Neurology July 2012 Volume 79 Issue 2

Objective: Genetic heterogeneity is common in many neurologic disorders. This is particularly true for the hereditary ataxias where at least 36 disease genes or loci have been described for spinocerebellar ataxia and over 100 genes for neurologic disorders that present primarily with ataxia. Traditional genetic testing of a large number of candidate genes delays diagnosis and is expensive. In contrast, recently developed genomic techniques, such as exome sequencing that targets only the coding portion of the genome, offer an alternative strategy to rapidly sequence all genes in a comprehensive manner. Here we describe the use of exome sequencing to investigate a large, 5-generational British kindred with an autosomal dominant, progressive cerebellar ataxia in which conventional genetic testing had not revealed a causal etiology.Methods: Twenty family members were seen and examined; 2 affected individuals were clinically investigated in detail without a genetic or acquired cause being identified. Exome sequencing was performed in one patient where coverage was comprehensive across the known ataxia genes, excluding the known repeat loci which should be examined using conventional analysis.Results: A novel p.Arg26Gly change in the PRKCG gene, mutated in SCA14, was identified. This variant was confirmed using Sanger sequencing and showed segregation with disease in the entire family.Conclusions: This work demonstrates the utility of exome sequencing to rapidly screen heterogeneous genetic disorders such as the ataxias. Exome sequencing is more comprehensive, faster, and significantly cheaper than conventional Sanger sequencing, and thus represents a superior diagnostic screening tool in clinical practice.GLOSSARY: SCA: spinocerebellar ataxia(C)2012 American Academy of Neurology

Objective: We determined whether site of care explains a previously identified racial disparity in carotid artery imaging.Methods: In this retrospective cohort study, data were obtained from a chart review of veterans hospitalized with ischemic stroke at 127 Veterans Administration hospitals in 2007. Extensive exclusion criteria were applied to obtain a sample who should have received carotid artery imaging. Minority-serving hospitals were defined as the top 10% of hospitals ranked by the proportion of stroke patients who were black. Population level multivariate logistic regression models with adjustment for correlation of patients in hospitals were used to calculate predictive probabilities of carotid artery imaging by race and minority-service hospital status. Bootstrapping was used to obtain 95% confidence intervals (CIs).Results: The sample consisted of 1,534 white patients and 628 black patients. Nearly 40% of all black patients were admitted to 1 of 13 minority-serving hospitals. No racial disparity in receipt of carotid artery imaging was detected within nonminority serving hospitals. However, the predicted probability of receiving carotid artery imaging for white patients at nonminority-serving hospitals (89.7%, 95% CI [87.3%, 92.1%]) was significantly higher than both white patients (78.0% [68.3%, 87.8%] and black patients (70.5% [59.3%, 81.6%]) at minority-serving hospitals.Conclusions: Underuse of carotid artery imaging occurred most often among patients hospitalized at minority-serving hospitals. Further work is required to explore why site of care is a mechanism for racial disparities in this clinically important diagnostic test.GLOSSARY: CI: confidence intervalCMS: Centers for Medicare and Medicaid ServicesCTA: CT angiographyFY: fiscal yearMRA: magnetic resonance angiographyOQP: Offices of Quality and PerformancePCS: Patient Care ServicesVA: Veterans Health AdministrationVAMC: Veterans Affairs Medical CenterWVMI: West Virginia Medical Institute(C)2012 American Academy of Neurology

Objective: Both brain and body temperature rise after stroke but the cause of each is uncertain. We investigated the relationship between circulating markers of inflammation with brain and body temperature after stroke.Methods: We recruited patients with acute ischemic stroke and measured brain temperature at hospital admission and 5 days after stroke with multivoxel magnetic resonance spectroscopic imaging in normal brain and the acute ischemic lesion (defined by diffusion-weighted imaging [DWI]). We measured body temperature with digital aural thermometers 4-hourly and drew blood daily to measure interleukin-6, C-reactive protein, and fibrinogen, for 5 days after stroke.Results: In 44 stroke patients, the mean temperature in DWI-ischemic brain soon after admission was 38.4[degrees]C (95% confidence interval [CI] 38.2-38.6), in DWI-normal brain was 37.7[degrees]C (95% CI 37.6-37.7), and mean body temperature was 36.6[degrees]C (95% CI 36.3-37.0). Higher mean levels of interleukin-6, C-reactive protein, and fibrinogen were associated with higher temperature in DWI-normal brain at admission and 5 days, and higher overall mean body temperature, but only with higher temperature in DWI-ischemic brain on admission.Conclusions: Systemic inflammation after stroke is associated with elevated temperature in normal brain and the body but not with later ischemic brain temperature. Elevated brain temperature is a potential mechanism for the poorer outcome observed in stroke patients with higher levels of circulating inflammatory markers.GLOSSARY: CI: confidence intervalDVT: deep venous thrombosisDWI: diffusion-weighted imagingFLAIR: fluid-attenuated inversion recoveryFOV: field of view1H MRSI: proton magnetic resonance spectroscopy imagingIL-6: interleukin-6IQR: interquartile rangeMR: magnetic resonanceMRS: magnetic resonance spectroscopyNIHSS: NIH Stroke ScalePRESS: point resolved spectroscopy(C)2012 American Academy of Neurology

Objective: Fipamezole, a selective [alpha]2-adrenergic receptor antagonist, reduced levodopa-induced dyskinesias (LID) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. In 10 dyskinetic subjects with Parkinson disease (PD), a proof-of-concept study showed beneficial effects at single doses of 60 and 90 mg. The primary study objective was to assess suppression of LID by fipamezole at day 28, as measured by the Levodopa-Induced Dyskinesia Scale (LIDS), a modification of the Abnormal Involuntary Movement Scale.Methods: This was a double-blind, randomized, placebo-controlled, dose-escalating 28-day study in levodopa-treated patients with PD experiencing LID, conducted at 25 centers in the United States (115 subjects) and 7 centers in India (64 subjects). Dyskinesias were evaluated 3 times after subjects became "on" from levodopa. Outcome assessment was performed with analysis of variance, which evaluated fipamezole dose-effects in a hierarchical stepwise manner and the Jonckheere test for dose responsiveness.Results: The total study population showed no statistically significant primary endpoint difference. However, because of inhomogeneity recognized between US and Indian study populations, a prespecified subgroup analysis of US subjects was conducted, showing fipamezole at 90 mg reduced LID (mean, 95% CI, LID rating improvement vs placebo -1.9 [0.0 to -3.8; p = 0.047]). Dose responsiveness was demonstrated (p = 0.014 for placebo, 30, 60, and 90 mg fipamezole). Fipamezole induced mild, transient blood pressure elevation and was associated with an acceptable profile of adverse effects.Conclusions: The evidence of efficacy in the US subgroup suggested that fipamezole at 90 mg TID may be useful to treat LID in PD without exacerbating parkinsonism.Classification of evidence: This study provides Class III evidence that fipamezole is well-tolerated and, in the US subpopulation, lessens LID at 90 mg TID.GLOSSARY: AE: adverse eventCGI-I: Clinician Global Impression of ImprovementCI: confidence intervalITT: intention-to-treatLID: levodopa-induced dyskinesiaLIDS: Levodopa-Induced Dyskinesia ScaleLOCF: last observation carried forwardOC: observed casesPD: Parkinson diseasePDYS-26: 26-item Parkinson Disease Dyskinesia ScaleSAE: serious adverse eventTID: 3 times per dayUPDRS: Unified Parkinson's Disease Rating Scale(C)2012 American Academy of Neurology

Objectives: To evaluate the whole-brain resting-state networks in a homogeneous group of patients with acute mild traumatic brain injury (MTBI) and to identify alterations in functional connectivity induced by MTBI.Methods: Thirty-five patients with acute MTBI and 35 healthy control subjects, matched in age, gender, handedness, and education, underwent resting-state fMRI, susceptibility weighted imaging, neuropsychological, and postconcussive symptom assessments. We ensured the homogeneity of the patient group by limiting the injury mechanism to fronto-occipital impacts. Alterations in functional connectivity were analyzed by using data-driven independent component analysis, which is not biased by a priori region selection.Results: We found a decrease in functional connectivity within the motor-striatal network in the MTBI group. At the same time, patients showed deficits in psychomotor speed as well as in speed of information processing. We propose that although disorders in motor function after MTBI are rarely reported, injury still has an effect on motor functioning, which in its turn may also explain the reduction in speed of information processing. Further, we found a cluster of increased functional connectivity in the right frontoparietal network in the MTBI group. We suggest that this abnormal increased connectivity might reflect increased awareness to external environment and explain excessive cognitive fatigue reported by patients with MTBI. It might also underlie the physical postconcussive symptoms, such as headache and increased sensitivity to noise/light.Conclusions: We proved that whole-brain functional connectivity is altered early (within 4 weeks) after MTBI, suggesting that changes in functional networks underlie the cognitive deficits and postconcussive complaints reported by patients with MTBI.GLOSSARY: BOLD: blood oxygen level-dependentDNC: dynamic network connectivityFTT: Finger Tapping TestGCS: Glasgow Coma ScaleGOSE: Glasgow Outcome Scale ExtendedICA: independent component analysisLOC: loss of consciousnessMTBI: mild traumatic brain injuryPCS: postconcussion syndromePTA: posttraumatic amnesiars-fMRI: resting state fMRIRSN: resting-state networkSWI: susceptibility weighted imagingTBI: traumatic brain injuryTE: echo timeTFCE: threshold-free cluster enhancementTOMM: Test of Memory MalingeringTR: repetition time.(C)2012 American Academy of Neurology