Safety and efficacy of prophylactic levetiracetam for prevention of epileptic seizures in the acute phase of intracerebral haemorrhage (PEACH): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The incidence of early seizures (occurring within 7 days of stroke onset) after intracerebral haemorrhage reaches 30% when subclinical seizures are diagnosed by continuous EEG. Early seizures might be associated with haematoma expansion and worse neurological outcomes. Current guidelines do not recommend prophylactic antiseizure treatment in this setting. We aimed to assess whether prophylactic levetiracetam would reduce the risk of acute seizures in patients with intracerebral haemorrhage. METHODS: The double-blind, randomised, placebo-controlled, phase 3 PEACH trial was conducted at three stroke units in France. Patients (aged 18 years or older) who presented with a non-traumatic intracerebral haemorrhage within 24 h after onset were randomly assigned (1:1) to levetiracetam (intravenous 500 mg every 12 h) or matching placebo. Randomisation was done with a web-based system and stratified by centre and National Institutes of Health Stroke Scale (NIHSS) score at baseline. Treatment was continued for 6 weeks. Continuous EEG was started within 24 h after inclusion and recorded over 48 h. The primary endpoint was the occurrence of at least one clinical seizure within 72 h of inclusion or at least one electrographic seizure recorded on continuous EEG, analysed in the modified intention-to-treat population, which comprised all patients who were randomly assigned to treatment and who had a continuous EEG performed. This trial was registered at ClinicalTrials.gov, NCT02631759, and is now closed. Recruitment was prematurely stopped after 48% of the recruitment target was reached due to a low recruitment rate and cessation of funding. FINDINGS: Between June 1, 2017, and April 14, 2020, 50 patients with mild-to-moderate severity intracerebral haemorrhage were included: 24 were assigned to levetiracetam and 26 to placebo. During the first 72 h, a clinical or electrographic seizure was observed in three (16%) of 19 patients in the levetiracetam group versus ten (43%) of 23 patients in the placebo group (odds ratio 0·16, 95% CI 0·03-0·94, p=0·043). All seizures in the first 72 h were electrographic seizures only. No difference in depression or anxiety reporting was observed between the groups at 1 month or 3 months. Depression was recorded in three (13%) patients who received levetiracetam versus four (15%) patients who received placebo, and anxiety was reported for two (8%) patients versus one (4%) patient. The most common treatment-emergent adverse events in the levetiracetam group versus the placebo group were headache (nine [39%] vs six [24%]), pain (three [13%] vs ten [40%]), and falls (seven [30%] vs four [16%]). The most frequent serious adverse events were neurological deterioration due to the intracerebral haemorrhage (one [4%] vs four [16%]) and severe pneumonia (two [9%] vs two [8%]). No treatment-related death was reported in either group. INTERPRETATION: Levetiracetam might be effective in preventing acute seizures in intracerebral haemorrhage. Larger studies are needed to determine whether seizure prophylaxis improves functional outcome in patients with intracerebral haemorrhage. FUNDING: French Ministry of Health.

Audit report and systematic review of orolingual angioedema in post-acute stroke thrombolysis.

RATIONALE: Post-intravenous recombinant tissue plasminogen activator (r-tPA) orolingual angioedema (PIROLA), including the life-threatening form, is an underappreciated complication of ischaemic stroke treatment. AIMS: We present an audit report and a systematic review of published observational studies on PIROLA occurrence in acute ischaemic stroke patients. METHODS: Clinical files of patients treated in the stroke unit of Bourg-en-Bresse General Hospital (France) from January 2010 to December 2012 were reviewed, and MEDLINE (inception to May 2013) were searched and bibliographies/citations of retrieved articles examined for evidence of PIROLA. RESULTS: Of the 129 acute ischaemic stroke patients treated at Bourg-en-Bresse between 2010 and 2012, four patients, all receiving angiotensin converting enzyme inhibitor (ACEI), developed a PIROLA (cumulative incidence rate: 32‰). The complication started within an hour of receiving r-tPA and integrally resolved within 3-24 hours, with antihistamines/steroid treatment in two patients. The systematic review identified 27 studies, totalising with ours, over 9050 acute ischaemic stroke patients from 12 countries, among whom 100 (cumulative incidence rate: 17‰; 95% confidence intervals: 8-26), developed a PIROLA within 6-240 minutes of receiving r-tPA, 0-100% of them occurring among patients on ACEI. The complication was contralateral to the stroke location in 47% cases, ipsilateral in 14%, and bilateral in 39%; and resolved within 24 hours with treatment in 90%. No related death was recorded. CONCLUSIONS: About 17‰ acute ischaemic stroke patients receiving r-tPA develop PIROLA, occurring essentially among those on concomitant ACEI. PIROLA occurrence should be actively monitored, particularly within the first few hours as some may require urgent lifesaving procedures.

Facial pain as first manifestation of anti-Hu paraneoplastic syndrome.

The diagnosis of anti-Hu-associated encephalomyelitis/sensory neuropathy may be particularly difficult when cranial nerve involvement represents the first clinical manifestation of the disease. We report a case of a patient who presented with facial pain as the first manifestation of an anti-Hu paraneoplastic syndrome, which needs a rapid detection and treatment of the underlying tumour. We suggest that paraneoplastic neuropathy should be considered during the management of trigeminal neuropathic pain, especially when brain imagery is normal.

Mutation in the catalytic domain of protein kinase C gamma and extension of the phenotype associated with spinocerebellar ataxia type 14.

BACKGROUND: Autosomal dominant cerebellar ataxias comprise a clinically, neuropathologically, and genetically heterogeneous group of neurodegenerative disorders. The vast majority of cases are caused by trinucleotide or pentanucleotide repeat expansions in 9 different genes. Spinocerebellar ataxia type 14 (SCA14) is a relatively pure form of autosomal dominant cerebellar ataxia mapped to chromosome 19q and caused by missense mutations in the gene encoding protein kinase C gamma (PRKCG), which are all located in the regulatory domain. OBJECTIVES: To identify new SCA14 families and to describe the associated phenotype. METHODS: We describe a new SCA14 family of French ancestry with 14 patients and 4 probably affected individuals. Linkage to the SCA14 locus was evaluated according to standard procedures using 5 markers covering the SCA14 candidate interval. All 18 exons of the PRKCG gene and splice junctions were screened with direct sequencing in the index patient. RESULTS: Linkage to the SCA14 locus was established with lod scores greater than 3 in the interval between DNA segments D19S571 and D19S926. Direct sequencing of the PRKCG gene revealed a T-to-C transition in exon 18 responsible for a novel missense mutation, F643L, which mapped to a highly conserved amino acid of the catalytic domain of protein kinase C gamma. The mutation showed complete segregation with the disease phenotype, was present in all affected and probably affected individuals, and was not observed on 410 control chromosomes from healthy white subjects. Age at onset, assessed in 14 affected individuals, was broader than in previous reports and ranged from childhood to age 60 years. All affected patients had slowly progressive cerebellar ataxia frequently associated with brisk reflexes. Cognitive impairment was also a striking feature in this family and has not been reported previously. Interestingly, there was no axial myoclonus as reported in a Japanese SCA14 family, but electrophysiological recordings in a single patient showed diffuse myoclonus in the arms and legs. CONCLUSIONS: We have identified a new SCA14 family with the first mutation (F643L) located in the catalytic domain of the enzyme. The wide range of ages at onset, the presence of myoclonus in the limbs, and the presence of cognitive impairment extend the phenotype associated with this genetic entity.

Orofacial dyskinesias in a patient with primary biliary cirrhosis: a clinicopathological case report and review.

We describe the pathological and clinical aspects, including video and radiological magnetic resonance imaging, of a case of chronic acquired hepatocerebral degeneration with orofacial dyskinesias in relation to a primary biliary cirrhosis. We provide a review of the literature on this subject.