Immune-mediated colitis associated with ocrelizumab: A new safety risk.

BACKGROUND: An association between certain immunomodulatory therapies (rituximab, ipilimumab, and other immune checkpoint inhibitors) and inflammatory (non-ischemic and non-infectious) colitis in oncologic and non-oncologic patient populations is well documented in the medical literature. OBJECTIVE: The purpose of this case series is to describe adverse event reports of new onset, inflammatory colitis in association with ocrelizumab in patients with multiple sclerosis submitted to U.S. Food and Drug Administration (FDA) or published in the medical literature. METHODS: The FDA Adverse Event Reporting System (FAERS) and medical literature were searched. RESULTS: A review of postmarketing cases from FAERS and published medical literature identified 38 cases consistent with inflammatory, non-ischemic, and non-infectious colitis in association with ocrelizumab. The median time-to-onset was 8 months. Cases were reported using the following diagnostic terms: Crohn's disease (13), unspecified colitis (11), microscopic colitis (5), ulcerative colitis (5), medication-induced colitis (3), and autoimmune colitis (2). CONCLUSIONS: This case series highlights ocrelizumab induced immune-mediated colitis that can be clinically severe and potentially life-threatening. Based on the findings of this review, the ocrelizumab Prescribing Information was amended to include immune-mediated colitis in the Warnings and Precautions section.

The neuroradiology of progressive multifocal leukoencephalopathy: a clinical trial perspective.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS caused by the JC virus, which infects white and grey matter cells and leads to irreversible demyelination and neuroaxonal damage. Brain MRI, in addition to the clinical presentation and demonstration of JC virus DNA either in the CSF or by histopathology, is an important tool in the detection of PML. In clinical practice, standard MRI pulse sequences are utilized for screening, diagnosis and monitoring of PML, but validated imaging-based outcome measures for use in prospective, interventional clinical trials for PML have yet to be established. We review the existing literature regarding the use of MRI and PET in PML and discuss the implications of PML histopathology for neuroradiology. MRI not only demonstrates the localization and extent of PML lesions, but also mirrors the tissue destruction, ongoing viral spread, and resulting inflammation. Finally, we explore the potential for imaging measures to serve as an outcome in PML clinical trials and provide recommendations for current and future imaging outcome measure development in this area.

Autologous Hematopoietic Cell Transplantation for Treatment-Refractory Relapsing Multiple Sclerosis: Position Statement from the American Society for Blood and Marrow Transplantation.

Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, demyelinating and degenerative disease of the central nervous system. Approved disease-modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. The use of immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. A review of recent literature identified 8 retrospective studies, 8 clinical trials, and 3 meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapse, magnetic resonance imaging-detectable lesion activity, and worsening disability and to reverse disability without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a "standard of care, clinical evidence available" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplantation physicians with experience performing AHCT for autoimmune disease is crucial for ensuring appropriate patient selection and optimizing transplantation procedures to improve patient outcomes. Transplantation centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.

Streamlined EDSS for use in multiple sclerosis clinical practice: Development and cross-sectional comparison to EDSS.

BACKGROUND: The Expanded Disability Status Scale (EDSS) is the standard measure of disability in multiple sclerosis clinical trials. The EDSS has limited application in the clinical setting due to required completion time and scoring complexity. Systematically recording an objective, simplified, less time-intensive, and neurologist-derived disability score would be beneficial for patient care. OBJECTIVE: To develop and validate a streamlined version of the Expanded Disability Status Scale (sEDSS) for clinical monitoring. METHODS: The EDSS was modified by eliminating maneuvers with no impact on function, consolidating redundancies, and simplifying scoring. This sEDSS was refined and preliminarily validated using a pilot cohort of 102 patients. Subsequently, the sEDSS was retrospectively validated using 968 patients from the CombiRx trial. We evaluated correlation and agreement between each functional system as well as the overall sEDSS and EDSS. RESULTS: The sEDSS correlated strongly with the EDSS, both overall (Spearman's rho = 0.93) and for each functional system (Spearman's rho 0.65-0.97). Correlation was slightly lower for functional systems where scoring was modified for consolidation and simplification. CONCLUSION: The sEDSS had strong agreement and correlation with the existing EDSS and can provide a useful measure of disability in clinical practice.

Predicting abdominal closure after component separation for complex ventral hernias: maximizing the use of preoperative computed tomography.

BACKGROUND: Component separation techniques (CSTs) have allowed for midline fascial reapproximation in large midline ventral hernias. In certain cases, however, fascial apposition is not feasible, resulting in a bridged repair that is suboptimal. Previous estimates on myofascial advancement are based on hernia location and do not take into account variability between patients. Examination of preoperative computed tomography (CT) may provide insight into these variabilities and may allow for prediction of abdominal closure with CST. STUDY DESIGN: A retrospective review was conducted of patients who underwent abdominal wall reconstruction from 2007 to 2012 with CST. Preoperative CT was obtained, and specific parameters were analyzed using image analysis software. Logistic regression was used to predict ideal operative closure. Multivariate analyses were adjusted for age and sex. An a priori value was set at P < 0.05. RESULTS: Fifty-four patients met the criteria and had preoperative CT available for analysis. Forty-eight patients had fascial reapproximation achieved, whereas 6 patients had a bridged repair. Age, sex, weight, and body mass index were similar between groups (P > 0.05). Significant differences were seen between groups in 3 variables: transverse defect size (19.8 vs 10 cm, P < 0.05), defect area (420 vs 184.2 cm, P < 0.05), and percent abdominal wall defect (18.9% vs 10.6%, P < 0.05). CONCLUSIONS: Preoperative determination of abdominal wall defect ratios and hernia defect areas may represent a more accurate method to predict abdominal wall closure after CST. Predicting midline approximation after CST is critical because outcomes after bridged repair can result in higher recurrence rates.

Added sampling improves reproducibility of multipoint motor unit estimates.

Motor unit number estimation (MUNE) has been used to track motor unit attrition. Studies have used the modified multiple-point stimulation (MPS) technique, collecting three surface motor unit action potentials (sMUAPs) from 3 sites to calculate MUNE. Factoring additional sMUAPs should theoretically improve reproducibility, but the optimal number has not been defined. We evaluated the effect of increased sMUAP sampling on test-retest reproducibility of the modified MPS MUNE technique and found that MUNE reproducibility increased with additional sampling. Muscle Nerve, 2010.

Validation of an incremental motor unit number estimation technique in rabbits.

Motor unit number estimation (MUNE) allows for quantitative assessment of functional motor units in a nerve. Several techniques have been applied to human studies. Although MUNE has been performed in animals to study neurological disorders, reproducibility has not been addressed. We analyzed the test-retest reproducibility of an incremental MUNE technique in rabbits and performed histological correlation. A peroneal MUNE was performed in 9 rabbits on two occasions separated by 30 days. MUNE was then performed on 18 rabbits prior to euthanize. A count of total fibers and a second count of large myelinated fibers were performed on nerve cross-sections. Test-retest reproducibility revealed an intraclass correlation coefficient (ICC) of 0.75. The average test-retest relative difference was 26.6%. Comparison of MUNE and histomorphometrical counts revealed a correlation coefficient (r) of 0.21 (total fiber counts) and 0.27 (large fibers). Although incremental MUNE has a high degree of reproducibility in rabbits, there is poor correlation with histological fiber counts.

Technology-enabled comprehensive characterization of multiple sclerosis in clinical practice.

BACKGROUND: Objective and longitudinal measurements of disability in patients with multiple sclerosis (MS) are desired in order to monitor disease status and response to disease-modifying and symptomatic therapies. Technology-enabled comprehensive assessment of MS patients, including neuroperformance tests (NPTs), patient-reported outcome measures (PROMs), and MRI, is incorporated into clinical care at our center. The relationships of each NPT with PROMs and MRI measures in a real-world setting are incompletely studied, particularly in larger datasets. OBJECTIVES: To demonstrate the utility of comprehensive neurological assessment and determine the association between NPTs, PROMs, and quantitative MRI measures in a large MS clinical cohort. METHODS: NPTs (processing speed [PST], contrast sensitivity [CST], manual dexterity [MDT], and walking speed [WST]) and physical disability-related PROMs (Quality of Life in Neurological Disorders [Neuro-QoL], Patient Determined Disease Steps [PDDS], and Patient-Reported Outcomes Measurement Information System Global-10 [PROMIS-10] physical) were collected as part of routine clinical care. Fully-automated MRI analysis calculated T2-lesion volume (T2LV), whole brain fraction (WBF), thalamic volume (TV), and cervical spinal cord cross-sectional area (CA) for brain MRIs completed within 3 months of a clinic visit during which NPTs and PROMs were assessed. Spearman's rank correlation coefficients evaluated the cross-sectional associations of NPTs with PROMs and MRI measures. Linear regression was utilized to determine which combination of clinical characteristics, patient demographics, MRI measures, and PROMs best cross-sectionally explained each NPT result. RESULTS: 997 unique patients (age 47.7 ±â€¯11.4 years, 71.8% female) who underwent assessments over a 2-year period were included. Correlations among NPTs and PROMs were moderate. PST correlations were strongest for Neuro-QoL upper extremity (NQ-UE) (Spearman's rho = 0.43) and lower extremity (NQ-LE) (0.47). CST correlations were strongest for NQ-UE (0.33), NQ-LE (0.36), and PDDS (-0.31). MDT correlations were strongest for NQ-UE (-0.53), NQ-LE (-0.54), and PDDS (0.53). WST correlations were strongest for PDDS (0.64) and NQ-LE (-0.65). NPTs also had moderate correlations with MRI metrics, the strongest of which were observed with PST (with T2LV (-0.44) and WBF (0.49)). Spearman's rho for other NPT-MRI correlations ranged from 0.23 to 0.36. Linear regression identified age, disease duration, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV and WBF as significant cross-sectional explanatory variables for PST (adjusted R2=0.46). For CST, significant variables included age and NQ-LE (adjusted R2 = 0.30). For MDT, significant variables included PDDS, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV, and WBF (adjusted R2=0.37). For WST, significant variables included sex, PDDS, NQ-LE, T2LV, and CA (adjusted R2=0.39). CONCLUSIONS: Impaired performance on NPTs correlated with worse physical disability-related PROMs and MRI disease severity, but the strongest cross-sectional explanatory variables for each NPT component varied. This study supports the use of comprehensive, objective quantification of MS status in clinical and research settings. Future longitudinal analyses can determine predictors of treatment response and disability worsening.

Technology-enabled assessments to enhance multiple sclerosis clinical care and research.

BACKGROUND: Comprehensive and efficient assessments are necessary for clinical care and research in chronic diseases. Our objective was to assess the implementation of a technology-enabled tool in MS practice. METHOD: We analyzed prospectively collected longitudinal data from routine multiple sclerosis (MS) visits between September 2015 and May 2018. The MS Performance Test, comprising patient-reported outcome measures (PROMs) and neuroperformance tests (NPTs) self-administered using a tablet, was integrated into routine care. Descriptive statistics, Spearman correlations, and linear mixed-effect models were used to examine the implementation process and relationship between patient characteristics and completion of assessments. RESULTS: A total of 8022 follow-up visits from 4199 patients (median age 49.9 [40.2-58.8] years, 32.1% progressive course, and median disease duration 13.6 [5.9-22.3] years) were analyzed. By the end of integration, the tablet version of the Timed 25-Foot Walk was obtained in 89.0% of patients and the 9-Hole Peg Test in 94.8% compared with 74.2% and 64.3%, respectively before implementation. The greatest increase in data capture occurred in processing speed and low-contrast acuity assessments (0% prior vs 78.4% and 36.7%, respectively, following implementation). Four PROMs were administered in 41%-98% of patients compared with a single depression questionnaire with a previous capture rate of 70.6%. Completion rates and time required to complete each NPT improved with subsequent visits. Younger age and lower disability scores were associated with shorter completion time and higher completion rates. CONCLUSIONS: Integration of technology-enabled data capture in routine clinical practice allows acquisition of comprehensive standardized data for use in patient care and clinical research.

Tuberculosis screening in multiple sclerosis: effect of disease-modifying therapies and lymphopenia on the prevalence of indeterminate TB screening results in the clinical setting.

BACKGROUND: Tuberculosis screening is recommended in multiple sclerosis patients starting certain disease-modifying therapies. Disease-modifying therapies may affect interferon-gamma release assay results. OBJECTIVE: To determine the effects of multiple sclerosis disease-modifying therapies on interferon-gamma release assay results. METHODS: Indeterminate interferon-gamma release assay results among multiple sclerosis patients were compared across disease-modifying therapies by Fisher's exact test. Logistic regression evaluated the effects of lymphopenia on interferon-gamma release assay results. RESULTS: A total of 1058 patients underwent interferon-gamma release assay: 2.0% (21) positive, 6.1% (65) indeterminate, with 59.4% (628) on disease-modifying therapies. Results were significantly different across disease-modifying therapies (P = 0.002). Absolute lymphocyte count less than 0.5 k/µL had 9.39 times (95% confidence interval 5.2-17.0) increased odds of indeterminate interferon-gamma release assay results. CONCLUSIONS: Disease-modifying therapies affecting lymphocytes had a higher risk of indeterminate interferon-gamma release assay results.

Serum neurofilament light chain concentration in a phase 1/2 trial of autologous mesenchymal stem cell transplantation.

BACKGROUND: Serum neurofilament light chain concentration is a proposed biomarker of axonal injury in multiple sclerosis. Mesenchymal stem cells have anti-inflammatory and repair-promoting activities, making them of interest for potential multiple sclerosis treatment. OBJECTIVES: The purpose of this study was to assess correlation of serum neurofilament light chain concentration and measures of multiple sclerosis disease activity/severity, longitudinal stability of serum neurofilament light chain concentration, and treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration. METHODS: Twenty-four multiple sclerosis patients underwent intravenous infusion of autologous mesenchymal stem cells. Clinical assessments, serum collection, and brain magnetic resonance imaging were performed at months -1, 0 (transplant), 1, 3, and 6. Matched control serum was collected once (n = 10). Serum neurofilament light chain concentration was measured by single-molecule array. Serum neurofilament light chain concentration correlations with disease measures were analyzed by Spearman correlations and linear mixed effect models. Pre-post transplant serum neurofilament light chain concentration was compared by Wilcoxon signed rank testing. RESULTS: There were significant (p<0.01) correlations between serum neurofilament light chain concentration and gadolinium-enhancing lesion number (rho = 0.55) and volume (rho = 0.65), and new/enlarging T2 lesions (rho = 0.65). Patients without disease activity had lower fluctuation in serum neurofilament light chain concentration (p = 0.01). Mean pre- versus post-treatment serum neurofilament light chain concentration values were not significantly different. CONCLUSIONS: Serum neurofilament light chain concentration correlated with magnetic resonance imaging measures of disease activity cross sectionally and longitudinally, and was stable in patients without disease activity. There was no clear treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration.

Developing therapeutic strategies to promote myelin repair in multiple sclerosis.

Introduction: Approved disease-modifying therapies for multiple sclerosis (MS) lessen inflammatory disease activity that causes relapses and MRI lesions. However, chronic inflammation and demyelination lead to axonal degeneration and neuronal loss, for which there currently is no effective treatment. There has been increasing interest in developing repair-promoting strategies, but there are important unanswered questions regarding the mechanisms and appropriate methods to evaluate these treatments. Areas covered: The rationale for remyelinating agents in MS is discussed, with an overview of both myelin physiology and endogenous repair mechanisms. This is followed by a discussion of the identification and development of potential remyelinating drugs. Potential biomarkers of remyelination are reviewed, including considerations regarding measuring remyelination in clinical trials. Information and data were obtained from a search of recent literature through PubMed. Peer-reviewed original articles and review articles were included. Expert opinion: There are several obstacles to the translation of potential remyelinating agents to clinical trials, particularly uncertainty regarding the most appropriate study population and method to monitor remyelination. Refinements in clinical trial design and outcome measurement, potentially via advanced imaging techniques, are needed to optimize detection of repair in patients with MS.

Therapeutic Advances and Challenges in the Treatment of Progressive Multiple Sclerosis.

Despite the fact that majority of patients with multiple sclerosis (MS) have relapsing-remitting disease, many transition to secondary progressive disease (SPMS) over time. This transition is thought to be related to neurodegenerative processes increasingly predominating over inflammatory processes as the driving forces of disability. However, some patients initially present with primary progressive disease (PPMS) that is characterized by a gradual accumulation of neurological symptoms and subsequent disability accumulation. The treatment of both PPMS and SPMS, collectively referred to as progressive MS, has proven quite challenging due to the multifactorial and poorly understood pathophysiology of multiple sclerosis in general, specifically that of progressive disease. The purpose of this article is to discuss important clinical and pathophysiologic differences between relapsing and progressive forms of MS, review previous notable trials of drugs in progressive MS, examine current literature regarding recent and promising progressive MS treatments, and discuss future considerations for progressive MS therapeutics and management. Specifically, the current evidence regarding treatment of progressive MS with ocrelizumab, simvastatin, ibudilast, alpha-lipoic acid, high-dose biotin, siponimod, and cell-based therapies are discussed.

Daclizumab: Development, Clinical Trials, and Practical Aspects of Use in Multiple Sclerosis.

Daclizumab is a humanized monoclonal antibody directed towards CD25, the alpha subunit of the high-affinity interleukin (IL)-2 receptor. Daclizumab exerts its effects via multiple mechanisms, including reduction of IL-2-mediated lymphocyte activation and upregulation of CD56-bright natural killer cells. Intravenous daclizumab (Zenapax™) was initially approved for prevention of rejection in renal transplant. In subsequent early testing, followed by larger-scale phase II and phase III trials, both intravenous and subcutaneous daclizumab have demonstrated clinical efficacy in the treatment of multiple sclerosis. The subcutaneous daclizumab prepared by high-yield process was utilized in the advanced phase II and phase III trials (SELECT and DECIDE). High-yield process daclizumab is now approved by the US Food and Drug Administration for relapsing-remitting multiple sclerosis, and is now formally termed daclizumab beta (DAC-beta; Zinbryta™). In this review, the early development of anti-IL-2 receptor alpha monoclonal antibodies and the properties of IL-2 and its receptor are discussed, and diverse mechanisms of action for daclizumab are presented. Results of the CHOICE, SELECT, and DECIDE clinical trials are discussed in detail. Adverse events observed in clinical trials included cutaneous reactions, liver enzyme elevations, infections, and autoimmune phenomena. DAC-beta is a monthly, patient-administered subcutaneous injection that requires enrollment in a safety monitoring (REMS) program for monthly liver function testing. Prescribers should be aware of the potential adverse events, as early recognition and management is important, particularly in cutaneous and hepatic reactions. Continued clinical experience with DAC-beta, including observations from the REMS program, will define its place in the armamentarium of immunotherapeutics for relapsing-remitting multiple sclerosis.

A 9-loci Y chromosome haplotype in three Italian populations.

Three geographic areas of Italy have been sampled and genotyped for 9 Y chromosome STRs: DYS19, DYS385, DYS388, DYS389 I and II, DYS390, DYS391, DYS392, DYS393. Sampling was focused on residents of small areas, well distant from major urban centres. Only individuals whose grandfather would live in the same area were included. A total of 210 unrelated individuals were collected. Distribution of genetic variation across the three samples and comparison with previously published Italian database indicated that so far Y chromosome diversity has been only partially explored in the Italian Peninsula.

A case-control study of wicket spikes using video-EEG monitoring.

PURPOSE: To investigate clinical characteristics associated with wicket spikes in patients undergoing long-term video-EEG monitoring. METHODS: A case-control study was performed in 479 patients undergoing video-EEG monitoring, with 3 age- (±3 years) and gender-matched controls per patient with wicket spikes. Logistic regression was utilized to investigate the association between wicket spikes and other factors, including conditions that have been previously associated with wicket spikes. RESULTS: Wicket spikes were recorded in 48 patients. There was a significantly higher prevalence of dizziness/vertigo (p=0.002), headaches (p=0.005), migraine (p=0.015), and seizures (p=0.016) in patients with wickets. The majority of patients with wicket spikes did not exhibit epileptiform activity on EEG; however, patients with history of seizures were more likely to have wickets (p=0.017). There was no significant difference in the prevalence of psychogenic non-epileptic seizures between the groups. Wickets were more common on the left, during sleep, and more likely to be first recorded on day 1-2 of monitoring. CONCLUSIONS: Patients with wicket spikes are more likely to have dizziness/vertigo, headaches, migraine, and seizures. Patients with history of seizures are more likely to have wickets. The prevalence of psychogenic non-epileptic seizures is not significantly higher in patients with wickets.