A gentleman in his late 40s developed a “pins and needles” sensation and numbness
in his left hand that was exacerbated by leaning on his left arm or hyperextending
his neck. The numbness developed over a few weeks. Over the next 2 months, the numbness
spread proximally in the left arm, then to the right arm, and in patches over his
bilateral upper chest and next to the bilateral posterior thighs. He denied pain,
weakness, fatigue, cognitive changes, vision changes, dysarthria, or dysphagia or
changes in bladder or bowel function. A review of systems was otherwise negative or
normal. Past medical history was notable for hyperlipidemia, treated with atorvastatin
20 mg daily. There was no family history of neurologic or autoimmune disease. Vital
signs and general physical examination were normal. Neurologic examination was notable
for normal mental status and cranial nerve examinations. Gait, coordination, and the
remainder of the motor examinations were normal. Sensation was mildly reduced to light
touch circumferentially throughout both arms, in patches over the anterior chest,
and over the posterior thighs, with preserved sensation to vibration, pinprick, and
temperature. The Romberg sign was not present. Deep tendon reflexes were normal. The
plantar response was flexor bilaterally.
Serum testing was negative for aquaporin-4 IgG, and targeted infectious, metabolic,
and hematologic studies were unrevealing (table 1). The MRI showed a longitudinally
extensive transverse myelitis (LETM, where the T2 hyperintensity extends ≥3 vertebral
(figure 1). CSF examination showed no pleocytosis, normal glucose, elevated total
protein (84 mg/dL), normal IgG index, and zero oligoclonal bands (table 2).
Laboratory results: blood
MRI of inflammatory myelitis before and after treatment
(A and B) Sagittal and axial T2-weighted images that reveal hyperintensity from C4
to C7 involving the central gray and dorsal white matter bilaterally. T1 post-gadolinium
images revealed partial, dorsal enhancement of the lesion with likely pial involvement
(C and D) with some involvement of the leptomeninges (arrowhead). Repeat MRI after
2 months of oral prednisone (E–H) shows near resolution of the hyperintense lesion
previously extending from C4 to C7, but persistent dorsal enhancement likely indicating
a nidus of active granulomatous inflammation.
Laboratory results: CSF
This patient's symptom onset and evolution were both subacute. The differential of
a partial myelopathy includes structural (compressive), inflammatory, metabolic, toxic,
infectious, paraneoplastic, vascular (especially spinal dural arteriovenous fistula),
and malignant causes. Genetic/inherited causes usually present more insidiously.
In acute cases of myelopathy where inflammation of the spinal cord is demonstrated
by imaging or in CSF, but no more specific etiology is found, the label idiopathic
acute transverse myelitis may be applied, typically reaching nadir in 4–21 days.
This case presented as a subacute partial myelitis.
A key clinical feature of this patient's presentation is the relative lack of early
major clinical deficits despite such an extensive longitudinal spinal cord lesion,
which favors neurosarcoidosis, differing from neuromyelitis optica spectrum disorder
(NMOSD) pathophysiology (which typically causes extensive tissue destruction all along
the lesion, and profound early deficits). While LETM is exceptionally uncommon in
MS, it is highly characteristic of NMOSD and can be associated with other inflammatory
myelitides, particularly with neurosarcoidosis. Dorsal subpial post-gadolinium enhancement
is characteristic of neurosarcoidosis myelitis when compared to NMOSD, whereas the
ring configuration of enhancement is highly reminiscent of the inflammatory pattern
most commonly affiliated with those diagnostic entities under the rubric of the NMOSD.
The “trident sign” describes central canal enhancement with dorsal subpial enhancement
in neurosarcoidosis myelitis.
This pattern of enhancement can also be seen with CNS infection (including granulomatous
infection) and lymphoma.
The circumferential, nondermatomal pattern of sensory loss favors a CNS lesion. The
contiguous spread from arms to chest to legs, yet sparing the face, suggests an evolving
or expanding cervical spinal cord process below the level of the spinal trigeminal
nucleus, which carries pain and temperature as low as C2–C4.
The syndrome points towards a partial cervical myelopathy with only 1 of the 3 main
spinal cord pathways affected (sensory, specifically dorsal column, but not motor
or bowel/bladder), as opposed to a true transverse myelopathy.
Given a strong clinical suspicion and high pretest probability for neurosarcoidosis
causing his myelitis, a chest CT with IV contrast was performed. The chest CT revealed
bilateral hilar and mediastinal calcified lymph nodes and perilymphatic pulmonary
nodules, consistent with pulmonary sarcoidosis. Fine needle aspiration revealed rare
nonnecrotizing granulomas consistent with sarcoidosis, with no evidence of infection
Probable neurosarcoidosis, manifesting as a partial longitudinally extensive transverse
cervical myelitis, supported by biopsy-confirmed pulmonary sarcoidosis.
Pathobiological mechanisms of noncaseasting granulomatous inflammation
CNS involvement from sarcoidosis occurs in approximately 5%–15% of sarcoidosis patients
and can manifest with variable combinations of leptomeningitis, meningoencephalitis,
pachymeningitis, optic neuropathy, other cranial neuropathies, hypothalamic/pituitary
involvement, myelitis, or radiculitis.
While sarcoidosis is classically and formally described as a multisystem disease,
about 10%–20% of neurosarcoidosis cases have seemingly exclusive CNS involvement.
On MRI, neurosarcoidosis spinal cord parenchymal involvement can appear longitudinally
extensive, smaller segmental or multifocal.
In addition to the enhancement pattern seen in this case, there may also be enhancement
involving the central canal, nerve roots, meninges, or other parts of the CNS if also
affected by neurosarcoidosis.
Neurosarcoidosis lesions can exhibit persistent T1 post-gadolinium enhancement for
months or years at a time, even with treatment, whereas inflammatory-demyelinating
lesions of MS and NMO typically remit within 1–2 months.
Our patient's chest CT revealed bilateral hilar and mediastinal calcified lymph nodes
and perilymphatic pulmonary nodules, consistent with pulmonary sarcoidosis. If the
CT is negative, a whole-body Fludeoxyglucose Positiron Emission Topography (FDG-PET)
can be diagnostically valuable to look for metabolically active but still normal sized
lymph nodes that may be targets for biopsy. A skin examination looking for evidence
of cutaneous sarcoidosis and eye examination (and sometimes conjunctival biopsy) may
also be helpful in this context.
Angiotensin-converting enzyme (ACE) level is commonly considered in the diagnostic
evaluation for sarcoidosis, but it is a nonspecific marker. While serum ACE tends
to be higher on average in patients with sarcoidosis (and especially active pulmonary
sarcoidosis) compared to those without sarcoidosis, sensitivity for sarcoidosis is
low, 29%–60%, with specificity of about 89%.
Similarly, in the CSF, sensitivity and specificity of ACE for neurosarcoidosis are
24%–55% and 94%, respectively.
In summary, a normal ACE should not exclude neurosarcoidosis, and an elevated ACE
can be nonspecific and sometimes seen in association with other inflammatory, infectious,
malignant, or metabolic processes or polymorphisms in the ACE gene.
The inflammation of sarcoidosis is characterized by well-formed, noncaseating (nonnecrotizing)
granulomas containing monocytes and macrophages, T lymphocytes, B lymphocytes, and
fibroblasts, among other cell types (figure 2).
Granulomas in the CNS tend to have a perivascular predilection. The granulomatous
inflammation of sarcoidosis is primarily T cell mediated, and classically considered
Th1 driven, but emerging evidence promotes a Th17-driven process, at least in the
lungs and mediastinal lymph nodes.
Common cytokines involved in signaling in sarcoidosis include IFNγ, TNFα, and various
interleukins and chemokines.
Environmental and infectious exposures have been proposed as possible contributors
to sarcoidosis susceptibility, but none have yet been convincingly demonstrated.
Genetic susceptibility to sarcoidosis has been associated with specific human leukocyte
antigen alleles, supporting an autoimmune etiology.
Putative mechanisms of noncaseating granulomatous inflammation in neurosarcoidosis
This figure illustrates putative mechanisms the assembly and organization of the complex
coordination of putative cellular and molecular mechanisms, which are thought to represent
the pathobiological underpinnings for noncaseating granulomatous inflammation in neurosarcoidosis.
Immune cells traffic into the “target tissue” via arterioles and can subsequently
exhibit properties of antigen presentation. A collection of various immune cell types
(e.g., B and T cells, macrophages, and plasma cells) acquire an affinity to become
part of what we analogize as an “island of inflammatory cells,” delimited by a perimeter
principally composed of hyaline collagen (shown on the figure). As opposed to granulomatous
inflammation associated with tuberculosis and other processes, those compositional
cellular elements in sarcoidosis usually do not undergo necrotic granulomatous transformation.
The M1 designated macrophage is an important constituent of the sarcoid granuloma,
and most particularly with respect to its ability to coordinate the inception and
prolongation of “pro-inflammatory” cascades, thereby representing a key feature of
the noncaseating granuloma of sarcoidosis. Alternatively, the M2 macrophage is characterized
by its ability to provide reciprocal properties, in striking contradistinction, to
the M1 macrophage, by exhibiting cardinal anti-inflammatory characteristics, including,
but not limited to, the elaboration of a highly stereotyped set of anti-inflammatory
cytokines and chemokines. Taken together, the repertoire and heterogeneity of intragranulomatous
mononuclear cells serve to orchestrate the immune regulatory networks that provide
for both the ignition and the complex coordination of the cellular and humoral factors,
which have now become classic hallmarks of granulomatous inflammation. The noncaseasting
granuloma is equipped with counterbalancing mechanisms (i.e., the inflammatory “braking
system”) capable of both high precision attenuation, as well as a corresponding ability
to abolish those cascades that serve to provoke and perpetuate granulomatous inflammation
in nearly every organ and tissue within the human body. TCR = T cell receptor.
Several proposed diagnostic approaches to neurosarcoidosis have been used in the literature
over the years.
Updated consensus diagnostic criteria for neurosarcoidosis were published in 2018.
Diagnosis of “definite” neurosarcoidosis is supported by a confirmatory biopsy from
the nervous system consistent with sarcoidosis in the context of a consistent clinical
phenotype and rigorous exclusion of other causes, particularly infection and malignancy.
However, CNS biopsy is often not preferable or advisable due to risk of morbidity.
A diagnosis of “probable” neurosarcoidosis, as in this case, can be made with a syndrome
consistent with granulomatous inflammation of the CNS and a confirmatory biopsy of
sarcoidosis from another organ system. Cases in which sarcoidosis is suspected but
in which there is no biopsy confirmation are best designated as “possible” neurosarcoidosis.
There are no randomized controlled trials of treatment of CNS neurosarcoidosis. While
glucocorticoids are effective for most patients with neurosarcoidosis, the doses needed
to achieve or sustain remission can be prohibitive due to glucocorticoid toxicity.
Common steroid-sparing therapies in clinical practice include methotrexate, azathioprine,
mycophenolate mofetil, leflunomide, hydroxychloroquine, and, increasingly, infliximab.
Retrospective analyses suggest that mycophenolate mofetil may be less effective than
methotrexate (at least for preventing “relapse”), but such studies risk confounding
In retrospective analyses, infliximab, a TNFα inhibitor, is associated with favorable
outcomes, including some cases refractory to other therapies.
In the patient presented here, given concern about glucocorticoid adverse effects,
the patient elected to initiate infliximab with weekly oral methotrexate and tapered
off glucocorticoids completely within 4 months with gradual resolution of symptoms
without functional limitation. Surveillance MRIs at 7 and 12 months showed complete