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Biomedical subjects

Samuel F Berkovic

Publications and source records attributed to Samuel F Berkovic.

At least 37 records · Page 2Linked to original sources
PubMed2005

Mutation in the Na+ channel subunit SCN1B produces paradoxical changes in peripheral nerve excitability.

To determine the effect of an established mutation of the beta1 subunit of Na(+) channels on nerve excitability, studies were undertaken in patients diagnosed with generalized epilepsy with febrile seizures plus (GEFS+). Multiple nerve excitability measurements were used to investigate the membrane properties of sensory and motor axons in five patients (aged 18-55 years) who were currently experiencing no seizures and were not on anticonvulsants. There was no history of paraesthesiae, fasciculation or cramps to suggest hyperexcitability of peripheral nerve axons. The median nerve was stimulated at the wrist, and compound muscle action potentials (CMAPs) were recorded from abductor pollicis brevis and the antidromic compound sensory nerve action potential (CSAPs) from digit 2. Stimulus-response behaviour, strength-duration time constant, threshold electrotonus, current-threshold relationship and the recovery of excitability following a supramaximal conditioning stimulus were recorded using threshold tracking. Compared with normal controls (n = 29), the axons of patients were of higher threshold. CMAPs and CSAPs were relatively small, although individual values remained within the normal ranges. Refractoriness and relative refractory period (markers of transient Na(+) channel function) were significantly reduced in GEFS+ patients with established mutations in SCN1B (P < 0.05), and strength-duration time constants (dependent on persistent Na(+) conductances) were reduced. It is suggested that, in peripheral nerve axons, the mutation underlying GEFS+ reduces the number of functioning Na(+) channels at the node of Ranvier and that this rather than any change in gating of individual channels dominates axonal excitability in these patients.

Action Potentials↗
PubMed2005

Efficacy and safety of levetiracetam 1000-3000 mg/day in patients with refractory partial-onset seizures: a multicenter, open-label single-arm study.

PURPOSE: To evaluate the efficacy and tolerability of levetiracetam as add-on therapy in patients with refractory partial-onset seizures in a protocol designed to reflect clinical practice. METHODS: All patients in this open-label, single-arm study entered an 8-week baseline period followed by a 4-week titration period and a 12-week maintenance period. Patients initially received levetiracetam 1000 mg/day (administered bid) and could increase to 2000 mg/day after 2 weeks, and to 3000 mg/day after another 2 weeks, to obtain adequate seizure control. During the 12-week maintenance period, the dose of levetiracetam could not be increased but could be decreased once if tolerability warranted. Seizure count and adverse events were recorded by patients in a diary. Quality of life and global evaluation of disease evolution were also evaluated. RESULTS: Ninety-nine patients were enrolled and 91 completed the study. A steady dose was maintained over the last 8 weeks of treatment or longer in 84 patients, with 89.3% of these patients receiving 3000 mg/day, 9.5% receiving 2000 mg/day, and 1.2% receiving 1000 mg/day. A 35.9% median percent reduction from baseline in weekly frequency of partial-onset seizures was observed over the entire treatment period. The median partial-onset seizure count decreased from 2.3 per week during the baseline period to 1.3 per week over the treatment period. A total of 42.4% of patients were responders (> or = 50% reduction from baseline in weekly seizure frequency) over the treatment period; two patients were seizure-free from the first day of treatment throughout the treatment period. The most frequent drug-related adverse events were fatigue (27.3% of patients), somnolence (11.1%), headache (8.1%), and dizziness (8.1%). CONCLUSION: Levetiracetam as add-on therapy at doses up to 3000 mg/day effectively reduced the frequency of partial-onset seizures in patients with refractory epilepsy and was well-tolerated in this study, bridging conditions of placebo-controlled clinical trials and clinical practice.

Adolescent↗
PubMed2005

A new clinical and molecular form of Unverricht-Lundborg disease localized by homozygosity mapping.

Progressive myoclonus epilepsy (PME) has a number of causes, of which Unverricht-Lundborg disease (ULD) is the most common. ULD has previously been mapped to a locus on chromosome 21 (EPM1). Subsequently, mutations in the cystatin B gene have been found in most cases. In the present work we identified an inbred Arab family with a clinical pattern compatible with ULD, but mutations in the cystatin B gene were absent. We sought to characterize the clinical and molecular features of the disorder. The family was studied by multiple field trips to their town to clarify details of the complex consanguineous relationships and to personally examine the family. DNA was collected for subsequent molecular analyses from 21 individuals. A genome-wide screen was performed using 811 microsatellite markers. Homozygosity mapping was used to identify loci of interest. There were eight affected individuals. Clinical onset was at 7.3 +/- 1.5 years with myoclonic or tonic-clonic seizures. All had myoclonus that progressed in severity over time and seven had tonic-clonic seizures. Ataxia, in addition to myoclonus, occurred in all. Detailed cognitive assessment was not possible, but there was no significant progressive dementia. There was intrafamily variation in severity; three required wheelchairs in adult life; the others could walk unaided. MRI, muscle and skin biopsies on one individual were unremarkable. We mapped the family to a 15-megabase region at the pericentromeric region of chromosome 12 with a maximum lod score of 6.32. Although the phenotype of individual subjects was typical of ULD, the mean age of onset (7.3 years versus 11 years for ULD) was younger. The locus on chromosome 12 does not contain genes for any other form of PME, nor does it have genes known to be related to cystatin B. This represents a new form of PME and we have designated the locus as EPM1B.

Adolescent↗
PubMed2005

Early seizures after temporal lobectomy predict subsequent seizure recurrence.

Patients are understandably anxious if seizures occur immediately after temporal lobectomy. Such "neighborhood" seizures are commonly regarded as irrelevant to seizure outcome and discounted in outcome measurement. We conducted an in-depth examination of early postoperative seizures (<28 days) and outcome. The risk of recurrence at one postoperative year was calculated using Poisson regression, and statistical adjustments were made for preoperative pathology. Of 321 patients, 69 (22%) experienced early postoperative seizures. These early seizures were associated with subsequent seizure recurrence (rate ratio [RR] 5.9; 95% confidence interval [CI], 4.1-8.4). Among patients with early seizures, the only significant factor was the presence of seizure precipitants, which was associated with a lower recurrence risk. However, when compared with patients with no early seizures, those with precipitants to early seizures had a higher risk of recurrence (RR, 3.0; 95% CI, 1.8-5.2). The risk was higher again for patients without precipitants to early seizures (RR, 7.6; 95% CI, 5.0-11.5). Early seizures and other seizure recurrences in the first postoperative year did not differ in their effect on subsequent outcome (X(2) [3] = 3.4, p = 0.33). We conclude that early postoperative seizures are associated with subsequent seizure recurrence. These findings have implications for patient counseling and the measurement of outcome.

Anterior Temporal Lobectomy↗
PubMed2005

SCN1A mutations and epilepsy.

SCN1A is part of the SCN1A-SCN2A-SCN3A gene cluster on chromosome 2q24 that encodes for alpha pore forming subunits of sodium channels. The 26 exons of SCN1A are spread over 100 kb of genomic DNA. Genetic defects in the coding sequence lead to generalized epilepsy with febrile seizures plus (GEFS+) and a range of childhood epileptic encephalopathies of varied severity (e.g., SMEI). All published mutations are collated. More than 100 novel mutations are spread throughout the gene with the more debilitating usually de novo. Some clustering of mutations is observed in the C-terminus and the loops between segments 5 and 6 of the first three domains of the protein. Functional studies so far show no consistent relationship between changes to channel properties and clinical phenotype. Of all the known epilepsy genes SCN1A is currently the most clinically relevant, with the largest number of epilepsy related mutations so far characterized.

Alternative Splicing↗
PubMed2005

Is variation in the GABA(B) receptor 1 gene associated with temporal lobe epilepsy?

PURPOSE: gamma-Aminobutyric acid (GABA)-receptor genes are prime candidates for a role in seizure susceptibility. An association between the c.1465G-->A variant in the GABA(B) receptor 1 gene (GABBR1) and susceptibility to temporal lobe epilepsy (TLE) has been reported in an Italian cohort. We sought to replicate this association in an independent Australian cohort. METHODS: The 234 patients with TLE and 164 healthy controls were genotyped for the c.1465G-->A variant, by using inclusion criteria identical to those of the first study. RESULTS: The c.1465G-->A variant was found in one TLE patient and one control subject. Genotype and allele frequencies did not differ between groups. CONCLUSIONS: We did not replicate the reported associations between the c.1465G-->A variant and susceptibility to TLE. We suggest that the initial positive association may be due to undetected population stratification; the importance of genomic control is emphasized. Population-specific effects also may play a role, and we highlight the need to demonstrate an in vitro functional effect to give biologic meaning to any proposed association.

Adolescent↗
PubMed2005

Treatment with anti-epileptic drugs.

BACKGROUND: The principles of epilepsy management are accurate diagnosis coupled with education, lifestyle advice, and drug therapy. There are a large number of anti-epileptic drugs now available. OBJECTIVE: This article deals with initial treatment, the role of the newer agents, and practical issues such as monitoring of therapy and the use of generic drugs. The difficult issues of when to stop therapy and management of epilepsy in pregnancy are highlighted. DISCUSSION: Accurate seizure and syndrome diagnosis determines the optimal choice of medication. In most patients with new onset epilepsy, seizures can be easily controlled with lifestyle modification and medication. In general, valproate is first line treatment for generalised epilepsy and carbamazepine for partial epilepsies. New anti-epileptic drugs offer benefits in patients who are not controlled or intolerant of the older agents. Monitoring of therapy is primarily clinical; not necessarily requiring testing for serum levels or other blood tests.

Anticonvulsants↗
PubMed2004

Endozepine stupor: disease or deception? A critical review.

Presentation of patients with recurrent stupor associated with apparently elevated levels of an endogenous benzodiazepine-like agent, endozepine-4, has been reported from several centers, and a new syndrome, endozepine stupor has been proposed. We recently reported a case with typical features of this syndrome, which proved to be an example of surreptitious administration of exogenous benzodiazepine. This and other examples of clandestine drug use, together with uncertainties about the validity of tests used to distinguish exogenous and endogenous benzodiazepines, prompted us to undertake a reappraisal of this clinical syndrome.

Benzodiazepines↗
PubMed2004

Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder.

Action myoclonus-renal failure syndrome (AMRF) is a distinctive form of progressive myoclonus epilepsy associated with renal dysfunction. The syndrome was not recognized prior to the advent of dialysis and renal transplantation because of its rapidly fatal course if renal failure is untreated. The first and only description of AMRF was in four French Canadian patients in three families (Andermann et al., 1986). We now describe 15 individuals with AMRF from five countries, including a follow-up of the four French Canadian patients, allowing a more complete characterization of this disease. Our 15 patients with AMRF belong to nine different families. Segregation analyses were compatible with autosomal recessive inheritance. In addition, our findings show that AMRF can present with either renal or neurological features. Tremor (onset 17-26 years, mean 19.8 years, median 19 years) and progressively disabling action myoclonus (onset 14-29 years, mean 21.7 years, median 21 years), with infrequent generalized seizures (onset 20-28 years, mean 22.7 years, median 22 years) and cerebellar features are characteristic. Proteinuria, detected between ages 9 and 30 years in all cases, progressed to renal failure in 12 out of 15 patients within 0-8 years after proteinuria detection. Brain autopsy in two patients revealed extraneuronal pigment accumulation. Renal biopsies showed collapsing glomerulopathy, a severe variant of focal glomerulosclerosis. This study extends the AMRF phenotype, and demonstrates a more extensive ethnic and geographic distribution of a syndrome originally believed to be confined to individuals of French Canadian ancestry. The independent progression of neurological and renal disorders in AMRF suggests a unitary molecular lesion with pleiotropic effects. Our results demonstrate that the renal lesion in AMRF is a recessive form of collapsing glomerulopathy. Genes identified for focal segmental glomerulosclerosis and involved with the function of the glomerular basement membrane and related proteins are thus good candidates. Treatment can improve quality of life and extend the lifespan of these patients. Dialysis and renal transplantation are effective for the renal but not the neurological features, which continue to progress even in the presence of normalized renal function; the latter can be managed with anti-myoclonic and anti-epileptic drugs.

Adolescent↗
PubMed2004

Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence.

There is little information available relevant to long-term seizure outcome after anterior temporal lobectomy, particularly at extended postoperative periods. The aim of this study was an in-depth examination of patterns of longitudinal outcome and potential risk factors for seizure recurrence after lobectomy, utilizing a large patient sample with long follow-up. Included were 325 patients who underwent anterior temporal lobectomy between 1978 and 1998 (mean follow-up 9.6 +/- 4.2 years). Retrospective data were analysed using survival analysis and multivariate regression with Cox proportional hazard models. The probability of complete seizure freedom at 2 years post-surgery was 55.3% [95% confidence interval (CI) 50-61]; at 5 years, 47.7% (95% CI 42-53); and at 10 postoperative years it was 41% (95% CI 36-48). Patients with discrete abnormalities preoperatively (i.e. lesions and hippocampal sclerosis) had a significantly higher probability of seizure freedom than patients without obvious abnormality. The latter group had a pattern of recurrence similar to that in patients with lesions outside the area of excision. After adjustment for preoperative pathology, only the presence of preoperative secondarily generalized seizures had a significant association with recurrence [occasional preoperative generalized seizures, hazard ratio (HR) 1.6, 95% CI 1.1-2.3; frequent seizures, HR 2.0, 95% CI 1.4-2.9 compared with absence of preoperative generalized seizures]. Duration of preoperative epilepsy, age of seizure onset and age at surgery did not have an effect on outcome. Patients with two seizure-free postoperative years had a 74% (95% CI 66-81) probability of seizure freedom by 10 postoperative years. This late seizure recurrence was not associated with any identified risk factors. Specifically, patients with hippocampal sclerosis were not at higher risk. Surprisingly, complete discontinuation of anti-epileptic drugs (AEDs) after two postoperative years was not associated with an increased risk of recurrence (HR 1.03, 95% CI 0.5-2.1). This may be because selection of patients for AED discontinuation is biased towards those individuals perceived as 'low risk'. The results of this study indicate that the lack of an obvious abnormality or the presence of diffuse pathology, and preoperative secondarily generalized seizures are risk factors for recurrence after surgery. Late recurrence after initial seizure freedom is not a rare event; risk factors specific to this phenomenon are as yet unidentified.

Adolescent↗
PubMed2004

Juvenile myoclonic epilepsy and idiopathic photosensitive occipital lobe epilepsy: is there overlap?

Although epileptic photosensitivity is well known, its genetics and syndromic associations are incompletely understood. Seizures triggered by photic stimulation are usually a manifestation of the idiopathic generalized epilepsies, especially juvenile myoclonic epilepsy (JME), or of the occipital epilepsies. Idiopathic photosensitive occipital epilepsy (IPOE) is a focal epilepsy with colourful elementary visual auras, often with conscious tonic head and eye version; myoclonus is not a feature. All seizures are induced by photic stimuli. We describe four families with phenotypic overlap between JME and IPOE. Families were identified if two or more affected individuals had visual auras and electro-clinical features of an idiopathic epilepsy. Family members underwent detailed electro-clinical assessment. In addition, 40 unrelated JME probands were investigated systematically for unrecognized features of IPOE (visual aura and conscious head version). There were 12 affected individuals in four families; 11 were female. Clinical onset was at 8-21 years of age. Of 10 patients with visual auras, six had conscious head version and five also experienced myoclonic jerks; eight had non-photic induced tonic-clonic seizures (TCS). Of the remaining individuals, one had myoclonic jerks and occipital spikes; the other had TCS without visual aura or myoclonic jerks. Of 10 patients with EEG studies, eight had generalized spike and wave (GSW) and six had occipital spikes. All had photosensitivity with GSW and four had additional occipital spikes. Of the 40 JME probands, six had visual aura and/or conscious head version; five of these were photosensitive. There is overlap between the clusters of clinical features used to diagnose IPOE and JME. Half of the affected individuals in our families with visual aura had myoclonic jerks; the former is characteristic of IPOE and the latter of JME. Importantly, visual aura is not regarded as part of JME, nor myoclonus part of IPOE, but our data emphasize that these symptoms may occur in both disorders. Moreover, two-thirds of individuals with visual aura had spontaneous TCS; the latter feature is not described in IPOE. Additionally, we demonstrate that visual aura and conscious head version are under-recognized features of JME, particularly among photosensitive patients. These findings could be explained by shared genetic determinants underlying IPOE and JME. Understanding the genetic basis of these disorders must account for the striking female predominance, the variable phenotypes associated with photosensitivity and the overlap of clinical features classically regarded as distinguishing focal and generalized syndromes.

Adolescent↗
PubMed2004

GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies.

A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177Ala variant which is heterozygously associated with generalized epilepsy with febrile seizures plus. We also report an Arg220His allele in GABRD which is present in the general population. Compared with wild-type receptors, alpha1beta2Sdelta GABAA receptors containing delta Glu177Ala or Arg220His have decreased GABAA receptor current amplitudes. As GABAA receptors mediate neuronal inhibition, the reduced receptor current associated with both variants is likely to be associated with increased neuronal excitability. Since delta subunit-containing receptors localize to extra- or peri-synaptic membranes and are thought to be involved in tonic inhibition, our results suggest that alteration of this process may contribute to the common generalized epilepsies.

Amino Acid Substitution↗
PubMed2004

Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy.

We recently reported mutations in the sodium channel gene SCN2A in two families with benign familial neonatal-infantile seizures (BFNISs). Here, we aimed to refine the molecular-clinical correlation of SCN2A mutations in early childhood epilepsies. SCN2A was analyzed in 2 families with probable BFNIS, 9 with possible BFNIS, 10 with benign familial infantile seizures, and in 93 additional families with various early childhood epilepsies. Mutations effecting changes in conserved amino acids were found in two of two probable BFNIS families, in four of nine possible BFNIS families, and in none of the others. Our eight families had six different SCN2A mutations; one mutation (R1319Q) occurred in three families. BFNIS is an autosomal dominant disorder presenting between day 2 and 7 months (mean, 11.2 +/- 9.2 weeks) with afebrile secondarily generalized partial seizures; neonatal seizures were not seen in all families. The frequency of seizures varied; some individuals had only a few attacks without treatment and others had clusters of many per day. Febrile seizures were rare. All cases remitted by 12 months. Ictal recordings in four subjects showed onset in the posterior quadrants. SCN2A mutations appear specific for BFNIS; the disorder can now be strongly suspected clinically and the families can be given an excellent prognosis.

Adolescent↗
PubMed2004

Is benign rolandic epilepsy genetically determined?

Benign rolandic epilepsy (BRE) is considered to be a genetically determined idiopathic partial epilepsy. We studied twins with BRE and compared the concordance with a twin sample of idiopathic generalized epilepsy (IGE). All eight BRE pairs (six monozygous [MZ], two dizygous [DZ]) were discordant. MZ pairwise concordance was 0 (95% confidence interval [CI], 0-0.4) for BRE compared with 0.7 (95% CI, 0.5-0.9) for 26 IGE MZ pairs. Our data suggest that conventional genetic influences in BRE are considerably less than for IGE, and other mechanisms need to be explored.

Adolescent↗
PubMed2004

Glioneuronal tumours in neurofibromatosis type 1: MRI-pathological study.

Neurofibromatosis type 1 (NF1) is an inherited disorder in which affected individuals develop both benign and malignant tumours at an increased frequency. Glioneuronal tumours, such as ganglioglioma and dysembryoplastic neuroepithelial tumour, have been previously reported in patients with NF1. We describe two patients with glioneuronal tumours and typical clinical features of NF1. Molecular analysis of these tumours did not demonstrate loss of the NF1 gene by fluorescence in situ hybridization (FISH) or immunohistochemistry analysis, suggesting they might not be causally associated with gross defects in NF1 expression. Because of the excellent prognosis following the resection of these tumours, it is important to distinguish them from other NF1-associated tumours.

Adult↗