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International audience; Mutations in the gene encoding polymerase gamma (POLG) are a common cause of mitochondrial diseases in adults. We retrospectively analyzed volumetric and diffusion tensor imaging data from 20 adult POLG-mutated patients compared to healthy controls. We used an original clinical binary load score and electroneuromyography to evaluate disease severity. Patients showed atrophy in the basal ganglia, amygdala, and brainstem (p

Background and Purpose— Proximal large vessel occlusion (LVO) is present in up to 30% of minor strokes. The effectiveness of mechanical thrombectomy (MT) in the subgroup of minor stroke with LVO in the anterior circulation is still open to debate. Data about MT in this subgroup of patients are sparse, and their optimal management has not yet been defined. The purpose of this multicenter cohort study was to evaluate the effectiveness of MT in patients experiencing acute ischemic stroke (AIS) because of LVO in the anterior circulation, presenting with minor-to-mild stroke symptoms (National Institutes of Health Stroke Scale score of Methods— Multicenter cohort study involving 4 comprehensive stroke centers having 2 therapeutic approaches (urgent thrombectomy associated with best medical treatment [BMT] versus BMT first and MT if worsening occurs) about management of patients with minor and mild acute ischemic stroke harboring LVO in the anterior circulation. An intention-to-treat analysis was conducted. The primary end point was the rate of excellent outcome defined as the achievement of a modified Rankin Scale score of 0 to 1 at 3 months. Results— Three hundred one patients were included, 170 with urgent MT associated with BMT, and 131 with BMT alone as first-line treatment. Patients treated with MT were younger, more often received intravenous thrombolysis, and had shorter time to imaging. Twenty-four patients (18.0%) in the medical group had rescue MT because of neurological worsening. Overall, excellent outcome was achieved in 64.5% of patients, with no difference between the 2 groups. Stratified analysis according to key subgroups did not find heterogeneity in the treatment effect size. Conclusions— Minor-to-mild stroke patients with LVO achieved excellent and favorable functional outcomes at 3 months in similar proportions between urgent MT versus delayed MT associated with BMT. There is thus an urgent need for randomized trials to define the effectiveness of MT in this patient subgroup.

Background and Purpose— In acute ischemic stroke patients, diffusion-weighted imaging (DWI)–Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is correlated with infarct volume and is an independent factor of functional outcome. Patients with pretreatment DWI-ASPECTS ≤6 were excluded or under-represented in the recent randomized mechanical thrombectomy trials. Our aim was to assess the impact of reperfusion in pretreatment DWI-ASPECTS ≤6 patients treated with mechanical thrombectomy. Methods— We analyzed data collected between January 2012 and August 2015 in a bicentric prospective clinical registry of consecutive acute ischemic stroke patients treated with mechanical thrombectomy. Every patient with a documented internal carotid artery or middle cerebral artery occlusion with pretreatment DWI-ASPECTS ≤6 was eligible for this study. The primary end point was a favorable outcome defined by a modified Rankin Scale score ≤2 at 90 days. Results— Two hundred and eighteen patients with a DWI-ASPECTS ≤6 were included. Among them, 145 (66%) patients had successful reperfusion at the end of mechanical thrombectomy. Reperfused patients had an increased rate of favorable outcome (38.7% versus 17.4%; P =0.002) and a decreased rate of mortality at 3 months (22.5% versus 39.1%; P =0.013) compared with nonreperfused patients. The symptomatic intracranial hemorrhage rate was not different between the 2 groups (13.0% versus 14.1%; P =0.83). However, in patients with DWI-ASPECTS P =0.68) with a high mortality rate (45.7% versus 57.1%; P =0.38) with or without successful reperfusion. Conclusions— Successful reperfusion is associated with reduced mortality and disability in patients with a pretreatment DWI-ASPECTS ≤6. Further data from randomized studies are needed, particularly in patients with DWI-ASPECTS

Background Quantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B ([11C]PiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS. Methods Patients with active relapsing-remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with [11C]PiB and magnetic resonance imaging. Voxel-wise maps of [11C]PiB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination. Results At baseline, there was a progressive reduction in [11C]PiB binding from the normal-appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow-up, high between-patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p = 0.006 and beta-coefficient = –0.67 with the Expanded Disability Status Scale; p = 0.003 and beta-coefficient = –0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index. Interpretation [11C]PiB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs. Ann Neurol 2016;79:726–738

Background Patients with Huntington disease (HD) and their spouses often complain of agitation during sleep, but the causes are mostly unknown. Objective To evaluate sleep and nocturnal movements in patients with various HD stages and CAG repeats length. Methods The clinical features and sleep studies of 29 patients with HD were retrospectively collected (11 referred for genotype–phenotype correlations and 18 for agitation during sleep) and compared with those of 29 age- and sex-matched healthy controls. All patients had videopolysomnography, but the movements during arousals were re-analyzed in six patients with HD with stored video. Results The patients had a longer total sleep period and REM sleep onset latency, but no other differences in sleep than controls. There was no correlation between CAG repeat length and sleep measures, but total sleep time and sleep efficiency were lower in the subgroup with moderate than milder form of HD. Periodic limb movements and REM sleep behavior disorders were excluded, although 2/29 patients had abnormal REM sleep without atonia. In contrast, they had clumsy and opisthotonos-like movements during arousals from non-REM or REM sleep. Some movements were violent and harmful. They might consist of voluntary movements inappropriately involving the proximal part of the limbs on a background of exaggerated hypotonia. Giant (>65 mcV) sleep spindles were observed in seven (24%) patients with HD and one control. Conclusion The nocturnal agitation in patients with HD seems related to anosognostic voluntary movements on arousals, rather than to REM sleep behavior disorder and other sleep problems.

Objective:Polyglutamine (PolyQ) diseases are dominantly transmitted neurologic disorders, caused by coding and expanded CAG trinucleotide repeats. Cancer was reported retrospectively to be rare in patients with PolyQ diseases and we aimed to investigate its prevalence in France.Methods:Consecutive patients with Huntington disease (HD) and spinocerebellar ataxia (SCA) were questioned about cancer, cardiovascular diseases, and related risk factors in 4 university hospitals in Paris, Toulouse, Strasbourg, and Montpellier. Standardized incidence ratios (SIR), based on age- and sex-adjusted rate of the French population, were assessed for different types of cancer.Results:We questioned 372 patients with HD and 134 patients with SCA. SIR showed significantly reduced risk of cancer in HD: 23 observed cases vs 111.05 expected ones (SIR 0.21, 95% confidence interval [CI] 0.13–0.31), as well as in SCA: 7 observed cases vs 34.73 expected (SIR 0.23, 95% CI 0.08–0.42). This was surprising since risk behavior for cancer was increased in these patients, with significantly greater tobacco and alcohol consumption in patients with HD vs patients with SCA (p < 0.0056). There was no association between CAG repeat size and cancer or cardiovascular disease. However, in patients with HD, skin cancers were more frequent than expected (5 vs 0.98, SIR 5.11, 95% CI 1.65–11.95).Conclusions:There was a decreased cancer rate in PolyQ diseases despite high incidence of risk factors. Intriguingly, skin cancer incidence was higher, suggesting a crosstalk between neurodegeneration and skin tumorigenesis.

Background: The objective of the study was to evaluate the sensitivity to change of the Scale for the Assessment and Rating of Ataxia (score, 0–40) in Friedreich's ataxia. Methods: This was a follow-up study in adult patients with genetically confirmed Friedreich's ataxia evaluated at least twice (minimum interval, 6 months). Participants were outpatients at the Center for Neurogenetics of the Pitie-Salpetriere Hospital in Paris. Results: We included 84 patients; 60% had 3 or more evaluations. The mean score on first assessment was 22.7 ± 9, and the mean follow-up was 1.84 ± 1.10 years. The mean increase was 1.36 ± 2.3 points/year; this variation was not significantly linked to factors known to influence disease severity such as age at onset, disease duration, GAA expansion length, and wheelchair use. Conclusions: In adult Friedreich's ataxia patients the Scale for the Assessment and Rating of Ataxia can detect annual changes independently of disease severity. In future therapeutic trials no patient stratification is globally required. © 2011 Movement Disorder Society

Background: Responsive ataxia rating scales are essential for determining outcome measures in clinical trials. Methods: We evaluated the responsiveness over time of the composite cerebellar functional severity score, a quantitative score measuring cerebellar ataxia in 133 patients with autosomal dominant cerebellar ataxias (ADCA), which were prospectively evaluated at inclusion and after one-year of follow-up. A more responsive tool was developed, the Cerebellar Functional Severity score writing, incorporating the writing test at dominant hand to the Cerebellar Functional Severity score. Results: Within the one-year follow-up period, the Cerebellar Functional Severity score and its writing version increased significantly and the Scale for the Assessment and Rating of Ataxia decreased significantly reflecting increased severity of the cerebellar symptoms. The Cerebellar Functional Severity score writing responsiveness was best in genotypes SCA1, 2, and 3 compared with the other genotypes (effect size = 0.196, standardized response mean (SRM) = 0.624 versus effect size = −0.051, SRM = −0.150). The Cerebellar Functional Severity score writing used as an outcome measure would require only 163 SCA1, 2, or 3 patients per group in a two-arm interventional trial for a 50% reduction in progression and 80% of power. Discussion: Our study demonstrates that the Cerebellar Functional Severity score and Cerebellar Functional Severity score writing are responsive quantitative scores for evaluating sensitivity to change in ADCA patients and can be used as outcome measures in clinical trials, especially when targeting genotypes SCA1, 2 and 3. © 2011 Movement Disorder Society

Responsive ataxia rating scales are essential for determining outcome measures in clinical trials.We evaluated the responsiveness over time of the composite cerebellar functional severity score, a quantitative score measuring cerebellar ataxia in 133 patients with autosomal dominant cerebellar ataxias (ADCA), which were prospectively evaluated at inclusion and after one-year of follow-up. A more responsive tool was developed, the Cerebellar Functional Severity score writing, incorporating the writing test at dominant hand to the Cerebellar Functional Severity score.Within the one-year follow-up period, the Cerebellar Functional Severity score and its writing version increased significantly and the Scale for the Assessment and Rating of Ataxia decreased significantly reflecting increased severity of the cerebellar symptoms. The Cerebellar Functional Severity score writing responsiveness was best in genotypes SCA1, 2, and 3 compared with the other genotypes (effect size = 0.196, standardized response mean (SRM) = 0.624 versus effect size = -0.051, SRM = -0.150). The Cerebellar Functional Severity score writing used as an outcome measure would require only 163 SCA1, 2, or 3 patients per group in a two-arm interventional trial for a 50% reduction in progression and 80% of power.Our study demonstrates that the Cerebellar Functional Severity score and Cerebellar Functional Severity score writing are responsive quantitative scores for evaluating sensitivity to change in ADCA patients and can be used as outcome measures in clinical trials, especially when targeting genotypes SCA1, 2 and 3.

Background: There have been few epidemiologic studies on neuromyelitis optica (NMO) and none used the recent 2006 diagnostic criteria. Here we describe the clinical, laboratory, MRI, and disability course of NMO in a French cohort of 125 patients. Methods: We performed an observational, retrospective, multicenter study. Data were collected from September 2007 through August 2008, corresponding to the endpoint of the study. We identified 125 patients fulfilling the 2006 NMO criteria. Selection was made using hospital files and a specific clinical questionnaire for NMO. Results: Mean age at onset was 34.5 years (range 4–66) with a mean disease duration of 10 ± 7.8 years at the endpoint. The patients were mainly (87%) Caucasian, with a female:male ratio of 3:1. In 90% of cases, the association of optic neuritis, longitudinal extensive myelitis, and a Paty-negative initial brain MRI was sufficient to fulfill the supportive criteria. Eighty-eight percent of patients were treated with immunosuppressive therapies. Median delay from onset to Expanded Disability Status Scale (EDSS) score 4 was 7 years; score 6, 10 years; and score 7, 21 years. The first episode of myelitis was immediately followed by an EDSS score ≥4 in 37.3% of cases, and a severe residual visual loss was observed in 22% of patients after the first episode of optic neuritis. Multivariate analysis did not reveal any predictors of a poor evolution other than a high number of MRI brain lesions at diagnosis, which were predictive of a residual visual acuity ≤1/10. Conclusions: Our demographic data provide new data on disability in patients with neuromyelitis optica, most of whom were receiving treatment.

Background & Aims Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder caused by intestinal dysmotility and characterized by chronic symptoms suggesting bowel obstruction in the absence of fixed, occluding lesions. CIPO has been associated with primary defects of the mitochondrial oxidative phosphorylation pathway, although the frequency of mitochondrial disorders in patients with CIPO is unknown. This study evaluates mitochondrial function in patients with CIPO. Methods A retrospective study was performed of data collected from 80 CIPO patients at a tertiary centre over a 25-year period. Mitochondrial disorders were detected by analysis of serum lactate and thymidine phosphorylase activities, brain magnetic resonance images, and muscle biopsies. Genes encoding thymidine phosphorylase, mitochondrial DNA tRNA leu(UUR) or tRNA lys , and DNA polymerase-γ were analyzed for mutations. Results Mitochondrial defects were identified in 15 patients (10 women; median age at diagnosis 32 years), representing 19% of the study cohort. All 15 patients had extra-digestive symptoms, 5 had mutations in the thymidine phosphorylase gene, 2 had mutations in tRNA leu(UUR) , and 5 had mutations in the DNA polymerase-γ gene. No genetic defect was detected in 3 of the patients with mitochondrial disorders. Patients with mitochondrial CIPO differed from patients without mitochondrial defects in their very severe nutritional status (frequent and long-term requirement for parenteral nutrition) and poor prognosis (frequent digestive and neurologic complications that led to a high incidence of premature death). Conclusion Mitochondrial disorders seem to be an important cause of CIPO. Patients with CIPO, especially severe cases with associated neurologic symptoms, should be tested for mitochondrial defects.

Objective: To evaluate disease progression and determine validity of clinical tools for therapeutic trials in a cohort of dominant ataxias. Background Autosomal dominant cerebellar ataxias (SCAs) are genetically heterogeneous with more than 30 loci involved. Cerebellar degeneration is accompanied by changes in the brainstem, basal ganglia, cerebral cortex, spinal cord and peripheral nervous system. Design/Methods: 162 patients with SCAs, including SCAs with polyglutamine expansions (25 SCA1, 35 SCA2, 58 SCA3, 5 SCA6, 10 SCA7) and other SCAs (1 SCA5, 1 SCA14, 2 SCA21,1 SCA25, 2 SCA28, 22 unknown genotypes) were followed prospectively for 3 years in the national French Referral Network including 7 centers. The outcome measures were the quantitative composite cerebellar functional score with writing (CCFSw) and the scale for the assessment and rating of ataxia (SARA). Results: Disease worsened in patients with SCA1, 2, 3 mutations and remained stable in patients with SCA6, SCA7 or other SCA mutations with both the CCFSw and the SARA. CCFSw progression was faster in SCA3 patients with Parkinsonism and/or dystonia at baseline (p=.003) while SARA progression in SCA2 patients depend of the gender, the age at onset and at inclusion, the number of repeats of the normal SCA2 allele, and the posterior column dysfunction. A two-arm trial with SARA as the outcome measure would require 57 SCA2, 70 SCA1 and 75 SCA3 patients per group to detect a 50% reduction in disease progression (power 80%, alpha 0.05). Conclusions: Disease progressed faster in SCAs with polyglutamine expansions in SCA1, 2 and 3 than the other groups. Both outcome measures are suitable for therapeutic trials; SARA requires fewer patients to attain the same power, but CCFSw needs less stratification. We demonstrate that the choice of clinical outcome measure is critical for reliable evaluation of progression in neurodegenerative diseases. Disclosure: Dr. Tezenas Du Montcel has nothing to disclose. Dr. Charles Ignatiew has nothing to disclose. Dr. Goizet has received research support from Genzyme Corporation. Dr. Marelli has nothing to disclose. Dr. Anheim has nothing to disclose. Dr. Guyant-Marchal has nothing to disclose. Dr. Le Bayon has nothing to disclose. Dr. Vandenberghe has nothing to disclose. Dr. Tchikviladze has nothing to disclose. Dr. Devos has received personal compensation for activities with Novartis and Aguettant. Dr. Le Ber has nothing to disclose. Dr. N9Guyen has nothing to disclose. Dr. Cazeneuve has nothing to disclose. Dr. Tallaksen has nothing to disclose. Dr. Brice has nothing to disclose. Dr. Durr has nothing to disclose.

Objectives To evaluate disease progression and determine validity of clinical tools for therapeutic trials. Design Prospective cohort study (36 months). Setting Referral center. Patients One hundred sixty-two patients with autosomal dominant cerebellar ataxia and 64 with hereditary spastic paraplegia. Main Outcome Measures The quantitative Composite Cerebellar Functional Severity Score with the writing test (CCFSw) and Scale for the Assessment and Rating of Ataxia (SARA) score. Results Disease worsened in patients with SCA1, SCA2, and SCA3 mutations (mean [SE] increase in CCFSw, +0.014 [0.005] to +0.025 [0.004] per year), improved in patients with SPG4 mutations (mean [SE] increase in CCFSw, −0.012 [0.003] per year; P = .02), and remained stable in patients with SCA6, SCA7, or other SCA mutations (mean [SE] increase in CCFSw, −0.015 [0.011] to +0.009 [0.013] per year) or hereditary spastic paraplegia with other SPG mutations (mean [SE] increase in CCFSw, −0.005 [0.005] per year). Progression was faster in patients with SCA2 mutations and normal alleles with 22 or fewer repeats (P = .02) and in patients with SCA3 mutations with parkinsonism and/or dystonia at baseline (P = .003). Whereas CCFSw distinguished between patients with ataxia and spasticity, SARA scores increased in both groups. A 2-arm trial with SARA score as the outcome measure would require 57 patients with SCA2 mutations, 70 with SCA1 mutations, and 75 with SCA3 mutations per group to detect a 50% reduction in disease progression (power, 80%; α = .05). Conclusions Disease progressed faster in SCA s with polyglutamine expansions in SCA1, 2, and 3 than the other groups. Both outcome measures are suitable for therapeutic trials; SARA requires fewer patients to attain the same power, but CCFSw needs less stratification. We demonstrate that the choice of clinical outcome measure is critical for reliable evaluation of progression in neurodegenerative diseases. Trial Registration clinicaltrials.gov Identifier: NCT00136630