Ocrelizumab reduces progression of upper extremity impairment in patients with primary progressive multiple sclerosis: Findings from the phase III randomized ORATORIO trial.

BACKGROUND: Upper extremity (UE) impairment is common with primary progressive multiple sclerosis (PPMS). OBJECTIVE: This exploratory analysis examined the effects of ocrelizumab on confirmed progression (CP) and confirmed improvement (CI) in UE impairment in patients from ORATORIO. METHODS: Patients with PPMS received ocrelizumab 600 mg or placebo every 24 weeks for ⩾120 weeks. The Nine-Hole Peg Test (9HPT) was administered at baseline (BL) and every 12 weeks thereafter. Prespecified exploratory endpoints included change in 9HPT time and proportion of patients with CP of ⩾20% in 9HPT. Analysis populations included intention-to-treat (ITT) patients and subgroups stratified by BL 9HPT time and Expanded Disability Status Scale. Post hoc analyses included the proportion of patients achieving more severe thresholds of CP and the proportion achieving CI in 9HPT. RESULTS: Among ITT patients, ocrelizumab significantly reduced the change in 9HPT time over 120 weeks, the risk of CP of ⩾20% in 9HPT time for both hands and the risk of more severe 9HPT progression versus placebo. Numerical trends also favoured ocrelizumab versus placebo with respect to achieving CI. Consistent directional trends were observed in subgroup analyses. CONCLUSION: Ocrelizumab reduces the risk of UE disability progression and may increase the possibility of improvement versus placebo in PPMS.

Syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis presenting as acute neurological emergencies.

Background The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a self-limited benign disorder of unclear pathogenesis, with diverse clinical manifestations. Cases We report two unusual presentations of this entity. The first case developed a catastrophic picture, characterized by acute elevation of intracranial pressure, necessitating emergency life support. The second case presented with hyperacute-onset mixed aphasia and facial droop, masquerading as acute ischemia of the middle cerebral artery territory. Both patients made full recoveries. Conclusion The possibility of HaNDL should be considered in individuals presenting with unusual patterns of headaches and transient neurological symptoms. Our report will expand the spectrum of this disorder, which will help physicians not only to recognize the unusual manifestations of this rare disorder, but also consider potential therapeutic interventions.

In vivo quantitative whole-brain T1 rho MRI of multiple sclerosis.

BACKGROUND: To apply quantitative whole-brain T1 -rho (T1ρ ) and T2 imaging to the detection and quantification of brain changes resulting from multiple sclerosis (MS). METHODS: Twenty-three MS patients with clinically isolated syndrome (10) and relapsing remitting MS (13) phenotypes, compared with 24 age-matched healthy controls were imaged at 3 Tesla. An axial T1ρ -weighted three-dimensional turbo spin echo sequence with a variable flip angle and fluid suppression was used. Spin-lock times of 0, 20, 40, 60, 80, and 100 ms were used. Corresponding T2 maps were also acquired. RESULTS: Whole brain white matter (WM) T1ρ maps were elevated compared with controls (P = 0.002). WM lesion T1ρ and T2 values were highly correlated (r = 0.83), but T1ρ demonstrated 25% better contrast to noise ratio (P < 0.001). WM lesion T1ρ correlated with disease duration. Gray matter T1ρ was negatively correlated with the Expanded Disability Status Scale, r = -0.45, P = 0.03. Normal appearing gray matter and cortical gray matter lesions were negatively correlated on T1ρ , but not on T2 (rT1ρ = -0.63, pT1ρ = 0.03; rT2 = -0.17, pT2 = 0.6). CONCLUSION: T1ρ MRI demonstrates enhanced lesion contrast compared with T2 , and in some cases may provide complementary information. T1ρ may provide a useful measure of demyelinating processes in MS.

Patterns of disease-modifying therapy utilization before, during, and after pregnancy and postpartum relapses in women with multiple sclerosis.

BACKGROUND: Pregnancy is a common consideration for people with multiple sclerosis (pwMS); MS onset is typically between 20 and 45 years of age, during potential child-bearing years. Pregnancy and postpartum care are a significant factor influencing disease-modifying therapy (DMT) selection for many pwMS. To date, few DMTs are considered safe to continue during pregnancy and real-world treatment patterns before, during, and after pregnancy remain uncharacterized. Evolving guidance is needed regarding how to optimize management of the pregnancy and postpartum periods considering the changing DMT landscape. This analysis in two large claims databases describes DMT utilization for the treatment of MS before, during, and after pregnancy and relapse patterns during pregnancy and postpartum. METHODS: In this retrospective, observational study, the US MarketScan Commercial and Medicaid claims database was assessed for female patients aged 18-55 years with ≥1 insurance claim submitted under the diagnosis code of MS from 01 January 2016-30 April 2021 and continuous enrollment eligibility from ≥6 months prior to pregnancy date (preconception) through 6 months of follow-up following delivery (postpartum period). Comorbid conditions were examined preconception and postpartum, including anxiety and depression. Moderate/severe relapse was defined as MS-related hospitalization, or an outpatient visit and one claim within 7 days of the visit with steroids or total plasma exchange. RESULTS: A total of 944 patients (mean [standard deviation] age, 32.4 [5.0] years) were eligible; 688 (73%) were commercially insured and 256 (27%) received Medicaid. Compared with commercially-insured patients, use of DMTs was lower among Medicaid patients at 6 months preconception (25.4% vs 40.4%; p < 0.001), with similar patterns observed both during pregnancy and postpartum. Overall, prevalence of DMT use declined sharply during pregnancy, from 36.3% of patients in the 6 months preconception to 17.9%, 5.3%, and 5.8% in trimesters 1, 2 and 3, respectively. Postpartum DMT utilization increased to 20.9% at 0-3 months and 24.4% at 4-6 months. Of all patients in the preconception period, the most frequently used DMTs were glatiramer acetate (14.3%), dimethyl fumarate (6.0%), interferon (5.2%), and natalizumab (4.9%). Due to small sample size, information was limited for anti-CD20s and alemtuzumab. The proportion of patients with any moderate/severe relapse declined over pregnancy (preconception, n = 82 [8.7%]; pregnancy, n = 25 [2.6%]), but increased postpartum (n = 94 [10.0%]). Of the 889 patients who stopped DMT during pregnancy, the risk of postpartum relapses was lower in the patients who resumed DMT postpartum (10/192) than in patients who did not (76/697) (5.2% vs 10.9%; odds ratio, 0.455 [95% confidence interval 0.216-0.860], p = 0.018). Cases of postpartum depression and anxiety were significantly lower in commercially-insured patients vs Medicaid patients (postpartum depression, 13.7% vs 27.0%, p < 0.01; postpartum anxiety, 16.3% vs 30.5%, p < 0.01). CONCLUSION: DMT utilization declined sharply during pregnancy; it gradually increased postpartum but remained below pre-pregnancy use. The proportion of pwMS experiencing a moderate/severe relapse and number of relapses declined over pregnancy but increased postpartum. Reinitiation of DMT during the postpartum period was associated with lower risk of relapses, supporting a role for early reinitiation of DMT postpartum. STUDY SUPPORTED BY: Biogen.

The clinical overlap of multiple sclerosis and headache.

Multiple sclerosis (MS) and migraine headache coexist in many young female patients. Whether this is coincidental or causally linked remains unclear. The presenting symptoms and signs of MS relapse and migraine aura can be similar and should be differentiated by careful history and examination to ensure proper diagnosis and treatment. White matter lesions on magnetic resonance imaging have specific patterns for each entity and also need to be interpreted carefully. Although a clear link has not been established between migraine and MS, numerous studies have been reported assessing risks, prevalence, and causation. Complicating these assessments are the disease-modifying therapies used to treat MS which have been known to be implicated in causing headache. The recent development of novel treatment options for MS requires practitioners to be aware of polypharmacy and potential drug interactions.

The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study.

OBJECTIVE: To characterize patients misdiagnosed with multiple sclerosis (MS). METHODS: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. RESULTS: Of 110 misdiagnosed patients, 51 (46%) were classified as "definite" and 59 (54%) "probable" misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. CONCLUSIONS: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

Effects of Dalfampridine Extended-release Tablets on 6-minute Walk Distance in Patients With Multiple Sclerosis: A Post Hoc Analysis of a Double-blind, Placebo-controlled Trial.

PURPOSE: Dalfampridine extended-release (ER) tablets 10 mg BID have been approved for use in improving walking in people with multiple sclerosis (MS). This subgroup analysis evaluated the effects of dalfampridine ER 5 and 10 mg BID on distance walked, as assessed using the 6-minute walk (6MW) test. METHODS: This analysis of data from a randomized, placebo-controlled, double-blind study (N = 430) included only the 153 patients with 6MW data available. Participants (aged 18-70 years) were randomly assigned in a 1:1:1 ratio to receive dalfampridine ER 5 or 10 mg or placebo, BID for 4 weeks. The 6MW was used for assessing walking distance at baseline and 2 weeks after the start of treatment at the 26 study sites that were able to perform this test. Participants were administered the 12-item MS Walking Scale (MSWS-12), a patient-reported measure of the impact of MS on walking. Post hoc outcomes included the percentages of patients who achieved an increase from baseline in 6MW distance of ≥20% and who achieved a minimal clinically important difference (MCID) from baseline in 6MW distance, defined as ≥+55 m. Changes from baseline in walking speed (MSWS-12) were compared, stratified by subgroup that achieved ≥20% versus <20% improvement on the 6MW. The correlation between change in walking speed over time and subgroup (by change in distance walked) was evaluated. The tolerability of dalfampridine was assessed based on the prevalence of treatment-emergent adverse events (TEAEs). FINDINGS: In the post hoc analysis, the percentage of patients with an improvement in 6MW distance that met or exceeded the MCID was significantly greater with dalfampridine ER 10 mg BID relative to placebo (37.3% vs 12.2%; nominal P = 0.004). Similarly, the percentage with an improvement in 6MW distance of ≥20% was significantly greater with dalfampridine 10 mg BID relative to placebo (45.1% vs 14.3%; nominal P < 0.001). Regardless of treatment allocation, improvement in MSWS-12 was significantly greater in the subgroup that achieved a ≥20% improvement on the 6MW compared with the subgroup with <20% improvement (mean changes, -15.5 vs -7.2; nominal P = 0.041). The prevalences and types of TEAEs were consistent with those reported in previous studies. IMPLICATIONS: Based on the MCID for 6MW, the use of dalfampridine ER 10 mg BID but not 5 mg BID was associated with statistically significant and clinically meaningful improvements in walking relative to placebo. The correlation between improvement on MSWS-12 and the 20% increase in 6MW distance suggests that an improvement on MSWS-12 is clinically relevant. These results, although highlighting a lack of efficacy of dalfampridine ER 5 mg BID, suggest that the 10-mg BID dose is effective for improving walking speed, as observed on short timed-walk tests, and for increasing distance walked over longer timed-walk periods. ClinicalTrials.gov identifier: NCT01328379.

Evaluation of Dalfampridine Extended Release 5 and 10 mg in Multiple Sclerosis: A Randomized Controlled Trial.

BACKGROUND: Dalfampridine extended-release (ER) tablets, 10 mg twice daily, have been shown to improve walking in people with multiple sclerosis. We evaluated the safety and efficacy of dalfampridine-ER 5 mg compared with 10 mg. METHODS: Patients were randomized to double-blind treatment with twice-daily dalfampridine-ER tablets, 5 mg (n = 144) or 10 mg (n = 143), or placebo (n = 143) for 4 weeks. Primary efficacy endpoint was change from baseline walking speed by the Timed 25-Foot Walk 3 to 4 hours after the last dose. At 40% of sites, 2-week change from baseline walking distance was measured by the 6-Minute Walk test. RESULTS: At 4 weeks, walking speed changes from baseline were 0.363, 0.423, and 0.478 ft/s (placebo, dalfampridine-ER 5 mg, and dalfampridine-ER 10 mg, respectively [P = NS]). Post hoc analysis of average changes between pretreatment and on-treatment showed that relative to placebo, only dalfampridine-ER 10 mg demonstrated a significant increase in walking speed (mean ± SE): 0.443 ± 0.042 ft/s versus 0.303 ± 0.038 ft/s (P = .014). Improvement in 6-Minute Walk distance was significantly greater with dalfampridine-ER 10 mg (128.6 ft, P = .014) but not with 5 mg (76.8 ft, P = .308) relative to placebo (41.7 ft). Adverse events were consistent with previous studies. No seizures were reported. CONCLUSIONS: Dalfampridine-ER 5 and 10 mg twice daily did not demonstrate efficacy on the planned endpoint. Post hoc analyses demonstrated significant increases in walking speed relative to placebo with dalfampridine-ER 10 mg. No new safety signals were observed.

Treatment of walking impairment in multiple sclerosis: an unmet need for a disease-specific disability.

INTRODUCTION: Walking impairment is a clinical hallmark of multiple sclerosis (MS), a chronic neurologic disease characterized by axonal demyelination and dysfunction that results in progressive disability. Until recently, there were no therapies that specifically targeted the axonal dysfunction associated with walking impairment in MS. AREAS COVERED: The purpose of this review is to discuss the unmet need for the treatment of walking impairment in MS patients and to evaluate how a new class of pharmacologic therapies, neurofunctional modifiers, potentially addresses this unmet need. Discussion is based on clinical experience and opinions supported by publications identified in the PubMed literature using the search terms 'multiple sclerosis' and 'mobility OR walking'. EXPERT OPINION: The development and approval of new treatments for MS show promise for improving adherence to therapy and increasing the potential for clinical effectiveness. Renewed emphasis on integrating strategies that target the underlying pathophysiology with those that address symptoms of concern to patients also has the potential to improve the lives of MS patients and their caregivers. The introduction of neurofunctional modifiers, such as dalfampridine for the improvement of walking impairment, may be of benefit by improving function, mobility and overall quality of life for MS patients.

Effect of eszopiclone on sleep disturbances and daytime fatigue in multiple sclerosis patients.

The prevalence of moderate-to-severe sleep problems is significantly higher among people with multiple sclerosis (MS) than in the general population. In 2002, we found a significant relationship between fatigue and disrupted sleep in patients with relapsing-remitting MS (RRMS). The objectives of this study were to determine whether eszopiclone (Lunesta; Sunovion Pharmaceuticals Inc, Marlborough, MA) was superior to placebo in improving sleep among patients with MS-related fatigue and sleep complaints (primary end point); and to assess the impact of improved sleep on daytime fatigue and functioning (secondary end point). This was a double-blind, placebo-controlled pilot trial lasting 7 weeks. Thirty ambulatory adults under age 65 years with RRMS, fatigue, and sleep disturbances were randomized to receive either eszopiclone or placebo. The outcome measures included subjective and objective changes in sleep-onset latency (SOL), total sleep time (TST), wakefulness after sleep onset (WASO), sleep efficiency (SE), fatigue scales, and neuropsychological measures of daytime functioning. Compared with placebo, eszopiclone was superior only in increasing TST. Fatigue improved in both groups, but there was no statistically significant correlation between increased TST and improved fatigue, and no statistically significant differences were observed between the two groups. Thus, in this study, eszopiclone did not improve sleep sufficiently to improve fatigue in MS patients. This result may be due to the multifactorial nature of sleep disturbances and fatigue in people with MS.

Early stage and long term treatment of multiple sclerosis with interferon-beta.

Multiple sclerosis (MS) affects young adults during the most productive years of their lives, and until recently many neurologists were limited to treating symptoms and attacks without any ability to alter the disease course. The 1990s ushered in an era of possibility with the approval of three interferon-beta (IFNbeta) therapies for the treatment of MS. Though the mechanism of action of these agents is not completely understood, it is clear they reduce magnetic resonance imaging (MRI) activity as well as improve clinical outcomes. The principal randomized, blinded, multicenter trials of IFNbeta all point to the need for early treatment soon after the diagnosis of MS is made. Efficacy has also been shown in patients treated after a first demyelinating event. Data on IFNbeta in the treatment of secondary progressive MS (SPMS) is not impressive, although it shows some benefit in SPMS patients who continue to experience MRI activity and clinical relapses, signifying a continued inflammatory component to their disease. There has been no proven efficacy of IFNbeta in the treatment of primary progressive MS (PPMS). The IFNbeta therapies are generally well tolerated with a favorable side effect profile. Despite benefits in MRI and clinical measures such as relapse rates and Expanded Disability Status Scale progression, patients continue to exhibit clinical progression and radiological atrophy, pointing to confounding factors and perhaps multiple etiologies of a disease that is not yet fully understood. In addition, the subject of neutralizing antibodies has recently assumed importance. The significance of these on treatment efficacy is uncertain, and until a universally accepted reliable assay is adopted, the decision to change treatment continues to rely on the clinical interpretation of the patient's history and physical examination. Additional recommendations for management of patients, informed by the best available evidence, are also presented.

Cluster-migraine: does it exist?

The nosological boundaries between cluster headache and migraine are sometimes ill-defined. Although the two disorders are distinct clinical entities, patients sometimes present with clinical scenarios having characteristics of both headache types, but either do not fully meet International Classification of Headache Disorders, Second Edition diagnostic criteria for either disorder or have sufficient symptoms and signs to allow both diagnoses to be present. These occasions provide diagnostic challenges and include what is variously described as migraine-cluster, cyclical migraine, clustering episodes of migraine, cluster with aura, or atypical cluster without autonomic symptoms or severe pain. Patients with symptoms overlapping cluster headache and migraine likely reflect the inherent clinical variability in each of these two disorders, rather than distinct diagnostic entities in their own right.