High-efficacy therapies reduce clinical and radiological events more effectively than traditional treatments in neuromyelitis optica spectrum disorder.

BACKGROUND: People with neuromyelitis optica spectrum disorder (pwNMOSD) experience debilitating neurological attacks, resulting in permanent disability. OBJECTIVE: To evaluate if high-efficacy treatment was better than traditional agents at preventing disease advancement in pwNMOSD. METHODS: A retrospective study of pwNMOSD at one academic center was performed. Timelines were created for treatments subjects were exposed to along with clinical/radiological events related to disease worsening. High-efficacy treatments included eculizumab, inebilizumab, satralizumab, rituximab, ocrelizumab, tocilizumab, and sarilumab while therapies such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil were classified as traditional agents. Poisson regression and mixed effects logistics models were constructed, and a subject-specific random intercept was used for intrasubject correlation. RESULTS: Of 189 pwNMOSD identified, 161 were aquaporin-4 IgG positive (AQP4 +) with 92 (77 female; median disease duration (MDD) (range) of 6.6 years (y) (1.2-18.6)) exposed only to high-efficacy therapy, 33 (28 female; 10.4 y (0.8-32.7)) only to traditional therapy, and 64 (54 female; 10.8 y (0.7-20.2)) to both. High-efficacy treatments reduced the rate of MRI advancement by 62.4% (95% CrI = [- 86.9%, - 16.8%]), relapses by 99.8% (95% CrI = [- 99.9%, - 99.6%]), and hospitalizations by 99.3% (95% CrI = [- 99.6%, - 98.8%]) when compared to traditional treatments. For AQP4 + subjects, a 655.7-fold increase in the odds of new spinal cord lesion development (95% CrI = [+ 37.4-fold, + 3239.5-fold]) was observed with traditional agents (p < 0.0001). CONCLUSION: High-efficacy treatments maximize opportunity for preventing disease advancement in newly diagnosed and established pwNMOSD.

Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis.

Identifying effective therapies for the treatment of progressive forms of multiple sclerosis (MS) is a highly relevant priority and one of the greatest challenges for the global MS community. Better understanding of the mechanisms involved in progression of the disease, novel trial designs, drug repurposing strategies, and new models of collaboration may assist in identifying effective therapies. In this review, we discuss various therapies under study in phase II or III trials, including antioxidants (idebenone); tyrosine kinase inhibitors (masitinib); sphingosine receptor modulators (siponimod); monoclonal antibodies (anti-leucine-rich repeat and immunoglobulin-like domain containing neurite outgrowth inhibitor receptor-interacting protein-1, natalizumab, ocrelizumab, intrathecal rituximab); hematopoetic stem cell therapy; statins and other possible neuroprotective agents (amiloride, riluzole, fluoxetine, oxcarbazepine); lithium; phosphodiesterase inhibitors (ibudilast); hormone-based therapies (adrenocorticotrophic hormone and erythropoietin); T-cell receptor peptide vaccine (NeuroVax); autologous T-cell immunotherapy (Tcelna); MIS416 (a microparticulate immune response modifier); dopamine antagonists (domperidone); and nutritional supplements, including lipoic acid, biotin, and sunphenon epigallocatechin-3-gallate (green tea extract). Given ongoing and planned clinical trial initiatives, and the largest ever focus of the global research community on progressive MS, future prospects for developing targeted therapeutics aimed at reducing disability in progressive forms of MS appear promising.

Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis.

OBJECTIVE: We sought to determine whether vitamin D status is associated with developing new T2 lesions or contrast-enhancing lesions on brain magnetic resonance imaging (MRI) in relapsing multiple sclerosis (MS). METHODS: EPIC is a 5-year longitudinal MS cohort study at the University of California at San Francisco. Participants had clinical evaluations, brain MRI, and blood draws annually. From the overall cohort, we evaluated patients with clinically isolated syndrome or relapsing-remitting MS at baseline. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking, and MS treatments) repeated measures analyses, annual 25-hydroxyvitamin D levels were evaluated for their association with subsequent new T2-weighted and gadolinium-enhancing T1-weighted lesions on brain MRI, clinical relapses, and disability (Expanded Disability Status Scale [EDSS]). RESULTS: A total of 2,362 3T brain MRI scans were acquired from 469 subjects. In multivariate analyses, each 10ng/ml higher 25-hydroxyvitamin D level was associated with a 15% lower risk of a new T2 lesion (incidence rate ratio [IRR], 0.85; 95% confidence interval [CI], 0.76-0.95; p = 0.004) and a 32% lower risk of a gadolinium-enhancing lesion (IRR, 0.68; 95% CI, 0.53-0.87; p = 0.002). Each 10ng/ml higher vitamin D level was associated with lower subsequent disability (-0.047; 95% CI, -0.091 to -0.003; p = 0.037). Higher vitamin D levels were associated with lower, but not statistically significant, relapse risk. Except for the EDSS model, all associations were stronger when the within-person change in vitamin D level was the predictor. INTERPRETATION: Vitamin D levels are inversely associated with MS activity on brain MRI. These results provide further support for a randomized trial of vitamin D supplementation.

Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis.

Glutamate is the main excitatory neurotransmitter in the mammalian brain. Appropriate transmission of nerve impulses through glutamatergic synapses is required throughout the brain and forms the basis of many processes including learning and memory. However, abnormally high levels of extracellular brain glutamate can lead to neuroaxonal cell death. We have previously reported elevated glutamate levels in the brains of patients suffering from multiple sclerosis. Here two complementary analyses to assess the extent of genomic control over glutamate levels were used. First, a genome-wide association analysis in 382 patients with multiple sclerosis using brain glutamate concentration as a quantitative trait was conducted. In a second approach, a protein interaction network was used to find associated genes within the same pathway. The top associated marker was rs794185 (P < 6.44 x 10(-7)), a non-coding single nucleotide polymorphism within the gene sulphatase modifying factor 1. Our pathway approach identified a module composed of 70 genes with high relevance to glutamate biology. Individuals carrying a higher number of associated alleles from genes in this module showed the highest levels of glutamate. These individuals also showed greater decreases in N-acetylaspartate and in brain volume over 1 year of follow-up. Patients were then stratified by the amount of annual brain volume loss and the same approach was performed in the 'high' (n = 250) and 'low' (n = 132) neurodegeneration groups. The association with rs794185 was highly significant in the group with high neurodegeneration. Further, results from the network-based pathway analysis remained largely unchanged even after stratification. Results from these analyses indicated that variance in the activity of neurochemical pathways implicated in neurodegeneration is explained, at least in part, by the inheritance of common genetic polymorphisms. Spectroscopy-based imaging provides a novel quantitative endophenotype for genetic association studies directed towards identifying new factors that contribute to the heterogeneity of clinical expression of multiple sclerosis.

Connecting white matter injury and thalamic atrophy in clinically isolated syndromes.

Previous studies suggest that thalamic degeneration is prominent in multiple sclerosis (MS) and even in pre-MS patients presenting with a clinically isolated syndrome (CIS). However, the relationships between white matter lesions and deep grey matter loss are not well understood. We analyzed the association between white matter lesions and the thalami in CIS patients to determine if connectivity is an important determinant. We studied 24 CIS patients and 18 normal controls with anatomical and diffusion tensor (DTI) MRI images. DTI fiber tracking was used to create probabilistic templates of the thalamocortical white matter and to define white matter connecting lesions and thalami. DTI metrics in the lesions and normal-appearing white matter (NAWM) regions were compared between CIS and controls, and correlated with thalamic volume changes estimated by voxel-based morphometry. There was 10 times higher density of lesions in thalamocortical compared to other brain white matter. Increased diffusivities and decreased fractional anisotropies were measured in the thalamocortical NAWM of CIS patients compared to controls. A step-wise regression analysis demonstrated that thalamocortical lesion volume and the mean diffusivity in track regions connecting lesion and thalami were significantly correlated with thalamic volumes in patients (Rsq=0.66, p<0.001), a finding not observed in regions outside the thalamocortical white matter. These results provide compelling evidence for a direct relationship between white matter lesions and thalamic atrophy in CIS patients.

Acute pathological laughter.

Pseudobulbar affect is a condition characterized by uncontrollable episodes of inappropriate laughing or crying that are disproportionate and discordant to the situation at hand. We report on a 16-year-old woman presenting with acute pathological laughter in the context of CNS demyelinating disease. Brain MRI scans fortuitously obtained before and after the onset of this symptom demonstrated acute gadolinium-enhancing lesions in the cerebral peduncles. The etiology of this condition remains theoretical; however, the results here provide further insights into the pathways of emotional control.