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Objectives -To evaluate, for the first time in patients with epilepsy, the tolerability and safety of escalating doses of oral perampanel, a novel, selective, non-competitive AMPA antagonist, as adjunctive therapy for refractory partial-onset seizures. Materials and methods -Two consecutive, randomized, double-blind, dose-escalation studies recruited adults (18-70 years) with uncontrolled partial-onset seizures receiving one to three concomitant antiepileptic drugs. In study 206, patients were treated for 12 weeks (8-week dose-titration, 4-week dosemaintenance) with placebo or perampanel (up to 4 mg ⁄ day, dosed once-or twice-daily). In study 208, patients received placebo or perampanel once-daily (up to 12 mg) for 16 weeks (12-week titration, 4-week maintenance). Results -Overall, 153 patients were randomized into study 206 (perampanel twice-daily, n = 51; perampanel oncedaily, n = 51; placebo, n = 51). Study 208 included 48 patients (perampanel once-daily, n = 38; placebo, n = 10). The highest dose in study 206 -4 mg ⁄ day -was well tolerated, with similar proportions of patients tolerating once-daily (82.4%) and twice-daily (82.4%) perampanel and placebo (82.4%) treatments. In study 208 most patients tolerated doses of ‡ 6 mg perampanel once-daily in a KaplanMeier analysis. In both studies, the most common adverse events were CNS-related; most were of mild ⁄ moderate severity. ConclusionsPerampanel was well tolerated across doses of 4-12 mg ⁄ day. The studies showed preliminary evidence of efficacy and identified doses to be evaluated in larger clinical studies.

Background. Alzheimer's disease (AD) is the most common form of dementia. It is a degenerative, incurable and terminal disease. The increasing prevalence of AD is, among other reasons, due to population aging, which is, to a certain extent, seen worldwide. Continuous advances in health care keep increasing life expectancy. Official statistics are likely to significantly underestimate the actual prevalence of AD. Alzheimer's disease represents an important public health problem. Its aetiology is still unknown and for this reason, it is necessary to study all potential risk factors which may contribute to the development of this disease. Methods. We searched original and review articles addressing Alzheimer´s disease using key words Alzheimer's disease, epidemiology, risk factors and prevention. We found and used one hundred and four references. Conclusions. Based on epidemiological studies, genetic studies, neuroimaging methods and neuropathology research, three basic etiological hypotheses of the development of AD have been formulated: genetic, vascular and psychosocial. At present, the level of evidence is insufficient for the etiological role of other factors, such as nutrition, occupational exposure to various substances and inflammation. From the point of view of early diagnosis and application of primary or secondary prevention principles, genetic factors are the most important.

Objectives -Evaluate interim long-term tolerability, safety and efficacy of adjunctive perampanel, a novel a-amino-3-hydroxy-5-methyl-5-isoxazolepropionic acid (AMPA)-receptor antagonist, in patients with refractory partial-onset seizures. Materials and methods -Study 207, an open-label extension (OLE) study (ClinicalTrials.gov identifier: NCT00368472), enrolled patients (18-70 years) who completed one of two randomized, placebocontrolled, dose-escalation Phase II studies. The OLE Treatment Phase comprised a 12-week Titration Period (2 mg increments of perampanel every 2 weeks to 12 mg/day, maximum) and a Maintenance Period, during which patients continued treatment up to a planned maximum of 424 weeks (~8 years). Interim analysis data cut-off date was 1 December, 2010. Results -Of 180 patients completing the Phase II studies, 138 enrolled in study 207. At the time of interim analyses (approximately 4 years after study start), over a third (n = 53, 38.4%) remained on perampanel; 41.3% (n = 57) of patients had >3 years of exposure; and 13.0% (n = 18) had at least 4 years' exposure. Mean ± standard deviation (SD) duration of exposure was 116 ± 75 weeks and mean ± SD dose during the OLE Maintenance Period was 7.3 ± 3.3 mg. No new safety signals emerged with long-term treatment. Consistent with previous studies, the most common treatment-emergent adverse events were as follows: dizziness, headache and somnolence. Overall median (range) per cent change from baseline in seizure frequency per 28 days during open-label treatment was À31.5% (À99.2 to 512.2). Conclusions -Long-termup to 4 years -adjunctive perampanel had a favourable tolerability profile in patients with refractory partial-onset seizures. Improvements in seizure control were maintained with long-term treatment.

on behalf of SITS InvestigatorsAbstract Purpose: Beyond intravenous thrombolysis, evidence is lacking on acute treatment of minor stroke caused by large artery occlusion. To identify candidates for additional endovascular therapy, we aimed to determine the frequency of non-haemorrhagic early neurological deterioration in patients with intravenous thrombolysis-treated minor stroke caused by occlusion of large proximal and distal cerebral arteries. Secondary aims were to establish risk factors for non-haemorrhagic early neurological deterioration and report three-month outcomes in patients with and without nonhaemorrhagic early neurological deterioration. Method: We analysed data from the SITS International Stroke Thrombolysis Register on 2553 patients with intravenous thrombolysis-treated minor stroke (NIH Stroke Scale scores 0-5) and available arterial occlusion data. Non-haemorrhagic early neurological deterioration was defined as an increase in NIH Stroke Scale score 4 at 24 h, without parenchymal hematoma on follow-up imaging within 22-36 h. Findings: The highest frequency of non-haemorrhagic early neurological deterioration was seen in 30% of patients with terminal internal carotid artery or tandem occlusions (internal carotid artery þ middle cerebral artery) (adjusted odds ratio: 10.3 (95% CI 4.3-24.9), p < 0.001) and 17% in extracranial carotid occlusions (adjusted odds ratio 4.3 (2.5-7.7), p < 0.001) versus 3.1% in those with no occlusion. Proximal middle cerebral artery-M1 occlusions had non-haemorrhagic early neurological deterioration in 9% (adjusted odds ratio 2.1 (0.97-4.4), p ¼ 0.06). Among patients with any occlusion and non-haemorrhagic early neurological deterioration, 77% were dead or dependent at three months. Conclusions: Patients with minor stroke caused by internal carotid artery occlusion, with or without tandem middle cerebral artery involvement, are at high risk of disabling deterioration, despite intravenous thrombolysis treatment. Acute vessel imaging contributes usefully even in minor stroke to identify and consider endovascular treatment, or intensive monitoring at a comprehensive stroke centre, for patients at high risk of neurological deterioration.

Objective: To characterize the clinical, EEG, and brain imaging findings in an adult case series of patients with de novo refractory status epilepticus (SE) occurring after a febrile illness.Methods: A retrospective study (2010)(2011)(2012)(2013) was undertaken with the following inclusion criteria: (1) previously healthy adults with refractory SE; (2) seizure onset 0-21 days after a febrile illness; (3) lacking evidence of infectious agents in CSF; (4) no history of seizures (febrile or afebrile) or previous or concomitant neurologic disorder.Results: Among 155 refractory SE cases observed in the study period, 6 patients (17-35 years old) fulfilled the inclusion criteria. Confusion and stupor were the most common symptoms at disease onset, followed after a few days by acute repeated seizures that were uncountable in all but one. Seizures consisted of focal motor/myoclonic phenomena with subsequent generalization. Antiepileptic drugs failed in every patient to control seizures, with all participants requiring intensive care unit admission. Barbiturate coma with burst-suppression pattern was applied in 4 out of 6 patients for 5-14 days. One participant died in the acute phase. In each patient, we observed a reversible bilateral claustrum MRI hyperintensity on T2-weighted sequences, without restricted diffusion, time-related with SE. All patients had negative multiple neural antibodies testing. Four out of 5 surviving patients developed chronic epilepsy.Conclusions: This is a hypothesis-generating study of a preliminary nature supporting the role of the claustrum in postfebrile de novo SE; future prospective studies are needed to delineate the specificity of this condition, its pathogenesis, and the etiology. Neurology ® 2015;85:1224-1232 GLOSSARY ADC 5 apparent diffusion coefficient; AED 5 antiepileptic drug; FIRES 5 febrile infection-related epilepsy syndrome; ICU 5 intensive care unit; IVIg 5 IV immunoglobulin; NORSE 5 new-onset refractory status epilepticus; PEX 5 plasma exchange; SE 5 status epilepticus.In the last 2 decades, several authors described a series of syndromes characterized by the development of a difficult to treat status epilepticus (SE) in previously healthy children after a febrile illness.1-7 The condition is characterized by a refractory SE and followed by drug-resistant epilepsy, with often severe neuropsychiatric sequelae or death. These entities have been identified by different acronyms, but febrile infection-related epilepsy syndrome (FIRES) is the one that best underscores the main features of the disorder.8 Cases with a similar clinical picture have been described also in adults and in these case series the most frequently used definition is new-onset refractory SE (NORSE).9-13 Recently, it was pointed out that different terms probably have been used to describe the same condition.14,15 However, there is no consensus among investigators. Adult cases are more heterogeneous, some with clear similarities with FIRES cases (with only the age at onset as the main difference), other...

ObjectiveRepetitive transcranial magnetic stimulation (rTMS) is currently being tested for suppressing the symptoms of subjective chronic primary tinnitus, although its effect is controversial. The aim of this randomized double‐blinded controlled trial was to determine the effect of rTMS with unique settings for tinnitus treatment.MethodsFifty‐three adult patients suffering from chronic subjective unilateral or bilateral nonpulsatile primary tinnitus for at least 6 months were randomly assigned to rTMS (group 1, n = 20), sham stimulation (group 2, n = 12), or medicament therapy only (group 3, n = 21). The dorsolateral prefrontal cortex (frequency 25 Hz, 300 pulses, and 80% resting motor threshold [RMT]) on the left side and primary auditory cortex (1 Hz, 1000 pulses, 110% RMT) were stimulated on both sides in patients in group 1 for 5 consecutive days. The Tinnitus Reaction Questionnaire (TRQ), Tinnitus Handicap Questionnaire (THQ), Tinnitus Handicap Inventory (THI), Beck Depression Inventory (BDI), pure‐tone audiometry with Fowler scoring of hearing loss, and tinnitus analysis were used to evaluate tinnitus in all patients. Data were recorded the day the patient was included in the study and at 1‐ and 6‐month follow‐up.ResultsThe study groups were homogenous. No significant effect of rTMS was found at 1 or 6 months based on the BDI, THQ, and TRQ scores or tinnitus masking. There was a significant but clinically irrelevant effect on the THI score after 1 and 6 months.InterpretationNo significant effect of bilateral low‐frequency rTMS of the primary auditory cortex and high‐frequency stimulation of the left dorsolateral prefrontal cortex was demonstrated.

Background and PurposeMechanical thrombectomy (MT) is indicated for the treatment of large vessel occlusion (LVO) stroke. MT should be provided as quickly as possible; therefore, a test identifying suspected LVO in the prehospitalization stage is needed to ensure direct transport to a comprehensive stroke center (CSC). We assume that patients with clinically severe hemiparesis have a high probability of LVO stroke. We modified the FAST test into the FAST PLUS test: The first part is the FAST test and the second part evaluates the presence of severe arm or leg motor deficit. This prospective multicenter study evaluates the specificity and sensitivity of the FAST PLUS test in detecting LVO stroke.MethodsParamedics were trained through e‐learning to conduct the FAST PLUS test.All prehospital suspected stroke patients who were administered the FAST PLUS test were included. Demographics, National Institutes of Health Stroke Scale (NIHSS) score, brain computed tomography (CT), and CT angiography (CTA) were recorded. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating curve (ROC) area for LVO were calculated.ResultsThe study included 435 patients. LVO were found in 124 patients (28%). Sensitivity was 93%, specificity was 47%, PPV was 41%, NPV was 94%, and ROC area for ICA/MCA occlusion was 0.65. Intracerebral hemorrhage (ICH) was identified in 48 patients (11%).ConclusionWe found that the FAST PLUS test had a high sensitivity for LVO stroke. Of the 435 patients, 41% were all directly transported to a CSC based on positive FAST PLUS test scores and were potential candidates for MT.