Summary Background Some encephalitides or seizure disorders once thought idiopathic now seem to be immune mediated. We aimed to describe the clinical features of one such disorder and to identify the ...autoantigen involved. Methods 15 patients who were suspected to have paraneoplastic or immune-mediated limbic encephalitis were clinically assessed. Confocal microscopy, immunoprecipitation, and mass spectrometry were used to characterise the autoantigen. An assay of HEK293 cells transfected with rodent GABAB1 or GABAB2 receptor subunits was used as a serological test. 91 patients with encephalitis suspected to be paraneoplastic or immune mediated and 13 individuals with syndromes associated with antibodies to glutamic acid decarboxylase 65 were used as controls. Findings All patients presented with early or prominent seizures; other symptoms, MRI, and electroencephalography findings were consistent with predominant limbic dysfunction. All patients had antibodies (mainly IgG1) against a neuronal cell-surface antigen; in three patients antibodies were detected only in CSF. Immunoprecipitation and mass spectrometry showed that the antibodies recognise the B1 subunit of the GABAB receptor, an inhibitory receptor that has been associated with seizures and memory dysfunction when disrupted. Confocal microscopy showed colocalisation of the antibody with GABAB receptors. Seven of 15 patients had tumours, five of which were small-cell lung cancer, and seven patients had non-neuronal autoantibodies. Although nine of ten patients who received immunotherapy and cancer treatment (when a tumour was found) showed neurological improvement, none of the four patients who were not similarly treated improved (p=0·005). Low levels of GABAB1 receptor antibodies were identified in two of 104 controls (p<0·0001). Interpretation GABAB receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies. Funding National Institutes of Health.
Summary Some patients with early-onset Alzheimer's disease (AD) present with a distinct phenotype. Typically, the first and most salient characteristic of AD is episodic memory impairment. A few ...patients, however, present with focal cortical, non-memory symptoms, such as difficulties with language, visuospatial, or executive functions. These presentations are associated with specific patterns of atrophy and frequently with a young age at onset. Age is not, however, the only determinant of phenotype; underlying factors, especially genetic factors, seem also to affect phenotype and predispose patients to younger or older age at onset. Importantly, patients with atypical early-onset disease seldom carry the APOE ε4 allele, which is the most important risk factor for lowering the age of onset in patients with AD. Additionally, the APOE ε4 genotype seems to predispose patients to vulnerability in the medial temporal areas, which leads to memory loss. Conversely, patients negative for the APOE ε4 allele and with early-onset AD are more likely to be predisposed to vulnerability of cerebral networks beyond the medial temporal lobes. Other factors are probably involved in determining the pattern of atrophy, but these are currently unknown.
Summary Background In September, 2008, the European Acute Stroke Study III (ECASS III) randomised trial and the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry ...(SITS-ISTR) observational study reported the efficacy and safety of the extension of the time window for intravenous alteplase treatment from within 3 h to within 4·5 h after stroke onset. We aimed to assess the implementation of the wider time window, its effect on the admission-to-treatment time, and safety and functional outcome in patients recorded in SITS-ISTR. Methods Patients treated according to the criteria of the European Summary of Product Characteristics, except for the time window, were included. Patients were grouped according to whether they were registered into SITS-ISTR before or after October, 2008. We measured admission-to-treatment time and rates of symptomatic intracerebral haemorrhage, mortality, and functional independence at 3 months. Findings 23 942 patients were included in SITS-ISTR between December, 2002, and February, 2010, of whom 2376 were treated 3–4·5 h after symptom onset. The proportion of patients treated within 3–4·5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 22% vs 67 of 1023 7%). The median admission-to-treatment time was 65 min both for patients registered before and after October, 2008 (p=0·94). 352 (2%) of 21 204 patients treated within 3 h and 52 (2%) of 2317 treated within 3–4·5 h of stroke had symptomatic intracerebral haemorrhage at 3 months (adjusted odds ratio OR 1·44, 95% CI 1·05–1·97; p=0·02). 2287 (12%) of 18 583 patients who were treated within 3 h and 218 (12%) of 1817 who were treated within 3–4·5 h had died by the 3-month follow-up (adjusted OR 1·26, 95% CI 1·07–1·49; p=0·005); 10 531 (57%) of 18 317 patients treated within 3 h of stroke and 1075 (60%) of 1784 who were treated within 3–4·5 h were functionally independent at 3 months (adjusted OR 0·84, 95% CI 0·75–0·95; p=0·005). Interpretation Since October, 2008, thrombolysis within 3–4·5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased. Safety and functional outcomes are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier. Thrombolysis should be initiated within 4·5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset. Funding Boehringer Ingelheim, Ferrer, the European Union Public Health Executive Authority, and Medical Training and Research (ALF) from Stockholm County Council and Karolinska Institutet.
Summary Background In the European Cooperative Acute Stroke Study III (ECASS III), alteplase administered 3·0–4·5 h after the onset of stroke symptoms resulted in a significant benefit in the primary ...endpoint (modified Rankin scale mRS score 0–1) versus placebo, with no difference in mortality between the treatment groups. Compared with the 0–3 h window, there was no excess risk of symptomatic intracranial haemorrhage. We assessed the usefulness of additional endpoints and did subgroup and sensitivity analyses to further investigate the benefit of alteplase. Methods In a double-blind, multicentre study in Europe, patients with acute ischaemic stroke were randomly assigned to intravenous alteplase (0·9 mg/kg bodyweight) or placebo. Additional outcome analyses included functional endpoints at day 90 or day 30 (mRS 0–1 day 30, mRS 0–2, Barthel index ≥85, and global outcome statistic day 30) and treatment response (8-point improvement from baseline or 0–1 score on the National Institutes of Health stroke scale NIHSS, and a stratified responder analysis by baseline NIHSS score). The subgroup analyses were based on the mRS 0–1 at day 90, symptomatic intracranial haemorrhage, and death. Analyses were by intention to treat and per protocol. This study is registered with ClinicalTrials.gov , number NCT00153036. Findings 418 patients were assigned to alteplase and 403 to placebo. Although not significant in every case, all additional endpoints showed at least a clear trend in favour of alteplase. Alteplase was effective in various subgroups, including older patients (<65 years: odds ratio 1·61, 95% CI 1·05–2·48; ≥65 years: 1·15, 0·80–1·64; p=0·230), and the effectiveness was independent of the severity of stroke at baseline (NIHSS 0–9: 1·28, 0·84–1·96; NIHSS 10–19: 1·16, 0·73–1·84; NIHSS ≥20: 2·32, 0·61–8·90; p=0·631). The incidence of symptomatic intracranial haemorrhage seemed to be independent of previous antiplatelet drug use (no: 2·41, 1·09–5·33; yes: 2·33, 0·79–6·90; p=0·962) and time from onset of symptoms to treatment (181–210 min: 1·62, 0·26–10·25; 211–240 min: 1·97, 0·82–4·76; 241–270 min: 3·15, 1·01–9·79; p=0·761), but not of age dichotomised at 65 years (<65 years: 0·74, 0·28–1·96; ≥65 years: 5·79, 2·18–15·39; p=0·004). Interpretation Our results support the use of alteplase up to 4·5 h after the onset of stroke symptoms across a broad range of subgroups of patients who meet the requirements of the European product label but miss the approved treatment window of 0–3 h. Funding Boehringer Ingelheim.
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