domenica 29 gennaio 2017
Importance Childhood arterial ischemic stroke (CAIS) affects approximately 1.6 per 100 000 children per year, while stroke recurs in up to 20% of patients at 5 years. Factors determining the risk of recurrence are incompletely understood.
Objective To investigate the incidence of the recurrence of CAIS in the posterior and anterior circulations to determine if the risk differs between the 2 locations.
Design, Setting, and Participants A retrospective analysis of CAIS was conducted among children enrolled in a single-center prospective consecutive cohort at The Children’s Hospital of Philadelphia between January 1, 2006, and January 1, 2015. Children with confirmed CAIS occurring between 29 days and 17.99 years were evaluated for inclusion. Patients were excluded if infarcts were located in both the anterior and posterior distributions or if CAIS occurred as a complication of intracranial surgery or brain tumor.
Main Outcomes and Measures Stroke recurrence.
Results The study population included 107 patients (75 boys [70.1%] and 32 girls [29.9%]; median age at AIS, 7.7 years [interquartile range, 3.1-13.6 years]). Sixty-one children had anterior circulation CAIS (ACAIS) and 46 had posterior circulation CAIS (PCAIS). Median follow-up was 20.9 months (interquartile range, 8.7-40.4 months). For ACAIS, recurrence-free survival was 100% at 1 month and 96% (95% CI, 85%-99%) at 1 and 3 years. For PCAIS, recurrence-free survival was 88% (95% CI, 75%-95%) at 1 month and 81% (95% CI, 66%-90%) at 1 and 3 years. The hazard ratio for recurrence after PCAIS compared with ACAIS was 6.4 (95% CI, 1.4-29.8; P = .02) in univariable analysis and 5.3 (95% CI, 1.1-26.4; P = .04) after adjusting for sex and cervical dissection.
Conclusions and Relevance We identified a subgroup of patients that comprise more than 80% of recurrences of CAIS. Three years after incident stroke, 19% of children with PCAIS had a recurrence compared with 4% of patients with ACAIS. Different mechanisms of stroke may account for this difference. Children with PCAIS may warrant increased monitoring. This study highlights the necessity for further research focused on recurrence prevention.
JAMA Neurology 2017
Association Between Serum MicroRNAs and Magnetic Resonance Imaging Measures of Multiple Sclerosis Severity
Importance MicroRNAs (miRNAs) are promising multiple sclerosis (MS) biomarkers. Establishing the association between miRNAs and magnetic resonance imaging (MRI) measures of disease severity will help define their significance and potential impact.
Objective To correlate circulating miRNAs in the serum of patients with MS to brain and spinal MRI.
Design, Setting, and Participants A cross-sectional study comparing serum miRNA samples with MRI metrics was conducted at a tertiary MS referral center. Two independent cohorts (41 and 79 patients) were retrospectively identified from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital. Expression of miRNA was determined by locked nucleic acid–based quantitative real-time polymerase chain reaction. Spearman correlation coefficients were used to test the association between miRNA and brain lesions (T2 hyperintense lesion volume [T2LV]), the ratio of T1 hypointense lesion volume [T1LV] to T2LV [T1:T2]), brain atrophy (whole brain and gray matter), and cervical spinal cord lesions (T2LV) and atrophy. The study was conducted from December 2013 to April 2016.
Main Outcomes and Measures miRNA expression.
Results Of the 120 patients included in the study, cohort 1 included 41 participants (7 [17.1%] men), with mean (SD) age of 47.7 (9.5) years; cohort 2 had 79 participants (26 [32.9%] men) with a mean (SD) age of 43.0 (7.5) years. Associations between miRNAs and MRIs were both protective and pathogenic. Regarding miRNA signatures, a topographic specificity differed for the brain vs the spinal cord, and the signature differed between T2LV and atrophy/destructive measures. Four miRNAs showed similar significant protective correlations with T1:T2 in both cohorts, with the highest for hsa.miR.143.3p (cohort 1: Spearman correlation coefficient rs = −0.452, P = .003; cohort 2: rs = −0.225, P = .046); the others included hsa.miR.142.5p (cohort 1: rs = −0.424, P = .006; cohort 2: rs = −0.226, P = .045), hsa.miR.181c.3p (cohort 1: rs = −0.383, P = .01; cohort 2: rs = −0.222, P = .049), and hsa.miR.181c.5p (cohort 1: rs = −0.433, P = .005; cohort 2: rs = −0.231, P = .04). In the 2 cohorts, hsa.miR.486.5p (cohort 1: rs = 0.348, P = .03; cohort 2: rs = 0.254, P = .02) and hsa.miR.92a.3p (cohort 1: rs = 0.392, P = .01; cohort 2: rs = 0.222, P = .049) showed similar significant pathogenic correlations with T1:T2; hsa.miR.375 (cohort 1: rs = −0.345, P = .03; cohort 2: rs = −0.257, P = .022) and hsa.miR.629.5p (cohort 1: rs = −0.350, P = .03; cohort 2: rs = −0.269, P = .02) showed significant pathogenic correlations with brain atrophy. Although we found several miRNAs associated with MRI outcomes, none of these associations remained significant when correcting for multiple comparisons, suggesting that further validation of our findings is needed.
Conclusions and Relevance Serum miRNAs may serve as MS biomarkers for monitoring disease progression and act as surrogate markers to identify underlying disease processes.
JAMA Neurology 2017
The ability to assess the distribution and extent of tau pathology in Alzheimer’s disease and progressive supranuclear palsy would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in their potential as tau biomarkers. We assessed the radiotracer F-AV-1451 with positron emission tomography imaging to compare the distribution and intensity of tau pathology in 15 patients with Alzheimer’s pathology (including amyloid-positive mild cognitive impairment), 19 patients with progressive supranuclear palsy, and 13 age- and sex-matched controls. Regional analysis of variance and a support vector machine were used to compare and discriminate the clinical groups, respectively. We also examined the F-AV-1451 autoradiographic binding in post mortem tissue from patients with Alzheimer’s disease, progressive supranuclear palsy, and a control case to assess the F-AV-1451 binding specificity to Alzheimer’s and non-Alzheimer’s tau pathology. There was increased F-AV-1451 binding in multiple regions in living patients with Alzheimer’s disease and progressive supranuclear palsy relative to controls [main effect of group, (2,41) = 17.5, < 0.0001; region of interest × group interaction, (2,68) = 7.5, < 0.00001]. More specifically, F-AV-1451 binding was significantly increased in patients with Alzheimer’s disease, relative to patients with progressive supranuclear palsy and with control subjects, in the hippocampus and in occipital, parietal, temporal, and frontal cortices (t’s > 2.2, ’s < 0.04). Conversely, in patients with progressive supranuclear palsy, relative to patients with Alzheimer’s disease, F-AV-1451 binding was elevated in the midbrain (t = 2.1, < 0.04); while patients with progressive supranuclear palsy showed, relative to controls, increased F-AV-1451 uptake in the putamen, pallidum, thalamus, midbrain, and in the dentate nucleus of the cerebellum (t’s > 2.7, ’s < 0.02). The support vector machine assigned patients’ diagnoses with 94% accuracy. The post mortem autoradiographic data showed that F-AV-1451 strongly bound to Alzheimer-related tau pathology, but less specifically in progressive supranuclear palsy. F-AV-1451 binding to the basal ganglia was strong in all groups Postmortem histochemical staining showed absence of neuromelanin-containing cells in the basal ganglia, indicating that off-target binding to neuromelanin is an insufficient explanation of F-AV-1451 positron emission tomography data , at least in the basal ganglia. Overall, we confirm the potential of F-AV-1451 as a heuristic biomarker, but caution is indicated in the neuropathological interpretation of its binding. Off-target binding may contribute to disease profiles of F-AV-1451 positron emission tomography, especially in primary tauopathies such as progressive supranuclear palsy. We suggest that F-AV-1451 positron emission tomography is a useful biomarker to assess tau pathology in Alzheimer’s disease and to distinguish it from other tauopathies with distinct clinical and pathological characteristics such as progressive supranuclear palsy.
Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial
Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1G93A mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS.
This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18–80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed.
Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was −14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of −30·0 (95% CI −67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group).
Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS.
Lancet Neurology 2017
sabato 21 gennaio 2017
In 2007, the clinical and research profile of illusions, hallucinations, delusions and related symptoms in Parkinson disease (PD) was raised with the publication of a consensus definition of PD psychosis. Symptoms that were previously deemed benign and clinically insignificant were incorporated into a continuum of severity, leading to the rapid expansion of literature focusing on clinical aspects, mechanisms and treatment. Here, we review this literature and the evolving view of PD psychosis. Key topics include the prospective risk of dementia in individuals with PD psychosis, and the causal and modifying effects of PD medication. We discuss recent developments, including recognition of an increase in the prevalence of psychosis with disease duration, addition of new visual symptoms to the psychosis continuum, and identification of frontal executive, visual perceptual and memory dysfunction at different disease stages. In addition, we highlight novel risk factors — for example, autonomic dysfunction — that have emerged from prospective studies, structural MRI evidence of frontal, parietal, occipital and hippocampal involvement, and approval of pimavanserin for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research to explore the clinical management and biomarker potential of PD psychosis.
Nature Reviews Neurology 2017
Electroencephalographic Periodic Discharges and Frequency-Dependent Brain Tissue Hypoxia in Acute Brain Injury
Importance Periodic discharges (PDs) that do not meet seizure criteria, also termed the ictal interictal continuum, are pervasive on electroencephalographic (EEG) recordings after acute brain injury. However, their association with brain homeostasis and the need for clinical intervention remain unknown.
Objective To determine whether distinct PD patterns can be identified that, similar to electrographic seizures, cause brain tissue hypoxia, a measure of ongoing brain injury.
Design, Setting, and Participants This prospective cohort study included 90 comatose patients with high-grade spontaneous subarachnoid hemorrhage who underwent continuous surface (scalp) EEG (sEEG) recording and multimodality monitoring, including invasive measurements of intracortical (depth) EEG (dEEG), partial pressure of oxygen in interstitial brain tissue (Pbto2), and regional cerebral blood flow (CBF). Patient data were collected from June 1, 2006, to September 1, 2014, at a single tertiary care center. The retrospective analysis was performed from September 1, 2014, to May 1, 2016, with a hypothesis that the effect on brain tissue oxygenation was primarily dependent on the discharge frequency.
Main Outcomes and Measures Electroencephalographic recordings were visually classified based on PD frequency and spatial distribution of discharges. Correlations between mean multimodality monitoring data and change-point analyses were performed to characterize electrophysiological changes by applying bootstrapping.
Results Of the 90 patients included in the study (26 men and 64 women; mean [SD] age, 55  years), 32 (36%) had PDs on sEEG and dEEG recordings and 21 (23%) on dEEG recordings only. Frequencies of PDs ranged from 0.5 to 2.5 Hz. Median Pbto2 was 23 mm Hg without PDs compared with 16 mm Hg at 2.0 Hz and 14 mm Hg at 2.5 Hz (differences were significant for 0 vs 2.5 Hz based on bootstrapping). Change-point analysis confirmed a temporal association of high-frequency PD onset (≥2.0 Hz) and Pbto2 reduction (median normalized Pbto2 decreased by 25% 5-10 minutes after onset). Increased regional CBF of 21.0 mL/100 g/min for 0 Hz, 25.9 mL/100 g/min for 1.0 Hz, 27.5 mL/100 g/min for 1.5 Hz, and 34.7 mL/100 g/min for 2.0 Hz and increased global cerebral perfusion pressure of 91 mm Hg for 0 Hz, 100.5 mm Hg for 0.5 Hz, 95.5 mm Hg for 1.0 Hz, 97.0 mm Hg for 2.0 Hz, 98.0 mm Hg for 2.5 Hz, 95.0 mm Hg for 2.5 Hz, and 67.8 mm Hg for 3.0 Hz were seen for higher PD frequencies.
Conclusions and Relevance These data give some support to consider redefining the continuum between seizures and PDs, suggesting that additional damage after acute brain injury may be reflected by frequency changes in electrocerebral recordings. Similar to seizures, cerebral blood flow increases in patients with PDs to compensate for the increased metabolic demand but higher-frequency PDs (>2 per second) may be inadequately compensated without an additional rise in CBF and associated with brain tissue hypoxia, or higher-frequency PDs may reflect inadequacies in brain compensatory mechanisms.
JAMA Neurology 2017