Early prognosis of epilepsy.

In 94 previously untreated new referrals to a neurological clinic with tonic-clonic or partial seizures or both the failure rate for optimum single-drug treatment with phenytoin or carbamazepine after a median of 32 months was 17%. Failure of single-drug treatment was associated especially with the presence of additional neuropsychiatric handicaps but also with partial or mixed seizures, symptomatic epilepsy, and a higher number and frequency of tonic-clonic or partial seizures before treatment. Analysis of the recurrence of seizures suggested that the first year of treatment may be crucial in determining the long-term prognosis. These findings are in keeping with the concept that seizures may predispose to further seizures, and imply that early, effective treatment may be important to prevent evolution into chronic and more intractable epilepsy.     

The Effect of Time of Administration of Phenytoin on its Serum Levels and Pharmacodynamic Parameters in Patients of Generalised Tonic Clonic Seizures

The role of the time of administration of phenytoin on its serum levels and pharmacodynamic parameters was studied in two comparable groups of patients of grand mal_epilepsy stabilized on serum phenytoin therapy. In these patients, phenytoin was advised to be taken as a single daily dose either at 08.00 (Group M) or 20.00 (Group E) every day. A serum phenytoin level profile over 24 hours was obtained and all patients were clinically followed up for six months. Maximum serum concentration (C-max) of phenytoin was achieved significantly faster (p < 0.001) in patients of Group E. The total number of serum samples having toxic concentrations and also the incidence and severity of toxic effects of phenytoin was less in Group E. The study suggests that bedtime administration of phenytoin in patients of grand mal–epilepsy may lead to faster absorption of the drug and less side effects as compared with drug administration in the morning.     

Treatment of Epilepsy

The main clinical types of epilepsy and their treatment are described. The treatment of choice in petit mal epilepsy is trimethadione (Trimedone) 0.3 g., three to six times a day, or acetazolamide (Diamox) 125-250 mg., three to four times a day. Phenobarbital is usually given as well to prevent grand mal seizures. Diphenylhydantoin sodium (Dilantin Sodium), 100 mg., and/or phenobarbital, 30-100 mg., three to four times a day, is recommended in patients with focal and grand mal epilepsy. Psychomotor automatisms are a form of focal seizure. Primidone (Mysoline), in doses of 125-250 mg. two to three times a day, is a very useful anticonvulsant in patients with myoclonic features, psychomotor automatisms and grand mal seizures. Primidone should be started in small doses. Drug reactions, especially cerebellar ataxia in the case of diphenylhydantoin and blood dyscrasias in the case of some drugs, should be recognized. Excessive drowsiness can be avoided by proper dosage and proper timing of drug administration. Patients should be seen regularly at least two to three times a year. The objective of treatment is to achieve optimum control of seizures by using the appropriate drug in adequate dosage. Social adaptation is good in the majority of patients, who should be encouraged to carry on their life independently, usually free to marry and have children. Attention to special occupational hazards has to be considered. Education of employers and employees is often necessary. Special work arrangements are occasionally indicated for selected patients. Patients should be seizure-free for two to three years before permission is given to drive an automobile.     

Mexiletine and its Interactions with Classical Antiepileptic Drugs: An Isobolographic Analysis

Using the mouse maximal electroshock test, the reference model of tonic–clonic seizures, the aim of the present study was to determine the type of interaction between mexiletine (a class IB antiarrhythmic drug) and classical antiepileptics: valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis of obtained data indicated antagonistic interactions between mexiletine and valproate (for fixed ratio combinations of 1:1 and 3:1). Additivity was observed between mexiletine and valproate applied in proportion of 1:3 as well as between mexiletine and remaining antiepileptics for the fixed ratios of 1:3, 1:1, and 3:1. Neither motor performance nor long-term memory were impaired by mexiletine or antiepileptic drugs regardless of whether they were administered singly or in combination. Mexiletine did not significantly affected brain concentrations of carbamazepine, phenobarbital or phenytoin. In contrast, the antiarrhythmic drug decreased by 23 % the brain level of valproate. This could be, at least partially, the reason of antagonistic interaction between the two drugs. In conclusion, the observed additivity suggests that mexiletine can be safely applied in epileptic patients treated with carbamazepine, phenytoin or phenobarbital. Because of undesirable pharmacodynamics and pharmacokinetic interactions with valproate, mexiletine should not be used in such combinations.

     

Differential effect of antiepileptic and non-antiepileptic drugs on the reticular formation

The effect of the antiepileptic drugs carbamazepine and phenytoin, and of the non-antiepileptic drug baclofen, was compared on various inhibitory and excitatory mechanisms in the feline trigeminal nucleus. Baclofen resembled carbamazepine and phenytoin in depressing segmental excitatory and facilitating segmental inhibitory mechanisms. However, baclofen facilitated the periventricular and periaqueductal inhibition of the trigeminal nucleus, while carbamazepine and phenytoin depressed these descending inhibitory mechanisms. Baclofen also resembles carbamazepine and phenytoin in its effectiveness in trigeminal neuralgia, but baclofen is not a clinically effective antiepileptic agent. Our experiments indicate that the ability to depress the reticular formation of the diencephalon and midbrain is an important characteristic of antiepileptic drugs. This suggests that the reticular core is involved in the spread and generalization of seizures.     

Incidence of seizures and EEG abnormalities among offspring of epileptic patients

Summary The marriage rate of epileptic patients was 62% in males und 78% in females. Compared with the rates in the general population, the male patients had a 15% lower rate, but there was no difference in females. There were 263 patients with at least one offspring selected for the study. There were 243 sons and 272 daughters (506 total, 1.9 per patient). Distribution by types of seizure was awakening grand mal, absence or myoclonic petit mal in 24%, grand mal with no aura in 21%, grand mal during sleep in 23%, diffuse grand mal in 7%, grand mal with aura in 13%, psychomotor seizure in 9%, and focal seizure in 3%. The probands were composed of 79% idiopathic and 21% symptomatic in pathogenetic classification. An epileptic EEG abnormality was demonstrated in 22% of male and 44% of female probands.The incidence of seizures among offspring was 2.4% (4.2% age-corrected) in a narrow sense (epilepsy) and 9.1% in a broad sense including febrile convulsions. The latter morbidity was 11.0% for the idiopathic and 3.2% for the symptomatic group; 11.0% for female and 6.9% for male probands; 10.2% for sons and 8.1% for daughters. The figure was higher for the probands with the age range at onset of seizure of 0–4 years (20.6%) and 20–29 years (12.6%) than for those with other age ranges; higher for those with awakening grand mal, absence, myoclonic petit mal, or grand mal with no aura than for those with other types of seizure; and higher for those with family history of epilepsy than those without it.Possible correlation of types of seizure between probands and offspring was demonstrated. Thirty-seven percent of offspring exhibited epileptic EEG abnormalities, and the ratio of epileptic EEG abnormalities to clinical manifestation is about 4:1.Possible existence of familial aggregation of EEG abnormalities and of two kinds of families with large or small epileptic predisposition was indicated.The importance of the role of hereditary and environmental factors in epileptic pathogenesis is proved, and the results of an investigation of congenital malformation among offspring of epileptic mothers are presented. These results were considered to be useful for genetic counseling of epileptic patients.     

Influence of Ivabradine on the Anticonvulsant Action of Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

Although the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in neuronal excitability and synaptic transmission is still unclear, it is postulated that the HCN channels may be involved in seizure activity. The aim of this study was to assess the effects of ivabradine (an HCN channel inhibitor) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice. Tonic seizures (maximal electroconvulsions) were evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles of the combinations of ivabradine with classical antiepileptic drugs were measured in mice along with total brain antiepileptic drug concentrations. Results indicate that ivabradine (10 mg/kg, i.p.) significantly enhanced the anticonvulsant activity of valproate and considerably reduced that of phenytoin in the mouse maximal electroshock-induced seizure model. Ivabradine (10 mg/kg) had no impact on the anticonvulsant potency of carbamazepine and phenobarbital in the maximal electroshock-induced seizure test in mice. Ivabradine (10 mg/kg) significantly diminished total brain concentration of phenytoin and had no effect on total brain valproate concentration in mice. In conclusion, the enhanced anticonvulsant action of valproate by ivabradine in the mouse maximal electroshock-induced seizure model was pharmacodynamic in nature. A special attention is required when combining ivabradine with phenytoin due to a pharmacokinetic interaction and reduction of the anticonvulsant action of phenytoin in mice. The combinations of ivabradine with carbamazepine and phenobarbital were neutral from a preclinical viewpoint.     

Reduction of intractable seizures using cerebellar stimulation

Of the 32 patients with active intractable seizures, 27 had spastic cerebral palsy (CP) and 5 had epilepsy (EP), and all underwent chronic cerebellar stimulation (CCS) (amplitude 1-2 microC/cm2/phase, rate 10-180 pps, duration of implantation 0.5-7 years, average 4.5 years). Grand mal seizures occurred in 23 patients (19 CP, 4 EP); with CCS 17 patients stopped, 4 had a reduction, 3 were unchanged. Petit mal occurred in 9 patients (8 CP, 1 EP); with CCS 4 patients ceased seizuring, 3 reduced and 2 were unchanged. Myoclonic seizures were present in 6 patients (5 CP, 1 EP); with CCS 1 patient stopped, 3 had a reduction while 2 patients were unaffected. Severe psychomotor seizuring affected 2 EP patients, 1 had a marked behavioral improvement and finally stopped seizuring for the past 9 months. Overall, CCS stopped 18 (57%) of the patients seizuring, reduced a further 9 (28%), with no effect in 5 patients (15%).     

Chronotherapeutic dose schedule of phenytoin and carbamazepine in epileptic patients

The objective of this study was to compare the efficacy and safety of a chronotherapeutic dosing schedule of phenytoin and carbamazepine versus a conventional dosing schedule for the treatment of tonic-clonic epileptic patients. Of 148 epileptic subjects found to have subtherapeutic trough drug levels (subtherapeutic group, STG), 103 subjects who completed the study were randomized to either STG I (n=51) for treatment by the conventional dosing schedule (tablet phenytoin 100-400 mg/day OD or BD, tablet carbamazepine 200-800 mg BD, or both, equally divided doses with no fixed time of drug intake), with a dose increment but no change in usual time of drug administration allowed; or to STG II (n=52), with no dose increment permitted but a shift in all or most (two-thirds or three-fourths) of the daily dose of one or both medications to 20:00 h. The 62 patients who experienced drug toxicity reactions (toxicity group, TG) and who had serum drug levels in the toxic range were assigned to TG I for dose reduction or TG II for dose reduction and drug administration at 20:00 h. Those 16 subjects in STG I and 47 subjects in STG II who initially evidenced subtherapeutic trough drug concentrations exhibited therapeutic drug levels by the end of four weeks of treatment (p<0.01). A significantly greater number of TG II, as compared to TG I, subjects who experienced toxic reactions showed improved drug tolerance. There were no poor responders and more good responders (control of epilepsy for one year) in STG II compared to STG I subjects. The findings of this study indicate that a chronotherapeutic dosing schedule of phenytoin and carbamazepine involving the administration of most or all the daily dose of medication(s) at 20:00 h can improve the response of diurnally active epileptic patients not responding to standard doses, achieve therapeutic drug levels, and reduce toxic manifestations in subjects having drug concentrations beyond the therapeutic range.     

Which drug for the adult epileptic patient: phenytoin or valproate?

A series of 140 previously untreated patients with tonic-clonic or partial seizures were randomised to receive either phenytoin or sodium valproate. There was no difference between the treatment groups in pretreatment variables that might influence outcome. Sodium valproate and phenytoin in the treatment of tonic-clonic or partial seizures showed no difference in efficacy as regards time to two year remission or time to first seizure. When the possible prognostic factors were studied, including history and results of clinical examination and investigations before treatment; the only factor which influenced the proportion of patients achieving two year remission was type of seizure. Patients with a clinical history of partial seizures did significantly less well than those with a history of tonic-clonic seizures only. This study showed no major difference in efficacy between sodium valproate and phenytoin in adults with recent onset of epilepsy, irrespective of the type of seizures that the patient suffered.     

Anticonvulsants and thyroid function.

Serum total and free thyroid hormone concentrations were estimated in 42 patients with epilepsy taking anticonvulsants (phenytoin, phenobarbitone, and carbamazepine either singly or in combination). There was a significant reduction in total thyroxine (TT4), free thyroxine (FT4), and free triiodothyronine (FT3) in the treated group compared with controls. Free hormone concentrations were lower than total hormone concentrations, suggesting that increased clearance of thyroid hormones occurs in patients receiving anticonvulsants. Detailed analysis indicated that phenytoin had a significant depressant effect on TT4, FT4, FT3, and reverse T3 (rT3). Phenobarbitone and carbamazepine had no significant main effects, but there were significant interactions between phenytoin and carbamazepine for TT4 and FT4. phenobarbitone and carbamazepine for FT3, and phenytoin and phenobarbitone for rT3.     

卡马西平与丙戊酸钠对儿童癫痫部分性发作脑电图的临床对照研究

目的:探究卡马西平与丙戊酸钠对儿童癫痫部分发作患儿发作脑电图影响,并实施组间对照研究。方法:选择2017年1月至2020年1月于我院接受治疗的81例癫痫部分性发作患儿为研究对象,按照其接受治疗的差异将其分为卡马西平组(40例)和丙戊酸钠组(41例),对比两组患儿接受药物治疗后脑电图以及脑电地形图变化情况。结果:(1)卡马西平组患儿接受治疗后脑电图检测显示间歇期痫样活动减少≥50%者占比高达67.50%(27/40),而丙戊酸钠组占比仅为43.90%(18/41),两组比较差异明显(P<0.05);(2)脑电背景活动变化比较显示,治疗后卡马西平组患儿α波无影响者占比65.00%,明显高于丙戊酸钠组36.59%,同时丙戊酸钠组患儿δ波数(20 s内)药物治疗后变化较卡马西平组更为明显;(3)脑电功率比较显示,卡马西平组患儿治疗后仅θ频段相对功率出现明显变化(P<0.05),但丙戊酸钠组患儿α频段相对功率、θ频段相对功率和θ频段绝对功率均出现明显变化(P<0.05)。结论:丙戊酸钠应用于儿童癫痫部分性发作时患儿脑电背景活动会明显变慢,甚至有出现间歇期痫样放电的风险,而卡马西平相对更为稳定,对患儿脑电图的影响更小,安全性更高。     

Absence of a general association between ABCB1 genetic variants and response to antiepileptic drugs in epilepsy patients

Over-expression of efflux transporter P-glycoprotein (PgP) encoded by ABCB1 gene has been implicated in poor responsive epilepsy. Several genetic variants have been shown to influence the expression levels of P-glycoprotein. The aim of the present study was to investigate the role of ABCB1 polymorphisms: C1236T, G2677T/A and C3435T in determining drug response to first line antiepileptic drugs (AEDs) namely phenobarbitone, phenytoin, carbamazepine and valproate in North Indian cohort of epilepsy patients. DNA samples were obtained from 392 consecutive epilepsy patients, out of which 228 had completed follow-up evaluation at 12 months. After attaining steady state of the AEDs in the first two months of study, 133 patients showed complete freedom from seizures (no-seizure group) and 95 patients continued to have seizures (recurrent-seizures group) in the remaining period of study. Comparison of “no-seizure” and “recurrent-seizures” groups revealed no significant differences in allelic, genotypic and haplotypic frequencies for all the studied variants. In conclusion, our finding disproves a general association between ABCB1 polymorphisms and drug response in epilepsy patients.     

Chronotherapeutic Dose Schedule of Phenytoin and Carbamazepine in Epileptic Patients

The objective of this study was to compare the efficacy and safety of a chronotherapeutic dosing schedule of phenytoin and carbamazepine versus a conventional dosing schedule for the treatment of tonic‐clonic epileptic patients. Of 148 epileptic subjects found to have subtherapeutic trough drug levels (subtherapeutic group, STG), 103 subjects who completed the study were randomized to either STG I (n=51) for treatment by the conventional dosing schedule (tablet phenytoin 100–400 mg/day OD or BD, tablet carbamazepine 200–800 mg BD, or both, equally divided doses with no fixed time of drug intake), with a dose increment but no change in usual time of drug administration allowed; or to STG II (n=52), with no dose increment permitted but a shift in all or most (two‐thirds or three‐fourths) of the daily dose of one or both medications to 20:00 h. The 62 patients who experienced drug toxicity reactions (toxicity group, TG) and who had serum drug levels in the toxic range were assigned to TG I for dose reduction or TG II for dose reduction and drug administration at 20:00 h. Those 16 subjects in STG I and 47 subjects in STG II who initially evidenced subtherapeutic trough drug concentrations exhibited therapeutic drug levels by the end of four weeks of treatment (p<0.01). A significantly greater number of TG II, as compared to TG I, subjects who experienced toxic reactions showed improved drug tolerance. There were no poor responders and more good responders (control of epilepsy for one year) in STG II compared to STG I subjects. The findings of this study indicate that a chronotherapeutic dosing schedule of phenytoin and carbamazepine involving the administration of most or all the daily dose of medication(s) at 20:00 h can improve the response of diurnally active epileptic patients not responding to standard doses, achieve therapeutic drug levels, and reduce toxic manifestations in subjects having drug concentrations beyond the therapeutic range.     

Recent advances in drug therapy for epilepsy.

Recent advances in drug therapy for epilepsy have contributed to the reduction in the proportion of persons whose epilepsy is uncontrolled. New knowledge of the pharmacokinetics of phenytoin has led to a better understanding of the drug''s bioavailability and uses. Carbamazepine has recently been introduced for the treatment of generalized tonic-clonic and partial seizures. Clonazepam has been found of particular benefit in the treatment of absence and myoclonic seizures. Valproic acid is a promising antiepileptic drug with broad-spectrum activity, and is particularly useful in the treatment of absence and myoclonic seizures, although further clinical experience is required before it can supplant ethosuximide as the preferred drug for the treatment of absence seizures. Monitoring of the plasma concentration of antiepileptic drugs has added greatly to the achievement of optimal drug therapy and the prevention of toxic effects.     

Outbreak of Anticonvulsant Intoxication in an Australian City

An outbreak of anticonvulsant intoxication occurred in epileptic patients in Australia during 1968-9. All affected patients studied in Brisbane were taking one brand of phenytoin. In 87% of them the blood phenytoin levels were above the therapeutic range. Reduction of phenytoin dosage relieved the intoxication in all patients. The excipient in the responsible phenytoin capsules had been changed several months before the outbreak, and this change was probably related causally to the altered blood phenytoin concentrations.     

Anticonvulsant effects of clonazepam on chemically induced convulsions

The anticonvulsant effects of two doses of clonazepam (CZP, Rivotril Roche, 0.1 and 1 mg/kg i.p.) were studied on model motor seizures induced by strychnine, bicuculline, 3-mercaptopropionic acid and metrazol in male laboratory rats (Wistar strain). In the first part the effects of different doses of the convulsants were investigated and for interaction with CZP doses were chosen after which more than 70% of the animals displayed generalized tonic-clonic convulsions (a grand mal seizure). Strychnine induced this type of seizure only: two doses (2 and 3 mg/kg s.c.) were used. CZP reduced the incidence of convulsions only after the larger dose, but plain solvent (propylene glycol, ethanol, water) was equally effective. The other substances first induced a seizure of minimal (mainly clonic) convulsions and only later a grand mal seizure. CZP was highly effective against bicuculline (3 mg/kg s.c.) and metrazol (100 mg/kg s.c.), but was less so against 3-mercaptopropionic acid. The effect on grand mal seizures was more pronounced in every case than on minimal seizures. The decisive role in the anticonvulsant effect of CZP is played by the mechanisms by which the convulsants induce epileptic manifestations. CZP is most effective against substances acting on the supramolecular complex GABA receptor (benzodiazepine receptor) chloride ionophore (bicuculline and probably metrazol).     

Reduction in polypharmacy for epilepsy.

A two-year prospective study of 40 adult outpatients with chronic epilepsy was carried out in which blood drug concentrations were monitored, and anticonvulsant polypharmacy was reduced to treatment with a single drug in 29 patients (72%). In the year after the reduction of treatment the control of seizures was improved in 16 patients (55%), unchanged in eight(28%), and worse in five (17%). Mental function was improved in 16 (55%). The main reason for failure to reduce to or maintain treatment with a single drug was exacerbation of seizures during the difficult withdrawal period, especially in patients with frequent seizures, taking several drugs, or with additional neuropsychological handicaps. It is more difficult to reduce polypharmacy than to avoid it in the first place. Polypharmacy may sometimes aggravate control of seizures.     

Low Levels of γ-Aminobutyric Acid in Cerebrospinal Fluid of Dogs with Epilepsy

gamma-Aminobutyric acid (GABA) levels were determined in cisternal cerebrospinal fluid (CSF) of 19 epileptic dogs with generalized tonic-clonic (grand mal) seizures using a radioreceptor assay. Thirty-four healthy age-matched dogs served as controls. The average CSF GABA level in epileptic dogs (40 pmol/ml) was significantly lower than that determined in controls (66 pmol/ml). Treatment with phenobarbital or primidone seemed not to affect CSF GABA levels.