Ailsa McLellan

Lengthening of corrected QT during epileptic seizures

Purpose:  To measure the corrected QT cardiac repolarization time before and during epileptic seizures.

Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum

Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100,000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.

Phenotypic comparison of two Scottish families with mutations in different genes causing autosomal dominant nocturnal frontal lobe epilepsy.

Summary:  Purpose: Mutations in genes coding for the α4 and β2 subunits of the neuronal nicotinic acetylcholine receptor receptor (CHRN) are known to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we examined the phenotypes in two families, from the same ethnic and geographic backgrounds, with ADNFLE as a result of mutations in these two different subunits of CHRN.

Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial

BACKGROUND Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. METHODS In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. FINDINGS Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. INTERPRETATION Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. FUNDING GW Pharmaceuticals.

A novel inherited mutation in the voltage sensor region of SCN1A is associated with Panayiotopoulos syndrome in siblings and generalized epilepsy with febrile seizures plus.

We report 2 families harboring a novel SCN1A mutation, one of whom had Panayiotopoulos syndrome and the other a phenotype consistent with generalized epilepsy with febrile seizures plus. Two siblings had recurrent episodes of autonomic status epilepticus with focal features consistent with the diagnosis of Panayiotopoulos syndrome. Both have the SCN1A mutation p.Phe218Leu. The mutation was present in their father who has never had a seizure. The same mutation was identified in a child diagnosed with intractable childhood epilepsy with generalized tonic clonic seizures. From the age of 5, he developed complex focal seizures associated with left hippocampal sclerosis. The mutation was present in his mother, aged 25, who had febrile seizures and developed generalized tonic clonic seizures and his sister who had 1 febrile seizure. Our findings suggest that SCN1A mutations may cause susceptibility to an idiopathic focal epilepsy phenotype, the final phenotype depending on other (genetic or nongenetic) factors.

Mortality in Dravet syndrome

We measured the mortality rate and the rate of Sudden Unexpected Death in Epilepsy (SUDEP) in Dravet Syndrome (DS). We studied a cohort of 100 consecutively recruited, unrelated patients with DS; 87 had SCN1A mutations. Living cases had a median follow-up of 17 years. Seventeen patients died, at a median age of seven years (inter-quartile range 3-11 years) with causes of death: 10 SUDEP, four status epilepticus, two drowning and one asphyxia. The SUDEP classification included three Definite, one Definite Plus and six Probable. The Dravet-specific mortality rate/1000-person-years was 15.84 (98% CI 9.01-27.85). The Dravet-specific SUDEP rate was 9.32/1000-person-years (98% CI 4.46-19.45). The Dravet-specific SUDEP rate is the only documented syndrome-specific SUDEP rate. SUDEP in DS occurs mainly in childhood. It is also the highest SUDEP rate, considerably higher than the recent 5.1 SUDEP rate/1000-person-years for adults with refractory epilepsy.

Parasympathetic alteration during sub-clinical seizures

INTRODUCTION Autonomic instability is considered a contributing factor in sudden unexpected death in epilepsy (SUDEP). The aim of this pilot study was to measure parasympathetic activity in sub-clinical seizures to investigate autonomic instability. MATERIALS AND METHODS A prospective study based on Video-electroencephalography (EEG)/electrocardiography (ECG)/oxygen saturation (SAO2) recordings was selected from patients having sub-clinical seizures during stage 3 or 4 sleep. We analysed R-R intervals in the ECG from 1-min prior to the electrographic onset to the end of sub-clinical seizures. Matched non-ictal R-R baseline measurements were selected from stages 3 or 4 sleep. R-R interval data were analysed using NeuroScope software providing a cardiac index of parasympathetic activity (CIPA). BioSignal short-term heart rate variability (HRV) software was used to analyse the same R-R interval data previously analysed using NeuroScope except that sub-clinical seizure data was embedded within 5-min epochs and compared to 5-min epochs of non-ictal measurements. RESULTS A total of 33 sub-clinical seizures were recorded from 11 patients comprising 19 generalised sub-clinical seizures (2 patients), 9 right temporal lobe sub-clinical seizures (5 patients) and 5 left temporal lobe sub-clinical seizures (4 patients) were compared to matched non-ictal measurements. Parasympathetic activity was clearly altered during total sub-clinical seizures in terms of the CIPA (p<0.001) and 5-min HRV high frequency (HF) % (p=0.026) measures. Generalised sub-clinical seizures resulted in increased cardiac parasympathetic activity whereas temporal lobe seizures were associated with a decrease in parasympathetic activity. CONCLUSION This pilot study indicates that parasympathetic changes occur during sub-clinical seizures. Generalised sub-clinical seizures may be associated with more autonomic instability compared to temporal lobe sub-clinical seizures.

'If you're gonna die, you're gonna die': Young adults' perceptions of sudden unexpected death in epilepsy.

Objectives To explore the views and experiences of young adults with epilepsy on the risks associated with, and information giving in relation to sudden unexpected death in epilepsy (SUDEP). Methods In-depth interviews with 27 young adults (aged 18–29 years) with epilepsy. Results Participants reported everyday experiences of seeking to control the risk of seizure occurrence or injury from seizures. In contrast, SUDEP was reported in more fatalistic terms as a risk that was considered to be largely unpreventable. Participants stated that information on SUDEP should be given to those with epilepsy, in a consultation, at or soon after the diagnosis, though clinical judgement on patients’ readiness was considered important in timing decisions. Many had a limited, sometimes incorrect understanding of SUDEP, yet were satisfied with the information they had received. Very few engaged in independent information seeking on SUDEP, and many deliberately avoided searching for further information. Discussion Our findings suggest that SUDEP was bracketed off from other aspects of participants’ epilepsy, in terms of the meanings attributed to it, perceptions of risk status and ways of coping. SUDEP is a case through which to consider how people give meaning to information about risk of sudden death related to chronic conditions.

Novel de novo EEF1A2 missense mutations causing epilepsy and intellectual disability.

Exome sequencing has led to the discovery of mutations in novel causative genes for epilepsy. One such gene is EEF1A2, encoding a neuromuscular specific translation elongation factor, which has been found to be mutated de novo in five cases of severe epilepsy. We now report on a further seven cases, each with a different mutation, of which five are newly described.

The hazards of honey: infantile botulism

Infantile botulism is a rare cause of neuromuscular weakness resulting from ingestion of Clostridium botulinum—an anaerobic Gram-positive bacillus found universally in soil. The only definite food source known to cause infantile botulism is honey; previously, links to formula milk have been postulated but not definitely sourced. We present an interesting case report of a 2-month-old infant with this rare condition, including the diagnostic difficulties that ensued. A brief overview of the condition follows. This is the first case in the UK in which C botulinum was successfully isolated from both the patient and the suspected source—a jar of honey. The importance of food labelling as a public health message is highlighted.