Flanagan, Eoin P.

Background Elevated intrathecal immunoglobulin G (IgG; oligoclonal bands (OCBs)) or IgG in people with progressive motor impairment due to “critical” demyelinating lesions are of uncertain significance. Objective Compare clinical/radiological features of people with “critical” demyelinating lesion-induced progressive motor impairment with/without elevated intrathecal IgG synthesis. Methods A total of 133 people with progressive motor impairment attributable to “critical” demyelinating lesions (corticospinal tract location, consistent with the progressive motor deficit) were compared regarding clinical and radiological presentation with and without ≥2 unique cerebrospinal fluid (CSF) OCB and/or IgG index ≥0.85. Results Ninety-eight (74%) had CSF-elevated OCB and/or IgG index, higher with increased magnetic resonance imaging-lesion burden. No differences were found with/without CSF abnormalities in sex (46 of 98 female (47%) vs. 22 of 35 (63%), p = 0.11), onset-age (median 49 vs. 50 years, p = 0.5), progression from onset (62 of 98 (63%) vs. 25 of 35 (71%)), progression post-relapse (36 of 98 (37%) vs. 10 of 35 (29%), p = 0.4), and duration between demyelinating disease onset and CSF examination (30 (0–359) vs. 48 (0–323) months p = 0.7). “Critical” lesions were radiologically similar, most commonly cervical spine located (72 of 98 (74%) vs. 19 of 35 (54%), p = 0.18) both with/without CSF abnormalities. Conclusions People with “critical” demyelinating lesion-induced progressive motor impairment typically have elevated intrathecal IgG (OCB and/or IgG) and similar clinical and radiological presentation regardless of CSF findings, therefore representing valid presentations of progressive demyelinating disease.

AbstractErdheim–Chester disease (ECD) is a histiocytic neoplasm that predominantly harbors mitogen‐activated protein kinase (MAPK) pathway variants. MAPK inhibitors typically are effective treatments, but mutations outside the MAPK pathway, such as CSF1R variants, may cause refractory ECD. We describe a patient with a novel somatic mutation in CSF1R (CSF1RR549_E554delinsQ) that resulted in refractory ECD affecting the central nervous system. Cell model studies, RNA sequencing analysis, and in silico protein modeling suggested that she had a gain‐of‐function mutation occurring in a region critical for autoinhibition. The patient was treated with pexidartinib, a CSF1R inhibitor, and has had a complete clinical and metabolic response lasting more than 1.5 years to date. To our knowledge, this is the first report to describe successful treatment of a patient with ECD by using an agent that specifically targets CSF1R. This case also highlights the critical role of individualized molecular profiling to identify novel therapeutic targets in ECD.

Objective Determine the utility of aquaporin 4 IgG (AQP4-IgG) testing (live cell-based assay) for Neuromyelitis Optica Spectrum Disorders (NMOSD). Methods We included Mayo Clinic patients (1/1/2018-12/31/2019) tested for serum AQP4-IgG by live cell-based flow-cytometric assay. Medical records were reviewed to assess if patients fulfilled 2015 NMOSD criteria. Results Of 1371 patients tested, 41 were positive (3%) and all fulfilled NMOSD criteria with AQP4-IgG (specificity = 100%). Only 10/1330 testing negative met NMOSD criteria without AQP4-IgG (sensitivity = 80%) and seven of these 10 were MOG-IgG positive. Conclusions AQP4-IgG by live cell-based assay was highly specific and without false positives in a high throughput setting.

Background Myelin-oligodendrocyte-glycoprotein (MOG)-IgG-positivity in patients with typical MS lesions on MRI may lead to diagnostic/therapeutic uncertainty. Objective and Methods We reviewed reports of cases with MS phenotype on MRI and MOG-IgG-positivity published in Pubmed between 01/2012–06/2021. Results Sixteen patients were included (median age [range], 37,5 [25–66] years; 60% female). Three patients initially tested negative for MOG-IgG. Disease course was: relapsing-remitting, 10; or progressive, 6. Intrathecal IgG-synthesis was common (79%). Low and high-efficacy MS-targeted agents prevented relapses in 30% and 100%, respectively. None of the patients showed resolution of MRI T2-lesions over time. Conclusions MOG-IgG-positivity is unlikely to alter the expected treatment response and outcomes in patients with otherwise typical MS phenotype on MRI.

AbstractBackground and purposeTumefactive demyelination (TD) presents with large inflammatory lesions mimicking tumors or other space‐occupying lesions. Limited epidemiological, clinical and radiological data exist for TD. We aimed to report the incidence rate, and clinical and radiological features of TD in Olmsted County, Minnesota.MethodsWe retrospectively reviewed patients with central nervous system inflammatory demyelination‐related diagnostic codes (January 1, 1998 to December 31, 2018) in the Rochester Epidemiology Project database, and adjusted incidence rates by age and sex to the 2010 US total population. We used the Expanded Disability Status Scale (EDSS) to assess outcomes (index attack and last follow‐up).ResultsOf 792 multiple sclerosis (MS) patients, 15 (eight males, seven females) had tumefactive MS, representing 1.9% of the MS population. The median (range) age at attack onset was 34.2 (2–61) years. Tumefactive lesion was the first clinical MS attack in 8/16 patients. Cerebrospinal fluid oligoclonal bands (OCBs) were present in 8/12 patients and 11/16 patients met the Barkhof criteria for dissemination in space. Most patients remained fully ambulatory (EDSS score ≤4 in 13/16 patients [81%]) after a median (range) follow‐up duration of 10.5 (1–20.5) years. Age‐adjusted annual incidence rates were 0.46/100,000 (95% confidence interval [CI] 0.12–0.81) for female patients, 0.66/100,000 (95% CI 0.23–1.02) for male patients, and 0.56/100,000 [95% CI 0.28–0.83] overall. When age‐ and sex‐adjusted to the 2010 US total population, the overall annual incidence rate was 0.57 (95% CI 0.28–0.84). Despite aggressive clinical presentation at disease onset, most patients remained fully ambulatory (EDSS score ≤4 in 13/16 patients) with a relapsing‐remitting course.ConclusionsAlthough incidence is rare, TD should be suspected in patients presenting with subacutely progressive neurological deficits associated with magnetic resonance imaging findings of ring enhancement, apparent diffusion coefficient restriction, and OCB on spinal fluid analysis.

AbstractAcute myelopathies are spinal cord disorders characterized by a rapidly progressive course reaching nadir within hours to a few weeks that may result in severe disability. The multitude of underlying etiologies, complexities in confirming the diagnosis, and often unforgiving nature of spinal cord damage have always represented a challenge. Moreover, certain slowly progressive myelopathies may present acutely or show abrupt worsening in specific settings and thus further complicate the diagnostic workup. Awareness of the clinical and magnetic resonance imaging characteristics of different myelopathies and the specific settings where they occur is fundamental for a correct diagnosis. Neuroimaging helps distinguish compressive etiologies that may require urgent surgery from intrinsic etiologies that generally require medical treatment. Differentiation between various myelopathies is essential to establish timely and appropriate treatment and avoid harm from unnecessary procedures. This article reviews the contemporary spectrum of acute myelopathy etiologies and provides guidance for diagnosis and management.