Plasma Concentrations Of Antiepileptic Drugs Research Articles

EPILEPSY AND ORAL HORMONAL CONTRACEPTION-INDIAN PERSPECTIVE

There are about 50 million people with epilepsy in the world and a quarter of them are in the reproductive age group. India alone contributes to 10% of this fig. Because of the advances in therapeutic drugs, the women affected with epilepsy easily enter into reproductive life. These women like others are highly fertile and frequently need to adopt effective and safe contraceptive measures to avoid unplanned pregnancy. There are several concerns regarding the efficacy and safety of natural methods or barrier methods in women who are taking antiepileptic drugs (AED), failure of which poses a great risk to the affected person because pregnancy can result in exposure of fetus to the teratogenic effect of AEDs and also the hemodynamic changes in pregnancy can lower the plasma concentrations of AED and there can be poor seizure control. Oral hormonal pills are prescribed to epileptic women, not only for birth control but also in certain situations such as polycystic ovaries, irregular menstruation, acne and dysfunctional uterine bleeding. There are major bidirectional interactions between reproductive hormones and antiepileptic drugs which the physician should be aware of while dealing with these women. There are now enough evidence that oral contraceptive pills can reduce the efficacy of AEDs by affecting their metabolism and also AEDs by themselves may affect the contraceptive efficacy of oral pills by different pathways. Though estrogen free hormonal contraception is least likely to be effected by this nature of drug interaction, but still caution should be exercised in drug prescription as progesterone by itself has a lesser contraceptive effect and hence even slighted drug interaction too can lead to contraceptive failure. This extensive review focusses upon potential drug interactions between constituents of various oral pills and anti-epileptic drugs, the formulations available in India with different dosages for oestrogen and newer progestogens with their advantages with a special note on ormeloxifene which is exclusively marketed for birth control in Rural India. Special conditions such as contraception during lactation and emergency contraception for epileptic women are also discussed

Tablet Splitting of Antiepileptic Drugs in Pediatric Epilepsy: Potential Effect on Plasma Drug Concentrations.

Tablet splitting is the process of dividing a tablet into portions to obtain a prescribed dose of medication. Very few studies have investigated whether split parts of a tablet deliver the expected amount of drug to patients. Our objectives were to evaluate the split parts of adult-dose tablet formulations for percentage of weight deviation, weight uniformity, weight loss, drug content, and the content uniformity of four antiepileptic drugs (AEDs) prescribed to pediatric patients. We also measured AED plasma concentrations in the children. We chose to study first-line AEDs (phenytoin sodium [PHE], sodium valproate [SVA], carbamazepine, and phenobarbitone) as they are routinely prescribed in India. We asked caregivers to perform the same splitting process they follow in their homes on three whole tablets during their routine visit to the outpatient department. After caregivers split the tablets, we studied the weight and content of the split parts. We also used high-performance liquid chromatography to study plasma drug concentrations in children who had received split AEDs for at least 4months. A total of 168 caregivers participated in the study, and we analyzed 1098 split tablet parts. In total, 539 (49.0%) split parts were above the specified limit of the 2010 Indian Pharmacopeia (IP) acceptable percentage weight deviation (PHE 169 [48.8%], SVA 187 [51.9%], carbamazepine 56 [41.1%], phenobarbitone 127 [49.6%]); 456 (41.5%) split parts were outside the proxy IP specification for drug content (PHE 135 [39.0%], SVA 140 [38.8%], carbamazepine 51 [37.5%], phenobarbitone 130 [50.7%]), and 253 split parts were outside the acceptable content uniformity range of <85% and >115% (PHE 85 [24.5%], SVA 98 [27.2%], carbamazepine 14 [10.2%], phenobarbitone 56 [21.8%]). In total, 130 (72.2%) patients had plasma drug concentrations outside the therapeutic range (PHE 36 [72.0%], SVA 39 [78.0%], carbamazepine 34 [68.0%], phenobarbitone 21 [70.0%]). Splitting adult-dosage formulations of AEDs results in patients not receiving the optimal dose. Plasma drug concentrations are also not optimal. Pediatric dosage formulations should be preferred to splitting adult-dosage formulations in pediatric epilepsy.

Intrapatient variation in antiepileptic drug plasma concentration after generic substitution vs stable brand-name drug regimens

Generic substitution of antiepileptic drugs (AEDs) is still a matter of controversy and concern among clinicians and patients. We aimed to assess intrasubject variation in plasma concentrations of lamotrigine (LTG), levetiracetam (LEV) and topiramate (TPM) after generic substitution compared with a stable brand-name drug regimen in a population of patients with epilepsy. A retrospective analysis was performed on prospectively collected and stored data from our therapeutic drug monitoring (TDM) database for the years 2009–2014. The main outcome variable was the proportion of patients who, after switching from branded to generic formulations, showed a greater than ±20% change in AED plasma concentrations compared to the proportion of control patients showing a change in AED plasma concentrations of the same extent while receiving stable branded formulations over repeated TDM tests. Fifty patients on LTG, 27 on LEV and 16 on TPM showing at least one TDM test while receiving generic products fulfilled the inclusion/exclusion criteria for the analysis and were compared with 200 control patients for LTG, 120 for LEV and 80 for TPM. The proportion of patients showing an intrasubject change greater than ±20% in AED plasma concentrations was similar in the brand name vs generic group compared with the control one for LTG (22% vs 33%) and LEV (44% vs 38%), while it was higher in the control group for TPM (41% vs 6%, p<0.01). These are the first data in the literature about the within-patient variation in steady-state plasma concentrations of a series of stable treatments with brand-name AEDs in a real clinical setting. In conclusion, a significant interday variability in intrapatient LTG, LEV and TPM plasma concentrations can be observed even in patients stabilized with the same brand name product over time. This suggests that any change in plasma AED concentration and possible related clinical effects after generic substitution may be not necessarily related to the switch. Our results should be confirmed by large, prospective, blinded, randomized controlled studies in people with epilepsy.

P34 – 2727: Optimization of approaches in treatment of patients with epilepsy

Objective Optimization of adequate plasma concentrations of antiepileptic drugs (AED)s to achieve a prolonged and sustained remission of epilepsy. Methods The study is based on the results of a survey of 40 patients with epilepsy, varying in age debut, duration and etiology of the disease, clinical phenomenology of seizures, but all of them taking carbamazepine as AED. Conducted therapeutic drug monitoring (TDM), MRI, EEG. Results The majority of patients were between the ages of 1 to 5 years of life 52.5%. Selection criteria were the children taking AEDs for at least 3 months. Therapeutic range of carbamazepine concentration is 4–12 mkg/ml, toxicity develops at the level of circulating carbamazepine above 15 mkg/ml TDM allowed to establish causes of no adequate treatment strategy, such as, prescribing AEDs in unreasonable low doses, the appointment of two and more AEDs from different groups without regard to their pharmacokinetic interactions, that caused subtherapeutic drug levels in the blood serum in 33 (82.5%) cases. Level of drugs was at the recommended therapeutic range in 6 (15%) cases, which directly reflects the high individual variability between the received dose and drug levels in the blood. Feedback was analyzed assignable dose of drugs in mg per patient's weight with its concentration in blood plasma. In patients with low drug concentration in blood plasma confirmed adequate calculation of the drug per body weight. Its once again confirm individual tolerability of each patient and the presence of unknown causes which impact on the drug perception, such as helminthes, enzymes deficiency, lack of the liver functional activity and not identified blood minerals. Conclusion Treatment correction on the basis of TDM in patients with various forms of epilepsy lead to the decreasing of the attacks frequency. Clinical positive trend was confirmed by EEG data.

The effect of combination therapy on the plasma concentrations of traditional antiepileptics

The present study aimed at determining the differences in plasma concentrations of traditional antiepileptics such as phenytoin, carbamazepine, and valproic acid in patients receiving monotherapy and combination therapy. In addition, the effect of gender and age on plasma drug concentration was evaluated in these patients. For this purpose, plasma trough concentrations obtained during routine therapeutic monitoring of these drugs were assessed retrospectively. The average plasma concentrations reached the apparent therapeutic ranges, except for the average plasma concentration of phenytoin, which was below the therapeutic range in patients who received only phenytoin or in combination with the other agents. Phenytoin when combined with carbamazepine or valproic acid significantly decreased the average plasma concentrations of these drugs to subtherapeutic concentrations. The results showed that plasma carbamazepine concentrations were higher in men than in women, whereas plasma concentrations of valproic acid and phenytoin were higher in women than in men. The difference in this regard between men and women was found to be statistically significant for phenytoin. The difference between the average plasma concentrations of carbamazepine, phenytoin, and valproic acid among age groups was not significant. In conclusion, our study measured the average plasma antiepileptic drug concentrations in patients with epilepsy who were receiving monotherapy and combination therapy and were routinely monitored, and has thus shown the importance of drug monitoring in the evaluation of the effectiveness of these drugs.

Safety and tolerability of dapsone for the treatment of patients with drug-resistant, partial-onset seizures: an open-label trial

Dapsone has shown anti-convulsive properties in animal models of epilepsy. In the present study, we tested the safety and tolerability of dapsone as adjunctive therapy in adult patients with drug-resistant partial-onset seizures. Twenty-two adult patients with drug-resistant partial-onset seizures were included. After a 3-month baseline period, patients received dapsone 100mg per day, for a 3-month evaluation period. Plasma concentrations of anti-epileptic drugs (AEDs) did not significantly change during the study. No alteration of mean clinical laboratory values was observed. The reported adverse events were: mild methemoglobinemia (50%), headache (31.8%), paleness (27.3%) and somnolence (4.5%).Sixteen of 22 patients reduced their seizure frequency in more than 50% as a result of dapsone treatment. Three subjects remained seizure-free during the entire dapsone treatment period. This open-label study of adjunctive dapsone therapy at 100mg/day suggests that dapsone is safe, and well-tolerated in adults with drug-resistant partial-onset seizures.

Valproic acid and phenobarbital blood levels during the first month of treatment with the ketogenic diet

The aim of this study was to assess how the ketogenic diet influences the blood levels of antiepileptic drugs in the first month of treatment in a pediatric population with drug-resistant epilepsy. The plasma concentrations of antiepileptic drugs were investigated in an open study on 36 consecutive children and adolescents (20 males), aged between 6 months and 16 years (mean age 4.7 years), who were put on the ketogenic diet because of medically refractory epilepsy. The plasma levels of antiepileptic drugs were determined 30 days and immediately before the diet and on days 8, 15, 22 and 29 after the start of the diet. The daily dose of each drug was not changed during the first month of treatment, while the daily dose of benzodiazepines was reduced by up to 30% if excessive sedation or drowsiness occurred. While plasma concentrations of phenobarbital did not change in the first month on the ketogenic diet (mean increase of 2.3 mg/l ± 1.0), valproic acid showed a slight but not significant decrease (mean decrease of 6.7 mg/l ± 3.2), 2 weeks after the start of the diet. Adjustments in the daily dose of either drug before the start of the diet do not however appear to be justified.

Effect of sildenafil on the anticonvulsant action of classical and second‐generation antiepileptic drugs in maximal electroshock‐induced seizures in mice

The goal of the present study was to evaluate the effects of sildenafil on the threshold for electrically induced seizures in mice. In addition, interactions between sildenafil and classical and second-generation antiepileptic drugs (AEDs), that is, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC) were evaluated. Two electroconvulsive tests were used: maximal electroshock seizure threshold (MEST) and maximal electroshock seizure (MES) tests in mice. Acute adverse effects of the studied combinations were investigated in the chimney test, step-through passive avoidance task, and grip-strength test. Total brain and free plasma concentrations of AEDs were also determined. Sildenafil raised the threshold for electroconvulsions in a dose-dependent manner. It also increased the anticonvulsant activity of CBZ, VPA, and TPM in the MES test, whereas the activity of the remaining AEDs was not significantly changed. Sildenafil increased total brain and free (protein unbound) plasma CBZ concentrations and total brain VPA concentration. Neither sildenafil nor its coadministration with the studied AEDs affected motor coordination and long-term memory in mice. Interestingly, sildenafil dose-dependently enhanced the skeletal muscle strength in mice, although combinations of sildenafil with AEDs were ineffective in this respect. Sildenafil significantly raised the threshold for electroconvulsions in mice without any impairment of motor performance and long-term memory, but it enhanced muscle strength. Treatment of patients on CBZ or VPA with sildenafil may not be recommended due to pharmacokinetic interactions. Coadministration of sildenafil with other AEDs, especially with TPM, seems to be a reasonable choice.

Pregnancy and epilepsy: what should we tell our patients?

Women with epilepsy that plan to become pregnant can in general look forward to uneventful pregnancies and to giving birth to normal children. However, there are certain risks associated with epilepsy and antiepileptic drug (AED) treatment, and it is likely that these risks can be reduced with appropriate prepregnancy counseling. Women with epilepsy should be informed that maintained control of tonic-clonic seizures is important for their health as well as for the well-being of the fetus; that pregnancy in general has little effect on seizure control; but that pregnancy may affect plasma concentrations of AEDs, and that drug level monitoring and dosage adjustments may be needed. They should be informed of the moderately increased risk of birth defects, and that this risk appears to be higher with the use of valproate, in particular at doses above 800 mg/day. The possibility of changing from valproate to another AED should be considered, but such changes should be tried out before conception. Withdrawing or changing an AED should generally be avoided during pregnancy. Women with epilepsy on AED treatment should be encouraged to breast-feed.

Importance of monotherapy in women across the reproductive cycle

Special treatment considerations are warranted in women with epilepsy, particularly those of childbearing age. Treatment guidelines generally recommend the use of antiepileptic drug (AED) monotherapy at the lowest dose possible during pregnancy. The UK Epilepsy and Pregnancy Register reported that the risk for major congenital malformations is higher with AED polytherapy than with monotherapy (6.0% vs 3.7%, respectively) and that valproate carries the highest individual risk. The AEDs that induce hepatic cytochrome CYP450 enzymes carry particular concern both before and after pregnancy. Hepatic enzyme inducers alter steroid metabolism in women receiving oral contraceptives, increase the risk for contraceptive failure, and interfere with calcium absorption and vitamin D metabolism, thus increasing the risk for osteoporosis and fractures. Vitamin K deficiency is another potential consequence of treatment with a hepatic enzyme-inducing AED, increasing the risk for coagulopathy and neonatal intraparenchymal and intracerebral hemorrhage during the first 24 hours of life. Supplemental vitamin K therapy during the last month of pregnancy is warranted. Preconceptional and gestational folate supplementation may also be warranted to prevent neural tube malformation related to AED treatment. Because AED pharmacokinetics may be altered during pregnancy, plasma AED concentrations should be measured before conception and monthly during pregnancy to prevent seizure breakthrough.

Plasma Levels of Antiepileptic Drugs in Children on the Ketogenic Diet

Influence of the ketogenic diet on plasma concentrations of antiepileptic drugs was investigated in an open clinical study of 51 children (mean age 6.6 years) with medically refractory epilepsy. The plasma levels of concomitantly used antiepileptic drugs were determined immediately before and 3 months after initiating the ketogenic diet. To compensate for adjustments in dosing, the plasma concentration in relation to the dose per kilogram of body weight per day, i.e. the level-to-dose ratio, was used for comparison; it was calculated as the plasma concentration (micromol/L) divided by the corresponding weight-normalized dose (mg/kg body weight/day) for each drug and child. The level-to-dose ratios of each drug before and during the diet were compared. No significant changes in these ratios could be found for valproic acid, lamotrigine, topiramate, clonazepam, or phenobarbital. In 16 children, the ratio of the free unbound concentration of valproic acid to its total plasma concentration was compared before and during the diet, but it did not change significantly. Thus, the ketogenic diet did not change the plasma concentrations of commonly used antiepileptic drugs in children in any significant way. Therefore, when initiating the diet, it does not seem necessary to adjust drug doses due to pharmacokinetic interactions.

Carbamazepine extended-release capsules vs. oxcarbazepine: computer simulations of the effect of missed doses on drug plasma concentrations

ABSTRACTObjective: Plasma concentrations of antiepileptic drugs (AEDs) can vary and are not always an indication of clinical utility. However, adverse event occurrence can be correlated to fluctuations in plasma drug levels that occur with varying dosing regimens of the many AEDs. In this study, we present the results of computer simulations of plasma concentrations of the AEDs carbamazepine (CBZ) extended-release capsules (CBZ‐ERC) (Carbatrol) and oxcarbazepine (OXC).* Carbatrol is a registered trade name of Shire, Wayne, Pa, USAResearch design and methods: A one-compartment open model with first-order absorption and elimination was generated from the results of a previous study measuring plasma concentrations following one 400 mg fasting dose of CBZ‐ERC. This model was used to simulate plasma concentrations of CBZ following multiple 400 mg doses of CBZ‐ERC at 12-hour intervals, and then when a missed dose is taken 3, 6, or 9 hours late; when two doses are taken at one time; and when a single dose is taken at the time of the next dosing. In comparison, similar modeling was done for monohydroxy derivative (MHD) of OXC at doses of 600 or 1200 mg.Results: Plasma drug concentrations after 24 hours without medication were 4.1 mg/L for CBZ‐ERC, 8 mg/L for 600 mg OXC, and 16 mg/L for 1200 mg OXC. If a patient was to take only a single dose 24 hours late, it would take 24 hours to reach steady-state trough values for CBZ‐ERC, 36 hours for 600 mg OXC, and 2 days for 1200 mg OXC. The trough plasma concentration following a missed dose and the peak plasma concentration following a double dose (administered 12 hours after the missing of a dose) differed by a factor of two in the CBZ‐ERC simulation, compared with a factor of three in both OXC simulations.Conclusions: The ultimate goal of antiepileptic therapy is a seizure-free state without side effects. The current computer simulation study indicates that AEDs such as CBZ‐ERC and OXC, which produce relatively stable plasma concentrations, should be useful in attaining this goal. Nonetheless, simulated plasma concentrations resulting from CBZ‐ERC treatment tended to oscillate less dramatically compared with simulated plasma concentrations resulting from treatment with 600 or 1200 mg OXC.

Interactions between non-barbiturate injectable anesthetics and conventional antiepileptic drugs in the maximal electroshock test in mice—an isobolographic analysis

The aim of this study was the isobolographic evaluation of interactions between three non-barbiturate intravenous anesthetics and conventional antiepileptic drugs in the maximal electroshock-induced seizures in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Plasma levels of antiepileptic drugs were measured by immunofluorescence. Obtained results indicate that ketamine acts synergistically with valproate and carbamazepine. Also the combinations of propofol and valproate or phenobarbital led to synergistic interactions. An antagonism was found between etomidate and carbamazepine or phenobarbital. On the other hand, interactions between diphenylhydantoin and injectable anesthetics proved to be additive. The only exception was the combination of diphenylhydantoin and propofol (1:3). Pharmacokinetic phenomena do not seem to interfere with the observed interactions, since none of anesthetics influenced the free plasma concentrations of antiepileptic drugs. Referring to undesired effects, only propofol impaired long-term memory. Although propofol did not disturbed motor coordination, it enhanced motor impairment caused by carbamazepine and diphenylhydantoin. Results of the present study suggest that etomidate needs to be avoided in epileptic patients due to a possibility of negative interactions with some antiepileptic drugs and seizure precipitation.

Interaction of antiepileptic drugs with human P-glycoprotein in vitro.

About one-third of epilepsy patients are resistant to treatment with antiepileptic drugs (AEDs). This refractoriness is not fully understood, but is thought to be attributed to overexpression of multidrug transporters at the blood-brain barrier, particularly P-glycoprotein (Pgp). In certain cases pharmacoresistance can be overcome by add-on therapy, raising the question of whether the coadministered drugs act as inhibitors of Pgp. Indeed, several AEDs are substrates and to some extent also inducers of Pgp. To date nothing is known about possible Pgp inhibitory activities of AEDs. Therefore, we investigated whether AEDs commonly used in mono or add-on therapy inhibit Pgp using a calcein acetoxymethylester uptake assay with L-MDR1 cells and primary porcine brain capillary endothelial cells, as well as confocal laser-scanning microscopy with L-MDR1 cells and bodipy-verapamil as Pgp substrate. In the calcein assay only carbamazepine inhibited Pgp, which was confirmed in confocal laser-scanning microscopy. In this assay, also phenytoin, lamotrigine, and valproate revealed Pgp inhibitory potency. Because Pgp inhibition by AEDs appeared at significantly higher concentrations than that of well known inhibitors and because the effective concentrations exceeded therapeutic AED plasma concentrations, Pgp inhibition appears not to be of clinical relevance, at least in antiepileptic monotherapy. However, it is possible that this inhibition may contribute to the effectiveness of certain add-on therapies.

Assessment of teratogenic risk

Although the association between prenatal exposure to old generation antiepileptic drugs (AEDs) and major congenital malformations has been studied for many years, it is not clear whether any specific AED, or AED combination, is more harmful than others, or whether any pattern of malformations can be considered specific for any given drug. Relationships between dosage and plasma concentrations of AEDs and the risk of malformations also need to be clarified. The greatest limitation of all studies performed to date is the fact that none included a sufficiently large number of pregnancies. For newer generation AEDs the teratogenic risk, if any, is unknown. Large prospective studies are needed. The best approach is the establishment of registries through international collaboration. Inclusion of non-epileptic controls and untreated women is not strictly necessary to evaluate the comparative teratogenic risk of AEDs. The modalities of data collection should be pre-defined; common protocols, sufficiently exhaustive but at the same time easy to perform, should be shared from the beginning. Information on the presence or absence of major malformations or prenatal growth retardation, and on all major factors that may affect the teratogenic endpoints should be obtained. Study designs should ensure high quality data recording, and adequate quality assurance and auditing procedures. Further requisites are a clear definition of congenital malformation and prolonged follow-up to detect the occurrence of congenital malformations not detected at birth.

Rational polypharmacy

The development of assays for plasma antiepileptic drug concentrations has led to the discovery of many pharmacokinetic interactions, some causing drug intoxication and others resulting in ineffective drug concentrations. In the 1970s, a number of epileptologists began to argue that single drug therapy was desirable in the treatment of epilepsy and this has become the accepted policy when initiating therapy. About 75% of patients treated in this way will achieve remission with a minimum of adverse drug reactions. The remainder, however, continue to have unacceptable seizures and usually receive combinations of drugs. Evidence indicates that the response rate on adding a second drug is low, although in some studies of new drugs such as vigabatrin up to one-half of patients receiving add-on therapy experience a 50% or greater reduction in seizure frequency, and 10-15% are seizure-free in the short term. Unfortunately, randomized placebo-controlled studies have not been undertaken to compare the relative merits of monotherapy and combination therapy with respect of seizure control and adverse effects. It is argued that the time has come to do so, particularly in view of the known mode of action of some of the new drugs. Perhaps blocking excitation with one drug at the same time as enhancing inhibition with another may be better than doing only one or the other.

The Management of Epilepsy in the 1990s

The pharmacological treatment of epilepsy has made considerable progress during the last decade, due to improved knowledge of the clinical pharmacology of individual drugs, acquisition of new information on the factors affecting response and need for drug treatment, and development of promising new agents. Once a clinical diagnosis of epilepsy has been made (which generally requires the occurrence of more than one seizure), treatment should be started with a single drug selected on the basis of seizure type and tolerability profile. Although there are important regional differences in prescribing patterns and individual circumstances may dictate alternative choices, carbamazepine is generally regarded as the preferred treatment for partial seizures (with or without secondary generalisation) while valproic acid (sodium valproate) is usually the first choice in most forms of generalised epilepsies. To achieve therapeutic success, the daily dosage must be tailored to meet individual needs, and there is suggestive evidence that in some patients the dosage prescribed initially may be unnecessarily large. Plasma antiepileptic drug concentrations may aid in the individualization of dosage, but should not be regarded as a substitute for careful monitoring of clinical response. Although overall about 70% of patients can be completely controlled, response rate is influenced by a number of factors, the most important of which are seizure type and syndromic form. The importance of a correct syndromic classification for rational drug selection has been poorly assessed and represents a major area for future research. Patients who do not respond to the highest tolerated dose of the initially prescribed drug may be switched to monotherapy with an alternative agent or may be given add-on treatment with a second drug. Appropriate prospective trials are required to assess the merits of either strategy. If add-on therapy is selected and the patient becomes seizure free, it may be possible to discontinue the drug prescribed initially and reinstitute monotherapy. Only a minority of patients are likely to require multiple drug therapy, and it remains to be established whether specific drug combinations are more effective than others. Until further information becomes available, the new agents should be reserved for patients failing to respond to the conventional treatments of first choice. Patients whose seizures cannot be controlled by available drugs should be reassessed, and polytherapy should be maintained only when there is clear evidence that benefits outweigh possible adverse effects. In many patients who have been seizure free for at least 2 years it may be possible to gradually discontinue all medications.(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma Antiepileptic Drug Monitoring in a Neurological Practice

Rates for being free of all epileptic seizures for at least 1 year and for ceasing therapy after 3-5 years of full seizure control were similar in 548 treated epileptic patients referred from 1962 to 1970, during which period plasma antiepileptic drug concentration monitoring became available (32.7 and 17.0%, respectively), in 960 patients referred from 1971 to 1979, when such monitoring was used increasingly (29.6 and 14.9%, respectively), and in 348 patients referred from 1980 to 1989, when this monitoring was widely available (30.5 and 10.1%, respectively). However, monitoring was associated with higher rates of full seizure control in patients seen within 6 months of their first seizure, even when patients with only a solitary seizure were excluded. Possibly, monitoring then helped achieve early complete suppression of not yet established seizure processes, but had less effect on already entrenched seizure mechanisms. Plotting cumulative percentages of patients with fully controlled seizures versus plasma antiepileptic drug concentrations yielded data that were broadly in keeping with conventional 'therapeutic' ranges for phenytoin, carbamazepine, phenobarbital, and ethosuximide monotherapy. With a given plasma phenobarbital (but not phenytoin or carbamazepine) concentration, rates of full seizure control were appreciably higher for generalized onset than for partial onset seizures. Use of a second antiepileptic drug was associated with improved full seizure control in both generalized onset and partial onset seizures, which had not been controlled by monotherapy; adding a third drug yielded little further benefit.

Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin.

Seizure control and plasma concentrations of antiepileptic drugs (AEDs) were determined in a prospective, population-based study of 93 pregnancies (cases) of 70 patients with epilepsy. Seventy-seven cases were treated with monotherapy, which in 70 cases consisted of carbamazepine (CBZ) or phenytoin (PHT). Dosage was kept constant unless poor seizure control prompted an increase. Plasma concentrations were determined at monthly intervals throughout pregnancy and compared with baseline levels obtained at least 10 weeks postpartum. Both free and total CBZ and PHT concentrations were analyzed. Seizure frequency during pregnancy for the group as a whole was not different as compared with the 9 pregestational months and was unaltered or improved in 85% of cases. Total CBZ concentration was slightly lower during the third trimester as compared with baseline, whereas free concentration was unchanged. In contrast, PHT levels decreased steadily as pregnancy progressed. Total plasma concentration was 39% of baseline during the third trimester, whereas free PHT concentration decreased far less, being 82% of baseline level during the third trimester. No clear-cut relation could be demonstrated between seizure control and plasma concentrations, which may be explained by the limited changes in free AED concentrations and the small number of cases with an increased seizure frequency. Our results indicate that total plasma concentrations may be misleading and that monitoring of free concentrations, in particular of PHT concentrations, may be advantageous during pregnancy.

Risks of pregnancy in women with epilepsy.

Pregnant women with epilepsy are at increased risk of seizures and complications. An increase in seizure frequency is seen in 25-30% of pregnant women with epilepsy; the offspring of mothers who experienced seizures during pregnancy are at a 2.5 times higher risk for seizures later in life. One of the main reasons for the increase in seizures during pregnancy is a decline in plasma concentrations of antiepileptic drug (AED) that occurs as pregnancy progresses, largely as a result of marked alterations in plasma protein binding. It is well known that epilepsy represents a risk for a variety of adverse pregnancy outcomes or malformations, especially in polytherapy. The adverse outcomes range from dysmorphic features to hemorrhagic disorders resulting from a deficiency of vitamin K-dependent clotting factors or to spina bifida. Folic acid supplements appear to reduce the risk of spina bifida. A strong genetic link seems to exist for many of the malformations that occur, and more research is required in this field. In the meantime, there are interventions that clinicians can already make to reduce the risk of adverse outcomes, such as seizure control without toxicity, monotherapy, and preconceptual use of vitamins with folate.