Longitudinal Disability, Cognitive Impairment, and Mood Symptoms in Patients With Anti-NMDA Receptor Encephalitis.

BACKGROUND AND OBJECTIVES: Longitudinal outcomes in anti-NMDA receptor encephalitis (anti-NMDARe) are still not fully understood and may not be adequately captured with the modified Rankin Scale (mRS), often the sole reported outcome. We aim to characterize longitudinal outcomes in anti-NMDARe using multiple outcome measures. METHODS: This single-center, retrospective, observational study examined outcome measures (mRS and Clinical Assessment Scale in Autoimmune Encephalitis [CASE]) in adults with NMDA receptor-IgG in CSF at short- and long-term follow-ups using linear and logistic regression modeling. Patients with evaluations for cognitive impairment (Montreal Cognitive Assessment/Mini-Mental State Examination), depression (Patient Health Questionnaire-9), and anxiety (General Anxiety Disorder-7) >6 months from symptom onset were correlated with final CASE scores. RESULTS: Thirty-eight patients (76% female, median disease onset age = 28 years, range = 1-75 years) were included. The majority received first-line immunosuppressants (97%) at a median of 3.9 weeks (interquartile range [IQR] = 2.1-9.7) from symptom onset and 68% received second-line therapies. At baseline, median/mean mRS and CASE were 4 (IQR = 3-5) and 12.9 (SD = 7.2), respectively. At short-term follow-up (median = 10 weeks, IQR = 6-17), factors associated with higher CASE and mRS included dysautonomia, coma/lethargy, seizures/status epilepticus, and intensive care unit admission (p < 0.05). At long-term follow-up (median = 70 weeks, IQR = 51-174), median/mean mRS and CASE were 2 (IQR = 1-3) and 4.4 (SD = 4.2), respectively. Only weakness at symptom onset predicted higher mRS scores (odds ratio = 5.6, 95% confidence interval 1.02-30.9, p = 0.047). Despite both mRS and CASE improving from baseline (p < 0.001), only 9 patients (31%) returned to their premorbid function. Among patients with cognitive and mood evaluations >6 months from onset, moderate-severe cognitive impairment (42%), depression (28%), and anxiety (30%) were frequent. Cognitive and depression measures were associated with final CASE subscores (including memory, language, weakness, and psychiatric). DISCUSSION: Multiple clinical factors influenced short-term outcomes, but only onset weakness influenced long-term mRS, highlighting that mRS is predominantly affected by global motor function. Although mRS and CASE improved over time for most patients, these outcome measures did not capture the full extent of long-term functional impairment in terms of mood, cognition, and the ability to return to premorbid function. This emphasizes the need for increased utilization of more nuanced cognitive and mood outcome measures.

Dopaminergic Therapy for Motor Symptoms in Early Parkinson Disease Practice Guideline Summary: A Report of the AAN Guideline Subcommittee.

BACKGROUND AND OBJECTIVES: To review the current evidence on the options available for initiating dopaminergic treatment of motor symptoms in early-stage Parkinson disease and provide recommendations to clinicians. METHODS: A multidisciplinary panel developed practice recommendations, integrating findings from a systematic review and following an Institute of Medicine-compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence. RESULTS: Initial treatment with levodopa provides superior motor benefit compared to treatment with dopamine agonists, whereas levodopa is more likely than dopamine agonists to cause dyskinesia. The comparison of different formulations of dopamine agonists yielded little evidence that any one formulation or method of administration is superior. Long-acting forms of levodopa and levodopa with entacapone do not appear to differ in efficacy from immediate-release levodopa for motor symptoms in early disease. There is a higher risk of impulse control disorders associated with the use of dopamine agonists than levodopa. Recommendations on initial therapy for motor symptoms are provided to assist the clinician and patient in choosing between treatment options and to guide counseling, prescribing, and monitoring of efficacy and safety.

Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances.

OBJECTIVES: Alteplase is commonly recommended for acute ischaemic stroke within 4.5 hours after stroke onset. The Third European Cooperative Acute Stroke Study (ECASS III) is the only trial reporting statistically significant efficacy for clinical outcomes for alteplase use 3-4.5 hours after stroke onset. However, baseline imbalances in history of prior stroke and stroke severity score may confound this apparent finding of efficacy. We reanalysed the ECASS III trial data adjusting for baseline imbalances to determine the robustness or sensitivity of the efficacy estimates. DESIGN: Reanalysis of randomised placebo-controlled trial. We obtained access to the ECASS III trial data and replicated the previously reported analyses to confirm our understanding of the data. We adjusted for baseline imbalances using multivariable analyses and stratified analyses and performed sensitivity analysis for missing data. SETTING: Emergency care. PARTICIPANTS: 821 adults with acute ischaemic stroke who could be treated 3-4.5 hours after symptom onset. INTERVENTIONS: Intravenous alteplase (0.9 mg/kg of body weight) or placebo. MAIN OUTCOME MEASURES: The original primary efficacy outcome was modified Rankin Scale (mRS) score 0 or 1 (ie, being alive without any disability) and the original secondary efficacy outcome was a global outcome based on a composite of functional end points, both at 90 days. Adjusted analyses were only reported for the primary efficacy outcome and the original study protocol did not specify methods for adjusted analyses. Our adjusted reanalysis included these outcomes, symptom-free status (mRS 0), dependence-free status (mRS 0-2), mortality (mRS 6) and change across the mRS 0-6 spectrum at 90 days; and mortality and symptomatic intracranial haemorrhage at 7 days. RESULTS: We replicated previously reported unadjusted analyses but discovered they were based on a modified interpretation of the National Institutes of Health Stroke Scale (NIHSS) score. The secondary efficacy outcome was no longer significant using the original NIHSS score. Previously reported adjusted analyses could only be replicated with significant effects for the primary efficacy outcome by using statistical approaches not reported in the trial protocol or statistical analysis plan. In analyses adjusting for baseline imbalances, all efficacy outcomes were not significant, but increases in symptomatic intracranial haemorrhage remained significant. CONCLUSIONS: Reanalysis of the ECASS III trial data with multiple approaches adjusting for baseline imbalances does not support any significant benefits and continues to support harms for the use of alteplase 3-4.5 hours after stroke onset. Clinicians, patients and policymakers should reconsider interpretations and decisions regarding management of acute ischaemic stroke that were based on ECASS III results. TRIAL REGISTRATION NUMBER: NCT00153036.

Summary of comprehensive systematic review: Rehabilitation in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

OBJECTIVE: To systematically review the evidence regarding rehabilitation treatments in multiple sclerosis (MS). METHODS: We systematically searched the literature (1970-2013) and classified articles using 2004 American Academy of Neurology criteria. RESULTS: This systematic review highlights the paucity of well-designed studies, which are needed to evaluate the available MS rehabilitative therapies. Weekly home/outpatient physical therapy (8 weeks) probably is effective for improving balance, disability, and gait (MS type unspecified, participants able to walk ≥5 meters) but probably is ineffective for improving upper extremity dexterity (1 Class I). Inpatient exercises (3 weeks) followed by home exercises (15 weeks) possibly are effective for improving disability (relapsing-remitting MS [RRMS], primary progressive MS [PPMS], secondary progressive MS [SPMS], Expanded Disability Status Scale [EDSS] 3.0-6.5) (1 Class II). Six weeks' worth of comprehensive multidisciplinary outpatient rehabilitation possibly is effective for improving disability/function (PPMS, SPMS, EDSS 4.0-8.0) (1 Class II). Motor and sensory balance training or motor balance training (3 weeks) possibly is effective for improving static and dynamic balance, and motor balance training (3 weeks) possibly is effective for improving static balance (RRMS, SPMS, PPMS) (1 Class II). Breathing-enhanced upper extremity exercises (6 weeks) possibly are effective for improving timed gait and forced expiratory volume in 1 second (RRMS, SPMS, PPMS, mean EDSS 4.5); this change is of unclear clinical significance. This technique possibly is ineffective for improving disability (1 Class II). Inspiratory muscle training (10 weeks) possibly improves maximal inspiratory pressure (RRMS, SPMS, PPMS, EDSS 2-6.5) (1 Class II).

Observations on the brain vasculature in multiple sclerosis: A historical perspective.

OBJECTIVES: To review the literature on vascular aspects of multiple sclerosis (MS) specifically pathological observations of the perivenular distribution of MS lesions and venous pathology in MS. METHODS: Comprehensive literature search from 2012 back to 1839. RESULTS: One hundred and thirty two papers from 1839 to 2012 were included in this study. Multiple authors observed central venules in MS lesions as a feature of MS with the first specific mention by Rindfleisch in 1863. Recent high field strength MRI has reintroduced the perivenular distribution of MS lesions to a new generation, and has suggested that there is disease specificity to this distribution. In addition Putnam and others in the 1930s hypothesized that venous disease was causative for MS. Treatments based on these observations have included anticoagulation, hyperbaric oxygen therapy, and recently endovascular venous procedures. The significance of these findings in terms of MS pathogenesis has been debated over the same period of time. CONCLUSIONS: While the controversy over venous disease in MS is new, the observation of perivenular MS plaques and venous theories about MS pathogenesis are as old as the history of MS research.

Extended-release dalfampridine in the management of multiple-sclerosis-related walking impairment.

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system that causes neurological impairment in young adults. As part of the disease, ambulation remains one of the most disabling features of multiple sclerosis. Extended-release dalfampridine is a long-acting form of 4-aminopyridine that has been shown in two phase III trials to increase ambulation speed in a subset of patients with multiple sclerosis (timed walk responders). The primary endpoint of these studies was 'responder status', analyzing difference in the proportion of timed walk responders between extended-release dalfampridine and placebo groups. Extended-release dalfampridine exerts its effects by inhibiting voltage-activated K(+) channels and has been previously demonstrated to improve action potential propagation in demyelinated nerve fibers in vitro. Side effects of extended-release dalfampridine include increased urinary tract infections, insomnia, headache, asthenia, dizziness, back pain, and paresthesias. Rare seizure events are also reported on the approved dose of 10 mg every 12 h. In this review we will summarize the results of key phase II and phase III trials of extended-release dalfampridine, its safety, and potential use in patients with multiple sclerosis.

Self-management in neurological disorders: systematic review of the literature and potential interventions in multiple sclerosis care.

Our objective was to review the current body of evidence supporting the efficacy of self-management programs in individuals with multiple sclerosis (MS) and other chronic neurological conditions. We reviewed published literature using standardized search terms; examined self-management interventions in a variety of chronic neurological disorders, including MS; and classified studies using the evidence classification established by the American Academy of Neurology. We reviewed 527 abstracts, of which 39 met our inclusion criteria for evaluation. Of the 39 studies, 3 provided class I evidence assessing the efficacy of self-management interventions: a randomized controlled trial of a telephone counseling program for health promotion in MS, a home-based exercise program for reducing falls in people with Parkinson disease, and the comparison of a fitness center program versus a home-based exercise program for people with traumatic brain injury. The remaining studies provided additional support for self-management interventions with a lesser degree of methodologic rigor (class II, class III, or class IV evidence). We concluded that self-management strategies are applicable to chronic neurological diseases, but a need exists for more rigorous studies in this area. We provide recommendations for future intervention study methodologies with a specific emphasis on MS care.

Management of acute exacerbations in multiple sclerosis.

A key component of multiple sclerosis is the occurrence of episodes of clinical worsening with either new symptoms or an increase in older symptoms over a few days or weeks. These are known as exacerbations of multiple sclerosis. In this review, we summarize the pathophysiology and treatment of exacerbations and describe how they are related to the overall management of this disease.