Sphingosine 1-phosphate receptor modulators in multiple sclerosis treatment: A practical review.

Four sphingosine 1-phosphate (S1P) receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are approved by the US Food and Drug Administration for the treatment of multiple sclerosis. This review summarizes efficacy and safety data on these S1P receptor modulators, with an emphasis on similarities and differences. Efficacy data from the pivotal clinical trials are generally similar for the four agents. However, because no head-to-head clinical studies were conducted, direct efficacy comparisons cannot be made. Based on the adverse event profile of S1P receptor modulators, continued and regular monitoring of patients during treatment will be instructive. Notably, the authors recommend paying attention to the cardiac monitoring guidelines for these drugs, and when indicated screening for macular edema and cutaneous malignancies before starting treatment. To obtain the best outcome, clinicians should choose the drug based on disease type, history, and concomitant medications for each patient. Real-world data should help to determine whether there are meaningful differences in efficacy or side effects between these agents.

Differential Diagnosis of Tumor-like Brain Lesions.

Purpose of Review: Tumor-like brain lesions are rare and commonly suggest a neoplastic etiology. Failure to rapidly identify non-neoplastic causes can lead to increased morbidity and mortality. In this review, we describe 10 patients who presented with atypical, non-neoplastic tumor-like brain lesions in which brain biopsy was essential for a correct diagnosis and treatment. Recent Findings: There has been increasing recognition of autoimmune conditions affecting the nervous system, and many of those diseases can cause tumor-like brain lesions. Currently available reports of non-neoplastic tumor-like brain lesions are scarce. Most case series focus on tumefactive demyelinating lesions, and a comprehensive review including other neuroimmunological conditions such as CNS vasculitis, neurosarcoidosis, histiocytic and infectious etiologies is lacking. Summary: We review the literature on tumor-like brain lesions intending to increase the awareness and differential diagnosis of non-neoplastic brain tumor mimics. We advocate for earlier brain biopsies, which, in our case series, significantly changed diagnosis, management, and outcomes.

Autologous Hematopoietic Stem Cell Transplant in Multiple Sclerosis: Recommendations of the National Multiple Sclerosis Society.

Importance: Autologous hematopoietic stem cell transplant (AHSCT) for multiple sclerosis has gained increasing interest in recent years. Despite the availability of many US Food and Drug Administration-approved disease-modifying therapies, some patients do not respond adequately and others may have very early aggressive disease that prompts consideration of alternative, highly effective, long-lasting therapy. The National Medical Advisory Committee of the National Multiple Sclerosis Society has reviewed recent literature on AHSCT for the purpose of making recommendations about its use based on current knowledge, as well as pointing out areas of controversy and issues requiring further research. Observations: Studies on AHSCT have repeatedly demonstrated high efficacy and a durable outcome in people with relapsing multiple sclerosis. Recent studies have shown considerable improvement in the safety of the procedure, with much lower mortality rates than were reported earlier. Consensus is emerging about the characteristics of the best candidates for the procedure. Questions remain about the ideal protocol, particularly about the best conditioning regimen to be used to kill immune cells. Larger randomized clinical trials are needed to address the question of whether AHSCT has advantages over the most efficacious disease-modifying agents currently available. One such trial (Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis [BEAT-MS) is currently in progress. Conclusions and Relevance: The National Multiple Sclerosis Society believes that AHSCT may be a useful treatment option for people with relapsing multiple sclerosis who demonstrate substantial breakthrough disease activity (ie, new inflammatory central nervous system lesions and/or clinical relapses) despite treatment with high-efficacy disease-modifying therapy or have contraindications to high-efficacy disease-modifying therapies. The best candidates are likely people younger than 50 years with shorter durations of disease (<10 years). The procedure should only be performed at centers with substantial experience and expertise. Ideally, recipients of the procedure should be entered into a single database, and further research is needed to establish ideal cell mobilization and immune-conditioning regimens.

Clinical and MRI efficacy of sc IFN ß-1a tiw in patients with relapsing MS appearing to transition to secondary progressive MS: post hoc analyses of PRISMS and SPECTRIMS.

This study evaluated efficacy of subcutaneous (sc) interferon beta-1a (IFN ß-1a) 44 µg 3 × weekly (tiw) in patients appearing to transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS). The PRISMS study included 560 patients with RRMS (EDSS 0-5.0; ≥ 2 relapses in previous 2 years), and the SPECTRIMS study included 618 patients with SPMS (EDSS 3.0-6.5 and ≥ 1-point increase in previous 2 years [≥ 0.5 point if 6.0-6.5]) randomly assigned to sc IFN ß-1a 44 or 22 µg or placebo for 2-3 years, respectively. These post hoc analyses examined five subgroups of MS patients with EDSS 4.0-6.0: PRISMS (n = 59), PRISMS/SPECTRIMS (n = 335), PRISMS/SPECTRIMS with baseline disease activity (n = 195; patients with either ≥ 1 relapse within 2 years before baseline or ≥ 1 gadolinium-enhancing lesion at baseline), PRISMS/SPECTRIMS without baseline disease activity (n = 140), and PRISMS/SPECTRIMS with disease activity during the study (n = 202). In the PRISMS and PRISMS/SPECTRIMS subgroups, sc IFN ß-1a delayed disability progression, although no significant effect was observed in PRISMS/SPECTRIMS subgroups with activity at baseline or activity during the study (regardless of baseline activity). In the PRISMS/SPECTRIMS subgroup, over year 1 (0-1) and 2 (0-2), sc IFN ß-1a 44 µg tiw significantly reduced annualized relapse rate (p ≤ 0.001), and relapse risk (p < 0.05) versus placebo. Similar results were seen for the PRISMS/SPECTRIMS with baseline disease activity subgroup. Subcutaneous IFN ß-1a reduced T2 burden of disease and active T2 lesions in the PRISMS/SPECTRIMS subgroups overall, with and without baseline activity. In conclusion, these post hoc analyses indicate that effects of sc IFN ß-1a 44 µg tiw on clinical/MRI endpoints are preserved in a patient subgroup appearing to transition between RRMS and SPMS.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Cladribine tablets added to IFN-ß in active relapsing MS: The ONWARD study.

OBJECTIVE: To evaluate the safety and efficacy of cladribine tablets in patients still experiencing active relapsing MS despite interferon (IFN)-ß treatment. METHODS: A 96-week phase II study, randomizing patients treated with IFN-ß to cladribine tablets 3.5 mg/kg/IFN-ß or placebo/IFN-ß. Patients were to receive cladribine tablets 3.5 mg/kg/IFN-ß or placebo/IFN-ß in a 2:1 ratio (n = 172) with safety and exploratory efficacy outcomes being assessed. RESULTS: Adverse events (AEs) and serious AEs were similar across treatment groups, except lymphopenia. Fifty of 124 (40.3%) cladribine/IFN-ß recipients vs 0% of placebo/IFN-ß recipients reported lymphopenia as an AE, with grade 3/4 lymphopenia (laboratory lymphocyte count < 500 cells/mm3) experienced by 79/124 (63.7%) vs 1 (2.1%), respectively. Patients treated with cladribine tablets 3.5 mg/kg/IFN-ß were 63% less likely to have a qualifying relapse than placebo/IFN-ß recipients, and cladribine tablets 3.5 mg/kg/IFN-ß reduced most MRI measures of disease activity. CONCLUSIONS: In patients with active relapsing MS despite IFN-ß treatment, cladribine tablets 3.5 mg/kg/IFN-ß reduced relapses and MRI lesion activity over 96 weeks compared with placebo/IFN-ß but led to an increased incidence of lymphopenia. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with active relapsing MS despite IFN-ß treatment, cladribine tablets added to IFN-ß reduced relapses and MRI lesion activity over 96 weeks and increased the incidence of lymphopenia. CLINICAL TRIAL REGISTRATION: NCT00436826.

Acute Exertional Upper-Extremity Rhabdomyolysis as a Result of a Single Training Event: Report of 3 Female Trainees.

Early diagnosis and comprehensive management of exertional rhabdomyolysis are crucial to ensure full recovery and avoidance of complications.

Robot-guided ankle sensorimotor rehabilitation of patients with multiple sclerosis.

BACKGROUND: People with multiple sclerosis (MS) often develop symptoms including muscle weakness, spasticity, imbalance, and sensory loss in the lower limbs, especially at the ankle, which result in impaired balance and locomotion and increased risk of falls. Rehabilitation strategies that improve ankle function may improve mobility and safety of ambulation in patients with MS. This pilot study investigated effectiveness of a robot-guided ankle passive-active movement training in reducing motor and sensory impairments and improving balance and gait functions. METHODS: Seven patients with MS participated in combined passive stretching and active movement training using an ankle rehabilitation robot. Six of the patients finished robotic training 3 sessions per week over 6 weeks for a total of 18 sessions. Biomechanical and clinical outcome evaluations were done before and after the 6-week treatment, and at a follow-up six weeks afterwards. RESULTS: After six-week ankle sensorimotor training, there were increases in active range of motion in dorsiflexion, dorsiflexor and plantar flexor muscle strength, and balance and locomotion (p<0.05). Proprioception acuity showed a trend of improvement. Improvements in four biomechanical outcome measures and two of the clinical outcome measures were maintained at the 6-week follow-up. The study showed the six-week training duration was appropriate to see improvement of range of motion and strength for MS patients with ankle impairment. CONCLUSION: Robot-guided ankle training is potentially a useful therapeutic intervention to improve mobility in patients with MS.

Demonstration of equivalence of a generic glatiramer acetate (Glatopa™).

Glatiramer acetate (GA) has been available under the brand name Copaxone® for nearly two decades. Recently, the US Food and Drug Administration (FDA) approved the first generic GA, Glatopa™, as fully substitutable for all indications for which Copaxone 20mg is approved; Glatopa also represents the first FDA-approved "AP-rated," substitutable generic for treating patients with MS. Glatiramer acetate is a complex mixture of polypeptides and, consequently, its characterization presented challenges not generally encountered in drug development. Despite its complexity, and without requiring any clinical data, approval was accomplished through an Abbreviated New Drug Application in which equivalence to Copaxone was evaluated across four criteria: starting materials and basic chemistry; structural signatures for polymerization, depolymerization, and purification; physicochemical properties; and biological and immunological properties. This article describes the rigorous overall scientific approach used to successfully establish equivalence between Glatopa and Copaxone, and presents key representative data from several of the comprehensive sets of physicochemical (structural) and biological (functional) assays that were conducted.

Diagnostic utility of aquaporin-4 in the analysis of active demyelinating lesions.

OBJECTIVE: To assess, in a surgical biopsy cohort of active demyelinating lesions, the diagnostic utility of aquaporin-4 (AQP4) immunohistochemistry in identifying neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD) and describe pathologic features that should prompt AQP4 immunohistochemical analysis and AQP4-immunoglobulin G (IgG) serologic testing. METHODS: This was a neuropathologic cohort study of 20 surgical biopsies (19 patients; 11 cord/9 brain), performed because of diagnostic uncertainty, interpreted as active demyelinating disease and containing 2 or more of the following additional features: tissue vacuolation, granulocytic infiltrates, or astrocyte injury. RESULTS: AQP4 immunoreactivity was lost in 18 biopsies and increased in 2. Immunopathologic features of the AQP4 loss cohort were myelin vacuolation (18), dystrophic astrocytes and granulocytes (17), vascular hyalinization (16), macrophages containing glial fibrillary acid protein (GFAP)-positive debris (14), and Creutzfeldt-Peters cells (0). All 14 cases with available serum tested positive for AQP4-IgG after biopsy. Diagnosis at last follow-up was NMO/NMOSD (15) and longitudinally extensive transverse myelitis (1 each relapsing and single). Immunopathologic features of the AQP4 increased cohort were macrophages containing GFAP-positive debris and granulocytes (2), myelin vacuolation (1), dystrophic astrocytes (1), Creutzfeldt-Peters cells (1), and vascular hyalinization (1). Diagnosis at last follow-up was multiple sclerosis (MS) and both tested AQP4-IgG seronegative after biopsy. CONCLUSIONS: AQP4 immunohistochemistry with subsequent AQP4-IgG testing has diagnostic utility in identifying cases of NMO/NMOSD. This study highlights the importance of considering NMOSD in the differential diagnosis of tumefactive brain or spinal cord lesions. AQP4-IgG testing may avert biopsy and avoid ineffective therapies if these patients are erroneously treated for MS.

Therapy optimization in multiple sclerosis: a prospective observational study of therapy compliance and outcomes.

BACKGROUND: Data sources for MS research are numerous but rarely provide an objective measure of drug therapy compliance coupled with patient-reported health outcomes. The objective of this paper is to describe the methods and baseline characteristics of the Therapy Optimization in MS (TOP MS) study designed to investigate the relationship between disease-modifying therapy compliance and health outcomes. METHODS: TOP MS was designed as a prospective, observational, nationwide patient-focused study using an internet portal for data entry. The protocol was reviewed and approved by Sterling IRB. The study was registered with ClinicalTrials.gov. It captured structured survey data monthly from MS patients recruited by specialty pharmacies. Data collection included the clinical characteristics of MS such as MS relapses. Disability, quality of life and work productivity and activity impairment were assessed quarterly with well-validated scales. When events like severe fatigue or new or worsening depression were reported, feedback was provided to treating physicians. The therapy compliance measure was derived from pharmacy drug shipment records uploaded to the study database. The data presented in this paper use descriptive statistics. RESULTS: The TOP MS Study enrolled 2966 participants receiving their disease-modifying therapy (DMT) from specialty pharmacies. The mean age of the sample was 49 years, 80.4% were female, 89.9% were Caucasian and 55.7% were employed full or part time. Mean time since first symptoms was 11.5 years; mean duration since diagnosis was 9.5 years. Patient-reported EDSS was 3.5; 72.2% had a relapsing-remitting disease course. The most commonly reported symptoms at the time of enrollment were fatigue (74.7%), impaired coordination or balance (61.8%) and numbness and tingling (61.2%). Half of the sample was using glatiramer acetate and half was using beta-interferons. CONCLUSION: Demographic and clinical characteristics of the TOP MS sample at enrollment are consistent with other community-based MS samples, and the sample appears to be representative of DMT users in the US. TOP MS data can be used to explore the associations between disease-modifying therapy compliance and health outcomes. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00819000).

Characterizations of reflex and nonreflex changes in spastic multiple sclerosis.

BACKGROUND: Spasticity, an increased resistance of a limb to movement, is associated with functional limitations and a major source of disability in neurological disorders, including multiple sclerosis (MS) and stroke. Despite the clinical significance of spasticity in brain and spinal cord injuries, it is often not clear whether the spasticity is due to reflex or non-reflex changes. NEW METHOD: Reflex and nonreflex properties of the human knee joint were studied in eight MS patients with spasticity and ten healthy subjects. A digitally controlled joint driving device was used to apply small-amplitude, and band-limited white-noise perturbations to the knee to manifest the reflex and nonreflex properties. The subjects were asked to maintain a steady level of background muscle torque during the perturbation. A nonlinear delay differential equation model was used to characterize the reflex and intrinsic properties of the knee in terms of phasic stretch reflex gain, tonic stretch reflex gain, joint elastic stiffness, and coefficient of viscosity. RESULTS: It was found that joint coefficient of viscosity and tonic stretch reflex gain of the spastic MS patients were significantly lower than those of normal controls. On the other hand, spastic MS patients showed higher phasic stretch reflex gains than normal controls and a trend of increased joint stiffness. CONCLUSIONS: Simultaneous characterizations of changes in tonic and phasic reflexes and nonreflex changes in joint elastic stiffness and viscosity in neurological disorders may help us gain insight into mechanisms underlying spasticity and develop impairment-specific treatment.

Constructing an adaptive care model for the management of disease-related symptoms throughout the course of multiple sclerosis--performance improvement CME.

BACKGROUND: Symptom management remains a challenging clinical aspect of MS. OBJECTIVE: To design a performance improvement continuing medical education (PI CME) activity for better clinical management of multiple sclerosis (MS)-related depression, fatigue, mobility impairment/falls, and spasticity. METHODS: Ten volunteer MS centers participated in a three-stage PI CME model: A) baseline assessment; B) practice improvement CME intervention; C) reassessment. Expert faculty developed performance measures and activity intervention tools. Designated MS center champions reviewed patient charts and entered data into an online database. Stage C data were collected eight weeks after implementation of the intervention and compared with Stage A baseline data to measure change in performance. RESULTS: Aggregate data from the 10 participating MS centers (405 patient charts) revealed performance improvements in the assessment of all four MS-related symptoms. Statistically significant improvements were found in the documented assessment of mobility impairment/falls (p=0.003) and spasticity (p<0.001). For documentation of care plans, statistically significant improvements were reported for fatigue (p=0.007) and mobility impairment/falls (p=0.040); non-significant changes were noted for depression and spasticity. CONCLUSIONS: Our PI CME interventions demonstrated performance improvement in the management of MS-related symptoms. This PI CME model (available at www.achlpicme.org/ms/toolkit) offers a new perspective on enhancing symptom management in patients with MS.

Opportunistic infections of the central nervous system in the transplant patient.

Therapeutic advances in transplantation medicine have resulted in ever expanding patient populations that receive organ or stem cell transplantation. Modern potent immunomodulatory therapies have resulted in improvements in allograft and patient survival, but, consequently, as a result of the immunosuppressive state, transplant recipients are highly vulnerable to infection, including those that affect the central nervous system (CNS). CNS infections present a diagnostic and therapeutic challenge for clinicians involved in the care of the transplant patient, with a propensity to result in profound morbidity and often high mortality in this patient population. Here, we review major opportunistic pathogens of the CNS seen in transplant patients, highlighting distinguishing epidemiologic and clinical features.

Enhancing the quality of care for patients with multiple sclerosis through performance improvement CME.

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease marked by a heterogeneous clinical presentation and disease course. Although improvements in the recognition and management of MS have been made in recent years, challenges remain due to the complex nature of the disease. Clinicians must remain current with their skills as knowledge surrounding MS care continues to advance. Here we report results of a performance improvement (PI) continuing medical education (CME) activity that was designed to promote evidence-based care of patients with MS. Participants demonstrated significant improvements in assessing disease-related complications, treating cognitive dysfunction, assessing adherence, and providing disease-related educational materials. These data support the role of PI CME in improving clinician practices that align with quality MS patient care.

Presentation of neuromyelitis optica spectrum disorder after more than twenty years of systemic sclerosis.

Neuromyelitis optica is an autoimmune disorder characterized by optic neuritis, transverse myelitis, and aquaporin-4 autoantibodies. The term "neuromyelitis optica spectrum disorder" refers neuromyelitis optica features occurring in association with other systemic rheumatologic conditions. We present a case of a 51-year-old woman with long-standing systemic sclerosis who developed transverse myelitis in association with the presence aquaporin-4 autoantibodies. This is the first report case of neuromyelitis optica spectrum disorder associated with systemic sclerosis. Given that patients with neuromyelitis optica spectrum disorder with aquaporin-4 autoantibodies have a high risk for clinical relapse, this report underscores the need for recognition of this disorder in patients with systemic sclerosis and neurological dysfunction.

Biomarkers of neurological status in HIV infection: a 3-year study.

PURPOSE: To evaluate circulating cytokines and chemokines as correlates of the degree of brain injury in individuals with advanced human immunodeficiency virus (HIV) infection. EXPERIMENTAL DESIGN: Study participants included ten well-characterized subjects in advanced stage HIV infection. High-throughput multiplexed analysis was used to quantify markers of interest at baseline and 3 years later in the clinical course. Objective measurements of the brain were derived in vivo with quantitative magnetic resonance segmentation algorithms and with diffusion tensor imaging. RESULTS: Of the markers examined, monocyte chemoattractant protein-1 (MCP-1 or CCL-2) was the most prominent correlate of brain injury. Elevated MCP-1 levels correlated with brain white matter alterations at the initial assessment. The relationship to injury was more extensive 3 years later; elevated MCP-1 was significantly correlated with measures of brain microstructural alterations and of abject atrophy. CONCLUSIONS AND CLINICAL RELEVANCE: The findings build on our prior observations that elevated MCP-1 levels may be a useful predictive marker for HIV-associated neurocognitive disorder. As a potent chemoattractant, MCP-1 may mediate injury through participation in self-reinforcing cycles of chronic immune activation and cytokine/chemokine-mediated neurotoxicity.

PRISMS: the story of a pivotal clinical trial series in multiple sclerosis.

BACKGROUND: The PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study was initiated in 1994, at which time there were few disease-modifying drugs for multiple sclerosis (MS). The PRISMS series of studies has since provided up to 8 years of clinical, magnetic resonance imaging (MRI), safety, and immunogenicity data on the use of subcutaneous (sc) interferon (IFN) beta-1a in patients with relapsing-remitting MS. This review is the first collation of all these data in one article, with a look ahead to the next generation of studies involving the new formulation of sc IFN beta-1a. METHODS: Published efficacy, safety, and immunogenicity data, in terms of prospectively defined endpoints and later post hoc analyses, from years 1-8 of the PRISMS series are summarized and collated for the first time. Some of the studies of sc IFN beta-1a that evolved from the PRISMS studies are also discussed. FINDINGS: In the 2-year, double-blind, randomized, placebo-controlled study, IFN beta-1a (22 or 44 mcg three times weekly [tiw]) was associated with significantly lower relapse rates, disability progression, and MRI burden of disease compared with placebo (p