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Biomedical subjects

S F Berkovic

Publications and source records attributed to S F Berkovic.

At least 19 recordsLinked to original sources
PubMed2006

Severe myoclonic epilepsy of infancy (Dravet syndrome): recognition and diagnosis in adults.

Establishing an etiologic diagnosis in adults with refractory epilepsy and intellectual disability is challenging. We analyzed the phenotype of 14 adults with severe myoclonic epilepsy of infancy. This phenotype comprised heterogeneous seizure types with nocturnal generalized tonic-clonic seizures predominating, mild to severe intellectual disability, and variable motor abnormalities. The diagnosis was suggested by a characteristic evolution of clinical findings in the first years of life. Ten had mutations in SCN1A and one in GABRG2.

Adolescent↗
PubMed2006

New-onset temporal lobe epilepsy in children: lesion on MRI predicts poor seizure outcome.

OBJECTIVE: To determine factors predictive of long-term seizure outcome in children with new-onset temporal lobe epilepsy (TLE). METHODS: A community-based cohort of 77 children with new-onset TLE, including 14 with possible TLE, were followed prospectively with formal review 7 and 14 years following seizure onset. Diagnoses were re-evaluated at each review, and changed when new clinical, EEG, or imaging data were compelling. RESULTS: Sixty-four patients sustained the diagnosis of TLE over time; two were lost to follow-up. Age at follow-up was 12 to 29 years (median 20 years). Median follow-up was 13.7 years, 95% being followed for greater than 10 years. Nineteen patients were seizure free (SF) and off treatment, having not had seizures for 5 to 15 years. Duration of active TLE in the SF group was 1 to 8 years, the children being treated with 0 to 3 antiepileptic drugs (AEDs). Forty-three patients were not seizure free (NSF) and had ongoing seizures or had undergone epilepsy surgery. These children were treated with 1 to 10 AEDs. Fifteen NSF patients experienced 22 nonterminal seizure remissions of 1 to 7 years duration. Seventeen children had a significant antecedent to TLE. Lesions were identified on neuroimaging in 28 and included hippocampal sclerosis (HS) in 10, tumor in 8, and dysplasia in 7. All children with lesions on MRI were NSF (p < 0.001). Focal slowing on EEG was also associated with persistent seizures (p = 0.05), although this was correlated with a lesion on MRI. Infantile onset of epilepsy, family history of seizures, initial seizure frequency, antecedents, and early seizure remissions were not predictive of seizure outcome. CONCLUSION: Seizures spontaneously remit in approximately one third of children with new-onset TLE. A lesion on MRI predicts intractable seizures in TLE and the potential need for epilepsy surgery.

Adolescent↗
PubMed2006

Sleep deprivation increases cortical excitability in epilepsy: syndrome-specific effects.

OBJECTIVE: To use transcranial magnetic stimulation (TMS) to investigate the hypothesis that sleep deprivation increases cortical excitability in people with epilepsy. METHODS: We performed paired pulse TMS stimulation, using a number of interstimulus intervals (ISIs) on each hemisphere of 30 patients with untreated newly diagnosed epilepsy (15 idiopathic generalized epilepsy [IGE] and 15 focal epilepsy) and on the dominant hemisphere of 13 healthy control subjects, before and after sleep deprivation. RESULTS: Both hemispheres in patients with IGE and the hemisphere ipsilateral to the EEG seizure focus in those with focal epilepsy showed an increase in cortical excitability following sleep deprivation at a number of ISIs. This change in excitability was most prominent in the patients with IGE. Although there were minor changes after sleep deprivation in control subjects and the contralateral hemisphere in the focal epilepsy group seen at the 250-millisecond ISI, it was less than in the other groups. CONCLUSIONS: Sleep deprivation increases cortical excitability in epilepsy; the pattern of change is syndrome dependent.

Adolescent↗
PubMed2005

Effect of antiepileptic medication on bone mineral measures.

OBJECTIVE: Long-term antiepileptic drug (AED) use has been associated with bone disease, but many previous studies have been limited by inadequate control subjects. We used a cotwin affected sib-pair model to investigate this issue. METHODS: The authors studied 31 female twin (15 monozygous and 16 dizygous) and four sibling pairs (< 3 years age difference) aged 21 to 75 years, in which one member had > 12 months of AED treatment. Areal bone mineral density (ABMD, g/cm2) was measured at the lumbar spine (LS), total hip (TH), femoral neck (FN), and total forearm (FA). Three primary a priori defined subgroups were analyzed: a) use for > 2 years, b) use of enzyme-inducing AEDs, or c) age older than 40 years. RESULTS: For all pairs (n = 35), there were no significant within-pair differences in any ABMD measure. However, in Subgroup a (n = 27), there was a within-pair difference at the FA (0.513 vs 0.534, -3.9%, p = 0.016). In Subgroup b (n = 29), there was also a within-pair difference at the FA for AED user vs nonuser (0.508 vs 0.529, -3.8%, p = 0.010). In Subgroup c (n = 15), there were within-pair differences at the FA (0.492 vs 0.524, -6.1%, p = 0.017) and the LS (0.884 vs 0.980, -9.8%, p = 0.036). CONCLUSIONS: Patients using AEDs for > 2 years, in particular those taking enzyme-inducing AEDs and those older than 40 years, have significantly lower bone mineral density at clinically relevant fracture risk sites.

Adult↗
PubMed2005

Familial clustering of seizure types within the idiopathic generalized epilepsies.

OBJECTIVE: To examine the genetic relationships among epilepsies with different seizure types--myoclonic, absence, and generalized tonic-clonic--within the idiopathic generalized epilepsies (IGEs). BACKGROUND: Careful phenotype definition in the epilepsies may allow division into groups that share susceptibility genes. Examination of seizure type, a phenotypic characteristic less complex than IGE syndrome, may help to define more homogeneous subgroups. METHODS: Using the approach that found evidence of distinct genetic effects on myoclonic vs absence seizures in families from the Epilepsy Family Study of Columbia University, the authors examined an independent sample of families from Australia and Israel. They also examined the familial clustering of generalized tonic-clonic seizures (GTCs) within the IGEs in two combined data sets. Families were defined as concordant if all affected members had the same type of seizure or IGE syndrome, as appropriate for the analysis performed. RESULTS: The proportion of families concordant for myoclonic vs absence seizures was greater than expected by chance in the Australian families. In addition, GTCs clustered in families with IGEs to a degree greater than expected by chance. CONCLUSIONS: These results provide additional evidence for distinct genetic effects on myoclonic vs absence seizures in an independent set of families and suggest that there is a genetic influence on the occurrence of generalized tonic-clonic seizures within the idiopathic generalized epilepsies.

Australia↗
PubMed2005

An autosomal recessive cerebellar ataxia syndrome with upward gaze palsy, neuropathy, and seizures.

The authors describe three siblings born to consanguineous parents with early onset ataxia, dysarthria, myoclonic, generalized tonic clonic seizures, upward gaze palsy, extensor plantar reflexes, sensory neuropathy, and normal cognition. Direct screening excluded mutations in FRDA, TDP1,and SACS genes and at 8344, 3243, and 8993 positions of mitochondrial DNA. Linkage analysis excluded AOA-1, EPM1, EPM2A, EPM2B, CAMOS, and recessive ataxias linked to chromosome 9q34-9qter. This clinical constellation may represent a distinct form of early onset cerebellar ataxia.

Cerebellar Ataxia↗
PubMed2004

Failure to confirm association of a polymorphism in ABCB1 with multidrug-resistant epilepsy.

Alteration of ATP-binding cassette subfamily B member 1 transporter (ABCB1) can plausibly cause drug-resistant epilepsy as it influences brain penetration of drugs. The CC genotype at the ABCB1 C3435T polymorphism was reported to be associated with multidrug resistance. A replication study in 401 drug-resistant and 208 drug-responsive subjects with epilepsy showed no significant association between the CC genotype and drug-resistant epilepsy. The authors suggest the initial association may have arisen by chance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Epilepsy in twins: insights from unique historical data of William Lennox.

OBJECTIVE: To classify the Lennox twin pairs according to modern epilepsy classifications, use the classic twin model to identify which epilepsy syndromes have an inherited component, search for evidence of syndrome-specific genes, and compare concordances from Lennox's series with a contemporary Australian series. METHODS: Following review of Lennox's original files describing twins with seizures from 1934 through 1958, the International League Against Epilepsy classifications of seizures and epileptic syndromes were applied to 169 pairs. Monozygous (MZ) and dizygous (DZ) pairs were subdivided into epilepsy syndromes and casewise concordances estimated. RESULTS: The authors excluded 26 pairs, with 71 MZ and 72 DZ pairs remaining. Seizure analysis demonstrated strong parallels between contemporary seizure classification and Lennox's terminology. Epilepsy syndrome diagnoses were made in 75%. The MZ and DZ casewise concordance estimates gave strong evidence for a major genetic influence in idiopathic generalized epilepsies (0.80 versus 0.00; n = 23). High MZ casewise concordances also supported a genetic etiology in symptomatic generalized epilepsies and febrile seizures. The pairs who were concordant for seizures usually had the same syndromic diagnoses in both twins (86% in MZ, 60% in DZ), suggesting syndrome-specific genes. Apart from partial epilepsies, the MZ casewise concordances were similar to those derived from Australian twin data. CONCLUSIONS: The authors were able to apply contemporary classifications to Lennox's twins. The data confirm genetic bases for common generalized epilepsies as well as febrile seizures and provide further support for syndrome-specific genes. Finally, comparable results to our Australian series were obtained, verifying the value of twin studies.

Adolescent↗
PubMed2004

LGI1 mutations in temporal lobe epilepsies.

BACKGROUND AND OBJECTIVES: A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations. METHODS: The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4. RESULTS: Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T-->G; C42G) and 8 (c.1418C-->T; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families. CONCLUSION: In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.

Adult↗
PubMed2004

Idiopathic recurrent stupor: a warning.

A proposal that an endogenous benzodiazepine-like agent named endozepine-4 might be responsible for presentations of recurrent stupor has gained wide acceptance. A case of recurrent stupor over two decades is presented with many similarities to previous cases of "endozepine stupor". This case, however, was caused by exogenous benzodiazepine administration and serves as a warning to clinicians to beware of this diagnosis.

Aged↗
PubMed2003

Sodium channel alpha1-subunit mutations in severe myoclonic epilepsy of infancy and infantile spasms.

BACKGROUND: Mutations in SCN1A, the gene encoding the alpha1 subunit of the sodium channel, have been found in severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). Mutations in SMEI include missense, nonsense, and frameshift mutations more commonly arising de novo in affected patients. This finding is difficult to reconcile with the family history of GEFS+ in a significant proportion of patients with SMEI. Infantile spasms (IS), or West syndrome, is a severe epileptic encephalopathy that is usually symptomatic. In some cases, no etiology is found and there is a family history of epilepsy. METHOD: The authors screened SCN1A in 24 patients with SMEI and 23 with IS. RESULTS: Mutations were found in 8 of 24 (33%) SMEI patients, a frequency much lower than initial reports from Europe and Japan. One mutation near the carboxy terminus was identified in an IS patient. A family history of seizures was found in 17 of 24 patients with SMEI. CONCLUSIONS: The rate of SCN1A mutations in this cohort of SMEI patients suggests that other factors may be important in SMEI. Less severe mutations associated with GEFS+ could interact with other loci to cause SMEI in cases with a family history of GEFS+. This study extends the phenotypic heterogeneity of mutations in SCN1A to include IS.

Amino Acid Sequence↗
PubMed2003

Hypertensive encephalopathy: antecedent to hippocampal sclerosis and temporal lobe epilepsy?

The authors describe three patients with refractory temporal lobe epilepsy (TLE) following an episode of hypertensive encephalopathy as their only identified antecedent event. All patients had typical MR features of hippocampal sclerosis (HS), and the two operated cases had typical HS histology and became seizure-free postoperatively. These cases suggest that hypertensive encephalopathy may be a rare form of initial precipitating injury, leading to TLE and HS.

Anterior Temporal Lobectomy↗
PubMed2003

Generalized epilepsy in hypothalamic hamartoma: evolution and postoperative resolution.

OBJECTIVE: To better understand the epileptogenesis of symptomatic generalized epilepsy in patients with hypothalamic hamartoma and intractable epilepsy, many of whom experience remission of generalized seizures and slow spike-wave discharges following surgery. METHODS: The authors documented the evolution of symptomatic generalized epilepsy in 12 of 20 children who underwent transcallosal microsurgical hypothalamic hamartoma resection. In seven patients they recorded intraoperative EEG from the hamartoma and simultaneously from the scalp and frontal cortex before, during, and after resection. RESULTS: Gelastic seizures began on average at 6 months of age (range birth to 3 years); tonic seizures began at 6 years (range 2 months to 9 years). Normal EEG were reported in early childhood; thereafter, abnormalities were progressive. Interictal spike-wave was recorded intraoperatively over the scalp and cortex in six patients, but not from the hypothalamic hamartoma. Hamartoma resection had no immediate effect on cortical spike-wave, but waking spike-wave was absent in seven patients on subsequent postoperative EEG. Tonic seizures ceased in 11 of 12 patients, but 6 of these had postoperative generalized seizures that resolved over 1 to 6 months. CONCLUSION: Gelastic seizures in hypothalamic hamartoma arise from the hamartoma itself; the interictal spike-wave does not. The evolution of EEG abnormalities, the development of generalized seizures years after onset of gelastic seizures, and the postoperative running down of interictal spike-wave and generalized seizures in these patients may reflect secondary epileptogenesis.

Child↗
PubMed2003

Hippocampal atrophy and T2-weighted signal changes in familial mesial temporal lobe epilepsy.

OBJECTIVE: To correlate the clinical phenotype with hippocampal volumes (HcVs) and signal changes in patients with familial mesial temporal lobe epilepsy (FMTLE). METHODS: FMTLE was defined when at least two first-degree relatives in a family had a clinical-EEG diagnosis of MTLE. Hippocampal formation measurements were performed using 1- to 3-mm coronal T1-weighted MRIs. The presence of hyperintense T2 signal was evaluated by visual analysis. For statistical analyses, analysis of variance, chi(2) test, and regression analysis were used. RESULTS: A total of 142 patients from 45 unrelated families were studied: 113 individuals with MTLE (80 with good seizure control) and 29 family members with other seizure types. There were 99 patients (69.7%) with hippocampal atrophy (HA). Sixty-seven of the 99 patients with HA also had a hyperintense T2 signal. Hyperintense T2 signal was associated with more severe HA (p = 0.04). Patients with refractory FMTLE had more frequent HA (p = 0.03) and hyperintense T2 signal (p = 0.004) and more severe atrophy (p < 0.0001). Duration of epilepsy correlated with HcV asymmetry index (r(2) = 0.12, p = 0.00008) and with the more atrophic hippocampi but not with contralateral hippocampi. CONCLUSION: In familial mesial temporal lobe epilepsy, seizure severity is variable in affected individuals. Hippocampal atrophy was present in 70% of these patients and 69% of these had an associated hyperintense T2 signal. Although hippocampal atrophy associated with abnormal T2 signal was more frequent and more severe in patients with poor seizure control, it was also frequent in affected individuals across families. These observations suggest that one or more genes resulting in familial mesial temporal lobe epilepsy predisposes both to the clinical features of mesial temporal lobe epilepsy and to the development of hippocampal sclerosis.

Adolescent↗
PubMed2003

Electroencephalographic characterisation of pentylenetetrazole-induced seizures in mice lacking the alpha 4 subunit of the neuronal nicotinic receptor.

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) is associated in some kindreds with mutations in the genes encoding the alpha 4 or beta 2 subunits of the neuronal nicotinic acetylcholine receptor (nAChR). Functional characterisation of the described ADNFLE mutations in oocyte preparations has produced conflicting results, with some studies suggesting hypofunction but others showing increased ligand sensitivity or delayed desensitisation. Knockout mice were studied to investigate extreme hypofunction of alpha 4 nAChRs in vivo. Mutant (Mt) and control mice underwent epidural electroencephalographic (EEG) recording for 2 h in the untreated state and for 1 h following administration of the gamma-amino butyric acid (GABA) antagonist, pentylenetetrazole (PTZ, 80 mg/kg). No spontaneous seizures occurred and no EEG differences were observed between the genotypes in drug naïve mice. Following PTZ, however, Mt mice showed markedly increased mortality compared to controls (85 vs 30%, P<0.001). Mts also had a greater number of generalised clonic seizures in the first 40 min following injection. In the same period, the EEGs of Mt mice showed an excess of spikes (P=0.033), multi-spike complexes (P=0.002) and continuous fast activity (P=0.017) compared to controls. These findings demonstrate that intact alpha 4 nAChR subunits provide significant in vivo protection against the proconvulsant effects of GABA antagonism.

Animals↗