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PubMed1995

Efficacy and adverse effects of established and new antiepileptic drugs.

Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEDs. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic-clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic-clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second-choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No "drug of choice" can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.

Adult↗
PubMed1992

Cognition in epilepsy: a multichannel event related potential (P300) study.

Auditory event-related potentials (AERP) were elicited in 68 epileptic patients and 30 age-matched controls. Epileptic patients had significantly prolonged N2 and P300 (P3) latencies compared with controls. Seven patients were above the range of 3 standard deviations from the control mean values. Amongst epileptics, patients with temporal lobe epilepsy had significantly prolonged P3 latencies compared to patients with idiopathic generalized epilepsy. Patients with abnormal EEGs had significantly prolonged P3 latencies compared to those with normal EEGs. Patients on anticonvulsant monotherapy had shorter P3 latencies, compared to patients taking a combination of two or more anticonvulsants. Patients on shorter duration of treatment had less prolonged P3 latencies compared to those on longer anticonvulsant treatment.

Adolescent↗
PubMed1985

Classification of the epilepsies.

We review the development of the classification of the epilepsies. Primary epilepsies are relatively benign, usually age-limited syndromes without clinical or radiologic evidence of brain lesions, and are related to a heritable constitutional predisposition to epilepsy. They usually respond well to antiepileptic drugs. The biochemical correlates of primary generalized epilepsy have been demonstrated in animals and man and have been related to diffuse cortical hyperexcitability, which has been linked to this disorder. The pathophysiology of the primary partial or focal epilepsies is poorly understood but does not appear to depend on focal brain lesions. We suggest that these are due to relatively localized areas of cortical hyperexcitability confined to isolated corticothalamic sectors and depend on interrelations between a constitutional cortical hyperexcitability and normal cortical maturation. The secondary epilepsies are associated with clinical and radiologic evidence of brain lesions and are often resistant to anticonvulsants. Secondary generalized epilepsies, with an associated diffuse encephalopathy, are typified by the Lennox-Gastaut syndrome. The presentation of the secondary partial epilepsies depends on the site of the lesion. The pathogenesis of epilepsy is multifactorial, and a preexisting constitutional predisposition can interact with an acquired diffuse or focal encephalopathy, facilitating the clinical expression of one or the other.

Adolescent↗
PubMed1991

Vigabatrin in childhood epilepsy.

Sixty-six children with various types of severe drug-resistant epilepsy were entered into a long-term, dose-rising study of vigabatrin after a 4-week run-in placebo period. All the children were receiving one to three other antiepileptic drugs, the doses of which were not changed during the 6-month dose titration phase. Following the introduction of vigabatrin, 11 patients became seizure free, and 28 responded with a greater than 50% reduction in seizure frequency. The following types of epilepsy responded favorably in order of decreasing efficacy: cryptogenic and symptomatic partial epilepsy, other symptomatic generalized epilepsy, and Lennox-Gastaut syndrome. However, three of nine patients with myoclonic epilepsy showed an increase in seizure frequency. Optimal responses were found with vigabatrin doses of 40 to 80 mg/kg/day, although no significant adverse effects were noted with doses of higher than 100 mg/kg/day. Thirty-eight responders continued on vigabatrin, 19 of whom have been treated for more than 1 year, with generally good efficacy. As a result of discontinuing concomitant antiepileptics, six patients are on monotherapy with vigabatrin, four of whom are seizure free. Vigabatrin tolerability was good, with 39 of 66 children reporting no adverse effects. Hyperkinesia was reported in 17 patients (26%), and two had to drop out of the study. All these patients had a history of hyperkinesia or mental retardation. In patients in whom vigabatrin dose was reduced because of hyperkinesia, a dose increase could later be instituted without recurrence of symptoms. There was no change in neurologic examination and no drug-related abnormalities in clinical laboratory data.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2005

One-year mortality in Bordeaux cohort: the value of syndrome classification.

PURPOSE: To evaluate the usefulness of the International Classification of Epilepsy Syndromes for 1-year mortality in a prospective incidence study of first epileptic seizures. METHODS: Date and cause of death from the treating physician in an incidence study of first afebrile seizures collected 15 years ago in Southwest France. Cases were classified by epilepsy syndrome. A total of 804 patients were included: acute symptomatic (n = 277), unprovoked (n = 439), or unclassifiable (n = 88). RESULTS: One hundred and fifty-one patients died within the first year: none with idiopathic partial or generalized epilepsy, 16/104 with symptomatic (standardized mortality ratio (SMR) 6.4, 95% CI 3.6-10.3), 1/59 with cryptogenic (SMR 1.7, 95% CI 0.1-9.7 CI) partial epilepsy, 1/14 (SMR 28.1, 95% CI 0.4-156.6) with symptomatic/cryptogenic generalized epilepsy, 2/23 with undetermined epilepsy, 1/135 with isolated seizure (SMR 0.6, 95% CI 0.1-3.1), and 90/277 (SMR 10.3, 95% CI 8.3-12.7) with acute symptomatic seizures. Unclassifiable seizures could not be classified as acute symptomatic or unprovoked: associated with alcohol abuse (death: 3/32, SMR 7.7, 95% CI 1.6-22.6), brain tumors (death: 31/39, SMR 41.5, 95% CI 28.2-58.9), and dementia (death: 6/17, SMR 5.4, 95% CI 2.0-11.7). Most deaths were due to progression of underlying disease, only 5.9% were seizure-related. CONCLUSIONS: Although a syndromic diagnosis is important for treatment decisions and some prognostic aspects of seizure disorders, its value in mortality studies is limited. Mortality can be calculated only at the first (partial, generalized, and undetermined epilepsies, and special syndromes) and the second (idiopathic vs. symptomatic or cryptogenic) levels of the International Classification of Epilepsies.

Cause of Death↗
PubMed1985

Sleep and epilepsy.

Sleep has a marked influence on local epileptogenicity. Sleep deprivation appears to have an independent activating effect. It is effective in provoking spike-wave paroxysms in primary generalized epilepsy. Sleep recordings help in differentiating between partial and generalized epilepsies. Anterior temporal lobe discharges and partial seizures are facilitated by non-rapid eye movement (NREM) sleep, which also has a facilitatory effect on generalized discharges. Rapid eye movement (REM) sleep may activate frontal lobe, amygdaloid and supplementary motor area seizures, whereas it de-activates partial seizures from other regions, often revealing an occult focus. REM sleep also deactivates generalized seizures. Specific epileptic syndromes are related to the sleep-wakening cycle, i.e. Rolandic epilepsy, other benign partial epilepsies in childhood, and awakening epilepsy. Patients with an uncertain or unknown type of epilepsy should always be examined with routine electroencephalography (EEG) recording, sleep deprivation and spontaneous or sedated sleep recordings.

Anticonvulsants↗
PubMed2004

Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility.

PURPOSE: Our research program uses genetic linkage and association analysis to identify human seizure sensitivity and resistance alleles. Quantitative trait loci mapping in mice led to identification of genetic variation in the potassium ion channel gene Kcnj10, implicating it as a putative seizure susceptibility gene. The purpose of this work was to translate these animal model data to a human genetic association study. METHODS: We used single stranded conformation polymorphism (SSCP) electrophoresis, DNA sequencing and database searching (NCBI) to identify variation in the human KCNJ10 gene. Restriction fragment length polymorphism (RFLP) analysis, SSCP and Pyrosequencing were used to genotype a single nucleotide polymorphism (SNP, dbSNP rs#1130183) in KCNJ10 in epilepsy patients (n = 407) and unrelated controls (n = 284). The epilepsy group was comprised of patients with refractory mesial temporal lobe epilepsy (n = 153), childhood absence (n = 84), juvenile myoclonic (n = 111) and idiopathic generalized epilepsy not otherwise specified (IGE-NOS, n = 59) and all were of European ancestry. RESULTS: SNP rs#1130183 (C > T) alters amino acid 271 (of 379) from an arginine to a cysteine (R271C). The C allele (Arg) is common with conversion to the T allele (Cys) occurring twice as often in controls compared to epilepsy patients. Contingency analysis documented a statistically significant association between seizure resistance and allele frequency, Mantel-Haenszel chi square = 5.65, d.f. = 1, P = 0.017, odds ratio 0.52, 95% CI 0.33-0.82. CONCLUSION: The T allele of SNP rs#1130183 is associated with seizure resistance when common forms of focal and generalized epilepsy are analyzed as a group. These data suggest that this missense variation in KCNJ10 (or a nearby variation) is related to general seizure susceptibility in humans.

Chi-Square Distribution↗
PubMed1979

Classification of the epilepsies. An investigation of 402 children.

The frequency distribution of different types of epilepsy (according to the classification model of the International League against Epilepsy) concerning 402 children is reported. The investigation showed a moderate preponderance of partial as against generalized epilepsies. Elemental and complex symptomatology were about equally frequent. As regards generalized epilepsies, the petit mal group was considerably smaller than most often reported previously; conversely, myoclonic-astatic epilepsy (Lennox-Gastaut's syndrome) was more frequently encountered. The definitory criteria and the concept of the Lennox-Gastaut Syndrome are discussed. 91.8% of the whole pediatric population (age less than 15 years at time of investigation) could be categorized according to the classification model. This, in agreement with earlier investigations on this subject, shows the contemporary international classified model to be useful and relevant.

Adolescent↗
PubMed1996

Lamotrigine: clinical experience in 200 patients with epilepsy with follow-up to four years.

This open, clinical study describes the use of lamotrigine in 200 adults and children with drug resistant epilepsy. Lamotrigine was used largely as add-on therapy and outcome was assessed by the patients, parents and carers and the physician in terms of reduction of seizure frequency, drug side-effects and improvement in quality of life. Of the 200 patients, 70 (35%) were rendered seizure free. Lamotrigine was especially helpful in resistant primary generalized epilepsy, complex partial seizures, mixed seizures subsequent to brain damage, Lennox-Gastaut syndrome and in complex partial seizures which secondarily generalized. Fifty-three patients ceased lamotrigine; 30 due to lack of effect, and 13 due to side-effects. Lamotrigine is a very useful antiepileptic medication of a "broad spectrum' nature being effective in primary generalized epilepsy and partial seizures as add-on therapy. The side-effect profile is good with most side-effects being avoidable.

Adolescent↗
PubMed2006

Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy (IGE) with complex inheritance. Previous studies have suggested maternal inheritance and female excess in IGEs but have not been specific for JME. We investigated evidence for maternal inheritance, female excess and patterns of familial seizure risk in a well-characterized sample of JME families. METHODS: We ascertained 89 families through a JME proband and 50 families through a non-JME IGE proband. JME families were divided into those with and without evidence of linkage to the EJM1 susceptibility locus on chromosome 6. We analyzed transmission in 43 multigenerational families, calculated the adjusted sex ratio for JME, and looked for evidence of seizure specific risk in 806 family members. RESULTS: We found evidence for preferential maternal transmission in both EJM1-linked and unlinked families (2.7:1), evidence even more marked when potential selection factors were excluded. The adjusted female: male risk ratio was very high in JME (RR=12.5; 95% CI: 1.9-83.7). Absence seizures in JME probands increased the overall risk of seizures in first degree relatives (15.8% vs. 7.0%, P=0.011), as well as first-degree relatives' specific risk of absence seizures (6% vs. 1.6%, P=0.01), but not myoclonic seizures. CONCLUSIONS: We have confirmed the finding of maternal inheritance in JME, which is not restricted to JME families linked to the EJM1 locus. The striking female excess in JME may relate to anatomical and/or endocrine sexual dimorphism in the brain. Evidence for independent inheritance of absence and myoclonic seizures in JME families reinforces a model in which combinations of loci confer susceptibility to the component seizure types of IGE.

Chromosomes, Human, Pair 6↗
PubMed2005

Plasma folate and homocysteine levels may be related to interictal "schizophrenia-like" psychosis in patients with epilepsy.

Genetic and clinical data suggest that folate and homocysteine may play a role in the pathogenesis of psychiatric disorders. The total plasma homocysteine level is a sensitive measure of a functional folate deficiency. We thus investigated whether a functional folate deficiency and/or elevated levels of plasma homocysteine may be related to interictal "schizophrenia-like" psychosis (interictal psychosis ) of epilepsy. We studied the plasma folate, vitamin B12, and homocysteine levels of 32 age- and sex-matched epileptic patients with or without interictal psychosis. Each group included 25 localization-related epilepsies and 7 generalized epilepsies. The epileptic patients with interictal psychosis had significantly lower folate levels and higher homocysteine levels than those without interictal psychosis. There were no significant differences in the vitamin B12 levels between the two groups. The present study suggests that low plasma folate and high plasma homocysteine levels may be related to the pathophysiology of interictal psychosis of epilepsy. In future studies, we should investigate whether folate supplementation, in addition to antipsychotics, might play a beneficial role in the treatment of interictal psychosis in epileptic patients. Furthermore, the present findings should be confirmed by prospective longitudinal studies in a larger group of patients with epilepsy.

Adult↗
PubMed2004

Genital automatisms: a video-EEG study in patients with medically refractory seizures.

PURPOSE: Genital automatisms (GAs) are rare clinical phenomena during or after epileptic seizures. They are defined as repeated fondling, grabbing, or scratching of the genitals. The anatomic correlates of GAs have been discussed controversially. The aim of this investigation was to assess the localizing and lateralizing value of GAs. METHODS: The authors studied 207 consecutive patients with intractable seizures referred to a University Hospital for presurgical evaluation between 1998 and 2002: 135 had temporal lobe epilepsy (TLE); 23, frontal lobe epilepsy (FLE); 29, generalized epilepsies (GEs); and 20 had extratemporal or multifocal epilepsy. RESULTS: Twenty-three (11%) of 207 patients showed GAs in 42 (3%) of 1,299 seizures. GAs occurred significantly more often in men (17 of 93, 18%) than in women (six of 114, 5%; p = 0.0037). Twenty-one (16%) of 135 patients with TLE performed GAs, one (4%) of 23 with FLE and one (3%) of 29 with GE. GAs were associated with unilateral hand automatisms in 16 (70%) of 23 and with periictal urinary urge in five (22%) of 23. All patients had amnesia for the performance of GAs. CONCLUSIONS: GAs appear in the ictal or postictal period with impaired consciousness. Men exhibit GAs significantly more often than do women. GAs do not localize or lateralize per se, but may localize seizure onset in the presence of periictal urinary urge or unilateral hand automatisms. They show a tendency to occur more often in TLE.

Adolescent↗
PubMed2005

Molecular analysis of the A322D mutation in the GABA receptor alpha-subunit causing juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) belongs to the most common forms of hereditary epilepsy, the idiopathic generalized epilepsies. Although the mode of inheritance is usually complex, mutations in single genes have been shown to cause the disease in some families with autosomal dominant inheritance. The first mutation in a multigeneration JME family has been recently found in the alpha1-subunit of the GABAA receptor (GABRA1), predicting the single amino acid substitution A322D. We further characterized the functional consequences of this mutation by coexpressing alpha1-, beta2- and gamma2-subunits in human embryonic kidney (HEK293) cells. By using an ultrafast application system, mutant receptors have shown reduced macroscopic current amplitudes at saturating GABA concentrations and a highly reduced affinity to GABA compared to the wild-type (WT). Dose-response curves for current amplitudes, activation kinetics, and GABA-dependent desensitization parameters showed a parallel shift towards 30- to 40-fold higher GABA concentrations. Both deactivation and resensitization kinetics were considerably accelerated in mutant channels. In addition, mutant receptors labelled with enhanced green fluorescent protein (EGFP) were not integrated in the cell membrane, in contrast to WT receptors. Therefore, the A322D mutation leads to a severe loss-of-function of the human GABAA receptor by several mechanisms, including reduced surface expression, reduced GABA-sensitivity, and accelerated deactivation. These molecular defects could decrease and shorten the resulting inhibitory postsynaptic currents (IPSCs) in vivo, which can induce a hyperexcitability of the postsynaptic membrane and explain the occurrence of epileptic seizures.

Amino Acid Substitution↗
PubMed1983

The epilepsy of Fyodor Mikhailovitch Dostoevsky (1821-1881).

Over 100 years ago, on the 27th of January 1881, Fyodor Mikhailovitch Dostoevsky died. Since that time, many biographies, monographs, memoirs, and, to a lesser extent, articles in the medical literature have discussed the fact that Dostoevsky was a patient with epilepsy. An attempt is made here to integrate the details of his illness into a medical case history, as we now do for every patient who visits a physician for the first time. The information pertinent to the case history includes: a description of all seizures, frequency of seizures, provocative factors, course of the disease, treatment, and family history. Even though we do not have the benefits of the results of electroencephalography (invented by Hans Berger in 1929), classification of the type of epilepsy Dostoevsky had is attempted. The existence or absence of the so-called ecstatic aura is crucial to such classification. Based on the data, it is likely that Dostoevsky suffered from partial complex epilepsy with secondarily generalized nocturnal seizures rather than primary generalized epilepsy.

Epilepsies, Partial↗
PubMedDate not supplied

Classifications of epileptic syndromes: advantages and limitations for evaluation of childhood epileptic syndromes in clinical practice.

The advantages and limitations of the two most recent International League Against Epilepsy classifications of the epilepsies and epileptic syndromes have been assessed after examining the clinical records of 645 consecutive outpatients aged 1 month to 15 years followed at the Children's Epilepsy Center of the University of Milan, Italy, from 1977 through 1985. The percentage of cases that could be classified according to the 1970 and 1985 proposals for classification were 94.1 and 98.1%, respectively. According to the 1985 proposal, partial epilepsies (PE) and generalized epilepsies (GE) were almost equally represented (45.0 vs. 47.2%). Among PE, symptomatic epilepsies were the commonest variety. In the group of GE, idiopathic and/or symptomatic epilepsies were most common. Childhood absence epilepsy was the largest subgroup among idiopathic GE. Newly diagnosed patients, a less biased sample of the epileptic population represented 38.9% of the entire sample, and a proper classification was possible in 96% of cases. Idiopathic epilepsies were about twice as frequent and idiopathic and/or symptomatic GE less frequent in newly diagnosed patients when compared with the remainder. Marked differences in the frequency of the epilepsies were found in comparison with other reports in the literature which used the 1970 classification. This finding probably depends on different diagnostic assessment, selection bias, and different geographic and ethnic components, but it can also reflect the variable interpretation of the clinical and EEG features of a patient with epilepsy in the light of the artifactual categories of the classification.

Adolescent↗
PubMed2000

Evidence favoring genetic heterogeneity for febrile convulsions.

PURPOSE: Two large Canadian kindreds appearing to segregate febrile convulsions as an autosomal dominant trait were evaluated for linkage to three known FC loci, as well as other epilepsy loci. METHODS: Members of the two families were genotyped with microsatellite markers linked to the previously identified febrile convulsion loci, FEB1, FEB2, and GEFS+, and we performed two-point linkage analyses by assuming an autosomal dominant mode of inheritance. RESULTS: We report the exclusion of the FC trait in our families to FEB1 on 8q13-21 and to a second febrile convulsion locus on 19p13. Furthermore, we also excluded the GEFS+ locus on 19q13.1 as the cause of febrile convulsions in both kindreds. Microsatellite markers linked to juvenile myoclonic epilepsy (EJM1), benign neonatal familial convulsions EBN1 and EBN2, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), idiopathic generalized epilepsy (EGI), progressive myoclonic epilepsy of Unverricht-Lundborg (EPM1), and partial epilepsy with auditory features (EPT), were also excluded as potential loci linked to the FC trait in our families. CONCLUSIONS: These findings favor considerable genetic heterogeneity for febrile convulsions.

Age of Onset↗
PubMed1978

Classification of the epilepsies. An investigation of 1,508 consecutive adult patients.

The relative frequency of different types of epilepsy in accordance with the International Classification of Epilepsies is reported, concerning 1,508 consecutive outpatients with epilepsy, who at the time of investigation were at age 15 years and above. The investigation showed a marked preponderance for partial epilepsies as against generalized epilepsies; partial epilepsies with complex symptomatology were especially frequent, contributing by more than one third of all cases.

Adolescent↗