Tillema, Jan‐Mendelt

AbstractObjectiveIn this observational study on a cohort of biopsy‐proven central nervous system demyelinating disease consistent with MS, we examined the relationship between early‐active demyelinating lesion immunopattern (IP) with subsequent clinical course, radiographic progression, and cognitive function.MethodsSeventy‐five patients had at least one early‐active lesion on biopsy and were pathologically classified into three immunopatterns based on published criteria. The median time from biopsy at follow‐up was 11 years, median age at biopsy ‐ 41, EDSS ‐ 4.0. At last follow‐up, the median age was 50, EDSS ‐ 3.0. Clinical examination, cognitive assessment (CogState battery), and 3‐Tesla‐MRI (MPRAGE/FLAIR/T2/DIR/PSIR/DTI) were obtained.ResultsIP‐I was identified in 14/75 (19%), IP‐II was identified in 41/75 (56%), and IP‐III was identified in 18/75 (25%) patients. Patients did not differ significantly by immunopattern in clinical measures at onset or last follow‐up. The proportions of disease courses after a median of 11 years were similar across immunopatterns, relapsing–remitting being most common (63%), followed by monophasic (32%). No differences in volumetric or DTI measures were found. CogState performance was similar for most tasks. A slight yet statistically significant difference was identified for episodic memory scores, with IP‐III patients recalling one word less on average.InterpretationIn this study, immunopathological heterogeneity of early‐active MS lesions identified at biopsy does not correlate with different long‐term clinical, neuroimaging or cognitive outcomes. This could be explained by the fact that while active white matter lesions are pathological substrates for relapses, MS progression is driven by mechanisms converging across immunopatterns, regardless of pathogenic mechanisms driving the acute demyelinated plaque.

Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. Objective: To test whether genes harboring rare variants associated with adult-onset MS risk ( PRF1, PRKRA, NLRP8 , and HDAC7 ) and 52 major histocompatibility complex (MHC) genes are associated with POMS. Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method “SKAT-O,” we tested the association between candidate genes and POMS risk. Results: After correction for multiple comparisons, one adult-onset MS gene ( PRF1, p = 2.70 × 10 −3 ) and two MHC genes ( BRD2, p = 5.89 × 10 −5 and AGER, p = 7.96 × 10 −5 ) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER . These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Cerebral cortical encephalitis (CCE) is a recently described myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) phenotype. In this observational retrospective study, we characterized 19 CCE patients (6.7% of our MOGAD cohort). Headache (n = 15, 79%), seizures (n = 13, 68%), and encephalopathy (n = 12, 63%) were frequent. Magnetic resonance imaging revealed unilateral (n = 12, 63%) or bilateral (n = 7, 37%) cortical T2 hyperintensity and leptomeningeal enhancement (n = 17, 89%). N‐Methyl‐D‐aspartate receptor autoantibodies coexisted in 2 of 15 tested (13%). CCE pathology (n = 2) showed extensive subpial cortical demyelination (n = 2), microglial reactivity (n = 2), and inflammatory infiltrates (perivascular, n = 1; meningeal, n = 1). Most received high‐dose steroids (n = 17, 89%), and all improved, but 3 had CCE relapses. This study highlights the CCE spectrum and provides insight into its pathogenesis. ANN NEUROL 2023;93:297–302

Objective: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. Methods: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. Results: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery’s composite mean score or individual test scores ( ps > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p = 0.83); Cogstate Brief Battery (26% vs. 32%, p = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite ( p = 0.03), Symbol Digit Modalities Test ( p = 0.02), Rey Auditory Verbal Learning Test ( p = 0.01), and Cogstate choice reaction time ( p < 0.001). Conclusion: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

Abstract Objective To report the clinical presentations and outcomes of patients with seizure and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD). Methods We retrospectively reviewed the electronic medical records for clinical and paraclinical features among patients with seizures and MOG‐IgG (immunoglobulin G) seropositivity. Results We identified 213 patients with MOG‐IgG seropositivity who fulfilled criteria for MOGAD. Seizures attributed to central nervous system (CNS) autoimmunity were observed in 10% of patients ( n = 23: 19 children, 4 adults). The majority ( n = 19, 83%) had pediatric disease onset. Focal motor seizures were the most common seizure semiology (16/23; 70%). Focal to bilateral tonic‐clonic seizures were present in 12 patients (53%), and 3 patients (13%) developed status epilepticus. All patients had features of encephalitis at onset of seizures. Cerebral cortical encephalitis (CCE) was the most common radiological finding (10 unilateral and 5 bilateral cases). Eight of 23 patients (35%) had only CCE, six of 23 patients (26%) had only acute disseminated encephalomyelitis (ADEM), and seven of 23 patients (30%) had features of both. Fifteen patients (65%) had leptomeningeal enhancement. Three patients (13%) had coexistence of N ‐methyl‐ d ‐aspartate receptor (NMDAR) IgG. Only 3 of 23 patients (13%) developed drug‐ resistant epilepsy. Although the majority had MOGAD relapses (14/23, 60%) had only 5 of 23 patients had recurrence of episodes of encephalitis with associated seizures. Twenty‐one of 23 patients (91%) had seizure freedom at last follow‐up. Significance MOG‐IgG evaluation should be considered in patients who present with encephalitis and focal motor and/or focal to bilateral tonic‐clonic seizures, especially pediatric patients with magnetic resonance imaging (MRI) brain findings consistent with CCE, ADEM, or other MOGAD presentations. The majority of these seizures are self‐limited and do not require maintenance/chronic antiseizure medications. Although seizure recurrence is uncommon, many patients have MOGAD relapses in the form of encephalitis and optic neuritis.

Objective The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)‐IgG and aquaporin‐4 (AQP4)‐IgG among patients with pediatric‐onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG‐IgG‐associated disease (MOGAD), and identify clinical features associated with final diagnosis. Methods Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case–control study on POMS risk factors. Serum AQP4‐IgG and MOG‐IgG were assessed using live cell‐based assays. Results AQP4‐IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG‐IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty‐five of 30 patients positive with MOG‐IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re‐review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein–Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). Interpretation MOG‐IgG and AQP4‐IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4‐IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271–284

AbstractA 17‐year‐old Caucasian boy presented with progressive left‐sided weakness, transient slurred speech, and skin lesions characterized by 3‐5 mm, pink, asymptomatic papules with white atrophic centers on his central abdomen, back, and lower extremities. Skin biopsy confirmed the diagnosis of malignant atrophic papulosis, a rare vasculopathy that leads to the occlusion of small‐ and medium‐sized arteries. He was treated with cyclophosphamide, eculizumab, treprostinil, pentoxifylline, heparin, and acetylsalicylic acid. Despite the aggressive immunosuppression, humanized monoclonal antibodies, and antiplatelet therapy, he died two months after presentation. We report this case to highlight diagnostic features, as well as to highlight the importance of early diagnosis and treatment.

Abstract Objective To identify features of the gut microbiome associated with multiple sclerosis activity over time. Methods We used 16S ribosomal RNA sequencing from stool of 55 recently diagnosed pediatric‐onset multiple sclerosis patients. Microbiome features included the abundance of individual microbes and networks identified from weighted genetic correlation network analyses. Prentice‐Williams‐Peterson Cox proportional hazards models estimated the associations between features and three disease activity outcomes: clinical relapses and both new/enlarging T2 lesions and new gadolinium‐enhancing lesions on brain MRI. Analyses were adjusted for age, sex, and disease‐modifying therapies. Results Participants were followed, on average, 2.1 years. Five microbes were nominally associated with all three disease activity outcomes after multiple testing correction. These included butyrate producers Odoribacter (relapse hazard ratio = 0.46, 95% confidence interval: 0.24, 0.88) and Butyricicoccus (relapse hazard ratio = 0.49, 95% confidence interval: 0.28, 0.88). Two networks of co‐occurring gut microbes were significantly associated with a higher hazard of both MRI outcomes (gadolinium‐enhancing lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.29 (1.08, 1.54) and 1.42 (1.18, 1.71), respectively; T2 lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.34 (1.15, 1.56) and 1.41 (1.21, 1.64), respectively). Metagenomic predictions of these networks demonstrated enrichment for amino acid biosynthesis pathways. Interpretation Both individual and networks of gut microbes were associated with longitudinal multiple sclerosis activity. Known functions and metagenomic predictions of these microbes suggest the important role of butyrate and amino acid biosynthesis pathways. This provides strong support for future development of personalized microbiome interventions to modify multiple sclerosis disease activity.