Citations

Abstract Severe neuropathies with predominant involvement of motor fibres can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibres. Target antigens were identified using immunoprecipitation combined with mass spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays and knock-out models. A retrospective study cohort consisting of different neuropathies (chronic inflammatory demyelinating polyradiculopathy n = 86, Guillain–Barré syndrome n = 37, multifocal motor neuropathy n = 18, diabetic neuropathy n = 30, other inflammatory neuropathies n = 10), amyotrophic lateral sclerosis (n = 50), multiple sclerosis (n = 50) and healthy controls (n = 50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and the sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over 4 years. Among 3543 total samples tested, three patients (two male, one female)—diagnosed with the LMND variant of amyotrophic lateral sclerosis (aged 65, 72 and 79 years, respectively)—showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt–Lanterman incisures (SLIs), paranodes and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs (‘incisuropathy’). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over 3 years. The other two patients died of rapid disease progression: one of them received no immunotherapy while the other had ineffective treatments with single administrations of intravenous immunoglobulin and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor-predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome and responses to immunotherapy in larger cohorts.

Background: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS). Objectives: We determined MFAP4 CNS expression and measured 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), and 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 meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 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). Patients with acute ON ( n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = −0.41, p = 0.017). Conclusion: MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity.

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.

Although Epstein–Barr virus (EBV) is hypothesized to be a prerequisite for multiple sclerosis (MS), up to 15% of children with a diagnosis of MS were reported to be EBV‐seronegative. When re‐evaluating 25 EBV‐seronegative children out of 189 pediatric patients with a diagnosis of clinically isolated syndrome/MS, we found anti–myelin oligodendrocyte glycoprotein (MOG) antibody in 11 of 25 (44%) EBV‐seronegative but only 9 of 164 (5.5%,p < 0.001) EBV‐seropositive patients. After critical review, MS remained a plausible diagnosis in only 4 of 14 EBV‐seronegative/MOG antibody–negative patients. In children with an MS‐like presentation, EBV seronegativity should alert clinicians to consider diagnoses other than MS, especially MOG‐antibody disease. ANN NEUROL 2021;89:1234–1239