DEFEROXAMINE ALLEVIATES CHRONIC HYDROCEPHALUS AFTER INTRAVENTRICULAR HEMORRHAGE THROUGH
IRON CHELATION AND WNT1/WNT3A INHIBITION[4]
Study Question: Does deferoxamine (DFX) alleviate posthemorrhagic chronic hydrocephalus
(PHCH) by chelation of iron and suppression of the Wnt1/Wnt3a cellular pathway?
To explore the putative role and mechanism by which iron may mediate PHCH resultant
from intraventricular hemorrhage (IVH), the authors utilized a PHCH animal model comprising
rats receiving intraventricular injections of blood (IVH) or iron (Fe) either alone
or in combination with DFX, an iron chelator shown to be neuroprotective in intracerebral
hemorrhage. Intraventricular injections of saline were used as controls. Blood and
iron injections increased rates of hydrocephalus significantly at 1 (80% and 60%)
and 4 (80% and 70%) weeks compared to saline controls, which did not produce any hydrocephalus.
Treatment with DFX drastically decreased rates of hydrocephalus down to 20% and 10%
when given alongside IVH or Fe, respectively. DFX treatment additionally significantly
decreased the severity of hydrocephalus following IVH and Fe injections. DFX treatment
significant decreases in CSF iron and brain ferritin levels following blood and iron
injections thereby decreases frequency and severity of hydrocephalus following IVH
and iron injections. Treatment with DFX decreased elevated Wnt1/Wnt3a messenger RNA
and protein levels induced by IVH. Finally, treatment with DFX following IVH significantly
improved performance on the Water Morris navigation test, a measure of rat behavior.
Perspective: PHCH is a common complication following IVH. Prognosis remains poor resulting
in neurological disability and possible mortality. Management is challenging to do
limited understanding of the underlying pathogenesis of PHCH. Previous studies have
collectively demonstrated (1) Increased iron in mediating posthemorrhagic neurotoxicity,
(2) aberrant iron and ferritin levels following hydrocephalus secondary to IVH, (3)
subarachnoid fibrosis is key pathological sequelae following intracranial hemorrhage,
and (4) Wnt1/Wnt3a is involved with fibrosis in a variety of pathological processes.
The present study is the first to describe the role of DFX in the treatment of PHCH
and elaborate on the cellular pathway involved. Findings suggest that iron, a product
of red blood cell catabolism, may stimulate the Wnt1/Wnt3a pathways, which may be
involved with subarachnoid fibrosis, following intracerebral hemorrhage. Importantly,
the data demonstrates the therapeutic promise of DFX, which suppresses posthemorrhagic
induction of Wnt expression and decreases the severity and frequency of consequent
hydrocephalus.
Summary Written by: Winward Choy and Zachary A. Smith, MD
THE ROLE OF LABORATORY DISSECTION TRAINING IN NEUROSURGICAL RESIDENCY: RESULTS OF
A NATIONAL SURVEY[3]
Study Question: What is the role of laboratory dissection training in neurosurgery
residency programs within the United States?
A detailed survey regarding the use of laboratory dissections and other stimulators
and its role in the residency program was sent to 100 neurosurgical programs from
the American Association of Neurological Surgeons residency directory database. In
total, 65% of institutions responded, 93.8% of which used dissection as an educational
adjunct. Common reasons for not utilizing lab time were limitations in: Resident time,
available lab director, specimen procurement, and storage. Dissection lab opportunities
were variable and included: Scheduled sessions plus independent free time (58.3%),
scheduled sessions only (31.7%), and independent resident study time only (10%). Number
of scheduled sessions varied from 1 to 26 per year, but most offered 4–6 dissections
(39.3%). Formal curriculum for the dedicated laboratory time was common in programs
offering > four sessions per year (55%). Approaches taught included cranial approaches
(100%), spinal approaches (88.5%), spinal instrumentation (80.3%), endoscopy (50.8%),
microvascular anastomosis (50.8%), and peripheral nerve procedures (34.4%). Eight
programs are formulated a grading regimen to evaluate the residents’ surgical skills.
Funding primarily came from industry alone (33.3%) or from both industry and the institution
(33.3%). In addition, to cadaver or animal use, 31 programs (47.7%) also implemented
training with other types of simulators. Most programs advised better learning was
obtained from the dissections; however, 30.8% of programs did express equal learning
from both dissections and simulators. Moreover, 89% agreed that a universal lab curriculum
and dissection manual would be beneficial to resident training.
Perspective: Changes in neurosurgical training and healthcare have added obstacles
to providing trainee's with comparable levels of exposure as those who proceed the
current time. Implementation of the 80-h work week has limited the clinical exposure
and operative experience of residents since 2003 and has been met with strong opposition.
Surgeons are now faced with increasing scrutiny following the advent of quality improvement
initiatives, which may ultimately limit resident autonomy and experience as well.
There is a strong need for educational adjuncts to provide trainees with the skills
they may not obtain or master during residency. While the present study demonstrates
that, most residency programs offer cadaveric dissection sessions and find them useful
in improving resident technique and surgical comprehension, only 21 programs had a
formal curriculum of incorporation. Neurosurgical education and curriculum adaptation
seem to be lesser progressed when compared to our general surgery colleagues. After
identifying a significant gap of knowledge in general surgery residents attempting
to obtain certification, the Surgical Council on Resident Education task force was
developed alongside numerous initiatives aimed at strengthening surgical education
and standardizing a national curriculum. For example, the Residency Review Committee
for Surgery requires a skills lab implemented into training, and the Surgical Skills
Curriculum Task Force works to promote “operating room readiness” among residents
by teaching through modules prior to performing in the OR where the participant learns
via video, practices, and then is judged for proficiency.[1] The surgery program at
Northwestern University revamped its training structure in 2003 that allowed the organization
to not only meet their work-hour restrictions, but also improve the quality of education.
The changes promoted better perceived quality of life by trainees, improved American
Board of Surgery In-Training Examination scores, and allowed for increased operative
experience.[6]
Neurosurgery is dynamic. Our training should be as well. From a resident's perspective,
we ought to look to other specialty for solutions to help ensure competency upon graduation.
The most frightening concept is to go through years of training only to feel inept
at the end. The sponge mentality is no longer acceptable as our time in the hospital
is limited. Our education needs to be supplemented and excuses such as lack of resident
time and lack of resources should not be satisfactory. Requiring lab time and practice
prior to contributing to critical portions of a case should be standard, and at some
point, one should have to prove themselves technically skillful to their institution
and arguably to a National Committee prior to graduation. Mental performance on an
oral board exam may not represent the skill behind the applicant.
Summary Written by: Angela M Bohnen, MD
TETANUS TOXOID AND CCL3 IMPROVE DENDRITIC CELL VACCINES IN MICE AND GLIOBLASTOMA PATIENTS[5]
Study Question: Can vaccine site preconditioning with tetanus/diphtheria (Td) toxoid
improve dendritic cell vaccines for glioblastoma (GBM) multiforme?
The authors[5] conducted a randomized, blinded clinical trial of 12 newly diagnosed
GBM multiforme patients who had gross total resection, residual radiographic contrast
enhancement on postresection magnetic resonance imaging ≥1 cm in diameter in two perpendicular
axial planes, and a Karnofsky performance scale score of ≥80 were eligible for the
clinical study. Patients completed a 6-week course of external beam radiotherapy to
a dose of 60 Gy with concurrent temozolomide (TMZ) at a targeted daily dose of 75
mg/day/m. Exclusion criteria were a subtotal resection, use of 5-aminolevulinic acid
dye during resection, receiving intensity-modulated radiation therapy, receiving steroid
therapy >2 mg/day of dexamethasone, or radiological evidence of progressive disease.
The first vaccine was administered on day 21 ± 2 of TMZ cycle 1. The first three dendritic
cell (DC) vaccines were administered bi-weekly. At the time of administration of vaccine
four, patients were randomized to preconditioning of the vaccine site with either
mature, unpulsed, autologous DCs or Td toxoid unilaterally before bilateral vaccination
with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. The authors reported
that the accumulation of injected DCs in vaccine site draining lymph nodes was significantly
greater in patients given Td (two sample t-test, P = 0.049). Progression-free survival
and overall survival were significantly increased in Td-treated patients compared
to DC-treated patients (log-rank test, P = 0.013). Using both a previously published
recursive partition analysis and the European Organization for Research and Treatment
of Cancer nomogram for predicting outcome of patients with GBM, the authors found
that Td-treated patients exceeded expected survival times by a far greater degree
than did DC-treated patients in both cases by nearly the same amount.
To validate these results and investigate the mechanism of the response to Td preconditioning,
the authors performed analogous studies in the mouse model where vaccine sites of
Td-immune mice were preconditioned with Td and subsequently administered a bilateral
vaccine of ovalbumin RNA-pulsed DCs. Similar to their finding in humans, Td-immune
mice that received Td preconditioning had a 3-fold increase in DCs within the afferent
inguinal lymph nodes (two sample t-test, P = 0.0001). The authors found that this
effect is mediated by CD4+ T cells (post-hoc Tukey t-test, P = 0.005) and is generalizable
to other CD4+ T-cell-dependent protein antigens (post-hoc Tukey t-test, P < 0.05).
Unilateral Td preconditioning was also observed to increase DC migration bilaterally
in both humans and mice. Furthermore, the ability of Td preconditioning and CD4+ T-cells
to increase DC migration is dependent upon the expression of chemokines CCL3 (two
sample t-test, P = 0.023 and P = 0.029, respectively) and CCL21 (two sample t-test,
P < 0.05). Similar to the clinical trials, Td preconditioning significantly inhibited
tumor growth and increased progression-free and overall survival in an antigen-dependent
manner in a mouse subcutaneous tumor model.
Perspective: There is limited data examining the mechanism underlying DC vaccines.
In this study, the authors use a randomized, blinded clinical trial and analogous
studies in a mouse model to examine the value and underlying mechanism of preconditioning
a DC vaccine site with a potent recall antigen, such as Td, for the treatment of GBM.
The authors reported that: (1) Preconditioning the DC vaccine site with Td resulted
in increased progression-free and overall survival in humans and in mice, (2) preconditioning
with Td improved DC migration to lymph nodes bilaterally, and (3) the underlying mechanism
of this response was mediated by CD4+ T-cells, CCL3, and CCL21. Their findings suggest
that modulation of DC vaccines with Td preconditioning increases the migratory capacity
of DCs and may improve clinical outcomes in GBM patients. The authors suggest that
DC migration should be further investigated as a predictive biomarker for immunotherapy
studies.
Summary Written by: Panayiotis Pelargos and Isaac Yang, MD
INTRACRANIAL HYPERTENSION AFTER SURGICAL CORRECTION FOR CRANIOSYNOSTOSIS: A SYSTEMATIC
REVIEW[2]
Study Question: What is the incidence of intracranial hypertension (IH) after surgery
for craniosynostosis?
Craniosynostosis is typically diagnosed and surgically treated in childhood. In untreated
patients, up to 8–15% of single suture synostosis and at least 33% of multisuture
synostosis patients are affected by elevated intracranial pressure (ICP). Postsurgical
IH has also been described to occur up to years after surgical remodeling, such as
with restenosis at the surgical site or synostosis at another suture. The incidence
and circumstances of such occurrences have been reported in single institution series.
The authors performed a systematic review of the English language literature on pediatric
patients published between 1985 and 2014 to further characterize the incidence of
IH following craniosynostosis surgery.
Seven studies representing over 700 patients met the authors’ inclusion criteria for
analysis of the primary outcome, which was defined as the incidence of IH after surgery,
with confirmation by ICP monitoring. Other studies not included in the calculations
reported IH based on lumbar puncture, papilledema findings, and/or clinical symptoms.
Other signs and symptoms reported to suggest raised ICP in this population include
decreasing head circumference percentiles, worsening head shape deformity, bulging
fontanelle/craniectomy defects, headaches, irritability, and developmental delay.
The authors found insufficient data on syndromic patients. Patients who had specifically
nonsyndromic sagittal synostosis surgery had a 5% incidence of postoperative IH. The
incidence of postoperative IH for all nonsyndromic craniosynostosis patients (single
or multiple suture involvement) was 4%.
There was a variety of surgical techniques described in the reviewed studies, which
limited the ability to describe outcomes based on technique. The authors grouped surgery
type by cranial remodeling procedures without frontal orbital advancement versus cranial
remodeling procedures with advancement. In postoperative nonsyndromic craniosynostosis
patients, 23/471 (5%) patients without craniofacial advancement had IH after surgery
while 3/255 (1%) patients developed IH after craniofacial advancement surgery.
Perspective: The incidence of postoperative IH in the pediatric craniosynostosis population
is difficult to study. The mechanism for the development of postoperative IH is not
completely understood. There is variation in the determination of IH. Screening is
not standardized. Noninvasive detection methods are often not optimally sensitive
or reliable. Lack of papilledema does not guarantee lack of elevated ICP. As pediatric
patients age (>8 years old), this finding becomes more sensitive. Currently, imaging
techniques and findings do not reflect ICP. A long-term multidisciplinary clinical
follow-up on an at least annual basis until school age is recommended for patients
who have had surgery for any type of craniosynostosis.
Chronic elevated ICP in children may have long-term sequelae in neurocognitive and
visual domains though the association and consequences are not clearly established.
Recent literature suggests an impact of earlier age and more extensive surgery on
more favorable neuropsychological outcomes in children with craniosynostosis. There
are no Class 1 studies to guide practice at this time. There remain many unanswered
questions in craniosynostosis management and outcomes; bringing this issue of postoperative
IH to light points to the need for well-designed multicenter studies to accumulate
data and knowledge about the large spectrum of craniosynostosis care.
Summary Written by: Sandi Lam. MD