Immune-Mediated Neurological Disorders.

Autoimmune disorders are increasingly recognized causes of several neurological disorders leading to significant clinical disability. This article reviews recent developments in our understanding on the pathophysiology, clinical presentations, and diagnoses of selected immune-mediated neurological disorders. It also provides a brief summary of current theories on autoimmunity and the role that certain environmental factors play in the development of immune-mediated neurological disorders. Recently recognized biomarkers might play a pathogenetic role or simply serve as a diagnostic tool.

Non-invasive brain stimulation to assess neurophysiologic underpinnings of lower limb motor impairment in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory disease resulting in axonal demyelination and an amalgamation of symptoms which commonly result in decreased quality of life due to mobility dysfunction and limited participation in meaningful activities. NEW METHOD: The use of non-invasive brain stimulation (NIBS) techniques, specifically transcranial magnetic and transcranial direct current stimulation, have been essential in understanding the pathophysiological decrements related to disease progression, particularly with regard to motor impairments. Although the research in this area has primarily focused on the upper extremities, new interest has arisen in understanding the neurophysiological underpinnings of lower limb impairment. Therefore, the purpose of this review is to: first, provide an overview of common NIBS techniques used to explore sensorimotor neurophysiology; second, summarize lower limb neuromuscular and mobility impairments typically observed in PwMS; third, review the current knowledge regarding interactions between TMS-assessed neurophysiology and lower limb impairments in PwMS; and fourth, provide recommendations for future NIBS studies based on current gaps in the literature. RESULTS: PwMS exhibit reduced excitability and increased inhibitory neurophysiologic function which has been related to disease severity and lower limb motor impairments. Comparison with existing methods: Moreover, promising results indicate that the use of repetitive stimulation and transcranial direct current stimulation may prime neural adaptability and prove useful as a therapeutic tool in ameliorating lower limb impairments. CONCLUSIONS: While these studies are both informative and promising, additional studies are necessary to be conclusive. As such, studies assessing objective measures of lower limb impairments associated with neurophysiological adaptations need further evaluation.

Brain atrophy rates in patients with multiple sclerosis on long term natalizumab resembles healthy controls.

BACKGROUND: Clinically stable multiple sclerosis (MS) patients often have negligible inflammatory MRI changes. Brain atrophy may provide insight into subclinical disease progression. The objective was to compare brain atrophy rates in stable patients on long term natalizumab treatment vs. age and gender matched healthy non-MS controls (HC) prospectively over two-years examining brain volume, cognition, and patient reported outcomes (PROs). METHODS: MS patients treated with natalizumab for a minimum of 2 years, age 18-60 were recruited and compared with age- and gender-matched healthy controls (HC). Both groups were followed prospectively to obtain two years of consecutive magnetic resonance imaging, clinical and PRO data. Baseline normalized brain volume (NBV), yearly T2 lesion volume (T2LV), and percent brain volume change (PBVC) were measured using SIENAX, JIM 6.0, and SIENA respectively. Neuropsychological tests from the MACFIMS battery were selected to optimize assessments for impairments in the domains of information processing speed and memory. Patient reported outcomes (PROs) for domains of physical, mental and social quality of life were evaluated using the NeuroQol short forms. RESULTS: Forty-eight natalizumab and 62 HC completed all study visits. At baseline, unadjusted mean NBV (natalizumab=1508.80cm (Popescu et al., 2013) vs. HC=1539.23cm (Popescu et al., 2013); p=0.033) and median baseline T2LV (natalizumab=1724.62mm (Popescu et al., 2013) vs. HC=44.20mm (Popescu et al., 2013); p=<0.0001) were different. The mean PBVC at year 2, adjusted for gender and baseline age was -0.57% (CI: 0.7620, -0.3716) for natalizumab and -0.50% (-0.7208, -0.2831) for HC, but the difference between groups was not statistically significant (0.073%; p=0.62). Over the 2-year period, HC demonstrated mild improvements in some cognitive tests vs. natalizumab subjects. However, PROs were similar between the two groups. CONCLUSION: Stable MS patients on natalizumab have similar brain volume loss as people who do not have MS, suggesting normalization of brain atrophy.

CLICK-MS and MASTER-2 Phase IV trial design: cladribine tablets in suboptimally controlled relapsing multiple sclerosis.

Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) are approved for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS and active secondary progressive MS. However, real-world data on cladribine tablets are limited. CLICK-MS and MASTER-2 are single arm, observational, 30-month, Phase IV studies in the US evaluating the effectiveness and safety of cladribine tablets 3.5 mg/kg in patients with relapsing-remitting MS or active secondary progressive MS who had suboptimal response to prior injectable (CLICK-MS), or infusion/oral (MASTER-2) disease-modifying therapy. The primary end point is 24-month annualized relapse rate. Key secondary end points include patient-reported outcomes on quality of life measures, treatment adherence and adverse events. Studies began in 2019 and are expected to be completed in 2023. Trial registration number • CLICK-MS: NCT03933215 (ClinicalTrials.gov) Full title; CLadribine tablets: observational evaluation of effectIveness and patient-reported outcomes in suboptimally Controlled patients previously taKing injectable disease-modifying drugs for relapsing forms of Multiple Sclerosis • MASTER-2: NCT03933202 (ClinicalTrials.gov) Full title; Cladribine tablets: observational evaluation of effectiveness and patient-reported outcomes in suboptiMAlly controlled patientS previously Taking oral or infusion disEase-modifying dRugs for relapsing forms of multiple sclerosis.

Anti-JCV antibody index does not change during ocrelizumab-treatment.

OBJECTIVE: To prospectively assess anti-JCV antibody index (AI) and its relationship to immunoglobulin levels in ocrelizumab-treated MS patients. METHODS: Monocentric prospective observational study over 24 months assessing anti-JCV AI and immunoglobulin levels in MS patients before and after initiation of ocrelizumab. RESULTS: No significant change in anti-JCV AI titers was observed 458 ± 300 days after initiation of ocrelizumab (n = 45, 0.7 ± 2.21 vs. 0.6 ± 2.06, p = 0.8). Seroconversion occurred in 1/20 initially anti-JCV seronegative patients. There was no correlation between changes in anti-JCV AI and immunoglobulins. CONCLUSION: Treatment with ocrelizumab is not associated with an increase in anti-JCV AI titers.

Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis.

BACKGROUND: Natalizumab (NTZ) is sometimes discontinued in patients with multiple sclerosis, mainly due to concerns about the risk of progressive multifocal leukoencephalopathy. However, NTZ interruption may result in recrudescence of disease activity. OBJECTIVE: The objective of this study was to summarize the available evidence about NTZ discontinuation and to identify which patients will experience post-NTZ disease reactivation through meta-analysis of existing literature data. METHODS: PubMed was searched for articles reporting the effects of NTZ withdrawal in adult patients (⩾18 years) with relapsing-remitting multiple sclerosis (RRMS). Definition of disease activity following NTZ discontinuation, proportion of patients who experienced post-NTZ disease reactivation, and timing to NTZ discontinuation to disease reactivation were systematically reviewed. A generic inverse variance with random effect was used to calculate the weighted effect of patients' clinical characteristics on the risk of post-NTZ disease reactivation, defined as the occurrence of at least one relapse. RESULTS: The original search identified 205 publications. Thirty-five articles were included in the systematic review. We found a high level of heterogeneity across studies in terms of sample size (10 to 1866 patients), baseline patient characteristics, follow up (1-24 months), outcome measures (clinical and/or radiological), and definition of post-NTZ disease reactivation or rebound. Clinical relapses were observed in 9-80% of patients and peaked at 4-7 months, whereas radiological disease activity was observed in 7-87% of patients starting at 6 weeks following NTZ discontinuation. The meta-analysis of six articles, yielding a total of 1183 patients, revealed that younger age, higher number of relapses and gadolinium-enhanced lesions before treatment start, and fewer NTZ infusions were associated with increased risk for post-NTZ disease reactivation (p ⩽ 0.05). CONCLUSIONS: Results from the present review and meta-analysis can help to profile patients who are at greater risk of post-NTZ disease reactivation. However, potential reporting bias and variability in selected studies should be taken into account when interpreting our data.

Rituximab vs placebo induction prior to glatiramer acetate monotherapy in multiple sclerosis.

OBJECTIVE: To examine whether rituximab induction followed by glatiramer acetate (GA) monotherapy is more effective than GA alone for the treatment of relapsing multiple sclerosis with active disease. METHODS: This was a single-center, double-blind, placebo-controlled study. Fifty-five participants were randomly assigned (1:1 ratio) to either rituximab (R-GA) or placebo (P-GA) induction, followed by GA therapy initiated in all participants. Participants were followed up to 3 years. The primary endpoint was the number of participants with no evidence of disease activity (NEDA): those without relapse, new MRI lesions, and sustained change in disability. RESULTS: Twenty-eight and 27 participants received rituximab and placebo induction, respectively, with one participant in each arm withdrawing before 6-month MRI. There were no significant differences in baseline characteristics. At end of study, 44.44% of R-GA participants demonstrated NEDA vs 19.23% of P-GA participants (p = 0.049). Treatment failed for a smaller proportion of R-GA participants (37.04% R-GA vs 69.23% P-GA, p = 0.019), and time to treatment failure was longer (23.32 months R-GA vs 11.29 months P-GA, p = 0.027). Fewer participants in the R-GA arm had new lesions (25.93% R-GA vs 61.54% P-GA, p = 0.009), and there were fewer new T2 lesions (0.48 R-GA vs 1.96 P-GA, p = 0.027). Probability of demonstrating NEDA in the R-GA arm returned to baseline within the study period. There were no differences in adverse events. CONCLUSIONS: Induction therapy with rituximab followed by GA may provide superior efficacy in the short term than GA alone in relapsing multiple sclerosis, but this benefit appears to wane within the study period. Larger studies are needed to assess sustainability of results. CLINICALTRIALSGOV IDENTIFIER: NCT01569451.

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis.

BACKGROUND: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS: A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

Remyelination Therapy in Multiple Sclerosis.

Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system that results in destruction of the myelin sheath that surrounds axons and eventual neurodegeneration. Current treatments approved for the treatment of relapsing forms of MS target the aberrant immune response and successfully reduce the severity of attacks and frequency of relapses. Therapies are still needed that can repair damage particularly for the treatment of progressive forms of MS for which current therapies are relatively ineffective. Remyelination can restore neuronal function and prevent further neuronal loss and clinical disability. Recent advancements in our understanding of the molecular and cellular mechanisms regulating myelination, as well as the development of high-throughput screens to identify agents that enhance myelination, have lead to the identification of many potential remyelination therapies currently in preclinical and early clinical development. One problem that has plagued the development of treatments to promote remyelination is the difficulty in assessing remyelination in patients with current imaging techniques. Powerful new imaging technologies are making it easier to discern remyelination in patients, which is critical for the assessment of these new therapeutic strategies during clinical trials. This review will summarize what is currently known about remyelination failure in MS, strategies to overcome this failure, new therapeutic treatments in the pipeline for promoting remyelination in MS patients, and new imaging technologies for measuring remyelination in patients.

Encephalitis complicating smallpox vaccination.

A smallpox vaccination program has been initiated. The vaccine is a live virus that was used in the last century. Postvaccinal encephalitis is a complication of this vaccine. The clinical presentation, course, neuroimaging findings, and spinal fluid abnormalities are similar to a disorder that physicians are familiar with, acute disseminated encephalomyelitis. This complication can be prevented with the administration of antivaccinia gamma globulin at the time of vaccination. Antivaccinia gamma globulin is not efficacious once this complication occurs. Intravenous methylprednisolone is the recommended therapy, although intravenous immunoglobulin and plasmapheresis should be investigated in the treatment of postvaccinal encephalitis.

Neurologic complications of vaccinations.

This chapter reviews the most common neurologic disorders associated with common vaccines, evaluates the data linking the disorder with the vaccine, and discusses the potential mechanism of disease. A literature search was conducted in PubMed using a combination of the following terms: vaccines, vaccination, immunization, and neurologic complications. Data were also gathered from publications of the American Academy of Pediatrics Committee on Infectious Diseases, the World Health Organization, the US Centers for Disease Control and Prevention, and the Vaccine Adverse Event Reporting System. Neurologic complications of vaccination are rare. Many associations have been asserted without objective data to support a causal relationship. Rarely, patients with a neurologic complication will have a poor outcome. However, most patients recover fully from the neurologic complication. Vaccinations have altered the landscape of infectious disease. However, perception of risk associated with vaccinations has limited the success of disease eradication measures. Neurologic complications can be severe, and can provoke fear in potential vaccines. Evaluating whether there is causal link between neurologic disorders and vaccinations, not just temporal association, is critical to addressing public misperception of risk of vaccination. Among the vaccines available today, the cost-benefit analysis of vaccinations and complications strongly argues in favor of vaccination.

Burden of multiple sclerosis on direct, indirect costs and quality of life: National US estimates.

BACKGROUND: MS imposes a significant burden on patients, caregivers, employers, and the healthcare system. OBJECTIVE: To comprehensively evaluate the US MS burden using nationally representative data from the Medical Expenditure Panel Survey. METHODS: We identified non-institutionalized patients aged ≥18 with MS (ICD-9 code 340) from 1998 to 2009 and compared them to individuals without an MS diagnosis (non-MS) during the interview year. The cohorts were compared using multivariate regression on direct costs, indirect costs (measured in terms of employment status, annual wages, and workdays missed), and health-related quality of life (HRQoL; measured using Short Form 12, SF-6 Dimensions, and quality-adjusted life years [QALYs]). RESULTS: MS prevalence was 572,312 (95% CI: 397,004, 747,619). Annual direct costs were $24,327 higher for the MS population (n=526) vs. the non-MS population (n=270,345) (95% CI: $22,320, $26,333). MS patients had an adjusted 3.3-fold (95% CI: 2.4, 4.5) increase in the odds of not being employed vs. non-MS individuals and a 4.4-fold higher adjusted number of days in bed (95% CI 2.97, 6.45). On average, MS patients lost 10.04 QALYs vs. non-MS cohort. CONCLUSIONS: MS was associated with higher healthcare costs across all components, reduced productivity due to unemployment and days spent in bed, and lower HRQoL.

Current and emerging therapies for the treatment of multiple sclerosis: focus on cladribine.

Multiple Sclerosis (MS) is a chronic inflammatory, immune-mediated, demyelinating disorder of the central nervous system with a heterogeneous clinical presentation and pathology in which activated lymphocytes play an important role in mediating tissue damage. Until recently, all first line therapies for MS were injectable. Several oral medications have been studied for preventative treatment of MS. Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog that has been used for the treatment of several hematologic neoplasms, with a unique lymphcytotoxic mechanism of action. Cladribine has been investigated as treatment of MS for more than 15 years. A recent placebo-controlled, double-blind study of cladribine, CLARITY, showed decreased relapse rates, risk of disability progression and MRI measures of disease activity at 96 weeks. Cladribine's strengths included high efficacy and convenient, biannual oral dosing. However, concerns about safety prevented the FDA from approving cladribine in 2011. Thus, use of cladribine for treatment of relapsing and remitting multiple sclerosis will remain off-label.

Update on PML and PML-IRIS occurring in multiple sclerosis patients treated with natalizumab.

The use of natalizumab to treat multiple sclerosis (MS) has been associated with the development of progressive multifocal leukoencephalopathy (PML), with 242 PML cases reported as of May 3, 2012. Fortunately, rapid withdrawal of the drug and administration of plasma exchange has allowed survival in many of these patients, but a new problem, immune reconstitution inflammatory syndrome (IRIS), has emerged after drug withdrawal. This report provides an update on PML in natalizumab-treated patients and reviews what is currently known about PML-IRIS in this setting; autopsy findings from a well-studied patient are illustrated. This patient with relapsing-remitting MS had been treated for 4 years with natalizumab, with discontinuation of drug after diagnosis of PML by cerebrospinal fluid polymerase chain reaction testing. Disease was manifested by severe paraparesis and expressive aphasia, which progressed before and after the diagnosis of PML. Immune reconstitution inflammatory syndrome was diagnosed, comfort care was instituted, but demise did not occur until 9 months later. Autopsy showed ongoing severe PML-IRIS, with massive cavitary brain lesions containing abundant perivascular and parenchymal CD8-positive T-cell infiltrates. Bone marrow and spleen, but not brain, contained monoclonal T-cell populations by polymerase chain reaction-based gene rearrangement studies, indicating overstimulation of peripheral T cells; T-cell lymphoma was not identified by morphological or immunohistochemical criteria.

Guidelines and best practices for appropriate use of dalfampridine in managed care populations.

Multiple sclerosis (MS) is a complex chronic, progressing disease that contributes to poor quality of life (QOL) for patients and high costs for managed care organizations. Currently, disease-modifying treatments (DMTs) constitute the platform pharmacotherapy for MS patients. Despite their efficacy, for many patients taking DMTs there is little evidence of their effect on QOL in general or symptom management. Impaired mobility contributes to direct and indirect costs. Annual direct medical costs for MS with gait impairment average nearly $21,000 per patient. Decreased mobility is also associated with higher absenteeism rates, thus raising indirect costs. Dalfampridine has been shown to improve walking in patients with MS. The effects of dalfampridine can complement those of DMTs by improving walking ability as a key component of overall mobility and a primary concern among many MS patients. Improved walking could potentially help contain some of the direct and indirect costs associated with MS care.

Recent insights into the mechanism of action of glatiramer acetate.

Glatiramer acetate (GA, Copaxone®, co-polymer 1) is an immunomodulatory therapy approved in 1996 by the United States Food and Drug Administration for treatment of relapsing-remitting multiple sclerosis. GA has a good safety profile, moderate efficacy, and a unique mode of action. Recent evidence in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), suggests that GA effects on NK cells and B cells may contribute to therapeutic efficacy. We review the mechanism of action of GA, with particular focus on recent data suggesting a role for regulatory B cells.