An analysis of suicidal and self-injurious behavior reports with antiseizure medications in the FDA adverse event database.

BACKGROUND: Pharmacovigilance systems such as the FDA Adverse Event Reporting System (FAERS), are established models for adverse event surveillance that may have been missed during clinical trials. We aimed to analyze twenty-five anti-seizure medications (ASMs) in FAERS to assess for increased reporting of suicidal and self-injurious behavior. METHODS: Twenty-five ASMs were analyzed: brivaracetam, cannabidiol, carbamazepine, clobazam, clonazepam, diazepam, eslicarbazepine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, stiripentol, tiagabine, topiramate, valproate, vigabatrin, zonisamide. Reports of "suicidal and self-injurious behavior" were collected from January 1, 2004, to December 31, 2020, using OpenVigil 2.1 tool with indication as "Epilepsy". Relative reporting ratio, proportional reporting ratio, and reporting odds ratio were calculated utilizing all other drug reports for epilepsy patients as a control. RESULTS: Significant relative operating ratio, ROR (greater than 1, p<0.05) were observed for diazepam (2.909), pregabalin (2.739), brivaracetam (2.462), gabapentin (2.185), clonazepam (1.649), zonisamide (1.462), lacosamide (1.333), and levetiracetam (1.286). CONCLUSIONS: Of the 25 ASMs that were analyzed in this study, 4 (16%) were identified to have been linked with a likely true adverse event. These drugs included diazepam, brivaracetam, gabapenetin, and pregabalin. Although several limitations are present with the FAERS database, it is imperative to closely monitor patient comorbidities for increased risk of suicidality with the use of several ASMs.

Impact of neuromyelitis optica spectrum disorder on employment and income in the United States.

BACKGROUND AND OBJECTIVES: We aim to characterize the sociodemographic and clinical factors associated with loss of jobs, income, and work hours in people with neuromyelitis optica spectrum disorder (NMOSD) in the United States. METHODS: A REDCap-based survey was administered to working-age NMOSD patients (18-70 years old) querying demographic information, symptoms, immunosuppression, work hours, income, and caregiver work (11/2022-07/2023). Regression models were developed using MATLAB. RESULTS: Of 127 participants (97 female; 55% AQP4-antibody, 19% MOG antibody; 69% Caucasian, 7% Hispanic), with an average diagnosis age of 38.7 years, average disease duration of 6.4 years, mean 3.1 attacks, and 94% of whom were treated with immune system-directed therapy (53% rituximab, 8% satralizumab, 7% eculizumab, 6% mycophenolate mofetil, 4% inebilizumab, 2% azathioprine, 10% IVIg, 10% other), 56% lost a job due to NMOSD. Employment decreased 12% (80% pre- to 68% post-diagnosis). Thirty-six percent of participants said they no longer worked outside the home. Significant predictors for post-NMOSD diagnosis employment status included younger age, lower pain level, no walking aids, and having a job prediagnosis. Sixty-eight percent of those employed prediagnosis reduced their work hours, dropping an average of 18.4 h per month since being diagnosed (±10.1 h). Average annual income grew slowly at $1998 during the average 6.4 years of disease duration (14% of the value predicted by the U.S. Bureau of Labor Statistics). Sixty percent of participants had a regular unpaid caregiver; 34% of caregivers changed their work hours or job to help manage NMOSD. DISCUSSION: We provide a structured analysis of the impact of NMOSD on employment, work hours, and income in the United States, demonstrating its major effect on the livelihoods of patients and their caregivers.

Increased healthcare utilization in the year before multiple sclerosis diagnosis.

BACKGROUND: Studies have suggested possible multiple sclerosis (MS) prodrome with non-routine healthcare utilization as an indicator. The objective of this project was to compare utilization in the four years (years -1, -2, -3, -4) before clinically definite diagnosis and examine demographic associations. METHODS: i2B2 database search at the Medical College of Wisconsin Comprehensive MS center yielded 613 patients between 07/01/2018 and 07/01/2022. Patients with established MS diagnosis, MS mimicker diagnoses, and pediatric-onset MS were excluded; 108 met the criteria for adult patients ≥ 18 years of age newly diagnosed with clinically definite MS after manual chart review. Utilization score for each of the four years before diagnosis was calculated; demographic variables were also collected. Adjusted repeated measures mixed model and Pearson correlation analysis were performed; P value was set at <0.05 for statistical significance. RESULTS: Utilization was greatest for year -1 compared to years -2, -3, and -4 after demographics adjustment (p < 0.001). Utilization was greater (p < 0.05) for older age and unmarried, patients. CONCLUSIONS: Utilization increased a year before formal MS diagnosis, suggestive of prodromal presentation.

Progressive multifocal leukoencephalopathy in patients with chronic kidney disease.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system infection caused by the human polyomavirus 2, leading to demyelination from oligodendrocyte death and rapid neurologic decline. Most commonly, PML affects patients in immunocompromised states. However, rare reports of PML in an immunocompetent host exist. Here, we report two cases of PML in older individuals with chronic kidney disease (CKD). CKD can ultimately lead to immune system dysfunction and place patients in a relatively immunosuppressed state. Testing for JC virus should remain a consideration for rapid, unexplained neurologic decline even without known immunocompromised status in the appropriate clinical setting.

Identification and management of subclinical disease activity in early multiple sclerosis: a review.

IMPORTANCE: Early treatment initiation in multiple sclerosis (MS) is crucial in preventing irreversible neurological damage and disability progression. The current assessment of disease activity relies on relapse rates and magnetic resonance imaging (MRI) lesion activity, but inclusion of other early, often "hidden," indicators of disease activity may describe a more comprehensive picture of MS. OBSERVATIONS: Early indicators of MS disease activity other than relapses and MRI activity, such as cognitive impairment, brain atrophy, and fatigue, are not typically captured by routine disease monitoring. Furthermore, silent progression (neurological decline not clearly captured by standard methods) may occur undetected by relapse and MRI lesion activity monitoring. Consequently, patients considered to have no disease activity actually may have worsening disease, suggesting a need to revise MS management strategies with respect to timely initiation and escalation of disease-modifying therapy (DMT). Traditionally, first-line MS treatment starts with low- or moderate-efficacy therapies, before escalating to high-efficacy therapies (HETs) after evidence of breakthrough disease activity. However, multiple observational studies have shown that early initiation of HETs can prevent or reduce disability progression. Ongoing randomized clinical trials are comparing escalation and early HET approaches. CONCLUSIONS AND RELEVANCE: There is an urgent need to reassess how MS disease activity and worsening are measured. A greater awareness of "hidden" indicators, potentially combined with biomarkers to reveal silent disease activity and neurodegeneration underlying MS, would provide a more complete picture of MS and allow for timely therapeutic intervention with HET or switching DMTs to address suboptimal treatment responses.

Time to involve the multiple sclerosis expert community at large when revising the McDonald diagnostic criteria.

Prof. Kurtzke once said, "Multiple sclerosis is what a good clinician would call multiple sclerosis." Recent McDonald's diagnostic criteria revisions have allowed for earlier diagnoses over the past decades. Revisions often allowed increasing sensitivity but at the expense of lowering specificity. In this correspondence, I suggest that the multiple sclerosis expert community worldwide should be given the opportunity to comment and provide feedback on the proposed revisions of the diagnostic criteria before their publication via providing a duration where open commentaries are welcomed to allow for the expert panel to incorporate diverse feedback to improve the final product.

Clinical and radiologic differences between early onset, late onset, and very late onset adult multiple sclerosis.

BACKGROUND: Previous studies suggested possible differences in clinical and radiologic characteristics between early-onset multiple sclerosis (EOMS) and late-onset MS (LOMS). However, differences between LOMS and very late onset MS (VLOMS) are largely unknown. METHODS: We performed a retrospective review of medical records of patients diagnosed with MS between 8/1/2017 and 3/1/2022 at the comprehensive MS center of the Froedtert and Medical College of Wisconsin. We included adult patients with MS diagnosis who were 60 years or older - VLOMS, 50-59 years old at diagnosis - LOMS, or were 18-30 years old at diagnosis - EOMS and had complete imaging and clinical records. Clinical presentation and location of demyelinating lesions at the onset of diagnosis were extracted and compared using the chi-square test, p<0.05. RESULTS: A total of 246 newly diagnosed patients were identified. Of which 54 were EOMS, 29 were LOMS, and 35 were VLOMS. The sex ratio was not different between groups. EOMS had a higher percentage of patients who self-identified as black, while LOMS had a higher percentage of patients who self-identified as white. LOMS and VLOMS showed significant differences in the presence of tremors and lesion distribution at the onset. Older onset patients were more likely to present with motor symptoms, sphincter dysfunction, fatigue, and tremor. EOMS was more likely to present with cerebellum and occipital lobe lesions, and lesions were more likely to show contrast enhancement on MRI at diagnosis. CONCLUSION: Our findings revealed novel clinical and imaging characteristics differences between VLOMS and LOMS. The current classification of LOMS may benefit from revision to better align with chronological age classification for old age >60 instead of the current standard in the literature of >50 years.

Visual oscillation effects on dynamic balance control in people with multiple sclerosis.

BACKGROUND: People with multiple sclerosis (PwMS) have balance deficits while ambulating through environments that contain moving objects or visual manipulations to perceived self-motion. However, their ability to parse object from self-movement has not been explored. The purpose of this research was to examine the effect of medial-lateral oscillations of the visual field and of objects within the scene on gait in PwMS and healthy age-matched controls using virtual reality (VR). METHODS: Fourteen PwMS (mean age 49 ± 11 years, functional gait assessment score of 27.8 ± 1.8, and Berg Balance scale score 54.7 ± 1.5) and eleven healthy controls (mean age: 53 ± 12 years) participated in this study. Dynamic balance control was assessed while participants walked on a treadmill at a self-selected speed while wearing a VR headset that projected an immersive forest scene. Visual conditions consisted of (1) no visual manipulations (speed-matched anterior/posterior optical flow), (2) 0.175 m mediolateral translational oscillations of the scene that consisted of low pairing (0.1 and 0.31 Hz) or (3) high pairing (0.15 and 0.465 Hz) frequencies, (4) 5 degree medial-lateral rotational oscillations of virtual trees at a low frequency pairing (0.1 and 0.31 Hz), and (5) a combination of the tree and scene movements in (3) and (4). RESULTS: We found that both PwMS and controls exhibited greater instability and visuomotor entrainment to simulated mediolateral translation of the visual field (scene) during treadmill walking. This was demonstrated by significant (p < 0.05) increases in mean step width and variability and center of mass sway. Visuomotor entrainment was demonstrated by high coherence between center of mass sway and visual motion (magnitude square coherence = ~ 0.5 to 0.8). Only PwMS exhibited significantly greater instability (higher step width variability and center of mass sway) when objects moved within the scene (i.e., swaying trees). CONCLUSION: Results suggest the presence of visual motion processing errors in PwMS that reduced dynamic stability. Specifically, object motion (via tree sway) was not effectively parsed from the observer's self-motion. Identifying this distinction between visual object motion and self-motion detection in MS provides insight regarding stability control in environments with excessive external movement, such as those encountered in daily life.

Alopecia in Multiple Sclerosis Patients Treated with Disease Modifying Therapies.

BACKGROUND: There is currently limited literature addressing the reporting of alopecia in multiple sclerosis (MS) patients treated with disease-modifying therapies (DMTs). Anecdotal reports of hair thinning from patients on various DMTs prompted further investigation of a large database. OBJECTIVE: To analyze total reports, source of reporting, age distribution, and sex distribution of alopecia associated with DMTs. METHODS: FDA Adverse Event Reporting System (FAERS) public dashboard and OpenFDA database were analyzed for alopecia reports between January 1, 2009, and June 30, 2020, attributed to usage in MS of FDA approved DMTs. The main outcomes included total reports for each drug, age, sex distribution, and reporting source. OpenFDA data was used for statistical analyses including reporting odds ratios (ROR) and information components. RESULTS: 8759 alopecia reports were identified among 44 114 adverse events in skin and subcutaneous tissue disorders (19.9%). 3701 (42.3%) with teriflunomide, 1675 (19.1%) with dimethyl fumarate, 985 (11.2%) with natalizumab, 926 (10.6%) with fingolimod, 659 (7.5%) with interferon beta-1a, 257 (2.9%) with glatiramer acetate, 243 (2.8%) with ocrelizumab, 124 (1.4%) with interferon beta-1b, 117 (1.3%) with alemtuzumab, 36 (.4%) with siponimod, 24 (.3%) with cladribine, and 12 (.1%) with rituximab. Reports were mostly made by patients (78.3%) and highest in fifth and sixth decades of life. OpenFDA analyses showed increased ROR (ROR 95% confidence interval) of alopecia in females with teriflunomide (18.00, 17.12-18.93), alemtuzumab (1.43, 1.16-1.76), dimethyl fumarate (1.26, 1.18-1.34), and ocrelizumab (1.28, 1.11-1.49). Increased ROR in males was associated with teriflunomide (24.65, 20.72-29.31). CONCLUSION: We identified many reports of alopecia for DMTs in addition to teriflunomide. Within the limitations of the database, increased RORs of alopecia were observed for females treated with alemtuzumab, dimethyl fumarate, and ocrelizumab. The source of reporting was largely driven by female patients. Possible alopecia, even if transient, should be considered during patient education when starting DMTs.

Disproportional increase in psoriasis reports in association with B cell depleting therapies in patients with multiple sclerosis.

BACKGROUND: Some pathways involved in the pathogenesis of psoriasis share similarities with processes involved in multiple sclerosis (MS) pathogenesis. However, the association between MS and psoriasis is poorly understood. Since disease-modifying therapies for MS have various targets, it may be possible that the occurrence of psoriasis varies by drug. OBJECTIVE: To analyze the frequency of psoriasis reports in patients treated with various disease-modifying therapies for MS. METHODS: Data was collected using the FDA Adverse Event Reporting System (FAERS) and OpenFDA database between January 2009 and June 2020. The study analyzed total reports of psoriasis out of total reports in the "Skin and Subcutaneous Tissue Disorders" category for each drug and explored age, sex distribution, and report source. OpenFDA data was used to perform statistical analyses including reporting odds ratios (ROR) and information components. RESULTS: The study identified 517 psoriasis reports of 45,547 total skin and subcutaneous tissue disorders (1.13%) in FAERS. The highest proportions of reports in this study were associated with rituximab, ocrelizumab, and interferon beta 1a. The lowest proportion of reports were associated with glatiramer acetate, alemtuzumab, dimethyl fumarate and teriflunomide. Reports of other autoimmune skin disorders were minimal (29 vitiligo, 33 pemphigoid, and 7 pemphigus). Patients primarily drove reports for most DMTs versus healthcare providers. The proportion of reports from female patients were the highest for each DMT except alemtuzumab. OpenFDA query retrieved 302 total reports of psoriasis. Significantly increased reporting odds ratios (RORs, 95% confidence interval) of psoriasis were noted for rituximab (7.14, 3.92-13.00), ocrelizumab (3.79, 2.74-5.23), and fingolimod (1.33, 1.01-1.76). Significantly decreased RORs were noted for natalizumab (0.53, 0.36-0.80), glatiramer acetate (0.58, 0.35-0.96), and dimethyl fumarate (0.71, 0.53-0.94). CONCLUSION: There are frequent reports of psoriasis in MS patients treated with various DMTs. However, reports and RORs were disproportionally high in association with B cell depleting therapies. Further research is required to determine if certain DMTs may serve as better options for individuals affected by, or at high-risk for developing psoriasis.

A Targeted Literature Search and Phenomenological Review of Perspectives of People with Multiple Sclerosis and Healthcare Professionals of the Immunology of Disease-Modifying Therapies.

INTRODUCTION: The mechanisms of action of disease-modifying therapies (DMTs) for multiple sclerosis (MS) are complex and involve an interplay of immune system components. People with MS (PwMS) may lack a clear understanding of the immunological pathways involved in MS and its treatment; effective communication between healthcare professionals (HCPs) and PwMS is needed to facilitate shared decision-making when discussing the disease and selecting DMTs and is particularly important in the coronavirus disease 2019 (COVID-19) era. METHODS: In this patient-authored two-part review, we performed a targeted literature search to assess the need for better communication between HCPs and PwMS regarding treatment selection, and also conducted a qualitative survey of four patient and care-partner authors to obtain insights regarding their understanding of and preferences for the treatment and management of MS. RESULTS: Following a search of the Embase and MEDLINE databases using Ovid in June 2020, an analysis of 40 journal articles and conference abstracts relating to patient empowerment and decision-making in DMT selection for MS showed a preference for safety and efficacy of treatments, followed by autonomy and convenience of administration. A need for better communication between HCPs and PwMS during treatment selection to improve patient satisfaction was also identified. The open survey responses from the patient authors revealed a need for greater involvement in decision-making processes and desire for improved communication and information tools. CONCLUSIONS: This targeted literature search and phenomenological review confirms PwMS preferences for empowered decision-making in disease management and treatment selection, to optimize independence, safety, and efficacy. It also identifies an unmet need for improved communication and information tools that convey MS information in a relatable manner. Furthermore, this review seeks to address this unmet need by providing plain language figures and descriptions of MS immune mechanisms that can be used to facilitate discussions between HCPs and PwMS.

In multiple sclerosis (MS), there are different cells in the immune system that contribute to the disease. The main cells in the immune system are T and B cells. People with MS (PwMS) might not be familiar with details about the immune system, and healthcare professionals might not always communicate details about how treatments work clearly to PwMS when choosing treatments with them. It is important for PwMS to have all the information they need to help make decisions about treatments. This information needs to be given in a way they can understand. This is especially important during the coronavirus disease 2019 (COVID-19) pandemic. In this paper, we first looked at what research has already been published about what is most important to PwMS when making treatment decisions. The existing research says that safety and effectiveness are the most important things and that PwMS prefer treatments that they can take themselves. PwMS also need better communication and information from doctors to make decisions and to help explain how MS treatments work in the body. Next, we gave a survey to the patients who are authors of this paper to ask about what is important to them when making treatment decisions. Their answers were very similar to the existing research. Overall, PwMS need better communication from healthcare professionals about the immune system. This paper also includes plain language descriptions and figures to help healthcare professionals explain and discuss the importance of the immune system in MS with PwMS.

Curriculum Innovations: Virtual Didactics as a Tool for Harmonizing Education About Rare Topics in Neuroimmunology.

Introduction and Problem Statement: Neuroimmunology is a rapidly evolving subspecialty. At this time, fellowship training is not standardized. Discrepancies exist in fellowship programs across the United States, including in faculty expertise in rarer neuroimmunologic conditions. Many graduating fellows feel uncomfortable managing the full spectrum of diseases within neuroimmunology. Objectives: To evaluate the feasibility and efficacy of a series of live, virtual, interinstitutional seminars educating neuroimmunology fellows on topics that may be infrequently encountered by trainees. Methods and Curriculum Description: A steering committee of 6 neuroimmunology and multiple sclerosis fellowship program directors selected 18 topics felt to be high yield but representing unique areas of expertise. A live, interactive seminar series was organized. Recognized experts on each topic led seminars using a teleconferencing platform over the 2020-2021 academic year. Recordings were subsequently made available for asynchronous learning. Trainees were surveyed before and after the seminar series and comfort levels with each topic were recorded. Results and Assessment Data: An average of 41 trainees participated in each live seminar and an additional average of 17 trainees viewed each seminar on demand. Trainee comfort levels with each topic increased after the seminar series was completed. An average of 72% of trainees self-identified as at least "comfortable" with each topic after the series compared with 26% beforehand (p < 0.0001). Discussion and Lessons Learned: A year-long series of live, interactive, interinstitutional seminars focusing on unique topics within a single subspecialty represents an effective way to increase trainee comfort levels with such topics.

Consensus Curriculum for Fellowship Training in Multiple Sclerosis and Neuroimmunology.

Management of multiple sclerosis and neuroimmunologic disorders has become increasingly complex because of the expanding number of recognized neuroimmune disorders, increased number of therapeutic options, and multidisciplinary care management needs of people with multiple sclerosis and neuroimmunologic disorders. More subspecialists are needed to optimize care of these patients, and many fellowship programs have been created or expanded to increase the subspecialty workforce. Consequently, defining the scope and standardizing fellowship training is essential to ensure that trainees receive high-quality training. A workgroup was created to develop a consensus fellowship curriculum to serve as a resource for all current and future training programs. This curriculum may also serve as a basis for future accreditation efforts.

"Peppering the pons": CLIPPERS or myelin oligodendrocyte glycoprotein associated disease?

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a distinct pathologic entity of unknown etiology. Here, we describe the clinical and radiologic presentation of myelin oligodendrocyte glycoprotein associated disease (MOG-AD) with features mimicking CLIPPERS. Three patients met the 2017 CLIPPERS diagnostic criteria, while one patient had a single lesion in the pons that mimicked CLIPPERS lesions. All had an excellent response to steroids, but the three who met the CLIPPERS criteria had a relapsing course. When CLIPPERS is observed, it is crucial to test for mimickers. The ever-expanding spectrum of MOG-AD calls for further research into the immunopathogenesis of its several phenotypes.

A national telemedicine program in the Kingdom of Jordan - Editorial.

The coronavirus disease 2019 (COVID19) is on the rise in the Kingdom of Jordan. The healthcare system is under pressure to handle the increasing numbers of COVID19 cases while providing routine and emergent care to the population. Telemedicine represents an opportunity to utilize during the pandemic. The feasibility of telemedicine in Jordan has been established in a few small projects over the past two decades. Here, we present a timely proposal for a national telemedicine program to be designed and deployed during the pandemic and sustain after the pandemic. Further, we identify the stakeholders and the steps to design and implement the program.

Serum vitamin d inversely correlates with depression scores in people with multiple sclerosis.

BACKGROUND: Vitamin D (Vit.D) deficiency is a risk factor for multiple sclerosis (MS) and correlates with its severity. Depression is also common in people with MS (PWMS). We aim to investigate Vit.D correlation with depression risk scores in PWMS. METHODS: A cross-sectional cohort of PWMS were studied. Clinical and demographic data were collected. The Hospital Anxiety Depression Scale (HADS) and the Beck Depression Inventory-II (BDI-II) were used to evaluate the risk of depression. Expanded Disability Status Scale (EDSS) and Patient Determined Disease Steps (PDDS) were used to evaluate the disability. Serum concentrations of 25-hydroxyvitamin D were measured. Bivariate and partial correlations of Vit.D status and scores of depressive and disability scales were statistically analyzed. The IBM Statistical Package for Social Sciences software, version 25.0, was used for data processing. RESULTS: A total of 88 PWMS were enrolled. More than half of them had potential depression, and 68% had below-normal serum Vit.D levels (normal ≥ 30 ng/ml, insufficient = 21-29 ng/ml, and deficient ≤ 20 ng/ml). Serum Vit.D levels significantly correlated with scores of depression scales in both males and females, which was more robust in males. This association was maintained with a partial correlation analysis controlling for age, sex, body mass index, disease duration, type of MS, and EDDS HADS: r=-0.513, p<0.001; BDI-II: r=-0.401, p<0.001). Serum Vit.D had significant inverse correlations with EDSS score (r=-0.353, p = 0.001) and PDDS score (r=-0.341, p = 0.001), with more robust correlations in females compared to the whole group. CONCLUSION: Vit.D levels correlate with depression risk scores in PWMS with differential sex effects.