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    ABSTRACT: Migraine headaches are a common comorbidity in Rolandic Epilepsy (RE) and familial aggregation of migraine in RE families suggests a genetic basis not mediated by seizures. We performed a genome-wide linkage analysis of the migraine phenotype in 38 families with RE to localize potential genetic contribution, with a follow-up in an additional 21 families at linked loci. We used two-point and multipoint LOD (logarithm of the odds) score methods for linkage, maximized over genetic models. We found evidence of linkage to migraine at chromosome 17q12-22 (multipoint HLOD 4.40 (heterogeneity LOD), recessive, 99% penetrance), replicated in the second dataset (HLOD 2.61); and suggestive evidence at 1q23.1-23.2, centering over the FHM2 locus (2PT LOD 3.00, MP HLOD 2.52). Sanger sequencing in 14 migraine-affected individuals found no coding mutations in the FHM2 gene ATP1A2. There was no evidence of pleiotropy for migraine and either reading or speech disorder, or the electroencephalographic endophenotype of RE when the affected definition was redefined as those with migraine or the comorbid phenotype, and pedigrees re-analyzed for linkage.
    Genes Brain and Behavior 11/2013;
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    ABSTRACT: The GGGGCC (G4C2) intronic repeat expansion within C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Intranuclear neuronal RNA foci have been observed in ALS and FTD tissues, suggesting that G4C2 RNA may be toxic. Here, we demonstrate that the expression of 38× and 72× G4C2 repeats form intranuclear RNA foci that initiate apoptotic cell death in neuronal cell lines and zebrafish embryos. The foci colocalize with a subset of RNA binding proteins, including SF2, SC35, and hnRNP-H in transfected cells. Only hnRNP-H binds directly to G4C2 repeats following RNA immunoprecipitation, and only hnRNP-H colocalizes with 70% of G4C2 RNA foci detected in C9ORF72 mutant ALS and FTD brain tissues. We show that expanded G4C2 repeats are potently neurotoxic and bind hnRNP-H and other RNA binding proteins. We propose that RNA toxicity and protein sequestration may disrupt RNA processing and contribute to neurodegeneration.
    Cell Reports 11/2013;
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease of motor neurons, resulting in worsening weakness of voluntary muscles until death from respiratory failure occurs after about 3 years. Although great advances have been made in our understanding of the genetic causes of ALS, the contribution of environmental factors has been more difficult to assess. Large-scale studies of the clinical patterns of ALS, individual histories preceding the onset of ALS, and the rates of ALS in different populations and groups have led to improved patient care, but have not yet revealed a replicable, definitive environmental risk factor. In this Review, we outline what is currently known of the environmental and genetic epidemiology of ALS, describe the current state of the art with respect to the different types of ALS, and explore whether ALS should be considered a single disease or a syndrome. We examine the relationship between genetic and environmental risk factors, and propose a disease model in which ALS is considered to be the result of environmental risks and time acting on a pre-existing genetic load, followed by an automatic, self-perpetuating decline to death.
    Nature Reviews Neurology 10/2013;
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    ABSTRACT: Post-extubation dysphagia is a common and serious problem. The presence of neuromuscular disease at the time of intubation is likely to increase this. Until recently, the prevalence and the association with length of intubation had not been clarified. Results published in this journal suggest that 93% of extubated patients with neuromuscular disease had post-extubation dysphagia, which in 33% of cases was considered severe. The number of days ventilated was the single predictor of severe dysphagia and a consequent prolonged hospital stay. Further work to build on these results to unravel the complex interplay between disease, trauma, and other unknown factors will be required.
    Critical care (London, England) 10/2013; 17(5):194.
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    ABSTRACT: To evaluate the lateralizing and localizing values of interictal focal slow activity (IFSA), single pulse electrical stimulation (SPES) and (18)FDG PET, in order to estimate their potential to complement ictal intracranial recordings and reduce prolonged monitoring in patients with temporal lobe epilepsy. The study includes 30 consecutive patients with bilateral temporal subdural electrodes and focal seizure onset. IFSA, SPES and (18)FDG PET when available, were visually assessed and their combined lateralization was based on the majority of the individual lateralizing tests. In the 18 patients who had all three tests, lateralization was congruent with seizure onset areas in 15 (83%). When lateralized (15 patients), (18)FDG PET was always congruent with intracranial seizure onset. In all 12 patients without (18)FDG PET, lateralization combining IFSA and SPES was congruent with seizure onset, including two with bilateral independent seizure onset on subdural monitoring. 22 out of the 23 patients who had surgery enjoyed favorable outcome (Engel I or II). Intracranial IFSA and SPES can reliably predict the side and site (mesial versus lateral temporal) of seizure onset when they lateralize to the same side. (18)FDG PET can be useful in planning electrode implantation. During intracranial recordings, IFSA and SPES have the potential to reduce telemetry time, risks and costs.
    Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 08/2013;
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    ABSTRACT: Cost-of-illness studies and health-related quality of life (HRQoL) measurements are needed to assess the effects of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN) and paraproteinaemic demyelinating neuropathy (PDN) on society. This study was conducted in 2008 in a southeast England population of 3 557 352 people. Data on service use and treatment were collected with a client service receipt inventory and service costs were calculated by combining these data with national unit costs. The EuroQol was used to calculate utility scores, a measurement of HRQoL. The total annual cost-of-illness per patient was £22 085 for CIDP, £22 812 for MMN and £7566 for PDN. The annual total cost per patient was £49 430 for individuals on intravenous immunoglobulin (IVIg) and £9046 for those not on IVIg (P < 0.01). The mean (SD) utility scores were 0.62 (0.23) for CIDP, 0.63 (0.22) for PDN and 0.72 (0.14) for MMN (P = 0.52). The mean (SD) utility score for those on IVIg was 0.65 (0.16) and those not on IVIg 0.63 (0.23) (P = 0.77). The use of IVIg was the most important determinant of cost in all three diseases and the higher frequency of its use in CIDP and MMN accounted for the much greater average cost per patient in these diseases. There was no significant difference in HRQoL amongst the three diseases or between those receiving or not receiving IVIg.
    European Journal of Neurology 08/2013;
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    ABSTRACT: Thrombolysis in patients >80 years remains controversial; we hypothesized that >80-year-old patients with wake-up ischemic stroke (WUIS) will benefit from thrombolysis despite risks because of poor outcomes with no treatment. The study included 68 thrombolysed patients with WUIS (33 [48%] >80 years), 54 nonthrombolysed patients with WUIS (21 [39%] >80 years), and 117 patients (>80 years old) thrombolysed within 4.5 hours of symptom onset (reference group). Mortality and modified Rankin Scale (mRS) were assessed at 90 days. Baseline characteristics of thrombolysed and nonthrombolysed >80 and ≤80-year-old patients with WUIS were comparable. Thrombolysis outcomes in >80-year-old patients with WUIS were better than in nonthrombolysed >80-year-old patients with WUIS (90-day mortality: 24% versus 47%, P=0.034; mRS 0-2: 30% versus 5%, P=0.023; mRS 0-1: 15% versus 5%, P=0.24) and comparable with thrombolysed ≤80-year-old patients with WUIS. Thrombolysis was associated with odds ratio 0.27 (95% confidence interval, 0.05-0.97) for mortality and odds ratio 28.6 (95% confidence interval, 1.8-448) for mRS 0 to 2 at 90 days in >80-year-old patients with WUIS after adjusting for stroke severity and risk factors. Thrombolysis may be associated with greater benefit in >80-year-old patients with WUIS but a selection bias favoring thrombolysis in those most likely to benefit may significantly reduce interpretability of these findings.
    Stroke 08/2013;
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    ABSTRACT: C. Troakes, T. Hortobágyi, C. Vance, S. Al-Sarraj, B. Rogelj and C. E. Shaw (2013) Neuropathology and Applied Neurobiology39, 553–561 Transportin 1 colocalization with Fused in Sarcoma (FUS) inclusions is not characteristic for amyotrophic lateral sclerosis-FUS confirming disrupted nuclear import of mutant FUS and distinguishing it from frontotemporal lobar degeneration with FUS inclusions Aims: Transportin 1 (TNPO 1) is an abundant component of the Fused in Sarcoma (FUS)-immunopositive inclusions seen in a subgroup of frontotemporal lobar degeneration (FTLD-FUS). TNPO 1 has been shown to bind to the C-terminal nuclear localizing signal (NLS) of FUS and mediate its nuclear import. Amyotrophic lateral sclerosis (ALS)-linked C-terminal mutants disrupt TNPO 1 binding to the NLS and impair nuclear import in cell culture. If this held true for human ALS then we predicted that FUS inclusions in patients with C-terminal FUS mutations would not colocalize with TNPO 1. Methods: Expression of TNPO 1 and colocalization with FUS was studied in the frontal cortex of FTLD-FUS (n = 3) and brain and spinal cord of ALS-FUS (n = 3), ALS-C9orf72 (n = 3), sporadic ALS (n = 7) and controls (n = 7). Expression levels and detergent solubility of TNPO 1 was measured by Western blot. Results: Aggregates of TNPO 1 were abundant and colocalized with FUS inclusions in the cortex of all FTLD-FUS cases. In contrast, no TNPO 1-positive aggregates or FUS colocalization was evident in two-thirds, ALS-FUS cases and was rare in one ALS-FUS case. Nor were they present in C9orf72 or sporadic ALS. No increase in the levels of TNPO 1 was seen in Western blots of spinal cord tissues from all ALS cases compared with controls. Conclusions: These findings confirm that C-terminal FUS mutations prevent TNPO 1 binding to the NLS, inhibiting nuclear import and promoting cytoplasmic aggregation. The presence of TNPO 1 in wild-type FUS aggregates in FTLD-FUS distinguishes the two pathologies and implicates different disease mechanisms.
    Neuropathology and Applied Neurobiology 08/2013; 39(5).
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    ABSTRACT: Predicting seizure control after epilepsy surgery is difficult. The objectives of this work are: (a) to estimate the value of surgical procedure, presence of neuroimaging abnormalities, need for intracranial recordings, resection lobe, pathology, durations of epilepsy and follow-up period to predict postsurgical seizure control after epilepsy surgery and (b) to provide empirical estimates of successful outcome after different combinations of the above factors in order to aid clinicians in advising patients presurgically about the likelihood of success under their patients' individual circumstances. We report postsurgical seizure control from all 243 patients who underwent resective surgery for epilepsy at King's College Hospital between 1999 and 2011. Among the 243 patients, 233 had lobar or sub-lobar resections, 8 had multilobar resections and 2 had excision of a hypothalamic hamartoma. We examined the relation between postsurgical seizure control and type of surgical procedure, presence of neuroimaging abnormalities, pathology, resection lobe and the need of intra-cranial electrodes to identify seizure onset. Among the 243 patients, 126 (52%) enjoyed outcome grade I, 40 (16%) had grade II, 51 (21%) had grade III and 26 (11%) had grade IV (mean follow-up 41.1 months). Normal neuroimaging or need for intracranial recordings was not associated with poorer outcome. Patients undergoing temporal resections showed better outcome than those with frontal resections, due to the poor outcome seen in frontal patients with normal neuroimaging. Among temporal resections, there was no difference in outcome between patients with and without neuroimaging abnormalities. Among patients with lesions on imaging, temporal and frontal resections showed similar outcomes. Likelihood of favourable outcome under the patient's individual circumstances was estimated by the tables provided. There was an 8-9% decrease in the percentage of grade I between follow-up at 12 and >36 months. Overall, nearly 70% of patients undergoing resective surgery enjoy favourable post-surgical seizure control. Normal neuroimaging should not discourage surgery in temporal patients but is a negative prognostic sign in normal MRI frontal patients. There were no statistical differences in outcome between patients with neuroimaging lesions in frontal or temporal lobes.
    Seizure 07/2013;
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    ABSTRACT: BACKGROUND AND PURPOSE: Wake-up ischemic stroke (WUIS) patients are not thrombolysed even if they meet other criteria for treatment. We hypothesized that patients with WUIS showing no or early ischemic changes on brain imaging will have thrombolysis outcomes comparable with those with known time of symptom onset. METHODS: Consecutive sampling of a prospective registry of patients with stroke between January 2009 and December 2010 identified 394 thrombolysed patients meeting predefined inclusion criteria, 326 presenting within 0 to 4.5 hours of symptom onset (Reference Group) and 68 WUIS patients. Inclusion criteria were last seen normal <12 hours or >4.5 hours (WUIS) or presented <4.5 hours (Reference Group), had National Institutes of Health Stroke Scale score ≥5, and no or early ischemic changes on imaging at presentation. The primary outcome measure was the modified Rankin Scale of 0 to 2 at 90 days measured by trained assessors blinded to patient grouping. Other outcome measures were symptomatic intracerebral hemorrhage, modified Rankin Scale 0 to 1, and mortality at 90 days. RESULTS: The groups were comparable for mean age (72.8 versus 73.9 years; P=0.58) and baseline median National Institutes of Health Stroke Scale score (median 13 versus 12; P=0.34). The proportions of patients with modified Rankin Scale 0 to 2 (38% versus 37%; P=0.89) and modified Rankin Scale 0 to 1 (24% versus 16%; P=0.18) at 90 days, any ICH (20% versus 22%; P=0.42) and symptomatic intracerebral hemorrhage (3.4% versus 2.9%; P=1.0) were comparable after adjusting for age, stroke severity, and imaging changes. Only 9/394 (2%) patients were lost to follow-up. CONCLUSIONS: Thrombolysis in selected patients with WUIS is feasible, and its outcomes are comparable with those thrombolysed with 0 to 4.5 hours.
    Stroke 05/2013;
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