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.

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.

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.

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.

Cerebellar volumes in newly diagnosed and chronic epilepsy.

Cerebellar atrophy is assumed to be a common finding in patients suffering from epilepsy. Anticonvulsants as well as seizure activity itself have been considered to be responsible for it but many studies have addressed these questions in specialised centres for epilepsy thus having a referral bias towards patients with severe epileptic syndromes. The purpose of this study was: 1. To develop a quantitative method on 3D-MRI data to achieve volume or planimetric measurements (of cerebrum, cerebellum and cerebellar substructures). 2. To investigate the prevalence of cerebellar atrophy (and substructure atrophy) in a prospectively investigated population-based cohort of patients with newly diagnosed and chronic epilepsy. 3. To quantify cerebellar atrophy in clinic-based patients, who had had atrophy previously diagnosed on routine visual MRI assessment. 4. To correlate the measures of atrophy with clinical features in both patient groups. A total of 57 patients with either newly diagnosed or chronic active epilepsy and 36 control subjects were investigated with a newly developed semiautomated method for cerebral as well as cerebellar volume measurements and substructure planimetry, corrected for intracranial volume. We did not find any significant atrophy in the population-based cohort of patients with newly diagnosed epilepsy or with chronic epilepsy. Visually diagnosed cerebellar atrophy was mostly confirmed and quantified by volumetric analysis. The clinical data suggested a correlation between cerebellar atrophy and the duration of the seizure disorder and also the total number of lifetime seizures experienced and the frequency of generalised tonic-clonic seizures per year. Volumetry on 3D-MRI yields reliable quantitative data which shows that cerebellar atrophy might be common in severe and/or longstanding epilepsy but not necessarily in unselected patient groups. The results do not support the proposition that cerebellar atrophy is a predisposing factor for epilepsy but rather are consistent with the view that cerebellar atrophy is the aftermath of epileptic seizures or anticonvulsant medication.

The dynamics of drug treatment in epilepsy: an observational study in an unselected population based cohort with newly diagnosed epilepsy followed up prospectively over 11-14 years.

OBJECTIVES: To study prospectively long term dynamics and patterns of treatment in a population based cohort of patients with newly diagnosed epilepsy. METHODS: 564 patients with definite epilepsy entered the UK National General Practice Study of Epilepsy (NGPSE), between 1984 and 1987, and were prospectively followed up for between 11-14 years. RESULTS: Treatment was started in 433 (77%) patients. Only 15% of single seizure patients had medication prescribed initially, although due to high seizure recurrence, more than 70% ultimately received antiepileptic medication. 209/564 patients (37%) were on drug therapy for epilepsy at the time of last follow up. 168/564 patients (30%) have stayed continuously on medication and another 41/564 patients (7%) restarted drug therapy because of seizure recurrence, having withdrawn medication. 98/209 (47%) of those on treatment are known to be in 5 year terminal remission. Phenytoin (29%) and carbamazepine (27%) were the most commonly preferred first line drugs followed by valproate (15%). Less than half of treated patients with partial seizures received carbamazepine as a first line drug and less than a third with generalised seizures were prescribed valproate as first choice drug. Nine out of 31 (29%) patients with one or more seizures a week at last follow up had never tried a second drug and only seven (23%) had tried four or more drugs. 11% of all treatment changes involved a new antiepileptic drug. Treatment changes were associated with low terminal remission rates. CONCLUSIONS: Out of 30 000 patients with newly diagnosed epilepsy every year in the United Kingdom, about 6000 have inadequate seizure control in the long term. About a third of the patients in this group have one or more seizures every month. Only two thirds of these patients with frequent seizures are likely to switch medication to try and achieve better seizure control. There is probably still considerable room for improvement in prescribing practice in the United Kingdom.

A longitudinal quantitative MRI study of community-based patients with chronic epilepsy and newly diagnosed seizures: methodology and preliminary findings.

Experimental and human data suggest that progressive cerebral damage may result from the cumulative effect of brief recurrent seizures. Longitudinal studies addressing this fundamental question, however, are lacking. We have addressed this need with a large prospective community-based observational study, which aims to rescan 154 patients with chronic active epilepsy and 90 patients with newly diagnosed seizures, after an interval of 3.5 years. Here, we describe the quantitative magnetic resonance methods used to identify subtle volume changes in hippocampal, cerebellar, and neocortical structures over time and report preliminary findings. Using this methodology, we have previously shown that we can reliably detect individual hippocampal volume (HV) and cerebellar volume (CBV) changes greater than 3.1 and 3.0%, respectively (Lemieux et al, 2000). Analysis of the first 53 subjects (24 patients with chronic active epilepsy, 9 patients with newly diagnosed seizures, and 20 controls) has demonstrated significant HV losses in 4 individuals. Automated and semiautomated calculation has detected significant reductions in CBV, total brain volume, and gray matter volume in 2, 3, and 1 subject, respectively. There were no significant white matter volume losses detected. Data collected from rescanning the entire cohorts will help to provide further information on the relationship between recurrent seizures and secondary brain damage.

PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.

Landmark-based morphometrics of the normal adult brain using MRI.

We describe the application of statistical shape analysis to homologous landmarks on the cortical surface of the adult human brain. Statistical shape analysis has a sound theoretical basis. Landmarks are identified on the surface of a 3-D reconstruction of the segmented cortical surface from magnetic resonance image (MRI) data. Using publicly available software (morphologika) the location and size dependence of the landmarks are removed and the differences in landmark distribution across subjects are analysed using principal component analysis. These differences, representing shape differences between subjects, can be visually assessed using wireframe models and transformation grids. The MRI data of 58 adult brains (27 female and 15 left handed) were examined. Shape differences in the whole brain are described which concern the relative orientation of frontal lobe sulci. Analysis of all 116 hemispheres revealed a statistically significant difference (P < 0.001) between left and right hemispheres. This finding was significant for right- but not left-handed subjects alone. No other significant age, gender, handedness, or brain-size correlations with shape differences were found.

Mortality in epilepsy in the first 11 to 14 years after diagnosis: multivariate analysis of a long-term, prospective, population-based cohort.

The United Kingdom National General Practice Study of Epilepsy is a prospective, population-based study of newly diagnosed epilepsy. A cohort of 792 patients has now been followed for up to 14 years (median follow-up [25th, 75th percentiles] 11.8 years, range 10.6-11.7 years), a total of 11,400 person-years. These data are sufficient for a detailed analysis of mortality in this early phase of epilepsy. Over 70% of patients in this cohort have developed lasting remission from seizures, although the mortality rate in the long term was still twice that of the general population. The standardized mortality ratio (SMR), the number of observed deaths per number of expected deaths, was 2.1 (95% confidence interval [CI] = 1.8, 2.4). Patients with acute symptomatic epilepsy (SMR 3.0; 95% CI = 2.0, 4.3), remote symptomatic epilepsy (SMR 3.7; 95% CI = 2.9, 4.6), and epilepsy due to congenital neurological deficits (SMR 25; 95% CI = 5.1, 73.1) had significantly increased long-term mortality rates, whereas patients with idiopathic epilepsy did not (SMR 1.3; 95% CI = 0.9, 1.9). This increase in mortality rate was noted particularly in the first few years after diagnosis. Multivariate Cox regression and time-dependent co-variate analyses were utilized for the first time in a prospective study of mortality in epilepsy. The former showed that patients with generalized tonic-clonic seizures had an increased risk of mortality. The hazard ratio (HR), or risk of mortality in a particular group with a particular risk factor compared to another group without that particular risk factor, was 6.2 (95% CI = 1.4, 27.7; p = 0.049). Cerebrovascular disease (HR 2.4; 95% CI = 1.7, 3.4; p < 0.0001), central nervous system tumor (HR 12.0; 95% CI = 7.9, 18.2; p < 0.0001), alcohol (HR 2.9; 95% CI = 1.5, 5.7; p = 0.004), and congenital neurological deficits (HR 10.9; 95% CI = 3.2, 36.1; p = 0.003) as causes for epilepsy and older age at index seizure (HR 1.9; 95% CI = 1.7,2.0; p < 0.0001) were also associated with significantly increased mortality rates. These hazard ratios suggest that epilepsy due to congenital neurological deficits may carry almost the same risk of mortality as epilepsy due to central nervous system tumors and that epileptic seizures subsequent to alcohol abuse may carry almost the same risk of mortality as epilepsy due to cerebrovascular disease. The occurrence of one or more seizures before the index seizure (the seizure that led to the diagnosis of epilepsy and enrolment in the study) was associated with a significantly reduced mortality rate (HR 0.57; 95% CI = 0.42, 0.76; p = 0.00001). Time-dependent co-variate analysis was used to examine the influence of ongoing factors, such as seizure recurrence, remission, and antiepileptic drug use, on mortality rates in the cohort. Seizure recurrence (HR 1.30; 95% CI = 0.84, 2.01) and antiepileptic drug treatment (HR 0.97; 95% CI = 0.67, 1.38) did not influence mortality rate. There were only 5 epilepsy-related deaths (1 each of sudden unexpected death in epilepsy, status epilepticus, burns, drowning, and cervical fracture), suggesting that death directly due to epileptic seizures is uncommon in a population-based cohort with epilepsy.

Combined functional magnetic resonance imaging and diffusion tensor imaging demonstrate widespread modified organisation in malformation of cortical development.

A patient with a mild left hemiparesis and a malformation of cortical development in the right hemisphere was investigated with fMRI (functional magnetic resonance imaging) and DTI (diffusion tensor imaging). The motor cortex was studied using a finger tapping fMRI experiment. The fibre orientation was studied by displaying the principal eigenvector of the diffusion tensor in the spatially normalised brain of the patient and of control subjects. In addition, the anisotropy (directionality) of water diffusion of the patient was statistically compared with control subjects. The malformation was located in the right central region in the expected position of the motor cortex. fMRI showed activation anterior and posterior to the malformation. DTI disclosed that fibres with rostrocaudal orientation, presumably representing the pyramidal tract, were deviating from their normal orientation and passing around the malformation. There were widespread regions of reduced anisotropy affecting both hemispheres. In conclusion, fMRI and DTI provided concordant information showing widespread modified functional and structural organisation including regions which appeared normal on standard imaging.

Comparing the cost of epilepsy across eight European countries.

To observe the degree to which prices for medical services and anti-epileptic drugs (AEDs) vary between eight European Union (EU) countries, to identify the factors that are likely to contribute to these variations and to consider the validity of international cost-of-illness comparisons. Cost-of-illness study methodology has been used to estimate the national cost of epilepsy in several developed countries. The validity of comparing these studies is unknown. Eight EU member countries were selected. Charges and prices were obtained for important aspects of medical care of patients with epilepsy including AEDs. The perspective taken was that of the major health care payer within each country. Prices were validated by a local panel of doctors expert in treating epilepsy. Prices for similar services were compared between countries. Charges and prices levied to health service payer vary widely between the eight countries considered. The cheapest and most expensive medical services vary by as much as 24 times, whereas the price of AED varies up to 4.4 times. These wide variations suggest that prices do not reflect the true cost of providing these important aspects of epilepsy treatment. International comparisons between national cost-of-illness estimates relying on such prices should be interpreted with caution.