicine, Hanover, NH, USA; 9Department of Neurology,
Ohio State University, Columbus, OH, USA; 10Department of Neurology, St. Elizabeth's
Medical Center, Tufts University School of Medicine, Boston, MA, USA; 11Department
of Neurology, Cedars‐Sinai, Los Angeles, CA, USA; 12AxelaCare Health Solutions (BriovaRx
Infusion Services), Lenexa, KS, USA; 13AxelaCare Health Solutions (BriovaRx Infusion
Services), Lenexa, KS, USA.
Although IVIg efficacy for the treatment of CIDP has been demonstrated in randomized
controlled trials, the optimal treatment approach for patients on chronic therapy
is unknown. Herein we update progress on the investigator‐initiated, multi‐center
“GRIPPER” study that prospectively evaluates “wear‐off” or other IVIg treatment‐related
fluctuations in patients with CIDP. The primary outcome measure is Jamar grip strength
(GS), performed daily for 6 months. Home nursing visits also capture Rasch‐built Overall
Disability Score (R‐ODS), Timed Up and Go Test (TUGs), Overall Neuropathy Limitations
Scale (ONLS), Modified Fatigue Severity Scale (mFSS), and Visual Analog Pain Severity
Scale (VAS) weekly for 6 months. The QOL Short Form Physical Component Summary (SF‐36v2®)
is collected at baseline, week 12, and week 24. Serum IgG levels are collected at
3 time‐points surrounding IVIg infusions (peak, trough, and mid‐cycle). Total recruitment
is anticipated to be 30 subjects. Upon study completion “wear‐off” frequency will
be analyzed by assessing the proportion of subjects with any given degree of GS and
RODS intracycle fluctuation and the proportion of cycles in which GS and R‐ODS fluctuation
occurs. To determine the extent of “wear‐off” the degree of difference between maximum
and minimum GS, R‐ODS, TUGs, ONLS, and VAS scores will be analyzed. Currently 22 subjects
from 4 different sites have been enrolled (7 sites eligible for enrollment). This
interim study report will provide preliminary representative data, demonstrating IVIg
“wear‐off” effects on GS and other outcome measures. By better understanding the frequency
and extent of IVIG treatment‐related fluctuations we expect that these results will
help facilitate development of CIDP treatment optimization strategies. We also expect
that this information will be important in forming hypotheses to be tested in future
studies (for example, comparing different dosage intervals, optimal IVIg taper guidelines,
or assessing the long‐term outcome of short‐term cycle to cycle clinical fluctuations).
EVALUATION OF MOLECULAR INVERSION PROBE VERSUS TruSeq® CUSTOM‐NEXT GENERATION SEQUENCING
METHODS TO IDENTIFY GENETIC VARIATIONS IN PAINFUL NEUROPATHIES: THE PROPANE STUDY
Almomani R
1, Marchi M2, Lindsey P1, Sopacua M3, Santoro S4, Smeets H1, Lauria G2, Boneschi FM4,
Dib‐Hajj S5,6,7, Waxman SG5,6,7, Merkies ISJ3,8, Faber CG3, Gerrits MM1 and the PROPANE
study group.
1Department of Clinical Genetics, Maastricht University Medical Center, Maastricht,
The Netherlands; 2Neuroalgology Unit, IRCCS Foundation, “Carlo Besta”, Milan, Italy;
3Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands;
4Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental
Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan,
Italy; 5Department of Neurology; 6Center for Neuroscience and Regeneration Research,
Yale University School of Medicine, New Haven, USA; 7Center for Neuroscience and Regeneration
Research, Veterans Affairs Medical Center, West Haven, USA; 8Department of Neurology,
St Elisabeth Hospital, Willemstad, Curaçao.
Neuropathic pain is a frequent feature of peripheral neuropathy causing a significant
impact on patients' quality of life and health care costs. Resolving the genetic architecture
of painful neuropathy will lead to better disease management strategies, risk stratification,
and counselling. Therefore, we aim to develop a reliable technique to rapidly and
accurately re‐sequence multiple genes in a large cohort of painful neuropathy patients
at low cost. Whole exome sequencing of thousands of samples remains expensive for
clinical use. Several targeted enrichment approaches are currently available to selectively
enrich for genomic regions of interest. In this study, we compared the sensitivity,
specificity, targeting efficiency, reproducibility of performance and cost effectiveness
of TruSeq® Custom Amplicon‐Next generation sequencing (TSCA‐NGS) and Molecular Inversion
Probes‐ Next generation sequencing (MIPs‐NGS) methods. For both methods, we constructed
a targeted enrichment kit to capture the coding and exon‐flanking intron sequences
of nine sodium channel genes (SCN3A, SCN8A‐SCN11A, and SCN1B‐4B) expressed in nociceptive
neurons. Probes were designed for the two methods using their respective informatics
pipelines. In total, 180 patients with diabetic and idiopathic neuropathy were tested
by both methods. Among the 180 patients, 70 patients were tested previously by Sanger
sequencing for SCN9A‐SCN11A. Approximately 39kb was captured and sequenced. 95% of
the targeted regions showed an average coverage of ≥20x in TSCA‐NGS, and 96% in MIPs‐NGS.
We managed to identify 12 potential pathogenic mutations and 1294 polymorphism variants
by MIPs‐NGS and TSCA‐NGS. Moreover, we observed a perfect agreement (100%) between
Sanger sequencing data and those obtained using MIPs‐NGS and TSCA‐NGS. Both NGS approaches
showed user‐friendly software to design probes and exhibited a similar on‐target efficiency.
Although the overall coverage per region varied across different DNA samples, it was
sufficient to detect any variant in these regions. MIPs‐NGS has more versatile assay
design, demonstrated a high degree of flexibility with probes re‐placement and >10x
cheaper than TSCA‐NGS. MIPs‐NGS is a reliable, flexible, and inexpensive method to
detect genetic variations in thousands of patients. In our centers, this technology
is currently implemented as a routine diagnostic tool for screening of sodium channel
genes in painful neuropathy patients.
ACUTE DEMYELINATING POLYNEUROPATHY RESEMBLING GUILLAIN‐BARRE SYNDROME IN A PATIENT
TAKING THE SLIMMING PRODUCT PURA ALEGRÍA®
Alonso‐Jiménez A
1,2, Belvis‐Nieto R3, Diaz‐Manera J1,2, Illa I1,2, Querol L1,2.
1Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu i Sant
Pau, Universitat Autònoma de Barcelona, Spain; 2Centro para la Investigación Biomédica
en Red para Enfermedades Raras, CIBERER, Madrid, Spain; 3Neurology Department, Hospital
Universitario Dexeus, Barcelona, Spain.
Most acute demyelinating polyneuropathies have an immune‐mediated pathogenesis and
are included within the Guillain‐Barré syndrome spectrum. Occasionally, other mechanisms
such as metabolic, infectious or toxic may lead to GBS‐like presentations. Thermatrim®
and Pura Alegria® are different brands of the same illegal slimming product that is
sold through online vendors and in which the exact composition is unknown. Here we
present a patient with an acute demyelinating polyneuropathy secondary to the intake
of the slimming product "Pura Alegría".
A 50 year‐old woman with no remarkable medical history reported 7 days history of
distal numbness in her feet that progressed in one week to her knees and her left
hand. She had had an upper respiratory tract infection ten days prior to these symptoms.
The neurological examination showed absent distal vibratory and arthrokinetic sensations
and arreflexia in lower limbs, decreased vibratory sensation in her hands and a ataxic
gate. The lumbar puncture showed 0.89 g/l of proteins with no cells. The EMG fulfilled
diagnostic criteria for acquired demyelination. Intravenous immunoglobulin therapy
was started but the symptoms kept worsening and corticosteroids were started. The
patient mentioned then the slimming product. A brain MRI showed diffuse leukoencephalopathy
that was asymptomatic. Steroids and the Pura Alegria slimming products were withdrawn
and the patient recovered completely after one year of follow‐up.
"Pura Alegría", "Thermatrim" and "Thermatrim plus" are slimming products that were
forbidden in Spain after several cases of acute leukoencephalopathy and acute polyneuropathy.
Exact composition is unknown although the Spanish Drug Agency detected the pesticide
malonoben, a tyrosin kinase inhibitor, among the components. Since 2014 nine cases
of Pura Alegria/Thermatrim neurological toxicity, including leukoencephalopathy and
polyneuropathy have been described. All cases had good outcomes after treatment withdrawal,
although recovery is slow and may be incomplete.
Our case highlights the need to carefully consider drug toxicity, including dietary
supplements, in the differential diagnosis of GBS specially when evolution does not
follow typical patterns.
IMPAIRED MOTOR AXON EXCITABILITY IN A MOUSE MODEL OF CMT1A
Alvarez S
1, Klein D2, Martini R2, Moldovan M1,3, Krarup C1,3
. 1Center for Neuroscience, University of Copenhagen, Denmark; 2Department of Neurology,
Developmental Neurobiology, University Hospital Würzburg, Germany; 3Department of
Clinical Neurophysiology, Rigshospitalet, Copenhagen, Denmark.
Charcot‐Marie‐Tooth neuropathy type 1A (CMT1A) resulting from peripheral myelin protein
22 KDa (PMP22) overexpression is the most common hereditary motor and sensory neuropathy
in humans. The transgenic PMP22 (PMP22tg) mouse line C61 carrying 4 copies of the
human PMP22 gene, has a slowly progressing neuropathy phenotypically like CMT1A with
thin and abnormally thick myelin profiles and supernumerary Schwann cells. In addition,
PMP22tg nerves showed activated macrophages leading to axon‐myelin compartment disruption
and maldistribution of K+ channels (Kohl B et al, Am J Pathol. 2010; 176: 1390). The
aim of the present study was to investigate the motor axon excitability in PMP22tg
versus WT littermates. Multiple measures of motor axon excitability under anesthesia
were carried out by stimulation of the tibial nerve at ankle and “threshold‐tracking”
the plantar compound muscle action potential (CMAP). At age 3 months, when the post‐developmental
maturation was nearly complete in the WT, the PMP22tg CMAP showed an increase in latency
by 29%. The CMAP amplitude was decreased by 36%, although the mean motor unit size
(MScan method) appeared unchanged indicating a lack of collateral sprouting. Furthermore,
PMP22tg showed abnormalities in both passive cable properties and voltage dependent
parameters. At age 6 month, the CMAP latency of PMP22tg was increased by 70% as compared
to WT. In contrast to this marked conduction slowing along the tibial nerve from 3
to 6 months of age, the progression of excitability changes localized at ankle appeared
modest. Nevertheless, when pooling data from 3 to 6 months, the increase in PMP22tg
latency was correlated (Spearman P<0.05) with an increase in accommodation half‐time
during depolarizing electrotonus (+40% of threshold) from 29 to 35 ms and a reduction
of the late subexcitable period of the recovery cycle from 16 to 9% of threshold,
both changes consistent with a redistribution of K+ currents consistent with the maldistribution
of K+ channels. Our data suggest that in the PMP22tg CMT1A model, a functional, thus
potentially reversible abnormality in K+ channel distribution, accumulates along the
nerve and aggravates the conduction impairment due to impaired myelin formation and
maintenance.
LYSOPHOSPHATIDYLCHOLINE‐INDUCED ACUTE DEMYELINATION AGGRAVATES MOTOR AXON DYSFUNCTION
IN A MOUSE MODEL OF CMT1B
Alvarez S1, Krarup C1,2, Moldovan M
1,2.
1Center for Neuroscience, University of Copenhagen, Denmark; 2Department of Clinical
Neurophysiology, Rigshospitalet, Copenhagen, Denmark.
Mice heterozygously deficient of myelin protein P0 gene (P0+/−) show a mild progressive
dysmyelinating neuropathy, with conduction slowing and impaired excitability, phenotypically
similar with Charcot‐Marie‐Tooth Disease type 1B (CMT1B). We found that in P0+/− the
accumulating myelin abnormalities were paralleled by progressive changes in voltage‐dependent
motor axon function resulting in neurotoxic membrane depolarization (Rosberg MR, et.
al. Neurobiol Dis. 2016 93:201). The aim of this study was to investigate the relationship
between demyelination and motor axon function in P0+/−. Demyelination of the right
sciatic nerve by topic lysophosphatidylcholine (LPC) application was carried out in
P0+/− and wild‐type (WT) mice, in 1 year (mature) and 2 years (aged) groups. Multiple
measures of motor axon excitability under anesthesia were carried out by stimulation
of the tibial nerve at ankle (distal to LPC demyelination) and “threshold‐tracking”
the plantar CMAP responses. Live imaging studies by Cellvizio (Mauna Kea Technologies,
Paris, France) confocal laser endomicroscopy were carried out in transgenic mice expressing
the fluorescent reporter YFP in peripheral nerve axons under the Thy1 promoter. In
mature WT the sciatic morphological and electrophysiological demyelinating features
following LPC could be readily observed at 2 hours but disappeared by 2 weeks. No
morphological changes could be observed at the tibial level. Consistently, no conduction
or excitability changes could be observed at the right tibial neve level as compared
to the left tibial nerve in WT. In contrast, in P0+/− the motor axon function was
impaired at the tibial nerve level at 2 weeks after sciatic LPC demyelination. In
mature P0+/−, although the CMAP amplitude appeared preserved, the distal motor latency
was prolonged whereas the excitability measures showed reduced deviations during threshold
electrotonus and increased refractoriness at the expense of superexcitability of the
recovery cycle, both consistent with membrane depolarization. Furthermore, in aged
P0+/− the delayed tibial conduction was associated with a drop in CMAP amplitude and
a prolongation of the strength‐duration time constant. Taken together these data suggest
that focal demyelination aggravates membrane dysfunction along the entire motor axon
in P0+/− providing a novel experimental model to explore the link between demyelination
and axonal membrane dysfunction in CMT1B.
INFLUENCE OF BASELINE NEUROLOGIC SEVERITY ON DISEASE PROGRESSION AND THE ASSOCIATED
DISEASE‐MODIFYING EFFECTS OF TAFAMIDIS IN TRANSTHYRETIN FAMILIAL AMYLOID POLYNEUROPATHY
Amass L
1, Li H1, Gundapaneni B2, Schwartz J1, Keohane D1.
1Pfizer Inc., New York, NY, USA; 2inVentiv Health Inc., Burlington, MA, USA.
A number of factors can influence disease progression in transthyretin familial amyloid
polyneuropathy (TTR‐FAP), a rare, fatal, hereditary amyloidosis. This analysis evaluated
the specific role of baseline neurologic severity on neurologic disease progression
in TTR‐FAP. A predictive model was created based on longitudinal data from Val30Met
patients who participated in the tafamidis (a selective TTR stabilizer) clinical development
program. Data from the intent‐to‐treat population of the double‐blind, placebo‐controlled
registration study (tafamidis group, n=64; placebo group n=61) and its two consecutive
open‐label extension studies in which all patients received tafamidis were used. The
second extension study is ongoing, but a formal, prospectively‐planned interim analysis
was conducted with the cut‐off date of December 31, 2014. This analysis focused on
the first 12 months of treatment for the overall study cohort analyzed. The Neuropathy
Impairment Score–Lower Limbs (NIS‐LL) was used to assess neurologic functioning at
baseline and at subsequent study visits. A linear mixed‐effects model for repeated‐measures
(MMRM) analysis, with baseline NIS‐LL, treatment, and their interactions with time
as fixed effects, was used, and the slope and intercept for each patient were included
as random effects. Patients were primarily Caucasian with early‐stage neurologic disease
(baseline NIS‐LL mean [standard deviation]: tafamidis, 8.4 [11.4]; placebo, 11.4 [13.5]).
Across both groups, disease progression increased with increasing levels of baseline
severity (NIS‐LL) (p<0.0001). However, the predicted magnitude of change from baseline
to Month 12 for tafamidis was consistently less than that for placebo across a range
of observed baseline NIS‐LL values, suggesting a disease‐modifying effect of tafamidis.
Similar findings were observed for the NIS‐LL muscle weakness subscale. This MMRM
analysis in patients with Val30Met TTR‐FAP demonstrates that disease progression strongly
depends on baseline neurologic impairment and highlights the disease‐modifying effect
of tafamidis across a range of baseline levels of neurologic severity. http://ClinicalTrials.gov
identifiers: NCT00409175, NCT00791492, NCT00925002.
ERAMUS GUILLAIN‐BARRÉ SYNDROME RESPIRATORY INSUFFICIENCY SCORE IN JAPANESE PATIENTS
Amino H
1, Misawa S1, Sekiguchi Y1, Shibuya K1, Watanabe K1, Suichi T1, Kuwabara S1.
1Department of Neurology, Chiba University, Chiba, Japan.
Guillain‐Barré syndrome (GBS) is a potential life threatening neurological disorder
and respiratory insufficiency is one of the critical complications. Eramus GBS respiratory
insufficiency score (EGRIS) is a method for predicting the chance of respiratory insufficiency
in GBS. However, clinical characteristics and courses can vary for subtypes of GBS,
whose occurrences differ for each region: acute inflammatory demyelinating polyneuropathy
(AIDP) is very common in European countries, whereas acute motor axonal neuropathy
(AMAN) is frequently seen in Asian countries. The aim of this study is to investigate
the usefulness of EGRIS in Japan, where AMAN is more common than in the Netherlands.
Clinical and electrophysiological profiles of consecutive GBS cases, who visited our
hospital within 28 days after symptoms onset between 1998 and 2015, were reviewed.
Of the 150 GBS patients, 37 % were classified as AIDP and 20% as AMAN according to
the electrodiagnosis criteria by Ho and colleagues. Higher EGRIS scores correspond
to higher risk of respiratory insufficiency in total of the GBS patients, as well
as in AIDP patients. However, in patients with AMAN, EGRIS scores did not always match
the chances of respiratory insufficiency: up to 17% of the patients with low risk
of EGRIS showed respiratory failure, whereas only 25% of the patients with high risk
of EGRIS needs intubation/mechanical ventilation. In AMAN, associations with mechanical
ventilation were seen for rapid progression (shorter duration between onset and hospital
admission), more decreased vital capacity, and more frequent autonomic involvement.
EGRIS is useful also for Japanese GBS patients. However, for AMAN patients, it should
be used with discretion. Another score to predict respiratory insufficiency might
be required in Asian countries.
A QUALITY IMPROVEMENT STRATEGY: ULNAR NERVE CONDUCTION STUDY OF THE FIRST DORSAL INTEROSSEOUS
MUSCLE
Anandan C1, Litchy WJ1, Laughlin RS1, Leep Hunderfund AN1, Naddaf E
1.
1Mayo Clinic, Rochester, USA.
In patients with suspected ulnar neuropathy, nerve conduction studies (NCS) are commonly
requested to help with diagnosis and localization. However, routine NCS are often
normal or not localizing. Ulnar NCS recording from the first dorsal interosseous muscle
(NCS‐FDI) is thought to increase the diagnostic yield of electrodiagnostic testing,
although not commonly considered. We developed a quality improvement strategy to routinely
perform ulnar NCS recording from the abductor digiti minimi muscle (NCS‐ADM) as well
as ulnar NCS‐FDI in all patients referred for suspected ulnar neuropathy. We utilized
the DMAIC (Define, Measure, Analyze, Improve, Control) model of process improvement
to define our problem and create a map of the current process for ulnar neuropathy
diagnosis in our Electromyography laboratory. We determined baseline performance via
review of the most recent 100 patients referred to our lab for a suspected ulnar neuropathy.
Of the 100 patients reviewed, 38 patients demonstrated no electrodiagnostic evidence
of an ulnar neuropathy. Ulnar NCS‐FDI was not performed in any of these patients.
In the 62 patients with ulnar neuropathy, two had a purely sensory neuropathy and
one a dorsal cutaneous ulnar neuropathy. The 59 remaining patients had abnormal NCS‐ADM.
The ulnar neuropathy was localizable to the elbow in 20 (34%) of these patients and
not localizable in the rest. Having defined the quality gap and measured baseline
performance, the results of this analysis were used to develop targeted interventions
intended to improve the performance of ulnar NCS‐FDI. Data will then be remeasured
and presented, specifically addressing the degree of improvement in the diagnostic
yield of electrodiagnostic testing for ulnar neuropathy via routine performance of
NCS‐FDI.
DISTAL SENSORIMOTOR POLYNEUROPATHY FOLLOWING 13 YEARS OF TYPE 2 DIABETES ASSESSED
BY THE MICHIGAN NEUROPATHY SCREENING INSTRUMENT QUESTIONNAIRE: A PROSPECTIVE STUDY,
THE ADDITION DENMARK STUDY
Andersen ST1,2, Witte DR1,3, Dalsgaard EM1, Andersen H2,4, Nawroth P5, Flemming T5,
Jensen TM6, Finnerup NB2,7, Jensen TS
2,7, Lauritzen T1, Charles M1,2.
1Department of Public Health, Aarhus University, Aarhus, Denmark; 2International Diabetic
Neuropathy Consortium, Aarhus, Denmark; 3Danish Diabetes Academy, Odense, Denmark;
4Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; 5Department
of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg,
Germany; 6Steno Diabetes Center, Copenhagen, Denmark; 7Department of Clinical Medicine,
Danish Pain Research Center, Aarhus University, Aarhus, Denmark.
Distal sensorimotor polyneuropathy (DPN) is the most common complication of diabetes
and risk factors beyond hyperglycemia have proven important particularly in type 2
diabetes (T2DM). Only few prospective studies from early‐stage T2DM exist. We aimed
to study the development of DPN during the first 13 years after a screening‐based
diagnosis of T2DM. From the ADDITION‐Denmark study 1445 participants were eligible
for this study. DPN was assessed by the Michigan Neuropathy Screening Instrument questionnaire
(MNSI) at four time‐points during follow‐up. DPN was defined by a MNSI score ≥ 4.
189 participants (13%) were positive in MNSI at baseline and thus excluded from this
study. By Kaplan‐Meier plot we evaluated the cumulative incidence of DPN and in Cox
proportional hazard models we calculated hazard ratios (HR) for the intervention groups
in the ADDITION trial and for various covariates proposed to influence the development
of DPN. Models were adjusted in steps for intervention group, age, sex, baseline MNSI,
lipid‐lowering and anti‐hypertensive treatment. This study cohort consists of 1256
participants (59% men) with a median age of 60.8 years (p25;p75: 55.6;65.6) and median
baseline HbA1c of 6.3 (p25;p75: 6.0;6.9). A cumulative incidence of 10% was seen during
13 years of diabetes. There was no statistically significant difference in HR between
the intervention groups or by sex but a significantly higher HR of 1.03 (95%CI: 1.00;1.07)
was seen for age (per year). The highest HR was found for a history of cardiovascular
disease (myocardial infarction or stroke) up to ten years prior to the diabetes diagnosis
with a HR of 3.04 (1.38;6.68). Weight, waist circumference, body‐mass index and methylglyoxal
(log2 transformed) showed modest but statistically significant associations with incident
DPN with standardized HRs of 1.35 (95%CI: 1.11;1.63), 1.35 (95%CI: 1.08;1.67), 1.39
(95%CI: 1.14;1.69) and 1.44 (95%CI: 1.12;1.86) respectively. This study demonstrates
a fairly low cumulative incidence of DPN in people with screen‐detected T2DM and provides
evidence that macrovascular disease, obesity and oxidative stress are important risk
factors for DPN even at the earliest stages of T2DM.
CHARCOT MARIE TOOTH DISEASE ASSOCIATED WITH AGENESIS OF THE CORPUS CALLOSUM: A HETEROGENEOUS
ENTITY
Azzedine H
1,2, Elmalik SA3, Tonekaboni H2, Amer‐Lekhdoud W4, Kabiraj M5, Abdalla YM6, Mukhtar
MM7, Ahmed AE8, Katona I1, Chaouch A9, Leguern E2, Weis J1, Chaouch M5, Salih MAM10.
1Institute of Neuropathology, Uniklinik‐REWTH, Aachen, Germany; 2ICM, la Pitié‐Salpêtrière
Hospital, Paris, France; 3Department of Physiology, College of Medicine, King Saud
University, Riyadh, Saudi Arabia; 4Service of Neurology, Ben Aknoun Hospital, Algiers,
Algeria; 5Division of Clinical Neurophysiology, Department of Neuroscience, Prince
Sultan Medical City, Riyadh, Saudi Arabia; 6Kush Eye Center, Omdurman, Sudan; 7Institute
of Endemic Diseases, Faculty of Medicine, University of Khartoum, Sudan; 8Department
of Physiology, Faculty of Medicine, University of Khartoum, Sudan; 9Service of Neurophysiology,
Ben Aknoun Hospital, Algiers, Algeria; 10Division of Pediatric Neurology, College
of Medicine, King Saud University, Riyadh, Saudi Arabia.
Andermann syndrome, also known as agenesis of the corpus callosum and peripheral neuropathy
(ACCPN), is an autosomal recessive disorder with a broad spectrum of mild to severe
neuromuscular and psychiatric consequences. The gene variants causing disease were
first identified in French‐Canadian families. In the present study, we intended to
phenotype and genotype a series of non‐French‐Canadian familial cases presenting with
Charcot Marie Tooth disorder associated with agenesis/dysgenesis of the corpus callosum.
For this purpose, seven families, 5 of consanguineous marriage, were studied. Patients
were clinically and para‐clinically investigated using MRI and electrophysiology (MNCVs).
For some, a sural nerve biopsy was taken. Microsatellite markers around the ACCPN
locus were used in two large families; followed by Sanger sequencing of all the exons
and intron‐exons boundaries of the gene, in one patient from each of the 7 families.
The age at onset of the disease was at birth in the patients from the largest consanguineous
family (3 affected individuals). The biopsy from one patient showed a severe demyelinating
neuropathy with many hypomyelinated fibres and mostly secondary axonal changes. These
finding were compatible with electrophsiological data where the MNCVs are of demyelinating
range. Dysgenesis of the corpus callosum in one patient and Agenesis in another sib
were revealed by MRI. We identified one homozygous truncating mutation in this family.
Interestingly, no causative variant was found in a patient from another family and
showing homozygous haplotype. Two different heterozygous variants were identified
at one hit in two patients from two non‐consanguineous families. Genetic investigations
will be continued to identify the possible second hit. In the 4 remaining families,
no variant was found. The negative family cases will be subjected to NGS. At this
stage, it is tempting to speculate on the genetic heterogeneity of ACCPN in our series.
OCCURRENCE OF DIABETIC FOOT BY NCS‐SEVERITY OF DIABETIC NEUROPATHY: A 5‐YEAR PROSPECTIVE
OBSERVATION
Baba M
1, Suzuki C1, Ogawa C2, Tomiyama M1.
1Department of Neurology; 2Diabetes Center, Aomori Prefectural Central Hospital, Aomori,
Japan.
In 2007 we introduced a staging system of severity of diabetic polyneuropathy (DPN)
by nerve conduction study (NCS) of the lower limb: sensory NCS of the sural nerve
and motor NCS of the tibial nerve. The system consists of five stages; NCS‐0 (normal):
no abnormalities, NCS‐1 (mildly abnormal): presence of delay of MCV, SCV, minimal
F‐wave latency, or positive a‐wave, NCS‐2 (moderately abnormal): decrease in sural
SNAP less than 5uV, NCS‐3 (severely abnormal): decrease in plantar muscle‐CMAP to
2‐5mV, NCS‐4 (ultimately abnormal): plantar muscle‐CMAP lost or less than 2mV with
trace of sural‐SNAP. To examine validity of the system, we conducted 5‐year prospective
observation on development of diabetic foot (DF) by the NCS staging system. In addition,
occurrence of ischemic heart disease (IHD) and stroke (IS), and death of neuro‐vascular
events were also counted. 1n 2007–09, we carried out NCS in 308 diabetics, and categorized
them by the NCS staging system: 6% was NCS‐0, 38% was NCS‐1, another 38% was NCS‐2,
10% was NCS3, and 7% was NCS‐4. We then followed them and prospectively counted the
occurrence of DF, IHD and IS in 230 patients (mean age 57ys). The occurrence of DF
during the following 5years was; NCS‐0: 0%, NCS‐1: 0%, NCS‐2: 1%, NCS‐3: 16%, NCS‐4:
24%. Occurrence of any of DF, IHD and/or IS was as follows; NCS‐0: 0%, NCS‐1: 6%,
NCS‐2: 31%, NCS‐3: 54%, NCS‐4 59%. There was no death from NSC‐0, −1, and −2 groups
(n=189), while two from NCS‐3 group (n=24) were found dead in a bed or on a driver's
seat, and other two from NCS‐4 group (n=17) died of sudden cardiac arrest or infection
after foot amputation. In summary, the present NCS grading system seems to work satisfactory
not only for diagnosis of severity of the current DPN, but also for prognostic prediction
of the DPN‐related foot and vascular events.
A SENSITIVE MEASURE OF VIBRATION SENSE IN THE CMTNSv2
Bacon C
1, Feely SME1, Shy ME1.
1University of Iowa Hospital, Iowa City, IA, USA.
For patients with Charcot‐Marie‐Tooth disease, also known as hereditary motor and
sensory neuropathy, the Rasch modified CMTNSv2 is a validated measurement of symptoms
and impairment. The score is comprised of nine parameters of a clinical examination,
including nerve conduction studies (NCS). Each parameter has an individual score ranging
from zero to four, with the composite score having a maximum of 36 prior to Rasch
modification. For patients who do not complete a NCS, the CMT Exam Score (CMTESv2)
is used, with a maximum score of 28 before Rasch modification. One parameter of the
CMTESv2 is the vibration sense. Using a Rydel tuning fork, a care‐giver measures vibration
sense in a patient's feet, ankles, and knees and a score is determined by the severity
of reduced vibration sense. In 80 CMT1A patients, 50% received a score of 3 out of
4, noted by a reduced vibration sense at the knee. In order to capture a more sensitive
vibration measurement, we tested ways of taking the total raw score of the Rydel tuning
fork at each point of vibration sense, the toe, ankle, and knee bilaterally. Scores
range from zero to 48, with 48 reflecting full vibration sense. In this modified measurement,
vibration sense scores varied in wider distribution. For CMT1A patients captured in
this studied, a modified vibration sense score results in a potentially more sensitive
total CMTESv2 score.
ULTRASOUND FINDING IN ACUTE DIABETIC LUMBOSACRAL RADICULOPLEXUS NEUROPATHY
Bae DW1, An JY
1.
1St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea.
Diabetic lumbosacral radiculoplexus neuropathies (DLRPN) are usually subacute painful,
monophasic, asymmetrical lower limb neuropathies with incomplete recovery due to ischaemic
injury and microvasculitis. The diagnosis relies mostly on clinical suspicion and
characteristic electromyographic findings. However, in acute phase, neuroimaging has
more important diagnostic significance than electrophysiological studies. Here we
describe MRI and ultrasound findings in a 59‐year‐old woman with DLRPN who was diagnosed
with diabetes three years ago, but has not received any other treatment. She had a
7‐day history of acute‐onset severe pain with weakness of muscles innervated by left
femoral and obturator nerve and decreased sensation in left L2‐L4 dermatome. Nerve
conduction studies showed reduced amplitude in left femoral nerve and electromyography
showed only increased insertional activity in left iliopsoas muscle and no volitional
activity in muscles innervated by left femoral and obturator nerve. Ultrasound revealed
increased cross‐sectional area (CSA) of left femoral and lateral femoral cutaneous
nerve. MRI showed enhancement in left L3, 4 nerve roots and proximal femoral nerve
and increased signal intensity in left iliacus and iliopsoas. We diagnosed her with
DLRPN and started corticosteroid. Nerve ultrasound has not been previously reported
in a patient with DLRPN and this case showed that ultrasound may be the valuable supplement
to MRI and electrophysiological studies for the workup of DLRPN.
A COMPARISON OF CLINICAL AND ELECTROPHYSIOLOGICAL PROFILES IN POEMS SYNDROME AND CHRONIC
INFLAMMATORY DEMYELINATING POLYNEUROPATHY
Baek SH
1, Byun JM2, Kim I3, Choi K4, Choi SJ3, Kwun KH3, Shin JY3, Sung JJ3, Hong YH2.
1Korea University Anam Hospital, Seoul, South Korea; 2Seoul Metropolitan Government
Boramae Medical Center, Seoul, South Korea; 3Seoul National University Hospital, Seoul,
South Korea; 4Konkuk University Medical Center, Seoul, South Korea.
POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) syndrome
is a rare cause of polyneuropathy. Polyneuropathy is one of the major criteria for
the syndrome and usually associated with demyelinating pattern. About 50% of patients
with POEMS syndrome revealed only polyneuropathy in the early stages of disease. Therefore,
POEMS syndrome is often misdiagnosed as chronic inflammatory demyelinating polyneuropathy
(CIDP). The aim of this study is to investigate clinical and electrophysiological
findings which could differentiate between POEMS syndrome and CIDP. We reviewed medical
records and nerve conduction studies of 58 patients between 2005 and 2016. We enrolled
16 patients with POEMS syndrome and 42 patients with CIDP fulfilling EFNS/PNS criteria
for definite CIDP (8 with monoclonal gammopathy of undetermined significance (MGUS),
34 without MGUS). The median age of onset is older in CIDP with MGUS group than in
the other groups (CIDP with MGUS 62.0 years, CIDP without MGUS 57.0 years, POEMS 53.0
years; p=0.043). Neuropathic pain is more frequently in POEMS syndrome group (POEMS
50%, CIDP without MGUS 17.6%, CIDP with MGUS 12.5%; p=0.043). POEMS syndrome revealed
slower conduction velocity (NCV) (33.3 m/s vs 43.0 m/s; p=0.001), more prolonged F‐latency
(141.8% vs. 125.0%; p=0.025), and higher terminal latency index (TLI) (0.37 vs. 0.27;
p<0.001) in median motor nerve than CIDP without MGUS. Also, POEMS syndrome showed
more reduced tibial CMAP amplitude (3.6mV vs. 6.7mV; p=0.014) and more frequently
recordable tibial CMAP (59.4% vs. 6.3%; p<0.001) than CIDP without MGUS. On the other
hands, CIDP with MGUS group showed much slower NCV (33.5m/s vs. 43.0m/s; p=0.027)
than CIDP without MGUS. Compared with POEMS syndrome, CIDP with MGUS group revealed
more prolonged terminal latency (4.4ms vs. 7.0ms; p=0.02) and lower TLI (0.37 vs.
0.24; p=0.001). In conclusion, POEMS syndrome demonstrated much slower NCV, less prolonged
terminal latency, and higher TLI. Especially, TLI is much higher in POEMS than in
CIDP with/without MGUS. Therefore, TLI might be helpful in distinguishing POEMS from
CIDP.
PREVALENCE OF PERIPHERAL NEUROPATHY AMONG FREQUENT FLYERS – IS THERE A LINK TO “AEROTOXIC
SYNDROME”?
Balke M1, Sprenger A1, Wunderlich G1, Stettner M2, Fink GR1,3, Lehmann HC
1.
1University Hospital of Cologne, Germany; 2University Hospital of Essen, Germany;
3INM‐3 Research Centre Jülich, Jülich, Germany.
Cabin air in commercial airliners originates from aircraft engines or auxiliary power
units. This bleed air may occasionally be contaminated with hydraulic fluids and engine
oil that contains a number of potentially hazardous chemicals including tricresyl
phosphate (TCP). Over the last years reports are emerging about aircrew members that
experience symptoms such as tingling or burning of extremities in addition to headache,
and vertigo. This “aerotoxic syndrome” is controversially discussed in the literature
and has been attributed to exposure to organophosphate contaminated cabin air. Since
TCP has been associated with peripheral neuropathy we aimed to determine the frequency
of peripheral neuropathy among frequent flyers.
84 civilian air crew members and frequent flying passengers (m:f = 35:49, median age
48 years, median exposition time in aircrafts of 12.000 hours) were examined at the
University Hospital of Cologne or at the Frankfurt airport (IATA code FRA) by a detailed
questionnaire of past medical conditions, a standardized neurological examination
and nerve conduction studies of sural, tibial, and ulnar nerves. We identified 5 subjects
with clinical and electrophysiological evidence for large fiber peripheral neuropathy.
Incidence of peripheral neuropathy was not correlated to exposition time in aircrafts.
In addition 11 subjects showed signs of ulnar neuropathy, 13 subjects reported abnormal
vibration sensation, 27 subjects suffered from gait imbalance and 50 individuals reported
tingling of extremities.
Our study shows a 5.95% prevalence of large fiber peripheral neuropathy among frequent
flyers. Comparison of these data with prevalence rate in an age‐matched control group
will reveal a possible association of chronic exposure to cabin air and risk for peripheral
neuropathy. The high incidence of the symptom tingling in our cohort warrants further
studies to determine the risk for small fiber neuropathy in this condition.
IVIg EFFECT IN A WISTAR RAT MODEL OF BORTEZOMIB‐INDUCED PERIPHERAL NEUROPATHY
Ballarini E
1, Meregalli C1, Carozzi V1, Chiorazzi A1, Canta A1, Monza L2, Fumagalli G3, Pozzi
E3, Alberti P1,2,3, Rodriguez‐Menendez V1, Bossi M1, Marjanovic I4, Scali C4, Marmiroli
P1, Cavaletti G1.
1Experimental Neurology Unit, School of Medicine and Surgery, University of Milano‐Bicocca,
Monza, Italy; 2PhD Program in Translational and Molecular Medicine, DIMET, University
of Milano‐Bicocca, Milan, Italy; 3PhD Program in Neuroscience, University of Milano‐Bicocca,
Monza, Italy; 4Kedrion S.p.A., Loc. Ai Conti, Castelvecchio Pascoli (Barga) Lucca,
Italy.
Intravenous Immunoglobulin (IVIg) are human IgG derived from plasma pools of healthy
donors. Although there are studies in literature evaluating their effectiveness in
different pathological animal models, there are no data about their possible role
on Bortezomib (BTZ)‐induced peripheral neuropathies. Female Wistar rats were treated
following a preventive schedule (BTZ and IVIg co‐treatment for 3 and 8 weeks) and
a therapeutic schedule (4 weeks of BTZ treatment followed by a 4‐week IVIg‐BTZ co‐treatment).
Caudal nerve conduction velocity (NCV), plantar and dynamic tests were performed at
different time points. Animals were sacrificed after 3ws (acute phase) or 8ws (chronic
phase) and tissue samples (Dorsal Root Ganglias ‐DRG‐, sciatic nerve, caudal nerve,
skin) were collected for morphological, morphometrical and immunohistological analysis.In
the preventive schedule, IVIg was not able to rescue caudal NCV reduction caused by
BTZ neither after 3 nor after 8 weeks of co‐treatment. Same results were observed
in the therapeutic schedule. On the other hand, the evaluation of mechanical allodynia
and cold hyperalgesia showed that IVIg injection protected from BTZ effect in both
treatment schedules. Morphometric analysis evidenced that, even if not statistically
significant only the preventive schedule has a tendency to protect the caudal nerve
from BTZ damage. This result is consistent with the morphological evaluation of the
nerve. Also, intra‐epidermal nerve fibers density was preserved in the preventive
schedule but not in the therapeutic one. Finally, sciatic nerve and DRG macrophage
infiltration levels tended to be reduced in the therapeutic schedule and were brought
back to ctrl (rats not treated or injected with IVIg alone) levels in the preventive
one. In conclusion, we were able to demonstrate for the first time that IVIg treatment
especially used as preventive treatment option may reduce BTZ‐induced neuropathic
painful pointing out the possible role of inflammation in the pathogenesis of this
invalidating pathology.
This work was supported by Kedrion SpA.
GENETIC HETEROGENEITY OF MOTOR NEUROPATHIES
Bansagi B
1, Griffin H1, Whittaker R2, Antoniadi T3, Evangelista T1, Miller J2, Greenslade M3,
Forester N3, Duff J1, Bradshaw A1, Kleinle S4, Boczonadi V1, Steele H1, Ramesh V5,
Franko E1,6, Pyle A1, Lochmüller H1, Chinnery PF1,7, Horvath R1.
1MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research
Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne,
UK; 2Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK; 3Bristol
Genetics Laboratory, Pathology Sciences, North Bristol NHS Trust, Southmead Hospital,
Bristol, UK; 4Medical Genetic Center, Munich, Germany; 5Department of Paediatric Neurology,
Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle
upon Tyne, UK; 6Nuffield Department of Clinical Neurosciences, University of Oxford,
Oxford, UK; 7Department of Clinical Neurosciences, Cambridge Biomedical Campus, University
of Cambridge, Cambridge, UK.
We studied the prevalence, the molecular cause and clinical presentation of hereditary
motor neuropathies in a large cohort of patients from the North of England. Detailed
neurological and electrophysiological assessments and next generation panel testing
or whole exome sequencing were performed in 105 patients with clinical symptoms of
distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor
CMT2, 16 patients) or complex neurological disease predominantly affecting the motor
nerves (HMN plus, 25 patients). The prevalence of dHMN is 2.14 affected individuals
per 100.000 inhabitants (95% confidence interval: 1.62‐2.66) in the North of England.
Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic
rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%).
We detected a defect of neuromuscular transmission in 7 cases and identified potentially
causative mutations in 4 patients with demyelinating multifocal motor neuropathy.
Many of the genes were shared between dHMN and motor CMT2, indicating identical disease
mechanisms therefore we suggest changing the classification and include dHMN also
as a subcategory of CMT. Abnormal neuromuscular transmission in some genetic forms
provides a treatable target to develop therapies.
PATIENT‐ASSISTED INTERVENTION FOR NEUROPATHY: COMPARISON OF TREATMENT IN REAL LIFE
SITUATIONS (PAIN‐CONTRoLS)
Barohn RJ
1, Gajewski B1, Pasnoor M1, Brown L1, Herbelin L1, Kimminau K1, Jawdat O1, Parks C1,
Shlemon P1, Dimachkie MM1 and the PAIN‐CONTRoLs study team1
. 1The University of Kansas Medical Center, Kansas City, KS, USA.
Cryptogenic sensory polyneuropathy (CSPN) is a common slowly progressive neuropathy
that affects adults and presents with significant neuropathic pain for which multiple
medications have been tried including antiepileptics, antidepressants, topicals and
narcotics. A web based survey among neuromuscular experts suggested pregabalin as
being more effective than other medications, however there are presently no comparative
studies to assess the most effective medication. The objective of this study was to
determine which of the 4 pharmaceutical therapies (pregabalin, duloxetine, nortriptyline
or mexiletine) is most effective for neuropathic pain and best tolerated in CSPN.
To achieve this objective we performed a prospective randomized open labelled comparative
effectiveness adaptive design study of CSPN patients through the patient centered
outcomes research institute (PCORI). CSPN patients who fulfilled the inclusion and
exclusion criteria were enrolled into this study. Patients underwent a baseline neurological
evaluation and randomly assigned to one of the 4 neuropathic medications for 3 months.
The primary outcome is the change in likert‐like pain scale. The secondary outcomes
included NIH pain interference scale, NIH fatigue interference scale, NIH sleep disturbance
scale, SF‐12 and adverse events. The outcome measures are performed at baseline, month
1, 2 and 3. Statistical analysis using bayesian adaptive design developed by Berry
Consultant software will be performed to determine winner and losers (winner = greater
than 2 point improvement in pain). Total number of patients to be enrolled is 400.
Recruitment has been challenging and a number of recruitment techniques have been
used. To date, there have been 292 patients screened, 288 patients randomized from
40 US sites. Anticipated completion of enrollment by June 2017 and end of final patient
assessment by September 2017. Interim analysis performed after first 100 patients
completed their 3months as part of Bayesian adaptive design analysis and occurs every
13 weeks. The distribution of randomization of patients to the 4 medications at last
adaptive design randomization was 29.6% to medication 1, 30% to medication 2 , 20.8%
to medication 3 and 19.6% to the 4th medication. This study may give physicians and
patients evidence for future management of CSPN patients.
AUTONOMIC SYMPTOMS IN TRANSTHYRETIN AMYLOIDOSIS: AN ANALYSIS OF SYMPTOMATIC SUBJECTS
FROM THE THAOS REGISTRY
Barroso F
1, Ando Y2, Gonzalez‐Duarte A3, Schmidt H4, Mundayat R5.
1Department of Neurology, Raúl Carrea Institute for Neurological Research, FLENI,
Buenos Aires, Argentina; 2Department of Neurology, Graduate School of Medical Sciences,
Kumamoto University, Kumamoto, Japan; 3Instituto Nacional de Ciencias Médicas y Nutrición
Salvador Zubirán, Mexico; 4Department of Transplant Medicine, University Hospital
Münster, Münster, Germany; 5Pfizer, New York, NY, USA.
Transthyretin amyloidosis (ATTR), which encompasses a group of disorders with significant
clinical variability, is caused by transthyretin (TTR) derived amyloid deposition.
The clinical aspects of autonomic nervous system involvement in ATTR are only partially
known. The ongoing, multinational, longitudinal, observational Transthyretin Amyloidosis
Outcomes Survey (THAOS) provides the opportunity to expand our understanding of dysautonomia
in ATTR. Data from all symptomatic subjects enrolled in the THAOS registry with a
diagnosis of ATTR (cut‐off date: January 14, 2016) were assessed for the presence
and temporal course of autonomic symptoms, genotype and phenotype associations, and
clinical burden according to the frequency and severity of symptoms. Of 2362 symptomatic
subjects enrolled in THAOS, 1006 (42.6%) had autonomic symptoms at enrollment including:
gastrointestinal (1399 subjects, 59.2%), urinary (494, 20.9%), erectile dysfunction
(329, 13.9%), orthostatic hypotension (223, 9.4%), xerophthalmia (183, 7.7%) and dyshydrosis
(93, 3.9%). Subjects with autonomic manifestations, compared with those without, were
younger (mean age [standard deviation, SD] of 50.2 [15.1] vs 57.8 [17.7] years), with
a longer duration of ATTR symptoms (9.7 [7.1] vs 6.7 [6.5] years). Autonomic dysfunction
was less common with wild‐type ATTR (27 of 329 subjects, 8.2%) than in mutation groups:
Val30Met (824/1471, 56.0%); non‐Val30Met/non‐cardiac (114/355, 32.1%); and “cardiac
mutations” (Val122Ile, Leu111Met, Thr60Ala, or Ile68Leu mutations; 41/207, 19.8%).
Similarly, time (mean [SD], years) from first ATTR symptoms to onset of autonomic
symptoms, was longest for wild‐type ATTR (10.1 [11.4]) followed by “cardiac mutations”
(6.3 [7.7]), non‐Val30Met/non‐cardiac (5.1 [6.7]), and Val30Met (2.8 [4.9]). Autonomic
symptoms were present at disease onset in over a third of subjects (355, 35.3%). Autonomic
dysfunction was less frequent in subjects with cardiac phenotype (73 of 460 subjects,
15.9%), than with mixed (259/497, 52.1%) or neurologic (765/1171, 65.3%) phenotypes.
The burden of autonomic symptoms (mean [SD]) varied by genotype, Val30Met (4.3 [4.0],
non‐Val30Met/non‐cardiac (3.5 [3.1], “cardiac mutations” (2.5 [2.6]), wild‐type ATTR
(1.6 [1.2]), and by phenotype, mixed (5.5 [5.0]), neurologic (3.9 [3.4]), cardiac
(1.7 [1.2]). Dysautonomia is common, and a significant burden, in subjects with hereditary
forms of ATTR. Its prevalence is higher in Val30Met than in other genotypes, and in
the neurologic or mixed phenotypes.
MOTOR UNIT NUMBER INDEX CORRELATES WITH DISABILITY IN CHARCOT‐MARIE‐TOOTH DISEASE
TYPE 1A
Bas J
1, Delmont E1,2, Fatehi F1, Boulay C3, Chabrol B3, Salort‐Campana E1,4, Sévy A1, Verschueren
A1, Pouget J1,4, Lefebvre MN5, Grapperon AM1, Attarian S1,4.
1Reference Center for Neuromuscular Diseases and ALS, La Timone University, Aix‐Marseille
University, Marseille, France; 2Medicine Faculty, Aix‐Marseille University, UMR 7286,
Marseille, France; 3Reference Center for Pediatric Neuromuscular Disorders, La Timone
University Hospital, Aix‐Marseille University, Marseille, France; 4Aix‐Marseille University,
Inserm, GMGF, Marseille, France; 5CIC‐CPCET, La Timone University Hospital, Aix‐Marseille
University, Marseille, France.
The objective of this study is to assess the usefulness of motor unit number index
(MUNIX) technique in Charcot‐Marie‐Tooth type 1A (CMT1A) disease and to test correlation
between MUNIX and clinical impairment. MUNIX technique was performed in abductor pollicis
brevis (APB), abductor digiti minimi (ADM) and tibialis anterior (TA) muscles in the
non‐dominant side. A MUNIX sum score was calculated by adding MUNIX of these 3 muscles.
Muscle strength was measured using the MRC (medical research council) scale. Disability
was evaluated with several functional scales including CMT neuropathy score version
2 (CMTNSv2) and overall neuropathy limitation scale (ONLS). 33 CMT1A patients with
known PMP22 gene duplication were enrolled. The MUNIX of the ADM, APB and TA muscles
were correlated with the MRC of the corresponding muscle (p<0.05). MUNIX sum score
was correlated with clinical scales: CMTNSv2 (r=−0.54, p<0.01), ONLS (r=−0.57, p<0.01).
In conclusion, MUNIX correlates with muscle strength and clinical measurements of
disability in CMT1A patients. The MUNIX technique evaluates motor axonal loss and
correlates with disability. The MUNIX sum score may be a useful outcome measure of
disease progression in CMT1A.
MOTOR UNIT NUMBER INDEX CORRELATES WITH DISABILITY IN CHARCOT‐MRI FAT FRACTION OF
TIBIALIS ANTERIOR MUSCLE CORRELATES WITH DISABILITY IN CHARCOT‐MARIE‐TOOTH DISEASE
TYPE 1A
Bas J
1, Delmont E1,2, Le Troter A3, Fatehi F1, Salort‐Campana E1,5, Sévy A1, Verschueren
A1, Pouget J1,5, Lefebvre MN4, Grapperon AM1, Bendahan D3, Attarian S1,5.
1Reference Center for Neuromuscular Diseases and ALS, La Timone University, Aix‐Marseille
University, Marseille, France; 2Medicine Faculty, Aix‐Marseille University, UMR 7286,
Marseille, France; 3CRMBM, CNRS, La Timone University Hospital, Aix‐Marseille University,
Marseille, France; 4CIC‐CPCET, La Timone University Hospital, Aix‐Marseille University,
Marseille, France; 5Aix‐Marseille University, Inserm, GMGF, Marseille, France.
The objective of this study was to assess the usefulness of MRI in Charcot‐Marie‐Tooth
type 1A (CMT1A) disease and to test correlation between muscle fat fraction and clinical
impairment. MRI was performed in the non‐dominant lower limb of CMT1A patients and
healthy controls. Fat fraction of tibialis anterior muscle, cross section area and
volume of sciatic nerve were determined. Muscle strength of dorsiflexion was measured
using a dynamometer. Disability was evaluated with CMT neuropathy score version 2
(CMTNSv2). 15 CMT1A patients with known PMP22 gene duplication were enrolled. Fat
fraction of tibialis anterior muscle was significantly increased in patients compared
to healthy controls. It was correlated with muscle strength (r=−0.62, p<0.05) and
CMTNSv2 score (r=−0.65, p<0.05). Cross section area and volume of sciatic nerve were
significantly increased in patients compared to healthy controls. In conclusion MRI
fat fraction correlates with muscle strength and clinical measurement of disability
in CMT1A patients. It may thus be a useful outcome measure of disease progression
in CMT1A.
OVERALL DISEASE IMPACT OF CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP)
Basta I
1, Peric S1, Cobeljic M1, Bjelica B1, Bozovic I1, Kacar A1, Nikolic A1, Rakocevic
Stojanovic V1, Stevic Z1, Lavrnic D1.
1Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade,
Belgrade, Serbia.
There is a complete lack of data about epidemiological and clinical features of chronic
inflammatory demyelinating polyneuropathy (CIDP) in Serbia and surrounding countries.
Furthermore, there is a striking scarcity of information about quality of life (QoL)
in CIDP patients and all QoL studies have been conducted in countries with high standards
of health care. In August 2016 we have designed the INeSS (Inflammatory Neuropathy
Study of Serbia) in order to comprise as many patients with CIDP from Serbia, Republic
of Srpska (Bosnia and Herzegovina) and Montenegro covering population of more than
nine million people. Our first aim is to analyze overall impact of CIDP on physical,
mental and social areas of life measured with generic, symptom specific and disease
specific questionnaires – SF‐36, INQoL and CAP‐PRI, respectively. Furthermore, we
aim to analyze influence of the disease on patients' working status and presence of
depressive mood measured by Beck's inventory. Following features of patients are included:
sociodemographic data, clinical aspects of the disease, level of disability, severity
of sensory symptoms, presence of comorbidities, electrophysiological characteristics,
as well as fatigue, autonomic symptoms and neuropathic pain. We intend to define the
most significant predictors of decreased QoL in order to focus on patients with the
highest risk and to improve care of CIDP. We also want to see if CIDP patients in
complete remission as per clinical findings still have reduced quality of life. We
have recruited 58 patient so far and we expect to include around 80 subjects overall.
We will present the first data of the study at the PNS meeting 2017.
NEUROPHYSIOLOGICAL FINDINGS IN ASYMPTOMATIC STAGE OF FAMILIAL AMYLOID NEUROPATHY:
A CASE CONTROL STUDY
Beaudonnet G
1, Prud'hon S1, Cauquil C2, Labeyrie C2, Not A2, Bouilleret V1, Adams D2.
1Neurophysiology CHU Bicêtre, Le Kremlin Bicêtre, France; 2Neurology CHU Bicêtre,
Le Kremlin Bicêtre, France.
Familial amyloid neuropathy (FAP) is a life‐threatening disease of autosomal dominant
inheritance due to transthyretin (TTR) gene mutation, a liver‐produced protein. Current
treatments slow down its natural course and are indicated from the very first objective
symptoms. We aimed to evaluate two neurophysiological markers: sympathetic skin response
(SSR) and heart rate variability (HRV) in the early detection of sympathetic damages
due to FAP. SSR and HRV were assessed in 21 TTR gene mutated patients with neither
clinic nor electroneuromyographic abnormalities and 21 controls matched on gender
and age. Cases were recruited consecutively from current care in the French Reference
Center for Rare Diseases of Bicetre University Hospital. SSR was recorded on the two
palms and on the sole of the left foot with 3 to 7 stimulations between 15 and 20
mA. HRV was registered during three conditions of 60 seconds each: normal breathing,
deep breathing (6 cycles of 5 seconds of inspiration and 5 seconds of expiration)
and Valsalva manoeuver during 15 seconds. Valsalva ratio, defined by the ratio between
the longest and shortest RR intervals, was significantly higher in the control groups
after Bonferroni correction (means of 1.556 and 1.929, respectively, p< 0.0001). There
was no significant difference between the two groups for any SSR parameter, although
means of amplitudes were systematically higher in controls than among cases. Our results
confirm that autonomic nervous fibers are damaged early in both clinical and electroneuromyographic
asymptomatic patients mutated on the TTR gene. Valsalva ratio seemed to be the most
discriminative marker. Long‐term follow‐up with test repetition and confrontation
with cardiologic assessment will help to precise how these tests could be used in
current care. They might help to identify high risk patients to propose them an appropriate
early treatment and could be used to follow treatment efficacy.
RECURRENT PERIPHERAL AND CENTRAL DEMYELINATION IN A SERONEGATIVE PATIENT
Bekircan‐Kurt CE
1,2, Yildiz G1, Temuçin Ç1, Kurne AT1, Tan E1,2, Erdem‐Ozdamar SE1,2.
1Department of Neurology, Hacettepe University, Ankara, Turkey; 2Neuromuscular Disease
Research Laboratory, Hacettepe University, Ankara, Turkey.
The content and antigenic properties of central and peripheral myelin are different
therefore; simultaneous autoimmune central and peripheral demyelination is an extremely
rare condition. Here we present a unique patient diagnosed with recurrent acute immune
mediated central and peripheral demyelination. Eighteen year‐old man admitted due
to generalized weakness with respiratory insufficiency. The electrophysiological evaluation
was compatible with acute inflammatory demyelinating polyneuropathy (AIDP) and treated
with intravenous immunoglobulin (IVIg). In the second week of the treatment he started
to suffer from vision loss in left eye. The cranial magnetic resonance imaging (MRI)
showed multiple subcortical lesions with contrast enhancement compatible with acute
demyelinating encephalomyelitis (ADEM). His complaint benefited from 5 days 1000 mg
methylprednisolone. Twelve years later, he referred because of generalized weakness
with respiratory insufficiency. Bilateral shoulder abduction was 2, elbow flexion
and extension were 3, hip flexion was 3 and foot dorsiflexion was 4 according to Medical
Research Council scale. He was diagnosed with AIDP. His cranial MRI depicted right
cerebellar, temporal bilateral frontoparietal subcortical contrast enhanced active
lesions. IgG index was high as 1 and oligoclonal band was positive and cerebrospinal
fluid (CSF) protein was 305 mg/dL. Serum and CSF anti‐MOG and anti‐neurofascin antibodies
were both negative. The patient was successfully treated with plasma exchange. His
follow‐up MRI after 3 months was normal. Previously five patients with both multiple
sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy were followed
in our institute, all were negative for anti‐neurofascin. However, there are very
few reports of patients with simultaneous Guillain‐Barré Syndrome and ADEM. Our report
defers from these patients due to recurrent course.
WILD‐TYPE TRANSTHYRETIN AMYLOIDOSIS (ATTR‐WT) AND PERIPHERAL NEUROPATHY
Benson MD
1,2, Kluve‐Beckerman B1, Dasgupta NR3.
1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine,
Indianapolis, IN, USA; 2Department of Veterans Affairs, Richard L. Roudebush Veterans
Affairs Medical Center, Indianapolis, IN, USA; 3Division of Cardiology, Department
of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Familial amyloidotic polyneuropathy (FAP) was originally characterized by Andrade
as an axonal neuropathy which subsequently was found to be associated with a number
of mutations in the plasma protein transthyretin (previously named prealbumin). It
is now recognized that cardiomyopathy may be a significant factor in a majority of
patients with the hereditary form of transthyretin amyloidosis (FAP) and many of the
transthyretin (TTR) mutations are associated with cardiomyopathy with no or minimal
signs of peripheral neuropathy. ATTR‐WT also called senile cardiac amyloidosis and
senile systemic amyloidosis is recognized as late‐onset, usually in the 8th or 9th
decade of life, and the fact that the majority of patients are males. Transthyretin
neuropathy proven by nerve biopsy has been rarely reported in this population. Here
we report our experience with patients having ATTR‐WT characterized by cardiomyopathy
but also with varying degrees of peripheral neuropathy. Clinically, the neuropathy
appears as typical axonal or mixed axonal/demyelinating neuropathy as is seen in FAP.
Pathologically, two types of TTR deposition have been found, (1) intraneural TTR amyloid
deposits as seen in FAP are present in some patients and (2) other patients have extensive
vascular deposition of amyloid in both perineural arteries and veins without deposits
within nerve trunks. In conclusion, peripheral neuropathy may definitely be a part
of the ATTR‐WT clinical presentation and with the increase in numbers of ATTR‐WT cardiomyopathy
patients being identified, it is important to ascertain whether any evidence of peripheral
neuropathy is due to the amyloidosis and not to compounding syndromes such as diabetes
mellitus type II.
PERIPHERAL NEUROTOXICITY IN OXALIPLATIN RETREATMENT IN COLORECTAL CANCER PATIENTS
Besora S1, Santos C2, Izquierdo C1, Martinez‐Villacampa M2, Simó M1, Bruna J1,3, Velasco
R
1,3.
1Neuro‐Oncology Unit, Hospital Universitari de Bellvitge‐Institut Català d'Oncologia,
L'Hospitalet, Barcelona, Spain; 2Medical Oncology Department, Institut Català d'Oncologia,
L'Hospitalet, Barcelona, Spain; 3Department of Cell Biology, Physiology and Immunology,
Institute of Neurosciences, Universitat Autònoma de Barcelona and Centro de Investigación
Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
Oxaliplatin (OXA) is the first‐line chemotherapy agent in the treatment of colorectal
cancer (CRC). OXA‐induced peripheral neuropathy is the most frequent long‐term side‐effect.
Retreatment with OXA is frequently considered in patients as salvage treatment. Patients
receiving OXA‐based chemotherapy regimen at least twice at our institution between
2000 and 2016 were reviewed. The aim of this study was to investigate whether retreatment
with OXA increases the risk of developing or worsening previous OXA‐induced peripheral
neuropathy. The severity of neuropathy was measured by National Cancer Institute‐Common
Toxicity Criteria (NCI), Total Neuropathy Score (TNS)© and nerve conduction studies.
One hundred twenty‐five CRC patients were included. Median age was 64 [25–84] years.
After first‐line OXA‐based chemotherapy, 67.2% of patients developed neuropathy according
NCI, after a median of 11 [1–17] cycles. Severity of neuropathy was grade 1 (26.7%),
grade 2 (31%), and grade 3 (9.5%). Median time to retreatment with OXA was 30 [11–90]
months. Frequencies of neuropathy before retreatment were as follows: 60.2% grade
0, 32.4% grade 1, and 7.4% grade 2. After retreatment, severities of neuropathy were
34.4 % grade 1 and 38.4% grade 2. No patient developed grade 3. 22.4% of patients
did not develop neuropathy. Peripheral neuropathy was the reason for stopping prematurely
treatment after first‐line and retreatment in 20.5% and 16.4% of patients, respectively.
Worsening of previous NCI score was observed in 30.8% of patients. The great majority
of patients (69.2%) remained within the same NCI score than before retreatment after
median 8 [1–14] cycles. Among those patients that did not develop neuropathy after
first treatment (n=39), only 11 and 5 patients developed grade 1 and 2, respectively,
after a median of 7 [1–12] cycles. Among those patients who initially developed grade
2 and 3 neuropathy, no differences in TNSc© scores just before and after finishing
retreatment with OXA were identified (6 [3–11] vs 6 [4–12], p=0.214). Retreatment
with OXA in CRC patients is a feasible option even in patients who developed moderate
or severe neuropathy previously. Lack of worsening of previous neuropathy is observed
in the great majority of patients. Neurological monitoring of patients candidates
to retreatment with OXA should be considered.
SENSORY SMALL FIBERS IMPLICATION ON INFLAMMATION REGULATION DURING SKIN PRESSURE ULCER
DEVELOPMENT IN MICE
Bessaguet F
1, Sturtz F1, Magy L1,2, Desmouliere A1, Bourthoumieu S1, Demiot C1.
1EA 6309 – Myelin Maintenance & Peripheral Neuropathy, Faculties of Medicine and Pharmacy,
University of Limoges, Limoges, France; 2Department of Neurology, Reference Center
for Rare Peripheral Neuropathies, University Hospital of Limoges, Limoges, France.
Prolonged pressure and the resulting local ischemia are widely accepted as the primary
etiology of skin pressure ulcers (PUs) but precise mechanisms of their formation remain
unclear. In this study, we wanted to study the potential role of sensory small nerve
fibers in regulation of inflammation during PUs formation. To achieve this goal, we
developed a mouse model of a purely sensory neuropathy and this was induced by resiniferatoxin
(RTX). In this model, seven days after a single injection of RTX (50μg/kg; IP), mice
present a thermal and mechanical hypoalgesia associated with large Substance P (SP)
and Calcitonin Gene‐Related Peptide (CGRP) depletion without neurodegeneration. This
model mimic quite well what is observed in early stages of sensory nerve fiber defect.
Studies have shown that SP and CGRP are involved in cutaneous inflammation regulation.
In fact, these neuropeptides are released by sensory fibers and are pro‐inflammatory
mainly through recruitment of immune cells and vasodilation. Thus, we studied gene
expression of pro and anti‐inflammatory cytokines by a RNA Array approach during PUs
formation in control and RTX mice. Seven days after a single injection of RTX, epidermis,
dermis and subcutaneous tissue layer were pinched with magnetic plates during 12 hours.
Pressure induced a stage 3 PUs. Gene expression was evaluated in each compressed area
24h after pressure. Results showed mainly a down‐regulation of gene expression in
PUs of RTX mice compared to control mice. A decrease of CGRP/SP in skin sensory small
fiber increased PUs formation associated with an increase of interleukins (IL)‐1,
IL‐4, IL‐11 and IL‐20 expression and a decrease of IL‐16 expression in RTX mice. Supplementary
experiments with RT‐qPCR for each cytokine will be necessary to confirm these preliminary
results.
These observations suggest a CGRP/SP role in regulation of cytokines expression during
PUs formation. The new inflammatory profile exhibited in this study might help in
the design of new treatments improving the quality of life of neuropathic patients
prone to developing bedsores.
REVERSAL OF PAINFUL DIABETIC NEUROPATHY BY CONTROL OF NOCICEPTOR EXCITABILITY
Bhattacharyya BJ
1, Jayaraj ND1, Belmadani A2, Ren D2, Rathwell CA1, Hackelberg S1, Miller RJ2, Menichella
DM1.
1Department of Neurology, Northwestern University, Chicago, IL, USA; 2Department of
Pharmacology, Northwestern University, Chicago, IL, USA.
Painful diabetic neuropathy (PDN) is one of the most common and intractable symptoms
of diabetes, affecting 25% of diabetic patients. The hallmarks of PDN are neuropathic
pain and small fiber degeneration, manifested by the loss of dorsal root ganglion
(DRG) nociceptor axons. Neuropathic pain is associated with nociceptor hyper‐excitability
in the absence of physiologically appropriate stimuli. In states of neuropathic pain,
DRG nociceptors become increasingly responsive to a variety of excitatory influences,
including inflammatory cytokines. In particular, we have shown that stromal cell derived
factor‐1 (SDF‐1) and its receptor CXCR4 are necessary for the generation of neuropathic
pain in mouse models of PDN. However, the molecular mechanisms leading to the hyper‐excitability
of DRG nociceptors in PDN are unknown, as are the mechanisms leading to small fiber
degeneration. This fundamental gap in our knowledge represents a critical barrier
to progress in developing novel therapeutic approaches for PDN. The objective of this
study is to identify the molecular cascade linking CXCR4/SDF‐1 chemokine signaling
to DRG nociceptor hyper‐excitability, neuropathic pain, and small fiber degeneration
in PDN. DRG nociceptors can be identified by a series of molecular markers, including
expression of the sodium channel Nav1.8. Indeed, >90% of Nav1.8‐expressing DRG neurons
are nociceptors. Feeding mice a high fat diet (HFD) for several weeks induces glucose
intolerance, obesity, and mechanical allodynia, a particular pain hypersensitivity
associated with PDN. Using the HFD model combined with DREADD receptor technology,
we have shown that reducing excitability of Nav1.8‐expressing neurons prevents and
reverse neuropathic pain, neuronal calcium overload, mitochondrial dysfunction, and
small fiber degeneration. Furthermore, we have shown that CXCR4 receptors are necessary
for neuropathic pain and small fiber degeneration in PDN. Taken together these data
demonstrate that Nav1.8 nociceptor hyperexcitability in PDN is driven through the
activation of CXCR4 receptors. Inhibition of hyperexcitability can prevent and reverse
the development of PDN. Furthermore, these observations will advance our understanding
as to how changes in excitability, calcium influx, and mitochondrial dysfunction in
nociceptors contribute to neuropathic pain and small fiber degeneration in PDN, which
is a critical barrier to progression for effective and disease modifying treatment
for PDN.
COMPARISON OF TWO‐YEAR RESPONSE TO LENALIDOMIDE OR PERIPHERAL BLOOD STEM‐CELL TRANSPLANTATION
IN PATIENTS WITH POEMS
Bianco M
1, Terenghi F1, Gallia F1, Nozza A2, Scarale A1, Fayoumi MZ1, Giannotta C1, Morenghi
E3, Nobile‐Orazio E1.
1Department of Medical Biotechnology and Translational Medicine, Milan University,
Neuromuscular and Neuroimmunology Service, Humanitas Clinical and Research Center,
Rozzano, Milan, Italy; 2Department of Medical Oncology and Hematology, Humanitas Clinical
and Research Centre, Rozzano, Milan, Italy; 3Biostatistic Unit, Humanitas Clinical
and Research Centre, Rozzano, Milan, Italy.
POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) syndrome
is an unusual multisystem disease with neurological disability due to a severe disabling
polyneuropathy, with high mortality by multiorgan failure. Peripheral blood stem cell
transplantation (PBSCT) is considered the treatment of choice for POEMS while lenalidomide
is the most promising therapy for patients not eligible for PBSCT. The aim of the
present study was to compare the long‐term effects on clinical, biological and neurophysiologic
parameters in patients with POEMS treated with Lenalidomide or PBSCT. The clinical,
biological and neurophysiologic data were reviewed in 15 POEMS patients treated with
PBSCT (n: 6) or lenalidomide (n: 9). The MRC sumscore on 16 muscles, ONLS scale, VEGF
serum levels and nerve conduction studies were assessed before (T0) and after 1 (T1)
and 2 years (T2) of treatment and the differences were compared using ANOVA. Combining
the two groups of patients, there was a significant improvement after treatment in
the mean MRC sumscore (T0 = 65±15; T1 = 69±11; T2 = 71±8; p = 0.000), in the mean
ONLS score (T0 = 5.6+2.6; T1 = 3.6+1.9; T2 = 3.5+2; p = 0.000), in the ulnar mean
distal motor latency (T0 = 3.8±1.2 msec; T1 = 3.3±0.4 msec; T2 = 3.0±0.4 msec; p =
0.02), distal compound muscle action potentials amplitude (T0 = 6.8±2.8 mV; T1 = 7.2±3.2mV;
T2 = 7.4±2.9mV; p = 0.0000), motor conduction velocity (T0 = 37.4± 10.7 m/sec; T1
= 43±9 m/sec; T2 = 47.9±9.3 m/sec; p=0.0003) and serum VEGF levels (T0 vs T1: p =
0.011; T0 vs T2: p = 0.010). The difference was also significant when we separately
analyzed patients treated with lenalidomide and PBSCT and there was no difference
between the two groups in any of the analyzed parameters. Treatment with PBSCT and
lenalidomide significantly and similarly improved clinical, biological and neurophysiologic
parameters in patients with POEMS syndrome up to two years. Since PBSCT may not be
suitable for all patients, Lenalidomide may represent an effective and a valuable
alternative in these patients or in those relapsing after PBSCT inducing a prolonged
clinical, biological and neurophysiologic improvement.
MUTATIONAL BURDEN ANALYSIS IN INHERITED PERIPHERAL NEUROPATHIES
Bis D
1, Tao F1, Abreu L1, Sleiman P2, Hakonarson H2, Zuchner S1 and Inherited Neuropathy
Consortium.
1Dr. J.T. MacDonald Department for Human Genetics, Hussman Institute for Human Genomics,
University of Miami, Miami, FL, USA; 2Center for Applied Genomics, The Children's
Hospital of Philadelphia, Philadelphia, PA, USA.
Inherited peripheral neuropathies are clinically and genetically heterogeneous diseases
that can cause distal muscular atrophy and sensory loss. Alleles in over one hundred
different genes have been shown to cause peripheral neuropathies; yet, greater than
50% of axonal neuropathy patients do not receive a genetic diagnosis. Large scale
exome studies are now beginning to be sufficiently powered to perform mutational burden
analysis. This approach compares damaging allele frequencies of CMT cases with a control
group to identify additional causes for neuropathies. This approach will also identify
genes that require an oligogenic inheritance to cause a phenotype. In a deviation
from the classic linkage‐based and heuristic variant filtering approaches to gene
identification, we are performing burden analyses in a large cohort of 382 CMT families.
In 113 known neuropathy genes, we saw that neuropathy cases carried on average 7.04
rare, non‐synonymous variants, while 927 unrelated non‐neuropathy controls harbored
5.76 variants (p=4.23E‐06, Mann‐Whiney U‐test). Enrichment of rare, non‐synonymous
variants in CMT disease genes within inherited peripheral neuropathy cases suggests
the presence of multiple weaker alleles in individual patients. We also performed
an unbiased exome‐wide gene‐based burden analysis and ranked genes after multiple
testing correction. Several new candidate genes were identified that need further
follow up conformational studies. A number of known CMT and related genes were observed
in the list of top candidates. We are currently analyzing additional aspects of this
sample and are actively seeking more CMT exomes to enlarge our study. In summary,
statistical methods traditionally reserved for more ‘common’ phenotypes' increasingly
are becoming available for rare disease genetics.
EFFECTS OF MONASTROL IN BORTEZOMIB‐INDUCED PERIPHERAL NEUROPATHY
Bobylev I
1,2, Peters D3, Vyas M4, Barham M2, Klein I1,2, von Strandmann EP4, Neiss WF2, Lehmann
HC1,2.
1University Hospital of Cologne, Cologne, Germany; 2University of Cologne, Cologne,
Germany; 3University of Düsseldorf, Düsseldorf, Germany; 4Philipps University, Marburg,
Germany.
Peripheral neuropathy is a common side effect of bortezomib. There is experimental
evidence that bortezomib induces axonal degeneration by altering microtubule stabilization
and axonal transport. Based on results from previous studies that the kinesin‐5 inhibitor
monastrol enhances axonal transport and improves neuronal regeneration, we assessed
the utility of monastrol to protect against bortezomib induced neuropathy.
C57BL/6 mice were treated with bortezomib alone or in combination with monastrol.
Neuropathic changes were assessed by nerve conduction studies and histological analysis.
Analysis of axonal morphology was performed with light and electron microscopy. Anti‐neoplastic
properties of monastrol alone and in combination with bortezomib were assessed in
different blood cancer cell lines.
Prolonged treatment with bortezomib induced a sensory neuropathy in mice. Significant
changes in axonal morphology correlated with reduced function of peripheral nerves.
The administration of monastrol substantially ameliorated morphological features of
axonal alterations and sensory neuropathy. Cytotoxicity studies in blood cancer cell
lines showed no interference of monastrol with the cytostatic effects of bortezomib.
Our data indicate that monastrol may alleviate bortezomib induced neuropathy. The
favorable cytotoxic profile of monastrol makes it an interesting candidate as neuroprotective
agent to prevent bortezomib‐induced neuropathy.
MUTATION IN GLYCYL‐tRNA SYNTHETASE IMPAIR MITOCHONDRIAL METABOLISM IN NEURONS
Boczonadi V
1, Meyer K2, Gonczarowska‐Jorge H3,4, Bartsakoulia M1, Roos A1,3, Bansagi B1, Zahedi
RP3, Talim B5, Bruni F6, Kaspar B2,7, Lochmüller H1, Boycott KM8, Müller JS1, Horvath
R1.
1JWMDRC, WTCMR, IGM, Newcastle University, Newcastle upon Tyne, UK; 2RINCH, Columbus,
OH, USA; 3Leibniz‐Institute für Analytische Wissenschaften‐ISAS‐e.V., Dortmund, Germany;
4CAPES Foundation, Brazil; 5Department of Pediatrics, Hacettepe University Children's
Hospital, Ankara, Turkey; 6DBBB,University of Bari Aldo Moro, Bari, Italy; 7Department
of Neuroscience, The Ohio State University, Columbus, OH, USA; 8Department of Genetics,
CHEO, University of Ottawa, Ottawa, Canada.
While autosomal dominant mutations in GARS, encoding the glycyl‐tRNA synthetase, have
been identified in patients with Charcot–Marie–Tooth peripheral neuropathy (CMT2D)
and distal spinal muscular atrophy type V (dSMA‐V), autosomal recessive mutations
cause mitochondrial disease affecting skeletal muscle and heart. GARS is a bi‐functional
enzyme and it is responsible for normal protein translation both in mitochondria and
the cytoplasm. In this study we have focused on the mitochondrial function of the
GARS by investigating a mouse model (GarsC210R)
, human fibroblasts and induced neuronal progenitor cell lines (iNPCs). Mild mitochondrial
abnormalities were detected in skeletal muscle of the GarsC210R
mice while no other tissues were affected. Control and patient fibroblasts harboring
GARS mutation were directly converted into iNPCs. We identified tissue specific impairment
of mitochondrial function in neuronal cells carrying not only recessive but also dominant
GARS mutations, suggesting neuron‐specific effects of mitochondrial alterations.Comparative
proteomic analysis of iNPCs showed significant changes in 41 mitochondrial proteins.
Furthermore, the reduction of the vesicle‐associated membrane protein‐associated protein
B (VAPB) and its downstream pathways in GARS‐deficient iNPCs suggests that altered
mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM) may also contribute
to the motor neuropathy.
MITOCHONDRIAL OXODICARBOXYLATE CARRIER DEFICIENCY: METABOLIC MODELLING IDENTIFIES
DISEASE MECHANISM
Boczonadi V
1, King MS2, Bansagi B1, Roos A1,3, Eyassu F2, Borchers C4, Lane M1, Ramesh V5, Lochmüller
H1, Pyle A1, Griffin H1, Smith AC2, Chinnery PF1,2, Alan J Robinson AJ2, Edmund RS
Kunji ERS2, Horvath R1
.
1JWMDRC, WTCMR, IGM, Newcastle University, Newcastle upon Tyne, UK; 2Mitochondrial
Biology Unit, Medical Research Council, Cambridge; 3Leibniz Institute of Analytic
Sciences (ISAS), Dortmund, Germany; 4UVic‐Genome BC Proteomics Centre, Vancouver,
Canada; 5Paediatric Neurology, Royal Victoria Infirmary, Newcastle upon Tyne Foundation
Hospitals NHS Trust, Newcastle upon Tyne, UK.
Members of the mitochondrial carrier family (SLC25) transport nucleotides, keto acids,
amino acids, fatty acids, co‐factors and inorganic ions across the mitochondrial inner
membrane. Several inherited diseases with very variable clinical presentations are
associated with dysfunctional mitochondrial carriers. We report a patient with childhood‐onset
spinal muscular atrophy and mitochondrial myopathy caused by a homozygous mutation
in SLC25A21, encoding the mitochondrial oxodicarboxylate carrier (ODC). The mutation
renders the carrier dysfunctional and, consequently, 2‐oxoadipate cannot be imported
into the mitochondrial matrix. Computer modelling of the metabolic defect caused by
the mutation predicted that the impaired transport leads to accumulation of 2‐oxoadipate,
pipecolic acid and the known neurotoxin quinolinic acid, which were precisely confirmed
by targeted metabolomics in serum and urine. Exposure of 2‐oxoadipate and quinolinic
acid reduced the level of mitochondrial complexes in SH‐SY5Y cells in‐vitro suggesting
a possible pathomechanism. Here we demonstrate that 2‐oxoadipate and quinolinic acid
are toxic for spinal motor neurons and their increased levels may contribute to neuropathy.
A KNOCK‐IN/KNOCK‐OUT MOUSE MODEL FOR SMALL HEAT SHOCK PROTEIN HSPB8 MIMICKING DISTAL
HEREDITARY MOTOR NEUROPATHY AND MYOFIBRILLAR MYOPATHY
Bouhy D1, Katona I2, Juneja M1, Haidar M1, Holmgren A1, De Winter V1, Irobi J1, Weis
J2, Timmerman V
1.
1Peripheral Neuropathy Research Group, Institute Born Bunge, University of Antwerp,
Antwerp, Belgium; 2Institute of Neuropathology, University Hospital, RWTH Aachen University,
Aachen, Germany.
Patients with distal hereditary motor neuropathy (dHMN) develop progressive motor
impairments, weakness and atrophy of distal limb muscles. Since our first description
of the K141N missense mutation in the small heat shock protein HSPB8, a number of
additional dHMN patients and families have been reported. Interestingly, most mutations
target the same amino acid residue (K141E, K141M, K141N, K141T) in the highly conserved
α‐crystallin domain of the HSPB8 protein. The spectrum of diseases caused by mutations
in the HSPB8 gene was recently expanded to distal myopathy. HSPB8 is ubiquitously
expressed, but is highly expressed in motor neurons and muscles. The HSPB8 is a chaperone
that participates in clearing misfolded poly‐Q containing proteins such as mutant
huntingtin and ataxin‐3 involved in respectively Huntington's disease and spino‐cerebellar
ataxia. HSPB8 directly interacts with the co‐chaperone BAG3 and their role in chaperone‐assisted
selective autophagy is well described. To delineate the molecular deficits and functional
consequences of HSPB8 mutations we generated a knock‐in (KI) mouse model for the K141N
missense mutation mimicking the neuropathy phenotype. We observed that homozygous
mutant mice (HspB8K141N/K141N) develop a progressive axonopathy, with decreased compound
motor action potential amplitudes, and loss of large and medium myelinated axons.
This results in locomotor deficits with an impaired performance at the rotarod and
grip strength tests. At the ultrastructural level, the HspB8‐KI model displays severe
signs of axon degeneration and a clear myofibrillar myopathy, as observed in some
patients with HSPB8 mutations. Interestingly, HspB8 positive aggregates were found
in the sciatic nerve and gastrocnemius muscle of our mutant mice. Additionally, our
model allowed us to generate HSPB8 knock‐out (KO) mice using the same targeting vector.
Strikingly, the homozygous HspB8‐KO animals do not show any sign of axonopathy and
display a much milder myopathy than the HspB8‐KI animals. These data suggest that
part of the pathomechanisms is due to toxic gain‐of‐function of the mutant protein.
RABBIT ANTI‐FGFR3 ANTIBODIES INDUCE NEURON CELL DEATH AND MODULATE FGFR3 AND NMDA
AND AMPA RECEPTORS THROUGH THE P38‐MAP KINASE PATHWAY
Boutahar N1, Reynaud E1, Nasser Y1, Camdessanché JP1, Antoine JC
1.
1University Hospital, Saint‐Etienne, France.
Dysimmune sensory neuronopathies (SNN) depend on neuron cell death induced by an inflammatory
reaction in dorsal root ganglia. We have recently identified the intracellular tyrosine
kinase (TRK) domain of the Fibroblast Growth Factor Receptor‐3 (FGFR3) as the target
of antibodies in a subset of patients with non paraneoplastic SNN. FGFR3 is one of
the four FGFRs and has been involved in sensory neurons maintenance during development
and cell death induction after axotomy. FGFRs ligand fixation results in the activation
of several intracellular pathways through adaptator protein interactions with the
TRK domain. In particular Ras activation may lead to cell proliferation or apoptosis
through Erk1/2 or p38 MAP kinase signaling. The p38 MAPK pathway is also involved
in neuronal cell death induced by NMDA and AMPA receptor activation. As FGFR3 is a
cell surface protein, human antibodies may interfere with the receptor functioning
as a growing number of evidence has showed with other cell surface antibodies in neurological
diseases. To test this hypothesis we developed an in vitro model using FVBN mice cortical
neurons culture exposed to a rabbit polyclonal antibody reacting with the TRK domain
of FGFR3. Comparatively to normal rabbit IgGs, the FGFR3 antibody induced neuron cell
death in a dose dependent manner. Neuron cells were exposed to FGFR3 antibody concentration
leading to 10–20 % cell death in absence or presence of the p38 MAPK inhibitor SB203580
and the expression of FGFR3, GLUR1 subunit of AMPA receptors and NR1 subunit of NMDA
receptor was measured by quantitative RT‐qPCR. The FGFR3 antibody induced an upregulation
of FGFR3 while the GLUR1 and NR1 subunits were modulated. These changes were prevented
in presence of SB203580. These preliminary results indicate that anti‐FGFR3 IgGs may
interfere with the functioning of the intracellular domain of the protein and the
expression of NMDA and AMPA receptors through the p39 MAP kinase pathway. This model
may be used to test the effect of human anti‐FGFR3 IgGs in vitro.
NOVEL, LIKELY PATHOGENIC, SEQUENCE VARIANTS IN HEREDITARY NEUROPATHY GENES
Braathen GJ
1, Tveten K1, Holla ØL1, Busk ØL1, Hilmarsen HT1, Svendsen M1, Høyer H1.
1Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital,
Skien, Norway.
Next‐generation sequencing (NGS) has during the last years entered the clinical diagnostics.
NGS has proven to be very efficient in the diagnostics of disorders where multiple
genes can be involved. Our NGS‐based targeted gene panel consists of 99 hereditary
neuropathy genes, i.e. mostly Charcot‐Marie‐Tooth genes. This study is a retrospective
study of clinic samples received between May 1 2014 and February 1 2017. We describe
the identified novel likely pathogenic sequence variants, according to International
Guidelines. In this period we identified novel, not previously described, likely pathogenic
sequence variants in the following genes: AARS, FGD4, GAN, HINT1, LITAF, LRSAM1, MME,
MPZ, NEFL, PMP22, SBF1, SH3TC2 and YARS. There is now a large range of genes causing
hereditary peripheral neuropathies and many likely pathogenic sequence variants. Likely
pathogenic sequence variants are not only identified in old well established neuropathy
genes but also in the newer genes like MME.
MODELLING BROWN‐VIALETTO‐VAN LAERE SYNDROME IN C. ELEGANS
Brewer MH
1,2, Attrill G2, Ellis M1, Ly C1, Nicholson GA1,2,3, Menezes MP4,5*, Kennerson ML1,2,3*.
1Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, Australia; 2Sydney
Medical School, University of Sydney, Sydney, Australia; 3Molecular Medicine, Concord
Repatriation General Hospital, Sydney, Australia; 4The Institute for Neuroscience
and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia; 5Pediatrics
and Child Health, University of Sydney, Sydney, Australia, * equal last author.
Brown‐Vialetto‐Van Laere syndrome (BVVL) is an autosomal recessive neurodegenerative
disease caused by mutations in SLC52A2 and SLC52A3, which encode the riboflavin transporters
RFVT2 and RFVT3. Patients with RFVT2 deficiency exhibit proximal and distal limb weakness,
sensory ataxia, diaphragmatic paralysis, optic atrophy, sensorineural deafness and
bulbar palsy. Riboflavin is critical for the biosynthesis of flavin mononucleotide
and flavin adenine dinucleotide, essential cofactors for carbohydrate, amino‐acid
and lipid metabolism. Mutations in SLC52A2 reduce or abolish RFVT2 expression resulting
in impaired riboflavin uptake into sensory and motor neurons. High‐dose riboflavin
treatment can improve or stabilise a patient's condition, however the optimum dose
and long term effects of riboflavin treatment, and disease pathomechanisms remains
poorly understood. To further understand the pathophysiological consequences of SLC52A2
mutations, we propose developing an animal model for BVVL. Caenorhabditis elegans
(C. elegans) are small round transparent nematodes extensively used for studying the
genetics and molecular biology of neurodegenerative diseases. There are two C. elegans
riboflavin transporter genes, rft‐1 and rft‐2. Based on protein sequence homologies
and expression profiles for both genes, RFT‐1 is the ortholog of RFVT2. The expression
of RFT‐1 is regulated by riboflavin availability and knock‐down of the rft‐1 gene
by siRNA perturbs C. elegans development. Our aim is to develop a knock‐in C. elegans
model of BVVL. Human RFVT2 and C. elegans RFT‐1 protein sequences were aligned with
Clustal Omega to identify conserved amino acid residues associated with BVVL mutations.
The amino acid involving the L339P RFVT2 mutation is conserved in RFT‐1 (residue L324).
To create our model, we will introduce the L324P RFT‐1 mutation into the rft‐1 locus
in C. elegans genomic DNA using CRISPR/Cas‐9 technology. This BVVL C. elegans model
will allow us to explore the pathogenic consequences of RFVT2 deficiency underlying
motor nerve degeneration and to evaluate drug therapy regimes by determining the optimal
riboflavin dose and treatment initiation, and trialing other compounds that may improve
benefits seen with riboflavin supplementation.
EFFECTIVE THERAPEUTIC EFFECT OF HUMAN IMMUNOGLOBUMIN AND A RECOMBINANT Fc PORTION
ON A RAT MODEL FOR CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY (CIDP)
Brun S
1, Kremer L1,2, Mondon P3, Jacque E3, Chtourou S3, Masiello NC4, De Seze J1,2.
1UMR_S INSERM U1119 Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques,
University of Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS),
Strasbourg, France; 2Department of Neurology, University Hospital of Strasbourg, Strasbourg,
France; 3Direction of Innovative Therapeutic, LFB Biotechnologies, Loos, France; 4LFB
USA, Framingham, MA, USA.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune‐mediated
inflammatory disease of the peripheral nervous system. CIDP can present chronic progressive
or relapsing‐remitting courses and can predominantly affect motor but also sensory
nerve fibers causing weakness of proximal and distal muscles. It represents the most
common chronic autoimmune neuropathy and is pathologically characterized by focal
inflammatory‐mediated demyelination followed by axonal degeneration. Recently, we
have developed a new animal model for CIDP, the chronic‐EAN, induced in Lewis rats
by active immunization with S‐palmitoylated P0(180–199) peptide. This model fulfills
electrophysiological criteria of demyelination with axonal degeneration, a result
confirmed by immunohistopathology. The late phase of the chronic disease is characterized
by an accumulation of IL‐17+ cells and macrophages in sciatic nerves and as well as
high serum IL‐17 levels. It is a reliable and reproducible animal model for CIDP that
can now be used for translational drug studies for chronic human autoimmune‐mediated
inflammatory diseases of the peripheral nervous system, particularly CIDP, for which,
there is a real need for new immunotherapies. The aim of this study was to test the
therapeutic efficacy of IVIg and a recombinant Fc fragment (FcRec) in this new CIDP
animal model. Treatments with IVIg and FcRec proved effective in preventing further
progression of CIDP in rats. The therapeutic treatments not only decreased the maximal
clinical scores of the CIDP rats compared to albumin treatment but also abolished
the disease chronicity. Interestingly, a better efficacy of FcRec treatment compared
to IVIg was demonstrated at histological level, with the myelinated fibers well preserved
and the greatly reduced accumulation of macrophages and IL‐17+ cells in sciatic nerves.
IVIg and FcRec therapeutic activities in this model can also be followed by measurement
of IL‐17 and anti‐P0(180–199) antibodies in the serum and could therefore be used
as biological markers. The current study provides for the first time direct evidence
that IVIg is effective in the treatment of CIDP rats and suggests that a novel FcRec
compound is more effective than IVIg. It will contribute to the development of more
effective and safer drugs for the treatment of autoimmune peripheral neuropathies
like CIDP.
INVESTIGATION OF THE VARIATION OF MOTOR CONDUCTION VELOCITY BY USING HOPF'S COLLISION
TECHNIQUE IN CIDP PATIENTS
Buermann J
1, Singh P1, Rapp D2, Fassbender K1, Dillmann U1.
1Department of Neurology, Medical University of the Saarland, Homburg, Germany; 2Institute
for Medical Biometry, Epidemiology and Medical Informatics, Medical University of
the Saarland, Homburg, Germany.
A prompt and correct diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP) is very important to initiate an appropriate therapy in CIDP patients. Normally,
conventional nerve conductions studies (NCS) are used to detect demyelination. But
especially in cases of “probable” or “possible” CIDP according to the EFNS criteria,
additional electrodiagnostic parameters indicating demyelination more precisely are
desirable. In our study, we examined the variation of motor nerve conduction velocity
by applying Hopf's collision technique in CIDP patients. The collision technique was
performed at the ulnar nerve of 24 CIDP patients and at a control group of 37 healthy
individuals. Each time, one measurement with supramaximal stimulation according to
the conventional NCS and another measurement with 50% enhanced stimulation intensity
were conducted. We analyzed the results with special consideration of minimal and
maximal fiber velocities and of the velocity with maximal fiber proportion. As a result,
we detected statistically significant differences between CIDP patients and controls
in all these parameters. Compared with controls, CIDP patients had slower minimal
and maximal fiber velocities and also the spectrum of motor conduction velocities
was definitively shifted to slower velocities. Slower minimal conduction velocities
could be detected in some CIDP patients by using the enhanced stimulation intensity.
Interestingly, in some CIDP patients the conventional ulnar NCS were normal, but the
collision technique showed fibers with a conduction velocity of less than 35 m/s,
indicating demyelination. To our knowledge, this is the first study using Hopf's collision
technique systematically in CIDP patients. Significant differences between the variation
of ulnar motor nerve conduction velocity of CIDP patients and controls could be detected.
This method also showed signs of demyelination in some CIDP patients with normal ulnar
NCV. By enhancing stimulation intensity above the threshold of supramaximal stimulation
in conventional NCS, the collision technique may be even more valuable.
TREATMENT‐RELATED FLUCTUATIONS AND ACUTE‐ONSET CIDP IN THE IGOS COHORT
Bunschoten C
1, Miry F1, Vytopil M2, van Doorn PA1, Jacobs BC1,3 and the IGOS Consortium.
1Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; 2Department
of Neurology, Lahey Hospital & Medical Center, Burlington, USA; 3Department of Immunology,
Erasmus Medical Center, Rotterdam, The Netherlands.
The clinical course of Guillain‐Barré syndrome (GBS) is highly variable and some patients
may develop treatment‐related fluctuations (TRFs) as an indication of ongoing disease
activity and temporary treatment effect. Other patients present as GBS, but subsequently
develop repetitive relapses as an indication of acute‐onset chronic inflammatory demyelinating
polyneuropathy (A‐CIDP). This distinction is important because treatment may differ.
We determined the frequency and clinical presentation of patients with GBS‐TRF and
A‐CIDP in the first 1000 patients included in the International GBS Outcome Study
(IGOS) with a follow‐up of at least 12 months. Thirty‐eight patients (4%) were excluded
because of alternative diagnoses. Of the remaining 962 patients, 40 (5%) had at least
one TRF, 35 (4%) had A‐CIDP. Preliminary analysis showed no significant differences
between the 3 groups (total‐GBS, GBS‐TRF and A‐CIDP) for sex, age, sensory symptoms,
cerebrospinal fluid results and mechanical ventilation. A‐CIDP patients had a median
age of 54 years (IQR 40–70), 66% was male, and all patients were treated in the acute
phase of the disease (intravenous immunoglobulins (IVIg) (31), plasma‐exchange (PE)
(3) or methylprednisolone (MP) (1)). GBS‐TRF patients has a median age of 57 years
(IQR 40–67), 48% was male and all patients received treatment (IVIg (35) and PE (5).
GBS‐TRF patients showed more antecedent events (78% versus 49%, p=0.011), a higher
GBS disability score (≥3) at nadir (100% versus 86%, p=0.018) and less frequently
developed ataxia (32% versus 71%, p=0.001) than patients with A‐CIDP. Onset to nadir
was longer in A‐CIDP than in GBS‐TRF (33 days (IQR 12–60) versus 17 days (IQR 8–33),
p=0.023) and the total GBS group (9 days (IQR 5–13), p=0.000). The time until the
first clinical deterioration tends to be longer in the A‐CIDP patients (median 41
days (IQR 26–56) versus median 31 days (IQR 20–33) in the GBS‐TRF group, not significant).
The diagnosis A‐CIDP was made after a median of 69 days (IQR 53–111). In conclusion,
this first analysis identified distinctive characteristics of GBS‐TRF and A‐CIDP in
support of a different pathogenesis that may help with early identification of these
disorders in clinical practice. Additional results will be presented at the conference.
INTERNATIONAL CIDP OUTCOME STUDY (ICOS): A PROSPECTIVE STUDY ON CLINICAL AND BIOLOGICAL
PREDICTORS OF DISEASE COURSE AND OUTCOME
Bunschoten C1, van Lieverloo GGA2, Adrichem MA2, Broers MC
1, van der Pol WL3, Eftimov F2, Jacobs BC1,4 and the ICOS Consortium.
1Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; 2Department
of Neurology, Academic Medical Center, Amsterdam, The Netherlands; 3Department of
Neurology, University Medical Center, Utrecht, The Netherlands; 4Department of Immunology,
Erasmus Medical Center, Rotterdam, The Netherlands.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a disorder with a highly
diverse clinical presentation, electrophysiological phenotype, response to treatment
and outcome. This heterogeneity may indicate the presence of distinct subtypes of
CIDP, which may have a different pathogenesis and require more personalized treatment.
The International CIDP Outcome Study (ICOS) is a prospective, observational, international
multi‐center study that aims to describe this variation in clinical and electrophysiological
subtypes and to define the clinical and biological determinants of these subtypes,
disease activity, treatment response and outcome. In addition ICOS aims to provide
an infrastructure for conducting new (therapeutic) studies in CIDP, similar to the
International GBS Outcome Study (IGOS). All patients fulfilling the EFNS/PNS (2010)
diagnostic criteria for CIDP can be included in ICOS, independent of age, duration
and severity of disease or treatment. We collect information on neurological deficits,
diagnostic characteristics, various validated clinical outcome measures, previous
and current treatment and we collect biomaterials (DNA, cerebrospinal fluid, nerve
biopsies and repeated serum samples). ICOS was started as a pilot study in 3 Dutch
University Centers. By February 2017, 78 patients were included in ICOS, 35 patients
recently diagnosed with CIDP and 43 previously diagnosed patients. Included were 49
(63%) males and 29 (37%) females with a median age of 63 years (IQR 52–71). The current
cohort consists of 52 classic (sensory‐motor) CIDP, 16 MADSAM and 5 pure motor variants.
Of the 43 patients diagnosed in the past, 36 patients (84%) were treated (intravenous
immunoglobulins (IVIg) (29), prednisolone (2), subcutaneous immunoglobulins (SCIg)
(2), dexamethasone (1), plasma‐exchange (1) and IVIg with methylprednisolone (MP)
(1)). The 35 recently diagnosed patients all received treatment (IVIg (12), dexamethasone
(3), plasma‐exchange (1) and 19 patients were treated in a pilot study with IVIg with
methylprednisolone (MP)). The protocol has been evaluated and adjusted and will be
shared with other researchers via the Inflammatory Neuropathy Consortium and IGOS
Consortium. Our aim is to include at least 1000 CIDP patients worldwide with a minimum
follow‐up period of 2 years.
TRANSCRIPTIONAL AND TRANSLATIONAL PROFILING AND PRECLINICAL TESTING IN GARS/CMT2D
MOUSE MODELS
Burgess RW
1,2, Morelli KH1,2, Spaulding EL1,2, Seburn KL1, Harper SQ3.
1The Jackson Laboratory, Bar Harbor, ME USA; 2The Graduate School of Biomedical Science
and Engineering, University of Maine, Orono, ME, USA; 3Center for Gene Therapy, The
Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Dominant mutations in glycyl tRNA synthetase (GARS) cause inherited axonal neuropathy
(Charcot‐Marie‐Tooth type 2D). Mutations in the mouse Gars gene cause a similar phenotype,
and represent valid disease models. We routinely use two mouse strains, one with a
severe neuropathy, and one with a milder, later onset neuropathy. Using these mouse
models, we are exploring the mechanisms through which Gars mutations cause peripheral
axon degeneration. Efforts include ribosome tagging to isolate ribosome‐associated
mRNAs specifically from motor neurons, and non‐canonical amino acid tagging to visualize
and isolate newly synthesized proteins. Taking advantage of the anatomy of motor neurons,
we are able to analyze cell bodies separately from peripheral axons in both of these
approaches. In addition, we are using these mouse models for preclinical studies testing
gene therapy approaches to treat CMT2D. Consistent with our previous genetic studies
in mice, knockdown of the mutant transcript, while preserving sufficient levels of
the wild type, is a very successful approach when administered before the onset of
neuropathy. We are now testing this approach in mice after the onset of symptoms,
and in mice carrying a mutant Gars allele associated with human disease. These studies
are potentially translational, and also address mechanistic questions such as the
timing and cell autonomy of the pathophysiology.
NEUROFASCIN ANTIBODIES IN AUTOIMMUNE, GENETIC AND IDIOPATHIC NEUROPATHIES
Burnor E1, Yang L2, Hao Z1, Patterson K1, Quinn C1, Scherer SS1, Lancaster E
1.
1The University of Pennsylvania, Philadelphia, PA, USA; 2The Second Xiangya Hospital,
Central South University, Hunan, China.
Autoantibodies to two isoforms of neurofascin (NF155 and NF186) have been reported
in patients with Guillain‐Barre syndrome (GBS) or chronic inflammatory demyelinating
neuropathy (CIDP). It is not clear which of these responses reliably distinguish autoimmune
neuropathies from other severe neuropathies, which responses are transient versus
persistent, or which responses may target multiple isoforms of neurofascin. In addition,
approximately 30% of neuropathy patients have no known cause, and it is unknown whether
a subset of these patients may have autoantibodies to neurofascins. We have studied
cohorts of patients with autoimmune neuropathy (n=150), genetic neuropathy (n=100),
and idiopathic neuropathy (n=40) for IgG and IgM responses to Neurofascins. Neurofascin
antibodies were found in 12 (8%) of patients with autoimmune neuropathy, and 3 (7.5%)
idiopathic neuropathy patients, but only 1% (1 of 100) in patients with genetic neuropathy.
Follow‐up serum samples were available for 7 positive cases. Persistent responses
were associated with chronic neuropathy while transient responses were seen in GBS
or with remission of CIDP. Most patients had responses specific to either NF155 of
NF186. However, a particularly severe, treatment‐resistant form of CIDP, approaching
a locked‐in state, was seen in a patient with a unique response to all three isoforms
of neurofascin (NF186, NF155, NF140). Treatment of this patient with rituximab resulted
in clinical improvement and resolution of the neurofascin antibody response. In conclusion,
autoantibodies to neurofascins distinguish autoimmune neuropathies from severe genetic
neuropathies, but the clinical phenotype may depend on the persistence and isoform
specificity of the immune response. Antibodies to the common domains shared by NF155
and NF186 may portend a severe but treatable neuropathy. A subset of idiopathic neuropathy
patients may have an autoimmune mechanism.
RANDOMISED TRIAL OF PROGRESSIVE RESISTANCE EXERCISE FOR CHILDHOOD CHARCOT‐MARIE‐TOOTH
DISEASE
Burns J
1,2, Sman AD1, Cornett KMD1, Wojciechowski E1,2, Walker T1, Menezes MP1,2, Mandarakas
MR1, Rose KJ1,2, Bray P1,2, Sampaio H2, Farrar M2,3, Refshauge KM1, Raymond J1 and
the FAST study group.
1University of Sydney, New South Wales, Australia; 2Sydney Children's Hospitals Network
(Randwick and Westmead), New South Wales, Australia; 3University of New South Wales,
Sydney, Australia.
Exercise has undisputed benefits for human health and potentially as a treatment for
neuromuscular disease. But there is also a risk of harm due to overwork weakness.
We report the results of a 24‐month randomised, double‐blind, sham‐controlled trial
evaluating progressive resistance exercise of foot dorsiflexor muscles in pediatric
CMT. Sixty patients (47 CMT1A, 1 CMT1E, 2 CMT1F, 1 CMT2A, 2 CMT4C, 4 CMTX1, 3 CMTX3)
aged 6–17 years were randomly assigned to undergo 24‐weeks (72 sessions) of moderate‐intensity
progressive resistance exercise or sham exercise. The primary endpoint was change
in isometric dorsiflexion strength between groups assessed by hand‐held dynamometry
(expressed as a z‐score based on age‐ and sex‐matched normative reference values,
positive values indicate an improvement in strength). The primary safety endpoint
was change in muscle and fat volume of the muscles responsible for dorsiflexion by
MRI between groups. Secondary outcomes were function (balance, long jump, 6‐min walk
test), walking ability (3D gait analysis), self‐reported ankle instability, parent‐reported
quality of life (Physical Summary, Psychosocial Summary and Global Impression of Change
scores), and adverse events. Fifty‐five (92%) children completed the trial. Adherence
was comparable between exercise (77%) and sham (81%) groups. While patients experienced
muscle soreness during training in the exercise group, adverse events did not differ
between groups. The mean z‐score for dorsiflexion strength increased in the exercise
group by 8% at 24‐months (from −2.5±1.0 to −2.3±0.9) and decreased in the sham group
by 24%, mirroring the natural history of CMT (from −2.1±0.7 to −2.6±1.2). Between‐group
ANCOVA‐adjusted difference at 24‐months was 0.6 (95%CI, 0.03 to 1.12; P=0.041). The
mean scaled scores for MRI muscle volume and fat volume were comparable between groups
at 24 months (P>0.05). The Global Impression of Change scores favoured the exercise
group at 12‐months (P=0.021) and 24‐months (P=0.009). There was no other measurable
effect of exercise. Pre‐specified subgroup analyses according to age (6–11 years vs.
12–17 years) showed a larger treatment effect with exercise in adolescents. Targeted
progressive resistance exercise was effective at halting progression of dorsiflexion
weakness without detrimental effect on muscle morphology or other signs of overwork
weakness in children with CMT.
INFLAMMATORY POLYRADICULOPATHY ASSOCIATED WITH SJOGREN'S SYNDROME
Byung‐Nam Y
1, Yoon‐Ho H2, Suk‐Won A3, Seok‐Jin C4, Jung‐Joon S4.
1Inha University Hospital, Incheon, South Korea; 2Seoul Metropolitan Government Boramae
Medical Center, Seoul National University, Seoul, South Korea; 3Joong Ang University
Hospital, Seoul, South Korea; 4Seoul National University Hospital, Seoul, South Korea.
A 51 years old female patient visited the hospital with weakness in both upper limbs
from 9 months under the suspicion of motor neuron disease with the finding of extensive
denervation changes on electromyography. Whole spine MRI showed ventral nerve rootlet
enhancement in the C and T bundles. The EMG had confirmed active denervation changes
in the muscles innervated by bilateral C5∼C7 roots. The cerebrospinal fluid culture
test showed a protein (CSF) elevation to 65 mg / dl. She got a steroid pulse therapy.
She had the symptoms of dry mouth and dry eyes during the recent 2 years. A salivary
gland scan test was performed for the possibility of Sjögren's syndrome, and as a
result, absorption of the contrast agent in both parotid and submandibular glands
was decreased. The Shammer test showed 8 mm on the right side and 7 mm on the left
side. She was diagnosed of Sjögren's syndrome. After 2 weeks, overall strength improvement
was observed, and bilateral shoulder abduction was improved to MRC grade 4 or higher.
The follow‐up spine MRI also showed that the initially seen ventral nerve root enhancement
was disappeared. The case had visited the hospital with major symptoms of weakness
and atrophy of the muscles, showing similar pattern to motor neuron disease, and was
diagnosed as inflammatory polyradiculopathy and confirmed as primary SS during differential
diagnosis. This case suggests that primary SS may induce inflammatory polyradiculopathy,
which shows motor symptoms as major symptoms rather than sensory symptoms, and that
a fast and accurate diagnosis is needed in terms that it can be treated with steroids
and appropriate immune suppressive agents.
LOCAL INFUSION OF A LOW DOSE OF CURCUMIN IMPROVES NERVE REGENERATION AND FUNCTIONAL
RECOVERY IN RATS SUBMITTED TO SCIATIC NERVE CRUSH INJURY
Caillaud M
1, Richard L1,2, Vignaud L1, Vallat JM1,2, Desmouliere A1, Billet F1.
1EA 6309 – Myelin Maintenance & Peripheral Neuropathies, Faculties of Medicine and
Pharmacy, University of Limoges, Limoges, France; 2Department of Neurology, Reference
Center for Rare Peripheral Neuropathies, University Hospital of Limoges, Limoges,
France.
Traumatic injuries to peripheral nerves are frequent. However, effective pharmacological
treatments are lacking. Curcumin, a polyphenol found in rhizomes of Curcuma longa,
has been shown to develop antioxidant, anti‐inflammatory, and neuroprotective properties.
However, due to its poor hydrosolubility and its extensive metabolism, the use of
large curcumin doses is required for therapeutic purpose. The aim of the present study
was to investigate the effects of a local infusion of a low curcumin dose on nerve
regeneration and functional recovery after sciatic nerve injury in rats. The experiments
were conducted in 200 g SD male rats submitted to unilateral sciatic nerve crush at
d0. Curcumin was solubilized in polyethylene glycol and continuously administered
using osmotic pumps (0.2 mg/day until d35) with a catheter delivering the drug near
the lesion site. Functional analyses using Von Frey, beam walking, static sciatic
index (SSI) and grip strength tests were carried out at d0 (reference test) and every
week after injury (d7, d14, d21, d28 and d35). In addition, an evoked electromyogram
was performed at d0 and d35. After euthanasia (d35), nerve and muscle samples were
collected and analyzed by light and electron microscopy. Functionally, a significant
improvement of the mechanical sensitivity (+34%) was observed at d14 in the curcumin‐treated
group (n=12) vs. vehicle group (n=12). In curcumin‐treated group, skillful walking
and finger spacing of the ipsilateral paw (SSI) were fully restored respectively at
d28 and d35 contrary to vehicle group. Furthermore, curcumin treatment improved the
grip strength recovery (+24% at d35). The electrophysiological results indicated a
full recovery of motor nerve conduction velocities (MNCV) after 35 days of curcumin
treatment, while MNCV remained altered in vehicle group (79% of the MNCV at d0). Morphometric
analysis of nerve sections using g‐ratio showed an improvement in the thickness of
the myelin sheath in curcumin treated animals (+13% vs. vehicle group). Histological
investigation of gastrocnemius muscle indicated decreased neurogenic lesions in curcumin
group. Proteomic analysis is currently under investigation to understand the mechanisms
involved in curcumin effects. Our data could lead to the development of new therapeutic
strategies in peripheral nerve regeneration using low doses of curcumin.
THE ASSOCIATION BEWTEEN THE METABOLIC SYNDROME AND NEUROLOGIC OUTCOMES IN A BARIATRIC
SURGERY POPULATION
Callaghan BC1, Villegas‐Umana E
2, Reynolds E3, Averill S4, Feldman EL5
.
1University of Michigan, Ann Arbor, MI, USA.
Previous studies suggest that the metabolic syndrome (MetS) is associated with distal
symmetrical polyneuropathy (DSP), and that diabetes, pre‐diabetes, and obesity are
the main metabolic drivers. The aim of this study is to investigate the association
of MetS components with retinal and cognitive function in a bariatric surgery cohort
prior to surgery. Patients were recruited from the Adult Bariatric Surgery Clinic
at the University of Michigan and lean controls from a research website (no MetS components
based on NCEP/ATPIII definition). Participants underwent extensive metabolic phenotyping
including a glucose tolerance test and fasting lipid profile. DSP was defined using
the Toronto consensus definition of probable clinical neuropathy. Retinal function
was measured with frequency doubling technology perimetry (average mean deviation),
and cognitive function with the NIH Toolbox (composite score). Univariate linear regression
models were used to evaluate the association between MetS components and retinal and
cognitive function. To date, we have recruited 45 bariatric surgery participants and
21 lean controls. In the bariatric population, the mean (SD) age was 47 (11.1) with
78% female compared with a mean age of 46.5 (11.3) with 76% female in the lean group.
In the bariatric group, 35.6% had diabetes, 31.1% pre‐diabetes, and 33.3% normoglycemia.
The DSP prevalence was 0% in lean controls, 6.7% in normoglycemic, 7.1% in pre‐diabetic,
and 31.3% in diabetic bariatric participants (p<0.001 for trend). Retinal function
was 0.01 (2.97), −0.21 (2.59), −3.36 (4.50), and −1.98 (4.27) (p=0.02 for trend),
and cognitive function was 115.0 (12.0), 115.2 (20.0), 118.5 (20.9), 107.4 (14.4)
(p=0.36 for trend) in these same groups for lean controls, normoglycemics, pre‐diabetics
and diabetics, respectfully. Pre‐diabetes (−3.2, 95%CI: −5.97,‐0.34) was the only
MetS component associated with retinal function, and waist circumference was the only
one associated with cognitive function (−1.76, 95%CI −3.4,‐0.1). DSP and retinal function,
but not cognitive function decline with worsening glycemic status. Similar to previous
data for DSP, pre‐diabetes and obesity are associated with retinal and cognitive function
respectively. Interestingly, while clinical DSP is common in this population, clinical
retinopathy and dementia are not, indicating that DSP may be the first metabolic complication
in the morbidly obese.
PREVALENCE OF ANTI‐NEUROFASCIN‐155, ANTI‐CONTACTIN‐1 AND CONTACTIN‐ASSOCIATED PROTEIN
1 ANTIBODIES IN CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY: A SEROLOGICAL
MULTICENTER STUDY IN ITALY
Callegari I
1, Cortese A2, Lauria G3, Briani C4, Luigetti M5, Fazio R6, Benedetti L7, Marfia G8,
Clerici M9, Carpo M10, Corbo M11, Mazzeo A12, Ferrari S13, Giannini F14, Manganelli
F15, Manso C16, Giannotta C17, Berardinelli A1, Zardini E18, Romagnolo S18, Currò
R1, Gastaldi M1, Spina E15, Topa A15, Dacci P3, Lombardi R3, Campagnolo M4, Bisogni
G5, Cerri F6, De Michelis C7, Mataluni G8, Stancanelli C12, Mariotto S13, Piccolo
L11, Schenone A7, Moglia A1, Marchioni E18, Nobile‐Orazio E17, Devaux J16, Franciotta
D18.
1Neuroscience Consortium, University of Pavia, Monza Policlinico and Pavia Mondino,
Italy; 2MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and
Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; 3Department of
Clinical Neurosciences, IRCCS Foundation, "Carlo Besta" Neurological Institute, Milan,
Italy; 4Department of Neurosciences, University of Padova, Padova, Italy; 5Department
of Geriatrics, Neurosciences and Orthopedics, Institute of Neurology, Catholic University
of Sacred Heart, Rome, Italy; 6Department of Neurology, San Raffaele Scientific Institute,
Milan, Italy; 7Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics,
Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy; 8Department
of Neuroscience, University of Rome Tor Vergata, Rome, Italy; 9Department of Neurology
and Stroke Unit, Ospedale di Circolo/Fondazione Macchi, Varese, Italy; 10Neurology
Unit, Ospedale Treviglio, Bergamo, Italy; 11Department of Neurorehabilitation Sciences,
Casa Cura Policlinico (CCP), Milan, Italy; 12Department of Neurosciences, University
of Messina, Messina, Italy; 13Department of Neurological and Movement Sciences, University
of Verona, Verona, Italy; 14Department of Medicine, Surgery and Neurosciences, University
of Siena, Siena, Italy; 15Department of Neurosciences, Odontostomatological and Reproductive
Sciences, University of Naples "Federico II", Naples, Italy; 16Aix‐Marseille Université,
CNRS, CRN2M‐UMR7286, Marseille, France; 17Department of Medical Biotechnology and
Translational Medicine (BIOMETRA), University of Milan, 2nd Neurology, Humanitas Clinical
and Research Center, Rozzano, Milan, Italy; 18Department of General Neurology – C.
Mondino National Institute of Neurology Foundation, IRCCS, Pavia, Italy.
Antibodies to neurofascin‐155 (Nfasc155), contactin‐1 (CNTN1) and contactin‐associated
protein (Caspr1) have been identified in 3‐18% of patients with chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP). However, their prevalence and associated
clinical features in Italian CIDP patients are unknown. Serum samples from 150 patients
fulfilling the ENFS/PNS criteria for definite CIDP were tested for anti‐Nfasc155,
anti‐CNTN1 and anti‐Caspr1 antibodies. Sera from additional 85 CIDP patients were
tested for reactivity to anti‐NFASC155 and anti‐CNTN1. By ELISA, antibodies to Nfasc155
were found in 6 (3,5%) CIDP patients and to CNTN1 in 3 (1,3%). Anti‐Nfasc155 and anti‐CNTN1
antibody‐positive cases were confirmed by CBA and were of IgG4 subclass in half of
them. By CBA we identified additional 3/150 (2%) anti‐Caspr1 seropositive patients,
whose isotype is currently being tested. Sera of anti‐Nfasc155 and anti‐CNTN1 IgG4
seropositive patients and patients with anti‐Caspr1 antibodies stained paranodes by
indirect immunofluorescence on mouse teased nerve fibers. Of note, 35 seronegative
patients for known antibodies showed reactivity against node and/or paranodes. Compared
to other 35 seronegative CIPD patients, seropositive patients had more frequently
subacute onset of the neuropathy and a younger age at onset, particularly for Nfasc155
or Caspr1 antibodies. Weakness was more severe and was often associated with proprioceptive
loss, sensory ataxia and tremor. Neuropathic pain was not a feature of Caspr1‐seropositive
patients. Frequent findings were increased distal motor latencies and temporal dispersions
on nerve conduction study and a higher protein level in CSF. Finally seropositive
patients tended to have a higher disability and showed worst response to IVIg. Rituximab
was effective in one patient with anti‐Nfasc155 antibodies and two patients with anti‐CNTN1
antibodies showed good and persistent recovery after Cyclophosphamide.
Prevalence of antibodies was 7% in Italian CIDP patients and their presence was associated
with distinctive clinical features. Their determination, followed by characterization
of IgG subclass in positive cases, has clear clinical impact, by helping to guide
therapeutic choices. The reactivity against nodal and paranodal components in sera
from patients without known antibodies suggests that other targets could play a role
in the autoimmune response in CIDP and they still need to be identified.
CMT2 WITH PYRAMIDAL TRACT INVOLVEMENT DUE TO ARG329HIS MUTATION IN ALANYL‐TRNA SYNTHETASE
(AARS)
Callegari I
1, Cortese A2, Rossor AM2, Houlden H3, Reilly MM2.
1Neuroscience Consortium, University of Pavia, Monza Policlinico and Pavia Mondino,
Italy; 2MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and
Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; 3Department of
Molecular Neuroscience, UCL Institute of Neurology, London, UK and National Hospital
for Neurology and Neurosurgery, Queen Square, London, UK.
Mutations in amynoacyl tRNA synthetases (ARSs), enzymes that catalyse the covalent
attachment of amino acids to their cognate tRNA, are responsible for autosomal dominant
CMT2, Intermediate CMT (CMT‐I) and dHMN. We report the case of a male of Italian ancestry
who first presented with bilateral ankle clonus at three months, followed by toe walking
and ankle instability. The ankle clonus subsided during adolescence. In the third
decade he developed progressive walking difficulties followed by distal sensory loss.
Neurological examination at the age of 37 revealed a steppage gait, distal lower limb
weakness, decreased pinprick to the ankles, and reduced vibration sensation at the
knees. Reflexes were brisk in the upper limbs, reduced at the knees and absent at
the ankles. Muscle tone was increased in the lower limbs and plantar responses were
extensor. Nerve conduction studies revealed an axonal neuropathy. Brain and spinal
cord MRI were normal. Sanger sequencing of PMP22, GJB1, MPZ, GDAP and MFN2 were negative.
SureSelect Focused Exome sequencing (Agilent Technologies, Santa Clara CA, USA) demonstrated
a c.986G>A, p.Arg329His mutation in AARS.
The p.Arg329His mutation in AARS has previously been reported in 7 families with intermediate
or axonal motor‐sensory neuropathy, and in one case was associated with sensory‐neuronal
deafness. CNS involvement has not previously been described with this mutation. Mutations
in AARS have been associated with a range of phenotypes including CMTI, CMT2 and dHMN
with variable age on onset ranging from 0 to 55 years (mean 24 years). Of note, the
AARS p.Gly102Arg mutation has been reported in a family with CMT2 and pyramidal signs.
This study provides further evidence that pyramidal tract involvement can be an early
feature of CMT2N due to mutations in AARS, further expanding the spectrum of ARSs‐associated
phenotypes.
RECESSIVE DYSTROPHIC EPIDERMOLYSIS BULLOSA RESULTS IN PAINFUL SMALL FIBRE NEUROPATHY
Calvo M
1, Bennett DLH2.
1Pontificia Universidad Catolica de Chile, Santiago, Chile; 2NDCN Oxford University,
UK.
Small fibres in the skin are vulnerable to damage in metabolic or toxic conditions
such as diabetes mellitus or chemotherapy resulting in small fibre neuropathy and
associated neuropathic pain (NP). Whether injury to the most distal portion of sensory
small fibres due to a primary dermatological disorder can cause NP is still unclear.
Recessive Dystrophic Epidermolysis Bullosa, (RDEB) is a rare condition in which mutations
of proteins of the dermo‐epidermal junction lead to cycles of blistering followed
by regeneration of the skin. Damage is exclusive to the skin and mucous membranes,
with no known direct compromise of the nervous system. It is increasingly recognised
that most RDEB patients experience daily pain, the aetiology of which is unclear but
may include inflammation (in the wounds), musculoskeletal (due to atrophy and retraction
scars limiting movement) or NP. In this study we investigated the incidence of NP
and examined the presence of nerve dysfunction in RDEB patients. Around three quarters
of patients presented with pain of neuropathic characteristics which had a length
dependent distribution. Quantitative sensory testing of the foot revealed striking
impairments in thermal detection thresholds combined with an increased mechanical
pain sensitivity and wind up ratio (temporal summation of noxious mechanical stimuli).
Nerve conduction studies showed normal large fibre sensory and motor nerve conduction
however skin biopsy showed a significant decrease in intraepidermal nerve fibre density.
Autonomic nervous system testing revealed no abnormalities in heart rate and blood
pressure variability however the sympathetic skin response of the foot was impaired
and sweat gland innervation was reduced. We conclude that chronic cutaneous injury
can lead to injury and dysfunction of the most distal part of small sensory fibres
in a length dependant distribution resulting in disabling NP. These findings also
support the use of neuropathic pain screening tools in these patients and treatment
algorithms designed to target neuropathic pain.
ALTERED POTASSIUM CHANNEL DISTRIBUTION AND COMPOSITION IN MYELINATED AXONS SUPPRESSES
HYPEREXCITABILITY FOLLOWING INJURY
Calvo M
1, Richards N2, Schimd A3, Barroso A2, Zhu L2, Ivulic D1, Zhu N3, Anwandter P1, Bhat
M4, Court F1, McMahon SB2, Bennett DLH3
. 1Pontificia Universidad Catolica de Chile, Santiago, Chile; 2Wolfson CARD, Kings
College London, UK; 3NDCN Oxford University, UK; 4UT Health Science Center, San Antonio,
TX, USA.
Neuropathic pain (NP) following peripheral nerve injury is associated with hyperexcitability
in damaged myelinated sensory axons which begins to normalise over time. We investigated
the composition and distribution of shaker type potassium channels (Kv1 channels)
within the nodal complex of myelinated axons following injury. At the neuroma that
forms after damage, expression of Kv1.1 and 1.2 (normally localised to the juxtaparanode)
was markedly decreased. In contrast Kv1.4 and 1.6, which were hardly detectable in
the naïve state, showed increased expression within juxtaparanodes and paranodes following
injury, both in the rat and in humans. Within the dorsal root (a site remote from
injury) we also noted a redistribution of Kv1 channels towards the paranode. Blockade
of Kv1 channels with αDTX after injury reinstated hyperexcitability of A‐fibre axons
and enhanced mechanosensitivity. Changes in the molecular composition and distribution
of axonal Kv1 channels, therefore represents a protective mechanism to suppress the
hyperexcitability of myelinated sensory axons that follows nerve injury.
THE FRANCOPHONE ANTI‐MAG COHORT: LESSONS LEARNED FROM THE ANALYSIS OF 202 PATIENTS
Camdessanché JP
1, Petiot P2, Antoine JC1, Vial C3, Delmont E4, Viala K5, Magot A6, Cauquil C7, Zarea
A8, Echaniz‐Laguna A9, Iancu Ferfoglia R10, Guegen A11, Magy L12, Léger JM13, Kuntzer
T14, Steck A15, Ferraud K1, Lacour A1, Svahn J3 and the Francophone anti‐MAG cohort
group.
1Department of Neurology, University Hospital of Saint‐Etienne, 42055 Saint‐Étienne
Cedex 2, France; 2Department of Neurology, Croix‐Rousse Hospital, Hospices Civils
de Lyon, 103 grande rue de la Croix‐Rousse, 69004 Lyon, France; 3Electroneuromyography
and Neuromuscular Department, GHE Neurologic Hospital, 69677 Lyon, Bron Cedex, France;
4Department of Neurology, Timone Hospital, Marseille Teaching Hospital, Marseille,
France; 5Department of Neurophysiology and Neuropathology, AP‐HP, GHU Pitié‐Salpêtrière,
Paris, France; 6Neuromuscular Reference Center, CHU Nantes, France; 7Department of
Neurology, Bicêtre Hospital, APHP, Le Kremlin Bicêtre, France; 8Neuromuscular Competence
Center, CHU Rouen, France; 9Reference Center of Neuromuscular Disorders, Neurology
Department, Hautepierre Hospital, Strasbourg, France; 10Electroneuromyography and
Neuromuscular Disorders Unit, Department of Clinical Neurosciences, Geneva University
Hospital, Geneva, Switzerland; 11Department of Neurology, Fondation Ophtalmologique
A. de Rothschild, Paris, France; 12Department of Neurology, Centre de Référence "Neuropathies
Périphériques Rares", University Hospital of Limoges, Limoges, France; 13Department
of Neurology, National Referral Center for Rare Neuromuscular Diseases, University
Hospital Pitié‐Salpêtrière and University Paris VI, Paris, France; 14Nerve‐Muscle
Unit, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), Lausanne,
Switzerland; 15Department of Neurology, Basel University Hospital, Basel, Switzerland.
Members of the Francophone anti‐MAG cohort Group are listed in “Appendix”.
Appendix: The Francophone anti‐MAG cohort Group: Other members of the Francophone
anti‐MAG cohort Group who provided cases for the study are, in alphabetical order:
David Adams, Hôpital Bicêtre; Sharam Attarian, CHU de Marseille; Anne‐Laure Bedat‐Millet,
CHU de Rouen; Françoise Bouhour, CHU de Lyon; Célia Boutte, CHU de Grenoble; Guy Chauplannaz,
CHU de Lyon; Raquel Costa, Hôpital Pitié‐Salpêtrière; Perrine Devic, CHU de Lyon;
Chantal Grand, CHU de Lyon; Guillemette Jousserand, CHU de Lyon; Timothée Lenglet,
Hôpital Pitié‐Salpêtrière; Pierre Lozeron, Hôpital Bicêtre; Thierry Maisonobe, Hôpital
Pitié‐Salpêtrière; Cristina Muntean, Hôpital Pitié‐Salpêtrière; Yann Pereon, CHU de
Nantes; Jean Pouget, CHU de Marseille.
Polyneuropathy with anti‐MAG IgM antibodies is classically progressive, predominantly
sensory, and distal with ataxia and sometimes postural‐intention tremor.
We assessed clinical, biological, electrophysiological, and histopathological features
in patients with IgM gammopathy and anti‐MAG antibody titres higher than 1000 BTU.
We focused on characteristics of patients according to the anti‐MAG antibody titres
at diagnosis.
We retrospectively and prospectively analysed standardized report forms of 202 patients
from fourteen French‐speaking neuromuscular centres.
Mean age at onset was 62.6 years (range 25–91.4). Mean time between symptoms onset
and last follow‐up was 8.4 years (0.3‐33.3). About 33.2 % of patients presented with
a “variant” clinical phenotype independently of anti‐MAG titres (< or ≥ 10 000 BTU).
This included acute or chronic sensorimotor polyradiculoneuropathies, paucisymptomatic
sensory polyneuropathy and multifocal neuropathy. At the most severe disease stage,
22.4% of patients were significantly disabled. Anti‐MAG antibody titres at diagnosis
were low (<10 000 BTU), medium (10 000–70 000) or high (≥70 000) in respectively 11,
51 and 38 % of patients. Patients presented with MGUS or Waldenström's macroglobulinemia
in respectively 68 % and 29 % of cases. Sixteen percent of patients did not meet the
electrodiagnostic criteria of definite demyelinating neuropathy, independently of
anti‐MAG titres (< or ≥ 10 000 BTU). Nerve biopsy, performed in nineteen patients,
provided support to the diagnosis of anti‐MAG neuropathy in some particular issues
(low titres of anti‐MAG, unusual clinical or electrophysiological phenotype). We assessed
the degree of probability (probable, possible or uncertain) that patient neuropathies
are directly related to anti‐MAG antibodies, according to anti‐MAG titre, electrophysiological
data and nerve biopsy characteristics if available. It appears uncertain in 5 patients
with low anti‐MAG titres (2.5 % of the whole population).
The clinical phenotype didn't appear to be different according to anti‐MAG antibody
titre. Many of the patients with low anti‐MAG titres presented “genuine” anti‐MAG
neuropathy as demonstrated by EDX studies, clinical presentation and sometimes nerve
biopsies. For a small proportion of these patients, a direct relation between neuropathy
and anti‐MAG antibodies is uncertain due to atypical clinical presentation, axonal
neuropathy pattern or nerve biopsies, and positivity of antigangliosides antibodies.
THE FRANCOPHONE ANTI‐MAG COHORT: ANALYSIS OF THERAPEUTIC MANAGEMENT IN 202 PATIENTS
Camdessanché JP
1, Petiot P2, Antoine JC1, Vial C3, Delmont E4, Viala K5, Magot A6, Cauquil C7, Zarea
A8, Echaniz‐Laguna A9, Iancu Ferfoglia R10, Guegen A11, Magy L12, Léger JM13, Kuntzer
T14, Steck A15, Ferraud K1, Lacour A1, Svahn J3 and the Francophone anti‐MAG cohort
group.
1Department of Neurology, University Hospital of Saint‐Etienne, France; 2Department
of Neurology, Croix‐Rousse Hospital, Hospices Civils de Lyon, Lyon, France; 3Electroneuromyography
and Neuromuscular Department, GHE Neurologic Hospital, Lyon, Bron Cedex, France; 4Department
of Neurology, Timone Hospital, Marseille Teaching Hospital, Marseille, France; 5Department
of Neurophysiology and Neuropathology, AP‐HP, GHU Pitié‐Salpêtrière, Paris, France;
6Neuromuscular Reference Center, CHU Nantes, France; 7Department of Neurology, Bicêtre
Hospital, APHP, Le Kremlin Bicêtre, France; 8Neuromuscular Competence Center, CHU
Rouen, France; 9Neurology Department, Reference Center of Neuromuscular Disorders,
Hautepierre Hospital, Strasbourg, France; 10Electroneuromyography and Neuromuscular
Disorders Unit, Department of Clinical Neurosciences, Geneva University Hospital,
Geneva, Switzerland; 11Department of Neurology, Fondation Ophtalmologique A. de Rothschild,
Paris, France; 12Department of Neurology, Centre de Référence "Neuropathies Périphériques
Rares", University Hospital of Limoges, Limoges, France; 13Department of Neurology,
National Referral Center for Rare Neuromuscular Diseases, University Hospital Pitié‐Salpêtrière
and University Paris VI, Paris, France; 14Nerve‐Muscle Unit, Department of Clinical
Neurosciences, Lausanne University Hospital (CHUV), Lausanne, Switzerland; 15Department
of Neurology, Basel University Hospital, Basel, Switzerland.
Members of the Francophone anti‐MAG cohort Group are listed in “Appendix”.
Appendix: The Francophone anti‐MAG cohort Group: Other members of the Francophone
anti‐MAG cohort Group who provided cases for the study are, in alphabetical order:
David Adams, Hôpital Bicêtre; Sharam Attarian, CHU de Marseille; Anne‐Laure Bedat‐Millet,
CHU de Rouen; Françoise Bouhour, CHU de Lyon; Célia Boutte, CHU de Grenoble; Guy Chauplannaz,
CHU de Lyon; Raquel Costa, Hôpital Pitié‐Salpêtrière; Perrine Devic, CHU de Lyon;
Chantal Grand, CHU de Lyon; Guillemette Jousserand, CHU de Lyon; Timothée Lenglet,
Hôpital Pitié‐Salpêtrière; Pierre Lozeron, Hôpital Bicêtre; Thierry Maisonobe, Hôpital
Pitié‐Salpêtrière; Cristina Muntean, Hôpital Pitié‐Salpêtrière; Yann Pereon, CHU de
Nantes; Jean Pouget, CHU de Marseille.
We assessed therapeutic management, response to immunotherapies and adverse events
in a cohort of 202 patients presenting with IgM gammopathy and anti‐MAG antibody titres
higher than 1000 BTU.
We retrospectively and prospectively analysed standardized report forms of 202 patients
from 14 French speaking neuromuscular centres.
Mean age at onset was 62.6 years (range 25–91.4). Mean time between symptoms onset
to diagnosis and last follow‐up were respectively 3.1 (0–30) and 8.4 years (0.3‐33.3).
Anti‐MAG antibody titres at diagnosis were low (<10 000 BTU), medium (10 000–70 000)
or high (≥70 000) in 11, 51 and 38 % of patients. Patients presented with MGUS or
Waldenström's macroglobulinemia in respectively 68 % and 29 % of cases.
Seventy eight percent (n = 158) of patients received immunotherapies. Transient response
to IVIg or plasma exchanges at six month was observed in less than 30 and 20% of patients
respectively. Chemoimmunotherapies and rituximab were more frequently administered
in the group of patients with malignant hemopathies (n = 65) compared to MGUS (n =
137) (mean lines of therapy = 1.2, range 0–4, SD 0.7 versus 0.85, range 0–3, SD 0.85,
p = 0.002). More than 45% of patients (n = 92) received rituximab monotherapy. Clinical
worsening, mostly transient and reversible, was observed in 11/92 patients after rituximab.
Clinical response to rituximab at 6 months and/or during 7–12 months follow‐up period
was observed in 31.5% of patients, and correlated with anti‐MAG titre ≥ 10 000 BTU
(30/31 responder versus 50/61 non‐responder patients, p = 0.05). At 7–12 months follow‐up,
responder patients presented shorter symptom duration compared to non‐responders,
though not significant after logistic regression (3.6 years, range 0.13‐16.23, SD
3.7 in 29 responder patients versus 5.1 years, range 0.13‐17.6, SD 4.2, in 63 non
responder patients, p = 0.1). In some cases, electrodiagnostic studies were recorded
during rituximab treatment follow‐up and showed in responder patients a clear improvement
of motor conduction velocities. These data may support another clinical trial to study
benefice of rituximab in anti‐MAG neuropathies early in the disease. It raises issues
about the value of incorporating electrodiagnostic parameters as end‐points.
N‐METHYL‐D‐ASPARTATE RECEPTOR (NMDA‐R)‐ACTIVATED CELL‐SIGNALING IN RESPONSE TO GLUTAMATE
IN SCHWANN CELLS
Campana WM
1,3, Mantuano E2,4, Azmoon P2, Henry KW1, Shibayama M1, Kim J1, Pizzo J2, Banki M2,
Gonias SL2.
1Department of Anesthesiology, UCSD School of Medicine, La Jolla, CA, USA; 2Department
of Pathology, UCSD School of Medicine, La Jolla CA, USA; 3Program in Neurosciences,
UCSD School of Medicine, La Jolla, CA, USA; 4Department of Experimental Medicine,
Sapienza University of Rome, Rome, Italy.
Schwann cells (SCs) are essential for axon integrity and myelination in the uninjured
PNS. After PNS injury, SCs function as “first responders”, undergoing phenotypic re‐programming
and orchestrating many processes that lead to functional nerve repair. Receptors in
SCs that contribute to SC repair programs remain incompletely understood. We identified
a member of the ionotropic glutamate receptor (IGR) family, N‐methyl‐D‐aspartate receptor
(NMDA‐R), in SCs that is upregulated after nerve injury and acts as a co‐receptor
with LDL‐receptor related protein (LRP1). LRP1 is a well‐known regulator of the SC
response to PNS injury. Herein, we used PCR to profile IGR expression in cultured
rat SCs. Obligate receptor subunits required for assembly of NMDA‐Rs, AMPA‐Rs, and
Kainate Receptors were identified. Treatment of rat SCs with 40–100 microM glutamate
or 0.5‐1.0 microM NMDA robustly activated Akt and ERK1/2. The response was transient
and bimodal; glutamate concentrations greater than 250 microM failed to activate cell‐signaling.
Phosphoprotein profiling demonstrated other cell‐signaling and transcription factors
regulated by glutamate in rat and human SCs, including p70 S6‐kinase, glycogen synthase
kinase‐3, ribosomal S6 kinase, c‐Jun, and CREB. Activation of cell‐signaling by glutamate
in SCs was blocked by eliminating calcium from the medium, by the selective NMDA‐R
antagonist, MK801, and by genetic silencing expression of the obligate NMDA‐R NR1
subunit. Phosphoinositide 3‐kinase/PI3K functioned as an essential upstream activator
of both Akt and ERK1/2 in glutamate‐treated SCs. By activating PI3K and ERK1/2, glutamate
promoted SC migration. Glutamate (200 microM) or NMDA (20 microM) injected into crush‐injured
sciatic nerves robustly activated p‐ERK1/2 in both myelinating and non‐myelinating
SCs in vivo. These results identify IGRs as potentially important cell‐signaling receptors
in SCs that may promote axon‐glial interactions. Understanding the function of SC
NMDA‐R is important given current efforts to develop NMDA‐R‐targeting drugs for patients
with pain, depression, and Alzheimer's Disease. While frequently overlooked in a therapeutic
context, SCs are extremely important in the pathogenesis of chronic neuropathic pain.
If these drugs modulate the activity of SC NMDA‐R and SC physiology, the response
to PNS injury may be altered and the possibility that neuropathic pain develops increased.
MUTATION SPECTRUM IN A TURKISH CHARCOT‐MARIE‐TOOTH DISEASE COHORT
Candayan A
1, Atkinson D2, Durmus Tekce H3, Parman Y3, Jordanova A2, Battaloglu E1.
1Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey;
2Center for Molecular Neurology, Antwerp University, Antwerp, Belgium; 3Istanbul Medical
School, Istanbul University, Istanbul, Turkey.
Charcot‐Marie‐Tooth (CMT) disease is a group of inherited peripheral neuropathies
affecting one in 2500 individuals worldwide. The disease presents both clinical and
genetic heterogeneity. So far, mutations in 80 genes and 10 loci are associated with
CMT with autosomal dominant, autosomal recessive, X‐linked and mitochondrial inheritance.
Despite the advances in genetic testing, approximately 35% of all CMT patients worldwide
remain without a molecular diagnosis. We have investigated 93 unrelated CMT patients
of Turkish descent, in all of which PMP22 duplication has been excluded previously.
We used Multiplex Amplification of Specific Targets for Resequencing (MASTR) assay
to sequence exonic regions of 28 common CMT genes. Recurrent mutations were identified
in 14 cases in MFN2, GJB1, MPZ and HINT1 genes. We have also identified novel variants
in 11 cases in MFN2, PMP22, GARS, AARS, IGHMBP2 and GDAP1 genes, all of which are
very rare or not present in the variation databases and are predicted to be pathogenic
by in silico tools. Familial segregation analyses are ongoing for novel variations.
MFN2 and GJB1 genes were the most commonly mutated causative genes in this cohort.
Cases without molecular diagnosis after the MASTR testing are candidates for further
analyses such as whole exome sequencing or whole genome sequencing. Outcomes of the
current study and our previous experience with Turkish CMT patients suggest a high
genetic heterogeneity. Our insight is that different genetic strategies or larger
panels are essential to determine the causes underlying CMT especially in regions
where rare recessive types of the disease can be observed due to high frequency of
consanguineous marriages.
TOTAL COMPOUND MUSCLE ACTION POTENTIAL DURATION: A NEW USEFUL ELECTROPHYSIOLOGICAL
MEASURE FOR EARLY GBS DIAGNOSIS
Capoccitti G
1, Giannini F1, Ginanneschi F1, Casali S1, Insana L1, Rossi A1.
1University of Siena, Siena, Italy.
Several efforts have been made to elaborate new electrophysiological criteria for
early diagnosis of Guillain‐Barré Syndrome (GBS) and to differentiate demyelinating
(AIDP) from axonal (AMAN/AMSAN) forms. The aims were to verify the diagnostic power
of total CMAP (TCMAP) duration, firstly applied in GBS field. This parameter was compared
with commonly used neurophysiological measures, including negative phase CMAP duration
(NCMAP), and was added to modified Rajabally criteria. We reviewed the clinical and
electrophysiological data of 38 patients with GBS (level 1 or 2 of Brighton clinical
criteria). Each patient underwent at least two neurophysiological studies, the first
within 2 weeks, the second between 3 and 7 weeks from symptom onset. At least four
motor and three sensory nerve conduction studies were recorded for each test. Regarding
early diagnosis, the binary logistic regression model with multiple variables, including
NCMAP duration, showed that the 3 features of predictive model presenting greater
significance (p <0.1) were TCMAP duration, Sural Sparing and A‐waves. Among these,
TCMAP duration showed greater significance (p = 0.002). The TCMAP was diffusely prolonged
in AIDP compared to AMAN/AMSAN, already in first examination and confirmed in the
second one. ROC analysis for TCMAP duration in AIDP vs. AMAN/AMSAN showed: cut‐off
15.7 ms, AUC 0.89, PPV 91.3%. We propose the TCMAP duration as a new useful electrophysiological
measure for early diagnosis of "generic" GBS and for early differentiation between
AIDP and AMAN/AMSAN. Moreover, the prolongation of TCMAP, the presence of A‐waves
and Sural Sparing represent a strongly diagnostic predictive triad of AIDP.
NOVEL PHE210LEO MISSENSE MUTATION IN AIFM1 GENE IS ASSOCIATED WITH AN AXONAL POLYNEUROPATHY
Castoro R
1, Wang M1, Simmons M1, Hu B1, Li J1.
1Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN,
USA.
AIFM1 (apoptosis‐inducing factor, mitochondrion‐associated‐1) has captured great attention
from biomedical researchers due its critical role in the regulation of cell apoptosis.
This flavoprotein is typically located in the mitochondrial intermembrane space where
it is associated with respiratory chain complex‐I. Upon a cell‐death insult, AIFM1
is cleaved into a 57Kd protein that is released into the cytosol. The 57Kd peptide
may enter the nucleus to trigger chromosome condensation and fragmentation, initiating
a caspase‐independent pathway of apoptosis. However, this nuclear translocation may
be blocked by cytosolic Heat‐Shock Protein‐70 (HSP70) that binds with the FAD domain
(aa 150 – 228) of AIFM1. Mutations in AIFM1 gene have resulted in several clinical
phenotypes, including a family with CMTX4 (Glu493Val). Clinical deficits in these
patients usually involve multiple organs. In this study however, we identified a family
with a novel missense mutation (Phe210Leu) in AIFM1 that developed a late‐onset sensory
motor axonal polyneuropathy by nerve conduction criteria. The proband and affected
siblings exhibited distal muscle weakness and atrophy with normal cognitive and cranial
nerve functions. There was no obvious phenotype from other organs. Interestingly,
this Phe210Leu mutation affects a highly conserved amino acid at the center of the
FAD domain. We hypothesize that this mutation impairs the binding between AIFM1 and
HSP70, leading to an enhancement of cell‐death signaling. This family therefore provides
a unique opportunity to explore how altered apoptotic signaling affects peripheral
nerve system. Supported by grants from NINDS (R01NS066927) and the National Center
for Advancing Translational Sciences (UL1TR000445).
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY ASSOCIATED WITH LYMPHOMA: MONOCENTRIC
STUDY
Cauquil C
1, Noel N2, Beaudonnet G3, Laurenge A1, De Menthon M2, Labeyrie C1, Lazure T4, Adam
C4, Chrétien P5, Goujard C2, Lambotte O2, Adams D1.
1Neurologie Adulte, CHU Bicêtre, Le Kremlin Bicêtre, France; 2Unité de neurophysiologie
clinique et épileptologie, CHU Bicêtre, France; 3Service de médecine interne et immunologie,
CHU Bicêtre, France; 4Service d'anatomopathologie, CHU Bicêtre, France; 5Laboratoire
d'immunologie, CHU Bicêtre, France.
Chronic inflammatory demyelinating polyneuropathy (CIDP) can be the key symptom leading
to diagnosis of associated lymphoma. Patients with diagnosis of CIDP according to
EFNS/PNS criteria associated with B cell lymphoproliferative disorders (BLD), in one
center, between November 2013 and November 2016 were included. Demographical, clinical,
nerve conduction, immunological, histological data and response to treatment were
recorded retrospectively. Eight patients (5 men), median age 70yo [53–77] were included.
Onset of polyradiculoneuropathy was either chronic (n=6) or acute (n=2). Neurological
condition led to diagnosis of BLD in all but one case, because of onset (n=4) or worsening
of neuropathy (n=3). Clinical presentation was that of CIDP in 5 patients or pseudo‐CANOMAD
in 2 and plexopathy in one. Lymphoma type was: lymphoplasmacytic (n=3), diffuse large
B cell (n=2), small lymphocytic (n=1), marginal zone (n=1), unclassified small B cell
(n=1). Only 2 patients presented with lymphadenopathies. BLD was diagnosed in all
8 patients on myelogram or bone marrow biopsy, performed because of cytopenia (n=2),
atypical (n=3) or severe (n=3) neuropathy. Monoclonal gammapathy was identified in
5/8 patients (IgM n=4, IgG n=1). Neuromuscular biopsy was performed in 6 patients
and disclosed endoneural infiltration in 2. Anti‐neuronal or antigangliosides antibodies
were positive in 5 patients. None of the patients presented a systemic autoimmune
disease, hemolytic anemia associated with BLD (n=2). Immunomodulating treatment was
administered in all patients (IVIG n=7, plasma exchange n=3, steroids n=3) and immunosuppressants
(n=1). Immunochemotherapy for lymphoma was initiated because of lymphoma type or severity
in 3 cases, in 5 cases because of the associated neuropathy. Median follow‐up was
of 8 months [1–24] after treatment initiation. Four out of 5 patients treated within
3 months of neurological onset improved as well as one out of 3 patients whose preexisting
neurological condition had worsened. Two patients presented neurological relapse during
progression of lymphoma. Two patients died. Unusual presentation of CIDP –i.e., rapid
progression or treatment failure ‐ should lead to further testing for associated lymphoma.
Because general symptoms and lymphadenopathy often lack, diagnosis requires analysis
of bone marrow with lymphocyte phenotyping. Early treatment with immunochemotherapy
was associated with better prognosis in our series.
CARDIAC SCINTIGRAPHY IS A USEFUL TOOL FOR THE DIAGNOSIS, PROGNOSIS AND PRE‐SYMPTOMATIC
EARLY DETECTION OF FAMILIAL AMYLOIDOSIS‐ASSOCIATED NEUROPATHIES
Cavaliere MG1, Ferrari AT1, Medeiros KQM1, Ferreira JMC1, Macedo PHA1, Westin LK1,
Marques JW1, Romão TT
1, Bittar C1, Pupe C1, Nascimento OJM1.
1Universidade Federal Fluminense (UFF), Rio de Janeiro, Brazil.
Familiar amyloidosis is a group of diseases characterized by tissue deposition of
amyloid fibrils. There are three main types of familiar amyloidosis: transthyretin
(TTR), apolipoprotein A1 and gelsolin. Cardiac involvement is a leading cause of morbidity
and mortality; one new described mutation strongly related with isolated cardiac amyloidosis
is the TTR Val122Ile. The discovery of tests that allow early diagnosis of cardiac
involvement in amyloidosis and to infer about the etiology of the disease is of major
importance. In a cohort of patients with different types of familiar TTR amyloidosis,
we aimed to assess the role of 99mTc‐3,3‐diphosphono‐1,2‐propanodicarboxylic acid
(99mTc‐DPD) in detecting myocardial amyloid infiltration. We enrolled four patients
diagnosed with late familiar amyloidosis, which mutations were documented at deoxyribonucleic
acid analysis: three patients with TTR Val30Met mutation and one patient with TTR
Val122Ile mutation. Three patients were asymptomatic for cardiac involvement and one
patient (Val122Ile mutation) had a previous diagnosis of heart failure. Myocardial
uptake of 99mTc‐DPD scintigraphy was semiquantitatively and visually assessed at five
minutes and three hours.The uptake of 99mTc‐DPD highly demonstrated amyloid in cardiac
area in two out the three cases of TTR Val30Met and in TTR Val122Ile. TTR Val122Ile
case presented the highest uptake due to the exclusive deposition of amyloid in cardiac
area resulting in severe heart failure.
In hereditary transthyretin‐related amyloidosis, including the mutations TTR Val30Met
and Val122Ile, 99mTc‐DPD cardiac scintigraphy can identify infiltration even in asymptomatic
individuals, allowing an early diagnosis of cardiac compromise in this group of diseases.
We can consider that this non‐invasive test would be a tool with potential importance
in the diagnosis, prognosis and pre‐symptomatic early detection of cardiac amyloidosis,
giving emphasis on its applicability in familial forms of amyloidosis.
MILD ERK/MAPK ACTIVATION IN ADULT SCHWANN CELLS NEGATIVELY AFFECTS AXON SURVIVAL,
MYELIN STABILITY AND SMALL FIBRES REINNERVATION AFTER NERVE INJURY
Cervellini I
1, Galino J1, Zhu N1, Birchmeier C2, Bennett DL1.
1NDCN University of Oxford, Oxford, UK; 2Max‐Delbrück‐Center for Molecular Medicine,
Berlin, Germany.
ERK/MAPK pathway has a critical role in PNS development since its involvement in many
physiological processes. Sustained ERK1/2 MAPK activation in Schwann cells enhances
myelin growth during development and overcomes signals ending myelination leading
to a continuous myelin production. However, strong activation of ERK has also been
shown to cause Schwann cells dedifferentiation and demyelination in vivo. Our aim
was to investigate whether a mild activation of this signalling pathway in adult Schwann
cells (SCs), by expression of gain of function Mek1DD allele, could have a beneficial
role in remyelination and regeneration after injury. Erk/MAPK activation in adult
SCs in PLPCreERT2;Mek1DD mutant mice, did not affect myelination during development.
Following sciatic nerve injury, Wallerian degeneration was enhanced in mutants pushing
towards a dedifferentiation stage of SCs as previously described. However, MAPK activation
was detrimental during regeneration with a delay in functional recovery and a negative
impact in both myelinated and non‐myelinated fibres compared to controls. One month
after injury the total number of axons in mutant sciatic nerves was half of the controls.
Although no differences in g‐ratio have been found in the two groups, mutants presented
a higher number of myelinated axons showing myelin disruption with start of myelin
decompaction, lack of Cajal bands, abundant SC processes surrounding axons and a shorter
SC elongation, as seen by decreased internodal distance. In addition, we found a negative
effect of MAPK activation also in small diameter axons with the presence of abnormal
Remak bundle structures, reduced number of c‐fibres/Remak bundle and a significant
decrease in intra epidermal nerve fibres density in the skin.
We concluded that mild MAPK activation has a different role in development and remyelination
where negatively affects axon survival, myelin stability, Remak bundle formation and
small fibres regeneration.
NEPRILYSIN IS NOT INVOLVED IN REGENERATION AND RE‐MYELINATION AFTER NERVE INJURY
Cervellini I
1, Galino J1, Zhu N1, Bao Lu2, Bennett DL1.
1NDCN, University of Oxford, Oxford, UK; 2Harvard Medical School, Boston, MA, USA.
Neprilysin (NEP) is an endopeptidase which has been of interest due to its potential
role in neurodegeneration and pain as a consequence of its ability to degrade amyloid
and substance‐P respectively. NEP expression is not limited to CNS and it has been
reported to be expressed in Schwann cells, nodes and Schmidt‐Lanterman incisures.
Our interest in this gene was related to recent findings that have associated homozygous
and heterozygous NEP mutations with Charcot‐Marie‐Tooth type‐2. In old mice lacking
NEP subtle morphological changes have been reported.
Our aim was to determine whether NEP expression was modulated by nerve injury and
to investigate its role in axon regeneration and re‐myelination.
We find that NEP gene expression was decreased after nerve crush and furthermore was
dependent on the growth factor (and pro‐myelin signal) Neuregulin‐1. In control mice
NEP expression was transiently reduced and returned to baseline at day 28 after injury,
in Neuregulin‐1 knock‐out (KO) mice, in which re‐myelination was impaired, the expression
was still decreased at day 28. In assessing behavioural measures of locomotor and
sensory function one month after sciatic nerve crush, NEP KO mice showed a functional
regeneration comparable to WT, as seen by sciatic functional index measurement, beam
and toe spreading tests. The only significant difference we observed between WT and
KO was in the sensorial test, showing KO mice recovering faster in the pinch test
by 13 days after crush. The results for all the tests at baseline did not differ between
the two groups. Detailed histological analysis of nerve repair was undertaken using
electron microscopy. There was no difference between WT and KO in total axon number,
g‐ratio, axon diameters and other myelin features one month post crush.
In summary, although NEP expression is regulated by nerve injury in a Neuregulin‐1
dependent fashion this endopeptidase is dispensable for axon regeneration and re‐myelination
after nerve injury in the rodent.
SENSORY AXONAL DYSFUNCTION IN THE PAINFUL DIABETIC POLYNEUROPATHY
Chang TS
1, Lin CS1,2, Tani J3,4, Sung JY1,4.
1School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;
2University of New South Wales, Sydney, Australia; 3Taipei Medical University and
National Health Research Institutes, Taipei, Taiwan; 4Wan Fang Hospital, Taipei, Taiwan.
Diabetes neuropathy is a common complication of diabetes, and neuropathic pain has
a detrimental impact on quality of life. This study investigated sensory nerve excitability
properties to elucidate the axonal changes of diabetic neuropathy. A total of 95 diabetes
patients (93 type II, and 2 type I) were enrolled in this study. Clinical assessment,
nerve conduction studies, and nerve excitability testing data were analyzed to determine
axonal dysfunction in diabetic neuropathy. Among those patients, seventeen subjects
had complained of spontaneous painful sensation over feet or hands (painful cohort),
and seventy‐eight patients had no sensory symptoms or decreased the sensation over
foot (non‐painful cohort). Sensory nerve excitability of the painful cohort showed
reduced late subexcitability (P=0.01), increased superexcitability (P=0.03) in compared
to the non‐painful cohort. There is no difference in disease duration, blood glucose
levels (HbA1c) between these two cohorts. These findings suggested the possible pathogenesis
of painful sensory axons might be hyperpolarized or slow potassium channels dysfunction.
These insights our further understanding of painful diabetic neuropathy, and may provide
a basis for neuroprotective or therapeutic approaches for painful polyneuropathy.
MRI OF THE BRACHIAL PLEXUS AND CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY:
ASSESSMENT OF DTI‐DERIVED MEASUREMENTS AT 3.0‐T
Chanson E
1,2, Barriol M1,3, Taithe F1,2, Zerroug A1,3, Lhoste A1,3, Pereira B4, Boyer L1,3,
Jean B1,3, Clavelou P1,2.
1Clermont University, Clermont‐Ferrand, France; 2Neurology and Neurophysiology Department,
CHU Gabriel Montpied Clermont Ferrand, Clermont Ferrand, France; 3Radiology Department,
CHU Gabriel Montpied Clermont Ferrand, Clermont Ferrand, France; 4Biostatistics Unit
(RCI), CHU Clermont Ferrand, Clermont Ferrand, France.
The main purpose of this study was to assess the clinical feasibility of diffusion
tensor imaging (DTI) for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP).
Between March 2013 and December 2015, we prospectively enrolled 15 patients with definite
CIDP according to the EFNS 2010 criteria and two control groups: 15 healthy volunteers
matched on age and sex and 15 patients with CMT‐1A. Using a 3‐T magnetic resonance
imaging scanner, we obtained DTI scans of brachial plexus of these 3 groups and prepared
Fractional Anisotropy (FA) maps, and compared these values between groups. ADC values
and cervical nerve roots diameters on STIR sequences were evaluated too. Two neuroradiologists,
blinded to clinical informations, reviewed MRI studies independently. In all patients
with CIDP, we also performed clinical evaluation and electroneuromyography.
Significantly decreased FA values (p<0.001) and increased ADC values were observed
in CIDP patients compared with healthy subjects. There is no significant difference
between CIDP and CMT group. Inter‐observer concordance was excellent for FA values
(ρc=0.891; p<0.001) and moderate for ADC values (ρc=0.537; p<0.001) and cervical nerve
root diameters (ρc=0.495; p<0.001). There is a significant correlation between FA
and disease duration (r = −0.5, p <0.05), inclusion MRC score (r = 0.56, p <0.05)
and between FA mesured on C7C8 and INCAT score at inclusion (r = −0.53, p <0.05).
No significant correlation is observed between FA and electrophysiological indices.
Compared with healthy subjects, cervical nerve root diameters were significantly increased
(p<0.001) in patients with CMT and CIDP. Contrary to FA values, moderate level of
concordance was found between inter‐observers measurements of diameters (CClin = 0.495).
Our preliminary data prove the clinical feasibility and reproductibility of DTI for
the evaluation of plexus and cervical nerve roots in patients with CIDP.
DISRUPTION OF BLOOD‐NERVE BARRIER AT ENTRAPMENT SITES RATHER THAN NERVE ENDINGS IS
THE LIKELY CAUSE OF SURAL‐SPARING PATTERN IN GUILLAIN‐BARRE SYNDROME
Cheng YJ
1, Teng A1, Goh EJH1, Umapathi T2.
1Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 2Department
of Neurology, National Neuroscience Institute, Singapore.
The sural‐sparing pattern of the sensory nerve action potentials (SNAP) of Guillain‐Barré
syndrome (GBS) has been attributed to greater immunological injury of the blood‐nerve
barrier at its most vulnerable regions. We asked if entrapment sites, such as median
nerve at the wrist, are more predisposed than the distal nerve endings to such injury.
We compared the median SNAP with radial SNAP measured antidromically at digit 1 in
GBS patients whose nerve conduction study showed the sural‐sparing pattern. The terminal
nerves at digit 1 are of similar length, but those of median nerve are prone to compression,
often subclinically, at the carpal tunnel while those of radial nerve are not. We
defined the sural‐sparing pattern as a greater decrease in median and or ulnar SNAP
than that of the sural, compared to age and height‐matched normal controls. A total
of 35 GBS and Miller Fisher patients from our institution's database were studied.
15 patients had the sural‐sparing pattern, of whom 1 had pre‐existing carpal tunnel
syndrome. Of the remaining 14 patients with sural‐sparing, 11 had abnormal median
SNAP at digit 1, while 3 had both abnormal median and radial SNAPs at digit 1. None
had isolated abnormality of the radial digit 1 SNAP. Among the 3 cases that had abnormal
median and radial SNAPs at digit 1, the mean percentage decrease when compared to
age and height matched norms was greater in median nerve compared to radial nerve
(97% and 75% respectively). Of the 20 patients without sural‐sparing pattern, 18 had
normal SNAPs; 1 patient had inexcitable sensory nerves while the other had a length‐dependent
decrease in SNAP. In the latter patient, unlike those with sural‐sparing, there was
no differential decrease of median SNAP over radial SNAP at digit 1. Our findings
suggest that the disruption of blood nerve barrier at entrapment sites rather than
the distal nerve endings may underlie the pathophysiology of the sural‐sparing pattern
seen in GBS.
Ca(2+)‐DEPENDENT ANTI‐GQ1B ANTIBODY IN FISHER SYNDROME: DETECTION AND INSIGHT INTO
THE MOLECULAR MECHANISM
Chiba A
1, Uchibori A1, Gyohda A1.
1Kyorin University, Tokyo, Japan.
Serum IgG anti‐GQ1b antibody is the most specific biomarker for Fisher syndrome and
its related disorders (FS‐RD), but approximately 10‐30% of the patients are seronegative
for it in conventional assays (GQ1b‐seronegative). Some molecules need Ca2+ cation
to interact with their ligands, and antibodies with such a property (Ca2+‐dependent
antibodies) are reported. We have found that such a Ca2+‐dependency is also present
in IgG anti‐GQ1b antibody, and majority of GQ1b‐seronegative patients with FS‐RD have
this type of antibodies. In 66 patients with final clinical diagnoses as FS‐RD (Fisher
syndrome, Guillain‐Barré syndrome with ophthalmoplegia, Bickerstaff brainstem encephalitis,
and acute ophthalmoplegia), 55 were seropositive for IgG antibodies against GQ1b‐related
antigens (isolated GQ1b in 53, and GQ1b‐conatinig complexes in two) in conventional
ELISA using phosphate‐buffered saline. In the remaining 11 patients, eight (73%) turned
positive for IgG antibody against GQ1b‐related antigens (isolated GQ1b in seven and
GQ1b‐conatinig complexes in one) in ELISA using Ca2+‐added Tris‐buffered saline. The
reaction strengths increased depending on Ca2+ concentration, and reached to nearly
maximum level in the physiological concentration. All the patients with the Ca2+‐dependent
antibodies were also positive for IgG antibody against GT1a‐related antigens, suggesting
that the terminal disialo residue common to both the gangliosides would be important
as an epitope also for the Ca2+‐dependent antibodies. In the 55 patients with Ca2+‐non‐dependent
antibodies, only two showed increased titers of IgG anti‐GQ1b antibody by adding Ca2+,
and 31 showed significantly decreased titers. This difference in the effect of Ca2+‐addition
between Ca2+‐dependent and Ca2+‐non‐dependent antibodies suggests that Ca2+ would
not be just an enhancer of the antigen‐antibody reaction. There are four single bonds
between the two pyranose rings in the terminal disialo, and those rotatable bonds
make it possible for the disialo structure to take various conformations. A molecular
model shows that the distance between two minus‐charged carboxy groups in the disialo
could vary from nearly zero to approximately 1,000 pm and that the disialo would take
specific conformations, if divalent Ca2+ cation, which size is approximately 400 pm
in diameter, interacts with these two minus‐charged groups. The Ca2+‐dependent antibodies
might recognize such particular conformations of GQ1b.
AMINOACYL tRNA SYNTHETASE GENE MUTATIONS INCLUDING GARS, MARS AND YARS GENES IN KOREAN
PATIENTS WITH CHARCOT‐MARIE‐TOOTH DISEASE
Choi BO
1, Chung KW2, Jung SC3
. 1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School
of Medicine, Seoul, South Korea; 2Department of Biological Science, Kongju National
University, Gongju, South Korea; 3Department of Biochemistry, Ewha Womans University
School of Medicine, Seoul, South Korea.
Charcot‐Marie‐Tooth disease (CMT) is a genetically and clinically heterogeneous disorder
with variable inheritance modes. It is characterized by loss of muscle tissue and
touch sensation, predominantly in the feet and legs but also in the hands and arms
in the advanced stages of disease. As several molecules have been reported to have
therapeutic effects on CMT, depending on the underlying genetic causes, exact genetic
diagnostics have become important for executing personalized therapy. Aminoacyl‐tRNA
synthetase (ARSs) genes encode enzymes responsible for charging tRNA with corresponding
amino acids. ARSs are ubiquitously expressed, essential enzymes responsible for performing
the first step of protein synthesis. Specifically, ARSs attach amino acids to their
cognate tRNA molecules in the cytoplasm and mitochondria. Recent studies have demonstrated
that mutations in genes encoding ARSs can result in neurodegeneration, raising many
questions about the role of these enzymes in neuronal function. Mutations in six cytoplasmic
ARS genes have been reported as the cause of CMT. This study was performed the whole
exome sequencing to identify genetic defects in 392 Korean CMT patients from 280 unrelated
families. Variants were sorted with CMT gene list that includes almost 80 genes were
related CMT neuropathy, and additionally sorted WES data as ARS genes. Capillary sequencing
for family members and more than 500 controls revealed five novel mutations, c.598G>A
(p.D200N), c.794C>T (p.S265F), and c.1007C>A (p.P336H) in GARS; c.2398C>A (p.P800T)
in MARS; 241_242GA>AT (p.D81I) in YARS gene in each family. The mutation sites were
well conserved between different species and each mutation were located in the well‐conserved
catalytic domain or between two catalytic domains or anticodon‐binding domain. In
silico analysis predicted all mutations may affect protein function. Clinical features
were similar to those reported in other countries, but differed in terms of age at
onset and degree of disability. We believe that those novel ARS mutations are the
underlying causes of the each family.
SPINOBULBAR MUSCULAR ATROPHY COMBINED WITH CHARCOT‐MARIE‐TOOTH DISEASE: “DOUBLE TROUBLE”
IN NEUROMUSCULAR DISORDERS
Choi K
1, Choi SJ2, Kwon KH2, Ahn SH2, Kim JS2, Baek SH2, Shin JY2, Kim SM2, Hong YH3, Sung
JJ2.
1Konkuk University Hospital, Seoul, South Korea; 2Seoul National University Hospital,
Seoul, South Korea; 3Boramae Medical Center, Seoul Metropolitan Government, Seoul
National University, Seoul, South Korea.
A 64‐year‐old man presented with a 26‐year‐history of weakness in biltearal upper
limbs. He was complaining of intermittent fasciculation of upper and lower limbs with
gradually worsening of paresthesia for 20 years. Dysphagia and dysarthria were also
presented 5 years ago. There was no patient affected muscle weakness and bulbar symptoms
in his family members. In neurological examination, the patient had weakness in biltereal
upper and lower limbs (MRC grade 3) and prominent distal sensory loss were combined
in length dependant pattern. Deep tendon reflexes were absent on bilataral biceps
and knee joints. In nerve conduction study, there was consistent with demyelinating
sensorimotor polyneuropathy. Molecular diagnostic analyses those spinobulbar muscular
atrophy (SBMA) and mutation related to peripheral myelin protein 22 (PMP22) gene were
performed and confirmed expansion of expansion of a polymorphic CAG in androgen‐receptor
(AR) gene and deletion of PMP22 gene. SMBA, also known as Kennedy disease, is an adult‐onset,
X‐linked recessive trinucleotide, polyglutamine (poly‐G) disorder caused by expansion
of a polymorphic CAG tandem‐repeat in exon 1 of AR gene on chromosome Xq11‐12. Charcot‐Marie‐Tooth
disease (CMT) is the most common hereditary neuropathies and CMT cases with motor
conduction velocities(MCVs) of upper limb below 38 m/s are defined as demyelinating
(CMT1) and those with MCVs above 38 m/s are defined as axonal (CMT2). Most families
with CMT1 linked to duplication of PMP22 gene on the short arm of chromosome 17(17p11.2),
called CMT1A. The reciprocal deletion of PMP22 gene is a responsible genetic defect
in 70% of hereditary neuropathy with liability to pressure palsy (HNPP). These “classical”
phenotypes of CMT1A and HNPP have been considered which are determined by different
mutation mechanism of the same gene. However, an overlap of CMT1A and HNPP due to
PMP22 gene deletion was reported that suggestion the phenotype of hereditary neuropathies
may differ variably. Herein, we report a patient who simultaneously presented clinical
and electrophysiologic features of SMBA and CMT1A with genetical confirmation of CAG
expasion and deletion of PMP22 gene.
A COMBINATION OF THREE REPURPOSED DRUGS (PXT3003) SYNERGISTICALLY INCREASES MYELINATION
IN CO‐CULTURES OF SCHWANN CELLS AND NEURONS DERIVED FROM CMT1A RATS
Cholet N
1, Laffaire J1, Guedj M1, Murphy PN1, Chumakov I1, Nabirotchkin S1, Hajj R1, Cohen
D1.
1Pharnext, Issy les Moulineaux, France.
Charcot‐Marie‐Tooth type 1A disease (CMT1A) is an inherited peripheral neuropathy
stemming from overexpression of PMP22 protein in Schwann cells due to the duplication
of the PMP22 gene. This leads to abnormal Schwann cell differentiation and dysmyelination,
eventually leading to axonal loss and muscle wasting. No approved treatment is currently
available for CMT1A. We conducted a systems biology level analysis of the signaling
network putatively underlying the processes driving CMT1A pathology. Based upon this,
we identified and tested three repurposed drugs – baclofen, naltrexone and sorbitol
– alone and in combination to determine their ability to rescue aberrant myelination
in cultures derived from CMT1A transgenic rats overexpressing PMP22 gene. To this
end, we studied a validated in vitro co‐culture model of sensory neurons and Schwann
cells adapted to 96‐well culture plates. This model allows measurement of the appearance
of myelin proteins as an index of the physiological process of in vivo myelination.
Total myelin length was quantified with an automatic image analyzer following PMP22
immunostaining. We first determined the full dose–response curves of single drugs,
emphasizing their promyelinating activities. We then tested binary combinations of
very low and inactive doses of each drug and compared these to the activity of the
combination of the three, namely PXT3003. Whereas combination of any two drugs was
not significantly active at the doses tested, combination of all three produced a
synergistic improvement in myelination. These findings clearly demonstrate the necessity
of using PXT3003 over its single components and highlight the value of pleiotropic
combinational repurposing of drugs at low doses as a novel approach for rapid drug
development in CMT1A and other disorders.
AN UP‐TO‐DATE REVIEW ON SWEATING DISTURBANCES IN GUILLAIN‐BARRÉ SYNDROME
Conde RM
1, Barreira AA1.
1Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
Autonomic dysfunction is frequently observed in Guillain‐Barré Syndrome (GBS) and
affects approximately 75% of the patients. It has been shown that the sweating function
can be impaired in GBS. The aim of the present investigation is to summarize the current
knowledge on sweating disturbances in GBS patients. We have used appropriate terms
to systematically search for references published until 2016 and indexed in the following
databases: Medline, Embase, Lilacs and Cochrane. The inclusion criteria were a diagnosis
of GBS and a description of the methods used to test the sudomotor function. The search
was limited to the English language. Relevant information about study design, methods
of assessing the deficit of sweating, patient's characteristics and main results were
collected. We selected 13 original references for the final analyses. The majority
of the studies were cross‐sectional in nature and there were two longitudinal studies.
The severity of sweating impairment varied according to the applied method, ranging
from normal to almost sympathetic nervous system failure. In seven research papers,
the sympathetic skin response was used to evaluate the sudomotor function in 99 patients,
and approximately 30% demonstrated abnormal results. However, researchers used different
stimulation protocols and parameters to interpret their results. Regarding whole‐body
sweating test, four research papers applied the thermoregulatory sweating test in
14 patients and they showed areas of anhidrosis on the lower limbs in all of them.
Eight patients presented sweating impairment on the upper limbs and abdominal wall.
Results on the sudomotor axon reflex test suggested a length‐dependent pattern of
sweating loss according to one case report. In another study, eight GBS patients were
tested only on the distal leg and foot dorsum and the authors proposed an association
between post‐ganglionic sudomotor function and antiganglioside antibodies. The present
literature review showed that the studies of sweating disturbances in GBS patients
included only small cohorts. Future studies with larger patients sample sizes are
necessary to investigate the patterns of sweating loss in GBS and their changes along
the follow up. Funding: grants #2013/03150‐3 and #2012/07165‐2, São Paulo Research
Foundation (FAPESP).
SWEATING DISTURBANCES IN SENSORY NEURONOPATHY
Conde RM
1, Fusco T1, Martinez AR2, França MC Jr2, Marques W Jr1, Barreira AA1.
1Department of Neuroscience, University of São Paulo, Medical School of Ribeirão Preto,
SP, Brazil; 2Department of Neurology, Faculty of Medical Sciences, University of Campinas,
SP, Brazil.
Sensory Neuronopathy (SN) represents a rare subgroup of peripheral neuropathies characterized
by degeneration of primary sensory neurons at the dorsal root ganglia on the spinal
cord. Depending on the neuronal population affected, its clinical presentation may
manifest as gait ataxia, proprioceptive sensory loss and positive and negative sensory
symptoms. Although a few reports have mentioned areas of anhidrosis in SN, we were
not been able to find previous case series studies on the sweating function in sensory
neuronopathies. The aim of the present investigation was to study the whole‐body distribution
of sweating on both anterior and posterior surfaces in patients diagnosed with SN.
Quantitative Sensory Testing for cold and warm sensation threshold (method of Levels)
was performed on the dorsum of the hands and feet in a randomized order. We tested
the thermoregulatory sweating using a sweat chamber (440 to 47°C air temperature and
30% relative humidity). The oral and skin temperature was monitored and the test time
did not exceed 45 min. In order to study the sudomotor axon reflex we employed the
Q‐SWEAT device on standardized body sites. The test was performed on both sides, simultaneously.
We included seven patients (three male; mean age 50.25 years) with a mean disease
duration of 67.7 months (range 24–180) and a confirmed diagnose of SN. Patients presented
an asymmetrical loss of cold and warm threshold on hands or feet compared with healthy
control (P<0,05). Regarding the TST results, we found a striking variation of sweating
disturbances, ranging from small areas of anhidrosis on the trunk to complete failure
of the sympathetic nervous system. Two patients underwent the axon reflex test and
there was an asymmetrical and mostly distal pattern of sweating loss in one of them
and a distal‐symmetrical on the second one. Our findings indicate a great variability
of sweating losses in SN, not overlapped to the sensory loss areas. Currently, we
are testing more patients in order to confirm our results. Funding: grants #2013/26410‐0,
#2013/03150‐3 and #2012/07165‐2, São Paulo Research Foundation (FAPESP).
RATS BRED FOR LOW AND HIGH RUNNING CAPACITY MAY OFFER A NEW MODEL OF INFLAMMATORY
PAIN
Cooper M
1, Jack M1, Ryals J1, Hayley P1, Escher T1, Koch L2, Britton S2, Winter M1, McCarson
K1, Geiger P1, Thyfault J1, Wright D1.
1University of Kansas Medical Center, Kansas City, KS, USA; 2University of Michigan,
Ann Arbor, MI, USA.
Diet, exercise, and inflammation are established modulators of peripheral nervous
system function, including pain. Prior work examining exercise consistently demonstrates
a benefit on heightened pain from a number of acute and chronic pain models. In the
present work, we investigated several parameters of peripheral nerve function relevant
to pain in rats bred for high (high capacity runners, HCR) or low running capacity
(low capacity runners, LCR). The longtime selective breeding of these rat substrains
has created divergent intrinsic aerobic capacities and predisposition of metabolic
conditions between LCR and HCR rats. Examination of the role of sex in the development
of chronic pain has established key differences in males and females. To understand
gender specific differences, this study focused on female rats to understand the role
of metabolic status and peripheral nerve function in females. Our analysis identified
numerous parameters of peripheral nerve function relevant to pain and neuropathy that
are different among LCR and HCR female rats. LCR female rats display reduced hind
paw mechanical sensitivity, increased hind paw intraepidermal nerve fiber density
and TrkA‐positive epidermal axons, increased numbers of Langerhans and mast cells
in the hind paw dermis, and increased overall fat mass relative to body weight compared
to female HCR rats. Examination of sensory and motor nerve conduction velocities,
thermal sensitivity, and mRNA expression of selected genes relevant to peripheral
sensation found no differences between HCR and LCR females. Together these results
suggest that a genetic component of aerobic capacity and metabolic status can influence
sensory sensitivity and specific aspects of inflammation and immune responses in peripheral
tissues, which may lead modify the animal's responses to tissue damage and painful
stimuli. The LCR and HCR rat model will provide a useful model in the future to assess
the involvement of metabolic status in the development of pain.
EFFICACY AND SAFETY OF THREE DIFFERENT DOSAGES OF IVIG (PANZYGA®) IN PATIENTS WITH
CHRONIC INFLAMMATORY DEMYELINATING POLY(RADICULO)NEUROPATHY (ProCID STUDY): DESIGN
OF A PHASE 3 STUDY
Cornblath DR
1, van Doorn PA2, Hartung HP3, Katzberg HD4, Merkies ISJ5.
1Johns Hopkins University, Baltimore, MD, USA; 2Erasmus University Medical Center,
Rotterdam, The Netherlands; 3Heinrich Heine University, Düsseldorf, Germany; 4University
of Toronto, Toronto, Canada; 5Maastricht University Medical Center, Maastricht, The
Netherlands.
IVIG is often considered treatment of first choice in chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) because of its rapid onset of action and its relatively
safe long‐term adverse event profile. Clinical trials published so far focused on
a loading dose of 2.0 g/kg IVIG and/or a standard maintenance dosage of 1.0 g/kg IVIG
once every 3 weeks, but have not investigated different dosing options. This study
is a prospective, double‐blind, randomized, parallel group, multi‐center phase III
efficacy study and will be conducted in 44 centres in Canada, EU, Russia, Ukraine
and Australia. 140 adult patients with definite or probable CIDP according to the
EFNS/PNS Criteria will be enrolled and randomized 1:2:1 to receive either 0.5 g/kg
or 1.0 g/kg or 2.0 g/kg IVIG (panzyga®) for seven maintenance infusions at 3‐week
intervals during the Dose‐evaluation Phase. The starting loading dose will be 2.0
g/kg IVIG (panzyga®) for all patients. Primary objective: Efficacy measured as percentage
of responders (decrease in adjusted INCAT score by at least 1 point) in the 1.0 g/kg
IVIG (panzyga®) arm (given every 3 weeks) at Week 24 as this should corroborate the
existing and published evidence on efficacy of IVIG in CIDP. Secondary outcome: percentage
of responders at week 24 in the 0.5g/kg and 2.0 g/kg IVIG (panzyga®) arms relative
to baseline and compared to the 1.0 g/kg arm. The ProCID study aims to confirm published
clinical results obtained with the 1.0 g/kg standard dose and will in addition evaluate
one higher and one lower maintenance dose, with the aim to offer CIDP patients a more
adequately dosed and effective treatment policy.
* Este medicamento no se encuentra comercializado en España.
RATE OF PROGRESSION IN PEDIATRIC CHARCOT‐MARIE‐TOOTH DISEASE
Cornett KMD
1, Menezes MP2, Shy RR3, Moroni I4, Pagliano E4, Pareyson D4, Estilow T5, Yum SW6,
Bhandari T7, Muntoni F7, Laurà M8, Reilly MM8, Finkel RS9, Eichinger K10, Herrmann
DN10, Bray P1, Halaki M11, Shy ME12, Burns J1 and for the CMTPedS study group.
1Sydney Children's Hospitals Network, University of Sydney, Sydney, Australia; 2Paediatrics
and Child Health, University of Sydney, Sydney, Australia; 3Department of Pediatrics,
Carver College of Medicine, University of Iowa, Iowa City, IA, USA; 4IRCCS Foundation,
Carlo Besta Neurological Institute, Milan, Italy; 5Neuromuscular Program, The Children's
Hospital of Philadelphia, PA, USA; 6Division of Neurology, The Children's Hospital
of Philadelphia, Department of Neurology, Perelman School of Medicine, University
of Pennsylvania, USA; 7UCL Institute of Child Health & Great Ormond Street Hospital,
London, UK; 8MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen
Square, London, UK; 9Neuromuscular Program, Division of Neurology, Nemours Children's
Hospital, Orlando, USA; 10Department of Neurology, University of Rochester, Rochester,
USA; 11Paediatrics and Child Health, University of Sydney, Sydney, Australia; 12Department
of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Understanding the rate of disease progression in patients with Charcot‐Marie‐Tooth
disease (CMT), both within and between subtypes is important for clinical prognosis
and is crucial for clinical trial design. Due to the progressive nature of CMT, intervening
at the earliest stages of the disease is a priority. Measuring progression of a disease
with both motor and sensory deficits requires a multi‐item composite scale. The CMT
Pediatric Scale (CMTPedS) is a well‐tolerated psychometrically robust 11‐item scale
measuring fine and gross motor function, strength, sensation and balance for children
and adolescents aged 3–20 years with CMT. The aim of this study was to determine the
rate of disease progression of children and adolescents within and between genetic
subtypes of CMT. 206 (103 female) participants aged 3–20 years enrolled in the Inherited
Neuropathies Consortium were included in this study. Demographic, anthropometric and
diagnostic information were collected at baseline and 2‐year follow‐up. Disease progression
was measured with the CMTPedS. On average CMTPedS scores progressed at a rate of 2.4
points over 2‐years (14% change from baseline, p<0.001). There was no difference in
rate of disease progression between males and females. Of the most common genetic
subtypes, 111 participants with CMT1A/PMP22 duplication progressed by 1.8 points (12%
change from baseline, p<0.001), nine participants with CMT1B/MPZ mutation progressed
by 2.2 points (11% change), six participants with CMT2A/MFN2 mutation progressed by
6.2 points (23% change) and seven participants with CMT4C/SH3TC2 mutation progressed
by 3.0 points (12% change). Participants with CMT2A progressed faster than those with
CMT1A (p=0.02). Children with CMT1A progressed consistently during childhood and adolescence
while children with CMT1B and CMT2A progressed faster during childhood than adolescence.
Overall, children with CMT progress at a significant rate over 2‐years according to
the CMTPedS. Understanding the rate at which affected children deteriorate is essential
for adequately powering clinical trials of disease‐modifying interventions.
TARGETED NEXT‐GENERATION SEQUENCING (NGS) PANELS IN CMT: A RETROSPECTIVE COMPARATIVE
STUDY IN UK AND US TERTIARY REFERRAL CENTRES
Cortese A
1, Phetteplace J2, Polke J3, Poh R3, Houlden H4, Rossor AM1, Laurà M1, Shy ME2, Reilly
MM1.
1MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery,
UCL Institute of Neurology, Queen Square, London, UK; 2Department of Neurology, University
of Iowa Carver College of Medicine, Iowa City, IA, USA; 3Department of Neurogenetics,
The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology,
London, UK; 4Department of Molecular Neuroscience, UCL Institute of Neurology, London,
UK and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
In recent years, targeted NGS panels have changed the diagnostic work‐up in patients
with inherited neuropathies. However, there is limited data on the impact of targeted
NGS panels on the diagnosis of CMT patients in everyday practice. The aim of this
study was to investigate the impact of targeted NGS panels on the diagnosis of CMT
across two tertiary referral centres in the United Kingdom (London) and United States
(Iowa). In London, 128 patients with a diagnosis of CMT (previous PMP22 duplication
and common CMT genes excluded in appropriate cases) underwent targeted NGS panel sequencing
covering 50 genes associated with CMT and 26 additional genes associated with HSP
or ALS. A variable number of genes, ranging from 11 to 76, were analysed depending
on the clinical phenotype of the patients. A definite molecular diagnosis was achieved
in 37 cases (28%) including pathogenic and likely pathogenic mutations in SH3TC2 (5
cases), GJB1 (4 cases, including 2 cases with mutations in the promoter and 3'UTR
regions), GDAP1 (3 cases), FGD4 (3 cases), AARS (2 cases), IGHMBP2 (2 cases), MPZ
(2 cases), NEFL (2 cases). VUS were further identified in 20 patients. The diagnostic
rate was higher in demyelinating CMT cases (21/42, 50%), compared to cases with axonal
CMT (10/53 19%), dHMN (4/20, 20%) and HSN (1/13, 8%). In Iowa, 50 patients were investigated
by NGS panels covering 18 to 79 genes associated with CMT. A molecular diagnosis was
reached in 22/50 (44%), and in particular 8/10 (80%) demyelinating and 14/40 (35%)
axonal CMT cases. The most frequent genes identified were GJB1 (6 cases), MFN2 (4
cases), SH3TC2 (3 cases) and IGHMBP2 (2 cases). VUS were identified in 22 patients,
including 5 cases with novel variants in AARS, warranting additional testing such
as segregation of the variant in the family or functional validation studies. In clinical
practise, targeted NGS panels represent an effective approach for the diagnosis of
CMT. The lower diagnostic rate in London is likely to be due to prior Sanger sequencing
and exclusion of mutations in common CMT genes in this patient population.
DIAGNOSTIC YIELD OF A 6000 DISEASE‐ASSOCIATED GENE FOCUSED EXOME IN CMT AND COMPLEX
NEUROPATHY CASES: AN EXPLORATORY STUDY
Cortese A
1, Bugiardini E1, Hughes D2, Pittmann A2, Laurà M1, Rossor AM1, Houlden H2, Reilly
MM1.
1MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery,
UCL Institute of Neurology, Queen Square, London, UK; 2Department of Molecular Neuroscience,
UCL Institute of Neurology, London, UK and National Hospital for Neurology and Neurosurgery,
Queen Square, London, UK.
More than 80 genes are known to cause CMT and an even larger number are known to cause
peripheral neuropathy as part of a more complex neurological disorder. Despite the
use of custom panels, a significant proportion of patients with inherited neuropathy
have no molecular diagnosis. The aim of this study was to investigate the diagnostic
yield of a 6000 disease‐associated gene exome (SureSelect Focused Exome, Agilent Technologies,
Santa Clara CA, USA) in the diagnosis of CMT and in cases with complex neurological
syndromes associated with neuropathy. Thirty‐one patients with molecularly undiagnosed
inherited neuropathy were analysed with SureSelect Focused Exome sequencing. Six patients
had a more complex phenotype including learning difficulties, cerebral white matter
changes, ataxia and pyramidal tract involvement. A genetic diagnosis was achieved
in 13/30 (43%) of cases by detecting a mutation in CMT‐associated genes MPZ (2 cases),
AARS, NEFL, BSCL2, BICD2 and TRPV4. Of note, six cases had mutations in genes which
are not covered by currently available diagnostic targeted NGS panels, including KIF1A,
POLG, MME (2 cases), DNAJB2, and a novel candidate gene. The average coverage was
higher compared to the usual coverage of whole‐exome sequencing; 95% of the targets
were covered at 30x or more, and 98% of the targets were covered at 10x or more. This
study provides evidence that the SureSelect Focused Exome is a useful tool for the
diagnosis of CMT and complex neurological disorders and provides further insight into
the phenotypic spectrum of genes associated with inherited neuropathy.
FUNCTIONAL VALIDATION OF NON‐CODING VARIANTS OF GJB1 IN PATIENTS WITH CMTX1
Cortese A
1, Manole A2, Simone R3, Ashokkumar B2, Tomaselli PJ1, Rossor AM1, Laurà M1, Gutowski
J1, Polke H4, Poh R4, Houlden H2, Reilly MM1.
1MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery,
UCL Institute of Neurology, Queen Square, London, UK; 2Department of Molecular Neuroscience,
UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen
Square, London, UK; 3Department of Neurodegenerative Disease, UCL Institute of Neurology,
Queen Square, London, UK; 4Department of Neurogenetics, National Hospital for Neurology
and Neurosurgery, UCL Institute of Neurology, London, UK.
Changes in the cis‐regulatory sequences of a gene's untranslated regions (UTR) are
increasingly recognised as a significant cause of inherited disease in humans. For
example, variants in the non‐coding region of GJB1 account for 10% of all mutations
in our cohort of CMTX patients. One of the biggest challenges in analysing the large
number of non‐coding variants in a gene is identifying those that are disease‐causing
and those which are polymorphisms. The aim of this study was to implement a reliable
method for the in‐vitro functional validation of non‐coding variants in the promoter
and 3'UTR regions of GJB1. In our cohort of CMTX patients we have previously identified
seven mutations (c.‐592_591insT, c.‐570G>A, c.‐529T>G, c.‐529T>C, c.528T>C, c.‐527G>C,
c.‐459C>T) in the promoter region and one novel mutation in the 3'UTR (c.876C>T),
which were considered likely to be pathogenic based on the clinical phenotype, segregation
in affected family members and absence in control databases. We have now generated
a luciferase‐based reporter system and optimised it in a Hela cell line. Mutations
in the promoter region were generated by site‐directed mutagenesis using a commercially
available GJB1 promoter clone (Genecopoeia). Our preliminary results show a reduction
of luciferase activity for the c.‐528T>C and c.‐592_591insT mutations compared to
the wild‐type promoter. This difference was increased when transcription factors SOX10
or EGR2 were co‐transfected with the 528T>C and c.‐592_591insT mutations respectively.
Validation of other variants is currently ongoing. If successful, our study will provide
a useful tool for the validation of mutations in non‐coding regions of GJB1. Moreover,
it will constitute a proof‐of‐principle approach to the functional validation of non‐coding
variants in other CMT genes known to cause disease by a loss of function.
CHARCOT‐MARIE‐TOOTH DISEASE TYPE 2 (CMT2P) DUE TO LRSAM1 MUTATIONS: CLINICAL AND GENETIC
FINDINGS
Cortese A
1, Laurà M1, Polke H2, Poh R2, Rossor AM1, Tomaselli P1, Blake J1, Lunn M1, Houlden
H3, Reilly MM1.
1MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery,
UCL Institute of Neurology, Queen Square, London, UK; 2Department of Neurogenetics,
National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London,
UK; 3Department of Molecular Neuroscience, UCL Institute of Neurology and National
Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Recessive and dominant mutations in leucin‐rich repeat and sterile alpha‐motif‐containing
1 (LRSAM1) have been associated with CMT2P. LRSAM1 is a ubiquitin E3 ligase containing
a RING domain in its C‐terminal, which is crucial for correct protein folding and
ubiquitination activity. To date, the majority of dominant mutations reported have
resulted in a frame shift disrupting a major portion of the RING‐domain, although
point mutations in this domain have also been described. The aim of this study was
to report the prevalence, clinical features and genetic findings of patients with
CMT2P in our centre. We performed targeted next‐generation sequencing in 57 genetically
undiagnosed CMT2 patients and identified 6 cases with heterozygous mutations in LRSAM1
(10.5%) from 6 unrelated families. The mutations Identified included frameshift insertions
and deletions, a non‐frameshift deletion and non‐sense and missense point mutations.
All of the mutations were novel and were located in or flanking the RING domain. The
average age of disease onset was in the 3rd decade but an earlier onset was reported
in two cases. Four had a positive family history in keeping with autosomal dominant
inheritance. Symptoms at presentation were heterogeneous and encompassed distal numbness,
unsteadiness, distal weakness of upper or lower limbs and foot deformities. Positive
sensory symptoms, including tingling and shooting pains, and cramps were also frequently
reported. Neurological examination showed mild to moderate distal atrophy and weakness,
with early ankle plantar flexion involvement in three patients. Loss of vibration
and reduced joint position sense were often prominent in the lower limbs and appeared
to be disproportionate to the degree of weakness and impairment of pinprick sensation.
Ankle jerks were absent but knee and upper limb reflexes could be normal or brisk.
After an average disease duration of 20 years, all but one patient was able to walk
independently. Nerve conduction studies showed a sensory and motor axonal neuropathy
with normal conduction velocities. Our study highlights that mutations in LRSAM1 are
a relevant cause of CMT2 and are associated with prominent large fibre sensory loss.
DIAGNOSTIC CHALLENGES IN THE MOLECULAR DIAGNOSIS OF CMT IN THE ERA OF NEXT GENERATION
SEQUENCING (NGS)
Cortese A
1, Polke J2, Poh R2, Houlden H3, Rossor AM1, Laurà M1, Reilly MM1.
1MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery,
UCL Institute of Neurology, Queen Square, London, UK; 2Department of Neurogenetics,
National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London,
UK; 3Department of Molecular Neuroscience, National Hospital for Neurology and Neurosurgery,
UCL Institute of Neurology, Queen Square, London, UK.
In recent years, the implementation of NGS panels for the molecular diagnosis of CMT
has increased the number of patients with a genetic diagnosis. Nevertheless the interpretation
of a particular variant as disease causing can be challenging especially when multiple
variants are identified in a single patient. We report two illustrative cases of such
challenges. The first index case was born of non‐consanguineous healthy parents. He
presented with falls in early childhood. Over the years he developed foot deformities
and progressive length dependent weakness. He had multiple orthopaedic operations
to his feet. The past history was also notable for kyphoscoliosis, sensorineural deafness
from the age of 30 and bilateral cataracts. Nerve conduction studies at the age of
54 revealed a demyelinating neuropathy consistent with the clinical phenotype of CMT1.
His younger brother had a similar, although more severe phenotype. A LITAF (c.115C>T,p.Pro39Ser)
mutation was identified by Sanger sequencing and was present in both affected brothers
but also in the unaffected sister. NGS for CMT1‐associated genes was therefore performed
and identified two compound heterozygous pathogenic mutations detected in SH3TC2 (c.2860C>T,
p.Arg954*;3303delG, p.Arg1101Serfs*15), which segregated with the disease in the family.
The second case describes a brother and sister with early onset demyelinating CMT
associated with scoliosis and cranial nerve involvement. The male proband underwent
NGS and a single previously reported pathogenic intronic splice‐site mutation in SH3TC2
(c.286‐2A>C) was found. Relative read‐depth analysis of NGS was performed to look
for possible copy number variants in SH3TC2, thus identifying a deletion of exon 7,
which was confirmed by long PCR.
COWCHOCK SYNDROME, 2 FAMILIAL CASES WITH A NEW MUTATION IN AIFM1 GENE
Cruz‐Velásquez GJ
1, Miramar‐Gallart MD2, Alarcia‐Alejos R1, Roche‐Bueno JC1, Rodríguez‐Valle A2, Capablo‐Liesa
JL1.
1Neurology Service, University Hospital Miguel Servet, Zaragoza, Spain; 2Genetics
Unit, Clinical Biochemistry Service, University Hospital Miguel Servet, Zaragoza,
Spain.
Charcot‐Marie‐Tooth disease (CMTD) defines a clinical and genetically heterogeneous
group of inherited peripheral neuropathies characterized by chronic motor and sensory
impairment. The type CMTD‐4 also known as Cowchock syndrome, is the product of the
mutation in the apoptosis inducing factor mitochondria associated 1 gene (AIFM1).
It is a slowly progressive, recessive, X‐linked disease characterized by axonal neuropathy,
deafness, and cognitive impairment.
Our purpose is to describe 2 new cases, brothers, children of non‐consanguineous parents,
with a characteristic phenotype and a new mutation in the AIFM1 gene.
Both siblings present from childhood, progressive weakness in lower limbs with diffuse
amyotrophies. Needing tenotomy before the 7 year due to equinovarus foot. Likewise
they develops sensory deafness and one of them requires unilateral support at 39 and
the other wheelchair at 38, this one need a pacemaker for an atrioventricular block
at 40.
With brain functions and normal language, sensorial deafness, proximal and distal
weakness in the four limbs with intense amyotrophies, predominantly distal. Tactile
and painful sensitivity decreased in glove and sock pattern.
An extensive metabolic and biochemical study was normal. The electroneurography demonstrates
an axonal neuropathy without response in most of the nerves explored. The electromyography
shown a myogenic pattern with distal predominance. Brain MRI was normal in both cases.
Through a genetic study by exoma targeting 53 genes associated with CMT and inherited
related neuropathies was identified the homicigosis mutation in the AIFM1 gene (p.Glu366Lys),
located in the chromosomal region Xq26.1 (CMTX4).
Cowchock syndrome is a rare entity, with few cases described in the literature. The
in silico analysis indicates in 7 of the 9 predictors used (PROVEAN, SIFT, PolyPhen2,
LRT, MutationTaster, MutationAssessor and CONDEL), that it is a deleterious variant.
TREATMENT OF PARAPROTEINAEMIC NEUROPATHIES: A SINGLE‐CENTRE AUDIT
Cruz‐Velásquez G1,3, Mahdi‐Rogers M1, Kazmi M2, Hadden RDM
1.
1Neurology Department, King's College Hospital, London, UK; 2Haematology Department,
King's College Hospital, London, UK; 3Department of Neurology, University Hospital
Miguel Servet, Zaragoza, Spain.
We audited all patients with peripheral neuropathy caused by a paraprotein, who received
treatment and attended King's College Hospital peripheral nerve service between 2004–16.
Patients were identified retrospectively from our database of patients attending the
peripheral nerve outpatient clinic. Clinical information was obtained retrospectively
from hospital electronic patient records. We excluded patients with POEMS syndrome
or in whom the neuropathy was not felt to be caused by the paraprotein. We identified
61 patients with a diagnosis of paraproteinaemic neuropathy. We excluded four who
did not fulfill the diagnostic criteria and eleven who had received no treatment or
were under diagnostic study. We included 46 patients in the final audit. 45 (98%)
had IgM paraprotein. The haematological diagnosis was monoclonal gammopathy of undetermined
significance (MGUS) in 65%, Waldenstrom's macroglobulinaemia 30%, and lymphoma or
plasmacytoma 5%. After treatment, overall 13 (28%) patients improved neurologically,
11 (24%) stabilised, and 22 (48%) worsened. In the 19 patients who received more than
one type of treatment, we analysed outcomes according to the most powerful treatment
received. 23 patients received rituximab alone of which 5 (22%) improved, 6 (26%)
stabilised and 12 (52%) worsened. Nine patients received rituximab combined with cyclophosphamide
or bendamustine, of which 3 (33%) improved, 2 (22%) stabilized and 4 (44%) worsened.
Eight patients received intravenous immunoglobulin, of which 3 (38%) improved, 2 (25%)
stabilized and 3 (38%) worsened. Four patients received other chemotherapy, of which
2 improved, 1 stabilised, 1 worsened. Two patients received corticosteroids and both
worsened. There was improvement in 7/29 (24%) with MAG antibodies and 6/17 (35%) without.
There was improvement in 5/26 (19%) with MGUS and 5/14 (36%) with haematological malignancy.
There was improvement in 11/32 (34%) with kappa light chains and 2/14 (14%) with lambda.
Factors associated with better outcome (by univariate analysis) were negative MAG
antibodies, kappa light chain, and haematological malignancy. There was no significant
difference between treatments in the proportions who improved.
SWITCHING FROM IVIG TO FLEXIBLY DOSED SCIG IN PATIENTS WITH CIDP AND MMN: CLINICAL
AND PATIENT EXPERIENCE
Cumberbatch M
1, Cox A1.
1Addenbrooke's Hospital, Cambridge, UK.
Treatment of patients with autoimmune neuropathies such as chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) has centred on
the use of intravenous immunoglobulin (IVIg). However, IVIg therapy is associated
with systemic side‐effects, treatment wear‐off effects and regular hospital attendance.
Subcutaneous immunoglobulin (SCIg) is an efficacious alternative that can be flexibly
dosed, self‐administered at home and avoids the ‘peaks’ and ‘troughs’ observed with
IVIg. These factors may combine to improve patient satisfaction and alleviate hospital
capacity issues. Here, we report on clinical and patient experience of switching from
hospital‐based IVIg to home‐based manual push SCIg for the treatment of CIDP and MMN.
This was a clinical case series of 10 patients (8 CIDP, 2 MMN; mean age 59.5 years)
who were clinically stable on IVIg and wished to switch to manual push SCIg. Starting
SCIg dose was equivalent to the final IVIg dose for each patient (mean 0.23 g/kg week).
Clinical efficacy (Medical Research Council sum score, 10‐m walk, modified Inflammatory
Neuropathy Cause and Treatment score, Overall Neuropathy Limitations Scale, Romberg
test) and patient‐reported outcomes (36‐item Short Form Health Survey [SF‐36], Life
Quality Index [LQI]) were assessed at baseline and at regular intervals until the
final visit (10–14 months after switching). At baseline, patients cited ‘convenience’
as their primary reason for switching to SCIg. Eight patients completed the full assessment
period and successfully undertook administrations at home (via hospital‐at‐home service
in 2 cases). Dose adjustments, based on clinical need, were required in 6 patients.
Treatment efficacy and patient quality of life, measured by SF‐36, were maintained
after switching to SCIg; overall patient satisfaction, measured by LQI, increased
from 75% to 90%. In the LQI, 'convenience', 'travel time/cost' and ‘interference‐work’
were significantly improved (p<0.05) after switching to SCIg therapy. Adverse events
included mild erythema and localised swelling, as expected for a 20 mL subcutaneous
injection. These findings suggest that manual push SCIg therapy is a viable alternative
to IVIg for patients with CIDP and MMN, as it maintains disease stability, is more
convenient for patients and may help ease hospital capacity concerns.
A RETROSPECTIVE AUDIT OF IVIG INFUSION RATES IN THE TREATMENT OF AUTOIMMUNE NEUROLOGICAL
DISEASE
Cumberbatch M
1, Soares Regua D1, Cox A1.
1Addenbrooke's Hospital, Cambridge, UK.
Intravenous immunoglobulin (IVIg) is used to treat a number of chronic autoimmune
neurological diseases. In most centres, infusions are given at slow rates as there
is a perception that this reduces the risk of adverse events (AEs). This results in
longer in‐patient admissions, or frequent day case attendances, impacting on both
the patients' quality of life and hospital capacity. However, there is little evidence
to suggest that slow infusion rates are required. We used the manufacturer recommendations
to optimise infusion rates and reduce the time patients spend in hospital. We report
a retrospective audit which describes the impact of different IVIg infusion rates
on patients' clinical condition. The audit comprised three 6‐month assessment periods:
January–June 2015 (cohort 1; infusion rates of 1.2 ± 0.1 mL/kg/hr, n = 27); January–June
2016 (cohort 2; 2.4 ± 0.1 mL/kg/hr, n = 42) and July–December 2016 (cohort 3; 3.9
± 0.2 mL/kg/hr, n = 39). Clinical data were reviewed to determine: patient demographics,
duration of infusion; time spent in hospital; and incidence of AEs. The three cohorts
were well matched in terms of patient demographics (14 patients were treated in all
3 treatment periods). Cohorts 2 and 3 had significantly shorter treatment episodes
than cohort 1 (3.2 and 2.7 vs. 4.1 hours, p<0.01), spent less time on the unit over
the 6 month period (25.6 and 20.3 vs. 39.4 hours, p<0.05) and had fewer admissions/patient
(6.5 and 5.9 vs. 8.5, p<0.05). The overall incidence of confirmed AEs (mainly headaches)
was similar across the cohorts (cohort 1: 15%; cohort 2: 19%; cohort 3: 18%). These
findings indicate that increases in IVIg infusion rate are well tolerated and significantly
reduce treatment time, which benefits patients and offers potential cost savings and
reduced pressures on hospital capacity for healthcare providers.
DEVELOPMENT OF A SUBACUTE ANTI‐GANGLIOSIDE ANTIBODY‐MEDIATED MOUSE MODEL OF GBS
Cunningham ME
1, Yao D1, Meehan GR1, Barrie JA1, Willison HJ1.
1University of Glasgow, Glasgow, UK.
One mechanism of injury in the acute motor axonal neuropathy (AMAN) form of Guillain‐Barré
syndrome (GBS) is the attack of peripheral nerve axons by anti‐ganglioside antibodies
(AgAbs). Rodent models have demonstrated that that binding of these antibodies activates
the complement cascade, resulting in the insertion of the terminal component, membrane
attack complex (MAC) into the axonal membrane. Complement activation also results
in the release of anaphylatoxins, which are known to recruit phagocytic immune cells
to the site of injury. Our current in vivo mouse model of AgAb and complement‐mediated
injury are acute and severe, resulting in respiratory distress over several hours
of such magnitude to warrant termination of experimental procedures. To observe and
potentially target immune cell infiltration following AgAb and complement‐mediated
injury, a subacute model extending over days is required. Here, we demonstrate the
development of such a model. To compare differences in immune cell infiltration subacutely
under control and injury conditions, mice with endogenous expression of eGFP in monocytes
and macrophages underwent a modified AgAb and complement‐mediated injury, resulting
in a less severe phenotype than previously published models. Six days following injury,
immune cells in the diaphragm were compared by immunofluorescence and flow cytometry.
Flow cytometry found overall presence of neutrophils was significantly increased in
the diaphragm. Macrophages were also increased in injured mice, although did not achieve
statistical significance at this timepoint. These results were reflected in immunofluorescent
staining of the diaphragm where eGFP+ macrophages were quantified surrounding the
neuromuscular junction (the primary injury target in this model). The development
of an extended mouse model of AgAb and complement‐mediated injury is important, since
acute models do not take into consideration either the late‐term effects of complement‐mediated
activation at the nerve membrane, or the recovery phase. Future studies will look
at the effect of inhibiting complement activation on the presence of immune cells
in distal motor nerves.
UNRAVELLING THE DISEASE MECHANISMS UNDERLYING THE DHMN1 INSERTION
Cutrupi AN
1,2,3, Perez‐Siles G1, Brewer MH1, de Moraes Maciel R4, Ly C1, Drew A1, Zuchner S5,
Nicholson G1,2,6, Saporta MA4*, Kennerson ML1,2,6*.
1Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, Australia; 2Sydney
Medical School, University of Sydney, Sydney, Australia; 3Sydney Medical School Foundation,
Sydney, Australia; 4Department of Neurology, University of Miami, Miller School of
Medicine, Miami, USA; 5Department of Human Genetics, Hussman Institute for Human Genomics,
University of Miami, Miller School of Medicine, Miami, USA; 6Molecular Medicine Laboratory,
Concord Repatriation General Hospital, Sydney, Australia, *equal last author.
Family‐54 is a large Australian family with an autosomal dominant form of dHMN (DHMN1:
OMIM %182960) ‐ a group of length‐dependent neurodegenerative disorders affecting
the lower motor neurons leading to chronic disability. We recently reported a novel
1.35 Mb chromosomal insertion within the DHMN1 locus which we hypothesise is likely
to cause disease by dysregulating the expression of one or more nearby genes. Studying
gene dysregulation in peripheral nerve disease is challenging as the relevant tissues
(spinal cord and peripheral nerve) are not easily accessible in patients. Therefore,
alternative strategies are needed to elucidate the disease mechanisms and pathways
involved in peripheral nerve degeneration. To address this problem, we have devised
a two‐tiered strategy to assess dysregulation of candidate genes using patient lymphoblast
and fibroblast cell lines. These cell lines can be easily established, are minimally
invasive to obtain, and will harbour the natural mutation and genetic background of
patients. Our strategy firstly uses lymphoblast gene expression profiles as an initial
screening tool to prioritise candidate genes for assessing altered expression. Differentially
expressed genes will then be modelled in C.elegans where behavioural and nerve morphology
can be assessed. Using RT‐PCR, we have screened 21 DHMN1 candidate genes in patient
and control lymphoblast cell lines. Eighteen candidate genes were expressed in lymphoblasts.
Twelve of the eighteen genes were prioritized for further analysis based on expression
in both lymphoblast and neural tissues. Quantitative analysis using qRT‐PCR TaqMan
assays revealed that UBE3C, was differentially expressed between patients and controls.
It is important that patterns of differential expression can be recapitulated in neural
cell‐specific models. As part of our second strategy, we have generated patient and
control induced pluripotent stem cell derived motor neurons (iPSC‐MNs) from reprogrammed
fibroblasts. Using this model, we will perform RNA‐seq and qPCR experiments to examine
disease‐relevant alterations in gene expression in neural tissue. We predict that
utilization of these two strategies will shed light on the pathogenic mechanisms underlying
the DHMN1 insertion and provide useful insights of pathways leading to peripheral
nerve degeneration.
INHIBITION OF COMPLEMENT IN GUILLAIN‐BARRÉ SYNDROME: THE ICA‐GBS STUDY
Davidson AI
1, Halstead SK2, Goodfellow JA1, Chavada G1, Mallik A3, Overell J1, Lunn MP4, McConnachie
A5, van Doorn P6, Willison HJ1.
1Department of Neurology, Institute of Neurological Sciences, Southern General Hospital,
Glasgow, UK; 2Institute of Infection, Immunity and Inflammation, College of Medical,
Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; 3Department of Clinical
Neurophysiology, Institute of Neurological Sciences, Southern General Hospital, Glasgow,
UK; 4Department of Neurology, National Hospital for Neurology and Neurosurgery, Queen
Square, London, UK; 5Robertson Centre for Biostatistics, Boyd Orr Building, University
of Glasgow, Glasgow, UK; 6Department of Neurology, Erasmus, MC, Rotterdam, The Netherlands.
The outcome of Guillain‐Barré syndrome remains unchanged since plasma exchange and
intravenous immunoglobulin were introduced over 20 years ago. Pathogenesis studies
on GBS have identified the terminal component of complement cascade, the membrane
attack complex, as a key disease mediator and thus a therapeutic target. The Inhibition
of Complement in Guillain‐Barré Syndrome (ICA‐GBS) trial looked at the first use of
C5 pathway inhibition with eculizumab in humans with GBS in a randomised, double‐blind,
placebo‐controlled trial. Its primary outcome was to look at safety and tolerability
of administration concomitantly with IVIg and in the context of severe (GBS disability
score 3 or greater) disease. Participants were recruited for a 6 month period, with
regular follow up. 28 subjects were screened, with 8 (29%) being randomised. The two
main causes for failure to proceed were participant concerns around eculizumab side
effect profile, specifically the meningitis risk, and also intercurrent infection
precluding treatment. Five received eculizumab for four weeks, alongside standard
intravenous immunoglobulin treatment, with 3 receiving placebo. The safety outcomes,
monitored via adverse events capture at each trial visit, showed eculizumab to be
well tolerated and safe when administered in conjunction with IVIg. The most common
adverse events were mild derangement in transaminases or infection. There were no
infusion reactions. Primary and secondary efficacy outcomes were captured via GBS
disability scores, MRC sum scores, Rasch Overall Disability Scores and Overall Neuropathy
Limitation Scores. For the primary efficacy outcome at 4 weeks after recruitment,
2 of 2 placebo and 2 of 5 eculizumab‐treated subjects had improved by 1 or more grades
on the GBS disability score. All patients had improvements in other measured parameters.
This trial highlights the challenges in recruiting acutely unwell patients, due to
time constraints and intercurrent infection. Although the small sample size precludes
a statistically meaningful analysis, these pilot data indicate further studies on
complement inhibition in GBS are warranted.
CHARCOT‐MARIE‐TOOTH 2W. A NEW MUTATION?
de Freitas M
1, Dias J1, Vidal C1, Szklarz D1, Nascimento O1, Kok F2.
1Federal Fluminense University, Niterói, Brazil; 2São Paulo University, São Paulo,
Brazil.
Charcot‐Marie‐Tooth disease (CMT) affects about one in 2.500 people. Currently more
than 44 genes have been identified, with the most different phenotypes. The majority
of cases in Western countries are autosomal dominant and classified as demyelinating
and axonal according to electroneuromyography (ENMG). The clinical condition is characterized
by weakness and predominant sensory changes in the feet and hands. Sometimes there
are different phenotypes. Recently, variants in heterozygotes in the HARS gene (Histidil‐tRNA
synthetase) have been described associated with CMT called type 2W.To report a case
of CMT‐sensitive phenotype with a probable new mutation in HARS gene (p.Leu41Arg).A
male patient, adopted son, Caucasian, drug addict, for three years suffered pain in
lower limbs, of great intensity, refractory to drug treatment. The examination showed
retrognathism, abolition of patellar and achilleas reflexes, painful and thermal anaesthesia
and apalesthesia in the feet.The ENMG showed reduced sensory action potentials in
sural and superficial fibular nerves. Laboratory investigations for painful polyneuropathy
of thick and fine fibres was normal. Sural nerve biopsy revealed axonal predominance
neuropathy. Exome sequencing revealed a mutation in the HARS gene with a pathogenic
variant in heterozygosity, with replacement of the amino acid leucine at position
41 by arginine. Our patient, although we did not know the antecedents, presented painful
polyneuropathy, whose genetic research, although not unequivocal, indicated a variant
called CMT W. Few cases of this variant were described, with several mutations. Our
case revealed mutation hitherto unknown (p.Leu41Arg). We conclude by the importance
of a thorough genetic evaluation, in cases of sensory polyneuropathy of unknown cause.
A RANDOMIZED CONTROLLED TRIAL OF THE EFFICACY, SAFETY, AND TOLERABILITY OF LACOSAMIDE
IN PATIENTS WITH GAIN‐OF‐FUNCTION NAv1.7 MUTATION‐RELATED SMALL FIBER NEUROPATHY:
THE LENSS STUDY
de Greef BTA
1, Geerts M1, Faber CG1, Merkies ISJ1,2, Hoeijmakers JGJ1.
1Department of Neurology, School of Mental Health and Neuroscience, Maastricht University
Medical Center, Maastricht, The Netherlands; 2Department of Neurology, St. Elisabeth
Hospital, Willemstad, Curaçao.
Small fiber neuropathy (SFN) is a condition that affects the small Aδ‐ and C‐fibers,
leading to severe neuropathic pain and autonomic dysfunction. Several sodium channel
gene mutations have been found in patients with SFN, with SCN9A‐gene mutations being
the most frequent. Because current available sodium channel blockers are not selective
for NaV1.7, these treatments often result in numerous side effects. Lacosamide is
an anticonvulsant that targets specific sodium channels with a slow‐inactivation state,
while sparing those with normal activity. Several mutations of the SCN9A‐gene with
an impaired slow‐inactivation of Nav1.7 have been found in patients with SFN. Therefore,
a positive effect of lacosamide on pain reduction in these patients is expected. The
primary objective of this study was to determine the effect of lacosamide versus placebo
on pain in subjects with SCN9A‐associated SFN. Secondary objectives were to determine
the effect of lacosamide on autonomic symptoms, sleep interference, and quality of
life, and to examine the safety and tolerability. The Lacosamide‐Efficacy‐‘N’‐Safety
in SFN (LENSS) study was a randomized, placebo‐controlled, double‐blind, crossover‐design
study. Subjects were randomized to start with lacosamide and end with placebo or vice
versa. During both of the two phases of the study, the subjects were treated for a
period of eight weeks of 200mg BID, preceded by a titration period, and ended by a
tapering period. Patients filled in a pain diary twice daily and scored a set of validated
questionnaires on autonomic symptoms, sleep interference, and quality of life at multiple
study visits. In total 25 patients with SCN9A‐associated SFN were included between
November 2014 and February 2017. The subjects had a median age of 58 years, ranging
from 24 to 78 years. Sixty percent of the patients were female. The final results
of the study, including the primary and secondary outcomes, will be presented.
DEXAMETHASONE REDUCES THE FOREING BODY RESPONSE TO PARYLENE‐C INTRANEURAL IMPLANTS
IN RATS
De la Oliva N
1, Del Valle J1, Navarro X1.
1Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences,
Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red sobre
Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
Intraneural interfaces must be in intimate contact with nerve fibres to have a proper
function, but it has been shown that this is compromised due to the foreign body reaction
(FBR). This FBR is the first response of the nonspecific immune system against an
implanted device and is characterized by a first inflammatory phase followed by a
second antiinflammatory and fibrotic phase. This process results in the formation
of a tissue capsule around the interface causing function loss due to the physical
separation between the active sites of the electrode and nerve axons. Taking this
into account, here we have tested several anti‐inflammatory drugs such as dexamethasone,
ibuprophen and maraviroc to reduce macrophage activation as well as clodronate liposomes
to reduce monocyte/macrophage infiltration. Moreover, sildenafil have been administered
as an antifibrotic drug to reduce collagen deposition in a FBR model with longitudinal
Parylene C‐based intraneural devices implanted in rat sciatic nerve. Briefly, animals
were systemically treated with dexamethasone, ibuprophen, sildenafil, maraviroc or
clodronate liposomes for two weeks, and nerve damage, inflammatory reaction and matrix
thickness around the implant were assessed. Treatment with dexamethasone, ibuprophen
or clodronate liposomes significantly reduced the inflammatory response in the nerve
in comparison to saline group while sildenafil or maraviroc had no effect on iba1
positive cells infiltration in the nerve. However, only dexamethasone was able to
significantly reduce the matrix deposition around the implant after two weeks of treatment.
These results support the idea that inflammation triggers the foreign body response
in peripheral nerves and a potent anti‐inflammatory treatment with dexamethasone could
have a beneficial effect on lengthening intraneural interfaces lifespan.
TIME‐COURSE CHARACTERIZATION OF FOREIGN BODY REACTION TO IMPLANTED DEVICES IN RAT
PERIPHERAL NERVE
De la Oliva N
1, Del Valle J1, Navarro X1.
1Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences,
Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red sobre
Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
Intraneural interfaces functionality decreases over time, among other factors, due
to the foreign body response (FBR), which encapsulates the implanted devices and physically
separates the active sites from the nervous tissue. Here we have studied the FBR to
parylene C or polyimide thin devices implanted in rat sciatic nerves, assessing thickness
of the tissue capsule, signs of inflammation and nerve damage. We have characterized
the responsible cells of this response and several molecular mediators over 8 months
of implant to find differences between the FBR to both materials. After 2 weeks of
implant, the inflammatory response due to the surgery was already decreased, whereas
in the implanted nerves it reached its highest levels to then decrease at chronic
time points. Besides, the amount of foreign body giant cells (FBGC), as a result of
macrophage fusion, found in the tissue capsule around the implant also increases progressively
to reach a maximum after 2 weeks. On the other hand, molecular analysis of the environment
revealed a peak of inflammatory cytokines during the first day of implant to return
to standard levels thereafter. However, an increase on CCLs molecules was found at
later time‐points for both materials. With regard to the capsule thickness, all the
devices were surrounded by a tissue deposition which appeared soon after the implantation.
However, in the case of polyimide devices, the tissue capsule showed a peak 2 weeks
after the implant and signs of remodeling thereafter, while the parylene C devices
showed a second increase from 8 to 16 weeks in comparison to polyimide devices. Immunohistochemical
and electron microscopy analysis revealed two different cell types implicated in the
FBR in nerve to both materials: macrophages, in close contact with the interface,
and fibroblasts which appear after 8 weeks surrounding the tissue capsule. Although
further analyses are needed to elucidate the differences in the FBR to parylene C
and polyimide polymers, these results can help to determine therapeutic targets in
order to reduce this response and to improve the intraneural interfaces lifespan.
VALUE OF ANTI‐HNK1 ANTIBODIES IN ANTI‐MAG NEUROPATHIES: AN ANALYSE OF 144 SERA
Delmont E
1, Antoine JC2, Paul S3, Boucraut J4, Attarian S1.
1Referral Centre for ALS and Neuromuscular Diseases, Marseille, France; 2Referral
Centre for Neuromuscular Diseases, Saint Etienne, France; 3Immunology Laboratory,
Saint Etienne, France; 4Immunology Laboratory, Marseille, France.
Peripheral neuropathies with antibodies against Myelin Associated Glycoprotein (MAG)
are chronic sensory neuropathies characterized by the presence of an IgM monoclonal
gammopathy and high levels of anti‐MAG antibodies. These antibodies recognize a specific
epitope called Human Natural Killer 1 (HNK1) shared by NK lymphocytes and several
components of the peripheral nerve (MAG, P0, PMP22, SGPG, phosphocan). Recently an
ELISA test has been developed to detect antibodies against HNK1 epitope.
Our objectives were to determine the sensitivity and the specificity of anti‐HNK1
antibodies in the diagnosis of anti‐MAG neuropathy and to know if these antibodies
were correlated with the severity of the disease.
Anti‐HNK1 antibodies were assessed in 42 anti‐MAG neuropathies and in 102 negative
controls: 29 chronic inflammatory demyelinating polyradiculoneuropathies (CIDP), 3
Miller Fisher syndromes, 11 sensory neuronopathies, 58 length‐dependant axonal sensory
polyneuropathies, 5 healthy controls. In anti‐MAG neuropathies, were recorded age,
disease duration, INCAT sensory sum score (ISS), Overall Neuropathy Limitation Scale
(ONLS), Rasch‐built Overall Disability Scale (RODS), MRC sum score, anti‐MAG antibodies
titer, peak dosage of the IgM monoclonal gammopathy. Anti‐HNK1 antibodies were measured
with GanglioCombi™ MAG ELISA test and anti‐MAG antibodies with Anti‐MAG Autoantibodies
ELISA test both from Buhlmann company.
Anti‐HNK1 antibodies were positive in 41/42 anti‐MAG neuropathies, and in 1/102 controls
(sensitivity 98%, specificity 99%). In anti‐MAG neuropathies, anti‐HNK1 titer was
correlated with sensory deficiency evaluated with the ISS score (r=0.5, p=0.006) and
with disability evaluated with the RODS (r= −0.4, p=0.013) and ONLS scales (r=0.4,
p=0.025). Anti‐HNK1 titers were not related to age, disease duration, MRC sum score,
anti‐MAG antibodies titer, peak dosage of the paraproteinemia. Anti‐MAG antibodies
titers were associated with none of the characteristics of the patients with anti‐MAG
neuropathy.
Anti‐HNK1 antibodies have good sensitivity and specificity in the diagnosis of anti‐MAG
neuropathy. Compared to anti‐MAG antibodies, their value is that their titers are
related to the disease severity. These results need to be confirmed in a larger prospective
cohort.
AUTOANTIBODIES TO NODAL ISOFORMS OF NEUROFASCIN IN CHRONIC INFLAMMATORY DEMYELINATING
POLYNEUROPATHY
Delmont E
1,2, Manso C2, Querol L3, Cortese A4, Berardinelli A4, Belghazi M2, Malissart P5,
Labauge P5, Taieb G5, Yuki N6, Illa I3, Attarian S1, Devaux J2.
1Referral Center for ALS and Neuromuscular Diseases, La Timone University Hospital,
Aix‐Marseille University, France; 2Aix‐Marseille Université, CNRS, CRN2M‐UMR7286,
Marseille, France; 3Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant
Pau, Universitat Autónoma de Barcelona, Barcelona, Spain; 4IRCCS, C. Mondino National
Neurological Institute, Pavia, Italy; 5Department of Neurology, Gui de Chauliac Hospital,
Montpellier University Hospital Center, Montpellier, France; 6Department of Neurology,
Mishima Hospital, Niigata, Japan.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)is a heterogeneous
and treatable immune‐mediated disorder that critically lacks biomarkers to support
diagnosis. Recent evidences indicate that paranodal proteins (contactin‐1, contactin‐associated
protein‐1, and neurofascin‐155) are the targets of autoantibodies in a subset of patients
with CIDP showing distinct clinical presentations. Particularly, these biomarkers
appear to have clinical relevance and help to orientate therapeutic choice. Here,
we examined five patients presenting an IgG reactivity against the nodes of Ranvier
and the axon initial segment. Using a proteomic approach, cell‐based assays and ELISA,
we identified neurofascin‐186 (Nfasc186) and neurofascin‐140 (Nfasc140) as the main
targets of autoantibodies at the nodes of Ranvier. Four patients displayed predominantly
antibodies of the IgG4 subclass, whereas one patient presented IgG3 antibodies that
activated the complement pathway in vitro. These antibodies recognized different epitopes
than the previously described anti‐neurofascin‐155 IgG4 suggesting different pathogenic
functions. Accordingly, patients with anti‐Nfasc186/140 IgG showed a distinctive clinical
presentation. Most patients had a severe phenotype associated with conduction block
or decreased distal motor amplitude. Tremors or neuropathic pain were not observed.
Four patients presented with a subacute‐onset and sensory ataxia. Of interest, the
neuropathy occurred concomitantly with nephrotic syndromes in two patients and with
an IgG4‐related retroperitoneal fibrosis in one patient. This suggested that autoantibodies
could be responsible for the occurrence of both disorders. Intravenous immunoglobulin
and corticosteroids were effective in three patients, and one patient improved following
cyclophosphamide and rituximab treatment. Clinical remission was found to correlate
with the depletion of anti‐Nfasc186/140 antibodies and the loss of IgG reactivity
toward the nodes of Ranvier. In addition, recovery of conduction block and of distal
motor amplitude were observed following remission and suggested a nodo‐paranodopathy.
Our data demonstrate that nodal antigens are the target of autoantibodies in a subgroup
of patients with CIDP. This emphasizes that the pathogenic mechanisms involved in
chronic immune‐mediated demyelinating neuropathies are broad and may include dysfunctions
of the nodes of Ranvier.
NOVEL NEFH MUTATIONS AS A CAUSE OF AN AUTOSOMAL AXONAL FORM OF CHARCOT‐MARIE‐TOOTH
DISEASE WITH PROXIMAL MUSCLE INVOLVEMENT
Delorme C
1, Jacquier A2,3, Morales‐Juntas R4, Zuchner S5, Sole G6, Schaeffer L2,7, Stojkovic
T8, Latour P3.
1Département de Neurologie, Hôpital Pitié‐Salpêtrière, Paris, France; 2Institut NeuroMyoGène,
Université Lyon1, CNRS UMR 5310, INSERM U1217, Lyon, France; 3Unité fonctionnelle
de neurogénétique moléculaire, CHU de Lyon, HCL groupement Est, Bron, France; 4Clinique
du motoneurone et pathologies neuromusculaires, CHRU de Montpellier, Montpellier,
France; 5Dr John T. MacDonald Foundation Department of Human Genetics, Institute of
Human Genomics, University of Miami, Miller School of Medicine, Miami, USA; 6Centre
de références des maladies neuromusculaires, CHU de Bordeaux, Bordeaux, France; 7Centre
de Biotechnologie Cellulaire, CBC Biotec, CHU de Lyon, HCL groupement Est, Faculté
de médecine Lyon Est, Bron, France; 8Institut de Myologie, Hôpital Pitié‐Salpêtrière,
Paris, France.
Mutations in the neurofilament heavy (NEFH) gene have been recently identified as
a rare cause of autosomal dominant, axonal Charcot‐Marie‐Tooth disease (CMT2). The
clinical spectrum of this condition remains to be delineated. We report two French
families with an axonal, predominantly motor, dominantly inherited form of CMT caused
by two previously unreported mutations in the NEFH gene. Twelve patients belonging
to two different families were included in the study. They displayed an axonal motor
and sensory neuropathy, with no mutations in known axonal CMT2 genes. A remarkable
feature in all patients was the early involvement of proximal muscles of the lower
limbs, occurring approximately 10 to 15 years after the onset of motor deficit. Proximal
weakness affected predominantly the iliopsoas muscle, whereas quadriceps and hamstring
muscles were relatively preserved. Muscle weakness and muscle wasting progressed rapidly,
with most of the patients requiring walking assistance after 20 years of disease evolution.
Three patients in family 1 had brisk reflexes. Nerve‐conduction velocity studies displayed
evidence of a motor and sensory axonal neuropathy predominantly affecting the lower
limbs. Original deletions of 2 nucleotides near the end of the coding sequence of
NEFH were identified: in family 1, c.3008_3009del (p.Lys1003Argfs*59), and in family
2 c.3043_3044del (p.Lys1015Glyfs*47) causing a frameshift. Interestingly, this frameshift
leads to the loss of the terminating codon and to the translation of 40 additional
amino acids encoding a cryptic amyloidogenic element, suggesting that this type of
mutations could induce protein aggregation. Consistently, we showed that overexpression
of the mutated forms of NEFH in a human neuroblastoma cells induced the formation
of protein aggregates. We also observed that it triggered caspase 3 activation and
apoptosis. Using electroporation of chick embryo spinal cord, we confirmed in vivo
that mutated NEFH formed aggregates and triggered apoptosis of spinal cord neurons.
Altogether, this suggests that these mutations in NEFH cause protein aggregation and
neurotoxicity in neurons expressing NEFH. Progressive loss of such neurons would explain
the early motor involvement and the pyramidal signs observed in some patients. Our
results provide a physiological explanation to the presence of CMT and ALS clinical
features in affected patients.
FASCICULAR NERVE STIMULATION AND RECORDING USING A NOVEL DOUBLE‐AISLE REGENERATIVE
ELECTRODE
Del Valle J
1,2, Delgado‐Martínez I1, Righi M3, Santos D1,2, Cutrone A3, Bossi S4, D'Amico S3,
Micera S3,5, Navarro X1,2.
1Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences,
Universitat Autònoma de Barcelona, Bellaterra, Spain; 2Centro de Investigación Biomédica
en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain; 3The Biorobotics
Institute, Scuola Superiore Sant'Anna, Pontedera, Italy; 4Robotics Laboratory, ENEA,
Casaccia Research Center, Rome, Italy; 5Bertarelli Chair in Translational NeuroEngineering,
Center for Neuroprosthetics and Institute of Bioengineering, School of Engineering,
Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.
Neuroprosthetic devices that are aimed to restore sensorimotor limb function of amputee
patients require highly selective electrodes designed to establish a tight relationship
with the nerve, allowing the bidirectional transduction of signals between nerve fibres
and the interface and enabling close‐loop control from the user. Differently from
extra‐ or intraneural interfaces, regenerative nerve electrodes are designed to enable
electrical interface with regrowing axonal bundles of injured nerves, aiming to achieve
high selectivity for recording and stimulation. However, most of the developed designs
pose an obstacle to the regrowth mechanisms due to low transparency and cause an impairment
of the nerve regeneration.
In this work, we present a novel double‐aisle planar regenerative electrode, a new
type of highly transparent, non‐obstructive regenerative electrode, which allows the
selective stimulation and recording of separated nerve fascicles. The design consists
of a thin and flexible double‐sided electrode longitudinally inserted across a conduit
thus creating two separated aisles in which regenerating fascicles can independently
regrow after nerve transection.
Electrodes implanted in acutely transected nerves of rats showed the capability of
selectively stimulating and recording different fascicles inserted in the aisles.
Moreover, chronic implantation of the electrode in a nerve gap of 6mm after sciatic
nerve section allowed for fascicle regeneration and reinnervation of distal muscles
as confirmed by the high number of myelinated axons inside each aisle, good biocompatibility,
and adequate nerve conduction. In addition, three and six months after implantation,
independent stimulation and recording of each separately regenerated fascicle were
possible.
Our results demonstrate the potential contribution of the doubled‐aisle regenerative
electrode to selectively interface different fascicles of an injured nerve with no
deleterious effects on nerve regeneration. Therefore, this multi‐aisle regenerative
electrode may be suitable for neuroprosthetic applications, such as prostheses for
the restoration of hand function after amputation or severe nerve injuries.
ACUTE‐ONSET OF CIDP WITH IGG4 ANTI‐NF155 ANTIBODIES RESISTANT TO CONVENTIONAL THERAPIES
AND RESPONSIVE TO RITUXIMAB
Demichelis C
1, Garnero M1, Franciotta D2, Cortese A2, Callegari I2, Mancardi GL1, Schenone A1,
Leonardi A3, Benedetti L1.
1Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and
Child Health, University of Genoa and IRCCS AOU San Martino‐IST, Genoa, Italy; 2Laboratory
of Neuroimmunology, IRCCS, “C. Mondino” National Neurological Institute, University
of Pavia, Pavia, Italy; 3U.O. Neurology, ASL1 Imperiese, Imperia, Italy.
Querol et al. showed that Neurofascin155 (NF155) antibodies identify a Chronic Inflammatory
Demyelinating Polyradiculoneuropathy (CIDP) phenotype characterized by severe polyradiculoneuropathy,
poor response to intravenous immunoglobulins (IVIg), and disabling tremor. Neurological
improvement after therapy with rituximab has been previously reported in three patients
with CIDP with IgG4 anti‐NF155 antibodies. Herein we describe the acute‐onset of a
case of CIDP positive for NF155 IgG4 antibodies resistant to conventional therapies
and responsive to Rituximab. The patient is a 64 year‐old woman who presented acute
onset ataxia and gait disturbances; her symptoms progressed over two weeks and distal
weakness, numbness and paresthesias appeared too. The nerve conduction study was suggestive
for a motor‐sensory polyradiculoneuropathy mainly demyelinating. The cerebrospinal
fluid analysis showed elevated protein level and normal cellular count. The patient
was initially diagnosed with Guillain‐Barré syndrome (GBS) and treated with plasma
exchange without improvement. An IVIg cycle was started with a partial relief but
at the time of admission to the rehabilitation center the patient still had a marked
weakness in all four limbs. After six months she presented a further clinical deterioration
and she was restricted to wheelchair. There was no response to additional treatment
with IVIg, while pulse corticosteroid treatment determined a significant clinical
improvement.
During the next 6 months, despite the maintenance of steroid therapy, the patient
presented a progressive deterioration and she was again restricted to wheelchair.
Postural and intention tremor appeared at upper limbs and became progressively more
disabling. Anti‐NF155 Ab dosage resulted positive. Rituximab was administered at a
dosage of 375 mg/m2/weekly for 4 weeks. After three months the tremor improved, allowing
her to eat independently and the patient was able to walk with bilateral support.
Antibodies anti‐NF155 were negative. After six months she walked without support and
she was able to stitch crochet. As previously reported, in this case a CIDP positive
for IgG4 NF155 developed severe polyradiculoneuropathy with predominant distal weakness,
ataxia, disabling tremor and resistance to conventional therapies. Interestingly the
onset was GBS‐like. The correct identification of these CIDP subtypes has diagnostic,
prognostic and therapeutic implications. Rituximab con be useful in these patients.
EFFECT OF NİFEDİPİNE ON SURGICALLY ANASTOMIZED PERIPHERAL NERVE REGENERATION
Demir Ö
1, Yazıcı T2.
1Department of Neurosurgery, University of Gaziosmanpaşa School of Medicine, Tokat,
Turkey; 2Department of Neurosurgery, Kent Hospital, Giresun, Turkey.
It is still challenging problem to maintain motor and sensory functions of peripheral
nerve after nerve transection. After the nerve injury, calcium concentration in the
damaged area increases. Then the calcium ions act like cytotoxic agents in the damaged
area. Nifedipine is calcium channel blocker. We aimed to investigate the effects of
nifedipine on nerve regeneration by modulating calcium in the damaged area. Twenty‐four
Swiss albino male rats were divided into two groups. Left sciatic nerve transection
surgery was performed to the all rats in both groups. Then the all transected nerves
were sutured primarily with epineural interfascicular method. In the experimental
group, the anastomosis sites were wrapped with a piece of gel foam soaked into diluted
nifedipine solution. In the control group, the anastomosis sites were wrapped with
a piece of gel foam soaked into saline solution. We evaluated the effect of nifedipine
by using functional, electro‐physiological and histopathological studies after the
surgeries. In the postoperative second week, walking test was performed and sciatic
function index was calculated. In the postoperative third week electroneuronography
(ENoG) was performed. There are significant differences between two groups. Nifedipine
improved nerve recovery functionally (p<0.001) and electro‐physiologically (p<0.001).
In the postoperative fourth week, we performed histopathological examination. In the
experimental group with nifedipine there were more organized axons that reached the
aim. We conclude from these results that nifedipine is an effective nerve protective
agent when used locally at the anastomosis site after the transection of the nerve.
HUMAN MOTOR NEURON NEUROSPHERES AS A NEW PLATFORM TO STUDY AXONAL PHENOTYPES IN PERIPHERAL
NEUROPATHIES
de Moraes Maciel R
1,2, Saporta Mario A1,2.
1Department of Neurology, University of Miami Miller School of Medicine, Miami, FL,
USA; 2Department of Human Genetics, Hussman Institute for Human Genomics, University
of Miami Miller School of Medicine, Miami, FL, USA.
The lack of effective, disease‐modifying therapies for CMT highlights the need for
novel preclinical models suitable for drug discovery. Studies in rodent models of
CMT tend to be time‐consuming, and findings so far have translated poorly into clinical
trials. Primary and induced pluripotent stem cell (iPSC)‐derived neuronal cultures
are an established model of neurological diseases. However, due to the random distribution
of neuronal bodies and neurites that happen when plating these cells, this system
is not ideal to investigate axonal, length‐dependent processes like peripheral neuropathies
and particularly CMT. To optimize this well‐established model system, we developed
a robust human platform to study axonal morphology and physiology based on motor neuron
neurospheres. We differentiated motor neurons from human induced pluripotent stem
cells, purified them by magnetic sorting and cultured them in suspension until they
formed neurospheres. Floating neurospheres can be maintained in agitation for months
as a reliable source of motor neurons. After neurospheres are platted, axons rapidly
grow out of them in a radial fashion, resembling dorsal root ganglia cultures. This
configuration allows for a better visualization of axons in imaging studies and for
continued axonal growth over at least a 50‐day period. Axons grew at an average rate
of 500 micrometers/day and reached up to 1 cm in length. Neurospheres can be fixed
and stained allowing for morphological analysis and investigation of protein distribution
in axons. This system is also ideal for time‐lapse imaging to study axonal transport
of organelles and neurofilament kinetics. Lastly, our motor neuron neurosphere system
lends itself well for high content screening platform. Neurospheres can be plated
in 96‐well plates where multiple compounds can be tested and the axons easily imaged
by a high content screening microscope. In summary, we developed a new platform to
investigate motor axons in vitro, which are particularly useful to study length‐dependent
processes such as inherited peripheral neuropathies and may facilitate the identification
of new therapeutic compounds using high content screening systems.
ALTERED NEUROFILAMENT DISTRIBUTION IN HUMAN CMT2E MOTOR NEURON AXONS
de Moraes Maciel R1,2, Cutrupi AN1, Rebelo A2, Zuchner S2, Saporta MA
1,2.
1Department of Neurology, University of Miami Miller School of Medicine, Miami, FL,
USA; 2Department of Human Genetics, Hussman Institute for Human Genomics, University
of Miami Miller School of Medicine, Miami, FL, USA.
Mutations in the neurofilament light chain (NFL) gene cause autosomal dominant axonal
Charcot‐Marie‐Tooth neuropathy (CMT2E). NFL is a major component of the neuronal cytoskeleton,
and is believed to function in conjunction with NFM and NFH to provide structural
support for the axon and regulate axon diameter. Despite the significant advances
in understanding its biological basis, there is still no effective, disease‐modifying
therapy for CMT2E, in part due to the paucity of preclinical models suitable for drug
discovery. The development of novel preclinical platforms that can faithfully mimic
mechanisms of axonal degeneration in vitro would be an essential and valuable resource
to better understand the biology of CMT2E and identify potential targets for therapy
development. To address this, we generated control and CMT2E patient‐derived motor
neurons and cultured them in suspension until they formed neurospheres. Immunostaining
of CMT2E neurospheres with NFL and TUBB3 antibodies revealed numerous areas of NFL
accumulation in N98S CMT2E axons, resembling the accumulations of mutant NFL protein
seen in the processes of catecholaminergic neuronal cell line CAD overexpressing several
NFL mutants. Further analysis demonstrated that areas of NFL accumulation were also
immunopositive for NFH, pNFH and NFM and that at least NFL and NFM co‐localized in
the same areas of deposits. Taken together, these results demonstrate that abnormal
axonal neurofilament distribution is a feature of CMT2E iPSC‐derived motor neurons
and involve all three neurofilament subunits. We also developed an image analysis
routine to allow for automatized quantification of neurofilament distribution. Preliminary
quantification of NFL signal intensity revealed that axons from patients have a weaker
NFL signal compared to control axons, but present several signal peaks above the range
observed in controls, which related to the areas of NFL accumulation. These results
suggest that NFL accumulates in certain regions of CMT2E axons but is reduced in the
areas with no accumulation. These findings can be readily adapted into a high content
screening platform and will be used to identify compounds able to reverse this axonal
phenotype. In summary, we identified a strong axonal phenotype in human CMT2E motor
neurons with potential as a screening platform for drug discovery.
PARANODAL ANTIBODIES IN AUSTRIAN PATIENTS WITH ACUTE ONSET INFLAMMATORY NEUROPATHY
De Simoni D
1,2, Hagen H1, Löscher W1, Lindeck‐Pozza E3, Breu M2,4, Lang J2, Varga T1, Rath J5,
Zimprich F2, Höftberger R2, Wanschitz J1.
1Department of Neurology, Medical University of Innsbruck, Austria; 2Institute of
Neurology, Medical University of Vienna, Austria; 3Department of Neurology, SMZ Süd,
Vienna, Austria; 4Department of Pediatric and Adolescent Medicine, Medical University
of Vienna, Austria; 5Department of Neurology, Medical University of Vienna, Austria.
Nodal and paranodal proteins have been identified as antigens in peripheral inflammatory
neuropathies, however the frequency and clinical relevance of antibody responses against
these targets remain poorly investigated in GBS. Patients with acute onset inflammatory
neuropathies were identified by exploration of the local databases of the Departments
of Neurology and the Institute of Neurology of the Medical Universities in Innsbruck
and Vienna. Patient data, electrophysiological classification and presence of anti‐gangliosid
antibodies were retrospectively retrieved by review of patient records. Only patients
with typical clinical presentation and electrophysiological results consistent with
one of the subtypes of GBS were included in the study.
Among forty‐nine patients, thirty‐five were classified as AIDP, six AMAN, three AMSAN,
three MFS, and two pharyngo‐cervico‐brachial GBS. 21 of the included patients had
anti‐ganglioside‐antibodies. Ten patients with the initial suspicion of AIDP had a
disease duration of more than 6 months and were reclassified as CIDP.
All patient and twenty sera of control patients with non inflammatory polyneuropathy
were screened by an optimized tissue based assay using rat brains for immune responses
against surface antigens, and by cell‐based assays with transfected HEK cells for
antibodies against contactin1 (CNTN1), contactin2 (CNTN2), contactin‐associated‐protein1
(CASPR1) and neurofascin‐155 (NF155).
In the tissue based assay some of the patients showed a light neuropil staining. None
of GBS patient's sera had antibody reaction to CNTN1, CNTN2, CASPR1 or NF155 in cell‐based
assays. Among the CIDP patients, two patients demonstrated reactivity against CNTN1
with similar clinical presentation as previously described. None of the control patients
had any antibody reaction to the performed tests. Our results suggest that antibody
responses to CNTN1, CNTN2, CASPR1 or NF155 are absent in Austrian GBS patients, although
more patients will be screened to substantiate these preliminary results. Furthermore,
it remains to be established whether antibodies against CNTN1 may predict a chronic
course in acute onset inflammatory neuropathies.
FREQUENCY, PROGRESSION AND THERAPY OF ATYPICAL CIDP: DATA FROM THE ITALIAN DATABASE
ON CIDP
Doneddu PE
1, Cocito D2, Santoro L3, Fazio R4, Filosto M5, Mazzeo A6, Jann S7, Cortese A8, Beghi
E9, Carpo M10, Clerici M11, Luigetti M12, Lauria G13, Fierro B14, Antonini G15, Briani
C16, Cavaletti G17, Rosso T18, Benedetti L19, Marfia G20, Liberatore G1, Peci E2,
Manganelli F3, Velardo D4, Todeschini A5, Toscano A6, Verrengia EP7, Piccolo L8, Nobile‐Orazio
E1.
1IRCCS Humanitas Clinical and Research Center, Milan University, Milan, Italy; 2Città
della Salute e della Scienza Hospital, Turin, Italy; 3Università degli Studi di Napoli
"Federico II", Naples, Italy; 4IRCCS San Raffaele Hospital, Milan, Italy; 5Spedali
Civili Hospital, University of Brescia, Brescia, Italy; 6Azienda Ospedaliera Universitaria
"G. Martino", Messina, Italy; 7Niguarda Cà Granda Hospital, Milan, Italy; 8IRCCS Fondazione
Mondino, Pavia, Italy; 9IRCCS Mario Negri Institute, Milan, Italy; 10Treviglio Hospital,
Treviglio, Italy; 11Fondazione Macchi Hospital, Varese, Italy; 12Università Cattolica
del Sacro Cuore, Rome, Italy; 13IRCCS Carlo Besta Neurological Institute, Milan, Italy;
14Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, Palermo, Italy; 15Sant'Andrea
Hospital, Univesity of Rome, Rome, Italy; 16Università di Padova, Padua, Italy; 17Milano
Bicocca University, Monza, Italy; 18Azienda UL.SS. 8 Asolo, Castelfranco Veneto, Italy;
19Ospedale Sant'Andrea, La Spezia, Italy; 20Policlinico Tor Vergata, Rome, Italy.
A few variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
have been described with a frequency of 1‐50%. Their relation and possible evolution
into typical‐CIDP remain unclear, as is their treatment response possibly because
of differences in diagnostic criteria. We used the data from a web‐based database
on Italian patients with CIDP to determine the frequency and characteristic of these
variants, the possible evolution into typical‐CIDP, and their treatment response.
All the patients were assessed at study entry and the disease course before inclusion
was analyzed. By February‐2017, we included 360 patients (227 men, 133 women), aged
12–89 years (median 59 years) with a mean disease duration of 8.2 years (range 0.5‐52
years) and complete data available from 320. Based on the clinical data and our revised
diagnostic criteria, 84 patients (26%) were classified to have atypical CIDP at onset
and for the following two years including 29 with DADS (9%), 22 with motor CIDP (7%),
20 with sensory CIDP and 2 CISP (6.2%), 11 with Lewis‐Sumner syndrome (3.5%), and
2 with recurrent cranial neuropathy. At study entry, 36 patients (43%) had progressed
into typical CIDP after 2–38 years (median 5 years) while 48 (57%, 15% of total) still
had atypical CIDP after 0.5‐28 years (median 4 years) with a similar proportion of
progression (50‐60%) within each group. The diagnosis of atypical CIDP at entry fulfilled
EFNS/PNS criteria in 59 (70%). CSF studies were diagnostic in 47/58 (81%) patients,
nerve biopsy in 5/13 (38%), and nerve imaging in 8/9 (89%) tested patients. Similarly
to typical CIDP, 81% of treated patients with atypical CIDP improved after treatment
with a proportion of response varying from 67% to 100% in the different forms. Most
patients with sensory or motor CIDP had however an unsatisfactory response to steroids.
This study shows that he proportion of patients with atypical CIDP varies during the
course of the disease with almost 50% of the patients evolving into typical CIDP within
5 years from onset. In addition, response to treatment is frequent in atypical CIDP
even if not all the forms respond to the same therapies.
LIFESTYLE AND DIETARY HABITS AS PREDISPOSING FACTORS FOR THE ONSET AND PROGRESSION
OF CIDP: A CASE–CONTROL STUDY FROM THE ITALIAN CIDP DATABASE
Doneddu PE
1, Cocito D2, Santoro L3, Fazio R4, Filosto M5, Mazzeo A6, Jann S7, Cortese A8, Beghi
E9, Carpo M10, Clerici M11, Luigetti M12, Lauria G13, Fierro B14, Antonini G15, Briani
C16, Cavaletti G17, Rosso T18, Benedetti L19, Marfia G20, Liberatore G1, Peci E2,
Manganelli F3, Velardo D4, Todeschini A5, Toscano A6, Verrengia EP7, Piccolo L8, Nobile‐Orazio
E1.
1IRCCS Humanitas Clinical and Research Center, Milan University, Milan, Italy; 2Città
della Salute e della Scienza Hospital, Turin, Italy; 3Università degli Studi di Napoli
"Federico II", Naples, Italy; 4IRCCS San Raffaele Hospital, Milan, Italy; 5Spedali
Civili Hospital, University of Brescia, Brescia, Italy; 6Azienda Ospedaliera Universitaria
"G. Martino", Messina, Italy; 7Niguarda Cà Granda Hospital, Milan, Italy; 8IRCCS Fondazione
Mondino, Pavia, Italy; 9IRCCS Mario Negri Institute, Milan, Italy; 10Treviglio Hospital,
Treviglio, Italy; 11Fondazione Macchi Hospital, Varese, Italy; 12Università Cattolica
del Sacro Cuore, Rome, Italy; 13IRCCS Carlo Besta Neurological Institute, Milan, Italy;
14Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, Palermo, Italy; 15Sant'Andrea
Hospital, Univesity of Rome, Rome, Italy; 16Università di Padova, Padua, Italy; 17Milano
Bicocca University, Monza, Italy; 18Azienda UL.SS. 8 Asolo, Castelfranco Veneto, Italy;
19Ospedale Sant'Andrea, La Spezia, Italy; 20Policlinico Tor Vergata, Rome, Italy.
Only few studies investigated the frequency of antecedent events and comorbidities
in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP),
and little is known on the role of possible predisposing factors, dietary, and lifestyle
habits, on the onset and progression of the disease. We used the data from a web‐based
database on Italian patients with CIDP to determine the frequency of antecedent events
and comorbidities and the possible role of predisposing factors including lifestyle
and dietary habits and exposure to toxic agents, using a structured questionnaire.
Partners of patients served as controls. Impairment was evaluated using the MRC sumscore
and disability with INCAT and R‐ODS scales. Logistic regression was used to calculate
odds ratio (OR) with 95% confidence interval (CI) for the risk of CIDP. Sex and disease‐duration
were included as covariates. By February‐2017, 360 patients were enrolled, with complete
data on 340 patients for antecedent events and comorbidities and 295 patients and
273 controls for lifestyle habits. Ninety‐two patients (27%) reported an antecedent
event, mostly infection or vaccination (20%). One or more comorbidity were present
in 71% of the patients including hypertension (35.5%), thyroid disorders (17%) and
diabetes (12.6%) and in 53% influenced the choice of initial therapy. Exposure to
toxic environmental agents (odds ratio [OR] = 2.55; 95% CI, 1.42‐4.55), cigarette
smoke (OR = 2.02; 95% CI, 1.4‐2.93), and dietary supplements (OR = 1.97; 95% CI, 1.08‐3.58)
were associated with a higher risk of CIDP while rice consumption was associated with
a reduced risk (OR = 0.47; 95% CI, 0.25‐0.87). Concerning disease severity, more severely
affected patients more frequently consumed raw‐meat (OR = 2.19; 95% CI, 1.05‐4.58)
and white meat (OR = 1.65; 95% CI, 1.03‐2.63), while rice (OR = 0.42; 95% CI, 0.20‐0.92)
and soft drink consumption (OR = 0.57; 95% CI, 0.36‐0.93) and physical activity were
associated with lower disability (OR = 0.47; 95% CI, 0.29‐0.77). This study confirms
that comorbidities are frequent in patients with CIDP and often influence the choice
of initial therapy. In addition preliminary data show that toxic exposure and some
lifestyle and dietary habits may influence the onset and progression of CIDP.
CONDUCTION BLOCKS AND PARESIS INDUCED BY PASSIVE TRANSFER OF ANTI‐CONTACTIN‐1 IGG
OF PATIENTS WITH CIDP
Doppler K
1, Schuster Y1, Weishaupt A1, Sommer C1.
1Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
Autoantibodies against the paranodal protein contactin‐1 have recently been described
in patients with CIDP. In most patients, autoantibodies of the IgG4 subclass are predominant
and are supposed to be pathogenic. The role of IgG3 anti‐contactin‐1 is so far unclear.
In the present study, IgG of three different patients, one with IgG3 anti‐contactin‐1,
one with a low titer of IgG4 anti‐contactin‐1 and one with a high titer of IgG4 anti‐contactin‐1,
and of controls were injected into the sciatic nerves of Lewis rats. Nerve conduction
studies of the injected nerve and motor and sensory testing were performed before
and after injection.
Conduction blocks and motor deficits were detectable in the two patients with high
titers of IgG3 and IgG4, not in the patient with low titers. The percentage of conduction
blocks was 83.3% in rats injected with IgG of the IgG3 patient and 35% in those injected
with IgG4. Motor deficits were detectable in both patients with conduction blocks
but were most apparent in the patient injected with IgG of the IgG3 patient. No differences
in sensory testing were observed. Conduction blocks and motor deficits improved after
five days and were normal after seven to eight days.
Our data give the first evidence of pathogenicity of IgG3 anti‐contactin‐1 autoantibodies,
not only IgG4. IgG of the IgG3 patient induced a more severe clinical and electrophysiological
phenotype compared to the IgG4 patient. Remarkably, this reflected the clinical phenotype
of the patients, as the IgG3 patients showed an acute‐onset of sensorimotor symptoms
at the time of blood withdrawal whereas the IgG4 patient presented with a more chronic
course of disease.
NODES OF RANVIER IN SKIN BIOPSIES OF PATIENTS WITH DIABETES MELLITUS
Doppler K1, Frank F1, Koschker A‐C2, Reiners K1, Sommer C
1.
1Department of Neurology, University Hospital Würzburg, Würzburg, Germany; 2Endocrinology
and Diabetes Unit, Department of Medicine I, University Hospital Würzburg, Würzburg,
Germany.
Axoglial dysjunction and paranodal demyelination have been discussed as potential
mechanisms of nerve fiber damage in diabetic neuropathy. Studies on human tissue are
limited, as nerve biopsies are invasive and only rarely performed in patients with
confirmed diabetic neuropathy. Skin biopsy has recently been suggested as a good tool
to analyze paranodal and nodal changes of myelinated fibers. In the present study,
we analyzed the paranodal and nodal region in myelinated fibers of skin biopsies of
35 patients with diabetic neuropathy, 17 patients with diabetes mellitus without neuropathy,
and 30 normal controls. Immunofluorescence of skin sections with antibodies against
Caspr, neurofascin, sodium channels and myelin basic protein was performed to assess
paranodal/nodal architecture, segmental demyelination and myelinated nerve fibers.
Staining with antibodies against protein gene product 9.5 was used to quantify unmyelinated
nerve fibers. We found an increase of elongated Ranvier nodes and a dispersion of
neurofascin at the distal leg in patients with diabetes mellitus with and without
neuropathy and at the finger in patients with diabetic neuropathy. An increased dispersion
of Caspr was only found in biopsies of the finger in patients with diabetic neuropathy.
Our data show that skin biopsy is an appropriate tool to analyze nodes of Ranvier
in patients with diabetes mellitus. Structural nodal changes are detectable in diabetic
neuropathy, and even in diabetic patients without neuropathy.
EGOS DID NOT HAVE A GOOD CAPACITY TO PROGNOSIS IN GBS IN RIO GRANDE DO NORTE, BRAZIL
Dourado ME
1, Fernandes U1, Vital AL1, Ramos E1, Urbano JC1, Sena A1, Queiroz JW1, Jeronimo SMB1.
1Federal University of Rio Grande do Norte, Natal, Brazil.
The Erasmus GBS outcome score (EGOS) is a validated prognostic model that uses acute
phase and easy‐to‐obtain clinical characteristics to determine outcome at 6 months
in patients with GBS. This study aims to assess the validity of EGOS in Rio Grande
do Norte, Brazil, and to compare with another European study. Data collected prospectively
from a cohort of 324 patients with GBS of Rio Grande do Norte, Brazil, between June
1994 and August 2016, was assessed. Ninety patients were excluded for missing data
or diagnoses of Miller Fisher Syndrome and atypical forms of GBS. To calculate the
EGOS, the GBS disability score was assessed in the second week of disease and at 6
months. To compare this study with the European one in independent group proportions,
we used the Student's t‐test, being considered statistically significant p<0,005.
The 234 patients included were divided in four groups based on EGOS. Thus, 21 patients
had EGOS between 1 and 3; 89 had EGOS between 3.5 and 4.5; 93 had EGOS 5 and 31 had
EGOS between 5.5 and 7. In the first, second, third and fourth group, 0 (0%), 3 (3.4%),
10 (10.8%) and 6 (19.4%) of the patients were unable to walk independently after six
months of the disease, respectively. Overall, of the 234 patients analyzed, 19 (8.1%)
had poor outcomes in this study. In the European paper, based on the same group division,
1 of 193 (0.5%), 16 of 226 (7%), 43 of 161 (27%) and 94 of 182 (52%) were unable to
walk independently. Comparing both studies, the patients of this study were younger,
more seriously ill in the first weeks and with more sensitive deficits. There were
no difference relative to sex, cranial nerves deficits and presence of anti‐gangliosides
antibodies. Using the Student's t‐test for ability to walk after 6 months according
to EGOS stratification, we achieve in the first group p=0.1629; in the second p=0.0784;
in the third p=0.0004; and in the fourth p<0.0001.The EGOS did not have a good capacity
to predict the ability to walk after 6 months of GBS in Rio Grande do Norte, Brazil.
HIGH INCIDENCE OF GUILLAIN‐BARRÉ SYNDROME AFTER ZIKA VIRUS INFECTION IN THE STATE
RIO GRANDE DO NORTE, IN NORTHEAST BRAZIL
Dourado ME
1, Fernandes U1, Vital AL1, Ramos E1, Urbano JC1, Sena A1, Fraiman PHA1,Luz K1, Queiroz
JW1, Jeronimo SMB1
. Federal University of Rio Grande do Norte, Natal, Brazil.
Historically, Guillain‐Barré syndrome (GBS) epidemics are rarely seen. Between 1994
and 2014, we treated and followed 264 cases of GBS in the state of Rio Grande do Norte
with a yearly incidence of 0.3/100,000. No seasonality was observed. The mean age
of the patients was 27 years (range, 1 – 83), with 50% of the cases younger than 20
years. Demyelinating variant was the most frequent subtype of GBS. In March 2015,
the first report of autochthonous transmission of Zika Virus (ZIKV) was determined
in Natal, Brazil. Later that month, we documented an increase in incidence of GBS
in Natal, Brazil. The incidence in 2015 was of 0.69/100.000. Of the 38 cases of GBS
diagnosed in 2015, 24 were diagnosed from March through May, which coincided with
the outbreak of ZIKV in Natal, Brazil. Eighteen patients (75% of the 24 cases) had
a history of rash and fever prior to onset of GBS symptoms, with the median age of
45 years (range, 15–69). The electroneuromyography studies of these 18 patients indicated
that 16 (88.9%) had acute inflammatory demyelinating polyneuropathy, 1 (5.5%) had
acute motor axonal neuropathy, and 1 (5.55%) was inconclusive. The mean time from
onset of ZIKV infection symptoms to onset of the GBS were 7 days (range, 3–30). The
mean time of NADIR was 7 days (ranged, 4–25). Cranial neuropathies were present in
12 patients (66.66%). Nine patients were bedridden (50%) and 3 (16.66%) required mechanical
ventilation. The mean protein content of the central spinal fluid was 0.77 g/L, with
the white blood cell count below 5/mm in all patients. They were all treated with
intravenous IgEV. They all improved quickly. Anti‐GM1 was negative in all patients.
RT‐PCR was negative for Dengue, Chikungunya and Zika. Serum MAC‐ELISA IgM for ZIKA
and Dengue was made in 11 patients and it had 100% of positivity. PRNT for Zika and
Dengue had 100% positivity. In summary, we report a geographically and temporally
defined cluster of GBS associated with an outbreak of acute rash in the state of Rio
Grande do Norte, Brazil.
CAPILLARY DYSFUNCTION IN THE DEVELOPMENT OF DIABETIC PERIPHERAL NEUROPATHY IN ANIMAL
MODELS
Dudele A
1,2, Gutiérrez Jiménez E1, Iversen NK1, Frische S3, Jensen TS2,4, Østergaard L1,5.
1Center for Functionally Integrative Neuroscience and MINDLab, Aarhus University Hospital,
Aarhus, Denmark; 2International Diabetic Neuropathy Consortium, Aarhus University,
Aarhus, Denmark; 3Department of Biomedicine, Aarhus University, Aarhus, Denmark; 4The
Danish Pain Research Centre, Aarhus University Hospital, Aarhus, Denmark; 5Department
of Neuroradiology, Aarhus University Hospital, Aarhus, Denmark.
As the prevalence of diabetes mellitus continues to increase worldwide, diabetic complications
represent a growing burden to patients and society. Distal symmetrical polyneuropathy
(DSP) is a common complication that affects up to 30% of diabetic patients. DSP reduces
patient quality of life due to chronic pain, ulcerations, and may lead to lower extremity
amputations. Despite its high prevalence, the mechanisms underlying diabetic DSP are
poorly understood and several mechanisms are believed to play a role. We hypothesize
that diabetic DSP arises from microvascular complications characteristic to diabetes.
Specifically, capillary dysfunction ‐ disturbances in capillary flow patterns – is
a likely candidate to explain development of DSP, as it can limit oxygen and nutrient
delivery to nervous tissue, causing nerve dysfunction and damage, and thus development
of DSP. We will study this hypothesis utilizing the state‐of‐the‐art blood flow imaging
techniques to visualize and quantify endoneureal blood flow and then link these findings
with measures of DSP (e.g. nerve conduction velocity; intra‐epidermal nerve fibre
density) in animal models. We will include several animal models of diabetic DSP caused
by either type 1 or type 2 diabetes. Two photon microscopy and optical coherence tomography
allow visualisation and quantification of capillary transit times and blood flow within
peripheral nerves at high resolution. We hypothesise that changes in blood flow patterns
and subsequent impairment of nutrient and oxygen delivery to nervous tissue precede
the onset of diabetic DSP. If our experiments support this prediction, we will attempt
to develop interventions that improve capillary blood flow to prevent or delay the
development of DSP.
TWO CASES OF IVIG RESPONSIVE INFANTILE ONSET AXONAL POLYNEUROPATHY
Duman O
1, Saracoglu M1, Haspolat S1, Bozkurt O1.
1Department of Child Neurology, Akdeniz University Hospital, Antalya, Turkey.
Axonal polyneuropathies are very heterogeneous group of diseases which are very rarely
seen during infantile age. Some of them may be accompanied by developmental retardation,
severe muscle weakness and progressive course. We aimed to present two cases of axonal
sensorymotor neuropathy with infantile onset and atypical course. Our 1‐year‐old boy
patient was admitted to our clinic for progressive gait loss since one month. He was
the first offspring of consanguineous parents with normal prenatal and natal history.
Electromyography revealed axonal sensorymotor polyneuropathy. Metabolic and cerebrospinal
fluid (CSF) examinations for etiology were all normal. Brain and spinal magnetic resonance
imaging (MRI) were normal. He had partial benefit from oral steroid treatment. In
the course of disease along with four neuropathy attacks he had significant benefit
from serial intravenous immunoglobulin treatments in two years clinical course. A
6 month‐old girl who is the first offspring of nonconsanguineous parents was admitted
to the clinic for acute tetraparesis. Axial sensorymotor polyneuropathy was detected
in the electromyography. Metabolic and cerebrospinal fluid (CSF) examinations were
normal. She had three more acute polyneuropathy attacks during IVIG cessation period.
Both patients revealed with serial immunoglobulin treatments but unresponsive to riboflavine
treatment. We aimed to discuss our rarely seen and the pathogenesis is not completely
understood cases' course. Serial IVIG treatment may be helpfull for such patients'
treatment.
GENOTYPIC AND PHENOTYPIC PRESENTATION OF TRANSTHYRETIN‐RELATED FAMILIAL AMYLOID POLYNEUROPATHY
(TTR‐FAP) IN TURKEY
Durmuş H
1, Çakar A1, Sahin E1, Matur Z2, Poda M3, Altunoğlu U4, Oflazer‐Serdaroğlu P1, Deymeer
F1, Parman Y1.
1Neurology Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey;
2Neurology Department, Medical Faculty, Istanbul Bilim University, Istanbul, Turkey;
3Genetics Department, Institute of Experimental Medical Research, Istanbul University,
Istanbul, Turkey; 4Department of Medical Genetics, Istanbul Medical Faculty, Istanbul
University, Istanbul, Turkey.
Transthyretin‐related familial amyloid polyneuropathy (TTR‐FAP) is an autosomal dominantly
inherited disorder caused by mutations of the transthyretin (TTR) gene. The mutant
amyloidogenic transthyretin protein causes the systemic accumulation of amyloid fibrils
that result in organ dysfunction. TTR‐associated FAP is a progressive and fatal disease,
if left untreated, and should be considered in the differential diagnosis of any person
presenting with a progressive polyneuropathy, particularly with accompanying autonomic
involvement.
The clinical, electrophysiological, histopathological, and genetic characteristics
of 21 patients from Turkey (6 female, 15 male) from eleven families with polyneuropathy
and mutations in TTR were evaluated. Two patients had no family history of TTR‐FAP
and were considered as sporadic cases, and the remainders were familial cases displaying
an autosomal dominant inheritance pattern. Sequence analysis of the TTR gene revealed
five mutations (p.Val30Met, p.Glu89Gln, p.Gly53Glu, p.Glu54Gly and p.Gly47Glu). Most
common mutation was p.Val30Met (in 6 unrelated families). Mean age at disease onset
was 41.4±14.2 years (range 21–66 years). The most commonly reported initial complaint
was paresthesia in the feet (asymmetric in three patients). Four patients (2 male)
with the p.Glu89Gln mutation presented with carpal tunnel syndrome. Two patients with
the p.Gly53Glu mutation showed episodes of dysarthria and hemiparesis, consistent
with this genotype. Seven patients died during the follow‐up period as a result of
systemic involvement.
This study suggests that our cohort of TTR‐FAP patients from Turkey exhibits clinical
and genetic heterogeneity.
CUTANEOUS NERVE FIBER ANALYSIS AS A BIOMARKER IN TRANSTHYRETIN FAMILIAL AMYLOID POLYNEUROPATHY
Ebenezer GJ
1, Liu Y1, Judge DP2, Cunningham K1, Truelove S3, Carter ND1, Sebastian B1, Byrnes
K1, Polydefkis M1.
1Department of Neurology, Johns Hopkins University, Baltimore, MD, USA; 2Division
of Cardiology, Johns Hopkins University, Baltimore, MD, USA; 3Department of Epidemiology,
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Effect of amyloid deposition on cutaneous nerves was assessed in subjects with pathogenic
TTR variants and control subjects. Three groups of 20 subjects each including TTR‐FAP
patients, age/gender‐matched healthy subjects and disease controls as well as 10 TTR
mutation carriers without neuropathy (TTR‐noPN) and 2 with AL‐amyloid underwent neurological
examination and 3mm skin biopsies. 50 micron sections were stained with anti‐PGP9.5,
anti‐TTR and Congo red. Amyloid burden with ImageJ, intraepidermal (IENFD) sweat gland
(SGNFD) and pilomotor densities (PMNFD) measured and correlations between amyloid
burden, fiber subtype, Neuropathy Impairment Score‐LL (NIS‐LL) and NIS sensory subscore
were evaluated. IENFD, SGNFD, and PMNFD were all significantly reduced in TTR‐FAP
patients vs. healthy controls while mutation carriers had intermediate reductions.
Lower nerve fiber densities were associated with NIS‐LL (p<0.001). Congo red staining
revealed brilliant red amyloid deposits with apple‐green birefringence within dermal
collagen, sweat glands, and arrector pili muscles. Amyloid infiltration was observed
in the endoneurium and perineurium of small fiber sensory and autonomic nerves that
innervate sweat glands and arrector pili muscles. Cutaneous amyloid deposition was
detected in 70% of TTR‐FAP and not in healthy or disease controls subjects. Both AL
and 2/10 TTR‐noPN subjects were Congo red positive. Amyloid burden was inversely correlated
with IENF (p<0.001, r=−0.63) SGNF (p<0.001, r=−0.67), PMNF (p=0.005, r=−0.50) distal
leg densities, and correlated with NIS‐LL (p=0.001, r=0.57) and NIS sensory subscore
(p=0.004, r=0.54). Wild‐type TTR staining was less prominent in pathogenic TTR carriers.
The diagnostic sensitivity and specificity to detect amyloid in skin were 70% and
100% in TTR‐FAP. The repeat measurement of the amyloid burden from the same section
with ImageJ was r2=0.81, p<0.0001 and different sections from the same biopsy was
r2=0.91 and p<0.01. We conclude that endoneurial amyloid contributes to sensory and
autonomic nerve injury. Amyloid burden correlated strongly with sensory/autonomic
axon densities and NIS‐LL. Skin punches offer a convenient alternative to establishing
a tissue diagnosis. Amyloid burden is an attractive biomarker marker for TTR‐FAP and
treatment effect.
The study was supported through a grant from Pfizer.
OBESITY ATTENUATES EPIDERMAL NERVE FIBERS IN THE DISTAL LIMB
Ebenezer GJ
1, Truelove S2, Polydefkis M1.
1Department of Neurology, Johns Hopkins University, Baltimore, MD, USA; 2Department
of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
We investigated differences of unmyelinated sensory nerve fibers in the distal limb
among 45 healthy‐weight subjects (BMI < 25kg/m2) and 72 overweight/obese subjects
(BMI ≥ 25kg/m2), aged 20–69 years. Subjects underwent neurological examination and
3mm skin punches from distal leg (DL), thigh (DT), and proximal thigh (PT) sites,
from which 50 micron sections were stained with anti‐PGP9.5 antibody; intraepidermal
nerve fiber density (IENFD; fibers/mm) and epidermal thickness were assessed. A second
DL biopsy was processed for electron microscopic examination and both thick and thin
sections were examined for ultrastructural changes. Multivariable linear regression
models were used to assess the effect of age, gender, height and weight. After controlling
for height, age, and obesity, females were found to have lower distal leg IENFD (−2.6;
p=0.02). Increasing age and height were significantly associated with decreasing DL
IENFD, with decreases of −1.6 fibers/mm per 10 years (p<.001) and −2.55 fibers/mm
per 10cm (p<0.001), respectively. Even after controlling for height, being overweight/obese
was associated with reduced DL IENFD, with 2.5 fibers/mm lower DL ENFD than healthy‐weight
individuals (p=.01). These findings remained consistent across distal thigh and proximal
thigh ENFD, though not all associations remained significant. The epidermis was thicker
in obese subjects across the lower limb, most pronounced at the distal leg (µm, mean±
SD, Healthy‐ DL:101±14.76, DT: 99.0 ± 10.3, PT: 107.7±12.2, Obese‐ DL:129.1± 48.3,
DT:117± 33.0, PT:116.4±20.2). Under EM very few intact dermal nerve bundles were identified
at the proximal thigh sites. The atrophic and degenerating axons were seen with perineurial
infiltration by dense collagen in obsess/overweight subjects but not age/gender matched
controls. Obesity further accelerates attenuation of epidermal nerve fibers across
the lower limb even after controlling for other associated factors.
AXONAL NEUROPATHIES DUE TO MUTATIONS IN SMALL HEAT SHOCK PROTEINS: CLINICAL, GENETIC
AND FUNCTIONAL INSIGHTS INTO NOVEL MUTATIONS
Echaniz‐Laguna A
1, Geuens T2, Petiot P3, Péréon Y4, Adriaenssens E2, Haidar M2, Capponi S2, Maisonobe
T5, Fournier E5, Dubourg O5, Degos B5, Salachas F5, Lenglet T5, Eymard B5, Delmont
E6, Pouget J7, Juntas Morales R8, Goizet C9, Latour P3, Timmerman V2, Stojkovic T5.
1Strasbourg University Hospital, Strasbourg, France; 2Peripheral Neuropathy Group,
VIB Department of Molecular Genetics and Institute Born Bunge, University of Antwerp,
Antwerpen, Belgium; 3Lyon University Hospital, Lyon, France; 4Nantes University Hospital,
Nantes, France; 5Hôpital de la Pitié‐Salpétrière, Paris, France; 6Nice University
Hospital, Nice, France; 7Marseille University Hospital, Marseille, France; 8Montpellier
University Hospital, Montpellier, France; 9Bordeaux University Hospital, Bordeaux,
France.
In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy
caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate
the functional consequences of newly discovered variants. Among 510 unrelated patients
with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510;
5.5%) and HSPB8 (4 index patients/510; 0.8%) genes. Patients have slowly progressive
distal (100%) and proximal (13%) weakness in lower limbs, mild lower limbs sensory
involvement (31%), foot deformities (73%), progressive distal upper limb weakness
(29%), mildly raised serum creatine kinase levels (100%) and central nervous system
involvement (9%). We found a broad range of disease onset with some patients presenting
with foot drop at the age of 5 years, and others presenting symptoms only after 60
years. Disease progression was slow in all patients, and even with a disease duration
of more than 40 years patients were still able to walk. None of our patients were
wheelchair dependent. Muscle pathology, nerve pathology and electrophysiology showed
in all cases a slowly progressive, mostly symmetrical and predominantly distal motor
axonal neuropathy. Mild sensory involvement was observed upon nerve conduction studies,
mostly the lower limbs, in 42% of cases. We identified 12 HSPB1 and 4 HSPB8 mutations,
including respectively 5 and 3 not previously reported. Transmission was either dominant
(78%), recessive (3%) or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser,
Gly53Asp, Gln128Arg) cause hyperphosphorylation of neurofilaments, while the C‐terminal
mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs,
Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations
in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that
HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy.
Mutations lead to diverse functional outcomes further demonstrating the pleotropic
character of small heat shock proteins.
INTERNATIONAL STANDARD FOR CIDP REGISTRY AND BIOBANK, RESULTS OF THE 231ST ENMC CONSENSUS
MEETING
Eftimov F
1, Querol L2, Rajabally YA3 and on behalf of all participants of the 231st ENMC workshop.
1Academic Medical Center, Amsterdam, The Netherlands; 2Hospital de la Santa Creu i
Sant Pau, Universitat Autònoma de Barcelona, Spain; 3Aston University, Birmingham,
UK.
Although chronic inflammatory demyelinating polyneuropathy (CIDP) is a treatable neuropathy
further research is urgently needed to define the diagnostic clinical and electrophysiological
boundaries of CIDP and its subtypes, and to define the role of biomarkers in supporting
the diagnosis, monitoring disease activity and predicting response to treatment and
outcome. In recent years, several national registries and biobanks have been developed
to enable systematic data collection in CIDP. An international registry with large
number of patients is needed to allow answering many important questions and develop
validated prognostic models to predict outcome in individual patients with CIDP. At
the Inflammatory Neuropathy Consortium (INC) Meeting in 2016, the INC members agreed
that a European Neuromuscular Center (ENMC) workshop would be the ideal setting to
reach a consensus on the infrastructure of database and biobanks. The 231st ENMC Workshop
will take place on May 12–14, 2017 with participants representing 12 different countries.
Primary objective of the workshop is to reach a consensus on inclusion and exclusion
criteria, core sets and recommended sets of clinical data, diagnostic data and follow‐up
points and a manual of operations for collection of biomaterials. A secondary objective
is to construct an infrastructure to allow sharing data between different databases
and biomaterials. Conclusions of the consensus meeting and outline of further perspectives
will be presented at the Peripheral Nerve Society Meeting in 2017.
DEVELOPMENT AND PILOT TESTING OF A FUNCTIONAL OUTCOME MEASURE FOR ADULTS WITH CHARCOT‐MARIE‐TOOTH
NEUROPATHY (CMT‐FOM)
Eichinger KJ1, Burns J2, Cornett K2, Bacon C3, Shepherd M4, Mountain J1, Sowden J1,
Shy R5, Shy ME3, Herrmann DN
1.
1Department of Neurology, University of Rochester, Rochester, NY, USA; 2University
of Sydney & Children's Hospital at Westmead, Sydney Australia; 3Department of Neurology,
Carver College of Medicine, University of Iowa, Iowa City, IA, USA; 4Department of
Physical Therapy, Carver College of Medicine, University of Iowa, Iowa City, IA, USA;
5Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City,
IA, USA.
Clinical outcome assessments that measure functional ability are important endpoints
for clinical trials. Dr. Burns has led the development/validation of a functional
outcome assessment (CMTPedS) for individuals with Charcot Marie Tooth Disease (CMT)
ages 3–20 years in the INC RDCRN. The CMTPedS is reliable and sensitive to change.
However a validated Functional Outcome Measure (FOM) for adults with CMT is needed.
Our data in 18–21 year‐olds indicated that the CMTPedS could be modified for adult
use. However, some items of the CMTPedS (e.g. balance beam and jumping) have floor
effects in adults with CMT. We have developed an adult CMT‐FOM modeled on the CMTPedS,
and refined based on literature review, patient interviews, a large‐scale CMT patient
survey and expert opinion. The CMT‐FOM is a performance‐based Scale comprising 13
items that are combined to form a composite score to quantify functional ability of
adults with CMT. The CMT‐FOM shares 9 items with the CMTPedS. Four items were added
to measure functional abilities relevant to adults (sit to stand, 10 meter walk/run,
stair climb, and timed up and go test). The CMT‐FOM scoring mirrors the CMTPedS. To
generate a score ranging from 0–52, raw item scores are converted to z scores, based
on age‐ and sex‐matched normative reference values form the 1000 Norms Project and
categorized to a 0–4 Likert along a continuum of impairment levels. We have conducted
a pilot study of the CMT‐FOM in adults with CMT1A (9 male, 12 female, age 39.7 ± 16.1
yrs) of differing severity (CMT Exam score (CMTES) range 1–20). The CMT‐FOM is feasible,
individuals were able to complete all items, and takes 35 minutes to perform. The
mean CMT‐FOM score was 22.0 ± 8.2 (range 11–37). Concurrent validity of the CMT‐FOM
is supported by an association with the CMTES (r = 0.51). The overall score did not
demonstrate floor or ceiling effects. In summary the adult CMT‐FOM is well‐tolerated
and captures upper and lower limb strength, dexterity, balance, speed, ambulation
and endurance. The CMT‐FOM requires validation in a large longitudinal cohort, prior
to application in clinical trials.
FUNCTIONAL IMPLICATIONS OF HAND IMPAIRMENT IN PEDIATRIC CHARCOT‐MARIE‐TOOTH
Estilow T
1, Glanzman AM1, Burns J2
, Cornett KMD2, Menezes MP2, Shy R3, Moroni I4, Foscan M4, Pagliano E4, Pareyson D4,
Laurà M5, Bhandari T6, Muntoni F6, Reilly MM5, Finkel RS7, Sowden J8, Eichinger K8,
Herrmann DN8, Shy ME9, Yum SW10, Ramchandren S11 and on behalf of the Inherited Neuropathies
Consortium.
1The Children's Hospital of Philadelphia, Philadelphia, PA, USA; 2University of Sydney
& Children's Hospital at Westmead, Sydney, Australia; 3Department of Pediatrics, Carver
College of Medicine, University of Iowa, Iowa City, IA, USA; 4IRCCS Foundation, Carlo
Besta Neurological Institute, Milan, Italy; 5MRC Centre for Neuromuscular Diseases,
UCL Institute of Neurology, Queen Square, London, UK; 6UCL Institute of Child Health
& Great Ormond Street Hospital, London, UK; 7Neuromuscular Program, Division of Neurology,
Nemours Children's Hospital, Orlando, USA; 8Department of Neurology, University of
Rochester, Rochester, NY, USA; 9Department of Neurology, Carver College of Medicine,
University of Iowa, Iowa City, IA, USA; 10Department of Neurology, The Children's
Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania,
PA, USA; 11Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
CMT is associated with progressive impairment of the hands. Reducing this impairment
by treating children who are in the early stages of the disease is crucial. Studies
assessing measures of CMT hand function in children and their associations with patient‐reported
outcomes are lacking. We analyzed the upper extremity items from the CMT Pediatric
Scale (CMTPedS) and Pediatric CMT Quality of Life Scale (pCMT‐QOL) in 179 children
ages 8–18 years enrolled in the Inherited Neuropathies Consortium, to explore the
relationships between measures of hand function (impairment, activity, and activities
of daily living), and patient‐reported outcomes. Weak grasp (67%), hand pain (30%),
and tremor (40%) were prevalent impairments. Performance on activity level tasks,
the Nine Hole Peg Test (9HPT) and Functional Dexterity Test (FDT), were impaired in
68% and 78% of the cases, respectively. Patients reported difficulty “sometimes” to
“always” in opening a jar/lid (46%), zipping/buttoning (20%), writing (19%), carrying
a plate without spilling food (17%) and putting on shoes (16%). Patients reporting
tremor showed significant differences on the 9HPT (p=.04). Grip strength was shown
to have a moderately significant correlation with performance on the FDT (r=.50; p<.0001).
Stepwise multiple linear regression showed that grip strength (Beta=−.01; p<.001),
hand pain (Beta=.86; p<.001) and FDT (Beta .01; p<.001) were predictive of ability
to open a jar (adjusted R2=.35; p<.001. Grip strength (Beta=−.003; p<.001), and FDT
(Beta .01; p<.001) were predictive of ability to carry plate without spillage (adjusted
R2=.19; p<.001). Grip strength (Beta=−.003; p<.01), 9HPT (Beta=.01; p<.05) and FDT
(Beta .01; p<.001) were predictive of ability to put on shoes (adjusted R2=.23; p<.001).
Hand pain (Beta=.39; p<.001) and FDT (Beta .02; p<.001) were predictive of ability
to zip/button (adjusted R2=.22; p<.001). Hand pain (Beta=.61; p<.001) and 9HPT (Beta
.01; p<.05) were predictive of ability to use a pen/pencil (adjusted R2=.09; p<.001).
Children with CMT present with frequent limitations in ADL performance impacting QOL.
The upper limb measures of the CMTPedS are associated with hand performance and interventions
to improve grip strength and reduce pain should be investigated further with respect
to their impact on improving function, and ultimately QOL.
MRI QUANTIFICATION OF INTRAMUSCULAR FAT ACCUMULATION IN CMT1A: FOUR YEAR FOLLOW UP
DATA
Evans ME1, Morrow JM
1, Wastling S2, Sinclair CDJ2, Fischmann A3, Shah S2, Emira AK2, Hanna MG1, Yousry
TA2, Thornton JS2, Reilly MM1.
1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK; 2Neuroradiological
Academic Unit, UCL Institute of Neurology, London, UK; 3University of Basel Hospital,
Basel, Switzerland.
Responsive outcome measures are needed in Charcot‐Marie‐Tooth disease (CMT) to allow
adequately powered clinical trials to test novel therapeutics. We have shown high
responsiveness of MRI quantified intramuscular fat accumulation in calf muscles of
CMT1A patients over 12 months. The aim of the present study was to assess the responsiveness
and longitudinal validity of quantitative MRI over a 4 year follow‐up period. We undertook
two further sets of quantitative MRI, myometric and clinical assessments in the original
MRC Centre CMT1A quantitative MRI cohort. MRI sequences included fat quantification
using the 3 point Dixon fat‐water separation method, T2 quantification and magnetisation
transfer imaging. Of the 20 patients with genetically confirmed CMT1A were assessed
at baseline (11 male, mean age 42.8 ± 13.9 years), 17 underwent repeat assessments
a median on 12 months (data already published), 14 underwent repeat assessments at
a median of 27 months, and 11 underwent a final assessment at a median of 49 months.
The primary outcome measure currently being analysed is mean calf muscle fat fraction
at a single axial slice a fixed distance distal to the knee joint. Results of this
analysis and correlation with clinical measures will be presented at the Peripheral
Nerve Society meeting.
ULNAR NERVE ENTRAPMENT IN MASSIVE MUSCLE FIBROSIS FOLLOWING INTRAMUSCULAR ANABOLIC
STEROID INJECTIONS: A CASE REPORT
Fainmesser Y1, Dori A2,3, Drory VE
1,3.
1Department of Neurology and Neuromuscular Service, Tel‐Aviv Medical Center, Tel‐Aviv,
Israel; 2Department of Neurology, Sheba Medical Center, Ramat Gan, Israel; 3Sackler
Faculty of Medicine, Tel Aviv University, Israel.
The use of anabolic drugs by those who wish to increase lean body mass is widespread
and not well supervised medically. A 36 years old man was referred for evaluation
of a slowly progressive sensory and motor disturbance in the distribution of the left
ulnar nerve. His symptoms began 10 months after repeated self‐injections of anabolic
steroids and vitamin E into the biceps and triceps brachii muscles bilaterally. His
examination showed increased muscle mass of the injected muscles with a hard‐rubbery
consistency, atrophy and weakness of left interossei, mild weakness of the bilateral
biceps brachii and sensory loss in an ulnar nerve distribution. Nerve conduction studies
showed a left ulnar neuropathy with reduced motor and sensory response amplitudes
and denervation in the left first dorsal interosseus, as well as mild myopathic changes
with significantly reduced insertional activity in both biceps muscles. MRI of the
soft tissues of the arms showed massive fibrosis and infiltration of fat in the arm
muscles compressing the ulnar and median nerves on the left. Neurolysis of the left
ulnar nerve was performed, and the ulnar nerve was found enclosed in a fibrotic mass
throughout the entire length of the upper arm. The brachial artery and the median
nerve were similarly enclosed in fibrotic tissue and were released. A biopsy of the
affected muscles showed muscle necrosis and fibrosis. The patient was treated with
physiotherapy and losartan with only mild improvement in the consistency of the muscles,
but without clinical improvement in ulnar nerve function, and worsening of nerve conduction.
This case illustrates severe peripheral nerve damage due to entrapment in massive
muscle fibrosis following improper intramuscular injection of anabolic steroids for
cosmetic purposes.
PHENOTYPICAL AND GENOTYPICAL CROSSROADS BETWEEN INHERITED DISEASES OF NERVE AND MUSCLE:
TWO EXAMPLES OF VCP AND GNE‐RELATED DISORDERS
Fabrizi GM
1, Testi S1, Høyer H2, Braathen GJ2, Squintani G3, Bertolasi L1, Ferrarini M1, Taioli
F1, Cabrini I1, Pancheri E1, Cavallaro T1, Tonin P1.
1Department of Neuroscience, Biomedicine and Movement, University of Verona and Department
of Neuroscience, AOUI Verona, Italy; 2Section of Medical Genetics, Department of Laboratory
Medicine, Telemark Hospital, Skien, Norway.
Inherited diseases of nerve and muscle may overlap phenotypically or coexists as facets
of the same disorder. Two families whose probands were initially diagnosed with a
lower motor‐neuron (LMN) syndrome and a hereditary distal motor neuropathy (dHMN)
turned out to represent a VCP (valosin‐containing protein)‐related syndrome and a
GNE (UDP‐N‐acetylglucosamine 2‐epimerase/N‐acetylmannosamine kinase)‐related “distal
myopathy”. Both conditions shared the presence of rimmed vacuoles (RV) in muscle biopsies.
In family 1, the 61 year‐old male proband had a LMN syndrome manifesting at age 58
years (wasting/weakness, cramps, fasciculations of thigh muscles, later involving
the distal upper limbs). His 64 year‐old brother had lower limb weakness and diffuse
pain in bones/joints since age 54. The father was diagnosed with a “muscular dystrophy”
thirteen years before dying a 76 years; by age 69 years he had developed a behavioural
frontotemporal dementia (FTD). Electrodiagnosis (EDX) disclosed myopathic changes
with ongoing denervation together with a mild sensory‐motor axonal polyneuropathy
in the proband, and a chronic sensory‐motor axonal polyneuropathy in the brother.
MRI showed fatty replacement of weakened muscles in both siblings and diffuse changes
of bones consistent with Paget disease (PD) in the elder sibling. In family 2, a 32
year‐old African woman was affected by weakness and wasting starting at the distal
lower‐limb muscles at age 23 years and soon progressed proximally; parents were not
consanguineous and two sisters out of six siblings, deceased in their thirties for
post‐partum complications, had a similar disease. EDX mainly disclosed a neurogenic
process with ongoing denervation. Muscle biopsies from the three family‐1 patients
and from the family‐2 proband showed a myopathy with RV. Next‐generation sequencing
demonstrated a heterozygous c.277C>T change of VCP leading to a known pathogenic p.Arg93Cys
substitution in all family‐1 patients, and two compound heterozygous c.1441G>A and
c.1561G>A changes of GNE in the family‐2 proband leading to known p.Ala481Thr and
p.Ala521Thr substitutions.
VCP is known to cause autosomal dominant Amyotrophic Lateral Sclerosis‐14, Charcot‐Marie‐Tooth
disease type 2Y or Inclusion Body Myopathy (IBM) with PD and FTD (IBMPFD); GNE causes
the autosomal recessive Nonaka myopathy (alias IBM2). Both cases emphasize the clinical
and neurophysiological heterogeneity of those disorders.
VARIED PATTERN ON PLEXUS MRI IN CIDP WITHOUT EFNS PNS DEFINITE ELECTROPHYSIOLOGICAL
CRITERIA
Fargeot G
1, Vandendries C2, Labeyrie C1, Viala K3, Theaudin M1, Adams D1
. 1Neurologie, CRMR NNERF, APHP, Filnemus, CHU Bicêtre, Le Kremlin‐Bicêtre, France;
2Neuroradiologie, CRMR NNERF, APHP, Filnemus, CHU Bicêtre, Le Kremlin‐Bicêtre, France;
3Neurologie, Groupe Hospitalier Universitaire Pitié Salpêtrière, Paris, France.
The diagnosis of CIDP is often challenging, especially when electrophysiological signs
of demyelination are lacking. Plexus MRI has documented nerve abnormalities in small
series of typical CIDP but its contribution in patients with no electrophysiological
signs of demyelination remains to be proved. We report the results of plexus MRI in
a serie of patients suspect of having CIDP without EFNS PNS definite electrophysiological
criteria. We did a retrospective study of 44 patients consulting in Kremlin Bicetre
and Pitié Salpétrière hospital. Lumbar or brachial plexus MRI (or both) were performed
and we assessed nerve trophicity, T2‐STIR signal intensity and gadolinium enhancement
as well as the topography of abnormalities. A consensus diagnosis was made by a group
of experts (based on clinical data and other supportive criteria) and allowed us to
classified patients in "CIDP" or "other diagnosis". The practical contribution of
plexus MRI to the diagnostic algorithm has been studied. Diagnosis of CIDP was made
in 27 patients. MRI was abnormal in 67% of CIDP patients and showed nerve roots hypersignal/hypertrophy/enhancement
in respectively 66.7/55.6/25.9% of patients. The pattern of abnormalities was often
asymetrical (77.8%), diffuse (47.1%) or multifocal (41.2%). After unblinding, the
MRI confirmed the diagnosis of experts in 61.4% of patients and changed the diagnosis
in 20% of patients. Plexus MRI has shown to be useful in our serie to confirm the
diagnosis of experts or to modify it in 9 patients (20%) . The "classical" pattern
described in definite CIDP (diffuse nerve root hypertrophy and hypersignal) was documented
in 30% of our CIDP patients whereas less typical pattern (focal or multifocal abnormalities,
hypersignal without hypertrophy) was found in 37%. Plexus MRI seems usefull when facing
patients suspected of having CIDP when electrophysiological criteria are not met:
both symetrical diffuse or asymetrical multifocal patterns can be found and should
be always correlated to the clinical examination and other supportive criteria. The
specificity of such abnormalities remains to be studied.
MUTATIONS IN BAG3 CAUSE ADULT ONSET CHARCOT‐MARIE‐TOOTH DISEASE
Feely SME
1, Rebelo A2, Abreu L2, Tao F2, Bacon C1, Zuchner S2, Shy ME1.
1University of Iowa, Iowa City, IA, USA; 2Dr. John T. Macdonald Department of Human
Genetics and Hussman Institute for Human Genetics, Miller School of Medicine, University
of Miami, Miami, FL, USA.
Mutations in Bcle‐associated athanogene 3 (BAG3) have been shown to cause a distal
myofibrillar myopathy and cardiomyopathy that can severely affect children or only
affect adults depending upon the particular mutation. Children with severe cardiomyopathy
and myopathy have also developed axonal peripheral neuropathy, consistent with the
known localization of BAG3 in neurons as well as in muscle. We have identified two
large autosomal dominant families with adult onset Charcot‐Marie‐Tooth disease (CMT2)
with the identical novel missense mutation Pro209Ser, a codon previously shown to
cause severe or mild myopathy depending on the amino acid substitution. These families
expand the phenotypes caused by mutations in BAG3 to include CMT2 and provide an additional
example of adult onset CMT2 that may previously have been diagnosed as chronic idiopathic
axonal neuropathy (CIAP).
DUPLICATION OF MYELIN PROTEIN ZERO CAUSING EARLY ONSET CHARCOT‐MARIE‐TOOTH DISEASE
TYPE 1B
Feely SME
1, Saade D1, Shy ME1.
1Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Myelin Protein Zero (MPZ), expressed only by myelinating Schwann cells, has sequence
alterations that have previously been reported to cause demyelinating, intermediate,
and axonal forms of Charcot Marie Tooth (CMT) disease. We describe a rare duplication
in MPZ which is causing an early onset, demyelinating form of CMT in our patient.
Patient was a product of a normal pregnancy and delivery. Early milestones were delayed.
She began walking at 23 months of age. She was not able to keep up with her peers
and was the slowest runner. She started wearing SMOs at 3 years of age and AFOs by
11 years of age. She was diagnosed with scoliosis at 2 years of age and started wearing
a brace at 3 years. Her examination at 11 years of age showed that her FDI, APB, and
ADM were all 4/5 bilaterally. Weakness in her lower extremities included 4/5 foot
eversion and 3/5 great toe dorsi flexion. She had tight heel cords bilaterally. Pinprick
sensation was reduced throughout in her upper and lower extremities and absent at
her toes bilaterally. Vibration sensation with a Rydel tuning fork was absent at her
toes and ankles and reduced at her knees and fingers. Nerve conduction studies were
performed and revealed no responses in all sensory nerves tested with the exception
of the radial nerve which had normal latency and mildly slowed conduction velocity
(37 m/s). Prolonged latencies, demyelinating range slowing (between 13–16 m/s), and
low CMAP amplitudes in almost all segments of the median and ulnar motor nerves were
also observed. These findings were consistent with a hereditary sensorimotor demyelinating
polyneuropathy. She was diffusely areflexic and her total CMT Pediatric Score (CMTPeds)
was 34/44 which is in the severe range. Her CMT Neuropathy Score (CMTNS) was 14/36
in the moderate range. The duplication of MPZ has previously been identified as a
rare cause of CMT1B.
Inherited Neuropathy Consortium is part of the NIH Rare Diseases Clinical Research
Network (grant#1U54NS065712‐01).
EXTREME VARIABILITY IN DISEASE SEVERITY IN A FAMILY WITH A NOVEL EGR2 MUTATION
Feely SME
1, Saade D1, Shy ME1.
1Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Mutations in EGR2 cause a severe, demyelinating form of CMT, CMT1D. We describe a
novel mutation in EGR2 which led to extreme variability in severity in a family. Proband
was a 12 year old girl who was the product of a normal pregnancy and delivery. Early
milestones were on time. Problems with walking started at 2 years of age. At 2.5 she
was unable to use stairs, run, or jump. At 4 she was wearing bilateral AFOs. By 5
she was using a wheelchair and started breathing assist at night. She lost arm lift
but could still hold a pen. By 10 she could not ambulate independently and breathing
assist was required day/night. She lost the ability to write and developed a head
drop. By 12 years she could not sit up. On exam her head and neck muscles were 4/5.
Upper limbs, deltoids, biceps, wrist ext/flex, finger ext, FDI, and ADM were 0/5 bilaterally.
Triceps were 2/5; finger flexors and APB were 1/5 bilaterally. Lower limbs were 0/5
and she had contractures on the right. Sensory examination was normal. She was diffusely
areflexic. NCVs were absent. Both the CMTNS and CMT Pediatric Score were severe at
26/36 and 42/44. Exome sequencing revealed a R381L variant in EGR2 which was likely
pathogenic. The probands' mother also had this mutation. She had no reported symptoms
at the age of 33 with strength at 5/5 throughout with the exception of left foot eversion
which was 4+/5 and great toe dorsi flexion which was 4‐/5 bilaterally. Sensory exam
showed a decrease of vibration and pinprick sensation at left toe. She had a normal
gait, tandem gait and could toe walk, but not heel walk. She was diffusely areflexic.
NCVs showed absent sensory responses. Motor NCVs showed her latencies were prolonged
and velocities reduced (29–33 m/s). CMTNS was mild (5/36). Additional family members
who had the R381L mutation were evaluated including maternal grandmother who was moderately
impaired (19/36) and maternal aunt who was severe (26/36). No other mutations that
could cause another known neuropathy or myopathy were identified and mitochondrial
sequencing was normal.
Inherited Neuropathy Consortium is part of the NIH Rare Diseases Clinical Research
Network (grant#1U54NS065712‐01).
SARM1 DELETION AND WLDS ARE NEUROPROTECTIVE IN THREE MODELS OF CHEMOTHERAPY‐INDUCED
PERIPHERAL NEUROPATHY
Fisgun A1, Luan X1, Hoke A
1.
1Johns Hopkins University, Baltimore, MD, USA.
Molecular mechanisms that underlie slow distal axonal degeneration seen in chemotherapy
induced peripheral neuropathy (CIPN) are unclear. However, several identified molecular
targets suggest shared mechanisms with Wallerian degeneration. Since spontaneous mutation
in Wlds mice and genetic deletion of Sarm1 gene lead to slow Wallerian degeneration,
we asked if Wlds or Sarm1 knockout (KO) mice are resistant to distal axonal degeneration
induced by several chemotherapy agents. We chose chemotherapeutic drugs from 3 different
classes of agents, paclitaxel (taxane), cisplatinum (platin‐based drugs) and bertozomib
(proteasome inhibitor), to model CIPN in mice. Primary outcome measure was evaluation
of epidermal nerve fibers in the hind paw plantar footpads. Secondary outcome measures
included thermal sensation and nerve conduction studies. Sarm1 KO mice were almost
100% protected against development of sensory neuropathy but the protection in Wlds
mice was partial. This study confirms the pivotal role Sarm1 plays in mediating axonal
degeneration and identifies inhibition of Sarm1 activity as a potential therapeutic
target for prevention of CIPN.
LIMITED SCHWANN CELL DIFFERENTIATION AS A PROTECTIVE MECHANISM IN CMT1B NEUROPATHY
WITH ACTIVATED UNFOLDED PROTEIN RESPONSE
Florio F
1, Scapin C1, Ferri C1, Feltri ML2, Wrabetz L2, D'Antonio M1.
1Myelin Biology Unit, San Raffaele Scientific Institute, Milan, Italy; 2HJKRI‐University
of Buffalo, NY, USA.
Myelin Protein Zero is the most abundant structural protein in myelin of the PNS.
In humans, more than 200 mutations in P0 are associated with hereditary neuropathies.
Deletion of serine 63 causes Charcot‐Marie‐Tooth (CMT) 1B disease in humans and a
similar demyelinating neuropathy in mice (Wrabetz et al., 2006). P0S63del protein
is misfolded and is retained in the ER where it gives rise to a dose‐dependent Unfolded
Protein Response (UPR) (Pennuto et al., 2008). The UPR results in the activation of
transcriptional and translation control programs that reduce protein synthesis and
increase the folding and degradative capacity of the cell. Usually, when this first
response is not sufficient the cells may activate apoptosis resulting in cell death.
However, in P0S63del Schwann cells there is no cell death suggesting that these cells
may respond differently to chronic stress. Transcriptomic analysis performed on P0S63del
nerves showed increased expression of transcription factors normally present only
in the early phases of differentiation such as c‐Jun, Sox2 and Id2 (D'Antonio et al.
2013). In order to understand the role of the expression of these factors in the peripheral
nerve myelination we used ex vivo and in vivo approaches and we showed that Sox2 and
Id2 act as negative regulators of myelination. These results suggest that the expression
of Sox2 and Id2 may contribute to the hypomyelination observed in P0S63del mice. As
such, we reasoned that their ablation could ameliorate the phenotype. Surprisingly,
the ablation of these factors in the P0S63del mouse severely worsens the neuropathy
bursting Schwann cell differentiation and increasing the expression of both P0 wild
type and mutant allele with concomitant exacerbation of the UPR. This suggests that
the overexpression of early differentiation factors in Schwann cell under chronic
ER‐stress is an adaptive mechanism that limits differentiation and reduces the expression
of toxic proteins.
MODELLING THE PHARMACOKINETICS OF INTRAVENOUS IMMUNOGLOBULIN IN GUILLAIN‐BARRÉ SYNDROME
Fokkink WJR
1,2, de Winter BCM3, van Gelder T3, Koch BCP3, Jacobs BC1,2.
1Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands;
2Department of Neurology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands;
3Hospital Pharmacy, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Intravenous immunoglobulin (IVIg) is the treatment of choice for the Guillain‐Barré
syndrome (GBS). The working mechanism of IVIg in GBS is undefined, but most likely
all potential effects are dose dependent. The pharmacokinetics (PK) and pharmacodynamics
(PD) of IVIg in GBS are highly variable between patients and a rapid consumption or
clearance of IVIg is associated with poor recovery. In the current study we developed
a model to predict the PK of a standard dosage of IVIg (0.4 g/kg for 5 consecutive
days) in individual patients with GBS. Non‐linear mixed‐effects modelling (NONMEM)
was used to construct a model based on a cohort of 177 GBS patients, with a total
of 811 sequential serum IgG levels. The final model accurately describes the day to
day increment in IgG levels during the 5‐day course and the initial rapid fall and
graduate decline to steady‐state levels thereafter. We explored several potential
covariates that improved the predictive capabilities and decreased the between‐subject
variation in the model. The model including these covariates were evaluated successfully
(bootstrap analysis) and through numerous simulation studies each based on 1000 (simulated)
GBS patients. In conclusion, a first accurate and robust NONMEM model for the PK/PD
of standard IVIg treatment in GBS was developed. The model can be used to predict
the PK in individual patients applying a few simple baseline characteristics. In addition,
the effect of different treatment regimens of IVIg in GBS on a population PK/PD level
can be simulated. This modeling technique is a new tool to optimize the PK in individual
patients and the study design for new trials with IVIg in GBS.
ROLE OF L‐PGDS IN SCIATIC NERVE REGENERATION AFTER INJURY
Forese MG
1, Pellegatta M1, Rivellini C2, Podini P3, Quattrini A3, Previtali SC2, Taveggia C1.
1Division of Neuroscience and INSPE, Axo‐Glia Interaction Unit, San Raffaele Scientific
Institute, Milan, Italy; 2Division of Neuroscience and INSPE, Neuromuscular Repair
Unit, San Raffaele Scientific Institute, Milan, Italy; 3Division of Neuroscience and
INSPE, Experimental Neuropathology Unit, San Raffaele Scientific Institute, Milan,
Italy.
Axonal Neuregulin 1 (NRG1) type III is an essential instructive signal for Peripheral
Nervous System (PNS) myelination, as its expression determines whether axons are myelinated
as well as the thickness of the myelin sheath. We recently demonstrated that gamma‐secretase
cleavage of NRG1 type III generates an axonal intracellular fragment, which translocates
in the nucleus to upregulate the expression of the Prostaglandin D2 Synthase (L‐PGDS)
gene in neurons. L‐PGDS catalyzes the conversion of prostaglandin H2 into prostaglandin
D2 (PGD2). We also showed that specific inhibition of L‐PGDS activity impairs in vitro
myelination. Accordingly, myelin in L‐PGDS null mice is noticeably thinner, thus indicating
that L‐PGDS is a new modulator of developmental PNS myelination. Previous studies
have shown that prostaglandins are involved in the process of Wallerian Degeneration
(WD) and axonal regeneration after injury. Thus, to determine whether L‐PGDS and PGD2
could be important in PNS regeneration and remyelination, we performed sciatic nerve
crush injury in 2 months old L‐PGDS null and wild type control mice and we analysed
nerves by morphologic, biochemical, histological and molecular approaches at different
time points (T) after crush. We focused on three phases: degeneration (T3 – T7), axon
regeneration (T14 ‐ T21) and remyelination (T60). Our results indicate that in L‐PGDS
null mice the amount of myelin proteins synthesized after crush as well as the number
of remyelinated fibers do not change, suggesting that L‐PGDS might be dispensable
for remyelination. However, we observed an increased number of macrophages in null
nerves during regeneration (T14), possibly as a consequence of an increase in the
Blood‐Nerve Barrier (BNB) permeability, indicating potential alteration in the regeneration
process in L‐PGDS null mice. These results suggest that L‐PGDS could have a different
role in developmental PNS myelination and after injury. Whether other prostaglandins
and synthases might compensate for L‐PGDS activity is currently under investigation.
ENRICHEMENT OF CHITOSAN TUBES WITH SKELETAL MUSCLE FIBRES TO IMPROVE PERIPHERAL NERVE
REGENERATION
Fornasari BE
1,2, Raimondo S1,2, Ronchi G1,2, Crosio A3, Budau CA1, El Soury M1, Muratori L1,2,
Tos P4, Battiston B3, Geuna S1,2, Gambarotta G1.
1Department of Clinical and Biological Sciences, University of Turin, Italy; 2Neuroscience
Institute Cavalieri Ottolenghi, Turin, Italy; 3Microsurgery Unit, Health and Science
City, CTO, Turin, Italy; 4Hand Microsurgery and Surgery, Gaetano Pini Hospital, Milan,
Italy.
To repair nerve gaps following severe peripheral nerve injuries, chitosan tubes were
proved to give good results, comparable with those obtained with nerve autografts,
the gold standard technique.
To further improve peripheral nerve regeneration using chitosan tubes, a conduit enrichment
strategy was developed using longitudinal skeletal muscle fibres, which have been
previously shown to be good fillers in the “muscle in vein” experimental paradigm,
where they played a trophic and a structural role.
To this aim, rat median nerve gaps were repaired using two different conduits: 10mm
chitosan tubes filled with a longitudinal piece of pectoralis major muscle (“muscle
in tube”) and hollow chitosan tubes. Samples were harvested at early time points (1,
7, 14, 28 days) for biomolecular and morphological analysis, and later (3 months)
for stereological analysis. Autologous nerve grafts were used as gold standard positive
control in the early time points.
Biomolecular analysis carried out on in vitro degenerating muscle and on “muscle in
tube” at early time points show that the muscle produces high levels of soluble isoforms
of Neuregulin1, a key factor for Schwann cell survival and activity, usually released
by Schwann cells after nerve injury.
Functional assay and stereological analysis carried out on the distal part of regenerated
nerve 3 months after nerve repair, show no significant differences in the regeneration
outcome between hollow chitosan tube and “muscle in tube” groups.
Therefore, we conclude that for short gaps (≤10mm), both hollow chitosan tube and
“muscle in tube” are good techniques to repair nerve defects and we suggest that the
“muscle in tube”, which spontaneously releases Neuregulin1, might be a promising strategy
to promote regeneration when the gap is longer or the repair is delayed in time.
SENSITIVITY TO CHANGE OF THE CHARCOT‐MARIE‐TOOTH NEUROPATHY SCORE (CMTNS) AND OVERALL
NEUROPATHY LIMITATION SCALE (ONLS) IN A DATABASE OF FRENCH PATIENTS WITH CMT1A
Foucquier J1, Bertrand V1, Jouve E2, Truillet R2, Mandel J1, Laffaire J1, Blin O2,
Magy L3, Lehert P4,5, Hajj R1, Guedj M
1, Cohen D1, Attarian S2.
1Pharnext, Issy‐Les‐Moulineaux, France; 2Aix Marseille Université, APHM, Marseille,
France; 3Hôpital Dupuytren, Limoges, France; 4University of Melbourne, Melbourne,
VIC 3010, Australia; 5Faculty of Economics, Louvain, Belgium.
Charcot‐Marie‐Tooth disease Type 1A (CMT1A) is a rare disease belonging to a group
of inherited, progressive, chronic motor and sensory peripheral neuropathies. The
Charcot‐Marie‐Tooth Neuropathy Score (CMTNS) (Shy et al., 2005) and the Overall Neuropathy
Limitations Scale (ONLS) (Graham & Hughes, 2006) are considered as the main clinical
scales for evaluating progression of disability associated with CMT. As CMT1A is a
slowly progressive neurodegenerative disease, the choice of endpoints and their ability
to monitor small changes over time remain a major concern for clinical drug development.
With this in mind, we studied a cohort of 225 French CMT1A patients with a follow‐up
ranging from 3 months to 8.5 years resulting from the merge of two multicentre clinical
trials (Micallef et al., 2009; Attarian et al., 2014) and a non‐interventional study
(unpublished). The sensitivity to change of both CMTNS and ONLS were assessed using
a mixed effect model estimating annual progression with time in years, CMTNS or ONLS
baseline value as covariates, study centre as a fixed factor and patients as a random
effect to account for the repeated measures. Disease progression was estimated to
be +0.13 points per year on the CMTNS (p = 0.0037) and +0.052 points per year on the
ONLS (p = 1.1x10−5), both corresponding to a deterioration of impairment and disability.
While both endpoints have similar and favourable properties, our set of observations
led us to conclude that the ONLS could be more promising to monitor disease progression
in CMT1A.
CLINICAL AND MAGNETIC RESONANCE IMAGING FEATURES OF THREE NOVEL MUTATIONS IN THE BICD2
GENE
Frasquet M
1,2, Lupo V3, Mas F1,4, Vílchez R2, Chumillas MJ1,5, Espinós C3, Sevilla T1,5,6.
1Hospital Universitari i Politècnic La Fe, Valencia, Spain; 2Instituto de Investigación
Sanitaria La Fe, Valencia, Spain; 3Centro de Investigación Príncipe Felipe, Valencia,
Spain; 4ERESA, Valencia, Spain; 5Centro de Investigación Biomédica en enfermedades
raras (CIBERER), Valencia, Spain; 6Departamento Medicina, Universitat de Valencia,
Valencia, Spain.
Mutations in the BICD2 gene are a cause of dominant spinal muscular atrophy, lower
extremity predominant (SMALED). We report six patients belonging to three Spanish
families who carry three different novel mutations in the BICD2 gene. We describe
clinical, electrophysiological and Magnetic Resonance Imaging (MRI) data. We provide
results of muscle biopsy of one patient and skin biopsy for the study of Epidermal
Nerve Fiber Density (ENFD) of other two patients. Genetic diagnosed was reached using
a gene panel for genetic testing of CMT and dHMN. Three novel mutations in the BICD2
gene that segregated with the disease were detected: p.Val485Gly; p.Tyr557His and
p.S681L. The most frequent clinical phenotype consisted of mild weakness in proximal
muscles of lower limbs combined with foot deformities. One patient had prominent sensory
symptoms and abnormalities on sensory examination. Other two patients had minor sensory
abnormalities on examination. In one patient sensory and motor nerve action potentials
were reduced, in the rest of patients electrophysiological studies showed normal motor
and sensory nerve responses, with chronic denervation predominantly in muscles of
lower limbs. MRI studies at the level of tight and calf were performed in all patients.
The most affected muscles were rectus femoris, vastus lateralis and medial gastrocnemius.
MRI studies at the level of feet were obtained from five patients and showed that
there was not fatty infiltration in intrinsic foot muscles. MRI at the level of pelvis
muscles performed in four patients showed marked fatty infiltration of gluteus medius
muscle in two of them. Muscle biopsy performed in one patient showed myopathic features.
Skin biopsy was performed in two patients of the same family. In the older patient,
who had minor sensory abnormalities on examination, there was a marked reduction of
ENFD that followed a length‐dependent pattern. In conclusion, we report three new
pathogenic mutations in the BICD2 gene. In our study we include MRI findings at the
level of pelvis and feet, which allow us to better define the pattern of muscle involvement
related with this gene. Our results also raise the subject of a possible sensory involvement
in the disease.
Study funding: grants IIS La Fe 2015/0085, ISCIII (PI12/00946), PI Fundación Grupo
ERESA 2013.
PILOT STUDY OF CLINICAL SEVERITY SCORE FOR HEREDITARY NEUROPATHY WIITH LIABILITY TO
PRESSURE PALSIES
Fridman V
1, Skorupinska M2, Laurà M2, Sillau S1, Shy ME3, Reilly MM2.
1University of Colorado Hospital, Aurora, CO, USA; 2MRC Centre for Neuromuscular Diseases,
UCL Institute of Neurology, Queen Square, London, UK; 3University of Iowa Hospitals
and Clinics, Iowa City, IA, USA.
Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) is an autosomal dominant
disorder that usually results from deletions in the PMP‐22 gene. The neuropathy is
unique in that it manifests with recurrent mono‐neuropathies at common sites of compression.
While spontaneous recovery from episodes of nerve injury usually occurs, it is often
incomplete, and over time patients may develop a length dependent polyneuropathy.
Given the relapsing/remitting nature of HNPP symptoms, standard clinical scores, such
as the CMT Neuropathy Score, are not effective at capturing the severity or progression
of the disease. A specific tool is therefore needed for measuring clinical severity
of HNPP in preparation for emerging clinical trials. In the current study, we evaluate
a new pilot measure, the HNPP Severity Score (HNPPS). The score is composed of 32
patient reported questions addressing current and prior sensory and motor symptoms,
and the impact of symptoms on quality of life, followed by 7 items based on a motor
examination. Total scores vary from 0–85, with higher scores indicating increased
disease severity. In this study, the HNPPS was administered to 41 patients with genetically
confirmed HNPP at the UCL Institute of Neurology. Subjects included 21 males and 20
females with a mean age of 41 years (+/−15, range 16–70). The mean HNPPS was 24.4
points (+/−12.4, range 3–56) and the data did not demonstrate major skew. The Cronbach
alpha for the HNPPS was 0.90, and items based on the physical examination showed the
least variability. A modest correlation was observed between the HNPPS and the CMT
examination scores (Pearson correlation 0.57, CI 0.3‐0.74). We conclude that the HNPPS
may be a useful measure of clinical severity in HNPP, and should be refined in larger
patient cohorts.
DISEASE PROGRESSION IN CHARCOT‐MARIE‐TOOTH DISEASE TYPE 1A: A LONGITUDINAL STUDY USING
RASCH ANALYSIS‐BASED WEIGHTED CMT NEUROPATHY SCORES
Fridman V
1
, Sillau S1
and on behalf of the Inherited Neuropathies Consortium (INC)2.
1University of Colorado Hospital, Aurora, CO, USA; 2University of Iowa Hospitals and
Clinics, Iowa City, IA, USA.
The most common of the hereditary neuropathies (HN) is CMT1A, an autosomal dominant
demyelinating neuropathy that results from duplications in the PMP‐22 gene. Recent
advances in defining the pathomechanisms of the disease have led to an increasing
number of potential therapies; however, the absence of reliable natural history data
and the paucity of sensitive clinical outcome measures have been barriers to effective
clinical trials. The Charcot Marie Tooth Neuropathy Score (CMTNS) was developed to
quantify impairment and measure progression in HN. It was observed that while the
score discriminates well between mildly and severely impaired patients, it tends to
cluster together patients in the middle range of severity. To improve the score's
sensitivity, Rasch analysis‐based weighted category responses were developed. We report
a longitudinal study of weighted CMTNS and CMT examination scores (CMTES) over a three‐year
time frame in patients with CMT1A. Baseline, one year, two year and three year wCMTNSv2/wCMTESv2
scores were available for 434/730, 49/236, 31/148 and 17/74 patients respectively.
Mean wCMTNS (SD)/wCMTES (SD) scores were as follows: 19.2(7.2)/12.7(6.5) at baseline,
19.0 (7.1)/13.0(6.0) at one year, 22.1 (7.6)/13.7 (6.3) at two years and 22.7 (7.6)/14.1(6.8)
at three years. A mixed regression model showed significant change in wCMTNS and wCMTES
at 2 years (mean change from baseline at 2 years was 1.7 points (p=.003) for wCMTNS
and 0.59 points (p=.02) for wCMTES. Significant change as compared to baseline was
also seen at 3 years (mean change from baseline 2.0 points (p=0.02) for wCMTNS and
0.69 points (p=0.04) for wCMTES. We conclude that weighted CMTNSv2 scores show change
over the first three years of the Inherited Neuropathies Consortium natural history
study and are a helpful measure of progression in CMT1A.
A RANDOMIZED, DOUBLE‐BLIND, PLACEBO‐CONTROLLED TRIAL EVALUATING THE SAFETY AND EFFICACY
OF L‐SERINE IN SUBJECTS WITH HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE 1 (HSAN1)
Fridman V
1, Novak P2, David W1, Macklin EA1, McKenna‐Yasek D1, Walsh K
, Oaklander AL1, Brown R2, Hornemann T3, Eichler F1.
1Massachusetts General Hospital, Boston, MA, USA; 2University of Massachusetts Medical
School, Worcester, USA; 3University Hospital Zurich, Zurich, Switzerland.
HSAN1 is an autosomal dominant, severe sensory motor polyneuropathy caused by mutations
to serine palmitoyl‐CoA transferase. Mutations shift the substrate preference from
serine to alanine leading to formation of neurotoxic 1‐deoxysphingolipids (1‐deoxySL).
Treatment with high‐dose L‐serine has been shown to reduce 1‐deoxySL accumulation
and improve neuropathy in transgenic HSAN1 mice. We report a two‐year, delayed‐start,
placebo‐controlled clinical trial evaluating the safety and efficacy of oral L‐serine
in HSAN1. Eighteen HSAN1 subjects were equally randomized to L‐serine (400 mg/kg/d)
or placebo for 1 year. At 48‐weeks, the placebo group crossed‐over and all participants
took open‐label L‐serine for one additional year. Sixteen subjects completed their
96‐week visit, and no serious adverse events related to L‐serine were reported. Participants
randomized to L‐serine experienced a decline in Charcot Marie Tooth Neuropathy Scores
(CMTNS) over 1 year relative to placebo (−1.8 units, 95% CI −3.3 to −0.3, p = 0.02).
Both groups improved in the second year of the study, with a diminished difference
in CMTNS at 96 weeks (−1.45 units, 95% CI −3.7 to 0.81, p=0.20). Skin biopsies from
the distal leg site were largely devoid of intra‐epidermal nerve fibers (IENF), but
at 1 year, a greater increase in IENF density was seen in participants on L‐serine
versus those on placebo (median change of 8 vs. 0 fibers/µm2, p=0.014). 1‐deoxySL
levels declined among participants on L‐serine versus those on placebo after one year
of treatment (60% decrease in deoxysphinganine vs. 9% increase on placebo, p < 0.001),
and placebo participants experienced similar declines in 1‐deoxySL levels after crossing
over to L‐serine. We conclude that L‐serine is a safe and potentially efficacious
treatment for HSAN1.
MALIGNANCY IN GUILLAIN‐BARRE SYNDROME: A TWELVE‐YEAR SINGLE‐CENTER STUDY
Fu Liong H
1, Yusuf R2.
1Regional Neuromuscular Clinic, Queen Elizabeth Hospital, University Hospitals of
Birmingham, Birmingham, UK; 2School of Life and Health Sciences, Aston Brain Centre,
Aston University, Birmingham, UK.
The relationship between Guillain‐Barré syndrome (GBS) and malignancy is uncertain.
Under the diagnostic criteria of Paraneoplastic Neurological Syndrome (PNS) by Euronetwork,
2004, neuropathy with no definite onconeural antibodies identified due to GBS has
been classified as “non‐classical” paraneoplastic disorder. We retrospectively analyzed
data of 118 consecutive patients admitted with GBS from Birmingham, U.K. (2001–2012)
to calculate the relative cancer risk using different definitions and determined characteristics
of malignancy‐associated GBS. Patients were classified according to 2 definitions:
1) all cases of malignancies excluding preceding diagnoses >1 year before GBS and
with no evidence of malignant disease activity at the time of GBS diagnosis, and 2)
malignancies diagnosed >2 years post‐GBS onset as per PNS criteria. Total number of
GBS patients with malignancy was 10 (9.2%). A total of 6 patients (5.5%) fulfilled
requirements for inclusion as malignancy‐associated GBS as per existing criteria for
PNS. Associated malignancy consisted of angioimmunoblastic T‐cell lymphoma (1), poorly
differentiated squamous cell carcinoma of nasal septum (1), gastric adenocarcinoma
(1), hepatocellular carcinoma due to hepatitis B (1), rectal carcinoma with liver
metastasis (1) and myelodysplastic syndrome (1). Malignancy was globally commoner
in our GBS cohort compared to the general population (odds ratio: 2.08; CI: 1.06–3.71;
p = 0.036). However, this was unconfirmed if paraneoplastic criteria were applied.
GBS patients with cancer were significantly more likely to be older (p = 0.043), hyponatremic
(p = 0.037) and demonstrate more electrophysiological axonal loss (p < 0.05). Cerebrospinal
fluid (CSF) protein levels were lower in the malignancy group (p = 0.002) and neurological
improvement was less likely (p = 0.023). In‐patient mortality was significantly higher
in patients with malignancy (p < 0.01). None of the patients in the malignancy group
had positive anti‐ganglioside antibodies or anti‐neuronal antibodies (anti‐Hu, Yo,
Ri, CRMP5). We conclude global cancer risk is higher in GBS than in the general population,
although definition‐dependent. Application of the strict published criteria for paraneoplastic
syndrome reduced the number of cases and suggested absence of a link. Malignancy requires
consideration in elderly, hyponatremic subjects with normal CSF protein, severe electrophysiological
axonal loss who fail to improve post‐treatment.
QUALITY OF LIFE IN ANTI‐MAG NEUROPATHY: EVALUATION OF DETERMINANTS IN A MULTICENTRE
EUROPEAN SETTING
Fu Liong H
1, Aude‐Marie G2, Anne‐Catherine AN3, Emilien D4, Julien C3, Shahram A5, Yusuf R6.
1Regional Neuromuscular Clinic, Queen Elizabeth Hospital, University Hospitals of
Birmingham, Birmingham, UK; 2Referral Centre for Neuromuscular Diseases and ALS, University
hospital La Timone, Marseille, France; 3Centre de Référence Maladies Neuromusculaires
de l'Enfant et de l'Adulte Nantes‐Angers, Centre Hospitalier Universitaire d'Angers,
Angers, France; 4Referral Centre for Neuromuscular Diseases and ALS, University hospital
La Timone, Marseille, France and Aix‐Marseille University, CNR2M, CNRS UMR 7286, Medicine
Faculty, Marseille, France; 5Referral Centre for Neuromuscular Diseases and ALS, university
hospital La Timone, Marseille, France and Aix‐Marseille University, Inserm UMR S 910
Medical Genetics and Functional Genomics, Marseille, France; 6Regional Neuromuscular
Clinic, Queen Elizabeth Hospital, University Hospitals of Birmingham, Birmingham,
UK and School of Life and Health Sciences, Aston Brain Centre, Aston University, Birmingham,
UK.
Anti‐myelin associated glycoprotein antibody (Anti‐MAG) neuropathy is a slowly progressive
neuropathy resulting in disability through distal sensory more than motor deficits
and tremor. There are currently no evidence‐based treatments for anti‐MAG neuropathy
and the effect of the disease on quality of life (QoL) in this patient population
is unknown. Our objective was to assess determinants of QoL in patients with anti‐MAG
neuropathy. The SF‐36 questionnaire was assessed in 55 patients, from Marseille, Angers
(France) and Birmingham (United Kingdom). Routine clinical evaluations included MRC
sum score, INCAT sensory score, Inflammatory Rasch built Overall Disability Score
(I‐RODS), ataxia score, Jamar grip dynamometry, timed 10 meter‐walk, Neuropathic Pain
Symptom Inventory (NPSI) score, and Fatigue Severity Score (FSS). There were 38 males
and 17 females. Mean age was 71.5 years (SD: 10.3 years). Mean disease duration was
7.4 years (S.D.: 5.9 years). There were no significant differences between the French
and U.K. cohorts in terms of gender distribution, age, disease duration, anti‐MAG
antibody titre. All physical assessments, including MRC sum score (p=0.87), Jamar
grip dynamometry (p=0.54), ONLS (p=0.11), IRODS (p=0.66), INCAT sensory score (p=0.60),
10‐meter timed walk (p=0.46), ataxia score (p=0.65), tremor score (p=0.25), were comparable.
Prevalence and/or severity of pain (p=0.55), fatigue (p=0.86), restless legs syndrome
(p=1) and cramps (p=0.54) were also similar. Physical Component Summary (PCS) and
Mental Component Summary (MCS) of the SF36 questionnaire were significantly lower
than in reported normal subjects of both countries (p<0.001). All SF‐36 QoL domains
correlated with I‐RODS, except MCS for which significance was however approached (p=0.056).
PCS correlated with MRC sum score, ataxia score, timed 10 m‐walk, tremor, Jamar grip
dynamometry, NPSI pain score, FSS and level of social support. MCS correlated exclusively
with FSS and level of social support. In multivariate regression, PCS was associated
independently with I‐RODS (p<0.001) and NPSI pain score (p=0.011), whereas MCS was
associated independently with FSS (p=0.022). QoL is accurately predicted in anti‐MAG
neuropathy by the I‐RODS and FSS, lending support to their use in clinical and research
settings. Effective measures to improve QoL should include tremor and neuropathic
pain treatment, fatigue management and improved social support.
OPTIMIZING ELECTRODIAGNOSTICS FOR GUILLAIN‐BARRE SYNDROME: CLUES FROM CLINICAL PRACTICE
Fu Liong H
1, Yusuf R2.
1Regional Neuromuscular Clinic, Queen Elizabeth Hospital, University Hospitals of
Birmingham, Birmingham, UK; 2School of Life and Health Sciences, Aston Brain Centre,
Aston University, Birmingham, UK.
The electrophysiological diagnosis of Guillain‐Barré syndrome (GBS) is dependent on
a number of abnormalities affecting different parameters in peripheral nerves on nerve
conduction studies (NCS). Diagnostic sensitivity varies with different electrodiagnostic
criteria, practices as well as extensiveness of nerve study. However, the most efficient
method of performing electrophysiology for Guillain‐Barré syndrome (GBS) is unknown.
We retrospectively analyzed electrophysiological data of 97 consecutive GBS patients
from Birmingham, UK (2001–2012), studied ≤ 3 weeks post‐onset. We first identify abnormal
nerves from various regions which produced GBS electrodiagnosis using the recently
described criteria by Rajabally et al. We subsequently used pre‐established hypothetical
nerve conduction study protocols to determine the potential optimal method of achieving
electrodiagnosis. We found the sensitivity of electrophysiology for each GBS subtype
was dependent on the upper and lower limb nerves tested. In acute inflammatory demyelinating
polyneuropathy (AIDP), abnormalities were predominant in the arms, whereas leg abnormalities
predominated in axonal GBS. In AIDP, the most common abnormal parameters were distal
motor latency (46.4%) and conduction block (46.7%), and the most frequently affected
nerve was the median (40.1%). Prolonged F‐waves were present in 32% and F‐waves were
absent in 29%. MCV was the least frequently abnormal (23.7%) with demyelinating range
slowing, significantly lower than CB or DML prolongation (p<0.001 in both cases).
In axonal GBS, reduced motor amplitudes (38.1%) and conduction block (35.1%) were
the most common parameters, and the most frequently abnormal nerve was the tibial
(46.9%). F‐waves were absent in 32.1%. 12.5% of all motor nerves were unexcitable,
significantly more common in lower limb nerves compared to upper limb nerves (p=0.03).
On comparison of different hypothetical NCS protocols (2 unilateral protocols with
2 nerves, 2 with 3 nerves as well as the protocols with 4‐nerves and with exclusive
bilateral upper limb and lower limb testing), unilateral 4‐nerve (median, ulnar, common
peroneal and tibial) testing produced the highest diagnostic sensitivity for both
AIDP (95.6%) and axonal (91.1%) GBS. Electrodiagnostic sensitivity in GBS is thus
dependent on nerves tested and parameters considered. Each subtype preferentially
involves specific nerves and parameters. These findings may help per‐procedure interpretation,
improve electrodiagnostic sensitivity, and reduce patient discomfort.
ANTI‐GANGLIOSIDE COMPLEX ANTIBODIES IN CHRONIC IMMUNE‐MEDIATED NEUROPATHIES
Funakoshi K
1, Nagashima T1, Kokubun N1, Hirata K1, Yuki N2.
1Department of Neurology, Dokkyo Medical University, Tochigi, Japan; 2Department of
Neurology, Mishima Hospital, Nagaoka, Japan.
Recently, IgG anti‐ganglioside complex (GSCs) antibodies have been reported in patients
with Guillain‐Barré and Miller Fisher syndrome. Some researchers (Nobile‐Orazio et
al., 2010) reported IgM anti‐GSCs antibodies in multifocal motor neuropathy (MMN)
and other chronic immune‐mediated neuropathies. In ten of eleven MMN patients with
anti‐GM1 antibody, there was a decreased reactivity to GM1/GD1a compared to single
antigen GM1. Similarly, in one of two chronic inflammatory degenerative polyradiculoneuropathy
(CIDP) patient with anti‐GM1 antibody, there was a decreased reactivity to GM1/GM2,
GM1/GD1a, GM1/GD1b, GM1/GT1b compared to GM1. These relationships were defined negative
interaction. In one CIDP with anti‐GD1b antibody, anti‐GM1/GT1b and ‐GM2/GT1b reactivity
increased although GM1 and GM2 were negative (positive interaction). In japan, on
the other hand, this correlation remains unclear. Sera were investigated from one
MMN patient (38 y/o male) with anti‐GM1, and anti‐GD1a antibody, one CIDP patient
(72 y/o female) with anti‐GM1, and one subacute sensory motor polyradiculoneuropathy
(70y/o male) with anti‐GD1b, and anti‐GQ1b. IgM antibodies to GSCs GM1/GD1a were tested
with a mixture of GM1 and GD1a (each 5 pmol/well) as antigen. Anti‐GM1/GD1a antibodies
were judged to have positive interactions when the optical density was 0.5 greater
than the sum of the antibodies against individual GM1 and GD1a, and negative interactions
when the optical density was 50% or less compared to the antibodies against individual
GM1 or GD1a. Antibodies to at least one combination of two of the six gangliosides
(GM1, GM2, GD1a, GD1b, GT1b, and GQ1b) were similarly tested and judged for positive
or negative interactions. In one MMN, anti‐GM1/GD1a had negative interactions. In
one CIDP, anti‐GM1/GD1a, and anti‐GM1/GQ1b had negative interactions. In one subacute
sensory motor polyradiculoneuropathy, various anti‐GSCs antibodies including GD1b
or GQ1b had negative interactions. In the CIDP patient mentioned above, anti‐GM1/GT1b
or anti‐ GM2/GT1b had no positive interactions. The relationship between this attenuated
reactivity presumably driven by adjacent gangliosides and the mechanism of chronic
immune‐mediated neuropathies needs to be clarified.
RALGTPASES CONTROL SCHWANN CELL'S REPAIR FUNCTION AFTER NERVE INJURY BY CONTROLLING
LAMELLIPODIA FORMATION
Galino J
1, Cervellini I1, Zhu N1, Stöberl N1, Fricker FR1, Lee G1, Hütte M1, Lalli G2, Bennett
DL1.
1The Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University
of Oxford, Oxford, UK; 2Wolfson CARD, King's College London, Guy's Campus, London,
UK.
Schwann cells (SCs) are the myelinating cells in peripheral nerve system and are important
for normal peripheral nerve development and repair. RALA and RALB are small GTPases
that have been implicated in neural tube closure, neurite branching and have been
described as upstream effectors of proteins involved in cell migration and membrane
dynamics. Due to their potential role in SC function here we investigated, by genetic
ablation in transgenic animals of one or both GTPases, their importance in SC function
in adulthood and in nerve repair. We showed that Ral GTPases are dispensable for SC
function in the naïve state. However Ral signalling (provided by RalA or RalB) is
required for effective remyelination of axons following nerve injury. Moreover, absent
Ral signalling produced defects in axon reinnervation of distal organs and a delay
in motor function recovery after nerve injury. We also studied the Ral dependent cellular
mechanisms that may be responsible for impaired SC remyelination and noted abnormal
SC lamellipodia formation that prevent normal axial and radial axon remyelination.
This work demonstrates for the first time a novel mechanism for RalGTPases that controls
SC lamellipodia formation and their importance in normal SC function during peripheral
nerve repair.
CHARACTERIZATION OF A TRANSGENIC MOUSE MODEL OVEREXPRESSING TNF ALPHA IN MYELINATING
SCHWANN CELLS
García‐Lareu B1,2,3, Ariza L2, Cobianchi S1,4, Chillón M1,2,5,6, Navarro X1,3,4, Bosch
A
1,2,3.
1Institut de Neurociències (INc), UAB, Barcelona, Spain; 2Departament de Bioquímica
i Biologia Molecular, UAB, Barcelona, Spain; 3Centro de Investigación Biomédica en
Red Enfermedades Neurodegenerativas (CiberNed), Insituto de Salud Carlos III, Madrid,
Spain; 4Departament Biologia Cel·lular, Fisiologia i Immunologia, UAB, Barcelona,
Spain; 5Institut Català de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; 6Unitat
Mixta UAB‐VHIR, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain.
Tumor Necrosis Factor (TNF) alpha has been implicated in the pathogenesis of diabetic
peripheral neuropathy (DPN), among other inflammatory demyelinating diseases and neuropathic
pain. TNF alpha is a pro‐inflammatory cytokine that can act at several stages in the
demyelination process. It is produced by Schwann cells (Scs) in the peripheral nervous
system (PNS) after nerve injury and released into the local environment to attract
and activate macrophages at the site of injury, contributing to Wallerian degeneration.
In vivo studies demonstrated a local inflammation in the sciatic nerve of rats after
injection of TNF alpha, followed by demyelination and axonal degeneration. Furthermore,
the application of TNF alpha resulted in acute mechanical hiperalgesia, a main characteristic
of neuropathic pain and therefore TNF alpha is postulated as a biomarker for painful
changes after nerve injury. With the aim to characterize TNF alpha effects in chronic
neuropathic pain and in diabetic neuropathy, a transgenic mouse model overexpressing
TNF alpha cDNA under the peripheral myelin protein P0 promoter was generated. Here
we characterized the overexpression of TNF alpha in myelinated Scs at different stages
of myelination (postnatal days 5, 21 and 65) showing that high levels of TNF alpha
in sciatic nerve leads to the downregulation of the major PNS myelin proteins (P0,
MBP, PMP22, MAG) compared to wild type mice, correlating with the loss of structured
myelin and an increase in p75NTR, a marker for immature and non‐myelinated Scs in
the sciatic nerve. Iba1 staining showed high levels of macrophage infiltration in
both sciatic nerve and spinal cord tissues, compared with wild type animals. Stress
conditions were induced by sciatic nerve crush surgery after which recovery and subsequent
remyelination were delayed in the transgenic mice, as evaluated by the Sciatic Functional
Index (SFI) and electrophysiological tests. On the other hand, mechanical and thermal
nociception seemed to be unaltered, with or without lesion. This model could be helpful
in the characterization of the role TNF alpha in pain development, injury and DPN
as well as in developing efficient therapeutic strategies to modulate such pathological
conditions.
CHARCOT‐MARIE‐TOOTH DISEASE: GENETIC SUBTYPES IN NORTHWESTERN SPAIN
García‐Sobrino T
1,2, Blanco‐Arias Patricia2,3, Vidal‐Lijó MP4, Quintáns Bea2,3, Sobrido MJ2,3, Pardo
J1,2.
1Department of Neurology, Hospital Clínico, Santiago de Compostela, Spain; 2Neurogenetics
Research Group, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela,
Spain; 3Genomic Medicine Group (U711), Centre for Biomedical Network Research on Rare
Diseases (CIBERER), Spain; 4Department of Neurophysiology, Hospital Clínico, Santiago
de Compostela, Spain.
Charcot‐Marie‐Tooth (CMT) disease is a genetically heterogeneous group of hereditary
motor and sensory neuropathies. More than 80 genes were involved in the disease pathogenesis.
The objective of this study was to assess the genetic distribution of CMT disease
in Galicia (Northwestern Spain). Patients were diagnosed as CMT if they had a consistent
neurological and/or neurophysiological examination or if they had sensory motor neuropathy
with a positive family history. A total of 215 CMT adult patients (55% females) were
evaluated with a median age of 48 [39–60] years. The molecular diagnosis was achieved
in 168 patients (78%) with a higher success in CMT1 (60%) than CMT2 (20%). Globally,
PMP22 duplication was the most frequent finding (55%), followed by mutations in MPZ
(11%), MFN2 (8%), GJB1 (8%) and GDAP1 (6%). In CMT1, with expception of the PMP22
duplication, pathogenic variants in EGR2, NEFL and MPZ gene were most common. Pathogenic
variants in MFN2 and GDAP1 accounted for 70% of CMT2 patients. Several patients referred
to our institution as CMT2 were diagnosed as hereditary motor neuropathy (HMN) and
pathogenic variants in the BSCL2 gene were the most frequent. Pathogenic variants
not previously related to CMT were identified in MPZ, MFN2, GJB1, EGR2, NEFL and SH3TC2
genes. Sporadic or autosomal recessive (AR) CMT accounted for the 30% of all diagnoses.
The genetic epidemiology of CMT in Galicia follows a similar pattern to other populations,
although some remarkable features are axonal GDAP1 and demyalinating EGR2 pathogenic
variants as well a seemingly elevated proportion of AR cases.
A MPZ R98C CMT PATIENT PRESENTING A FLUCTUATING NEUROPATHY SUSCEPTIBLE TO TREATMENT
Germano CSB1, Onofre PTBN1, Bordini EC1, Gouvea S1, Barreira AA1, Marques W Jr
1.
1Division of Neuromuscular Diseases, Department of Neurosciences and Behaviour Sciences,
Clinical Hospital of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Mutations in MPZ gene are associated to a wide range of phenotypes. The R98C, in particular,
is associated to a severe and early onset disease. Some CMT patients respond to immunosuppressive
or immunomodulatory treatment, some of them harbouring MPZ mutations. We present the
case of a 34‐year‐old Brazilian female with a severe CMT1B (R98C) that presented an
acute episode of worsening after a febrile exanthematic disease. She complained of
tingling, stopped walking without support, and could not raise her arms. Her EMG showed
an asymmetrical reduction of motor CV, reduced amplitudes, severe temporal dispersion
and possibly conduction block. CSF protein was 130mg%, with normal cell count. Diagnosed
as GBS, she received IVIg. Curiously, she markedly improved, regaining the functional
status of youth, recovering functions that she had long lost. On EMG, motor amplitudes
improved significantly, but CV remained the same. Reviewing carefully her past history,
we identified some motor fluctuations along her adult life. At age 26, while pregnant,
she developed positive sensory symptoms, became unable to get up from the chair and
could not walk without assistance. After delivery, she improved, but did not return
to baseline. One year later, she presented a new transitory functional worsening after
an influenza illness. Her parents were healthy but two out her 3 children have a severe
CMT. Her first daughter never walked and died at the age of six. Six months after
treatment with IVIg, she faced a new relapse. We pulsed with corticosteroids, with
great response. She remains stable to date, four months after treatment. The episodic
fluctuations and the evident response to treatment clearly suggest an associated immunomediated
process. The fast improvement of the amplitude with maintenance of CV suggests that
another mechanism in addition to demyelination and axonal degeneration is involved.
We propose the existence of an associated channelopathy.
Funded by CNPq, FAEPA, PRONAS (MINISTRY OF HEALTHY)
GBS CLASSIFICATION ACCORDING TO TWO‐SETS OF EMG EXAMINATION IN A SAMPLE OF THE BRAZILIAN
POPULATION
Germano CSB1, Moreira CL1, Marques VD1, Santos ACJ1, Onofre PTBN1, Barreira AA1, Marques
W Jr
1.
1Division of Neuromuscular Diseases, Department of Neurosciences and Behaviour Sciences,
Clinical Hospital of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
GBS is an acute, immune‐mediated neuropathy that comprises three major subtypes: AIDP,
AMAN, and AMSAN. On clinical grounds, this distinction is based on nerve conduction
studies (NCS): AIDP is a demyelinating neuropathy, AMAN is an axonal motor neuropathy,
and AMSAN, an axonal sensory and motor neuropathy. Recently, it has been demonstrated
that axonal GBS, in addition to axonal degeneration, may present conduction block
(CB) that can progress to axonal regeneration or revert, characterising a reversible
conduction failure (RCF), a finding usually associated to good prognosis. Patients
presenting axonal CB are frequently diagnosed as having AIDP, a mistake that can be
avoided with two sets of NCS, one as early as possible and the second after three
weeks of disease. Following these recommendations, we retrospectively classified a
Brazilian group with GBS followed in our institution that had been submitted to two
NCS sets. From September 2010 to January 2017, 52 patients fulfilled clinical criteria
for GBS at Clinical Hospital of Ribeirão Preto and had more than one NCS accomplished.
At least four motor nerves (median, ulnar, peroneal, and posterior tibial) and five
sensory nerves (medial, ulnar, radial, sural, and peroneal superficial) were evaluated
in each examination, according to routine procedures. First NCS revealed 12 patients
with AIDP (23%), 29 cases of axonal GBS (21 AMAN, 8 AMSAN, 56%), and 11 patients with
equivocal results (21%). At follow‐up study, 15 patients (29%) had their classification
changed. The main shifts were from AIDP to axonal group and from equivocal results
to AIDP. AIDP increased to 31% (n = 16), axonal GBS increased to 69% (n = 36, 22 AMAN,
14 AMSAN), and there were no more equivocal patients. Although the majority of studies
have shown that AIDP is more frequent in Western countries while axonal GBS predominates
in Eastern countries, we found a different pattern of distribution in our population,
with predominance of the axonal subtypes. The considerable increase of axonal GBS
at follow‐up studies reinforces that serial EMG are mandatory for accurate diagnosis
of GBS subtypes. Prospective studies are now being carried out in order to confirm
these results.
Funded by: FAEPA
NEOD001 DEMONSTRATES DURABLE PERIPHERAL NEUROPATHY RESPONSES IN PATIENTS WITH LIGHT
CHAIN AMYLOIDOSIS AND PERSISTENT ORGAN DYSFUNCTION: RESULTS FROM A PHASE 1/2 STUDY
Gertz M1, Comenzo RL2, Landau H3, Sanchorawala V4, Weiss BM5, Zonder JA6, Walling
J7, Kinney GG8, Koller M8, Schenk DB8, Guthrie SD8, Liu E8, Alvarez‐Baron E
8, Liedtke M9.
1Mayo Clinic, Rochester, USA; 2Tufts Medical Center, Boston, USA; 3Memorial Sloan
Kettering Cancer Center, New York, USA; 4Boston University School of Medicine, Boston,
USA; 5University of Pennsylvania, Philadelphia, USA; 6Karmanos Cancer Institute, Detroit,
USA; 7JW Consulting, Hillsborough, USA; 8Prothena Biosciences Inc, South San Francisco,
USA; 9Stanford University School of Medicine, Stanford, USA.
In amyloid light chain (AL) amyloidosis, misfolded light chain (LC) accumulates and
causes progressive peripheral neuropathy (PN) and progressive failure of critical
organs such as the heart and kidneys. Progressive ascending sensorimotor neuropathy
is often a related clinical finding. The deposition of toxic LC amyloid in peripheral
nerves is associated with paresthesias, pain, muscle weaknesss, orthostatic hypotension,
and diarrhea or constipation in approximately 35% of patients with AL amyloidosis.
There are no approved treatments for AL amyloidosis. Current therapeutic approaches
for AL amyloidosis are intended to limit LC production but do not directly target
misfolded LC deposited as amyloid in organs. We report phase 1/2 trial results of
NEOD001, an investigational monoclonal antibody that targets misfolded LC and may
neutralize circulating LC aggregates and clear insoluble deposits. Trial inclusion
criteria were one or more plasma cell–directed treatment completed before enrollment,
partial or greater hematologic response to any previous therapy, and persistent organ
dysfunction. NEOD001 was administered intravenously every 28 days during a dose‐escalation
phase (27 patients; 0.5, 1, 2, 4, 8, 16, or 24 mg/kg in a 3+3 study design) and an
expansion phase (42 patients; 24 mg/kg). We assessed safety, tolerability, pharmacokinetics,
immunogenicity, organ responses based on consensus criteria, and PN responses using
the Neuropathy Impairment Score–Lower Limb (NIS‐LL). NEOD001 treatment was not associated
with dose‐limiting toxicities or serious adverse events, drug‐related discontinuations,
or antidrug antibody development in any patient (N = 69). Of patients with measurable
PN at baseline (N = 11), 82% achieved PN response based on the NIS‐LL score after
9 months of treatment, which resulted in a median 23% NIS‐LL score reduction (mean
baseline NIS‐LL, 28.1). In a best response analysis, 53% of cardiac‐evaluable patients
(n = 36) and 64% of renal‐evaluable patients (n = 36) met respective criteria for
organ response. Improvements in neuropathy have not been previously shown in AL amyloidosis.
These results demonstrated that monthly NEOD001 infusions were safe, well tolerated,
and associated with responses across three different organ systems.
VENTRAL ABDOMINAL SENSORY LOSS IS COMMON IN LENGTH DEPENDENT SENSORIMOTOR PERIPHERAL
NEUROPATHY
Gervais CBL1, Ross MA1, Goodman BP1, Khoury JA1, Muzyka I1, Smith BE
1
. 1Mayo Clinic in Arizona, Scottsdale, AZ, USA.
This work describes clinical, examination and electrophysiologic findings in a cohort
of patients with length dependent sensorimotor peripheral neuropathy (LDSMPN) with
ventral abdominal sensory loss. LDSMPN affects the longest nerve fibers, namely those
innervating structures in the feet and hands. What is less well appreciated is that
length dependent involvement of sensory nerve fibers in LDSMPN from the thoracic segments
gives rise to ventral abdominal sensory loss. Consecutive patients seen for LDSMPN
(n= 77) were evaluated for the presence or absence of ventral abdominal sensory loss.
Demographic variables, symptoms and quantitative neurologic findings (Neuropathy Impairment
Score [NIS]) were examined using descriptive statistics. Final diagnoses were noted.
Ventral abdominal sensory loss to pinprick (which was asymptomatic in all patients
tested) was documented in 52/77 LDSMPN patients (67.5%), mean age was 61.7 years (range
33–89), M:F gender ratio was 1.7 (33:19), mean NIS was 19.1 (range 0–77), NCS/EMG
abnormalities were found in 60/77 patients (the remaining 17 showing objective evidence
of small fiber sensory involvement). LDSMPN patients without ventral abdominal sensory
loss (n=25) had a mean age of 59.4 (range 31–77), M:F of 2.6 (18:7), and mean NIS
of 21.8 (range 0–95). No patient (0/77) had dorsal torso sensory loss between the
shoulder and buttock levels on either side. Diagnoses of the LDSMPN patients with
vs. without ventral abdominal sensory loss included Charcot Marie Tooth or other hereditary
neuropathy (n=3 vs.1), abnormal carbohydrate metabolism (n=17 vs. 3), idiopathic (n=12
vs.10), hypothyroidism (n=6 vs. 2), inflammatory (n=9 vs. 5) and other (n=5 vs. 4).
Ventral abdominal sensory loss appears to be common in patients diagnosed with LDSMPN
of a variety of causes including inherited neuropathies; in addition to those innervating
distal limb territories, distal sensory fibers from the thoracic region represent
another category of length dependent involvement in LDSMPN; 3) the clinical examination
of LDSMPN should include the ventral abdomen.
STRUCTURAL AND FUNCTIONAL TESTS OF NEUROPATHY IN DIABETES
Gibbons C
1, Garcia J1, Casasola M1, Freeman R1.
1Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
Objective: To determine the relationship between measures of autonomic function, electrochemical
sweat conductance (ESC) and intra‐epidermal (IENFD) and sudomotor nerve fiber density
(SGNFD).
Background: Structural and functional measures of small fiber neuropathy have been
studied in patients with diabetes, but little information comparing these techniques
exists.
Design/Methods: We studied 25 patients with diabetes (ages 57±11yrs, gender 9F) and
14 healthy control subjects (Age 54±13yrs, gender 7F). Subjects underwent examination
scores (NIS‐LL), quantitative sensory testing, autonomic testing (heart rate variability,
Valsalva maneuver, tilt test), ESC, and 3 millimeter punch skin biopsies at the distal
leg and distal thigh for IENFD & SGNFD.
Results: There were strong correlations between exam scores (NIS‐LL) and biopsy IENFD
(R=−0.83, P<0.01 distal leg; R=−0.78, P<0.01 distal thigh), and SGNFD (R=−0.61, P<0.05
distal leg; R=−0.73, P<0.01 distal thigh). Moderate correlations were noted between
exam scores and QST (R values 0.3‐0.5, P<0.05), IENFD and QST (R=0.40‐0.47). Modest
correlations were noted between ESC and parasympathetic function (R=0.33‐0.47, P<0.05).
Modest correlations were noted between ESC and IENFD (R=0.34, P<0.05, but only at
the distal leg) and ESC and NIS‐LL (−0.33, P<0.05). No correlations between exam scores
and autonomic function were noted. No correlations were detected between ESC and SGNFD
(R=−0.09‐0.32) or ESC and sympathetic adrenergic function (R=0.06).
Conclusions: Differences between tests are expected based on our understanding of
the pathophysiology and natural history of diabetic neuropathy. Exam scores, QST results
and biopsy results do correlate, and are consistent with prior studies. In contrast,
there was little relationship between tests of autonomic function and exam scores,
similar to prior studies and our understanding of autonomic function and differences
in p. ESC had little correlation with either exam scores or biopsy IENFD or SGNFD.
There was a modest correlation between ESC and parasympathetic function. The exact
relationship between ESC and diabetic peripheral neuropathy is not clear, and further
research studies are needed to determine the role this technique has in clinical practice.
IMPLICATIONS OF SKIN BIOPSY TISSUE THICKNESS ON STUDY OUTCOMES
Gibbons C
1, Wang N1, McCormick M1, Freeman R1.
1Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
Objective: To determine the optimal tissue thickness of skin biopsy sections for studies
of cutaneous nerve fibers.
Background: Although analysis of intra‐epidermal nerve fiber density (IENFD) is routinely
reported using 50 µm thick tissue sections, many recent studies of peripheral alpha‐synuclein
deposition use 20 or 10 µm frozen sections, or 5 µm paraffin embedded tissue sections.
Design/Methods: We compared the results of biopsies from 30 patients with Parkinson's
disease (PD), using 4 tissue sections each of 50, 20 and 10 µm thickness. Tissues
were stained with PGP9.5 and stained for phosphorylated alpha‐synuclein (P‐SYN). The
total number of dermal structures (hair follicles, sweat glands, pilomotor muscles)
were quantified, nerve densities analyzed, and the frequency of P‐SYN positive results.
We also studied 5 µm paraffin embedded tissue samples from 11 patients with PD.
Results: In the 30 biopsies of patients with PD there were no differences in the number
of sweat glands, hair follicles or pilomotor muscles in 50, 20 or 10 µm sections.
There were significantly fewer blood vessels noted in 20 and 10 µm sections compared
to 50 µm sections (P<0.05). IENFD and SGNFD declined with tissue thickness (P.0.01,
all) and there was increased variability in results in thinner tissue sections. There
was a highly significant reduction in P‐SYN positive sections in thinner tissue sections
(P<0.001, all tissues compared to 50 µm sections). Paraffin embedded tissue sections
had significantly lower nerve densities and positive P‐SYN results (P<0.01) compared
to all frozen tissue sections of 50, 20 and 10 µm thickness. Thinner tissue sections
carried a greater risk of false positive result or indeterminate results due to difficulty
interpreting overlap with PGP9.5.
Conclusions: Tissue sample thickness plays a critical role in interpretation of skin
biopsy results. Thinner tissue sections, or paraffin embedded tissue sections, do
not provide equivalent data and significantly underestimate nerve densities and positive
alpha‐synuclein results with increase false positive results despite similar numbers
of dermal tissue structures.
AN ONGOING PHASE 2 STUDY EVALUATING THE SAFETY, EFFICACY, AND PHARMACOKINETICS OF
ACE‐083 IN PATIENTS WITH CMT1 AND CMTX
Glasser CE1, Walk D2, Thomas FP3, Shy M4, D'Eon S1, Wilson D1, Sherman ML1, Attie
KM
1.
1Acceleron Pharma, Cambridge, USA; 2University of Minnesota, Minneapolis, USA; 3Hackensack
University Medical Center, Hackensack, USA; 4University of Iowa, Iowa City, IA, USA.
ACE‐083 is an investigational protein therapeutic that acts as a localized ligand
trap for myostatin and other negative regulators of muscle growth. Local injection
of ACE‐083 into the gastrocnemius muscle of wild‐type, mdx, and SOD1 mice produced
dose‐dependent increases in muscle mass and force without systemic effects. In a Phase
1 single‐center, double‐blind, placebo‐controlled dose escalation study in post‐menopausal
women, unilateral injections of ACE‐083 into the rectus femoris (RF) or tibialis anterior
(TA) muscle were generally safe and well tolerated. Mean percent changes from baseline
in muscle volume of the injected muscle were +14.5% in the RF and +8.9% in the TA
at the highest dose administered with minimal changes observed in the contralateral
side and placebo‐treated subjects. Frequent related AEs (≥15%) included injection
site pain, pain in extremity, injection site discomfort, and muscle twitching, with
similar incidence in ACE‐083 and placebo‐treated groups. All AEs were grade 1–2 and
reversible. Together, these preclinical and clinical results support further studies
of ACE‐083 in myogenic and/or neurogenic diseases with focal loss of muscle strength
and function, including CMT. A Phase 2 study is ongoing in facioscapulohumeral muscular
dystrophy (FSHD). Study A083‐03 is an ongoing multicenter, two‐part, Phase 2 study
to evaluate the safety, tolerability, pharmacodynamics, efficacy, and pharmacokinetics
of ACE‐083 in patients with CMT1 and CMTX. Part 1 is open‐label and will enroll up
to 3 dose‐escalating cohorts (6 patients per cohort); Part 2 is randomized, double‐blind,
and placebo‐controlled, and will enroll an additional 24 patients. ACE‐083 will be
administered bilaterally to the TA muscle once every three weeks for up to five doses.
A Safety Review Team will meet periodically throughout the study to review safety
data and make dosing recommendations, including the recommended dose level for Part
2. Eligible patients must have genetically confirmed CMT1 or CMTX with mild‐moderate
weakness in ankle dorsiflexion. Safety and tolerability will serve as the primary
outcome for Part 1, muscle volume evaluated by MRI for Part 2. Additional outcome
measures of interest include strength by quantitative muscle testing, function by
motor tests, and quality of life by the CMT‐Health Index questionnaire.
FUNCTIONAL AND MORPHOLOGICAL CONSEQUENCES OF CELLULAR AND HUMORAL RESPONSES IN TREATMENT‐NAIVE
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY: A COMBINED SONOGRAPHIC AND NERVE
CONDUCTION STUDY
Goedee HS
1,2, van der Pol WL1,2, Herraets IJT1,2,3, van Asseldonk JTH3, Visser LH3, van den
Berg LH1,2.
1Department of Neurology, UMC Utrecht, Utrecht, The Netherlands; 2Department of Neuroscience,
Brain Center Rudolf Magnus, UMC Utrecht, Utrecht, The Netherlands; 3Department of
Neurology and Clinical Neurophysiology, St. Elisabeth Hospital, Tilburg, The Netherlands.
Our study was aimed to evaluate the functional and morphological consequences of cellular
and humoral responses in chronic inflammatory demyelinating neuropathy (CIDP), using
extensive standardized high‐resolution sonography (HRUS) and nerve conduction study
(NCS) protocols in incident treatment‐naive patients.
We enrolled 50 consecutive, newly diagnosed, treatment naive patients with CIDP. In
addition to all relevant clinical examinations, all patients underwent a standardized
NCS and extensive HRUS protocol, of median, ulnar, tibial, fibular and sural nerves.
We assessed standard nerve and fascicle size, and echogenicity.
We found focal sonographic enlargements in multiple nerves and nerve segments with
and without NCS abnormalities. The degree of nerve hypertrophy was not associated
with presence of NCS features of demyelination, i.e. 84/132 (64%) of median nerve
segments showed enlargement without strong decrease in motor conduction velocity and
102/111 (92%) hypertrophic median nerve segments revealed no conduction block. A lower
distal CMAP of median nerve was related with lower MRC sums‐scores (p < 0.001). We
found no correlation between age, disease duration or MRC sum‐score and nerve size.
Cellular and humoral responses in CIDP may lead to nerve enlargement along the length
of nerves, that can be detected by HRUS, whereas NCS allows identification of its'
specific focal disruption in nerve function.
SCHWANN CELL p75NTR EXPRESSION AND DIABETIC NEUROPATHY
Gonçalves NP
1,2, Murray SS3, Jensen TS2,4, Vaegter CB1,2.
1Danish Research Institute of Translational Neuroscience DANDRITE Nordic‐EMBL Partnership,
Department of Biomedicine, Aarhus University, Aarhus, Denmark; 2The International
Diabetic Neuropathy Consortium, Aarhus University, Aarhus, Denmark; 3Department of
Anatomy and Neuroscience, The University of Melbourne, Victoria, Australia; 4Department
of Neurology and Danish Pain Research Center, Aarhus University, Aarhus, Denmark.
The most common complication of diabetes is peripheral neuropathy, which has prevalence
as high as 50% and is characterized by damage to neurons, Schwann cells and blood
vessels within the nerve. The concept of Schwannopathy as an integral factor in the
pathogenesis of diabetic neuropathy is re‐emerging, and it is now known that Schwann
cells cultured in hyperglycemic environments underproduce neurotrophins and exhibit
loss of axonal associations, further indicating a non‐optimal glial cell activation
and function. Furthermore, the increased expression of p75NTR in myelin sheaths around
fibers that are susceptible to axonal degeneration in diabetic neuropathy suggest
an important role for this molecule in disease progression. With this project, it
is our main goal to evaluate how disruption of p75NTR signaling in the Schwann cells
affects the pathophysiology of diabetic neuropathy.
By using a fluorescent live/death cell viability assay, our preliminary data indicate
that wild‐type Schwann cell cultures present increased cell death rate 24h after stimulation
with high levels of glucose. The p75NTR has a highly recognized role in the activation
of death signals and when absent, we observed that Schwann cells are significantly
more resistant to apoptosis in hyperglycemic conditions. The role of p75NTR receptor
signaling in neuron‐Schwann cell communication and myelination under in vitro diabetic
conditions was investigated with primary Schwann cell‐sensory neuron co‐cultures.
After eight days of ascorbic acid stimulation, both under euglycemic and hyperglycemic
conditions, myelination was assessed by confocal microscopy using specific markers
for neurons and myelin. Results highlight a compromised ability of wild‐type Schwann
cells to myelinate axons when exposed to a hyperglycemic environment, which was even
intensified in co‐cultures with Schwann cells lacking the p75NTR. To complement the
in vitro studies, we are modeling type 2 diabetes in a p75NTR Schwann cell conditional
KO mouse model and plan to investigate nerve mRNA expression profile to disclose genetic
regulation depending on this receptor signaling and its modulatory role in endoneurial
hypoxia and neuroinflammation.
The results from this project will provide an integrated vision of how impaired Schwann
cell activity guides neuropathy progression.
DEFINITION AND DIAGNOSIS OF SMALL FIBER NEUROPATHY (SFN): RECOMMENDATIONS FROM THE
BRAZILIAN ACADEMY OF NEUROLOGY
Gondim FAA
1, Barreira AA1, Cruz MW1, Cunha FMB1, De Freitas M1, França MC Jr1, Marques W Jr1,
Nascimento OJM1, Oliveira ASB1, Pereira RC1, Pupe C1, Rotta FT1, Schestatsky P1.
1Panelists on behalf of the Scientific Department of Peripheral Neuropathy, Brazilian
Academy of Neurology, Brazil.
Neuropathy is one of the most common neurological manifestations of several diseases
and SFN has been progressively receiving more attention in the medical literature.
The aim of this study is to generate a set of recommendations to define and diagnose
SFN in Brazil. A group of 13 neurologists, members of the Scientific Department of
Peripheral Neuropathy from the Brazilian Academy of Neurology reviewed a preliminary
draft prepared by the first author that was distributed by email. The panelists got
together on 6.4.2017 at the city of Fortaleza, Brazil, to discuss and finish the text
for the first submission of the manuscript. SFN can be defined as a subtype of neuropathy
characterized by selective involvement of unmyelinated or thinly myelinated sensory
(sometimes also autonomic) fibers. It is usually characterized by sensory (pain/dysesthesias/pruritus)
or combined sensory and autonomic complaints, associated with an almost entirely normal
neurological examination (except for sensory changes). Electromyography is normal.
A growing list of medical conditions has been linked to SFN, although there is no
evidence‐based literature to support the use of any specific set of screening tests
to diagnose the etiology of SFN (the panelists will suggest a basic screening panel).
SFN may also serve as a fallacious but useful terminology to uncover discrepancies
in the normal values from different neurophysiology laboratories. In Brazil, skin
biopsy is not usually performed and initial forms of leprosy may have predominant
small fiber involvement. There are several tests to demonstrate involvement of small
sensory and autonomic fibers. Skin wrinkling test, sympathetic skin responses & heart
rate variability (conducted on EMG machines) and thermoregulatory sweat test may be
low‐cost screening alternatives. After the final meeting on 6.4.2017, we finished
the first draft for submission to Arquivos de Neuropsiquiatria (together with a translation
to Portuguese as supplementary material), the official journal of the Brazilian Academy
of Neurology to serve as a source for the definition and diagnosis of SFN in Brazil.
The final draft will be submitted after presentation at the PNS Meeting in Barcelona
on 7.2017.
IMAGING OF THE LOWER CRANIAL NERVES (LCN) IN THE EXTRACRANIAL COURSE
Grisold A
1, Grisold W2, Finsterer J3, Meng S4,5.
1Department of Neurology, Medical University of Vienna, Vienna, Austria; 2Ludwig Boltzmann
Institute for Experimental and Clinical Traumatology, Vienna, Austria; 3Department
of Neurology, Krankenanstalt Rudolfstiftung, Vienna, Austria; 4Department of Radiology,
Kaiser Franz Josef Hospital, Vienna, Austria; 5Center for Anatomy and Cell Biology,
Medical University of Vienna, Vienna, Austria.
The lower cranial nerves (LCN) include the paired glossopharyngeal, the vagal, the
accessory and the hypoglossal nerves. These are involved in the execution of swallowing,
speech, phonation, tasting, as well as sensory and autonomic functions. LCN can be
affected in central and peripheral nervous system diseases.
This study investigates the use of ultrasound (US) to detect lesions of the peripheral
course of LCN. In addition MRI can be used in unilateral LCN local lesions to demonstrate
indirect signs of nerve lesions such as muscle atrophy.
The patients were examined in supine position with the neck in maximum extension with
either a regular or a portable US system (LOGIQ e and Logiq E9 GE Healthcare, Milwaukee,
Wisconsin) and high frequency transducers (12 to 20 Mhz). According to the detected
pathology longitudinal or transversal images were recorded.
A series of exemplary observations are demonstrated.
In one case a paraganglioma in the glossopharyngeal nerve at the carotid sinus was
found. In another patient an US of the thyroid gland revealed a nerve tumor, which
was later identified to be a schwannoma. In another case multiple neurofibroma were
identified in the vagal nerve during a routine neurofibromatosis screening.
US has become also important in investigations of lesions of the accessory nerve,
following damage by surgery. Nerve continuity and scar formation can be distinguished.
Lesions of the hypoglossal nerve can be caused by tumor infiltration. In one patient
an infiltration of the nerve by a squamous cell carcinoma, and in another case by
a low grade sarcoma were detected. In addition MRI demonstrated an atrophy of the
tongue.
Identification and assessment of the LCN from the point of exit of the skull to their
endpoint can be pursued by US techniques, which have been described for the individual
nerves. US is easily applicable and – in addition to the “static” image of the MRI
– allows assessing nerve positions during different movements, as well as detecting
muscle movements as fasciculations.
MRI can also be used to detect not only more proximal lesions, but also changes of
the skeletal muscle by denervation.
AUTOIMMUNE T CELLS IN AN EX VIVO MODEL OF THE PERIPHERAL NERVOUS SYSTEM
Grümme L1, Hattenhauer ST2, Wolffram K2, Kleinschnitz C1, Mausberg AK
1, Stettner M1.
1University Hospital Essen, Essen, Germany; 2Heinrich‐Heine‐University, Düsseldorf,
Germany.
In chronic inflammatory demyelinating polyneuropathy (CIDP), T cells are suspected
to play a crucial role in myelin destruction. CD4 and CD8 T cells contribute to the
inflammatory process, while the exact mechanism of myelin damage is still under debate.
To elucidate the molecular interaction of T cells and myelin sheets, we compared neuritogenic
and control cells in a live imaging in vitro model.
The myelinated fibres of rat dorsal root ganglia (DRG) served as model for the peripheral
nervous system. DRGs of embryonic (E16) Lewis rats were cultured; myelination was
initiated after one week in vitro and continued for two additional weeks.
Lewis rats immunized with P2 and neuritogenic T cells of the lymph nodes were obtained
ten days after immunization. Control T cells were prepared from healthy rats. For
vital tracking, neuritogenic T cells were stained with Orange Cell Tracker, while
the control cells were labelled with CFSE. Myelin detection in vital cultures was
assessed by incorporation of C16 fatty acids conjugated with a fluorophore into the
myelin layer. Experiments were performed in a conditioned microscope chamber, the
two T cell populations were added simultaneously to the DRG culture and migration
was tracked using live cell imaging.
We observed differing migration patterns for neuritogenic and control T cells. The
velocity as well as the directionality was altered. After initial contact, the non‐
neuriotgenic T cells in close proximity to myelin subsequently decreased over time,
while the numbers of neuritogenic T cells close to myelin remained stable. Long term
incubation with neuritogenic T cells affected the myelin integrity in regard to the
intermodal length as well as the myelin ratio. Further experiments will elucidate
the specific effects of neuritogenic T cells to decipher the role of T cells during
inflammation in the PNS, which could be useful in developing targeted therapies.
TAFAMIDIS DELAYS DISEASE PROGRESSION COMPARABLY ACROSS VAL30MET AND NON‐VAL30MET GENOTYPES
IN TRANSTHYRETIN FAMILIAL AMYLOID POLYNEUROPATHY
Gundapaneni B
1, Sultan MB2, Keohane DJ2, Schwartz J2.
1inVentiv Health Inc., Burlington, MA, USA; 2Pfizer Inc., New York, NY, USA.
Transthyretin familial amyloid polyneuropathy (TTR‐FAP) is a rare, life‐threatening
disorder caused by protein destabilizing TTR gene mutations, broadly classified as
Val30Met (the most common mutation worldwide) and non‐Val30Met genotypes. Tafamidis,
a highly‐specific TTR‐stabilizer, is the only medicine approved to delay neurologic
progression in TTR‐FAP. The objective of this post‐hoc analysis was to compare the
effects of tafamidis on neuropathy progression in patients with Val30Met and non‐Val30Met
genotypes. Val30Met patients were participants in a randomized, double‐blind, placebo‐controlled
clinical trial of tafamidis, while non‐Val30Met patients were participants in an open‐label
tafamidis study. Patients were grouped into three cohorts: Val30Met tafamidis (n=64);
Val30Met placebo (n=61); and non‐Val30Met tafamidis (n=21). Baseline disease severity
and change in disease severity from baseline to month 12 was assessed using the Neuropathy
Impairment Score‐Lower Limbs (NIS‐LL). The effect of tafamidis in the Val30Met and
non‐Val30Met cohorts versus the Val30Met placebo cohort was determined using a mixed‐effects
model for repeated measures (MMRM). At baseline, patients in the non‐Val30Met cohort
were older, had longer symptom duration, and more advanced neurologic impairment than
the Val30Met cohorts. At month 12, the baseline‐adjusted mean ± standard error change
in NIS‐LL was comparable between the Val30Met tafamidis and non‐Val30Met tafamidis
cohorts (1.60±0.78 and 1.62±1.43, respectively). These changes were smaller than that
observed in the Val30Met placebo cohort (4.72±0.77; P=0.0055 vs Val30Met and P=0.0592
vs non‐Val30Met) indicating less disease progression. Based on predicted values from
the MMRM analysis, the size of the change in NIS‐LL across the full range of baseline
NIS‐LL scores was remarkably similar in the Val30Met tafamidis and non‐Val30Met tafamidis
cohorts and was consistently smaller than that observed in the Val30Met placebo cohort.
Moreover, in all three cohorts, as baseline NIS‐LL increased, the predicted level
of disease progression also increased. In conclusion, while controlling for baseline
disease severity, tafamidis delayed disease progression to a comparable extent in
Val30Met and non‐Val30Met patients. The similar trajectories of disease progression
across Val30Met and non‐Val30Met patients suggest that these two genotype groups may
be more similar than previously considered. http://ClinicalTrials.gov identifiers:
NCT00409175; NCT00630864.
PROLONGED POST‐TETANIC POTENTIATION
Gutmann L
1, Shy M1.
1University of Iowa, Iowa City, IA, USA.
Post tetanic potentiation (PTP) is a physiological phenonmenon seen with disorders
of the neuromuscular junction (NMJ). It is caused by the influx of Ca++ into the terminal
axon during the tetanus resulting in an increased number of acetylcholine (Ach) vescicles
released by each axonal action potential. In myasthenic syndromes it results in improved
NMJ function by increasing the probability of achieving a large enough end plate potential
to generate a muscle action potential. PTP has different appearances depending on
whether the NMJ defect is pre‐synaptic or post‐synaptic. In pre‐synaptic defects (the
most common being Lambert‐Eaton syndrome) there is an increased amplitude of the muscle
action potential after a tetanus that persists up to minutes. Prolonged PTP has now
been reported in 2 disorders, one on a genetically determined neuropathy/myasthenic
basis and the other on an acquired toxic origin.
Prolonged PTP up to 60 minutes was reported in 2 families with a motor neuropathy
(having leg weakness and foot deformites) and a congenital myasthenic syndrome caused
by a heterozygous mutation of the synaptotamin II (SYT2) gene (c920T>G p.Pro308[p.Asp307Ala]
and c923G>A [p.Pro308Leu]). Electrophysiological testing showed features of a presynaptic
defect with prolonged PTP persisting up to 60 minutes. The same phenomenon has been
noted in the acquired pre‐synaptic defect caused by botululinum toxin. The PTP continued
up to 21 minutes. SYT2 is the synaptic vescicle calcium sensor in the terminal axon,
allowing for fusion of Ach containing vescicles with the presynaptic membrane and
the synchronous release of Ach. The fusion requires a complex assembly process involving
SNARE proteins. Both the SYT2 gene mutation and botulinum toxin affect normal SYT2
function, the mutation by altering amino acids in the calcium‐binding domain and the
toxin by binding to SYT2 as well as gangliosides GD1a and GT1b on the neural membrane.
The mechanism for the PTP prolongation remains unknown. Prolonged PTP appears to be
a unique physiological abnormality resulting from altered SYT2. This phenomenon has
been decribed to occur in SYT2 mutations causing congenital motor neuropathy/myasthenic
syndrome and botulism. The abnormality may represent a physiological marker for a
presynaptic NMJ defect involving altered SYT2.
THE MODIFIED MULTIPLE POINT STIMULATION METHOD FOR MOTOR NUMBER UNIT ESTIMATION
Hachisuka A
1,2, Senger J3, Curran M3, Chan KM1,3.
1Division of Physical Medicine and Rehabilitation, University of Alberta, Edmonton,
Canada; 2Department of Rehabilitation and Medicine, University of Occupational and
Environmental Health, Kitakyushu, Japan; 3Division of Plastic surgery, University
of Alberta, Edmonton, Canada.
Background: Motor unit number estimation (MUNE) techniques are valuable tools in neuromuscular
disease. Among them, the multiple point stimulation (MPS) is one of the most common
used. Contamination by distant single motor unit potentials (SMUPs) generated by neighboring
muscles is a potential confounding factor. This is particularly problematic in ulnar
neuropathy, one of the most common neuropathies in humans. Reason being that the ulnar
nerve innervates the majority of hand muscles. The goals of this study are to test
the hypotheses that 1) distant SMUPs all have an initial positive deflection and 2)
elimination of SMUPs generated by distal muscles will significantly lower the MUNE
results in the hypothenar muscles.
Methods: To address the first hypothesis, we tested 10 subjects by stimulating their
median nerve while recording SMUPS simultaneously over the hypothenar and thenar muscles.
For the second hypothesis, we carried out MPS MUNE of the hypothenar muscles using
multi‐channel recordings placed over ulnar innervated intrinsic muscles across the
hand. When a SMUP with an initial positive deflection was detected at the hypothenar
electrodes, its original was systemically tracked through all the recording channels.
Results: In the first series of experiments, in accordance with the dipole theory,
all SMUPs recorded at the hypothenar recording electrodes had an initial positive
polarity. In the second series of experiments, of the 41 studies carried out in 28
subjects, distant SMUPs generated by muscles other than those in the hypothenar eminence
represented 17±9.5% (mean±SD) of the overall sample. MUNE calculated using only SMUPs
generated by the hypothenar muscles was 423± 204, compared to 537±290 if all SMUPs
were included (p < 0.05). The extent of increase in MUNE was highly correlated with
the proportion of distant SMUPs found in each study (r = 0.89, p < 0.05).
Conclusion: In contrary to some studies suggesting that SMUPs from distant muscles
could have an initial negative deflection, we found all SMUPs from distant muscles
had a positive deflection. Exclusion of those SMUPs from the sample had a significant
impact on the MUNE results.
CILOSTAZOL MODULATES SEQUENTIAL EXPRESSION OF MATRIX METALLOPROTEINASES AND THEIR
INTRINSIC INHIBITOR WITHIN PERIPHERAL NERVOUS TISSUE DURING EXPERIMENTAL AUTOIMMUNE
NEURITIS
Hagiwara W1, Konno S1, Kihara Inoue M1, Fujioka T
1.
1Toho University, Tokyo, Japan.
Matrix metalloproteinase (MMP) plays crucial roles in developing immune‐mediated neuritis
as Guillain‐Barré syndrome (GBS) and its animal model experimental autoimmune neuritis
(EAN). To investigate the intraneural expression of MMPs during EAN and the effect
of a phosphodiesterase‐3 inhibitor cilostazol (CLZ) on it, EAN rats were treated with
either 30 mg/kg/day of CLZ or vehicle from one day post immunization (dpi). To induce
EAN female Lewis rats were immunized with synthetic peptide from bovine P2 protein.
Cauda equina (CE) were removed in several time points, total RNA was extracted and
reverse‐transcribed to obtain cDNA that was subjected to Real‐time PCR analysis for
expression of MMP‐7, MMP‐9 and tissue inhibitor of matrix metalloproteinase‐1 (TIMP‐1)
messages. MMP‐7 and MMP‐9 messages peaked at 7 dpi, that is presymptomatic phase of
EAN. All rats developed motor paralysis at 11 dpi, MMP‐7 and MMP‐9 messages subsided
at this moment. However, TIMP‐1 message reciprocally increased at 11 dpi, persisted
through 21 dpi. Treatment of CLZ suppressed motor paralysis of EAN significantly.
MMP‐7 message peaked at 14 dpi and MMP‐9 message peaked at 11 dpi. On the other hand,
both messages at 7 dpi were suppressed compared to untreated EAN rats. TIMP‐1 message
in CLZ treated rats peaked at 14 dpi coincided with motor paralysis peak. Both MMP‐7
and MMP‐9 messages might result in subsequent upregulation of TIMP‐1 that finally
downregulates MMPs activity and inflammatory process. CLZ treatment suppressed and
delayed expression of MMPs and facilitate TIMP‐1 expression, resulting suppression
of EAN. The precise mechanism of expression of MMPs and TIMP‐1 remain unclear, however,
that MMP‐7 and MMP‐9 messages peaked at 7 dpi suggests involvement of pro‐inflammatory
cytokines such as tumor necrosis factor‐alpha or interleukin‐1. CLZ might suppress
these cytokines resulted in MMPs down regulation. MMP‐9 less affected by CLZ and thus
stimulated TIMP‐1 expression at 14 dpi. CLZ might rational treatment for immune‐mediated
neuropathy via MMPs modulation although further investigation especially in‐vivo study
is needed.
IMPAIRMENT OF AUTOPHAGY AS A POSSIBLE PATHOMECHANISM FOR CMT CAUSING MUTATIONS IN
HSPB1
Haidar M
1, De Winter V1, Asselbergh B1, Bouhy D1, Timmerman V1.
1Peripheral Neuropathy Research Group, VIB, University of Antwerp, Antwerp, Belgium.
The small heat shock protein HSPB1 (HSP27) gene is ubiquitously expressed and encodes
for a chaperone protein with essential cellular functions. Our lab was the first to
identify missense mutations in HSPB1 responsible for axonal Charcot‐Marie‐Tooth neuropathy
(CMT2F). Since then we became interested in understanding the physiological functions
of HSPB1 and its association with CMT neuropathies. We demonstrated the involvement
of HSPB1 in microtubule stability. Because of the link between autophagosome formation
and its intracellular transport, and microtubules stability, we believed that the
macro‐autophagy process could be regulated by HSPB1. Macro‐autophagy is a cellular
housekeeping process during which autophagosomes target, envelop and degrade aberrant
protein aggregates and damaged organelles. There is strong evidence for an essential
role for autophagy in the maintenance of neuronal homeostasis; hence its impairment
can lead to a neuropathic condition. Our data indicate that macro‐autophagy is disrupted
by HSPB1 CMT‐causing mutations. Combining novel microscopy and interactomics techniques
we unravelled the way different CMT‐causing mutations in HSPB1 impair the autophagic
pathway. Our data present the impairment of autophagy as a possible pathomechanism
for CMT‐causing HSPB1 mutations.
GENE THERAPY ON RAT MODELS OF THE PERIPHERAL NEUROPATHY CHARCOT‐MARIE‐TOOTH
Hajjar H
1, Gautier B1, Berthelot J1, Gonzalez E1, Gess B2, Young P2, Tricaud N1.
1Institute of Neurosciences of Montpelllier, INSERM, University of Montpellier, Montpellier,
France; 2Universitätsklinikum Münster, Klinik für Schlafmedizin und neuromuskuläre
Erkrankungen, Münster, Germany.
CMT1A, the most common of Charcot‐Marie‐Tooth diseases, results from the duplication
of Peripheral Myelin Protein 22 (PMP22) gene. This gene encodes for a small protein
of 22 kDa, PMP22, mainly produced by Schwann cells and the excess of PMP22 leads to
demyelination. There is no cure for this disease but one approach for a treatment
is gene therapy. A transgenic rat model exists for CMT1A, which possesses 3 copies
of the mouse PMP22 gene. Our goal is to provide a proof of principle for gene therapy
in peripheral nerves using this rat model of CMT1A. Our strategy is to reduce the
overexpression of mouse PMP22 protein in rats Schwann cells using short hairpin RNAs
(shRNAs). shRNAs are small non‐coding RNAs that specifically bind to targeted mRNAs
resulting in their degradation. We tested for the efficiency of several shRNAs targeting
mouse PMP22 in vitro to find two shRNAs that reduce PMP22 levels. The shRNAs have
been cloned in an adeno‐associated serotype 9 (AAV9) viral vector together with Green
Fluorescent Protein in order to detect infected cells. AAV9 was selected for its high
transduction rate of myelinating Schwann cells, for its good diffusion and low immunogenicity.
We plan bilateral injections in the sciatic nerve of control and diseased rats. The
efficiency of this gene therapy will be checked by assessing muscle strength (grip
test), way of walking (catwalk), mobility (rotarod) and nerve conduction velocity
of treated CMT1A rats versus non‐treated. The process of myelination and myelin maintenance
in Schwann cells will be analyzed by biochemistry and electron microscopy. Biochemical
tests include Western Blot for PMP22 protein expression in sciatic nerve, immunohistochemistry
for PMP22 protein expression in myelinating Schwann cells and PCR for mRNA PMP22 expression.
If the therapy is successful in rats, it could possibly be later on used in clinical
trials.
MEDIAN NERVE ULTRASOUND MORPHOLOGY CADAVER SCREENING
Hamscha U
1, Grisold A2, Grisold W3, Meng S1,4
. 1Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria;
2Department of Neurology, Medical University of Vienna, Vienna, Austria; 3Ludwig Boltzmann
Institute for Experimental and Clinical Traumatology, Vienna, Austria; 4Department
of Radiology, Kaiser Franz Joseph Hospital, Vienna, Austria.
Ultrasound is a widely‐used tool in diagnosing carpal tunnel syndrome (CTS). Several
different methods for sonographical evaluation of median nerve damage exist, such
as calculating the ratio of cross sectional areas (CSA) of median nerves in various
sites. This enables detection of actual nerve swelling proximal to the carpal tunnel
as an expression of median nerve damage inside the carpal tunnel (as seen in CTS).
In comparison to other diagnostic methods no data exist about the prevalence of CTS
like changes in an unselected population.
A series of 166 non‐selected fresh cadavers were examined. 332 arms of 166 fresh,
non‐embalmed whole body cadavers were examined. The medical record did not allow to
obtain conclusive information on the peripheral nerves. Using a regular ultrasound
system with a 14 Mhz transducer, median nerves were identified and tracked along their
course in the forearms. CSA measurements of the median nerves were performed at two
sites in each arm: 1.) halfway between the elbow joint and wrist, 2.) directly proximal
to the carpal tunnel. CSA ratio was calculated with the following formula:
C
S
A
ratio
=
C
S
A
wrist
c
m
2
C
S
A
forearm
c
m
2
CSA ratio < 1.5 was found in 282 (84.93%) arms, CSA ratio ≥ 1.5 in 40 (12.04%) arms
and CSA ratio ≥ 2 in 10 (3%) arms. CSA ratio ≥ 1.5 was detected in 17.58% of women
and 12% of men. The overall mean (± SD) age was 80.52 ± 10.04 years. Men (78.56 ±
10.16) were significantly younger than women (82.14 ± 9.6; p = 0.001). A weak but
significant correlation between age and CSA ratio was found in women (Spearman ‐−
0.185; p=0.013), but not in men (p=0.79). The mean BMI for CSA ratio ≥ 1.5 was 26.54
± SD 5.35.
Based on a CSA ratio ≥ 1.5 as a criterion for CTS, the present ultrasound results
are consistent with the average CTS prevalence reported in previous studies, which
were obtained with electrophysiological methods. This study on a large unselected
series of cadavers confirms the comparability of both methods.
POLYNEUROPATHY RELATES TO IMPAIRMENT IN DAILY ACTIVITIES, WORSE GAIT AND FALL‐RELATED
INJURIES
Hanewinckel R
1,2, Drenthen J2,3, Verlinden VJA1, Darweesh SKL1, van der Geest JN3, Hofman A1,5,
van Doorn PA2, Ikram MA1
.
1Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands;
2Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands;
3Department of Neuroscience, Erasmus University Medical Center, Rotterdam, The Netherlands;
4Department of Clinical Neurophysiology, Erasmus University Medical Center, Rotterdam,
The Netherlands; 5Department of Epidemiology, Harvard T.H. Chan School of Public Health,
Boston, MA, USA.
Polyneuropathy is a common and disabling disorder, but population‐based data about
important patient‐orientated outcomes, such as the ability to perform activities of
daily living, risk of falls and related injuries, and gait patterns is scarce. Therefore
we extensively investigated the association of chronic polyneuropathy with basic and
instrumental activities of daily living (BADL and IADL), falls and gait patterns in
the large, prospective, population based Rotterdam Study. In total, 1445 participants
of this study (mean age 71 years, 54% women) underwent a polyneuropathy screening
involving a symptom questionnaire, neurological examination and nerve conduction studies.
Screening yielded four groups: no, possible, probable and definite polyneuropathy.
Participants were interviewed about BADL (Stanford Health Assessment questionnaire),
IADL (Instrumental Activities of Daily Living scale) and frequency of falling in the
previous year. In a random subset of 977 participants, gait was assessed with an electronic
walkway (GAITRite). Associations of polyneuropathy with BADL and IADL were analyzed
continuously with linear regression, and dichotomously with logistic regression. History
of falling was evaluated with logistic regression and gait changes were evaluated
with linear regression. We found that participants with definite polyneuropathy had
more difficulty in performing BADL and IADL than participants without polyneuropathy.
Polyneuropathy related to worse scores of all BADL (especially walking) and three
IADL components (housekeeping, traveling, and shopping). Participants with definite
polyneuropathy were two times more likely to fall, and these falls more often resulted
in injury. Participants with polyneuropathy had worse gait parameters on the walkway,
including lower walking speed and cadence, and more errors in tandem walking. In summary,
chronic polyneuropathy is strongly associated with significant impairment in daily
life. Recognition of polyneuropathy and related disability is very important in order
to inform, support and possibly treat patients, and to prevent future falls and dependence
in daily functioning.
DIAGNOSTIC VALUE OF SYMPTOMS IN CHRONIC POLYNEUROPATHY: THE ERASMUS POLYNEUROPATHY
SYMPTOM SCORE (E‐PSS)
Hanewinckel R
1,2, van Oijen M1, Merkies ISJ3,4, Notermans NC5, Vrancken AFJE5, Ikram MA2, van Doorn
PA1.
1Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands;
2Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands;
3Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands;
4Department of Neurology, St. Elisabeth Hospital, Willemstad, Curaçao; 5Department
of Neurology, University Medical Center Utrecht, The Netherlands.
Patients with polyneuropathy often suffer from tingling sensations, numbness, weakness
and pain. These symptoms are used in several screening questionnaires, most of which
were developed for high‐risk patient groups, such as individuals with diabetes mellitus.
In most tools equal weights are applied to all symptoms, while some might be more
informative than others. We evaluated the diagnostic value and frequency of occurrence
of individual symptoms of chronic polyneuropathy and constructed and validated a simple
screening questionnaire that can reliably help to diagnose polyneuropathy in low‐risk
patient groups. In a multi‐step procedure, we initially compiled a twelve‐item questionnaire
concerning symptoms of polyneuropathy. The questionnaire was completed by 117 polyneuropathy
patients and 188 controls (headache, transient ischemic attack, multiple sclerosis).
We calculated the sensitivity, specificity and likelihood ratios of each individual
symptom. Next, stepwise multivariable logistic regression was used to create a compact
model, able to discriminate cases from controls using only the most informative symptoms.
A simple scoring system was subsequently developed based on the regression coefficients
of this reduced model. External validation was subsequently conducted in a population
of 140 cases with chronic idiopathic axonal polyneuropathy and 96 controls without
polyneuropathy. Performance was assessed with discrimination (area under the curve,
AUC), and calibration. Numbness and tingling feet were most frequently reported by
polyneuropathy patients and had the highest sensitivity. Feeling as if walking on
cotton wool and allodynia of the feet had the highest specificity. Multivariable logistic
regression yielded a model that contained these four symptoms, complemented with balance
problems and tingling hands. Based on this regression analysis, the Erasmus Polyneuropathy
Symptom Score (E‐PSS) was created, a score ranging from 0 to 14. This polyneuropathy
symptom score had a good performance (AUC 0.92) in de derivation set and proved to
be valid in the external population (AUC 0.95). In this study, we created a simple,
validated polyneuropathy symptom score (E‐PSS) that takes both the individual value
of only six different symptoms and its frequency into account. This tool can be helpful
as screening instrument in clinical practice and for future studies on polyneuropathy.
MR‐NEUROGRAPHY DETECTS INVOLVEMENT OF THE PERIPHERAL NERVOUS SYSTEM IN MULTIPLE SCLEROSIS
Hauck G1,2, Jende J2, Diem R3, Weiler M3, Heiland S4, Wildemann B3, Korporal‐Kuhnke
M3, Wick W3, Hayes JM5, Pfaff J2, Pham M2,6, Bendszus M2, Kollmer J
2.
1Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany;
2Department of Radiology, Hannover Medical School, Hannover, Germany; 3Department
of Neurology, Heidelberg University Hospital, Heidelberg, Germany; 4Division of Experimental
Radiology, Department of Neuroradiology, Heidelberg, Germany; 5Department of Neurology,
University of Michigan, Ann Arbor, MI, USA; 6Department of Neuroradiology, Würzburg
University Hospital, Würzburg, Germany.
Multiple sclerosis (MS) is traditionally viewed as a central nervous system disease.
To date, there is no unequivocal evidence implicating involvement of the peripheral
nervous system (PNS). This study aims to prove whether the PNS is additionally affected
and if so, to detect, localize and quantify these peripheral nerve lesions in patients
with multiple sclerosis (MS) by applying high‐resolution MR‐Neurography (MRN) with
large anatomical coverage in combination with standard electrophysiological and neurological
tests.
We prospectively enrolled 34 patients with confirmed MS (>3 years), two patients with
clinically isolated syndrome (CIS), and 35 age‐/sex‐matched healthy volunteers. Any
other potential causes for a concomitant polyneuropathy were excluded. All MS patients
underwent detailed neurological and electrophysiological testing. 3 Tesla MRN with
large anatomical coverage from lumbar plexus and spinal nerves down to ankle level
was performed in all participants by using fat‐saturated, T2‐weighted turbo‐spin‐echo
(TSE) sequences (TR/TE 5970/55 ms) and a dual echo TSE sequence for T2‐relaxometry
(TR 5210 ms; TE1/TE2 12/73 ms). A 3D T2‐weighted, fat‐saturated SPACE sequence (TR
3000 ms; effective TE 210 ms) was used for imaging of the lumbar plexus. Manual segmentation
of spinal/sciatic/tibial/peroneal nerves was performed on a total of 15,975 axial
slices. Besides evaluation of nerve T2w‐signal, detailed quantification of nerve lesions
by analyzing morphometric (nerve caliber) and microstructural markers (proton‐spin‐density
and T2‐relaxation‐time) was conducted.
Mean lesion load at thigh level was higher in MS (151.5±5.7) vs. controls (19.1±2.4;p<0.0001).
Nerve proton‐spin‐density was also higher in MS (tibial/peroneal: 371.8±7.7 / 368.9±8.2)
vs. controls (tibial/peroneal: 266.0±11.0 / 276.8±9.7;p<0.0001). In contrast, T2‐relaxation
time was significantly higher in controls (tibial/peroneal: 82.0±2.1 / 78.3±1.7) vs.
MS (tibial/peroneal: 64.3±1.0 / 61.2±0.9;p<0.0001). Proximal tibial and fibular nerve
caliber was also significantly higher in MS (tibial: p<0.0015; fibular: p=0.0049).
For the first time, PNS lesions in MS patients could be visualized and quantified
in vivo by high‐resolution MRN. Lesions are indicated by an increase of proton‐spin‐density
and a decrease of T2‐relaxation‐time. Nerve caliber as a morphometric criterion also
significantly increased. This proof‐of‐concept study may offer new insights into the
pathomechanism of MS and might have future implications on therapeutic approaches.
THE ROLE OF IMMUNOGLOBULIN G FC‐GAMMA RECEPTOR POLYMORPHISMS IN THE PATHOGENESIS OF
GUILLAIN‐BARRÉ SYNDROME IN BANGLADESH
Hayat S
1,2,3, Babu MG1, Jahan I1, Rahman I1, Mahmud I3, Hassan Z2, Islam Z1.
1Laboratory Sciences and Services Division, International Centre for Diarrheal Disease
Research (icddr,b), Dhaka, Bangladesh; 2Department of Physiology and Molecular Biology,
Bangladesh University of Health Sciences, Dhaka, Bangladesh; 3Department of Biochemistry
and Molecular Biology, University of Dhaka, Dhaka, Bangladesh.
Immunoglobulin G (IgG) Fc‐gammaRs confer diverse effector functions by linking the
cellular and humoral arms of the immune system that has been involved in the pathogenesis
of Guillain‐Barré syndrome (GBS). In the post‐polio era, the polymorphisms of Fc‐gammaR
and their relevant knowledge have become one of the main targets for new therapeutic
strategies for the treatment of GBS patients. Differences in severity and frequency
of GBS subtypes found between South‐Asian and Western populations can be attributed
to their genetic susceptibility. Therefore, we aimed to determine Fc‐gammaR polymorphic
alleles (Fc‐gammaRIIa: H131/R131; Fc‐gammaRIIIa: V158/F158; Fc‐gammaRIIIb: NA1/NA2)
and their possible link with GBS on the currently available large GBS cohort in Bangladesh.
Fc‐gamma R polymorphisms of 151 GBS patients and 151 healthy controls were genotyped
using sequence‐specific PCR. For validation, we carried out the sequencing of some
samples for Fc‐gammaRIIa and Fc‐gammaRIIIa alleles. No significant differences were
found regarding the distribution of Fc‐gammaR genotypes and allele frequencies in
GBS patients and controls. Fc‐gammaR‐H/H‐131 genotype was significantly predominant
in patients with severe disease compared to patients with mild disease (p=0.02, OR,
2.8; 95% CI, 1.2‐6.6). No other significant associations were found in GBS patients
for candidate alleles and disease severity. Fc‐gammaRIIIa‐F/F‐158 was found to be
significantly predominant in anti‐GM1 antibody positive GBS patients compared to anti‐GM1
antibody negative patients (p=0.02, OR, 2.5, 95% CI, 1.2‐5.3). Fc‐gammaRIIIa‐V158
alleles were significantly higher in patients with poor prognosis when compared to
patients with good outcome (p=0.047, OR, 1.76, 95% CI, 1.02‐3.02). No significant
association of Fc‐gammaRIIIb genotypes and alleles were found with GBS patients, disease
severity and disease outcome. Extensive subgroup analysis revealed no significant
association in genotype and allele frequencies between AMAN and AIDP subtype. In conclusion,
IgG Fc‐gammaR polymorphisms do not constitute significant risk markers for susceptibility
to GBS, however homozygous Fc‐gammaRIIa‐H131 might be involved in the severe form
of GBS. In addition, Fc‐gammaRIIIa‐F/F‐158 might play an important role in the molecular
mimicry against nerve gangliosides in GBS. Further studies that enroll a large number
of patients (e,g. IGOS) are required to confirm the present findings from different
geographical areas.
HIGH FAT FED FEMALE MICE DEVELOP PERIPHERAL NEUROPATHY DESPITE NORMAL SYSTEMIC INSULIN
SIGNALING
Hayes JM1, O'Brien PD
1, Backus C1, Feldman EL1.
1Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
Peripheral neuropathy (PN) is a common complication observed in patients with impaired
glucose tolerance and type 2 diabetes. Male mice fed a high fat diet (HFD) develop
metabolic impairments and PN serving as an appropriate animal model to study PN development
and progression. It is well documented that female mice fed a HFD display a degree
of protection against HFD‐induced metabolic changes with mice retaining relatively
normal insulin sensitivity. This protection is attributed to differences in fat accumulation
and to the anti‐diabetic effects of estrogen. Based on these sex‐dimorphisms we hypothesized
that HFD‐fed female mice would also exhibit resistance to developing PN. In the present
study male and female C57BL6/J mice were fed either a standard diet (10% kcal fat;
SD) or a high fat diet (60% kcal fat; HFD) from 5wk. At 16wk, 24wk and 36wk, neuropathy
phenotyping was performed on all groups complemented with longitudinal metabolic assessments
including insulin tolerance testing (ITT). Neuropathy phenotyping consisted of hindpaw
latency to heat stimulus, motor and sensory nerve conduction velocities (NCVs), and
terminal intraepidermal nerve fiber (IENF) counts. Assessment of insulin resistance
through ITT demonstrated that during early HFD feeding, female HFD‐fed mice exhibited
relatively normal insulin responsiveness, while male HFD mice exhibited insulin resistance.
Despite this finding, 16wk female HFD mice displayed a similar pattern of PN to that
of their male counterparts, with similar fold‐changes in hindpaw latency and sensory
and motor NCVs. Therefore, although female HFD‐fed mice exhibit resistance to HFD‐induced
metabolic changes, they display a PN comparable to male HFD‐fed mice suggesting that
systemic insulin resistance does not mediate PN. Further studies are underway investigating
the role of insulin signaling in the peripheral nerves of female HFD‐fed mice.
SELECTIVE IN VIVO REMOVAL OF PATHOGENIC ANTI‐MAG AUTOANTIBODIES: A NOVEL TREATMENT
OPTION FOR ANTI‐MAG NEUROPATHY
Herrendorff R1, Hänggi P
1, Pfister H
, Yang F1, Demeestere D1, Hunziker F1, Frey S1, Schaeren‐Wiemers N2, Steck AJ3, Ernst
B1.
1Institute of Molecular Pharmacy, University of Basel, Basel, Switzerland; 2Department
of Biomedicine, University Hospital Basel, Basel, Switzerland; 3Department of Neurology,
University Hospital Basel, Basel, Switzerland.
Anti‐MAG (myelin‐associated glycoprotein) neuropathy is a disabling autoimmune peripheral
neuropathy caused by monoclonal immunoglobulin M (IgM) autoantibodies that recognize
the carbohydrate epitope HNK‐1 (human natural killer‐1). This glycoepitope is highly
expressed on adhesion molecules, such as MAG, present in myelinated nerve fibers.
Since the pathogenicity and demyelinating properties of anti‐MAG autoantibodies are
well established, current treatments aim at a reduction of autoantibody levels. However,
the therapies applied so far are primarily immunosuppressive and lack selectivity
and efficacy. We therefore hypothesized that a significant improvement of the disease
condition could be achieved by selectively neutralizing the pathogenic anti‐MAG antibodies
with carbohydrate‐based ligands mimicking the natural HNK‐1 glycoepitope. In an inhibition
assay, a mimetic (mimHNK‐1) of the natural HNK‐1 epitope inhibited MAG‐binding by
pathogenic IgM antibodies from patient sera, however only with micromolar affinity.
Therefore, considering the multivalent nature of the MAG–IgM interaction, polylysine
polymers of different sizes were substituted with the mimetic. With the most promising
polylysine glycopolymer PL84(mimHNK‐1)45 the inhibitory effect on patient sera was
improved by a factor of up to 230,000 per epitope, consequently leading to a low nanomolar
inhibitory potency. Since clinical studies indicate a correlation between the reduction
of anti‐MAG IgM levels and clinical improvement, an immunological surrogate mouse
model for anti‐MAG neuropathy, producing high levels of anti‐MAG IgM, was developed.
The observed efficient removal of these antibodies with the glycopolymer PL84(mimHNK‐1)45
represents a first step towards an antigen‐specific therapy for anti‐MAG neuropathy.
ADIPOSE‐NERVE SIGNALING IN PERIPHERAL NEUROPATHY
Hinder LM1, Mendelson F
1, Backus C1, Feldman EL1
. 1University of Michigan, Ann Arbor, MI, USA.
In the United States 17% of children and young adults are obese and at risk of developing
prediabetes. Prediabetic patients largely develop the same macro‐ and microvascular
complications as patients with type 2 diabetes, including peripheral neuropathy (PN).
Moreover, recent clinical data suggest normoglycemic obese patients develop PN. Central
obesity, characterized by excess fat storage in visceral white adipose tissue, leads
to systemic metabolic dysfunction largely due to an imbalance between pro‐inflammatory/anti‐inflammatory
adipokine production. Subcutaneous adipose tissue is considered ‘benign’, but adopts
a visceral‐like phenotype in response to metabolic stress, with reduced thermogenicity,
reduced brown adipose identity, and increased pro‐inflammatory gene expression. The
popliteal adipose tissue (PAT) depot, corresponding to subcutaneous adipose, is adjacent
to the peripheral nerve affected in PN, contains the lymph node for lymphatic drainage
of the hind limb, and expands following local, sterile hind paw inflammation. The
aim of the current study was to characterize PAT changes in the high fat diet (HFD)
mouse model of obesity and PN, and consider its contribution to peripheral nerve dysfunction.
We previously reported C57BL6/J mice fed 60% HFD from 5–16 wk develop obesity, ‘prediabetes’
and PN; and switching mice back to a standard diet from 16–24 wk improves metabolic
and PN phenotypes. At 16 and 24 wk PAT was bilaterally dissected and the lymph node
removed. The left PAT was processed for histomorphometry, and the right PAT for RT‐qPCR.
At 16 wk HFD was associated with a significant shift in adipocyte size‐frequency distribution,
with a greater number of larger adipocytes. Switching the HFD mice back to standard
chow from 16–24 wk restored the size‐frequency distribution towards age‐matched controls.
RT‐qPCR was performed to assess changes in thermogenicity (Ucp1), brown adipose identify
(Cidea) and sterile inflammation (Saa3). At 16 and 24 wk HFD PAT had reduced thermogenicity
and brown adipose identify, and increased sterile inflammation. This switch towards
a visceral‐like phenotype was reversed in the HFD mice switched back to standard chow.
In summary, HFD‐induced changes in PAT histomorphometry and adipose identity closely
associate with PN phenotype. These preliminary data suggest a potential role for PAT‐nerve
signaling in PN.
CONSERVED BIOENERGETIC SIGNATURE IN PERIPHERAL NERVE OF BKS‐DB/DB AND HIGH FAT DIET
MICE WITH NEUROPATHY
Hinder LM
1, Backus C1, Hayes JM1, Feldman EL1. University of Michigan, Ann Arbor, MI, USA.
Peripheral neuropathy (PN) is a common and debilitating complication of obesity and
diabetes that triggers pain and loss of sensation. Substantial nerve damage occurs
in many patients prior to noticeable symptoms and no treatments are currently available;
therefore, there is a critical need to identify treatment strategies that impact the
underlying disease pathogenesis. Our in vivo fluxomics data in the BKS‐db/db mouse
model of type 2 diabetes (T2DM) and PN suggest that ‘metabolic reprogramming’ occurs
in the T2DM nerve to downregulate mitochondrial oxidative phosphorylation of substrates
derived from glycolysis and fatty acid beta‐oxidation. Therefore, we hypothesize that
distinct systemic metabolic alterations occur in obesity and diabetes which induce
tissue‐specific metabolic reprogramming within the peripheral nerve, altering fuel
utilization and ultimately leading to tissue dysfunction. We contend that identifying
conserved bioenergetic profiles across mouse models of PN will provide insight into
key PN mechanisms. The current study utilized two mouse models of PN: the 60% High
Fat Diet (HFD) mouse model of obesity and prediabetes at 20 wk of age (16 wk HFD),
and the leptin receptor‐deficient BKS‐db/db model of T2DM at 24 wk of age. Mitochondrial
function was determined in primary dorsal root ganglia (DRG) neurons and sural nerve
tissue from both models using the Seahorse XF24 Analyzer. Resting mitochondrial oxidative
metabolism was upregulated in DRG neurons from mice with PN, with increased resting
ATP production and maintained mitochondrial coupling. In contrast, resting ATP generation
was decreased in sural nerve from mice with PN, with decreased coupling efficiency.
Relative spare respiratory capacity was attenuated in both DRG neurons and sural nerve
from mice with PN, indicating that mitochondria were less able to increase respiration
in response to an energetic challenge. Moreover, mitochondrial copy number was unchanged
in DRG neurons, but decreased in sural nerve tissue of mice with PN compared with
respective controls. These data suggest a change in absolute number and function of
sural nerve mitochondria, and a conserved cross‐model proximal‐distal bioenergetic
profile in PN. We are currently exploring the relationship between these changes and
PN pathogenesis.
GUILLAIN BARRÉ SYNDROME IN A HO CHI MINH CITY, VIETNAM HOSPITAL
Hoang TTN
1, Umapathi T2.
1175 Hospital, Ho Chi Minh City, Vietnam; 2National Neuroscience Institute, Singapore.
Ho Chi Minh City (HCMC) is the biggest metropolitan city in southern Vietnam. Its
population is more than ten million. Adult patients with neurological disorders are
seen at six city public hospitals, including 175, Hospital. There has been no systematic
study of Guillain Barré syndrome (GBS) at HCMC or in Vietnam in general. We are in
the process of starting a prospective GBS database that we hope to expand to the other
public hospitals at HCMC. Here we describe our experience from 2016. We saw 5 GBS
patients at 175, Hospital. Most of the cases were admitted in the rainy season, from
late April to November, when mosquito‐borne flavivirus infections are more common.
Patients were seen in the first week of illness and reported antecedent fever. Two
patients had diarrhea. Diagnoses were made largely on clinical features, cerebrospinal
fluid analysis and nerve conduction study. Clinical findings include limb weakness,
numbness and VII cranial nerve palsy. Extraocular eye movements were affected in one
patient. None had respiratory involvement severe enough to require artificial ventilation
or intensive care. There were no pure Miller‐Fisher syndrome cases; we suspect this
might be related to the mild deficits that did not prompt hospitalization. Nerve conduction
studies showed typical features such as loss of F waves and abnormal blink reflex.
The electrophysiology of 3 patients' was dominated by demyelinating changes, one case
was largely axonal and the remaining patient had normal electrodiagnostic study. Repeat
nerve conduction studies were not feasible because of limited resources. Neurologists
use corticosteroids as the main treatment. Intravenous immunoglobulin and plasma exchange
are costly and not reimbursed by medical insurance. We are currently preparing to
systematically study GBS in southern Vietnam, specifically with regards to possible
role of antecedent flavivirus infections. We are also exploring the possibility of
using low volume plasma exchange as a feasible cost‐effective therapeutic modality.
SUBACUTE INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY WITH TREATMENT‐RELATED
FLUCTUATIONS
Hong YH
1, Choi SJ2, Yoon BN3, Sohn SY4, Baek SH2, Choi K2, Park KH5, Kwon KH2, Sung JJ2.
1Seoul Metropolitan Government Boramae Medical Center, Seoul National University,
Seoul, South Korea; 2Seoul National University Hospital, Seoul, South Korea; 3Inha
University Hospital, Incheon, South Korea; 4Eulji University Hospital, Daejeon, South
Korea; 5Gyeongsang National University Hospital, Jinju, South Korea.
About 10% of patients with Guillain‐Barré syndrome (GBS) treated with intravenous
immunoglobulin (IVIg) or plasma exchange deteriorate after initial improvement or
stabilization—a phenomenon that is termed treatment‐related fluctuation (TRF). It
is important to distinguish acute onset CIDP (A‐CIDP) from GBS‐TRF during early course
of the disease, because their therapeutic strategies and prognoses are different.
Herein, we describe a patient with GBS‐TRF, but with an extended progression phase
that exceeds 8 weeks. A 27‐year‐old woman was admitted due to acute onset progressive
leg weakness and diplopia that had developed 2 weeks prior (onset, D0). On neurological
examination, right facial palsy was also observed. Lower extremity weakness was moderate
in proximal and distal muscles (MRC grade IV) with absent knee and ankle jerks. Sensory
examination revealed no abnormality in all modalities. She denied any recent diarrhea
or upper respiratory infection, and vaccination. Albumino‐cytologic dissociation was
noted in CSF analysis; white blood cell count of 3/μL and protein level of 104.2 mg/dL.
Nerve conduction study revealed demyelinating sensorimotor polyneuropathy with prolonged
distal latency and conduction blocks. Anti‐ganglioside antibodies (GM1 IgM/G, GD1b
IgM/G, and GQ1b IgM/G) were all negative. Following IVIg treatment, she was discharged
with considerable improvement (D20). 11 days later, she was re‐admitted due to deterioration
of leg weakness and hand clumsiness (D31). After another IVIg treatment, she was discharged
with clinical improvement (D49). 17 days later, however, she was admitted again (D66)
due to another considerable deterioration with four extremity weakness being worst
at this time (MRC grade II‐IV in upper extremity, grade II in lower extremity). A‐CIDP
was considered given the progression phase exceeding 8 weeks, but, we decided to give
another treatment with IVIg instead of a switch to corticosteroids because of uncertainty
regarding distinction between A‐CIDP and GBS‐TRF. She was significantly improved following
IVIg treatment, and finally discharged (D92). Thereafter, there has been no further
deterioration during long‐term follow‐up of 1 year. Conclusively, this is a rare case
of GBS with extended progression phase and TRF. We propose that this could be referred
to as subacute inflammatory demyelinating polyradiculoneuropathy (SIDP) with TRF.
BIOMARKERS OF SMALL FIBER NEUROPATHY IN AMYLOID NEUROPATHY
Hsieh S
1, Chao C1.
1National Taiwan University Hospital, Taipei, Taiwan.
Transthyretin (TTR)‐related familial amyloid polyneuropathy (FAP) constitutes a major
etiology of adult‐onset hereditary neuropathies worldwide, in particular, a mutant
TTR of Ala97Ser (TTR‐A97S) in Taiwan, the most common cause of acquired genetic neuropathy
with adult onset (>50 years of age) of Taiwanese patients. FAP is a pan‐modality neuropathy
involving motor, sensory, and autonomic components of the peripheral nervous system
with early involvement of small fibers as a major symptom. The early symptoms of FAP
are sometimes minimal and difficult to ascertain, mainly related to the fact that
conventional electrophysiological examinations were not sensitive enough to detect
small fiber neuropathy. Skin biopsy with quantification of intraepidermal nerve fibers
(IENF) has become one of the standard approaches to diagnose small fiber sensory neuropathy
based on pathological documentation of nociceptive nerve degeneration. To explore
the issue of early biomarkers in FAP, we performed skin biopsy and compared IENF density
with parameters of nerve conduction studies (NCS) and quantitative sensory testing
(QST) on 36 subjects (23 men, aged 55.1 ± 11.1 years) with genetic confirmation of
TTR‐ A97S: 17 patients and 19 carriers. The IENF densities were significantly reduced
compared to the age‐ and gender‐matched controls in carriers (4.05 ± 2.01 vs. 10.39
± 3.75 fibers/mm, p = 0.0057) and patients (0.84 ± 1.06 vs. 7.96 ± 2.39 fibers/mm,
p = 0.0012). The latter was consistent with our previous report (Neurology, 75:532–538,
2010). The abnormal rate of IENF density was significantly higher than that of NCS
and QST, respectively. In conclusion, there was significant skin nerve degeneration
in carriers with TTR‐A97S. Compared with QST and NCS, IENF density assessment had
the highest abnormal rate and highest sensitivity to detect neuropathic changes in
the early stage of FAP.
A NOVEL CMT2P MISSENSE MUTATION IN THE RING DOMAIN OF LRSAM1 IMPAIRS NUCLEAR TRANSLOCATION
OF RNA‐BINDING PROTEINS
Hu B1, Arpag S1, Zuchner S2, Li J
1.
1Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN,
USA; 2Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Charcot‐Marie‐Tooth type 2P (CMT2P) has been associated with frame‐shift mutations
in the RING domain of LRSAM1 (an E3 ligase). This study describes families with a
novel missense mutation of LRSAM1 gene and explores pathogenic mechanisms of CMT2P.
This American family with dominantly inherited axonal polyneuropathy reveals a phenotype
similar to those in previously reported non‐US families. The affected members in our
family co‐segregated with a novel missense mutation Cys694Arg that alters a highly
conserved cysteine in the RING domain. This mutation leads to axonal degeneration
in the in vitro neuronal cell‐line. Moreover, using protein mass spectrometry, we
identified a group of RNA binding proteins (including FUS, a protein critically involved
in motor neuron degeneration) that interacted with LRSAM1. The interactions were disrupted
by the Cys694Arg mutation, which resulted in reduction of intranuclear RNA‐binding
proteins. A knockin mouse of Cys694Arg has been created for further explorations of
CMT2P mechanisms and therapeutic development. Together, our findings suggest that
the mutant LRSAM1 may aberrantly affect the formation of transcription machinery.
Given a similar mechanism has been reported in motor neuron degeneration of amyotrophic
lateral sclerosis, abnormalities of RNA/RNA‐binding protein complex may play a role
in the neuronal degeneration of CMT2P. Supported by grants from NINDS (R01NS066927)
and the National Center for Advancing Translational Sciences (UL1TR000445).
RANDOMIZED CONTROLLED TRIAL OF ORAL FINGOLIMOD IN CHRONIC INFLAMMATORY DEMYELINATING
POLYRADICULONEUROPATHY (FORCIDP TRIAL): SUBGROUP ANALYSES
Hughes R
1, Cornblath D2, Dalakas M3, Merkies ISJ4, Latov N5, Léger J‐M6, Nobile‐Orazio E7,
Sobue G8, Genge A9, Merschhemke M10, Ervin C10, Agoropoulou C10, Hartung H‐P11.
1National Hospital for Neurology and Neurosurgery, London, UK; 2Johns Hopkins Medical
School, Baltimore, MD, USA; 3University of Athens Medical School, Athens, Greece;
4Maastricht University Medical Center, Maastricht, The Netherlands and St. Elisabeth
Hospital, Willemstad, Curacao, Netherlands Antilles; 5Weill Cornell Medical College,
NY, USA; 6National Referral Center for Neuromuscular Diseases, University Hospital
Pïtié‐Salpêtrière, Paris, France; 7Humanitas Clinical and Research Center, Milan University,
Rozzano, Milan, Italy; 8Nagoya University Hospital, Nagoya, Japan; 9Montreal Neurological
Institute and Hospital, Montreal, Quebec, Canada; 10Novartis Pharma AG, Basel, Switzerland;
11Department of Neurology, Universitätsklinikum Düsseldorf, Heinrich‐Heine‐University,
Düsseldorf, Germany.
This double‐blind, multicenter, parallel‐group trial randomized (1:1) adult participants
(N=106) with chronic inflammatory demyelinating polyradiculoneuropathy being treated
with intravenous immunoglobulin (IVIg) or corticosteroids to 0.5 mg fingolimod (n=54)
or placebo (n=52) once‐daily. Previous treatment was discontinued (IVIg) or tapered
( corticosteroids). In the total trial population, there was no significant difference
between the groups in the primary outcome, time‐to‐first confirmed worsening (≥1‐point
increase on the adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] scale
vs. baseline), or time‐to‐first any worsening (confirmed on INCAT assessment or unconfirmed).
No significant difference between the two treatment groups was shown on secondary
outcomes; change from baseline in grip strength and Rasch‐built Overall Disability
Scale (R‐ODS) at six months or trial end. Analyses of pre‐specified subgroups were
performed for primary and secondary outcomes. Confirmed worsening in fingolimod vs.
placebo‐treated participants (hazard ratio, [95% confidence interval]) was analyzed
by the previous treatment (IVIg, 23/41 vs. 20/41,1.28 [0.70, 2.34]; corticosteroids,
2/13 vs. 6/11, 0.26 [0.05, 1.29]), baseline INCAT score (INCAT<3, 7/23 vs.7/23, 1.19
[0.42, 3.39]; INCAT=3, 9/18 vs. 12/17, 0.62 [0.26, 1.46]; INCAT>3, 9/13 vs. 7/12,
1.24 [0.46, 3.34]), duration of CIDP (<2 years, 6/15 vs. 6/8, 0.52 [0.17, 1.62]; 2–5
years, 8/16 vs. 4/18, 3.07 [0.92, 10.22]; >5 years, 11/23 vs. 16/26, 0.67 [0.31, 1.45]),
and the number of worsenings in the previous 2 years (1 worsening event, 9/22 vs.
12/23, 0.88 [0.37, 2.09]; 2 worsening events, 3/9 vs. 7/14, 0.68 [0.18, 2.64]; worsening
events>2, 13/23 vs. 7/15, 1.14 [0.46, 2.87]), respectively. Hazard ratios and p‐values
did not show significant differences between treatment groups in any of the pre‐specified
subgroups.
Acknowledgments: The authors consulted for or were employed by study sponsor Novartis
Pharma AG, Basel, Switzerland.
RANDOMIZED CONTROLLED TRIAL OF ORAL FINGOLIMOD IN CHRONIC INFLAMMATORY DEMYELINATING
POLYRADICULONEUROPATHY (FORCIDP TRIAL): PRIMARY AND SECONDARY OUTCOMES
Hughes R
1, Cornblath D2, Dalakas M3, Merkies ISJ4, Latov N5, Léger J‐M6, Nobile‐Orazio E7,
Sobue G8, Genge A9, Merschhemke M10, Ervin C10, Agoropoulou C10, Hartung H‐P11.
1National Hospital for Neurology and Neurosurgery, London, UK; 2Johns Hopkins Medical
School, Baltimore, MD, USA; 3University of Athens Medical School, Athens, Greece;
4Maastricht University Medical Center, Maastricht, The Netherlands and St. Elisabeth
Hospital, Willemstad, Curacao, Netherlands Antilles; 5Weill Cornell Medical College,
NY, USA; 6National Referral Center for Neuromuscular Diseases, University Hospital
Pïtié‐Salpêtrière, Paris, France; 7Humanitas Clinical and Research Center, Milan University,
Rozzano, Milan, Italy; 8Nagoya University Hospital, Nagoya, Japan; 9Montreal Neurological
Institute and Hospital, Montreal, Quebec, Canada; 10Novartis Pharma AG, Basel, Switzerland;
11Department of Neurology, Universitätsklinikum Düsseldorf, Heinrich‐Heine‐University,
Düsseldorf, Germany.
This trial evaluated the efficacy and safety of fingolimod in chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP). Corticosteroids, intravenous immunoglobulin
(IVIg) and plasma exchange are recognized treatment options but no other immunomodulators
demonstrated efficacy in a controlled trial. Fingolimod has been shown to be efficacious
and is approved for the treatment of relapsing multiple sclerosis. Results from experimental
autoimmune neuritis in rats suggested that it might show an effect in CIDP. In this
double‐blind, multicenter, parallel‐group trial, CIDP participants receiving IVIg
or corticosteroids were randomized to once‐daily fingolimod 0.5 mg or placebo (1:1).
Participants were stratified by Inflammatory Neuropathy Cause and Treatment Disability
(INCAT) scores and prior treatment. Previous IVIg treatment was discontinued after
one final course before randomization. Previous corticosteroid treatment was tapered
over 8 weeks. The primary outcome was time‐to‐first confirmed worsening (≥1‐point
increase on the adjusted INCAT score versus baseline). Secondary outcomes included
change in grip strength and Rasch‐built Overall Disability Scale (R‐ODS) score from
baseline to Month 6 and at trial end. The trial was stopped for futility by an independent
data monitoring committee after a pre‐planned interim analysis based on pre‐specified
criteria. In all, 54 participants received fingolimod (IVIg: 41, corticosteroids:
13; age: 54.3±13.32 years [mean±standard deviation]; male: 68.5%); 52 received placebo
(IVIg: 41, corticosteroids: 11; age: 54.6±11.68 years; male: 57.7%). The percentage
(95% confidence interval) of participants free from confirmed worsening at the trial
end was not significantly different between fingolimod (41.5% [22.7%—60.3%]) and placebo
(43.2% (27.7%—58.7%); p=0.91). In the first 45 days, approximately 20% participants
experienced worsening. At trial end, approximately 40% participants had no worsening.
There was no significant difference after six months or at the trial end (whichever
occurred earlier) in the secondary endpoints. Adverse events were reported in 41/54
and 44/52 participants in the fingolimod and placebo group, respectively. There were
no deaths. Nine participants in the fingolimod group and 4 in the placebo group had
serious adverse events. Adverse events leading to trial drug discontinuation occurred
in 7 (13%) participants on fingolimod and none on placebo. No new safety signals emerged
in this trial.
Acknowledgment: The authors consulted for or were employed by the study sponsor Novartis
Pharma AG, Basel, Switzerland.
THE CRYPTIC 68–104 REGION OF MYELIN BASIC PROTEIN (MBP) CAUSES PAIN FROM LIGHT TOUCH
EXCLUSIVELY IN FEMALE RODENTS: AUTOIMMUNE MECHANISMS OF SEXUAL DIMORPHISM IN MECHANICAL
ALLODYNIA
Hullugundi SK1,2, Chernov AV3, Remacle AG3, Eddinger KA1, Angert M1,2, Dolkas J1,2,
Jones III RCW1,2,4, Strongin AY3, Yaksh TL1, Shubayev VI
1,2.
1Department of Anesthesiology, University of California, San Diego, La Jolla, CA,
USA; 2VA San Diego Healthcare System, La Jolla, CA, USA; 3Sanford‐Burnham‐Prebys Medical
Discovery Institute, La Jolla, CA, USA; 4Center for Pain Medicine, University of California,
San Diego, La Jolla, CA, USA.
Myelin sheath enwraps non‐nociceptive mechanoselective Abeta‐afferents transmitting
touch/vibration sense. A prominent reduction in the mechanical stimulus required to
evoke a withdrawal response in rodents, a phenomena interpreted as mechanical allodynia,
arises due to peripheral nerve/myelin damage. Evidence has emerged that nerve injury‐induced
mechanical allodynia depends on the adaptive immune/T cell activity in female but
not male rodents. Having previously demonstrated both the release of the cryptic 68–104
peptide regions of myelin basic protein (MBP68‐104) following sciatic nerve chronic
constriction injury (CCI) and the direct, robust and T cell‐dependent ability of the
pure MBP68‐104 peptides to induce mechanical allodynia after injection into the intact
sciatic nerve, we hypothesized that MBP68‐104 contributes to sexual dimorphism in
mechanical allodynia. The pure MBP84‐104 wild‐type (WT), its histidine (His)89 mutant
or scramble peptides were administered into an intact sciatic nerve fascicle in male
and female rats or mice, followed by von Frey testing. Intra‐sciatic MBP84‐104‐WT
peptide induced robust and lasting allodynia in females. In contrast, males responded
with a brief and mild decline in mechanical sensitivity for one day post‐injection
of both wildtype and control peptides. The algesic ability of MBP84‐104‐WT was diminished
in the His89 mutant. We here present the molecular changes in the sciatic nerve, DRG
and the spinal cord after the intra‐sciatic MBP84‐104 injection in male and female
animals. In addition, using the biotin‐labeled MBP84‐104 peptide and the HRP‐labeled
goat anti‐rat IgG/IgM antibodies, we developed an ELISA to quantitatively assess seropositivity
for the specific anti‐MBP84‐104 peptide IgM/IgG autoantibodies in female and male
rats post‐CCI. Human serum from female patients with multiple sclerosis was used for
control. Our work corroborates the findings of sexual dimorphism of mechanical hyperpathia
and suggests its potentially autoimmune nature in females.
EFFICACY OF IMMUNOGLOBULINS FOR NOD B7‐2 KO MICE
Iijima M
1, Nishi R1, Ikeda S1, Kawagashira Y1, Koike H1, Sobue G1, Katsuno M1.
1Nagoya University, Nagoya, Japan.
Non‐obesity diabetic (NOD) B7‐2 knockout (KO) mice are characterized by chronic and
progressive neuritis and expected as models of immune‐mediated neuropathies, especially
CIDP. Hindlimb‐predominant weakness due to inflammatory demyelination followed by
axonal degeneration begins from around twenty week‐age in all female mice until thirty
week‐age. To clarify the efficacy of immunoglobulins as immune‐regulating therapeutics
and the similarity of pathogenesis of human CIDP, we injected intraperitoneally human‐derived
immunoglobulins (IPIg, 20mg/mg BW/week) and saline as a control to totally forty female
mice. Clinical and pathological estimations in sciatic nerves were performed in time
series. As a result, the IPIg‐treated group was protected from weight loss which could
be related to axon loss followed by muscle atrophy as well as inflammatory demyelination
between twenty‐five week‐age and thirty week‐age compared to the control. In addition,
the pathological findings in sciatic nerves showed that IPIg apparently suppressed
inflammatory infiltrates. About the subsets of inflammatory infiltrates, while macrophages
(CD68+) and lymphocytes (CD4+) highly existed and suggested to play a main role in
the neuritis until thirty week‐age, only macrophages naturally disappeared after thirty
week‐age without any therapeutic induction. Immunoglobulins effectively suppressed
only macrophages although that did not suppress CD4+ lymphocytes. In conclusion, NOD
B7‐2 KO mice respond to immunoglobulins in a similar manner to human CIDP and this
efficacy is due to the suppression of macrophage‐dominant pathogenesis. Therefore,
macrophage‐derived pathogenesis is for the main target of immunoglobulin therapy and
we should focus on the lymphocyte‐derived pathogenesis which might plays an important
role in non‐responders to immunoglobulins.
CLINICOPATHOLOGICAL FEATURES AMONG CIDP SUBTYPES
Ikeda S
1, Nishi R1, Kawagashira Y1, Iijima M1, Koike H1, Katsuno M1, Sobue G1,2.
1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan;
2Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate
School of Medicine, Nagoya, Japan.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune‐mediated
polyradiculoneuropathy that is characterized by heterogeneous clinical manifestations.
Typical CIDP is defined as neuropathy manifesting in a progressive manner, stepwise
manner, or with recurrent symmetrical proximal and distal weakness and sensory impairment
in all four limbs. Although they occur at a lower proportion than the so‐called typical
CIDP, atypical forms, such as multifocal acquired demyelinating sensory and motor
(MADSAM), distal acquired demyelinating symmetric (DADS), pure sensory, pure motor,
and focal, are considered to CIDP subtypes. Thus far, pathological features characterizing
each clinical subtype have not been fully elucidated. We analyzed clinical and pathological
correlations in 114 consecutive CIDP patients who underwent sural nerve biopsy and
fulfilled the definite or probable EFNS/PNS criteria. There were 64 male and 50 female
patients. The age at biopsy was 58.1 ± 16.1 (mean ± SD) years, and the duration from
the onset of neuropathy to biopsy was 27 ± 49 months. Fifty‐five percent (n = 63)
of the patients were classified as having typical CIDP. Regarding atypical CIDP, MADSAM
(n = 15, 13%), DADS (n = 18, 16%), and pure sensory (n = 16, 14%) subtypes were the
major subtypes, while pure motor (n=1, 1%) and focal (n=1, 1%) subtypes were rare.
No significant difference was found among these subtypes in terms of sex, age at biopsy,
and disease duration. Sural nerve biopsy specimens revealed that the densities of
large myelinated fibers significantly decreased in the MADSAM subtype than in the
other subtypes (p = 0.003). In addition, the variation in nerve fibers among fascicles
was more conspicuous in the MADSAM subtype than in typical CIDP (p=0.04). Patients
with the DADS subtype tended to show the formation of onion‐bulbs. In conclusion,
pathological findings of sural nerve biopsy specimens were different among the CIDP
subtypes. Further studies are needed to clarify mechanisms leading to different pathological
features.
SMALL VOLUME PLASMA EXCHANGE FOR GUILLAIN‐BARRE SYNDROME IN LOW INCOME COUNTRIES:
A SAFETY AND FEASIBILITY STUDY
Islam B
1, Islam Z2, Rahman S3, Endtz P4, Vos C5, Vanderjagt M5, VanDoorn P5, Jacobs C5, Mohammad
D6.
1International Centre for Diarrhoeal Disease Research (icddr,b), Dhaka, Bangladesh
and Erasmus MC, Rotterdam, The Netherlands; 2International Centre for Diarrhoeal Disease
Research (icddr,b), Dhaka, Bangladesh; 3Uttara Adhunik Medical College Hospital, Dhaka,
Bangladesh; 4Erasmus MC, Rotterdam, The Netherlands and Fondation Mérieux, Lyon, France;
5Erasmus MC, Rotterdam, The Netherlands; 6National Institute of Neurosciences, Dhaka,
Bangladesh.
Small volume plasma exchange (SVPE) can be an affordable and potentially effective
alternative form of plasma exchange. SVPE is the repeated removal of small volumes
of supernatant plasma over several days via sedimentation of patient whole blood.
The aim of this study is to assess the clinical feasibility and safety of SVPE in
patients with GBS in low‐income countries. Twenty adult patients with GBS diagnosed
as per the criteria for GBS of the National Institute of Neurological and Communicative
Disorders and Stroke (NINDS) were enrolled for SVPE at a centre in Bangladesh. Serious
adverse events (SAE) were defined as the number of patients developing severe sepsis
associated with the central venous catheter (CVC) or deep venous thrombosis in the
limb where the CVC is placed for SVPE. The SVPE procedure was considered safe if less
than 5 of 20 SVPE‐treated GBS patients have a SAE, and feasible if eight litres of
plasma could be removed in at least 15 of 20 SVPE‐treated GBS patients. Among the
20 cases who received SVPE, 13(65%) patients were male and the age range between 19
to 55 yrs. All the patients were quadriplegic and bedbound at enrolment for SVPE with
a median MRC score of 20 (IQR, 0–29). Cranial nerve involvement, autonomic dysfunction
and requirement for assisted ventilation were observed in 11(55%), 9(45%) and 3(15%)
patients respectively. Electro physiologically 15(75%) patients were motor axonal
and 5(25%) patients were sensory‐motor demyelinating type. During the SVPE none of
our patients experienced SAE and one patient experienced central line associated blood
stream infection. Common adverse effects were transient intravenous fluid responsive
hypotension during the SVPE sessions in 10(50%), CV catheter insertion site hemorrhage
in 10 (50%) and hypersensitivity reaction to fresh frozen plasma in 5(25%) patients.
There was no hypo‐albuminemia, anemia or electrolyte imbalance observed in most patients
(95%) treated with SVPE. Improvement in one or more grade of the GBS disability score
at four weeks after the onset of SVPE was observed in 14(70%) patients. In conclusion
SVPE can be a safe, feasible and cost effective alternative to standard PE in the
developing countries.
GUILLAIN BARRÉ SYNDROME IN BANGLADESH: PAST, PRESENT AND FUTURE PERSPECTIVE
Islam Z
1, Islam MB1,2, Endtz HP1,2,3, Jacobs BC3,4, Mohammad QD5.
1Laboratory Sciences and Services Division, International Centre for Diarrhoeal Disease
Research (icddr,b), Dhaka, Bangladesh; 2Department of Medical Microbiology and Infectious
Diseases, Erasmus University Medical Centre, Rotterdam, The Netherlands; 3Department
of Immunology, Erasmus University Medical Centre, Rotterdam, The Netherlands; 4Department
of Neurology; 5National Institute of Neurosciences and Hospital, Sher‐e‐BanglaNagar,
Agargaon, Dhaka, Bangladesh; 6Fondation Mérieux, Lyon, France.
Guillain‐Barré syndrome (GBS) is a descriptive disease entity defined by a set of
clinical, electrophysiological and laboratory criteria. Various clinical phenotypes
exist that may be triggered by different antecedent infectious events. Although the
disease appears to affect primarily the elderly in developed countries, but, scenario
is different in developing countries. Bangladesh has made an impressive progress towards
the eradication of poliomyelitis, and no new cases have been reported since 2000.
GBS, an acute polyradiculoneuropathy, is the most frequent cause of acute flaccid
paralyis. The crude incidence rate of GBS in <15 years of age reported here appears
to be 2.5× to 4× higher than that reported in the literature. We conducted a hospital
based observational study including 600 patients fulfilling the National Institute
of Neurological Disorders and stroke (NINDS) criteria for GBS patients between 2010
and 2016 in Dhaka Medical College Hospital, Dhaka, Bangladesh. Detailed clinical,
electrophysiological, serologic and microbiological data were obtained. GBS affected
predominantly in young adults males (M/F=2:1) living in rural areas. Antecedent events
were recorded in >70% of patients; frequent events being gastroenteritis (>40%) and
upper respiratory tract infection (18%). More than 60% of the patients were bed‐bound
(GBS disability score 4) at entry and about 20% patients required mechanical ventilator.
About 90% patients did not receive specific treatment either Intravenous Immunoglobulin
(IVIg) or plasmapheresis due to high expensive treatment cost. 13% patients had died
during hospitalization. 60% of patients had an axonal variant of GBS and evidence
for a recent C. jejuni infection (55%). C. jejuni infection was significantly associated
with serum antibodies to the gangliosides GM1 and GD1a, axonal neuropathy, and greater
disability. In conclusion, the majority of the patients do not receive standard treatment
with IVIg in view of its high price. Therefore, we developed low‐cost treatment strategies
and conducted a safety and feasibility trials for small volume plasma exchange (SVPE)
on GBS patients in Bangladesh. In future, it is essential to conduct a phase II clinical
trial to assess the efficacy of SVPE for low‐in‐come countries.
DOES INTRAVENOUS IMMUNOGLOBULIN SERVE AS AN EFFECTIVE TREATMENT FOR GUILLAIN‐BARRÉ
SYNDROME IN DEVELOPING COUNTRIES? A CONTROLLED MATCHED PAIR ANALYSIS
Islam Z1, Papri N
1, Ara G1, Haque MA1, Islam MB1,2, Mohammad QD3.
1International Centre for Diarrhoeal Disease Research (icddr,b), Dhaka, Bangladesh;
2Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical
Centre, Rotterdam, The Netherlands; 3National Institute of Neurosciences and Hospital,
Sher‐e‐Bangla Nagar, Agargaon, Dhaka, Bangladesh.
Prognosis of Guillain‐Barré syndrome (GBS) has not improved in last two decades. Current
therapies (Intravenous immunoglobulin, IVIg and plasma exchange, PE) had been proved
to be effective on two third of patients in developed world. Unpredictable and poorly
understood clinical course of GBS hamper treatment development. In Bangladesh, most
patients affected by GBS cannot afford specific treatments with IVIg or PE instead
most of them receive only supportive care. Therefore, we aimed to compare the outcome
of IVIg treated patients with supportive care patients in improvement of GBS disability
score and MRC sum score by using world's largest GBS cohort in Bangladesh. We conducted
a prospective observational study enrolling 600 GBS patients between 2010 and 2016
from Dhaka Medical College Hospital and National Institute of Neuroscience and Hospital,
Dhaka, Bangladesh. Only 53 GBS patients (9%) received standard IVIg treatment. In
current analysis, 53 IVIg treated patients and 53 age, sex and severity matched controls
(supportive care only) were considered. Outcome of both groups were compared using
Fisher's exact or Chi square test and survival analysis were performed by Kaplan Meier
method using log rank test. Among 106 patients (cases and controls), male/female (62/44),
median age 19 years, 60% patients were bed‐bound, one‐fourth patients required mechanical
ventilation and 63% were axonal. We did not found any significant differences of treatment
outcome in both cases and control groups in GBS disability score (Week 4: p=0.82,
6 months: p=0.84) and MRC sum score (Week 4: p=0.71, 6 months: p=0.86). Survival analysis
revealed, the differences of time required for independent locomotion, improvement
of one GBS disability score and improvement of MRC score were not statistically significant
between treatments (IVIg) and supportive care patients. In conclusion, our analysis
showed that standard dose of IVIg use has no considerable advantage to improve specific
outcome measures among GBS patients in Bangladesh. As the phenotype of GBS in Bangladesh
is different from developed world; therefore, an efficacy trial for IVIg is needed
for developing countries like Bangladesh or new targeted therapeutic strategies can
append beneficial effects for GBS patients.
PAIN‐RELATED SEP AFTER SELECTIVE A‐DELTA‐ AND C‐FIBER STIMULATION IN PATIENTS WITH
NEUROPATHIC PAIN AND ITS POST‐TREATMENT CHANGES
Isose S
1,2, Watanabe K1, Omori S1, Sekiguchi Y1, Beppu M1, Shibuya K1, Amino H1, Suichi T1,
Misawa S1, Kuwabara S1.
1Graduate School of Medicine, Chiba University, Chiba, Japan; 2National Hospital Organization
Chiba East National Hospital, Chiba, Japan.
Diabetic neuropathy is a frequent cause of neuropathic pain, suggesting the small‐fiber
involvement. Additionally, persistent peripheral pain‐related inputs could cause neuronal
hyperexcitability and complex interactions of the nociceptive pathways, i.e., central
sensitization. To investigate the pathophysiology of neuropathic pain in diabetic
neuropathy, we studied pain‐related evoked potentials (PREPs) after selective intraepidermal
electrical stimulation (IES) to A‐delta‐ and C‐fibers in diabetes patients with neuropathic
pain (n=24) and without neuropathic pain (n=20). We also conducted a longitudinal
study to assess changes in PREPs and pain profiles in patients with neuropathic pain
3 months after the start of treatment with duloxetine. This study is registered with
the UMIN Clinical Trials Registry, UMIN000017130.
IES was applied in the hand and foot, and PREPs were recorded from the Cz electrode
referenced to the linked earlobes. We evaluated PREP latencies, amplitudes, and amplitude
ratios of PREPs after C/A‐delta ‐fiber stimulation. In the conventional nerve conduction
studies, patients with neuropathic pain significantly showed conduction slowing and
decreased SNAP amplitudes in the median and sural nerves compared with those in patients
without neuropathic pain. In pain‐related SEP studies, there were no significant differences
in PREP amplitudes and latencies after A‐delta ‐ or C‐ fiber stimulation between the
patients with neuropathic pain and without it. PREP amplitude ratios after C/A‐delta
‐fiber stimulation tended to increase in patients with neuropathic pain compared to
patients without pain. After the treatment with duloxetine, C/A‐delta ‐PREP amplitude
ratios were significantly decreased after both hand and foot stimulation, and as for
numerical rating scale (NRS) scores as the intensity of pain. Patients with less pain
relief showed the tendency of higher C/A‐delta PREP amplitude ratios before treatment
compared to patients with better pain relief. The correlation between reduction of
C/A‐delta PREP amplitude ratios and NRS reduction did not reach statistical significance.
This pain‐related SEP study demonstrated that abnormal cortical response in patients
with neuropathic pain could improve after the treatment with duloxetine, this might
reflect the cortical hyperexcitability as a central sensitization.
Conflict of Interest
This study is funded by Shionogi & Co., Ltd. The sponsors played no role in the design
and management of the study, collection and analysis of data, interpretation of the
results, or the writing of the writing of the report.
VOLUNTARY EXERCISE MODULATES MACROPHAGE POLARIZATION FOLLOWING SCIATIC NERVE INJURY
AND IMPROVES FUNCTIONAL RECOVERY IN MICE
Jack MM
1, Wright DE1.
1University of Kansas Medical Center, Kansas City, KS, USA.
Peripheral nerve injury is commonly associated with traumatic injury which is often
amenable to surgery. Despite improved methods in surgical repair, functional recovery
remains a challenging clinical problem that often leads to significant morbidity in
patients. Alternative therapies that could augment surgical repair may be beneficial
in functional outcomes. Neuroinflammation is a complex pathway with different cellular
components and cytokines that are activated following peripheral nerve injury. Macrophages
are responsible for the breakdown of debris following injury as well as promotion
of regenerative signals. Macrophage polarization is the process by which macrophages
take on phenotypically distinct functions based on the local environment and signaling
cues. Exercise has been shown to drive macrophage polarization from a pro‐inflammatory
M1 phenotype towards an anti‐inflammatory M2 phenotype in numerous tissues, but remains
uninvestigated in the peripheral nervous system. The purpose of our study was to identify
how exercise affects macrophage polarization, motor and sensory function, and neuroregeneration
following sciatic nerve crush. C57BL/6 mice underwent sciatic nerve crush injury and
were then given access to running wheels (exercised) or not given access to running
wheels (sedentary) for 4 weeks. Exercised mice ran an average of 2.9 km per night.
Injured exercised mice were protected from the development of thermal hyperalgesia
when compared to injured sedentary mice. Exercised mice had fewer paw slips on beam
walk testing compared to sedentary mice. No differences were measured in mechanical
sensitivity or motor coordination and balance assessed by Rotarod. While motor nerve
conduction velocities were significantly reduced for injured mice compared to uninjured
controls, motor nerve conduction velocities from injured exercised animals were significantly
higher than injured sedentary animals suggesting improved nerve recovery with exercise.
Injured sciatic nerves from exercised mice demonstrated increased M2 macrophages compared
to sciatic nerves from injured sedentary mice. The behavioral changes and altered
macrophage polarization correlated with increased epidermal nerve fiber density, improved
myelination, and increased in vitro neurite outgrowth from injured exercised animals.
Therefore, exercise alters macrophage polarization towards an anti‐inflammatory phenotype
which improves repair and recovery of the injured peripheral nerve.
THE USE OF MAGNETIC RESONANCE NEUROGRAPHY IN PERIPHERAL NERVE SHEATH TUMORS
Jack MM
1, Shah K1, Everist B1, Reyna J1, Hylton P1.
1University of Kansas Medical Center, Kansas City, KS, USA.
Diffusion tensor imaging (DTI) has long been used to evaluate the location and integrity
of white matter tracts in the brain. DTI uses quantitative data and directionality
of water diffusion to determine axonal connectivity of the nervous system. The technology
has only recently been utilized in limited settings in the peripheral nervous system
due to challenging technical factors and lack of widespread availability. Magnetic
Resonance (MR) neurography or peripheral neurography is a technique which uses diffusion
to differentiate between intraneural and perineural tissues. It allows for fascicle
patterns to be visualized particularly in the setting of peripheral nerve sheath tumors.
Peripheral nerve sheath tumors of various pathologies cause surrounding nerves to
be involved or displaced in a range of directions. This technique helps determine
the anatomic location of these nerve fibers in relation to the mass, which is particularly
helpful at distinguishing neuromas from schwannomas. This data is invaluable to the
surgeon to ensure a safe and low morbidity operation. While this technology has benefit
particularly with surgical planning, it has been underutilized due to the challenges
of requiring complex software to produce fiber tracks and the inability to translate
these images into the operating room. Here, we utilized BrainLab software that is
commonly available and utilized in surgical suites to produce images of the radial
nerve fiber tracts with an associated peripheral nerve sheath tumor prior to surgical
resection. While the software is commonly used in the central nervous system, it has
not been reported to have been used in the peripheral nervous system. This software
offers a high usability and produces anatomically correct and reliable fiber tracts.
This technique overcomes the reliance on highly specialized software and extensive
training required for use that most other tractography software has. Utilizing peripheral
neurography in this case allowed for complete surgical resection without postoperative
deficits. This data offers clinicians an option to investigate peripheral nerve fibers
in various pathologic states, to plan appropriate operative trajectories to peripheral
nerve pathology, and to improve surgical outcomes for patients with peripheral nerve
sheath tumors.
RITUXIMAB IN INTRACTABLE CIDP
Jacobsen B
1, Parry G2, Allen J2, Walk D2, Muley S1, Ortega E1.
1Barrow Neurological Institute, Phoenix, AZ, USA; 2University of Minnesota, Minneapolis,
MN, USA.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune mediated neuropathy
that is responsive to immunomodulatory agents such as glucocorticoids, intravenous
immunoglobulin (IVIg) and plasma exchange (PE). The specific immunopathogenic mechanisms
of CIDP remain unclear but there is increasing interest in nodal proteins as a site
of the immune attack. Even though the majority of patients respond to one of the aforementioned
immunomodulatory agents there are some who are unresponsive or incompletely responsive
to these first line agents and other more aggressive treatments may be necessary.
Cyclophosphamide and stem cell transplantation may be effective but are associated
with considerable morbidity. Anecdotal reports suggest that rituximab may be beneficial
for some patients that fail first‐line therapy, especially if they have antibodies
to nodal proteins. We present four patients with intractable CIDP who responded to
rituximab. One of the three patients had diabetes. Disease duration prior to starting
rituxan was short (4 months) in two patients and longer 24 and 27 months in the other
two. All patients had failed treatment with glucocorticoids and IVIg, and in two,
plasma exchange and IVIg‐PE were also ineffective. Two of the four patients were quadriparetic
and non‐ambulatory. Two 1 gm doses two weeks apart of intravenous rituximab were instituted
in all patients. All patient tolerated the treatments well without adverse effects.
All patients responded within four weeks and continued to improve at six months. Other
immunomodulatory agents were successfully tapered but not totally discontinued. It
remains unclear whether antibodies to nodal proteins were present in these patients.
In conclusion, although rituximab efficacy remains uncertain on the basis of randomized
controlled clinical trials, it may be beneficial in selected patients otherwise intractable
to first‐line treatments. Further studies are necessary to better understand which
patients may benefit most from rituximab and where in the treatment algorithm rituximab
should be applied.
THE FORGOTTON CELL TYPE IN NEUROPATHIC PAIN: SATELLITE GLIAL CELLS
Jager SB
1, Denk F2, Richner M1, Goncalves N1, Pallesen LT1, McMahon S2, Vægter CB1.
1Department of Biomedicine, Aarhus University, Aarhus, Denmark; 2King's College London,
London, UK.
Neuropathic pain is a chronic condition seen in patients suffering a direct injury
to the peripheral or central nervous system or an indirect injury due to, e.g., diabetes
or multiple sclerosis. Current treatment options fall short of preventing or completely
relieving patients of their pain. For years, research has focused on understanding
the role of neurons in neuropathic pain pathogenesis while overlooking the role of
supportive cells in general and satellite glial cells (SGCs) in the dorsal root ganglion
in particular. These cells not only buffer the neuronal microenvironment they are
also involved in controlling the electrical activity flowing through the neurons and
in neuropathic pain pathogenesis. The aim of this project is to understand the role
of SGCs in neuropathic pain development and thereby aid the identification of new
drug targets. To purify the SGCs from adult mice we optimized a fluorescently activated
cell sorting (FACS) protocol. The success of our purification method was confirmed
using qRT‐PCR and visual inspection of the sorted cells. Finally, we are running RNA
sequencing on SGCs after peripheral nerve injury to compare their transcriptome to
that of uninjured cells at different time points. The results from our study are likely
to deepen our understanding of how SGCs contribute to the development and maintenance
of neuropathic pain.
FUNCTIONAL FAS/FASL PROMOTER POLYMORPHISMS ASSOCIATED WITH INCREASED RISK OF NERVE
DAMAGE IN GUILLAIN–BARRE' SYNDROME IN BANGLADESH
Jahan I1, Khalid MM2, Ahammad RU1, Shahnewaj1, Mohmmad QD3, Islam Z
1
. 1Laboratory Sciences and Services Division, International Centre for Diarrheal Disease
Research (icddr,b), Dhaka, Bangladesh; 2Department of Biochemistry, Erasmus University
Medical Centre, Rotterdam, The Netherlands; 3National Institute of Neurosciences and
Hospital, Sher‐e‐Bangla Nagar, Agargaon, Dhaka, Bangladesh.
Guillain–Barre' syndrome (GBS) is an immune‐mediated disorder in the peripheral nervous
system (PNS) triggered by molecular mimicry against nerve gangliosides. One of the
cell surface receptors (Fas)‐ligand (FasL) interaction transmits apoptotic signal
to eliminate the auto‐reactive B and T‐cells, which generates cross‐reactive antibody
against nerve cells. Host genetic polymorphism of Fas and FasL may alter their expression
and induce aberrant apoptotic response to develop GBS. Therefore, we determined the
single nucleotide polymorphisms (SNPs) of both Fas receptor (−1377G/A and ‐670A/G)
and FasL ligand (−843C/T) in GBS patients (N=100) as well as healthy controls (N=97)
using the LightCycler technique. Serum level of soluble form of Fas and FasL was measured
using commercially available sandwich ELISA kit. Comparison of genotype, allele and
haplotype frequencies was done with the GBS subgroups based on the clinical and serological
data. AG heterozygote (p=0.0494, OR=2.5, 95% CI=1.03‐6.1) and polymorphic G‐allele
(p=0.0387, OR=1.9, 95% CI=1.1‐3.5) of Fas receptor ‐670A/G promoter SNPs were significantly
associated with anti‐ganglioside (GM1) antibody positive GBS patients. In addition,
−670G‐allele (p=0.02, OR=4.8, 95% CI=1.3‐17.4) and ‐1377G/‐670G haplotype (p=0.0251,
OR=4.833, 95% CI=1.3‐18.04) were predominantly associated with the axonal variant
of GBS patients. Serum soluble form of sFas (median levels 259 pg/ml vs. 221 pg/ml,
p=0.0373) and sFasL (median levels 260 pg/ml vs. 202 pg/ml, p=0.0528) were found to
be elevated in anti‐GM1 antibody positive GBS patients compared to anti‐GM1 negative
patients. No significant association was found in genotypic distribution between GBS
patients and healthy controls. In conclusion, Fas/FasL promoter SNPs are not a susceptible
factor for GBS but could be one of the influencing factors to develop cross‐reactive
anti‐ganglioside antibodies in GBS patients in Bangladesh. Furthermore, functional
studies with a larger sample size (using cohort like International GBS outcome studies‐IGOS)
are required to explain the immune pathogenic role of these SNPs for GBS patients.
AUTOPHAGOLYSOSOME‐MEDIATED MYELIN CORPSE FORMATION BY SCHWANN CELLS IN SEGMENTAL DEMYELINATION
Jang SY1, Yoon BA
1, Shin YK1, Yun SH1, Jo YR1, Park JI1, Shin KJ
2
, Kim JK1, Park HT1.
1Dong‐A University, Busan, South Korea; 2Inje University, Busan, South Korea.
Myelination is essential for the proper function of the nervous system. Schwann cells,
which form the peripheral myelin sheath, have the unique ability to dedifferentiate
and to destroy the myelin sheath under various demyelination conditions. During Schwann
cell dedifferentiation‐associated demyelination in Wallerian degeneration after axonal
injury, Schwann cells exhibit myelin and junctional instability, down‐regulation of
myelin gene expression and autophagic myelin decomposition. However, in inflammatory
demyelinating neuropathy, it is still unclear how Schwann cells react and contribute
to segmental demyelination before myelin scavengers, macrophages, are activated for
myelin clearance. Here, we show that Schwann cell dedifferentiation‐associated demyelination
is a mechanism involved in the initial demyelination observed in a mouse model of
inflammatory demyelinating neuropathy using ultrastructural, biochemical and microarray
analyses. Myelin uncompaction and myelin membrane instability generated by dedifferentiated
Schwann cells lead to autophagolysosome‐dependent cytoplasmic amputation between the
axon‐containing myelin sheath and the Schwann cell body, resulting in the formation
of the “myelin corpse”, thereby allowing macrophages to phagocytose the myelin corpse
in the end stage of segmental demyelination. We found myelin corpse formation in inflammatory
demyelination to be a process similar to the myelin rejection during Wallerian degeneration,
which appeared to be dependent on Schwann cell autophagolysosome activation since
Schwann cell‐specific Atg7 knockout mice exhibited delayed myelin rejection following
nerve injury. Finally, lysosome inhibition in Schwann cells not only prevented segmental
demyelination but also delayed the progression of clinical stages by suppressing the
myelin corpse formation in inflammatory demyelinating neuropathy. Thus, our findings
indicate that demyelination by Schwann cells and macrophages might be part of a process
that includes sequential divisions of labor with respect to myelin rejection and digestion,
respectively. In conjunction with previous studies showing Schwann cell dedifferentiation
and autophagy in toxic and hereditary neuropathies, the concept of “Schwann cell dedifferentiation‐Associated
Demyelination” provides insight into the development of possible therapeutic strategies
to prevent Schwann cell demyelination in peripheral demyelinating neuropathies.
CHARCOT‐MARIE‐TOOTH DISEASE TYPE 4C: NOVEL MUTATIONS, CLINICAL PRESENTATIONS, AND
DIAGNOSTIC CHALLENGES OF AN ATYPICAL CMT
Jerath NU
1, Mankodi A2, Crawford TO3, Grunseich C2, Baloui H4, Nnamdi‐Emeratom C2, Schindler
AB2, Heiman‐Patterson T5, Chrast R4, Shy ME1.
1Department of Neurology, University of Iowa Carver College of Medicine, Iowa City,
IA, USA; 2Neurogenetics Branch, National Institute of Neurological Disorders and Stroke,
National Institutes of Health, Bethesda, MD, USA; 3Department of Pediatric Neurology,
Johns Hopkins University, Baltimore, MD, USA; 4Department of Neuroscience and Department
of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 5Department of
Neurology, Drexel University College of Medicine, Philadelphia, PA, USA.
Objective: To analyze and describe atypical presentations of CMT4C.
Methods: We present clinical and physiologic features of five subjects with CMT4C
caused by biallelic private mutations of SH3TC2.
Results: All cases manifested scoliosis and nerve conduction studies in the demyelinating
range. All exhibited signs of motor impairment within the first years of life. We
describe two or more different genetic diseases in the same patient, atypical presentations
of CMT and 3 new mutations in CMT4C patients.
Discussion: A new era of unbiased genetic testing has led to this small case series
of individuals with CMT4C, and highlights the recognition of different genetic diseases
in CMT4C patients for accurate diagnosis, genetic risk identification and therapeutic
intervention. The phenotype of CMT4C, in addition, appears to be enriched by a number
of features unusual for the broad CMT category.
CHARCOT‐MARIE‐TOOTH DISEASE TYPE 1A: INFLUENCE OF BODY MASS INDEX ON NERVE CONDUCTION
STUDIES AND ON THE CHARCOT‐MARIE‐TOOTH EXAM SCORE
Jerath NU
1, Shy ME1.
1Department of Neurology, University of Iowa Carver College of Medicine, Iowa City,
IA, USA.
Introduction: Charcot‐Marie‐Tooth Disease Type 1A (CMT1A) is caused by a duplication
of the peripheral myelin protein 22 gene at chromosome 17p11.2‐12. Whether body mass
index (BMI) affects electrophysiological or clinical data for CMT1A patients is not
clear because the relevant data are limited.
Methods: Electrophysiological data, the Charcot Marie Tooth exam score (CMTES), and
BMI from 112 patients with known CMT1A were obtained and analyzed.
Results: When controlled for age, BMI does not affect studies of ulnar motor nerve
conduction in CTM1A patients, but rather specific components of the CMT exam scores
(CMTES, loss of pinprick sensation and motor strength in the lower extremities).
Discussion: BMI and clinical components of the CMTES are correlated, but it is uncertain
which is the primary effect – i.e., whether the reductions in pinprick sensation and
motor strength in the lower extremities lead to a higher BMI, or higher BMI results
in these signs.
CHARCOT‐MARIE‐TOOTH DISEASE TYPE 1C: CLINICAL AND ELECTROPHYSIOLOGICAL FINDINGS FOR
THE C.334G>A (P.GLY112SER) LITAF/SIMPLE MUTATION
Jerath NU
1, Shy ME1.
1Department of Neurology, University of Iowa Carver College of Medicine, Iowa City,
IA, USA.
Introduction: Charcot‐Marie‐Tooth Disease type 1 C (CMT1C) is a rare, dominantly inherited
neuropathy caused by mutations in the lipopolysaccharide‐induced tumor necrosis factor
(LITAF) or small integral membrane protein of the lysosome/late endosome (SIMPLE)
gene.
Methods: We present a case series comprised of 10 patients in whom CMT1C is caused
by a Gly112Ser substitution in the encoded protein. We focus on clinical presentation,
electrodiagnostic analyses, and our findings in the context of previously described
cases.
Results: The Gly112Ser mutation causing CMT1C is a mild form of CMT, as patients walked
on time, had less weakness than those with Charcot‐Marie‐Tooth Disease type 1A (CMT1A),
had a Charcot Marie Tooth neuropathy score (CMTNS) indicative of mild disease, and
had faster ulnar and median motor nerve conduction velocities compared to those with
CMT1A.
Discussion: The G112S mutation in LITAF seems to be clinically indistinguishable from
a mild presentation of CMT1A.
CRITICAL ROLE FOR MONOCARBOXYLATE TRANSPORTER (MCT1) IN DEVELOPING AND REGENERATING
PERIPHERAL NERVES
Jha MK1, Russell K1, Lee Y1, Rothstein JD1, Morrison BM
1.
1Johns Hopkins University, Baltimore, MD, USA.
Peripheral nerves are highly dependent on metabolic energy to maintain both basic
cellular functions such as axon transport, Na+/K+ ion gradients, and myelination,
as well as to support regeneration following injury. Though glucose certainly provides
some metabolic support, our recent studies have shown that monocarboxylates, such
as lactate, pyruvate, and ketone bodies, also contribute to recovery from peripheral
nerve injury. Monocarboxylate transporters, particularly MCT1, are the predominate
transporters for monocarboxylates in the peripheral nerve. In a recent publication,
we found that MCT1 heterozygous null mice, which express 50% less MCT1 in all cells,
have slowed nerve regeneration and reduced myelination following sciatic nerve crush.
This study was limited by the global reduction of MCT1, which is widely expressed
in Schwann cells (SC), dorsal root ganglia (DRG) neurons, endothelial cells, macrophages,
and perineurial cells within the regenerating peripheral nerve. To better understand
the mechanism by which MCT1 contributes to normal nerve function and nerve regeneration,
we produced and validated conditional MCT1 null (MCT1LoxP) mice that allow selective
deletion of MCT1 from SCs, DRG neurons, endothelial cells, or macrophages through
mating to cell‐specific Cre lines. We are currently quantifying peripheral nerve development,
aging, and regeneration in each of these mouse lines. Following SC‐, but not DRG‐,
specific MCT1 knockdown, sensory peripheral nerves develop demyelination by 4 months
of age, manifest by reduced myelin thickness, increased g‐ratio, and reduced conduction
velocity. Studies are ongoing in cultured SCs to determine the mechanism for demyelination.
Neither SC nor DRG knockdown of MCT1 impairs nerve regeneration following sciatic
nerve crush. These results suggest that SC‐specific MCT1 is critical for maintaining
myelin in sensory, but not motor, peripheral nerves as they age. They also suggest
that MCT1 expression in peripheral nerve cell types, other than SC and DRG, is important
for nerve regeneration. Ongoing studies are determining the contribution of MCT1 in
other peripheral nerve cell types, particularly endothelial cells and macrophages,
to normal development and regeneration following injury. Our results will clarify
the role of lactate and its transporter, MCT1, in peripheral nerve function, potentially
suggesting novel targets for demyelinating neuropathies or nerve injuries.
DIGIT WRINKLE SCAN©: FROM NORMATIVE VALUES TO ITS CLINICAL APPLICABILITY IN SMALL
FIBER NEUROPATHY
Joosten IBT
1, Sopacua M1, Bovenkerk DSH1, Potten RMM1, Faber CG1, Merkies ISJ2, Hoeijmakers JGJ1
. 1Maastricht University Medical Center, Maastricht, The Netherlands; 2St. Elisabeth
Hospital, Willemstad, Curaçao.
Small fiber neuropathy (SFN) is a condition in which the smallest nerve fibers are
affected, characterized by neuropathic pain and autonomic dysfunction. According to
international criteria, SFN diagnosis is based on clinical symptoms in combination
with abnormal temperature threshold testing (TTT) and/or reduced intraepidermal nerve
fiber density (IENFD) in skin biopsy. Skin biopsy is moderately sensitive, invasive
and the process is time consuming and expensive. TTT is a widely available diagnostic
tool, but lacks specificity. Previous studies introduced stimulated skin wrinkling
(SSW) as an objective, non‐invasive diagnostic tool to detect sympathetic nerve dysfunction
in SFN by means of a categorical assessment. However, our unpublished data has shown
that inter‐observer reliability of categorically assessed SSW is quite low. In this
current study we will use a new digital method for SSW quantification: the Digit Wrinkle
Scan© (DWS©). The primary study objective is to define normative values for DWS© expressed
as total wrinkle length per fingertip surface (mm/mm2). Subsequently we investigate
the applicability of DWS© in patients with definite SFN, based on abnormal IEFND and/or
TTT, determining the DWS© sensitivity and specificity, as well as its validity. For
this cross‐sectional study, we will include 60 healthy participants and 200 patients
diagnosed with SFN. Eligibility is based on meeting the inclusion and exclusion criteria
and providing written informed consent. Skin wrinkling is induced by EMLA (eutectic
mixture of local anesthetics) cream© application and captured by taking pictures.
The primary outcome measure is total length of wrinkles per mm2 as shown on the photographs,
which will be calculated by a new software program. Patients are stratified according
to age and gender. Based on the results of healthy participants, normative values
will be defined. Inter‐ and intra‐observer reliability will be determined. In the
SFN group, additional correlation analysis will be conducted to determine the correlation
between DWS© and different outcome measures (SFN‐Symptom Inventory Questionnaire,
visual analogue pain scale, neuropathic pain scale, SFN‐ Rasch‐built Overall Disability
Scale, IENFD and TTT). We expect to provide digitally quantified SSW (dSSW©) normative
values that can be used in clinical practice in the diagnostic workup for SFN.
IDENTIFICATION OF COMMON MOLECULAR PLAYERS INVOLVED IN THE PROGNOSIS AND PATHOGENESIS
OF AXONAL CMT SUBTYPES
Juneja M
1, Azmi A2, Baets J2, Emmerson I3, Bansagi B3, Saveri P4, Pisciotta C4, De Jonghe
P2, Maudsley S2, Horvath R3, Pareyson D4, Timmerman V1.
1Peripheral Neuropathy Research Group, University of Antwerp, Belgium; 2VIB and University
of Antwerp, Belgium; 3Institute of Genetic Medicine, Newcastle University, UK; 4Department
of Clinical Neurosciences, C. Besta Neurological Institute, Milan, Italy.
CMT2, characterized by axonal degeneration, is an inherited motor and sensory neuropathy
accounting for about 20% of total CMT patients. The CMT2 subtype shows on its own,
a vast genetic heterogeneity with more than 140 mutations in 26 known genes rendering
the identification of relevant drug targets and therapies very challenging. So far,
only HDAC inhibitors have shown promising results in mouse models for HSPB1 mediated
axonal CMT (CMT2F), albeit such a single gene approach may have a limited relevance
at clinical levels owing to the limited number of patients per genotype. In this study,
we investigated common causative molecular players of CMT2 associated axonal degeneration.
For this, an iTRAQ based proteome analysis was performed on five patient's derived
lymphoblasts bearing different CMT2 causal mutations alongwith respective age and
gender matched unaffected controls. Software‐assisted interpretations of the obtained
data led us to identify two proteins which were significantly downregulated in CMT2
patients compared to controls. These two proteins were then validated using Western
blotting and qPCR on patient derived lymphoblasts and fibroblasts. Our results prompted
us to unveil whether these two proteins can be used as potential biomarkers for identifying
CMT2 patients. Therefore, through a Europe‐wide collaboration, we constructed a cohort
of 43 CMT2 patients and 21 healthy controls. These two proteins exhibited significant
downregulation in this cohort suggesting a potential new role of these proteins as
CMT2 biomarkers. Remarkably, we were also able to validate the significant decrease
in iNeurons (neurons differentiated from patient derived iPSCs) strengthening the
importance of our finding and also suggesting the relevance of these proteins in the
pathogensis of axonal CMT. This will be the first study involving multiple CMT causal
genes at once, thereby holding the potential to offer new drug targets and potential
biomarkers with wider application both clinically and pharmaceutically.
RESTORATION OF NEUROMUSCULAR FUNCTION IN A MOUSE MODEL OF CHARCOT‐MARIE‐TOOTH TYPE
1A BY DIFFERENTIATED HUMAN TONSIL‐DERIVED MEESENCHYMAL STEM CELLS
Jung SC
1, Park S1, Choi Y1, Kwak G2, Hong YB2, Jung N1, Kim J1, Chung KW3, Choi BO2.
1Ewha Woman's University, Seoul, South Korea; 2Sungkyunkwan University, Seoul, South
Korea; 3Kongju National University, Gongju, South Korea.
Mesenchymal stem cells (MSCs) represents a valuable source of stem cell therapy, can
differentiate into various cell types. We investigated of the neuromuscular potential
of human tonsil‐derived MSCs (T‐MSCs) for neuromuscular regeneration in trembler‐j
mice that is considered to be a model for Charcot‐Marie‐Tooth disease type 1A (CMT1A
diseases), which is involving hereditary motor and sensory peripheral neuropathies.
The T‐MSCs differentiated toward skeletal myocytes, as evidenced by increased expression
of skeletal muscle‐related markers (including troponin I type 1, and myogenin) and
the formation of myotubes in vitro. In situ transplantation of T‐MSC‐derived myocytes
(T‐myocytes) into gastrocnemius in trembler‐j mice, a mouse model of CMT1A, enhanced
motor function, as identified with recovery by a compound muscle action potential
(CMAP) amplitude. And the regenerated shape of the sciatic nerve and skeletal muscle
by immunochemistry, without the formation of teratomas. Furthermore, the expression
levels of nerve growth factor (NGF) and glial cell line‐derived neurotrophic factor
(GDNF) were significantly increased in T‐myocyte compared with T‐MSCs in vitro. These
results indicate that the transplantation of T‐myocyte can be a therapeutic option
of cell therapy for the neuromuscular regeneration in hereditary peripheral neuropathy,
comprising CMT1A disease.
INTRATHECAL GENE THERAPY IN DIFFERENT MUTANT MOUSE MODELS OF CMT1X
Kagiava A
1, Karaiskos C1, Richter J2, Tryfonos C2, Lapathitis G1, Sargiannidou I1, Christodoulou
C2, Kleopa KA1,3.
1Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Nicosia,
Cyprus; 2Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics,
Nicosia, Cyprus; 3Neurology Clinics, Cyprus School of Molecular Medicine, The Cyprus
Institute of Neurology and Genetics, Nicosia, Cyprus.
X‐linked Charcot‐Marie‐Tooth disease (CMT1X) is a common form of inherited demyelinating
peripheral neuropathy resulting from mutations affecting the gap junction protein
connexin32 (Cx32). Using a Cx32 knockout (KO) mouse model of the disease, we have
shown that targeted expression of virally delivered Cx32 results in morphological
and functional improvement. Since patients with CMT1X express mutant forms of Cx32
in Schwann cells, that could potentially interact with virally delivered wild type
(WT) Cx32 through dominant‐negative effects, we also treated mutant mice expressing
the T55I, R75W and N175D mutations associated with CMT1X on a Cx32 KO background.
All three mutants were localized in the perinuclear compartment of myelinating Schwann
cells consistent with retention in the ER (T55I) or Golgi (R75W, N175D) with loss
of physiological expression in non‐compact myelin areas. Following intrathecal delivery
of the human GJB1 gene we could detect the virally delivered WT Cx32 correctly localized
in the non‐compact myelin areas only in T55I/Cx32KO mutant mice, but not in the other
two mutants, suggesting dominant effects of the R75W and N175D mutant but not of the
T55I mutant. GJB1 treated T55I/Cx32 KO mice showed improved motor performance, along
with lower ratios of abnormally myelinated fibers and reduced numbers of inflammatory
cells in all tissues examined compared to mock‐treated animals. In contrast, GJB1
treated R75W and N175D mutant mice showed only slight but not statistically significant
improvement. This study provides additional proof of principle for a clinically translatable
gene therapy to treat CMT1X even in the presence of endogenously expressed Cx32 mutants,
since at least one ER‐retained Cx32 mutant did not interfere with the expression of
virally delivered Cx32 allowing a therapeutic benefit similar to Cx32 KO mice. However,
Golgi‐retained mutants may interfere with virally delivered WT Cx32 and other approaches
besides gene addition may be needed for effective treatment.
Funding: Muscular Dystrophy Association (Grant MDA 277250 to KAK).
ANTIBODIES TO NEUROFASCIN155 IN CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY:
DIAGNOSTIC UTILITY OF A CONVENTIONAL ASSAY
Kaida K
1, Kadoya M1, Koike H2, Iijima M2, Takazaki H1, Ogata H3, Moriguchi K1, Shimizu J4,
Nagata E5, Takizawa S5, Chiba A6, Yamasaki R3, Kira J‐I3, Sobue G2, Ikewaki K1.
1National Defense Medical College, Tokorozawa, Japan; 2Nagoya University Graduate
School of Medicine, Nagoya, Japan; 3Kyushu University, Fukuoka, Japan; 4University
of Tokyo, Tokyo, Japan; 5Tokai University School of Medicine, Isehara, Japan; 6Kyorin
University, Tokyo, Japan.
Antibodies to a glial protein, neurofascin (NF)155 have recently been identified in
approximately 10% of patients with chronic inflammatory demyelinating polyneuropathy
(CIDP), which are IgG4‐predominant. IgG4 anti‐NF155‐associated CIDP may be a distinct
subtype from typical CIDP in terms of clinical features and response to immunotherapy.
However, a diagnostic criterion of anti‐NF155‐associated CIDP has not established
yet. To develop optimal criteria and design the best treatment plan for the anti‐NF155‐associated
CIDP, procedures for determining anti‐NF155 antibodies should be simplified, prevalent,
and reproducible, as well as being accurate. Cell‐based assay (CBA) has hitherto been
utilized for determining antibodies to NF155 in sera from patients, results of which
have been confirmed by immunohistochemistry (IHC) using teased nerve fibers from rodents.
These methods are the most reliable techniques, while not necessarily easy‐to‐use
and easy to maintain in most laboratories. In the present study, we aimed to validate
the diagnostic utility of a conventional enzyme‐linked immunosorbent assay (ELISA)
for determination of anti‐NF155 antibodies and the IgG subclass. Sera from 191 patients
with EFNS/PNS criteria‐met CIDP were examined with ELISA using human recombinant NF155.
To verify ELISA results, IHC on rat sciatic nerves, western blot (WB) and CBA using
NF155‐transfected and naive HEK293 cells were conducted. The human NF155‐based ELISA
clearly distinguished between anti‐NF155 antibody‐positive and ‐negative sera. Fifteen
CIDP patients (8%) were IgG4 anti‐NF155 antibody‐positive, which were confirmed by
WB, IHC and CBA studies. None of disease controls or healthy subjects had positive
results. Twenty‐five sera randomly selected from 176 anti‐NF155‐negative CIDP sera
were also negative on CBA. The anti‐NF155 activities on ELISA were significantly positively‐correlated
with those on CBA (p < 0.01). Analyses of clinical and laboratory findings showed
that anti‐NF155‐associated CIDP was characterized by younger onset, distal dominant
phenotype, tremor, sensory ataxia, higher protein levels in cerebrospinal fluid, and
poor response to IVIg, which were consistent with those in previous studies. This
ELISA combined with determination of the IgG4 subclass is a simple and reliable method
for initial screening for anti‐NF155 antibodies.
CLINICAL AND NEUROPHYSIOLOGICAL PROFILE OF CMTX3 IN CHILDHOOD
Kanhangad M1, Cornett K2,3, Brewer MH2,4, Nicholson GA2,4,5, Ouvrier RA1,2,3, Ryan
MM6,7,8, Smith RL9, Subramanian GM9, Young HK2,10, Kennerson ML2,4,5, Burns J2,3,11,
Menezes MP
1,2,3.
1T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at
Westmead, Westmead, Australia; 2University of Sydney, Camperdown, Australia; 3Institute
for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead,
Australia; 4Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord,
Australia; 5Molecular Medicine Laboratory, Concord Repatriation General Hospital,
Concord, Australia; 6Department of Neurology, Royal Children's Hospital, Parkville,
Australia; 7Murdoch Children's Research Institute, Parkville, Victoria, Australia;
8Department of Paediatrics, University of Melbourne, Parkville, Australia; 9Department
of Neurology, John Hunter Children's Hospital and University Faculty of Health, Newcastle,
Australia; 10Department of Paediatrics, Royal North Shore Hospital, St Leonards, Australia;
11Paediatric Gait Analysis Service of New South Wales, Sydney Children's Hospitals
Network (Randwick and Westmead), Australia.
The genetic abnormality responsible for X‐linked Charcot‐Marie‐Toothy neuropathy subtype
CMTX3 was recently identified by whole genome sequencing to be a 78 kb insertion into
chromosome Xq27.1. The clinical profile of CMTX3 in childhood is not well described.
We reviewed the clinical characteristics, neurophysiological profile and CMT Pediatric
Scale (CMTPedS) assessments of 11 children with genetically confirmed CMTX3. CMTX3
was characterized by early onset, and early and progressive hand weakness. Most affected
children were symptomatic within the first two years of life. The most common presentation
was with equinovarus foot deformity in the first year of life. CMTPedS analysis in
these children revealed that CMTX3 progressed more rapidly (4.3 ± 4.1 points/2 year,
n=7) than CMT1A and CMTX1. Grip strength in the second decade of life in most affected
males was two standard deviations below age‐ and sex‐matched normative reference values.
The most severely affected individual was wheelchair bound at 14 years of age and
two individuals had no movement in the small muscles of the hand in the second decade
of life. There was only a single symptomatic female identified and she had mild signs.
Nerve conduction studies showed a demyelinating sensorimotor neuropathy with motor
conduction velocity in eight children while one child had a length‐dependent sensorimotor
axonal neuropathy. Understanding the unique phenotype of CMTX3 is essential for directing
genetic testing, as the CMTX3 insertion will not be detected on the SNP microarrays,
multi‐gene panels or whole‐exome sequencing currently used for the diagnosis of CMT.
The early onset of disease coupled with rapid progression means that many children
with CMTX3 will have severe disability within the first two decades of life and hence
early diagnosis is needed for early commencement of rehabilitation.
THE SUCCESSFUL USE OF VERY HIGH DOSE IVIG IN ACQUIRED, DEMYELINATING NEUROPATHIES
– 3 CASES
Kapoor M
1, Catania S2, Sarri‐Gonzales S1, Lunn MP1, Manji H1, Reilly MM1, Carr AS1.
1Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery,
London, UK; 2Department of Neurophysiology, National Hospital for Neurology and Neurosurgery,
London, UK.
The conventional dosing of IVIg in CIDP and MMN is based on treatment trials that
used bolus and maintenance dosing of IVIg between 1–2.5g/kg. There are rare published
articles reporting the efficacy of higher maintenance IVIg doses. We present three
cases of inflammatory neuropathies, who are currently stabilized on IVIg doses of
2mg‐8mg/kg of IVIg per month, refractory to standard dose IVIg and other immunosuppressants.
The first case is a 35 year‐old‐lady with CIDP who presented with 3 episodes of ascending
sensory disturbance, weakness, and diplopia. She had activity related fluctuations
and pre‐dose deterioration on 2g/kg/month IVIg. She then had an acute deterioration
with MRC sum score dropping from 70 to 49 even with additional plasma exchange. Her
bilateral foot drop (MRC Grade 2–3) and fluctuations persisted with an increase of
IVIg to 4.6g/kg/month. She is now clinically stable (ankle dorsiflexion MRC Grade
4–5, MRC sum score 67) on mycophenolate and 80g IVIg weekly (5.3g/kg/month). Case
2 is a 45‐year‐old male fitness instructor with MMN and Sjogren's syndrome. He presented
with recurrent proximal and distal weakness that responded to 2g/kg of IVIg and deteriorated
with IV methylprednisolone. He had peri‐dose fluctuations, intermitted proximal weakness,
and persistent foot drop (ankle dorsiflexion MRC grade 2–3) at 2.83mg/kg/month, worsening
to MRC grade 1–2 on 4.33g/kg/month and fluctuating between MRC grade 0–3 on 5.7g/kg/month.
An increase of IVIg to 180g weekly (8.52g/kg/month), has resulted in MMN RODS scores
of 50/50, improved distal power and return to full capacity at work. Case 3 is a 52‐year‐old
man with predominantly upper limb CIDP. He received 2g/kg IVIg without any benefit,
had no response to 2 doses of plasma exchange, 10 doses of cyclophosphamide or 1 dose
of rituximab between 2010 and 2012. Since 2013, he has received 2g/kg/month IVIg with
improvement of MRC sum score from 50 to 68. These cases highlight that some patients
require a much higher than conventionally prescribed dose of IVIg, and that these
doses are tolerated over years without serious adverse events.
REDUCED INTRAEPIDERMAL NERVE FIBER DENSITY IN PATIENTS WITH REM SLEEP BEHAVIOUR DISORDER
Katona I
1, Schrempf W2, Dogan I3,4, von Felbert V5, Wienecke M2, Heller J3,4, Maier A3, Hermann
A2,6, Linse K2, Brandt MD2, Reichmann H2, Schulz JB3,4,7, Schiefer J3, Oertel WH8,
Storch A2,6,9,10, Weis J1, Reetz K3,4,7.
1Institute of Neuropathology, RWTH Aachen University, Aachen, Germany; 2Department
of Neurology, Technische Universität Dresden, Dresden, Germany; 3Department of Neurology,
RWTH Aachen University, Aachen, Germany; 4JARA – Translational Brain Medicine, Jülich
and Aachen, Germany; 5Department of Dermatology and Allergology, RWTH Aachen University,
Aachen, Germany; 6German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden,
Germany; 7Institute of Neuroscience and Medicine (INM‐11), Research Center Jülich
GmbH, Jülich, Germany; 8Department of Neurology, Philipps University Marburg, Germany;
9Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität
Dresden, Germany; 10Department of Neurology, University of Rostock, Rostock, Germany.
Idiopathic rapid eye movement sleep behaviour disorder (iRBD) has been identified
as a precursor of alpha‐synucleinopathies, such as Parkinson's disease, dementia with
Lewy bodies, multiple system atrophy. Several studies linked changes in cutaneous
innervation with central nervous system pathology in neurodegenerative disorders.
Recently small fiber neuropathy and alpha‐synuclein deposition in the skin found to
be a potential biomarker in Parkinson's disease. We evaluated the epidermal innervation
of 18 iRBD patients and 22 age and sex‐matched controls from skin punch biopsies from
the distal leg using PGP9.5 immunohistochemistry. Furthermore, a battery of clinical
examinations were performed on patients and controls alike, including structured interviews,
clinical motor and non‐motor questionnaires and rating scales (e.g. Unified Parkinson's
disease rating scale [UPDRS], non‐motor symptoms questionnaire [NMS‐Quest] and Beck
depression inventory, Epworth Sleepiness Scale, evaluation of cognitive and olfactory
functioning as well as blood samples. iRBD patients, compared to controls, showed
a significant reduction in intraepidermal nerve fiber density (p = 0.037), whereas
the axon swelling ratio, did not differ between groups. Patients with iRBD reported
non‐motor symptoms more frequently than controls (UPDRS I, NMS‐Quest). Olfaction and
daytime sleepiness differed between both groups, whereas there were no differences
regarding cognition.
These in vivo findings demonstrate small fiber neuropathy in iRBD patients that are
associated with non‐motor symptoms indicating that peripheral abnormalities may occur
early in iRBD. They warrant larger scale longitudinal studies in order to investigate
their prognostic value.
FIRST GLOBAL MULTIFOCAL MOTOR NEUROPATHY (MMN) QUALITY OF LIFE (QOL) PATIENT SURVEY
IDENTIFIES NEEDS IN EDUCATION AND TREATMENT
Katz J1, Lewis R2, Spatafora D
3.
1California Pacific Med Center, San Francisco, USA; 2Cedars‐Sinai Medical Center,
Los Angeles, USA; 3Neuropathy Action Foundation (NAF), Santa Ana, USA.
Multifocal Motor Neuropathy (MMN) is a rare condition that affects 0.6 in every 100,000
individuals worldwide and is associated with motor dysfunction and moderate to severe
disability. The Neuropathy Action Foundation conducted a global survey to determine
the impact of MMN on patient Quality of Life (QOL) and gaps in patient/provider educational
needs. The first global MMN QOL survey was an 87 item internet questionnaire available
between January 21 and July 21, 2016. The survey focused on three primary areas: timely
and accurate diagnosis, the efficacy of treatment, and the impact of the disease on
patients QOL. The survey was completed by 214 patients from 24 countries. The majority
of respondents said they were diagnosed between the ages of 41 and 65 years (56.52%),
more than 67% reported that it took more than one year to be diagnosed and more than
44% reported that it took 2–3 years or longer to be accurately diagnosed. With respect
to treatment options : 91.43% reported receiving intravenous immune globulin and 8.57%
reported receiving subcutaneous immune globulin therapy. Other therapies being used
to treat MMN were gabapentin (6.6%), and pregabalin (5%). Almost half (49.49%) said
that MMN often impacts their overall schedule. Half of the participants reported that
MMN often or always interferes with their employment; 46% had difficulty typing on
a computer or using a telephone, 46.19% had trouble concentrating, and 38.07% said
they had to work really hard to pay attention or else they would make a mistake. This
is the first assessment of MMN from a patient's perspective. The survey highlighted
critical issues relating to the diagnosis, management, and impact on the QOL of individuals
with MMN. The data also identified gaps and insights in provider education relating
to proper diagnoses and management of the condition from a patient's perspective.
IMPROVING REVIEW PROCESSES FOR IVIG THERAPY: GETTING TO KNOW OUR AUNTS (AUSPICOUSLY
UNINTERPRETABLE NOTE TAKING) AND UNCLES (UNCERTAIN NEUROLOGICAL CLINICAL ENTITIES)
Katz J
1, Levine T2, Dimachke M3, Barohn R3.
1Forbes Norris Center, San Francisco, CA, USA; 2Phoenix Neurological Institute, Phoenix,
AZ, USA; 3Kansas University Medical Center, Kansas City, KS, USA.
In the United States, CIDP cases are submitted to insurance companies to determine
whether IVIg therapy is appropriate. This is done using specified diagnostic criteria,
which reduce diagnosis to a Boolean analysis, where a disease can only be present
or absent. This leaves no room for uncertainty, even when it truly exists. Boolean
criteria are useful for clinical trials, but fall short where real decisions are made
under uncertainty and based on perceived cost/benefit analysis. This project attempts
to elucidate root causes of uncertainty and to find solutions to this dilemma. We
asked 8 CIDP experts to select a single diagnosis in 29 cases where IVIg was approved
using the submitted case records. While there was agreement on many cases, in the
five most “uncertain” cases no more than 4 reviewers agreed on a single condition,
who chose up to four separate entities. Among these, at least three reviewers diagnosed
an immune neuropathy in all five. The root cause of the disagreement, to a large degree
was unclear documentation (AUNTs) which consisted of pasted, missing, and disorganized
data. Reviewers missed useful information, admitting it was too difficult to fully
parse records. To resolve uncertainty, reviewers admitted to discounting certain reported
datum to help fit the entity they suspected, such as reported therapeutic responses
or certain electrodiagnostic/exam findings. Other disagreement, however, reflected
the complexity of neuropathy diagnosis, such as knowing if improvement was due to
natural history or treatment, unawareness of rare presentations, or analyzing a true
UNCLE (complex case). Reviewers used Bayesian (select most likely diagnoses from a
list) and Fuzzy logic (compare best fits to base cases). When the “best” diagnosis
did not fit the base case, they had to re‐interpret the data. Improving review procedures
requires eliminating AUNTS by collecting all key information and simplifying how records
are presented. It also needs more advanced data methods to analyze common and rare
borderline presentations (UNCLES like MAMA v PMA, CIDP v CSPN, etc..), developing
diagnostic algorithms that address real uncertainty, educating prescribers and patients
on process, and creating systems that measure outcomes longitudinally after induction
or tapering of therapy.
DIFFERENCES OF ANTIBODY REACTIVITIES AGAINST GLYCOLIPID COMPLEXES AMONG GUILLAIN‐BARRÉ
SYNDROME, MILLER FISHER SYNDROME AND BICKERSTAFF BRAINSTEM ENCEPHALITIS
Keisuke Y
1, Miyuki M1, Motoi K1, Susumu K1.
1Department of Neurology, Faculty of Medicine, Kinki University, Osaka, Japan.
Anti‐ganglioside antibodies are closely associated with clinical phenotype and specific
symptoms in acute immune‐mediated neuropathies. IgG anti‐GQ1b antibodies are specifically
associated with Miller Fisher syndrome (MFS), Bickerstaff brainstem encephalitis (BBE)
and Guillain‐Barré syndrome (GBS) with opthalmoplegia (GBS‐OP). In addition, ganglioside
complexes (GSCs) containing GQ1b also can be targets in such diseases, and might be
associated with the clinical features. However, factors regulating clinical phenotype
in those GQ1b‐associated antibodies‐positive diseases have not yet been known. For
investigating the differences of antibody reactivities among those diseases, we examined,
using combinatorial glycoarray, IgG antibodies to ten individual glycolipids [GM1,
GM2, GM4, GD1a, GD1b, GQ1b, Galactocerebroside (Gal‐C), Lactosylceramide (LacCer),
GA1, Sulfatide] and 45 glycolipid complexes consisting of two of the glycolipids listed
above in sera from 36 patients with GBS‐OP who were positive for anti‐GQ1b antibody
by ELISA (GBS‐OP‐GQ1b), 40 patients with MFS with the clinical triad (opthalmoplegia,
ataxia, and areflexia), and 27 patients with BBE. By combinatorial glycoarray, overall
sensitivity of antibodies to GQ1b and GSCs containing GQ1b was 97.2% (35/36) in GBS‐OP‐GQ1b,
87.5% (35/40) in MFS, and 74.1% (20/27) in BBE, respectively. There were no significant
differences in antibody reactivities between MFS and BBE. It is notable that antibodies
to GSCs containing GD1b were more frequently found in GBS‐OP‐GQ1b patients than in
MFS or BBE patients (e.g., GD1b/Sulfatide: p=0.024 and p<0.01, respectively). Presence
of the antibody reactivities to GSCs containing GD1b may possibly be related with
clinical features of GBS‐OP‐GQ1b, including frequent need of artificial ventilation.
GAIT IN CHILDREN AND ADOLESCENTS WITH CHARCOT‐MARIE‐TOOTH DISEASE: A CASE‐CONTROLLED
STUDY OF GAIT IN DIFFERENT FOOTWEAR CONDITIONS
Kennedy R
1,2,3, Carroll K1,3, Paterson K2, Ryan MM1,2,3, McGinley JL2,3.
1Royal Children's Hospital, Parkville, Australia; 2University of Melbourne, Parkville,
Australia; 3Murdoch Childrens Research Institute, Parkville, Australia.
Problems with walking and footwear fit are often reported by children and adolescents
with Charcot‐Marie‐Tooth disease (CMT). A cross‐sectional, case controlled study of
gait was conducted in children with CMT and typically developing (TD) children. Gait
was assessed barefoot and in two types of the participants' own typical footwear;
optimal (e.g. athletic shoes) and suboptimal (e.g. slip‐on footwear). The aims were
to determine differences in spatio‐temporal (S‐T) gait variables between children
with CMT and TD children; and to investigate the effect of footwear choices. Twenty‐nine
independently ambulant children aged 4–18 years with confirmed genetic or clinical
diagnoses of CMT, and 29 age and gender matched TD children participated (mean age
11.5 years; 40 males). Exclusion criteria included developmental disorders, other
neuromuscular conditions or musculo‐skeletal diseases that could affect gait, and
lower limb injury or surgery in the preceding 6 months. Assessment included S‐T gait
patterns, footwear characteristics, 10 metre run, and CMTPedS. Gait was assessed at
self‐selected speed with an electronic walkway (GAITRite™), with 6 trials for each
condition. The primary gait variable assessed was speed; other variables included
step length, step time, cadence, base of support width and step‐to‐step gait variability.
Across all footwear conditions children with CMT walked more slowly (optimal CMT 1.26
[0.15] m/s, TD 1.40 [0.13] m/s; suboptimal CMT 1.18 [0.20] m/s, TD 1.31 [0.14] m/s;
barefoot CMT 1.20 [0.16] m/s, TD 1.31 [0.13] m/s; all p<0.05) with shorter steps (optimal
CMT 64.4 [8] cm, TD 69.9 [9] cm; suboptimal CMT 61.6 [11] cm, TD 66.3 [10] cm; barefoot
CMT 59.0 [8] cm, TD 63.8 [10] cm; all p<0.05) and wider base of support (optimal CMT
9.9 [2.8] cm, TD 7.3 [2.5] cm; suboptimal CMT 10.3 [3.0] cm, TD 7.5 [2.5] cm; barefoot
CMT 9.2 [2.9] cm, TD 7.1 [2.5] cm; all p<0.05). Gait performance in optimal footwear
for both groups was significantly faster compared to suboptimal and barefoot. Children
with CMT had significantly greater step‐to‐step variability in base of support width
in all footwear conditions. Children with CMT walk slower than TD children with shorter,
wider steps and increased variability. Footwear type affects gait.
LONG‐TERM OUTCOME OF INTRAEPIDERMAL NERVE FIBER REGERNATION IS IMPAIRED IN DIABETIC
PATIENTS, BUT IS INDEPENDET OF AXON LENGTH OR BLOOD GLUCOSE LEVEL
Khoshnoodi M
1, Truelove S1, Polydefkis M1.
1Johns Hopkins University, Baltimore, MD, USA.
Regeneration of cutaneous unmyelinated axons is known to be slowed in DM‐patients
and after 3‐months, the density of intraepidermal nerve fibers (IENF) does not return
to baseline levels after chemical or mechanical axotomy. However, the long‐term outcome
of regeneration in DM or control subjects is not known. Additionally, it is not clear
if the regeneration of sensory distal axons is length‐dependent. Here we measured
the rate of axonal regeneration 6‐months after chemical denervation using a capsaicin
model in DM patients (n=11/37 DM1/DM2) without neuropathy, and 5 controls. DM skin
punches were performed at distal thigh at baseline, 48‐hours post‐capsaicin, and at
28, 90, 150 and 180 days. Blood glucose and HgbA1C were measured at baseline, 90,
150 and 180 days. Healthy controls had skin punches at both distal leg and proximal
thigh at baseline, after capsaicin chemical axotomy, and days 28, 60, 90 and 180.
Regeneration rate was significantly higher at the thigh in healthy controls (0.1 fibers/mm/day
(95% CI: 0.04–0.18 fibers/mm/day) compared to DM (p=0.043), but no difference between
DM1 (0.07 fibers/mm/day 95% CI: 0.01–0.13 fibers/mm/day) or DM2 (0.06 fibers/mm/day
95% CI: 0.01–0.12 fibers/mm/day) (p=0.4). Comparing regeneration rate at different
time intervals, showed that regeneration was significantly slowed between day 150
and 180 DM patients, while it continued with the same rate in controls. Blood glucose
or HgA1C had no effect on regeneration rate. IENFD returned to baseline in controls
by 6‐months (118% of baseline) while it is did not in DM subjects, 76%/58% (DM1/DM2)
of IENFD baseline, (p=0.003 DM vs. controls). There was no difference in regeneration
rate IENFD %‐baseline by 6‐months at distal leg and proximal thigh in controls (p=0.61).
These results suggest that the rate and outcome of regeneration is independent of
the length of the axon. Additionally diabetic patient have incomplete nerve regeneration
after 6 months regardless of diabetes type or the level of glycemic control. Regeneration
of axons slowed down over time in patients with DM and reached a plateau after 150
days.
SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF THE FCRN INHIBITOR UCB7665: A PHASE
I STUDY
Kiessling P
1, Lledo‐Garcia R2, Watanabe S3, Langdon G4, Tran D2, Bari M2, Christodoulou L2, Price
G2, Smith B2, Byrnes W5, Brock M5, Jolles S6.
1UCB Pharma, Monheim, Germany; 2UCB Pharma, Slough, UK; 3UCB Pharma, Braine‐l'Alleud,
Belgium; 4PTx Solutions Ltd, London, UK; 5UCB Pharma, Raleigh, Durham, USA; 6University
Hospital of Wales, Cardiff, UK.
UCB7665 is a humanised high‐affinity monoclonal IgG antibody developed to bind human
neonatal Fc receptor (FcRn), selectively inhibiting IgG salvage and recycling. Conditions
such as myasthenia gravis (MG) are characterised by pathogenic IgG autoantibodies;
inhibition of FcRn may provide a suitable therapeutic approach.1 This Phase I, double‐blind,
dose‐escalating, first‐in‐human study (NCT02220153) evaluated the safety and pharmacology
of UCB7665. Forty‐nine healthy adults (mean age 44 years, range 22–65) were randomised
and received a single dose of intravenous (IV) or subcutaneous (SC) placebo (n=7 and
n=6, respectively), or a single dose of IV or SC UCB7665 (1, 4 or 7 mg/kg; n=6 per
dose, per administration). Subjects were followed up until Day 85. One placebo IV
subject did not complete the study. Twenty‐seven of 36 subjects (75%) receiving UCB7665,
and 9/13 (69%) receiving placebo, reported ≥1 treatment‐emergent adverse event (TEAE)
of mild/moderate intensity. Severe TEAEs occurred in four subjects, all in the UCB7665
7 mg/kg IV group (headache [n=3], back pain [n=1]). No serious AEs occurred. Incidence
of infections was similar with UCB7665 and placebo. The most frequently reported infection
was nasopharyngitis. Treatment‐related TEAEs were reported by 67% of subjects receiving
UCB7665 and 54% receiving placebo: the most common in the UCB7665‐treated groups were
headache (14/36; 39%) and vomiting (9/36; 25%); these occurred more frequently with
the IV than SC route. Non‐linear increases in UCB7665 plasma concentration–time profile
with increasing dose were observed with UCB7665. Serum IgG was reduced in a dose‐depended
manner with UCB7665 IV and SC: decreases from baseline to Day 10 with UCB7665 IV were
14.5%, 33.4% and 47.6% for 1, 4 and 7 mg/kg doses, respectively, and 16.8%, 25.9%
and 43.4%, with UCB7665 SC doses, respectively. These data indicated that the FcRn
inhibitor UCB7665 effectively reduced serum IgG, with SC administration generally
better tolerated than IV. Further to these observations, the efficacy, safety and
tolerability of UCB7665 SC for chronic–intermittent treatment of moderate‐to‐severe
MG are being evaluated in an ongoing Phase II, multi‐centre, randomised, double‐blind,
placebo‐controlled study (EudraCT 2016‐002698‐36).
1Roopenian and Akilesh. Nat Rev Immunol 2007;7:715–25
We thank Alexandra Webster, MSc, from iMed Comms an Ashfield Company, part of UDG
Healthcare plc, who provided medical writing support funded by UCB Pharma.
NEUROLOGICAL COMPLICATIONS IN MIDDLE EAST RESPIRATORY SYNDROME
Kim JE
1*, Won HY1, Heo JH1, Kim HO2, Song SH2, Park SS1, Park TH1, Ahn JY1, Kim MK1, Choi
JP3
*.
1Department of Neurology, Seoul Medical Center, Seoul, South Korea; 2Division of Pulmonology
and Critical Care Medicine, Department of Internal Medicine, Seoul Medical Center,
Seoul, South Korea; 3Division of Infectious Diseases, Department of Internal Medicine,
Seoul Medical Center, Seoul, South Korea.
Middle East respiratory syndrome (MERS) has a high mortality rate and pandemic potential.
However, very little information has become available on this syndrome since it first
erupted in 2012. This study aimed to evaluate the frequency of neurological complications
and their clinical presentations in MERS. We reviewed the medical records of all patients
who were diagnosed with laboratory‐confirmed MERS coronavirus (CoV) infections and
subsequently admitted to a single reference center for MERS treatment during the 2015
outbreak in Korea. In total, 4 patients (17.4%) reported neurological symptoms during
or after MERS‐CoV infection. The potential diagnoses in these 4 cases included Bickerstaff's
encephalitis overlapping with Guillain‐Barré syndrome, critical illness polyneuropathy
or other toxic or infectious neuropathies. Neurological complications did not appear
concomitantly with respiratory symptoms, but were instead delayed by 2–3 weeks. Neuromuscular
complications were not rare in MERS‐CoV‐infected patients, and they may have previously
been underdiagnosed. Understanding neurological manifestations is important in an
infectious disease like MERS, because evaluation is frequently limited during treatment,
but it can interfere with prognosis and sometimes require modification of treatment.
USEFULNESS OF VARIOUS ULTRASONOGRAPHIC FINDINGS IN CARPAL TUNNEL SYNDROME
Kim HJ
1, Hyun JK1, Kim TU1.
1Dankook University, Cheonan, South Korea.
The diagnosis of carpal tunnel syndrome (CTS) is based on clinical symptoms, physical
examinations and supported by nerve conduction study (NCS). Ultrasonographic examinations
can be performed to assess peripheral nerves with less discomfort and the surrounding
anatomic structures. While the usefulness of ultrasonography (USG) in the CTS has
been reported, no study to date has compared the diagnostic utility of various USG
findings for CTS. We investigated the correlation of various USG findings to the clinical
symptoms/signs and NCS findings in patients with CTS. Twenty‐eight hands (17 patients)
with CTS based on electrodiagnostic criteria and clinical symptoms such as tingling
sensation or pain in the first to third fingers, burning sensation, paresthesia and
weakness of hand grip power. All subjects were examined with USG. Cross‐sectional
area (CSA) and flattening ratio (FR) of the median nerve was calculated at level of
radio‐ulnar joint, pisiform and hamate. Swelling ratio of the median nerve and palmar
displacement of the flexor retinaculum was also calculated. Clinical assessment was
conducted using the Boston carpal tunnel questionnaire (BCTQ) scale and Historical‐Objective
(Hi‐Ob) scale. The analysis of correlation between USG findings and clinical symptom
scales/NCS findings was performed using correlation analysis. The CSA of the median
nerve at level of radio‐ulnar joint was significant correlated with BCTQ scale, Hi‐Ob
scale, distal motor latency, and conduction velocity (CV). The CSA of the median nerve
at level of pisiform was significantly correlated with Hi‐Ob scale, distal motor latency,
and CV. The FR of the median nerve at level of radio‐ulnar joint was significantly
correlated with BCTQ scale, Hi‐Ob scale, distal motor latency, and CV. The swelling
ratio of the median nerve was also significantly correlated with distal motor latency
and CV. In patients with CTS, CSA of the median nerve at level of radio‐ulnar joint
was most closely related to NCS findings and clinical symptoms. So, CSA of the median
nerve at radio‐ulnar joint might be a complementary tool for the diagnosis of CTS.
SONOGRAPHIC NERVE ENLARGEMENT IN SARCOID PERIPHERAL NEUROPATHY – A CASE REPORT
Kitaoji T1, Tsuji Y
1, Ashida S1, Yamada T1, Ishii R1, Tanaka A1, Mizuno T1.
1Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University
of Medicine, Kyoto, Japan.
The case was a 73‐year‐old woman. First, she noticed paresthesia in the right plantar
eight months before admission and in the left plantar four months before admission.
Three months before admission, she developed muscle weakness in her feet. The muscle
weakness and paresthesia extended to the lower legs in a few months. Twenty days before
admission, she experience difficulty in walking. On admission, the muscle weakness
was observed in the legs, especially in the right tibial anterior muscle (TA). There
was severe sensory disturbance and loss of deep tendon reflex in the legs. She had
trouble walking due to the weakness and sensory aphasia. In nerve conduction study
(NCS), conduction block was observed between the ankle and popliteal in both tibial
nerves. The blood level of angiotensin converting enzyme (ACE) was elevated. Cerebrospinal
fluid analysis was normal. There was no enhancement in the lumbar nerve roots shown
on MRI. Gallium‐67 scintigraphy showed hot spots on bilateral hilar lymph nodes and
mediastinal nodes and biopsy of mediastinal nodes showed non‐caseating epithelioid
granuloma. Therefore, we diagnosed her with sarcoid peripheral neuropathy by sarcoidosis.
By using the nerve ultrasound, partial spindle‐shaped nerve enlargement was observed
at the part of conduction block in the left tibial nerve. We started the treatment
with methyl prednisolone (1000mg, 3days) and oral prednisolone therapy (1mg/kg/day).
After treatment, the paresthesia and muscle weakness in the legs had gradually improved.
The partial enlargement in the left tibial nerve also improved on the 52‐hospital
day. In NCS, the conduction block improved, however, the compound muscle nerve potential
of tibial nerve decreased because of axonal damage. This partial spindle‐shaped nerve
enlargement by using ultrasound has never been reported in sarcoid peripheral neuropathy
before. The nerve ultrasound may be useful for evaluation of therapeutic effect of
sarcoid peripheral neuropathy.
THE EFFECT OF CURCUMIN ON PERIPHERAL NERVE REGENERATION
Kılınç M1, Oksuz E1, Demir O
1, Ersay FD1, Cevik B2.
1Department of Neurosurgery, Gaziosmanpaşa University, Tokat, Turkey; 2Department
of Neurology, Gaziosmanpaşa University, Tokat, Turkey.
Peripheral nerve injuries are still debating problems in the world because of poor
recovery. There is absolutely a need for new therapeutic agents to improve outcome
by altering nerve regeneration. There are some studies in the literature about some
therapeutic agents that used in the cases of peripheral nerve injuries. Despite these
studies, an agent with clinical use has not been presented yet. In this experimental
study, we aimed to analyze the effects of curcumin (CUR) in the cases of peripheral
nerve injuries. Forty rats were randomly and equally divided into four groups. The
first group was control group. Rats in this group were not operated. Right sciatic
nerve injuries were performed to the other groups. The second group was operation
group with no therapeutic agent. The third group was operation and local CUR applied
group. The fourth group was operation and systemic CUR applied group. Electrophysiological
evaluations were performed with electroneurography (ENoG) before and after the surgeries.
Systemic use of CUR although caused improvement in the ENoG values but could not make
a positive contribution to the nerve regeneration statistically. Additionally local
use of CUR made negative effect to the nerve regeneration statistically. According
to our statistical results we could not recommend CUR as a nerve protective agent.
GENOMIC ANALYSIS REVEALS FREQUENT TRAF7 MUTATIONS IN INTRANEURAL PERINEURIOMAS
Klein CJ1, Wu Y1, Jentoft ME1, Mer G1, Spinner RJ1, Dyck PJB1, Dyck PJ1, Mauermann
ML
1.
1Mayo Clinic, Rochester, USA.
Intraneural perineurioma is a hypertrophic peripheral nerve tumor having immunoreactivity
to epithelial membrane‐antigen, negative for S‐100. The origin of perineurial cells
is debated to be similar to meningeal cells. IP does not metastasize, but motor deficits
accumulate over time from tumor growth in nerve and plexus. After schwannomas and
neurofibromas, perineuriomas are the most common nerve tumor of young adults. A chromosome
22q deletion has been reported in one patient. We identified16 IP cases from our previously
published clinical cohort with available flash frozen IP tissue for DNA isolation.
WES with CNV analysis and CGH microarray analysis (Agilent 2x400K SuperPrintG3) were
performed on extracted DNA; 7 had available germline DNA (lymphocytes and buccal tissue).
We compared the exome data against online and in‐house control data (∼100,000) examining
variants less than 0.0001 frequencies, predicted damaging or nonsynonymous. WES identified
three novel, heterozygous, damaging mutations in Tumor Necrosis Factor Receptor‐Associated
Factor 7 (TRAF7) in 10 of 16 (60%) cases; p.L519P (n=3), p.H521R (n=3) and p.S561R
(n=4). Mutations were within the WD40 domain, p.L519P, p.H521R within exon 17 and
p.S561R within exon 18, and mapped to a limited region of TRAF7 with protein structure
modeling. Two of 16 cases (12.5%) showed macroduplications/deletions on multiple chromosomes,
including chromosome 22, confirmed with CGH microarray analysis and CNV results from
exome data analysis. Four of 16 (25%) had no discovered mutation. Age of onset or
severity did not correlate with type of mutations. This study provides strong evidence
that TRAF7 is a specific tumor driver of IP. Mutations in TRAF7 are also linked to
benign intracranial meningiomas suggesting a shared pathogenesis and close origins
of perineurial and meningeal cells.
Study supported by: Mayo Foundation and the Mayo Center of Individualized Medicine.
NEUROTOXICITY OF PACLITAXEL: IMPACT OF NANOPARTICLE AND SOLVENT‐BASED FORMULATION
Klein I
1,2, Bobylev I1,2, Lehmann HC1,2.
1University Hospital Cologne, Cologne, Germany; 2Center for Molecular Medicine Cologne
(CMMC), Cologne, Germany.
Peripheral neuropathy is a common side effect of paclitaxel. Clinical evidence suggests
that the delivery mechanism of paclitaxel formulations influence time course and severity
of paclitaxel induced peripheral neuropathy. In a preclinical model we studied access,
distribution and toxicity of two paclitaxel formulations (nanoparticle albumin‐bound
paclitaxel (nab) and solvent‐based paclitaxel) in the peripheral nervous system (PNS).
C57BL/6 mice were treated with 5 mg/kg or 10 mg/kg of nab‐paclitaxel or solvent based
paclitaxel. Kinetics of paclitaxel in neurons was assessed by a newly established
immunostaining technique. Neurotoxicity was evaluated by functional assays and nerve
morphology. Paclitaxel accumulated mostly in dorsal root ganglia, whereas distal nerve
segments showed only low uptake of paclitaxel. Treatment of mice with the two paclitaxel
formulations resulted in paclitaxel uptake mostly in NF200+ larger fiber neurons.
In IB4+, and CGRP+ small fiber neurons, paclitaxel was less frequently detected. Nab‐paclitaxel
was incorporated more rapidly compared to solvent‐based paclitaxel but neurons also
showed a faster clearance of nab‐paclitaxel compared to solvent based paclitaxel.
Functional assays and nerve conduction studies indicated that nab‐paclitaxel was less
neurotoxic compared to solvent‐based paclitaxel. This is the first study that characterizes
in detail the access of nab‐paclitaxel and solvent based paclitaxel into the PNS.
Our findings have important implications to understand the pathomechanisms of paclitaxel
induced neurotoxicity and to develop neuroprotective strategies by preventing access
of paclitaxel to the PNS.
NEUROPATHY IN RHEUMATOID ARTHRITIS: VASCULITIC OR IMMUNE‐MEDIATED NEUROPATHY
Kobayashi M
1, Takeuchi M1, Suzuki M1, Kitagawa K1.
1Department of Neurology, Tokyo Women's Medical University, Tokyo, Japan.
The aim of our study was to investigate the etiology of neuropathy in patients with
rheumatoid arthritis (RA). Subjects were 9 neuropathy patients with RA admitted to
our department. Laboratory investigations, nerve conduction studies (NCS) and sural
nerve biopsy were performed. Mean patient age was 66.1 years (range, 41–84 years),
and mean disease duration was 10.5 years (range, 2–24 years). Clinical diagnosis for
neuropathy was rheumatoid vasculitis (RV) in 5 patients, RV with acute motor axonal
neuropathy (RV‐AMAN) in 1 and chronic inflammatory demyelinating polyneuropathy with
RA (RA‐CIDP) in 3. Rheumatoid factor (4/5) and rheumatoid arthritis particle agglutination
(3/3) was high and C4 tended to be lower in the RV group (RV and RV‐AMAN). Anti‐ganglioside
antibodies were examined in 4 patients, with positive results in 2. An RV‐AMAN case
was diagnosed with motor‐dominant clinical presentation and the presence of anti‐GalNac‐GD1a
immunoglobulin (Ig)G antibody. No other cases with RV were examined for anti‐ganglioside
antibodies. Positive results for anti‐GM1 and GM2 IgG antibody were seen in one RA‐CIDP
patient. We evaluated sural/median (S/M) ratio) for sensory nerve action potential
(SNAP). S/M ratio was low in RV cases (4/5) and high (3/3) in immune‐mediated cases,
suggesting a so‐called normal sural abnormal median pattern in immune‐mediated neuropathies.
The RV‐AMAN case showed a moderate value in S/M ratio. Nerve biopsy revealed thinly
myelinated nerve fibers in RA‐CIDP cases compatible with demyelination, while the
RV group showed the typical pathology for necrotizing vasculitis. RV cases were treated
with prednisolone (PSL), intravenous methylprednisolone, intravenous cyclophosphamide
and increased PSL dose. RA‐CIDP and RV‐AMAN were treated with intravenous Ig. In conclusion,
neuropathy in RA can be divided into vasculitic and immune‐mediated groups. NCS, and
the S/M ratio of SNAP with some laboratory parameters in particular, may be of use
in differential diagnosis and deciding treatment strategies.
TREATMENT‐INDUCED NEUROPATHY OF DIABETES MELLITUS IS UNCOMMON IN A GENERAL DIABETES
MELLITUS COHORT
Koh S
1, Wong SHJ2, Loh KW2, Chng YSK3, Pawa C3, Ei MA4, Lee BJH2, Subramaniam T5, Umapathi
T1.
1National Neuroscience Institute, Singapore, Singapore; 2Lee Kong Chian School of
Medicine, Nanyang Technological University, Singapore; 3Yong Loo Lin School of Medicine,
National University Singapore, Singapore; 4Tan Tock Seng Hospital, Singapore; 5Khoo
Teck Puat Hospital, Singapore.
Treatment‐induced neuropathy of diabetes mellitus (DM) (TIND) is an acute painful
autonomic neuropathy that develops with abrupt improvement in glycaemic control. Typically,
Type 1 or 2 DM patients on insulin or oral hypoglycaemic agents (OHGA), present with
painful neuropathy and autonomic dysfunction within 8 weeks of rapid improvement in
glucose control. Current emphasis to achieve good glycaemic control rapidly may inadvertently
increase incidence of TIND, hence the impetus to understand risk of over‐zealous glycaemic
control. We therefore set out to study the occurrence of TIND in a DM cohort of a
tertiary hospital. We screened all patients who had two HbA1c measurements between
2014 and 2015. During this period, approximately 5000 patients were seen per year.
We found 1562 patient‐encounters that showed HbA1c decrease of ≥2% over 3 months or
≥4% over 6 months. We then used a structured checklist of TIND symptoms to shortlist
62 cases. These case‐encounters were scrutinised and classified as; ‘Probable TIND’:
acute painful neuropathy AND acute dysautonomia WITH temporal relationship to the
decrease in HbA1c; ‘Possible TIND’: acute painful neuropathy OR acute dysautonomia
OR uncertain temporal relationship to decrease in HbA1c; Unlikely TIND: alternative
explanation exists for symptoms. Only one case was deemed ‘Probable TIND’‐ a middle‐aged
man with newly diagnosed type 2 DM who presented to emergency department with palpitations
and worsening ‘frozen feet’ sensation that disturbed sleep. His HbA1c decreased by
2.3% in 2 weeks. His symptoms improved within a month with neuropathic pain medications
and resolved 4 months later. He also developed maculopathy and proliferative retinopathy.
Ten months later, he developed significant proteinuria. Four other cases were classified
as ‘Possible TIND’ while the remaining 57 were unlikely TIND. Our study is limited
by retrospective design and reliance on hospital records. Nevertheless, our findings
suggest that TIND is uncommon in a general cohort of DM patients. On the other hand,
the number of patients with painful neuropathy and acute dysautonomia symptoms contemporaneous
with rapid decline in HbA1c raises the intriguing possibility that forme fruste of
TIND exists and one should interrogate the rate of HbA1c decline in DM patients with
these symptoms.
PARANODAL DISSECTION IN CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY WITH ANTI‐NEUROFASCIN
155 AND ANTI‐CONTACTIN 1 ANTIBODIES
Koike H
1, Kadoya M2, Kaida K2, Ikeda S1, Kawagashira Y1, Iijima M1, Kato D3, Ogata H4, Yamasaki
R4, Matsukawa N3, Kira JI4, Katsuno M1, Sobue G1.
1Nagoya University Graduate School of Medicine, Nagoya, Japan; 2National Defense Medical
College, Tokorozawa, Japan; 3Nagoya City University Graduate School of Medical Sciences,
Nagoya, Japan; 4Kyushu University, Fukuoka, Japan.
We investigated the morphological features of chronic inflammatory demyelinating polyneuropathy
(CIDP) with autoantibodies directed against paranodal junctional molecules, particularly
focusing on the fine structures of the paranodes. Sural nerve biopsy specimens obtained
from 9 CIDP patients with anti‐neurofascin 155 antibodies and 1 patient with anti‐contactin
1 antibodies were assessed. These antibodies were examined using sera obtained from
131 patients with CIDP who fulfilled the criteria of the European Federation of Neurological
Societies/Peripheral Nerve Society. Thirteen CIDP patients without these antibodies
were also examined to compare pathological findings. Characteristic light and electron
microscopy findings in transverse sections from patients with anti‐neurofascin 155
and anti‐contactin 1 antibodies indicated a slight reduction in myelinated fiber density,
with scattered myelin ovoids, and the absence of macrophage‐mediated demyelination
or onion bulbs. Teased‐fiber preparations revealed that segmental demyelination tended
to be found in patients with relatively high frequencies of axonal degeneration and
was tandemly found at consecutive nodes of Ranvier in a single fiber. Assessment of
longitudinal sections by electron microscopy revealed that detachment of terminal
myelin loops from the axolemma was frequently found at the paranode in both anti‐neurofascin
155 and anti‐contactin 1 antibody‐positive CIDP patients compared with antibody‐negative
CIDP patients. Patients with anti‐neurofascin 155 antibodies showed a positive correlation
between the frequencies of axo‐glial detachment at the paranode and axonal degeneration,
as assessed by teased‐fiber preparations (p < 0.05). In conclusion, paranodal dissection
without classical macrophage‐mediated demyelination is the characteristic feature
of patients with CIDP with autoantibodies to paranodal axo‐glial junctional molecules.
SCHWANN CELL AND ENDOTHELIAL CELL DAMAGE IN TRANSTHYRETIN FAMILIAL AMYLOID POLYNEUROPATHY
Koike H
1, Ikeda S1, Takahashi M1, Kawagashira Y1, Iijima M1, Misumi Y2, Ando Y2, Ikeda SI3,
Katsuno M1, Sobue G1
. 1Nagoya University Graduate School of Medicine, Nagoya, Japan; 2Kumamoto University,
Kumamoto, Japan; 3Shinshu University Hospital, Matsumoto, Japan.
Peripheral neuropathy is the cardinal feature of familial amyloid polyneuropathy (FAP),
but its mechanism has not been fully elucidated. We used electron microscopy to examine
Schwann cells and endoneurial microvessels. Sural nerve biopsy specimens from 49 FAP
patients with transthyretin Val30Met mutation were assessed. Patients were consisted
of 11 early onset cases from endemic foci and 38 late onset cases from non‐endemic
areas. Loss of nerve fibers with or without neighboring amyloid deposition was a common
feature. The amount of amyloid deposition was greater relative to the extent of nerve
fiber loss in early onset cases than in late onset cases. The atrophy of Schwann cells,
particularly nonmyelinating cells, that were apposed to amyloid fibrils was more conspicuous
in early onset cases than in late onset cases. The numbers of endothelial cell nuclei,
endothelial cell profiles, and occluded microvessels were significantly increased
in the FAP patients compared with 37 patients with nutritional/alcoholic neuropathies
(p < 0.05, 0.01, and 0.01, respectively). Findings suggestive of the disruption of
blood‐nerve barriers, such as the loss of tight junctions and the fenestration of
endothelial cells, were also more frequently found in the FAP patients (p < 0.001),
irrespective of the presence or absence of amyloid deposition. In conclusion, these
findings suggest that direct insult of amyloid fibrils causes Schwann cell damage
resulting in the predominant loss of small‐fiber axons characteristic of early onset
cases. In addition, vasculopathy may also participate in the pathogenesis of neuropathy,
particularly in late onset cases.
A RANDOMIZED TRIAL OF AN AUTOMATED CIPN SYMPTOM MANAGEMENT SYSTEM
Kolb N
1, Smith AG2, Singleton JR2, Beck S2, Howard D1, Dittus K1, Karafiath S2, Mooney K2.
1University of Vermont, Burlington, VT, USA; 2University of Utah Health, SLC, UT,
USA.
Chemotherapy induced peripheral neuropathy (CIPN) is a major cause of morbidity due
to numbness, pain, and gait instability. This prospective study compares the current
standard care for CIPN symptom management to a new care delivery model which utilizes
an automated symptom tracking program paired with a nurse practitioner led intervention
triggered by moderate to severe symptoms. All participants beginning taxane or platin
based chemotherapy called a telephone based automated symptom tracking program daily
(Symptom Care at Home ‐ SCH) to report chemotherapy related numbness and tingling.
SCH tracked the presence and severity of neuropathic symptoms and their interference
with activities of daily living (ADLs) on a 0–10 scale. Participants were randomized
to two groups. The usual care (UC) group was advised to call their oncology provider
for recommendations on symptom management. In the nurse practitioner (NP) group, when
symptom severity was ≥ 4 participants received automated self care strategies and
a call from a nurse practitioner to provide treatment recommendations based on consensus
guidelines. 252 patients participated in the study. Mean duration of follow up was
90.2 ± 39.9 days with 81.1 ± 40.3 calls. The NP group had fewer days with any neuropathic
symptom (12.7% ± 18.3 vs. 21.1% ± 26.1, p=0.005), with moderate to severe neuropathic
symptoms (7.5% ± 12.4 vs. 15.4% ± 22.8, p< 0.001) or days of distress from neuropathic
symptoms (12.7% ± 18.3 vs. 21.1% ± 26.1, p=0.005). On days with moderate to severe
symptoms participants also reported burning (20.4 ± 30.3 %), weakness (18.4 ± 27.2%),
balance problems, (17.9 ± 28.1%), and tripping (16.7 ± 28.3%). There was no significant
difference between groups in the interference in ADLs (NP 3.3 ± 1.9 vs. UC 3.8 ± 2.1,
p=0.08). Overall the automated telephone system effectively identified neuropathy
symptoms and their severity. Compared to usual care in which patients must independently
reach out to their care team for symptom management, SCH is effective in decreasing
symptom prevalence, severity and distress.
ANTIBODIES AGAINST THE NODE OF RANVIER: A FLOW CYTOMETRY ANALYSIS
Kouton L1, Kremer L2, Tard C3, Morales R4, Kuntzer T5, Attarian S1, Boucraut J6, Delmont
E
1.
1Referral Centre for ALS and Neuromuscular Diseases, Marseille, France; 2Neurology
Department, Strasbourg, France; 3Neurology Department, Lille, France; 4Neurology Department,
Montpellier, France; 5Neurology Department, Lausanne, Switzerland; 6Immunology Laboratory,
Marseille, France.
Antibodies against proteins of the Node of Ranvier have been recently described in
severe chronic inflammatory demyelinating polyradiculoneuropathies (CIDP). They target
paranodal proteins, namely contactin (CNTN1) and neurofascin 155 (NF155). Cell‐based
assay and ELISA are available in research, but no gold standard technic is admitted
for the detection in routine of these antibodies.
Our objective was to evaluate if flow cytometry analysis is an efficient technic to
detect antibodies against CTN1 and NF155 in a large cohort of CIDP patients.
Flow cytometry analysis were performed on a BD FACS‐Diva. Human Embryonic Kidney (HEK)
cells were transfected either with NF155 or CNTN1. Sera were diluted 1/100. Antibodies
anti‐CNTN1 or NF155 were revealed using FITC conjugated anti human IgG antibodies.
Delta MFI (mean fluorescence intensity) was calculated as MFI of transfected cells
less MFI of non‐transfected cells. Measures were normalized using positive controls
and 60 negative controls from healthy blood donors.
156 sera of CIDP patients from different French neuromuscular referral centres were
analysed with flow cytometry. Respective delta MFI were 25 (standard deviation 22)
and 34 (standard deviation 29) for antibodies against NF155 and CNTN1 in CIDP antibodies
negative patients.
Antibodies against NF155 were found in 3 patients (respective MFI 2036, 79, 15591)
and against CNTN1 in two other patients (respective MFI 4693 and 708). Isotype of
these antibodies was IgG4 in 3 patients and IgG4 and IgG3 in the remaining patient.
All the patient had severe CIDP. Four patients had poor response to intravenous immunoglobulins
(IVIg) and have been treated with immunosuppressive drugs. As usually reported, the
patient with anti‐NF155 antibodies had postural tremor.
Flow cytometry seems effective to detect antibodies against NF155 and CNTN1. Compared
to other assays, benefits of flow cytometry are: to analyse a large number of sera
in the same time and to give objective numerical results expressed in MFI that can
be compared to the results of other samples. Further studies are needed to confirm
that flow cytometry can be the best test to assess antibodies against CNTN1 and NF155
in routine.
INFLUENCE OF IVIG ON NERVE EXCITABILITY IN MULTIFOCAL MOTOR NEUROPATHY
Kovalchuk M
1, Franssen H1, van Schelven LJ2, van den Berg L1, Sleutjes BTHM1.
1Department of Neuromuscular Disorders, University Medical Centre Utrecht, Utrecht,
The Netherlands; 2Department of Medical Technology and Clinical Physics, University
Medical Centre Utrecht, Utrecht, The Netherlands.
The mechanism by which intravenous immunoglobulins (IVIg) improves peripheral nerve
function in multifocal motor neuropathy (MMN) is unknown. The rapid clinical improvement
following IVIg could be related to blocking complement deposition on GM1 epitopes,
change in ion‐channel properties of affected motor axons, or both. The present study
investigated median nerve motor excitability parameters at 37°C just before IVIg administration
as well as at the peak of clinical improvement in 17 patients with MMN. The investigated
nerves were characterized either by conduction block (n= 5), demyelinative slowing
without block (n= 3), or motor axon loss (n=9). The results of motor excitability
testing in MMN showed no difference between pre‐ and post IVIg recordings. Clinical
assessment of APB muscle showed increase in MRC score in 6 patients and decrease in
1 patient after IVIg administration. In 10 patients MRC score of the APB remained
the same. Those findings indicate that clinical changes following IVIg administration
are not related to excitability parameters of affected motor axons in MMN.
SENSORY AXON EXCITABILITY IN MULTIFOCAL MOTOR NEUROPATHY
Kovalchuk M
1, Franssen H1, van Schelven LJ2, van den Berg L1, Sleutjes BTHM1.
1Department of Neuromuscular Disorders, University Medical Centre Utrecht, Utrecht,
The Netherlands; 2Department of Medical Technology and Clinical Physics, University
Medical Centre Utrecht, Utrecht, The Netherlands.
Nerve conduction studies (NCS) in multifocal motor neuropathy (MMN) show localized
segments in mixed nerves where impulse conduction is blocked or markedly slowed in
motor axons but is normal in sensory axons. Sensory symptoms or signs are usually
absent but have occasionally been reported in skin areas innervated by nerves with
prominent motor axon loss. Although the mechanism of selective motor involvement in
MMN is unresolved, it may be related to differences in antigenic properties between
motor and sensory axons or differences in biophysical properties. The objective of
the present study was to compare ion‐channel activity in both motor and sensory axons
of nerves affected by MMN. Affected nerves had to have motor conduction block, demyelinative
slowing on motor NCS, or motor axon loss, whereas sensory NCS had to be normal. We
performed excitability tests of motor and sensory axons in affected median nerves
of 20 MMN patients and 20 healthy controls at 37°C. Conditioning and test stimuli
were delivered at the median nerve at the wrist; CMAPs were recorded from the thenar
muscle and SNAPs from the 3rd digit. Results of motor excitability testing in MMN
showed fanning‐out of threshold electrotonus, decreased I/V slope, and increased superexcitability,
all compatible with persistent hyperpolarization of resting membrane potential in
motor axons. Sensory excitability testing in MMN showed decreased subexcitability
but was otherwise normal. This may indicate minimal involvement of sensory axons in
MMN.
MOTOR AXON EXCITABILITY IN CHARCOT‐MARIE‐TOOTH DISEASE TYPE 1B WITH A NULL MUTATION
IN THE P0 GENE – INSIGHTS FORM A MOUSE MODEL
Krarup C
1,2, Moldovan M1,2, Alvarez S1, Ciano C3, Pisciotta C3, Pareyson D3.
1University of Copenhagen, Copenhagen, Denmark; 2Rigshospitalet, Copenhagen, Denmark;
3Fondazione IRCCS Istituto Neurologico C. Besta, (INCB), Milan, Italy.
Mutations in the gene coding for myelin protein zero (MPZ, P0) are associated with
different forms of Charcot‐Marie‐Tooth (CMT) disease. We describe a family harboring
a frameshift mutation (c.306delA / p.Asp104ThrfsTer14) in the P0 gene, predicted to
result in a nonfunctional P0 truncated very early in the extracellular domain. This
offered the rare opportunity to assess the consequences P0 deficiency in absence of
the potential gain‐of‐function effects of the mutations itself. Conventional conduction
studies and multiple measures of nerve excitability by “threshold tracking” were carried
out in 2 heterozygote parents (aged 63 and 52) and their two homozygote sons (aged
31 and 39). In the homozygous patients, all distal limb CMAPs and SNAPs were absent.
For neurophysiological assessment, the spinal accessory nerve was stimulated at the
neck and CMAP was recorded over the upper trapezius muscle. Eight normal subjects,
mean age 34, were used as control. The two sibs showed a severe phenotype with early
onset, severe scoliosis, complete loss of distal movements and relevant proximal weakness,
CMT Examination Score (CMTES) 23‐25/28; both heterozygous parents had very mild adult‐onset
neuropathy with CMTES <4/28. Control subjects had a trapezius CMAP with a latency
of 6.2 ms and an amplitude of 7.4 mV. Heterozygotes had a mild CMT type 1B phenotype,
with a CMAP latency of 7.5 ms and an amplitude of 2.9 mV whereas the homozygotes had
a severe neuropathy with a CMAP latency of 35.9 ms and an amplitude of 0.2 mV. Consistently,
the homozygotes had a more severe impairment in excitability with a rheobase of 16.2
mA as compared to 4.7 mA in the heterozygote and 3.5 mA in controls. Deviations in
excitability measures were similar to our previous reports in P0+/− and P0−/− mice.
Mathematical modeling, indicated both altered passive cable properties due to dysmyelination
and depolarizing features with increased Na+ currents. Our data suggest that P0 deficiency
is associated with impaired axonal Na+ channel function, arguing for the translational
value of Na+ channel blocker treatments as found in P0 null mouse models.
THE BURDEN AND JOURNEY OF PATIENTS WITH CIDP: A CASE–CONTROL ANALYSIS
Krishnarajah S
1, Divino V2, Mallick R1, DeKoven M2.
1CSL Behring, King of Prussia, PA, USA; 2QuintilesIMS, Fairfax, VA, USA.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare neurological disorder
of the peripheral nervous system. The objectives of this retrospective real‐world
study were to compare demographic and clinical characteristics among CIDP cases and
matched controls and to assess CIDP treatment utilization. Adults newly diagnosed
with CIDP between 7/1/2010 and 6/30/2014 were identified in the QuintilesIMS PharMetrics
Plus Health Plan Claims Database (first diagnosis date termed the index date). Eligibility
requirements were: confirmation of CIDP (second CIDP diagnosis or initiation of CIDP
therapy) within 1 year of initial diagnosis, continuous health plan enrollment in
the 6 months prior to diagnosis (the pre‐index) and the 2 years following diagnosis
(the follow‐up), and no CIDP diagnosis or use of CIDP therapy in the pre‐index. A
total of 1,041 CIDP cases met the study eligibility criteria. Cases were direct‐matched
to controls based on age, gender, region, health plan, and payer type at index, and
pre‐index Charlson Comorbidity Index score. The final sample consisted of 790 cases
matched to 790 controls (both: mean [SD] age 49.7 [11.4]; 53.7% male; 63.9% commercially‐insured).
Alternative pre‐index diagnoses among cases included inherited neuropathies (38.9%)
and chronic acquired polyneuropathies (17.6%). In the pre‐index, neuropathic pain
(39.7% vs. 2.9%), back pain (30.5% vs. 10.1%), and use of opioids (33.4% vs. 16.2%)
and anti‐convulsants (30.6% vs. 5.1%) were significantly higher among cases compared
to controls (p<0.0001 for all). Median total pre‐index healthcare costs were 2.2x
higher for cases than controls ($4,751 vs. $2,209, p<0.0001). Over the follow‐up,
median total healthcare costs were 8.2x higher for cases than controls ($47,827 vs.
$5,823, p<0.0001 [mean $116,330 and $15,586]). CIDP‐related therapy costs accounted
for 51.4% of total healthcare costs for cases. The majority of cases (83.2%) initiated
CIDP therapy over the follow‐up, in a mean of 115.5 (146.3) days from initial diagnosis.
Half (48.7%) of cases initiated treatment with corticosteroids only, while 24.8% initiated
IVIg only. Over the follow‐up, 69.1% of cases used any corticosteroid, while 34.3%
used any IVIg. Our findings suggest a substantial clinical and economic burden of
CIDP compared to matched controls. Corticosteroids and IVIg were most commonly used
to treat CIDP.
LARGE COVERAGE MR NEUROGRAPHY IN CIDP – DIAGNOSTIC ACCURACY AND ELECTROPHYSIOLOGICAL
CORRELATION
Kronlage M1, Baeumer P
, Pitarokoili K2, Schwarz D1, Schwehr V1, Godel T1, Heiland S1, Gold R2, Bendszus
M1, Yoon MS
2.
1Department of Neuroradiology, Heidelberg University Hospital, Germany; 2Department
of Neurology, St. Josef Hospital, Ruhr University of Bochum, Germany.
Objective: To evaluate large coverage magnetic resonance neurography (MRN) in chronic
inflammatory demyelinating polyneuropathy (CIDP).
Methods: In this prospective study 18 patients with CIDP and 18 healthy controls were
examined by a standardized MRN protocol at 3 Tesla. Lumbosacral plexus was imaged
by a T2‐weighted 3D‐sequence (1 mm isotropic voxel size); peripheral nerves of the
upper and lower extremity by axial T2‐weighted turbo‐spin‐echo sequences (0.5 x 0.3
mm in‐plane resolution). Lesions were characterized by nerve cross sectional area
(CSA) and T2‐weighted signal (nT2). Additionally, T2‐relaxometry of the sciatic nerve
was performed using a multi‐spin‐echo sequence. All patients received a complementary
electrophysiological exam.
Results: Patients with CIDP exhibited increased nerve CSA and nT2 compared to controls
(p < 0.05) in a proximally predominating pattern. ROC analysis revealed best diagnostic
accuracy for CSA of the lumbosacral plexus (AUC = 0.88) and nT2 of the sciatic nerve
(AUC = 0.88). CSA correlated with multiple electrophysiological parameters of demyelinating
neuropathy (f‐wave latency, nerve conduction velocity) of sciatic and median nerve,
while nT2 only correlated with f‐wave latency of sciatic and not median nerve. T2‐relaxometry
indicated that MR‐signal increase in CIDP was due to increase in proton‐spin‐density
(p < 0.05), and not increase in T2‐relaxation time.
Conclusion: Both nT2 and CSA might aid in diagnosis of CIDP, but CSA correlates more
robustly with electrophysiological parameters. Since best diagnostic accuracy was
shown for proximal nerve locations, MRN may be a useful complementary tool in select
CIDP cases.
PHYSIOLOGICAL CHARACTERIZATION OF NOCICEPTORS INNERVATING THE PLANTAR SKIN FOLLOWING
NEUROPATHIC INJURY
Kühnemund J
1, Wetzel C2, Bégay V2, Moshourab R3, Lewin GR2.
1MDC & BIH, Berlin, Germany; 2MDC, Berlin, Germany; 3Charité, Berlin, Germany.
Damage of peripheral sensory nerves due to diabetes, Herpes zoster infection, chemotherapy
or trauma can cause chronic neuropathic pain. Common symptoms include increased pain
sensation (hyperalgesia), touch‐induced pain (allodynia), paresthesia and spontaneous
pain. We currently have poor understanding about the underlying molecular mechanisms
at the peripheral level and treatment of patients suffering from neuropathic pain
is inadequate. Recent meta‐analysis studies show that common first‐line medications
only yield NNTs (numbers needed to treat) between 10.6 to 6.4. It is still unclear
to what extent allodynia can be attributed to changes in the physiological properties
of intact sensory afferents. In this study, we aimed to elucidate whether changes
occur in intact sensory afferents that innervate the plantar skin of the hind‐paw
following induction of neuropathic symptoms. This question was of particular interest
considering that blocking mechanotransduction in the skin can alleviate mechanical
hypersensitivity in neuropathic pain models (Wetzel et al 2016 Nature Neuroscience
20(2):209–218). We used the chronic constriction injury (CCI) model in mice which
is behaviourally characterized by robust mechanical hypersensitivity. We made electrophysiological
recordings from primary afferent neurons which had intact axons passing through the
constriction to innervate the plantar skin using an ex‐vivo skin‐nerve preparation.
We were able to record from 220 myelinated afferent fibers and 72 unmyelinated C‐fibers
with receptive fields in the control uninjured plantar skin as well as plantar skin
of CCI mice. We will present evidence that changes in the mechanosensitivity of sensory
fibers innervating the glabrous skin may contribute to the symptoms of neuropathic
pain.
NATURAL HISTORY STUDY IN HEREDITARY SENSORY NEUROPATHY TYPE 1 (HSN1): IMPROVING THE
RESPONSIVENESS OF OUTCOME MEASURES
Kugathasan U
1, Evans M1,2, Laurá M1, Sinclair C1,2, Hornemann T3, Suriyanarayanan S3, Phadke R4,
Miller K4, Lauria G5, Lombardi R5, Polke J6
, Bennett D7, Houlden H1, Blake J8, Reilly MM1.
1MRC Centre for Neuromuscular Diseases, London, UK; 2Academic Neuroradiological Unit,
UCL Institute of Neurology, UK; 3Institute for Clinical Chemistry, University Hospital
Zurich, Switzerland; 4Division of Neuropathology, National Hospital for Neurology
and Neurosurgery, London, UK; 5IRCCS Foundation “Carlo Besta” Neurological Institute,
Milan, Italy; 6Neurogenetics Unit, National Hospital for Neurology and Neurosurgery,
London, UK; 7Nuffield Department of Clinical Neurosciences, Oxford, UK; 8Department
of Clinical Neurophysiology, Norfolk and Norwich University Hospital, UK.
HSN1 secondary to SPTLC1/2 is a rare slowly progressive neuropathy resulting in marked
sensory loss, especially nociception and significant motor deficit. Despite most of
the patients having the same C133W mutation in SPTLC1, there is marked heterogeneity
in the phenotype. L‐serine oral supplementation has been suggested as potential therapeutic
candidate however the lack of outcome measures is a major limiting factor in the initiation
of a clinical trial. We undertook a natural history study to identify outcome measures
that are responsive enough to be used in a clinical trial. The assessments used were
CMT Neuropathy score (CMTNS version 2 and CMTNS version 2 Rasch modified), MRI of
calves and thighs, computerised myometry, quantitative sensory testing (QST), comprehensive
neurophysiological assessment, proximal thigh skin biopsy for intra‐epidermal nerve
fibre density (IENFD), plasma dSL levels and patient based questionnaires (Neuropathic
Pain Symptom Inventory and SF‐36v2). Standardised Response Mean, SRM (mean change/standard
deviation of change) was used to compare responsiveness between tests. 35 patients
were recruited: 31 with SPTLC1 (C133W) and 4 with SPTLC2 mutations. When analysed
as a whole cohort, proximal calf MRI fat fractions showed the most significant change
over 12 months. IENFD, plasma dSL levels, NPSI and SF‐36v2 showed minimal change or
the change was not in the clinically expected direction. For subsets of the remaining
assessments which showed the highest responsiveness, the cohort was sub‐divided into
mild‐moderate (CMTNS ≤20) and severe (CMTNS>20) subgroups. In the mild‐moderate subgroup,
the greatest improvement in responsiveness was seen in computerised myometry (ankle
plantarflexion: SRM=−0.80 and ankle eversion: SRM=−0.79). In the severe subgroup,
QST (Vibration detection thresholds on hands: SRM=−0.80 and face: SRM=−0.92 and Pressure
pain threshold on the face: SRM=1.27) and proximal calf MRI fat fractions (SRM range=0.73‐1.26)
showed the greatest improvement. Focusing on subgroups classified according to disease
severity improved the responsiveness of some tests into the highly responsive range
with MRI still being the best outcome measure. This will reduce the number of participants
required to power a clinical trial and might be a possible solution for designing
a clinical trial for a rare, slowly progressive disease with a heterogeneous phenotype.
HUMAN IPSC‐DERIVED SENSORY NEURON MODEL OF HEREDITARY SENSORY NEUROPATHY TYPE 1 (HSN1)
Kugathasan U
1, Clark AJ2, Suriyanarayanan S3, Laurá M1, Wilson E1,4, Kalmar B4, Greensmith L1,4,
Hornemann T3, Reilly MM1*, Bennett DLH2*.
1MRC Centre for Neuromuscular Diseases, London, UK; 2Neural Injury Group, Nuffield
Department of Clinical Neurosciences, University of Oxford, Oxford, UK; 3Institute
for Clinical Chemistry, University Hospital Zurich, Switzerland; 4Sobell Department
of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London,
UK, * jointly supervised the work.
HSN1 secondary to SPTLC1/2 mutation is a slowly progressive sensory motor neuropathy
leading to profound sensory loss with variable but often severe motor deficit. The
genes SPTLC1 and 2 encode for the essential enzyme serine palmitoyltransferase (SPT)
which catalyses the rate limiting step in the sphingolipid de‐novo biosynthesis. Mutations
in these two genes alter the substrate specificity of SPT leading to the synthesis
and accumulation of atypical metabolites called 1‐deoxysphingolipids (1‐deoxySL).
Plasma levels of 1‐deoxySL are raised in HSN1 patients. Deoxysphingolipids have been
shown to be toxic in avian and by our group, in mammalian primary DRG and motor neuron
cultures. Firstly, this study looked at the effects of 1‐deoxySL on the survival and
neurite integrity of human iPSC derived sensory neurons following exposure to different
concentrations of deoxysphingolipids. Later, we determined if there was autonomous
1‐deoxySL production in HSN1 patient iPSC derived sensory neurons. Sensory neurons
were differentiated from human iPSCs using a combination of small molecular inhibitors.
Deoxysphingolipids were found to be neurotoxic in this model after 48 hours of treatment.
In control lines, there is a significant reduction in neuronal survival following
treatment with both 1‐deoxysphinganine (1‐deoxySA) and 1‐deoxymethylsphinganine (1‐doxmethSA).
A clear dose‐dependent increase in the expression of the axonal injury marker, ATF3,
is seen with both 1‐deoxysphngoid bases. In both instances, 1‐deoxySA is more neurotoxic
than 1‐doxmethSA, which is similar to the findings in avian and mammalian primary
neuronal cultures. Autonomous 1‐deoxySL production is seen in iPSC derived neurons
obtained from three different HSN patients with the levels being significantly greater
than that seen in multiple control lines. This is the first study to demonstrate that
human iPSC derived sensory neurons can be used as an in‐vitro model for HSN1, providing
a great opportunity both to probe the pathomechanisms mediating deoxysphingolipid
toxicity and to test potential therapeutic agents.
ANTI‐NFASC155 NEUROPATHY: A RELAPSING‐REMITTING NEUROPATHY
Kuntzer T
1, Cuendet D1, Maulucci F1, Tsouni P1, Magot A2, Boucraut J3, Devaux J3, Attarian
S4, Delmont E4.
1DCN, CHUV, Lausanne, Switzerland; 2Centre de Référence Maladies Neuromusculaires,
Nantes‐Angers, CHU de Nantes, Nantes, France; 3CNRS, CRN2M‐UMR 7286, Université Aix‐Marseille,
Marseille, France; 4Centre de Référence maladies neuromusculaires et SLA, Hôpital
La Timone, Marseille, France.
Recent studies have demonstrated an association between autoantibodies directed against
antineurofascin‐155 (anti‐Nfasc155) and a subpopulation of CIDP patients characterized
by sensory ataxia, tremor and poor response to IVIg treatment. Here we report on the
clinical features of three patients who developed acute changes in their phenotype
during the course of their neuropathy, a potential clue to recognize a neuropathy
with predominantly humoral dysimmunity. Case reports: Our index patient had developed
sensory changes over 6 weeks, followed by irregular locomotion, and muscle weakness
with general areflexia. A first run of IVIG improved the patient in a week, but he
relapsed within 10 days. A second IVIG course with prednisone again normalized deficits
within 10 days. IVIG runs and rituximab were still necessary to treat a 2nd, and then
a 3rd relapse before obtaining complete improvement. The course of the neuropathy
was 5 months. Two other patients were encountered with more chronic courses but in
whom periods of worsening or improvement suggested a relapsing‐remitting neuropathy,
either spontaneously or following immunomodulating treatments. In all three, extensive
work‐ups were negative, anti‐Nfasc155 IgG4 were positive, and detailed repeat nerve
conduction studies demonstrated fluctuating conduction blocks. Discussion: Our report
underscores that in chronic CIDP patients a relapsing‐remitting course could be encountered
as a key feature of anti‐Nfasc155 neuropathy. This not yet described characteristic
course could be of value when deciding using rituximab instead of immunomodulating
treatments.
INVESTIGATION OF SERUM ANTIBODIES AGAINST GLYCOLIPIDS AND GLYCOLIPID COMPLEXES IN
IMMUNE‐MEDIATED NEUROPATHIES BY COMBINATORIAL GLYCOARRAY
Kusunoki S
1, Morikawa M1, Kuwahara M1, Ueno R1, Samukawa M1, Hamada Y1.
1Faculty of Medicine, Kindai University, Osaka‐Sayama, Japan.
Anti‐glycolipid antibodies are often detected in sera from patients with autoimmune
neuropathies, such as Guillain‐Barré syndrome (GBS), chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP), and multifocal motor neuropathy (MMN). Not only individual
glycolipid antigens but also mixtures of two different glycolipids (glycolipid complexes)
are sometimes recognized by serum antibodies. To investigate antibody activities against
large number of glycolipid complexes in serum samples from patients with GBS, MMN,
and CIDP, we examined IgM and IgG antibodies against 10 glycolipids [GM1, GM2, GD1a,
GD1b, GQ1b, GalNAc‐GD1a, LM1, galactocerebroside (Gal‐C), asialo‐GM1 (GA1), and sulfatide]
and 45 glycolipid complexes consisting of two different glycolipids listed above,
by using combinatorial glycoarray. Serum was obtained from 100 patients with GBS,
100 patients with CIDP and 24 patients with MMN, all in the acute or relapsing phase.
Serum was also obtained from 30 healthy controls and 99 patients with other neurological
diseases. We investigated the relationships between the clinical features and presence
of those antibodies. High titers of IgG antibodies were detected almost exclusively
in GBS patients. In contrast, IgM antibodies were frequently present in MMN and GBS.
Among the anti‐glycolipid complex antibodies in GBS, anti‐GM1/sulfatide, anti‐GA1/sulfatide,
anti‐GM1/GD1a, and anti‐GQ1b/sulfatide IgG antibodies were common (20, 19, 17, and
14 patients, respectively). IgG antibodies against antigens containing GM1 were significantly
correlated with pure motor GBS (p < 0.01) and those against antigens containing GQ1b
were significantly correlated with GBS with ophthalmoplegia (p < 0.01). In seven of
the 14 patients with anti‐GQ1b/sulfatide complex antibodies, the antibodies were specific
to the GQ1b/sulfatide complex rather than the individual GQ1b and suldfatide antigens.
Moreover, four patients did not have antibodies other than those to the anti‐GQ1b/sulfatide
complex. In patients with MMN, IgM antibodies to antigens containing GM1 or GalNAc‐GD1a
were present in 50% and 37.5%, respectively. Glycoarray is efficient for detecting
antibodies against numerous glycolipid complexes in immune‐mediated neuropathies.
We need further investigations on other immune‐mediated diseases using larger number
of antigens.
JAPANESE ECULIZUMAB TRIAL FOR GUILLAIN‐BARRÉ SYNDROME (JET‐GBS)
Kuwabara S
1, Misawa S1, Sekiguchi Y1, Susumu Kusunoki2 and the JET‐GBS study group3
. 1Department of Neurology, Chiba University, Chiba, Japan; 2Department of Neurology,
Kindai University, Osaka, Japan; 3Japanese Eculizumab Trial for Guillain‐Barré Syndrome,
Chiba, Japan.
Guillain‐Barré syndrome is a monophasic immune‐mediated neuropathy, but a substantial
number of patients with severe disease have poor recovery, even if treated with immunoglobulin.
Recent studies suggest that complement activation plays a pivotal role in GBS‐associated
axonal degeneration, and eculizumab is a monoclonal antibody that specifically binds
to complement component 5 and inhibits complement activation. JET‐GBS is an investigator‐led,
phase 2, randomized, placebo‐controlled trial conducted in 13 hospitals, This trial
aims to investigate the safety and efficacy of eculizumab for treatment of severe
GBS. 34 patients were randomly assigned (2:1) to treatment with immunoglobulin plus
either eculizumab (900 mg/day; n=23) or placebo (n=11) once weekly for 4 weeks. The
primary outcome measures are safety and efficacy (the proportion of subjects who regain
their ability to walk independently at Week 4). The secondary outcome measures included
the proportion of subjects who were able to walk independently at Week 24, and other
measures such as MRC sum scores, nerve conduction parameters. Enrollment for the trial
began in August 2015, and follow‐up of the last patient was completed in October 2016.
Analyses will be made in April 2017, and the results will be presented at this meeting.
This trial is registered with http://ClinicalTrials.gov Identifier: NCT02493725, and
funded by the Japanese Agency for Medical Research and Development, and Alexion Pharmaceuticals
Inc.
CLINICAL AND PATHOLOGICAL FEATURES IN FOUR PATIENTS WITH ANTI‐NEUROFASCIN 155 IGG4
ANTIBODY‐POSITIVE CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
Kuwahara M
1, Oka N2, Ogata H3, Suzuki H1, Yanagimoto S1, Sadakane S1, Fukumoto Y1, Yamana M1,
Yuhara Y1, Yoshikawa K1, Morikawa M1, Kawai S1, Okazaki M1, Kira J3, Kusunoki S1.
1Department of Neurology, Faculty of Medicine, Kindai University, Osaka, Japan; 2Department
of Neurology, National Hospital Organization Minami‐Kyoto Hospital, Kyoto, Japan;
3Department of Neurology, Neurological Institute, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan.
Neurofascin 155, a paranodal protein in peripheral nerve, is a target antigen for
autoantibodies in a subset of chronic inflammatory demyelinating polyneuropathy (CIDP).
Anti‐neurofascin 155 antibody‐positive CIDP is characterized by onset at younger age,
tremor, and refractoriness to IVIg. We have treated four patients with anti‐neurofascin
155 antibody‐positive CIDP at Kindai University Hospital. Anti‐neurofascin 155 antibody
was detected by both ELISA and cell‐based assay in those patients. IgG subclass was
predominantly IgG4 in all four cases. The median age of the patients at admission
was 39.5 years [range: 30–43 years]. Among the four patients, three had tremor, and
two had severe cerebellar ataxia. Cerebrospinal fluid protein levels were remarkably
increased [median: 494.5 mg/dl, range: 216–882 mg/dl]. Although IVIg treatment was
administered in all four patients, the responses were poor or partial. In contrast,
plasma exchange (PE) was performed in all four patients and the clinical symptoms
dramatically improved in two of them. Corticosteroids were also effective in those
two patients. Sural nerve biopsy was performed in all four patients. Although sensory
nerve action potentials of the sural nerves from those patients were not evoked, the
transverse semithin sections of sural nerves from three patients revealed only slight
or mild loss of myelinated fibers. Partial paranodal demyelination was observed in
teased‐nerve fibers from three patients. In addition, abnormal paranodal lesions such
as loss of the transvers bands were observed by electron microscope in all four patients.
Those electron microscopic findings were not observed in control patients with anti‐neurofascin
155 antibody‐negative CIDP. Anti‐neurofascin 155 IgG4 antibody‐positive CIDP shows
distinctive clinical and pathological features.
PLEXIC MRI AND POSITRON EMISSION TOMOGRAPHY (PET) MERGE: A NEW TOOL FOR THE INVESTIGATION
OF PERIPHERAL NERVES
Labeyrie C
1, Besson F2, Vandendries C3, Cauquil C1, Beaudonnet G4, Not A1, Durand E2, Adams
D1.
1Neurologie adulte, CHU Bicêtre, Le Kremlin Bicêtre, France; 2Médecine nucléaire,
CHU Bicêtre, Le Kremlin Bicêtre, France; 3Clinique Bizet, Paris, France; 4Unité de
neurophysiologie clinique, CHU Bicêtre, Le Kremlin Bicêtre, France.
Study of the proximal portion of the peripheral nervous system (PNS) is difficult
because less accessible to electrophysiological exploration and biopsy. The indications
of MRI are increasing in proximal neuropathies to analyse morphology of the roots,
plexus and proximal nerves: integrity of the nerve bundle, inflammation or infiltration
of these structures. PET‐computed tomography (PET‐CT) can detect infiltration of the
proximal segments of the PNS, with hypermetabolism of roots, plexuses and large nerve
trunks. PET‐CT is also useful in detection of solid neoplasm which can infiltrates
PNS and primary nerve sheath tumors. However, spatial resolution of PET ‐CT scan is
limited to explore the roots and plexuses for moderate hypermetabolisms. We believe
that a mild hypermetabolism could be highlighted in inflammatory neuropathies or in
mild tumor infiltrations. We performed a fusion of whole body PET (performed because
of suspected neoplasia) and plexus MRI (PET‐MRI) images in ten patients with a peripheral
neuropathy for which we suspected proximal involvement. The PET‐CT and MRI were first
read separately, then with merge of the images by a nuclear physician and a neuroradiologist.
Five out of ten patients presented with hypermetabolism of PNS (HMPN+) on PET‐MRI:
root (n=4), and/or dorsal root ganglia (n=2). Median SUL of lesions was 1.9. Among
the HMPN+ patients: hypermetabolism was already apparent on PET‐CT in 2 cases, the
merge invalidated abnormalities seen on PET‐CT in 2 patients and MRI detected additional
lesions, not visible on PET‐CT, in one patient. All HMPN+ patients had hypersignal
and or hypertrophy of PNS on MRI either diffuse (n=4), or multifocal (n=1). Among
HMPN‐ (no hypermetabolism) 2 out of 5 (40%) had abnormal MRI (1 multifocal and 1 diffuse).
Gadolinium enhancement was found in all patients receiving gadolinium in the HMPN+
(n=4) and only in 2/5 patients in the HMPN‐ group. Final diagnoses of HMPN+ patients
were neurolymphoma in one (20%), and idiopathic CIDP in the 5 others (80%) with histological
proof on nervous root biopsy in one of them. Final diagnosis in HMPN‐ patients was
CIDP in 4 out of 5 and sequelae of neuropathy in relation to lymphoma without relapse
for the last one. CIDP was more disabling (ONLS≥4) in HMPN+ than in HMPN‐ group 100%
vs. 20%. PET‐MRI could be helpful to detect a proximal inflammation of the PNS, and
to plan further testing. Further studies are needed to evaluate the prognostic value
of HMPN+.
THE DEVELOPMENT OF NEUROPATHY IN A MOUSE MODEL OF CMT2E – SEQUENTIAL NERVE CONDUCTIONS
Lancaster E
1, Li J1, Liem R2, Scherer SS1.
1Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Columbia
University School of Medicine, New York, NY, USA.
Heterozygous Nefl
N98S/+ mutant mice are the first animal model of a Charcot‐Marie‐Tooth disease 2E
(CMT2E). People with this mutation have a severe, early onset axonal neuropathy. Axons
in the mutant mice have reduced number of neurofilaments and decreased diameters.
They also show early onset of tremor and abnormal hindlimb clasping behavior. We measured
the compound action potentials (CAPs) from tails every 4 weeks from the same cohort
of Nefl
N98S/+ mutant mice and their WT littermates from 8 to 48 weeks. Even at the age of
8 weeks, the amplitude of mutant CAPs was only ∼20 % of WT CAPs (29 ± 3.7 microV,
n=15 vs 142 ± 10.7 microV, n=15), and the CAPs stayed substantially smaller than those
in WT mice for 48 weeks (40 ± 6.0 microV, n=13 vs 263 ± 26.7 microV, n=15). The conduction
velocity and the duration of CAPs in mutants were slower and wider compared to those
of WT. Separate cohorts of mice (n=6 mutants and n=6 WT) were sacrificed at different
time points for analysis by light microscopy. In caudal nerve of mutant mice, the
number of axons was significantly reduced compared to that of WT at 8 weeks and, by
48 weeks, it was reduced more than 50%. This model system may be useful for preclinical
studies of treatments for CMT2E since the animals show progressive neuropathy over
48 weeks, which can be objectively measured electrophysiologically and anatomically.
ATP1A1 REPRESENTS A SIGNIFICANT NOVEL DOMINANT CMT2 GENE
Lassuthova P1, Rebelo A2, Ravenscroft G3, Lamont P3, Baxter M3, Ong R3, Davis M8,
Manganelli F7, Tao F2, Saghira C2, Abreu L2, Bai Y6, Isom D4, Laing N3, Choi, B‐O5,
Seeman P1, Shy M6, Santoro L7, Zuchner S
2
.
1DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles
University in Prague and University Hospital Motol, Prague, Czech Republic; 2Dr. John
T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute
for Human Genomics, University of Miami, Miller School of Medicine, Miami, USA; 3Centre
for Medical Research, University of Western Australia and Harry Perkins Institute
of Medical Research, Nedlands, Australia; 4Department of Pharmacology, Sylvester Comprehensive
Cancer Center and Center for Computational Sciences, University of Miami, Miami, USA;
5Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of
Medicine, Seoul, South Korea; 6Department of Neurology, Carver College of Medicine,
University of Iowa, Iowa City, IA, USA; 7Department of Neuroscience, Reproductive
Sciences and Odontostomathology, Naples, Italy.
Despite more than 90 CMT genes identified today, at least 50% of CMT2 patients do
not carry a mutation in any of these genes. Progress in gene identification in recent
years suggests that there are still many more CMT2 disease genes to be discovered;
however, it has become rare to gather support from multiple large families that allow
for conclusive linkage analysis. We have studied multiple extended dominant CMT2 families
with linkage support for a gene at chromosome 1p13.1. Originally a Czech family yielded
a two point LOD score of 2.4 at this locus and a family from Southern Italy showed
a LOD score of 3.2. Whole exome sequencing of multiple family members identified missense
mutations in the gene ATPase Na+/K+ Transporting Subunit Alpha 1 (ATP1A1). ATP1A1
has not been associated with human diseases thus far. In expression studies on teased
fiber preparations we already confirmed predominant expression in the nodes of Ranvier
of peripheral nerves. Through collaborative efforts in the Inherited Neuropathy Consortium
and beyond we identified five additional multigenerational families via exome or Sanger
sequencing resulting in a total of seven unique segregating missense changes: Leu48Arg,
Ile592Thr, Ala597Thr, Asp601Phe, Pro600Ala, Pro600Thr and Asp811Ala. Five of these
mutations fall into a remarkably narrow motif associated with the sodium binding structure
of ATP1A1, flanking the flexible hinge motif. Functional studies in different model
systems (mammalian cell lines, Xenopus oocytes, patient fibroblast lines) are underway
to determine whether a loss or a dominant gain‐of‐function represents the disease
mechanism. Taken together, we show strong support for a major new dominant CMT2 gene,
ATP1A1. This finding represents a new pathway and an attractive new target for therapy
development in axonal CMT.
SURGICAL MANAGEMENT OF FOOT AND ANKLE DEFORMITIES IN CHARCOT‐MARIE‐TOOTH DISEASE:
RESULTS OF A PROSPECTIVE STUDY
Laurá M
1, Ramdharry G1,2, Singh D3, Kozyra D1, Skorupinska M1, Reilly MM1.
1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK; 2School
of Rehabilitation Sciences, St George's University of London/Kingston University,
UK; 3Royal National Orthopaedic Hospital, Stanmore, UK.
Charcot‐Marie‐Tooth (CMT) Disease is the most common inherited peripheral neuropathy.
Foot deformities are frequent complications and orthopaedic surgery is often required.
However there are no evidence based guidelines on the type or timing of the surgery.
Only few studies have described the long‐term results of surgical procedures and evidence
regarding optimal surgical management of these patients is lacking. We prospectively
studied surgical management of CMT patients attending our centre. We collected data
and assessed CMT patients before and after surgery. Data included: history of ankle
instability, pain, skin condition, details of physiotherapy and orthotic management,
assessment of lower limb strength, Charcot‐Marie‐Tooth Examination Score (CMTES),
Foot Posture Index, ankle dorsiflexion range of movement and specific questionnaires
(foot index and Manchester‐Oxford foot questionnaire, modified fatigue severity scale
and modified falls efficacy scale), details of surgical procedures. Patients were
assessed yearly after surgery. So far 23 patients (16 males and 7 females, age range
20 – 58) have been evaluated prior to surgery. All patients but one had genetically
confirmed CMT (18 CMT1A, 3 CMTX, 1 CMT4A). 12 patients have been assessed after 1
year, 6 patients after 2 years, 7 patients after 3 years and 1 patient after 4 years
from surgery. A wide range of surgical procedures were performed by one dedicated
orthopaedic surgeon. Preliminary results showed reduction of number of falls in 5/9
(55%) patients and improvement of callosities in 6/12 (50%) patients at 1 year follow
up. There was also significant improvement of alignment of the operated foot (p=0.02)
and pain (p=0.003). There were no significant changes in measures of strength and
ankle range of motion. Further analysis on a larger number of patients will be important
to determine the long‐term outcome of surgery. Data acquired from this study will
help develop orthopaedic intervention guidelines and identify areas for further research.
EMG PATTERNS IN FAMILIAL AMYLOIDOTIC POLINEUROPATHY (FAP) DUE TO TTR MUTATIONS
Lavigne‐Moreira C1, Oliveira MF1, Marques VD1, Onofre PTBN1, Dos Santos ACJ1, Nascimento
OJM2, Barreira A1, Marques W Jr
1.
1Division of Neuromuscular Diseases and Neurogenetics, Department of Neurosciences
and Behaviour Sciences, Clinical Hospital of Ribeirão Preto, University of São Paulo,
Ribeirão Preto, Brazil; 2Department of Neurology, Fluminense Federal University, Rio
de Janeiro, Brazil.
FAP associated to TTR mutations is defined as a length‐dependent axonal sensory and
motor polyneuropathy that at early stages affects mainly the small nerve fibers, associated
to autonomic and thermo‐algesic sensations. The expected EMG pattern was that of an
axonal sensory and motor polyneuropathy, but in fact several unexpected patterns may
be found. In this study we present the results found in a Brazilian population with
TTR mutation. Patients were divided in three groups: TTR‐Met30 of early onset, TTR‐Met30
of late onset and TTR non‐Met30.
In the first group (TTR‐Met30 of early onset), 10 (34.5%) examinations were normal,
12 (41.4%) were axonal, 5 were demyelinating fulfilling PIDC criteria, one suggested
a predominately motor polyneuropathy and the final one presented a lower motor neuron
disease pattern. In the second group (TTR‐Met30 of late onset), 4 (44.4%) had an axonal
pattern, 2 (22.2%) had an intermediate CV, 1 (11.1%) had a demyelinating pattern,
1 had a lumbossacral pattern and the final one had no definite pattern. Among the
non‐TTR Met30, two patients had the TTR ‐Asp38Tyr, one presented an axonal pattern,
while the second presented initially an axonal pattern, that changed to a demyelinating
pattern in the second examination. Patients with Ile107Val mutation presented an axonal
neuropathy associated to CTS. Most patients with demyelinating or intermediate pattern
were treated with corticosteroids or IVIg, with no satisfactory results. This small
series of patients shows clearly that FAP‐TTR is associated to several EMG patterns
in addition to the expected sensory and motor axonal polyneuropathy. This variability
is present in the same family and in the same patient in different occasions. Clinicians
should be alert to these possibilities to do not delay diagnosis and treatment. Identifying
the mechanisms involved in this variability could improve our knowledge of this intriguing
disease.
DE‐NOVO SUBCUTANEOUS IMMUNOGLOBULIN G FOR CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY.
A SINGLE CENTRE EXPERIENCE OF 3 PATIENTS
Lavin TM
1. 1
Greater Manchester Neurosciences Centre, Salford Royal Hospital, Manchester, UK.
Subcutaneous immunoglobulin (ScIg) has evidence from small trials for its use following
Intravenous IgG (IVIG) loading in Chronic Inflammatory Demyelinating Polyneuropathy
(CIDP). Potential advantages of ScIg include stable IgG levels and reduced complication
rates. ScIg de novo can be considered as IgG levels gradually rise with subcutaneous
delivery and maybe beneficial for patients for whom complications are a concern. We
present 3 cases of CIDP who were initiated on subcutaneous immunoglobulin G (2g/kg/month,
20% ScIg, Hizentra, CSL Behring) following corticosteroids; without Intravenous IgG
loading. Patient 1 is 67 year old with a history of IHD with a progressive lower limb
sensory changes and sensory ataxia over 3 years. Neurophysiology confirmed sensory
demyelinating changes. He did not respond to corticosteroids. Concerns were raised
about the potential risk orf adverse cardiac events with IV immunoglobulin. ScIg therapy
was introduced at 30g weekly. Initial therapy has been well tolerated and objective
measures (RODS‐CIDP score, JAMAR Grip strength, 9 hole PEG) have remained stable through
initiation, and at 3 months. Patient 2 is 65 yr old male with a past history of Branch
Retinal Vein Thrombosis. He developed a sensorimotor polyneuropathy over 2 years with
neurophysiology fitting EFNS criteria for CIDP. Given concerns regarding previous
thrombosis, a trial of ScIg was given at 34g/week, with resolution of sensory ataxia
and improvement in objective markers (JAMAR Grip strength, RODS‐CIDP score, 9 hole
PEG) at 3 months. Unfortunately an adverse event occurred of an urticarial skin reaction.
Patient 3 is a 55 yr old male who presented with motor predominant CIDP. There was
no response to corticosteroids but improvement following plasma exchange. Due to a
past history of transient ischaemic attack, ScIg was started. There has been a positive
response after 3 months with improvement in walking distances and stable objective
markers (RODS‐CIDP score, Grip and Pinch strength). Our cohort remained neurologically
stable during initiation of ScIg, with 1 adverse reaction. Our experience would support
further trials in this area regarding the efficacy of ScIg compared to IVIg in both
the short and long term.
CHARACTERIZING IN VITRO MODELS OF TYPE 2 DIABETIC PERIPHERAL NEUROPATHY
Leal‐Julià M
1,2, Pagès G2, Casas C1,3,4, Chillón M1,2,5,6, Bosch A1,2,4.
1Neurociències Institute, UAB, Barcelona, Spain; 2Biochemistry and Molecular Biology
Department, UAB, Barcelona, Spain; 3Cell Biology, Physiology and Immunology Department,
UAB, Barcelona, Spain; 4Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas
(CiberNed), Insituto de Salud Carlos III, Spain; 5Institut Català de Recerca i Estudis
Avançats (ICREA), Barcelona, Spain; 6Unitat Mixta UAB‐VHIR, Vall d'Hebron Institut
de Recerca (VHIR), Barcelona, Spain.
Diabetic peripheral neuropathy is the most common and debilitating complication of
diabetes and it is associated to neuropathic pain and non‐traumatic amputations. Despite
the economic burden and human costs, nowadays there is not a specific treatment to
cure diabetic peripheral neuropathy. Hyperglycaemia and dyslipidemia‐mediated oxidative
and endoplasmic reticulum stress has been linked to diabetic peripheral neuropathy,
among other altered pathways. In order to study in more detail the molecular mechanisms
that lead to the development of diabetic peripheral neuropathy we set up in vitro
models of the disease using NSC‐34 (motoneurons) and Med17.11 (sensory neurons) cell
lines or primary cultures of dorsal root ganglia and motoneurons exposed to saturated
fatty acids. It has been reported that palmitic acid is able to induce endoplasmic
reticulum stress and oxidative stress in multiple cell types including Schwann cells
and myenteric neurons, resulting in a good model of dyslipidemia‐mediated stress.
Here we found that palmitate induces upregulation of the molecular chaperone BIP/Grp78
and the CCAAT‐enhancer‐binding protein homologous protein (CHOP) mRNAs and a dose‐dependent
downregulation of the apoptosis marker Bcl‐2 in primary cultures. Moreover, palmitic
acid induces loss of neuron dendrites and cell death at high doses and upregulation
of heme oxygenase (HO‐1) and CHOP at lower doses in the NSC‐34 cell line. We are currently
characterizing multiple molecules implicated in oxidative stress, endoplasmic reticulum
stress and inflammation pathways in these cell types to find new therapeutic targets
to treat type 2 diabetic sensorimotor polyneuropathy, that will be subsequently validated
in the Db/Db mouse model by pharmacological or gene therapy strategies.
NOSOCOMIAL TREATMENT‐INDUCED NEUROPATHY OF DIABETES MELLITUS (TIND)?
Lee BJH
1, Ohnmar O2, Wong J1, Koh SJ2, Umapathi T2.
1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; 2National
Neuroscience Institute, Singapore.
Treatment‐Induced Neuropathy of Diabetes Mellitus (DM) (TIND) is an acute painful
peripheral neuropathy and autonomic dysfunction that occurs within 8 weeks of tight
glycaemic control. Therapy with either insulin or oral hypoglycaemic agents (OHGA)
may result in TIND. The quantum and rate of decline in HbA1c predicts development
and severity of TIND. Both type I and II DM patients are prone to this iatrogenic
complication. Besides the expected morbidity associated with painful somatic and autonomic
neuropathy, TIND patients also develop life‐threatening eye complications such as
maculopathy. With greater awareness, we picked up at least 3 typical cases of TIND
in recent few months. However, there was a fourth possible TIND case, whom we feel
deserves special attention. The circumstances surrounding this case are common and
may go under‐recognised in acute hospitals. A 66 year‐old man with 11‐year history
of poorly controlled Type II DM was admitted with a partial left middle cerebral artery
stroke. One month before admission, his HbA1c was 14.4%. His hospitalization was prolonged
because of his considerable disability that required rehabilitation. He stayed 11
weeks. His blood sugar was difficult to control with hyperglycaemic episodes requiring
2 OHGAs and insulin. The highest capillary blood glucose recorded was 20 mmol/L. He
also had 3 episodes of hypoglycaemia. Three weeks into hospitalization, he developed
severe orthostatic hypotension. He came to our attention two months later when he
was sent for autonomic screening tests for severe postural hypotension, in spite of
therapy with fludrocortisone and midodrine. His HbA1c was 9.6%. He had marked orthostatic
hypotension suggestive of sympathetic dysfunction. We were not able to discern if
he had a painful neuropathy because of his aphasia. There was no recent ophthalmology
review. We suggested a diagnosis of possible TIND. He was discharged with lower doses
of OHGA. However, 1 day after discharge, he attended the emergency department for
a syncopal episode. This case raises intriguing questions on the safety of glucose
control paradigms commonly employed in patients with acute stroke and myocardial infarction
as well as the possible role of major fluctuations in blood glucose in the development
of TIND.
A RARE CASE OF NEUROFIBROMATOSIS PRESENTING WITH DEMYELINATING POLYNEUROPATHY
Lee HS
1, Kim SM2.
1Presbyterian Medical Center, Jeonju, Korea; 2Yonsei University College of Medicine,
Seoul, Korea.
The occurrence of peripheral neuropathy by a tumor within or compressing a nerve in
neurofibromatosis (NF) type 1 and 2 is relatively well known. However, NF presenting
with demyelinating polyneuropathy unrelated to tumor masses is rarely reported. We
report a rare presentation of an NF patient with demyelinating polyneuropathy of subacute
onset. A 30‐year‐old woman was referred to our hospital with paresthesia on both limbs
5 months before. She was healthy and had no family history. The symptoms worsened
over the next 3 months, tremor and weakness in both limbs occurred. Although she treated
as a chronic inflammatory demyelinating polyneuropathy (CIDP) with intravenous steroid
and immunosuppressant in another hospital, symptoms were getting worse. Bifacial numbness
and left eyeball pain occurred 2 weeks ago and she visited our hospital. On neurologic
examination, bilateral facial sensory hypoesthesia and symmetrical both limbs weakness
(MRC grade IV+) were observed. Decreased touch and pinprick sensation on both limbs
were observed like stocking‐glove distribution. The reflexes were sluggish. On nerve
conduction study, sensorimotor demyelinating polyneuropathy with conduction blocks
and temporal dispersions was observed. Bilateral R1, R2 responses were prolongation
on facial blink test. MRI of cervical spine and brain revealed contrast enhancing
tumor‐like enlargement of multiple nerve roots and cranial nerves. Nerve biopsy was
performed on right supraorbital nerve, neurofibromatous changes were observed. The
symptom deterioration was stopped without treatment. Gene test dose not revealed NF
type 1 and 2. On review of the literature, polyneuropathy in NF patient can result
from tumor masses within the proximal nerve roots, or along the peripheral nerve,
or in the extramedullary lesion affecting neighboring nerve roots. Thus, axonal type
polyneuropathy and focal amyotrophy have been reported in NF. Demyelinating polyneuropathy
has not been reported before in our knowledge. Although the etiology of demyelinating
polyneuropathy in NF requires further clarification, some authors claim that unknown
local toxic or metabolic influences of the endoneurial pathological cells on adjacent
nerve fibers. In this patient, atypical symptoms were observed in CIDP such as cranial
nerve involvement and stocking‐glove sensory distribution. In this case, a nerve biopsy
can be helpful the accurate diagnosis.
COEXISTENCE OF ACUTE DISSEMINATED ENCEPHALOMYELITIS AND GUILLAIN‐BARRÉ SYNDROME WITH
IG G ANTI‐GT1A ANTIBODY POSITIVITY
Lee JY1, Yoo JH1, Kang DK1, Bae JS
1.
1Department of Neurology Hallym University, Seoul, Korea.
Acute disseminated encephalomyelitis (ADEM) is an uncommon post‐infectious inflammatory
demyelinating disorder of central nerve system, while Guillain‐Barre syndrome (GBS)
is a prototype of acute post‐infectious peripheral neuropathy. Previous reports regarding
the coexistence of these relatively rare diseases suggest that certain immunogenicity
within central and peripheral nerves may share a common autoimmune process during
the disease course. A previous healthy 20 years old man was admitted because of fever,
headache, nausea and myalgia in department of infectious disease. Two weeks before
admission, he suffered from watery diarrhea for 3 days and spontaneously recovered.
At initial presentation, he had high fever(39°C), headache and myalgia and intermittent
horizontal diplopia. A few days after admission, he began to complain of drowsy mentality,
bilateral extremities weakness, especially lower limbs, dysarthria, bilateral facial
paralysis, urinary retention, dyspnea. On neurologic examination, he had mildly drowsy
mentality, symmetric muscle weakness scoring 4 of 5 on bilateral hip, knee flexion
and finger extension, but he had no sensory symptoms. He showed gazed evoked nystagmus
with no extraocular muscle palsies. Deep tendon reflexes were not present. Pulmonary
function test revealed a severe restrictive pattern. CSF studies disclosed a dissociative
increase of protein contents (66mg/dL) without pleocytosis. Anti ganlioside antibody
assay identified an anti‐GT1a IgG positivity in his serum. Nerve conduction study
(NCS) showed prolonged motor terminal latencies and slow motor conduction velocity
on multiple nerves. In contrast, sensory NCS revealed no abnormal findings. Imaging
studies unexpectedly revealed apparently symmetrical lesions across bilateral brainstem
and basal ganglia suggesting a diagnosis of ADEM. After both IVIG and high dose steroid
treatment, he remarkably recovered from disturbed mental state and motor weakness.
About 1month after the symptom onset, he could walk with assistant aid and discharge
to other hospital for rehabilitation. Our case suggest that certain component of autoimmunity
simultaneously result in both CNS and PNS inflammation. Specific immunological mechanism
is remained to be elucidated. Although we could not conclude whether cellular component
or humoral component is dominant for our case, the presence of anti GT1a antibody
suggest a role of humoral mechanisms.
NEUROPATHY AND PRIMARY HEADACHES DO NOT AFFECT THE SAME SUBGROUPS OF PATIENTS WITH
INFLAMMATORY BOWEL DISEASE (IBD)
Leitao AMF1,2, Araújo DF1, Marques H2, Pamplona L2,3, Gondim FAA
2,4.
1Department of Anatomy, Universidade Federal do Ceará, Brazil; 2Unicristus, Fortaleza,
Brazil; 3Department of Public Health, Universidade Federal do Ceará, Brazil; 4Department
of Internal Medicine, Fortaleza, Brazil.
Peripheral Neuropathies and Primary Headaches are common in patients with IBD (Oliveira,
Inflamm Bowel Dis 2008;14:389; Gondim, Inflamm Bow Dis 2015;21:2123). The aim of this
study is to evaluate whether peripheral neuropathies and headaches affect the same
subgroups of patients with IBD. Since 2004, we have established a cohort study to
evaluate the prevalence and incidence of neurological diseases in patients with IBD.
Over a period of 2 years, all patients with IBD (either Crohn's disease or ulcerative
colitis) were invited to participate in a study designed to evaluate the risk factors
for the presence of headaches and peripheral neuropathy in IBD. A separate group of
control patients (age‐matched relatives of IBD patients) was also formed. After a
clinical interview and neurological examination, patients were invited to undergo
skin wrinkling test (SWT) to evaluate small fiber function and/or electromyography.
Headaches were present in 49.3% of the patients with IBD, and were more common in
patients with ulcerative colitis than in control patients (P<0.05). Migraine comprised
61.2% of all cases of headache and was more prevalent in patients with Crohn's disease
than control patients (P<0.05). Tensional headaches were also common affecting 25.4%
of the IBD patients. Electromyography was abnormal in 21.1% of the IBD patients tested
(19/90). SWT was abnormal in 42.2% of the IBD patients tested (38/90). 14.4% of the
IBD patients had abnormal SWT but had no neuropathy symptoms. Patients with abnormal
SWT or EMG were not more likely to have headaches (P=0.30 and 0.87, respectively).
Overall, patients with symptomatic polyneuropathy were not more likely to have headache
(P=0.48). Patients with abnormal SWT or EMG were also not more likely to have migraine
(P=0.43 and 0.28, respectively). Patients with abnormal SWT or EMG were also not more
likely to have tension‐type headache (P=0.31 and 0.62, respectively). In summary,
although highly prevalent in this population of Brazilian IBD patients, primary headaches
and neuropathy do not affect the same subgroups of IBD patients. Further studies are
necessary to understand the mechanisms of both conditions in IBD patients.
NEUROPATHY AND PRIMARY HEADACHES DO NOT AFFECT THE SAME SUBGROUPS OF PATIENTS WITH
INFLAMMATORY BOWEL DISEASE (IBD)
Leitao AMF
1,2, Araújo DF1, Marques H2, Pamplona L2,3, Souza MH2,4, nBraga LL2,4, Gondim FAA2,4.
1Department of Anatomy, Universidade Federal do Ceará, Brazil; 2Christus Universitary
Center, Fortaleza, Brazil; 3Department of Public Health, Universidade Federal do Ceará,
Brazil; 4Department of Internal Medicine, Fortaleza, Brazil.
Peripheral Neuropathies and Primary Headaches are common in patients with IBD (Oliveira,
Inflamm Bowel Dis 2008;14:389; Gondim, Inflamm Bow Dis 2015;21:2123). The aim of this
study is to evaluate whether peripheral neuropathies and headaches affect the same
subgroups of patients with IBD. Since 2004, we have established a cohort study to
evaluate the prevalence and incidence of neurological diseases in patients with IBD.
Over a period of 2 years, all patients with IBD (either Crohn's disease or ulcerative
colitis) were invited to participate in a study designed to evaluate the risk factors
for the presence of headaches and peripheral neuropathy in IBD. A separate group of
control patients (age‐matched relatives of IBD patients) was also formed. After a
clinical interview and neurological examination, patients were invited to undergo
skin wrinkling test (SWT) to evaluate small fiber function and/or electromyography.
Headaches were present in 49.3% of the patients with IBD, and were more common in
patients with ulcerative colitis than in control patients (P<0.05). Migraine comprised
61.2% of all cases of headache and was more prevalent in patients with Crohn's disease
than control patients (P<0.05). Tensional headaches were also common affecting 25.4%
of the IBD patients. Electromyography was abnormal in 21.1% of the IBD patients tested
(19/90). SWT was abnormal in 42.2% of the IBD patients tested (38/90). 14.4% of the
IBD patients had abnormal SWT but had no neuropathy symptoms. Patients with abnormal
SWT or EMG were not more likely to have headaches (P=0.30 and 0.87, respectively).
Overall, patients with symptomatic polyneuropathy were not more likely to have headache
(P=0.48). Patients with abnormal SWT or EMG were also not more likely to have migraine
(P=0.43 and 0.28, respectively). Patients with abnormal SWT or EMG were also not more
likely to have tension‐type headache (P=0.31 and 0.62, respectively). In summary,
although highly prevalent in this population of Brazilian IBD patients, primary headaches
and neuropathy do not affect the same subgroups of IBD patients. Further studies are
necessary to understand the mechanisms of both conditions in IBD patients.
SENSORY GUILLAIN BARRE SYNDROME
León Cejas L
1, Pantiu F1, Rattagan L1, Chaves M2, Mackinnon A2, Marchesoni C1, Pardal A1, Calandra
C3, Rodriguez A4, Muro V1, Reisin R1.
1Británico Hospital, Buenos Aires, Argentina; 2San Martín Hospital, Entre Ríos, Argentina;
3El Cruce Hospital, Buenos Aires, Argentina; 4INEBA, Buenos Aires, Argentina.
The classic Guillain Barré syndrome (GBS) is characterized by motor weakness, hyporreflexia,
but limited sensory deficits. Sensory variants involving either small or large fibers
or both are unusual and represent a diagnostic challenge. We described 6 patients
presenting with the sensory variant of GBS and retrospectively analyzed the clinical
and electrophysiological findings of patients fulfilling the criteria for Sensory
GBS according to Oh et al. criteria. Six patients were identified (mean age 38 years:
range 15–54 years). Four had a previous infection. They all consulted due to distal
painful paresthesias and allodynia. On examination the 6 patients presented normal
strength and normal cranial nerves through the course of the disease with reduced
knee and ankle reflexes in 3 patients. Distal hyperesthesia to pinprick was identified
in 3 and one of them additionally had hyperhidrosis and constipation. Two additional
patients presented hypoesthesia to pinprick and temperature. One patient had distal
proprioceptive sensory loss with sensory ataxia. CSF albumin cytological dissociation
was present in 3 patients. Nerve conduction studies (NCS) identified a sensory motor
demyelinating neuropathy in 2 patients. Among the 4 with normal NCS, 2 had abnormal
cold and warm threshold in their QST evaluation. All patients received symptomatic
treatment for the neuropathic pain and only two IvIg therapies. Longstanding pain,
fatigue or both were persistent findings in 5 patients after a mean follow up of 6
months. In conclusion the sensory variant of GBS is both an infrequent presentation
and a diagnostic challenge. Longstanding pain and fatigue are common persisting findings.
INTERNATIONAL ZIKA VIRUS RELATED GUILLAIN‐BARRÉ SYNDROME OUTCOME STUDY (IGOS‐ZIKA):
A CASE‐CONTROLLED STUDY
Leonhard SE
1, Amorelli M2, Barreira AA3, Cornblath D.R4, Deen Mohammed M5, Van Doorn PA1, Islam
Z6, Marques Jr. W3, Pardo CA4, Shahrizaila N7, Umapathi T8, Willison HJ9, Jacobs BC1,10
and the IGOS‐Zika Consortium. 1Department of Neurology, Erasmus Medical Centre, Rotterdam,
The Netherlands; 2Department of Infectious Diseases, Secretary of State for Health
of the Federal District, Brasília, Brazil; 3Department of Neuroscience Medical School
of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; 4Department
of Neurology, Johns Hopkins University School of Medicine, Baltimore, USA; 5National
Institute of Neurosciences and Hospital (NINS), Dhaka, Bangladesh; 6Laboratory Sciences
and Services Division, icddr,b, Dhaka, Bangladesh; 7Department of Neurology, University
of Malaya, Kuala Lumpur, Malaysia; 8National Neuroscience Institute, Singapore; 9Department
of Neurology, University of Glasgow, Glasgow, UK; 10Department of Immunology, Erasmus
Medical Centre, Rotterdam, The Netherlands.
The epidemic of Zika virus (ZIKV) throughout the Americas and Asia, and the subsequent
rise in reported cases of Guillain‐Barré syndrome (GBS) caused worldwide concern.
As of January 2017, 76 countries have reported evidence of mosquito‐borne ZIKV transmission
and in 16 of these countries, a sudden increase of GBS has been reported. Moreover,
case studies and a case–control study further indicate that ZIKV may trigger GBS.
However, accurate diagnosis of both ZIKV and GBS in many of these studies is disputed,
and a comprehensive description of the clinical phenotype of GBS related to ZIKV is
lacking. The International GBS Outcome Study (IGOS) is a prospective observational
study on the factors determining the onset, clinical course and outcome of GBS. At
present, a research consortium of 150 centers from 19 countries has included 1461
patients in IGOS. Our aim is to investigate ZIKV‐related GBS in IGOS as is already
occurring in Colombia. In IGOS‐ZIKA, data on clinical features and ancillary investigations
will be collected in ZIKV endemic areas according to the IGOS protocol with some modifications.
First, IGOS‐ZIKA has a case‐controlled study design to define the association between
GBS and ZIKV and other arboviruses. Second, urine samples will be collected and additional
questions on preceding events will be asked, focusing on arbovirus infections. Third,
a more limited follow‐up is required. Our aim is to recruit additional centers via
the Inflammatory Neuropathy Consortium (INC) and centers in all arbovirus endemic
regions that are willing to participate. The focus of IGOS‐ZIKA will be on the accuracy
of the diagnosis of both GBS and ZIKV and on defining the associated clinical phenotype,
course and outcome. IGOS‐ZIKA provides the opportunity to combine data and biobanks
from various geographical regions using a standardized protocol and to compare these
data with data and biosamples already collected in IGOS. Studying these cases will
help to optimize diagnostics and care for GBS patients in arbovirus endemic countries
and provides a unique opportunity to further understand the pathogenesis of GBS. Moreover,
this study design and network can be used to adequately respond to other future viral
epidemics related to GBS.
A COMPLEX HOMOZYGOUS MUTATION IN ABHD12 RESPONSIBLE FOR PHARC SYNDROME DISCOVERED
BY NGS
Lerat J1, Cintas P2, Dzugan H1,3, Magdelaine C1,3, Sturtz F1,3, Lia AS
1,3.
1Service de Biochimie et Génétique Moléculaire ‐ CHU de Limoges, Limoges, France;
2Service de Neurologie et d'explorations fonctionnelles ‐ CHU de Toulouse, Toulouse,
France; 3EA6309–Université de Limoges, Limoges, France.
PHARC syndrome is an autosomal recessive neurodegenerative pathology leading to demyelinating
Polyneuropathy, Hearing loss, cerebellar Ataxia, Retinis pigmentosa and early‐onset
Cataract. These various symptoms can occur at different ages, so that PHARC syndrome
can be a differential diagnosis of Charcot‐Marie‐Tooth disease (CMT) associated with
deafness. Only 13 ABHD12 mutations have been reported in 33 patients. We described
the 14th mutation and compared our results to the literature data. We analysed by
Next Generation Sequencing (NGS) strategy using a targeted CMT and associated neuropathies
92‐gene panel the DNA of a 36‐year old male who has suffered from demyelinating sensory
and motor polyneuropathy and ataxia since the age of 15. Bilateral sensorineural deafness
was diagnosed at the age of five. Bilateral congenital cataracts were operated on
at the age of 28. A new large complex homozygous mutation, with one deletion of seven
base pairs and one insertion of 38 base pairs, was detected. By analyzing our patient
data and those of the literature, we evaluated that, in PHARC syndrome, sensorineural
deafness always occurs as the first feature in late teens. The ophthalmological symptoms
are cataracts that occur at a mean age of 25 yo and then retinis pigmentosa at a mean
age of 29. Demyelinating sensory‐motor polyneuropathy is the most variable characteristics,
which occurs in the thirties. We report the first large complex homozygous mutation
in PHARC syndrome, which is certainly under‐diagnosed. Therefore, it seems interesting
to include ABHD12 in the panels of the five symptoms, especially deafness ones.
REFINEMENT OF DIAGNOSTIC CRITERIA FOR CIDP BEYOND ELECTROPHYSIOLOGY: DATA FROM THE
ITALIAN DATABASE FOR THE DIAGNOSIS AND THERAPY OF CIDP AND VARIANTS
Liberatore G
1, Cocito D2, Fazio R3, Santoro L4, Filosto M5, Mazzeo A6, Jann S7, Cortese A8, Carpo
M9, Clerici M10, Luigetti M11, Lauria G12, Fierro B13, Antonini G14, Cavaletti G15,
Rosso T16, Benedetti L17, Briani C18, Marfia G19, Doneddu P1, Peci E2, Velardo D3,
Manganelli F4, Todeschini A5, Toscano A6, Verrengia EP7, Piccolo L8, Nobile‐Orazio
E1.
1IRCCS Humanitas Clinical and Research Center, Milan University, Milan, Italy; 2Città
della Salute e della Scienza Hospital, Turin, Italy; 3IRCCS San Raffaele Hospital,
Milan, Italy; 4Università degli Studi di Napoli "Federico II", Naples, Italy; 5University
of Brescia, Spedali Civili Hospital, Brescia, Italy; 6Azienda Ospedaliera Universitaria
"G. Martino," Messina, Italy; 7Niguarda Cà Granda Hospital, Milan, Italy; 8IRCCS Fondazione
Mondino, Pavia, Italy; 9Treviglio Hospital, Treviglio, Italy; 10Fondazione Macchi
Hospital, Varese, Italy; 11Università Cattolica del Sacro Cuore, Rome, Italy; 12IRCCS
Carlo Besta Neurological Institute, Milan, Italy; 13Azienda Ospedaliera Universitaria
Policlinico Paolo Giaccone, Palermo, Italy; 14Sant'Andrea Hospital, Univesity of Rome,
Rome, Italy; 15Milano Bicocca University, Monza, Italy; 16Azienda UL.SS. 8 Asolo,
Castelfranco Veneto, Italy; 17Ospedale Sant'Andrea, La Spezia, Italy; 18Università
di Padova, Padua, Italy; 19Policlinico Tor Vergata, Rome, Italy.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic disabling
disease that often improves with immune therapy. To date, the most reliable diagnostic
criteria for CIDP are the 2010 EFNS/PNS revised criteria, with a reported sensitivity
of 80% and specificity of 90%. We implemented a web‐based database to collect data
from patients with CIDP followed by Italian Centers with expertise on CIDP to determine
the frequency and characteristic of CIDP and it variants, the diagnostic criteria
used for their diagnosis, the possible evolution into typical CIDP, the association
with specific anti‐nerve antibodies, and their response to therapy. All the patients
were evaluated at the time of inclusion and will be followed for two years to monitor
their outcome and response to therapy. By February 2017 we included 360 patients with
CIDP and variants (227 men, 133 women), aged 12–86 years (median 59) with a mean disease
duration of 8.2 years (range 0.5‐52 years). Based on clinical symptoms, CIDP was defined
as typical in 85% and atypical in 15%. The diagnosis of typical CIDP fulfilled EFNS/PNS
criteria in 84% of the patients while nerve conduction studies were not diagnostic
in 14% (grouped as clinical CIDP) or not available in 2%. We analyzed the frequency
of supportive criteria for the diagnosis of CIDP in patients with clinical CIDP and
found that increased CSF proteins, demyelination or cell infiltration on nerve biopsy
and imaging abnormalities consisting with CIDP on US or NMR were present in 81%, 47%
and 57% of the patients, respectively. A relapsing course was present in 79% of patients
with clinical CIDP, increasing the reliability of the diagnosis for CIDP. In addition
an improvement after one or more therapies was reported by 87% of the patients, with
a positive response to IVIg in 74%, steroids in 52% and plasma exchange in 59%, similarly
to what observed in patients fulfilling EFNS/PNS criteria. In 84% of the patients
with clinical CIDP two or more supplementary criteria for CIDP were present. This
study on a large population of patients is providing useful information that may help
to revise the current diagnostic criteria for CIDP.
ACE‐083, A LOCALLY‐ACTING GDF/ACTIVIN LIGAND TRAP, AUGMENTS DORSIFLEXOR MUSCLE FUNCTION
IN A MURINE MODEL OF CHARCOT‐MARIE‐TOOTH (CMT) DISEASE
Li J
1, Cannell M1, Suragani R1, Pearsall R1, Kumar R1.
1Acceleron Pharma Inc, Cambridge, USA.
Charcot‐Marie‐Tooth (CMT) is the most common hereditary peripheral neuropathy and
is characterized by demyelination and/or axonal damage of peripheral nerves and muscle
weakness. Foot drop, steppage gait, and foot deformities are a typically seen in CMT
patients. Consequently, falls are commonly reported in these patients. Improvement
of dorsiflexor muscle function to prevent falls may improve quality of life and activities
of daily living in patients with CMT. ACE‐083, a locally‐acting ligand trap that binds
growth and differentiation factors (GDFs) and activins, has previously been shown
to increase muscle mass and force in both Duchene muscle dystrophy (DMD) and amyotrophic
lateral sclerosis (ALS) mouse models. In the current study, we evaluated the therapeutic
effects of ACE‐083 to improve muscle strength in the trembler (Tr‐J) mouse model of
CMT1A. These mice harbor a mutation in the peripheral myelin protein 22 (PMP22) known
to cause CMT1A. Seven‐month old (B6.D2‐Pmp22Tr‐J
/J) mice were administered ACE‐083 (100μg, twice weekly) intramuscularly to one of
the unilaterally tibialis anterior (TA) muscle for 4 weeks. The contractility of the
TA muscle was evaluated during isometric contraction. All data were compared to the
uninjected contralateral control hind‐limb. After 4 weeks of ACE‐083 treatment, TA
muscle mass was increased by 63% (p<0.01) and its physiological cross‐sectional area
was increased by 69% (p<0.01). The increase in muscle mass correlated with an increase
in strength, with maximum tetanic force and twitch force improved by 65% (p<0.001)
and 44% (p<0.001), respectively. In addition, temporal properties during isometric
contraction, such as maximum rate of contraction and relaxation, were accelerated
by 46% and 56% respectively (p<0.001) in the ACE‐083‐treated TA muscle compared to
its contralateral hind‐limb. Pathological and biochemical assessment of ACE‐083‐treated
mice showed enlarged myocyte area (+14%, p<0.05) and reduced atrogin‐1 mRNA expression
(−49%, p<0.001). Together, these results demonstrated that ACE‐083 attenuates the
degree of muscle atrophy and also improves muscle function in a mouse model of CMT1A.
The current study provides proof of concept for the use of ACE‐083 as a therapy for
CMT to improve dorsiflexor muscle function and alleviate foot drop.
A RAT MODEL OF CMT2A DEVELOPS A PROGRESSIVE NEUROPATHY
Li J1, Lancaster E1, Yousaf A1, Hanania T2, Chan D3, Lunn JS4, Kidd G4, Svaren J5,
Scheideler M6, Scherer SS
1.
1Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,
USA; 2PsychoGenics, Tarrytown, NY, USA; 3California Institute of Technology, Pasadena,
CA, USA; 4Renovo Neural Inc, Cleveland, OH, USA; 5University of Wisconsin, Madison,
WI, USA; 6HumanFirst Therapeutics LLC, Silver Spring, MD, USA.
We have generated a rat model of Charcot‐Marie‐Tooth disease 2A (CMT2A) harboring
the p.Arg364Trp Mfn2 mutation, whose human counterpart results in a severe, early‐onset
axonal neuropathy. The mutation was made using zinc finger nuclease‐mediated genome
editing in fertilized rat eggs. A large cohort of mutant and WT littermates were characterized
behaviorally and found to develop multiple motor deficits that worsened over time.
Nerve conductions of the tail (caudal nerve) was performed on a separate cohort of
mutant (n=14) and WT littermates (n=13) every 4 weeks from 8 to 48 weeks. Mutant rats
showed a progressively decline in the amplitude of the compound action potential after
20 weeks, whereas the amplitude progressively increased in their WT littermates. Separate
cohorts of rats were sacrificed at 7, 40, and 48 weeks and analyzed by light microscopy.
In mutant rats, there was a reduced density of myelinated axons and active axonal
degeneration in distal but not proximal nerves, and in the fasciculus gracilis of
the cervical spinal cord at 40 and 48 weeks. These findings were not present in the
7‐week‐old cohort of mutant rats, or in WT rats at 7 or 40 weeks. A genetically authentic
animal model of CMT2A that develops a progressive, length‐dependent axonal neuropathy
will be a valuable tool for examining the pathogenesis and treatment of CMT2A.
THE ROLE OF IMMUNE CELLS IN NERVE DEGENERATION AND REGENERATION: A NEW PERSPECTIVE
Lindborg JA1, Niemi, JP1, DeFrancesco A1, Zigmond RE
1.
1Case Western Reserve University, Cleveland, USA.
Traditionally the role of immune cells in nerve degeneration and regeneration has
focused on the infiltration of inflammatory monocytes into the distal nerve after
nerve injury and the phagocytosis by the resulting macrophages of myelin and axonal
debris, thereby clearing a path for regenerating axons. Therefore, it was surprising
when we discovered that in CCR2 knockout (KO) animals, in which the entry of these
inflammatory monocytes does not occur, that Wallerian degeneration precedes normally.
We now report that the reason for this is that neutrophils and Schwann cells compensate
for the decrease in macrophage accumulation. Furthermore, nearly complete depletion
of circulating neutrophils by systemic injection of an antibody to Ly6G leads to an
inhibition of myelin clearance both in CCR2 KO and in wild type animals. On the other
hand, we have demonstrated a second site of macrophage accumulation in wild type animals,
namely around axotomized sensory neurons in dorsal root ganglia (DRGs). Blockade of
that accumulation, for example as occurs in CCR2 KO animals, leads to a dramatic impairment
of nerve regeneration. To examine the relationship between macrophages and regeneration
further the monocyte chemokine CCL2 was overexpressed in DRG neurons in intact animals
by viral infection using an AAV5 containing the CCL2 coding sequence. The resulting
overexpression of CCL2 led to the accumulation of macrophages in DRGs even though
no injury had taken place and subsequently to an increase in the intrinsic growth
capacity of the sensory neurons. Examination of changes in gene expression in the
DRGs in these animals revealed increased expression of the cytokine leukemia inhibitory
factor and an increase in its downstream signaling pathway that involves the phosphorylation
and nuclear translocation of STAT3. Strikingly, pharmacological blockade of STAT3
activation inhibited the increase in the neurons' growth capacity produced by the
virus. These results reveal unexpected interactions between immune cells and neurons
facilitating nerve degeneration and regeneration and could lead to therapies to improve
regeneration after injury or in disease.
DIFFERENTIATION POEMS AND CIDP BY TERMINAL LATENCY INDEX
Lin J
1,2, Qiao K1,2, Huang J1,2, Zhao CB1,2, Lu JH1,2.
1Institute of Neurology, Fudan University, Shanghai, China; 2Department of Neurology,
Huashan Hospital, Fudan University, Shanghai, China.
We used terminal latency index (TLI) as a tool in differentiation between POEMS syndrome
and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Comparison of
median and ulnar nerve conduction studies including motor conduction velocity (MCV),
distal motor latency (DML) and terminal latency index (TLI) were studied in 18 POEMS
patients, 58 matched CIDP patients and 30 normal controls. In this cohort, the average
age at evaluation was 51.56±8.77 years old in POEMS group and that of 58 CIDP patients
was 46.34±16.38 years old. Except the ulnar terminal latency index in CIDP group,
POEMS and CIDP patients demonstrated prolonged distal latencies, low conduction velocities
and increased terminal latency indexes compared with the normal group. Reduced conduction
velocities and higher terminal latency indexes in POEMS group than in CIDP group was
found. Increased TLI was demonstrated in 55.6%(median nerve) and 52.9%(ulnar nerve)
POEMS and that in CIDP patients was 25.9%(median nerve) and 22.4%(ulnar nerve). Decreased
TLI was found in 24.1%(median) and 20.7%(ulnar) CIDP patients and none in POEMS. Temporal
dispersion (TD) and conduction block (CB) were more often seen in CIDP patients with
increased TLI than that in POEMS. Compared with CIDP and POEMS showed greater slowing
of the intermediate nerve segments and relatively more uniform demyelination. About
25% CIDP demonstrated more distal conduction slowing and more TD and CB especially
in those with increased TLI. Terminal latency index combined with TD and CB may be
helpful in differentiating POEMS from CIDP.
THE AXONAL PROPERTIES IN PREDIABETIC PATIENTS
Lin Y
1, Sung J1, Chang T1, Jowy T1.
1Department of Neurology, Taipei Municipal Wanfang Hospital, Taipei, Taiwan.
The purpose of our study is to exam whether electrophysiology changes could be detected
in prediabetes patients and to discover the possible mechanism of nerve injury in
prediabetes stage. We analysis and compare the nerve excitability test data between
prediabetic patients and age‐matched normal control subjects. Prediabetes is defined
by American diabetes association (ADA) as one of the three following: HbA1C 5.7% to
6.4%, fasting glucose 100mg/dL to 125mg/dL, and 2 hour oral glucose tolerance test
140 to 199 mg/dL. Patients with radiculopathy, myelopathy, entrapment neuropathy such
as carpel tunnel syndrome, and polyneuropathy were excluded. The strength‐duration
time constant (SDTC) and superexcitability showed significant difference (p<0.05)
between two groups. We also find increased threshold electrotonus in depolarization
(TEd) and reduced relative refractory period (RRP) and refractoriness in 2.5 msec.
These early changes in prediabetic patient are similar in nerve excitability feature
of diabetic patients. However, the above changes are not found in motor axonal excitability
test. Our data supports that nerve excitability test may be a useful, non‐invasive,
and less time dependent tool to detect peripheral nerve injury in prediabetic stage.
The sensory axons are more vulnerable than motor axons. Superexcitability is the most
sensitive parameter in prediabetes.
TRANSTHYRETIN‐RELATED FAMILIAL AMYLOID POLYNEUROPATHY IN POLAND‐ GENOTYPIC AND CLINICAL
PRESENTATION
Lipowska M
1, Drac H1, Rowczenio D2, Gilbertson J2, Philip N Hawkins PN2, Ptasińska‐Perkowska
A3, Lasek‐Ball A4, Brydak‐Godowska J5, Chandoga J6, Kostera‐Pruszczyk A1.
1Department of Neurology, Medical University of Warsaw, Poland; 2National Amyloidosis
Centre, University College London, Rowland Hill Street, London, UK; 3Transplantation
Institute, Medical University of Warsaw, Poland; 4Department of Neurology, Medical
University of Silesia, Katowice, Poland;
5Department of Ophthalmology, Medical University of Warsaw, Poland; 6
Centrum Lekarskej Genetiky, Bratyslava, Slovakia.
Transthyretin‐related familial amyloid polyneuropathy (TTR‐FAP) is an autosomal dominant
disorder caused by mutations of TTR gene and is associated with variable penetrance.
TTR‐FAP is rare, except for endemic areas. This is a retrospective study of TTR‐FAP
patients diagnosed at our center between 1970–2016. We identified four families with
different TTR mutations. In one family with V71A mutation, nine family members over
four generations diagnosed with TTR‐FAP was followed since 1970. In the other families
the index cases with different mutations were identified between 2014–2016. Affected
family members with V71A mutation developed severe progressive polyneuropathy with
cachexia, with onset of the disease between ages 29 and 44. Three patients presented
with marked visual symptoms (one patient underwent vitrectomy). Nine patients died
4 to 11 years after disease onset. Two patients (sisters) underwent liver transplantation
– one died after 11 years of disease at age 40, second is 49 years old and wheelchair‐bound
as her symptoms continue to progress. The TTR mutations diagnosed in the index cases
of three other families are: D38V, F33L and V30M. They all presented with similar
clinical picture of late‐onset TTR‐FAP with predominant progressive axonal sensory,
motor and autonomic polyneuropathy. All three index cases were men, the onset of symptoms
was between 50–54 years with numbness and paresthesia in the feet followed by weakness
and autonomic dysfunction. All had excessive weight loss resulting in cachexia and
were diagnosed with cardiomyopathy. No patient suffered from visual symptoms. All
three patients progressed to stage II of TTR‐FAP – walking with assistance. Time to
diagnosis was 3.5‐5 years. Due to advanced stages of their disease these patients
were not suitable for therapy with tafamidis or the liver transplantation. The TTR
D38V (p.D58V) was confirmed as a de novo mutation, which is uncommon in TTR‐FAP. In
the remaining families carriers of TTR mutations were identified and are followed
up. Pedigree analysis of the family with F33L mutation revealed affected members who
with high probability died from TTR‐FAP. Our study suggests that patients with TTR‐FAP
in Poland exhibits clinical and genetic heterogeneity.
THE GENE MUTATION OF CHINESE PROBANDS WITH CHARCOT‐MARIE‐TOOTH DISEASE
Liu X1, Fan D
1.
1Department of Neurology, Peking University Third Hospital, Beijing, China.
Objective: To identify the gene mutation of Chinese Charcot‐Marie‐Tooth pedigrees
and investigate the correlation among the clinical manifestation, electrophysiology
and mechanism of different genotype.
Methods: We included 105 pedigrees with CMT enrolled in our hospital from January,
2007 to December 2013. We recorded clinical features, CMTNS and electrophysiological
data at diagnosis. The patients underwent mutation analysis of PMP22, Cx32, MPZ, MFN2,
HSPB1, HSPB8 using MLPA, DHPLC and Sanger gene sequencing.
Results: We found 31 PMP22 duplication pedigrees (29.5%), 8 Cx32 pedigrees (7.6%),
4 MFN2 pedigrees (3.8%), 3 MPZ pedigrees (2.8%)
Conclusions: In Chinese Han population, the proportion of PMP22 duplication is relatively
low, the majority of clinical manifestation is classical CMT. Axonal CMT can show
isolated lower extremity injury, with central nervous system involvement. HMN may
be an underestimated clinical types, the identification should be done with caution
in differential diagnosis.
AUTONOMIC NERVE FIBER INVOLVEMENT IN CHEMOTHERAPY‐INDUCED PERIPHERAL NEUROPATHY
Liu Y
1, Liu B1, Sebastian B1, Wozniak KM1, Wu Y1, Slusher B1, Polydefkis M1.
1Johns Hopkins School of Medicine, Baltimore, USA.
Chemotherapy‐induced peripheral neuropathy (CIPN) is a common dose‐limiting toxicity
in the treatment of many cancers. Most CIPN studies preferentially focus on sensory
fiber loss and dysfunction. Here, we compared the structural and functional recovery
of autonomic fibers in sweat glands (sweat gland nerve fiber density, SGNFD) and sensory
fibers (intra‐epidermal fiber density, IENFD) in mouse footpads after exposure to
a maximum tolerated dose (MTD) of several common chemotherapy agents. Additionally,
we assessed footpad sweat production as a functional correlate to SGNFD reductions.
Female Balb‐c mice (3‐animals/group) were treated with a MTD of four anti‐tubulin
drugs: paclitaxel (PCA, 30 mg/kg), ixabepilone (IXA, 2 mg/kg), eribuline (ERIB, 1.2
mg/kg), vinoelbine (VINO, 11 mg/kg), or corresponding placebo given intravenously,
MWF for two weeks. Recovery was assessed at 24‐hours, 1, 2, 4, 8, 12 and 24 weeks
following the last dose. Footpads were processed to visualize epidermal nerve fibers
using PGP9.5 and autonomic nerve fibers with tyrosine hydroxylate and PGP9.5. Ixabepilone‐treated
mice experienced significant reductions in SGNFD at 24hrs, while IENFD nadir occurred
at a later time point, 2‐weeks. The recovery to baseline levels occurred more quickly
for IENFD (4‐weeks) than SGNFD (8‐weeks). In contrast, Vinorelbine and Eribuline treated
mice experienced a maximum deficit in SGNFD and IENFD at 24hrs and SGNFD recovery
was slower (24‐weeks) compared to IENFD (4‐weeks). PCA‐treated animals showed more
severe IENFD and SGNFD deficits compared to the other agents with both IENFD and SGNFD
not recovering completely until 24‐months. Reductions in TH‐SGNFD were comparable
or more pronounced to decreases in PGP9.5‐SGNFD for all agents and timepoints. PCA‐treated
animals demonstrated reductions in footpad sweat droplet number thereby providing
a functional correlate. Together, these data indicate that in mouse models of CIPN,
autonomic nerve fibers are affected more severely than sensory nerve fibers, and also
recover more slowly than intraepidermal nerve fibers. Autonomic dysfunction may be
an important and under‐appreciated consequence of chemotherapy exposure.
SCHWANN CELL‐SPECIFIC DELETION OF THE ENDOSOMAL PI 3‐KINASE VPS34 LEADS TO DELAYED
RADIAL SORTING OF AXONS, ARRESTED MYELINATION, AND ABNORMAL ERBB2‐ERBB3 TYROSINE KINASE
SIGNALING
Logan AM1,2, Mammel AE1,3, Robinson DC1,2, Chin AL1, Condon AF1,2, Robinson FL
1,4.
1Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health
& Science University, Portland, Oregon, USA; 2Neuroscience Graduate Program, Oregon
Health & Science University, Portland, Oregon, USA; 3Cell, Developmental & Cancer
Biology Graduate Program, Oregon Health & Science University, Portland, Oregon, USA;
4Vollum Institute, Oregon Health & Science University, Portland, Oregon, USA.
The PI 3‐kinase Vps34 (Pik3c3) synthesizes phosphatidylinositol 3‐phosphate (PI3P),
a lipid critical for both endosomal membrane traffic and macroautophagy. Human genetics
have implicated PI3P dysregulation, and endosomal trafficking in general, as a recurring
cause of demyelinating Charcot‐Marie‐Tooth (CMT) peripheral neuropathy. Here, we investigated
the role of Vps34, and PI3P, in mouse Schwann cells by selectively deleting Vps34
in this cell type. Vps34‐Schwann cell knockout (Vps34SCKO
) mice show severe hypomyelination in peripheral nerves. Vps34−/−
Schwann cells interact abnormally with axons, and there is a delay in radial sorting,
a process by which large axons are selected for myelination. Upon reaching the promyelinating
stage, Vps34−/−
Schwann cells are significantly impaired in the elaboration of myelin. Nerves from
Vps34SCKO
mice contain elevated levels of the LC3 and p62 proteins, indicating impaired autophagy.
However, in the light of recent demonstrations that autophagy is dispensable for myelination,
it is unlikely that hypomyelination in Vps34SCKO
mice is caused by impaired autophagy. Endosomal membrane traffic is also disturbed
in Vps34−/−
Schwann cells. We investigated the activation of the ErbB2/3 receptor tyrosine kinases
in Vps34SCKO
nerves, as these proteins, which play essential roles in Schwann cell myelination,
are known to traffic though endosomes. In Vps34SCKO
nerves, ErbB3 was hyperphosphorylated on a tyrosine known to be phosphorylated in
response to Nrg1 exposure. The overall level of ErbB2 was also decreased during myelination.
Our findings suggest that the loss of Vps34 alters the trafficking of ErbB2/3 through
endosomes. Abnormal ErbB2/3 signaling may contribute to the hypomyelination observed
in Vps34SCKO
mice.
EVALUATION OF DERMAL NERVE FIBERS IN CIDP NODO‐PARANODOPATHY PATIENTS
Lombardi R
1, Devaux J2, Cortese A3, Dacci P1, Benedetti L4, Demichelis C4, Lauria G1.
1IRCCS Foundation “Carlo Besta” Neurological Institute, Milan, Italy; 2Aix‐Marseille
Université, Marseille, France; 3IRCCS C. Mondino National Neurological Institute,
Pavia, Italy; 4University of Genoa and IRCCS AOU San Martino‐IST, Genoa, Italy.
The recent identification of IgG4 anti‐neurofascin (Nfascin) antibodies in a group
of patients has widened the spectrum of presentation for Chronic Inflammatory Demyelinating
Polyradiculoneuropathy (CIDP). These patients can be distinguished by disabling tremor,
poor response to intravenous immunoglobulin and distal and sensory disturbances. Cell‐adhesion
molecule Nfasc155 and CNTN1 are expressed on the Paranodal Junction (PNJ) of nodes
of Ranvier, and play key roles on sodium channel clustering and glia‐axon interactions.
Quantification of unmyelinated intraepidermal nerve fibers (IENF) is a useful parameter
employed in small nerve fiber pathology diagnosis. In addition the immunohistochemistry
evaluation of dermal nerve fibers allows to examine morphological changes of myelin
sheath and Ranvier nodes structure. We performed immunofluorescent colocalization
studies using antibodies to visualize axons (Protein‐gene‐product 9.5, Neurofilament,
Tubulin), sheath of myelin (Myelin‐Basic‐Protein) and specifically nodal/paranodal/juxtaparanodal
structures (panNfascin, Nfascin155, Nfascin186, Caspr, CNTN1, potassium and sodium
channels) in skin tissues from seronegative and seropositive CIDP patients. We analyzed
axon and myelin sheath damage, abnormal nodal‐paranodal‐juxtaparanodal architecture
and morphometric parameter as internodal length of Ranvier nodes. Our results on skin
biopsies from three IgG4 Nfasc155‐positive CIDP patients revealed complete loss of
Nfasc155 staining at the paranodes, asymmetrical paranodes and widening of the nodes
of dermal myelinated nerve fibers. One IgG4 CNTN1‐positive CIDP patient showed abnormal
nodal/paranodal immunostaining with different features as compared with IgG4 Nfasc155‐positive
patients suggesting specific changes. However, such alterations were not found in
four seronegative CIDP patients. Our data support the hypothesis that examining specific
axonal and myelin markers could provide diagnostic and prognostic clues on nodo‐paranodopathies.
The goal of this study is attempt a possible correlation between the presence of serum
autoantibodies and structural changes in nodal/paranodal regions of dermal nerve fibers
in CIDP patients. Knowledge of autoantibodies expression in the peripheral myelinated
nerves of CIDP patients could serve for stratifying patients and potentially guiding
personalized treatments.
CHARCOT‐MARIE‐TOOTH DISEASE ASSOCIATED WITH DEAFNESS AND/OR SCOLIOSIS: NEW MUTATIONS
DISCOVERED IN SH3TC2 GENE
Lunati A
1, Lerat J1, Dzugan H1,2, Rego M2, Magdelaine C1,2, Bieth E4, Calvas P4, Cintas P5,
Gilbert‐Dussardier B6, Goizet C7, Journel H8, Magy L9, Toutain A10, Urtizberea J11,
Sturtz F1,2, Lia AS1,2.
1Service de Biochimie et Génétique Moléculaire ‐ CHU de Limoges, Limoges, France;
2EA6309 ‐ Université de Limoges, Limoges, France; 3Service Oto‐rhino‐laryngologie
‐ CHU de Limoges, Limoges, France; 4Service de Génétique Médicale ‐ CHU de Toulouse,
Toulouse, France; 5Service de Neurologie et d'explorations fonctionnelles ‐ CHU de
Toulouse, Toulouse, France; 6Service de Génétique Médicale ‐ CHU de Poitiers, Poitiers,
France; 7Service de Neurogénétique ‐ CHU de Bordeaux, Bordeaux, France; 8Service de
Génétique Médicale ‐ Centre hospitalier Bretagne Atlantique, Vannes, France; 9Service
de Neurologie ‐ CHU de Limoges, Limoges, France; 10Service de Génétique Médicale ‐
CHU de Tours, Tours, France; 11Centre de référence Neuromusculaire ‐ Hôpital marin,
Hendaye, France.
Charcot‐Marie‐Tooth disease is one of the most frequent inherited peripheral neuropathies
(1/2500). So far, mutations in more than 80 genes have been identified causing either
the demyelinating form (type 1) or the axonal form (type 2). Duplication of PMP22
gene is the most frequent cause of autosomal dominant demyelinating form. Autosomal
recessive demyelinating form is often due to SH3TC2 gene mutations. Patients suffer
then from early severe neuropathy starting in the first decade. Scoliosis and deafness
are often observed. We analysed 200 patients suffering from peripheral neuropathy,
by multiplex‐ligation‐dependant‐probe‐amplification (MLPA), followed by targeted next‐generation‐sequencing
(NGS) using a 92‐gene custom panel designed for the diagnosis of Charcot‐Marie‐Tooth
and associated neuropathies. Mutations of interest were verified by Sanger sequencing.
Diagnosis was positive for 114 patients. As expected, the most frequent mutation was
the PMP22 duplication detected in 30 patients. Deletion of PMP22 was observed in 18
patients and pathogenic point mutations were detected in 66 patients. SH3TC2 gene
appeared to be the most frequently mutated with nine patients diagnosed. Associated
with known mutations, four new mutations have been identified: two nonsense mutations
and two missense mutations. All these patients presented deafness and/or scoliosis.
SH3TC2 appears to be an important gene involved in Charcot‐Marie‐Tooth disease, often
associated with deafness and /or scoliosis. It is important to pay attention to these
associated symptoms in Charcot‐Marie‐Tooth patients in order to guide their diagnosis
and to improve their medical care.
AUTOSOMAL RECESSIVE MME MUTATIONS BROADEN THE CLINICAL PHENOTYPE ASSOCIATED WITH CMT2T
Lupo V
1,2, Frasquet M3,4, Sánchez‐Monteagudo A1,2, Barreiro M3, Alberti MA5, Casasnovas
C5, Quintáns B4,6,7, Camacho A8, Domínguez C8, Sedano MJ9, Pelayo AL9, Pardo J10,
Sobrino T10, Sobrido MJ4,6,7, Sevilla T3,4, Espinós C1,2.
1Centro de Investigación Príncipe Felipe, Valencia, Spain; 2INCLIVA & IIS La Fe Rare
Diseases Joint Units, Valencia, Spain; 3Hospital Universitari i Politècnic La Fe,
Valencia, Spain; 4CIBER of Rare Diseases (CIBERER); 5Hospital Bellvitge, Barcelona,
Spain; 6Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain;
7Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain; 8Hospital
12 de Octubre, Madrid, Spain; 9Hospital Universitario Marqués de Valdecilla, Santander,
Spain; 10Hospital Clínico Universitario Santiago de Compostela, Santiago de Compostela,
Spain.
MME (membrane metalloendopeptidase) mutations, inherited in an autosomal recessive
fashion, have been recently identified in 10 Japanese probands (Higuchi et al. 2016).
Thus, MME has been included in the list of CMT genes as a new autosomal recessive
axonal form, CMT2T (MIM 617017), and moreover, it is considered a strong candidate
for the genetic diagnosis of unsolved late‐onset CMT2 cases. In fact, few months later
Auer‐Grumbach et al. (2016) reported 19 European probands with autosomal dominant
late‐onset CMT2 and mutations in MME. We have investigated a clinical series of 190
patients diagnosed of motor or sensory‐motor peripheral neuropathy using an updated
version of our custom gene panel, which includes MME. In this study, we report 6 probands
with CMT2, intermediate CMT or dHMN/CMT2 and homozygous or compound heterozygous mutations
in MME, and 1 proband with CMT1 and a heterozygous mutation in MME. We have identified
7 different type of mutations: 1 novel splice donor variant, 1 frameshift, 2 nonsense
and 3 missense mutations. The two nonsense changes, p.Trp24* and p.Arg448*, and the
splice donor variant c.196+1G>A, were detected in homozygous or compound heterozygous
state in 3 patients, while the frameshift mutation, p.Pro156Leufs*14, was detected
in homozygous or heterozygous in the remaining 3 patients. Strikingly, the two nonsense
and the frameshift mutations had been previously reported as causative for autosomal‐dominant
CMT2T (Auer‐Grumbach et al. 2016). Out of three missense mutations, one is novel (p.His712Tyr),
and two are reported in control databases (p.Asn689Lys and p.Arg748Trp). This study
shows that the autosomal recessive CMT2T is common in Spanish population, and moreover,
it suggests that screening of MME using gene panel testing could help to improve diagnosis
of unclarified inherited peripheral neuropathies cases.
Funds: ISCIII (PI12/00453, PI15/00187); Fundació per Amor a l'Art.
MOLECULAR DIAGNOSIS OF INHERITED PERIPHERAL NEUROPATHIES: GENE PANEL VS. EXOME SEQUENCING
Lupo V
1,2, Frasquet M3,4, Sánchez‐Monteagudo A1,2, Barreiro M3, García‐Romero M5, Alberti
MA6, Márquez‐Infante C7, Pascual SI5, Casasnovas C6, Quintans B4,8,9, Camacho A10,
Domínguez C10, Sedano MJ11, Pelayo AL11, Pardo J12, Sobrino T12, Sobrido MJ4,8,9,
Sevilla T3,4, Espinós C1,2.
1Centro de Investigación Príncipe Felipe, Valencia, Spain; 2INCLIVA & IIS La Fe Rare
Diseases Joint Units, Valencia, Spain; 3Hospital Universitari i Politècnic La Fe,
Valencia, Spain; 4CIBER of Rare Diseases (CIBERER); 5Hospital La Paz, Madrid, Spain;
6Hospital Bellvitge, Barcelona, Spain; 7Hospital Virgen del Rocio, Sevilla, Spain;
8Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain; 9Fundación
Pública Galega de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades
Raras (CIBERER), Spain; 10Hospital 12 de Octubre, Madrid, Spain; 11Hospital Universitario
Marqués de Valdecilla, Santander, Spain; 12Hospital Clínico Universitario Santiago
de Compostela, Santiago de Compostela, Spain.
Inherited peripheral neuropathies (IPNs) encompass a group of disorders highly heterogeneous,
clinically and genetically. Charcot‐Marie‐Tooth (CMT) disease is closely related to
distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (DSMA),
and some patients show additional signs associated with amyotrophic lateral sclerosis
(ALS). Targeted gene panel and exome sequencing are considered to be powerful and
cost‐effective tools for diagnosis of these disorders. We have investigated a clinical
series of 226 patients diagnosed of motor or sensory‐motor peripheral neuropathy:
24 families were investigated by exome sequencing and, 202 cases were tested using
different updated versions of a gene panel (Neuro‐104, Neuro‐111, and Neuro‐119).
Each version comprises 104, 111 or 119 IPN genes, respectively and it shows a high
coverage performance: percentage of analyzable target base with >20 coverage was 99,99%.
Both exome and gene panel capture libraries were based on SureSelect capture technologies
( Agilent Technologies), and sequencing was performed in MiSeq or HiSeq Illumina equipment.
We have identified novel genes and novel mutations in known genes, broadening the
phenotypical spectrum associated with IPNs. Exome sequencing has allowed us to identify
causative gene in 58% of familiar or sporadic cases: MORC2, AARS, BSCL2, KIF1A, GARS,
EGR2, FIG4, DNAJB2, DRP2, IGHMBP2, DAO, SOD1, FIG4. Gene panel testing has been mostly
performed in sporadic cases, and it has allowed us to identify either disease‐causing
or candidate mutations in 40% of cases: KIF1A and BICD2 were the most common genes
mutated. Update gene panels Neuro 111 and Neuro119 have revealed novel mutations in
genes recently associated to CMT2 and CMT1 disease: MME and PMP2, respectively. In
sum, both strategies have helped us to achieve a more accurate clinical and genetic
reclassification of these disorders, an impossible challenge using conventional sequencing
methods. Our study expands the clinical phenotype previously associated to known IPN
causing‐gene, and emphasizes that gene panels should be considered as a first diagnosis
method for unclarified IPN patients.
Funds: ISCIII (PI12/00453, PI12/00946, PI15/00187); Fundació per Amor a l'Art.
UPDATING THE CLASSIFICATION OF CMT AND RELATED NEUROPATHIES. RESULTS OF AN INTERNATIONAL
SURVEY
Magy L
1, Mathis S2, Goizet S3, Tazir M4, Vallat J‐M1.
1Department and laboratory of Neurology, National reference center for rare peripheral
neuropathies, CHU Limoges, France; 2Department of Neurology, CHU Bordeaux, France;
3Department of Medical Genetics, CHU Bordeaux, France; 4Department of Neurology, CHU
Algiers, Algeria.
Charcot‐Marie‐Tooth (CMT) disease is a hereditary neuropathy with a relatively homogeneous
phenotype but is genetically heterogeneous. Moreover, nerve conduction studies distinguish
different forms, adding another level of complexity. The current classification of
CMT being difficult to understand for physicians, scientists and patients, we presented
and published a proposal for updating this classification, based on inheritance, nerve
conduction findings and gene/mutation involved. Inputs from colleagues prompted us
to conduct a survey in order to try to reach some consensus about our proposals.
We conducted an internet survey between October and December 2016. The link to complete
the survey was sent several times by email with an introduction to more than 300 people.
Participants were contacted through the emailing list from the last CMT meeting in
Venice (September 2016) and additional physicians and scientists who are involved
in CMT care and research were contacted as well.
One hundred seven people from various countries (mainly France, Italy and the USA)
answered the survey. Most (81%) of the participants were between 30 and 60 years of
age, 60% being physicians and 37% being scientists. The vast majority (65%) considered
the proposal constituted an improvement over the historical classification whereas
23% wanted to keep the old one. About the order of information, 39% of participants
thought the mode of inheritance should come first, whereas 33% felt the phenotype
should be placed at the beginning. Ninety‐one percent of people thought CMT should
be kept as a generic name for hereditary sensory and motor neuropathy. For pure sensory
neuropathy, 48% favoured HSN over HSAN although 41% thought the opposite and 80% of
participants felt dHMN should be kept for distal motor neuropathy. About nerve conduction
findings, 70% of participants thought the intermediate phenotype has to be kept and
68% favoured our proposal to replace "1" by "de" (for demyelinating) and "2" by "ax"
(for axonal). Finally, 88% of responders thought that genetic information should be
included in the classification of CMT.
Overall, our proposal of a new classification received a very good appreciation from
physicians and scientists implicated in the care of patients with hereditary neuropathy.
HEMOLYTIC SIDE EFFECTS OF IVIG: MODELING PREDICTS RISK REDUCTION WITH ANTI‐A/B IMMUNOAFFINITY
CHROMATOGRAPHY AND TO A LESSER EXTEND WITH ANTI‐A DONOR SCREENING
Mallik R1, Hubsch A
2, Gaida A2, Barnes D3.
1CSL Behring, KOP, USA; 2CSL Behring, Bern, Switzerland; 3CSL Behring, Ottawa, Canada.
The risk of hemolytic events (HEs) with intravenous immunoglobulin (IVIG) therapy
appears to be linked to the isoagglutinin (anti‐A and anti‐B) level of the specific
IVIG product. Using published anti‐A and anti‐B titers for seven IVIG products and
corresponding HE rates reported to the EudraVigilance database, we developed a mathematical
model to predict the risk of HE to patients receiving IVIG products of given anti‐A
and anti‐B levels. Modeling was performed separately for the risk to patients with
blood groups A, B, AB and O and the overall population risk was estimated assuming
a blood group distribution of 42% A, 10% B, 4% AB and 44% O. Applying the prediction
model, we calculated the HE risk for an IVIG product produced via a chromatographic
process (Privigen®, CSL Behring) a) without any isoagglutinin reduction measures (2007–2013),
b) with an anti‐A donor screening program eliminating approximately 5% of donors with
high anti‐A titers (2013–2015), c) incorporating an anti‐A/anti‐B specific immunoaffinity
chromatography (IAC, IgIsoLoTM) step in the manufacturing process (since 2016) and
d) with both measures (b and c) combined; as well as for an IVIG product produced
with a Cohn‐like cold ethanol fractionation process (Carimune® NF/Sandoglobulin®,
CSL Behring). Isoagglutinin titers in IVIG products, measured by European Pharmacopoeia
direct assay, were provided by Dr C Bellac, SwissMedic, Bern, Switzerland. The predicted
risk was highest with the chromatographically purified IVIG without isoagglutinin
reduction (1.87 cases expected per 1000 kg IVIG used). Anti‐A donor screening reduced
the predicted risk to 0.78 cases/1000 kg. A greater risk reduction was predicted with
the IAC isoagglutinin reduction step (0.11 cases/1000 kg). The combination of both
methods produced little benefit (0.09 cases/1000 kg) versus IAC alone. The predicted
hemolytic risk with IVIG produced by Cohn‐like ethanol fractionation was low (0.09
cases/1000 kg). An observational cohort study to confirm these hemolytic risk reductions
is in progress. At present, the observed hemolytic risk for anti‐A donor screening
appears consistent with the prediction calculated by the model; results for IAC isoagglutinin
reduction are expected in 2019.
SENSITIVITY OF THE CMT INFANT SCALE: PRELIMINARY ANALYSIS OF CMT SUBTYPES AND COMPARISON
TO CONTROLS
Mandarakas M
1,2, Shy R3, Kennedy R4, Herbert K2, Rose K1,2, Menezes MP1,2, Ryan M4, Yiu E4, Farrar
M2, Sampaio H2, Estilow T5, Moroni I6, Yum S5, Finkel R7, Acsadi G8, Eichinger K9,
Laurà M10, Reilly MM10, Muntoni F11, Refshauge K1, Shy M3, Burns J1,2, Sanmaneechai
O for the Inherited Neuropathies Consortium12
. 1University of Sydney, Sydney, Australia; 2Sydney Children's Hospitals Network (Randwick
and Westmead), New South Wales, Australia; 3University of Iowa Hospitals and Clinics,
Iowa City, USA; 4The Royal Children's Hospital and University of Melbourne, Victoria,
Australia; 5The Children's Hospital of Philadelphia, Philadelphia, USA; 6Istituto
Neurologico Carlo Besta, Milan, Italy; 7Nemours Children's Hospital, Orlando, USA;
8Connecticut Children's Medical Center, Hartford, USA; 9University of Rochester, Rochester,
USA; 10MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square,
London, UK; 11Great Ormond Street Hospital, London, UK; 12Siriraj Hospital, Mahidol
University, Bangkok, Thailand.
The CMT Infant Scale (CMTInfS) is an outcome measure of functional ability for young
infants and children aged <5 years. CMTInfS aligns with the CMT Pediatric Scale and
CMT Neuropathy Score to measure disease severity across the lifespan. To measure gross
motor and fine motor function, CMTInfS comprises of two subscales: 16 gross motor
(e.g. head control, crawling, walking, jumping and hopping) and 15 fine motor function
items (e.g. grasping, reaching, tearing paper and buttoning). Overall and subscale‐specific
function is expressed as a z‐score based on normative reference values (positive z‐scores
indicate poorer function). A total of 109 controls aged 0–58 months (mean age 22,
SD 15m) have been assessed across Australia (n=75), Thailand (n=33) and USA (n=1).
Total CMTInfS z‐scores did not differ significantly between sites (Australia vs Thailand)
(p=0.293) or gender (p=0.126). Data collection is ongoing and infants aged <5 years
are eligible for inclusion. To date, 17 infants (53% male) aged 8–58 months (mean
age 36, SD 16m) with a range of CMT subtypes (13 CMT1A, 1 CMT1D, 1 CMT4C, 1CMT X3
and 1 unidentified gene) have been assessed with CMTInfS. Mean total z‐score for infants
with CMT (1.5, SD 2.4, range: −0.9 – 8.0) was significantly higher than controls (0.0,
SD 1.0, range: −2.0 – 3.6, t=−2.50, p=0.023). Differences between affected infants
and controls were larger in infants older than 12 months. Infants with CMT1A (CMTInfS
z‐score 0.8, SD 1.6) and CMT4C (z‐score 0.1) were less affected than CMTX3 (z‐score
3.5) and CMT1D (z‐score 8.0). The gross motor function subscale differed significantly
between CMT cases and controls (2.4, SD 3.8 vs 0.0, SD 1.0; p=.019) and a significant
difference was also observed for the fine motor function subscale (0.7, SD 1.5 vs
0.0, SD 1.0; p=0.009). Reliability, Factor and Rasch analysis of the CMTInfS is underway
to assess validity. Initial results support the sensitivity of CMTInfS in distinguishing
between infants with and without CMT. Preliminary analyses also suggest the scale
is sensitive to genetic subtype. With increased power, CMTInfS promises to become
a useful outcome measure of disease severity and function in infants with CMT.
ANTI‐NFASC155 IGG4 AFFECT PARANODE STRUCTURE IN ANIMAL MODELS
Manso C1, Querol L2, Mekaouche M1, Illa I2, Devaux J
1.
1Aix‐Marseille Université, Marseille, France; 2Universitat Autónoma de Barcelona,
Barcelona, Spain.
Contactin‐1, contactin‐associated‐protein‐1 (Caspr1), and neurofascin‐155 (Nfasc155)
are essential for the formation of paranodal axoglial junctions. IgG4 autoantibodies
to contactin‐1, Caspr1, and Nfasc155 are associated with subsets of patients with
chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) presenting with common
clinical features. Anti‐contactin‐1 IgG4 autoantibodies have been shown to be pathogenic
and to affect the paranodal axoglial junctions in vivo and in vitro. By contrast,
the pathogenic effect of anti‐Nfasc155 IgG4 have not been demonstrated. Here, we purified
anti‐Nfasc155 IgG4 from CIDP patients' plasma and investigated their effects after
passive transfer. To determine whether these antibodies can pass the paranodal barrier,
we performed intraneural injections of anti‐Nfasc155 IgG4 autoantibody. By contrast
to anti‐contactin‐1 IgG4, anti‐Nfasc155 did not penetrate the paranodal regions after
intraneural injections, but bound to the surface of the Schwann cell. To perform chronic
exposure, Lewis rats were implanted with intrathecal catheter and anti‐Nfasc155 IgG4
were administrated in a daily manner during three weeks. IgG4 to Nfasc155, but not
control IgG4, induced progressive clinical deteriorations characterized by gait ataxia
and hindlimb paraparesis. These deteriorations were associated with nerve activity
loss in motor spinal nerves and with a selective loss of the paranodal specialization
characterized by the disappearance of the Caspr1/contactin‐1/Nfasc155 complex at paranodes.
The passive transfer of anti‐Nfasc155 IgG4 thus seem to induce similar pathogenic
effects as the anti‐contactin‐1 IgG4. However, the pathogenic mechanisms leading to
paranode disappearance appear different. Our findings indicate that IgG4 directed
against Nfasc155 are pathogenic and further show that these antibodies are reliable
biomarkers of a specific subset of CIDP patients.
ENHANCEMENTS TO THE RARE DISEASES CLINICAL RESEARCH NETWORK CONTACT REGISTRY FOR THE
INHERITED NEUROPATHIES CONSORTIUM
Marking D
1, Shy M2.
1University of South Florida, Tampa, USA; 2University of Iowa Health Care, Iowa City,
USA.
The Rare Diseases Clinical Research Network (RDCRN) Contact Registry for the Inherited
Neuropathies Consortium (INC) is an interactive online platform that empowers patients
with inherited neuropathies and their family members by providing relevant information
about clinical studies being conducted by INC investigators, enabling them to participate
in online studies, and facilitating communication and interaction with the inherited
neuropathies community. As of February 12, 2017, over 2,700 individuals enrolled in
the RDCRN INC Contact Registry, including patients with CMT1A, CMT2A, CMT1B, CMT4,
CMTX, patients with multiple, other or unknown CMT disease types, and unaffected family
members of patients with CMT. The RDCRN INC Contact Registrants and their participation
in RDCRN INC Contact Registry studies to date have proven essential to the Inherited
Neuropathies Consortium, and have resulted in completed protocols, publications and
the development of Patient‐Reported Outcome Measures (PROMs) currently being investigated
within INC clinical sites. These results have made a large contribution towards the
goal of improving care for people with inherited neuropathies. Recently, several enhancements
have been made to the RDCRN INC Contact Registry to better fit the needs of the consortium
and improve patient experience. These enhancements include creating mobile friendly
webpages, updating enrollment form content, access to a customized dashboard, and
the ability of registrants to explore their data in comparison to other registrants.
We will review these enhancements in depth, and demonstrate their impact on the growth
and development of the RDCRN INC Contact Registry.
The Inherited Neuropathies Consortium (U54NS065712‐07) is part of the Rare Diseases
Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research
(ORDR) at the National Center for Advancing Translational Science (NCATS). This consortium
is funded through collaboration between NCATS, and the National Institute of Neurological
Disorders and Stroke (NINDS). The content is solely the responsibility of the authors
and does not necessarily represent the official views of the NIH.
ANTI‐A DONOR SCREENING AND THE RISK OF HEMOLYTIC ANEMIA WITH HIGH‐DOSE INTRAVENOUS
IMMUNOGLOBULIN TREATMENT – A HOSPITAL‐BASED COHORT STUDY IN THE US
Martinez C1, Hubsch A
2, Watson DJ3, Shebl A4, Wallenhorst C1, Simon TL3.
1Institute for Epidemiology, Statistics and Informatics GmbH, Frankfurt, Germany;
2CSL Bering AG, Bern, Switzerland; 3CSL Behring LLC, King of Prussia, USA; 4CSL Bering
GmbH, Marburg, Germany.
Hemolytic anemia (HA) is a complication of intravenous immunoglobulin (IVIG) treatment,
particularly in patients receiving high dose IVIG for immune modulation, such as Guillain‐Barré
syndrome or chronic inflammatory demyelinating polyneuropathy. The primary mechanism
for the increased risk is believed to be passive acquisition of anti‐blood group A
and B antibodies (isoagglutinins) from the IVIG product. To reduce the quantity of
isoagglutinins, an anti‐A donor screening was implemented for the IVIG Privigen® from
2013–15 and donors with high titers were excluded from contribution to pooled plasma.
Anti‐A donor screening was replaced since 2015 with an immunoaffinity chromatography
step, which decreases isoagglutinins to a greater extent, but no data are available
to test its clinical effectiveness. To test the effectiveness of the donor screening,
two cohorts of patients treated with Privigen® before and after start of donor screening
were identified from a hospital‐based administrative database of 862 US hospitals
with in‐ and outpatient discharge diagnoses, procedures, drug utilization and laboratory
tests between 1/2008 and 12/2012 (period 1) and between 10/2013 and 12/2015 (period
2). Privigen® dose per kg body weight was estimated from the daily quantity administered
and age‐ and sex‐specific US population body weight estimates. HA within 30 days of
Privigen® use was assessed from manual records review and the incidence rate of HA
in the two periods compared. Incidence rate ratios (IRR) of HA were adjusted for sex,
age, treatment setting, indication and dose per kg body weight using period 1 as reference.
The incidence rate of HA was 1.05/10,000 person‐days (95% confidence interval: 0.82–1.34)
in period 1 (68 HAs in 644,756 person‐days) and 0.82 (0.58–1.12) in period 2 (39 HAs
in 476,931 person‐days). The adjusted IRR was 0.82 (0.55–1.23). Significantly less
HA risk was found with high dose (≥1.75 g/kg body weight) Privigen®, IRR 0.48 (0.22–1.04,
p=0.03). We conclude that anti‐A donor screening and exclusion of donors with high
anti‐A titers from plasma pools is associated with a decreased risk of HA with IVIG.
CLONICAL SYMPTOMS OF SUBACUTE MYELO‐OPTICO NEUROPATHY ARE ELOCITED BY MYELOPATHY RATHER
THAN PERIPHERAL NEUROPATHY
Matsumoto A
1.
1 Department of Neurology, Keijinkai Jozanki Hospital, Sapporo, Japan.
Subacute myelo‐optico neuropathy (SMON) is the intoxication of clinoquinol with main
clinical symptoms of paresthesia and spasticity of legs. These symptoms have been
considered to be elicited by the disturbance of spinal cord and peripheral nerve as
the intoxication of clinoquinol. However, as to the patients with SMON who have been
still living after the onset of disease, the examination of nerve conduction velocities
are in normal ranges and the clinical symptoms of peripheral neuropathy are not observed
now. In order to investigate whether the peripheral neuropathy were observed in the
early stage of SMON, We investigated the longtidunal changes of electrophysiological
results in 4 patients who could examine the nerve conduction studies from early stage
of SMON until the present time. As to the disturbance of pyramidal tract functions
(myelopathy) in SMON patients, the central motor conduction times were calculated
by transmagnetic stimulation of motor cortex, cervical roots and lumbar roots. The
peripheral nerve conduction velocities of sensory nerve were examined with the sural
nerves. As the results, in 4 patients with SMON who could examine the electrophysiological
examination from the early stages of SMON until 20 to 27 years later, the central
motor conduction times of leg muscles from motor cortex to lumbar roots were prolonged
in the SMON patients compared to the normal cases. These results suggest the presence
of disturbances of conduction velocities of spinal cord. Conduction velocities of
sensory nerve velicities (SNCVs) showed the delayed SNCVs of sural nerves(24‐33m/sec)
at the first examination from the onset of 2–5 years. However from 20 to 27 years
later, SNCVs of these cases were covered to35‐42m/sec. From these electrophysilogical
examinations, it was suggested that the presenting main symptoms of SMON were the
disturbance of myelopathy, and the disturbance of peripheral nerve function had been
recovered after onset of SMON being elapsed a long time,
CAN NK CELLS HELP DISCRIMINATE IVIG TREATMENT RESPONSE IN PATIENTS WITH CIDP?
Mausberg AK
1, Heininger MK2, Meyer zu Horste G3, Cordes S4, Kleinschnitz C1, Kieseier BC2, Stettner
M1.
1Department of Neurology, University Hospital Essen, Essen, Germany; 2Department of
Neurology, Heinrich‐Heine‐University, Düsseldorf, Germany; 3Department of Neurology
, University of Münster, Münster, Germany; 4Department of Hematology, Oncology & Tumor
Immunology, Charite Berlin, Berlin, Germany.
Natural Killer (NK) cells are part of our innate immune system with regulatory and
effector functions. They comprise the first line of defence in the recognition and
destruction of virus‐infected and pathologically altered cells.
Different studies suggest that the treatment with intravenous immunoglobulins (IVIg)
has an immunomodulatory effect on NK cells. IVIg is a first‐line treatment for various
autoimmune diseases in particular in chronic inflammatory demyelinating polyneuropathy
(CIDP). The lack of a predictive marker for IVIg responsiveness in CIDP avoids the
early preservation of non‐responding patients.
To better understand the effect of IVIg in patients with CIDP, we tested whether IVIg
treatment altered the NK cell status. Additionally, we analysed if the alteration
in the populations may serve as a surrogate marker in predicting the outcome of IVIg
treatment. Using semi‐quantitative PCR and flow cytometry in the peripheral blood
of patients with CIDP, we analysed the effects of IVIg on the NK cell population before
treatment initiation and 24h after first dose and correlated the changes with the
reponsiveness to IVIg.
IVIg administrations induced a reduction in the expression of several typical NK cell
genes. Interestingly, this IVIg‐induced reduction of NK cells was reversible four
weeks after the IVIg treatment. Flow cytometry data revealed that IVIg reduced the
cytotoxic CD56dim NK cell population, while regulatory CD56bright NK cells remained
almost unaffected or were even increased. Interestingly, we found that the observed
effects on NK cells almost exclusively occurred in CIDP patients who responded to
IVIg therapy.
Correlation between the changes in the NK cell population and treatment efficiency
suggests a crucial role for NK cells in the immunomodulatory mechanism of IVIg. Further
studies are warranted to investigate whether the differences in the NK cell status
of patients with CIDP represent a reliable surrogate marker in predicting the outcome
of IVIg therapy.
PATHOGENESIS OF CHARCOT‐MARIE‐TOOTH DISEASE TYPE 2C DUE TO MUTATIONS IN TRPV4
McCray B
1, Sullivan J1, Woolums B1, Aisenberg W1, Lloyd T1, Sumner C1.
1Johns Hopkins University, Baltimore, USA.
Mutations in transient receptor potential vanilloid (TRPV4), a calcium‐permeable non‐selective
ion channel, cause Charcot‐Marie‐Tooth disease type 2C (CMT2C). TRPV4 is unique in
that it represents the only membrane‐expressed ion channel in CMT and thus a potential
therapeutic target. Previous work has suggested that TRPV4 mutations lead to gain
of channel function and toxicity in cultured cells. Neuropathy‐causing mutations of
TRPV4 largely cluster in the cytosolic ankyrin repeat domain (ARD) that is known to
mediate protein‐protein interactions, suggesting that pathogenesis may be related
to disruption of such interactions. In order to identify TRPV4‐interacting proteins,
we performed two unbiased proteomics screens and identified multiple cytoskeletal‐modifying
proteins including syndapin‐1, a neuronal protein known to promote axonal outgrowth
by influencing the actin cytoskeleton. In cultured cells, we have shown that TRPV4
and syndapin‐1 co‐localize to highly dynamic actin‐rich cellular processes and together
stimulate robust neurite extension, but this facilitation of neuritogenesis is impaired
by disease‐causing mutations in TRPV4. We have also shown that over‐expression of
syndapin reduces TRPV4‐mediated calcium influx in cultured cells and rescues toxicity
of mutant TRPV4. In addition, syndapin over‐expression suppresses mutant TRPV4 phenotypes
in a Drosophila model of TRPV4‐related neuropathy. Further, we have demonstrated that
treatment of Drosophila with a specific TRPV4 channel antagonist ameliorates TRPV4
mutant toxicity. Together, our data highlight the importance of TRPV4 interaction
with cytoskeletal proteins such as syndapin‐1 in the pathogenesis of CMT2C. Specifically,
our results suggest that mutations in TRPV4 disrupt the normal role of TRPV4 in regulation
of cytoskeletal dynamics and that interactions with the cytoskeleton reciprocally
modulate TRPV4 channel function and influence toxicity of mutant TRPV4.
ANTI‐GM1 ANTIBODY MEDIATED MODELS OF AXONAL AND DEMYELINATING GBS IN GLYCOSYLTRANSFERASE‐MODIFIED
TRANSGENIC MICE
McGonigal R
1, Yao D1, Barrie JA1, Crawford C1, Willison HJ1.
1University of Glasgow, Glasgow, UK.
Guillain‐Barré syndrome (GBS) is in part mediated by anti‐GM1 ganglioside antibodies
induced by preceding infections. Anti‐GM1 antibodies target plasma membrane GM1 that
is extensively distributed in both glial and axonal membranes, particularly at the
node of Ranvier. Antibodies deposited at this site in models of GBS are associated
with complement deposition, conduction block, structural disruption of ion channels
and macrophage infiltration. The wide distribution of the GM1 ganglioside target leads
to unwanted complexity in ascribing pathological outcomes to injury of cell‐specific
membranes, in particular unravelling the consequence of paranodal Schwann cell membrane
injury on axonal function, and vice versa. To overcome this impasse, we have generated
transgenic mice through glycosyltransferase manipulation that express GM1 exclusively
in neurons or glia, thus allowing us to very specifically target and injure axonal
or glial membranes with a single anti‐GM1 ganglioside antibody. Through this route
we can create mouse models of both the axonal and demyelinating forms of GBS, induced
by a single anti‐GM1 antibody, thus creating otherwise highly comparable conditions.
Here, we show anti‐GM1 antibody binding is restricted to the nodal axolemma in GalNAcT−/−‐Tg(neuronal)
mice and conversely to paranodal loops in GalNAcT−/−‐Tg(glial) mice. When anti‐GM1
antibody and a source of complement is added to a nerve‐muscle ex vivo injury paradigm,
there is a loss of axonal integrity (i.e. loss of neurofilament immunolabeling) when
the neuronal membrane is targeted in GalNAcT−/−‐Tg(neuronal). Conversely, axonal integrity
is maintained when the paranodal membranes are decorated by antibody and complement
products ex vivo in GalNAcT−/−‐Tg(glial) mice. In a passive immunisation model in
vivo, GalNAcT−/−‐Tg(neuronal) mice acutely develop weakness, respiratory dysfunction,
associated complement deposition, and degenerative pathology in distal axons. In contrast,
GalNAcT−/−‐Tg(glial) mice have significantly fewer abnormalities under the same acute
conditions. These data indicate the high vulnerability of axonal membranes to acute
injury and underline the importance of developing specific axonal protection strategies.
In summary, targeting the nodal axolemmal or glial membranes allows us to study associated
nodal pathology, and determine the downstream consequences on function and axon fate,
currently a major area in GBS clinical research.
TERMINAL LATENCY INDEX (TLI) AND SENSORY ELECTROPHYSIOLOGY IN PARAPROTEINEMIC CHRONIC
INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY (CIDP)
Memon A
1, Madani S1, Schultz L1, Grover K1, Arcila‐Londono X1, Sripathi N1, Ahmad BK1.
1Neuromuscular Division, Department of Neurology, Henry Ford Hospital, Detroit, Michigan,
USA.
Objective: To differentiate sensory electrophysiology, TLI and treatment response
in patients with paraproteinemic CIDP.
Background: Low TLI has been reported as a useful electrophysiological marker for
MAG‐CIDP. To our knowledge comparison of sensory electrophysiology and TLI of paraproteinemic
CIDP subgroups have not been previously reported.
Methods: Retrospective review(January 2000‐December 2015) of 89 patients with CIDP
fulfilling electrophysiological criteria(AAN ad hoc subcommittee and Albers and colleagues).CIDP
patients with diabetes(n=18) were excluded. 71 patients were divided into idiopathic
(n=40) and paraproteinemic CIDP(n=31). Paraproteinemic CIDP sub‐groups: MAG(8), non‐MAG(8)
and IgG(15) were compared to idiopathic CIDP(40). These groups were compared for demographics,
history of cancer, CSF protein, sensory conductions, TLI measurements and response
to treatment using chi‐square tests for binary and categorical variables and t‐tests
for continuous measures.
Results: There was a higher proportion of females in idiopathic‐CIDP compared to non‐MAG‐CIDP
(50% vs 13%). Idiopathic group having a higher proportion of patients on monotherapy(59%
vs 50%) and combination therapy(38% vs 17%) compared to non‐MAG. Higher mean CSF protein
compared to MAG‐CIDP(p=0.001) was seen in the idiopathic. The difference between idiopathic
and IgG‐CIDP was significant for overall Rx response(p=0.025) and Rx response in patients
with follow‐up(p=0.01). For both variables, patients in the idiopathic group had a
higher proportion of patients on combination therapy and lower proportion of no treatment
offered compared to patients in the IgG‐CIDP. 50% of non‐MAG‐CIDP patients had a history
of cancer vs 0% of MAG‐CIDP. None of the other differences were significant. There
were no group differences in sensory electrophysiology and TLI.
Conclusions: Sensory electrophysiology and TLI may have no value in differentiating
paraproteinemic CIDP. CSF protein is higher in idiopathic CIDP compared to MAG‐CIDP.
Idiopathic‐CIDP has a higher proportion of females compared to non‐MAG‐CIDP and a
higher proportion of patients on combination therapy compared to IgG‐CIDP. Cancer
screening should be considered in patients with non‐MAG‐CIDP.
DOES ELECTROPHYSIOLOGY AND TREATMENT RESPONSE DIFFER IN IDIOPATHIC VS DIABETIC CHRONIC
INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP)?
Memon A
1, Madani S1, Ahmad BK1, Schultz L1, Grover1, Arcila‐londono X1, Sripathi N1
. 1Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
Introduction: Sensory electrophysiology and Terminal latency index (TLI) differences
have been described in various CIDP sub‐groups.
Objective: Evaluate electrophysiology, TLI and treatment response in idiopathic and
diabetic CIDP.
Methods: Retrospective review of 147 patients with CIDP who underwent electrodiagnostic
evaluation (January 2000‐December 2015). 89 patients fulfilled electrophysiological
criteria described by Ad hoc subcommittee of American Academy of Neurology (AAN) and
Albers et al. We excluded patients(31) with acute inflammatory demyelinating neuropathy,
hereditary sensorimotor neuropathy, vasculitis and polyneuropathy with paraproteinemia.
58 patients were divided into idiopathic(40) and diabetic(18) groups. These groups
were compared for age, sex, history of cancer, CSF protein, response to treatment,
sensory response abnormalities and TLI measurements using chi‐square tests for binary
and categorical variables and t‐tests for continuous measures. All testing was at
the alpha=0.05 level.
Results: Group differences for age, sex, history of cancer, CSF protein and treatment
response were not significant. Comparing TLI values in measurable responses, the difference
between the two groups for tibial TLI was significant (p=0.012), with idiopathic group
having a lower mean as compared to the diabetic. TLI values differences for median,
ulnar and peroneal nerves were not significant. The difference in abnormal rates of
sensory responses was significant for the sural nerve with the idiopathic group having
a lower rate compared to the diabetic group (80% vs 100%, p<0.05). No differences
were noted for the ulnar, median and radial nerves.
Conclusion: Tibial TLI and sural sensory responses have some value in differentiating
the two groups. Larger prospective studies are needed to confirm our findings.
INTRAVENOUS IMMUNOGLOBULIN (IVIG) FOR RESTABILIZATION TREATMENT AFTER IVIG WITHDRAWAL
IN CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP). RESULTS FROM THE PRE‐RANDOMIZATION
PHASE OF THE PATH STUDY
Mielke O
1, Bril V2, van Geloven N3, Hartung H‐P4, Lewis RA5, Sobue G6, Lawo J‐P1, Durn BL1,
Cornblath DR7, Merkies ISJ8, van Schaik IN9 and on behalf of the PATH study group.
1CSL Behring, Marburg, Germany and King of Prussia, PA, USA; 2Department of Medicine
(Neurology), University Health Network, University of Toronto, Toronto, Canada; 3Department
of Biostatistics and Bioinformatics, Leiden University Medical Center, Leiden, The
Netherlands; 4Department of Neurology, Heinrich Heine University, Düsseldorf, Germany;
5Department of Neurology, Cedars‐Sinai Medical Center, Los Angeles, CA, USA; 6Department
of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan; 7Department
of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 8Department
of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands; 9Department
of Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
IVIg is an important treatment option for CIDP. Although recommended by treatment
guidelines, little is known about the consequences of temporary IVIg withdrawal to
assess ongoing immunoglobulin need. PATH is a randomized, double‐blind trial of the
subcutaneous immunoglobulin (SCIg) IgPro20 (Hizentra®, CSL Behring) in CIDP. Before
SCIg randomization, subjects underwent periods of IVIg withdrawal (12 weeks or until
pre‐determined indications of clinical deterioration) and IVIg restabilization (IgPro10;
Privigen®, CSL Behring). Subjects not showing deterioration during withdrawal period
were withdrawn from study. To proceed to SCIg randomization, subjects had to achieve
“CIDP stability” (no relevant change in INCAT score at last two restabilization visits
and at least the same total score as at screening). 245 subjects entered the IVIg
withdrawal period. 208 (85%) of these qualified for IgPro10 restabilization; 28 subjects
(11%) were not IVIg dependent, and 9 (4%) were withdrawn for other reasons. One subject
withdrew consent before IgPro10 dosing. At the end of the IgPro10 restabilization
period, CIDP stability was achieved in 83% of subjects (22 did not reach stability,
13 were withdrawn for other reasons). Post‐study follow‐up information was available
for 16/22 subjects who did not reach stability: 9 (56%) had improved to baseline clinical
status and 7 had not, meaning at least 87% of the subjects improved to their pre‐study
status. During the restabilization period, 188/207 subjects (91%) improved in at least
one of the predefined outcome measures. On average, subjects improved by 1.2 points
in INCAT total score, 5.7 points in I‐RODS centile score, 12 kPa in mean grip strength
(dominant hand), and 3.6 points in MRC sum score. Improvement occurred with a median
of 23 days after the first IgPro10 dose in one or more efficacy outcome measures and
in 99% of cases after the third IgPro10 maintenance infusion. Headache and nasopharyngitis
were the most frequently reported adverse events (AEs) during restabilization. AEs
deemed causally related were mostly mild or moderate. No unexpected AEs or laboratory
or vital sign findings associated with IgPro10 occurred during the study. In summary,
IgPro10 reversed neuromuscular disability and improved activity/participation after
previous clinical deterioration during an IVIg withdrawal period.
IS PMP22 DUPLICATION THE ONLY COPY NUMBER VARIATION (CNV) RESPONSIBLE FOR CHARCOT‐MARIE‐TOOTH
DISEASE? NEW CNV DISCOVERED USING COV'COP
Miressi F1, Derouault P1, Dzugan H1,2, Cintas P3, Magdelaine C1,2, Sturtz F1,2, Merillou
S4, Lia AS
1,2.
1EA6309 – Université de Limoges, Limoges, France; 2Service de Biochimie et Génétique
Moléculaire–CHU de Limoges, Limoges, France; 3Service de Neurologie et d'explorations
fonctionnelles ‐ CHU de Toulouse, Toulouse, France ; 4UMR7252‐XLIM – Université de
Limoges, Limoges, France.
PMP22 duplication is the most frequent cause of Charcot‐Marie‐Tooth disease (CMT).
Since it discovery, more than 80 genes have been identified to be potentially responsible
for CMT disease. However only Single Nucleotide Variations (SNVs) or small indels
have been described. This could be due to the new sequencing strategy (NGS), especially
NGS by amplicon sequencing, for whose few convenient tools are available and easily
usable to detect CNVs responsible for inherited disease. To overcome this problem,
we designed “Cov'Cop”, a user‐friendly tool able to detect CNVs among amplicons sequencing
data. Using the run's coverage file provided by the sequencer, “Cov'Cop” simultaneously
analyzes all the patients of the run using a two‐stages algorithm containing correction
and normalization levels and provides an easily understandable output, showing with
various colors, potentially deleted and duplicated amplicons. We validated our method
on several datasets, including those of our targeted NGS panel screening 89 genes
known to be involved in CMT and close pathologies. Cov'Cop detected easily PMP22 duplication
and deletion in our patients, confirmed by MLPA. In addition, Cov'Cop permitted the
detection of new CNVs different from the PMP22 duplication, in CMT patients. We confirmed
these CNVs by quantitative PCR and CGH array. We present here one of these CNVs: the
duplication of AARS gene detected in CMT patients and we discuss the pathogenicity
of this new CNV. Additional CNVs responsible for CMT disease are probably still to
be discovered and we believe that Cov'Cop will help molecular geneticists to rapidly
identify them.
THALIDOMIDE THERAPY FOR POEMS SYNDROME: A MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO
CONTROLLED TRIAL WITH LONG‐TERM EXTENSION STUDY
Misawa S
1, Sato Y2, Katayama K2, Sekiguchi Y1, Amino H1, Suichi T1, Kuwabara S1 and J‐POST
trial study group.
1Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan;
2Clinical Research Center, Chiba University Hospital, Chiba, Japan.
POEMS (polyneuropathy, organomegaly, endocrinopathy, M‐protein, and skin changes)
syndrome is a rare cause of demyelinating neuropathy associated with plasma cell dyscraisia
and vascular endotherial (VEGF) overproduction. Although number of therapeutic interventions
for plasma cell dysorders have been applied to POEMS syndrome, there have been no
randomized clinical trials. This phase 2/3 double blind, randomized, placebo comtrolled
trial was performed to investigate the safety and efficacy of thalidomide for patients
with POEMS syndrome who are not eligible for stem‐cell transplantation. The primary
endpoint was the reduction rate of serum VEGF concentrations at 24 weeks in intention
to treat analysis. Additional outcomes of long‐term extension study included progression‐free
survival. Twenty‐five POEMS patients were randomly assigned to either thalidomide
plus dexamethasone or placebo plus dexamethasone from Nov 11, 2010, to July 3, 2014.
one patient in the placebo group was excluded from analyses because of a protocol
violation. The adjusted mean serum VEGF reduction rate at 24 weeks was 0.39 (SD, 0.34)
in the thalidomide group compared with −0.02 (0.54) in the placebo group (p=0.04).
The Kaplan‐Meier rate of progression‐free survival at 12 months was 0.77 in the thalidomide
group, as compared with 0.50 in the placebo group (HR, 0.373 ; 95% CI, 0.080 to 1.343).
In the randomized study period, mild sinus bradycardia was more frequent in the thalidomide
group than in the placebo group (54% vs 0%; p=0.006). Thalidomide suppresses serum
VEGF concentrations and lengthened pregression‐free survival in POEMS patients who
are ineligible for stem cell transplantation. Although thalidomide treatment has a
risk of bradycardia, the benefits would exceed the risk. This study is registered
with the UMIN Clinical Trials Registry, UMIN000004179.
A NEW SYT2 MUTATION CAUSING PRESYNAPTIC NEUROMUSCULAR JUNCTION DYSFUNCTION AND DISTAL
MOTOR NEUROPATHY (LEMS‐CMT)
Montes‐Chinea NI
1, Coutts M1, Vidal C1, Courel S2, Rebelo A2, Abreu L2, Zuchner S2, Saporta, MA1,2
. 1Department of Neurology, University of Miami, Miami, USA; 2Department of Human
Genetics, University of Miami, Miami, USA.
Autosomal dominant mutations in Synaptotagmin‐2 (SYT2), a synaptic vesicle protein
that functions as a calcium sensor for neurotransmission, have been previously linked
to presynaptic neuromuscular junction (NMJ) dysfunction and motor neuropathy in two
families. Both pathogenic mutations (Asp307Ala and Pro308Leu) were located in the
C2B domain of SYT2, which is essential for neurotransmitter release at the NMJs. We
report a family with a new missense mutation in the C2B domain of SYT2 and a similar
phenotype characterized by a slowly progressive, predominantly motor neuropathy and
evidence of presynaptic NMJ dysfunction on nerve conduction studies. The index case
is a 50 year‐old woman with gradually progressive weakness of her extremities. She
had normal developmental milestones, but was found to have bilateral high arched feet
and hammertoes and occasional falls around the age of 8. She gradually developed progressive
leg weakness, worsening bilateral hand cramping, weak handgrip, and only mild paresthesias
on distal extremities. Family history is remarkable for similar symptoms reported
by her maternal grandfather, two maternal uncles, her mother and a younger sister.
Her neurological exam revealed inability to walk on heels or toes, significant distal
lower extremity weakness and absent ankle deep tendon reflexes. Cranial nerve examination
and coordination were normal and there were only non‐specific sensory changes in the
lower extremities. EMG/NCS revealed normal sensory responses throughout; however,
motor nerve evaluation demonstrated globally reduced amplitudes with a >200% increment
after brief isometric contraction. Further electrophysiological evaluation with slow
(3Hz) repetitive nerve stimulation of the right ulnar motor nerve revealed a 40% decremental
response in amplitude and a >200% increase in amplitude immediately after a one‐minute
period of sustained muscle contraction, which rapidly extinguished after one minute.
Voltage‐gated calcium channel (VGCC) antibodies and a chest CT were normal. Targeted
Sanger sequencing revealed an Ile371Lys mutation in SYT2, which is located in the
C2B domain and is predicted to impair protein function. SYT2‐related neuropathy is
a rare disease, but should be suspected in patients presenting with a combination
of pre‐synaptic NMJ dysfunction (resembling Lambert‐Eaton myasthenic syndrome) and
a predominantly motor neuropathy, especially in the context of a positive family history.
PRELIMINARY RESULTS FOR CHARCOT‐MARIE‐TOOTH PATIENT‐REPORTED SURVEY
Moore A1, Ekins S1, Tockarshewsky T1, Nguyen TQ2, Miller B2, Glasser CE2, Attie KM
2, Johnson K2, Statland JM3, Ramchandren S4, Walk D5, Nussbaum J6.
1Hereditary Neuropathy Foundation, New York, USA; 2Acceleron Pharma, Cambridge, USA;
3University of Kansas Medical Center, Kansas City, USA; 4University of Michigan, Ann
Arbor, USA; 5University of Minnesota, Minneapolis, USA; 6ProHealth & Fitness New York,
USA.
Charcot‐Marie‐Tooth (CMT) disease affects roughly 1 in 2,500 individuals and is described
as an inherited peripheral neuropathy primarily affecting distal muscles. Limited
studies detail patient‐reported impact of muscle weakness on functional activities.
This anonymous survey was developed with input from clinical experts and patient interviews
and aimed to better understand the prevalence and impact of various CMT clinical manifestations
on patients’ lives. The survey was administered online to the Hereditary Neuropathy
Foundation's (HNF) patient contact database and is ongoing through June 2017. Here
we present preliminary data on patient characteristics and disease impact for 626
CMT patients collected February 17–21, 2017. Respondents were mostly female (61%)
and mostly from the US (74%). Median age (range) at symptom onset was 14 years (0–84
years), at diagnosis was 36 years (2–83 years), and at present was 55 years (6–89
years). The sample was representative of all CMT types (CMT1,2,3,4,and X). The most
common physical and clinical manifestations of CMT were problems with balance (87%),
ankle weakness/foot drop (81%), loss of feeling or abnormal sensation in the lower
leg/foot (81%), and hand muscle weakness (78%). Maintaining balance, walking long
distances, and climbing up and down stairs were key challenges associated with ankle
weakness/foot drop. Foot drop was considered by 72% to be the primary factor contributing
to falls, which averaged 2.5 falls to ground per month. Of those with foot drop, 86%
had bilateral weakness. A majority of respondents (76%) used some form of assistive
device for mobility, including ankle‐foot orthotics/below‐the‐knee leg braces (40%),
canes/walking sticks (34%), and custom foot orthotics/inserts (26%). The most common
drug therapy included pain and anti‐inflammatory medications (41%). Foot surgery was
the most common surgical procedure received (24%) and toe surgery was the most common
surgery considered (23%). Key symptoms that affected quality‐of‐life “very much” included
problems with balance (65%), ankle weakness (foot drop) (62%), and fatigue (49%).
These data suggest a high prevalence of lower leg muscle weakness; therefore, therapies
aimed at improving ankle weakness and the resulting foot drop and imbalance may be
beneficial to patients' daily functioning and quality of life.
CRITICAL FACTORS AFFECTING FUNCTIONAL RECOVERY AFTER PERIPHERAL NERVE INJURY
Morano M
1,2, Gambarotta G1, Ronchi G1,2, Cillino M3, Fornasari BE1,2, Fregnan F1,2, Tos P4,
Cordova A3, Moschella F3, Geuna S1,2, Raimondo S1,2.
1Department of Clinical and Biological Sciences, University of Turin, Orbassano (TO),
Italy; 2Neuroscience Institute of the “Cavalieri Ottolenghi” Foundation (NICO), University
of Turin, Orbassano (TO), Italy; 3Plastic and Reconstructive Surgery. Department of
Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy; 4Hand
Microsurgery and Surgery, Gaetano Pini Hospital, Milan, Italy.
Nerve fiber regeneration and complete functional recovery after peripheral nerve injury
do not always occur and can be influenced by many factors including patient age, gender,
lesion site, injury severity, size of the gap between damaged nerve stumps and time
interval that elapses before performing surgical repair.
The poor outcome occurring after a long delay can be due to loss of the neuron ability
to regenerate, loss of the Schwann cell ability to support regeneration and, of course,
progressive muscle atrophy.
The aim of this study was to investigate the nerve regeneration after delayed repair
and to study the degenerative processes of the denervated distal nerve stump and denervated
muscle. In particular, the analyses were focused on the role of NRG/ErbB system, that
is expressed both in nerve and in muscle tissue, during degenerating and regenerating
processes.
Functional recovery analysis performed after nerve repair showed that only the group
repaired immediately and not the groups repaired with a delay of 3 or 6 months, recovered
partially. Nevertheless, morphological analyses demonstrated that, despite the delay,
the nerve fibers are still able to regenerate, even if they are fewer and smaller
than the immediate repaired group. Moreover, the analysis of the NRG1/ErbB system
showed a significant decrease of soluble NRG1 in both degenerating and delayed‐repaired
nerves. The poor outcome after delayed nerve regeneration might be explained by Schwann
cell impairment and the consequent ineffective support for nerve regeneration.
As regards denervated muscle analysis, results showed that ErbB receptors expression
is related to the innervated state of the muscle, with an upregulation of ErbB2 clearly
associated with denervation state. Interestingly, NRG1 isoforms are differently regulated
depending on the type of nerve injury.
Future experiments will be needed to address the in vivo efficacy of different isoforms
of NRG1 both in injured nerve and denervated muscle.
AEROBIC EXERCISE FOR SUBJECTS AFFECTED BY CHARCOT MARIE TOOTH (CMT) NEUROPATHY: RESULTS
OF A MULTICENTER, PROSPECTIVE, RANDOMIZED, SINGLE BLIND, CONTROLLED CLINICAL TRIAL
Mori L1, Francini L1, Prada V1, Signori A2, Pareyson D3, Padua L4,5, Fabrizi G5, Schenone
A
1.
1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and
Child Health, University of Genoa, Genoa, Italy; 2Department of Health Science, Biostatistics
section, University of Genoa, Genoa, Italy; 3IRCCS Foundation, Carlo Besta Neurologic
Institute, Milan, Italy; 4Don Carlo Gnocchi Foundation Onlus − Centro Santa Maria
della Pace, Rome, Italy; 5Catholic University of the Sacred Heart, Rome, Italy; 6GB
Rossi Policlinic, Department of Neurologic and Visual Science, University of Verona,
Verona, Italy.
We planned a multicenter, prospective, randomized, single blind, controlled study
to evaluate the efficacy and safety of an innovative rehabilitation protocol based
on the use of treadmill training in a CMT1A population.
The protocol required that subjects were blindly randomized into two treatment groups,
SPE (three months of respiratory, proprioceptive and stretching exercises) or TreSPE
(the same treatment plus aerobic training at the treadmill). Subjects were evaluated
at baseline (T0), after three month of treatment (T1) and further three months of
follow up free of therapy (T2). The full assessment included: 6‐MWT (primary outcome
measure), 10‐MWT, Walk‐12, Short physical performance battery (SPPB); lower limbs
dynamometric strength evaluation; Berg Balance scale (BBS); CMT neuropathy score;
Medical Outcomes Study Short Form 36 (SF36).
A total of 53 subjects (mean age of 52.1±11.9 years) were recruited. At T1 we found
a significant improvement in both groups in the 6‐MWT (p<0.05), 10‐MWT (p<0.05), BBS
(p<0.05) and SPPB (p<0.01), while at T2 only the 6‐MWT was still significantly improved
(p<0.05) in the SPE group. No significant differences between groups were observed
for any of the outcome measures. Performances on Walk 12 did not significantly change
during follow‐up (p=0.27). Concerning the SF36, we did not observe consistent changes
during follow‐up or consistent differences comparing the two treatments.
In conclusion, this multicenter, prospective, randomized, single blind, controlled
study shows that the combination of respiratory, proprioceptive and stretching exercises
has a positive impact on the performance of CMT patients, especially regarding walking
tests. The aerobic exercise at the treadmill, is well tolerated but apparently does
not add any further improvement to the conventional treatment. We speculate that the
relatively low clinical severity of the patients, due to the selection criteria, may
have prevented a positive effect of treadmill exercise.
SEMI‐AUTOMATED MUSCLE MRI‐VOLUMETRY FOR MYOPATHY AND NEUROPATHY PATIENTS
Müller M1, Dohrn M1, Romanzetti S1, Reetz K1, Gess B
1.
1University RWTH Aachen, Department of Neurology, Aachen, Germany.
Muscle MRI is increasingly used in neuromuscular patients to detect changes in muscle
volume, muscle fat infiltration and edema. Muscle MRI are mostly analyzed by qualitative
means as quantitative analysis is time‐consuming and not well established. Here, we
developed a novel method for semi‐automated segmentation of muscle MRI data sets.
Based on axial T1‐weighted Dixon MRI stacks, muscle volumes were quantified by an
adapted water‐shed algorithm. Muscle volumes of thighs and calves were determined
separately and the ratio of thigh/calf was calculated. 24 myopathy, 8 neuropathy patients
and 28 healthy controls were included in the study. Muscle volumes determined by semi‐automated
segmentation were very similar to manually segmented data sets, differences being
<2%. This was the case for patients as well as healthy controls. The time‐saving effect
of automated segmentation was very strong (400 vs 30 min. per patient). Muscle volumes
of the thigh and also of the calf of myopathy patients showed a highly significant
difference (p<0.001) compared to healthy subjects. In neuropathy patients there was
a just significant difference (p<0.05) of muscle volumes compared to healthy patients
that did not sustain in Bonferroni's Multiple Comparison Test. The ratio of thigh/calf
muscle volume was significantly different comparing patients with myopathy and neuropathy
(p<0.05). Subgroup analyses of different groups of myopathy patients showed highly
significant differences (p<0.001) in myositis, limb‐girdle‐muscular dystrophy and
metabolic myopathy, compared to healthy patients, but no significant differences in‐between
these groups. Taken together, the data shows that automated segmentation of muscle
MRI allows for exact and fast quantification of muscle volumes in neuromuscular patients.
Higher patient numbers are necessary to test differences between specific disease
groups. Further studies should also address the possible use as a marker of disease
progress for clinical studies or therapy monitoring.
CLINICAL AND PATHOLOGICAL FINDINGS IN FAMILIAL AMYLOIDOTIC POLYNEUROPATHY DUE TO TRANSTHYRETIN
E61K
Murakami T
1, Nishimura H2, Nagai T1, Hemmi S1, Kutoku Y1, Sunada Y1.
1Department of Neurology, Kawasaki Medical School, Kurashiki, Japan; 2Department of
Pathology, Kawasaki Medical School, Kurashiki, Japan.
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant hereditary systemic
amyloidosis caused by mutation of transthyretin (TTR) gene, and usually shows sensory
dominant polyneuropathy and autonomic neuropathy at the initial stage. The pathogenesis
of neuropathy is not well understood, and explained by several mechanisms, including
such as mechanical compression, vessel occlusion, TTR toxicity and Schwann cell dysfunction.
We describe a sporadic patient with late‐onset FAP due to TTR E61K. She noticed dysesthesia
first in the foot at age 70. The symptoms were slowly progressive, and abnormal sensations
were extended up to the both upper arms and the both knees at age 76. Distal muscle
weakness and atrophy was also observed in the extremities. She noticed difficulties
in walking and frequent diarrhea. Echocardiogram revealed diffuse left ventricular
hypertrophy, suggesting cardiac amyloidosis. Amyloid deposits were not detected in
the endoneurim or perineurium of the sural nerve 7 years after the onset of the disease,
but a marked loss of myelinaed and unmyelinated nerve fibers was observed in it. TTR‐derived
amyloid deposits were confirmed in the peroneous brevis muscle, salivary gland and
heart tissue. DNA analysis revealed the heterozygote mutation, p.E81K (E61K)/c.241G>A,
of TTR gene, and she was diagnosis as FAP. These findings suggest that the proximal
parts of peripheral nervous system might be strongly involved by TTR aggregates or
amyloid fibrils. Blood‐nerve barrier in the distal part of peripheral nerves could
be preserved until later in the patient. Several biopsy sites other than nerve may
be helpful and necessary for diagnosis of TTR amyloidosis in mild or late‐onset FAP
as our case.
AXONAL CMT WITH ATYPICAL PROXIMAL WEAKNESS CAUSED BY TRANSLATIONAL ELONGATION OF THE
3' UTR IN NEFH
Nam DE1, Jung S‐C2, Choi B‐O3, Chung KW
1.
1Kongju National University, Gongju, Korea; 2Ewha Womans University School of Medicine,
Seoul, Korea; 3Sungkyunkwan University School of Medicine, Seoul, Korea.
Mutations in NEFH gene encoding the heavy neurofilament protein are usually associated
with neuronal damage and susceptibility to amyotrophic lateral sclerosis (ALS). Recently,
frameshift variants in NEFH (p.Asp1004Glnfs*58 and p.Pro1008Alafs*56) have been reported
to be the underlying cause of the axonal CMT (CMT2CC). The frameshift mutation resulted
in stop loss and translation of a cryptic amyloidgenic element (CAE) encoded by the
3' UTR. This study also identified a de novo c.3015_3027dup frameshift mutation predicting
p.Lys1010Glnfs*56 in NEFH from a CMT2 family with atypical clinical symptom of proximal
dominant weakness. This mutation is located near the previously reported frameshift
mutations, suggesting a mutational hot spot. These relatively frequent deletion/duplication
events with this resign might be caused by the putative hairpin structure. Patient's
lower limb MRI revealed a marked hyperintense signal changes in the hip muscles than
those in the thigh or lower leg muscles. This study also observed an anticipation
pattern of earlier onset (12 yrs old for mother to 6 yrs old for daughter) and more
severe symptoms in later generation. Therefore, this study suggests that the stop
loss and translational elongations by the 3' UTR of the NEFH mutations may be relatively
a frequent genetic cause of axonal peripheral neuropathy with the specific characteristics
of proximal dominant weakness and an anticipation pattern.
DO ANTI‐MAG TITERS HAVE A GOOD CORRELATION WITH CLINICAL STATUS IN IgM ANTI‐MAG NEUROPATHY?
Neil J
1, Haghi Ashtiani B2, Choumet V3, Musset L1, Léger JM2.
1Department of Immunology, Pitié‐Salpêtrière Hospital (AP‐HP), Paris, France; 2Department
of Neurology, National Referral Center for Rare Neuromuscular Diseases, Pitié‐Salpêtrière
Hospital (AP‐HP), Paris, France; 3Institut Pasteur, Emerging Diseases Epidemiology
Unit, Paris, France.
The myelin‐associated glycoprotein (MAG) is a transmembrane glycoprotein localized
in periaxonal Shwann cells and oligodendroglial membranes of myelin sheaths. MAG contains
a carbohydrate epitope (HNK‐1) that is a target antigen in autoimmune peripheral neuropathy
associated with monoclonal IgM gammopathy. In these neuropathies, numerous studies
report the absence of correlation between the titers of anti‐MAG antibodies and the
disease course. Anti‐MAG titers and IgM level at diagnosis are not always associated
with disease severity and there is not good correlation between pre‐ and post‐ treatment
anti‐MAG titers in patients who respond clinically to immunomodulators. MAG belongs
to siglec‐4a family and the linkage of sialic acid to the underlying sugars is an
important determinant of siglec binding. MAG shows high affinity for alpha‐ 2,3‐linked
sialic acid (2,3‐SA).Moreover, human monoclonal IgM possesses 5 heavy chain glycosylation
sites at Asn 171, 332, 395, 402 and 563 with sialylated olidgosaccharides and high‐mannose
type oligosaccharides. IgM may bind to MAG via these glycan epitopes as an alternative
and additional route of antigen binding other than through the Fab V regions. This
MAG‐Glycans IgM interaction may be clinically neutral but could lead to an overvaluation
of the biological results. In this study, we analyzed 8 sera from patients with IgM
reactivity against MAG: 7 of them had an anti‐MAG neuropathy with various degrees
of severity, and the last one had IgM monoclonal gammopathy, strong serum anti‐MAG
reactivity but no neurological disease. IgM were extracted and purified from these
sera by affinity chromatography. For each batch, an aliquot was digested by Jack bean
alpha‐mannosidase and anti‐MAG reactivity was performed by ELISA and indirect immunofluorescence
(IIF), before and after demannosylation. These extracts, tested in an iso quantitative
way with regard to the original serum, showed a decrease of activity (ELISA) and intensity
(IIF) after demannosylation. Furthermore, ELISA anti‐MAG was carried out in 49 sera
from patients with IgM monoclonal gammopathy without neurological impairment: 6 of
them (12.2%) showed a significant biological response. Taking into account the fact
that anti‐MAG antibodies are pathogenic (in animals models), these results support
the hypothesis of neutral intermolecular interactions between IgM and MAG.
THE RELATIONSHIP BETWEEN CENTRAL AORTIC SYSTOLIC PRESSURE AND PERIPHERAL BLOOD PRESSURE
IN PATIENTS WITH POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME
Ng CJB
1, Ng JPH2, Tay LB, T3, Umapathi3.
1Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 2Lee
Kong Chian School of Medicine, Nanyang Technological University, Singapore; 3National
Neuroscience Institute, Singapore.
Recent developments have validated non‐invasive means of measuring central arterial
blood pressure (CASP) and have shown that CASP and peripheral blood pressure (pBP)
are unidentical entities. Patients with postural orthostatic tachycardia syndrome
(POTs) have marked tachycardia with no associated decrease in pBP. We asked if the
reflex tachycardia, which corresponds to postural dizziness in these patients, could
be a result of a decrease in CASP. Two male patients, 19 and 21 years of age, with
clinical features typical of POTs went through a complete battery of autonomic screening
tests. The sympathetic and parasympathetic responses were normal other than a heart
rate increase of 31 and 41 beats per minute, respectively, on standing. There was
no significant decrease or increase in pBP on standing for 2 and 5 minutes. CASP was
measured non‐invasively by a device BproR that imputes the measured radial waveform
onto the brachial blood pressure to generate a pressure waveform from which a numerical
CASP value is derived. The CASP measurements for both patients did not decrease on
standing for 2 and 5 minutes. Our preliminary observation suggests that the basis
of tachycardia in POTs patients may not be a decrease in central blood pressure. We
are proceeding to systematically study more POTs patients to corroborate the above
observation. We are also trying to compare the difference between pBP and CASP in
POTs and age, gender‐matched normal controls. The major limitation of the study is
the model‐based mathematical derivation, rather than direct measurement, of CASP.
We are proceeding to systematically stud y more POTs patients to corroborate the above
findings.
THE RELATIONSHIP BETWEEN CENTRAL AORTIC SYSTOLIC PRESSURE, PERIPHERAL BLOOD PRESSURE
AND SYMPTOMATIC IN PATIENTS WITH AUTONOMIC DYSFUNCTION
Ng JPH
1, Ng CJB2, T Umapathi3.
1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; 2Yong
Loo Lin School of Medicine, National University of Singapore, Singapore; 3National
Neuroscience Institute, Singapore.
Recent developments have validated non‐invasive means of measuring central arterial
blood pressure (CASP) and have shown that CASP and peripheral blood pressure (pBP)
are unidentical entities. Orthostatic hypotension (OH) is a prominent component of
autonomic dysfunction (AD), the consequent hypoperfusion of vital organs responsible
for considerable morbidity and mortality. These structures are exposed to CASP rather
than pBP. We sought to understand the relationship of CASP to peripheral blood pressure
(pBP) in patients with autonomic dysfunction exposed to orthostatic stress. We reviewed
autonomic function tests of patients tested at our laboratory over a 3‐year period.
The patients were divided into 5 cohorts: (1) no AD and no OH (2) no AD, with OH (3)
mixed AD (4) parasympathetic dysfunction (5) sympathetic dysfunction. CASP was measured
non‐invasively by a device, BproR, that imputes the measured radial waveform onto
the brachial blood pressure to generate a pressure‐wave form from which a numerical
CASP value is derived. The difference and ratio of CASP to pBP was recorded at rest
and after 2 minutes of standing. Out of 361 patients 168 had complete data and a definitive
final diagnosis. Cohorts 1–5 had 74, 48, 15, 18, 13 patients respectively. Mean CASP‐pBP
difference in cohorts 1–5 were −10.55, −11.02, −11.59, −13.44, −8.69 respectively
at 0 minutes, and −13.52, −13.15, −13.18, −10.11, −8.46 respectively at 2 minutes.
Mean CASP/pBP ratio in cohorts 1–5 were 0.91, 1.08, 0.92, 0.91, 0.93, 0.93 respectively
at 0 minutes, and 0.89, 0.90, 0.89, 0.92, 0.92 respectively at 2 minutes. There was
no significant difference in the response of CASP and pBP to orthostatic stress across
abnormal cohorts 2 to 5 and in comparison with the “normal” cohort 1(p=0.268 to 0.983).
There was also no relationship to symptoms, namely postural dizziness. In conclusion,
autonomic dysfunction does not seem to affect the CASP‐pBP relationship as measured
by non‐invasive means. The absence of true normal controls, the exclusion of significant
number of patients because of incomplete data and the model‐based mathematical derivation
rather than direct measurement of CASP are limitations that we aim to address in follow‐on
studies.
AFTERDISCHARGES FOLLOWING M WAVES IN PATIENTS WITH VOLTAGE‐GATED POTASSIUM CHANNELS
ANTIBODIES
Niu JW
1, Guan HZ1, Cui LY1, Guan YZ1, Liu MS1.
1The Department of Neurology, Peking Union Medical College Hospital, Chinese Academy
of Medical Sciences, Beijing, China.
We aimed to explore the correlation between afterdischarges in motor nerve conduction
studies and clinical motor hyperexcitability in patients with voltage‐gated potassium
channels (VGKC) antibodies. Six patients with positive serum antibodies to contactin‐associated
protein‐like 2 (CASPR2) or/and leucine‐rich glioma‐inactivated protein 1 (LGI1) were
recruited, including 5 with autoimmune encephalitis, and 1 with cramp‐fasciculation
syndrome. Electromyography (EMG), nerve conduction studies (NCS) and F waves were
performed, and afterdischarges were assessed. One patient was followed up. Five patients
had clinical evidence of peripheral motor nerve hyperexcitability (myokymia or cramp),
and four of them had abnormal spontaneous firing in concentric needle electromyography.
Prolonged afterdischarges following normal M waves were present in all six patients,
including the two patients who had no EMG evidence of peripheral nerve hyperexcitability
(PNH). In the patient who was followed up, afterdischarges disappeared after treatment
with intravenous immunoglobulin (IVIG). Afterdischarges in motor nerve conduction
study might be more sensitive than needle electromyography for detecting peripheral
motor nerve hyperexcitability in patients with VGKC antibodies, and could disappear
gradually in accordance with clinical improvement and reduction of antibodies.
MUTIPLE SITES NERVE ULTRASOUND OF CHARCOT‐MARIE‐TOOTH TYPE 1A AND CHRONIC INFLAMMATORY
DEMYELINATING POLYRADICULONEUROPATHY
Niu JW
1, Cui LY1, Liu MS1.
1The Department of Neurology, Peking Union Medical College Hospital, Chinese Academy
of Medical Sciences, Beijing, China.
In our research, multiple sites measurement of cross sectional areas (CSA) by ultrasound
was performed to differentiate Charcot‐Marie‐Tooth type 1A (CMT1A) and chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP). Twenty‐eight patients with CIDP, 9 patients
with CMT1A, and 14 healthy controls (HC) were recruited prospectively. Consecutive
ultrasonography scanning was performed from wrist to axilla on median and ulnar nerves.
CSAs were measured at 10 predetermined sites of each nerve. CMT1A had significantly
larger CSAs at all sites of median and ulnar nerves (all P<0.01). In CMT1A, CSAs increased
gradually and homogeneously from distal to proximal along the nerve, except potential
entrapment sites. CIDP displayed three different morphological patterns, including
mild enlargement in 15 patients, prominent segmental enlargement in 12, and slight
enlargement in one, among which different treatment responses were observed. All patients
with mild nerve enlargement treated with intravenous immunoglobulin (IVIG) were responsive
(7/7), while less than half of those with prominent segmental enlargement (3/7) were
responsive (p<0.01). The patterns of CSA enlargement were different in CMT1A and CIDP
patients. Consecutive scan along the nerve and multiple sites measurement by ultrasound
could supply more detailed morphological feature of the nerve and help to differentiate
CIDP from CMT1A.
THE VALUE OF ELECTROPHYSIOLOGICAL TYPING AND CONDUCTION BLOCK FOR PREDICTION OF FUNCTIONAL
OUTCOME IN GUILLAIN‐BARRE SYNDROME
Niu JW
1, Cui LY Guan YZ1, Liu MS1.
1The Department of Neurology, Peking Union Medical College Hospital, Chinese Academy
of Medical Sciences, Beijing, China.
Guillain‐Barre syndrome (GBS) mainly consists of acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). In AMAN, conduction
block (CB) could be reversible or followed by axonal degeneration. We aimed to identify
the correlation between existence of CB and the functional outcome for patients with
GBS. 52 GBS patients were prospectively recruited for serial electrophysiological
tests and disability evaluation. All patients received treatment of intravenous immunoglobulin
(IVIG), and their disabilities were evaluated on the Hughes functional grading scale
before and 1 month after treatment. Patients were classified into AIDP, AMAN, equivocal
or normal according to electrodiagnostic criteria described by Rajabally et al. AMAN
patients who had follow‐up nerve conduction studies were further classified into three
groups. Group 1 was typical AMAN without conduction block, group 2 had reversible
conduction block, group 3 had conduction block and subsequential axon degeneration.
Electrophysiological study results showed 20 AIDP, 24 AMAN, 7 equivocal and 1 normal.
Probable or definite conduction block was observed in 11 AIDP patients and 16 AMAN
patients. AMAN with CB had higher reduction of Hughes grade at one month (1.71±0.83
vs 0.43±0.79,p=0.003), and lower percentage of patients with slow recovery (unable
to walk independently at six months) (7% vs 57%, p=0.025) compared with AMAN without
CB. There were no significant differences between AIDP with CB and without CB, in
the reduction of Hughes grade at one month. Among the 13 AMAN patients who were followed
up, 4 were typical AMAN without CB (type1), 7 had reversible CB (type 2), 2 had CB
and subsequential axon degeneration (type 3). Hughes grades at nadir were similar,
while patients with reversible CB (type 2) had the largest Hughes Grade reduction
at one month (type 2–2.14 vs type 1–0.25 vs type 3–1.5). None of the patients with
axon degeneration (type1) showed rapid recovery, while 86% of those with reversible
CB (type 2) had rapid recovery (improvement by two or more Hughes grades within four
weeks after onset). Electrodiagnosis of AMAN with conduction block, especially reversible
conduction block, might be a marker of good recovery.
FOLLOW‐UP STUDY OF NERVE ULTRASOUND IN A PATIENT WITH PRIMARY NEUROLYMPHOMATOSIS
Niu JW
1, Guan HZ1, Cui LY1, Yang YM1, Liu MS1.
1The Department of Neurology, Peking Union Medical College Hospital, Chinese Academy
of Medical Sciences, Beijing, China.
We report a follow‐up study of nerve ultrasound in a patient with primary neurolymphomatosis.
A 54‐year‐old female presented with 5‐months history of asymmetric limb pain, paresthesia,
and weakness. Electrodiagnostic studies and spinal cord MRI showed an axonal neuropathy
involving cervical and lumbosacral root, brachial plexus and left median nerve. Detection
of malignant B lymphocytes by cytology and flow cytometry of cerebral spinal fluid
confirmed the diagnosis of B‐cell non‐Hodgkin lymphoma. Nerve ultrasound showed dramatic
enlargement of upper, middle and lower trunks of left brachial plexus (cross sectional
area‐CSAs 21 mm2, 30 mm2, 26 mm2 respectively), middle trunk of right brachial plexus
(CSA 15 mm2), and proximal part of left median nerve (CSA 15–18 mm2). Five months
later, after five chemotherapy of rituximab and high‐dose methotrexate, and intrathecal
injection of cytosine arabinoside and dexamethasone, the patient had clinical improvement.
Nerve ultrasound also showed alleviation of nerve enlargement. The CSAs of upper,
middle and lower trunks of left brachial plexus were 5 mm2, 14 mm2, 14 mm2 respectively;
the CSA of middle trunk of right brachial plexus was 11 mm2; the CSA of proximal part
of left median nerve was 12–13 mm2. Peripheral nerve ultrasound could help locate
the distribution of nerve involvement, and reveals disease progression.
IENF AND MC ARE EARLY MARKERS OF PERIPHERAL INVOLVEMENT IN PD AND ARE DIFFERENTLY
AFFECTED BY LDOPA TREATMENT
Nolano M
1, Provitera V1, Stancanelli A1, Caporaso G1, Saltalamacchia AM1, Borreca I1, Lullo
F1, Califano F1, Lanzillo B1, Iodice R2, Manganelli F2, Barone P3, Santoro L2.
1IRCCS "Salvatore Maugeri" Foundation, Institute of Telese Terme (BN), Italy; 2“Maugeri”
Clinical and Scientific Institutes IRCCS, Institute of Telese Terme (BN), Italy; 3Center
for Neurodegenerative Diseases (CEMAND), Department of Medicine and Surgery, Neuroscience
Section, University of Salerno, Italy.
A peripheral nerve involvement has been demonstrated in PD with the evidence of a
small fiber pathology as possible intrinsic feature of the disease and a higher occurrence
of large fiber neuropathy in patients longtime treated with L‐Dopa. However the role
that disease itself and Ldopa have on small and large fiber pathology in PD is still
debated. We studied morphology and function of cutaneous innervation, in 85 idiopathic
PD patients (49 male, aged 60.7±10.9), including 47 Naïve and 38 L‐Dopa treated subjects
without electrophysiological signs of neuropathy, with the aim to assess and characterize
small and large fiber involvement and the effect of L‐Dopa on it. All patients underwent
a screening to rule out potentially neurotoxic conditions such as glucose intolerance,
dysendocrinopathies, Vitamin E, B12 and folic acid deficiency, hepatic or renal failure,
HIV or connective tissue disorders. Skin biopsies were obtained from thigh, leg and
fingertip from the more affected side and bilaterally from thigh and leg in 35 patients.
Samples were processed with indirect immunofluorescence technique using primary antibodies
to mark different sensory and autonomic fiber populations. Density of intrapapillary
myelinated endings (IME), Meissner's corpuscles (MC) and epidermal nerve fibers (ENFs)
was obtained as well as a semi‐quantitative assessment of sudomotor, pilomotor and
vasomotor innervation. Further evaluation included sympathetic skin response, quantitative
sensory testing and dynamic sweat test. Morphological and functional findings were
compared with data extracted from our age and sex stratified normative dataset. IENF,
IME, MC densities were lower (p<0.01) compared to controls in both naïve and L‐dopa
treated patients without differences between them except for MC density that was lower
in L‐dopa treated subjects (8.7±5.6 vs 14.5±8.9/mm2). A loss of autonomic nerves was
also found in both groups compared to controls. Significant abnormalities (p<0.01)
of thermal sensory thresholds, tactile thresholds, mechanical pain perception and
reduced sweating output were present and similar in both groups. Our work confirms
in PD an intrinsic peripheral nerve pathology involving both small and large fibers.
Small fiber pathology isn't affected by L‐Dopa treatment while sensory large fibers
involvement, already present in naïve patients worsens with Ldopa treatment.
THE FOREARM/UPPER ARM RATIOS OF CROSS‐SECTIONAL AREA ADD THE DIAGNOSTIC VALUE IN AMYOTROPHIC
LATERAL SCLEROSIS
Noto Y
1, Garg N1, Li T1, Timmins HC1, Park SB1, Shibuya K1, Kiernan MC1.
1Brain and Mind Centre, The University of Sydney, Sydney, Australia.
The diagnosis of amyotrophic lateral sclerosis (ALS), a progressive, fatal neurodegenerative
disorder defined by combined upper and lower motor neuron involvement, remains clinically
based. The purpose of this study was to determine the ultrasound appearance of peripheral
nerves in ALS patients, and to investigate whether parameters such as distal/proximal
ratios of nerve cross‐sectional areas (CSAs) may effectively differentiate disease
mimics from ALS. Nerve ultrasound of the median, ulnar, and tibial nerves was performed
in 53 ALS patients compared to 32 mimic patients (23 patients with peripheral nerve
hyperexcitability syndromes (PNHS) and 9 patients with multifocal motor neuropathy
(MMN)). Comparison of nerve and the distal/proximal ratios was undertaken by ultrasound
and compared across clinical and neurophysiological parameters.Compared to normal
controls, CSA of the median nerve at the upper arm was decreased in ALS (p <0.001).
In comparison to ALS mimic disorders, CSA at the proximal site of the median, ulnar
and tibial nerve and the forearm/upper arm ratio of the median and ulnar nerves had
diagnostic values. In addition to CSA of the median, ulnar, and tibial nerves, the
median and ulnar nerve forearm/upper ratios may provide a useful marker in for the
diagnosis of ALS.
THE EFFECTS OF A PHYSICAL THERAPY PROGRAM ON BALANCE, MOBILITY, AND QULAITY OF LIFE
IN PATIENTS WITH CHARCOT MARIE TOOTH PERIPHERAL NEUROPATHY: A RETROSPECITVE REPORT
Nussbaum J
1
. 1ProHealth & Fitness, New York, NY, USA.
Approximately 1 in 2,500 individuals are diagnosed with Charcot MarieTooth (CMT) disease,
making it the most common hereditary peripheral neuropathy. There is no documented
cure for CMT, however, many of those affected, report difficulty with mobility, imbalance,
and weakness of the feet and hands. In the general population, patients reporting
difficulty walking, falls and/or fear of falling, and poor strength are often referred
to physical (PT) and occupational therapists (OT) to skillfully address the impairments
and help restore function and quality of life (QOL). For patients diagnosed with CMT
this is unfortunately not the norm, often leaving patients without any skilled guidance
on managing their functional impairments.
11 patients (6 males) with a mean age of 52.27 years (27–74), went through a progressive
and skilled PT intervention over the course of 3 months. The program included: therapeutic
activities and exercise, neuromuscular reeducation, and manual techniques to address
the documented deficits. Patients were progressed through the program based on the
Borg Scale. Each patient was assessed prior to and post the commencement of the program
with the Berg Balance Scale, 6 Minute Walk Test, Timed Up and Go, Sit To Stand in
30 seconds, 20 Foot Self Selected and Fast Gait Speed, the Lower Extremity Functional
Scale, Activities Balance Confidence form, Upper Extremity Functional Index, Oswestry,
and the SF‐36 QOL measure. The patients were seen by the same skilled PT 2–3 a week
for 12 weeks.
All but 2 patients improved in all measures taken, indicating an improvement in function
and overall quality of life. Participants reported a total of 8 falls in the 3 months
prior to the initiation of the study and only 1 fall was reported during the 3 month
PT intervention.
This study makes a strong case for the utilization of skilled PT to address deficits
in patients with CMT. Additionally, the utilization of objective, valid and reliable
outcome measures in this population may help healthcare practitioners establish baseline
function and response to change. A large randomized control trial is recommended to
study the effects of a specific PT intervention on outcome measures in patients with
CMT.
CLINICO‐ELECTROPHYSIOLOGICAL CORRELATION WITH ANTI‐NEUROFASCIN155 ANTIBODY LEVELS
IN THE ANTIBODY‐POSITIVE CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY PATIENTS
Ogata H
1, Fujita A1, Yamasaki R1, Matsushita T1, Kira JI1.
1Department of Neurology, Neurological Institute, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan.
Clinical features of chronic inflammatory demyelinating polyneuropathy (CIDP) patients
with autoantibodies against neurofascin (NF)155, one of the paranodal proteins, have
been elucidated while the relation between anti‐NF155 antibody levels and long‐term
clinical course in these patients still remains elusive. We retrospectively collected
clinical, electrophysiological and immunological data of three anti‐NF155 antibody‐positive
CIDP patients. They were all males and their ages at onset were 16, 26, and 34 years
old. Their clinical severity was evaluated by deep tendon reflexes (DTRs), grip strength
and Hughes functional scale. Anti‐NF155 antibody levels were measured by flow cytometry
using HEK293 cell lines stably expressing human NF155. After immunotherapies of various
combinations, including intravenous immunoglobulin, plasmapheresis, corticosteroids
and other immunosuppressants, were introduced, their clinical parameters were gradually
improved. Decreased or absent DTRs were normalized and grip strength was increased
by more than 10 kg. Hughes functional scale scores were decreased by at least one
point compared with those at nadir. NCS findings of all three patients also showed
obvious amelioration. For example, their F wave latencies in the right ulnar nerve
were improved from 63 to 38 ms, from 48 to 35 ms, and from 64 to 38 ms, respectively.
Anti‐NF155 antibody levels after treatment were decreased in two patients whose pre‐
and posttreatment sera were available. When dose of oral prednisolone was being tapered,
they experienced re‐exacerbation of clinical parameters, especially DTRs and grip
strength. Their NCS findings and serum anti‐NF155 antibody levels were also deteriorated.
Exacerbation of these laboratory data in one patient preceded his clinical fluctuation,
which suggests that NCS and serum anti‐NF155 antibody levels could be used as early
disease activity markers. In this case series, not only clinical but also laboratory
data support a notion that anti‐NF155 antibody‐positive CIDP patients were reactive
to combined immunotherapies including corticosteroids. Even though various treatments
were administered to them, efficacy of oral corticosteroids seemed to be dose‐dependent.
Optimal disease activity markers and immunotherapies for long‐term maintenance of
remission in anti‐NF155 antibody‐positive CIDP should be identified.
evaluated by deep tendon reflexes (DTRs), grip strength and Hughes functional scale,
After starting immunotherapies,
THE CHALLENGES OF ACCURATE DIAGNOSIS OF ZIKA VIRUS ASSOCIATED GUILLAIN‐BARRÉ SYNDROME
(GBS) IN A DENGUE ENDEMIC AREA
Ohnmar O
1, KamYW2, Ng LFP2, T Umapathi3.
1University of Medicine 1, Yangon, Myanmar; 2Singapore Immunology Network, A*STAR,
Singapore; 3National Neuroscience Institute, Singapore.
Singapore's Zika virus (ZIKV) outbreak started in late August 2016. Over a period
of 2 months, we studied 8 patients enrolled into our institution's prospective Guillain‐Barré
syndrome (GBS) database for relationship to ZIKV infection. We also studied 3 GBS
controls that were seen before the established outbreak and 3 non‐GBS controls. The
8 index cases tested negative for ZIKV PCR in blood and urine. We proceeded to test
ZIKV IgG, IgM, dengue virus (DENV) IgG and IgM, and neutralization assays against
ZIKV and DENV. One patient with anti‐ GQ1b IgG positive Miller Fisher syndrome had
detectable ZIKV IgM and ZIKV IgG. The serum showed low titre DENV IgM and DENV IgG.
Follow–up serum at about 2 months showed increase in ZIKV IgG. We believe this patient
has ZIKV‐GBS. One patient with acute motor sensory axonal neuropathy and another with
acute inflammatory demyelinating polyneuropathy had high ZIKV IgM but low DENV IgM
and IgG. Another patient with MFS showed high levels of ZIKV and DENV IgM but low
IgG. The latter two patients had GBS before the ZIKV outbreak in Singapore. We suspect
these 3 patients could have ZIKV‐GBS, but are awaiting convalescent sera for confirmation.
Two patients seen during the outbreak had detectable levels of ZIKV IgG but serial
testing showed a decline after a period of 2–3 months. The initial and follow‐up sera
showed raised DENV IgM and IgG levels in one and raised IgG levels in the other. In
addition, both had stronger neutralizing capacity against DENV than ZIKV suggesting
that the initially detectable ZIKV IgG levels was due to cross reactivity with previous
DENV infection. Four patients, 1 GBS control and 2 non‐GBS controls also showed serological
response consistent with previous exposure to DENV. One normal control showed nil
exposure to both viruses. In summary, using various overlapping serological methods
we diagnosed 1 definite and 3 suspect ZIKV GBS cases. Our findings highlight 1) Insensitivity
of blood and urine PCR to diagnose ZIKV‐GBS 2) The problems of interpreting ZIKV serology
from cross‐reaction with DENV 3) Serial serology increases diagnostic accuracy.
VECTOR‐BORNE VIRAL INFECTIONS IN GUILLAIN BARRE SYNDROME PATIENTS
Okar SV
1, Ergunay K2, Bekircan‐Kurt CE1,3, Erdem‐Ozdamar S1,3, Tan E1,3.
1Department of Neurology, Hacettepe University, Ankara, Turkey; 2Virology Unit, Department
of Medical Microbiology, Hacettepe University, Ankara, Turkey; 3Neuromuscular Disease
Research Laboratory Hacettepe University, Ankara Turkey.
Guillain‐Barré syndrome (GBS) is an acute monophasic immune‐mediated polyradiculoneuropathy.
It is believed that acute inflammatory demyelinating poliradiculoneuropathy is caused
by T‐cell mediated autoimmune response targeting peripheral nerve myelin. Molecular
mimicry plays a role in the pathogenesis of some GBS cases. This mechanism has been
well demonstrated in the acute motor axonal neuropathy (AMAN) variant, in which autoantibodies
to Camphylobacter jejuni share epitopes with peripheral nerve gangliosides. This molecular
mimicry mechanism can be attributed to some cases with atypical triggers such as Zika
Virus or West Nile virus infections. Moreover there are accumulating clinical data
for vector borne viral infections triggering GBS. We evaluated vector‐borne viral
infections in our GBS and AMAN patients.
Eight patients with GBS, two patients with AMAN and as a control group, seven patients
with normal pressure hydrocephalus were included. GBS and AMAN was diagnosed with
clinical, electroneuromyograpic and cerebrospinal fluid (CSF) findings. Cerebrospinal
fluid serum and urine samples were examined for vector borne viral infections via
generic Flavivirus and Phlebovirus PCR. We also documented our patients prognostic
scores such as Modified Erasmus GBS Outcome Score (mEGOS) and Modified Erasmus GBS
Respiratory Insufficiency Score (mEGRIS).
The mean age of the patients was 56,8 (24–74 years) , six of them were female. All
CSF, serum and urine samples of our patients and control patients were negative for
Flavivirus and Phlebovirus families.
The preliminary results of our study in this our small cohort did not show any correlation
between the vector‐borne viral infections and GBS. Further studies with broad number
of patients are needed for more suggestive results.
THE GENERATOR SITE IN ACQUIRED AUTOIMMUNE NEUROMYOTONIA
Oliveira Santos M
1,2, Swash M1,3, de Carvalho M1,2.
1Institute of Physiology Unit, Instituto de Medicina Molecular, Faculty of Medicine,
University of Lisbon, Portugal; 2Department of Neurology, Department of Neurosciences
and Mental Heath, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon,
Portugal; 3Departments of Neurology and Neuroscience, Barts and the London School
of Medicine, Queen Mary University of London, UK.
Neuromyotonia (NMT) consists of spontaneous motor unit activity that reflects increased
peripheral nerve excitability, leading to involuntary, persistent muscle activity,
visible as muscle twitching at rest, with generalized, easily provoked cramps. Since
the first electrophysiological (EMG) description of NMT by Denny‐Brown and Foley (1948),
there has been discussion about the origin of the abnormal electrical activity recorded
in needle EMG studies. We studied two patients. Patient 1's NMT is aggravated by cold,
and he has an associated non‐progressive mild polyneuropathy with demyelinating features.
He is now 73‐year‐old and has been followed in our centre for 20 years. He is negative
for anti‐VGKC antibodies. Firstly, he was treated with carbamazepine and phenylhydantoin
with poor response, but he has shown major improvement on intravenous immunoglobulin
(IVIg) during the last 15 years. Patient 2 is a 62 year‐old man with NMT, followed
for 1 year, with high titters of anti‐VGKC antibodies (505 pmol/L; normal<72). He
improved on IVIg during the last 12 months. Screening for neoplasia was unremarkable
in both patients (negative anti‐neuronal antibodies, in particular anti‐Hu, anti‐Yo
and anti‐Ri antibodies; normal computerized tomography scan of the chest and abdomen).
In addition to routine studies, we tested synchronicity to spontaneous discharges
in different motor units in simultaneous recordings made with two needle electrodes
in the first dorsal interosseus muscle. Time‐locked fasciculations in these double
recordings would represent abnormal ectopic activity initiated in a nerve trunk with
ephaptic stimulation of a nearby axon. In patient 1, this research protocol was applied
once, 15 years after regular IVIg treatment. Patient 2 was investigated before and
1 year after IVIg. Both patients improved after IVIg, mirrored by a striking decrease
in the amount of spontaneous activity on EMG. Moreover, our technique did not detect
synchronous spontaneous activity (time‐locked fasciculations) on the second assessment,
although this was predominant before treatment in patient 2. In NMT, abnormal discharges
originate both in distal axonal branches and in more proximal segments. It appears
that IVIg is more effective in blocking antibody activity in proximal axonal segments,
perhaps related to factors such as blood‐nerve barrier, temperature or differing ion
channel distributions.
PERIPHERAL NERVE INVOLVEMENT IN CELIAC DISEASE: A NOVEL ASSOCIATION WITH A MULTIFOCAL
ACQUIRED MOTOR AXONOPATHY (MAMA)
Oliveira Santos M
1,2, Ohana B1, de Carvalho M1,2.
1Institute of Physiology Unit, Instituto de Medicina Molecular, Faculty of Medicine,
University of Lisbon, Portugal; 2Department of Neurology, Department of Neurosciences
and Mental Heath, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon,
Portugal.
Celiac disease (CD) is a chronic, multisystem and immune‐mediated disorder characterized
by small‐bowel sensitivity to dietary gluten in genetically predisposed individuals.
Neurological manifestations may occur in about 10% of patients, including peripheral
nerve involvement. Recent growing evidence strongly suggests that peripheral neuropathy
in CD may be autoimmune and associated with anti‐ganglioside antibodies. A 36‐year‐old
woman presented with slowly progressive weakness of her right hand and fingers extensors.
Medical and family history were unremarkable. On examination, muscle strength (Medical
Research Council‐MRC) was scored 0 for right wrist and finger extensors, 2 for right
abductor pollicis longus and 4 for right ankle dorsiflexion. Right triceps brachii
and brachioradialis reflexes were weak, but normal elsewhere. The remainder of the
neurological examination was normal. Neuroaxis magnetic resonance was unremarkable,
specifically with no gadolinium‐enhancing lesions. Motor and sensory nerve conduction
studies were normal. No conduction block or abnormal temporal dispersion was found.
Needle electromyography showed severe neurogenic changes with abnormal spontaneous
activity in right radial‐innervated muscles, and chronic neurogenic changes in homolateral
tibialis anterior, peroneus longus and extensor digitorum brevis. Ganglioside antibody
testing was positive to IgG anti‐GM2 antibody, but negative to anti‐GM1 and other
anti‐ganglioside antibodies. Additional blood tests were unremarkable, in particular
cryoglobulin testing was negative. Intravenous immunoglobulin improved weakness, as
right extensors of the wrist and fingers scored 3 (MRC). A monthly treatment was initiated,
which after 6 months was changed to every 2 weeks to preserve function. A diagnosis
of MAMA was established. Later, CD was diagnosed in her daughter due to chronic diarrhoea.
Our patient underwent anti‐tissue transglutaminase antibodies determination and small‐bowel
biopsy after 7 years disease' duration, and a diagnosis of CD was made. Gluten‐free
diet was started, but her neurological picture did not change after six months. In
our case the presence of IgG anti‐GM2 antibody may support a causal link between MAMA
and biopsy‐confirmed CD, and the lack of response to gluten‐free diet may be explained
by chronic axonal injury induced by memory T‐cells. This case broadens our knowledge
about neurological manifestations in CD, raising a probable association with purely
axonal multifocal motor neuropathies and anti‐ganglioside antibodies.
FUNCTIONAL OUTCOMES OF SURGICAL INTERVETIONS IN ADOLESCENTS WITH CHARCOT‐MARIE‐TOOTH
DISEASE: A DETAILED EVALUATION USING MOTION ANALYSIS
Õunpuu S
1,2, Pogemiller K1, Acsadi G3, Pierz K1,2,4.
1Center for Motion Analysis, Connecticut Children's Medical Center, Farmington, CT,
USA; 2School of Medicine, University of Connecticut, Farmington, CT, USA; 3Division
of Neurology, Connecticut Children's Medical Center, Farmington, CT, USA; 4Division
of Orthopaedics, Connecticut Children's Medical Center, Farmington, CT, USA.
Orthopaedic surgical intervention of the foot and ankle is performed in persons with
Charcot‐Marie‐Tooth (CMT) for improving foot pain, ankle instability, orthosis fitting/comfort
issues and shoe wear. The impact of these surgeries on ankle function during gait
is not known. Therefore, the goal of this study was to measure gait changes in ankle
function following surgical intervention by means of computerized motion analysis.
Fourteen patients with CMT (10±4 years pre and 14±5 years post‐operative) with bilateral
orthopaedic surgery were included. All patients had a plantar fascia release plus
some combination of other soft‐tissue (posterior tibialis and tendo‐Achilles lengthenings;
extensor hallucis longus, peroneus longus and anterior tibialis transfers) and bony
procedures (metatarsal and cuboid osteotomies). All patients completed two gait analyses
(pre and on average 3.8 years post‐surgery) during barefoot walking using a standardized
3D motion analysis protocol. The changes in ankle kinematics and kinetics and temporal‐spatial
parameters were analyzed in reference to a control group of patients with CMT without
intervening surgeries with 2.2 years between gait analyses as well as normal reference
data. The surgical group showed a significant increase in height between the pre and
post‐operative analyses and no changes in walking velocity (pre: 105±24, post: 103±21,
normal: 127±10 cm/sec). Similarly, the ankle kinematics and kinetics showed no changes
as a result of surgery. However, there was a trend for increased peak ankle dorsiflexion
(pre: 13±9, post: 16±5, normal: 13±3 degrees). As in the surgical group, the control
group showed an increase in height but no simultaneous increase in walking velocity
(test 1: 102±18, test 2: 104±20 cm/sec). The control group also showed no changes
in ankle kinematics and kinetics suggesting that the impact of the disease is, for
the most part, not noticeable over 2.2 years. The results show that surgical intervention
that primarily addresses foot alignment does not negatively impact ankle kinematics
and kinetics during gait. The comparison with the control group supports this finding.
However, there are some other findings such as the increase in peak dorsiflexion during
stance in some patients that will need to be examined further in larger cohorts.
DO ORTHOSES IMPROVE GAIT IN CHILDREN AND ADOLESCENTS WITH CHARCOT‐MARIE‐TOOTH?
Õunpuu S
1,2, Pogemiller K1, Pierz K1,2,3, Acsadi G2,4
. 1Center for Motion Analysis, Connecticut Children's Medical Center, Farmington,
CT, USA; 2School of Medicine, University of Connecticut, Farmington, CT, USA; 3Division
of Orthopaedics, Connecticut Children's Medical Center, Farmington, CT, USA; 4Division
of Neurology, Connecticut Children's Medical Center, Farmington, CT, USA.
Ankle‐foot‐orthoses (AFOs) are commonly prescribed for patients with Charcot‐Marie‐Tooth
(CMT) to improve gait and reduce ankle instability and falling. There are no studies
that examine bracing outcomes using objective evaluations. The purpose of this study
was to examine the impact of various AFO designs on gait parameters in children and
adolescents with CMT. We predicted that the AFOs would improve excessive and delayed
peak dorsiflexion in stance and equinus in swing. Fifteen patients (mean age 12±5
years) were analyzed barefoot and with their prescribed AFOs by means of a standardized
motion analysis protocol. A full clinical examination was also completed including
strength and passive range of motion measures. The AFOs included solid, hinged and
posterior leaf spring (tapered, less supportive) designs. Sagittal plane ankle kinematics
and kinetics and temporal‐spatial parameters were analyzed in comparison to normal
controls. Walking velocity improved from 95±26 to 108±21 cm/sec demonstrating the
functional benefits of AFOs. Ankle plantar flexion angle at initial contact improved
from −8±8 to −1±4 degrees demonstrating improvement in drop foot in swing and at initial
contact reducing the risk of tripping. However, the degree of peak ankle dorsiflexion
in stance remained the same and excessive at 17±5 degrees barefoot and 16±5 degrees
with AFOs suggesting that in many patients the AFO design was not sufficiently supportive.
Peak ankle plantar flexor moment showed improvement from 0.69±0.29 to 0.79±0.25 Nm/kg
highlighting the improved base of support provided by the AFOs that compensate for
ankle plantar flexor weakness. However, peak power generation was reduced from 1.48±0.80
to 1.11±0.39 W/kg indicating that some of the available ankle strength was impeded
with the AFOs. The results of this study suggest that orthoses can provide improved
gait outcomes which will improve overall function. However, there are individual differences
in patient impairment (strength, range of motion and bony deformity) and associated
gait presentation that need to be accounted for in AFO design. AFOs do not always
function as intended due to the complex interaction between patient impairment, orthosis
stiffness and orthosis design. Motion analysis can assist in identifying the specific
AFO needs for an individual with CMT.
HEAD AND VOICE TREMOR IMPROVING WITH IMMUNOTHERAPY IN AN ANTI‐NF155 POSITIVE CIDP
PATIENT
Painous C
1, López‐Pérez MA2, Illa I1,3, Querol L1,3.
1Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu i Sant
Pau, Barcelona, Spain; 2Hospital San Pedro, Logroño, La Rioja, Spain; 3Centro para
la Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune
neuropathy with a heterogeneous clinical spectrum. Specific autoantibodies define
different clinical phenotypes. CIDP with NF155 antibodies constitutes a specific CIDP
subset in which a high incidence of postural and intention tremor has been described
and that responds poorly to immunoglobulins. We report a patient with an anti‐NF155
positive CIDP that presented head, voice and limb tremor that improved with immunotherapy.
A 64‐year‐old man with unremarkable medical history, presented at the age of 61 with
progressive distal weakness and paraesthesia. Numbness, gait ataxia and action tremor
involving voice, head and limbs appeared sequentially. The EMG showed features of
acquired demyelination fulfilling CIDP diagnostic criteria. A first course of intravenous
immunoglobulins was ineffective. The weakness, ataxia and tremor worsened significantly,
needing two walking aids first and becoming wheelchair bound later on. He received
six plasmapheresis cycles that were also ineffective and oral corticosteroids (1mg/Kg)
were started with mild improvement. After corticosteroid tapering the patient developed
a severe relapse and was referred to our centre. Five plasma exchange cycles followed
by rituximab (375mg/m2, 6 doses) were added to the corticosteroids. Three months later
the weakness, ataxia and tremor, including the head and voice tremor, started to improve
significantly. Six months later the patient presented a significant improvement and
was able to walk unaided. The anti‐NF155 antibody titres fell from 1/72900 pre‐rituximab
to be undetectable.
Limb tremor is known to occur in patients with inflammatory neuropathies and, specifically
in anti‐NF155+ CIDP patients but, to our knowledge, this is the first report of a
CIDP patient presenting with head and voice tremor ever reported. The improvement
of tremor with immunotherapy strongly suggest that anti‐NF155 autoantibodies are involved
in its pathogenesis, expanding the phenotype of anti‐NF155 specific clinical features.
CHARCOT–MARIE–TOOTH DISEASE TYPE 2G REDEFINED BY A NOVEL MUTATION IN LRSAM1
Palaima P
1, Peeters K1, L. Pelayo‐Negro A2, García A2, Gallardo E2, García‐Barredo R2, De Vriendt
E1, Infante J2, Berciano J2, Jordanova A1.
1VIB and University of Antwerp, Center for Molecular Neurology, Molecular Neurogenomics
Group, Antwerp, Belgium; 2University Hospital “Marqués de Valdecilla”, Santander,
Spain.
Charcot‐Marie‐Tooth disease type 2G is an autosomal dominant and slowly progressing
inherited neuropathy which was first described over 30 years ago. It has been attributed
to a single Spanish family consisting of 33 individuals with 13 affected members spanning
four generation. Initially, the genetic defect was linked to a 13.2Mb region in 12q12‐q13.3.
However, extensive sequence and structural variant analyses using whole genome sequences
(WGS) of three affected individuals did not reveal any known or novel genetic causes
within the region. Over the last decade, serial clinical re‐evaluation of the entire
pedigree was performed leading to changes to the affection status of seven individuals
redefining the disease‐linked region to chr9q31.3‐q34.2 (Zmax = 4.39 at Theta = 0).
Additional family members were then submitted for whole exome sequencing. This has
led to the identification of a novel missense variant in the E3 ubiquitin‐protein
ligase LRSAM1 (p.Cys694Tyr) that was previously not covered by WGS. The variants co‐segregated
with disease and were absent from controls. Other mutations that are known to disrupt
the RING domain of LRSAM1 have been previously reported to cause both autosomal dominant
and recessive CMT type 2P (CMT2P). Unlike prior reports, we demonstrated that the
mutation does not influence overall protein levels of LRSAM1, nor of its ubiquitylation
target TSG101 in patient derived lymphoblasts. Transcriptomics analysis identified
significant upregulation of another E3 ubiquitin‐protein ligase (NEDD4L) and of a
key regulator of axonal degeneration (TNFRSF21). Notably, magnetic resonance imaging
of lower‐limb musculature systematically showed fatty atrophy in both clinical and
subclinical mutation carriers emphasizing its use for the identification of mildly
affected members. Our findings demonstrate that the isolated genetic entity CMT2G
is caused by a missense mutation in LRSAM1 and should be reclassified as CMT2P. Moreover,
we reveal novel molecular players associated with LRSAM1 dysfunction, and highlight
pathways and therapeutic targets shared with amyotrophic lateral sclerosis and Alzheimer
disease.
TRPV1 EXPRESSION IN HUMAN PERIPHERAL SENSORY NERVES AND RELATIONSHIP TO NEUROPEPTIDES
CGRP AND SP
Pan B
1, Karlsson P2, Liu Y1, Caterina M3, Polydefkis M1.
1Department of Neurology, Johns Hopkins University, Baltimore, USA; 2Danish Pain Research
Center and Department of Clinical Medicine, Aarhus University Hospital, Denmark; 3Department
of Neurosurgery, Johns Hopkins University, Baltimore, USA.
Damage to peripheral nerves is a prerequisite for neuropathic pain. However, it remains
unclear why some neuropathy patients have pain, but others with identical nerve conduction,
QST and IENFD do not. We propose to examine the distribution of TRPV1 and its co‐localization
with CGRP and SP in epidermal nerve fibers in patients with and without neuropathic
pain. We aimed to define the expression pattern of TRPV1 in normal healthy subjects
first, and study the co‐localization of TRPV1 with CGRP and SP in normal controls
and patients with painful neuropathy. Skin biopsies from neuropathy patients and normal
subjects were utilized. Anti‐TRPV1 antibody generated in our university with support
from NINDS‐funded Dept. of Neuroscience Monoclonal Core (NS050274) was used. Combined
immunohistochemistry were performed to identify co‐expression of TRPV1 with CGRP,
SP and PGP 9.5. The distribution of TRPV1 in controls revealed a proximal to distal
gradient similar to that observed for IENF labeled by PGP 9.5. TRPV1 staining was
more intense in nerve terminals in the epidermis. Combined immunostaining revealed
that 65% of PGP 9.5 labeled fibers in the epidermis were TRPV1+, while 78% of CGRP+
fibers TRPV1+. Patients with pain had a higher density of TRPV1+ fibers compared to
that of patients with numbness. A greater proportion of CGRP+ fibers (94%) in the
painful patients were TRPV1+. Expression of TRPV1 in controls exhibits a distal to
proximal gradient. TRPV1 expression and co‐localization with CGRP were altered in
neuropathic pain patients, suggesting that this receptor plays an important role in
pathological states.
NOCICEPTIN/ORPHANIN FQ OPIOID PEPTIDE (NOP) RECEPTOR EXPRESSION IN PACHYONYCHIA CONGENITA
(PC)
Pan B
1, Schröder W2, Jostock R2, Schwartz M3, Polydefkis M1.
1Neurology, The Johns Hopkins University SOM, Baltimore, USA; 2Translational Science
& Intelligence (WS) and In‐vitro Biology & Biomarker Research Unit (RJ), Grünenthal
GmbH, Aachen, Germany; 3Pachyonychia Congenita Project. Salt Lake City, USA.
Activation of the NOP‐receptor (NOP‐R) by its endogenous ligand nociceptin/orphanin
FQ or non‐peptide agonists modulates nociception and analgesia in neuropathic pain
models. The wide distribution of NOP‐R and its endogenous ligand represents an attractive
treatment target. Since pain is the most prominent feature in PC, we defined expression
of the NOP‐R in plantar skin biopsies and assessed whether alterations exist in PC–affected
vs PC‐unaffected and anatomically matched control skin. Skin biopsies from k6a PC
and control subjects were immunohistochemically stained for NOP‐R. Combined immunostaining
for NOP‐R with PGP 9.5, neurofilament H (NFH) and CGRP was used to define NOP receptor
expression in the epidermis and upper dermis. Robust NOP‐R was detected in epidermal
keratinocytes and a subset of PGP9.5+ fibers in both epidermis and dermis. Staining
was inhibited through pre‐incubation with a NOP‐R blocking peptide and western blot
analysis using homogenized human skin tissue demonstrated a band at ∼50kd consistent
with NOP‐R molecular weight. NOP‐R expression occurred in dermal NFH+ A beta‐fibers
in all groups though no CGRP+ fibers co‐expressed NOP‐R. PC‐affected skin had slightly
lower NOP‐R expression than in PC‐unaffected skin and a similar pattern in anatomically
matched locations from healthy control subjects was observed. NOP‐R is expressed in
human plantar skin epidermal keratinocytes as well as a subset of epidermal and dermal
nerve fibers. These fibers are PGP 9.5+, CGRP‐ and many co‐express NFH. NOP receptor
is a viable pharmaceutical analgesic target in PC patients irrespective of its slight
down‐regulation as compared to PC‐unaffected skin. This work was supported by Grünenthal
GmbH.
A MULTICENTRE RETROSPECTIVE STUDY OF CHARCOT‐MARIE‐TOOTH DISEASE TYPE 4B (CMT4B)
Pareyson D
1, Stojkovic T2, Leonard‐Louis S2, Reilly MM3, Laurà M3, Parman Y4, Battaloglu E4,
Tazir M5, Bellatache M5, Bonello‐Palot N6, Sacconi S7, Guimarães‐Costa R2, Attarian
S6, Latour P8, Megarbane A2, Schenone A9, Ursino G9, Sabatelli M10, Luigetti M10,
Santoro L11, Manganelli F11, Quattrone A12, Valentino P12, Murakami T13, Scherer SS14,
Dankwa L14, Shy ME15, Bacon CJ15, Herrmann DN16, Pisciotta C1, Previtali S1, Bolino
A1.
1Milan, Italy; 2Paris, France; 3London, United Kingdom; 4Istanbul, Turkey; 5Algiers,
Algeria; 6Marseille, France; 7Nice, France; 8Lyon, France; 9Genoa, Italy; 10Rome,
Italy; 11Naples, Italy; 12Catanzaro, Italy; 13Kurashiki, Japan; 14Philadelphia, USA;
15Iowa City, USA; 16Rochester, USA.
CMT4B1 and B2 are characterized by recessive inheritance, early onset, severe course,
slowed nerve conduction, myelin outfoldings, association with loss‐of‐function mutations
in Myotubularin‐related protein‐2 and −13 (MTMR2, MTMR13/SBF2), respectively, involved
in the metabolism of PtdIns3P and PtsIns(3,5)P
2 phosphoinositides, key regulators of membrane trafficking. In a multicentre retrospective
study to better characterise CMT4B, we collected a minimal dataset of information
including CMTES/CMTNS on 41 CMT4B patients, 27 CMT4B1 (14 unrelated families) and
14 CMT4B2 (11 families). CMT4B1 patients were younger and with earlier onset than
CMT4B2: last visit was performed at a mean age of 22 years (SD 12.5; range 1–48) for
CMT4B1 and 35 years (13.1; 16–59) for CMT4B2; disease onset occurred at a mean age
of 2.8 years (3.2; 0–13) in CMT4B1 as compared to 5.9 years (5.3; 1–20) in CMT4B2;
delay in motor milestones occurred in 15/26 CMT4B1 and 4/14 CMT4B2 subjects. Eleven
CMT4B1 patients became chair‐bound, whereas all CMT4B2 subjects but one are still
ambulant, although with AFOs for 9 patients and requiring unilateral support in two
cases. Both disease types are characterised by vocal cord involvement (9/26 CMT4B1
and 6/14 CMT4B2); respiratory involvement was seen almost exclusively in CMT4B1 patients
(n=8, four requiring non‐invasive ventilation and one tracheostomy, as compared to
one CMT4B2 patient on NIV at age 49); two CMT4B1 subjects and an affected CMT4B1 relative
not included in the present study died of respiratory complications. Glaucoma (n=4)
and buphthalmos (n=2) occurred only in CMT4B2. CMTES/ CMTNS scores were higher in
CMT4B1 patients in spite of their younger age, indicating more severe disease: CMT4B1
= CMTES mean 17.9 (n=20; SD 6.0; range 8‐28/28), CMTNS mean 30.2 (n=10; SD 4.8; range
19‐36/36,; CMT4B2 = CMTES mean 16 (n=13; SD 5.0; range 6‐26/28), CMTNS mean 25 (n=12;
SD 4.7; range 19‐34/36). Our data confirm that CMT4B1 is more severe than CMT4B2.
Interestingly, MTMR2 interacts with MTMR13. MTMR2 is a catalytically active phosphatase,
whereas MTMR13 is a catalytically inactive protein, known to increase MTMR2 enzymatic
activity. Thus, in CMT4B2 nerves a residual enzymatic activity of MTMR2 may result
in a less severe clinical phenotype as compared to CMT4B1.
PREGNANCY, SLEEP, FATIGUE AND OTHER ITEMS IN CHARCOT‐MARIE‐TOOTH DISEASE: DATA FROM
QUESTIONNAIRES LINKED TO THE ITALIAN CMT NATIONAL REGISTRY
Pareyson D
1, Calabrese D1, Santoro L2, Manganelli F2, Fabrizi GM3, Schenone A4, Cavallaro T3,
Ursino G4, Previtali S5, Allegri I6, Padua L7,8, Pazzaglia C8, Quattrone A9, Villani
F1, Pisciotta C1, Mazzeo A10, Vita G10 and for the Italian CMT Network.
1IRCCS Foundation, "C. Besta" Neurological Institute , Milan; 2 Federico II University,
Department of Neurosciences, Reproductive Sciences and Odontostomatology, Naples;
3University of Verona, Department of Neurological, Biomedical and Motor Sciences,
Verona; 4University of Genoa, Department of Neurosciences, Rehabilitation, Ophthalmology,
Genetics and Maternal Infantile Sciences, Genoa; 5Ospedale San Raffaele, Vita Salute
San Raffaele University, Department of Neurology and INSPE, Milan; 6A.O. di Parma,
U.O. Neurologia, Parma; 7Università Cattolica del Sacro Cuore, Rome; 8Don Carlo Gnocchi
Onlus Foundation, Department of Neuroscience, Milan; 9Magna Graecia University, Department
of Medical Sciences, Catanzaro; 10University of Messina, Unit of Neurology, Department
of Clinical and Experimental Medicine, Messina; Italy.
The Charcot‐Marie‐Tooth disease (CMT) National Registry is fully operative (https://www.registronmd.it)
with collection of clinical/genetic information (minimal dataset) and reporting of
clinical scales; 537 CMT patients have registered thus far and have chosen one of
the 9 reference centers; information collected during the ad hoc visit have been entered
in the Registry for 420 of them. Registered patients have the chance to participate
to a study that requires filling online self‐reported questionnaires related to five
important issues: disease course and complications during pregnancy; use, efficacy
and tolerability of orthotics and assistive devices; outcome of surgery for skeletal
deformities; safety of anesthesia; occurrence of sleep disorders (including evaluation
of fatigue, anxiety and depression). By February 2016, 201 patients and 36 relatives/friends
(as healthy controls) have filled the questionnaires. We are performing a first explorative
analysis of results, but data collection on all questionnaires will be prolonged until
Novemebr 30, 2017, to obtain a larger sample. Pregnancy: 46/73 CMT women had at least
one pregnancy; complications ranging from mild to severe occurred in 44/108 pregnancies
vs 9/42 in controls. CMT worsened in 7 pregnancies (6 patients) with no recovery in
5 instances. Prenatal diagnosis was performed in 8/108 pregnancies. Satisfaction related
to surgical procedures for foot deformities, assessed with VAS (score 0–10), was 6.4±3.5
(n = 110). Repeat surgery was required in 9/72 instances. Sleep: the Epworth Sleepiness
Scale questionnaire revealed abnormalities of sleep in 44/142 CMT patients (31%) and
in 5/30 controls (17%). The vast majority of CMT subjects (123/138; mean 9.1 ± 3.2),
but also of controls (27/30; 8.6 ±2.9) were not good sleepers according to the Pittsburgh
Sleep Quality Index (PSQI) (range 0–21, 0 good sleep). Fatigue: scores of Modified‐Fatigue
Impact Scale (range 0–82, 0 no fatigue) were higher for CMT (mean 33±18.2) than controls
(mean 16.6±12.5). Hospital Scale for Anxiety and Depression: 63/138 CMT subjects had
mild‐to‐severe anxiety and 35/138 mild‐to‐severe depression as compared to 7/29 and
4/29 controls, respectively. Data analysis on orthotics and anesthesia is ongoing.
In conclusion, the first data analyses confirm that there are problems related to
all the five domains explored, that will need to be specifically addressed in patients'
care. Supported by Telethon‐UILDM grant GUP13006.
CLINICAL SIGNIFICANCE OF CONDUCTION BLOCK IN CMT1A PATIENTS WITH PMP22 DUPLICATION
Park J
1, Choi MS1, Seok JM1, Min JH1, Kim BJ1, Choi BO1.
1Samsung Medical Center, Seoul, Korea, Republic of.
Charcot‐Marie‐Tooth disease (CMT) is the most frequent motor and sensory peripheral
neuropathy and is known to have the uniform demyelination. The traditional definition
of conduction block is the reduction of negative peak of compound muscle action potential
(CMAP) of proximal segment relative to adjacent distal segment more than 50%. In this
study, we tried to find the frequency of conduction block in CMT1A patients and to
investigate the differences of the clinical manifestation. We enrolled unrelated 48
CMT1A patients (26 males and 22 females) with PMP22 duplication and undertook nerve
conduction studies from 2011 to 2015. Stimulation sites were wrist, elbow and axilla
for median nerve study. Eleven patients (22.9% of all enrolled patients) had NCS features
suggestive of conduction block. Compared to CMT1A patients without conduction block,
functional disability scale was significantly higher in CMT1A patients with conduction
block (p < 0.05). However, onset age and disease duration were not different between
CMT1A patients with and without conduction block. In addition, conduction block was
more frequently observed in distal segments than proximal segments. We suggest that
the frequency of conduction block in CMT1A patients is not low, and there is some
heterogeneity of demyelination in CMT1A patients. Also, in CMT1A patients, the conduction
block might have relationship with clinical disability.
SUBACUTE COMBINED DEGENERATION CAUSED BY CHRONIC ATROPHIC GASTRITIS WITH SPURIOUS
ELEVATION OF VITAMIN B12 LEVEL
Park JG1, Park MS
1.
1Yeungnam University College of Medicine, Daegu, Korea.
The subacute combined degeneration (SCD) is diagnosed by a characteristic clinical
manifestation, spinal MRI, and decreased serum vitamin B12 levels. We report a case
of SCD with elevated homocysteine and methlymalonic acid level in the situation of
spurious elevation of vitamin B12 concentration. An 80 years old man presented with
progressive gait disturbances and sensory disturbances. About a year ago, he felt
both hands and feet paresthesia and gait disturbances. Four months before the visit,
nerve conduction tests were performed elsewhere due to symptoms. Polyneuropathy was
found. The laboratory test showed megaloblastic anemia. However, serum vitamin B12
concentration was increased to 1649 pg / mL (normal: 200–950 pg / mL). His symptoms
progressed gradually. At presented, neurological examination showed spasticity of
the lower limb without weakness, and vibration and position sensation were decreased
in both lower limbs, and showed ataxic gait. Spinal cord MRI showed a lesion with
a long T2 high signal intensity from C1 to T4 in the posterior column of the spinal
cord. Further laboratory test were added, then while folate was normal level but homocysteine
at 21.2 umol/L (normal: 5–12 umol/L), and methylmalonic acid at 2.9 uM / L (normal:
0–0.4 uM / L) were increased. Finally, SCD caused by vitamin B12 deficiency was diagnosed.
In addition, gastric endoscopy was performed to find the cause of vitamin B12 deficiency
and chronic atrophic gastritis was found. After cobalamine treatment for 6 months,
hemoglobin level was improved and his symptoms were all improving with a little gait
disturbances. False‐elevation of vitamin B12 level could lead to delayed diagnosis
and cause irreversible changes in the nervous systems. One of the most commonly used
methods to measure vitamin B12 concentrations is competitive‐binding assay, which
may result in normal levels even with vitamin B12 deficiency due to the effect of
anti‐intrinsic factor antibodies. When vitamin B12 deficiency is suspected, even if
the vitamin B12 concentration is normal, additional tests of homocysteine and methylmalonic
acid should be considered.
CLINICAL AND GENETIC HETEROGENEITY IN CHARCOT‐MARIE‐TOOTH NEUROPATHY TYPE 2 PATIENTS
FROM TURKEY
Parman Y
1, Durmus H1, Deymeer F1, Oflazer‐Serdaroğlu P1, Battaloglu E2.
1Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Istanbul,
Turkey; 2Bogazici University, Istanbul, Turkey.
Hereditary motor and sensory neuropathies, also called CMT neuropathies, are the most
common group among the hereditary neuropathies. CMT subtypes are grouped by axonal,
demyelinating or intermediate phenotype, or by autosomal‐dominant (AD), autosomal‐recessive
(AR) or X‐chromosomal inheritance. CMT‐2 is considered axonal and characterized by
distal muscle wasting, mild sensory loss and normal or near‐normal nerve conduction
velocities. Mutations in more than 18 genes are known to be able to cause autosomal
dominant (AD) or recessive (AR) CMT‐2 to date. The genetic heterogeneity in Charcot‐Marie‐Tooth
(CMT) is a challenge for genetic diagnostics. Clinical clues and frequencies of mutations
in CMT genes from large cohorts may help to develop strategies for efficient genetic
testing. Here, we present the clinical, electrophysiological and genetic features
of 31 patients from Turkey, diagnosed as genetically confirmed CMT‐2 in the Department
of Neurology, Istanbul Faculty of Medicine our clinic between 1990 and 2015. Genetic
testing was performed for GDAP1 by DNA sequencing and samples from 16 patients were
exome sequenced (WES). Twenty‐one male and ten female patients from 16 unrelated families
were investigated. Segregation was AR in eight, AD in six families and two were isolated
cases. Intra‐ and interfamilial variability in the age of onset with a range of 2–48
(mean 12.6 ± 9.8 years) and disease progression rate were striking. Slowly progressive
weakness and atrophy of distal muscles in the feet and/or hands were the most common
presenting symptoms. MFN2 was found in four unrelated AD kinship and in 2 unrelated
AR kinships and was most common gene mutated among whole cohort. GDAP1 was the most
commonly mutated gene among AR families (5/8). WES revealed further mutations in AARS,
NEFL, KIF1B and HSPB1, however, the causative mutation could not be identified in
known CMT2 genes in about 40% of patients. Our data indicates the marked intra‐ and
inter‐familiar phenotype variability in CMT‐2 as previously described in literature.
Many more genes causing ARCMT‐2 remain to be discovered.
PAIN AND ANXIETY WITH ELECTRODIAGNOSTIC PROCEDURES
Pasnoor M
1, Veerapaneni K1, Murphy R1, Statland JM1, Kimple D1, Hamasaki A1, Glenn MD1, Herbelin
L1, Barohn RJ1, Jawdat O1, Dimachkie MM1. 1
Department of Neurology, Neuromuscular Division, The University of Kansas Medical
Center, Kansas City, KS, USA.
Electrodiagnostic (EDX) studies involving electromyography/nerve conduction study
(EMG/NCS) are useful for diagnosis of neuromuscular disorders. Although these are
safe procedures, EMG and NCS often evoke anticipated pain and anxiety. There are no
published research studies to support the notion that providing detailed information
to patients prior to these procedures would reduce procedural pain and ameliorate
anxiety levels afterwards. The objective of this study was to perform a prospective
survey to assess anticipated pain and anxiety in patients presenting for EDX studies,
design a detailed patient education form, and assess the change in perceived pain
and anxiety pre and post procedure in the standard of care (SOC) education versus
the printed detailed education instrument group. After completing a brief pain/anxiety
questionnaire, patients were randomly assigned to either SOC verbal education group
or to read the detailed education form. Another brief questionnaire was completed
post procedure. Seventy‐eight patients were enrolled at the time of abstract submission,
41 in intervention and 37 in SOC groups. Mean age of patients enrolled was 58±15 years.
Pain was anticipated by 81% patients as a visual analog scale (VAS) score mean of
4.9±2.5 with no significant difference between both groups (p=0.86). Post‐procedural
pain was reported in 75% of patients with mean pain score of 5.3±2.2 and no significant
difference between the two groups (p=0.09). Anxiety pre‐procedure was reported by
35% patients with a mean Likert‐like score of 5.3±2.2 score in all cases (p=0.12 between
both groups). Post‐procedural anxiety frequency was reduced to 8% with mean level
of 4.5±2.6 (p=0.72 between both groups). Most patients reported pain with both EMG
and NCS (53%). We found that EDX testing evokes moderate pain in most and in some
cases moderate anxiety level. The detailed education intervention did not attenuate
the frequency or severity of pain. Post‐procedural anxiety was expectedly reduced
in severity and frequency in both groups with a suggestion that anxiety severity is
lesser in the detailed education group but numbers were small. Further studies with
more detailed questionnaire and perhaps web‐based education in larger population may
be useful to reduce pain/anxiety in patients presenting for EDX studies.
CIDP DIAGNOSTIC CRITERIA AND TREATMENT RESPONSE
Pasnoor M
1, Roach C1, Barohn RJ1, Statland J1, Jawdat O1, Dick A1, Glenn M1, Dimachkie MM1.
1
Department of Neurology, Neuromuscular Division, The University of Kansas Medical
Center, Kansas City, KS, USA.
Diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) have
been designed for use in clinical trials. There is limited data on the comparative
diagnostic utility of these criteria in the clinic setting and it is unknown if some
of these criteria are better for predicting treatment response. The objective of this
study is to compare the sensitivity of various diagnostic criteria and review treatment
response. After obtaining local IRB approval, we performed a retrospective chart review
of CIDP patients seen at the University of Kansas Medical Center between 2008 and
2014. We abstracted the clinical, electrodiagnostic, and treatment information. We
determined the frequency of patients fulfilling each of the following criteria: EFNS
2010, AAN, Saperstein and INCAT. We defined treatment response based on treating physician's
impression of change, patient–reported functional improvement or one point grade change
in the MRC grade. Fifty‐three CIDP patients charts were reviewed, 15 were excluded
due to missing data. Mean age was 51.5, and 16(42%) were female. Elevated CSF protein
was seen in 18/23(78%). Twenty‐eight (73%) fulfilled EFNS definite criteria, 5 (13.16%)
EFNS probable, 10 (26.3%) AAN, 20 (52.6%) INCAT, and 20 (52.6%) the Saperstein criteria.
Treatment response in patients who fulfilled EFNS definite/probable criteria included
20/22 to IVIG, 5/8 to IV or oral corticosteroids, 2/3 to mycophenolate mofetil; among
patients who fulfilled AAN criteria, these were respectively 8/9, 2/3 and 1/1; among
those meeting INCAT criteria 10/15, 5/7 and 1/2; and for Saperstein criteria it was12/17,
4/6 and 1/2. Half to two‐thirds of patients responded to PLEX based on different criteria.
While all CIDP criteria can similarly predict IVIG treatment response, the EFNS 2010
criteria are most sensitive for the clinical diagnosis of CIDP.
ROLE OF THE ALPHA SECRETASE TACE DURING WALLERIAN DEGENERATION
Pellegatta M
1, Canevazzi P1, Forese MG1, Podini P2, Quattrini A2, Taveggia C1.
1Division of Neuroscience and INSPE, Axo‐Glia Interaction Unit, San Raffaele Scientific
Institute, Milan, Italy; 2Division of Neuroscience and INSPE, Experimental Neuropathology
Unit, San Raffaele Scientific Institute, Milan, Italy.
Axonal NRG1 type III is an essential instructive signal for PNS myelination, since
its expression determines whether axons are myelinated and also the thickness of the
myelin sheath. Previous studies have shown that secretases' cleavage controls NRG1
type III activity at post‐transcriptional level. Specifically, the beta‐secretase
BACE‐1 cleavage of NRG1 type III promotes myelination, whereas the alpha‐secretase
TACE inhibits PNS myelination by inactivating NRG1 type III.
After a damage, the axon located distally to the site of injury degenerates and loses
the myelin sheath, following a process termed as Wallerian degeneration. Unlike the
CNS, axons in the PNS can regenerate and regrow. Several studies have shown that regeneration
is favored by the trans‐differentiation of Schwann cells, which start to create a
permissive environment for axonal regrowth. In addition, it has been shown that NRG1
regulates the early stages of the dedifferentiation process and is essential for creating
a permissive environment to regeneration. Similarly, the beta secretase Bace‐1 promotes
PNS regeneration and remyelination.
In the present study, we analyzed the role of the alpha‐secretase TACE during Wallerian
degeneration. Our data indicate that TACE is upregulated in sciatic nerves after injury,
distally to the site of damage. Since TACE is expressed in Schwann cells and axons,
we analyzed the role of both glial and neuronal TACE during degeneration and regeneration
processes. Thus, we performed crush injury in sciatic nerves of two different transgenic
lines carrying a conditional deletion of TACE either in Schwann cells (P0‐Cre//TACEflox/flox)
or in neurons (Chat‐Cre//TACEflox/flox). The analyses of the different phases of the
Wallerian degeneration in these animals suggest a role of glial TACE during the early
stage of the process. In fact, we observed an increased number of myelinated axons
only in P0‐Cre//TACEflox/flox mice, while we did not detect substantial differences
in mutant ChatCre//TACEflox/flox mice. These results suggest that even during regeneration
TACE has an inhibitory role, as deletion of TACE in Schwann cell likely induces the
activation of a neuro‐protective program that we are currently investigating.
ARL6IP1 CAUSES CONGENITAL INSENSITIVITY TO PAIN, SELF‐MUTILATION AND SPASTIC PARAPLEGIA
Péréon Y
1, Nizon M2, Küry S2, Besnard T2, Quinquis D2, Boisseau P2, Magot A1, Mussini JP1,
Mayrargue E3, Barbarot S4, Bézieau S2, Isidor B2.
1Reference Centre for Neuromuscular Disorders; 2Dept. of Genetics; 3Dept. of Paediatric
Surgery; 4Dept. of Dermatology, University Hospital, Nantes, France.
The hereditary sensory and autonomic neuropathies (HSAN) constitute a clinically and
genetically heterogeneous group. HSAN are associated with sensory dysfunction, altered
pain and temperature perception with varying degrees of autonomic dysfunction, and
abnormal small fibers neurodevelopment. More than ten genes have been described so
far in the HSAN group. Original classification encompassed four entities, but additional
subgroups continue to be described. Hereditary sensory neuropathies (HSAN) type II
are characterized by autosomal recessive inheritance, onset at birth and self‐mutilating
behavior. Until now, one homozygous frameshift variant, c.[577_580del], p.(Lys193Phefs*37),
was reported in ARL6IP1 (ADPrRibosylation‐like factor 6‐interacting protein 1) in
a consanguineous family. Patients presented with spastic paraplegia, diffuse sensory
and motor polyneuropathy and acromutilation. The disorder was classified as autosomal
recessive spastic paraplegia SPG61. Here, we described a new patient with congenital
insensitivity to pain, sensory neuropathy, self‐mutilation, and spastic paraplegia.
Whole exome sequencing showed a homozygous frameshift variant c.[577_580del], p.(Lys193Phefs*37)
in ARL6IP1. The protein harbours reticulon‐like short hairpin transmembrane domains
and has a role in endoplasmic reticulum shaping. The variant causes an additional
C‐terminus hydrophobic domain which could alter its function. Arl6ip1 interacts with
atlastin‐1 responsible for SPG3A and HSAN type 1D. This report highlights the role
of ARL6IP1 in pathophysiology of insensitivity to pain and spastic paraplegia.
SEQUENTIAL EDX TESTING IDENTIFIES DIFFERENTIAL SUSCEPTIBILITY OF THE MEDIAN NERVE
TO PROLONGED WRIST EXTENSION IN NORMAL SUBJECTS
Péréon Y
1, Nguyen A‐L1, Leclair‐Visonneau L1, Fayet G1, Nguyen J‐M2, Magot A1.
1Laboratoire d'Explorations Fonctionnelles, Hôtel‐Dieu, Nantes, France; 2Département
de Statistiques Médicales, Hôtel‐Dieu, Nantes, France.
Carpal tunnel syndrome (CTS) is responsible for sensory and/or motor symptoms that
may be increased by wrist flexion or extension (Phalen sign). Previous studies have
shown that short duration (e.g.5 min or less) flexion or extension was not responsible
for significant changes of median nerve conduction parameters. The objective is the
study was to determine how prolonged extension (reverse Phalen's test) affects median
and ulnar nerve conduction parameters in normal subjects. After providing informed
consent, 30 normal subjects (17 females, age rank 18–55 years) underwent motor and
sensory testing of both median and ulnar nerves from the dominant side. EDX testing
was performed using standard techniques with wrist in neutral position, then during
passive wrist extension (90°) for 30 minutes, with sequential recording of both motor
action potential (CMAP) and sensory action potential (SNAP) latencies and amplitudes
every 5 minutes after extension onset. Ulnar nerve conduction parameters remained
unchanged in all the subjects. Regarding median nerve, 4 groups of subjects could
be individualized: 12 subjects with no changes; 8 subjects with only significant decrease
of SNAP amplitude (−50%); 6 subjects with both SNAP amplitude and velocity decrease;
4 subjects with both CMAP and SNAP significant changes. When present, changes did
not appear before 10 min, with SNAP decrease being the earliest observed abnormality.
Prolonged wrist extension was responsible for median nerve EDX parameter modifications
in 18/30 normal subjects. Sensory fibers were firstly affected, corresponding to the
chronology clinically encountered in CTS. Based upon these results, the same protocol
will be used in patients presenting with mild clinical CTS, in order to try and identify
an additional EDX technique being useful in the diagnosis of CTS. One could also wonder
whether the subjects with the most important changes would be more prone to present
CTS in the future.
DETERMINING THE PATHOGENICITY OF NEWLY IDENTIFIED ATP7A VARIANTS USING PRIMARY FIBROBLASTS
Perez‐Siles G
1,2, Drew A1,2, Ellis M1, Kidambi M1, Takata R I4, Speck‐Martins C E4, Hagerman K
A5, Siskind C E5, Day J W5
, Ginzberg M6
, Nicholson G1,2,3, Kennerson M L1,2,3.
1Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, Australia; 2Sydney
Medical School, University of Sydney, Sydney, Australia; 3Molecular Medicine Laboratory,
Concord Repatriation General Hospital, Sydney, Australia; 4Sarah Network Rehabilitation
Hospitals, Brasilia, DF, Brazil; 5Department of Neurology, Stanford Health Care, Stanford,
CA, USA; 6Pediatric Neuromuscular Unit, Wolfson Medical Center, Holon, Israel.
Mutations in the ATP7A gene cause of X‐linked hereditary distal motor neuropathy (dHMNX).
To date, missense mutations (T994I and P1386S) in this copper transporting ATPase
are the only confirmed mutations causing dHMNX in two independent families. Next generation
sequencing (NGS), including whole exome and whole genome sequencing, is increasing
the rapid detection of variants in genes known to cause disease, however the absence
and size of additional families, make it challenging to determine the pathogenic or
benign status of variants identified. We have recently identified new variants in
ATP7A in patients with progressive peripheral neuropathy, suggesting further genetic
heterogeneity of dHMNX. Two of these new variants, pE840V and pM1311V, are located
at highly conserved amino acids within domains of ATP7A (A‐Domain and P‐Domain, respectively)
that are critical for the catalytic cycle of the copper transporter. We have also
identified a third variant (c.3802‐9A>G) located 9 bases upstream exon 19 that is
predicted to abolish a conserved branch‐site, a consensus intronic sequence necessary
for the processing of immature RNA during splicing.
Our recent investigations using both patient fibroblasts and an Atp7a conditional
knock in mouse model for dHMNX expressing Atp7aT985I, the orthologue of the human
ATP7A T994I mutation, showed reduced ATP7A protein levels and defective retrograde
trafficking of ATP7A, as pathological hallmarks of dHMNX ATP7A causative mutations.
To elucidate if the newly identified pE840V, pM1311V and c.3802‐9A>G ATP7A variants
are pathogenic, we have systematically assessed patient fibroblasts harbouring these
mutations for altered parameters previously found in the pathogenic T994I ATP7A mutation.
We predict that functional characterisation of ATP7A using patient fibroblasts harbouring
newly identified variants will provide the evidence to ascertain whether these variants
are disease causing. Establishing a systematic functional readout for ATP7A variants
will improve accuracy of genetic counselling and patient management of dHMNX in those
cases where genetic evidence is limited. This study represents a complementary and
necessary approach to the use of NGS, for validating the pathogenic status of variants
identified and for expanding the genetic heterogeneity of dHMNX.
MONTH OF BIRTH AS A RISK FACTOR FOR GUILLAIN‐BARRÉ SYNDROME
Peric S
1, Bjelica B1, Berisavac I1, Lukic S2, Babic M3, Jovanovic D1, Dominovic A4, Cvijanovic
M2, Rakocevic Stojanovic V1, Lavrnic D1, Basta I1.
1Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade,
Belgrade, Serbia; 2Neurology Clinic, Clinical Center Novi Sad, Novi Sad, Serbia; 3Neurology
Clinic, Clinical Center Banjaluka, Banaluka, Republic of Srpska, Bosnia and Herzegovina.
Month of birth (MOB) have been defined as a risk factor for more than 50 diseases.
For instance, susceptibility for multiple sclerosis (MS) seems to be associated with
being born in May, while lower risk of MS is observed in those born in November. There
are no studies that assessed potential association between MoB and a risk for Guillain‐Barré
syndrome (GBS). We sought to determine if the risk of GBS is associated with the MoB.
Study included 446 GBS patients diagnosed in Serbia, Montenegro and Republic of Srpska
in the period from January 1, 2009 until December 31, 2015. MOB of patients and of
general population were compared. Patients with GBS had tendency to be born in October
(27% increase compared to general population, p=0.07) and were less likely to be born
in June (28% decrease, p=0.05). When consider specific seasons, GBS patients were
more likely to be born in winter months (16% increase, p<0.05). No associations were
found between month/season of birth and disease severity. Results of this pilot study
showed that GBS patients are more likely to be born in cold months, and less likely
to be born in June. This might be explained by higher exposure to different pathogens
during pregnancy in cold months. In accordance with this, it is well known that early
exposure to infective agents reduces risk of allergic and autoimmune diseases. Further
studies are needed to test our findings in different cohorts and in regions with different
climate. These results may shed new light on the disease pathogenesis.
GUILLAIN‐BARRÉ SYNDROME – ACUTE DISEASE WITH CHRONIC CONSEQUENCES
Peric S
1, Bozovic I1, Martic V2, Komatina N2, Djuric V3, Petrovic M4, Vujovic B5, Cukic M5,
Djordjevic G3, Stevic Z1, Basta I1.
1Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade,
Belgrade, Serbia; 2Military Medical Academy, Belgrade, Serbia; 3Neurology Clinic,
Clinical Center Nis, Nis, Serbia; 4Neurology Clinic, Clinical Center Kragujevac, Kragujevac,
Serbia; 5Neurology Clinic, Clinical Center of Montenegro, Podgorica, Montenegro.
Majority of patients with Guillain‐Barré syndrome (GBS) tend to have a successful
recovery, but in number of them significant long‐term consequences may negatively
affect their quality of life. Aim of this research was to analyze the outcome of the
disease one year after the acute episode of GBS. Among 82 patients diagnosed with
GBS in seven tertiary centers in Serbia, Montenegro and Republic of Srpska during
2014, 57 subjects were retested after one year (62% males, mean age 57±16 years).
Functional disability of patients was estimated based on the GBS Disability Scale
(GDS). Severe form of the disease (GDS score 4–6) was registered in 50% of patients
at admission, 73% at nadir, and 24% on discharge. After one year follow‐up period,
14% of patients had no symptoms of GBS, 42% had mild symptoms, 24% was able to walk
but not to run, 8% needed unilateral support during walking, while 3% was wheelchair
bound or bedridden. Lethal outcome was registered in three patients during acute phase
of GBS and in four more during one‐year follow‐up. Paresthesias were present in 60%
of GBS patients, musculoskeletal pain in 40%, and fatigue in 21% one year after acute
phase of the disease. Factors associated with the worse functional outcome (GDS grade
above 1) after one year were: age above 70, preceding respiratory infection, and worse
GDS on discharge. One year after the onset of the disease, significant number of our
GBS patients had neurological impairments including sensory symptoms, pain, fatigue
and muscle weakness which may significantly affect patients' everyday functioning.
HOMOZYGOUS DUPLICATION OF PMP22: A CASE REPORT
Phetteplace JE
1, Saade D1, Bacon C1, Shy ME
1. 1University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
Charcot‐Marie‐Tooth (CMT) disease, also known as hereditary motor and sensory neuropathy,
is a heritable peripheral neuropathy caused by genetic mutations in many different
genes. CMT type 1A is the most common form of CMT. Individuals affected with CMT1A
commonly have distal muscle atrophy, foot deformities, abnormal gait, and reduced
nerve conduction velocities caused by demyelination of the peripheral nerves. CMT1A
is known to be caused by a duplication of the PMP22 gene at 17p11.2. The proposed
disease mechanism of CMT1A is believed to be increased gene dosage of the PMP22 gene,
although the exact function of PMP22 is not known. There have been previous reports
in the literature of individuals who carry a homozygous duplication of PMP22, therefore
having four copies of the gene. However, many of these reports have focused on adult
patients who symptoms may not vary significantly from individuals who harbor only
a duplication of PMP22. A 23 month old male presented to the University of Iowa Hospital
due to a family history of CMT1A and concern for delay in independent ambulation.
He was known to have both a maternal and paternal family history of CMT1A, although
the families were believed to be unrelated. On exam he was unable to walk independently,
but could take a few steps when his hands were held. Per report he began crawling
and scooting at 18 months of age. He was not found to have any structural abnormalities
or atrophy in his upper or lower extremities. Electrodiagnostic testing revealed a
demyelinating neuropathy. Only one nerve was tested, as the patient was unable to
tolerate additional shocks. The peroneal nerve was found to have a nerve conduction
velocity of 7 m/s. Based on the clinical presentation, electrodiagnostic examination
and family history deletion and duplication testing for PMP22 was performed. This
testing revealed a homozygous duplication of PMP22, which has been previously reported
to cause CMT1A. This case supports the gene dosage disease mechanism, as our patient
appears to be more severely affected than a typical infant or toddler affected with
CMT1A.
CMT1B AND SENSORY ABNORMALITIES ASSOCIATED WITH A MPZ NULL MUTATION
Piscosquito G
1, Saveri P2, Provitera V1, Stancanelli A1, Ciano C3, Magri S4, Taroni F4, Fabrizi
GM5 Nolano M5, Pareyson D2.
1Neurorehabilitation Unit, “Maugeri” Scientific Clinical Institutes, Scientific Institute
of Telese Terme (BN), Italy; 2Unit of Rare Neurological Diseases of Adulthood, Department
of Clinical Neurosciences, IRCCS Foundation, “C. Besta” Neurological Institute, Milan,
Italy; 3Neurophysiopathology and Epilepsy Centre, Department of Diagnostics and Applied
Technology, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; 4Unit
of Genetics of Neurodegenerative and Metabolic Disease, Department of Diagnostic and
Applied Technology, IRCCS Foundation, “C. Besta” Neurological Institute, Milan, Italy;
5Section of Neuropathology, Department of Neurological and Movement Sciences, University
of Verona, Verona, Italy.
MPZ mutations are associated with the demyelinating early‐onset Charcot‐Marie‐Tooth
(CMT) type 1B and with the axonal later onset CMT2I/CMT2J. Paresthesias/dysesthesias
and pain have been already reported in some CMT types and also in CMT2I/J. We report
16 patients (13 from 5 families, 3 sporadic cases,) carrying the MPZ c.306delA mutation
(p.Asp104ThrfsTer14). This is predicted to be a loss‐of‐function mutation, leading
to P0 haploinsufficiency. Most of the subjects have genetic ancestry from Puglia region
(Southern Italy). Two patients carried the mutation in homozygosity, showing a severe
phenotype: onset at birth, severe scoliosis, proximal weakness, distal limb plegia,
no autonomous walking, CMT Examination Score (CMTES) 23‐25/28. All the other heterozygous
patients had mild adult‐onset (mean age 33, range 20–56) neuropathy, walked without
aids or ankle‐foot orthoses, had CMTES <4/28. Five showed mild foot deformities, 5/16
had foot and 7/16 hand weakness (MRC never less than 3/5), 10/16 sensory loss in lower
limbs (LL). Paresthesias/dysesthesias (mostly tingling and burning in type) localized
in hands and LL were reported by 15/16 subjects, neuropathic pain by 10/16. In the
homozygous patients, all CMAPs and SAPs were absent. In all other subjects, motor
conduction velocities (CV) were >31 m/s (range 31–50 m/s) and sensory CV >29 m/s (range
29–62 m/s). CMAPs as well as SAPs were normal or moderately reduced in amplitude,
indicating only slight axonal loss. We confirm that heterozygosity is associated with
very mild CMT, whereas homozygosity causes a very severe neuropathy. Our data suggest
that paresthesias and neuropathic pain are very common and should be considered as
part of the phenotype. Although the clinical picture suggests a small fiber neuropathy,
no such evidence is provided in the current literature. In the attempt to further
investigate this field, we found in a 37‐year‐old male patient of our series that
all thresholds were increased at quantitative sensory testing, and several abnormalities
of small nerve fibers were present in skin biopsy. Apparently, P0 aneuplody causes
neuropathy and small fiber involvement through a mechanism different from other MPZ
missense mutations.
A NOVEL PROTEIN, MAJOR URINARY PROTEIN (MUP) CONTRIBUTES TO THE BEHAVIOUR OF DIABETIC
AND NONDIABETIC SENSORY NEURONS
Poitras T
1, Chandrasekhar A1, Singh V1, Martinez J1, Zochodne DW1.
1Neuroscience Mental Health Institute, and Division of Neurology, Department of Medicine,
University of Alberta, Edmonton, Alberta, Canada.
A microarray mRNA analysis of dorsal root ganglia examined in long‐term diabetic mice
yielded an unexpected upregulation of a unique set of proteins known as Major Urinary
Proteins (MUPs 1&2). Originally, this family of barrel shaped proteins was described
as including mediators of pheromone secretion in the urine of rodents, apparently
unconnected to other functions. We identified its unanticipated expression in sensory
neurons of adult mice and rats and explored its potential impact on the properties
of these neurons. Analysis of rat and mouse sensory neurons showed widespread and
pan‐neuronal cytosolic MUP expression, not only in the cell body, but also in distal
sensory projections located in the dermis of the footpad. To assess the role that
MUP might offer in the growth behaviour of adult neurons, we examined siRNA‐induced
knockdown of MUP on pre‐injured dissociated DRG primary cultures. MUP knockdown in
both species showed a significant increase in neurite outgrowth following MUP siRNA
treatment when compared to a scrambled sequence control. Mice treated with streptozotocin
(STZ) model features of human type 1 diabetic polyneuropathy, including decreases
in multi‐fiber motor and sensory measurements, and changes in thermal sensation in
the extremities. To explore the potential role of MUP upregulation specifically in
diabetes, we examined the impact of non‐viral intranasal injection of MUP siRNA on
indices of neuropathy in chronic type 1 diabetic mice. Following treatment, mice treated
with MUP siRNA showed improvement in both motor and sensory nerve conduction velocities
compared to scrambled controls. Taken together, this data suggests that MUP plays
a growth‐suppressive role in both diabetic and non‐diabetic neurons and may also contribute
to the electrophysiological and behavioral abnormalities associated with diabetic
polyneuropathy. The repurposing of MUPs in sensory neurons identifies an interesting
role for a supposed pheromone protein. [Supported by CIHR, CDA and ADI]
TRPV1 ACTIVATION BY CAPSAICIN ENHANCES THE REGENERATION OF SENSORY NEURONS
Poitras T
1, Chandrasekhar A1, McCoy L1, Webber C1, Zochodne DW1
. 1Institute of Neuroscience, Mental Health and Addiction, Division of Neurology,
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Activation of small caliber TRPV1 ion channels is associated with intense sensory
activation, whereas overactivation induces neurotoxicity. Subtoxic activation of calcium
influx into electrically activated neurons is associated with enhancement of their
outgrowth properties (Singh et al, 2015). Here we asked whether similar activation,
using low dose capsaicin, might similarly ramp up the regenerative activity of sensory
neurons. Using rat adult primary sensory neurons, we identified a dose dependent relationship
between capsaicin exposure and their outgrowth with enhancement at lower doses and
expected neurotoxicity at higher doses. Doses that enhanced outgrowth were nonetheless
associated with rises in intraneuronal calcium. We next tested whether a similar impact
of TRPV1 activation in vivo might exist. We used a high sciatic crush injury mouse
model to assess the impact of capsaicin at low (100uM) or high (1mM) doses applied
directly at the site of axon outgrowth after injury. By 28 days following the single
application of capsaicin, low doses of capsaicin showed more rapid recovery of thermal,
but not mechanical sensation, whereas high dose capsaicin showed no significant difference
compared to vehicle treated mice. In parallel with the neurotoxicity observed in vitro,
the high dose capsaicin resulted in a decrease in sensory nerve conduction velocity,
while the low dose showed no significant difference when compared to the vehicle treated
animals. There was no impact on motor axon recovery. Taken together, subtoxic TRPV1
activation with intraneuronal calcium mobilization, as applied to regenerating sensory
axons, enhances their outgrowth after injury, and improves behavioural recovery similar
to that following extracellular electrical stimulation. [Supported by CIHR]
EFFECT OF PATISIRAN ON NERVE FIBER DENSITY AND AMYLOID CONTENT IN SKIN: RESULTS FROM
PHASE 2 OPEN LABEL EXTENSION (OLE) STUDY IN hATTR AMYLOIDOSIS
Polydefkis M
1, Ebenezer G1, Adams D2, Coelho T3, Conceicao I4, Waddington Cruz M5, Schmidt H6,
Buades J7, Campistol J8, Pouget J9, Berk J10, Partisano A11, Chen J11, Gollob J11,
Suhr O12.
1Johns Hopkins University, Baltimore, USA; 2National Reference Center for FAP (NNERF)/
APHP/ INSERM U 1195/ CHU Bicêtre, France; 3Hospital de Santo António, Centro Hospitalar
do Porto, Porto, Portugal; 4Hospital de Santa Maria, Lisbon, Portugal; 5Hospital Universitário,
Federal University of Rio de Janeiro; Rio de Janeiro, Brazil; 6University Hospital
Münster, Munster, Germany; 7Hospital Son Llatzer, Palma, Spain; 8Hospital Clinic,
University of Barcelona, Barcelona, Spain; 9Hôpital de La Timone, Marseille, France;
10Boston University, Boston, USA; 11Alnylam Pharmaceuticals, Cambridge, USA; 12Umeå
University, Umeå, Sweden.
Hereditary transthyretin (hATTR) amyloidosis is a rapidly progressive, life‐threatening
disease caused by TTR gene variants, resulting in TTR misfolding and amyloid deposition
in multiple organs, including peripheral nerves. hATTR amyloid polyneuropathy has
prominent small fiber involvement characterized by neuropathic pain and dysautonomia.
Measurement of intraepidermal and sweat gland nerve fiber density (IENFD, SGNFD) in
skin biopsies has been useful in identifying small fiber abnormalities in hATTR. We
report the effect of patisiran, an investigational RNAi therapeutic for the treatment
of hATTR, over a 24‐month period on IENFD, SGNFD and dermal amyloid content from the
Phase 2 open‐label extension (OLE) study. Skin biopsies (distal leg, distal thigh)
were obtained every 6 months for up to 2 years within the Phase 2 OLE study (patisiran
0.3mg/kg IV, q3W, NCT01961921) and analyzed in a blinded manner by a central laboratory.
All analyses are exploratory; nominal p‐values are reported without adjustment for
multiple testing. Twenty‐seven patients enrolled; preliminary data indicated patisiran
was generally well tolerated; resulted in sustained mean serum TTR lowering of ∼80%
for >24months and a mean 6.7‐point decrease in mNIS+7 (n=24). Twenty‐four patients
underwent serial skin punch biopsies. At baseline, mean IENFD was 10.2 and 3.5 fibers/mm,
while mean SGNFD was 6.8 and 3.8 m/mm3 for distal thigh and distal leg, respectively.
Amyloid was detected in ∼80% of skin biopsies, mean baseline dermal amyloid content
10.9% and 15.8% for distal thigh and distal leg, respectively, which inversely correlated
with IENFD and SGNFD. Overall, IENFD was stable throughout the 2‐year treatment. SGNFD
increased over time relative to baseline, reaching statistical significance at 6,
12, 18 and 24 months for distal thigh (p<0.05, all time points) and at 24 months for
distal leg (p=0.004). Dermal amyloid content decreased over time and reached statistical
significance at 6, 18 and 24 months for distal thigh (p<0.05, all time points) and
at 6, 12, 18, and 24 months for distal leg (p<0.05, all time points). In summary,
improvements in SGNFD and dermal amyloid content observed over a 2‐year period suggest
that these parameters have the potential to serve as biomarkers of response to patisiran
treatment.
DIAGNOSTIC CHALLENGES IN AMYLOID NEUROPATHIES
Polydefkis M
1, Neuhaus S1, Doherty L1, Ebenezer GJ1
. 1Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Misdiagnosis and delayed identification of an etiology for sensory neuropathies hampers
adequate management and delays initiation of therapy. We present several cases that
illustrate variable presentations of amyloid neuropathy (AN) and AN complicated by
amyloid arthropathy.
A 59‐year‐old former college athlete developed painless difficulty walking. He was
unable to keep up with family members during routine outings and subsequently was
unable to navigate uneven ground during a hike, something he had previously excelled
at. Balance decreased, making bicycling difficult. Neurological evaluation 12‐months
after symptom onset led to a diagnosis of peripheral neuropathy. A reversible neuropathy
panel was normal though A1C was elevated (6.5%). Over several months, his strength/sensation
deteriorated despite diet improvement, losing 20lbs and A1C improvement (5.9%). Upon
referral, EMG revealed a sensorimotor neuropathy with markedly reduced/absent sural,
peroneal and tibial motor amplitudes. There was mild orthostasis. NIS was 84.
Skin biopsies revealed severe IENFD, SGNFD reductions and positive Congo red staining,
confirmed with birefringence. A sural nerve biopsy confirmed amyloid deposits. Genetic
testing revealed the TTR‐FAP variant Leu58His. There was no history or suspicion for
a family history of amyloid.
A 60‐year‐old male with a history of controlled diabetes x20 years developed abrupt
onset of RLS 6 months after a lymphoma diagnosis. Treatment with rituximab led to
radiographic resolution of the lymphoma though the patient developed progressive peripheral
neuropathy confirmed by NCV/EMG. New‐onset early satiety, mild orthostasis and ED
emerged. Skin biopsies demonstrated a lichenoid pattern of amyloid deposition consistent
with AA‐amyloid.
A 72‐year old woman with Leu58His TTR‐FAP since 2002 developed progressive leg weakness,
reduced ability to walk and low back pain. EMG demonstrated progression of her sensorimotor
neuropathy and superimposed multilevel radiculopathy. Spine MRI demonstrated severe
lumbar stenosis requiring surgical decompression. Postoperatively, she regained strength,
walking more easily. Congo red staining of vertebral bone demonstrated widespread
positive staining with birefringence consistent with amyloid arthropathy.
These cases illustrate to wide sprectrum of amyloid neuropathy presentation, an example
of amyloid arthropathy‐induced spinal stenosis and the utility of skin biopsy to diagnose
and manage amyloid neuropathy.
HEREDITARY OR INFLAMMATORY CHILDHOOD NEUROPATHY – ELECTROPHYSIOLOGICAL ABNORMALITIES
HELPFUL IN THE DIFFERENTIATION
Potulska‐Chromik A
1, Lukawska M1, Kochanski A2, Kabzinska D2, Gawel M1, Seroka A1, Kostera‐Pruszczyk
A1.
1Department of Neurology, Medical University of Warsaw, Warsaw, Poland; 2Neuromuscular
Unit, Mossakowski Medical Research Centre; Polish Academy of Sciences, Warsaw, Poland.
The differentiation between hereditary neuropathy and chronic inflammatory demyelinating
polyneuropathy (CIDP) in children is especially significant because of completely
different treatment possibilities and prognosis in these conditions. The aim of the
study was to compare electrophysiological abnormalities in a group of children and
young adults with demyelinating neuropathy of chronic or subacute onset.
Retrospective analysis of clinical and nerve conduction study (NCS) data included
3 children and 4 young adults with Charcot‐Marie‐Tooth Neuropathy X type 1 (CMTX1),
24 children with Charcot‐Marie‐Tooth Neuropathy type 1a (CMT1a) and 18 children with
CIDP.
In our study 6/7 CMTX1 had both axonal and demyelinating changes in NCS study.
The AAN and EFNS electrophysiological CIDP criteria were fulfilled in 2/7 CMTX1, 23/24
CMT1a and 17/18 CIDP patients. Additionally 3 patients with CMTX1 are classified with
EFNS criteria as “probable/possible CIDP”.
A distal compound muscle action potential (dCMAP) was >9ms in all CMT1a and 14/18
CIDP patients but none with CMTX1. Abnormal median/normal sural SNAP (AMNS) parameter
was observed in 4//18 CIDP and 1/7 CTMX1 patients but not any CMT1a patient while
abnormal sural/normal median SNAP (ASNM) parameter was found in 2/18 patients with
CIDP. A difference between conduction velocities (CV) of two corresponding nerves
>10 m/s was seen in 4/7 CMTX1 and 5/18 CIDP patients but no one with CTM1a.
One patient with CMTX1 had especially conspicuous difference between nerve conduction
in lower limbs, with axonal neuropathy and demyelinating features, and upper limbs
with no changes. One 3‐years‐old patient with genetically confirmed CMTX1 had no abnormalities
in NCS.
Electrophysiological data of CMTX1, CMT1a and CIDP indicate diffuse demyelination,
however in CMTX1 axonal changes coexist, seen in 6/7 patients, and asymmetrical abnormalities
between corresponding upper and lower limb were observed in 4/7 patients.
Our study has showed that duration of dCMAP is useful not only in diagnosing an inflammatory
neuropathy but also in differentiating CMTx from CIDP. However presence of the not
homogenous abnormalities in NCS in patients with CMTx may mimic inflammatory neuropathy.
TESTING OVERWORK WEAKNESS IN CHARCOT‐MARIE‐TOOTH (CMT) DISEASE: IS IT TRUE OR FALSE?
Prada V
1, Mori L1, Francini L1, Accogli S1, Ursino G1, Gemelli C1, Schizzi S1, Grandis M1,
Bellone E1, Mandich P1, Schenone A1
. 1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal
and Child Health, University of Genoa, Genoa, Italy.
The overwork weakness (OW) problem in CMT disease has been debated for long time.
It has been reported that the non‐dominant hand (NDH) of patients with CMT disease
is stronger than the dominant hand (DH) as a result of OW and some authors verified
this hypothesis using MRC on different muscles (Van Pomeren, 2009). More recently,
Piscosquito et al. (2014) found that the OW phenomenon does not exist using a dynamometer
and the 9 hole peg test, a dexterity test.
We recruited 60 CMT patients and 60 healthy controls. We evaluated the strength of
the 3‐pinch and of the hand‐grip with a dynamometer, the opposition ability with the
Thumb Opposition Test (TOT) and applied an instrumental testing of hand function using
the Sensor Engineered Glove Test (SEGT), which previously demonstrated its sensitiveness
to measure severity of hands dysfunction in CMT patients.
TOT was significantly higher in the NDH compared to DH (NDH=8,23±1,60; DH=7,74±1,90,
p<0.05) in CMT patients, instead there was no difference in DH and NDH in healthy
controls. In the evaluation of 3‐pinch and of the hand‐grip, NDH performed slightly
but not significantly better than the DH (3‐pinch: DH=53,25±29,05 N; NDH=54,75±29,76
N; hand‐grip: DH=57,81±31,11 N; NDH=62,36±32,20 N, p:ns). In normal controls we confirmed
the 10% rule (Noguchi & Demura, 2009). Finally, SEGT results were similar between
the NDH and DH in CMT patients but in normal controls there was a better performance
in the DH.
In conclusion, this study supports the existence of the overwork weakness in CMT,
evident in every measurements. Dexterity and overall ability of the hands impaired
in the DH, probably because of compensating movements, compared with the healthy controls
in the weaker hand. Finally, our results support the importance of avoiding supramaximal
exercises and educating the CMT patients to prevent incorrect movements, which may
overload the hand muscles.
FLAVIVIRUS ASSOCIATED GUILLAIN‐BARRÉ SYNDROME IN SINGAPORE
Prasad K
1, Ohnmar O2, Teng A3, Cheng YJ3, Umapathi T1.
1National Neuroscience Institute, Singapore; 2Yangon General Hospital, Yangon, Myanmar;
3Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Antecedent infections that have been linked to Guillain‐Barré syndrome (GBS) include
Campylobacter jejuni, Haemophilus influenza, Epstein‐Barr virus, Cytomegalovirus,
Mycoplasma pneumoniae and Influenza A virus. In South‐ East Asia, the burden of mosquito‐borne
flavivirus infections is considerable. Even in a small country like Singapore, with
a population of only 5.5 million and in spite of excellent sanitation and public health
measures, dengue virus (DENV) infections can exceed 20,000 a year. Both symptomatic
and asymptomatic DENV infections are associated with GBS. Zika Virus (ZIKV) infections
were detected in Singapore in late August 2016. Doctors working in South‐East Asia
anecdotally report that GBS cases increase after rainy season when mosquitos breed.
We are currently planning studies to estimate the hitherto unknown burden of GBS associated
with DENV, ZIKV and other mosquito‐borne viruses in this region. As a preliminary
step, we reviewed the 27 GBS cases seen at our institution in 2016 for evidence of
DENV and ZIKV. Three out of the 20 tested cases were positive for DENV serology. One
of these 3 was also positive for DENV PCR. All these 3 patients had symptomatic dengue.
Two had acute inflammatory demyelinating polyneuropathy (AIDP) and 1 acute motor axonal
neuropathy (AMAN) subtype of GBS. None the 16 patients tested were positive for ZIKV
PCR in serum and urine. One patient, with Miller Fisher syndrome (MFS), had serological
evidence of recent ZIKV. He did not have clinical ZIKV symptoms. In 2 MFS cases, the
initial detectable ZIKV IgG was later proven to be due to cross reactivity with previous
DENV infection. In 3 cases (1 AMSAN, 1AIDP, 1 MFS) the initial ZIKV IgM was raised.
We await analysis of convalescent sera to decide if they indeed had ZIKV or the results
were related to previous and co‐infection with DENV. Our preliminary findings indicate
that flavivirus infections may account for at least some of the GBS cases in Singapore.
The lack of symptoms in some cases and the interactions between ZIKV and DENV antibodies
make accurate diagnoses challenging.
INVESTIGATION OF SELECTIVE HISTONE DEACETYLASE 6 INHIBITORS AS A TREATMENT FOR CHARCOT‐MARIE‐TOOTH
DISEASE TYPE 1A USING A CO‐CULTURE SYSTEM
Prior R
1,2, Benoy V1,2, Vanden Berghe P3, Van Den Bosch L1,2.
1KU Leuven–University of Leuven, Department of Neurosciences, Experimental Neurology
and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium;
2VIB–Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium;
3Laboratory for Enteric Neuroscience, Translational Research Center for Gastrointestinal
Disorders, K.U. Leuven, Leuven, Belgium.
Charcot‐Marie‐Tooth disease (CMT) is the most common inherited neurodegenerative disorder
of the peripheral nervous system. It is divided into two main subtypes, a demyelinating
subtype (CMT type 1) and an axonal form (CMT type 2). CMT is a length‐dependent disease,
in that it effects the longest neurons in the body, thus the muscles in the peripheral
regions are affected first and foremost. Moreover, the majority of CMT patients share
a classical phenotype with shared pathological hallmarks, such as distal muscular
atrophy, reduction in nerve conductions, etc. but also molecular pathological hallmarks,
like the breakdown in the transport of organelles and vesicles in neurons in a process
called axonal transport.
Currently, there is no cure or effective treatment available to CMT patients. Histone
deacetylase 6 (HDAC6) has been shown to be a key regulator in axonal transport. Moreover,
inhibiting HDAC6 has been demonstrated to stabilize microtubules, which act as molecular
tracks for motor proteins and facilitates axonal transport of cargos.
Our labs current focus is on CMT type 1A, the main cause of CMT, which is caused by
a duplication of a segment of chromosome 17p11.2 containing the gene encoding peripheral
myelin protein 22 (PMP22). PMP22 is mainly expressed by Schwann cells, the cells that
myelinate neurons in the peripheral nervous system.
In the work presented, the commercial mouse Schwann cell‐line, SW10 cells, was transfected
to overexpress PMP22 using a lentivirus vector system to mimic that of CMT1A patient
Schwann cells. The overexpression of PMP22 was confirmed using immunofluorescence
and western blot techniques. These transfected SW10 Schwann cells were then co‐cultured
with primary mouse dorsal root ganglion neurons (DRGs) isolated from adult mice. These
co‐cultures where then analysed after 3 weeks in vitro for axonal transport. The investigated
groups were: a co‐culture of DRGs + SW10 cells, a co‐culture of DRGs + SW10 cells
transfected with PMP22, and a co‐culture of DRGs + a SW10 cell‐line transfected with
Green Fluorescent Protein using a lentivirus vector system, and a monoculture of DRGs.
Furthermore, this work demonstrates that the overexpression of PMP22 in Schwann cells
can impair axonal transport in co‐cultured DRGs in comparison to the other co‐culture
groups. Moreover, these axonal transport defects were able to be rescued by the treatment
of a HDAC6 inhibitor, Tubstatin A.
To conclude, selective HDAC6 inhibitors have been shown to be a beneficial treatment
for a number of CMT subtypes in preclinical studies in our lab and offer as a viable
treatment for a currently, untreatable debilitating disease.
CARPAL TUNNEL SYNDROME AS A HUMAN IN VIVO MODEL TO STUDY LARGE FIBER REGENERATION
Provitera V
1, Caporaso G1, Stancanelli A1, Piscosquito G1, Di Caprio G1, Saltalamacchia AM1,
Santoro L2, Nolano M1.
1“Maugeri” Clinical and Scientific Institutes IRCCS, Institute of Telese Terme (BN),
Italy; 2Department of Neurosciences, Reproductive and Odontostomatological Sciences,
University 'Federico II' of Naples, Naples, Italy.
The observation of rate and patterns of cutaneous nerves regrowth after mechanical
or pharmacological distal axonotmesis, has proven to be an excellent tool to study
human nerve regeneration in normal and pathological conditions. Most of the observations,
however, are referred to small fibers, possibly due to the availability of excellent
models of reversible distal cutaneous small fiber axonopathy. No such model is available
to study the regeneration of myelinated fibers in human. We studied regrowth of cutaneous
large fibers in fingertip of patients with carpal tunnel syndrome after surgical decompression.
We recruited 15 patients (M/F 4/11; age 46.9±8.8 years) with carpal tunnel syndrome
candidate to surgery. Patients underwent clinical and electrophysiological evaluation,
quantitative evaluation of discriminative threshold at 3rd fingertip. In the same
site, patients also underwent 2mm punch skin biopsy. Skin sections were stained by
immunohistochemical techniques and cutaneous innervation was analyzed by confocal
microscopy. Meissner corpuscles and their myelinated afferences were assessed following
previously published procedures. Twelve months after surgery, patients repeated functional
evaluation and underwent a second skin biopsy two mm apart from the first one. Mean
density of MCs/mm2 was 31.5±18.8 at time 0 and 34.2±17.7 at follow‐up, mean density
of myelinated endings was 24.4±14.0 at time 0 and 30.8±18.9 at follow‐up. However,
not in all patients regeneration occurred. Based on the variation of MC density between
time 0 and follow‐up we were able to identify patients in which active regeneration
had occurred. In this subgroup mean density of MCs/mm2 was 23.1±16.6 at time 0 and
36.6±18.7 at follow‐up (p<0.01) with a mean delta of +13.5. In the same group, mean
density of myelinated endings was 18.6±13.4 at time 0 and 29.9±20.1 at follow‐up (p<0.01)
with a mean delta of +11.3. We describe morphological patterns associated to nerve
regrowth in the biopsies of patients in which nerve regeneration occurs. We propose
an in vivo model to study regeneration of large myelinated fiber endings in human
skin. In addition to the count of nerve endings, the identification of patterns associated
to nerve regeneration can increase the diagnostic yield of skin biopsy.
THE COMBINATIONAL DRUG PXT3003 IMPROVES NEUROMUSCULAR FUNCTION IN AN ANIMAL MODEL
OF CHARCOT‐MARIE‐TOOTH TYPE 1A DISEASE
Prukop T
1,2,4, Wernick S1, Adam J1, Zschüntzsch J5, Schmidt J5, Brureau A3, Foucquier J3,
Guedj M3, Cholet N3, Nave KA1, Nabirotchkin S3, Hajj R3, Cohen D3, Sereda MW1,4.
1Department of Neurogenetics, Max‐Planck‐Institute of Experimental Medicine, Göttingen,
Germany; 2Institute of Clinical Pharmacology, University Medical Center Göttingen,
Göttingen, Germany; 3Pharnext, Issy‐Les‐Moulineaux, France; 4Department of Clinical
Neurophysiology, University Medical Center Göttingen, Göttingen, Germany; 5Department
of Neurology, University Medical Center Göttingen, Göttingen, Germany.
The most common type of Charcot‐Marie‐Tooth disease is caused by a duplication of
PMP22, leading to dysmyelination, axonal loss and progressive muscle weakness (CMT1A).
Currently, no approved treatment for CMT1A patients is available. Among others, preclinical
therapeutic approaches aim to correct the Pmp22 overexpression in order to ameliorate
axonal loss and muscle weakness. We previously reported that the novel polytherapeutic
drug PXT3003, a low‐dose combination of baclofen, naltrexone and sorbitol, improved
dysmyelination and axonal loss after long‐term application in adult Pmp22 transgenic
rats, a known animal model of CMT1A. Interestingly, after short‐term application in
young CMT1A rats we observed a long‐lasting prevention of muscle weakness as well
but without obvious effects on dysmyelination and axonal loss. Improved distal motor
latencies in the electrophysiological recordings and a shift in the axonal diameter
distribution raised the hypothesis that therapy may improve the neuromuscular endplate
pathology as another therapeutic target for CMT1A. Here, we report a preclinical trial
in adult CMT1A rats treated from postnatal week 6 for 12 consecutive weeks as the
most effective regimen in order to facilitate a deeper understanding of the mode‐of‐action
of PXT3003. Long‐term therapy effects were confirmed by an ameliorated behavioral
phenotype, improved distal motor latencies and also nerve conduction velocity in the
electrophysiological recordings. Histological analysis revealed an increased number
of neuromuscular endplates, which were lowered to wildtype level after PXT3003 treatment.
Further investigations include detailed analysis of peripheral nerve myelin thickness,
internodal and nodal length, terminal axonal sprouting at the neuromuscular endplate
and muscle fiber subtyping in treated CMT1A rats.
THE GERMAN CHARCOT‐MARIE‐TOOTH DISEASE NETWORK (CMT‐NET): DISEASE SEVERITY AND PROGNOSTIC
BIOMARKERS FROM BLOOD AND SKIN OF CMT1A PATIENTS
Prukop T
1,2,3, Garcia‐Angarita N4, König LS4, Pieper D5, Dräger B5, Thiele S4, Hüttemann D5,
Schlotter‐Weigel B4, Walter MC4, Young P5, Sereda MW1,3.
1Department of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen,
Germany; 2Institute of Clinical Pharmacology, University Medical Center Göttingen,
Göttingen, Germany; 3Department of Neurogenetics, Max‐Planck‐Institute of Experimental
Medicine, Göttingen, Germany; 4Department of Neurology, Friedrich‐Baur‐Institute,
Ludwig‐Maximilians‐Universität, Munich, Germany; 5Department of Sleep Medicine and
Neuromuscular Disorders, University of Münster, Münster, Germany.
Charcot‐Marie‐Tooth disease (CMT) is a rare hereditary neuropathy for which novel
treatments are being developed and urgently needed. Only few clinical trials and natural
history studies have been performed. Evaluation of intervention efficacy is hampered
by slow progression and lack of sensitive outcome measures. The interindividual disease
variability is high and prognostic disease measures are not established for CMT patients.
Previously, we have identified skin‐derived disease and progression biomarkers in
a large European and US‐based CMT1A cohort. Within the German Charcot‐Marie‐Tooth
Disease Network (CMT‐NET, http://www.cmt-net.de) we aim to establish easier accessible
biomarkers in blood of CMT1A patients. Blood analysis is less invasive and can be
repeatedly performed during clinical trials and routine patient care. We have started
clinically assessing approximately 150 young, adolescent and adult CMT1A patients
at 3 clinical centres (Münster, München, Göttingen) including a large set of clinical
outcome measures (CMTNSv2, ONLS, 10MWT, 6MWT, Walk12, 9HPT, SF‐36, FSS, PSQI, ESS,
BDI‐II). We will sample blood and skin tissue once a year at 0, 12 and 24 months for
an observational period of 2 years. Tissue samples will be analyzed on the transcriptional,
translational and epigenetic level. We envision that the diagnostic and progression
biomarkers may be used to measure therapeutic effects within clinical trials and later
in clinical routine monitoring. This is the first trial testing “circulating” biomarkers
from blood in a prospective observational trial in CMT1A patients.
IGM ANTI‐MAG PERIPHERAL NEUROPATHY: FROM PROPER ASSESSMENT TO TRIAL NEEDS (IMAGINE
STUDY)
Pruppers MHJ
1,2, Merkies ISJ1, Faber CG1, Lunn MPT3, Léger J‐M4, Nobile‐Orazio E5, Notermans NC2
and on behalf of the IMAGiNe study group.
1Maastricht University Medical Centre, Maastricht, the Netherlands; 2University Medical
Centre Utrecht, Utrecht, the Netherlands; 3Centre for Neuromuscular disease/ National
Hospital for Neurology and Neurosurgery Queen Square, London, UK; 4Hopital de la Salpêtrière,
Paris, France; 5Milan University/ Humanitas Clinical Institute, Milan, Italy.
IgM peripheral neuropathy is a slowly progressive and heterogeneous disease with symptoms
ranging from mild foot numbness and minor imbalance to severe neuropathic pain and
sensory and motor dysfunction. International consensus regarding assessment and treatment
of patients with IgM peripheral neuropathy is lacking. This might be caused by the
repeated use of suboptimal outcome measures, the small trial sizes with low numbers
of treated patients, the indolent disease course needing a longer follow‐up period
to capture relevant changes, or the possibility that administered treatments were
not aggressive enough. The IMAGiNe study is an international, multi‐centre, prospective,
observational cohort study, which will result in a unique collection of a large number
of prospectively collected and highly standardized clinical data, and a biobank from
a large population of well‐defined patients with IgM peripheral neuropathy. The main
objective is to describe in detail the variation in clinical subtypes, clinical disease
course, past and current practice of treatment, antibody titres, and clinical picture
at the various levels of assessing outcome. Patients being at least 18 years, and
fulfilling the international criteria for IgM peripheral neuropathy are eligible.
Exclusion is primarily based on concomitant diseases influencing peripheral nerve
function. Several study parameters measuring weakness, sensation, activity and participation,
ataxia, pain, and quality of life are of interest. In February 2017 an ENMC kick of
meeting is organized, bringing together an IgM peripheral neuropathy study group.
The meeting will focus on the development of a core set of outcome measures to be
used in future studies in IgM peripheral neuropathy. The IMAGiNe study started in
the Netherlands in September 2016, and to date 51 patients were included. The IMAGiNe
study starts in the United Kingdom, Italy, and France in the beginning of 2017. Centres
recruiting at least 10 patients with IgM peripheral neuropathy are eligible to participate
in the study. During the PNS 2017 global recommendations from the ENMC meeting, as
well as the first results of the IMAGiNe study, will be presented.
IVIG CAN INDUCE A RENAL IMPAIRMENT IN PATIENTS AT RISK WITH DYSIMMUNE NEUROPATHIES
Puget S
1, Paolantonacci P2, Burlot L2
1LFB Biomédicaments, Les Ulis, France; 2LFB Biotechnologies, Les Ulis, France.
In dysimmune neuropathies patients (MMN, CIDP, GBS), IVIg have become the gold standard
due to their efficacy and tolerability. Acute renal impairment, a rare but serious
adverse event, can be induced by all IVIg. Its incidence is not determined precisely
for each IVIg. It mostly occurs in patients at risk, with pre‐existing conditions
(prior renal insufficiency, diabetes, mellitus, arterial hypertension, elderly > 65
years old, dehydratation, hypervolemia, sepsis, paraproteinemia or concomitant use
of other nephrotoxic drugs) and treated by immunomodulatory doses. As the number of
these patients increases over the years, the choice of IVIg in association with the
precautionary measures will be decisive to reduce or avoid the occurrence of this
adverse event. From 1990s to 2000s, the nephrotoxicity of IVIg has been explained
by tubular toxicity related to osmotic nephrosis. Sucrose, a stabilizer of some IVIg,
has been implicated as one of the causes of this. Even if several new IVIg without
sucrose are used, renal impairment cases have been described and studies have highlighted
that sucrose is not the only IVIg stabilizer associated with tubular damage. However,
in a recent study, renal impairment cases (4/5) have occurred in CIDP elderly patients
treated by free‐sucrose IVIg. The occurrence of renal failure seemed to be low (only
1/5) for patients treated with sucrose‐IVIg in association with precautionary measures
(hydratation, adaptation of dosage according body mass index, rate infusion). Otherwise,
since 2010s, cases of renal impairment secondary to hemolysis have been increased
with some IVIg but would be rare for full ethanolic fractionated products as they
have been identified to generate very low occurrence of hemolysis. The occurrence
of renal impairment related to IVIg seems to be multifactorial, need to find out all
causes (mechanisms of different stabilizers, hemolysis, and concentration of IVIg).
Registries would be helpful for physicians to define the incidence, relative risk
of IVIg‐related renal impairment and the right IVIg in association with precautionary
measures in these patients at risk.
CORRELATION BETWEEN ULTRA HIGH FREQUENCY ULTRASOUND (UHFUS) IMAGING AND HISTOLOGICAL
FINDINGS OF SURAL NERVE IN CIDP
Puma A
1, Panicucci E1, Cambieri C2, Butori C3, Garibaldi M1, Soriani MH1, Desnuelle C1,
Raffaelli C4, Sacconi S1.
1Université de Nice et de la Côte d'Azur (UCA) – Peripheral Nervous System, Muscle
& ALS Department, Pasteur 2 Hospital, Nice, France; 2Department of Neurology and Psychiatry
– «Sapienza» University of Rome, Rome, Italy; 3Laboratory of Clinical and Experimental
Pathology, Pasteur Hospital, Nice, France; 4Department of Radiology, Pasteur 2 Hospital,
Nice, France.
The published ultrasound (US) studies on chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP) report diffusely increased cross‐sectional area (CSA) of nerves. These data
have not been correlated with histological patterns. To date, no further information
about US ultrastructural nerve modification has been provided because of limited frequency
range (10–20 MHz) of the US probe.
The aim of this preliminary study is to evaluate the correlation between histological
findings from sural nerve biopsies and US patterns found with UHFUS (50 MHz) from
sural nerve at the ankle.
Four patients with CIDP underwent UHFUS nerve evaluation of clinically affected sural
nerve before undergoing a sural nerve biopsy. US findings included: cross‐sectional
area of the nerve, connective tissue depth and changes in echogenicity of fascicles.
Those data were then compared to the histological findings obtained in transversal
and longitudinal sections.
In all patients, UHFUS nerve changes were as following: CSA was increased; connective
tissue was thickened and in two of the four patients hyperechogenicity of fascicles
was observed. Also, thanks to the ultra‐high‐resolution of the probe, a direct correlation
of the histological and US images was possible, so as a direct measurement of internal
microstructure of the nerve.
UHFUS may be of adjunctive diagnostic value in CIDP assessment. More detailed images
of sural nerve can be obtained compared with high‐frequency US, allowing a better
evaluation of the internal structure of the nerve. The increased CSA observed in all
our subjects seems to relate to an enlargement of connective tissue, as confirmed
by the histological study. In particular, we have observed a hyperechogenicity of
fascicles in most severe patients; in those cases, histology confirmed an increase
of endoneurial depth.
We speculate that those findings may explain a preliminary involvement of connective
tissue in the pathogenesis of the CIDP; our findings of nerve enlargement may be tool
to monitor disease activity in CIDP, and better understand disease pathogenesis. Further
studies are needed to confirm these findings and additional data are being processed
and will be presented during the meeting.
ULTRA HIGH FREQUENCY ULTRASOUND (UHFUS) NERVE IMAGING IN CIDP PATIENTS
Puma A
1, Cambieri C2, Panicucci E1, Desnuelle C1, Raffaelli C3, Sacconi S1.
1Université de Nice et de la Côte d'Azur (UCA), Peripheral Nervous System, Muscle
& ALS Department, Pasteur 2 Hospital, Nice, France; 2Department of Neurology and Psychiatry,
«Sapienza» University of Rome, Rome, Italy; 3Department of Radiology, Pasteur 2 Hospital,
Nice, France.
High‐resolution ultrasound (hFUS, 20 MHz) of peripheral nerves is a valuable non‐invasive,
painless complement to neurophysiology, especially in the workup of CIDP. Nevertheless,
the current spatial resolution of echographic images doesn't allow a detailed study
of the nerves. Ultra‐high frequency ultrasound (uhFUS, 50 MHz) is a new tool with
a 3–5 times higher spatial resolution than traditional hFUS.
The aim of this preliminary study is to evaluate sensory and motor nerves structural
characteristics found with UHFUS in patients with definite CIDP.
Seven patients with CIDP underwent uhFUS nerve evaluation of median, ulnar, peroneal
and sural nerves, bilaterally. US findings included: cross‐sectional area of the nerve,
connective tissue depth, nerve vascularization and changes in echogenicity of fascicles.
Patients also underwent electroneurography (ENG) and plexus MRI.
In all patients, uhFUS nerve changes were as following: CSA was increased; connective
tissue was thickened. Two of the seven patients presented an epineural hypervascularization,
observed at the Doppler evaluation; none of them was treated by iv immunoglobulines.
Echographic changes were present even in the absence of MRI abnormalities (root hypertrophy).
ENG characteristics correlated with the US patterns.
uhFUS may be of adjunctive diagnostic value in CIDP assessment. More detailed images
of nerves can be obtained compared with high‐frequency US, allowing a better evaluation
of the internal structure of the nerve. The increased CSA observed in all our subjects
seems to relate to an enlargement of connective tissue. In particular, uhFUS allows
a more detailed study of nerves, demonstrating that the structural abnormalities hit
connective tissue, while – conversely to previous studies – fascicles anatomy seems
to be spared. We did not show nerve vascularization except in non‐treated patients.
We speculate that those findings may explain a preliminary involvement of connective
tissue in the pathogenesis of the CIDP; our findings of nerve enlargement may be tool
to monitor disease activity in CIDP, and better understand disease pathogenesis. Further
studies are needed to confirm these findings and additional data are being processed.
FUNCTIONAL CONSEQUENCES OF HIP DYSPLASIA IN PAEDIATRIC CHARCOT‐MARIE‐TOOTH DISEASE
Purcell L
1,2, Wojciechowski E1,2, Gibbons P1,2, Jamil K1,3, Menezes, M1,2, Burns J1,2.
1Sydney Children's Hospitals Network (Randwick and Westmead), New South Wales, Australia;
2University of Sydney, New South Wales, Australia; 3Universiti Kebangsaan, Kuala Lumpur,
Malaysia.
6‐20% of children with CMT are reported to have hip dysplasia. We aimed to investigate
the relationship between radiological hip dysplasia indicators and walking pattern
in children with CMT. Thirty children (15 female; 11.4±3.2yrs; 146±16.4cm; 44±18.3kg
21 CMT1A, 4 CMTX1, 2 CMTX3, 2 CMT1F, 1 CMT2A) underwent 3D gait analysis (3DGA), and
had an anterior‐posterior pelvis radiograph within 6 months of assessment. Radiographs
were reviewed by two orthopaedic surgeons, and the reliability of 14 measures of dominant
limb hip health via radiograph was assessed. Of the 14 measures, 8 measures had an
intraclass correlation coefficient >0.75 between raters, and the more experienced
surgeon's measures were used for further analysis. The 8 measures of acetabular index
(AI), centre edge angle (CEA), neck shaft angle (NSA), medial joint space, head width,
lateral uncoverage, migration percentage and triradiate were used to investigate correlations
with kinematic and kinetic 3DGA variables of the pelvis and dominant limb hip, knee
and ankle in 3 planes, temporal spatial parameters and Gait Profile Score. 3DGA data
were captured with an 8‐camera Vicon Nexus motion capture system using the lower body
Plug‐in‐Gait model. Gait data were compared to 50 typically developing children (35
female; 9.8±3.8yrs, 140±19.6cm, 39±19.0kg). Five of 30 affected children had a migration
percentage >20°, representing 17% of our sample. Maximum hip abductor moment in terminal
stance was significantly lower than normative reference values, and was moderately
correlated with 3 of the 8 radiographic measures (AI r=−0.52, p=0.023; NSA r=−0.50,
p=0.006 and medial joint space r=−0.59, p=0.001). Walking speed (normalised to leg
length) was correlated with medial joint space (r=0.51, p=0.004) head width (r=−0.68,
p=0.0001) and triradiate (r=−0.51, p=0.004). Gait cycle percentage of double support
correlated with medial joint space (r=0.56, p=0.001) head width (r=−0.78, p=0.0001)
and triradiate (r=−0.63, p=0.0001). These results suggest evidence of a relationship
between radiographic indicators of hip dysplasia and hip abductor function during
gait in children with CMT.
CLINICAL AND ELETRODIAGNOSTIC FEATURES OF GANGLIONOPATHIES WITH SPECIAL REFERENCE
TO ULNAR SENSORY‐MOTOR AMPLITUDE RATIO(USMAR) FROM A TERTIARY CARE CENTER IN INDIA
Pyal A
1, Sireesha Y1, Neeharika ML1, Meena AK1
. 1Department of Neurology Nizam's Institute of Medical Sciences, Hyderabad, Telangana,
India.
The ganglionopathies are a unique group of disorders with a varied etiology which
includes autoimmune disorders, paraneoplastic syndromes and toxin induced causes.
It has been observed that despite extensive investigations the cause of a sensory
neuronopathy is often idiopathic in approximately 40‐50% cases. Electrodiagnostic
criteria to diagnose a possible ganglionopathy requires at least one sensory action
potential absent or three sensory action potentials <30% of the lower limit of normal
in the upper limbs plus less than two nerves with abnormal motor nerve conduction
study in the lower limbs. Ulnar sensory‐motor amplitude ratio values (USMAR) lower
than 0.71 is useful in differentiating ganglionopathy from axonal length‐dependent
neuropathy.
We performed a retrospective analysis of 25 patients who were either admitted or evaluated
in the outpatient department in Department of Neurology, Nizam's Institute of Medical
Sciences, with a possible ganglionopathy as per the diagnostic criteria proposed by
Camdessanche' et al. Consecutive patients who sought treatment during a 5 year period
with a clinical pattern of sensory neuronopathy were analysed retrospectively. We
reviewed the electrodiagnostic studies of patients and calculated the ulnar sensory‐motor
amplitude ratio values in comparison with 25 patients with a clinical and electrophysiological
diagnosis of Diabetic axonal sensorimotor neuropathy.
The clinical profile of a ganglionopathy from the Indian subcontinent comprised of
a prominent sensory ataxia as the initial presenting clinical manifestation with a
predilection towards involvement of large‐fiber sensory modalities. Electrophysiologically
a pattern of absent SNAPs was characteristically encountered with a significant value
of USMAR less than 0.7, enabling differentiation from axonal length‐dependent neuropathy.
CD1A AND CD1E GENE POLYMORPHISMS ARE NOT ASSOCIATED WITH THE SUSCEPTIBILITY TO GUILLAIN–BARRÉ
SYNDROME IN BANGLADESH
Rahman IM1, Jahan IT1, Nahar S1, Khalid MM2, Jahan I1, Hayat S1,3,4, Islam Z
1.
1Laboratory Sciences and Services Division, International Centre for Diarrheal Disease
Research, Bangladesh (icddr,b), Dhaka, Bangladesh; 2Department of Biochemistry, Erasmus
University Medical Centre, Rotterdam, The Netherlands; 3Department of Physiology and
Molecular Biology, Bangladesh University of Health Sciences, Dhaka, Bangladesh; 4Department
of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh.
Guillain–Barré syndrome (GBS) is a post‐infectious autoimmune polyradiculoneuropathy
where immune response is triggered by molecular mimicry between glycolipid antigens
expressed by an infective agent such as Campylobacter jejuni (C. jejuni) and human
peripheral nerve gangliosides. CD1 molecules are MHC‐like structures specialized in
capturing and presenting a variety of glycolipids to antigen‐specific T lymphocytes.
The objective of this study was to investigate the possible role of coding region
polymorphisms of CD1 genes in the pathogenesis of GBS in Bangladeshi population. Single
nucleotide polymorphisms (SNPs) of exon 2 of CD1A (*1/*2) and CD1E (*1/*2) in 200
well defined GBS patients and 200 healthy controls were studied to delineate their
effect in developing GBS. We genotyped exon 2 of both CD1A (cys/tryp) and CD1E (gln/arg)
genes through PCR‐RFLP. To validate these findings, direct sequencing of PCR product
was performed for at least 10 samples for each position. We found no differences in
genotypes and allele frequencies of both genes in GBS patients compared to controls.
However, compared to control individuals with CD1A*2/CD1E*2 haplotype were 2.3 times
more likely to develop GBS, whereas individuals with CD1A*2/CD1E*1 haplotype had a
reduced relative risk by 4.3 times. A positive association of CD1A*2/CD1E*2 haplotype
was observed only in axonal form of GBS (27.8% vs. 10.8%, p = <0.01). Haplotype CD1A*1/CD1E*2
was prevalent among anti‐GM1 antibody positive GBS patient compared to anti‐GM1 antibody
negative patients (39.8% vs. 28.3%) though it was not statistically significant. SNPs
in CD1A and CD1E were not associated with antecedent C. jejuni infection, disease
severity and disease outcome at 6 months of follow up. In conclusion, CD1 polymorphisms
are not a susceptibility or disease causing factor in GBS. Conversely, increasing
knowledge of this field may offer new dimension for the research to elucidate better
answer for disease pathogenesis and also contribute to conduct high power meta‐analysis.
RECESSIVE SH3TC1 VARIANTS IN A CASE WITH PROGRESSIVE AND LETHAL PERIPHERAL DEMYELINATION
Rebelo A
1, Feely SM2, Bis D1, Tao F1, Shy R2, Zuchner S1, Shy M2.
1Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute
for Human Genomics, University of Miami Miller School of Medicine, Miami, USA; 2Department
of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USA.
Extensive genetic testing was performed on a unique patient, who received national
media attention due to her severe CMT phenotype. The index patient was never able
to walk independently, had difficulty breathing and swallowing and demonstrated aspiration
by a barium swallow study. Nerve conduction velocity testing revealed velocities of
10 m/s in her upper extremity. She required continuous positive airway pressure (CPAP)
for an upper respiratory infection and developed bilateral vocal cord paralysis. We
used the combined Brief Assessment of Motor Function (BAMF) scale to evaluate her
disability. Her fine motor scale was a 7/10, her upper extremity gross motor scale
was a 6/10 and her lower extremity gross motor scale was 3/10. Unfortunately, she
died at age 5 in her sleep, presumably from respiratory arrest. The proband's father
was asymptomatic, however, his neurological exam showed pes cavus bilaterally and
mild atrophy of the first dorsal interossei muscles in his hands. His nerve conduction
velocities were slowed to 30 m/s in the upper extremities and his CMT neuropathy score
(v2) was 9/36. We performed whole exome and subsequently whole genome sequencing in
the trio. Comprehensive structural variant analysis for copy number variations, large
deletions, and recombinations was completed by a combination of software tools. Known
CMT genes were excluded as the underlying cause and the only viable candidate gene
remaining was SH3TC1. We showed expression of SH3TC1 in peripheral nerve and Schwann
cells. SH3TC1 is a paralogue to SH3TC2, which causes the recessively inherited dysmyelinating
form CMT4C. Sanger sequencing confirmed the variants in our family, p.V41M (c.121G>A,
chr4:8207042) and p.A1076P (c.3226G>C, chr4:8235184), and showed the segregation of
the heterozygous variations. We hypothesize that the heterozygous paternal allele
had a minimal effect and let to a very mild or subclinical form of peripheral neuropathy.
Of interest, the recessive SH3TC2 gene has also been shown to cause mild aberrant
forms of peripheral nerve degeneration in carriers of heterozygous disease alleles.
In summary, this paper will present genetic and molecular evidence from an extensive
N=1 study proposing a novel CMT1 gene.
SCRENING OF HINT1 MUTATIONS ASSOCIATED WITH RECESSIVE AXONAL NEUROPATHY IN A BRAZILIAN
COHORT
Rocha AM1, Tomaselli PJ
1, Gouvea SP2, Figueiredo FB2, Lourenço CM1, Marques W Jr1,2.
1Division of Neuromuscular Diseases, Department of Neurosciences and Behaviour Sciences,
Clinical Hospital of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil;
2Neurogenetics, Department of Neurosciences and Behaviour Sciences, University of
São Paulo, Ribeirão Preto, Brazil.
Charcot‐Marie‐Tooth (CMT) is an important cause of morbidity worldwide. It is a heterogeneous
disease manifesting as progressive weakness, wasting and loss of feeling in a length‐dependent
pattern. There are an increasing number of CMT‐related genes in the literature. More
recently, recessive mutations in the HINT1 gene have been reported as causative of
predominant motor axonal neuropathy associated with neuromyotonic discharges on EMG.
One of the characteristics of autosomal recessive CMT is it varying frequency in different
populations and ethnic groups. We sought to evaluate the frequency of mutations in
the HINT1 gene in a Brazilian cohort with axonal hereditary neuropathy. All patients
included in this study born within South East area of Brazil. The group consists of
consecutive patients with axonal neuropathy screened for recessive or sporadic axonal
neuropathy in the Neurogenetics Laboratory of Clinical Hospital of Ribeirão Preto.
Direct sequencing of the coding region of HINT1 gene was done. Among 100 patients
screened, 98 were suspected of having recessive axonal neuropathy without neuromyothonic
discharges, and two have axonal neuropathy associated with neuromyothonic discharges
on EMG. We did not find any disease causing mutations among our patients. Some previously
reported studies reported a high frequency of mutations in the HINT1 gene among recessive
axonal neuropathies in some European countries. Our results demonstrated that frequencies
of mutation underlying genetic hereditary neuropathies are different between different
ethnic groups and have implications for the organization of services management of
CMT, for genetic counseling, and for gene flow in different world populations.
Funded by CNPq, FAPESP, FAEPA, PRONAS (Ministry of Health).
IN VITRO MORPHOLOGICAL STUDY OF BORTEZOMIB‐INDUCED PERIPHERAL NEUROTOXICITY
Rodriguez‐Menendez V1, Ballarini E1, Malacrida A
1,2, Ceresa C1, Semperboni S1,2, Meregalli C1, Cavaletti G1, Nicolini G1.
1School of Medicine and Surgery, Experimental Neurology Unit, University of Milano‐Bicocca,
Monza, Italy; 2PhD program in Neuroscience, University of Milano‐Bicocca, Monza, Italy.
Bortezomib (BTZ) is a proteasome inhibitor widely used for multiple myeloma treatment.
BTZ induced peripheral neuropathy (BIPN) is the most frequent adverse effect. BIPN
in humans, is a dose dependent painful sensory neuropathy characterized by nerve axonopathy
and a tendency to recover in the follow‐up period after BTZ withdrawal. BIPN affects
principally dorsal root ganglia (DRG) and different rodent models have shown alterations
in sensory neurons, small unmyelinated axons, large myelinated axons, axonal mitochondria
and Schwann cells. In this work, we evaluated the effects of BTZ in vitro on DRG neurons
isolated from adult mice. Our interest focused on dystonin, a protein able to interact
with all the three components of cytoskeleton (microtubules, microfilaments and intermediate
filaments) and able to bind MAP1B (a MT‐associated protein) through which can influence
Golgi apparatus morphology. There are different neuronal isoforms of dystonin and
in particular dystonin‐a2 is able to modulate tubulin acetylation and stability through
interaction with MAP1B. It is noteworthy to underline that MAP1B expression in the
mature nervous system is restricted to sensory neurons. Western blot analysis demonstrated
that a treatment with 10nM BTZ induces a statistically significant decrease in tubulin
acetylation. This result does not go along with our previous study where we observed
a tubulin polymerization increase after BTZ treatment. Therefore, we have decided
to focus our interest on soma organelle organization that is well known to be dependent
from cytoskeleton structure. Immunofluorescence images showed an altered distribution
of acetylated tubulin in soma cytoplasm after 24 hour treatment. Moreover, confocal
analysis of Cis Golgi (GM130) demonstrated that in BTZ treated neurons the normal
Golgi structure is lost showing a spot‐like non perinuclear labeling distribution.
Additionally, dystonin distribution seemed comparable to that of cis Golgi apparatus
suggesting that BTZ could induce a change in dystonin localization which in turn affects
Golgi organization, probably through MAP1B.These data suggest that the cytoskeleton
alterations, induced by BTZ, could probably cause wrong maturation and trafficking
alteration of Golgi vesicles consequently impairing the correct sensorial function.
A TYPICAL CASE OF ACUTE MOTOR AND SENSORY AXONAL NEUROPATHY (AMSAN) IN A PATIENT CO‐INFECTED
WITH SYPHILIS
Romão TT
1, Aleixo BFL1, Wedemann D1, Herculano FGN1, Prado H1, Cal H1, Pupe C1, Bittar C1,
Nascimento OJM1.
1Universidade Federal Fluminense (UFF), Rio de Janeiro, Brazil.
Acute motor and sensory axonal neuropathy (AMSAN) is a clinical variant of Guillain‐Barré
syndrome (GBS) which has rarely been reported in association with human immunodeficiency
virus (HIV) and neurosyphilis. We describe a case of a 21‐year‐old woman who started
with muscle weakness in the left leg followed by weakness in the right leg and in
upper limbs in one month. Motor symptoms were followed by urinary and fecal incontinence.
No preceding symptoms, as diarrhea or fever were referred. Neurological examination
showed global areflexia with impairment of vibratory and tactile modalities, as well
as loss of proprioception. Pinprick sensation was moderately compromised. No impairment
of higher mental functions was observed. Other causes of neuropathies were ruled out.
Cerebrospinal fluid (CSF) examination showed 0 cell/mm3, increased protein level,
normal glucose level and negative VDRL test. Blood analysis showed HIV 1 and 2 positive
serology tests, VDRL 1:16 and positive T. pallidum hemagglutination assay. IgM Cytomegalovirus
antibody was negative, CD4 was in normal range and HIV load was undetectable. Cranial
and spinal cord magnetic resonance imaging revealed extensive involvement of the posterior
spinal cord tracts which supports the diagnosis of neurosyphilis. Nerve conduction
studies showed a significant reduction in compound motor action potentials amplitudes,
particularly at lower limbs, and absent sural nerve responses. Electromyography revealed
positive waves and fibrillation at lower limbs. Treatment with methylprednisolone,
human intravenous immunoglobulin and ceftriaxone has been settled, resulting in improvement
of upper limbs paresis and sphincters dysfunction. Antiretroviral therapy was initiated.
This AMSAN case is associated with central nervous system involvement, encompassing
an encephalomyeloradiculopathyrelated to HIV/T. pallidum co‐infection. C.jejuni is
the main etiological agent associated with AMSAN, but there are some reports of HIV/CMV
co‐infected patients who presented this GBS variant. Facing a patient with AMSAN,
mainly when CNS involvement is present, it is of crucial importance to undergo investigation
of an ongoing infectious process, such as HIV and syphilis, considering the impact
of early treatment on prognosis.
UPDATE ON THE INTERNATIONAL GBS OUTCOME STUDY IN CHILDREN (IGOS‐KIDS)
Roodbol J1,2, Yiu E4, Doets A
1,2, de Wit MCY2, Monges MS5, van Nes S6, Catsman‐Berrevoets CE2, van den Berg B1,3,
Jacobs BC1,3 and on behalf of the IGOS‐Kids Consortium.
1Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; 2Department
of Paediatric Neurology, Sophia's Children's Hospital, Rotterdam, The Netherlands;
3Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands; 4Department
of Paediatric Neurology, Royal Children's Hospital, Melbourne, Australia; 5Department
of Paediatric Neurology, Hospital de Pediatría J.P. Garrahan, Buenos Aires, Argentina;
6Department of Neurology, Havenziekenhuis, Rotterdam, The Netherlands.
Only a few prospective cohort studies so far have investigated the clinical presentation
and course of Guillain‐Barré syndrome (GBS) in children using age‐adjusted outcome
scores. In 2015 we started a study based on the IGOS protocol but adjusted for children
with GBS (IGOS‐kids). (Pediatric)neurologists from Argentina, Australia and The Netherlands
joined forces to determine the clinical and biological determinants of disease progression
and recovery in GBS in children from different geographical areas. For each age category
specific pain scales are used including the Comfort score for children < 4 years old,
Pain faces revised age 5–12 years old and Numerical rating scale in children ≥ 12
years old and outcome measures. A new strength score was developed: GBS kids score.
This score will be used and validated in addition to the MRC‐sum score. The ONLS,
R‐ODS and FSS are also be used in IGOS‐kids. Age‐dependent quality of life questionnaires
were added to the IGOS‐kids protocol, namely the PedsQL and the PedsQL multidimensional
fatigue scale. These scales are available for children ≥ 2 years old. An activity
score validated for neuromuscular disorders for children ≥ 6 years old was also added.
Currently there are 13 children included in IGOS‐kids, eight children from Australia
and five from The Netherlands. Additional clinicians and researchers interested in
GBS in children are most welcome to participate in IGOS‐kids.
PREDICTORS OF SEVERITY AND OUTCOME OF GUILLAIN‐BARRÉ SYNDROME IN CHILDREN
Roodbol J
1,2, Korinthenberg R5, de Wit MCY2, Lingsma H4, Catsman‐Berrevoets CE2, Jacobs BC1,3.
1Department of Neurology; 2Paediatric Neurology; 3Immunology; 4Public health, Erasmus
MC– Sophia Children's Hospital, University Medical Center Rotterdam, The Netherlands;
5Division of Neuropaediatrics and Muscular Disorders, Department of paediatrics and
Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany.
Prognostic models have been developed to predict the highly variable clinical course
of Guillain‐Barré syndrome (GBS) in adults. The clinical course of GBS is equally
variable in children, but the current prognostic models have not been validated in
children. In this study, we aimed to identify in children with GBS the characteristics
at hospital admission that predict the clinical severity and outcome. The study was
conducted in two patient cohorts from Europe: one (largely) German cohort of 265 children
and one Dutch cohort of 140 children. Clinical information was obtained regarding
preceding infection, first symptoms, neurological deficits at admission and nadir,
results of additional investigations (cerebrospinal fluid and nerve conduction studies).
Clinical severity, course and outcome was defined by the GBS disability score, especially
the ability to walk unaided, at a follow‐up of 1 month, 2 months, 3 months and 6 months
after onset of symptoms. Univariate and multivariate regression analyses were performed
initially on the two separate cohorts. Combined the cohorts consisted of 405 children
(age median 7 years, range 0–17 years) including 222 boys (55%). The median duration
between onset of symptoms and hospital admission was 4 days (range 62). Pain at admission
was remarkably frequent and present in 129 (71%) children. In the combined cohorts,
77 children (18.4%) developed respiratory failure and one child died. Multivariate
regression analysis showed that in both cohorts strong predictors of respiratory failure
available at hospital admission were cranial nerve involvement, a higher GBS disability
score and a shorter period in days between onset of symptoms and admission. This information
was used to develop and validate a prognostic model for children with GBS that will
be presented at the conference. In conclusion, based on the analysis of two independent
cohorts of patients the predictors of respiratory failure and clinical recovery were
identified and validated. Similar factors were identified for adult patients, although
the prognosis in children in general is better than in adults. This information will
be used to develop a simple prognostic model for current clinical practice to predict
the chance of respiratory failure and outcome in children with GBS.
PLASMA NEUROFILAMENT LIGHT CHAIN LEVELS ARE RAISED IN PATIENTS WITH INHERITED PERIPHERAL
NEUROPATHY AND CORRELATE WITH DISEASE SEVERITY
Rossor AM
1, Sandelius A2, Adiutori R3, Malaspina A3, Blennow K2, Zetterberg H2,4, Reilly MM1.
1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital
for Neurology and Neurosurgery, London, UK; 2Department of Psychiatry and Neurochemistry,
Sahlgrenska Academy at the University of Gorthenburg, Sweden; 3Trauma and Neuroscience
Centre, Blizard Institute, Barts and the London School of Medicine and Dentistry,
Queen Mary University of London, London, UK; 4Department of Molecular Neuroscience,
UCL Institute of Neurology, Queen Square, London, UK.
The negative trials of vitamin C in CMT1A have highlighted the lack of sensitive outcome
measures in Charcot‐Marie‐Tooth disease (CMT). Neurofilaments are abundant neuronal
cytoskeletal proteins and their concentration in blood is likely to reflect axonal
breakdown. We therefore examined plasma neurofilament light chain (NFL) concentration
as a potential biomarker in CMT. Blood samples were collected from 75 patients with
CMT and 67 age matched healthy controls over a 1‐year period. Disease severity was
measured using the weighted CMT Examination and Neuropathy Scores. Plasma NFL concentration
was determined using an in house developed Simoa assay based on the NFL antibodies
from the NF‐L light ELISA kit (UmanDiagnostics). Plasma NFL concentrations were significantly
higher in CMT patients (median: 26.0 pg/ml; IQR: 17.3‐33.6) than in controls (median:
14.6 pg/ml; IQR 11.0‐21.1, p<0.0001) and correlated with disease severity as estimated
by the weighted CMT examination (n=75, r=0.43, p<0.0001) and neuropathy scores (n=30,
r=0.37, p=0.044). Concentrations were also significantly higher when subdividing CMT
patients by genetic subtype; CMT1A (n=31, p<0.001), SPTLC1 (n=20, p<0.001) and GJB1
(n=11, p=0.011) or into demyelinating, CMT1 (n=48, p<0.0001) or axonal, CMT2 (n=27,
p<0.001) forms compared to healthy controls. There was no significant difference in
the plasma NFL concentration after 1 year in patients with CMT (n=9, mean difference
−1.07 pg/ml, 95% confidence interval −8.2 ‐ 6.0) or healthy volunteers (n=13, mean
difference −1.2 pg/ml, 95% confidence interval 2.8 – 0.5) which is unsurprising as
CMT is a slowly progressive disease in which the rates of axonal degeneration are
likely to be constant and elevated. In summary, we have shown that plasma NFL levels
are significantly raised in patients with CMT and that they correlate with disease
severity. This is of relevance not only for the field of CMT but for peripheral neuropathies
in general, and suggests that plasma NFL holds promise as a biomarker of peripheral
neuropathy in both routine practice and clinical trials.
THE DIAGNOSTIC YIELD OF PCR‐BASED CLONALITY TESTING ON NERVE BIOPSY IN THE DIAGNOSIS
OF NEUROLYMPHOMATOSIS
Roussellet O1, Vallat J‐M1, Maisonobe T2, Gachard N3, Rizzo D3, Armand M4, Jaccard
A5, Magy L
1.
1Service de Neurologie, CHU Limoges, France ; 2Département de Neurophysiologie clinique,
GH Pitié‐Salpêtrière, Paris, France; 3Laboratoire d'Hématologie, CHU Limoges, France
; 4Service d'hématologie biologique, GH Pitié‐Salpêtrière, Paris, France; 5Service
d'Hématologie clinique et Thérapie cellulaire, CHU Limoges, France.
Neurolymphomatosis (infiltration of the peripheral nervous system by lymphoma cells)
is a rare and usually devastating condition belonging to the spectrum of lymphoma‐associated
neuropathies. Cerebrospinal fluid examination with cytologic examination, flow cytometry
and clonality testing by PCR may show malignant cells especially when nerve root involvement
is prominent. However, nerve biopsy remains a useful tool to confirm the presence
of malignant cells invading the nerve. Neuropathological features are important and
PCR‐based immunoglobulin or T‐cell receptor clonality testing on nerve fragments may
add notable value for the diagnosis of neurolymphomatosis, although this has not been
systematically investigated. We retrospectively studied clinicopathological data and
clonality results of nerve biopsy samples in patients with NL from 2 centres, performed
between 2005 and 2016.
Among 16 patients with NL, we found 94% of B‐cell lymphoma and one T‐cell lymphoma.
NL was the first manifestation in 62,5% of patients. The main clinical pattern was
symmetrical progressive sensorimotor polyneuropathy in 38% of patients and pain was
a prominent feature in 81%. Clonality testing showed a monoclonal rearrangement in
14 (88%) cases, oligoclonal rearrangement and no amplification in 2 (6%). The main
histological pattern was perivascular infiltration of predominant B‐cells in the epineurium,
without signs of vasculitis. The extent of axon loss was highly variable between patients.
Various chemotherapeutic regimens were used and the median overall survival was 19
months. Only one case showed a monoclonal pattern among 22 control nerve samples from
patients with other types of neuropathy including vasculitis and CIDP. Overall, we
found that clonality testing on nerve biopsy specimens may provide decisive information
on the presence of neurolymphomatosis, with a sensitivity of 87.5%, a specificity
of 95.4%, a positive predictive value of 93.3% and a negative predictive value of
91.3%.
We confirm the utility of nerve biopsy for the diagnosis of NL and show the great
yield of PCR‐based clonality testing to assess the malignant feature of peripheral
nervous system lymphoid infiltrates. Despite an accurate diagnosis, neurolymphomatosis
still remains a devastating disease with an overall poor prognosis.
SMALL FIBER NEUROPATHY CHARACTERIZATION IN THE SOD1G93A ALS MOUSE MODEL
Rubio MA
1,2, Herrando‐Grabulosa M2, Vilches JJ2, Navarro X2.
1Neuromuscular Unit, Department of Neurology, Hospital del Mar. Barcelona, Spain;
2Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences
and CIBERNED, Universitat Autònoma de Barcelona, Bellaterra, Spain.
In the last years, cumulative data have shown that patients with amyotrophic lateral
sclerosis (ALS) and mouse models of the disease present loss of small epidermal and
dermal nerve fibers and sensory dysfunctions, in addition to the classical motor symptoms.
Our objective is to characterize this small fiber neuropathy and to clarify if axonal
loss involves all sort of fibers equally, or if there is some specificity. For this
purpose, we performed an immunohistochemical characterization of total intraepidermal
nerve endings (protein gene product; PGP9.5), peptidergic (calcitonin gene‐related
peptide; CGRP) and nonpeptidergical nerve epidermal endings (isolectin B4; IB4) of
the SOD1G93A mouse at different stages: presymptomatic stage (8 weeks), disease onset
(12 weeks) and in symptomatic stage (16 weeks). The sympathetic sweat gland innervation
was immunolabeled for vasoactive intestinal peptide (VIP) from very early stage (4
weeks) to disease onset (12 weeks). The results showed a marked reduction of the intraepidermal
nerve fibers already in the presymptomatic stage compared to the wildtype littermates
(p<0.05). This axonal loss affected more markedly the nonpeptidergic axons from the
disease onset stage (39% axonal loss, p<0.05), whereas no significant differences
were found in the CGRP positive fibers (14.3% axonal loss). A reduction of the sympathetic
innervation of the sweat glands was also found from the disease onset stage (29% axonal
loss, p<0.05). In summary, we have found that nonpeptidergic and sympathetic innervation
of the skin are predominantly affected in the SOD1G93A mouse model. These findings
suggest that this specificity could be used as an accessible biomarker for the disease.
ARSENIC TRIOXIDE INDUCED PERIPHERAL NEUROPATHY: PROSPECTIVE EVALUATION OF TWO PATIENTS
WITH ACUTE PROMYELOCYTIC LEUKEMIA
Ruiz M
1, Lessi F2, Cacciavillani M3, Riva M2, Salvalaggio A1, Campagnolo M1, Briani C1.
1Neurology, Department of Neuroscience, University of Padua, Padua, Italy; 2Hematology
and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua,
Italy; 3CEMES, Data Medica Group, Padua, Italy.
Arsenic trioxide (ATO) is highly effective in treatment of acute promyelocytic leukemia
(APL). It is licensed in Italy for treatment of relapsed‐refractory APL and for first
line chemotherapy in low risk patients. ATO most frequent side effects are well described,
but less is known on ATO induced. We describe 2 APL patients who were treated with
all‐trans retinoic acid (ATRA)/ATO as first line therapy. The characteristics of ATO
induced neuropathy was prospectically analyzed by neurological evaluation using both
the total neuropathy score, clinical version (TNSc) (a validated scale for chemotherapy
induced peripheral neuropathy) and neurophysiological assessment. Patients have been
evaluated at baseline, at the end of the induction phase, at the end of ATO/ATRA treatment
and 1 year after discontinuation of treatment. Baseline neurophysiology was performed
at the end of induction phase. Both patients were men, respectively 41 and 53‐yr‐old.
None of the patients had previous history of neuropathy. Baseline TNSc was 0 (no clinical
signs of neuropathy) in both patients. Neurophysiological evaluation performed after
the end of induction cycle did not reveal signs of peripheral neuropathy in both patients.
Patient 1 received 387 mg of ATO during induction, total 1,040 mg. Patient 2 received
311 mg of ATO during induction, total 1,188. Both patients developed leg numbness
during consolidation cycles and patient 1 also hand numbness. TNSc at the end of therapy
was 1 in patient 1 and 3 in patient 2. Neurophysiology at the end of therapy detected
signs of sensitive axonal neuropathy in both patients. They received full doses of
ATO consolidation (0.15 mg/kg/day for 5 days/week, on alternate months for total 3
months and tretinoin 2 weeks on 2 weeks off). During the first year of follow‐up both
TNSc and neurophysiology 1 year after the end of consolidation cycle were consistent
with full recovery. Our patients developed sensory axonal neuropathy during ATO therapy,
that clinically manifested during consolidation cycles and improved up to complete
recovery during follow‐up. Published case reports show that outcomes may not be as
good as in our patients. A multicenter prospective study evaluating the characteristics
of ATO‐induced neuropathy in APL is ongoing.
CHARCOT‐MARIE‐TOOTH NEUROPATHY MISDIAGNOSED AS CHRONIC INFLAMMATORY DEMYELINATING
POLYRADICULONEUROPATHY: A CASE SERIES
Ruiz M
1, Campagnolo M1, Salvalaggio A1, Cacciavillani M2, Taioli F3, Fabrizi GM3, Briani
C1.
1Department of Neuroscience, Neurology Unit, University of Padua, Padua, Italy; 2Data
Medica Group, EMG Unit, CEMES, Padua, Italy; 3Department of Neurological and Movement
Sciences, University of Verona, Verona, Italy.
Hereditary and inflammatory neuropathies are peripheral nerve disorders of different
pathophysiology whose identification is crucial for therapeutic approach. Diagnosis
of CMT is easy when there is a family history, disease course is slowly progressive,
neurophysiological findings are homogeneously abnormal. Cases of CMT1 patients with
inflammatory‐like phenotypes leading to a misdiagnosis of chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) have been described. The presence of “red flag signs”,
such as slowly progressive decline, mild sensory symptoms, minimal electrophysiological
progression and no response to therapy should prompt re‐evaluation of the diagnosis
of CIDP. The introduction of nerve neuroimaging has contributed to the diagnostic
work‐up. We describe 7 CMT patients (5 men, 2 women, mean age 58.6 ± 14.4 yrs, mean
neuropathy duration 14.6 ± 8.9 yrs) with genetically confirmed CMT, who were initially
diagnosed with CIDP. Neurophysiology showed demyelinating features in 5 patients,
the remaining 2 patients had axonal features. CSF analysis showed albumin‐cytological
dissociation in 3 patients, oligoclonal IgG bands were present in 1 patient. Nerve
ultrasound in 2 patients with demyelinating neuropathy showed diffuse increased cross‐sectional
area. MR‐neurography in one patient confirmed diffuse nerve hypertrophy and increased
signal intensity, supporting the hypothesis of a overlap syndrome. All patients were
treated with immunomodulatory therapies. Among 5 patients with demyelinating features,
3 patients underwent IVIg for 6 months, without benefit; the remaining 2 were treated
with steroids, showing temporary improvement. The 2 patients with axonal neuropathy
complaining of a progressive history, underwent ex adjuvantibus plasma exchange and
IVIg, without benefit. Given the lack of benefit from therapies, screening for hereditary
neuropathies was performed. Among 5 patients with demyelinating neuropathy, 2 had
CMT1A, 1CMT1B, 1CMT1D. Among the 2 patients with axonal neuropathy, one was diagnosed
with CMT 2K. In 2 patients an overlap syndrome was present. Several clinical and laboratory
features (CSF protein elevation), might contribute to the misdiagnosis of CIDP in
CMT patients. Refractoriness to immune‐modulatory treatment should rise the suspicion
of a hereditary neuropathy. An overlap CMT/CIDP syndrome may be considered, in front
of acute/subacute deterioration and/or proximal muscles involvement. Two patient with
an overlap syndrome showed benefit after either steroids or IVIg.
FACIAL DIPLEGIA WITH BILATERAL FACIAL NERVE ENHANCEMENT AT 3T‐MRI AND ANTI‐GANGLIOSIDE
ANTIBODIES
Ruiz M
1, Tripodi SM1, Campagnolo M1, Zara G1, Salvalaggio A1, Ruggero S1, Toffanin E1, Anglani
M2, Briani C1.
1Neurology, Department of Neuroscience, University of Padua, Padua, Italy; 2Neuroradiology,
Padua Hospital, Padua, Italy.
Facial diplegia is a rare regional subtype of Guillain‐Barrè syndrome characterized
by rapidly progressive bilateral facial palsy in absence of other cranial neuropathies,
ataxia or limb weakness. The diagnosis is based on history, clinical examination,
laboratory data. The outcome of this variant appears to be better than that of classical
GBS. Although about 50% of GBS patients clinically exhibit facial nerve involvement,
there are only few reports that demonstrate MRI gadolinium facial nerves enhancement.
A 45‐year‐old previously healthy man sought neurological advice for the acute onset
of right perioral paresthesias and hyposthenia at the extensor hallucis longus bilaterally.
In the previous month, during a trip to China and Japan, he had suffered from gastroenteritis.
At neurological examination he presented with bilateral extensor hallucis longus hyposthenia.
Ankle jerk reflexes were absent. One week later, he developed bilateral facial palsy.
Neurophysiology disclosed absence of activity in the facial nerves innervated muscles
bilaterally and signs of mild partial denervation at right L5 metamer. CSF analysis
showed increased protein levels (73 mg%) and 2.3 leucocytes/μL. Serological tests
for infectious agents were negative and serum levels of Angiotensin Converting Enzyme
were normal. Antibodies to monosialoganglioside GM1 of IgG isotype were positive (1/12800).
3T brain MRI showed, after gadolinium administration, marked bilateral enhancement
of the facial nerves in their extra‐ and intra‐canalicular segments. 3T lumbosacral
MRI scan ruled out the presence of disc diseases as well as signal modifications within
conus medullaris and cauda equine nerve roots. The patient was treated with IV immunoglobulins
(0.4 g/Kg/die for 5 days) with benefit on facial weakness. At follow‐up examination
2 months later, the patient presented a further improvement of the facial diplegia
and neurophysiology disclosed a partial recovery of activity in the facial nerves,
with persistent axonopatic damage. Bilateral extensor hallucis longus hyposthenia
persisted. In conclusion, we report on a regional subtype of Guillain‐Barrè syndrome
with the curious association of facial diplegia and bilateral extensor hallucis longus
hyposthenia, and IgG anti‐ganglioside antibodies, that are not commonly described
in facial diplegia. Moreover, we provide 3T brain MRI evidence of facial nerve involvement.
IMPAIRMENT OF MITOCHONDRIAL TRAFFICKING IN DORSAL ROOT GANGLION NEURONS IS DEPENDENT
ON HYDROCARBON CHAIN LENGTH OF SATURATED FATTY ACIDS
Rumora AE1, Tabbey MA
1, LoGrasso G1, Dolkowski J1, Haidar J1, Lentz SI2, Feldman EL1.
1Department of Neurology, University of Michigan, Ann Arbor, USA; 2Department of Internal
Medicine, Division on Metabolism, Endocrinology and Diabetes, University of Michigan,
Ann Arbor, USA.
Diabetic neuropathy (DN) is the most common complication of diabetes affecting up
to 60% of diabetic patients. The pathogenesis of DN in Type 2 diabetes is directly
related to the metabolic syndrome associated with the western diet composed of elevated
levels of long chain saturated fatty acids (SFAs) and low levels of medium chain SFAs.
Long chain SFAs are associated with insulin resistance and dyslipidemia while medium
chain SFAs have been associated with decreased lipid accumulation and improved mitochondrial
function. Since DN is primarily a disorder of the sensory dorsal root ganglion (DRG)
neurons, we sought to evaluate the impact of SFA hydrocarbon chain length on mitochondrial
trafficking mechanisms that are critical for distributing ATP throughout DRG axon
to provide energy for synaptic transmission. We hypothesize that SFAs with longer
hydrocarbon chains will impair mitochondrial trafficking whereas medium length SFAs
will not impact mitochondrial movement along the DRG axon. In this study, we examined
the impact of SFA hydrocarbon chain length on mitochondrial trafficking, directionality
and velocity in primary mouse DRG neurons. DRG neurons were treated with increasing
concentrations of long chain SFAs, stearate and palmitate, or medium chain SFA, laurate,
ranging from 31.25 to 250 micromolar for twenty‐four hours. DRG neurons treated with
long‐chain SFAs, palmitate and stearate, showed a significant decrease in the percentage
of motile mitochondria whereas medium chain SFA, laurate, does not alter mitochondrial
motility. We next assessed whether motile mitochondria in DRG neurons treated with
palmitate or stearate exhibited altered directionality or velocity of mitochondrial
trafficking. Palmitate and stearate treatments resulted in a trending decrease in
the number of mitochondria trafficking in both anterograde and retrograde directions.
Furthermore, 62.5 to 250 micromolar palmitate and stearate induced a significant decrease
in mitochondrial velocity. Laurate treatment, on the other hand, retained directionality
and velocity of mitochondrial trafficking. These results suggest that hydrocarbon
chain length of saturated fatty acids plays an important role in regulating mitochondrial
trafficking mechanisms in dorsal root ganglion neurons. Impaired mitochondrial trafficking
in DRG neurons exposed to elevated levels of long‐chain SFAs may play a critical role
in the progression of DN.
DIFFERENTIAL EFFECT OF SATURATED AND UNSATURATED FATTY ACIDS ON MITOCHONDRIAL TRAFFICKING
IN DORSAL ROOT GANGLION SENSORY NEURONS
Rumora AE
1, Hayes JM1, LoGrasso G1, Haidar J1, Dolkowski J1, Lentz SI2, Feldman EL1.
1Department of Neurology, University of Michigan, Ann Arbor, MI, USA; 2Department
of Internal Medicine, Division on Metabolism, Endocrinology and Diabetes, University
of Michigan, Ann Arbor, USA.
Dyslipidemia is a critical factor that contributes to the development of diabetic
neuropathy (DN). The progressive nerve damage associated with DN correlates with the
dyslipidemic state characterized by elevated circulating levels of harmful saturated
fatty acids (FAs) and low levels of beneficial unsaturated FAs. In DN, primary sensory
dorsal root ganglion (DRG) neurons exhibit energy dyshomeostasis and mitochondrial
dysfunction, however, little is known about the differential impact of saturated and
unsaturated FAs on mitochondrial mechanisms in DRG neurons. Mitochondrial trafficking
is an essential mechanism for transporting mitochondria throughout DRG axons to provide
cellular ATP for neuronal function and neurotransmission. Since mitochondrial trafficking
is regulated by metabolic flux, we sought to determine whether saturated FA, palmitate,
and unsaturated FA, oleate, have differential effects on mitochondrial trafficking
in DRG neurons. We evaluated mitochondrial trafficking patterns and the mitochondrial
membrane potential (MMP) in primary DRG neurons treated with physiologically relevant
concentrations of palmitate, oleate, and combinations of both FAs. Primary DRG neurons
treated with 62.5 to 250 micromolar palmitate induced a significant and dose‐dependent
reduction in the percentage of motile mitochondria. These palmitate treatments also
induced a dose‐dependent reduction in mitochondrial velocity but did not impact the
directionality of mitochondrial movement. Alternatively, 31.25 to 250 micromolar oleate
treatments did not impair the percent of motile mitochondria, the direction of mitochondrial
movement, or mitochondrial velocity. Since palmitate and oleate have differential
effects on mitochondrial motility, we next assessed whether oleate could counter the
inhibitory effect of palmitate on mitochondrial trafficking. Surprisingly, oleate/palmitate
mixtures at ratios of 1:1 or 2:1 prevented palmitate‐induced impairment of mitochondrial
trafficking. We assessed the impact of palmitate and oleate on MMP by staining palmitate
and oleate‐treated DRG neurons with tetramethylrhodamine methyl ester. DRG neurons
treated with 250 micromolar palmitate exhibited an increase in the percentage of depolarized
mitochondria while mitochondria in oleate‐treated DRG neurons retained MMP. Interestingly,
DRG neurons treated with 1:1 oleate/palmitate mixtures also maintained polarized mitochondria.
These results suggest that saturated and unsaturated FAs have a distinct impact on
mitochondrial trafficking mechanisms in DRG neurons and that equimolar ratios of oleate/palmitate
can prevent impairment of mitochondrial trafficking.
SCO2 MUTATIONS CAUSE AUTOSOMAL RECESSIVE CHARCOT‐MARIE‐TOOTH DISEASE
Saade D
1, Pereira C2, Shon E3, Moraes C2, Zuchner S4, Shy M1, Rebelo A4.
1Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City,
USA; 2Department of Neurology, University of Miami, Miami, USA; 3Department of Neurology,
Columbia University Medical Center, New York, USA; 4Dr. John T. Macdonald Foundation
Department of Human Genetics, John P. Hussman Institute for Human Genomics, University
of Miami Miller School of Medicine, Miami, USA.
Mutations in the mitochondrial copper‐binding protein SCO2, cytochrome c oxidase assembly
protein, have been reported in several cases of fatal infantile cardioencephalomyopathy
with COX deficiency. We identified compound heterozygous variants in SCO2 in two unrelated
patients with isolated length dependent axonal sensorimotor polyneuropathy of variable
clinical severity (axonal autosomal recessive Charcot‐Marie‐Tooth disease type 4,
CMT4) by whole exome sequencing. Although peripheral neuropathy has been described
as a secondary feature in a few cases of fatal infantile cardioencephalomyopathy,
the disease onset, clinical phenotype and survival in our patients differ significantly
from the previously described cases. Our patients developed predominantly motor neuropathy;
moreover, they are still alive and they have not developed cardiomyopathy, which is
the main phenotype and cause of death at early infancy in reported patients. Both
of our patients harbor mutations adjacent or near the conserved copper‐binding motif
(CXXXC), including the common reported pathogenic variant E140K and the novel change
D135G. In addition, each patient carries a second mutation located in the same loop
region of the protein, P169T and R171Q. Western blots from fibroblasts from these
CMT patients showed reduced levels of COX2, a subunit of complex IV, indicating COX
deficiency. Our findings demonstrate that CMT4 can be the predominant phenotype associated
with SCO2 mutations, pointing to a broader phenotypic heterogeneity. The mechanism
linking mitochondrial respiratory chain dysfunction to isolated axonal loss of variable
severity remains to be elucidated.
MUSCARINIC RECEPTOR SIGNALING CONSTRAINS AXONAL OUTGROWTH BY AUGMENTING DISSOLUTION
OF THE CYTOSKELETON IN ADULT SENSORY NEURONS
Sabbir MG
1, Calcutt NA2, Fernyhough P3.
1Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research
Centre, Winnipeg, MB, Canada; 2Department of Pathology, University of California San
Diego, California, USA; 3Department of Pharmacology & Therapeutics, University of
Manitoba, MB, Canada.
The muscarinic acetylcholine (ACh) type 1 receptor (M1R) is a metabotropic G protein‐coupled
receptor expressed by adult sensory neurons. Cholinergic signaling through muscarinic
receptors can modulate axonal plasticity in invertebrates and lower vertebrates. We
have recently shown that selective (pirenzepine) and specific (muscarinic toxin 7:
MT7) M1R antagonists elevate neurite outgrowth and protect from small and large fiber
neuropathy in adult sensory neurons in various animal models (Calcutt, et al., 2017).
Furthermore, we demonstrated that excessive cholinergic signaling due to M1R overexpression
caused a significant reduction in neurite outgrowth (Calcutt, et al., 2017). The mechanism
of M1R‐antagonist driven neurite outgrowth remains poorly understood, however, we
have proposed that ACh constrains axonal outgrowth via M1R activation. Cholinergic
signaling is mediated via recruitment of trimeric G proteins, of which G Alpha‐12
and G Alpha‐13 regulate cytoskeleton dynamics by control of tubulin polymerization.
Activated GTP‐bound G‐Alpha proteins destabilize microtubules by increasing the intrinsic
GTPase activity of tubulin. We have therefore tested the hypothesis that cholinergic
signaling regulates neurite outgrowth via modulation of G protein mobilization and
the dynamics of the tubulin cytoskeleton. We found that over‐expression of M1R in
adult sensory neurons induced dissolution of the tubulin cytoskeleton in distal neurites.
G Alpha‐13 expression in adult sensory neurons was significantly higher (P<0.001,
7‐fold) than G Alpha‐12. Subsequent knockdown of G Alpha‐13 in M1R overexpressed sensory
neurons significantly reversed the M1R‐induced reduction in relative levels of total
neurite outgrowth (mean±SD: 347.96±190.12 (control) vs 545.40±321.97 (G Alpha‐13 knockdown),
P<0.0001, N=406 neurons). Further, treatment of M1R overexpressing neurons with MT7
or pirenzepine sequestered G Alpha‐12/13 proteins at the M1R and significantly reversed
the impaired cytoskeleton‐mediated reduction in total neurite outgrowth (mean±SD:
895.9±172.9 (control), 1887±807 (+100nM MT7), 1706±507.5 (+1 micromolar pirenzepine);
N=224, 230 and 198 neurons, respectively; for treated groups P value=0.0001 vs control
by one‐way ANOVA). MT7 and pirenzepine also significantly restored mitochondrial trafficking
and abundance of mitochondria in the distal neurites. Our findings suggest a novel
mechanism in which modulation of M1R influences tubulin polymerization, mitochondrial
distribution in nerve terminals and controls axonal outgrowth and regeneration. Funded
by CIHR and NIH.
SELECTIVE MUSCARINIC RECEPTOR ANTAGONISM ACTIVATES THE ERK/MAPK PATHWAY IN ADULT SENSORY
NEURONS
Sabbir MG
1, Fernyhough P2.
1Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research
Centre, Winnipeg, MB, Canada; 2Department of Pharmacology & Therapeutics, University
of Manitoba, MB, Canada.
Muscarinic receptors are a group of five G‐protein coupled receptors (GPCRs) that
are targeted by drugs for the treatment of several human pathophysiological conditions.
We have recently shown that selective (pirenzepine) and specific (muscarinic toxin
7: MT7) antagonists of the muscarinic acetylcholine type1 receptor (M1R) induced elevated
neurite outgrowth and protected from small and large fiber neuropathy in adult sensory
neurons in various animal models (Calcutt et al., 2017). One of the major cellular
effectors activated by GPCRs is extracellular signal‐regulated kinase (ERK). The ERK
signaling cascade regulates a variety of cellular processes including growth and proliferation.
Both G protein and beta‐arrestin mediated signaling pathways can lead to ERK activation
by phosphorylation through different kinases. Activated ERK in turn can phosphorylate
about 200 cellular substrates, thereby mediating diverse functions. In this study,
we have analyzed beta‐arrestin recruitment, as part of the receptor internalization
process induced by agonist/antagonist binding. In addition, we studied phosphorylation
of ERK by MT7 and pirenzepine using isoelectric focusing with phospho‐ERK specific
antibodies and a variety of cell‐based assays including beta‐arrestin and G protein
(GNAS/GNASL/GNAQ/GNA11/GNA12/GNA13) knockout cell lines. Our study revealed that beta‐arrestin
is recruited to the M1R upon MT7 and pirenzepine treatment. Treatment with 100nM MT7
and 1 micromolar pirenzepine significantly increased the dual phosphorylation of Tyr202
and Tyr204 residues of ERK1/2 in primary rat sensory neurons (P<0.0001) in comparison
to muscarinic agonist carbachol (10 micromolar) and general antagonist atropine (50
micromolar). We have identified multiple distinct phosphorylation events on the M1R
by isoelectric focusing that are specific to MT7 and pirenzepine induction. Further,
we have shown that MT7 and pirenzepine‐mediated ERK phosphorylation is dependent on
both G protein and beta‐arrestin recruitment to M1R. Finally, we reveal that increased
ERK phosphorylation by MT7 and pirenzepine significantly (p=0.005 and 0.063, respectively)
increased phosphorylation of cAMP responsive element binding protein (CREB) at Ser133.
These results show for the first time that antagonists of the M1R can activate the
ERK signaling pathway and possibly drive phenotypic change in adult sensory neurons.
Funded by CIHR # MOP‐130282.
THE INHERITED NEUROPATHY VARIANT BROWSER
Saghira C1, Bis D1, Rebelo A1, Abreu L1, Stanek D2, Zuchner S
1 and Inherited Neuropathy Consortium.
1Department of Human Genetics and Hussman Institute of Human Genomics, University
of Miami, Miami, USA; 2DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty
of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech
Republic.
Charcot‐Marie‐Tooth disease (CMT) is representative of inherited neuropathies affecting
an estimated 1 in 2500 people. The immense advances in gene discovery gained from
next‐generation sequencing (NGS) projects have revealed the extent of CMT's genetic
heterogeneity, with over 90 loci already identified. This knowledge is rapidly translated
into clinical comprehensive gene testing panels, often containing over 100 genes.
Such a large genomic space will invariantly yield variants of uncertain clinical significance
(VUS) in nearly any person tested. This rise of the number of VUS creates major challenges
for genetic counseling. In addition, less individual mutations in already known genes
are being published as the academic merit is decreasing, and most such testing now
happens in clinical laboratories. We propose to capture more of this data in the CMT
field to gain a more complete collection of alleles in CMT genes, ideally in conjunction
with detailed phenotypic data. This represents a rational approach to eventually reduce
the number of VUS. Thus, we have created a unique, community‐driven variant database
for CMT researchers and clinicians. The Inherited Neuropathy Variant Browser provides
simple, user‐friendly access to currently reported CMT variation, including patient‐level
genotypic and phenotypic information. We have also designed an interactive rating
system of genetic variation to assist the community with interpretation of VUS. For
the initial release, we have collected genetic variation, along with genotypic and
phenotypic data when available, from published literature, clinical lab reports, and
our in‐house database. We highly encourage new submissions of not only observed pathogenic
variation, but also variation of unknown significance. The goal is to provide a platform
for the CMT community to store, share, and discuss genetic data in order to resolve
variation of uncertain significance as a joint‐effort. With active participation,
we aim to provide the community with a more complete mutational spectrum in CMT genes
to assist allelic interpretation and patient diagnosis.
ABSENCE OF NEUROFILAMENT LIGHT CHAIN IN PATIENT‐SPECIFIC MOTOR NEURONS IN AUTOSOMAL
RECESSIVE CHARCOT‐MARIE‐TOOTH DISEASE
Sainio MT
1, Ylikallio E1,2, Auranen M1,2, Palmio J3, Tyynismaa H1.
1Reseach Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland;
2Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University
Hospital, Helsinki, Finland; 3Neuromuscular Research Center, University of Tampere
and Tampere University Hospital, Tampere, Finland.
Neurofilaments are strictly neuron‐specific intermediate filaments crucial for maintaining
axonal architecture. Pathogenic mutations in NEFL, which encodes the light chain of
neurofilament, cause dominantly and recessively inherited Charcot‐Marie‐Tooth neuropathy
(CMT). The NEFL‐associated neuropathy can be either axonal (type 2E) or demyelinating
(type 1F). Most pathogenic NEFL variants are dominantly inherited missense mutations,
which are thought to cause disease by inducing NEFL aggregation, leading to the disruption
of axonal transport. However, investigation of disease mechanisms caused by the mutations
has been complicated by the neuronal specificity of NEFL. We identified a homozygous
NEFL variant c.1099 C>T predicting a nonsense change p.Arg367* in a patient with early‐onset
CMT. To elucidate the disease mechanism, we used pluripotent stem cells, reprogrammed
from patient's skin fibroblasts, to differentiate patient‐specific spinal motor neurons.
The motor neurons revealed a near complete loss of NEFL mRNA, and absence of NEFL
protein. Our results establish that NEFL is not essential for the development of human
nervous system but its absence causes progressive axonal neuropathy. We currently
profile the transcriptomic alterations of the motor neurons lacking NEFL using single
cell RNA sequencing to identify compensatory pathways.
NERVE ULTRASOUND, MRI NEUROGRAPHY AND DIFFUSION TENSOR IMAGING ANALYSIS REVEALED PECULIAR
NERVE ABNORMALITIES IN FRIEDREICH'S ATAXIA
Salvalaggio A
1, Coraci D2, Cacciavillani M3, Ruiz M1, Manganelli F4, Antenora A4, Filla A4, Santoro
L4, Gasparotti R5, Padua L6, Briani C1.
1Department. of Neurosciences, University of Padua, Padua, Italy; 2Board of Physical
Medicine and Rehabilitation, Department of Orthopaedic Science, "Sapienza" University,
Rome, Italy; 3CEMES‐EMG Lab, Data Medica Group, Padua, Italy; 4Department of Neurosciences,
Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples,
Italy; 5Department of Medical and Surgical Specialties, Radiological Sciences and
Public Health, University of Brescia, Brescia, Italy; 6Department of Geriatrics, Neurosciences
and Orthopaedics, Università Cattolica del Sacro Cuore, Rome, Italy.
Friedreich's ataxia (FRDA) is the most common autosomic recessive ataxia, due to a
trinucleotide expansion within the Frataxin gene. Within the wide phenotype, FRDA
patients present also with an axonal neuropathy whose pathological mechanisms are
not completely known.
Eight patients (5 women, mean age 34.6 yrs, range 20–45) with genetically confirmed
FRDA underwent neurophysiological and nerve ultrasound evaluation at four limbs bilaterally.
Echogenicity and cross‐sectional area (CSA) of median, ulnar, radial, peroneal, tibial,
and sural nerves were recorded. MR neurography and diffusion tensor imaging (DTI)
analysis were performed in one patient; fractional anisotropy (FA), radial (RD) and
axial (AD) diffusivity of median, radial and ulnar nerve were calculated at proximal,
intermediate and distal sites.
All patients presented with sensory axonal neuropathy. Seven patients (88%) presented
with increased CSA of median and ulnar nerves at arm and axilla. Mean median nerve
CSA at mid‐upper arm was 20.9 mm2 (normal values < 11 mm2), mean ulnar nerve CSA at
mid‐upper arm was 13.6 mm2 (normal values < 8 mm2). Mean median nerve CSA at axilla
was 13.8 mm2 (normal values < 11 mm2), mean ulnar nerve CSA at axilla was 9.9 mm2
(normal values < 8 mm2). MR Neurography (performed in one patient) confirmed diffuse
swelling and signal hyperintensity of median and ulnar nerves at the arm and DTI analysis
showed abnormal values of FA, AD and RD along the whole course of evaluated nerves
thus suggesting a wide alteration of nerves structure.
FRDA patients presented with an axonal neuropathy characterized, at ultrasound, by
a nerve enlargement strictly limited to mid‐upper limbs in all patients, findings
that cannot be solely explained by a dying‐back axonopathy, as suggested by several
authors. Neither a dorsal root ganglia neural loss could explain by itself our findings,
because a diffuse CSA reduction would have been expected.
On the whole, these findings represent a peculiar feature in FRDA, but its pathophysiologic
meaning remains unclear.
A BREED‐PREVALENT CANINE MODEL OF LATE ONSET PERIPHERAL NEUROPATHY
Sample SJ
1, Salamat S2, Muir P1, Hao Z1, Rylander H1, Eminaga S1, Barnes‐Heller HL1, Binversie
EE1, Baker LA1, Hoffman CL1, Piazza A1, Volstad NJ1, Hans EC1, Svaren J1
. 1University of Wisconsin School of Veterinary Medicine, Madison, Wisconsin, USA;
2University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin,
USA.
Inherited peripheral neuropathies are an important health concern for which there
is currently no disease‐modifying therapy. Dogs are affected by a variety of peripheral
neuropathies that are breed‐specific, indicating a strong genetic component. The use
of in‐bred populations, such as pure‐bred dogs, is advantageous for genetic dissection
of disease. Acquired peripheral neuropathy (APN) is an inherited late‐onset generalized
polyneuropathy with high prevalence in Labrador Retrievers. The most prominent features
of APN, laryngeal paralysis and pelvic limb weakness, are associated with the longest
peripheral motor nerves in the dog. The pathologic features of APN are similar to
human peripheral neuropathy. Our aim is to understand the genetic and pathologic features
of APN for development of this condition as a naturally occurring large animal model
for human disease. We performed a genome‐wide association study (GWAS) and short‐read
high‐depth whole genome sequencing (WGS) to investigate the genetic underpinning of
APN in the Labrador. Our GWAS data indicates that APN is an autosomal dominant disease.
The initial analysis from the WGS study resulted in a potential causal variant with
an autosomal dominant pattern; this variant is associated with an axonal gene. The
neuropathologic progression and histologic features of APN are poorly defined. Using
genetic markers from our GWAS study, we are able to confidently identify Labradors
with pre‐clinical APN, from which nerve biopsies can be obtained. Preliminary analysis
of biopsies from Labradors suggest APN is an axonopathy. Further histologic data from
preclinical and symptomatic dogs is being obtained to further define the pathogenesis
in this model. Defining the causal genetic variant(s) and understanding the pathologic
features and progression of APN are necessary for the development of APN as a naturally
occurring canine model of peripheral neuropathy.
GLOBAL TRANSCRIPTOME ANALYSES REVEAL A KEY ROLE FOR MORC2 IN THE AXONAL METABOLISM
Sancho P
1,2, Lupo V1,2,3, García‐García F4, Ramírez‐Jiménez L3, Sevilla T5,6, Chrast R7, Espinós
C1,2,3.
1Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro
de Investigación Príncipe Felipe (CIPF), Valencia, Spain; 2INCLIVA & IIS La Fe Rare
Diseases Joint Units, Valencia, Spain; 3Department of Genomics and Traslational Genetics,
Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain; 4Computational Genomics
Department, Centro de Investigación Principe Felipe (CIPF), Valencia, Spain; 5Department
of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain; 6CIBER of
Rare Diseases (CIBERER), Spain; 7Department of Neuroscience, Karolinska Institutet,
Stockholm, Sweden.
Mutations in MORC2 lead to an axonal form of neuropathy (CMT2Z). To date, nine families
have been published with mutations in the MORC2 gene, showing that this gene is frequently
involved in CMT. While the recent genetic data clearly established the causative role
of MORC2 in CMT2Z, its phenotypic consequences in patients and role in neuronal biology
remains to be clarified. Therefore, we aim to look for altered genetic and biochemical
pathways with a transcriptomic approach in order to investigate the role of MORC2
in hereditary peripheral neuropathy. We have performed transcriptomic analysis using
a human gene expression microarray (v3 8x60K, Agilent Technologies), in three HEK‐293T
cell lines: Control, MORC2 knock‐down (Kd) and the overexpression of the most common
MORC2 mutation, the p.R252W (NP_001290185) (Kr). Differential gene expression assessment
was carried out using limma moderated t‐statistics. Standard analysis techniques perform
one test for each gene. Thus, for each gene, a t‐test statistic is reported together
with its corresponding p‐value. In this analysis we have used the conventional multiple
testing p‐value correction procedures proposed by Benjamini Hochberg to derive adjusted
p‐values. The preliminary results reveals that Kd shows up‐regulated genes involved
in transmission of nerve impulse and cilium metabolism, suggesting that MORC2 might
act at this level in the peripheral nervous system. Otherwise, Kr shows a major alteration
of main axonal metabolic pathways, including the overexpression of genes related to
the generation of neuronal action potential, transport through the axon and its targeting
in synapse formation. Kr also shows a marked alteration of gene expression related
to organization, assembly and cilium movement and with the axonemal dynein complex
assembly. This study provides an important step towards understanding the pathomechanism
underlying to MORC2 p.R252W and its role in CMT2Z. Funds: ISCIII (PI15/00187) and
Fundación Ramón Areces.
THE AIFM1 p.F210S MUTATION DOES NOT CAUSE AN APOPTOTIC FAILURE BUT AN ACTIVATION OF
SENESCENT PROGRAM IN FIBROBLASTS DERIVED FROM PATIENT BIOPSIES
Sancho P
1,2, Sánchez‐Monteagudo A1,2, Collado‐Padilla A1,2, Marco C3,4, Domínguez C5, Camacho
A6, Knecht E2,4,7, Espinós E1,2,8*, Lupo V1,2,8.
1Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro
de Investigación Príncipe Felipe (CIPF), Valencia, Spain; 2INCLIVA & IIS La Fe Rare
Diseases Joint Units, Valencia, Spain; 3Unit of Structural Enzymopathology, Instituto
de Biomedicina de Valencia, Spain; 4CIBER of Rare Diseases (CIBERER), Centro de Investigación
Príncipe Felipe (CIPF), Valencia, Spain; 5Department of Neurology, Hospital 12 de
Octubre, Madrid, Spain; 6Department of Neuropediatrics, Hospital 12 de Octubre, Madrid,
Spain; 7Unit of Intracellular Protein Degradation, Centro de Investigación Príncipe
Felipe (CIPF), Valencia, Spain; 8Department of Genomics and Traslational Genetics,
Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.
AIFM1 encodes a mitochondria associated apoptosis inducing factor. Mutations in AIFM1
lead to a wide spectrum of neurodegenerative disorders: Cowchock syndrome; a combined
oxidative phosphorylation deficiency 6 (COXPD6) with severe encephalomyopathy; X‐linked
deafness with peripheral sensory neuropathy; spondyloepimetaphyseal dysplasia (SEMD)
with mental retardation; and an infantile motor neuron disease. Previous studies showed
severe defects in mitochondrial metabolism, related to redox function, mitochondrial
fragmentation, and respiratory deficiencies. In addition, some mutations impair the
protein expression of AIFM1 and cause an increase in caspase‐independent apoptosis.
By targeted next‐generation sequencing, we detected the AIFM1 c.629C>T (p.Phe210Ser),
in a 12 year‐boy. This mutation was confirmed in his 7 year‐old affected brother.
Electromyography and nerve conduction velocities studies revealed an axonal polyneuropathy
with exclusive involvement of motor fibers, with an early childhood‐onset. Both children
currently show normal cognitive and cranial nerves functions. The in silico structural
modeling of human AIFM1 showed that the mutation of a phenylalanine to serine at position
210 disrupts the hydrophobic interaction between Phe210 and Pro207, and consequently,
it destabilizes an alpha‐loop domain. Cartoon of protein superposition between two
different human AIFM1 structures suggest that a lack of constraints in this region
could affect the interaction between 517–533 helix and the 190–202 β‐hairpin regions,
a very important stage for the functional activity of the AIFM1 protein. Patient‐derived
fibroblasts were used to investigate the pathological effect of the p.Phe210Ser mutation:
Fibroblasts from patients show a similar mRNA but different protein expression of
AIFM1 compared to healthy control fibroblasts. However, they have an aberrant morphology,
from fibroblastic to polygonal shape, and they are larger than control fibroblast;
mitochondria from mutant fibroblasts are markedly fragmented compared to controls;
the viability of the patient's fibroblasts is lower, but it does not correlate with
an increase in apoptosis. Instead, it seems to be caused by an increase in the expression
of genes activating the senescent program, like P21 and P16. Our study confirms that
variable effect of different mutations on the protein function may contribute to the
clinical variability observed in AIFM1 patients. Funds: ISCIII (PI12/00453); Fundació
per Amor a l'Art.
ESTABLISHMENT OF THE COCULTURE SYSTEM OF IMMORTALIZED SCHWANN CELLS IFRS1 AND MOTOR
NEURON‐LIKE CELLS NSC‐34
Sango K
1, Takaku S1, Niimi N1, Yako H1.
1Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo,
Japan.
Coculture models of neurons and Schwann cells have been utilized for the study of
myelination and demyelination in the peripheral nervous system; in most of the previous
studies, however, these cells were obtained from the primary culture with embryonic
or neonatal animals. Because it is recognized that some biological properties of both
neurons and Schwann cells change with maturation and aging, culture systems of adult
animal cells appear to mimic peripheral nerve degeneration and regeneration better
than those of immature animal cells. We have established spontaneously immortalized
Schwann cell lines from long‐term cultures of adult Fischer rat peripheral nerves.
One of these cell lines, designated IFRS1, has been shown to retain distinct Schwann
cell phenotypes, such as spindle‐shaped morphology with expression of glial cell markers,
synthesis and secretion of neurotrophic factors and cytokines, and fundamental ability
to myelinate neurites in cocultures with adult rat dorsal root ganglion neurons and
nerve growth factor‐primed PC12 cells. Our current investigation focuses on the establishment
of the coculture system of IFRS1 cells and NSC‐34 motor neuron‐like cells. NSC‐34
cells were seeded at a low density (1 x 104/mL) and maintained for a week in serum‐containing
medium supplemented with non‐essential amino acids and brain‐derived neurotrophic
factor (BDNF, 10 ng/mL). After overnight exposure to mitomycin C (MMC, 1 micro g/mL),
NSC‐34 cells were cocultured with IFRS1 cells (1 x 105/mL) and maintained in serum‐containing
medium supplemented with BDNF (10 ng/mL), ciliary neurotrophic factor (CNTF, 10 ng/mL)
and coenzyme Q10 (1 micro M). Under this culture condition, overgrowth of NSC‐34 cells
was prevented and gradual movement of IFRS1 cells toward the neurites emerging from
NSC‐34 cell bodies was observed. Double‐immunofluorescence staining carried out at
day 28 of the coculture showed myelin protein zero‐immunoreactive IFRS1 cells surrounding
the beta III tubulin‐immunoreactive neurites. This coculture system can be a beneficial
tool to study the pathogenesis of motor neuron diseases (e.g. amyotrophic lateral
sclerosis, Charcot–Marie–Tooth diseases and immune‐mediated demyelinating neuropathies)
and novel therapeutic approaches against them.
ACUTE TRANSIENT POLYNEURITIS ASSOCIATED WITH ZIKA VIRUS INFECTION
Santos PP1, Torezani GS1, Maciero L1, Pagliarini LFD1, Romão TT
1, Abunahman MS1, Ferreira IS1, Bittar C1, Pupe C1, Nascimento OJM1.
1Universidade Federal Fluminense (UFF), Rio de Janeiro, Brazil.
Zika virus (ZIKV) is a flavivirus related to Dengue, Yellow Fever and West Nile viruses,
and has been recently associated to the occurrence of neurological complications in
children and adults. Previous studies have linked ZIKV to the development of Guillain‐Barré
syndrome (GBS), myelitis, meningoencephalitis and ophthalmological manifestations
in adults. Guillain‐Barré syndrome (GBS) encompasses a spectrum of post‐infectious
neuropathies characterized by different distributions of weakness and sensory impairment.
Serum anti‐ganglioside antibodies are often found and are related to different clinical
patterns. Recently we have encountered patients in Rio de Janeiro, Brazil, with distal
edema in lower limbs, acute weakness, pain and sensory disturbances during the acute
stage of an acute febrile exanthematous illness. The symptoms persist for up to 7days,
with complete resolution afterwards, without specific therapy. Blood concentrations
of muscle enzymes show normal values, and electromyography and nerve conduction studies
(EMG/NCS) are usually unremarkable. Of note, all cases have had positive RT‐PCR for
Zika virus, indicating an illness that occurred during the viremic phase of this arbovirus
infection, and complete recovery within the expected timeframe for the resolution
of the systemic viremia. There is a subset of patients who developed acute weakness
very early after the initial viral symptoms, with clinical, laboratorial and electrophysiological
findings that substantially differ from GBS. We describe three cases with similar
features suggestive of an acute infective polyneuritis (AIPN). One might hypothesize
that ZIKV might lead to a direct neurotropic injury, significant enough to cause weakness
and sensory complaints, but not severe enough to cause permanent damage, resolving
in conjunction with decreasing blood viremia. We consider that these patients differ
from classical GBS because their illness begins during the acute febrile stage of
an infective illness and the clinical course is more rapid leading to complete resolution
in a few days.
A PEDIATRIC SERIES OF GUILLAIN BARRÉ SYNDROME INCLUDED IN IGOS PROTOCOL IN ARGENTINE
Savransky A
1, Mozzoni J2, Massaro Sanchez MP1, Reisin R3, Monges MS1.
1Department of Neurology, Hospital de Pediatria J.P. Garrahan, Buenos Aires, Argentine;
2Department of Physical Therapy, Hospital de Pediatria J. P Garrahan, Buenos Aires,
Argentine; 3Department of neurology, Britain Hospital, Buenos Aires, Argentine.
Our objective is To describe a series of children with Guillain Barré syndrome (GBS)
included in the IGOS protocol. As part of the IGOS multicenter protocol, pediatric
patients meeting GBS diagnostic criteria, who consulted within the first 2 weeks of
symptom onset and had parental consent to participate in the study were included.
Patients were also offered to participate in the extended 3‐year protocol. All patients
were evaluated according to the IGOS protocol. Patients were recruited between October
2013 and June 2015. Twenty‐four patients, eight girls, participated. Ages ranged from
6 months to 14 years (mean 5.8 years). All patients agreed to participate in the extended
protocol, which was completed by 10 of them. Eight patients completed the 2‐year follow‐up
and are still under evaluation. Five patients were lost to follow‐up.Twenty‐two had
the classic variant of GBS and two Miller Fisher. Radicular pain in the back or lower
limbs was reported by 70%. Twenty‐three patients underwent lumbar puncture and albumin‐cytological
dissociation was found in 22. In all cases, CSF was stored for proteomic studies.
All patients underwent EMG showing AIDP in 22, and AMSAN and AMAN in 1 each. One patient
with AIDP developed to CIDP. In 13 patients full‐spine MRI was performed and cauda
equina enhancement was found in every case. Three patients required UCIP, two with
invasive and one non‐invasive ventilation. All patients were treated with gammaglobulin,
with a second dose at 2 weeks in cases with a poor response. All 19 patients who followed
the protocol were evaluated with the GBS disability score. Median score was 4 at baseline
and between 0 and 1 at the 2‐year assessment. We describe a series of children with
GBS as a part of an international protocol including patients of different ages. Pain
was a frequent and early symptom and could be determined despite the young age of
our patients. Most patients fully recovered. We were invited to participate in IGOS
KIDS to better assess this age group.
A DESCRIPTION OF GUILLAIN‐BARRE SYNDROME IN LAO PEOPLE DEMOCRATIC REPUBLIC
Saysavath K
1, Somchit V2, T. Umapathi3.
1Mittaphab Hospital, Vientiane, Lao PDR; 2Setthathilath Hospital Vientiane; 3National
Neuroscience Institute, Singapore, Singapore.
Laos People Democratic Republic is a country of 6.5 million people in South East Asia.
Largely agricultural, its capital and metropolis is Vientiane. Adult neurological
services are concentrated at Mittaphab Hospital, Vientiane serviced by three Neurologists.
On the average about six cases of Guillain‐Barré syndrome (GBS) are seen per year.
It is believed that most patients do not seek medical attention. Cases appear to cluster
during the rainy season. Most patients present late, often at the second week of illness
when recovery is unapparent after seeking treatment from traditional medicine doctors
and at district hospitals. A substantial number of patients seek treatment at hospitals
across the border, in neighboring provinces of Thailand. Common antecedent symptoms
are viral prodrome and diarrhea. Miller Fisher syndrome appears to be rare, possibly
because of the mild deficits that do not prompt patients to seek medical attention.
Diagnosis is made largely from clinical features and from spinal fluid analysis. Nerve
conduction studies are not available. Patients are often treated with steroids by
internists. Intravenous immunoglobulin and plasma exchange are not available. Common
complications include pneumonia, autonomic dysfunction (fluctuating blood pressure),
pressure sores and depression. Patients who develop respiratory failure are nursed
at a twelve‐bedded intensive care units. Plans are afoot to set up a prospective GBS
database, systematically study antecedent infections, including of flaviviruses, and
develop low‐volume plasma exchange as a feasible therapeutic modality.
A GENE THERAPY APPROACH FOR TREATING CMT4C NEUROPATHY
Schiza N
1, Markoullis K1, Richter J2, Tryfonos C2, Kagiava A1, Sargiannidou I1, Christodoulou
C2, Kleopa KA1,3.
1Neuroscience Laboratory; 2Department of Molecular Virology; 3Neurology Clinics, Cyprus
Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia,
Cyprus.
Charcot‐Marie‐Tooth Type 4C (CMT4C) is the most frequent form among recessively inherited
demyelinating neuropathies and results from mutations in the SH3TC2/KIAA1985 gene.
SH3TC2 mutations cause loss of function of the SH3TC2 protein suggesting that gene
replacement therapy may be useful for treating CMT4C. Sh3tc2−/− mice develop all major
aspects of the human pathology including early onset progressive peripheral neuropathy
with hypo‐ and demyelination along with decreased motor and sensory nerve conduction
velocities, offering a relevant model for testing treatments for CMT4C. In order to
develop a gene replacement strategy for CMT4C, we generated a novel lentiviral vector,
LV‐Mpz‐SH3TC2.myc, to drive expression of the human SH3TC2 cDNA under the control
of the myelin protein zero (Mpz/P0) promoter specifically in myelinating Schwann cells.
A C‐terminus myc tag was included to facilitate expression analysis. A control vector
(mock) was also produced in which the SH3TC2 cDNA was replaced by the EGFP reporter
gene. We first confirmed expression of hSH3TC2 in Hela cells transfected with the
pcDNA3‐CMV‐SH3TC2.myc vector. Immunofluorescence analysis confirmed a strong expression
of SH3TC2 specifically at the plasma membrane with additional localization in a dotted
pattern intracellularly. For in vivo gene delivery we used both intraneural and intrathecal
injections of the LV‐Mpz‐SH3TC2.myc vector in 2‐week to 4‐month old sh3tc2−/− mice.
Expression of virally delivered hSH3TC2 was assessed 4 weeks after injection. Immunofluorescence
analysis showed hSH3TC2 immunoreactivity in perinuclear Schwann cell cytoplasm in
sciatic nerve teased fibers of sh3tc2−/− mice following both intraneural and intrathecal
delivery, while lumbar intrathecal gene delivery resulted additionally in expression
of hSH3TC2 in the lumbar roots. Real time PCR analysis confirmed hSH3TC2 mRNA expression
in both lumbar roots and sciatic nerves. Thus, we have developed a novel lentiviral
vector for Schwann cell targeted gene delivery to treat CMT4C and for testing possible
therapeutic effects in the mouse model of the disease.
Funded by: CMT Association (USA) and by AFM‐Téléthon
SARM1 AND NAD INVOLMENT IN AXONAL DEGENERATION IN DEMYELINATING HEREDITARY NEUROPATHY
CMT1A
Schmidt J
1, Gess B1.
1Uniklinikum RWTH Aachen, Germany.
Hereditary neuropathies are a group of disorders which are characterised by the systemic
impairment of peripheral nerves. More than 200 neuropathies are associated with causative
gene defects [1]. Charcot Marie Tooth (CMT1A) neuropathy is the most frequent hereditary
neuropathy, triggered by a mutation in the peripheral myelin protein gene 22 (PMP22).
CMT1A leads to a primary loss of myelin sheath and afterwards to a degeneration of
axons [2]. Symptoms appear with the degeneration of axons, whereas demyelination is
thought to be largely asymptomatic. For that reason, we investigate in the mechanisms
of axonal degeneration. For our analysis, we used purified axoplasma without detectable
myelin proteins of the sciatic nerves of 20 weeks old PMP22‐C61 mice. In this early
stage of the axonal degeneration SARM1 was significantly increased. The NAD+ concentration
in the axoplasma was dramatically reduced. This correlates to the previous finding
that SARM1 promotes axonal degeneration by cleavage of NAD+. Additional studies showed
an increase of the NAD+‐dependent axonal protective factor Sirt3 in PMP22‐C61 sciatic
nerves. NMNAT‐1, known as the active component of the Wallerian degeneration slow
gene, was unaffected in axoplasma of PMP22‐C61 sciatic nerves.
Summarised, these results indicate that the pathway of SARM1, NAD+ and Sirt3 may play
a critical role in axonal degeneration in neuropathy.
1. Weis, J., et al., Towards a functional pathology of hereditary neuropathies. Acta
Neuropathologica, 2016: p. 1–23.
2. Krajewski, K.M., et al., Neurological dysfunction and axonal degeneration in Charcot–Marie–Tooth
disease type 1A. Brain, 2000. 123(7): p. 1516–1527.
CMT2B2 IN CZECH PATIENTS WITH DIFFERENT GLAUCOMA PHENOTYPES AND THREE NOVEL SBF2 MUTATIONS,
ONE OF THEM DE‐NOVO
Seeman P
1, Laššuthová P1, Neupauerová J1, Mazanec R2, Senderek J3
1Dept of Pediatric Neurology, 2nd Medical Faculty, Charles University, Prague, Czech
Republic; 2Dept of Neurology, 2nd Medical Faculty, Charles University, Prague, Czech
Republic; 3Friedrich Baur Institute, Ludwig – Maximilian University, Munich, Germany.
Charcot‐Marie‐Tooth type 4B2 is a rare autosomal recessive, demyelinating neuropathy
caused by biallelic mutations in the SBF2/MTMR13 gene. Only 19 pathogenic mutations
were described since 2003, most of them truncating.
We report two unrelated Czech patients with CMT4B2, both sporadic cases in the family.
Patient 1 is a 27 year old man with congenital glaucoma after 8 ophthalmological surgeries.
His early motor development was normal. At the age of 10 years parents noted gait
problems, first neurological examination was at the age of 11 years, when EMG showed
diffuse motor and sensory neuropathy with severely decreased NCV (22–29 m/s). He developed
foot deformities (pes cavovarus) and underwent corrective orthopedic surgeries at
the age of 16 years. After several DNA tests for demyelinating CMT the SFB2 gene was
Sanger sequenced and a novel missense mutation p.Ile45Asn was found in homozygous
state in the patient and in heterozygous state in both parents. The patient was later
tested also by NGS of a panel of all 78 genes to be causal for hereditary neuropathies
and no other potentially causal variants were detected.
Patient 2 is 35 years old man, with normal early motor development. At the age of
4 years parents noted gait problems with distal leg weakness which progressed into
distal leg plegia at the age of 9 years. Hand weakness was noticed since the age of
10 years. He has severe atrophies of distal muscles of all extremities, is self ambulant.
At the age of 25, EMG showed unrecordable responses from nerves of lower limbs and
NCV was measurable only on ulnar nerve and was 13 m/s. At the age of 30 years increased
intraocular pressure was diagnosed and he uses anti glaucoma eye drops. After many
single gene tests for demyelinating CMT, we used NGS of a panel of 97 genes known
to be causal for hereditary neuropathies and two novel heterozygous, probably pathogenic
variants affecting invariant splice sites were detected: c.1601‐2A>G and c.5232‐10_5244del,
both confirmed by Sanger sequencing. The first variant is also in the father, but
the second is probably de‐novo (not detected in parents, despite correct parentity).
DOPPLER ULTRASONOGRAPHY FINDING BETWEEN PRE‐ AND POST‐ OPERATION IN CARPAL TUNNEL
SYNDROME
Sekiguchi Y
1, Kikuchi SI1, Konno SI1, Sekiguchi M1.
1Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine,
Fukushima, Japan.
Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy. Ultrasonography
can be used to detect anatomic changes in CTS. More recently, it has been shown that
Doppler ultrasonography can detect increased intraneural blood flow in CTS. The purpose
of this study was to determine the most suitable finding of pre‐ and post‐ operation
in CTS by ultrasonography. A total of 40 wrists of 25 patients with nerve conduction
study (NCS) proven CTS were evaluated with ultrasonography. We measured the median
nerve's cross‐sectional area (CSA) and intraneural blood flow of median nerve by ultrasonography.
The correlation between these ultrasonographic measurements, NCS severity and duration
of clinical CTS symptoms was analyzed. The CSA (mean, 13 mm2) was no significantly
reduction after successful carpal tunnel release. Morphologic median nerve changes
may persist for a longer period regardless of successful surgery and clinical improvement.
However, intraneural blood flow is increasing after successful carpal tunnel release.
We conclude that Doppler ultrasonography results strongly correlate with post operated
CTS improvement. Hence Doppler ultrasonography is a useful method for functional improvement
of pre‐ and post CTS operation.
ELECTRICAL STIMULATION AS A CONDITIONING LESION FOR PROMOTING PERIPHERAL NERVE REGENERATION
Senger JL
1, Chan KM1, Olson JL1, Webber CA1.
1University of Alberta, Edmonton, Canada.
The beneficial effects of a preinjury crush conditioning lesion (CL) on peripheral
nerve regeneration is well‐documented in animal models. No human studies have been
attempted to date, given the ethical dilemma of deliberately injuring an intact nerve,
and the difficulty in predicting the timing of a nerve injury. Recent studies demonstrate
that 1 hour of electrical stimulation (ES) produces effects similar to CL in neuronal
cultures. This, coupled with a surgical environment favoring nerve transfers, in which
an intact nerve is deliberately cut to reinnervated a denervated muscle, means that
ES may be clinically translatable to enhance regeneration. This study hypothesizes
that ES prior to nerve injury will enhance nerve regeneration. Twelve Sprague–Dawley
rats were divided into four groups based on conditioning‐type to the mid‐common peroneal
(CP) nerve: ES (4), crush (4), sham‐ES (2), and naïve (2). One week following conditioning,
they underwent a cut/coaptation of the CP nerve at the sciatic trifurcation. Post‐cut
day 14, nerves and dorsal root ganglia (DRGs) were collected. Axonal counts of nerves
stained with NF‐200 revealed similar regeneration between ES and crush (3.2 vs. 3.8
mm, p=0.6648) that was superior to sham‐stimulation (1.3 mm) or no‐conditioning (1.0
mm, p<0.05). A greater number of axons at the distal tip were present in animals that
received either type of conditioning compared to the unconditioned cohorts. DRGs were
stained with neuronal injury marker Growth Associated Factor‐43 (GAP‐43), and satellite
cell glial cells with Glial Fibrillary Acidic Protein (GFAP). Significant increase
in GAP‐43 expression at three days was observed in ES and crush cohorts compared to
sham or naïve (p<0.001) cohorts. The satellite glial cells of ES and crush conditioning
showed a significant increase in GFAP expression (29.3% and 39.3% respectively) compared
to sham (8.6%) and naïve (13.5%) DRGs. By demonstrating similar improvements in axon
regeneration, this proof of principle project suggests that ES conditioning may produce
regenerative outcomes comparable to the classical crush injury model. In turn, this
suggests that ES may be a promising method for delivering conditioning lesions in
clinical trials for conditioning nerves prior to surgical intervention.
NEWLY DEVELOPED WALDENSTROM MACROGLOBULINEMIA DURING IMMUNOMODULATORY TREATMENT FOR
ANTI‐MAG ANTI‐SULFATIDE CIDP
Serban V
1.
1Neurology Clinic, Turda, Cluj, Romania.
We report a unique case of newly developed Waldenstrom's macroglobulinemia (WM) in
a patient with chronic inflammatory demyelinating polyneuropathy (CIDP) with antibodies
against myelin‐associated glycoprotein (MAG) and sulfatide who was undergoing treatment
with intravenous immunoglobulines (iv‐IG). Subsequent Rituximab infusions did not
have a positive impact.
Patients with WM can develop demyelinating and axonal polyneuropathies and few patients
have anti‐MAG and/or anti‐sulfatide antibodies. Anti‐MAG antibodies (4% of WM) are
associated with sensorimotor axon loss and demyelination and anti‐sulfatide (5% of
WM) with sensory axonal loss. Rarely, both antibodies can be present, with a more
severe clinical phenotype.
CIDP associated with anti‐MAG and anti‐sulfatide antibodies can represent independent
entities, not associated with WM.
There are no reports to date of patients with CIDP associated with anti‐MAG and anti‐sulfatide
antibodies that developed WM during immunomodulatory therapy with iv‐IG. In addition,
subsequent Rituximab infusions after the iv‐IG were stopped have not been proven beneficial,
as has been previously reported for anti‐MAG CIDP patients.
Seventy‐six year old right‐handed gentleman presented with persistent numbness in
his left foot, three months following artificial disc placement in his lumbar spine.
Gradually he developed sensory ataxia. No radicular signs were present on exam or
impingement on serial spine MRI's. NCS/EMG studies were consistent with a CIDP variant
with severely prolonged distal motor latencies. Serum anti‐MAG and anti‐sulfatide
antibodies were elevated. Chronic therapy with iv‐IG was able to partially stabilize
the symptoms; however, six years later he newly developed WM. Subsequent infusions
with Rituximab, after iv‐IG was stopped, did not improve the clinical picture or the
NCS/EMG findings.
WM can newly develop in an autoimmune setting, such as CIDP associated with anti‐MAG
and anti‐sulfatide antibodies. In this particular case, there was an ongoing immunomodulatory
therapy for our CIDP patient, as he had monthly iv‐IG infusions. This may reflect
a possible induction of pathological B cell clone proliferation during the iv‐IG treatment.
Subsequent Rituximab infusions, after the iv‐IG was stopped, did not improve the symptoms
or the demyelination features on NCS/EMG. He continues to be symptomatic despite efforts.
THE GERMAN CHARCOT‐MARIE‐TOOTH DISEASE NETWORK (CMT‐NET): FROM RISK FACTORS TO THERAPEUTIC
ACTIONS
Sereda MW
1,2, Walter MC3, Martini R4, Young P4.
1University Medical Centre Göttingen, Germany; 2Max‐Planck‐Institute for Experimental
Medicine, Göttingen, Germany; 3Friedrich‐Baur‐Institute, Ludwig Maximilians University,
Munich, Germany; 4University Hospital Würzburg, Germany; 4 University of Münster,
Germany
Charcot‐Marie‐Tooth disease (CMT) is an inherited neuropathy without known cure (prevalance:
1:2500). Duplication of the gene encoding the peripheral myelin protein of 22kDA (PMP22)
underlies the most common subtype CMT1A. Severely affected CMT patients suffer from
sensory and motor symptoms with wheelchair‐boundness. The clinical phenotype is highly
variable and is determined by the amount of axonal loss, but the molecular mechanisms
of the disturbed neuron‐glia interaction are poorly understood. Risk factors have
not been investigated. Therefore, CMT‐NET, a German network funded by the German ministry
of education and research (BMBF, Bonn, Germany) includes interdisciplinary expertise
from molecular biology, neurology, neuropathology and human genetics in order to identify
genetic and non‐genetic risk factors of disease severity of CMT by: (i) examining
the mechanisms of the disturbed axon‐glia‐interaction and neuronal vulnerability,
(ii) identification of genetic modifiers and (iii) novel therapeutic targets, (iv)
validating outcome measures in children and adults, (v) establishing a biobank and
(vi) exploring the disease burden via an internationally harmonised patient registry.
CMT‐NET includes three service structures
CMT‐NET will focus on CMT1A, but also includes rarer subforms. We will provide the
scientific basis for the development of translational approaches to therapy in patients.
Our approach bridges cutting edge molecular screening techniques, transgenic animal
models of altered axon‐glia interactions (fly, chick, mouse, rat), state‐of‐the‐art
genomic technologies and human patient trials in order to understand and treat the
disease aggravation in CMT.
PERIPHERAL ANTINOCICEPTIVE EFFECT OF VENLAFAXINE IN RATS
Sezer G
1, Tekol Y2, Sezer Z2,3.
1Erciyes University, Betül Ziya Eren Genome and Stem Cell Centre, Kayseri, Turkey;
2Erciyes University, School of Medicine, Pharmacology Department, Kayseri, Turkey;
3Erciyes University, Good Clinical Practice and Research Centre, Kayseri, Turkey.
Analgesic effects of antidepressant drugs are well known for a long time, however,
their systemic side effects limit their usage as an analgesics. Venlafaxine is an
antidepressant drug that has different structure. Our purpose was to investigate whether
systemic analgesic effect has been proved drug, venlafaxine, has local peripheral
antinociceptive action. We applied vanlafaxine (25 µl 50, 100, 200, 400 µg) to male,
Sprague–Dawley rats' paws by intraplantar injection and also by intraperitoneal route
(5, 10, 20, 40 mg/kg) in formalin test, a model for acute and tonic pain. We also
pretreated another groups of rats with 2 mg/kg naloxone (opioid receptor antagonist),
2 mg/kg CPT (adenosine A1 receptor antagonist) or saline (ip.) before 200 µg/paw venlafaxine
injection. To check the effect is local or not, we determined the blood levels of
venlafaxine in at different time points after both the local and systemic applications
by GC‐MS method. Datas were expressed as number of flinches and total time for biting/licking
of the injected paw over phase 1 (0–12 min) or phase 2 (16–60 min) and analyzed using
the Student's t‐test.
Venlafaxine induced antinociception at 100, 200 and 400 µg concentrations by the local
peripheral application and at 20, 40 mg/kg doses by the systemic application in formalin
test and the effects were comparable. Pretreatment with naloxone diminished the effect
of venlafaxine in the both phases, however, it was not statistically significant.
Pretreatment with CPT decreased venlafaxine induced antinociception only in phase
1. Neither naloxone nor CPT changed formalin induced nociceptive behaviors alone.
This is the first that determines the peripheral antinociceptive actions of venlafaxine
in rat formalin test. with roles of opioid and adenosine A1 receptors in this action.
Our results suggest that venlafaxine has local peripheral antinociceptive effect and
such an activity may led to trials for to use this drug as a cream‐gel formulation
for analgesia in clinics in the future. Topical application might permit the attainment
of higher and more efficacious concentrations in the region of the sensory nerve terminal,
with limited systemic side effects.
INCIDENCE OF CHEMOTHERAPY‐INDUCED PERIPHERAL NEUROPATHY AND LONG TERM DISEASE BURDEN
ON CANCER SURVIVORS IN A POPULATION‐BASED COHORT
Shah A1, Hoffman EM1, Klein CJ1, Staff NP
1.
1Mayo Clinic, Rochester, USA.
CIPN is a common dose‐limiting complication for patients with cancer. The long‐term
disease burden of CIPN is compounded by increasing cancer survivorship, yet there
are minimal data on long term outcomes following onset of CIPN, especially in population‐based
studies. We utilized the Rochester Epidemiology Project to examine incidence and disease
burden of CIPN among individuals of Olmsted County, Minnesota with neurotoxic chemotherapy
exposure between 2006 and 2008. Clinical records were queried for the presence of
neuropathic signs, symptoms and ICD‐9 diagnostic codes as well as for patient provided
information on impairment with activities of daily living and use of pain medications.
A total of 511 individuals with incident exposure to neurotoxic chemotherapy agents
between 2006 and 2008 were identified. Based on AAN criteria for identifying peripheral
neuropathy, 268 (54.4%) of these individuals were determined to have CIPN, while 241
(45.6%) controls did not. The median time from incident exposure to reported symptom
onset was 71 days (IQR 28.5‐122). Patients with CIPN received a neuropathy ICD‐9 diagnosis
in merely 37 cases (13.8%). Median survival following incident chemotherapy exposure
among all cases and controls was 5.0 years with a significantly longer mean survival
in cases with CIPN as compared to that of controls (6.4 years vs. 1.8 years, p<0.0001).
In addition to acute effects in CIPN, individuals surviving greater than 5 years following
exposure to neurotoxic chemotherapy continue to self‐report increased symptoms of
numbness (OR 2.8, 95% CI 1.6‐5.2) and pain (OR 1.9, 95% CI 1.1.3.2) of the extremities.
Through utilization of patient provided information, our study was able to collect
data on long‐term impairment associated with previous history of exposure to neurotoxic
chemotherapy. Our results are consistent with previous reports of the high incidence
of CIPN in the first two years following incident exposure. Additionally, our results
provide evidence of high incidence of CIPN independent of individual chemotherapeutic
agent used. Additionally, our results indicate ICD‐9‐CM diagnostic code attribution
may dramatically underestimate the magnitude of CIPN. Increased survival following
exposure to neurotoxic chemotherapy and its long‐term disease burden necessitates
further study of among survivors.
QUANTITATIVE MUSCLE ULTRASOUND AS A BIOMARKER IN CHARCOT‐MARIE‐TOOTH NEUROPATHY
Shahrizaila N
1,2, Noto Y1, Simon NG3, Huynh W1, Shibuya K1, Matamala JM1, Dharmadasa T1, Devenney
E1, Kennerson ML4, Nicholson GA4, Kiernan MC1.
1Brain and Mind Centre, University of Sydney, Camperdown, Australia; 2Department of
Neurology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 3St
Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia;
4ANZAC Research Institute and Sydney Medical School, University of Sydney, Sydney,
Australia.
The utility of quantitative muscle ultrasound as a marker of disease severity in Charcot‐Marie‐Tooth
(CMT) disease subtypes was investigated. Muscle ultrasound was prospectively performed
on 252 individual muscles from 21 CMT patients (9 CMT1A, 8 CMTX1, 4 CMT2A) and compared
to 120 muscles from 10 age and gender‐matched controls. Muscle ultrasound recorded
echogenicity and thickness in representative muscles including first dorsal interosseus
(FDI) and tibialis anterior (TA). Muscle volume of FDI and thickness of TA correlated
with MRC strength. Muscle echogenicity was significantly increased in FDI (65.05 vs
47.09; p<0.0001) and TA (89.45 vs 66.30; p<0.0001) of CMT patients. In TA, there was
significantly higher muscle thickness (23 vs 18 vs 16 mm; p<0.0001) and lower muscle
echogenicity (80 vs 95 vs 108; p<0.0001) in CMT1A compared to CMTX1 and CMT2A. This
corresponded to disease severity based on muscle strength (MRC grading CMT1A vs CMTX1
vs CMT2A: 59 vs 48 vs 44; p=0.002). In CMT, quantitative muscle ultrasound of distal
limb muscles is a useful marker of disease severity. The current findings suggest
that quantitative muscle ultrasound has potential as a surrogate marker of disease
progression in future interventional trials in CMT.
MODELING THE PATHOGENESIS OF CHARCOT‐MARIE‐TOOTH DISEASE TYPE 1A USING PATIENT‐SPECIFIC
IPSCS
Shi L
1,2, He RJ1, Huang LH3,Zheng MY1, Lu XL1, Pei Z1, Su HX4, Huang WJ3, Ke Q3, Lai XQ2,
Xiang AP3,5, Li WQ3,5, Yao XL1.
1Department of Neurology, The First Affiliated Hospital, Sun Yat‐Sen University, Guangzhou,
China; 2Division of Neurosurgical Intensive Care Unit, Department of Critical Care
Medicine, The First Affiliated Hospital, Sun Yat‐Sen University, Guangzhou, China;
3 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells
and Tissue Engineering, Ministry of Education, Sun Yat‐Sen University, Guangzhou,
China; 4State Key Laboratory of Quality Research in Chinese Medicine, Institute of
Chinese Medical Sciences, University of Macau, Macao, China; 5Department of Biochemistry,
Zhongshan Medical School, Sun Yat‐sen University, Guangzhou, China.
Charcot‐Marie‐Tooth (CMT) disease is the most frequent inherited peripheral neuropathy,
and there is currently no available cure. The most common subtype of CMT, CMT1A, is
completely associated with duplication of the PMP22 gene, which encodes peripheral
myelin protein 22 of Schwann cells. Previous studies of CMT1A mainly relied on rodent
models, and it is not yet clear how PMP22 overexpression leads to the phenotype in
patients. Based on induced pluripotent stem cell (iPSC) technology, we herein developed
a brand new in vitro cell model of CMT1A, called CMT1A‐hiPSCs, in the hopes of simulating
the developmental progress of the disease and gaining new insights into its pathogenesis.
Here, we efficiently derived NCSCs from CMT1A‐iPSCs and assessed the potential of
the isolated CMT1A‐neural crest stem cells (NCSCs) to differentiate into peripheral
neurons and Schwann cells using defined media. We found that, unlike normal control
NCSCs, CMT1A‐NCSCs rarely generated Schwann cells. Instead, CMT1A‐NCSCs produced numerous
endoneurial fibroblasts in the Schwann cell differentiation system. We further established
a PMP22‐overexpressing iPSC model, and obtained similar results when PMP22‐NCSCs were
subjected to Schwann cell differentiation. These results suggest that the development
of Schwann cells in CMT1A patients is interrupted by the duplication of PMP22. With
the exception of the demyelination‐remyelination process, developmental disabilities
of Schwann cells should be considered as an underlying cause of CMT1A.
CHARACTERISTIC OF RECOVERY FROM MUSCLE FATIGUE IN CHARCOT‐MARIE‐TOOTH PATIENTS WITH
ELECTROMYOGRAPHIC STUDY (THIRD REPORT)
Shimoi T
1, Yamada T2.
1International University of Health and Welfare, Tochigi, Japan, 2CMT Japan, Tokyo,
Japan.
Charcot‐Marie‐Tooth (CMT) disease is the most common hereditary motor and sensory
neuropathy. Our preliminary report suggests that a certain CMT patient has the recruitment
disorder of motor units during muscle fatigue and this disorder may be a factor of
"super fatigability" in motor neuropathy patients. If the "super fatigability" occurs,
we would expect patients with this characteristic to become slower in recovery from
muscle fatigue than patients without this characteristic. In order to verify this
hypothesis, we measured characteristic of recovery from muscle fatigue in Charcot‐Marie‐Tooth
Patients with electromyographic study. Twenty three participants were asked to maintain
their 75% of maximal voluntary isometric contraction (MVC) of elbow flexor until exhaustion
as the fatigue exercise. In addition, the participants asked to perform 5s of their
50% of MVC at 30, 60, 90, 120, 180, 240, 300, 360, 420, 480s after the fatigue exercise
as recovery tasks. The surface EMG (sEMG) signals of biceps brachii muscle were determined
during the exercise and tasks. Muscle force, median power frequency (MdPF) and the
root mean square of sEMG amplitude (RMS) were used as objective parameters of muscle
fatigue. Borg scale was used as a subjective parameter of muscle fatigue. Six of twenty
three participants showed significant decrease of RMS during the fatigue exercise.
In consideration of this result, we compared alteration of MdPF in recovery task between
six participants with decrease of RMS (abnormal group) and seventeen participants
with increase of RMS (normal group). As the result, the abnormal group had at least
180s as the recovery time from muscle fatigue in contrast with 90s of normal group.
The recovery time from muscle fatigue in subjective parameter was shorter than the
time in objective parameters in each group. Our data support the "super fatigability"
hypothesis. And that hypothesis may induce “hidden muscle fatigue”.
COMPARISON BETWEEN COMPLEX REGIONAL PAIN SYNDROME TYPE 1 AND 2 BASED ON ELECTROPHYSIOLOGIC,
IMAGING AND CLINICAL FINDINGS
Shin JY
1, Moon JY1, Sung JJ1.
1Seoul National University Hospital, Seoul, Republic of Korea.
Complex regional pain syndrome (CRPS) is a constant regional neuropathic pain characterized
by various kinds of motor, sensory, and autonomic changes. Conventionally, the CRPS
is divided into type I and II according to the absence and presence of nerve injury.
But the pathogenesis of CRPS is not fully understood yet. And there is still no systematic
comparative study between CRPS type I and II. We compared between CRPS type I and
II using multimodal approaches including electrophysiologic, imaging, and clinical
findings. The 171 patients (135 type I and 36 type II) diagnosed with CRPS using the
International Association for the Study of Pain (IASP) diagnostic criteria were included.
Type I and II were divided by electromyography and nerve conduction study. We obtained
clinical information such as continuing pain, allodynia, hyperalgesia, edema, temperature,
skin color, sweating, trophic change from patients. All patients were evaluated by
bone scan, thermography, quantitative sudomotor axon reflex test (QSART), quantitative
somatosensory test (QST). The ratio of QSART and temperature threshold abnormality
in type II was higher compared to type I (85.7% vs 62.7%, 66.7% vs 46.3% respectively,
P = 0.01 and 0.03), Among clinical symptoms, sweating change significantly high in
type II compared to type I (77.8% vs 38.7%, P = 0.04). Other electrophysiologic and
imaging, clinical findings were not significantly different in both type. In this
study, we identified that CRPS type I and II are distinguished not only by the nerve
injury but also by the sudomotor function, and QSART can serve as a good technique
to differentiate between CRPS type I and II. It is estimated that there are two distinct
pathogenesis in CRPS. Our results may be helpful to diagnose CRPS correctly and understand
the pathogenesis of CRPS.
A CURIOUS CASE OF NUMBNESS, DIZZINESS, WETNESS, and DRYNESS – IS ROSS SYNDROME ON
THE SPECTRUM OF SJOGREN NEUROPATHY?
Shu F
1.
1University of California, Los Angeles, Medical Center, Los Angeles, California, USA.
Sjogren Syndrome (SS) is an autoimmune inflammatory disorder of exocrine glands resulting
in xerophthalmia and xerostomia. Ross Syndrome is a rare entity characterized by tonic
pupil, hyporeflexia, and segmental anhidrosis. We present a 33‐year‐old Hispanic woman
with debilitating sensory and autonomic neuropathies, and persistently elevated anti‐SS‐A
and anti‐SS‐B antibodies, without the classic sicca complex. She initially developed
diarrhea and an ear infection, then felt toe and later leg numbness, which eventually
spread to her cheeks and tongue, over few months. Four years later, her thumbs and
index fingers started tingling. Also, she developed orthostatic lightheadedness, tachycardia,
segmental hypohidrosis of the right abdomen, and hyperhidrosis of the remaining trunk,
intermittent erythema, chronic diarrhea, and a 40‐pound weight loss. Her exam demonstrated
orthostatic hypotension, bilateral tonic pupils and light‐near dissociation, sectoral
palsy of the right iris sphincter, stocking‐distribution diminished sensation to all
modalities, pseudoathetosis, areflexia, dysmetria, intention tremor, Romberg, and
sensory gait ataxia. MRI of neuraxis demonstrated T2‐weighted hyperintensity in the
dorsal spinal cord from C4 to the lower thoracic level, with mild atrophy. Electrodiagnostic
testing was consistent with moderate‐to‐severe, length‐dependent, asymmetric, sensory
polyganglionopathies. CSF showed 6 oligoclonal bands. Serology showed elevated Antinuclear
Antibody (1:1280, reference < 1:40), SS‐A (148, reference < 20 U), SS‐B (79, reference
< 20 U), and Rheumatoid Factor (24, reference < 14 IU/mL) titers. The remaining workup
was negative for infection (syphilis, HIV, HTLV, hepatitis, Lyme disease), paraneoplastic
syndrome (anti‐Hu and ganglionic nicotinic acetylcholine receptor antibodies), pyridoxine
intoxication, malignancy (chest/abdomen/pelvis CT, breast ultrasound, axillary lymph
node flow cytometry, colon and esophagus biopsy), celiac disease, vitamin deficiency,
autoimmune disease (anti‐aquaporin 4 and anti‐GQ1b antibodies), and adrenoleukodystrophy.
The patient received IVIg and steroid with some gait improvement and currently takes
mycophenolate. Midodrine and fludrocortisone resolved her dizziness. This case highlights
an important, treatable sensory ganglionopathy and systemic autonomic neuropathy due
to Sjogren Syndrome, and illustrates the overlapping clinical triad of Ross Syndrome,
which may guide future management.
REGULATORY B CELL FREQUENCIES INCREASE AFTER IVIG THERAPY IN INFLAMMATORY NEUROPATHIES
Siles AM
1,2, Assylbekova D1,2, Diaz‐Manera J1,2, Rojas‐Garcia R1,2, Cortes E1,2, Gallardo
E1,2, Illa I1,2, Querol L1,2.
1Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu i Sant
Pau, Univeristat Autònoma de Barcelona, Barcelona, Spain; 2Centro para la Investigación
Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
Inflammatory neuropathies are a heterogeneous group of peripheral nerve diseases that
respond to immune‐therapies. Chronic inflammatory polyradiculoneuropathy (CIDP) and
multifocal motor neuropathy (MMN) are two chronic inflammatory neuropathies responding
to intravenous immunoglobulins (IVIg). B lymphocytes are involved in their pathogenesis.
While widely used in clinical practice, IVIg's mechanism(s) remain not completely
understood. IVIg are reported to lead to B‐cell anergy and to increase regulatory
T‐cell function and frequency. Regulatory B cells (Bregs) are a rare subset of B lymphocytes
that suppress immunopathology acting upon several target cells in the immune system.
Impaired Breg yields have been described in a plethora of autoimmune conditions. The
presence of regulatory B cells in inflammatory neuropathies and the effect of IVIg
therapy on their frequencies has not been studied. The aim of this study is to describe
the frequencies of Bregs in CIDP and MMN and the effect of IVIg on their frequencies.
Patients fulfilling diagnostic criteria for CIDP or MMN and 14 matching controls were
included. PBMCs were obtained by gradient centrifugation before IVIG infusion and
one week after treatment. B‐cells were isolated with negative selection magnetic beads,
cultured and activated with the TLR9 agonist ODN and anti‐human IgG+IgA+IgM. IL‐10
secretion capacity was assessed by flow‐cytometry. Twenty‐eight patients were included
of whom 20 where CIDP and 8 MMN. Of all patients included, 16 received IVIg and were
suitable for pre and post IVIg Breg frequency comparisons. Breg frequencies did not
differ in patients (before IVIg treatment) and controls (p= 0.8518, Mann Whitney test,
Two‐tailed). However, the frequencies of Bregs significantly increased one‐week after
treatment with IVIg (p=0.0121, Wilcoxon matched pairs test, Two‐tailed). When stratifying
by disease subtype, Breg frequencies increased in CIDP patients after IVIg (p=0.0391,
Wilcoxon matched pairs test, Two‐tailed) and in MMN (p=0.1563, Wilcoxon matched pairs
test, Two‐tailed) although results did not reach statistical significance in MMN.
This is the first study that studies the Breg frequencies in CIDP and the first study
that addresses the effect of IVIg on Breg frequencies. Our study provides the proof
of principle that Bregs could become a biomarker for response to IVIg but this would
need a larger and prospective study.
ANTIBODIES AGAINST CELL ADHESION MOLECULES AND NEURAL STRUCTURES IN PARANEOPLASTIC
NEUROPATHIES
Siles AM
1,2, Martínez‐Hernández E3, Diaz‐Manera J1,2, Rojas‐Garcia R1,2, Gallardo E1,2, Illa
I1,2, Graus F3, Querol L1,2.
1Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu i Sant
Pau, Univeristat Autònoma de Barcelona, Barcelona, Spain; 2Centro para la Investigación
Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain; 3Neuroimmunology
Program, August Pi Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic,
University of Barcelona, Spain.
Paraneoplastic neuropathies (PN) are rare, immune‐mediated disorders of the peripheral
nerve with important prognostic implications. Ectopical expression of neural antigens
in the tumor leads to the development of onconeural antibodies. Several autoantibodies
associate to PN, including anti‐Hu, anti‐CASPR2 or anti‐CV2 antibodies but a significant
proportion of PN lack identifiable antigens. Adhesion molecules that are autoantigens
in other neuropathies, like contactin‐1, are present in several types of tumors. Our
study proposes a systematic screening of autoantibodies against neural cell‐adhesion
molecules and neural structures to detect novel antigenic reactivies in PN.
Thirty‐five patients followed in our centre and at the Neuroimmunology‐Multiple Sclerosis
Unit at Hospital Clínic de Barcelona, with PN fulfilling diagnostic criteria of possible
(n=8; 22.9%) and definite (n=27; 77.1%) paraneoplastic disease were included. Serum
samples were obtained and tested by immunocytochemistry against contactin‐1 (CNTNT1),
neurofascin 155 (NF155) and the CNTN1/CASPR1 complex. Primary cultures of dorsal‐root
ganglia (DRG) and rat Schwann cells were incubated with patients' sera to detect antibodies
targeting neural structures. Ten individuals (28.6%) presented with a tumor and a
neuropathy involving both sensory and motor symptoms. The remaining 25 patients (71.4%)
presented with a tumor and a classical sensory neuronopathy without anti‐Hu or any
other onconeuronal antibody. Among the latter, 8 (22.9%) patients were diagnosed with
Small‐cell lung carcinoma. The rest of the 27 individuals (77.1%) associated diverse
malignancies. We did not detect any sera reacting against CNTN1, NF155 or the CNTN1/CASPR1
complex. In IgG antibody screening experiments, 12 patients (34.3%) reacted against
DRG neurons, 3 of them (8.6%) reacting strongly, and 3 patients (8.6%) reacted mildly
against rat Schwann cells. In IgM experiments, 5 patients (14.3%) reacted slightly
against DRG neurons and 11 patients (31.4%) against rat Schwann cells, 4 of them (11.4%)
featuring strong staining. Experiments screening antibodies against motor neurons
and immunoprecipitation assays are ongoing. Overall, 20% of patients reacted strongly
against either neurons or Schwann cells. Our study did not detect antibodies against
the neural adhesion molecules CNTN1, NF155 and the CNTN1/CASPR1 complex in patients
with PN. However, a significant proportion of PN patients harbour antibodies targeting
neural structures, which suggests that novel neoplasm‐associated antigens remain to
be discovered.
CHARCOT‐MARIE‐TOOTH DISEASE TYPE‐1A (CMT1A) PLUS
Simmons M
1, Tao F2, Abreu L2, Zuchner S2, Li J1.
1Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee,
USA; 2Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
Objective: Despite of a shared genetic mutation of the trisomy of chromosome 17p12
(c17p12), patients with Charcot‐Marie‐Tooth type‐1A (CMT1A) present with a high variability
of their disease severities. The underlying cause for the variability is still unclear.
In this study, we tested a hypothesis whether a second genetic mutation known to damage
the nervous system is also present in CMT1A patients with early onset and severe phenotypes.
Methods: From a cohort of 72 patients with CMT1A mutation (chromosome 17p12 duplication),
we identified 11 patients with an early onset (< or = 5 years of age) of the disease.
Four of the eleven also had DNA testing for a panel of 50 known CMT‐related genes
and sequencing of mitochondrial DNA in addition to the DNA testing for c17p12 duplication.
Results: Besides the c17p12 duplication, we identified three additional mutations
in the four patients with early onset. The mutations were a missense mutation of Arg67His
in MPZ gene, an A10044G mutation in mitochondrial tRNA for glycin and a homozygous
mutation of c17p12 duplication. Three of the four had symptomatic onset at birth.
One showed symptoms at 3 years of age. Conduction velocities were severely reduced
in all four patients (from 15 to 6m/s).
Interpretation: Traditional approaches to identify genetic modifiers, including SNP
association, assume that those modifiers are clustered in a small region of human
genome and shared by the studied patients. However, our study suggests that genetic
modifiers in CMT1A may be highly diverse and scattered throughout the genome, which
could make the conventional approach via the genetic variants association difficult.
Supported by grants from NINDS (R01NS066927) and the National Center for Advancing
Translational Sciences (UL1TR000445).
PATTERN OF PERIPHERAL NEUROPATHY IN SJOGREN'S SYNDROME IN A TERTIARY CARE HOSPITAL
FROM SOUTH INDIA
Sireesha Y1, Meena AK1*, Pyal A
1, Sandeep G1, Megha SU1, Mridula KR1, Jabeen SA1, Varaprasad R1, Liza R1, Neeharika
ML1, Rupam B1.
1Nizam's Institute of Medical Sciences, Hyderabad, India.
Sjogren's syndrome(SS) is a systemic auto‐immune disease that apart from exocrine
glands may affect any organ. Involvement of peripheral nervous system results in wide
spectrum of neuropathic manifestations. The Aim of our study was to evaluate the clinico‐electrophysiological
patterns and pathological characteristics of neuropathy in Sjogren's syndrome (SS)
patients presented to neuromuscular clinic in a tertiary hospital from South India.
This is a retrospective study from the Departments of Neurology, Rheumatology and
Pathology from Nizam's Institute of Medical Sciences. Twenty one patients with diagnosis
of SS and peripheral neuropathy between 2010 to 2016 were analysed. Clinical records,
conventional nerve conduction studies, lip and nerve biopsy reports were collected.In
21 patients with SS associated neuropathy,male to female ratio was 2:1. In 14(66.7%)
neuropathy was the initial manifestation,while in 4(20%)exocrinopathy preceded neuropathy.
The patterns of neuropathy included mononeuropathy multiplex(MNM) in 7 patients (30%),ganglionopathy
in 4 (20%),length dependant, trigeminal, autonomic neuropathy and CIDP in 2(10%)and
cranial neuropathy in 1(10%).Eighteen(86%) were seropositive..Schirmer's test was
positive in 13(61.9%).Nerve biopsy showed vasculitis in 5 patients, demyelinating
and axonopathy in 2 patients each.We conclude that neuropathy is frequently the initial
presentation of SS.MNM is the common pattern followed by ganglionopathy. Pattern of
neuropathy helps in arriving at the diagnosis of SS. Confirmation of SS is not by
mere serology. Schirmer's test and lip biopsy are equally essential for the diagnosis
especially in seronegative patients when clinical index of suspicion is high.
A NEW AUTOSOMAL RECESSIVE AMYELINATING CAUSE OF CHARCOT MARIE TOOTH DISEASE WITH CNS
FEATURES AND RESPIRATORY DISTRESS
Siskind CE
1, Tesi Rocha C2.
1Stanford Health Care, Palo Alto, CA, USA; 2Stanford University, Stanford, CA, USA.
Here, we report the first case of a human found to have a homozygous, presumed disease
causing variant in the ARL6IP1 gene, causing Charcot Marie Tooth disease (CMT) with
central nervous system findings. The proband was born at term with Apgars of 3 and
9 at 1 and 3 minutes. He was found to have IUGR and was hospitalized for 9 days for
weight gain. He developed respiratory distress during the admission and was intubated.
Due to inability to extubate, he was transferred to Stanford Children's Hospital,
where he remained for three months. Noted during admission was hypotonia, areflexia,
minimal voluntary movment, sinus tachycardia, and dysautonomia. Brain MRI found polymicrogyria
and cerebral underdevelopment with generally normal‐appearing brainstem, with moderate
ventriculomegaly. NCS found length dependent polyneuropathy with axonal degeneration.
Follow up muscle and nerve biopsy found immature muscle and amyelinating neuropathy
The patient had normal plasma amino acid, acylcarnitine, lactate, pyruvate, urine
organic acid testing, opththalmology exam, newborn screen, and normal array CGH. Genetics
ordered whole exome sequencing through Baylor Genetics Laboratory (Houston, TX, USA),
which found a homozygous nonsense variant in ARL6IP1 : c.346C>T, p.R116X. A second
child had been identified by Baylor with two variants in this gene. That child had
hypotonia, respiratory distress and seizures, and a muscle biopsy consistent with
SMA. The parents of that child chose to withdraw care at 3 months of age. Our patient's
parents continued with aggressive therapies, including tracheostomy and G‐tube for
feedings. He had several subsequent hospitalizations for respiratory distress, possible
seizure activity, and buldging anterior fontenelle, but now, at two years of age,
has made developmental progress and is living at home with his family. He is able
to smile, reaching for toys and swatting objects. He has little voluntary movement,
and no longer responds to light touch stimuli. Overall, this is the first picture
of a child affected with a severe amyelinating form of CMT that causes weakness, hypotonia,
and possible seizures, with the main concerning feature being the severe respiratory
distress that may be life threatening, but can be managed with extreme care.
MONITORING PREGNANCY IN CHARCOT‐MARIE‐TOOTH DISEASE: RESULTS OF A SURVEY
Skorupinska M
1, Laurá M1, Bull K1, Byrne B2, Reilly M1.
1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK; 2Coombe
Women and Infants University Hospital, Dublin, Ireland.
Charcot Marie Tooth (CMT) disease is the most common inherited peripheral neuropathy.
Patients frequently ask whether pregnancy will affect their CMT, whether CMT will
affect their pregnancy, the optimal delivery and whether they or their child will
have a higher risk of complications during pregnancy or delivery. So far few studies
address these questions. Currently no guidelines exist for the management of pregnancy,
delivery and postnatal care in CMT patients.
The aim of the study is assess the impact of pregnancy on CMT and assess how CMT affects
pregnancy, delivery and care of the new born baby.
We designed a retrospective questionnaire with expert help from an obstetrician with
a special interest in pregnancy in patients with medical conditions.
The questionnaire is divided into four parts (prior, during, after pregnancy and delivery)
and includes 29 questions on impairment, falls, pain, fatigue and respiratory complications
during those periods; type of delivery, possible complications, details of anaesthesia
and difficulties looking after the baby in the first months postpartum.
So far 48 women (85 pregnancies) with CMT and related disorders have answered the
questionnaire. 50% of patients had CMT1A, the remaining had various subtypes of CMT
and related disorders. Patients reported deterioration of CMT symptoms during pregnancy
in 34% of pregnancies with resolution of symptoms after pregnancy in 52% of pregnancies.
Of symptoms questioned walking (29%), balance (28%), and hand function (17%) deteriorated
the most. There was an increased use of orthoses and walking aids during pregnancy.
The majority of women (59%) had natural delivery, 17% were assisted and 28% had caesarian
sections which was similar to the UK population (26%). No complications with anaesthesia
were reported.
The survey is currently ongoing. We plan to survey 100 consecutive patients. Data
acquired from this survey will provide valuable information on current practice and
will inform future guidelines and standard of care in Charcot Marie Tooth disease.
CMAP SCAN ANALYSIS IN MULTIFOCAL MOTOR NEUROPATHY
Sleutjes BTHM
1, Kovalchuk M1, van Schelven LJ1, van den Berg L1, Franssen, H1.
1Department of Neuromuscular Disorders, University Medical Center Utrecht, Utrecht,
The Netherlands.
Multifocal motor neuropathy (MMN) is a slowly progressive disorder in adults, characterized
by asymmetrical limb weakness, mainly affecting the arms. Despite beneficial effect
of immunoglobulins, weakness gradually progresses. A major determinant of muscle weakness
is the degeneration of affected motor axons. Treatments aiming to reduce loss of motor
axons require objective tools to quantify such an effect. Therefore, we applied the
compound muscle action potential (CMAP) scan, which is an electrophysiological method
that, with increasing transcutaneous stimulus‐currents, successively activates all
motor units (MUs) in a muscle. It captures the contribution of enlarged MUs due to
reinnervation by the presence of relative large discontinuities in the scan. The aim
of the present study was to identify pathophysiological changes of MU‐loss and reinnervation
in MMN patients by means of the CMAP‐scan. Recordings were obtained from 12 MMN patients.
CMAP‐scan recordings were performed in the median nerve at the wrist where motor responses
were recorded from the thenar muscle. We determined the number of largest CMAP‐scan
discontinuities by means of a novel marker, D50, where a low number is indicative
of MU‐loss and enlarged MUs. Furthermore, we applied the recently developed method
of professor Hugh Bostock for obtaining a MU‐number estimate from the CMAP‐scan. The
median peak CMAP amplitude was 7.6 mV (range 3.2 – 12.1 mV) and median D50 was 43
(range 12 – 54). In three MMN patients with a normal maximum CMAP amplitude (>5 mV)
a reduced D50 (<25) was found indicative of MU‐loss and enlarged MUs. Furthermore,
D50 and the estimate of MU number were significantly related (r = 0.85, p < 0.001,
n = 12). The findings suggest that the CMAP‐scan is a sensitive tool in detecting
the underlying pathological changes of reinnervation and MU‐loss in MMN, more so than
standard maximum CMAP amplitude. It is quick and easy to perform and has the potential
to be useful for follow‐up studies.
RESPONSIVENESS OF CORNEAL CONFOCAL MICROSCOPY TO DIABETIC NEUROPATHY PROGRESSION
Smith AG
1, Thurgood B1, Revere C1, Hauer P1, Aperghis A1, Singleton JR1.
1University of Utah, Salt Lake City, Utah, USA.
Corneal confocal microscopy (CCM) directly and quantitatively assesses corneal innervation
including nerve fiber length (NFL) and density (NFD). CCM has shown promise as a diagnostic
test. We have previously demonstrated that CCM has a diagnostic performance for diabetic
neuropathy (DPN) similar to skin biopsy with assessment of intraepidermal nerve fiber
density (IENFD) and nerve conduction studies (NCS). The responsiveness of these surrogate
measures to DPN progression and their relation to clinically meaningful outcomes has
not been well explored. 144 diabetic patients undergoing annual retinopathy examination
were recruited. Each underwent CCM, IENFD, NCS including sural sensory and peroneal
motor responses, the Utah Early Neuropathy Score (UENS), the Norfolk Quality of Life
– Diabetic Neuropathy (NQOL‐DN, a validated neuropathy specific QOL scale), and a
6 minute walk test (6MWT). 55 with DPN based on symptoms (82%) or signs underwent
repeat testing at 9 months and 35 at 18 months. At baseline, NQOL‐DN correlated with
sural sensory amplitude (SSA) (−0.295, p<0.0004), peroneal motor conduction velocity
(PCV) (−0.466, p<0.0003) and IENFD (−0.317, p<0.001). No CCM metric was related to
QOL. 6MWT distance correlated with SSA (0.320, p<0.0002), NFL (0.250, p<0.0038) and
NFD (0.217, p<0.0124). Over 18 months, there was a significant worsening in DPN signs
assessed by the UENS (increase 1.43 +/− 0.65, p<0.037). SSA declined 0.78 uV (p<0.079)
and IENFD 1.8 fibers/mm (p<0.063). There was no change in any CCM metric, PCV or NQOL‐DN.
These findings suggest measures of distal axonal integrity are most sensitive to neuropathy
progression, with IENFD having the greatest responsiveness. In contrast, CCM was not
responsive to DPN progression. Both NCS and IENFD (but not CCM) were significantly
correlated with neuropathy‐specific QOL, whereas NCS and CCM measures correlated with
physical functioning. The responsiveness of IENFD and SSA, and their relationship
to QOL support their selection as endpoints in DPN clinical trials.
INTERLEUKIN 10 DEFICIENCY PARADOXICALLY PROTECTS FROM SPONTANEOUS AUTOIMMUNE PERIPHERAL
NEUROPATHY IN A MOUSE MODEL OF CIDP
Smith C
1, Trout D1, Montgomery S1, Howard J1, Su M1.
1University of North Carolina at Chapel Hill, Chapel Hill, USA.
Chronic Inflammatory Demyelination Polyradiculoneuropathy (CIDP) affects 1 in 10,000
people, and is marked by chronic autoimmune infiltration of peripheral nerves and
destruction of the myelin sheath. With current therapies, only 26% of CIDP patients
achieve complete remission. To produce more effective, mechanism‐based therapies,
we study mice with a partial loss of function G228W substitution in the Autoimmune
Regulator (Aire) gene on the non‐obese diabetic (NOD) background (NOD.AireGW/+) that
develop spontaneous autoimmune peripheral polyneuropathy (SAPP) resembling CIDP. Autoimmunity
can result from defective immunosuppression. The potent, immunosuppressive cytokine
interleukin 10 (IL‐10) is increased in the peripheral blood mononuclear cells (PBMCs)
of active phase CIDP patients relative to remission phase patients. Further, PBMCs
from CIDP patients produce IL‐10 in response to the myelin protein P2. Despite these
findings, whether IL‐10 is important for CIDP pathogenesis is not known. Thus, we
sought to determine the role of IL‐10 in SAPP. IL‐10 was highly upregulated in sciatic
nerves of NOD.AireGW/+ mice with SAPP, suggesting it may play an immunosuppressive
role in pathogenesis. However, genetic ablation of IL‐10 in NOD.AireGW/+ mice lead
to a paradoxical delay in disease development. Age‐matched IL‐10‐deficient NOD.AireGW/+
mice exhibited no sciatic nerve infiltrate and no reduction in nerve conduction during
electrodiagnostic studies. Interestingly, the delay in SAPP was specific, since the
incidences of five other autoimmune manifestations in IL‐10‐deficient NOD.AireGW/+
mice were unchanged relative to IL‐10‐sufficient NOD.AireGW/+ controls. Importantly,
IL‐10‐deficient NOD.AireGW/+ mice did not have colitis, which is consistent with previous
studies of IL‐10 deficiency on the NOD background. IL‐10 is known to perform effector
functions in autoimmunity by promoting B cell secretion of immunoglobulins. However,
genetic ablation of B cells did not affect neuropathy development in NOD.AireGW/+
mice, suggesting B cells are dispensable for pathogenesis and unlikely to mediate
the protective effect of IL‐10 deficiency. IL‐10‐deficient NOD.AireGW/+ CD4+ T cells,
which are sufficient to transfer SAPP, exhibited increased activation, increased interferon
gamma secretion, and preserved nerve‐specific T cell activation. These data suggest
T cell activation and priming are unperturbed and not the mechanism of protection.
In summary, our data showed that IL‐10 was paradoxically an effector cytokine in SAPP.
MARKED DECREMENT IN CMAP AMPLITUDE FOLLOWING PROLONGED EXERCISE IN SECONDARY HYPOKALEMIC
PARALYSIS
Sohn SY
1, Lee SJ1, Hong JH2, Kim DK3.
1Department of Neurology, Eulji University Hospital, Daejeon, Republic of Korea; 2Department
of Endocrinology, Eulji University Hospital, Daejeon, Republic of Korea; 3Department
of Urology, Eulji University Hospital, Daejeon, Republic of Korea.
Long exercise test (LET) has been used especially in myotonic syndromes and muscle
channelopathies. Marked decrement in compound muscle action potential (CMAP) amplitude
after prolonged exercise was previously reported in patients with paramyotonia congenita,
hyperkalemic or hypokalemic periodic paralysis. We describe a patient with secondary
hypokalemic paralysis who showed abnormal LET results. A 43‐year‐old man presented
with ascending flaccid paralysis which evolved in a hyperacute fashion. The patient
became quadriplegic after two hours. Initial laboratory evaluation revealed severe
hypokalemia, with normal thyroid function. We performed electrodiagnostic studies
including long exercise test as proposed by McManis et al. Nerve conduction study
was normal, but marked decrement in CMAP amplitude (up to 60% decrease after 10 minutes)
was noted after prolonged exercise. Despite oral and intravenous potassium replacement,
serum potassium level was not corrected as expected. The unusual clinical course prompted
for evaluation of secondary etiologies. Abdomen computed tomography scan revealed
a 1.5 x 1.0 cm‐sized mass in the left adrenal gland. Aldosterone to renin ratio was
elevated, suggestive of primary hyperaldosteronism. Genetic study for CACNA1S mutation
turned negative. After receiving laparoscopic adrenalectomy, the patient experienced
no further attacks, and also was able to stop his antihypertensive medication. LET
may show abnormal results in condition with reduced membrane excitability, even without
true channelopathy.
THE APPLICABILITY OF CORNEAL CONFOCAL MICROSCOPY IN SMALL FIBER NEUROPATHY
Sopacua M
1, Hoeijmakers JGJ1, Dickman MM1, Nuijts RMMA1, Merkies ISJ2, Faber CG1
. 1Maastricht University Medical Center, Maastricht, the Netherlands; 2St. Elisabeth
Hospital, Willemstad, Curaçao.
According to international criteria, the diagnosis small fiber neuropathy (SFN) is
based on clinical symptoms in combination with a reduced intraepidermal nerve fiber
density (IENFD) in skin biopsy and/or abnormal temperature threshold testing (TTT).
The sensitivity of skin biopsy is moderate to good, although IENFD is normal in about
67% of patients with SFN complaints. Furthermore, TTT is a widely available diagnostic
tool, but lacks specificity. Corneal confocal microscopy (CCM) has been described
and is used in clinical practice as an objective, non‐invasive diagnostic tool to
detect small nerve fiber damage in patients with diabetes mellitus. This study examines
the applicability of CCM in patients with SFN, and the value of CCM as an additional
diagnostic tool in SFN. We will include 20 healthy participants to compare the results
with the recently published CCM normative values, and 200 patients referred to the
SFN center Maastricht with the clinical picture of SFN. Corneal nerve fiber density
(CNFD), branch density (CNBD), fiber length (CNFL), and the tortuosity coefficient
(CNFT) will be determined in all participants. The results will be compared with the
IENFD and TTT. Preliminary results will be presented.
CHALLENGES IN NEUROLOGICAL PRACTICE IN LAO P.D.R
Southanalinh K
1
, 1University of Health Sciences, Vientiane capital, Lao P.D.R.
Located in South East Asia, Lao PDR is a landlocked country with a population of about
6.8 million inhabitants. The health indicators are among the lowest in South East
Asia. The total health caregivers in 2014 consisted of 14,964 persons corresponding
to a ratio of 2.2 health workers per 1000 inhabitants. The main network for health
care service provision remains the public system. Its health care facilities consist
of four central teaching and referral hospitals; five regional hospitals, including
one teaching hospital; 13 provincial hospitals; 135 district hospitals, and about
970 health centers. Only one in seven sick people receives modern health care treatment.
Most people rely on self‐medication and/or reliance on self‐healing. Neurological
care is a very new field. Knowledge of common neurological disorders among both the
Lao population and medical staff is only beginning to be spread. There are three neurologists
in the country. Six neurology residents are currently being trained in a three‐year
program supported by the Association pour la Promotion des Neuro‐sciences au Laos
(Association for the promotion of neuro‐sciences in Laos) and the ASEAN Neurological
Association. Indeed, resources are scarce. In the Peripheral Nerve Diseases domain
for example, we have only one Electromyography Machine that was only temporary used
when EMG experts from France and from Singapore came to teach residents. A significant
mismatch between the provision of specialized neurologic services and the needs for
them exists, especially in rural areas. Also, health insurance is not available for
the majority. As a consequence, patients have to bear the costs themselves, which
constitutes a limit to the access of available healthcare facilities. Neurologic training
centers, laboratory facilities and equipments are limited. Optimizing available human
resources, integrating primary, secondary, and tertiary healthcare tiers and making
medical treatment more affordable are need to improve neurologic care in the developing
world. In certain low‐income countries with limited human and financial resources,
it may be difficult for governments to apply some of these recommendations on their
own. In these circumstances, it is suggested that countries work with international
agencies, nongovernmental organizations or other partners to put their plans into
practice.
THROMBOEMBOLIC EVENTS IN INFLAMMATORY NEUROPATHY PATIENTS ON IVIG
Spillane J1, Englezou C1, Sarri‐Gonzales S1, Rossor A1, Lunn MP1, Manji H1, Reilly
MM1, Carr AS
1.
1MRC Centre for Neuromuscular Diseases, National Hospital for Neurology, Queen Square,
London, UK.
Observational data suggest intravenous immunoglobulin (IVIg) increases risk of thromboembolic
events (TEE). Traditional vascular risk factors influence individual risk but the
pro‐coagulant mechanism of IVIg is not understood. Our aim was to ascertain frequency
of and risk factors for TEE, arterial (ATE) and venous thromboembolic events (VTE)
in neuromuscular patients receiving regular IVIg. We performed a retrospective case‐note
review of 112 inflammatory neuropathy patients receiving regular IVIg treatment. We
collected the following data over a 30 month study period (January 2014‐June 2016):
event occurrence and date, neuropathy diagnosis, dose, frequency, vascular risk factors,
pre and post‐treatment IgG levels and plasma viscosity. The cohort was made up of
CIDP (58.9%), MMN (36.6%), sensory neuropathy/ neuronopathy (4.5%). Patients received
a mean (S.D) dose of 1.6(1.2) g/kg/month, range:0.2‐6.5g/kg/month; at a mean (S.D.)
interval of 4.4(3.0) weeks, range:1–18 weeks. Twelve TEEs were documented during the
study period; including 6 MIs, 2 CVAs, and individual occurrences of TIA, DVT, PE,
SVC obstruction due to central line thrombosis. In the IVIg cohort, TEE incidence
(95%C.I.)= 42.1 (18.6, 67.1)/1000 patient‐years was higher than population‐based estimates
from UK hospital coding records over the same time period= 15.29 (15.25, 15.33) /1000
patient‐years. IVIg‐ATE incidence= 32.1(11.1, 53.1)/1000 patient‐years; UK population‐ATE
incidence= 12.9 (12.8, 13.0)/ 1000 patient‐years; IVIg‐VTE=10 (1.4, 22.8) /1000 patient‐years
UK population‐VTE incidence= 2.37 (2.36, 2.39)/ 1000 patient‐years. In IVIg patients
who had an event, age (p=0005) and QRISK2 score (p=0.01) were higher and dose/ day
(p=0.008) was lower than those who did not have an event. There was no difference
in dose/ kg/ month (p=0.66), treatment interval (p=0.62), post‐treatment plasma viscosity
(p=0.09), IgG level (p=0.28) or ΔIgG (p=0.08). This analysis suggests TEE incidence
is higher in IVIg treated patients than comparable population‐based rates. Examination
of TEE occurrence in age and vascular risk factor matched IVIg‐treated and IVIg‐naïve
individuals is required to appreciate the excess risk associated with IVIg treatment.
PREDICTIVE FACTORS OF LONG‐TERM DISABILITY IN CIDP
Spina E
1, Topa A1, Iodice R1, Tozza S1, Dubbioso R1, Ruggiero L1, Santoro L1, Manganelli
F1
. 1Department of Neuroscience, Odontostomatological and Reproductive Sciences, University
of Naples “Federico II”, Naples, Italy.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disabling disease
and about 10% of patients may become persistently disabled over time. Our aim was
identify clinical prognostic factors of long‐term disability in a large series of
CIDP patients. We collected data from 50 CIDP patients with definite diagnosis according
EFNS/PNS criteria and positive response to first‐line therapies (immunoglobulin or
corticosteroids) including sex, age of onset, phenotype, disease duration, course
of disease (monophasic/relapsing‐remitting or chronic progressive) and disability
at the time of diagnosis assessed using the modified Rankin Scale (baseline mRS).
All patients had clinical assessment of disability through mRS within the last 6 months
(last mRS). Ordinal logistic regression model was applied to evaluate the relationship
among the clinical parameters and last mRS, considered as ordinal outcome (0–6). Anova
test for repeated measures was applied to test the overall effects of different course
on disability accumulation while t‐test was performed to evaluate inter‐group differences
for parametric variables. We found a significant relationship between last mRS and
the course of disease [p<0.000, z=4.05, OR: 14.91]. Disability accumulation was greater
in patients with chronic progressive course than those with monophasic/relapsing‐remitting
course of disease [p=0.04]. Moreover, patients with progressive course were older
[p=0.01]. Our data suggest that chronic progressive course of disease may be a major
negative prognostic factor for long‐term disability in CIDP patients. To note that
a chronic progressive course of disease is also associated with an older age from
the beginning and a more pronounced worsening over the course of disease.
MRI BIOMARKERS TO ASSESS PROXIMAL NERVE INJURY IN CHRONIC INFLAMMATORY DEMYELINATING
POLYNEUROPATHY (CIDP)
Sprenger A
1, Lichtenstein T2, Henning T2, Lehmann HC3.
1Department of Neurology, University Hospital of Cologne, Cologne, Germany; 2Institute
of Diagnostic and Interventional Radiology, University Hospital of Cologne, Cologne,
Germany; 3Department of Neurology, University Hospital of Cologne, Cologne, Germany.
An unresolved problem in the treatment of inflammatory neuropathies is the lack of
valid and reliable diagnostic biomarkers to evaluate axonal damage. We investigated
if “diffusion tensor imaging” (DTI) and MRI T1w multi echo Dixon imaging are eligible
methods to determine proximal nerve injury in chronic inflammatory demyelinating polyneuropathy
(CIDP). In this prospective observational cohort study the sciatic nerve of 11 CIDP
patients and 11 age matched healthy controls was investigated. All subjects underwent
multimodal MRI imaging to determine fractional anisotropy (FA) and muscle fat fraction
of the biceps femoris and quadriceps femoris muscle. Patients were evaluated by MRI,
clinical examination and nerve conduction studies at baseline and after six months.
The mean fractional anisotropy (FA) value was significantly lower in the sciatic nerve
from CIDP patients compared to controls. Fat fraction of the biceps femoris and quadriceps
femoris muscle were significantly higher in CIDP patients compared to controls.
MRI outcome parameters remained unchanged after six months. Our study demonstrates
the utility of MRI imaging to differentiate between “healthy” and functional constricted
proximal nerve segments. We postulate that DTI and Dixon MRI might be eligible methods
to assess proximal nerve damage in CIDP.
THE FUNCTIONAL IMPACT OF PERIPHERAL MYELIN PROTEIN 2 (PMP2) FOLLOWING DEMYELINATION
IN VITRO AND VIVO
Stettner M
1, Zenker J2, Klingler F3, Mausberg AK1, Kleinschnitz CK1, Chrast R4, Kieseier B3.
1Department of Neurology, University Hospital Essen, Essen, Germany; 2Institute of
Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Singapore, Singapore; 3Department
of Neurology, Medical Faculty, Heinrich‐Heine‐University, Dusseldorf, Germany; 4Department
of Neuroscience and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm,
Sweden.
The presence of peripheral myelin protein 2 (PMP2) has been known for decades, but
its functional role was uncovered only recently. Recent characterization of PMP2‐deficient
mice revealed a role of PMP2 in the lipid homeostasis of myelinating Schwann cells.
In this study, we analyzed the functional impact of PMP2 on myelination. To decipher
the role of PMP2, experimental demyelination was performed in myelinating dorsal root
ganglia cultures, and in vivo re‐myelination was assessed after experimental peripheral
nerve damage. We used the myelinating dorsal root ganglia (DRG) model in PMP2‐deficient
Schwann cell cultures, combined with an established de‐ and remyelinating protocol
in order to analyze myelination in vitro. We also performed experimental nerve crush
in PMP2‐deficient mice. Morphometric parameters were defined for the in‐vitro experiments
and functional parameters such as nerve conduction velocity and the clinical score
were additionally measured for the in vivo experiments. Structural analyses of the
DRG cultures revealed fibers expressing myelin basic protein (MBP) and PMP2, as well
as fibers positive for MBP alone. In contrast to our previous in vivo data, we were
also able to detect myelin segments that stained positive for PMP2, but were negative
for MBP. PMP2‐deficient DRG‐cultures demonstrated slightly greater nodal lengths than
the control cultures. This trend was significantly augmented after in vitro de‐ and
remyelination, which also resulted in decreased internodal lengths only now, while
conserving an intact myelin structure. Concomitantly, in vivo nerve crush gives rise
to a more severe phenotype in PMP2‐deficient mice than in wild‐type controls. Consistent
with this, nerve conduction studies showed a delay in remyelination, and analysis
of semi‐thin sections demonstrated an altered fiber structure in the peripheral nerve
biopsies. Together, these data suggest that in addition to its role in glial cell
lipid homeostasis, PMP2 also plays a role in remyelination of the injured peripheral
nervous system.
LENALIDOMIDE‐RESPONSIVE ANTI‐MAG NEUROPATHY
Stino A
1, Efebra Y2.
1Ohio State University Department of Neurology, Columbus, USA; 2Ohio State University
Division of Hematology, Columbus, USA.
Anti‐MAG neuropathy remains a difficult diagnosis to treat given its limited therapeutic
options. Of all interventions, Rituximab has emerged as the most effective, although
its effect has been with mixed results, especially in patients with advanced axonal
loss. Lenalidomide is another promising immune modulating therapy, whose effect has
been well demonstrated in neuropathy associated with POEMS (Polyneuropathy, Endocrinopathy,
Organomegaly, M‐spike protein, and skin changes) syndrome, a condition that has several
striking parallels to anti‐MAG neuropathy. The use of Lenalidomide has not been previously
described in anti‐MAG neuropathy. Herein, we describe a case of Lenalidomide‐responsive
anti‐MAG neuropathy in a patient with advanced axonal loss.
PROPOSAL OF DIAGNOSTIC CRITERIA FOR POEMS SYNDROME WITH THE HIGH SENSITIVITY/SPECIFICITY
Suichi T
1, Misawa S1, Sato Y2, Beppu M1, Sekiguchi Y1, Shibuya K1, Watanabe K1, Amino H1,
Kuwabara S1.
1Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan;
2Clinical Research Center, Chiba University Hospital, Chiba, Japan.
Polyneuropathy, organomegaly, endocrinopathy, M‐protein, and skin changes (POEMS)
syndrome is a rare cause of demyelinating neuropathy associated with plasma cell dyscrasia
and VEGF overproduction. Several diagnostic criteria for the disorder have been published,
but sensitivity/specificity analyses, and their validation have never been performed.
The aim of this study is to establish valid diagnostic criteria for POEMS syndrome.
104 consecutive POEMS patients, seen at Chiba University Hospital since 2000, were
screened. Of these, we have set a gold standard group of POEMS syndrome, based on
treatment response and exclusion criteria during 1‐year follow‐up, and 66 patients
was diagnosed as having definite POEMS syndrome. We also collected 30 patients with
CIDP (demyelinating neuropathy control) and 30 with multiple myeloma, primary amyloidosis,
or MGUS (M‐protein control). Criteria for POEMS syndrome was defined as having two
of the three major criteria (polyneuropathy, M‐protein, and elevated serum VEGF level)
and at least two of the four minor criteria (extravascular volume overload, skin changes,
sclerotic bone lesions, and thrombocytosis) which were determined by logistic regression
analyses. According to the criteria the sensitivity was 99%, and the specificity was
100%. Our results indicate that the proposed criteria have an excellent diagnostic
accuracy, and are useful in clinical practice, presumably leading to early diagnosis
and treatment.
CHANGES IN PAIN THRESHOLD BY SKIN TEMPERATURE: A STUDY BY INTRAEPIDERMAL ELECTRICAL
STIMULATION
Suzuki C
1, Baba M1, Kon T1, Funamizu Y1, Ueno T1, Haga R1, Nishijima H1, Arai A1, Nunomura
J1, Tomiyama M1.
1Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan.
Intraepidermal electrical stimulation (IES) is a new technique to that assesses the
function of A‐delta fibers in the epidermis. Using this technique, we previously reported
that the epidermal pain threshold was two‐hold in asymptomatic diabetic patients than
in normal subjects (Muscle Nerve 54: 146–149, 2016). Subsequently, we reported that
the elevated pain threshold negatively correlated with intraepidermal nerve fiver
density (JPNS 18: S112, 2013). Empirically, it is known that lowering the skin temperature
makes it less likely to feel pain. Therefore, it is necessary to investigate whether
the results of IES are affected by skin temperature. The aim of this study was to
investigate the influence of a low skin temperature on pain threshold. We recruited
10 subjects with a mean age of 54.6 years. For nociceptive stimulation, we used an
IES method with a concentric micro‐needle electrode that was developed specifically
for the selective stimulation of cutaneous A‐delta fibers. We placed the IES electrode
onto the extensor digitorum brevis and began stimulation with intensity strong enough
for the subject to feel a pricking sensation, then reduced the current in steps of
0.01mA until no sensation was felt. We defined pain threshold as the minimum electrical
intensity at which a subject felt a pricking sensation. Firstly, we measured pain
threshold at skin temperature above 35 degrees Celsius. Then, we put an ice pack on
the extensor digitorum brevis for 10 min to lower the skin temperature, and measured
pain threshold at skin temperatures below 33 degrees. Mean pain threshold values above
35 degrees and below 33 degrees of skin temperature were 0.102 and 0.33 mA (p<0.05),
respectively. Our data indicated an elevated pain threshold in epidermis with a low
skin temperature. One of most common methods for nociceptive stimulation is painful
CO2 laser stimulation. Some CO2 laser stimulation studies reported pain threshold
increased with a low skin temperature. Our result is similar to that of CO2 laser
stimulation. Pain threshold using IES is very easy and non‐invasive technique. It
may be useful for the evaluation of small fiber neuropathy.
CHANGES OF SERUM IGG DIMER LEVELS AFTER TREATMENT WITH IVIG IN GUILLAIN‐BARRÉ‐SYNDROME
Svačina MKR
1, Röth P1, Bobylev I1, Sprenger A1, Zhang G2, Sheikh KA2, Lehmann HC1.
1Department of Neurology, University Hospital Cologne, Cologne, Germany; 2Department
of Neurology, University of Texas, Houston, USA.
Intravenous immunoglobulins (IVIg) are an effective treatment in Guillain‐Barré‐Syndrome
(GBS). In most patients, the optimal IVIg dose and regime is unknown. In serum and
IVIg preparations, immunoglobulin (Ig) G form IgG dimers, which are assumed to consist
of idiotypic/anti‐idiotypic antibody pairs. However, data about kinetics of IgG dimer
formation in GBS are lacking.
To study IgG dimer formation, C57Bl/6 mice were injected with IVIg and anti‐GD1b antibody
or PBS. Blood sera were collected 24h, 48h and 1 week post injection. A third cohort
received an anti‐GD1a/GT1b antibody and blood was collected 48h post injection. IgG
was extracted and subtyped into polymeric, dimeric and monomeric fractions using the
ÄKTA FPLC system. Dialysed dimeric and monomeric IgG fractions were examined for the
presence of anti‐ganglioside antibodies by anti‐ganglioside antibody ELISA. Further,
blood samples from 10 GBS patients were collected before (pre‐IVIg) and after treatment
with IVIg (post IVIg). Serum samples were examined for IgG dimers and monomers using
the ÄKTA FPLC system. In the mouse model, a maximum peak of IgG dimer formation was
observed 48h post injection. In GBS patients' samples, IgG serum levels and IgG dimer
content was significantly higher after treatment with IVIg. We demonstrate here the
feasibility to assess IgG dimer formation in an animal model and in GBS patients'
samples after treatment with IVIg. 48h after IVIg treatment appears to be the optimal
time point to assess IgG dimer formation. Further studies are warranted to determine
the utility of IgG dimer formation as surrogate marker for treatment response in GBS.
OPTIMIZING GENE EXPRESSION ANALYSIS IN CMT1A SKIN BIOPSIES
Svaren J
1, Moran JJ1, Wu X2, Gutmann L2, Shy M2.
1University of Wisconsin‐Madison, Madison, Wisconsin, USA; 2University of Iowa, Iowa
City, Iowa, USA.
Development of outcome measures for clinical trials in CMT1A is a major challenge
given the slowly progressive nature of the disease. Outcome measures can be used to
measure a) target engagement for a given therapy, as well as b) disease process and
c) disease burden. Several candidate therapies have been shown to reduce Pmp22 levels
in CMT1A rodent models and thereby ameliorate the symptoms of Pmp22 overexpression.
Measuring PMP22 mRNA reduction in human trials has so far been limited to analysis
of skin biopsies by qRT‐PCR, which did not demonstrate clear elevations of PMP22 mRNA
during, nor a reduction following, ascorbic acid trials. The analysis of skin biopsies
is hampered by variable amounts of Schwann cells (SC) in skin biopsies, as well as
the variable amount of PMP22 in SC as previously established by immuno‐EM in CMT1A
skin biopsies (Katona et al., 2009). Therefore, it is important to develop optimal
normalization criteria to address the variability inherent in skin biopsy analysis.
Ideally this will employ normalization to SC‐specific genes that are not altered by
CMT1A status. To optimize normalization, we have performed RNA‐seq analysis of skin
biopsies from patient and control skin biopsy samples. Analysis of these data after
normalization to read depth indicated that PMP22 levels were 1.5 fold higher in CMT1A
patient samples compared to control skin biopsies. However, there was significant
variability in PMP22 levels particularly in CMT1A samples, which may be due to variable
amounts of Schwann cells in CMT1A skin. Using a combination of SC‐specific genes for
normalization, we were able to reduce the apparent variability and optimize the differential
levels between CMT1A and control skin biopsy samples. We also identified other SC‐specific
genes that were apparently induced in CMT1A skin biopsies relative to control. These
studies provide a new framework for gene expression analysis in skin biopsies, enabling
more precise evaluation of PMP22 levels in clinical trials for CMT1A as a measure
of target engagement. In addition, the normalization framework may also be applicable
to other types of CMT.
OCTAGAM® FOR NEUROLOGICAL DISORDERS: FOCUS ON CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
– DATA FROM 3 OBSERVATIONAL STUDIES
Svorc D
1, Wietek S1.
1Octapharma Pharmazeutika Produktions.ges.m.b.H., Vienna, Austria.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic
autoimmune neuropathy, with an estimated prevalence of between 1 and 9 per 100,000
people. It can cause temporary disability in the affected individuals and may eventually
lead to permanent disability or death. CIDP is commonly treated with intravenous immunoglobulin
(IVIG) therapy or corticosteroids. Octagam® 5% is licensed for CIDP in France, while
Octagam® 10% is licensed for CIDP in Germany and Belgium. This analysis presents data
from three open, multicenter, non‐interventional, single‐arm, non‐controlled studies
of a Post‐Authorisation Safety Surveillance (PASS) program for the subset of patients
receiving octagam® 5% or 10% for neurological indications, focusing on patients with
CIDP. Briefly, data from in‐ and out‐patients in Austria, France, Germany, and UK
treated with octagam® for neurological disorders were collected by physicians and
analyzed to assess safety and tolerability of the treatment. Of 2314 patients included
in the three studies, 260 patients (11.2%) received octagam® for neurological indications,
of which 58 patients (22.3%; mean age 64.6 years [range 18–88]) had CIDP. The mean
dose of octagam® per course was 0.8 g/kg BW for patients with CIDP; for the other
neurologic indications, the dose ranged from 0.2 (for multiple sclerosis) to 1.4 g/kg
BW (for Guillain‐Barré syndrome). Premedication was not needed in 84.3% of these patients.
The development of clinical appearance since last observation (mean: every 9.7 months)
was assessed for 41 of the 58 CIDP patients by their treating physicians. The majority
of observations (81.1%) assessed the patients as stable and 16.6% showed even an improved
clinical appearance. Only 2.3% of the observation periods resulted in deteriorations.
Adverse drug reactions were rare: Of the 3374 infusions received by patients with
neurological disorders, 0.44% of infusions were associated with an ADR (0.61% of infusions
in CIDP patients). Overall, treatment with octagam® was effective and well‐tolerated
in patients with CIDP. These results are consistent with data for the overall patient
population (including patients with primary and secondary immunodeficiencies, dermatological
and other diseases).
LYSOPHOSPHATIDIC ACID CONTRIBUTES TO A SCHWANN CELL PHENOTYPE ASSOCIATED WITH PERIPHERAL
NERVE INJURY
Szepanowski F
1, Szepanowski LP1, Kleinschnitz C1, Kieseier BC2, Stettner M1.
1Department of Neurology, Medical Faculty, University Duisburg‐Essen, Essen, Germany;
2Department of Neurology, Medical Faculty, Heinrich‐Heine‐University, Düsseldorf,
Germany.
Lysophosphatidic acid (LPA) is a pleiotropic signaling lipid that acts as ligand for
at least six specific G protein coupled receptors. Schwann cells (SC) are known to
mainly express the LPA1 receptor subtype. An emerging body of in vivo evidence has
linked LPA with injury induced peripheral nerve demyelination as well as neuropathic
pain. However, the molecular mechanism underlying its demyelinating effect has remained
largely unclear.
Myelinated dorsal root ganglia (DRG) cultures were treated either with LPA, LPA +
AM095 (LPA1 antagonist) or vehicle. We assessed myelin basic protein, tumor necrosis
factor alpha (TNF‐alpha) as well as the SC differentiation marker Sox10 by immunocytochemistry.
Additionally, myelin was investigated by Sudan black staining. To better understand
the relevance of LPA1 signaling for demyelination in vivo, we performed sciatic nerve
crush in C57BL/6 mice treated with AM095 at 10 mg/kg in order to study Schwann cell
expression of TNF‐alpha, Sox10 and Sox2, a marker for SC dedifferentiation, by immunohistochemistry.
In DRG cultures, LPA caused a significant reduction of myelin as demonstrated by both
Sudan black staining and immunocytochemical analysis of myelin basic protein. Demyelination
was paralleled by an upregulation of TNF‐alpha as well as downregulation of Sox10.
LPA mediated effects were found to be blocked by addition of the LPA1 receptor antagonist
AM095. In C57BL/6 mice, AM095 treatment prior to crush injury increased Sox10 expression
in SCs in the distal nerve stump while reducing the number of cells expressing Sox2.
These data indicate that LPA may be a critical factor to shift SCs towards an injury‐associated
phenotype and contribute to the onset of Wallerian degeneration.
IN VITRO EFFECTS OF PURE GLYPHOSATE VS. GLYPHOSATE‐BASED HERBICIDE ON PERIPHERAL NERVOUS
SYSTEM MYELINATION
Szepanowski LP
1, Szepanowski F1, Kleinschnitz C1, Stettner M1.
1Department of Neurology, University Hospital Essen, Essen, Germany.
Glyphosate‐based formulations comprise the world's most commonly used herbicides.
In non‐resistant plants, glyphosate exerts toxic effects most likely via inhibition
of aromatic amino acid synthesis by interfering with the shikimate pathway. While
glyphosate is the active ingredient, herbicidal formulations contain several adjuvants,
including polyethoxlated alkylamines (POEAs). Although glyphosate has long been considered
safe for use in humans and animals, several studies have implicated glyphosate and/or
the commonly used adjuvants in cytotoxicity, carcinogenicity and endocrine disruption.
Furthermore, glyphosate‐ based herbicide has been reported to mediate neurotoxicity
in immature rat hippocampus involving glutamate excitotoxicity. However, it remains
unclear whether glyphosate alone or in combination with its adjuvants may have detrimental
effects on myelin integrity in the peripheral nervous system.
Myelinated dorsal root ganglia (DRG) cultures were treated over the course of ten
days with either pure glyphosate or a glyphosate‐based herbicide at concentrations
of 0.05 %, 0.005 % and 0.0005 %. The concentration of the glyphosate‐based herbicide
was matched with regard to glyphosate content (36 %). Controls were treated with equal
amounts of vehicle adjusted for the pH. Subsequently, cultures were stained with sudan
black and myelin content was assessed by determining the number of internodes per
neurons.
While glyphosate, regardless of its concentration, did not show any effect on myelin
content, the glyphosate‐based herbicide caused significant demyelination in a concentration‐
dependent manner. Notably, at 0.05 %, DRG cultures were completely devoid of myelin
and appeared severely necrotic.
These data raise the possibility that not glyphosate itself, but rather the adjuvants
in glyphosate‐based herbicide formulations may cause demyelination. The open question
whether demyelination is a direct effect of the adjuvants or a consequence of increased
cellular glyphosate uptake due to permeabilization warrants further investigation.
QUANTITATIVE AUTONOMIC ASSESSMENT IN GUILLAIN‐BARRÉ SYNDROME
Tan CY
1, Tan MP1, Yeoh KY1, Goh KJ1, Shahrizaila N1.
1Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
In Guillain‐Barré syndrome (GBS), autonomic dysfunction is common and accounts for
significant morbidity and mortality. There have been many studies investigating the
electrodiagnosis of GBS but few have studied autonomic dysfunction in GBS. The current
study comprehensively investigates quantitative autonomic function in patients with
GBS and its variant. Ten GBS patients were prospectively recruited and the results
were compared to 10 age‐ and gender‐matched healthy controls. A series of autonomic
function tests including computational (power spectrum analysis of heart rate variability
(HRV) and baroreflex sensitivity (BRS) at rest) and challenge tests (deep breathing,
eyeball compression, active standing, Valsalva manoeuvre, isometric exercise and ice‐water
hand immersion) were performed. Parasympathetic function was represented by high frequency
(HF) HRV, heart rate responses to deep breathing, eyeball compression, Valsalva manoeuvre
and active standing. Sympathetic function was represented by low frequency (LF) HRV,
blood pressure responses to active standing, sustained handgrip and ice‐water hand
immersion. In the frequency domain analysis of HRV, low frequency (LF: 89.47±85.92
vs 226.97±158.16; p=0.027), high frequency (HF: 35.10±37.18 vs 158.11±140.97; p=0.008)
and total power spectral densities (PSD: 188.03±121.59 vs 532.71±359.57; p=0.015)
were significantly reduced in patients compared to controls. The mean up slope (7.38±4.41
vs 11.86±5.53; p=0.034), down slope (7.32±4.53 vs 13.41±5.07; p=0.011) and total BRS
slope (7.32±4.37 vs 12.65±5.24; p=0.024) were significantly lower in the GBS group.
The diastolic rise in blood pressure upon ice‐water hand immersion was significantly
lower in GBS group compared to controls (3.1±4.0 vs 14.0±11.3; p=0.008). Our findings
suggest that computation dependent tests (HRV and BRS) were sensitive at detecting
autonomic dysfunction and baroreceptor reflex insensitivity in GBS patients. In contrast,
ice‐water hand immersion was the only reliable challenge test making it useful as
a bedside measure of autonomic function in GBS patients.
DIFFERENT AXONAL DYSFUNCTION PATTERN IN SEROPOSITIVE AND SERONEGATIVE SJÖGREN'S SYNDROME
Jowy Tani
1,2, Hsien‐Tzung Liao3, Hui‐Ching Hsu4, Lung‐Fang Chen4, Cindy Shin‐Yi Lin5, Tsui‐San
Chang6, Jia‐Ying Sung1,6.
1Department of Neurology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan;
2Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology,
Taipei Medical University and National Health Research Institutes, Taipei, Taiwan;
3Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine,
Taipei Veterans General Hospital, Taipei, Taiwan; 4Division of Allergy, Immunology
and Rheumatology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 5Translational
Neuroscience, Department of Physiology, School of Medicine Science, Faculty of Medicine,
University of New South Wales, Sydney, Australia; 6Department of Neurology, School
of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Sjögren's syndrome (SS) is an autoimmune disease that affects both East and West.
Nevertheless, we still have limited knowledge of how autoantibodies in SS affects
the peripheral nervous system. In this study, we investigated the peripheral neuropathy
in SS and sicca complex using the nerve excitability test, to elucidate how peripheral
nerves are affected. We have enrolled a total of 22 patients with SS or sicca complex.
Of these, two patients were excluded due to co‐morbid carpal tunnel syndrome. Each
patient received clinical evaluation, examination for SSA/SSB antibodies titer, the
nerve excitability test, conventional thermal quantitative sensory test, and conventional
nerve conduction study. Compared to 33 normal control subjects, motor nerve excitability
test of SS patients with positive SSA or SSB antibodies (n = 14) were found to have
increased rheobase (P<0.05), increased relative refractory period (RRP) (P<0.01),
increased refractoriness at 2.5 ms (P<0.01), increased accommodation toward depolarizing
current in threshold electrotonus (TE) (P<0.05), and decreased superexcitability (P<
0.05). The sensory axonal study in seropositive SS also revealed increased RRP (P<0.01),
increased refractoriness at 2.5 ms (P<0.01), and increased accommodation toward hyperpolarizing
current in threshold electrotonus (TE) (P<0.05). Meanwhile, in seronegative SS and
sicca complex (n = 6), we found no significant axonal properties changes. The present
study revealed that peripheral nerves are affected differently in seropositive SS
and in seronegative SS/sicca complex. In seropositive SS, motor axons tended to be
depolarized, and both sensory and motor axons have increased refractoriness. The findings
suggested that SSA and SSB antibodies might play a role in the inactivation of transient
sodium channels. The effects of the antibodies on transient sodium channels might
be the basis of peripheral neuropathies and even cardiac arrhythmias and heart block
in SS.
GENOME‐WIDE ASSOCIATION STUDY IDENTIFIES POTENTIAL GENETIC MODIFIERS IN CHARCOT‐MARIE‐TOOTH
DISEASE TYPE 1A
Tao F
1, Beecham G1, Blanton S1, Abreu L1, Baas F2, Choi BO3, Pareyson D4, Reilly M5, Shy
M6, Zuchner S1 and Inherited Neuropathy Consortium.
1Dr. J.T. MacDonald Department for Human Genetics, Hussman Institute for Human Genomics,
University of Miami, Miami, Florida, USA; 2Department of Genome Analysis, Academic
Medical Centre, Amsterdam, The Netherlands; 3Department of Neurology, Samsung Medical
Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Department of Clinical
Neurosciences, C. Besta Neurological Institute, Milan, Italy; 5MRC Centre for Neuromuscular
Diseases, UCL Institute of Neurology, London, UK; 6Department of Neurology, University
of Iowa, Iowa City, Iowa, USA.
Charcot‐Marie‐Tooth disease type 1A (CMT1A), caused by the PMP22 duplication on chromosome
17p11.2, is the most common subtype of inherited peripheral neuropathies and affects
1 in 10,000 individuals worldwide. While sharing the same genetic cause, CMT1A patients
often present great variability in their phenotypic presentation and disease severity.
The cause of the phenotypic variability is largely unclear. In this study, we performed
genome‐wide association study (GWAS) to identify novel genetic modifiers of various
phenotypes in CMT1A. DNA samples from 971 CMT1A patients were genotyped on Illumina
OmniExpress platform. After standard quality control, the dataset includes 600k markers
in 857 individuals (644 individuals from European ancestry, and 213 individuals from
Asian ancestry). We focused our analyses on the European population. Logistic regression
in PLINK was used to analyze the association between the clinical outcomes and patients'
genotypes in an additive model. For CMT neuropathy score (CMTNS), the analysis was
performed using linear regression in PLINK, adjusting for patients' age. The analyses
yielded several suggestive association signals. An association peak on chromosome
6 was identified in difficulty with eating utensils (lead SNP rs12192704, chr6:30792270,
P=1.15E‐06, odds ratio=3.25). The peak is located within a non‐coding gene LINC00243.
Hearing loss showed an association peak on chromosome 5 (lead SNP rs7720606, chr5:126551732,
P=2.22E‐07, odds ratio=3.457), located in an intergenic region near the MEGF10 gene.
In foot plantar flexion, an association signal was identified in the DSCAM gene on
chromosome 21 (lead SNP rs2249498, chr21:41431874, P=5.13E‐07, odds ratio=2.437).
CMTNS showed an association signal on chromosome 1 (lead SNP rs12137595, chr1: 4094068,
P=1.14E‐07, beta=3.014), located within an intergenic region close to DFFB, C1orf174,
and LINC01134. While these suggestive signals require further validation, our study
provides novel insights into the genetic architecture of CMT1A. Novel genetic modifiers
may serve as potential targets for therapeutic interventions in the future.
MYASTHENIA GRAVIS? MYOPATHY? OR A NEUROPATHY?
Teng A
1, Ohnmar2, Kalpana P2, Chai YH2, Umapathi T2.
1Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 2Department
of Neurology, National Neuroscience Institute, Singapore.
We present an intriguing diagnostic puzzle, that was eventually cracked serendipitously.
A 50‐year‐old man was seen for bilateral ptosis. Evaluation for myasthenia gravis
was negative. Nevertheless, a diagnosis of ocular myasthenia gravis was made and he
was put on pyridostigmine. He did not respond. The ptosis progressively worsened.
He sought a second opinion. At this evaluation, he was noted to have complex ophthalmoplegia
without diplopia, bilateral facial weakness and mild bulbar weakness. He had no sensory
complaints. The limb examination was remarkable for slightly reduced reflexes, normal
strength, and other than increased vibration threshold at the toes, intact sensory
examination. Repeat serological and electrodiagnostic work‐up for myasthenia gravis
was negative. A myopathic disorder such as chronic progressive external ophthalmoplegia
was considered. Serum creatine kinase and lactate were normal. He underwent biceps
muscle biopsy which showed increased COX‐negative and SDH positive fibers, supporting
the then clinical impression of a mitochondrial cytopathy. At this point, he underwent
blepharoplasty to improve his vision. Routine histological examination of the levator
palpebrae muscle showed amyloid deposits. This prompted a review of the earlier biceps
biopsy, which revealed amyloid deposits that were not appreciated before. At this
point, the significance of the patient and his son's history of lattice corneal dystrophy
became apparent. He also reported that his late mother had similar facial appearance
as his. The patient's nerve conduction study showed length‐dependent sensory axonal
polyneuropathy, right carpal tunnel syndrome and bilateral facial neuropathy. He had
no definite symptoms of autonomic neuropathy. Cardiac evaluation was unremarkable.
The final diagnosis of familial gelsolin amyloid polyneuropathy was made. Genetic
confirmation for the patient and his family is being planned. We highlight the key
clinical features of gelsolin neuropathy. The symmetric cranial neuropathy can resemble
a muscle or neuromuscular junction disorder and the relative sparing of the cardiac
muscle, somatic and autonomic nerves contrasts with transthyretin‐related amyloid
polyneuropathy.
IMPLICATIPON OF RARE Nav1.7 VARIANTS IN PAINFUL DIABETIC NEUROPATHY
Themistocleous AC
1, Blesneac I1, Fratter C2, Cox JJ3, Tesfaye S4, Shillo PR4, Ramirez JD1, Rice ASC5,
Bennett DLH1.
1Nuffield Department of Clinical Neurosciences, University of Oxford, UK; 2Oxford
Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The
Churchill Hospital, Oxford, UK; 3Molecular Nociception Group, University College London,
London, UK; 4Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust,
Sheffield, UK; 5Pain Research Group & Pain Medicine, Imperial College London, Chelsea
and Westminster Hospital Campus, London, UK.
Neuropathy is one of the most common long‐term complications of diabetes. Furthermore,
25% to 50% of diabetic neuropathy patients will develop neuropathic pain. The pathophysiology
of neuropathic pain in diabetic peripheral neuropathy is complex and not fully understood.
A potential mechanism is a change in voltage gated sodium channels, such as Nav1.7.
Loss of function mutations in this channel cause insensitivity to pain, whereas gain
of function mutations have been linked with different pain syndromes including small
fiber neuropathy. In a cohort of 190 patients with diabetic peripheral neuropathy
we investigated whether mutations in Nav1.7 were associated with diabetic neuropathic
pain. Twelve Nav1.7 variants were identified in nine participants all within a cohort
of 111 participants with painful diabetic peripheral neuropathy. Five of these variants
were previously associated with pain disorders: V991L, M932L; W1538R, R185H, L1267V.
Among the other variants two of them met the criteria of potential pathogenicity based
on predictive algorithms and were further studied. Functional analysis by whole cell
patch clamp showed that one of these variants (M1852T) drastically impairs the inactivation
of the channel by shifting the steady‐state fast‐inactivation towards more depolarizing
potentials. There were no phenotypic difference between those participants with pathogenic
variants and those participants without pathogenic variants. No rare Nav1.7 variants
were found in 79 participants with painless diabetic peripheral neuropathy. These
observations suggest that mutations in Nav1.7 may contribute to painful diabetic peripheral
neuropathy.
ANTI‐FGFR3 ANTIBODIES AND SENSORY‐NEUROPATHY. A FRENCH PROSPECTIVE STUDY
Tholance Y1, Rosier C1, F Bouhour2, Psimaras D3, Kuntzer T4, Taieb G5, Créange A6,
Delmont E7, Camdessanché JP1, Antoine JC
1.
1University Hospital, Saint‐Etienne, France; 2University Hospital, Lyon, France; 3University
Hospital, Paris, France; 4University Hospital, Lausanne, Switzerland; 5University
Hospital, Montpellier, France; 6University Hospital, Creteil, France; 7University
Hospital, Marseille, France.
Dysimmune sensory neuronopathies (SNN) encompass paraneoplastic SNN and SNN associated
with systemic autoimmune diseases such as Sjögren syndrome, lupus or inflammatory
bowel or rheumatic diseases but also a number of apparently idiopathic cases. Biomarker
antibodies are well‐known in paraneoplastic SNN but are lacking in non paraneoplastic
cases. From a mono‐center retrospective study we identified in 2015 anti‐FGFR3 antibody
as a potential biomarker of dysimmunity in patients with idiopathic or systemic autoimmune
disease associated sensory neuropathy. The identified patients were more frequently
women and had a non lenthg dependent neuropathy suggestive of SNN. Anti‐FGFR3 antibody
was the only immunological marker in 2/3 of cases at initial work‐up although 1/3
of patients eventually developed with time systemic autoimmune disease. To confirm
the incidence and the clinical pattern of patients with anti‐FGFR3 antibodies we launched
a prospective multicenter French study including patients with a sensory neuropathy
suspected to be a SNN of no paraneoplastic, genetic or metabolic origin. We present
here the results on the first 82 included patients compared to 54 healthy blood donors.
Anti‐FGCR3 antibodies were searched by Elisa using the TRK intracellular domain of
the protein (Invitrogen©). We found 7 patients positive for anti‐FGFR3 antibody (8.5%).
These patients were 5 women and 2 men aged 63.7 years as a mean (44–91). The neuropathy
was acute and subacute in one patient respectively and progressive in the 5 others.
Six patients fulfilled the diagnosis criteria of SNN and the last one had a sensory
neuropathy in the lower limb with abnormal sensory action potentials in the four limbs
suggesting SNN without reaching the requested criteria. One patient developed uveitis
which is a new symptom with anti‐FGFR3 AB. An unclassified dysimmune context was present
at the initial work up in 3 patients and one patient developed Sjögren syndrome with
follow‐up. As a whole the clinical pattern of these patients is consistent with that
of the initially published series. The lower prevalence of positive sera may be due
to more stringent criteria used for Elisa but needs to be confirmed on the complete
prospective series.
PERIPHERAL NEUROPATHY RESEARCH REGISTRY (PNRR)
Thomas S
1, Ajroud‐Driss S2, Dimachkie M3, Freeman R4, Simpson D5, Smith G6, Hoke A1
. 1Johns Hopkins School of Medicine, Baltimore, USA; 2Northwestern University Medical
Center, Chicago, USA; 3Kansas University Medical Center, Kansas City, USA; 4Beth Israel
Deaconess Medical Center, Boston, USA; 5Icahn School of Medicine at Mount Sinai Medical
Center, New York, USA; 6University of Utah Medical Center, Salt Lake City, Utah, USA.
The Peripheral Neuropathy Research Registry (PNRR) is a multicenter collaborative
research project sponsored by the Foundation for Peripheral Neuropathy to advance
the science in distal symmetrical polyneuropathies (DSP). The registry was designed
to prospectively characterize clinical phenotype and natural history of patients with
DSP and obtain biofluids to identify new causes and genetic modifiers of DSP with
careful genotype/phenotype correlations, and to develop biomarkers. The enrollment
in the registry is still ongoing but an interim analysis was carried at the end of
December 2016. Eligible study participants were 18 years or older with a diagnosis
of idiopathic, diabetic, chemotherapy‐ or HIV‐induced peripheral neuropathy. They
were examined by a physician at one of the six consortium members (Johns Hopkins University
School of Medicine, Icahn School of Medicine at Mount Sinai Medical Center, Beth Israel
Deaconess Medical Center, Northwestern University Medical Center, University of Utah
Medical Center and Kansas University Medical Center). The collected data set included
(1) a detailed questionnaire, discussing their symptoms, medical history and family
history, (2) a standardized neurological examination form, (3) electrodiagnostic evaluation
and (4) diagnostic laboratory testing. Blood samples (whole blood, plasma and serum)
were collected for future biomarker and genotyping evaluations. At the end of 2016,
complete data sets and blood samples were collected from 1150 patients. 31% had diabetic
PN, 10% had HIV‐associated PN, 7% had chemotherapy induced PN and 52% were diagnosed
with idiopathic PN. Detailed analysis of clinical presentation, examination findings
and diagnostic investigations will be discussed at the presentation. Standardized
phenotyping with linked bio‐specimen banking will help establish the minimum data
set required for neuropathy diagnosis and support genotype‐phenotype correlations
with next generation sequencing technologies and development of novel biomarkers.
PNRR data will improve our understanding of disease mechanisms paving the way for
new therapeutic discoveries in painful and non‐painful neuropathies.
NEUROPHYSIOLOGICAL MEASURES CORRELATE WITH PATIENT REPORTED SYMPTOMS OF CHEMOTHERAPY‐INDUCED
PERIPHERAL NEUROPATHY
Timmins HC
1, Li T1, Kiernan MC1, Horvath LG2,3,4, Harrison M2, Grimison P2,3, Cox KM2,6, Boyle
FM3,5, Goldstein D7,8, Park SB1
. 1Brain and Mind Centre, University of Sydney, NSW, Australia; 2Chris O'Brien Lifehouse,
Sydney, NSW, Australia; 3Sydney Medical School, University of Sydney, NSW, Australia;
4Department of Oncology, Royal Prince Alfred Hospital, NSW, Australia; 5Patricia Ritchie
Centre for Cancer Care and Research, The Mater Hospital, NSW, Australia; 6Sydney Nursing
School, University of Sydney, NSW, Australia; 7Prince of Wales Clinical School, UNSW,
NSW, Australia; 8Department of Medical Oncology at Prince of Wales Hospital, Sydney,
NSW, Australia.
Chemotherapy‐induced peripheral neuropathy (CIPN) is a major side effect of treatment,
typically presenting as a sensory neuropathy. Symptoms include pain, paraesthesia,
and numbness in the extremities, resulting in functional impairment. Increasingly,
patient reported outcomes (PROs) are utilized to accurately examine the impact of
CIPN symptoms on patient function. However, the links between objective neurological
assessment and PRO measures remain ill defined. This study aimed to identify links
between neurophysiological measures and PROs in patients treated with neurotoxic chemotherapy.
Assessments were conducted in 45 patients (F= 31, mean age 53.8 ±1.9 years) who had
completed neurotoxic chemotherapy on average 9.7 ± 2 months previously (Platinum‐based
N=17, Taxane‐based N=21 or taxane/platinum combination therapy N=7). Patients reported
the presence and severity of neuropathic symptoms via the FACT‐Gog Ntx13, a validated
patient questionnaire. Clinical neurological assessment was scored using the Total
Neuropathy Score clinical version (TNSc), comprising pinprick and vibration sensibility,
deep tendon reflexes, strength and patient symptom report. Compound sensory action
potential (CSAP) amplitudes were recorded antidromically at the lateral malleolus,
stimulating the sural nerve at the mid‐calf. Of the total sample, 75% reported lower
limb neuropathy, with 44% of patients reporting ‘quite a bit’ or ‘very much’ severity
of tingling and numbness in their feet. The average sural CSAP amplitude was 10.4±1.1μV
and 40% of patients had sural amplitudes below the lower limit of normal for age.
The total TNSc score correlated with the PRO FACT‐Gog Ntx13 score (r = −.532, P<.001)
and sural amplitude (r = −.338, P <.05). Vibration sensibility correlated with the
overall FACT‐Gog Ntx13 score (r =−.338, P <.05), and sural amplitude (r = −.299, P
<.05). Sural amplitude correlated with patient reported severity of numbness and tingling
in the lower limbs (r =−.3, P <.05) but not with the overall FACT‐Gog Ntx13 score.
Patient reports of neuropathic symptoms in the lower limb correlate with both objective
neurophysiological and clinical measures of neuropathy severity. Identifying links
between objective neurophysiological markers and patient reported outcomes are critical
to assess the impact of clinical interventions.
IDENTIFICATION OF FIVE NOVEL MUTATIONS IN BRAZILIAN FAMILIES WITH X‐LINKED CMT
Tomaselli PJ
1, Gouvea SP2, Nyshyama KFS2, Nicolau N Jr2, Lourenço CM1, Marques W Jr1,2.
1Division of Neuromuscular Diseases, Department of Neurosciences and Behaviour Sciences,
Clinical Hospital of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil;
2Neurogenetics, Department of Neurosciences and Behaviour Sciences, University of
São Paulo, Ribeirão Preto, Brazil.
Mutations in the gab junction beta 1‐protein gene (GJB1) are the second most frequent
cause of Charcot‐Marie‐Tooth disease (CMT), accounting for approximately 10% of CMT
cases worldwide. The GJB1 codes for connexin 32 protein (Cx32). In the peripheral
nervous system, the Cx32 is expressed in the Schwann cells and allows intercellular
traffic of ions and small molecules between opposed cells. We analysed retrospectively
detailed clinical and neurophysiological data of five families carrying novel GJB1
mutation submitted for testing at our Neurogenetics laboratory. Mutations were identified
by bidirectional Sanger sequence analysis of GJB1 coding region. We identified a total
of 11 subjects from five different kindreds with novel mutations (p.A96V, p.L144W,
p.L165Q, p.F193S, p.R224L). These five novel mutations segregate with phenotype, are
located in highly conserved amino acids among GJB1 and other gab junction protein
sequences and among different species, are not present in any public database (ExAC,
dbSNP and 1000 Genome database), and were not found in 100 normal Brazilian controls.
In silico analysis, predict these variants to be pathogenic, There was no male‐to‐male
transmission; males were more severely affected than females. Four out seven female
have subclinical neuropathy and were only identified after clinical and electrophysiological
evaluation. The conduction velocities were in the intermediated range in the males
patients and higher in the females included in this study. We describe five new pathogenic
mutations causing CMTX1 in a Brazilian population and expand the number of causative
mutations in the GJB1 gene.
FUNDED by CNPq, CAPES, FAPESP, FAEPA and PRONAS (Ministry of Healthy)
PURE NEURAL LEPROSY MIMIKING BRACHIAL AND LUMBOSACRAL PLEXOPATHY
Tomaselli PJ
1, Marques VD1, dos Santos AJC1, Lavigne CM1, Toscano PO1, Barreira AA1, Foss N2,
Frade MA2, Marques W Jr1,3.
1Division of Neuromuscular Diseases, Department of Neurosciences and Behaviour Sciences,
Clinical Hospital of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil;
2Dermatology, Department of Internal Medicine, Clinical Hospital of Ribeirão Preto,
University of São Paulo, Ribeirão Preto, Brazil; 3Neurogenetics, Department of Neurosciences
and Behaviour Sciences, University of São Paulo, Ribeirão Preto, Brazil.
Pure neural leprosy (PNL) is a slowly progressive, predominantly sensory patchy neuropathy
presenting with positive and/or negative sensory symptoms, which are usually followed
over time by distal asymmetrical weakness. Despite rare, monomelic involvement in
leprosy has already been reported. We sought to describe the clinical and electrophysiological
patterns of an unusual leprosy neuropathy presentation. Clinical data were retrospectively
collected from nine patients who had monomelic involvement and were referred for further
investigation to the EMG lab. Seven out nine patients were male. Four patients had
a brachial plexus like presentation and five have a lumbosacral plexus like presentation.
The initial complaint was hypoesthesia in four patients, tingling in two patients
and hypoesthesia with tingling in two patients. Severe pain was observed in just one
patient. All individuals from the group of patients with lumbosacral plexus‐like presentation
and three with brachial plexus‐like presentation had no sensory nerve action potentials
(SNAPs) for all nerves tested in the affected limb with or without motor involvement.
One patient with brachial plexus‐like presentation had focal slowing of conduction
velocity with temporal dispersion of both median and ulnar nerves in the affected
limb. One patient with plexus‐like presentation had SNAPs with low amplitude of all
nerves in the affect limb. The diagnosis of leprosy was confirmed by nerve biopsy
findings, anti‐PGL1 antibody, and positive response to specific treatment. Nerve biopsy
was performed in four patients, and the bacillus was found in two. The anti‐PGL1 antibody
was positive in four patients. Plexus MRI was performed in two patients and was normal.
We found the distribution of motor and sensory symptoms were restricted to on limb
in this group of patients. As a typically patchy disorder PNL may affect any nerve,
although the reason why damage are restrict to only one limb has to be elucidated.
The description of these cases increases the clinical spectrum of leprosy neuropathy.
This possibility should be considered in the differential diagnosis of patients with
plexopathy from endemic areas after excluding other causes.
FUNDED by CNPq, CAPES, FAPESP, FAEPA and PRONAS (Ministry of Healthy)
A PATIENT WITH ATAXIA WITH OCULOMOTOR APRAXIA TYPE 1 AND SLOW CONDUCTION VELOCITIES
Tomaselli PJ
1, Lourenço CM1, Cintra VP2, Barreira AA1, Marques W Jr1,2.
1Division of Neuromuscular Diseases, Department of Neurosciences and Behaviour Sciences,
Clinical Hospital of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil;
2Neurogenetics, Department of Neurosciences and Behaviour Sciences, University of
São Paulo, Ribeirão Preto, Brazil.
Ataxia with oculomotor apraxia type 1 (AOA1) is a very complex disorder characterized
by an early‐onset progressive cerebellar ataxia with cerebellar atrophy and peripheral
neuropathy and it is caused by recessive mutations in the aprataxin gene (APTX). When
the neuropathy is present, it has been described in 100% of cases as primarily axonal.
We describe a case of AOA1 due compound heterozygous mutations in APTX associated
with demyelinating neuropathy. The patient was born from healthy and non‐consanguineous
parents and presented in the first decade with progressive cerebellar ataxia, multidirectional
ophtalmoparesia, oculomotor apraxia, choreiform movements of limbs and peripheral
neuropathy. He had normal cognition and stopped walking at age of 19. Blood tests
were unremarkable with normal levels of leucocytes, serum proteins, immunoglobulin,
cholesterol, vitamin E, and alfa‐feto protein. Brain MRI showed severe cerebellar
atrophy. The motor conduction velocity in the upper limbs was slow with preserved
amplitudes. The distal latencies and the minimal F wave latencies were prolonged.
There was no evidence for superimposed acquired demyelinating neuropathy. Direct sequencing
of the APTX gene revealed two variants, c.544‐2A>G, p? and c.837G>A; p.W279X. The
first variant is novel and affects a highly conserved acceptor splice site of exon
5. The other variant is the most common Portuguese variant, the nonsense mutation
W279X is located in exon 6. Parental DNA was tested and confirmed the variants were
in different alleles. The presence of a demyelinating neuropathy in AOA1 suggests
that phenotypic variability in this condition may be larger than previously considered.
At the same time, it increases the differential diagnosis of inherited conditions
with cerebellar ataxia and demyelinating neuropathy. Finally, this finding opens the
functional effects of the APTX gene.
Funded by: CNPq, FAPESP, FAEPA, PRONAS (MINISTRY OF HEALTH).
SUBCUTANEOUS IMMUNOGLOBULIN IN CIDP: A TWO‐YEAR EXPERIENCE
Topa A
1, Spina E1, Iodice R1, Tozza S1, Ruggiero L1, Dubbioso R1, Esposito M1, Santoro L1,
Manganelli F1. 1
University of Naples “Federico II”, Naples, Italy.
We report our 2‐year experience of subcutaneous immunoglobulin (SCIG) in a cohort
of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) from a tertiary
care neuromuscular center.
We analyzed data from 13 CIDP patients (8 males and 5 females, mean age: 58 ± 11.4
years; mean age at onset: 45.9 ± 12.4 years; disease duration: 11.9 ± 8.3 years) treated
with SCIG and with a follow‐up period of 24 months. All patients were previously responders
to intravenous immunoglobulin (IVIG). Eight patients had a typical CIDP and five patients
had an atypical variant of CIDP.
Five patients switched to weekly maintenance SCIG therapy (continuous regimen) because
of short‐lasting response to IVIG therapy.
Eight patients with a longer lasting response to IVIG received SCIG with a pulsed
regimen similar to that used for IVIG (from 1 to 3 cycles per year); seven of them
because of difficulty in hospitalization and one for allergic reaction to IVIG.
Changes in clinical status were assessed over the period of follow‐up by using clinical
evaluation of muscle strength, modified Rankin scale, overall neuropathy scale and
Inflammatory Neuropathy Cause and Treatmentsum score. In 9 patients we evaluated also
six minute walking test, 9 hole‐peg‐test and 10 meter walking test.
All the five patients treated with a continuous regimen of SCIG remained clinically
stable throughout the follow‐up period. Among the patients receiving pulsed SCIG treatment,
4 out of 8 (50%) responded to SCIG similarly to IVIG, while three patients (37.5%)
worsened and needed to be treated again with IVIG and the other one (12.5%) stopped
any therapy. Subcutaneously administered immunoglobulin were well tolerated and no
patients complained of adverse events.
In conclusion, our findings confirm that continuous SCIG therapy is efficacious in
maintaining clinical stability in patients with short‐lasting response to IVIG.
Moreover, our data suggest that pulsed therapy with SCIG may represent an alternative
therapeutic option for the treatment of a subset of CIDP patients.
ROLE OF X‐BOX BINDING PROTEIN 1 (XBP1) IN CHARCOT‐MARIE‐TOOTH DISEASE TYPE 1B
Touvier T
1, Ferri C1, Mastrangelo R1, Glimcher L2,3, Wrabetz L4,5,6, D'Antonio M1.
1Myelin Biology Unit, Division of Genetics and Cell Biology, San Raffaele Scientific
Institute, DIBIT, Milan, Italy; 2Department of Cancer Immunology and Virology, Dana‐Farber
Cancer Institute, Boston, USA; 3Department of Medicine, Harvard Medical School, Boston,
USA; 4Hunter James Kelly Research Institute, University at Buffalo, Buffalo, USA;
5Department of Biochemistry, University at Buffalo, Buffalo, USA; 6Neurology, Jacobs
School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, USA.
Mpz glycoprotein is an abundant product of terminal differentiation in myelinating
Schwann cells. The mutant MpzS63del causes Charcot‐Marie‐Tooth (CMT) 1B disease in
humans and a similar demyelinating neuropathy in transgenic mice. MpzS63del protein
is retained in the endoplasmic reticulum (ER) of Schwann cells and induces an unfolded
protein response (UPR) characterized by activation of PERK, ATF6 and IRE1/XBP1 pathways.
We have previously reported that activation of CHOP and GADD34, two downstream mediators
of PERK, is pathogenetic in MpzS63del mice (Pennuto, 2008; D'Antonio, 2013) but the
role of the other UPR branches remains to be investigated. In this study, we investigated
the role of the ER stress sensor enzyme IRE1 and of XBP1 ‐ a transcription factor
specifically activated by IRE1 ‐ in MpzS63del pathogenesis. We generated a new mouse
model with Schwann cells‐specific ablation of XBP1 and in parallel we exploited MpzS63del
dorsal root ganglia (DRG) explant cultures in which XBP1 signaling is modulated by
gain/loss of function approaches. We observed that absence of XBP1 dramatically worsens
hypomyelination and electrophysiological/locomotor parameters in young and adult MpzS63del
neuropathic animals. Interestingly we observed that PERK, ATF6 and IRE1‐mediated RIDD
signalings are upregulated in neuropathic animals lacking XBP1. This suggests that
activation of XBP1 targets have an essential role in limiting MpzS63del toxicity,
which cannot be compensated by other stress responses. Moreover, we demonstrated in
MpzS63del DRG cultures that inhibition of XBP1 splicing by 4u8c (Cross, 2010) decreases
myelination whereas activation of XBP1 splicing by quercetin (Wiseman, 2010) slightly
ameliorates myelination. Altogether, these data demonstrate that XBP1 pathway has
a critical adaptive role in MpzS63del neuropathy and suggest that activation of this
pathway may be beneficial for CMT1B and perhaps for a broad range of neuropathies
characterized by UPR activation.
CMT1A PATIENTS GET OLD WORSE THAN HEALTHY PEOPLE
Tozza S
1, Bruzzese D2, Iodice R1, Esposito M1, Dubbioso R1, Ruggiero L1, Topa A1, Spina E1,
Santoro L1, Manganelli F1.
1Department of Neuroscience, Reproductive Sciences and Odontostomatology, University
of Naples "Federico II", Naples, Italy; 2Department of Public Health, University Federico
II of Naples, Naples, Italy.
In CMT1A patients, the clinical impairment progressively increases over time and correlates
with the axonal loss. Evidence has suggested that the decline of physical performance
in CMT1A patients may reflect a process of normal ageing.
The aim of our study was to describe, by a case–control cross‐sectional design, the
progression of physical impairment with ageing in CMT1A patients.
We enrolled 70 CMT1A patients (26 M; range 20–81 years) and 70 sex‐ and age‐matched
healthy controls. To assess physical performance, all patients and controls underwent
10‐Meter Walk Test (10MWT), 6‐Minute Walk Test (6MWT) and 9‐Hole Peg Test (9HPT) of
their dominant (d) and non‐dominant (nd) sides.
Moreover, to assess clinical disability, impairment and quality of life in the CMT1A
group we used the Charcot‐Marie‐Tooth Neuropathy Score (CMTNS), the MRC Sum Score
and the Short Form‐36 (SF‐36) questionnaire.
The linear regression model was used to evaluate the changes over time of clinical
measures in patients and controls. The Chow test was used to determine whether the
ageing had a different impact on clinical measures for the two groups.
Physical performance worsened with ageing in both patients and controls, but with
a greater slope for CMT1A patients [difference in slopes: 10MWT, 0.15 (C.I. 0.07 to
0.23), p<0.001; 6MWT, −4.59 (C.I. ‐6.41 to −2.77), p<0.001; 9HPT‐d, 0.59 (C.I. 0.39
to 0.78), p<0.001; 9HPT‐nd, 0.37 (C.I. 0.20 to 0.53), p<0.001].
The rate of deterioration of physical performance was not different between patients
and controls until the 50th year of age. After the 50th year of age the rate of deterioration
became greater in CMT1A group [difference in slopes: 10MWT, 0.31 (C.I. 0.02 to 0.61),
p<0.039; 6MWT, −7.13 (C.I. ‐12.02 to −2.24), p<0.006; 9HPT‐d, 1.47 (C.I. 0.72 to 2.21),
p<0.001; 9HPT‐nd, 1.11 (C.I. 0.62 to 1.6), p<0.001].
Moreover, in CMT1A patients also CMTNS, MRC sum score and SF‐36 worsened with ageing
and with a greater rate of deterioration after the 50th year of age.
Our study demonstrates that clinical decline in CMT1A patients goes parallel to the
normal ageing process until the 50th year of age, whereupon the clinical deterioration
accelerates.
IMMUNE CHECKPOINT INHIBITOR‐INDUCED ACUTE NEUROPATHIES
Tsouni P
1, Devic P2, Moura B1, Planque E3, Bédat‐Millet AL4, Devaux J5, Steck AJ1, Delmont
E6, Hottinger AF1, Kuntzer T1.
1DCN, CHUV, Lausanne, Switzerland; 2Centre de Référence Maladies Neuromusculaires,
Hospices Civils de Lyon, Lyon, France; 3Cabinet Médical, Epinal, France; 4Département
de neurologie, CHU de Rouen, Rouen, France; 5CNRS, CRN2M‐UMR 7286, Université Aix‐Marseille,
Marseille, France; 6Centre de Référence maladies neuromusculaires et SLA, Hôpital
La Timone, Marseille, France.
New therapeutic options in immuno‐oncology have allowed significant progress in the
management of melanomas. Treatment usually consists of a combination of two monoclonal
antibodies targeting cytotoxic lymphocyte‐associated protein 4 and programmed cell
death‐1. As a result, the immunologic barrier protecting tumor cells is overcome allowing
an antitumor response. We report 6 cancer patients with immune checkpoint inhibitor‐induced
neuropathies as a complication of this immunomodulating oncologic treatment. Case
reports: Our index patient developed severe myalgia 4 days after introduction of ipilimumab‐nivolumab
followed by painful paresthesias of the face and extremities 1 day after the 2nd cycle
of treatment. Generalized areflexic quadriparesis (MRC4) with Gowers'sign and distal
loss of vibratory sensation were found. A 5‐day course of IVIG plus corticosteroids
(CS) had no effect. Three monthly IVIG courses were necessary to improve the deficits
at 3 months. A survey of SFNP members revealed 5 other patients with similar acute
courses but with phenotypes varying from sensorimotor deficits with areflexia and
myalgia to purely sensory ataxic forms following immunomodulating treatment. Work‐up
including anti‐nodal antibodies were negative in 3 patients. From the other 3, 2 had
abnormal CSF and 1 had necrotizing myopathy. Detailed repeat NCS demonstrated signs
of nerve hyperexcitability and of demyelination or conduction blocks. Evolution was
slowly favorable following IVIG and CS. Discussion: Our report underscores that atypical
acute generalized demyelinating neuropathies are induced by these novel treatments.
They may be associated with severe myalgia or other systemic toxic effects. Discontinuation
of the oncologic treatment depends on severity of symptoms. Outcome was slowly favorable
following IVIG or CS, albeit slower than in the case of primary inflammatory neuropathies,
probably given the long half‐life of the monoclonal antibodies.
THE FUNCTIONAL ROLE OF CONNEXINS IN PERIPHERAL MYELINATED FIBERS
Tympanidou M
1, Kagiava A1, Kleopa KA1,2.
1Neuroscience Laboratory; 2Neurology Clinics, Cyprus School of Molecular Medicine,
The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Gap junctions (GJs) are membrane channels found in most tissues connecting adjacent
cells or different cell compartments as in Schwann cells. They are involved in electrical
connectivity and metabolic homeostasis allowing the passage of small molecules such
as ions, second messengers, nucleotides and peptides. An important functional role
of peripheral nerve connexins is suggested by their involvement in X‐linked inherited
neuropathy as well as in acquired neuropathy caused by oxaliplatin. Although GJs play
a role in electrical connectivity their specific role in the formation of the sciatic
nerve compound action potential (CAP) remains unclear. The aim of this study was to
investigate the role of peripheral nerve connexins in the electrical responses of
the mouse sciatic nerve under normal and stress conditions. For this purpose we used
sciatic nerves of three different mouse models, the Cx32 knockout (KO), Cx29 KO and
the Cx32/Cx29 double knockout (dKO) mice. Using our ex vivo model for extracellular
recordings we exposed sciatic nerves from different genotypes to three different GJ
blockers: octanol, 18‐beta‐glycyrrhetinic acid (GRA) and octanoic acid (OA) and recorded
the CAP. Amplitude and duration of the CAP were used as an indication for the effects
of the different blockers on the CAP formation. All GJ blockers caused a gradual decrease
of the CAP without any changes in the duration of the CAP in all genotypes, suggesting
progressive disturbance of axonal membrane excitability in the absence of one or two
GJ proteins. Comparison of the three genotypes showed that Cx32 may play a dominant
role in the maintenance of the CAP formation since nerves from Cx29KO mice proved
to be more sensitive to the GJ blockers compared to the Cx32KO nerves showing a faster
decline of the CAP amplitude. Moreover the effect of GJ blockers was similar in Cx32KO
and dKO nerves. Finally, the effect of GJ blockers on the dKO nerves implies the presence
of another GJ protein. In conclusion, our results confirm the direct functional involvement
of Cx32 GJ channels and Cx29 hemichannels in the CAP formation and indicate the existence
of at least one more connexin in peripheral nerve.
Ca(2+)‐DEPENDENT ANTI‐GANGLIOSIDE ANTIBODY IN SERONEGATIVE GUILLAIN‐BARRÉ SYNDROME
Uchibori A
1, Gyohda A1, Chiba A1.
1Kyorin University, Tokyo, Japan.
Background: We have reported Ca2+‐dependent IgG anti‐ganglioside GQ1b antibodies in
GQ1b‐seronegative patients with Fisher syndrome and its related disorders (FS‐RD).
In patients with FS‐RD who were GQ1b‐seronegative in conventional assays using phosphate‐buffered
saline without Ca2+, 73% turned seropositive for GQ1b‐related antigens in assays using
Ca2+‐added Tris–buffered saline.
Objective: We investigated whether Ca2+‐dependent anti‐ganglioside antibodies was
present also in ganglioside‐seronegative patients with other clinical disease types
of Guillain‐Barré syndrome (GBS) other than FS‐RD.
Methods: The subjects were the following: 23 patients with final clinical diagnosis
as GBS (acute motor axonal neuropathy [AMAN], n = 6, and acute inflammatory demyelinating
polyradiculoneuropathy [AIDP], n = 17), and 5 patients with final clinical diagnosis
as sensory ataxic neuropathy (SAN), n = 5. All subjects were ganglioside‐seronegative
in the conventional assays. We assayed serum IgG antibodies against various gangliosides
(including asialo‐GM1) in ELISA using Tris‐buffered saline as a basal buffer in both
Ca2+‐added and ‐non‐added conditions. Increase of the optical density (OD) more than
0.1 in Ca2+‐added condition compared with Ca2+‐non‐added one was taken significant,
i.e. positive for Ca2+‐dependent antibody.
Results: Ca2+‐dependent antibody was negative in all AMAN and SAN patients. In AIDP,
the antibody titers (ODs) against GaINAc‐GD1a were significantly increased in 2 patients,
and those against asialo‐GM1 were increased in 2 other patients in Ca2+‐added condition.
However, the titiers of those Ca2+‐dependent antibodies were all at low level.
Conclusions: In clinical disease types of GBS other than FS‐RD, Ca2+‐dependent IgG
antibodies against ganglioside were detected in a few patients with AIDP, but the
positive rate and the antibody titers were low compared with case of GQ1b‐seronegative
FS‐RD. Ca2+‐dependent antibodies against ganglioside are considered to be more specific
for GQ1b.
THE RELATIONSHIP BETWEEN MEDIAN SENSORY CONDUCTION OF MEDIAN NERVE AND ULNAR NERVE
IN PATIENTS WITH CARPAL TUNNEL SYNDROME
Unal Y1, Ozturk DA1, Emir GK1, Tosun K2, Kutlu G
1.
1Mugla Sitki Kocman University Faculty of Medicine, Department of Neurology, Mugla,
Turkey; 2Mugla Sitki Kocman University Faculty of Medicine, Department of Biostatistics,
Mugla, Turkey.
The aim of the study was to investigate the relationship between median sensory conduction
of median nerve and ulnar nerve in patients diagnosed with carpal tunnel syndrome.
Two hundred and eighty‐six hands with carpal tunnel syndrome and 52 hands in control
group were investigated. Patients were staged clinically and electrophysiologically.
Diagnosis of carpal tunnel syndrome was made according to the presence of paresthesia,
pain in the innervation area of the median nerve, weakness and atrophy in the median
nerve innervated muscles, positive Phalen and Tinel tests. Median motor and sensorial
nerve conduction study, including first, second, third finger and palm, and ulnar
motor and sensorial nerve conduction of fifth finger studies were performed to all
patients and control group. The ratio of distal latency and velocity of nerve conduction
of first, second, third and palmar branches to fifth finger was calculated. Distal
latency of first, second, third finger and palm of patients with CTS are longer and
velocity is more slowly than controls. In addition to these findings, the velocity
of fifth finger is also slower and distal latency of this one is longer than healthy
subjects. The most sensitive method of classifying the carpal tunnel syndrome as normal,
mild and moderate is the ratio of distal latency and velocity of second finger (p<0.001).
Carpal tunnel syndrome is the most common encountered neuropathy. In nerve conduction
studies can be used the ratio of distal latency and velocity of second finger as determine
the degree of carpal tunnel syndrome. The most surprising finding of this report is
the nerve conduction studies of fifth finger. The subclinical susceptibility of fifth
finger can be explained by overusing of wrist.
RELEVANCE AND FREQUENCY OF DIFFERENT TYPES OF CHARCOT‐MARIE‐TOOTH NEUROPATHY IN A
LARGE POPULATION OF PATIENTS STUDIED AT A SINGLE CLINICAL SITE
Ursino G
1, Gemelli C1, Grandis M1, Reni L2, Bellone E1, Geroldi A1, Gotta F1, Mandich P1,
Ferrara M1, Schenone A1
1DINOGMI University of Genoa, Genoa, Italy; 2IRCCS‐AOU San Martino Hospital Genoa,
Genoa, Italy.
Charcot‐Marie‐Tooth (CMT) neuropathy represents a clinically and genetically heterogeneous
group of hereditary peripheral neuropathies characterized by chronic motor and sensory
impairment. To date mutations in up to 80 genes may cause CMT. The aim of this study
is to describe our large population of CMT patients, and, within this, highlight specific
phenotypes. The CMT Clinic in Genova, started in 2004. During the years, patients
underwent complete neurological, rehabilitative, neurophysiological examinations and
genetic testing. The patients were routinely tested for common genes (as PMP22, GJB1,
MPZ, MFN2), while in specific cases we followed the candidate gene approach testing
single genes based on the genotype‐phenotype correlation. However, the NGS techniques
were used when routine genetic testing was negative and a clear genotype‐phenotype
correlation could not be identified. 679 cases are present to date in our database
of CMT patients. In 185 (27.2%) patients, in spite of a clinical diagnosis of CMT,
a genetic diagnosis is still lacking; 175 (25.7%) patients had alternative diagnosis
(i.e hereditary spastic paraparesis etc.). Instead, in 319 patients (46.9%) a defined
genetic diagnosis was reached, 180 of them being females (56.4%) and 139 males (43.5%).
Among these, except for the more common CMT1A, HNPP and CMT1X phenotypes, we frequently
observed patients affected by CMT1B and CMT2F. According to most literature data,
we observed 21 (6.5%) patients with CMT1B and 8 patients (2.5%) affected by CMT2F.
At the first visit, the CMT1B phenotype was clearly length‐dependent: 71.4% patients
showed impairment of the lower limbs and saving of the upper limbs; in terms of severity
of the neuropathy, the mean CMTNS was 11.9 and the mean age was 48.8 years. Similarly,
75% of patients affected by CMT2F, present with the same phenotype; the mean CMTNS
at the first visit was 8.1 and the mean age was 63.1 years. In conclusion, based on
the experience of the Genova CMT Clinic, we describe a large population of CMT patients
and a specific phenotype in CMT1B and 2F patients, characterized by involvement of
the lower limbs and selective sparing of the upper ones, which may help in addressing
the diagnostic algorithm.
CHRONIC NON‐FREEZING COLD INJURY RESULTS IN NEUROPATHIC PAIN DUE TO A SENSORY NEUROPATHY
Vale TA
1, Symmonds M1, Polydefkis M2, Rice A3, Themistocleous AC1, Bennett DLH1.
1Nuffield Department of Clinical Neurosciences, University of Oxford, UK; 2Department
of Neurology, Johns Hopkins University School of Medicine, USA; 3Pain Research Group,
Imperial College London, UK.
Non‐freezing cold injury (NFCI) develops following sustained exposure to cold temperatures,
resulting in tissue cooling but not freezing. This can result in persistent sensory
disturbance of the hands and feet including numbness, paraesthesia and chronic pain.
Both vascular and neurological aetiologies of this pain have been suggested but remain
unproven. We prospectively approached patients referred for clinical assessment of
chronic pain following non‐freezing cold injury between 12 February 2014 and 30 November
2016. Of 47 patients approached 42 consented to undergo detailed neurological evaluations
including: questionnaires to detail pain location and characteristics, structured
neurological examination, quantitative sensory testing, nerve conduction studies and
skin biopsy for intra‐epidermal fibre assessment. Of the 42 study participants all
had experienced NFCI whilst serving in the United Kingdom armed services and the majority
were of African descent (76.2%) and male (95.2%). Many patients reported multiple
exposures to cold. The median time between initial injury and referral was 3.72 years.
Pain was principally localised to the hands and the feet, neuropathic in nature and
in all study participants associated with cold hypersensitivity. Clinical examination
and quantitative sensory testing were consistent with a sensory neuropathy. In all
cases large fibre nerve conduction studies were normal. The intra‐epidermal nerve
fibre density, however, was markedly reduced; 90·5% of subjects having a count at
or below the 0·05 centile of published normative controls. Using the Neuropathic Pain
Special Interest Group (NeuPSIG) of the International Association for the Study of
Pain (IASP) grading for neuropathic pain 100% had probable and 95·2% definite neuropathic
pain. Chronic non‐freezing cold injury is a disabling neuropathic pain disorder due
to a sensory neuropathy. Why some individuals develop an acute painful sensory neuropathy
on sustained cold exposure is not yet known but individuals of African descent appear
vulnerable. Screening tools, such as the DN4 questionnaire, and treatment algorithms
for neuropathic pain should now be used in the management of these patients. Funded
by The Wellcome Trust and the UK Ministry of Defence
INTERNATIONAL GUILLAIN‐BARRÉ SYNDROME OUTCOME STUDY (IGOS): DESCRIPTION OF THE FIRST
1000 PATIENTS
van den Berg B
1, Verboon C1, Doets A1, Chavada G2, Davidson A2, Willison HJ2, Harbo T3, Gorson KC4,
Hartung HP5, Lehmann HC6, Kusunoki S7, Querol L8, Illa I8, Nobile‐Orazio E9, Reisin
RC10, Reddel SW11, Islam Z12, Islam B13, Deen Mohammad Q14, Van den Bergh P15, Feasby
TE16, Péréon Y17, Shahrizaila N18, Hsieh ST19, Bateman K20, Dardiotis E21, Wang Y22,
van Doorn PA1, Hughes RAC23, Cornblath DR24, Jacobs BC1,25 and the IGOS Consortium.
1Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands; 2Department
of Neurology, University of Glasgow, Glasgow, UK; 3Department of Neurology, Aarhus
University Hospital, Aarhus, Denmark; 4Department of Neurology, Tufts University School
of Medicine, Boston, USA; 5Department of Neurology, University of Düsseldorf, Düsseldorf,
Germany; 6Department of Neurology, University Hospital of Cologne, Köln, Germany;
7Department of Neurology, Kindai University Faculty of Medicine, Osaka, Japan; 8Department
of Neurology, Hospital Sant Pau, UAB, Ciberer, Barcelona, Spain; 9Department of Neurology,
Milan University, Humanitas Istitute, Milan, Italy; 10Department of Neurology, Hospital
Britanico, Buenos Aires, Argentina; 11Department of Neurology, Concord Repatriation
General Hospital, Sydney, Australia; 12Department of Neurology, ICDDR,B, Dhaka, Bangladesh;
13Laboratory Sciences and Services Division, ICDDR,B, Dhaka, Bangladesh; 14National
Institute of Neuroscience and Hospital, Dhaka, Bangladesh; 15Department of Neurology,
University Hospital St. Luc, Brussels, Belgium; 16Department of Clinical Neuroscience,
University of Calgary, Calgary, Canada; 17Reference Centre for Neuromuscular Diseases,
Nantes University Hospital, Nantes, France; 18Department of Neurology, University
of Malaya, Kuala Lumpur, Malaysia; 19Department of Neurology, National Taiwan University
Hospital, Taipei, Taiwan; 20Department of Neurology, University of Cape Town, Cape
Town, South Africa; 21Department of Neurology, University of Thessaly, Larissa Thessaly,
Greece; 22Department of Neurology, Affiliated Hospital of Jining Medical College,
Jining, China; 23Department of Neurology, Institute of Neurology, University College,
London, UK; 24Department of Neurology, Johns Hopkins University, Baltimore, USA; 25Department
of Immunology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Guillain‐Barré syndrome (GBS) is highly heterogeneous regarding clinical presentation,
course, electrophysiological subtype and outcome. In part this variety is associated
with differences between geographical regions, although this had not been investigated
in a single comparative study. One aim of IGOS is to define the influence of the geographical
origin on the heterogeneity of GBS. In IGOS all GBS patients within 2 weeks of onset
can participate, independent of age, variant, severity and treatment. In February
2017, 1456 patients were included from 19 countries. The first 1000 inclusions in
IGOS were used in this analysis. Seventy‐five patients (8%) were excluded because
of alternative diagnoses (n=59, including 35 A‐CIDP), protocol violations (n=5) or
missing data (n=11). Of the remaining 925 patients, 60% were males and 40% female
with a median age of 51 years (IQR 33–65). At entry 73% presented with tetraparesis
and 11% with paraparesis. During follow‐up 19% needed mechanical ventilation and 7%
died. Of all GBS patients 81% received treatment (91% IVIg, 9% PE). The remaining
19% received supportive care only (mild GBS or low social‐economic status). Antecedent
events were reported in 76% of patients, including upper respiratory tract infection
(36%) and gastro‐enteritis (26%) as the most frequent events. The pure motor form
was the predominant subtype in patients from Bangladesh (69%). In Europe/Americas
and Asia (without Bangladesh) the predominant subtype was the sensorimotor form (69%
in Europe/Americas and 43% in Asia). In Asia (without Bangladesh) there was a relatively
larger proportion of patients with MFS/MFS‐overlap syndrome (22%) than in other regions
(1‐11%, p<0.001). The proportion of patients able to walk unaided at 12 months after
follow‐up was 87% in Europe/Americas, 73% in Bangladesh and 93% in Asia (without Bangladesh).
Kaplan‐Meier analysis comparing electrophysiological subtypes of GBS (as reported
by neurologist) showed that patients with inexcitable nerves or axonal neuropathy
needed more time to regain the ability to walk unaided than the patients with demyelinating
or equivocal result (log‐rank test, p < 0.001). These findings demonstrate the extensive
geographical differences in GBS. Future IGOS studies will investigate the role of
genetic and environmental factors that additionally could explain these differences.
ELECTROPHYSIOLOGICAL CRITERIA FOR GBS SUBTYPE DIAGNOSIS: A PROSPECTIVE MULTICENTRIC
EUROPEAN STUDY
Van den Bergh PYK
1, Attarian S2, Grapperon AM2, Nicolas G3, Cassereau J4, Rajabally YA5, Delmont E2,
Woodard JL6, Piéret F7 and the University of Louvain GBS Electrodiagnosis Study Group*.
1Neuromuscular Reference Centre, University Hospital St‐Luc, Brussels, Belgium; 2Centre
de référence des maladies Neuromusculaires et la SLA, Hôpital de la Timone, Marseille,
France; 3Service de neurologie, Hôpital Raymond Poincaré, Garches, France; 4Centre
de Référence Maladies Neuromusculaires de l'Enfant et de l'Adulte Nantes‐Angers, Centre
Hospitalier Universitaire d'Angers, Angers, France; 5Regional Neuromuscular Service,
Neurology, University Hospitals Birmingham, Birmingham, UK; 6Department of Psychology,
Wayne State University, Detroit, Michigan, USA; 7St Elisabeth Hospital, Brussels,
Belgium; *The University of Louvain GBS Electrodiagnosis Study Group: P. Y. K. Van
den Bergh, V. Van Parijs (University Hospital St‐Luc, Brussels); F. Piéret (St Elisabeth
Hospital, Brussels); D. Verougstraete (Parc Leopold Hospital, Brussels); Ph. Jacquerye,
J. M. Raymackers (St‐Pierre Hospital, Ottignies); C. Redant (St‐Luc Hospital, Bouge);
C. Michel (Jolimont Hospital, Mons)
This study examines whether GBS subtypes can be diagnosed by a single electrophysiological
study (EDX) according to criteria by Rajabally (2014) (RA) as compared to Ho (1995)
(HO) and Hadden (1998) (HA) and whether temporal dispersion (TD) parameters are helpful.
Fifty‐eight patients diagnosed according to Asbury and Cornblath (1990) were prospectively
included between January 2015 and September 2016. EDX1 and 2 were performed 1–12 (mean=5)
and 23–51 days (mean=33) after disease onset, respectively. There were no differences
in classification consistency between HO and HA at EDX1 (p=0.41) and EDX2 (p=0.30),
but more patients were classified as AMAN when comparing RA with HO and HA at EDX1
(p<0.01). At EDX2, RA classified more patients as equivocal with HO (p<0.001) and
as AMAN with HA (p<0.001). Adding TD (≥ DCMAP or P/DCMAP duration prolongation) to
RA led to an increase in AIDP at EDX1 (p=0.01) and EDX2 (0.03). There were no differences
between the two EDX for HO (p=0.22), HA (p=0.75), RA (p=0.33), and RA with TD (p=0.68).
Reversible conduction failure (RCF), defined as a 50% increase of the DCMAP or PCMAP
at EDX2, was not related to subtypes at EDX1 (HO, Fisher's Exact Test [TE] p=0.45;
RA, FE p=0.14; RA with TD; FE p=0.31) or EDX2 (HO, FE p=0.55; HA, FE p=0.30; RA, FE
p=0.5; RA with TD, FE p=0.64). GM1, GD1a, GD1b and GQ1b IgG antibodies were tested
(Willison, 1999; Delmont, 2015). At EDX1, only HO showed maybe more antibodies with
AMAN compared to AIDP (FE p=0.02, Phi=−0.38) and with AMAN compared to equivocal cases
(FE p=0.03, Phi=−0.62). At EDX2, only with HA may antibodies be more frequent with
AMAN compared to AIDP (FE p=0.02, Phi=−0.40). Conclusion: Serial EDX at well‐defined
time intervals has no substantial effect on different GBS subtype proportions, regardless
of criteria used. Since correlation with factors associated with axonal GBS, in casu
RCF and antibodies, is far from exclusive, the usefulness of EDX subtype classification
using specific criteria sets, remains doubtful. The frequency of RCF indicates that
nodal/paranodal alterations may represent the main pathophysiology in more GBS patients
than currently thought (Uncini and Kuwabara, 2015).
INHIBITION OF HISTONE DEACETYLASE 6 (HDAC6) PROTECTS AGAINST VINCRISTINE‐INDUCED PERIPHERNAL
NEUROPATHIES AND INHIBITS TUMOR GROWTH
Van Helleputte L
1,2, Kater M1,2, Cook D3, Haeck W1,2, Jaspers T1,2, Geens N1,2, Vanden Berghe P4,
Geysemans C3, Robberecht W1,2, Van Damme P1,2,5, Cavaletti G6, Jarpe M7, Van Den Bosch
L1,2.
1Department of Neurosciences, Experimental Neurology and Leuven Research Institute
for Neuroscience and Disease (LIND), KU Leuven–University of Leuven, Leuven, Belgium;
2VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium;
3Clinical and Experimental Endocrinology, KU Leuven–University of Leuven, Leuven,
Belgium; 4Laboratory for Enteric Neuroscience, TARGID, KU Leuven–University of Leuven,
Leuven, Belgium; 5Department of Neurology, Leuven, University Hospitals Leuven, Belgium;
6Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine
and Surgery, University of Milano‐Bicocca, Monza, Italy; 7Acetylon Pharmaceuticals
Inc., Boston, MA, USA.
The most important neurological side effect of a large number of anti‐cancer drugs
is a painful peripheral neuropathy. Mainly chemotherapeutics that interfere with microtubules,
including the plant derived vinca‐alkaloids such as vincristine, are well known to
cause chemotherapy‐induced peripheral neuropathies (CIPN). To date, few treatments
are available and focus on symptom alleviation and pain reduction rather than on preventing
the neuropathy all together. For the first time, we highlight the potential of specific
histone deacetylase 6 (HDAC6) inhibitors as a preventive therapy for CIPN, using novel
rodent models for vincristine‐induced peripheral neuropathies (VIPN), characterized
by a sensory axonopathy. One reason so few therapies are available, is because the
exact pathophysiological mechanisms are poorly understood. Mounting evidence proposes
axonal transport, a pathway frequently disturbed in neurological disorders, as a major
player in the pathophysiology of VIPN. Proper axonal transport requires dynamic microtubules
which are highly modulated by post‐translational modifications. Since vincristine
interferes with the polymerization of microtubules, we reason disturbances in microtubule
dynamics, and by extension axonal transport, could contribute to VIPN. We illustrate
that increasing acetylation of α‐tubulin after HDAC6‐inhibition, can restore vincristine‐induced
defects in axonal transport in cultured dorsal root ganglion neurons. Also in vivo,
α‐tubulin acetylation was restored in the saphenous nerve and dorsal root ganglia,
two sensory tissues that are affected by vincristine. Ultimately, this correlates
to a reduced severity of the neurological symptoms, both on the electrophysiological
and on the behavioral level. Moreover, we discovered that HDAC6‐inhibition was not
only protective against neurotoxicity, but also reduced tumor progression in a mouse
model for acute lymphoblastic leukemia. Taken together, our results show that HDAC6‐inhibition
is an ideal strategy to prevent VIPN with beneficial effects both on the neurotoxicity
as well as on tumor growth.
CORTICOSTEROID TREATMENT IN CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY – A
MULTICENTER, RETROSPECTIVE STUDY
van Lieverloo G
1, Basta I2, Verhamme C1, Gallia F3, Stevic Z2, Peric S2, Nikolic A2, Liberatore G3,
Bianco M3, Doneddu P3, van Schaik I1, Nobile‐Orazio E3, Eftimov F1.
1Academic Medical Center (AMC), Amsterdam, The Netherlands; 2Neurology Clinic, Clinical
Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia; 3Neuromuscular
and Neuroimmunology Service, Humanitas Clinical and Research Center, Department of
Medical Biotechnology and Translational Medicine, Milan University, Rozzano, Milan,
Italy.
Corticosteroids are considered as one of the first line treatments for chronic inflammatory
demyelinating polyneuropathy (CIDP). Different types of corticosteroids are used and
there are no comparative studies assessing the improvement rates, remission rates,
tolerability and the side effect profiles of these treatment regimens. In addition,
there are currently no reliable predictors of favorable treatment response to steroids,
which would greatly ease the choice of first line treatment. In this retrospective
study we will compare efficacy, tolerability and safety of three different corticosteroid
regimens used as first line treatment in three large CIDP centers in Netherlands,
Serbia and Italy. Treatment naïve CIDP patients who received either pulsed dexamethasone,
pulsed methylprednisolone or daily prednisone will be included in the study. Data
will be extracted from patient charts. The primary outcome is the percentage of treatment
responders at 6 months after start of first treatment, in which treatment response
is defined as subjects who improved after treatment and are either without treatment
after six months or are still being treated with the first chosen therapy. Secondary
endpoints include the remission rates and in case of a relapse, the mean duration
of remission to relapse; the discontinuation rate within 6 months of treatment due
to inefficacy, adverse events or intolerance; and the frequency of adverse events
and serious adverse events (SAE) during treatment or within 1 month after stopping
treatment. Furthermore, we will explore the value of previously reported potential
predictors of treatment response. Results will be presented at the Peripheral Nerve
Society Meeting 2017.
EXPANDED B‐CELL RECEPTOR CLONES ARE PRESENT IN PERIPHERAL BLOOD SAMPLES IN PATIENTS
WITH CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
van Lieverloo G
1,2, Musters A2, Adrichem M1, Esveldt R2, Doorenspleet M2, Klarenbeek P2, van Schaik
I1, de Vries N2, Eftimov F1.
1Academic Medical Center, Department of Neurology, Amsterdam, the Netherlands; 2Academic
Medical Center/University of Amsterdam, Department of Clinical Rheumatology and Immunology,
Amsterdam, The Netherlands.
Following reports that pathogenic antibodies are present in a minority of patients
with chronic demyelinating inflammatory neuropathy (CIDP), we studied whether oligoclonal
expansions of B‐cell clones are present in patients with CIDP. Recently, we developed
a new method for B‐cell receptor (BCR) repertoire landscaping based on high throughput
sequencing (HTS) of RNA extracted from blood. BCR repertoire was analyzed in 30 patients
with CIDP: 10 patients with active disease and starting treatment (group 1), 10 patients
with stable disease using intravenous immunoglobulin (IVIg) treatment in which treatment
withdrawal was attempted (group 2), and 10 patients in remission (i.e. no treatment
in the last 12 months, group 3). Clinical parameters and sampling was performed at
baseline (group 1, 2 and 3), at 6 months after start of treatment (group 1), at 6
months or earlier in case of relapse in group 2 and at baseline only in group 3. Most
CIDP patients had highly expanded BCR clones, regardless of disease activity and response
to treatment. However, in group 1, the most expanded B‐cell clones at baseline showed
no overlap with the expanded BCR clones after improvement. Based on these preliminary
data expanded BCR clones are observed in the peripheral blood of most CIDP patients,
regardless of disease activity (active, stable disease or remission/cure). Functional
characterization of these expanded clones remains to be performed.
FREQUENCY AND ACTIVATION STATUS OF MYELOID CELLS IN THE GUILLAIN‐BARRÉ SYNDROME
Van Rijs W1, Fokkink WJR1, Tio‐Gillen AP1, Brem MD1, Jacobs BC1, Huizinga R
1.
1Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Myeloid cells, including monocytes, macrophages and dendritic cells, are critically
involved in the induction of adaptive immune responses, clearance of pathogens and
in the initiation of tissue repair. In the Guillain‐Barré syndrome (GBS), macrophages
are present in the peripheral nerve, where they phagocytose (damaged) myelin and axons.
Dendritic cells (DC) are increased in the cerebrospinal fluid of patients with GBS.
However, the composition and phenotype of monocytes and DC subsets in the peripheral
blood is unclear and it is unknown if these cells can be used as biomarker to monitor
disease activity or response to treatment. Here we investigated the frequency and
phenotype of six myeloid subsets in the peripheral blood mononuclear cells (PBMC)
using advanced 13‐color flow cytometry. PBMC were isolated from 20 patients with GBS,
before and after immunomodulatory treatment, and 20 age and gender‐matched, healthy
controls. The frequency of total monocytes, determined as percentage of CD45+ cells,
was increased in GBS patients compared to controls (p<0.05). The monocyte population
was skewed towards more intermediate (CD14+CD16+; p<0.05) and less non‐classical (CD14‐CD16+;
p<0.01) monocytes. Classical (CD14+CD16‐) and intermediate monocytes as well as CD1c+
DC expressed significantly higher levels of CD38 compared to healthy controls. In
contrast, the expression of CD40 and Siglec‐7 was significantly higher in the non‐classical
monocytes of GBS patients compared to controls. No differences were observed in the
expression of CD69, CD80, CD83 and Siglec‐1. Immunomodulatory treatment strongly reduced
the frequency of non‐classical monocytes and all DC populations in CD45+ PBMC. The
expression of CD40, CD1c and HLA‐DR was reduced in classical monocytes after treatment.
In addition, Siglec‐7 expression was reduced in several monocyte and DC populations
after treatment. In summary, our data identify significant changes in the monocyte
compartment in GBS. The decrease in non‐classical monocytes may suggest that these
cells have migrated to peripheral tissues, promoting the differentiation of classical
monocytes into intermediate monocytes. Further analysis should reveal whether these
changes are related to preceding infections, disease severity and response to treatment.
SUBCUTANEOUS IMMUNOGLOBULIN FOR MAINTENANCE TREATMENT IN CHRONIC INFLAMMATORY DEMYELINATING
POLYNEUROPATHY (CIDP), A MULTICENTER RANDOMIZED DOUBLE‐BLIND PLACEBO‐CONTROLLED TRIAL:
THE PATH STUDY
van Schaik IN
1, Bril V2, van Geloven N3, Hartung H‐P4, Lewis RA5, Sobue G6, Lawo J‐P7, Mielke O7,
Durn BL7, Cornblath DR8, Merkies ISJ9 and on behalf of the PATH study group.
1Department of Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam,
The Netherlands; 2Department of Medicine (Neurology), University Health Network, University
of Toronto, Toronto, Canada; 3Department of Biostatistics and Bioinformatics, Leiden
University Medical Center, Leiden, The Netherlands; 4Department of Neurology, Heinrich
Heine University, Düsseldorf, Germany; 5Department of Neurology, Cedars‐Sinai Medical
Center, Los Angeles, CA, USA; 6Department of Neurology, Nagoya University Graduate
School of Medicine, Nagoya, Japan; 7CSL Behring, Marburg, Germany and King of Prussia,
PA, USA; 8Department of Neurology, Johns Hopkins University School of Medicine, Baltimore,
MD, USA; 9Department of Neurology, Maastricht University Medical Center, Maastricht,
The Netherlands.
Approximately two‐thirds of CIDP subjects need long‐term corticosteroids or intravenous
immunoglobulins (IVIg), with IVIg being slightly preferred based on safety profiles.
Subcutaneous Ig (SCIg) is an alternative option for Ig delivery but has not previously
been investigated in a large‐scale clinical trial in CIDP.
We performed a randomized, double‐blind trial in CIDP investigating 0.2 and 0.4 g/kg
weekly doses of SCIg IgPro20 (Hizentra
®
, CSL Behring) versus placebo in 172 subjects for maintenance treatment. IVIg‐dependent
adults with definite or probable CIDP according to EFNS/PNS criteria were eligible.
The primary outcome was the percentage of subjects with a CIDP relapse (1‐point deterioration
on adjusted INCAT disability score) or who were withdrawn for any other reason during
the 24‐week SCIg‐treatment period. Multiple secondary endpoints were assessed. Superiority
of at least one IgPro20 dose over placebo was tested one‐sided using the Cochran‐Armitage
trend test for the primary outcome and the Jonckheere‐Terpstra tests for secondary
outcomes.
The primary outcome occurred in 33% of high‐dose SCIg, 39% of low‐dose SCIg, and 63%
of placebo subjects (p < 0.001); CIDP relapse occurred in 19% of high‐dose SCIg, 33%
of low‐dose SCIg and 56% of placebo subjects (p < 0.001), respectively. Both SCIg
doses were superior to placebo (low‐dose vs placebo p = 0.007; high dose vs placebo
p < 0.001). Median INCAT score, MRC sum score, and grip strength remained stable in
SCIg subjects. High‐dose SCIg prevented the R‐ODS decline seen with low‐dose SCIg
and placebo (p < 0.001). All placebo subjects deteriorated on measures of strength
and disability.
Causally related adverse events occurred in 47 (27%) subjects (18% placebo, 30% low
dose, and 35% high dose).
SCIg IgPro20 was efficacious and safe as maintenance treatment. High‐dose and low‐dose
SCIg were both superior to placebo, with the high dose potentially showing better
efficacy.
Funding: CSL Behring sponsored the study
Trial Registration: http://Clinicaltrials.gov, number NCT01545076.
CHARCOT‐MARIE‐TOOTH DISEASE TYPE‐2 ASSOCIATED WITH TWO MISSENSE MUTATIONS IN MME GENE
Vegezzi E
1, Cortese A2, Callegari I1, Rossor AM2, Houlden H3, Reilly MM2.
1Neuroscience Consortium, University of Pavia, Monza Policlinico and Pavia Mondino,
Italy; 2MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and
Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; 3Department of
Molecular Neuroscience, UCL Institute of Neurology, London, UK; National Hospital
for Neurology and Neurosurgery, Queen Square, London, UK.
Mutations in metalloendopeptidase (MME) gene have been associated with autosomal‐recessive
late‐onset Charcot‐Marie‐Tooth type‐2 (CMT2). To date, all patients have had at least
one truncating mutation, either in homozygosity or in trans with a missense mutation.
More recently, loss‐of‐function and missense heterozygous mutations were also identified
in autosomal‐dominant CMT. We report the case of a previously healthy Caucasian woman,
born to healthy unrelated parents, who presented at the age of thirty‐nine with numbness
and cold sensation in the lower limbs. Subsequently she developed progressive gait
disturbance and impaired hand dexterity. Her homozygous twin presented at the same
age with similar symptoms. The family history was otherwise uneventful, in particular
neither neuropathy nor dementia were described. Neurological examination at the age
of fifty‐three revealed a steppage gait, distal upper and lower limb atrophy and weakness,
distal sensory loss and bilateral pes cavus. Deep tendon reflexes were normal in the
upper limbs and absent in the lower limbs. Nerve conduction studies revealed an axonal
sensory and motor neuropathy. A sural nerve biopsy revealed a reduction in myelinated
nerve fibers and active axonal degeneration. Targeted Sanger sequencing of MPZ, GJB1,
GDAP1, NEFL, FKRP, BSCL2, HSPB8 and MFN2 were negative. SureSelect Focused Exome sequencing
was therefore performed and identified two missense heterozygous mutations [c.263G>A,p.C88Y;c.1279T>C,p.Y427H]
in MME. The two mutations were absent from control databases (e.g. Exac), affected
highly conserved aminoacids and were predicted to have deleterious effects by in silico
analysis. Unfortunately, both parents were deceased and we were therefore unable to
prove that the two mutations reside on separate alleles. MME encodes the metalloprotease
neprilysin whose role in peripheral nervous system is still unclear. Higuchi and colleagues
have described 10 Japanese CMT2 families with late‐onset sensory‐motor axonal neuropathy
and recessive loss‐of‐function mutations in MME. We report two novel missense mutations
in MME in a case of late‐onset CMT2. We hypothesize an autosomal‐recessive mode of
inheritance as most likely given the clinical phenotype and the absence of a family
history.
EFFICACY OF CYCLOPHOSPHAMIDE IN ANTI‐CONTACTIN‐1 ANTIBODIES ASSOCIATED TO CHRONIC
INFLAMMATORY DEMYELINATING POLYNEUROPATHY AND MEMBRANOUS GLOMERULONEPHRITIS: A CASE
REPORT
Vegezzi E
1, Cortese A2, Zardini E3, Devaux J4, Franciotta D3.
1Neuroscience Consortium, University of Pavia, Monza Policlinico and Pavia Mondino,
Italy; 2MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and
Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; 3Department of
General Neurology, C. Mondino National Institute of Neurology Foundation, IRCCS, Pavia,
Italy; 4Aix‐Marseille Université, CNRS, CRN2M‐UMR7286, Marseille, France.
Anti‐contactin‐1 (CNTN1) antibodies were recently identified in a subgroup of patients
with chronic inflammatory demyelinating polyneuropathy (CIDP) showing acute/subacute
onset of severe sensory‐motor neuropathy and poor response to intravenous immunoglobulin
(IVIg) and corticosteroids. These antibodies belong to the IgG4 isotype and interact
with CNTN1‐neurofascin 155 (NF155) complex at paranodes leading to loss of nodal integrity.
A 59‐year‐old man presented with acute onset of distal weakness in the lower limbs,
four limbs paraesthesias and sensory ataxia. At clinical examination ankle swelling
was also observed. Nerve conduction study showed a demyelinating polyneuropathy and
cerebrospinal‐fluid examination revealed cyto‐albuminologic dissociation. Sural nerve
biopsy disclosed diffuse loss of myelinated fibres. At routine blood test serum albumin
was reduced and proteinuria was 10 gr/24 hours, thus leading to the diagnosis of nephrotic
syndrome. Kidney biopsy showed changes consistent with membranous glomerulonephritis,
together with sub‐epithelial deposits of immune complexes and complement deposition.
Treatment with IVIg and corticosteroids did not improve neurological status, while
membranous glomerulonephritis showed moderate response to IVIg. A six‐month course
of cyclophosphamide was started leading to normalization of renal function and muscle
strength and partial improvement of sensory ataxia. The patient did not require any
further treatment and after 10 years his condition remains stable. CNTN1 antibodies
were tested on a recently collected patient's serum and resulted positive on both
ELISA and cell‐based assay. The patient here reported showed the typical clinical
features of anti CNTN1‐associated CIDP including older age, acute onset, severe motor
impairment and sensory ataxia. The contemporary occurrence of membranous glomerulonephritis
was reported in only one other case. Contactin‐1 is expressed at low levels in the
kidney and a direct damage of anti‐CNTN1 antibodies could be hypothesized. Alternatively,
renal damage might have been secondary to unspecific immune complexes deposition.
A good response to anti‐CD20 rituximab was recently reported in patients with CIDP
associated with anti‐CNTN1 and anti‐NF155 antibodies. Notwithstanding this single‐case
observation, our report suggests that also cyclophosphamide may be considered an effective
therapy in anti‐CNTN1 antibodies‐associated CIDP and membranous glomerulonephritis,
leading to persistent clinical remission.
DULOXETINE IN CHEMOTHERAPY‐INDUCED PERIPHERAL NEUROPATHY
Velasco R
1,2, Besora S1, Santos C3, Sala R1, Izquierdo C1, Simó M1, Gil‐Gil M1,3, Jiménez L3,
Pardo B3, Calvo M3, Palmero R3, Clapés V4, Bruna J1,2.
1Neuro‐Oncology Unit, Department of Neurology, University Hospital of Bellvitge–Catalan
Institute of Oncology, L'Hospitalet, Barcelona, Spain; 2Institute of Neurosciences,
Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona,
and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
(CIBERNED), Bellaterra, Spain; 3Department of Medical Oncology, Hospital Duran i Reynals,
Catalan Institute of Oncology, L'Hospitalet, Barcelona, Spain; 4Department of Clinical
Hematology, Hospital Duran i Reynals, Catalan Institute of Oncology, L'Hospitalet,
Barcelona, Spain.
Duloxetine is the only agent demonstrated effective in treating pain related with
chemotherapy‐induced peripheral neuropathy (CIPN). Patients with symptomatic CIPN
treated with duloxetine were retrospectively collected in a single‐institution. Aim
of the study was to evaluate the drug's efficacy and rate of compliance. Only patients
with CIPN with distressing positive symptoms (pain, numbness and/or paresthesia),
and non‐progressive disease were included. CIPN was graded employing the Total Neuropathy
Score (TNS©) and National Cancer Institute‐Common Toxicity Criteria. Response to duloxetine
was assessed with Patient Global Impression of Change (PIGC) scale (1: no benefit;
7: excellent response). Consecutive first one‐hundred CIPN patients treated with duloxetine
were analyzed. Median age was 62 (29–81). 59, 37, 2 and 2 received platinum, taxane,
bortezomib and vincristine‐based regimen, respectively. Median TNSc© was 9 (1–17).
Severity of neuropathy was grade 1 (20%), grade 2 (66%), and grade 3 (14%). Sixteen
patients were on treatment with other analgesic agents. Median time from finishing
chemotherapy to duloxetine initiation was 6 months [0–63]. Median PIGC score was 3
[1–7]. Among responders, 45.5% and 54.5% scored low (2–4) and high (5–7) benefit,
respectively. Fifty‐seven (57%) patients discontinued early duloxetine due to intolerable
side effects (n=37) or lack of efficacy (n=20). Most frequently reported adverse events
were cognitive (26%), gastrointestinal (14%) and genitourinary (9%). Discontinuation
due to perception of lack of efficacy was more frequently reported by men (75% vs
25% p=0.001). Women presented higher punctuations on PIGC scale compared with men
(3.8±2.1 vs 1.9±1.7, p=0.005). PIGC scores were significantly higher in patients receiving
taxane (3.8±2.4) than platinum (2.5±1.9) agents (p=0.027). No significant differences
according severity of neuropathy neither type of chemotherapy were observed in drop‐out
and retention rates. Patients with long‐lasting CIPN (>6 months) reported lower PIGC
scores (2.1±1.7 vs 3.7±2.3, p=0.008) and higher frequency of suspension due to adverse
events (22% vs 15%, p=0.039) and less rate of continuation of duloxetine (12% vs 26%,
p=0.024). More than one‐third of patients with disturbing CIPN discontinued duloxetine
prematurely due to intolerable side‐effects. Low tolerability, male gender and long‐lasting
CIPN may limit duloxetine usefulness in the treatment of symptomatic CIPN.
IMMUNOGLOBULIN TREATMENT FOR PATIENTS WITH MILD GUILLAIN‐BARRÉ SYNDROME: AN INTERNATIONAL
PROSPECTIVE OBSERVATRIONAL STUDY
Verboon C
1, Jacobs BC1,2 and the IGOS Consortium.
1Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands; 2Department
of Immunology, Erasmus Medical Centre, Rotterdam, The Netherlands.
The efficacy of intravenous immunoglobulin (IVIg) in Guillain‐Barré syndrome (GBS)
has only been demonstrated in severely affected patients who are unable to walk independently.
Although there is no proof that IVIg is effective in milder forms of GBS, some neurologists
are treating these patients with IVIg considering that even milder forms of GBS may
result in poor recovery, residual deficits, fatigue or pain.
We determined the effectiveness of a single course of IVIg (2 g/kg in 2–5 days) in
relatively mild forms of GBS in the ongoing observational International GBS Outcome
Study (IGOS). The GBS disability score, MRC sum score and patient reported outcome
measures (PROM) were compared at 4 and 26 weeks. Ordinal logistic regression analysis
was used to determine the effect of IVIg on the GBS disability score, adjusted for
previously identified prognostic factors.
Data were analyzed from the first 1300 patients enrolled in IGOS by December 2016,
including 238 patients with mild GBS at entry, of which 68 patients (29%) were treated
with supportive care, while 170 patients (71%) received IVIg (start IVIg after onset
of symptoms in days, median 6, IQR 4–9). At baseline, patients in the IVIg treated
group compared to the untreated group less frequently had pure motor GBS (10% versus
31%, p<0.001) and axonal damage or unresponsive nerves (7% versus 19%, p=0.032), but
a worse GBS disability scores at nadir (p=0.005). The adjusted common odds ratio for
a better GBS disability score at 4 weeks was 2.81 (95% CI 1.34‐5.89). At 4 weeks,
the median MRC sum scores and PROM were not significantly different between treated
and untreated patients. However, more patients in the IVIg group showed complete recovery
of muscle strength at 4 weeks than patients in the control group (71% versus 53%)
(p=0.01) and more frequently showed full neurological recovery on the GBS disability
scale (13% versus 3%, p=0.03). Additional results will be presented at the conference.
Based on the results of this interim analysis in observational data, we conclude that
patients with a relatively mild form of GBS may benefit from a single course of IVIg.
INTERNATIONAL SECOND IMMUNOGLOBULIN DOSE IN PATIENTS WITH GUILLAIN‐BARRÉ SYNDROME
WITH POOR PROGNOSIS (I‐SID GBS), A PROSPECTIVE OBSERVATIONAL STUDY
Verboon C
1, van den Berg B1, Cornblath DR2, Walgaard C1, Gorson KC3, Lunn MP4, Hartung HP5,
Steyerberg EW6, Lingsma H6, Jacobs BC1,7, van Doorn PA1 and the IGOS Consortium.
1Department of Neurology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands;
2Department of Neurology, Johns Hopkins University, Baltimore, USA; 3Department of
Neurology, Tufts University School of Medicine, Boston, USA; 4MRC Centre for Neuromuscular
Disease, National Hospital for Neurology and Neurosurgery, London, UK; 5Department
of Neurology, Heinrich Heine Universität, Düsseldorf, Germany; 6Department of Public
Health, Erasmus Medical Centre, Rotterdam, The Netherlands; 7Department of Immunology,
Erasmus Medical Centre, Rotterdam, The Netherlands.
Despite treatment with intravenous immunoglobulin (IVIg), many patients with Guillain‐Barré
syndrome (GBS) recover insufficiently. We primarily aimed to determine whether a second
IVIg course (2 g/kg in 2–5 days) in patients with a poor prognosis improves outcome
on the GBS disability scale after 4 weeks. We included patients from the prospective,
observational International GBS Outcome Study (IGOS) treated with IVIg and who had
a poor prognosis on the modified Erasmus GBS Outcome Score (mEGOS). Of 1300 patients
enrolled in IGOS, 239 patients were eligible; 200 patients (84%) were treated with
one IVIg course (control group); 19 patients (8%) received an ‘early’ second IVIg
course (1–2 weeks after start first course) and 20 patients (8%) a ‘late’ second IVIg
course (within 2–4 weeks). One week after study entry, patients receiving an ‘early’
or ‘late’ second IVIg course had significantly worse GBS disability scores and MRC
sum scores than controls, implying the need for adjustment of baseline characteristics.
The adjusted common odds ratio for a better GBS disability score at 4 weeks was 0.69
(95% CI 0.19‐2.42) for the ‘early’ group, and 0.51 (95% CI 0.15‐1.73) for the ‘late’
group, suggesting worse outcomes with a second course of IVIg compared to controls.
At 6 months, 10 patients (71%) in the ‘early’ second IVIg group, 100 patients (65%)
in the control group and only 2 (18%) in the ‘late’ second IVIg group were able to
walk unaided (p=0.006). The adjusted common odds ratio for a better GBS disability
score at 26 weeks was 1.66 (95% CI 0.44‐6.21) for the ‘early’ second IVIg group and
only 0.53 (95% CI 0.14‐1.96) for the ‘late’ second IVIg group. In GBS patients with
a poor prognosis, we did not find a beneficial effect of a second course of IVIg after
4 weeks follow‐up. Our results suggest that an ‘early’ administered second IVIg course
might improve outcome at 26 weeks. Given the limitations of this observational study,
a randomized controlled trial with a larger number of GBS patients with a poor prognosis
being treated early in the disease course is needed to confirm or refute these results.
ATYPICAL MULTIFOCAL MOTOR NEUROPATHY WITH SCAPULAR WINGING
Vidal C
1, Bhatt N1, Agudelo C1, Mahapatra A1, Saporta MA1.
1Department of Neurology, University of Miami Miller School of Medicine, Miami, USA.
Multifocal motor neuropathy (MMN) is an inflammatory demyelinating chronic neuropathy
characterized by progressive asymmetric weakness in the distribution of two or more
peripheral nerves, without objective sensory loss or upper motor neuron signs. The
cardinal neurophysiological finding is conduction block outside the usual sites of
nerve compression. Supportive clinical criteria include high titers of anti‐GM1 antibodies,
good response to IVIg, increased cerebrospinal fluid (CSF) protein (<1g/dL) and magnetic
resonance imaging (MRI) with diffuse swelling of the brachial plexus. We report a
case of a 31 year old woman with a two month history of progressive muscular weakness
which began in the right upper extremity, described as difficulty in gripping objects,
writing and typing on the computer, followed by progressive lower extremity weakness
with difficulty rising from a chair and left foot drop. She also complained of pain
in her right trapezius and scapular area. She denied any tingling or numbness. On
neurological examination there was right scapular winging and asymmetric weakness
predominantly involving the right upper and left lower extremities. Reflexes were
absent throughout. Lumbar puncture revealed albuminocytological dissociation (WBC
0 and protein 1.13 g/dL). NCS revealed slow conduction velocities for both ulnar and
median nerves and a median nerve conduction block at the forearm segment. Sensory
nerve action potentials were normal for all tested nerves. Needle EMG revealed acute
denervation of right periscapular muscles. Brachial plexus MRI showed symmetric bilateral
thickening from trunks to peripheral nerves. Anti‐GM1 IgG/IgM were negative. Two days
after lumbar puncture and the beginning of IVIg, patient presented binocular diplopia
on extreme left lateral gaze. Brain MRI with and without contrast showed no intracranial
pathologies. After five days of IVIg, patient was discharged with significant clinical
improvement and recovery of the right scapular winging. Diplopia improved a week after
discharge. We report an atypical multifocal motor neuropathy case. Although this patient
fulfills all clinical criteria for MMN, we report some features usually not found
in MMN such as scapular winging and a mild and transient left VI nerve palsy. MMN
should be included in the differential diagnosis of scapular winging.
SENSORY PHENOTYPE AND RISK FACTORS FOR PAINFUL DIABETIC NEUROPATHY: A CROSS SECTIONAL
OBSERVATIONAL STUDY
Vlckova E1,2, Raputova J1,2, Srotova I1,2, Sommer C3, Üçeyler N3, Birklein F4, Rebhorn
C4, Rittner HL5, Kovalova E1,2, Nekvapilova E1,2, Belobradkova J6, Olsovsky J7, Weber
P8, Dusek L9, Jarkovsky J9, Bednarik J
1,2.
1Central European Institute of Technology, Masaryk University, Brno, Czech Republic;
2Department of Neurology, University Hospital Brno, Brno, Czech Republic; 3Department
of Neurology, University of Würzburg, Germany; 4Department of Neurology, University
Medical Center, Mainz, Germany; 5Department of Anesthesiology, Centre for interdisciplinary
Pain Medicine, University Hospital Würzburg, Germany; 6 Diabetologic Centre, Department
of Internal Medicine and Gastroenterology, University Hospital Brno, Brno, Czech Repubic;
7Diabetologic Centre, St. Anne University Hospital, Brno, Czech Republic; 8Department
of Internal Medicine, Geriatrics and Practical Medicine, University Hospital Brno,
Brno, Czech Republic; 9Institute of Biostatististics and Analyses, Masaryk University,
Brno, Czech Republic.
Despite many studies addressing biomarkers for pain in diabetic polyneuropathy (DPN),
little is known about why it affects only a certain proportion of DPN patients. The
somatosensory system plays a key role in the pathophysiology of neuropathic pain (NeuP)
and subgroups with different sensory profiles might respond differently to pain treatment.
We aimed to characterize sensory phenotypes of patients with painful and painless
diabetic neuropathy and to assess demographic, clinical, metabolic, electrophysiological
and psychological parameters related to the presence of NeuP in a large cohort of
well‐defined DPN subjects.
This observational cross‐sectional multi‐centre cohort study (performed as part of
the ncRNAPain EU consortium) of 232 subjects with DPN (non‐painful, nDPN, n=74; painful,
pDPN n=158) associated with diabetes mellitus of type 1 and 2 (median age 63 years,
range 21–87 years; 92 women) comprised detailed history taking, neurological examination,
laboratory tests, quantitative sensory testing, nerve conduction studies, neuropathy
severity scores, and neuropsychological questionnaires. All parameters were analysed
with regard to the presence and severity of NeuP. The presence and severity of NeuP
were positively correlated with severity of neuropathy and thermal hyposensitivity
(p<0.001). A minority of pDPN patients (14.6%) had a sensory profile indicating thermal
hypersensitivity; this was associated with less severe neuropathy and better response
to pain therapy. The presence of NeuP was also associated with female gender (p<0.001)
and with higher cognitive appraisal of pain as assessed by the pain catastrophizing
scale (p<0.001), while parameters related to diabetes (duration, HbA1c, microangiopathy)
showed no influence on NeuP presence and severity. This study confirms the necessity
of comprehensive DPN phenotyping and underlines the importance of the severity of
neuropathy that should be taken into account in the stratification of patients with
pDPN for analgesic treatment and drug trials.
EVALUATING THE BENEFITS OF COMMUNITY BASED AEROBIC TRAINING ON THE PHYSICAL HEALTH
AND WELL‐BEING OF PEOPLE WITH CHARCOT‐MARIE‐TOOTH DISEASE TYPE 1A: A PILOT RANDOMISED
CONTROLLED TRIAL
Wallace A1, Pietrusz A1, Dewar E1, Dudziec M1,2, Jones K1, Hennis P3, Sterr A4, Baio
G5, Butcher K6, Laurà M1, Skorupinska I1, Skorupinska M1, Trenell M7, Hanna MG1, Reilly
MM1, Ramdharry GM
1,2.
1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK; 2Faculty
of Health, Social Care & Education, Kingston University/St George's University of
London, UK; 3Institute of Sport, Exercise and Health, UCL, UK; 4Department of Psychology,
University of Surrey, Guildford, UK; 5Department of Statistical Science, UCL, London,
UK; 6Charcot Marie Tooth United Kingdom, Registered charity number 1112370, UK; 7Movelab,
Newcastle University, UK.
People with Charcot Marie Tooth disease (CMT) experience slowly progressive muscle
weakness, sensory loss and musculoskeletal changes over time. This leads to disability
and risk of comorbidities due to inactivity. Exercise is important to maintain general
health but may also help to improve symptoms of CMT. We conducted a randomised controlled
crossover trial of aerobic exercise to ascertain the effect of training on fitness
levels, muscle strength, function and general well‐being. In addition, we monitored
the safety of training and feasibility of participation in this type of exercise in
local community gyms. Motivation, confidence and barriers to exercise were explored
using qualitative interviews. The recruitment target was 30 people. In total 282 people
with CMT 1A were approached to participate and 191 were unable to commit to the trial
or did not meet the study criteria on initial screening. Thirty‐one people underwent
more detailed screening but three failed to meet the study criteria, five people withdrew
before starting and three withdrew part way through the study. The data for the 23
people who started the study were analysed using a random effects model. There was
a 76% participation level in the training and it was well tolerated with no increases
in pain or blood serum creatine kinase. An increase in VO2peak (ml/min/kg) was observed
in the CMT group with (pre training: n=21, 22.28 ±4.43, 95% CI 20.57 to 24.28; post
training: n=21, 24.52 ±4.40, 95% CI 22.62 to 26.33; pre control: n=18, 22.67 ±5.29
95% CI 20.22 to 25.05; post control: n=18, 22.94 ±4.22, 95% CI 21.00 to 24.83). There
was wide between subject variation leading to a small overall effect size with Cohen
d of 0.1302785 (95% CI:‐0.33 to 0.59). A tentative regression model showed no effect
of group or time point. There were no major changes in other measures of impairment,
function or patient reported outcome measures. This pilot study showed that a community
based model of training had a small effect on cardiopulmonary fitness, and was well
tolerated with good participation.
PMP22 EXON 4 DELETION CAUSES ER RETENTION OF PMP22 AND A GAIN‐OF‐FUNCTION ALLELE IN
CMT1E
Wang D1*, Wu X1*, Bai Y1, Zaidman C3, Grider T
1,2, Kamholz J2, Lupski JR4, Connolly AM3, Shy ME1,2.
1Department of Neurology, Neuromuscular Division, University of Iowa Hospitals and
Clinics, Iowa City, Iowa, USA; 2Department of Neurology, Neurogenetics Division, University
of Iowa Hospitals and Clinics, Iowa City, Iowa, USA; 3Departments of Neurology and
Pediatrics, Washington University School of Medicine, Neuromuscular Division, St.
Louis MO, USA; 4 Department of Pediatrics, Baylor College of Medicine, Houston, Texas,
USA, *The two authors contributed equally.
The goal of this study was to determine whether predicted fork stalling and template
switching (FoSTeS) during mitosis deletes exon 4 in peripheral myelin protein 22 KD
(PMP22) and causes a gain‐of‐function mutation associated with peripheral neuropathy
in a family with Charcot Marie Tooth disease type 1E. Two siblings previously reported
to have genomic re‐arrangements predicted to involve exon 4 of PMP22 were evaluated
clinically and by electrophysiology. Skin biopsies from the proband were studied by
RT‐PCR to determine the effects of the exon 4 re‐arrangements on exon 4 mRNA expression
in myelinating Schwann cells. Transient transfection studies with wild type and mutant
PMP22 were performed in Cos7 and RT4 cells to determine the fate of the resultant
mutant protein. Both affected siblings had a length‐dependent demyelinating neuropathy
with severely slow nerve conduction velocities (<10 m/sec). RT‐PCR studies of Schwann
cell RNA from one of the siblings demonstrated a complete in frame deletion of PMP22
exon 4 (PMP22delta4). Transfection studies demonstrated that PMP22delta4 protein is
retained within the endoplasmic reticulum and not transported to the plasma membrane.
Our results confirm that that FoSTeS mediated genomic rearrangement produced a deletion
of exon 4 of PMP22, resulting in expression of both PMP22 mRNA and protein lacking
this sequence. In addition, we provide direct experimental evidence for endoplasmic
reticulum retention of the mutant protein suggesting a gain‐of‐function mutational
mechanism consistent with the observed CMT1E in this family. PMP22delta4 is another
example of a mutated myelin protein that is misfolded and thus likely to contribute
to the pathogenesis of the neuropathy.
BLINK R1 LATENCY UTILITY IN DIAGNOSIS AND TREATMENT ASSESSMENT OF POEMS AND CIDP
Wang W
1,2, Litchy WJ1, Mauermann ML1, Dyck PJB1, Dispenzieri A3, Mandrekar J4, Dyck PJ1,
Klein CJ1.
1Department of Neurology, Mayo Clinic, Rochester MN, USA; 2Department of Neurology,
China‐Japan Friendship Hospital, Beijing, China; 3Department of Hematology, Mayo Clinic,
Rochester MN, USA; 4Biomedical Statistics and Informatics, Mayo Clinic, Rochester
MN, USA.
In POEMS and CIDP, distal limb nerve conduction studies are limited in identifying
demyelination and detecting treatment effects in severely affected patients. Blink
reflex R1 latency may help to not only identify demyelination but also provide a meaningful
treatment outcome measure especially in severely affected patients. POEMS and CIDP
patients having undergone routine nerve conductions and blink reflex testing were
identified. Correlation between R1 latency, limb nerve conduction studies and neuropathy
impairment scores (NIS) was calculated with treatment. Blink reflexes were performed
in 182 patients (124 POEMS, 58 CIDP; NIS range: 12–145 points). Overall, R1 latency
prolongation occurred in 64.3% of patients (65.3% POEMS, 62.1% CIDP). Patients with
R1 prolongation (>13ms) had more severely affected nerve conductions in both POEMS
(ulnar CMAP 2.6mV vs 4.5mV, p=0.001) and CIDP (ulnar CMAP 2.0mV vs 6.1mV, p< 0.001).
R1 latency correlated with NIS severity in POEMS better than CIDP (R2=0.24 vs 0.10,
p=<0.001 vs. 0.014). Follow‐up NIS and R1 latency evaluations after treatment were
available in 31 patients (16 POEMS, 15 CIDP). The R1 latency changes were concordant
with the NIS changes in 94% of POEMS and 60% of CIDP patients. In severely affected
patients [ulnar CMAP amplitude ≤0.5mV (9.9%: 18/182)] except for one, all had prolonged
R1 (>13ms), allowing for treatment follow up and initial diagnosis. Blink reflex R1
latencies are valuable in defining demyelination in severely affected POEMS and CIDP
patients, but also provide a sensitive, early treatment outcome measure among those
same severely affected patients.
INTRAVENOUS IMMUNOGLOBULIN THERAPY FOR CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
IN PEDIATRIC PATIENTS: AN OBSERVATIONAL STUDY
Watson DJ1, Martinez C2, Wallenhorst C2, Hubsch A
3, Shebl A4, Simon TL1.
1CSL Behring LLC, King of Prussia, USA; 2Institute for Epidemiology, Statistics and
Informatics GmbH, Frankfurt, Germany; 3CSL Behring AG, Bern, Switzerland; 4CSL Behring
GmbH, Marburg, Germany.
Chronic inflammatory demyelinating polyneuropathy (CIDP) rarely occurs in children.
Clinical trials in pediatric patients have not been performed and there are little
data on therapy with intravenous immunoglobulin (IVIG). We performed an observational
trial to investigate the risk of Adverse Events of Special Interest (AESI) with IVIG,
i.e. hemolytic anemia, aseptic meningitis, acute renal failure, thromboembolic events
and anaphylactic reactions. The study cohort was derived from the US Premier Perspective
database and consisted of patients <18 years with a diagnosis of CIDP (ICD‐9 CM diagnosis
Code 357.81) treated with the IVIG Privigen® (CSL Behring, Bern Switzerland) between
Jan 2008 and Dec 2015. We identified 17 pediatric CIDP patients: 3 preschool children
(age 2–5 years at first treatment for CIDP), 6 children (6–12 years) and 8 adolescents
(13–18 years); 9 females and 8 males; 14 white, one black and two allocated to “other
race”. Six patients had a history of other IVIG use for Guillain‐Barré syndrome, one
patient for myasthenia gravis and one for immunodeficiency before the diagnosis of
CIDP. The mean Privigen® dose calculated from the cumulative quantity of Privigen®
per treatment episode and the corresponding age‐ and gender specific median of the
US population body weight estimate was 1.3 g/kg body weight. The number of recorded
treatment episodes per patient ranged from 1 to 21. Using an at‐risk period of 30
days for hemolytic anemia, and 10 days for other AESI after each Privigen® administration,
no AESI were observed in the 17 patients with CIDP with a total of 3720 person‐days
at‐risk for HA and 1380 person‐days at‐risk for other AESI. This observational study
shows that IVIG (Privigen®) is used for treatment of CIDP in pediatric patients with
or without concomitant conditions and revealed no particular safety issues in this
patient group.
MITOCHONDRIAL DYSFUNCTION AND ABNORMAL CALCIUM HANDLING IN CELLULAR MODELS OF HEREDITARY
SENSORY NEUROPATHY TYPE 1
Wilson ER
1,2, Kalmar B1, Kugathasan U1,2, Clark AJ4, Bennett DLH4, Abramov AY3, Reilly MM2,
Greensmith L1,2.
1Sobell Department of Motor Neuroscience and Movement Disorders; 2MRC Centre for Neuromuscular
Diseases; 3Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London,
UK; 4Neural Injury Group, Nuffield Department of Clinical Neurosciences, University
of Oxford, Oxford, UK.
HSN‐1 is a peripheral neuropathy most frequently caused by missense mutations in the
SPTLC1 or SPTLC2 genes, which code for two subunits of the enzyme serine palmitoyltransferase
(SPT). SPT catalyzes the first and rate limiting step of de novo sphingolipid synthesis.
It has been shown that mutations in SPT cause a change in enzyme substrate specificity
which results in the production of two atypical sphinganines, deoxysphinganine (DSp)
and deoxymethylsphinganine (DMSp), rather than the normal enzyme product, sphinganine
(Sp). Levels of deoxysphingolipids are elevated in the blood of HSN‐1 patients and
this has been shown to cause the peripheral nerve damage characteristic of the disease,
which affects both sensory as well as motor axons. However, the underlying pathomechanism
of how deoxysphingolipids damage neurons remains elusive. Here, DSp and DMSp‐mediated
neurotoxicity was examined in primary mouse motor and sensory neurons, by assessing
cell survival and neurite outgrowth following exposure to different concentrations
of Sp, DSp or DMSp. The abnormal enzyme products were found to have a rapid and dose‐dependent
neurotoxic effect in primary neurons. We also explored the potential mechanisms that
underlie deoxysphingolipid neurotoxicity, by characterizing mitochondrial function
and changes in calcium handling. We found that mitochondrial dysfunction and calcium
handling deficits may be key mediators of abnormal sphingolipid neurotoxicity, in
both motor and sensory cell models. Specifically, we revealed mitochondrial abnormalities,
signs of endoplasmic reticulum stress and dysfunction of store‐operated calcium channels.
We propose that early deficits in mitochondria and calcium handling may underlie deoxysphingolipid
neurotoxicity and thus present potential therapeutic targets for HSN‐1.
GAIT PATTERNS OF CHILDREN WITH CMT TO INFORM THE DESIGN OF 3D PRINTED ORTHOSES
Wojciechowski E
1,2, Little D1,2, Menezes MP1,2, Hogan S2, Burns J1,2.
1University of Sydney, New South Wales, Australia; 2Sydney Children's Hospital Network
(Randwick and Westmead), New South Wales, Australia.
Ankle‐foot orthoses (AFO) are commonly prescribed for children with Charcot‐Marie‐Tooth
disease (CMT) to manage foot drop, however the type and severity of functional impairment
results in gait deviations that might require alternate orthotic designs. The aim
of this study was to identify 3D gait patterns of children with CMT based on severity
of functional weakness (based on heel walk, toe walk and foot drop items during gait
using the CMT Pediatric Scale) to inform a design pipeline for 3D printed orthoses.
3D gait data were captured with an 8‐camera Vicon Nexus motion capture system using
the lower body Plug‐in‐Gait model in 60 children with CMT (34 male; 11±3.1yrs, 147±16.8cm,
44±17.4kg), of various CMT types: 47 CMT1A, 1 CMT1E, 2 CMT1F, 1 CMT2A, 2 CMT 4C, 4
CMTX1, 3 CMTX3 and compared to 50 typically developing children (15 male; 9.8±3.8yrs,
140±19.6cm, 9±19.0kg). Data were subdivided into three groups denoting increasing
severity of dorsiflexion and plantarflexion weakness: no difficulty heel or toe walking
(CMTND), difficulty heel walking (CMTDH), difficulty toe and heel walking (CMTDTH).
The CMTND group showed a near‐normal gait pattern. The only significant differences
noted at the ankle were reduced peak dorsiflexion in stance (p<0.05), indicating that
an orthotic intervention may not be required. In addition to reduced peak dorsiflexion,
the CMTDH group demonstrated significantly reduced dorsiflexion in swing (foot‐drop)
and a reduced dorsiflexor moment in loading response (p<0.001). This suggest, the
CMTDH group would require a flexible AFO to allow activation of the plantarflexors
during push‐off, prevent foot‐drop and restore a heel rocker in loading response.
In contrast, the CMTDTH group presented with significantly delayed and increased peak
dorsiflexion in stance and reduced plantarflexion and power at push‐off (p<0.05).
They also had significantly increased mean knee extensor moment (p<0.05) revealing
early signs of ‘crouch gait’. Therefore, the CMTDTH group would require a rigid AFO
to limit the amount of dorsiflexion and assist movement of the ground reaction force
anterior to the knee during stance. Three distinct gait patterns at the ankle were
identified in children with CMT, indicating patient‐specific orthotic design pathways
to target specific functional impairment.
3D PRINTING ANKLE‐FOOT ORTHOSES FOR CHILDREN WITH CMT: A REVIEW OF THE LITERATURE
Wojciechowski E
1,2, Chang A1, Cheng T1,2, Little D1,2, Menezes MP1,2, Hogan S2, Burns J1,2.
1University of Sydney, New South Wales, Australia; 2Sydney Children's Hospitals Network
(Randwick and Westmead), New South Wales, Australia.
Children with CMT are often prescribed ankle‐foot orthoses (AFO) to manage lower limb
impairment such as foot drop and foot deformities. They are handmade by plaster cast
followed by thermoplastic moulding. This traditional approach provides limited design
options, can be costly, with long outpatient wait times. 3D printing, also known as
additive manufacturing, has the potential to transform the way orthoses are prescribed,
designed and manufactured. The aim of this review was to evaluate the evidence of
3D printing AFOs compared to traditional manufacturing methods, for children with
CMT. There are currently no studies evaluating the application of 3D printing AFOs
for children with CMT. However, a small, but emerging evidence base exists for 3D
printed AFO's in adults from studies including healthy participants and populations
with rheumatoid arthritis, post‐polio syndrome, foot drop and ankle weakness secondary
to injury. Samples sizes ranged from 7–38 participants for studies related to in‐shoe
orthoses and from 1–10 for studies related to AFOs. The methods of 3D printing included
sterolithography, selective laser sintering and fused deposition modelling using materials
such as nylon 11, nylon 12, polylactide, polycarbonate and ABS. 3D printed AFOs were
comparable to traditional manufactured orthoses in terms of patient‐perceived comfort,
temporal‐spatial parameters, plantar pressure measurements and 3D gait analysis. However,
the effects of long‐term usage and durability of 3D printed AFOs has not been investigated.
3D printing orthoses have potential advantages including increased design possibilities,
improved productivity, higher compliance, and reduced labour needs. Disadvantages
include redesigning clinical pathways, limited evidence base for clinical effectiveness,
limited biocompatible materials, occupational safety considerations and a high level
of expertise required for software operation and fabrication of devices. Further research
is required to determine the feasibility of 3D printed AFOs for children with CMT,
and the most appropriate and effective printing pathway, materials to improve health
outcomes of affected patients.
TREATMENT INDUCED NEUROPATHY OF DIABETES IN PATIENTS WHO HAVE UNDERGONE BARIATRIC
SURGERY
Wong SHJ
1, Koh SJ2, Lee BJH1, Chng YSK3, Pawa C3, Subramaniam T4, Cheng KSA4, Umapathi T2.
1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; 2National
Neuroscience Institute, Singapore; 3Yong Loo Lin School of Medicine, National University
Singapore, Singapore; 4Khoo Teck Puat Hospital, Singapore.
Treatment‐Induced Neuropathy of Diabetes mellitus (DM) (TIND) is a complication of
rapid glycaemic control. Individuals present with neuropathic pain and autonomic dysfunction
within 8 weeks of improvement in glucose control. The use of both insulin and oral
hypoglycaemic agents has been associated with TIND. Its severity is determined by
the rate and quantum of HbA1c decline. Other predisposing factors include anorexia
and weight loss. We studied the incidence of TIND in DM patients who have undergone
massive weight loss and HbA1c decline after bariatric surgery. We screened electronic
records of 159 patients (74 DM, 85 non‐DM) who underwent bariatric surgery between
2012 and 2015. 14 DM patients fulfilled the TIND HbA1c criteria of a decrease of ≥2%
over 3 months or ≥4% over 6 months. One patient was excluded because the decrease
in HbA1c was not contemporaneous with weight loss. The mean and median decrease in
BMI per month was 2.01 and 1.82 respectively. The mean and median interval between
surgery and decrease in HbA1c was 88.2 and 89.5 days respectively. Records of these
14 patients were scrutinized and classified as: ‘Probable TIND’: acute painful neuropathy
AND acute dysautonomia WITH temporal relationship to the decrease in HbA1c; ‘Possible
TIND’: acute painful neuropathy OR acute dysautonomia OR temporal relationship to
decrease in HbA1c is uncertain; ‘Unlikely TIND’: when an alternative explanation exists
for symptoms. Only one patient was classified as ‘Possible TIND’: A 50‐year‐old woman
who developed neuropathic pain in both lower limbs 1 month after a rapid HbA1c decline
of 5.2% and about 5 months after bariatric surgery. She had no documented autonomic
symptoms. Our study is limited by small cohort size, retrospective design and reliance
on hospital records. Nonetheless, it demonstrates that besides nutritional neuropathies,
TIND should also be considered in DM patients who develop peripheral neuropathy after
bariatric surgery. In another study, we found TIND is uncommon in a general cohort
of diabetic patients. The occurrence of 1 ‘Possible TIND’ in only 14 DM patients corroborates
earlier data that weight loss may act in tandem to increase the risk of TIND.
TRPV4‐MEDIATED DISRUPTION OF CALCIUM SIGNALING AND MITOCHONDRIAL AXONAL TRANSPORT
IN A DROSOPHILA MODEL OF CMT2C
Woolums BM
1, Tabuchi M1, Sung H1, Sullivan JM1, Mamah C1, Yang M1, Blum ID1, Wu MN1, Sumner
CJ1, Lloyd TE1
. 1Johns Hopkins University, Baltimore, USA.
Dominant missense mutations in the gene encoding the cation channel transient receptor
vanilloid, family member 4 (TRPV4) cause inherited neuropathies including Charcot‐Marie‐Tooth
disease 2C (CMT2C). in vitro, mutations in TRPV4 that cause CMT2C cause a gain of
TRPV4 channel function and increased intracellular calcium which subsequently leads
to cellular toxicity. However, the mechanisms by which CMT2C mutations in TRPV4 lead
to neuronal dysfunction in vivo remain poorly understood. We generated transgenic
Drosophila that express either wild‐type or a CMT2C causing TRPV4 mutant (TRPV4R269C)
to assess the effect of TRPV4R269C on neuron function in vivo. Selective expression
of TRPV4R269C in Drosophila CCAP neurons (NCCAP) results in a failure of Drosophila
wing expansion that is blocked by genetically inactivating the channel pore, demonstrating
the requirement of channel function in mediating this phenotype. Perforated patch
clamp analysis of NCCAP reveals that TRPV4R269C causes a calcium‐dependent increase
in NCCAP neuronal excitability. This hyperexcitability is restored to control levels
by application of a TRPV4 selective antagonist. High level expression of TRPV4R269C
causes synaptic and dendritic degeneration, both of which are rescued genetically
by inactivating the channel pore or pharmacologically by feeding larvae a TRPV4 selective
antagonist. We conducted a genetic screen in NCCAP and found that CaMKII knockdown
potently suppresses the TRPV4R269C mediated wing expansion phenotype and selectively
rescues degeneration of synapses but not dendrites. We also find that TRPV4R269C,
but not controls, disrupts mitochondrial transport in axons by increasing the number
of stationary mitochondria. Our data demonstrate that TRPV4R269C elevates neuronal
intracellular calcium which disrupts mitochondrial transport and mediates neurodegeneration
through compartment‐specific calcium‐mediated signaling pathways, and supports the
further investigation of TRPV4 antagonists as potential therapeutics for the treatment
of CMT2C.
STRESS‐INDUCED MECHANICAL ALLODYNIA, BLADDER HYPERSENSITIVITY, AND ANHEDONIA IN AN
ANXIETY‐PRONE MOUSE STRAIN
Wu PY
1, Yang X1, Christianson JA1, Wright DE1.
1University of Kansas Medical Center, Kansas City, USA.
Mood disorders, including anxiety and depression, are commonly observed among chronic
pain patients with prevalence estimates ranging from 3 to 35%. Comorbidity between
mood and chronic pain disorders has been linked to altered limbic regulation of the
hypothalamic‐pituitary‐adrenal (HPA) axis. Stress activates the HPA axis and can initiate
and/or exacerbate symptoms related to both chronic pain and mood disorders. Previous
studies from our laboratory have investigated the influence of early life stress on
mechanical pain hypersensitivity, visceral hypersensitivity and behavioral evidence
of mood disorder later in life. Here, we are testing the hypothesis that chronic stress
exposure in adulthood can increase somatic and visceral sensitivity and anhedonic
behaviors in a mouse strain with a genetic predisposition to anxiety. Adult, female
A/J mice were exposed to repeated foot shock stress for 10 continuous days and tested
for alterations in mechanical sensitivity, sucrose preference, visceromotor response
(VMR) during urinary bladder distension, and serum corticosterone levels. Mice that
underwent shock stress had a significantly decreased mechanical withdrawal threshold
in the hind paw compared to their baseline and sham group measurements. Sucrose preference
was measured prior to shock exposure and throughout the shock paradigm as an indicator
of anhedonic behavior. Mice that underwent shock stress displayed a trend toward decreased
sucrose preference, indicating anhedonia, in comparison to mice in the sham group
that did not display anhedonia. Mice that underwent shock stress displayed significant
increases in VMR during bladder distension compared to sham mice. Finally, serum corticosterone
levels were significantly higher in the mice that underwent shock stress compared
to sham mice, indicating a stress‐induced increase in HPA axis output. Together these
data suggest that chronic stress exposure can induce mechanical allodynia, visceral
hypersensitivity, and depression‐like behaviors in an anxiety‐prone mouse strain.
Future studies will incorporate gene expression in the hypothalamus, amygdala, and
hippocampus, as well as investigation of possible downstream peripheral neuroimmune
modulation and neuronal morphology changes.
ANALYSIS OF THE ADAPTABILITY OF GUILLAIN‐ BARRÉ SYNDROME BIOMARKERS IN JAPAN
Yamagishi Y1, Suzuki H1, Masahiro Sonoo2, Satoshi Kuwabara3, Takanori Yokota4, Kyoichi
Nomura5, Atsuro Chiba6, Ryuji Kaji7, Takashi Kanda8, Kenichi Kaida9, Shuichi Ikeda10,
Tatsuro Mutoh11, Junichi Kira12, Hiroshi Takashima13, Makoto Matsui14, Gen Sobue15,
Kazutoshi Nishiyama16, Kusunoki S
1.
1Department of Neurology, Kindai University, Osakasayama, Japan; 2Teikyo University,
Tokyo, Japan; 3Chiba University, Chiba, Japan; 4Tokyo Medical and Dental University,
Tokyo, Japan; 5Saitama Medical University, Iruma gun, Japan; 6Kyorin University, Mitaka,
Japan; 7Tokushima University, Tokushima, Japan; 8Yamagichi University, Ube, Japan;
9National Defense Medical College University, Tokorozawa, Japan; 10Shinshu University,
Matsumoto, Japan; 11Fujita Health University, Toyoake, Japan; 12Kyushu University,
Fukuoka, Japan; 13Kagoshima University, Kagoshima, Japan; 14Kanazawa Medical University,
Kahoku gun, Japan; 15Nagoya University, Nagoya, Japan; 16Kitazato University, Sagamihara,
Japan.
Guillain‐ Barré syndrome (GBS) is an acute monophasic immune‐mediated neuropathy.
As prognostic markers of GBS, modified Erasmus GBS outcome score (mEGOS), Erasmus
GBS respiratory insufficiency score (EGRIS), and ΔIgG have been reported. However,
the proportions of subtypes of GBS are known to be different between the western countries
and Japan, it remains to be elucidated whether those markers can also be applied to
GBS in Japan or not. We here investigated retrospectively 177 GBS patients and determined
the mEGOS and the EGRIS of those cases. Among them, ΔIgG could be obtained in 79 cases.
We evaluated the prognosis using GBS outcome score (Functional grade: FG) at 6 months;
we called good prognosis when FG at 6 months was less than 3 and poor prognosis when
that was 3 or more. As a result, in 25 cases with higher score than 6 at mEGOS on
admission 8 cases (32%) had poor prognosis and in 32 cases with higher score than
9 at mEGOS at day 7 of admission 13 cases had poor prognosis. In 25 cases with higher
score than 6 on EGRIS 14 cases (56%) needed the mechanical ventilator. Patients with
good prognosis had higher ΔIgG(average: 1008mg/dl) than patients with poor prognosis(average:528mg/dl).
We calculated the cut‐off value of ΔIgG in 79 patients, which was 1108 mg/dl. 36 patients
with higher ΔIgG than 1108 mg/dl could significantly walk independently at six months
(p<0.05). 9 patients (21%) had poor prognosis in 43 patients with lower ΔIgG than
1108 mg/dl. 99 (60%) of 164 patients were treated with the single cycle of Intravenous
immunoglobulin (IVIg). Other patients (40 %) were treated with the combined therapies,
such as intra venous methylprednisolone and/or plasmapheresis or the second cycle
of IVIg in addition to IVIg. Although there was no difference in prognosis between
patients with the single cycle of Intravenous immunoglobulin (IVIg) and patients with
the combined therapies, in the 24 patients who had FG>3 and mEGOS >6 on admission,
the combined therapies made better prognosis than the single course of IVIg (p<0.05).
We found that mEGOS, EGRIS and ΔIgG were also available in Japan.
The efficacy of the combined therapies in severe GBS patients should be investigated
in the future large scale prospective studies.
DEVELOPMENT OF BEST PRACTICE GUIDELINES FOR PAEDIATRIC CHARCOT‐MARIE‐TOOTH DISEASE
Yiu EM1,2,3, Burns J
2,4,5, Menezes MP4,5, Ryan MM1,2,3 and for the Paediatric CMT Best Practice Guidelines
Consortium. 1Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia;
2Murdoch Childrens Research Institute, Melbourne, Victoria, Australia; 3University
of Melbourne, Melbourne, Victoria, Australia;
4University of Sydney, New South Wales, Australia; 5Sydney Children's Hospitals Network
(Randwick and Westmead), New South Wales, Australia.
Charcot‐Marie‐Tooth disease (CMT) often presents during childhood. Common symptoms
include weakness, limb pain and cramps, foot deformity, and balance impairment. Guidelines
for the optimal management of common problems experienced by children with CMT do
not currently exist. Development of these guidelines will provide an evidence base
for the management and monitoring of children with CMT. A series of systematic literature
reviews utilising the GRADE (Grades of Recommendation, Assessment, Development, and
Evaluation) approach were conducted to answer pre‐specified key clinical questions
related to the management of paediatric CMT. These included treatment recommendations
for symptoms such as weakness, pain, balance impairment, joint deformity, and impaired
upper limb function, and anticipatory monitoring for associated complications such
as hip dysplasia. This yielded minimal to no evidence for the pre‐specified clinical
questions, and evidence‐based management recommendations could not be made. Consensus‐based
statements will therefore be formulated via a three‐round Delphi process, to be conducted
in 2017. The Delphi panel will consist of local and international medical and allied
health professionals who have experience in the management of children with CMT.
PXT3003, A FIXED COMBINATION OF BACLOFEN, NALTREXONE AND SORBITOL, FOR THE TREATMENT
OF CHARCOT‐MARIE‐TOOTH DISEASE TYPE 1A (CMT1A): STATUS OF A MULTICENTER, DOUBLE‐BLIND,
PLACEBO‐CONTROLLED, PIVOTAL PHASE III STUDY (PLEO‐CMT)
Attarian S1, Sevilla T2, Van Damme P3, De Visser M4, Thomas FP5 Roberts M6, Young
P
7 and for the PLEO‐CMT Study Group.
1University Hospital La Timone, Marseille, France; 2Hospital Universitari i Politécnic
La Fe, Valencia, Spain; 3University Hospital, Leuven, Belgium; 4Academic Medical Centre,
Amsterdam, The Netherlands; 5Hackensack University Medical Center, Hackensack, USA;
6Salford Royal NHS Foundation Trust, Manchester, UK; 7University Hospital, Munster,
Germany.
Efficacy of PXT3003 in the treatment of adult patients CMT1A (n=80) was shown in a
multicenter, randomized, double‐blind, placebo‐controlled phase II study (Attarian
et al. 2014). PXT3003 taken 2x/day, orally, for 12 consecutive months was well tolerated
and safe. Significant improvement of disability was observed for the highest tested
dose, thought indicative for an early, meaningful change in disease course (meta‐analysis
by Mandel et al., 2015). This formed the rationale to initiate a multicenter, randomized,
double‐blind, placebo‐controlled pivotal phase III study (http://ClinicalTrials.gov:
NCT02579759) of PXT3003 in mildly to moderately affected CMT1A patients in December
2015. The primary objective is to assess the efficacy of 2 doses of PXT3003 compared
to placebo on disability as measured by the mean change from baseline Overall Neurology
Limitations Scale (ONLS) score at month 12 and 15. Furthermore, efficacy on the proportion
of responders (i.e. improvement of ONLS), impairment (CMTNS‐V2), functional tests
(10‐MWT, QMT, 9‐HPT), electrophysiological parameters (CMAP, SNAP and NCV) and quality
of life (EQ‐5D, VAS) are secondary endpoints. Pursuant this study, patients will be
eligible for a 9‐month extension study, in which PXT3003 assigned patients will continue
with the previously assigned dose, whereas placebo patients will be randomized to
one of the two PXT3003 doses. The study is conducted in 30 investigational sites in
8 countries (EU, Canada and US). In December 2016 patient randomization was completed
(n=323). The screen failure rate was 26%, as expected (437 patients were screened).
The independent DSMB recommended to continue the study as planned following a safety
analysis on the first 100 patients treated for >3 months. Preliminary baseline characteristics
are based on 313 patients (data not cleaned). The study population had a mean age
of 40.8±13.3 years (range 16–65; male 41.2%) of which 97.8% had a confirmed genetic
diagnosis of CMT1A. The mean CMTNS‐v2 was 13.9±3.09 and the mean motor nerve conduction
of the ulnar nerve was 23.4±11.3 m/s. Ten patients withdrew from the study, 3 due
to adverse events unrelated to study treatment. The last patient completing the study
is expected in March 2018.
IN VIVO IMAGING OF EPIDERMAL NERVE FIBERS
Zhang G
1, Ghosh P1, Lin J1, Ghauri A1, Sheikh KA1.
1Department of Neurology, University of Texas Health Science Center at Houston, Houston,
TX, USA.
Assessment of epidermal nerve fiber density and its structure integrity is critical
for the diagnosis and evaluating the effectiveness of potential therapies in small
fiber neuropathies. Currently, skin biopsies, at multiple sites, are most commonly
used to assess these diseases. These studies are expensive and time consuming due
to cumbersome processing and quantification techniques and serial biopsies over time
are often not feasible due to costs and patient acceptance. Moreover, vast majority
of normative data for skin biopsies in humans are available only for few distal sites
and a significant proportion of patients with small fiber neuropathies have focal
or regional symptoms not involving the commonly biopsied sites in the leg. Live imaging
could overcome these limitations and provide a noninvasive real time assessment of
epidermal nerve fibers all over the body. We previously found that anti‐ganglioside
antibody (AGA) is an effective neuronal delivery vector for transport of various cargos,
such as fluorescent dyes, to peripheral nerves. In the current proof of concept study,
we examined whether non‐invasive multiphoton microscopy can be used to probe/image
the epidermal nerve fibers in living animals after systemic and/or local delivery
of fluorescently conjugated AGA. We found that the individual nerve endings in skin
and cornea are distinctly labeled, and visualized under two‐photon microscope. The
epidermal nerve fiber labelling by fluorescent‐tagged AGA was further validated using
transgenic mice selectively expressing yellow fluorescent protein in their nervous
system. In‐vivo multiphoton imaging provide a tool with potential for dynamic longitudinal
evaluation of small fiber neuropathies, including nerve degeneration and regeneration,
without tissue removal. Thus, the use of multiphoton microscopy in conjunction with
fluorescently labeled AGA as neuronal vector can have many research and clinical applications,
such as labeling and live visualization of epidermal nerve fibers to assess small
sensory nerve fibers in health and disease.
DYSREGULATED LIPID METABOLISM IN THE ABSENCE OF PERIPHERAL MYELIN PROTEIN 22 (PMP22)
Zhou Y1, Tavori H2, Lee S1, Al Salihi M1, Fazio S2, Notterpek L
1.
1McKnight Brain Institute, University of Florida, Gainesville, Florida, USA; 2Knight
Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon,
USA.
The majority of hereditary neuropathies are due to abnormalities in peripheral myelin
protein 22 (PMP22), whose genetic variants include increased expression (gene duplication),
haploinsufficiency (gene deletion), or point mutations. Phenotypic heterogeneity in
clinical presentation is common among hereditary neuropathy patients even within the
same family, the cause of which has not been determined. To investigate the role of
PMP22 in the pathogenesis of the neuropathies we have generated and characterized
PMP22 null (PMP22−/−) mice (Amici et al., 2006) whose peripheral nerves show alterations
in lipid metabolism (Lee et al., 2014). To examine the molecular changes underlying
these abnormalities we determined the expression of cholesterol synthesis (SREBP2
pathway), and cholesterol uptake, transport and efflux genes (LXR pathway). In affected
nerves, we found the cholesterol synthesis pathway inhibited, while the LXR pathway,
and particularly apoE and ABCA1, upregulated at the mRNA and protein levels. Since
PMP22 is expressed at low levels in the liver, the central organ for the regulation
of cholesterol in the body, we studied liver tissue form PMP22−/− mice. Liver from
PMP22−/− mice showed significant hepatomegaly, clear features of microvesicular steatosis,
as well as marked increase in LXR pathway genes and proteins (ABCA1 and apoE), as
compared to WT. Ultrastructural studies identified lipid droplets and significantly
enlarged mitochondria in the liver of male PMP22−/− mice, which is not due to mitochondria
fusion, as the levels of MFN 1 and 2 remained similar to WT. As disturbed hepatic
cholesterol homeostasis induces the activation of Kupffer and stellate cells, we determined
the extent of inflammation in nerve and liver tissues from PMP22−/− mice with leukocyte
(CD11b) and macrophage markers (CD68). In nerve sections, we detected an increase
in the number of CD11b+ cells, which was confirmed by Western blots. In the liver
of PMP22−/− mice we found a significant increase in CD68‐reactive Kupffer cells and
elevated levels of TNF‐alpha. The severe dysregulation of cholesterol metabolism in
nerve and liver, including neuro‐ and hepatic inflammation in the absence of PMP22−suggest
that dysregulated cholesterol metabolism and inflammation may act as a disease modifier
in PMP22‐dependent neuropathies.