Myelin Oligodendrocyte Glycoprotein-Antibody Associated Disease: An Updated Review of the Clinical Spectrum, Pathogenetic Mechanisms and Therapeutic Management.

Clinical syndromes associated with antibodies against myelin oligodendrocyte glycoprotein (MOG) are now recognized as a distinct neurological disease entity, and are gaining increasing attention. The pathogenic mechanisms underlying MOG-antibody disease (MOGAD) remain incompletely understood. Case series, facilitated by registries, and observational studies over the past few years have shed increasing light on the clinical aspects and therapeutic approaches of MOGAD. MOGAD may manifest with a variety of clinical syndromes, including acute disseminated encephalomyelitis (ADEM), autoimmune encephalitis, optic neuritis (ON) and transverse myelitis (TM). MOGAD can be either monophasic or relapsing. This review aims to provide a comprehensive updated description of the clinical spectrum, paraclinical features, and prognosis of MOG-antibody disease, as well as summarize its therapeutic considerations. Randomized clinical trials, standardized diagnostic criteria and treatment guidelines are the steps forward.

Headache disorders in multiple sclerosis: Is there an association? A systematic review and meta-analysis.

OBJECTIVE: To look for any potential association of headache disorders with multiple sclerosis (MS). BACKGROUND: The prevalence of headache disorders has been found to be increased in people with MS (pwMS), however, an association has not been established. Existing studies have provided conflicting results mostly because of methodological differences. METHODS: PubMed, Embase and Scopus were searched to identify eligible studies. Studies were included if they were cross-sectional, case-control or cohort. Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias of the included studies. Case-control, cross sectional or cohort studies that used the International Classification of Headache Disorders (ICHD)-2 or-3 criteria for headache diagnosis and Mc Donald or Poser criteria for MS diagnosis were included. Data were extracted using standardized data collection form. Meta-analysis was conducted by calculating the overall prevalence of headache disorders in pwMS as well as the association of headache disorders with MS. The Newcastle-Ottawa Scale (NOS), a tool for assessing the quality of non-randomized studies, was used to assess the quality of the included studies. RESULTS: Twenty-three studies were included yielding a total of 5,440 MS patients and 28,0958 controls. The majority of them scored a NOS score between 5 and 6 (max 9), which indicates that they did not rank high in terms of quality, because most studies were cross-sectional and uncontrolled, and only one was prospective, controlled, and longitudinal, but with small population size. Pooled prevalence for all headache disorders, migraine and tension-type headache (TTH) in pwMS was 58 % (95 % CI 0.54-0.61), 30 % (95 % CI 0.25-0.34) and 19 % (95 % CI 0.15-0.23) respectively. A significant association between migraine and MS was found (OR = 2.02, 95 % CI = 1.14-3.57). CONCLUSION: PwMS are twice as likely to experience migraine as controls, but the results need to be translated with caution since most of the studies included in the meta-analysis were of low or moderate quality. Larger prospective cohort, controlled, longitudinal studies are needed to confirm whether there is indeed an association between MS and migraine.

Migraine in multiple sclerosis patients: potential links and treatment approach.

INTRODUCTION: Migraine has been reported to be twice as prevalent in patients with multiple sclerosis (MS) compared to the non-MS population. However, prospective, controlled studies that could lead to robust conclusions are still lacking. AREAS COVERED: Treatment of migraine in patients with MS can be challenging. Comorbidities need to be assessed and managed early, and preventive treatment should be initiated when indicated. Caution is warranted regarding the selection of the preventive medication since certain agents can magnify MS symptoms and particularly cognitive symptoms. This paper aims to discuss the association of MS and migraine, shed light on distinguishing points and red flags, as well as offer practical advice on the selection of treatment according to patients' characteristics. EXPERT OPINION: A holistic approach including pharmacological and non-pharmacological modifications is required to treat migraine in patients with MS effectively. Anti-CGRP monoclonal antibodies are a promising option due to limited drug-to-drug interactions; however, larger prospective studies are required to draw robust conclusions on the concomitant use of anti-CGRPs with MS disease modifying treatments. Early migraine preventive treatment might be needed to reduce the burden of disease in patients with MS.

Monoclonal Antibodies in Pregnancy and Breastfeeding in Patients with Multiple Sclerosis: A Review and an Updated Clinical Guide.

The use of high-efficacy disease-modifying therapies (DMTs) early in the course of multiple sclerosis (MS) has been shown to improve clinical outcomes and is becoming an increasingly popular treatment strategy. As a result, monoclonal antibodies, including natalizumab, alemtuzumab, ocrelizumab, ofatumumab, and ublituximab, are frequently used for the treatment of MS in women of childbearing age. To date, only limited evidence is available on the use of these DMTs in pregnancy. We aim to provide an updated overview of the mechanisms of action, risks of exposure and treatment withdrawal, and pre-conception counseling and management during pregnancy and post-partum of monoclonal antibodies in women with MS. Discussing treatment options and family planning with women of childbearing age is essential before commencing a DMT in order to make the most suitable choice for each individual patient.

Disease-modifying treatments for multiple sclerosis have not affected the incidence of neoplasms in clinical trials over 3 decades: a meta-analysis with meta-regression.

OBJECTIVE: Our study aimed to estimate the incidence of neoplasms in clinical trials of DMTs for MS and to test the hypothesis that DMTs increase the risk of neoplasms in the duration of MS randomized controlled trials (RCTs). METHODS: Data were extracted from 42 RCTs of DMTs published between 1991 and 2020. The incidence rate (IR) of neoplasms was estimated by pooling the neoplasms in the active and placebo-treatment arm per patient-year. The neoplasm incidence rate ratio (IRR) of active over placebo-treatment arms was used as measure of the effect of DMTs on the risk of developing neoplasms. RESULTS: The meta-analysis included 10,638 placebo and 16,360 active-treatment arm patients. A non-significant pooled neoplasm incidence rate ratio (IRR: 1.0797; 95% CI: 0.8281 to 1.4077; P = 0.5711) with no heterogeneity (I2 = 0%) was observed in active over placebo-treatment groups from 1991 to 2020. We found a significant association between the incidence of neoplasms and the year of publication in both active and placebo arms of RCTs. Trials of sequestrating and depletive DMTs were associated with significantly higher incidence of neoplasms in both active and placebo-treated arms compared to immunomodulatory treatment trials. CONCLUSIONS: Our study indicates that treatment with DMTs has not modified the risk of neoplasms in MS clinical trials from 1991 to 2020, which may reflect a low carcinogenic potential of DMTs and/or that the neoplasia latencies far exceed the typical MS trial observation periods.

The Role of Galcanezumab in Migraine Prevention: Existing Data and Future Directions.

Galcanezumab is a humanized monoclonal antibody blocking the calcitonin gene-related peptide (CGRP) pathway by targeting the CGRP. Data from four phase-3 randomized placebo-controlled clinical trials showed that galcanezumab is superior to placebo in reducing migraine headaches, migraine-specific quality of life, and headache-related disability. Most of the adverse events (AEs) were mild to moderate and did not affect trial completion rates significantly. Along with erenumab, fremanezumab, and eptinezumab, galcanezumab forms a novel class of anti-migraine preventative treatments that is disease-specific and mechanism-based, unlike the standard ones. In addition, galcanezumab has also been shown to be effective in cluster headache, though more clinical trials are required. Overall, galcanezumab is a promising emerging treatment in migraine prophylaxis. However, it needs to be tested in larger clinical trials focused on treatment-resistant migraine. Furthermore, its safety profile, especially its potential association with an increased cardiovascular risk, needs to be established through long-term, real-world data. This review aims to give an overview of its pharmacological properties as well as to report and discuss data from clinical trials and its potential place in headache therapeutics.

Monoclonal Antibodies as Neurological Therapeutics.

Over the last 30 years the role of monoclonal antibodies in therapeutics has increased enormously, revolutionizing treatment in most medical specialties, including neurology. Monoclonal antibodies are key therapeutic agents for several neurological conditions with diverse pathophysiological mechanisms, including multiple sclerosis, migraines and neuromuscular disease. In addition, a great number of monoclonal antibodies against several targets are being investigated for many more neurological diseases, which reflects our advances in understanding the pathogenesis of these diseases. Untangling the molecular mechanisms of disease allows monoclonal antibodies to block disease pathways accurately and efficiently with exceptional target specificity, minimizing non-specific effects. On the other hand, accumulating experience shows that monoclonal antibodies may carry class-specific and target-associated risks. This article provides an overview of different types of monoclonal antibodies and their characteristics and reviews monoclonal antibodies currently in use or under development for neurological disease.

Galcanezumab in migraine prevention: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Galcanezumab, along with three other monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, represents the latest disease-specific and mechanism-based treatment for the prophylaxis of migraine. Galcanezumab shares data also for the prophylaxis of cluster headache. OBJECTIVE: To provide a pooled safety and efficacy analysis of all phase III randomized controlled trials of galcanezumab in the preventive therapy of migraine. METHODS: A computer-based literature search was conducted on MEDLINE and the US National Institutes of Health Clinical Trials Registry for phase III randomized controlled trials of galcanezumab in migraine prevention. The primary outcome was the mean change in monthly migraine days (MMDs). The proportions of patients who reported at least one adverse event (AE), at least one serious adverse event (SAE) or withdrew from the study were used as safety outcomes. RESULTS: Two trials were included in the efficacy meta-analysis and three in the safety meta-analysis. Migraine preventive treatment with subcutaneous galcanezumab, at both 120 mg and 240 mg dosages, was associated with a significantly greater reduction in the mean number of MMDs versus placebo (120 mg, MD = -1.98, 95% CI = -2.33 to -1.63; p < 0.0001) or (240 mg, MD = -1.86, 95% CI = -2.20 to -1.53; p < 0.0001). Galcanezumab was found to be more efficacious in all key secondary outcomes as well. Regarding safety, most of the adverse events were mild to moderate, while drop-out rates and serious adverse events were low. CONCLUSIONS: Galcanezumab is an efficacious and well-tolerated preventive treatment for migraine. Larger clinical trials with longer follow-up periods need to be conducted in order to provide more safety data of the above-mentioned drug.

Neurological manifestations of COVID-19: a review of what we know so far.

Coronavirus disease 2019 (COVID-19) has become a pandemic disease globally. While it mostly presents with respiratory symptoms, it has already been found that it could manifest with a series of neurological symptoms as well, either at presentation or during the course of the disease. Symptoms vary from non-specific such as headache or dizziness to more specific such as convulsions and cerebrovascular disease (CVD). This study aims to give an overview of the neurological manifestations of COVID-19 and discuss the potential pathogenetic mechanisms of central nervous system (CNS) involvement. Clinicians and especially internists, neurologists, and infectious disease specialists should be aware of these symptoms and able to recognize them early. Prompt diagnosis and immediate management of the neurological manifestations of the novel coronavirus will not only improve the prognosis of COVID-19 patients but will also prevent the dissemination of the disease due to misdiagnosed cases.

Nocebo in multiple sclerosis trials: A meta-analysis on oral and newer injectable disease-modifying treatments.

BACKGROUND: Nocebo phenomena are linked to decreased adherence to treatments in clinical practice as well as difficulty in assessing the adverse effect profile in clinical trials. OBJECTIVE: To estimate the incidence and severity of nocebo responses in clinical trials of oral and newer injectable disease-modifying treatments (DMTs) for relapsing multiple sclerosis (MS). METHODS: Meta-analysis of the incidence of nocebo responses was performed by pooling the percentage of placebo-treated patients that exhibited adverse events (AEs) in randomized, placebo-controlled MS trials published between 2005 and 2018. Nocebo severity was estimated as a percentage of placebo-treated patients who discontinued the treatment due to drug-related AEs. RESULTS: The pooled incidence of nocebo was 89% (95% CI: 88%-90%) in trials for oral DMTs (cladribine, fingolimod, teriflunomide and dimethyl fumarate) and 66% (95% CI: 51%-80%) in trials of newer injectable DMTs (biosimilar glatiramer acetate 20 mg, innovator glatiramer acetate 40 mg and pegylated interferon beta). The pooled nocebo severity was 8% (95% CI: 5%-12%) for oral treatments and 2% (95% CI: 0-2%) for newer injectable DMTs. CONCLUSIONS: Oral DMTs may be associated with a higher incidence and greater nocebo severity than newer injectables.