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.

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.

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.

The National General Practice Study of Epilepsy. The syndromic classification of the International League Against Epilepsy applied to epilepsy in a general population.

In this prospective, population-based study of 594 cases of newly diagnosed epilepsy, proportions in categories as defined by the International League Against Epilepsy (ILAE) were as follows: (1) localization-related epilepsies: 1.1* idiopathic, 1.2%; 1.2* symptomatic, 16.2%; and 1.3 cryptogenic, 24.6%; (2) generalized epilepsies: 2.1* idiopathic (idiopathic generalized epilepsy) with 3-Hz spike and wave: absence epilepsy, 2.2%; juvenile myoclonic epilepsy, 1.5%; and nonspecific idiopathic generalized epilepsy, 5.6%; 2.3.1* symptomatic generalized epilepsies, 1.5%; 2.3.2* specific syndromes with generalized epilepsy, 0.3%; 3.2 seizures without unequivocal focal or generalized features, 32%; 4.1 situation-related syndromes, isolated seizures, 9.9%; seizures due to acute toxic or metabolic cause,* 4.5%. Only 33.6% were in diagnostic ILAE categories (asterisks) and many rare syndromes were not represented. The remainder (66.4%) were in various nonspecific categories. Only 24% of localization-related epilepsies could be clinically localized to a single ILAE-proposed site of origin and of these best localized cases, 14% had strongly discordant imaging or electroencephalograms. These major problems in applying the ILAE classification to epilepsy in the general population and its underemphasis of modern imaging techniques are discussed.

The demonstration of gyral abnormalities in patients with cryptogenic partial epilepsy using three-dimensional MRI.

BACKGROUND: Despite the use of high-resolution magnetic resonance imaging (MRI) in the demonstration of structural abnormalities underlying chronic partial epilepsy, a significant proportion of MRI scans in such cases still appear normal when viewed conventionally as two-dimensional images, especially in extratemporal epilepsies. OBJECTIVES: To increase the yield of MRI in patients with extratemporal epilepsies. To examine specific regions of three-dimensional surface renderings of the cerebral hemispheres. DESIGN: Postprocessing of volumetric MRI data was used to detect abnormalities of gyration that may not be seen otherwise. SETTING: Scans were obtained at a hospital clinical imaging facility. PARTICIPANTS: Sixty-four subjects were studied: 33 controls, 15 patients with hippocampal sclerosis (as disease controls), and 16 patients with cryptogenic partial epilepsy that on clinical grounds was extratemporal. MAIN OUTCOME MEASURES: Gyral patterns were evaluated for abnormality by visual comparison between subjects. RESULTS: Inspection of the routine two-dimensional images had failed to demonstrate relevant underlying neocortical abnormality in any of the patients' scans. Three-dimensional reconstruction revealed abnormal gyral patterns in the frontal lobe convexity in seven of the 16 cryptogenic clinically extratemporal cases. Macrogyria was revealed in one case and increased gyral complexity with altered disposition was seen in six cases. Similar gyral patterns were not seen in any subjects from the other groups. CONCLUSION: Three-dimensional analysis of volumetric MRI data can reveal structural abnormality that is not visible when the data are viewed as two-dimensional images only.

National General Practice Study of Epilepsy (NGPSE): partial seizure patterns in a general population.

The National General Practice Study of Epilepsy (NGPSE) is a prospective community-based study of newly diagnosed epileptic seizures. Of 594 patients with definite epileptic seizures, 160 (26.9%) had seizures with a clinically localizable onset: 36 (22.5%) frontal, 52 (32.5%) central sensorimotor, 43 (27%) temporal, nine (5.6%) frontotemporal, and 10 each (6.3%) parietal and other posterior cortex. There was no difference among these groups in seizure frequency or remission rate; 46.5% were seizure free and 6.9% had severe epilepsy. Etiology was identifiable in 41% and focal CT and EEG abnormalities in 33% and 19%, with results discordant with the clinical seizure localization in 21% and 20%. Temporal lobe epilepsy may be underreported, as it may be more difficult to localize clinically. Extratemporal seizures are extremely common in the general population, especially frontal and central sensorimotor, in relation to cerebrovascular disease. Prognoses are similar for partial epilepsies with different clinical patterns and regions of onset and are much better than suggested in hospital-based studies. The clinical, EEG, and CT localizations may frequently be discordant in this nonrefractory group.

The effect of seizures on memory for recently learned material.

We gave 58 patients with refractory partial seizures who were undergoing video-EEG telemetry a variety of memory tests shortly after the telemetry commenced, and we reassessed memory for this material 48 hours later. Thirty patients had one or more seizures during this period; 22 of these had complex partial seizures, secondary generalized seizures, or both. Eighteen patients did not have any seizures during the study period. Patients who had seizures forgot no more than patients who did not have seizures. There was no correlation between memory performance and the timing of seizures or the number of seizures. These findings indicate that isolated seizures do not generally cause patients to forget material they have recently learned.

Association of hippocampal sclerosis with cortical dysgenesis in patients with epilepsy.

The possible dual occurrence of hippocampal sclerosis (HS) and other structural lesions (especially cortical dysgenesis [CD]) is well established in patients with chronic partial epilepsy. We describe the frequency of additional CD in a series of 100 patients with evidence of HS, using volumetric MRI. Additional, often subtle, CD was present in 15 patients: subependymal heterotopia (six), forme fruste of tuberous sclerosis (two), focal macrogyria (two), focal cortical dysplasia (one), laminar heterotopia (one), bilateral schizencephaly (one), and simplified gyral patterns (two). In contrast, in 46 healthy volunteers, only one had possible CD (p < 0.05). Only 2 of 15 patients had a history of childhood febrile convulsions. HS is a heterogeneous condition; patients being evaluated for temporal lobe surgery should be carefully screened for additional CD using appropriate MR techniques.

Frequency and characteristics of dual pathology in patients with lesional epilepsy.

We studied 167 patients who had identifiable lesions and temporal or extratemporal partial epilepsy. Pathology included neuronal migration disorders (NMDs) (48), low-grade tumors (52), vascular malformations (34), porencephalic cysts (16), and gliotic lesions as a result of cerebral insults early in life (17). MRI volumetric studies using thin (1.5- or 3-mm) coronal images were performed in all patients and in 44 age-matched normal controls. An atrophic hippocampal formation (HF), indicating dual pathology, was present in 25 patients (15%). Abnormal HF volumes were present in those with lesions involving temporal (17%) but also extratemporal (14%) areas. Age at onset and duration of epilepsy did not influence the presence of HF atrophy. However, febrile seizures in early childhood were more frequently, although not exclusively, found in patients with hippocampal atrophy. The frequency of hippocampal atrophy in our patients with low-grade tumors (2%) and vascular lesions (9%) was low. Dual pathology was far more common in patients with NMDs (25%), porencephalic cysts (31%), and reactive gliosis (23.5%). Some structural lesions, such as NMDs, are more likely to be associated with hippocampal atrophy, independent of the distance of the lesion from the HF. In other types of lesions, such as vascular malformations, dual pathology was found when the lesion was close to the HF. A common pathogenic mechanism during pre- or perinatal development may explain the occurrence of concomitant mesial temporal sclerosis and other structural lesions because of either (1) associated developmental abnormalities or (2) predisposition to prolonged febrile convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Evidence for nodular epileptogenicity and gender differences in periventricular nodular heterotopia.

OBJECTIVE: To determine whether clinical differences between the sexes seen in periventricular nodular heterotopia (PNH) have structural correlates on imaging. BACKGROUND: PNH is the most common dysgenesis associated with hippocampal sclerosis (HS). Women with PNH have normal intellect; men may have mental retardation and other changes. Familial PNH, seen in women, is linked to Xq28-a region also abnormal in a sporadic male infant with PNH and retardation-suggesting sexual differences in gene expression. Epilepsy associated with PNH may be refractory to drugs, and surgery for associated HS does not stop seizures, suggesting intrinsic epileptogenicity of PNH. METHODS: Quantitative MRI analysis was performed using established techniques for detecting subtle structural changes in 13 female patients (11 sporadic and two familial) and four male patients (sporadic). RESULTS: There is structural heterogeneity in PNH, even in patients with bilateral PNH. On MRI, men have more cerebral abnormalities beyond PNH than control subjects or female patients (p < 0.005). CONCLUSIONS: The findings support the concept of intrinsic epileptogenicity of PNH. There may be additional structural abnormalities relevant to seizure generation, especially in men. Structural heterogeneity, and widespread abnormalities, may need consideration when patients are referred for surgical treatment or when additional studies of patients with PNH are conducted.

Disproportion in the distribution of gray and white matter: neuropsychological correlates.

OBJECTIVE: To examine the relationship between measures of disproportion in the regional distribution of gray and white matter and preoperative neuropsychological function in temporal lobe epilepsy patients with proved hippocampal sclerosis (HS). BACKGROUND: Subtle cerebral structural disruption, not evident on routine inspection of high-resolution MRI, is associated with poor surgical outcome in patients with histologically proved HS. Preoperative global memory dysfunction is also associated with poor postoperative seizure control. The authors hypothesize that patients with HS and abnormal regional distributions of gray and white matter would show more diffuse neuropsychological deficits preoperatively than patients with isolated HS alone. METHODS: A total of 28 adults with lateralized temporal lobe epilepsy and hippocampal volume loss measured on MRI were assessed preoperatively on neuropsychological tests of general intellect and the learning and recall of both verbal and nonverbal material. Quantitative MRI analysis of the regional distribution of gray and white matter was performed. Chi-square analyses were used to examine the relation between the presence or absence of cerebral abnormalities and preoperative performance on the neuropsychological tests. RESULTS: A total of 15 of 28 patients had extrahippocampal abnormalities on quantitative MRI analysis. Thirteen patients had global memory impairment. Bilateral memory deficits were significantly associated with both the presence of cerebral abnormalities (p < 0.02) and poor postoperative seizure control (p < 0.05). CONCLUSIONS: Disproportion in the regional distribution of gray and white matter in patients with HS may form the structural basis of global memory disturbance in a distinct group of patients with temporal lobe epilepsy.

Quantitative hippocampal MRI and intractable temporal lobe epilepsy.

OBJECTIVES: To evaluate and compare T2 relaxometry and volumetrics of hippocampus in the presurgical evaluation of patients with intractable temporal lobe epilepsy (TLE), and to correlate these quantitative MRI measures with the pathology of the resected hippocampus. PATIENTS: Forty patients with intractable TLE who underwent presurgical evaluation and subsequent temporal lobe surgery. MAIN OUTCOME MEASURES: Hippocampal T2 (HCT2), volumes of hippocampi and hippocampal volume ratio (HCVR) (volume of hippocampus with higher HCT2 divided by volume of hippocampus with lower HCT2), and qualitative pathology. RESULTS: Thirty-two patients had hippocampal sclerosis, three patients had end-folium sclerosis, one patient had amygdala sclerosis, and four patients had a foreign tissue lesion in the temporal lobe. HCT2 (R/L) correlated inversely with the ratio of hippocampal volumes (R/L) (r = -0.91; p < 0.0001). A high T2 signal in an atrophic hippocampus was characteristic of hippocampal sclerosis. All patients with hippocampal sclerosis had an HCVR below control values, and only one of these had an HCT2 in the normal range. HCVR produced one false-positive result. The patients with end-folium sclerosis had normal HCT2 and HCVR. The patient with amygdala sclerosis had a normal hippocampus on qualitative and quantitative assessment. Of the four patients with a lesion, one had a mildly increased HCT2 and one had mild volume asymmetry. Hippocampal volume asymmetry could be reliably detected on visual inspection of the MRI with an HCVR of 0.85 or less, and an increase of HCT2 with a T2 of 115 msec or higher. CONCLUSION: Quantitative MRI combining HCT2 and HCVR is a reliable method for diagnosing hippocampal sclerosis noninvasively. End-folium sclerosis and amygdala sclerosis should be considered in patients with intractable TLE and negative findings on MRI studies, including quantitative measures of the hippocampus.

Surgical treatment of patients with single and dual pathology: relevance of lesion and of hippocampal atrophy to seizure outcome.

Modern neuroimaging can disclose epileptogenic lesions in many patients with partial epilepsy and, at times, display the coexistence of hippocampal atrophy in addition to an extrahippocampal lesion (dual pathology). We studied the postoperative seizure outcome of 64 patients with lesional epilepsy (median follow-up, 30 months) and considered separately the surgical results in the 51 patients with a single lesion and in the 13 who had dual pathology. In patients with a single lesion, 85% were seizure free or significantly improved (Engel's class I-II) when the lesion was totally removed compared with only 40% when there was incomplete resection (p < 0.007). All three patients with dual pathology who had both the lesion and the atrophic hippocampus removed became seizure free. In contrast, only 2 of the 10 patients with dual pathology undergoing surgery aimed at the lesion or at the hippocampus alone became seizure free (p < 0.05), although 4 of them showed significant improvement (Engel's class II). We conclude that the outcome in patients with single epileptogenic lesions is usually dependent upon the completeness of lesion resection. In patients with dual pathology, surgery should, if possible, include resection of both the lesion and the atrophic hippocampus.

Diagnosis and treatment of status epilepticus on a neurological intensive care unit.

Status epilepticus refractory to first-line therapy is associated with a high morbidity and mortality. Correct diagnosis and adequate treatment of this condition require electrographic monitoring and anaesthetic facilities available in specialist intensive care units (ICUs). We carried out an audit of 26 patients admitted to a neurological ICU with a diagnosis of status epilepticus, to identify deficiencies in diagnosis and management prior to transfer to the ICU, and examine the effectiveness of ICU management. Or transfer, only 14 (54%) were in status epilepticus; six were in drug-induced coma or were encephalopathic, and six had pseudostatus epilepticus, of whom four had been intubated. The commonest treatments prior to transfer were benzodiazepines, chlormethiazole and phenytoin; the loading dose of phenytoin was adequate in at least 7/16 cases. All those in status epilepticus on transfer had their seizures successfully controlled, but ten required general anaesthesia with thiopentone, propofol, ketamine or midazolam. Two died--one had a severe encephalitis and the other had had a cardiac arrest prior to treatment. This study highlights deficiencies in the initial diagnosis and management of status epilepticus, the role of specialist neurological intensive care, and the importance of early referral.

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.

Methods for normalization of hippocampal volumes measured with MR.

PURPOSE: To investigate the use of six cerebral measures as correlates for hippocampal volumes and, therefore, to enable normalized absolute hippocampal volumes to be calculated via two correction processes. METHODS: Hippocampal volumes and six cerebral measures were estimated from MR data in 20 control subjects. Three of these measures (the cranial volume, the cerebral volume, and the midsagittal cranial area) were then applied to a group of 32 control subjects, and regression analysis was performed to investigate the linear relationship between hippocampal volume and each measure. Division of hippocampal volume by cerebral measure and correction via a covariance calculation enabled corrected absolute hippocampal volumes to be determined for 32 control subjects and 23 patients with temporal lobe epilepsy. RESULTS: Correction processes reduced the variance in absolute hippocampal volumes in control subjects and enabled abnormally small absolute volumes to be defined. Of 11 patients with unilateral volume ratio abnormalities, 8 had unilateral abnormally small absolute hippocampal volumes. Of 12 patients with normal volume ratios, 4 had bilateral abnormally small absolute hippocampal volumes. CONCLUSION: Correction processes can define absolute hippocampal volumes for correlation studies and may enable identification of unsuspected bilateral hippocampal volume loss.

Estimation of resection volumes in lesional epilepsy surgery.

An MR-based method for measuring resection volumes in lesional epilepsy surgery is described. The volume of the preoperative lesion, the resection cavity and, as a result, the volume of the brain surrounding the lesion resected during surgery have been calculated in 13 patients.

Rates of antiepileptic drug reduction in active epilepsy--current practice.

We have surveyed the rates at which clinicians in the U.K. and Eire withdraw antiepileptic drugs (AEDs) in patients with active epilepsy. Practice differed widely and there was a lack of consensus regarding the rates employed. Inpatient reductions were 2-4 times faster than outpatient reductions. AED reductions tended to be slower if reduction was from 2 to 1, than 4 to 3, agents; and in patients with adverse risk factors. In general, non-sedating AEDs were not reduced more quickly than was phenobarbitone.

Efficacy and tolerability of 1000-4000 mg per day of levetiracetam as add-on therapy in patients with refractory epilepsy.

The aim of this study was to determine the efficacy and tolerability of 1000-4000 mg/day of levetiracetam (LEV, Keppra) as add-on treatment for refractory epilepsy. This was a dose-escalation study of 29 patients with refractory epilepsy. Patients received placebo for 4 weeks (baseline) followed by levetiracetam 1000 and 2000 mg per day each for 2 weeks, and then 3000 and 4000 mg per day each for 4 weeks. Primary efficacy was assessed by seizure frequency (number/week). Tolerability was assessed by adverse events, laboratory parameters, clinical evaluations, and electrocardiogram. All the study periods were completed by 27 of the 29 patients. A substantially lower median seizure frequency was observed at all levetiracetam dosing periods (1000 mg per day, 1.0 seizures per week; 2000 mg per day, 1.5 seizures per week; 3000 mg per day, 1.0 seizures per week; 4000 mg per day, 0.75 seizures per week) compared with the placebo treatment (2.06 seizures per week). In addition, 22-33% of these patients were seizure free during treatment with levetiracetam compared with only 14% with placebo. Levetiracetam was well tolerated. The most common adverse events were somnolence and asthenia; frequency and severity increased with increasing doses of levetiracetam. Levetiracetam in doses from 1000 to 4000 mg per day is effective. Somnolence and asthenia were more frequent with the highest dose, suggesting that 4000 mg per day may be the upper limit in some patients, although individual susceptibility to somnolence was variable.