Neurology July 2012 Volume 79 Issue 1

Objective: To quantify the risk for bleeding complications after thrombolysis for ischemic stroke in patients on warfarin (international normalized ratio [INR] <=1.7) and to put these data into perspective with previous studies.Methods: A total of 548 consecutive stroke patients receiving IV recombinant tissue plasminogen activator (rtPA) were prospectively evaluated and details about warfarin pretreatment were carefully recorded. Prothrombin time-based INR values were measured before thrombolysis and 6 and 24 hours thereafter. Intracranial hemorrhage occurring within 72 hours was assessed by CT examinations and defined according to National Institute of Neurological Disorders and Stroke criteria. Main outcome variables were symptomatic intracranial and major systemic bleedings.Results: Of the 548 patients, 33 (6.0%) and 14 (2.6%) experienced symptomatic intracranial and major systemic bleedings, respectively. Patients taking warfarin until the day of or day before admission (n = 15, mean +/- SD INR 1.21 +/- 0.32 vs 1.01 +/- 1.12, p = 0.030) faced an approximately 4-fold risk for intracranial hemorrhage (20.0% vs 5.6%, unadjusted odds ratio [OR] [95% confidence interval (CI)] 4.2 [1.1-15.7], p = 0.033). Findings were similar after adjustment for age, NIH Stroke Scale score, and diabetes (adjusted OR [95% CI] 4.1 [1.0-16.1], p = 0.044) and when focusing on any major bleeding (intracranial or systemic) (unadjusted OR [95% CI] 4.1 [1.3-13.6], p = 0.019). Half of the patients with bleedings showed an INR rise above 1.7 6 hours after thrombolysis. A meta-analysis yielded confirmatory yet heterogeneous results (unadjusted OR [95% CI] derived from a random effects model, 2.31 [1.15-4.62], p = 0.018, I2 = 58% [11%-80%]).Conclusions: Our data suggest a statistically significant and clinically meaningful increase in the risk for symptomatic intracranial and major systemic bleedings among patients with stroke thrombolysis receiving warfarin up to the day of or day before stroke.GLOSSARY: CI: confidence intervalCRP: C-reactive proteinECASS: European Cooperative Acute Stroke StudyINR: international normalized ratiomRS: modified Rankin ScaleNIHSS: NIH Stroke ScaleNINDS: National Institute of Neurological Disorders and StrokeOR: odds ratioPACS: picture archiving and communication systemPT: prothrombin timePTT: partial thromboplastin timertPA: recombinant tissue plasminogen activatorSITS-MOST: Safe Implementation of Thrombolysis in Stroke-Monitoring Study(C)2012 American Academy of Neurology

Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of GABA degradation leading to elevations in brain GABA and [gamma]-hydroxybutyric acid (GHB). The effect of chronically elevated GABA and GHB on cortical excitability is unknown. We hypothesized that use-dependent downregulation of GABA receptor expression would promote cortical disinhibition rather than inhibition, predominantly via presynaptic GABAergic mechanisms.Methods: We quantified the magnitude of excitation and inhibition in primary motor cortex (M1) in patients with SSADH deficiency, their parents (obligate heterozygotes), age-matched healthy young controls, and healthy adults using single and paired pulse transcranial magnetic stimulation (TMS).Results: Long interval intracortical inhibition was significantly reduced and the cortical silent period was significantly shortened in patients with SSADH deficiency compared to heterozygous parents and control groups.Conclusions: Since long interval intracortical inhibition and cortical silent period are thought to reflect GABAB receptor-mediated inhibitory circuits, our results point to a particularly GABAB-ergic motor cortex dysfunction in patients with SSADH deficiency. This human phenotype is consistent with the proposed mechanism of use-dependent downregulation of postsynaptic GABAB receptors in SSADH deficiency animal models. Additionally, the results suggest autoinhibition of GABAergic neurons. This first demonstration of altered GABAB-ergic function in patients with SSADH deficiency may help to explain clinical features of the disease, and suggest pathophysiologic mechanisms in other neurotransmitter-related disorders.GLOSSARY: ANOVA: analysis of varianceCSP: cortical stimulation-induced silent periodFDI: first dorsal interosseusGHB: [gamma]-hydroxybutyric acidICF: intracortical facilitationISI: interstimulus intervalLICI: late intracortical inhibitionM1: primary motor cortexMEP: motor evoked potentialMVC: maximal voluntary contractionREC: recruitment curveRMT: resting motor thresholdSICI: short intracortical inhibitionSSADH: succinic semialdehyde dehydrogenaseTMS: transcranial magnetic stimulation(C)2012 American Academy of Neurology

Objectives: To quantify the overall contribution of mutations in the currently known amyotrophic lateral sclerosis (ALS) genes in a large cohort of sporadic patients and to make genotype-phenotype correlations.Methods: Screening for SOD1, TARDBP, FUS, ANG, ATXN2, OPTN, and C9ORF72 was carried out in 480 consecutive patients with sporadic ALS (SALS) and in 48 familial ALS (FALS) index patients admitted to a single Italian referral center.Results: Mutations were detected in 53 patients, with a cumulative frequency of 11. Seven of them were novel. The highest frequencies of positive cases were obtained in TARDBP (2.7%), C9ORF72 (2.5%), and SOD1 (2.1%). The overall group of mutated patients was indistinguishable from that without mutations as no significant differences were observed with regard to age and site of onset, frequency of clinical phenotypes, and survival. However, by separately evaluating genotype-phenotype correlation in single genes, clinical differences were observed among different genes. Duration of disease was significantly shorter in patients harboring the C9ORF72 expansion and longer in the SOD1 group. A high frequency of predominant upper motor neuron phenotype was observed among patients with TARDBP mutations. Two patients, 1 with C9ORF72 and 1 with SOD1 mutation, had concurrent ANG mutations. Mutations were detected in 43.7% of patients with FALS.Conclusions: A considerable proportion of patients with SALS harbored mutations in major ALS genes. This result has relevant implications in clinical practice, namely in genetic counseling. The detection of double mutations in 2 patients raises the hypothesis that multiple mutations model may explain genetic architecture of SALS.GLOSSARY: ALS: amyotrophic lateral sclerosisCI: confidence intervalFALS: familial ALSFTD: frontotemporal dementiaJALS: juvenile ALSLMN: lower motor neuronSALS: sporadic ALSSCA2: spinocerebellar ataxia type 2UMN-D: upper motor neuron dominant(C)2012 American Academy of Neurology

Objective: To assess patterns of reduced cortical thickness in different clinically defined variants of early-onset Alzheimer disease (AD) and to explore the hypothesis that these variants span a phenotypic continuum rather than represent distinct subtypes.Methods: The case-control study included 25 patients with posterior cortical atrophy (PCA), 15 patients with logopenic progressive aphasia (LPA), and 14 patients with early-onset typical amnestic AD (tAD), as well as 30 healthy control subjects. Cortical thickness was measured using FreeSurfer, and differences and commonalities in patterns of reduced cortical thickness were assessed between patient groups and controls. Given the difficulty of using mass-univariate statistics to test ideas of continuous variation, we use multivariate machine learning algorithms to visualize the spectrum of subjects and to assess separation of patient groups from control subjects and from each other.Results: Although each patient group showed disease-specific reductions in cortical thickness compared with control subjects, common areas of cortical thinning were identified, mainly involving temporoparietal regions. Multivariate analyses permitted clear separation between control subjects and patients and moderate separation between patients with PCA and LPA, while patients with tAD were distributed along a continuum between these extremes. Significant classification performance could nevertheless be obtained when every pair of patient groups was compared directly.Conclusions: Analyses of cortical thickness patterns support the hypothesis that different clinical presentations of AD represent points in a phenotypic spectrum of neuroanatomical variation. Machine learning shows promise for syndrome separation and for identifying common anatomic patterns across syndromes that may signify a common pathology, both aspects of interest for treatment trials.GLOSSARY: AAO: age at onsetAD: Alzheimer diseaseLPA: logopenic progressive aphasiaMDS: multidimensional scalingPCA: posterior cortical atrophySVM: support vector machinetAD: typical amnestic Alzheimer diseaset-SNE: t-distributed stochastic neighbor embeddingVBM: voxel-based morphometry(C)2012 American Academy of Neurology

Objective: To evaluate the safety and efficacy of botulinum toxin type A in disabling multiple sclerosis (MS)-related upper limb tremor.Methods: Twenty-three patients with MS contributed data from 33 upper limbs to this study. Each limb was randomized in a crossover design to receive botulinum toxin type A or placebo at baseline and the reverse treatment at 12 weeks. The 3 main outcomes were the median changes in Bain tremor rating scores for tremor severity, writing, and drawing an Archimedes spiral from baseline to 6 and 12 weeks after treatment with botulinum toxin type A compared with those after treatment with saline placebo. An independent rater scored randomized video assessments performed every 6 weeks over 6 months.Results: There was a significant improvement after botulinum toxin compared with that after placebo treatment in the Bain score for tremor severity at 6 weeks (p = 0.0005) and 12 weeks (p = 0.0001), writing at 6 weeks (p = 0.0001) and 12 weeks (p = 0.0003), and Archimedes spiral drawing at 6 weeks (p = 0.0006) and 12 weeks (p = 0.0002). More patients developed weakness after botulinum toxin treatment (42.2%) than after placebo injection (6.1%; (p = 0.0005). Weakness was mild (just detectable) to moderate (still able to use limb) and resolved within 2 weeks.Conclusions: Targeted botulinum toxin type A injections significantly improve arm tremor and tremor-related disability in patients with MS.Classification of evidence: This study provides Class III evidence that targeted injection of botulinum toxin type A is associated with significant improvement in MS-related upper limb tremor.GLOSSARY: BT: botulinum toxin type ACRST: Combined Rating Score for TremorICARS: International Cooperative Ataxia Rating ScaleIQR: interquartile rangeMS: multiple sclerosisMST: multiple sclerosis tremorQUEST: Quality of Life in Essential Tremor QuestionnaireSARA: Scale for the Assessment and Rating of Ataxia(C)2012 American Academy of Neurology

: Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is an uncommon outcome of prolonged focal status epilepticus in childhood. The prolonged focal motor seizure usually occurs during the course of a febrile illness and is followed by hemiplegia ipsilateral to the side of convulsions. This is accompanied by radiologic evidence of acute cytotoxic edema in the affected hemisphere followed by chronic atrophy. Intractable epilepsy may develop at a time remote from the initial presentation. The clinical features of HHE syndrome were first described more than 5 decades ago but its pathophysiology remains poorly understood and the long-term cognitive outcomes are unclear. Early recognition of the syndrome may help provide patients and families with an accurate prognosis regarding the subsequent development of epilepsy.GLOSSARY: FIRES: fever-induced refractory epileptic encephalopathy in school-aged childrenHH: hemiconvulsion-hemiplegiaHHE: hemiconvulsion-hemiplegia-epilepsyHHS: hemiconvulsion-hemiplegia syndromeMR: magnetic resonanceNORSE: new-onset refractory status epilepticus(C)2012 American Academy of Neurology