Neurology March 2013 Volume 80 Issue 12

Objective: To assess the 1-year safety profile of the dopaminergic stabilizer pridopidine in patients with Huntington disease.Methods: Patients received pridopidine 45 mg/day for 4 weeks then pridopidine 90 mg/day for 22 weeks in this 6-month open-label extension (OLE) of the 6-month MermaiHD randomized controlled trial (RCT). Any adverse events (AEs) were recorded. Patients were categorized by their RCT treatment group (placebo, pridopidine 45 mg/day, pridopidine 90 mg/day).Results: Of the 386 patients who completed the RCT, 353 entered the OLE and 305 (86.4%) completed. In 1 year, similar percentages of patients from each group reported >=1 AE (placebo, 79.6% [n = 90/113]; 45 mg/day, 80.8% [n = 101/125]; 90 mg/day, 82.6% [n = 95/115]) and >=1 serious AE (8.0% [n = 9/113], 12.8% [n = 16/125], and 8.7% [n = 10/115], respectively). The AE profile across both studies was similar; falls and worsening of chorea were most commonly reported. During the OLE, more patients previously receiving pridopidine reported >=1 AE (67.9% [n = 163/240]) than those who had received placebo (56.6% [n = 64/113]). Early in the RCT, small increases in heart rate were reported in patients receiving pridopidine. During 1 year, no clinically meaningful changes in laboratory parameters or EKG-related safety concerns were identified.Conclusion: Pridopidine (<=90 mg/day) has an acceptable safety profile and is well-tolerated for 1 year.Classification of evidence: This study provides Class IV evidence that pridopidine (<=90 mg/day) is generally safe and well-tolerated in patients with Huntington disease for up to 1 year.(C)2013 American Academy of Neurology

Objective: The aim of this fluorodeoxyglucose (FDG)-PET study was to determine whether the activation pattern in patients with an acute unilateral central vestibular lesion (e.g., lesion of the vestibular nucleus) differs from that known in patients with an acute peripheral vestibular deficit.Methods: Twelve patients with circumscribed unilateral medullary brainstem infarctions (6 right, 6 left) causing acute vestibular imbalance underwent resting-state 18F-FDG-PET. Regional cerebral glucose metabolism was measured twice without any stimulation and with eyes closed: in the acute phase after infarct onset on mean day 8 (range 4-12), and again 6 months later in 7 patients after recovery. Group subtraction analyses and comparisons with a dataset of 12 age-matched controls were done with Statistic Parametric Mapping.Results: In the acute stage, the pattern of signal increases differed from that in peripheral vestibular lesions: whereas signals in the infratentorial areas in the contralateral medulla and cerebellum (peduncle, vermis, hemispheres) were increased, areas at the cortical level were largely spared. Signal decreases were found in similar sites in the visual cortex bilaterally.Conclusions: The current data provide evidence that the lesion site significantly modifies the glucose metabolism pattern in an acute vestibular lesion. Different compensation strategies seem to be apparent: after vestibular nucleus lesions, compensation occurs preferably in brainstem-cerebellar loops; after peripheral lesions, it occurs at the cortical level.(C)2013 American Academy of Neurology

Objective: To characterize the patterns of brain atrophy in patients with amyotrophic lateral sclerosis (ALS) with and without cognitive and neuropsychiatric symptoms, in comparison to controls and patients with ALS-frontotemporal dementia (FTD).Methods: A total of 57 participants (ALS = 22; ALS-FTD = 17; controls = 18) were included, following current ALS and FTD criteria. Patients with ALS were further subclassified into ALS with cognitive and behavioral symptoms (ALS-plus; n = 8) and those without (ALS; n = 14). By definition, ALS-plus did not reach the diagnostic threshold for ALS-FTD. All patients underwent neuropsychological and neuropsychiatric assessments, and underwent a brain MRI. Voxel-based morphometry analysis was conducted to establish patterns of brain atrophy.Results: Cortical atrophy in ALS was linked to neuropsychiatric and cognitive changes (ALS-plus vs ALS). Patients with ALS-plus had significant atrophy across motor and somatosensory as well as adjacent frontal and parietal areas, even after strict multiple comparison correction. By contrast, patients with ALS showed no significant cortical atrophy, and only brainstem atrophy. Importantly, atrophy in ALS-plus was not as widespread as in ALS-FTD, with ALS-plus atrophy mostly confined to motor and somatosensory areas, while atrophy in ALS-FTD also included substantial frontal and temporal atrophy.Conclusions: The present findings establish that cortical atrophy in ALS is highly dependent upon neuropsychiatric and cognitive changes. Previous inconsistent findings of cortical atrophy in ALS likely relate to the inclusion of cognitively affected patients and patients with pure motor ALS.(C)2013 American Academy of Neurology

Objectives: To determine the characteristics of adult-onset autoimmune chorea, and compare paraneoplastic and idiopathic subgroups.Methods: Thirty-six adults with autoimmune chorea were identified at Mayo Clinic (Rochester, MN) from 1997 to 2012. Medical record and laboratory data were recorded. Nonparaneoplastic (n = 22) and paraneoplastic cases (n = 14) were compared.Results: Women accounted for 21 patients (58%). Median age at symptom onset was 67 years (range 18-87 years). We estimated the incidence for Olmsted County was 1.5 per million person-years. Symptom onset was subacute in all. Chorea was focal (20 patients) or generalized (16 patients). Although chorea predominated, other neurologic disorders frequently coexisted (29 patients); abnormal eye movements were uncommon (4 patients). No patient had NMDA receptor antibody or any immunoglobulin (Ig)G yielding a detectable immunofluorescence binding pattern restricted to basal ganglia. Two had synaptic IgG antibodies novel to the context of chorea (GAD65, 1; CASPR2, 1). In the paraneoplastic group, 14 patients had evidence of cancer. Of 13 with a histopathologically confirmed neoplasm, small-cell carcinoma and adenocarcinoma were most common; 6 patients had a cancer-predictive paraneoplastic autoantibody, with CRMP-5-IgG and ANNA-1 being most common. In the idiopathic group, 19 of the 22 patients had a coexisting autoimmune disorder (most frequently systemic lupus erythematosus and antiphospholipid syndrome); autoantibodies were detected in 21 patients, most frequently lupus and phospholipid specificities (19 patients). The paraneoplastic group was older (p = 0.001), more frequently male (p = 0.006), had more frequent weight loss (p = 0.02), and frequently had peripheral neuropathy (p = 0.008).Conclusions: Autoimmune chorea is a rare disorder with rapid onset. Male sex, older age, severe chorea, coexisting peripheral neuropathy, and weight loss increase the likelihood of cancer.(C)2013 American Academy of Neurology

Objective: Pediatric studies for new biological agents are mandated by recent legislation, necessitating careful thought to evaluation of emerging multiple sclerosis (MS) therapies in children with MS. Challenges include a small patient population, the lack of prior randomized clinical trials, and ethical concerns. The goal of this meeting was to assess areas of consensus regarding clinical trial design and outcome measures among academic experts involved in pediatric MS care and research.Methods: The Steering Committee of the International Pediatric MS Study Group identified key focus areas for discussion. A total of 69 meeting attendees were assembled, including 35 academic experts. Regulatory and pharmaceutical representatives also attended, and provided input, which informed academic expert consensus decisions.Results: The academic experts agreed that clinical trials were necessary in pediatric MS to obtain pharmacokinetic, safety and efficacy data, and regulatory approval allowing for greater medication access. The academic experts agreed that relapse was an appropriate primary outcome measure for phase III pediatric trials. An international standardized cognitive battery was identified. The pros and cons of various trial designs were discussed. Guidelines surrounding MRI studies, pharmacokinetics, pharmacodynamics, and registries were developed. The academic experts agreed that given the limited subject pool, a stepwise approach to the launch of clinical trials for the most promising medications is necessary in order to ensure study completion. Alternative approaches could result in unethical exposure of patients to trial conditions without gaining knowledge.Conclusion: Consensus points for conduct of clinical trials in the rare disease pediatric MS were identified amongst a panel of academic experts, informed by regulatory and industry stakeholders.(C)2013 American Academy of Neurology