Neurology March 2013 Volume 80 Issue 11

Objective: Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes.Methods: We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics.Results: We identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD.Conclusions: We confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.(C)2013 American Academy of Neurology

Objective: This study explores a large panel of cytokines in plasma and CSF of patients with Aicardi-Goutieres syndrome (AGS) at different ages, in order to establish signatures of cytokines most predictive of AGS.Methods: Plasma from 22 subjects with known mutations were assayed for cytokines using the Milliplex MAP Immunobead system, and compared to results from 8 age-matched normal controls. CSF of 11 additional patients with mutation-proven AGS was tested in an identical manner and compared to results from age-matched controls. Samples were banked and analysis was carried out retrospectively.Results: Significant elevations were seen in FMS-related tyrosine kinase 3 ligand, IP-10, interleukin (IL)-12p40, IL-15, tumor necrosis factor [alpha], and soluble IL 2 receptor [alpha] in both AGS patient plasma and CSF relative to controls. Additionally, this cytokine signature was able to correctly cluster 9 of 11 AGS cases based on CSF values. While most cytokines decreased exponentially with age, a subgroup including IP-10 demonstrated persistent elevation beyond early childhood.Conclusion: Patients with AGS exhibit plasma and CSF elevations of proinflammatory cytokines. Selected cytokines remain persistently elevated beyond the initial disease phase. This panel of proinflammatory cytokines may be considered for use as diagnostic and therapeutic markers of disease, and may permit improved understanding of disease pathogenesis.(C)2013 American Academy of Neurology

Objective: CHADS2 and CHA2DS2-VASc scores are used to assess stroke risk in patients with atrial fibrillation (AF). We investigated whether these scores are associated with stroke outcome in non-AF stroke patients.Methods: Consecutive patients with acute first-ever ischemic stroke but without AF were classified into subgroups according to prestroke CHADS2 and CHA2DS2-VASc scores and followed up for 5 years. The end points were death, stroke recurrence, and a composite of major cardiovascular events.Results: Among 1,756 patients (aged 67.2 +/- 12.3 years, 68.2% males), there were 258 (14.7%), 617 (35.3%), and 878 (50.0%) patients with low, intermediate, and high CHADS2 score, respectively. The corresponding figures for CHA2DS2-VASc subgroups were 110 (6.3%), 255 (14.5%), and 1,391 (79.2%). There were significant differences between CHADS2 subgroups in 5-year mortality (log-rank test = 74.5, p < 0.0001), stroke recurrence (log-rank test = 12.3, p = 0.002), and cardiovascular events (log-rank test = 19.4, p < 0.001). Similarly, there were significant differences between CHA2DS2-VASc subgroups in 5-year mortality (log-rank test = 74.5, p < 0.0001), stroke recurrence (log-rank test = 10.6, p = 0.005), and cardiovascular events (log-rank test = 16.4, p < 0.001). Compared with the low-risk group, patients in intermediate- and high-risk CHADS2 subgroups had higher 5-year mortality (hazard ratio [HR]: 2.22 [95% confidence interval {CI}: 1.78-2.77] and 3.66 [95% CI: 2.38-5.62], respectively), stroke recurrence (HR: 1.74 [95% CI: 1.09-2.79] and 1.71 [95% CI: 1.08-2.71], respectively), and cardiovascular events (HR: 1.78 [95% CI: 1.23-2.57] and 1.86 [95% CI: 1.30-2.67], respectively). Compared with the low-risk group, patients in the high-risk CHA2DS2-VASc subgroup also had higher 5-year mortality (HR: 3.56, 95% CI: 1.89-6.70), stroke recurrence (HR: 2.93, 95% CI: 1.30-6.61), and cardiovascular events (HR: 2.71, 95% CI: 1.49-4.95).Conclusions: Prestroke CHADS2 and CHA2DS2-VASc scores predict long-term stroke outcomes in non-AF patients with acute ischemic stroke. These scores may provide a simple way of stroke prognostic risk stratification among non-AF stroke patients.(C)2013 American Academy of Neurology

Objective: To investigate whether extent and severity of white matter (WM) damage, as measured with diffusion tensor imaging (DTI), can distinguish cognitively preserved (CP) from cognitively impaired (CI) multiple sclerosis (MS) patients.Methods: Conventional MRI and DTI data were acquired from 55 MS patients (35 CP, 20 CI) and 30 healthy controls (HC). Voxelwise analyses were used to investigate fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity of a WM skeleton. Regional gray matter volume was quantified and lesion probability maps were generated.Results: Compared to HCs, decreased FA was found in 49% of the investigated WM skeleton in CP patients and in 76% of the investigated WM in CI patients. Several brain areas that showed reduced FA in both patient groups were significantly worse in CI patients, i.e, corpus callosum, superior and inferior longitudinal fasciculus, corticospinal tracts, forceps major, cingulum, and fornices. In CI patients, WM integrity damage was additionally seen in cortical brain areas, thalamus, uncinate fasciculus, brainstem, and cerebellum. These findings were independent of lesion location and regional gray matter volume, since no differences were found between the groups.Conclusion: CI patients diverged from CP patients only on DTI metrics. WM integrity changes were found in areas that are highly relevant for cognition in the CI patients but not in the CP patients. These WM changes are therefore thought to be related to the cognitive deficits and suggest that DTI might be a powerful tool when monitoring cognitive impairment in MS.(C)2013 American Academy of Neurology

Objective: To measure changes in psychometric state, neural activation, brain volume (BV), and cerebral metabolite concentrations during treatment of minimal hepatic encephalopathy.Methods: As proof of principle, 22 patients with well-compensated, biopsy-proven cirrhosis of differing etiology and previous minimal hepatic encephalopathy were treated with oral L-ornithine L-aspartate for 4 weeks. Baseline and 4-week clinical review, blood chemistry, and psychometric evaluation (Psychometric Hepatic Encephalopathy Score and Cognitive Drug Research Score) were performed. Whole-brain volumetric and functional MRI was conducted using a highly simplistic visuomotor task, together with proton magnetic resonance spectroscopy of the basal ganglia. Treatment-related changes in regional BV and neural activation change (blood oxygenation level dependent) were assessed.Results: Although there was no change in clinical, biochemical state, basal ganglia magnetic resonance spectroscopy, or in regional BV, there were significant improvements in Cognitive Drug Research Score (+1.2, p = 0.003) and Psychometric Hepatic Encephalopathy Score (+1.5, p = 0.003) with treatment. This cognitive amelioration was accompanied by changes in blood oxygenation level-dependent activation in the posterior cingulate and ventral medial prefrontal cortex, 2 regions that form part of the brain's structural and metabolic core. In addition, there was evidence of greater visual cortex activation.Conclusions: These structurally interconnected regions all showed increased function after successful encephalopathy treatment. Because no regional change in BV was observed, this implies that mechanisms unrelated to astrocyte volume regulation were involved in the significant improvement in cognitive performance.(C)2013 American Academy of Neurology

Hospitals and physicians' practices are rapidly implementing the electronic health record (EHR) because it offers many demonstrated advantages over paper records. Issues of misuse of the EHR previously identified include breaches in confidentiality and privacy and inappropriate record sharing. I describe a separate set of ethical and quality problems of the EHR that result from its otherwise beneficial timesaving features that inadvertently enable carelessness and harmful shortcuts. These problems include copying and pasting data obtained from other clinicians, authorship ambiguities, inadvertent inclusion of unobtained data in templated notes, misleading history and physical examinations, failure to review prepopulated data, inadequate discharge summaries, impairments to patient-physician communication, and the transformation of the purpose of the medical record to billing documentation. I offer a brief analysis and recommendations to mitigate these problems.(C)2013 American Academy of Neurology