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      A young man with numbness in arms and legs : From the National Multiple Sclerosis Society Case Conference Proceedings

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          Abstract

          Case presentation 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 segments) 1 (figure 1). CSF examination showed no pleocytosis, normal glucose, elevated total protein (84 mg/dL), normal IgG index, and zero oligoclonal bands (table 2). Table 1 Laboratory results: blood Figure 1 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. Table 2 Laboratory results: CSF Differential diagnosis 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. 2 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. 3 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. 4 The “trident sign” describes central canal enhancement with dorsal subpial enhancement in neurosarcoidosis myelitis. 5 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. 2 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. 6 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 or malignancy. Final diagnosis Probable neurosarcoidosis, manifesting as a partial longitudinally extensive transverse cervical myelitis, supported by biopsy-confirmed pulmonary sarcoidosis. Discussion 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. 7 While sarcoidosis is classically and formally described as a multisystem disease, about 10%–20% of neurosarcoidosis cases have seemingly exclusive CNS involvement. 7,8 On MRI, neurosarcoidosis spinal cord parenchymal involvement can appear longitudinally extensive, smaller segmental or multifocal. 7,9 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. 9 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. 4,8,10,11 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%. 12 – 15 Similarly, in the CSF, sensitivity and specificity of ACE for neurosarcoidosis are 24%–55% and 94%, respectively. 16,17 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). 18,19 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. 20,21 Common cytokines involved in signaling in sarcoidosis include IFNγ, TNFα, and various interleukins and chemokines. 18,19 Environmental and infectious exposures have been proposed as possible contributors to sarcoidosis susceptibility, but none have yet been convincingly demonstrated. 19 Genetic susceptibility to sarcoidosis has been associated with specific human leukocyte antigen alleles, supporting an autoimmune etiology. 19 Figure 2 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. 22,23 Updated consensus diagnostic criteria for neurosarcoidosis were published in 2018. 24 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. 22 Common steroid-sparing therapies in clinical practice include methotrexate, azathioprine, mycophenolate mofetil, leflunomide, hydroxychloroquine, and, increasingly, infliximab. 25 Retrospective analyses suggest that mycophenolate mofetil may be less effective than methotrexate (at least for preventing “relapse”), but such studies risk confounding by indication. 25,26 In retrospective analyses, infliximab, a TNFα inhibitor, is associated with favorable outcomes, including some cases refractory to other therapies. 8 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 remission.

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          Most cited references 18

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          • Article: not found

          Central nervous system sarcoidosis--diagnosis and management.

          A series of 68 patients with neurosarcoidosis is reported, with particular emphasis on clinical aspects, diagnosis and treatment. A classification system based on clinical diagnostic probability is proposed, consisting of probable and definite disease, the latter being dependent on finding sarcoid granulomas on nervous system histology, which was obtained in 12 patients (18%). The role of investigations, including magnetic resonance imaging (MRI), chest radiography, Kveim skin test, Gallium 67 isotope scanning and cerebrospinal fluid (CSF) studies, is considered. Sixty-two percent of patients presented with nervous system disease, most commonly affecting the optic nerve and chiasm. Other common presentations included cranial nerve palsies, spinal cord and brainstem manifestations. Investigations yielding most diagnostic information included the Kveim test (41/48, 85% positive), raised CSF protein and/or cells (50/62, 81%) and gallium 67 scan (14/31, 45%). Eleven out of 29 patients (38%) patients showed meningeal enhancement on MRI scanning and 43% of scans demonstrated multiple white-matter lesions. Mean follow-up for the group was 4.6 years. Forty-seven patients were seen for > 18 months, and over half of these patients progressed despite corticosteroid and other immunosuppressive therapies. The benefit of a large patient database prospectively studied, with extended follow-up is discussed in order to learn more about prognosis and advance therapy in neurosarcoidosis.
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            Discriminating long myelitis of neuromyelitis optica from sarcoidosis.

            To compare longitudinally extensive myelitis in neuromyelitis optica spectrum disorders (NMOSD) and spinal cord sarcoidosis (SCS).
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              Neurosarcoidosis. Clinical description of 7 cases with a proposal for a new diagnostic strategy.

              Chronic involvement of the nervous system is relatively rare in sarcoidosis. We describe 7 cases that fulfil Zajicek's criteria for neurosarcoidosis (NS) and propose some modifications to such criteria. The patients were admitted for various neurological syndromes: 2 cases presented with chronic lymphocytic meningitis, 4 with spinal cord symptoms, one case was initially confused with multiple sclerosis. Serological tests, immunological screening, cerebrospinal fluid (CSF) analysis, bacteriological and viral testing were performed in all patients. Spinal and cerebral MRI, gallium scan, bronchoscopy with biopsy and bronchoalveolar-lavage fluid analysis, high-resolution computed tomography (HRCT) of the chest, biopsy of the lungs, skin, mediastinal lymph-node and meninges, were useful in diagnosing NS. Laboratory tests showed serum inflammatory abnormalities, but were negative for infectious diseases, while CSF showed inflammatory signs in all patients. MRI revealed meningeal enhancement or hypertrophic pachymeningeal lesions in 4 patients, white matter abnormalities and mass lesions in 2 patients, and a spinal mass lesion in 1 patient. Gallium scan, HRCT, bronchoscopy were positive in most cases. Patients were treated with steroid and immunosuppressive therapy, with improvement in six cases. One patient died from infectious complications. A definite diagnosis of NS requires demonstration of non-caseating granulomas affecting nervous tissues. In most cases, histological evidence of systemic disease (probable NS) is sufficient in the presence of compatible alterations in the CNS. In our patients the bronchoalveolarlavage fluid analysis, gallium scan, and chest HRCT were important for diagnosis, while serum ACE was always normal and chest radiographs were not suggestive of sarcoidosis.
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                Author and article information

                Contributors
                Journal
                Neurol Neuroimmunol Neuroinflamm
                Neurol Neuroimmunol Neuroinflamm
                nnn
                NEURIMMINFL
                Neurology® Neuroimmunology & Neuroinflammation
                Lippincott Williams & Wilkins (Hagerstown, MD )
                2332-7812
                23 October 2018
                November 2018
                23 October 2018
                : 5
                : 6
                Affiliations
                From the Department of Neurology (A.R.R., S.S.Z., J.M.G.) and Program in Immunology (S.S.Z.), University of California San Francisco; Department of Neurology (R.P.L.), Wayne State University, Detroit, MI; Partner's Neurology Training Program (E.M.); MGH and Brigham and Women's Hospitals, Harvard Medical School, Boston, MA; and E.M. is now with the Department of Neurology, Dell Medical School at the University of Texas at Austin; Central Texas Neurology Consultants (E.J.F.), and Department of Neurology, Dell Medical School at the University of Texas at Austin; Department of Neurology (E.M., A.L.), and Department of Neurology and Ophthalmology (T.C.F., E.F), Dell Medical School at the University of Texas at Austin; Department of Neurology (L.F.), University of Texas at Houston; and the National Multiple Sclerosis Society, New York, NY.
                Author notes
                Correspondence Dr. Gelfand Jeffrey.Gelfand@ 123456ucsf.edu or Dr. E.M. Frohman Elliot.frohman@ 123456austin.utexas.edu
                [*]

                National Multiple Sclerosis Society Case Conference Proceedings Faculty.

                Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NN.

                [†]

                Guest Assistant Editor: Ethan Meltzer, MD.

                [‡]

                Guest Managing Editors: Kathy Costello, MS, ANP-BC and Teresa C. Frohman, MPAS, MSCS, PA-C.

                [§]

                Guest Editors-in-Chief: Elliot M. Frohman, MD, PhD, and Scott S. Zamvil, MD, PhD.

                The Article Processing Charge was funded by the National Multiple Sclerosis Society.

                Article
                NEURIMMINFL2018018002
                10.1212/NXI.0000000000000509
                6225923
                Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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