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We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.

Background: Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the potential adverse effects caused by exposure to antiseizure medications (ASMs)., Objective: The objectives of this review were: to evaluate concentrations of ASMs in breastmilk of lactating WWE, qualitatively synthesize evidence that can be used to estimate theoretical doses as estimated daily intake (EDI) and relative infant dose (RID) of ASMs, and to evaluate potential risks to infants as a result of exposure to ASMs from breastmilk., Methods: This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42020223645. The databases: MEDLINE/PubMed, EMBASE, CINAHL/EBSCO, COCHRANE, SpringerLink, ScienceDirect, Summon, WHO International Clinical Trials Registry Platform, and SCOPUS were systematically searched. A qualitative synthesis was adopted in this study., Results: A total of 15 records were included in this systematic review. The included studies reported levels of 8 ASMs in the breastmilk of WWE. The highest RIDs of carbamazepine, lamotrigine, primidone, phenobarbital, gabapentin, valproic acid, ethosuximide, levetiracetam, and topiramate were 3.70%, 36.33%, 4.96%, 3.15%, 4.37%, 1.90%, 31.49%, 12.50%, and 12.18%, respectively. Breastfeeding might be limited or even discontinued when signs of excessive sedation/drowsiness and/or poor weight gain are evident on infants exposed to primidone and phenobarbital, ethosuximide/primidone, or ethosuximide/phenobarbital., Conclusions: Concentrations of ASMs can be detected in breastmilk of WWE and plasma/serum of infants exposed via breastmilk. Healthcare providers and WWE might use the findings of this study to make informed decisions on the safety of breastfeeding while taking ASMs., (Copyright © 2022 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: Angelman's syndrome (AS) is accompanied by specific changes in the EEG and genetically determined epilepsy. To analyze the neurological status, changes on EEG, MRI, the course of epilepsy in patients with Angelman syndrome (observed at the Svt. uca`s Institute of Child Neurology and Epilepsy)., Material and Methods: 47 patients with a genetically verified diagnosis of AS (aged 2 to 20 years, mean age 8.5 years; 26 boys and 21 girls) were included. The diagnosis was established by DNA methylation in 32 patients and sequencing in 15 patients (12 cases of deletion and 3 cases of nucleotide substitution were identified)., Results: Of the 47 patients, 45 have epilepsy. The seizures start up to 5 years of age, inclusive. For treatment, patients received various antiepileptic drugs. Long-term follow-up of epilepsy was followed in 40 of 47 patients, and 36 of 40 achieved drug remission. After several years without seizures, 24 out of 30 had a relapse, which was quickly stopped in 23 out of 30 patients. The severity of the disease is influenced by the nature of the mutation and the length of the deletion, as well as persistent epileptic seizures. The most effective AEDs in patients in our study are: in monotherapy, valproic acid, levetiraceiam, ethosuximide; in duotherapy, valproic acid in combination with levetiracetam or ethosuximide, less often levetiracetam with ethosuximide., Conclusions: Early genetic diagnosis of AS facilitates the selection of AET.

Purpose: Absence Status epilepticus (AS) is a form of Non Convulsive Status Epilepticus defined as a prolonged, generalized and non-convulsive seizure, with an altered content of consciousness. We aim to describe a group of healthy children, who presented recurrent and unprovoked de novo AS as the only manifestation of their epilepsy, with an excellent response to antiepileptic drugs., Method: We retrospectively reviewed the electroclinical and genetic features of 13 pediatric patients, referring to our epilepsy centers from 2005 to 2019, on the following criteria: (1) regular psychomotor development, (2) one or more unprovoked AS as the only epileptic manifestation, (3) normal blood testing, (4) normal neuroimaging, (5) EEG recording, (6) available follow-up (1-14 years)., Results: Patients are 7 females and 6 males, aged 7-22, with a mean age at AS onset of 9,3 years. All of them started an antiepileptic therapy, with an excellent response to Valproic Acid (VPA) or Ethosuximide (ETS). 5 patients did not start the therapy immediately after the first AS and they presented recurrent AS (from 2 to 4 episodes). 10 of them performed aCGH, karyotype, NGS panel or Whole Exome Sequencing., Conclusions: We suggest that de novo AS may be a well-defined age-related and self-limited epilepsy syndrome, with a good prognosis and excellent response to therapy, but it comes with a high risk of relapsing if not adequately treated with antiepileptic drugs., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: To estimate the comparative efficacy among antiepileptic drugs in the pediatric population (0-18 years)., Methods: Using the Embase and MEDLINE databases, we updated to February 2017 the search strategy of the National Institute for Health and Care Excellence guidelines for epilepsy. We only included randomized clinical trials conducted in children and mixed-age populations. According to the PRISMA network meta-analysis guideline, the study-level quality assessment was made with the Cochrane risk-of-bias tool. Three investigators independently selected articles. The efficacy outcome was considered to be seizure freedom or ≥50% seizure reduction., Results: We selected 46 randomized clinical trials. A total of 5652 individuals were randomized to 22 antiepileptic drugs and placebo. The point estimates of carbamazepine and lamotrigine efficacy showed their superiority with respect to all comparator antiepileptic drugs for the treatment of newly diagnosed focal epilepsy. In refractory focal epilepsy, levetiracetam (odds ratio [OR] = 3.3, 95% credible interval [CrI] = 1.3-7.6) and perampanel (OR = 2.5, 95% CrI = 1.1-5.8) were more effective compared to placebo. Ethosuximide and valproic acid were both superior to lamotrigine against absence seizures. The OR point estimate showed the superiority of adrenocorticotropic hormone over all comparators in infantile spasms. A wide heterogeneity in the length of follow-up was observed among the studies., Significance: This network meta-analysis suggests that the quality of studies should be improved through the use of comparative designs, relevant outcomes, appropriate follow-up length, and more reliable inclusion criteria., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

A 50-year-old man with known multidrug resistant coexistent focal and generalised epilepsy was commenced on ethosuximide, with normalisation of his electroencephalogram and cessation of absence seizures. Within 3 weeks, he developed a rapidly worsening paranoid psychosis with visual and olfactory hallucinations. A month after the cessation of ethosuximide and concurrent treatment with olanzapine, his psychosis resolved and permitted reinitiation of ethosuximide at a lower dose without recurrence of psychotic symptoms., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs.

We report an unusual association between idiopathic occipital epilepsy and childhood absence epilepsy in 2 pediatric patients. At first clinical and electroencephalographic evaluation, the patients presented the peculiar signs of idiopathic occipital epilepsy Gastaut type: focal sensory visual seizures, migraine-like symptoms (only in one patient) and unilateral spike-wave discharges over occipital regions. Both children were treated with valproic acid and their seizures were rapidly controlled. After a seizure-free period, the patients presented typical absence with ictal electroencephalographies showing 3 cycles/s generalized and symmetrical spike-wave complexes. We discuss the possible association between these two epileptic syndromes and its common pathophysiological mechanisms., (2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Aim of the Study: Electroencephalographic recording (electroencephalogram [EEG]) is frequent in specific language impairment (SLI), whereas the relations between epileptiform activity (EA) and language disorders remain uncertain and the therapeutic approach undetermined. The aim of this prospective study was to clarify EEG indications and interpretation in SLI., Methods: We present a prospective study of cognitive (speech-language measures, psychological assessments) and electroencephalographic data on 24 children (20 males, 4 females; mean age: 4 years 5 months; range: 3 years to 4 years 8 months) with a diagnosis of SLI, defined as a pathologic score on at least 2 speech-language measures and IQ performance of at least 80 points, within epileptic seizures. All participants had an EEG after partial deprivation of sleep at night. When nonsporadic EA was found, 24-h EEG was performed. Antiepileptic treatment was prescribed depending on the frequency of discharges and the SLI profile. The follow-up lasted 2 years., Results: All patients reached stage II sleep during their EEG. Seven children had abnormal electroencephalography results, including 5 children with EA. Two patients with mixed SLI prevailing on expression presented a left centrotemporal spike focus on EEG becoming subcontinuous during sleep. In the first case, the language progressed without antiepileptic treatment. The 2nd case was treated with ethosuximide; the EEG normalized on subsequent recordings, but the language disorder remained severe. The lexical and syntactic understanding and syntactic production scores were not different for children presented EA (5 cases) or without (19 cases) (Wilcoxon's test). Finally, the progression of the various linguistic skills was similar whether or not the children had EA (p<0.1)., Conclusion: Abnormal electroencephalographic activity is more frequent in SLI than in normal children. It can be seen in all types of SLI but preferentially in the mixed forms. The longitudinal systematic evaluation of all the children with or without EA has never been reported in the literature, which confirms that there is no parallel between EEG progression and language development, contrary to Landau-Kleffner's syndrome. Systematic EEG recording is not recommended in SLI. It is indicated in cases of fluctuation or stagnation of language development or if there is a family history of cognitive disorders or epilepsy. Antiepileptic treatment is justified in cases with fluctuation or stagnation in language development after 6 months of progression associated with frequent EA. However, when the EA is particularly diffuse and dense, an additional moderate aggravating effect on language development cannot be eliminated. The method most likely to clarify this question is to compare a child's baseline phase followed by a treatment phase, with the same double follow-up., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

In the past 20 years, a number of new antiepileptic drugs (AEDs) have been introduced and other molecules are in development, some of which are advantageous in terms of pharmacokinetics, tolerability and potential for drug interactions. These drugs are regarded as second generation compared to older agents such as barbiturates, phenytoin, carbamazepine, ethosuximide and valproic acid. Although some of these second generation compounds may be advantageous in terms of kinetics, tolerability and potential for drug interactions, all of them still target voltage-gated channels or GABA-mediated inhibition, predominantly, without any real improvement in epilepsy therapy. Studies on mechanisms of seizure generation and propagation have identified new potential targets for AEDs. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies. In this review the molecular targets for new AEDs are discussed, providing further suggestions on how future research can be improved.

Rationale: Evident seizures during sleep are common in clinical practice but are uncommonly considered in animal models of epilepsy. A previous observation of spontaneous spike-and-wave activity during sleep in several A/J mice (A/J JAX) from Jackson Laboratory (Bar Harbor, ME) prompted this description of the inheritance of epileptic activity., Methods: Mice from A/J, C57BI/6J (B6), and chromosomal substitutions strains were instrumented to record EEG and EMG activity over time without and with anti-epileptic drugs. Intercrosses were performed using linkage analysis to localize sub-chromosomal regions., Results: Spike-discharge patterns (n = 12 mice) were of average duration of 1.9 seconds at a rate per hour of 17, with an intrinsic frequency of 6.41 Hz and an amplitude of 634.8 microV. Clonic movements were observed in < 10% of the episodes. Episodes were expressed (> 75%) either in slow-wave sleep or in transitions to and from slow-wave sleep. Events were rare in paradoxical sleep. Compared with vehicle, intraperitoneal administration of ethosuximide (150 mg/kg) or diazepam (5 mg/kg) inhibited or eliminated seizure activity, respectively. In contrast, spontaneous spike-and-wave activity was not observed in A/J mice from Harlan National Laboratories (Indianapolis, Ind) or in B6 mice from Jackson Laboratory. In an intercross between A/J JAX and B6 mice, the trait was not present in the first generation. The trait was observed in 2 chromosome-substitution strains, B6.A4 and B6.A7. In the intercross second generation of these chromosome-substitution strains (n = 113), significant linkage was observed to loci on chromosome 4., Conclusions: This is a sleep-related epilepsy phenotype that exhibits an oligogenic pattern of allelic inheritance.

Movement disorders are rarely described in association with the "continuous spikes and waves during slow sleep (CSWS)" EEG pattern. We report the case of a young girl affected by an epileptic encephalopathy who, from the age of seven years and four months, has twice presented a movement disorder affecting the right arm, manifesting on awakening and disappearing by early afternoon. Sleep EEG during these periods showed continuous, high-amplitude, diphasic spikes and slow waves over the left hemisphere. Association of clobazam, valproic acid and, on the second occasion, ethosuccimide led to disappearance of the above-described EEG picture and associated motor symptoms. Neurophysiological investigations excluded other possible aetiologies. In view of this, and of the close relationship between the EEG picture and clinical course, we interpret the patient's impairment as "motor neglect" secondary to the continuous electrical activity recorded during sleep over the left hemisphere and involving the associative areas. This electrical activity in sleep, may be regarded as a "functional lesion" whose clinical consequences can be correlated with the site of the abnormalities.[Published with video sequences].

Purpose: Valproate (VPA) is a teratogenic anticonvulsant (AED), but vitamin supplementation has been suggested to limit the effect of VPA on the fetus. Maternal urinary metabolites were monitored to assess the metabolic effects of VPA before and after vitamin supplementation., Methods: A pregnant woman with epilepsy receiving VPA and ethosuximide (ESM) was given high-dose multivitamins from 13 to 28 weeks' gestation. Maternal urinary metabolites were measured throughout the pregnancy by gas chromatography/mass spectrometry., Results: Before multivitamin supplementation began, the patient had significantly increased excretion rates of alpha-ketoglutarate, beta-lactate, pyruvate, lactate, methylmalonate, and other metabolites compared with normal pregnant women. During multivitamin supplementation, many previously increased excretion rates decreased significantly. Fetal head growth was normal up to 30 weeks, but then lagged. Bitemporal narrowing was noted at birth., Conclusions: VPA may cause metabolic abnormalities in pregnancy. Many biochemical abnormalities attributable to VPA in this patient were corrected with high-dose multivitamin supplementation. The specific relation between biochemical abnormalities and VPA teratogenesis remains to be determined.

Purpose: We wished to determine the oral pharmacokinetics of lamotrigine LTG and to assess possible interactions with other AEDs in an unselected population of children. Concentration data in plasma and in CSF for lamotrigine as well as for the other AEDs are presented., Methods: Thirty-one children, children and young adults aged > 2 years with intractable generalized epilepsy despite adequate duration and dose of at least three conventional AEDs were studied., Results: There was a linear relation between the dose administered and the maximal plasma concentration, indicating that saturation of absorption or elimination mechanisms did not occur in the dose range studied. The median elimination half-life (t1/2) in patients receiving concomitant valproate (VPA) was 43.3 h; in patients receiving carbamazepine (CBZ) and/or phenobarbital (PB), it was 14.1 h; and in patients receiving both VPA and CBZ/ PB or other antiepileptic drugs (AEDs), it was 28.9 h. No clinically important changes in the plasma levels of CBZ, VPA, valproate, ethosuximide, or PB were observed in the follow-up period (2-12 months). No dose adjustments of concomitant AEDs were necessary. The plasma concentration of clonazepam (CZP) was reduced when LTG was introduced., Conclusions: The complex interaction between LTG and other AEDs in children with intractable epilepsy makes therapeutic drug monitoring (TDM) desirable.

Epilepsy is, for many patients, a lifelong condition that requires treatment with powerful drugs whose doses must be carefully titrated to avoid both breakthrough seizures and toxicity. The medication regimens used to treat epilepsy are further complicated by the fact that most seizure medications are metabolized in the liver and have the potential for serious pharmacokinetic drug-drug interactions with many other medications. Successful management of epilepsy requires a high degree of cooperation among the patient, the pharmacist, and the treating physician. Such cooperation can ensure that the appropriate treatment and drug preparation are selected, compliance is maintained, and dangerous drug-drug interactions are avoided.

Continuous, generalized 2.5 to 3.5-Hz spike-wave (SW) discharges were evident in an EEG performed 13 h after a first seizure associated with a viral illness, in an 8-year-old girl. On eye opening, the EEG abnormality was suppressed and replaced by delta activity and brief spike-wave paroxysms. No alteration in consciousness and seizures or behavioral abnormalities accompanied the EEG findings. Based on the EEG, she was diagnosed as having "diffuse electrical status," the rare EEG phenomenon that occurs during wakefulness without associated behavioral changes. Although the child was completely normal clinically, the EEG findings persisted during a 9-year-follow-up period. Ethosuximide (ESM) 1 gr daily resulted in temporary disappearance of the bioelectrical status. During the last 2 years without medication the EEG finding tended to be restricted to the posterior regions.

To test the feasibility of comparing epilepsy treatment policies and outcome, a secondary and a tertiary epilepsy care facility have been audited in a previous study (1). Marked differences were observed in the treatment policies and outcome and in the distribution of seizure types and duration of epilepsy. For this reason the patients of that study were matched according to seizure type and duration of epilepsy, resulting in two groups each of 32 patients per centre. The outcome of treatment was assessed by using clinimetrical indexes for seizure frequency and severity and toxicity of medication, resulting in the Composite Index of Impairments (CII), reflecting all treatment-related impairments. For the statistical analysis the X2-test and the Kruskal-Wallis test were used. Differences were found to be statistically significant when p < 0.05. No distinct differences were found in the treatment policies of both centres. However, differences were observed in the outcome of treatment. The toxicity ratings in this study were significantly higher for the Epilepsy Centre. Also the Composite Index of Impairments (CII) was significantly higher at the Epilepsy Centre. The number of patients with a CII score of > 100 did not differ significantly for both centres. The finding that pharmacotherapy is similar in both centres, suggests that pharmacotherapy is pushed to its limits in both, and that referral to a tertiary facility is mainly for the non-pharmacotherapeutic care modalities available. For the corroboration of this assumption the use of a quality of life index would be more appropriate than the CII.

One hundred twenty children aged 10 months to 16 years 9 months were included in three studies with lamotrigine (LTG): a single-blind study (n = 60), a pharmacokinetic study (n = 23), and a compassionate group (n = 37). At 3 months, 11 patients had become seizure-free and 34 had > 50% decrease in seizure frequency. The best results involved absence epilepsy, Lennox-Gastaut syndrome (LGS), and other symptomatic generalized epilepsy. Forty-two patients were followed > 1 year, 22 for a mean of 2.2 years, and there was no significant increase in seizure frequency as compared with 3-month follow-up. Fourteen patients became seizure-free for > 6 months; all except 1 had generalized epilepsy. For 12 patients, treatment could be reduced to monotherapy, but for those with valproate (VPA) comedication LTG dosage had to be increased; 25% of patients with VPA monotherapy exhibited skin rash, appearing 3-18 days after starting LTG. For 4 patients, LTG could be reintroduced after VPA was withdrawn. Ten patients had ataxia and/or drowsiness and 2 had vomiting. For all other patients, tolerance was excellent.

Epilepsy is a major cause of morbidity and accounted for up to 40% of psychiatric outpatient attendances in the experience of the author in Transkei, South Africa. In many cases clinical diagnosis and management were easy. In this paper, the author analyses the clinical management problems presented by seven patients between January 1986 and May 1989. A detailed case report is presented to illustrate difficulties in management. It is suggested that ethosuximide might be effective in the control of probable partial seizure disorders. Underlying electrophysiological considerations are discussed. It is noted, however, that it may not be easy to differentiate between partial or generalised seizure disorders on clinical grounds.

Antiepileptic drugs (AEDs) are administered to patients for acute and long-term treatment of seizures. Most patients with acute convulsions receive intravenous (i.v.) benzodiazepine (BZD), frequently followed by i.v. loading with phenytoin (PHT), especially when seizures continue. For patients with absence status epilepticus, BZD is usually followed by ethosuximide (ESM) or valproate (VPA). The decision to continue AED therapy is based on the likelihood that seizures will continue or recur. Once epilepsy is diagnosed, long-term treatment with AEDs is recommended, beginning with monotherapy. Two studies sponsored by the U.S. Veterans Administration (VA), which compared the efficacy of carbamazepine (CBZ), PHT, phenobarbital (PB), primidone (PRM), and VPA, recommend that most adults with recurrent partial seizures receive either CBZ or PHT. The 1992 VA study suggests that VPA is equal to CBZ or PHT in efficacy when partial seizures become secondarily generalized. Primary generalized epilepsies are most frequently treated with VPA when combinations of generalized seizures exist. ESM is prescribed most often when typical childhood absence seizures exist alone. Although many authorities do not recommend long-term treatment of childhood febrile seizures, PB is administered by some when febrile seizures have complex symptomatology. In general, AED monotherapy is currently preferred, but those with more refractory epilepsy receive polytherapy. CBZ, PHT, PB, PRM, VPA, and ESM are the primary AEDs prescribed in the United States. PHT, followed by CBZ and VPA, is the most frequently prescribed AED as both new and total prescriptions. The introduction of felbamate, gabapentin,and lamotrigine may alter these patterns in the future.

The drug encorat, an analogue of valproic acid (Sun, India) was given to 16 children aged from 4 month to 5 years suffering from resistant forms of early infantile epilepsy. Twelve of them had infantile spasms, four Lennox-Gastaut syndrome. The treatment produced good results in 75% of the patients. Encorat mono- or polychemotherapy is able to discontinue or decrease the frequency of the epileptic fits, improve the patients' condition in resistant early childhood epilepsy.

Four children with 'epilepsy and continuous spike-wave sleep' syndrome and mental and behavioural regression were followed prospectively with neuropsychological tests, behavioural questionnaires and sleep EEG performed at regular intervals between 1 1/2 and four years of age. The children showed a pattern of behavioural and cognitive disturbances similar to that found in some developmental autistic-like disorders, but also in adult frontal syndrome. Deterioration was probably due to an unusual long-standing epileptic dysfunction involving the frontal lobes. The process is potentially reversible and seems to be the same as postulated for acquired epileptic aphasia, but in a different localization.

Five children with epilepsy with "continuous spike-waves during slow sleep" (CSWS) are reported. The main clinical features of CSWS include (a) onset between 5 and 7 years of age, (b) the occurrence of several types of seizure (i.e., partial motor, generalized motor, and atypical absence), and (c) the presence of language disturbances and abnormal behavior based on emotional impairment. The EEG findings were characterized by sleep tracings showing almost continuous (greater than 95%), diffuse slow spike and wave activity. After treatment with valproate (VPA) (or ethosuximide, ESM) and clonazepam (CZP), the spike and wave complex status disappeared. Symptoms and signs of the CSWS also decreased. We suggest that combined treatment is an appropriate treatment for CSWS.

The possible synergistic effect of valproic acid and ethosuximide in combination on pentylenetetrazole-induced epilepsy was investigated in rats. Valproic acid and ethosuximide administered intraperitoneally both showed dose-dependent anti-epileptic activity towards pentylenetetrazole-induced myoclonias and tonic-clonic seizures. The valproic acid-ethosuximide combination had a synergistic pharmacological effect. Against myoclonias combined valproic acid-ethosuximide produced a non-significant decrease in the effective dose of both drugs compared with treatment with either drug alone. In the case of tonic-clonic seizures the protective effect against the seizures was significantly increased by combined treatment compared with treatment with either drug alone. Neither plasma concentrations nor any other pharmacokinetic parameters were significantly changed when the same doses of valproic acid and ethosuximide were given, singly or in combination.

Ethosuximide is the drug of first choice in absence seizures. Idiosyncratic side effects are rare. Valproate is effective against absence, generalized tonic-colonic, and partial seizures. It is the drug of choice in photosensitive seizures. Valproate is, on the whole, free from unpleasant side effects, but fatal hepatotoxicity and hyperamnionemia have been reported very rarely.

Electroencephalographic (EEG) studies were performed to examine the effects of several antiepileptic drugs (AEDS) on absence-like and tonic seizures in the spontaneously epileptic rat (SER: zi(zi), tm/tm,), a double mutant rat, which was obtained by mating the tremor heterozygous animals (tm/ +) with the zitter homozygous animals (zi/zi), and to determine whether the seizures in the SER correspond to human absence and tonic seizures. Spontaneous EEG was continuously recorded from the frontal cortex and hippocampus using implanted electrodes. The SER showed paroxysmal and synchronized 5-7-Hz spike-wave-like complexes in both cortical and hippocampal EEG during the absence-like state, which was characterized by immobility and staring. The animal also exhibited tonic convulsion without external stimulation concomitant with low-voltage fast waves on cortical and hippocampal EEG. In some animals, sporadic low-amplitude spikes appeared in the low-voltage fast waves during tonic convulsion. the absence-like seizures were inhibited by trimethadione (100 mg/kg intraperitoneally, i.p.) and ethosuximide 100 mg/kg i.p.), whereas the tonic convulsion was not affected by these drugs. In contrast, phenytoin (20 mg/kg i.p.) inhibited the tonic seizures without affecting the absence-like seizures. Phenobarbital (10 mg/kg i.p.) and valproate (200 mg/kg i.p.) inhibited both seizures to a similar degree. These results suggest that the SER, with both absence-like and tonic seizures, is a useful model for evaluation of AEDS.

Anticonvulsant properties of alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL) were compared with those of the antiepileptic drugs ethosuximide (ESM) and valproate (VPA) by testing their ability to block seizures in mice caused by maximal electroshock (MES), pentylenetetrazol (PTZ), picrotoxin (PICRO), bicuculline (BIC), methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), N-methyl-D,L-aspartate (NMDA), aminophylline (AMPH), strychnine (STR), beta-ethyl-beta-methyl-gamma-thiobutyrolactone (beta-EMTBL), and t-butylbicyclophosphorothionate (TBPS). ESM was able to prevent PTZ-, PICRO-, DMCM-, and beta-EMTBL-induced seizures. In contrast, VPA and alpha-EMTBL blocked all of these plus MESTBPS-, and BIC-induced convulsions. Only VPA prevented AMPH-induced seizures. None of the anticonvulsants blocked STR or NMDA seizures. Rotorod testing for acute neurotoxicity demonstrated that ESM was the least toxic and alpha-EMTBL and VPA were equivalent. Animals treated daily with high doses of alpha-EMTBL for a 2-week period appeared healthier and had a higher survival rate than animals treated with VPA in the same manner. After a single intraperitoneal (i.p.) injection, the duration of anticonvulsant action of alpha-EMTBL was 1.3 and 4 times longer than that of ESM and VPA, respectively. These results indicate that alpha-EMTBL has a wide spectrum of anticonvulsant action like VPA but may be less toxic and longer acting. We suggest that alpha-EMTBL is a compound worthy of further testing and development as an antiepileptic drug (AED).

We studied the effect of varying potassium (K+) concentrations on spontaneous and pentylenetetrazol (PTZ)-induced population burst discharges in mouse hippocampal slices. Standard techniques were used to obtain extracellular recordings in the CA3 region of hippocampal slices from Swiss-Webster mice (21-28 days old). No spontaneous burst discharges occurred at 3.25 mM K+, but population bursts were observed in 20 and 90% of the slices at 6.25 and 9.25 mM K+, respectively. In the presence of 3.25 mM K+, PTZ produced bursts in 12% of the slices at a concentration of 200 micrograms/ml, in 36% at 300 micrograms/ml, and in 40% at 400 micrograms/ml. Slices exhibiting no burst discharges in the presence of 6.25 mM K+ could be induced to do so with the addition of PTZ; bursts were produced in 11% of these slices at a PTZ concentration of 100 micrograms/ml, in 65% at 150 micrograms/ml, and in 87% at 200 micrograms/ml. The PTZ-induced bursting activity was reversible. Clonazepam abolished the bursting elicited with 200 micrograms/ml PTZ at 6.25 mM K+, and phenytoin reduced, but did not stop, bursting activity. Ethosuximide (ETH) was ineffective in stopping or reducing the burst discharges at a concentration of 125 micrograms/ml ETH was there a consistent reduction in the frequency of population bursts. The induction of PTZ discharges in the hippocampal in vitro preparation offers the advantage of a simplified model for studying the pharmacology of antiepileptic drugs.

Trends in the diagnosis of epilepsy have continued to focus on the fundamental cause of the seizures, as well as the seizure type. It is the latter that determines symptomatic therapy. New drugs have improved the lives of many epileptic patients, and emphasis on nonsedative medications, both new and old, is now possible and desirable in most patients. Finally, new and better drugs are needed for the many severely affected epileptic patients who are not helped by the currently available antiepileptic drugs.

Of 117 patients treated with anticonvulsants reduced plasma biotin levels were found in over 80% of cases. Significant negative correlations with the average daily dose and the total amount of anticonvulsants as well as with the plasma phenytoin level were also evident. It is proposed that the lowering of biotin--which is a co-factor of the carboxylating enzyme system--is an important mechanism in mode of action of anticonvulsants. Reduced biotin levels possibly lead to an accumulation of carbon dioxide or a diminution of aspartate in brain tissue. Low biotin levels may also be the cause of some well known side effects of anticonvulsants such as cerebellar disturbances and dermatitis. In comparison to the other epileptics the patients with cerebellar symptoms showed significantly lowered plasma biotin levels.

The management of a patient with seizures involves proper classification, etiologic evaluation, and administration of appropriate therapy. With proper evaluation and management, control of seizures can be expected in the majority of patients. The physician must realize that an epileptic adolescent has intrinsic anxieties and faces social, educational, and vocational restrictions. Failure to deal with these psychosocial problems may result in a greater handicap to the patient than the seizures themselves.

Epilepsy, one of the oldest identified neurological disorders, is now recognized as a major public health problem affecting about 1 percent of the population. The author differentiates between two major types of the disorder, the generalized and partial epilepsies, and describes different kinds of seizures in epileptic patients. The improved ability of the clinician to diagnose the disorder through use of electroencephalography, intensive monitoring, and CT scan is highlighted. The author concludes with a discussion of the major drugs used to control seizures, their biological half-lives, side effects, and how they interact with other antiepileptic drugs.

Power spectral analysis of spontaneous EEG activity recorded during non-rapid eye movement (REM) sleep was employed in an effort to identify characteristic EEG substrate abnormalities in epileptics. All-night polygraphic recordings were obtained from 10 poorly controlled subjects with mixed and generalized seizures. Similar data were obtained from 10 matched nonepileptic subjects. Continuous 10 min samples of non-REM sleep were identified at the beginning and end of these all-night recordings. EEG activity recorded during these periods from left sensorimotor and parieto-occipital bipolar leads was digitized, subjected to the fast Fourier transform, and then sorted into successive 4 Hz frequency bands between 0 and 23 Hz. Mean spectral density was determined for each frequency band from both samples in both groups. Comparison of these values disclosed both similarities and differences between the two groups. All subjects showed a significant "time-of-night effect," with power at 0-3, 4-7, and 8-11 Hz greater at the beginning of the night. This finding was related to a similar observation in developing infants and attributed to a circadian influence on neuronal generators. In group comparisons, epileptics showed selective differences in common when compared with nonepileptics. These differences were reduced when data from a small group of unmedicated epileptic subjects were partialled out. Medicated epileptics showed differences restricted to the early morning non-REM sleep sample, which included significantly greater power at 4-7 Hz and significantly lower power at 12-15 Hz. Unmedicated subjects showed these differences in both samples and also showed significantly greater power in the 0-3 Hz band. It was suggested that anticonvulsant medications may exert a general normalizing influence on EEG characteristics during sleep, particularly at the beginning of the night in proximity to their administration. The documentation of significant EEG deviations restricted to two basic rhythmic patterns during sleep suggests a disturbance of underlying thalamocortical mechanisms.

Current trends and controversies in the antiepileptic drug therapy are reviewed from a clinical view. The usefulness of prophylactic therapy of febrile seizures and posttraumatic seizures or posttraumatic epilepsy is compromised by difficulties in the management of the patients especially by noncompliance. Previously untreated epilepsies can be treated successfully in 70--80% of the patients. Phenytoin or carbamazepine are equally effective for generalized tonic-clonic seizures of focal seizures, while absence seizures are controlled by ethosuximide or valproic acid. Only when the epilepsy is uncontrolled despite high plasma concentrations which cannot be raised because of side effects, a second drug should be given. A second drug is successful in about one out of six patients with focal epilepsy. Phenytoin, carbamazepine, phenobarbital and primidone seem to be equally effective for these drug-resistant cases. Status epilepticus can be treated with intravenous diazepam or phenytoin and, if necessary, with an infusion of phenytoin. Rectal diazepam is useful for acute pediatric therapy. Drugs of second choice are clonazepam, phenobarbital, lidocaine, and clomethiazole. In the pregnant epileptic patient a drop in the plasma concentration of antiepileptic drugs mainly through non-compliance and seizure provocation through sleep deprivation are major sources for the deterioration of epilepsies during pregnancy. The "fetal antiepileptic drug syndrome", malformations and an increased risk for epilepsy in the child are discussed as an interaction of parental epilepsy and drug-exposure during pregnancy. Finally, the interpretation of abnormal clinical chemistry data is reviewed. Disorders of the liver, bone, thyroid gland and blood are rarely seen in treated epileptic patients usually when specific risk factors are present. The over-interpretation of laboratory abnormalities e.g. an isolated increase of gamma-GT may lead to iatrogenic deterioration of epilepsy when the effective dose of the drug is reduced for unfounded fear of hepatic toxicity.