Eslicarbazepine acetate: its effectiveness as adjunctive therapy in clinical trials and open studies.

Eslicarbazepine acetate (ESL) is a once-daily antiepileptic drug that is approved as adjunctive therapy in adults with focal-onset seizures. Following oral administration, ESL is rapidly metabolized to its active metabolite, eslicarbazepine, which acts primarily by enhancing slow inactivation of voltage-gated sodium channels. The efficacy and safety/tolerability of ESL in the adjunctive setting were established in a comprehensive Phase III program (n = 1702 randomized patients) and this evidence has been supported by several open studies (n = 864). ESL treatment has demonstrated improvements in health-related quality of life, in both randomized clinical trials and open studies. ESL has also been shown to be usually well tolerated and efficacious when used in the adjunctive setting in elderly patients. The effectiveness of ESL as the only add-on to antiepileptic drug monotherapy has been demonstrated in a multinational study (n = 219), subgroup analyses of which have also shown it to be efficacious and generally well tolerated in patients who had previously not responded to carbamazepine therapy. Open studies have also demonstrated improvements in tolerability in patients switched overnight from oxcarbazepine to ESL. Due to differences in pharmacokinetics, pharmacodynamics, and metabolism, there may be clinical situations in which it is appropriate to consider switching patients from oxcarbazepine or carbamazepine to ESL.

The 5th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures.

This paper describes the 5th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in London on April 9-11 2015. It reviews the progress made in this field since 2007, when the first London-Innsbruck Colloquium was held, and the program of the 2015 meeting. This article is part of a Special Issue entitled "Status Epilepticus".

Preliminary results of the global audit of treatment of refractory status epilepticus.

The treatment of refractory and super refractory status epilepticus is a "terra incognita" from the point of view of evidence-based medicine. As randomized or controlled studies that are sufficiently powered are not feasible in relation to the many therapies and treatment approaches available, we carried out an online multinational audit (registry) in which neurologists or intensivists caring for patients with status epilepticus may prospectively enter patients who required general anesthesia to control the status epilepticus (SE). To date, 488 cases from 44 different countries have been collected. Most of the patients had no history of epilepsy and had a cryptogenic etiology. First-line treatment was delayed and not in line with current guidelines. The most widely used anesthetic of first choice was midazolam (59%), followed by propofol and barbiturates. Ketamine was used in most severe cases. Other therapies were administered in 35% of the cases, mainly steroids and immunotherapy. Seizure control was achieved in 74% of the patients. Twenty-two percent of patients died during treatment, and four percent had treatment actively withdrawn because of an anticipated poor outcome. The neurological outcome was good in 36% and poor in 39.3% of cases, while 25% died during hospitalization. Factors that positively influenced outcome were younger age, history of epilepsy, and low number of different anesthetics tried. This article is part of a Special Issue entitled "Status Epilepticus".

Genetic mutations associated with status epilepticus.

This paper reports the results of a preliminary search of the literature aimed at identifying the genetic mutations reported to be strongly associated with status epilepticus. Genetic mutations were selected for inclusion if status epilepticus was specifically mentioned as a consequence of the mutation in standard genetic databases or in a case report or review article. Mutations in 122 genes were identified. The genetic mutations identified were found in only rare conditions (sometimes vanishingly rare) and mostly in infants and young children with multiple other handicaps. Most of the genetic mutations can be subdivided into those associated with cortical dysplasias, inborn errors of metabolism, mitochondrial disease, or epileptic encephalopathies and childhood syndromes. There are no identified 'pure status epilepticus genes'. The range of genes underpinning status epilepticus differs in many ways from the range of genes underpinning epilepsy, which suggests that the processes underpinning status epilepticus differ from those underpinning epilepsy. It has been frequently postulated that status epilepticus is the result of a failure of 'seizure termination mechanisms', but the wide variety of genes affecting very diverse biochemical pathways identified in this survey makes any unitary cause unlikely. The genetic influences in status epilepticus are likely to involve a wide range of mechanisms, some related to development, some to cerebral energy production, some to diverse altered biochemical pathways, some to transmitter and membrane function, and some to defects in networks or systems. The fact that many of the identified genes are involved with cerebral development suggests that status epilepticus might often be a system or network phenomenon. To date, there are very few genes identified which are associated with adult-onset status epilepticus (except in those with preexisting neurological damage), and this is disappointing as the cause of many adult-onset status epilepticus cases remains obscure. It has been suggested that idiopathic adult-onset status epilepticus might often have an immunological cause but no gene mutations which relate to immunological mechanisms were identified. Overall, the clinical utility of what is currently known about the genetics of status epilepticus is slight and the findings have had little impact on clinical treatment despite what has been a very large investment in money and time. New genetic technologies may result in the identification of further genes, but if the identified genetic defects confer only minor susceptibility, this is unlikely to influence therapy. It is also important to recognize that genetics has social implications in a way that other areas of science do not. This article is part of a Special Issue entitled "Status Epilepticus".

Long-term risk of developing epilepsy after febrile seizures: a prospective cohort study.

OBJECTIVE: We report the prospective follow-up of a cohort of people from the onset of febrile seizures for a median of 24 years to estimate the long-term risk of developing epilepsy. METHODS: The National General Practice Study of Epilepsy is a large prospective community study of 1,195 people with a first suspected seizure followed from the 1980s, of whom 220 (18%) had febrile seizures. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) for subsequent epilepsy were calculated in 5-year age bands. RESULTS: Follow-up information was obtained for 181 (83%) people with a mean follow-up for the whole cohort of 21.6 (SD 6.0) years. Of these, 175 (97%) were seizure-free in the preceding 5 years, whereas 171 (94%) were seizure-free and off antiepileptic drugs. Six percent developed epilepsy, but the risk of developing epilepsy in the cohort over the whole follow-up period was almost 10 times that of the general population (SIR 9.7, 95% CI 5.7-16.4). The SIR was significantly elevated in the 0- to 14-year age groups but not in the 15- to 19-year age group (SIR 4.5, 95% CI 0.6-32.1). CONCLUSION: The risk of developing epilepsy in people who had febrile seizures seems to decrease with time. Further long-term studies are needed to confirm this.

Prognostic factors, morbidity and mortality in tonic-clonic status epilepticus: a review.

OBJECTIVES: to determine how the duration of SE, the EEG findings during/after SE, the depth of coma at presentation and age impact on the prognosis of convulsive status epilepticus indepedent of aetiology and to analyse the outcome of status epilepticus with respect to mortality and morbidity (the latter measured in terms of functional decline, cognitive/intellectual decline and the prospective risk of epilepsy). DESIGN: a systematic review of all studies of status epilepticus (SE) with greater then 30 patients published from the 01/01/1990 up until 31/12/2009. RESULTS: oveall the longer the duration of SE the worse the prognosis particularly after 1-2h of continuous seizures although this affect may be lost after 10h. The depth of coma correlates well with outcome. Only periodic epileptiform discharges (PEDs) have been shown to be associated with a poorer outcome in most (but not all) studies although this is probably related to the underlying aetiology. Age is an important prognostic factor with children having a better prognosis then adults. CONCLUSIONS: age and depth of coma at presentation appear to be the strongest predictors of outcome of SE independent of aetiology with the duration of SE and the EEG findings less important.

The uncommon causes of status epilepticus: a systematic review.

This paper reports the first systematic review of uncommon causes of status epilepticus reported in the literature between 1990 and 2008. Uncommon causes are defined as those not listed in the main epidemiological studies of status epilepticus. 181 causes were identified. These were easily categorised into 5 specific aetiological categories: immunological disorders, mitochondrial disorders, infectious diseases, genetic disorders and drugs/toxins. A sixth category of 'other causes' has also been included. Knowledge of these causes is important for clinical management and treatment, and also for a better understanding of the pathophysiology of status epilepticus.

EFNS guideline on the management of status epilepticus in adults.

The objective of the current article was to review the literature and discuss the degree of evidence for various treatment strategies for status epilepticus (SE) in adults. We searched MEDLINE and EMBASE for relevant literature from 1966 to January 2005 and in the current updated version all pertinent publications from January 2005 to January 2009. Furthermore, the Cochrane Central Register of Controlled Trials (CENTRAL) was sought. Recommendations are based on this literature and on our judgement of the relevance of the references to the subject. Recommendations were reached by informative consensus approach. Where there was a lack of evidence but consensus was clear, we have stated our opinion as good practice points. The preferred treatment pathway for generalised convulsive status epilepticus (GCSE) is intravenous (i.v.) administration of 4-8 mg lorazepam or 10 mg diazepam directly followed by 18 mg/kg phenytoin. If seizures continue more than 10 min after first injection, another 4 mg lorazepam or 10 mg diazepam is recommended. Refractory GCSE is treated by anaesthetic doses of barbiturates, midazolam or propofol; the anaesthetics are titrated against an electroencephalogram burst suppression pattern for at least 24 h. The initial therapy of non-convulsive SE depends on type and cause. Complex partial SE is initially treated in the same manner as GCSE. However, if it turns out to be refractory, further non-anaesthetising i.v. substances such levetiracetam, phenobarbital or valproic acid should be given instead of anaesthetics. In subtle SE, in most patients, i.v. anaesthesia is required.

Limited chronic focal encephalitis: another variant of Rasmussen syndrome?

OBJECTIVE: To describe a more limited and less malignant form of Rasmussen encephalitis (RE). METHODS: Three subjects (all women; 37, 31, and 32 years of age) developed childhood or late onset chronic focal encephalitis, with a relatively nonprogressive form of the disorder. RESULTS: In our patients, clinical features were dominated by partial seizures without marked focal motor deficit and in two with choreo-dystonic movements. The diagnosis of RE was supported by histologic examination and anatomic and functional MRI. CONCLUSIONS: These cases extend the phenotypic presentations of Rasmussen encephalitis and confirm Theodore Rasmussen's suggestion that there may be mild and nonprogressive forms of the disease.

Seizure-related injury in an adult tertiary epilepsy clinic.

OBJECTIVE: To assess the frequency, characteristics, and risk of injury during seizure attacks. DESIGN: Questionnaire survey. SETTING: Epilepsy out-patient clinic of the National Hospital for Neurology and Neurosurgery, Institute of Neurology, London. PATIENTS: One hundred consecutive epileptic patients and their caretakers or relatives, who attended the hospital between 1 May and 30 June 2000. MAIN OUTCOME MEASURES: Details of epilepsy including the age of onset, causes, types, and number of seizures during the previous 12 months; injuries incurred as a result of seizures; and treatment required. RESULTS: The mean age of the 100 patients (38 male, 62 female) was 39 years (range, 16-78 years). Generalised tonic-clonic seizures occurred in 51% of patients and complex partial seizures in 40%. Hippocampal sclerosis was found in 12% of patients. Twenty-seven patients reported 222 seizure-related injuries. The total number of seizures per year was 4459 (mean, 45), of which 1094 (mean, 11) were with a fall (24.5%). Soft-tissue injury was the most common (61%), followed by burns (17%), head injury (14%), orthopaedic injury (5%), and injuries in water (3%). The most common site of soft-tissue injury and burns were to the face: 49% and 38% respectively. Burns occurred during cooking in 78% of cases. Two patients had skull fractures. Orthopaedic injuries usually occurred at home (73%). In cases of seizures in water, five of six occurred while swimming. Injury occurred once in every 20 seizures, every 11 generalised tonic-clonic seizures, and every five seizures with a fall. The significant risk factors for injury were generalised tonic-clonic seizures, high frequency of seizures, and seizures with a fall. CONCLUSION: Soft-tissue injury was the most common seizure-related injury. Injury occurred once in every 20 seizures. The risk factors were generalised tonic-clonic seizures, high frequency of seizures, and seizures with a fall.

EFNS guideline on the management of status epilepticus.

The objective of the current paper was to review the literature and discuss the degree of evidence for various treatment strategies for status epilepticus (SE) in adults. We searched MEDLINE and EMBASE for relevant literature from 1966 to January 2005. Furthermore, the Cochrane Central Register of Controlled Trials (CENTRAL) was sought. Recommendations are based on this literature and on our judgement of the relevance of the references to the subject. Recommendations were reached by informative consensus approach. Where there was a lack of evidence but consensus was clear we have stated our opinion as good practice points. The preferred treatment pathway for generalised convulsive status epilepticus (GCSE) is intravenous (i.v.) administration of 4 mg of lorazepam or 10 mg of diazepam directly followed by 15-18 mg/kg of phenytoin or equivalent fosphenytoin. If seizures continue for more than 10 min after first injection another 4 mg of lorazepam or 10 mg of diazepam is recommended. Refractory GCSE is treated by anaesthetic doses of midazolam, propofol or barbiturates; the anaesthetics are titrated against an electroencephalogram burst suppression pattern for at least 24 h. The initial therapy of non-convulsive SE depends on the type and the cause. In most cases of absence SE, a small i.v. dose of lorazepam or diazepam will terminate the attack. Complex partial SE is initially treated such as GCSE, however, when refractory further non-anaesthetising substances should be given instead of anaesthetics. In subtle SE i.v. anaesthesia is required.

Epilepsy in the United Kingdom: seizure frequency and severity, anti-epileptic drug utilization and impact on life in 1652 people with epilepsy.

OBJECTIVES: To describe the clinical characteristics of epilepsy in a representative sample of the UK population, including seizure frequency and severity; overall severity of epilepsy; patterns of anti-epileptic drug (AED) use; and the impact of epilepsy on patients' lives. Secondly, to determine if these characteristics differ according to age. METHOD: A large, geographically comprehensive survey of people with epilepsy by means of a postal questionnaire distributed by general practitioners to 3455 unselected patients receiving AEDs for epilepsy, regardless of age or type of epilepsy and including all regions of the UK. Data were collected on age and gender; age of onset of seizures; seizure frequency and severity; AED use and adverse effect levels; and impact on life of epilepsy. Sub-analyses were performed with stratification by epilepsy severity and age-group. RESULTS: There were 1652 completed replies. The mean age was 44.2 years; there were 47.2% males, 48.5% females (4.4% not recorded). The mean age at first seizure, 25.1 years, and the mean duration of epilepsy, 19.7 years, were comparable with previous studies. In the preceding one year, 51.7% of patients had no seizures; 7.9% one seizure, 17.2% 2-9 seizures and 23.2% 10 or more. Sixty-four percent of patients had epilepsy classified as mild and 32% severe. There was a marked and significant decrement of seizure frequency with increasing age. The most commonly used AEDs were carbamazepine (37.4%), valproate (35.7%), phenytoin (29.4%), phenobarbitone or primidone (14.2%) and lamotrigine (10.3%). Monotherapy was used in 68% of patients. Patients taking multiple AEDs reported significantly higher levels of adverse effects and worse seizure control. The major impacts of epilepsy on life were work and school difficulties, driving prohibition, psychological and social life. The impacts listed varied with the epilepsy severity and age. CONCLUSIONS: Seizures remain uncontrolled in up to half of all people with epilepsy in the UK with significant impact on work, family and social life. Previously, there has been a deficiency of data on the characteristics of epilepsy in older people, although it is recognized that the condition is of increasing epidemiological importance in this age group. We have found clear differences in the clinical characteristics of epilepsy in older people, particularly that seizure frequency appears to decline with increasing age.

A longitudinal study of brain morphometrics using quantitative magnetic resonance imaging and difference image analysis.

Serial quantitative magnetic resonance imaging (MRI) allows the detection of subtle volumetric changes in brain volume. We used serial volumetry and voxel-based difference image analysis to quantify and characterize longitudinal changes in the hippocampus, cerebellum, and neocortex in younger and middle-age individuals. Paired volumetric MRI brain scans 3.5 years apart were performed on 90 healthy subjects 14 to 77 years old. Quantitative assessment of registered images included hippocampal volumetry, cerebellar volumetry, and automatically determined regional brain volumes. Longitudinal volume changes in three age epochs (<35, 35-54, >54 years) were compared and neocortical changes beyond regions of interest were visualized using filtered difference images. Cross-sectional analysis revealed a significant association between age and reduction in all brain volumes except hippocampal volume. Changes in normalized hippocampal and white matter volume were significantly different among the three groups. Individual analysis revealed 5 subjects with significant longitudinal volume changes lying outside the normative range. Difference image analysis showed global involutional changes in the >54 age group. Our findings suggest that cross-sectional observations in intracranial volume, cerebellar volume, and gray matter volume are likely to reflect uniform rates of volume loss or secular changes. Accelerated brain atrophy was seen from the age of 35-54 and increased rates of hippocampal atrophy from the age of 54. Our findings emphasize the importance of controlling for age effects when studying pathological brain changes over a wide age range.

Information recalled by women taking anti-epileptic drugs for epilepsy: a questionnaire study.

Women with epilepsy have different needs from men, particularly associated with childbearing. Despite clinical guidelines, the care of women with epilepsy remains suboptimal. The aim of this study was to establish whether women with epilepsy recall being given information on topics relating to childbearing. Design of study and methods included a postal questionnaire study of 795 women with epilepsy and of childbearing age. The respondents were identified through both general practices and hospital clinics as part of the Clinical Standards Advisory Group study into Epilepsy Services. Of those women who considered the questions personally relevant, 38-48% recalled receiving information about contraception, pre-pregnancy planning, folic acid and teratogenicity, with lower overall proportions among adolescent women. The proportions that recalled receiving information about vitamin K, safety in child-care and breast-feeding were lower at 12, 24 and 24%, respectively. While it is recognised that information provided may not be recalled, our results suggest that further measures are required to improve the effectiveness of information provision in the UK in relation to women of childbearing age with epilepsy.

Anterior commissure absence without callosal agenesis: a new brain malformation.

The authors report a novel human brain malformation characterized by the absence of the anterior commissure without callosal agenesis, but associated with gross unilateral panhemispheric malformation incorporating subependymal heterotopia, subcortical heterotopia, and gyral abnormalities including temporal malformation and polymicrogyria. In contrast, a normal anterior commissure was found in 125 control subjects and in 113 other subjects with a range of brain malformations.

Antiepileptic drugs: coprescription of proconvulsant drugs and oral contraceptives: a national study of antiepileptic drug prescribing practice.

OBJECTIVES: To determine the frequency of coprescription of antiepileptic drugs (AEDs) and drugs with proconvulsant potential and of coprescription of AEDs and low dose oral contraceptives. METHODS: Using information from all 294 fully computerised general practices participating in the General Practice Research Database who entered complete data in 1995, persons were identified who had a prescription for an antiepileptic drug and who had a diagnosis of epilepsy or epileptic seizures in their medical records. Other medication was also recorded. RESULTS: Of women with epilepsy aged 15-45, 16.7% were on the oral contraceptive pill and of 200 on both an enzyme inducing AED and an oral contraceptive, 56% were on formulations with an estrogen content less than 50 microg. This will be associated with increased risk of contraceptive failure and unwanted pregnancy. Over 10% of all AED prescriptions in adults were associated with simultaneous prescription of at least one drug with a potential proconvulsant effect. CONCLUSIONS: Prescribers should be alert to the possibility of pharmacodynamic and pharmacokinetic interactions between AEDs and other medication. With the aging of the population of people with seizures, and the polypharmacy often associated with old age, the likelihood of adversely interacting drug combinations will increase.