Citations

Abstract Background and Objectives: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the central nervous system (CNS). We aimed to determine MFAP4 CNS expression and measure cerebrospinal fluid (CSF) and serum levels. Methods: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) (n=3), progressive MS (n=3), neuromyelitis optica spectrum disorder (NMOSD) (n=2), controls (n=9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients (49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein associated disease (MOGAD), and 19 isolated optic neuritis (ION). Results: MFAP4 localized to the meninges and the vascular/perivascular spaces, particularly intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and to a lesser degree in progressive MS. CSF MFAP4 levels were reduced in patients during acute attacks compared to HC. There was a positive correlation between number of relapses and CSF MFAP4 levels (rho=0.33, p=0.004). CSF MFAP4 levels were lower in 53 samples obtained at presenting attack (mean U/mL: 14.3, MOGAD 9.7 and ION 14.6 relative to HC 17.9. (p=0.013, p=0.000 and p=0.019 respectively). All patients with acute ON relapse (n=68) had reduced CSF MFAP4 relative to HC (mean U/mL: 14.5 vs. 17.9, p=0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho=-0.41, p=0.017). Discussion.: MFAP4 immunoreactivity was observed in CNS and reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following acute relapse and may serve as a marker of disease activity and attack severity.

Background: Progressive motor impairment anatomically associated with a “critical” lesion has been described in primary demyelinating disease. Most “critical” lesions occur within the spinal cord. Objective: To describe the clinical and radiological features of “critical” lesions of the cervicomedullary junction (CMJ). Methods: Observational study on people presenting with a CMJ lesion associated with primary demyelinating disease-related progressive motor impairment. Clinical data were extracted by chart review. Brain and spinal cord magnetic resonance images were reviewed to characterize the CMJ lesion and determine additional demyelination burden. Results: Forty-one people were included: 29 (71%) had progression from onset and 12 (29%) had a relapse onset (secondary progressive) course. Most had progressive hemiparesis (21 (51%)) or progressive quadriparesis (15 (37%)) with a median Expanded Disability Status Scale (EDSS) of 5.5 (2.0–8.5) at last follow-up. No “critical” CMJ lesion enhanced; most were bilateral (25 (61%)). Brain magnetic resonance images were otherwise normal in 16 (39%) or with a restricted demyelination burden in 15 (37%). Cervical and thoracic cord MRIs were without additional lesions in 25 (61%) and 22/37 (59%), respectively. Conclusion: CMJ “critical” lesions can correlate with progressive motor impairment even with few or no additional magnetic resonance imaging (MRI) lesions. Lesion location is an important determinant of progressive motor impairment in demyelinating disease.

AbstractObjectiveMultiple Sclerosis (MS) is often accompanied by myelopathy, which may be associated with progressive worsening. A specific finding of MS‐associated myelopathy is McArdle sign, wherein neck flexion is associated with prominent increased limb weakness relative to that detected with neck extension. In this study, we characterized neuromotor control properties of finger extensors in association with the McArdle sign.MethodsA custom‐built device was utilized to monitor torque production of the wrist extensors with simultaneous recording of surface electromyography of the extensor digitorum. The electromyography was decomposed and analyzed via both linear and nominal regressions.ResultsLinear regressions demonstrated a strong difference between groups for MS from healthy controls and other myelopathies for motor unit action potential amplitude and average firing rate (p < 0.001). Further, linear regression demonstrated good correlations of neuromotor variables to mechanical torque output (0.24 ≤ R2 ≤ 0.76). Nominal regression distinguished MS from healthy controls with an AUC of 0.87, specificity of 0.97, and sensitivity of 0.64. Nominal regression of MS from other myelopathies demonstrated an AUC of 0.88, specificity of 0.85, and sensitivity of 0.79.InterpretationThese data demonstrate the neuromotor control factors that largely determine muscle force production change with the observation of McArdle sign; these neuromotor control factors can differentiate MS from both healthy controls and other myelopathy conditions.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.