Early versus delayed treatment with glatiramer acetate: Analysis of up to 27 years of continuous follow-up in a US open-label extension study.

BACKGROUND: Glatiramer acetate (GA) is US-approved for relapsing multiple sclerosis. OBJECTIVES: To describe GA long-term clinical profile. To compare effectiveness of early start (ES) versus delayed start (DS; up to 3 years) with GA. METHODS: Phase 3 trial participants entered a randomized placebo-controlled period then an open-label extension (OLE) with GA. RESULTS: Overall, 208 out of 251 (82.9%) randomized participants entered the OLE; 24 out of 101 (23.8%, ES) and 28 out of 107 (26.2%, DS) participants completed the OLE. Median GA treatment was 9.8 (0.1-26.3) years. Annualized change in Expanded Disability Status Scale (EDSS) score was lower with ES versus DS (p = 0.0858: full study; p = 0.002; Year 5). Participants with improved/stable EDSS was consistently higher with ES versus DS: 40.3% versus 31.6% (p = 0.1590; full study); 70.8% versus 55.6% (p = 0.015; Year 5). ES prolonged time-to-6-month confirmed disease worsening (CDW) versus DS (9.8 vs 6.7 years), time-to-12-month CDW (18.9 vs 11.6 years), and significantly reduced time-to-second-6-month CDW (p = 0.0441). No new safety concerns arose. CONCLUSION: GA long-term treatment maintained clinical benefit with a similar safety profile to phase 3 results; a key limitation was that only 25% of participants completed the OLE. Early initiation of GA had sustained benefits versus delayed treatment.

Chronic cerebrospinal venous insufficiency: case-control neurosonography results.

OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) has been implicated in the pathophysiology of multiple sclerosis (MS). We sought to determine whether neurosonography (NS) provides reliable information on cerebral venous outflow patterns specific to MS. METHODS: This was a single-center, prospective case-control study of volunteer MS and non-MS participants. A neurosonologist, blind to the subjects' diagnosis, used high-resolution B-mode imaging with color and spectral Doppler to systematically investigate, capture, and record extracranial and intracranial venous drainage. These neuroimaging results were evaluated and scored by an expert blinded to subjects' information and with no interactions with the participants. RESULTS: Altogether, 276 subjects were studied: 206 with MS and 70 non-MS. MS patients were older than non-MS subjects (48.3±9.9 vs 44.3±11.8 years, p<0.007), with durations from first symptoms and diagnosis of 13.7±10 and 9.9±7.8 years, and Expanded Disability Status Scale of 2.6±2.0. Overall, 82 subjects (29.7%) fulfilled 1 of 5 NS criteria proposed for CCSVI; 13 (4.7%) fulfilled 2 criteria required for diagnosis, and none fulfilled >2 criteria. The distribution of subjects with 0, 1, or 2 criteria did not differ significantly across all diagnostic groupings, between MS and non-MS subjects, or within MS subgroups. CCSVI was present in 7.14% of non-MS and 3.88% of MS patients (p=0.266). No significant differences emerged between MS and non-MS subjects for extracranial or intracranial venous flow rates. INTERPRETATION: NS findings described as CCSVI are much less prevalent than initially reported, and do not distinguish MS from other subjects. Our findings do not support the hypothesis that CCSVI is causally associated with MS.

Trigeminal Neuralgia as a Primary Demyelinating Disease: Potential Multimodal Evidence and Remaining Controversies.

Trigeminal neuralgia is a heterogeneous disorder with likely multifactorial and complex etiology; however, trigeminal nerve demyelination and injury are observed in almost all patients with trigeminal neuralgia. The current management strategies for trigeminal neuralgia primarily involve anticonvulsants and surgical interventions, neither of which directly address demyelination, the pathological hallmark of trigeminal neuralgia, and treatments targeting demyelination are not available. Demyelination of the trigeminal nerve has been historically considered a secondary effect of vascular compression, and as a result, trigeminal neuralgia is not recognized nor treated as a primary demyelinating disorder. In this article, we review the evolution of our understanding of trigeminal neuralgia and provide evidence to propose its potential categorization, at least in some cases, as a primary demyelinating disease by discussing its course and similarities to multiple sclerosis, the most prevalent central nervous system demyelinating disorder. This proposed categorization may provide a basis in investigating novel treatment modalities beyond the current medical and surgical interventions, emphasizing the need for further research into demyelination of the trigeminal sensory pathway in trigeminal neuralgia. PERSPECTIVE: This article proposes trigeminal neuralgia as a demyelinating disease, supported by histological, clinical, and radiological evidence. Such categorization offers a plausible explanation for controversies surrounding trigeminal neuralgia. This perspective holds potential for future research and developing therapeutics targeting demyelination in the condition.

Chronic cerebrospinal venous insufficiency: masked multimodal imaging assessment.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) was implicated in the pathophysiology of multiple sclerosis (MS). OBJECTIVE: We evaluated neurosonography (NS), magnetic resonance venography (MRV), and transluminal venography (TLV) in subsets of MS patients drawn from a single-center, prospective, case-control study of 206 MS and 70 non-MS volunteers. METHODS: As previously reported, findings on high-resolution B-mode NS imaging with color and spectral Doppler of the extracranial and intracranial venous drainage consistent with CCSVI were similar among MS and non-MS volunteers (3.88% vs 7.14%; p = 0.266). Ninety-nine MS participants consented to intravascular contrast-enhanced 3D MRV to assess their major systemic and intracranial venous circulation, and 40 advanced to TLV that included pressure measurements of the superior vena cava, internal jugular, brachiocephalic, and azygous veins. RESULTS: NS findings and MRV patterns were discrepant for 26/98 evaluable subjects, including four with abnormal findings on NS that had normal venous anatomy by MRV. In no instance were TLV pressure gradients indicative of clinically significant functional stenosis encountered. The three imaging approaches provided generally consistent data with discrepancies referable to inherent technique properties. CONCLUSIONS: Our findings lend no support for altered venous outflow dynamics as common among MS patients, nor do they likely contribute to the disease process.

Trigeminal neuralgia in multiple sclerosis: Association with demyelination and progression.

BACKGROUND: Trigeminal neuralgia (TN) is a well-recognized symptom of multiple sclerosis (MS), yet its clinical characteristics related to MS subtype is poorly studied. Our aim was to evaluate whether development and clinical outcome of TN are influenced by MS phenotype. METHODS: In this retrospective cohort study, our database from 2007 to 2022 was reviewed to identify patients who had both the diagnosis of MS and TN, whether TN was an initial symptom of MS or developed later in diagnosis. A detailed medical history and treatment outcome was obtained. Pain status was assessed retrospectively using the Barrow Neurological Institute Pain Scale (BNI-PS), with BNI-PS I-III considered as good pain control and BNI-PS IV-V as poor pain control. RESULTS: 58 patients had MS-related TN. 44 patients had relapsing remitting multiple sclerosis (RRMS) at the time of TN diagnosis, 11 had secondary progressive multiple sclerosis (SPMS) at the time of TN diagnosis, and type of MS was not clear in 3 patients at the time of TN diagnosis (either RRMS or SPMS). Over a mean follow up of 18.8 (SD=10.9) years, 30 transitioned to SPMS. TN was refractory to medical management in 9 RRMS and 22 SPMS patients (p = 0.001). TN patients with RRMS required lower median number of pain medications compared to SPMS (p = 0.014). Brain MRI was available in 41 of the entire cohort. Of these, 27 patients had demyelinating lesions in the trigeminal sensory pathway and 14 did not. Patients with existing lesions had a higher chance of failure of medical management (74% versus 36%, p = 0.017) and required surgical intervention (55% versus 7%, p = 0.003). DISCUSSION: TN was not seen in primary progressive multiple sclerosis (PPMS). In patients who transitioned to SPMS, TN was more likely to be refractory to medical management. TN was more refractory in the presence of demyelinating plaque involving trigeminal sensory pathway.

COVID-19 severity and outcome in multiple sclerosis: Results of a national, registry-based, matched cohort study.

BACKGROUND: Risk factors associated with coronavirus disease 2019 (COVID-19) severity in patients with multiple sclerosis (MS) have been described. Recent improvements in supportive care measures and increased testing capacity may modify the risk of severe COVID-19 outcome in MS patients. This retrospective study evaluates the severity and outcome of COVID-19 in MS and characterizes temporal trends over the course of the pandemic in the United States. METHODS: We conducted a comparative cohort study using de-identified electronic health record (EHR) claims-based data. MS patients diagnosed with COVID-19 between February 2, 2020 and October 13, 2020 were matched (1:2) to a control group using propensity score analysis. The primary outcome was a composite of intensive care unit (ICU) admission, mechanical ventilation, and/or death. RESULTS: A total of 2,529 patients (843 MS and 1,686 matched controls) were included. Non-ambulatory and pre-existing comorbidities were independent risk factors for COVID-19 severity. The risk for the severe composite outcome was lower in the late cohorts compared with the early cohorts. CONCLUSIONS: The majority of MS patients actively treated with a disease-modifying therapy (DMT) had mild disease. The observed trend toward a reduction in severity risk in recent months suggests an improvement in COVID-19 outcome.

Safety evaluation of shorter infusion for ocrelizumab in a substudy of the Phase IIIb CHORDS trial.

The CHORDS trial evaluated ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis who had a suboptimal response to previous disease-modifying treatment. The objective of the present study was to assess the safety of shorter OCR infusions in a substudy of CHORDS. After completing four doses of OCR per initial US prescribing recommendations in the main study, participants in the substudy (N = 129) received a fifth dose over a 2-h duration (vs. 3.5 h). Infusion-related reactions occurred in 12.4% of patients. None were severe, life-threatening or led to treatment discontinuation. Shorter infusion time did not change the safety profile of OCR. Clinicaltrials.gov (NCT0237856).

Exploring the relationship between Endothelin-1 and peripheral inflammation in multiple sclerosis.

BACKGROUND: Identifying pathways linking neuroinflammation and neurodegeneration is essential to help prevent disability progression in people with multiple sclerosis (MS). Endothelin-1 (ET-1) is a potent vasoconstrictor thought to contribute to cerebral hypoperfusion and tissue damage in MS. Its link with the neuroinflammatory process remains poorly investigated. OBJECTIVES: To determine plasma ET-1 levels in treatment-naïve people with MS and controls, and the relationship between ET-1 and other peripheral immune mediator levels as potential markers of the disease process. METHODS: This is a retrospective study that included specimens previously collected from 35 treatment-naïve patients with clinically isolated syndrome highly suggestive of MS or definite MS and 35 sex- and age-matched controls. ET-1 plasma levels were measured by enzyme-linked immunosorbent assay (ELISA), and plasma cytokine levels [interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12(p70), IL-13, interferon (IFN)-γ and tumor necrosis factor (TNF)-α] were simultaneously measured by Multiplex assay. RESULTS: ET-1 levels were significantly increased in MS patients compared to controls. No significant difference in cytokine levels between the groups were found. However, a significant increase in IFN-γ/IL-4 ratio was observed in patients with MS in comparison with controls, suggestive of Th1 skewed response. Binary logistic regression was performed to ascertain the effects of age, sex, ET-1 and cytokine levels on the likelihood of MS diagnosis. In the final model, ET-1, IL-4 and IFN-γ levels remained as predictors of MS. There was no significant correlation between ET-1 and cytokine levels. CONCLUSIONS: Patients with MS presented increased levels of ET-1 and an immune response biased towards a Th1 profile. Although both ET-1 and Th1 cytokine profile were predictors of MS diagnosis, ET-1 levels were not associated with peripheral immune markers, suggesting that these changes may occur independently.