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Background A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Objective To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis ( n  = 50) as well as attack and long-term treatment outcomes. Methods Retrospective multicenter study. Results The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36%) and markedly impaired ambulation due to paresis or ataxia (25%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in only 13%, and blood-CSF-barrier dysfunction in 32%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9%). Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%, respectively; MS had been suspected in 36%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. Conclusion Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.

Background Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG + ) NMOSD. Methods sGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG + patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG + ) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG + patients over a median observation period of 4.25 years. Results In patients with AQP4-IgG + NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG + patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG + , but not MOG-IgG + patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = − 1.28, p = 0.01). While in AQP4-IgG + , but not MOG-IgG + patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = − 1.75, p = 0.06) in patients with AQP4-IgG + NMOSD. Patients with AQP4-IgG + NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3–105.6], p = 0.03). In contrast, baseline sNfL levels above the 75 th age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG + NMOSD. Conclusion These findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG + NMOSD in phases of clinical remission.

Background Women are more susceptible to multiple sclerosis (MS) than men by a ratio of approximately 3:1. However, being male is a risk factor for worse disability progression. Inflammatory genes have been linked to susceptibility, while neurodegeneration underlies disability progression. Thus, there appears to be a differential effect of sex on inflammation versus neurodegeneration. Further, gray matter (GM) atrophy is not uniform across the brain in MS, but instead shows regional variation. Here, we study sex differences in neurodegeneration by comparing regional GM atrophy in a cohort of men and women with MS versus their respective age- and sex-matched healthy controls. Methods Voxel-based morphometry (VBM), deep GM substructure volumetry, and cortical thinning were used to examine regional GM atrophy. Results VBM analysis showed deep GM atrophy in the thalamic area in both men and women with MS, whereas men had additional atrophy in the putamen as well as in localized cortical regions. Volumetry confirmed deep GM loss, while localized cortical thinning confirmed GM loss in the cerebral cortex. Further, MS males exhibited worse performance on the 9-hole peg test (9HPT) than MS females. We observed a strong correlation between thalamic volume and 9HPT performance in MS males, but not in MS females. Conclusion More regional GM atrophy was observed in men with MS than women with MS, consistent with previous observations that male sex is a risk factor for worse disease progression.

ObjectivesIn neuromyelitis optica spectrum disorders (NMOSD) thalamic damage is controversial, but thalamic nuclei were never studied separately. We aimed at assessing volume loss of thalamic nuclei in NMOSD. We hypothesised that only specific nuclei are damaged, by attacks affecting structures from which they receive afferences: the lateral geniculate nucleus (LGN), due to optic neuritis (ON) and the ventral posterior nucleus (VPN), due to myelitis.MethodsThirty-nine patients with aquaporin 4-IgG seropositive NMOSD (age: 50.1±14.1 years, 36 women, 25 with prior ON, 36 with prior myelitis) and 37 healthy controls (age: 47.8 ± 12.5 years, 32 women) were included in this cross-sectional study. Thalamic nuclei were assessed in magnetic resonance images, using a multi-atlas-based approach of automated segmentation. Retinal optical coherence tomography was also performed.ResultsPatients with ON showed smaller LGN volumes (181.6±44.2 mm3) compared with controls (198.3±49.4 mm3; B=−16.97, p=0.004) and to patients without ON (206.1±50 mm3 ; B=−23.74, p=0.001). LGN volume was associated with number of ON episodes (Rho=−0.536, p<0.001), peripapillary retinal nerve fibre layer thickness (B=0.70, p<0.001) and visual function (B=−0.01, p=0.002). Although VPN was not smaller in patients with myelitis (674.3±67.5 mm3) than controls (679.7±68.33; B=−7.36, p=0.594), we found reduced volumes in five patients with combined myelitis and brainstem attacks (B=−76.18, p=0.017). Volumes of entire thalamus and other nuclei were not smaller in patients than controls.ConclusionThese findings suggest attack-related anterograde degeneration rather than diffuse thalamic damage in NMOSD. They also support a potential role of LGN volume as an imaging marker of structural brain damage in these patients.

Very rarely, adult NMDAR antibody-associated encephalitis (NMDAR-E) leads to persistent cerebellar atrophy and ataxia. Transient cerebellar ataxia is common in pediatric NMDAR-E. Immune-mediated cerebellar ataxia may be associated with myelin oligodendrocyte glycoprotein (MOG), aquaporin-4 (AQP-4), kelch-like family member 11 (KLHL11), and glutamate kainate receptor subunit 2 (GluK2) antibodies, all of which may co-occur in NMDAR-E. Here, we aimed to investigate the frequency, long-term outcome, and immunological concomitants of ataxia in NMDAR-E. In this observational study, patients with definite NMDAR-E with a follow-up of >12 months were recruited from the GENERATE registry. Cases with documented ataxia were analyzed in detail. In 12 of 62 patients (19%), ataxia was documented. Bilateral cerebellar ataxia without additional focal CNS findings was found in four (one child and three adults); one of these was previously reported as a case with persistent cerebellar atrophy and ataxia. Two patients with bilateral cerebellar ataxia had additional focal neurological symptoms, optic neuritis and facial palsy. Two patients developed hemiataxia: one with diplopia suggesting brainstem dysfunction and the other probably resulting from cerebellar diaschisis due to contralateral status epilepticus. In all but the one developing cerebellar atrophy, cerebellar ataxia was transient and not associated with a worse long-term outcome. In all five patients with cerebellar ataxia tested, MOG, AQP-4, GluK2, and KLHL11 antibodies were negative. In two additional patients negative for both MOG and AQP-4 antibodies, ataxia was sensory and explained by cervical myelitis as part of multiple sclerosis (MS) manifesting temporal relation to NMDAR-E. One of the patients with bilateral ataxia with focal neurological deficits was also diagnosed with MS upon follow-up. Finally, in two patients, ataxia was explained by cerebral hypoxic damage following circulatory failure during an ICU stay with severe NMDAR-E. Ataxia of different types is quite common in NMDAR-E. Cerebellar ataxia in NMDAR-E is mostly transient. NMDAR-E followed by persistent ataxia and cerebellar atrophy is very rare. Cerebellar ataxia in NMDAR-E may not be explained by concomitant KLHL11, MOG, AQP-4, or GluK2 autoimmunity. Of note, ataxia in NMDAR-E may result from treatment complications and, most interestingly, from MS manifesting in temporal association with NMDAR-E.

Objective Prevalence, susceptibility genes, and clinical and radiological features may differ across different ethnic groups of multiple sclerosis (MS). We aim to characterize brain lesions in Chinese patients with MS by use of 7‐T MRI. Methods MS participants were enrolled from the ongoing China National Registry of Neuro‐Inflammatory Diseases (CNRID) cohort. 7‐T MRI of the brain was performed. Each lesion was evaluated according to a standardized procedure. Central vein sign (CVS) and paramagnetic rim lesions were identified. The characteristics of lesions at patient‐level and at lesion‐level from previous 7‐T MRI literature were also summarized. Results We included 120 MS patients. Their mean (SD) age was 34.6 (9.4) years. The female‐to‐male ratio was 1.7:1 and mean disease duration of patients with MS was 5.5 ± 6.1 years. The median EDSS score was 2 (range, 0–8). A total of 8502 lesions were identified with a median lesion count of 45 (IQR, 18–90) (range, 2–370). The median (IQR) percentage for these special locations were as follows: cortical lesions (CLs) 2.7% (0%–5.7%), juxtacortical lesions 16.2% (7.8%–25.7%), periventricular lesions 30.2% (17.2%–38.7%), and infratentorial lesions 5.8% (0.4%–11.9%). CLs occurred in 70 (58%) patients, accounting for only 443 (5%) of the total lesions. Out of the 443 CLs, 309 (69.8%) were leukocortical lesions. CVS appeared in 5392 (63%) lesions from 117 (98%) patients. 1792 (21%) lesions and 104 (87%) patients exhibited a paramagnetic rim. Interpretation Our study elaborated on the lesion features of Chinese patients with MS by use of 7‐T MRI. Lesion burden is heavy in Chinese patients with MS. The median lesion count and proportion of PRL are high. The reported heavy lesion burden calls for ramping up regional and global efforts to care for MS patients. The management and research of Chinese population with MS needs to be further strengthened.

The analysis of the MR phase provides additional information on the tissue microstructure. In multiple sclerosis (MS) lesions phase alterations may reflect different stages of inflammatory activity. Here we investigated lesion morphology in MS patients with short and long disease duration on T2* weighted, phase, magnitude and susceptibility weighted imaging (SWI) at 7 Tesla (T). 17 MS or clinically isolated syndrome patients with short (<60 months) and 11 with long (>60 months) disease duration underwent 7 T MRI. Lesions were subsequently analyzed side-by-side with regard to morphology and visibility on T2* weighted, SWI, magnitude and SWI-filtered phase images. 126 of 192 T2* weighted lesions (65.6%) were characterized by a phase alteration pattern, and hence could be differentiated on phase images. In detail, a significantly reduced proportion of lesions showing phase alterations was detectable in patients with longer disease duration (mean±SD 51 ± 37%, range 0-100%) compared to patients with short disease duration (mean ± SD 90 ± 19.5%, range 50-100%, p = 0.003). This cross-sectional study identified different patterns of phase changes in lesions of MS patients with short and long standing disease. Longitudinal studies are warranted to prove that MR phase imaging is useful in determining the activity and the developmental stage of individual MS plaques.

Background Myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) can radiographically mimic multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). The disease hallmarks cortical lesion, central vein sign (CVS) and paramagnetic rim lesions identified in MS have not yet been comprehensively investigated in MOGAD. Methods We have characterized 45 patients with MOGAD using 7.0 Tesla (7 T) MRI at two academic research hospitals in China and Germany. 7 T MRI, laboratory, and clinical data were collected. The classification of cortical lesions, proportion of CVS, and the phase shifts of lesions on susceptibility weighted imaging were analyzed. Results Of the 45 patients enrolled with MOGAD, 282 lesions were identified. We further detected 31 (11%) cortical lesions including leukocortical, intracortical, and subpial types, of which intracortical lesions (16/31, 52%) were frequently involved. CVS was identified in 53 (19%) lesions of 21 (47%) patients, 154 (55%) lesions showed multiple veins sign (MVS) in 30 (67%) patients. The number (4.3 ± 6.0 vs. 1.5 ± 2.1, p = 0.0049) and percentage (52% vs. 18%, p < 0.0001) of MVS lesions for each MOGAD patient were higher than those of CVS. Eight patients (18%) had 39 (14%) lesions of hypointense signal with paramagnetic phase shifts on SWI, showing nodular phase changes and irregular borders in appearance. Conclusions In our observational MOGAD cohort, all three types of cortical lesions were recognized, with intracortical lesions being the most common. The number and proportion of lesions with MVS were higher than those with CVS. Lesions with paramagnetic phase changes were rare and non‐rim‐like in appearance. These findings provide a better understanding of the underlying pathology of MOGAD and will help in the differentiation of MOGAD from other demyelinating disorders.

Background Visual symptoms are common in people with multiple sclerosis. The revised 2024 McDonald criteria include the optic nerve as a fifth anatomical region, underscoring the need for specific diagnostics. Although optical coherence tomography (OCT) and visual evoked potentials (VEP) are available, the extent of their routine pre-referral use is insufficiently documented. We evaluated pre-referral utilization and hypothesized that specific diagnostics are used less often than non-specific diagnostics and that differences are not explained by demographics alone. Methods Retrospective cross-sectional study of 305 patients referred for visual symptoms to a tertiary neuroimmunology clinic in Germany. Analyses focused on people with multiple sclerosis (n = 112) and disease controls with neuromyelitis optica spectrum disorders or myelin oligodendrocyte glycoprotein-associated disease (pwNM; n = 36). Results In people with multiple sclerosis, only 6.2% received OCT and 33% VEP for their visual complaints, compared to unspecific diagnostics such as cranial magnetic resonance imaging (58%) and lumbar puncture (42%) – independent of demographic factors. Conclusion The pre-referral use of specific neurovisual tests in people with multiple sclerosis with visual symptoms was low relative to non-specific procedures. This suggests heterogeneous integration of neurovisual testing across care levels. In light of the revised McDonald Criteria 2024, prospective multicenter studies should examine implementation and clinical impact.

Objective Retrograde trans‐synaptic neuroaxonal degeneration is considered a key pathological factor of subclinical retinal neuroaxonal damage in multiple sclerosis (MS). We aim to evaluate the longitudinal association of optic radiation (OR) lesion activity with retinal neuroaxonal damage and its role in correlations between retinal and brain atrophy in people with clinically isolated syndrome and early MS (pweMS). Methods Eighty‐five pweMS were retrospectively screened from a prospective cohort (Berlin CIS cohort). Participants underwent 3T magnetic resonance imaging (MRI) for OR lesion volume and brain atrophy measurements and optical coherence tomography (OCT) for retinal layer thickness measurements. All pweMS were followed with serial OCT and MRI over a median follow‐up of 2.9 (interquartile range: 2.6–3.4) years. Eyes with a history of optic neuritis prior to study enrollment were excluded. Linear mixed models were used to analyze the association of retinal layer thinning with changes in OR lesion volume and brain atrophy. Results Macular ganglion cell‐inner plexiform layer (GCIPL) thinning was more pronounced in pweMS with OR lesion volume increase during follow‐up compared to those without (Difference: −0.82 μm [95% CI:‐1.49 to −0.15], p = 0.018). Furthermore, GCIPL thinning correlated with both OR lesion volume increase (β [95% CI] = −0.27 [−0.50 to −0.03], p = 0.028) and brain atrophy (β [95% CI] = 0.47 [0.25 to 0.70], p < 0.001). Correlations of GCIPL changes with brain atrophy did not differ between pweMS with or without OR lesion increase (ηp2 = 5.92e−7, p = 0.762). Interpretation Faster GCIPL thinning rate is associated with increased OR lesion load. Our results support the value of GCIPL as a sensitive biomarker reflecting both posterior visual pathway pathology and global brain neurodegeneration.