Helen Cross

The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus.

In this issue of Epilepsia, we present the next in our series of review, opinion, and commentary (pp. 1277–1288). Other such series, published in Gray Matters over the past couple of years, include discussions about: ethical dimensions of epilepsy genetics [2006, 47(10):1747–1756]; internet research [2007, 48(7):1415–1424]; drug resistance [2007, 48(12):2369–2374]; SCN1A mutation and sudden unexplained death in epilepsy (SUDEP) [2008, 49(2)360– 369]; and Wada testing [2008-49(4):715–727]. One reader has pointed out that we have not explained the format or purpose of these series, and so we have now added a section heading to clarify our intent. In these series, we publish a lead paper followed by commentaries that have been invited by the editors specifically to put forward different views. In commissioning such commentary, we hope to encourage discussion and debate that will lead to further research and elucidation of these still controversial issues. We hope this initiative is of interest to readers, and we invite readers to suggest new topic areas for debate within the pages of Epilepsia.

Immune-mediated epilepsies

A pathogenic role of immunity in epilepsies has long been suggested based on observations of the efficacy of immune‐modulating treatments and, more recently, by the finding of inflammation markers including autoantibodies in individuals with a number of epileptic disorders. Clinical and experimental data suggest that both innate and adaptive immunity may be involved in epilepsy. Innate immunity represents an immediate, nonspecific host response against pathogens via activation of resident brain immune cells and inflammatory mediators. These are hypothesized to contribute to seizures and epileptogenesis. Adaptive immunity employs activation of antigen‐specific B and T lymphocytes or antibodies in the context of viral infections and autoimmune disorders. In this article we critically review the evidence for pathogenic roles of adaptive immune responses in several types of epilepsy, and discuss potential mechanisms and therapeutic targets. We highlight future directions for preclinical and clinical research that are required for improved diagnosis and treatment of immune‐mediated epilepsies.

A novel technique of detecting MRI-negative lesion in focal symptomatic epilepsy: Intraoperative ShearWave Elastography

Focal symptomatic epilepsy is the most common form of epilepsy that can often be cured with surgery. A small proportion of patients with focal symptomatic epilepsy do not have identifiable lesions on magnetic resonance imaging (MRI). The most common pathology in this group is type II focal cortical dysplasia (FCD), which is a subtype of malformative brain lesion associated with medication‐resistant epilepsy. We present a patient with MRI‐negative focal symptomatic epilepsy who underwent invasive electrode recordings. At the time of surgery, a novel ultrasound‐based technique called ShearWave Elastography (SWE) was performed. A 0.5 cc lesion was demonstrated on SWE but was absent on B‐mode ultrasound and 3‐T MRI. Electroencephalography (EEG), positron emission tomography (PET), and magnetoencephalography (MEG) scans demonstrated an abnormality in the right frontal region. On the basis of this finding, a depth electrode was implanted into the lesion. Surgical resection and histology confirmed the lesion to be type IIb FCD.

Sleep architecture and memory consolidation in children with focal epilepsy

Abstract Background Cognitive impairment is a major comorbidity in children with epilepsy. During the past decade, evidence has emerged that the consolidation of declarative memory (memory for facts and events) is promoted by slow-wave sleep. The aim of this study was to investigate whether sleep architecture is disrupted in children with epilepsy, and whether this disruption impacts on memory consolidation in these children compared with healthy children. Methods A within-subject comparison of memory retention across similar length intervals overnight (sleep condition) or daytime (wake condition) was performed in 20 children with focal epilepsy (aged 6–16 years) and 19 healthy, age-matched children (controls). For each condition, participants learned a list of semantically related word pairs for cued recall after the interval. Patients participated during admission for video electroencephalogram (EEG) telemetry, whereas controls underwent ambulatory EEG polysomnography across the sleep condition. Findings Children with epilepsy had less rapid eye movement sleep (ANCOVA with age as covariate F =8·2, p=0·007) and more stage 2 sleep ( F =5·335, p=0·027) than did controls, but a similar amount of slow-wave sleep and stage 1 sleep. Memory retention was greater in the sleep than the wake condition (repeated measures ANOVA F =7·876, p=0·008) and there was no significant interaction effect with group (patients vs controls) or order of conditions. The difference in memory retention scores between the sleep and wake conditions correlated with the proportion of time that the child spent in slow-wave sleep across the total sample (Pearson r =0·461, p=0·003). This association was significant in controls ( r =0·546, p=0·051), but did not reach significance in children with epilepsy, and was not altered after controlling for age. Interpretation Patients with focal epilepsy show benefit to memory consolidation with sleep similar to that seen in healthy individuals, despite the underlying disease and effects of treatment. The association with slow-wave sleep, which is preserved at the expense of rapid eye movement sleep, also seems robust. Our findings suggest that the enhancement of slow-wave sleep—by behavioural, pharmacological, or physical means—has the potential to improve cognitive outcome in this patient group. Funding Action Medical Research, Reta Lila Howard Foundation.

Do Glut1 (glucose transporter type 1) defects exist in epilepsy patients responding to a ketogenic diet

In the recent years, several neurological syndromes related to defects of the glucose transporter type 1 (Glut1) have been descried. They include the glucose transporter deficiency syndrome (Glut1-DS) as the most severe form, the paroxysmal exertion-induced dyskinesia (PED), a form of spastic paraparesis (CSE) as well as the childhood (CAE) and the early-onset absence epilepsy (EOAE). Glut1, encoded by the gene SLC2A1, is the most relevant glucose transporter in the brain. All Glut1 syndromes respond well to a ketogenic diet (KD) and most of the patients show a rapid seizure control. Ketogenic Diet developed to an established treatment for other forms of pharmaco-resistant epilepsies. Since we were interested in the question if those patients might have an underlying Glut1 defect, we sequenced SLC2A1 in a cohort of 28 patients with different forms of pharmaco-resistant epilepsies responding well to a KD. Unfortunately, we could not detect any mutations in SLC2A1. The exact action mechanisms of KD in pharmaco-resistant epilepsy are not well understood, but bypassing the Glut1 transporter seems not to play an important role.

ECG ABNORMALITIES IN ALTERNATING HEMIPLEGIA: A BROADENED PHENOTYPE

Introduction Alternating hemiplegia of Childhood (AH) caused by de novo mutations in ATP1A3, is characterised by recurrent plegic and dystonic episodes, seizures, non-paroxysmal neurological features, and dysautonomia. Premature mortality is observed and attributed to sudden unexpected death in epilepsy. A single case of asystole in AH is reported. Other neuronal channelopathies have cardiac involvement, and since ATP1A3 is expressed in cardiomyocytes, we hypothesised that ECG abnormalities are present in AH. Methods 52 patients fulfilling the diagnostic criteria for AH were recruited, and screened for ATP1A3 mutations. ECGs were analysed for heart rate, cardiac axis, PR, QRS, RR, and QTc intervals, repolarisation patterns, and J-point abnormalities. Results 53.8% exhibited abnormal resting 12-lead ECGs independent of seizures or AH episodes; 48.1% had repolarisation abnormalities. The proportion of intraventricular conduction delay or partial right bundle branch block was greater in this cohort compared to the general population. ECG abnormalities were significantly greater in patients >16 years than in those <16 years (p=0.0095), and also within the most common mutation group (D801N; p=0.045). Conclusions These ECG abnormalities reflect impaired repolarisation reserve in AH in an age-dependent manner, and may account for some cases of premature mortality observed. Long-term cardiac surveillance in AH is recommended.