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A 68-year-old woman tried to commit suicide using phenobarbital, which was initially prescribed for her dog that suffered from seizures. At admission she was unconscious and ventilated. Five days of intensive care therapy did not improve her state of consciousness. Subsequent continuous veno-venous hemodialysis accelerated the elimination of phenobarbital compared to endogenous elimination by a factor of five. The patient survived without sequelae. Detailed history taking and well-timed indication for dialysis were crucial.

A case of pregabalin misuse associated with delusional ideas in a drug addict is reported. Pregabalin has been approved as an adjunct therapy for epilepsy, but also for neuropathic pain and generalized anxiety disorders and is widely used today. It has also been used in clinical trials to study its potential utility as a treatment for tobacco, alcohol and benzodiazepine addiction. Web sites, case reports and an epidemiological study (Swedish National Register of Adverse Drug Reactions) suggest that the drug may be abused, especially by substance-dependent individuals. Pregabalin was analyzed by LC/MS/MS following precipitation of serum proteins. Vigabatrin was used as internal standard. The concentration of 25 pg pregabalin/mL serum determined in the present case is the second highest value published so far after misuse of the substance. Due to paradoxical agitation, anxiety attacks and abnormal thinking, the man was exculpated. Further studies are required to assess the actual abuse potential of pregabalin.

We evaluated factors possibly influencing serum concentrations of levetiracetam (LEV-SC). The study included 163 patients with epilepsy (91 men, 72 women; mean age 39.6 years). The duration of treatment on first analysis was 226 days; the mean daily dose amounted to 2,434 mg. In each patient between one and seven measurements were carried out (mean 2.2). LEV-SC significantly depended on daily dosage and the interval between the time the medication was taken and the time of blood extraction. A marked drop in LEV-SC was observed 4-5 h following ingestion. Carbamazepine, oxcarbazepine and clobazam reduced LEV-SC, whereas valproate elevated LEV-SC significantly. When assessing evaluation of compliance these factors have to be taken into consideration when comparing intraindividual LEV-SC.

An increasing number of second-generation antiepileptic drugs have become available as generics. There is an ongoing debate as to whether this opens up ways to save costs or if efficacy and tolerability of an established treatment are at stake. We here present a retrospective analysis of outpatients treated with lamotrigine regarding the frequency of treatment switches and its effects on seizure control and tolerability. In 13 of 285 patients under treatment with lamotrigine the prescribed drug was changed; in 6 of these seizure relapse occurred after a period of 3 months to 6 years of seizure freedom and 3 patients experienced new side effects. Compared to matched controls, the risk for loss of seizure control was significantly elevated by a factor of 17; adverse events were three times more frequent (n.s.). Consecutive determinations of serum levels suggest that these problems were related to changes in the pharmacokinetics of different formulations. Frequent problems related to a switch of medication are discussed under medical and socio-economic aspects.

Lacosamide (Vimpat) is an aniepileptic drug with a new, dual mode of action. Lacosamide enhances slow inactivation of voltage-gated sodium channels and modulates the collapsin response mediator protein-2 (CRMP-2), a protein, which is part of neuronal signal transduction pathways and which is attributed to neuroprotection. Reduction of seizure frequency could be demonstrated in several clinical studies in patients with partial-onset seizures who received lacosamide in addition to other antiepileptic drugs.

The indication and management of an appropriate therapy with antiepileptic drugs (AEDs) requires an individualized diagnostic evaluation considering the clinical situation. Based on the current scientific data the therapeutic options and special aspects of the available AEDs are discussed with emphasis on the possibility of rapid initiation (therapeutic loading doses on day 1) or need of slow uptitration over several days or weeks in the context of different clinical situations. A sudden discontinuation or withdrawal of AEDs is only justified due to life-threatening side effects or for diagnostic purposes in the context of a presurgical workup. The debate on the appropriate time for a slow AED discontinuation (over a few weeks or several months) is still ongoing.

Experts from epileptology and psychiatry reviewed the current significance of therapeutic drug monitoring (TDM) of antiepileptic drugs and psychiatric drugs in a workshop at Bethel Epilepsy Centre in December 2005. TDM has been essential in epileptology for about 30 years, and it is also increasingly important in psychiatry, in which consensus recommendations were published recently. With regard to cost-cutting in the health system, there are discussions about the financial effect of TDM and outsourcing it to bigger laboratories. In psychiatry it has however been shown that sensibly used TDM may lead to reduced costs. Many issues in TDM require the knowledge and experience of specialised laboratories. The use of TDM data for scientific purposes was discussed at the workshop as well.

After months of successful analgesic therapy with oxcarbazepine, a 52-year old woman with trigeminal neuralgia suddenly experienced episodes of heavy trigeminal attacks regularly in the evening at about the same time. Asked about changes in daily life or eating habits, she reported the ingestion of healing earth daily in the morning. After stopping the ingestion of healing earth, analgesic control of trigeminal neuralgia was restored without any changes of the initial pharmacotherapy. In daily practice, interactions which significantly influence the absorption of drugs are often overlooked. The documentation of these interactions in drug interaction databases, in the prescribing information, and in the literature is sparse though clinically relevant. Separating the ingestion of interacting substances by a time interval may not sufficiently avoid the interaction in every case. Particular caution is warranted when slow-release cation containing drugs or substances with entero-hepatic circulation are used.

We report a female patient who was admitted to the emergency ward with suspected cerebral ischemia and in whom transvenous clot lysis was performed. Following lysis the patient developed recurrent complex partial seizures and treatment with intravenous phenytoin was started. Initial phenytoin serum levels were within the therapeutic range. During the course of the in-hospital treatment a sudden fall of phenytoin serum levels was detected and could not be explained by pharmacokinetic changes. Only when the drug application process was further analysed the reason for the fall in serum levels became obvious. Phenytoin sodium injections had not been administered directly into the veins but had been diluted in 0.9% saline infusions. As a result phenytoin sodium injections precipitated and were retained by the particle filter, thus leading to subtherapeutic phenytoin serum levels.

A 22-year-old female with a history of developmental delay and seizures successfully treated with carbamazepine and levetiracetam developed fulminant hepatic failure and subsequently died. She had been admitted to the hospital following secondary generalized seizures of 35 min duration. A circulatory shock as well as intoxication was taken into consideration during the clinical course. Autopsy failed to reveal a macroscopically discernible cause of death. Significant findings on microscopic examination included acute tubular necrosis in the kidneys, pre-existing marked accumulation of neutral lipid within the hepatocytes as well as hyperacute liver damage with evidence of almost complete hepatocyte necrosis. Carbamazepine and levetiracetam were simultaneously determined from blood and tissues such as liver, lungs, muscle and kidneys by LC-MS/MS following addition of lamotrigine as an internal standard and liquid-liquid extraction. Validation data are given for levetiracetam. Both carbamazepine and levetiracetam were present in blood at concentrations within or below the therapeutic range, respectively. Moreover, tissue concentrations suggested long-term administration of anticonvulsant drugs, which is in accordance with the medical history. After excessive drug concentrations could be ruled out, the metabolic consequences of a prolonged carbamazepine therapy to cause severe hepatic injury in the present case are discussed. A mechanism of injury to the hepatocytes may be membrane damage by either an increased production of free radicals and/or a decreased free radical scavenging capacity. Following ischemia with reperfusion and during hyperthermia, large amounts of free radicals are formed. Induction of the mixed oxidase activity during longterm administration of carbamazepine may also increase production of free radicals, leaving the hepatic cell more vulnerable to oxidative injury.

Drug interactions with antiepileptic agents are based in large part on pharmacokinetic mechanisms. Most prominent are induction or inhibition of enzymes of the cytochrome P450 (CYP) system, which is of central importance for metabolic elimination of lipophilic xenobiotics. Potent inductors of CYP isoenzymes are carbamazepine, phenobarbital, phenytoin, and primidone, thereby decreasing not only their own plasma levels and efficacy but also that of other antiepileptics and other drugs. Felbamate, oxcarbazepine, and topiramate are weak inductors of the CYP isoenzyme 3A4, whereas they inhibit CYP2C19. Valproic acid is a potent inhibitor of several CYP isoenzymes and glucuronyltransferases, resulting in an increase in plasma concentrations and toxicity of antiepileptics and other drugs. Antiepileptics that are not involved in drug interactions include gabapentin, levetiracetam, and vigabatrine. The P-glycoprotein may mediate the exit of antiepileptics from the brain. This transport mechanism is inhibited by carbamazepine, which may explain the enhanced clinical efficacy of a combination of carbamazepin with other antiepileptics. Other possible pharmacokinetic interactions are precipitation of antiepileptics in the stomach by antacids or sucralfate and displacement from plasmaprotein binding of one antiepileptic agent by another. Therapeutic drug monitoring (TDM) may be helpful in assessing pharmacokinetic drug interactions. Pharmacodynamic interactions appear to be responsible for the enhanced efficacy of antiepileptic combination therapy. In prescribing drugs, their spectrum of interactions has to be known.

Oxcarbazepine (OXC, trade names Timox, Trileptal is a new antiepileptic drug (AED) for treatment of mono- and adjunctive therapy of partial seizures with or without secondary generalization for adults and children older than 6 years of age. Although OXC was developed through structural variation of carbamazepine in order to avoid side effects from metabolites, significant differences have emerged between the two drugs. The mechanism of action mainly involves blockade of sodium currents but differs from CBZ by modulating different types of calcium channels. In contrast to CBZ, which is oxidized by the cytochrome P-450 system, OXC undergoes reductive metabolism at its ketomoiety to form MHD, which is glucuronidated and excreted in the urine. Involvement of the hepatic cytochrome P450-dependent enzymes in the metabolism of OXC is minimal. This allows for better combining of OXC with other AEDs such as valproate. In postmarketing experience of over 800,000 patient-years, OXC also showed an advantageous risk-benefit ratio. Oxcarbazepine should be preferred over CBZ and other older AEDs due to its very good efficacy and better side effect profile in children, adolescents, and adults with partial seizures.

The manuscript deals with the tolerability of Lamotrigine in women. The recent literature is reviewed with respect to interactions with oral contraceptives, sexuality, infertility, interactions with sex hormones, polycystic ovarian syndrome, adipositas, cosmetic side effects, osteoporosis, pregnancy, breast feeding, and teratogenetic effects. The available data have practical implications for the safe use of Lamotrigine in women.

The therapeutic value of anticonvulsants in affective and schizoaffective disorders was documented in several clinical trials. Oxcarbazepine (OXC), a keto-derivative of carbamazepine, which appears to have a preferable side effect profile compared to carbamazepine, has also shown antimanic efficacy in affective and schizoaffective disorders in clinical studies since the early 80's, but was not further investigated regarding these indications. Therefore, the value of OXC in the treatment of affective and schizoaffective disorders requires evaluation. Literature was reviewed with regard to pharmacokinetic and pharmacodynamic characteristics of OXC, drug-drug interactions relevant in pharmacopsychiatry, and clinical effects in these disorders. According to the literature OXC is regarded effective in acute mania and appears to allow reduction of the neuroleptic medication required for the treatment of affective and schizoaffective disorders. In addition, it has a preferable pharmacokinetic profile with less severe side effects compared to other anticonvulsants and neuroleptics. Furthermore, it appears to be well tolerated if augmented to neuroleptics or antidepressants, since OXC does not interact substantially with the cytochrome P450-enzyme-system. However, despite promising effects of OXC, few clinical studies have been published in the last 16 years. We conclude that further studies should validate the antimanic efficacy of OXC and evaluate possible pharmacopsychiatric indications as well as limitations of this psychotropic compound.

Some important aspects of the therapy of epilepsies are treated. The practitioner is often confronted with an acute epileptic attack: guidelines for the management are given. As recurrences are not too frequent, treatment usually is only begun after a second seizure and the diagnosis must be confirmed. Compliance is of utmost importance, it can be improved by good advice and guidance. Recommendations for starting and stopping treatment are given. Pregnancy is a particular challenge. Most women can give birth by natural ways and have healthy children. Sudden unexpected death is a rare but important problem, mostly in connection with an attack.

The pharmacological treatment of epilepsies represents an important domain of neurological therapeutical strategies and is not only important for specialized epilepsy centres, but for all hospital -and office-based neurologists. The choice of the right anticonvulsive drug is not always simple since the development of new drugs during the last 10 years offers a broad range of possibilities. Therefore, pharmacological treatment has become more sophisticated than it was with relatively few anticonvulsive drugs before. The new drugs are better tolerated and have less side effects, but more knowledge is required about the specific aspects of each drug. Pharmacology, pharmacocinetics, indication, dosage and side effects of the substances will be summarized and discussed.

There is little knowledge about the effects of topiramate in intellectually impaired epileptic patients. This open prospective study compares seizure frequencies during a 3-month period of topiramate add-on therapy (after 3 months of titration) compared with a 3-month baseline period. An intention-to-treat analysis was made on the first 24 consecutive topiramate-treated adult patients (residents of the Bethel epilepsy centre, therapy-resistant epilepsy, intellectual impairment of different degrees, one half with neurological deficits). The responder rate (at least a 50% reduction in seizure frequency) was 37.5%. One patient became completely seizure-free during post-evaluation (up to 24 months). Efficacy was not different between different epileptic syndromes or seizure types (case number too small). Responders had topiramate dosages above 200 mg/day and serum concentrations above 2.2 micrograms/ml. Six patients (25%) experienced serious neuropsychiatric complications such as confusion and severe deceleration of thinking and acting, up to complete helplessness (at topiramate dosages from 50 mg/day to 900 mg/day and serum concentrations from 2.2 micrograms/ml to 8.0 micrograms/ml). Preexisting brain damage may enhance the risk of unwanted central nervous effects.

We examined whether high dose carbamazepine (CBZ) monotherapy (CBZ serum levels > 9 mg/l) is well tolerated. Forty-one patients with localisation-related epilepsy were enrolled. They received high dose monotherapy either from the time of recruitment (30/41), or their CBZ treatment was pushed into the high dose range (11/41) during the observation period (mean 145 days). CBZ and CBZ metabolite serum levels, full blood counts, liver function tests, electrolytes were measured in addition to clinical assessments. The mean daily CBZ dose was 1515 mg (median 1500, range 600-3600 mg). Mean CBZ serum level was 11.1 mg/l (median 11.1, range 5.3-16.4 mg/l). Eleven of 41 patients (26.8%) reported side effects (mean serum level 11.4, median 11.6, range 8.7-13.7 mg/l), but side effects were intolerable in only five patients so that the CBZ dose had to be reduced (mean CBZ serum level 11.4, median 11.6, range 8.7-13.7 mg/l). The total daily CBZ dose but not CBZ or CBZ metabolite levels were correlated with side effects. No treatment changes had to be undertaken because of abnormal laboratory parameters. High dose CBZ anticonvulsant monotherapy is well tolerated.

Some 25% of patients with epilepsy are under the sole care of their family doctors. Treatment is applied in accordance with clear guidelines. The leading aim of therapy is always freedom from seizures. The gold standard is monotherapy, with combination treatment taking second place. In focal epilepsy, the drug of first choice is still carbamazepine, and in generalized epilepsy valproic acid. The use of the new antiepileptics should be given careful consideration, not least on account of their high price. Switch-over from a proprietary to a generic drug may be associated with the problem of differences in bioavailability. Routine monitoring of serum levels is not useful, but is always necessary when a seizure occurs unexpectedly. On account of their disease, many people with epilepsy are discriminated against. Questions regarding the advisability of having children or driving a car, should, however, not automatically elicit a negative response.

Eight new antiepileptic drugs were licensed in the last decade in Switzerland for the treatment of epilepsies, more will follow. Their efficacy as add-on in comparison with placebo was shown in controlled studies. Comparative studies with the new anticonvulsive drugs are lacking. In the daily work after bringing into the market there was shown that the best indications were not always recommended in the approval studies. Other seizure types or epilepsy syndromes showed partially a better response. Also was detected that the recommended dosages and titration velocities were either too slow or too high. Consequences were partially a suboptimal treatment or too much side effects. Rare in some circumstances severe side effects which require a strong indication are seen only after a lot of patients are treated. In this review I deal with the pharmacological properties and interactions, the actual indications, important side effects and strength and weakness of the single compounds.

Oxcarbazepin (OXC; 10,11-dihydro-10-oxo-5H-dibenz-[b,f]azepin-5-carboxamid, trade name Trileptal) is a new antiepileptic drug for treatment of mono- and adjunctive therapy of partial seizures with or without secondary generalization for adults and children above 6 years of age. It was developed through structural variation of carbamazepine. Extensive postmarketing use includes more than 200,000 patient years. The mechanism of action mainly involves blockage of sodium currents. The recommended daily starting dose of oxcarbazepin for both mono- and adjunctive treatment is 8-10 mg/kg (600 mg/day for adults) in two doses and can be titrated according to clinical benefit up to 2400 mg/day. Oxcarbazepin undergoes reductive metabolism at its keto moiety to form MHD, which is glucuronidated and excreted in the urine, with minimal involvement of the hepatic cytochrome P450-dependent enzymes. Thus, OXC has limited drug interactions and does not require slow titration, allowing for better tolerability. Oxcarbazepin compares favorably to presently available new anticonvulsants of the second generation for two reasons: it is available immediately for both mono- and adjunctive therapy in adults and children, and extensive postmarketing experience from many countries is already available. In addition, OXC has been thoroughly tested in an unusually large clinical development program and been shown to be similarly effective as standard antiepileptic drugs.

The clinical relevance of being informed on the serum concentration of antiepileptic drugs has been judged very differently during the last decades. Therefore the Commission on the treatment of epilepsy (German section of the International League against Epilepsy) had the task to outline the importance of therapeutic monitoring of anticonvulsant serum concentrations. The possibility of determining the serum concentration of anticonvulsants induced the elaboration of "therapeutic drug level ranges". The usefulness of determining serum concentrations of antiepileptic drugs in clinical management of patients with epilepsy depends decisively on the following questions: Can the efficacy of antiepileptic drug treatment be increased by serum concentration monitoring? Can the rate of adverse effects of antiepileptic drugs be reduced by serum concentration monitoring? Clinical experience suggests numerous indications of therapeutic drug monitoring, scientific studies however, supporting these empirical guidelines are not available. Therefore, therapeutic drug monitoring may be restricted for some special situations which have to be justified in every single case. Tailored determinations with specific purposes are e.g.: resistance to therapy, including suspected irregular intake; suspected intoxication, particularly during combined therapy; the possibility of significant changes in the dosage-serum concentration relationship (interactions with other drugs, unusual pharmacokinetics in childhood, in pregnancy etc.).

Therapy of HIV infection is changing rapidly as new drugs are introduced. Many patients with HIV infection require anticonvulsants for therapy or prophylaxis of seizures. Antiretroviral drugs, above all protease inhibitors, and anticonvulsants may cause interactions since they are metabolised through common hepatic pathways and may substantially modulate the activity of numerous cytochrome P450 isoenzymes. We describe known interactions between anticonvulsants and antiretroviral drugs and advise on possible combinations.

A 11-year-old girl suffering from grand mal epilepsy underwent antiepileptic therapy with carbamazepine (600 mg/daily). Two weeks after increasing the dose (900 mg/day) she suddenly developed relatively sharply limited, sunburn-like brown reddish macular lesions with central scaling and partly hyperkeratotic areas on the hands, feet, face, knees, gluteal and axillar regions. Otherwise no health disorders were found; in particular no neurological or gastrointestinal symptoms occurred. After reduction of the doses (450 mg/day) these skin lesions faded away. With exception of elevated serum levels of carbamazepine, nicotinamide and vitamin B6, all blood tests were in normal range. Interactions of carbamazepine with the vitamin B6- nicotinamide metabolism are the reason for these previously undescribed cutaneous side effects in connection with carbamazepine therapy. The present case demonstrates a toxic, non-allergic reaction during carbamazepine treatment with pellagroid skin symptoms.

Parallel to the steady increase of the percentage of elderly people, treatment of epilepsy in the elderly is becoming more common. The pharmacotherapy of epilepsy in the elderly differs in some aspects from treatment in younger patients. In general, due to pharmacokinetic and pharmacodynamic changes with reduction of metabolism and elimination, dose reductions are suitable to avoid drug intoxications. A standard treatment rule is to "start low and go slow". As the prognosis is favourable in the majority of patients the choice of a drug is influenced not only by its efficacy but also by possible side effects.

When administering anticonvulsive drugs to the elderly, a number of peculiarities should be taken into consideration. Age-related changes in pharmacokinetics and drug interactions can make such treatment a complicated issue. Some of the side effects which hardly play a role among younger patients can lead to fatal consequences among the elderly. Both phenytoin (PHT), if submitted intravenously (but not in oral form), and carbamazepine (CBZ) may cause life-threatening cardiac arrhythmias. Valproate (VPA), otherwise well tolerated, seems to be less effective than CBZ and PHT in partial seizures. Cognitive dysfunction is a known side effect of barbiturates, but also seems to occur among the other drugs of first choice. In contrast to a widely held opinion, VPA, CBZ and PHT hardly differ in their effect on cognitive function if administered correctly.

Although standard anticonvulsants are effective in achieving complete seizure control in the majority of patients, an appreciable proportion (about 20 to 25%) is at least in part resistant to conventional pharmacotherapy. Efficacy of carbamazepine, phenytoin, phenobarbital and valproate is very similar. Should one drug fail because of inadequate efficacy or unacceptable adverse effects, an alternative monotherapy should be used. Surgical treatment is a feasible therapeutic option for only some of these patients. The development of newer, more effective drugs such as vigabatrin, lamotrigine, gabapentin and oxcarbazepine would be highly desirable. The search for new antiepileptic agents is justified to reduce the proportion of drug-resistant patients. Choice of conventional or new drugs should include not only expected efficacy and risk of adverse effects, but pharmacokinetic properties and expense. Consequently, no general rule is appropriate, and each decision and recommendation for treatment should be individualized.

New antiepileptic drugs such as vigabatrin, lamotrigine, gabapentin, oxcarbazepine and felbamate have been lately marketed. This article provides an overview, showing known modes of action, pharmacokinetics, efficacy, tolerability, interactions and indications. A table showing selected data of antiepileptic drugs is included.

The concentration of valproate was measured in plasma, CSF and brain tissue of patients who underwent resective surgical treatment because of severe temporal lobe epilepsy after pretreatment with either a sustained release formulation of valproate (Depakine Chrono: 5 patients), the conventional formulation of valproate (Depakine: 6 patients) or valpromide (Depamide: 2 patients). With a mean serum value for all 13 patients of 32.3 micrograms/g valproate, the mean brain/serum ratio was 15.1% (SD 6.1%). The valproate concentration of the hippocampus was significantly higher than that of the amygdala, and patients who had the sustained release formulation had significantly higher valproate concentration in the CSF and in the hippocampal formation than those patients who had the conventional valproate. Since a few patients had tumors, whereas others had varying degrees of gliosis, it cannot be ruled out that these differences are the result of different histopathological conditions with related differences in blood-brain barrier functions.

Felbamate is a new anticonvulsant which has already been marketed in some countries outside Germany, i. e., in the United States. Since marketing in Germany is in progress, one may soon expect felbamate to be in clinical use. Both the chemical structure and the probable mechanism of action are different from the currently available antiepileptic drugs. The studies already published allow to expect felbamate to improve substantially the possibilities of antiepileptic pharmacotherapy, since it is an anticonvulsant with a high efficacy in the treatment of partial epilepsy and especially with a very good tolerability. Its disadvantage are numerous interactions with other antiepileptic drugs. This article is an update review of the literature on felbamate.

4-p-Chlorphenylpyrrole-3-morpholino-2-carboxylic acid methylester (1; AWD 140-076) is a substance with anticonvulsive properties. After p.o. administration in male wistar rats many metabolites in relatively small concentration are excreted in urine and faeces, six of them could be isolated and identified as quantitative dominating compounds. Compound 1 is attacked in different sites of the molecule by the cytochrome P-450 system. At the morphine ring N- and O-dealkylation reactions take place leading to the cleavage of the ring. After that a stepwise degradation by oxidative and reductive processes occurs. Further reactions concern the N-oxidation of the morpholine nitrogen as well as the hydroxylation of the pyrrole skeleton forming the main metabolites. 5 metabolites are also present as sulfate or glucuronide conjugates. The quantity ratio of the phase I to phase II metabolites amounts to 9:1. In the in vitro test system isolated perfused rat liver and rat hepatocytes culture solely the two main metabolites are formed. Compound 1 is characterized by enzyme inducing activities. The oxidative demethylation of p-nitroanisole is increased 4-fold after pretreatment.

Epilepsy is the most common neurological disease of females in reproductive age. Problems concerning contraception, reproduction, teratogenicity and antiepileptic therapy preceding and during pregnancy are discussed and recommendations made. We underline the advantages of a planned pregnancy with optimal adjustment of antiepileptic drug therapy and recommend prophylactic treatment with folic acid before and during, and with vitamin K towards the end of pregnancy.

Phenytoin has been considered a possible cause of cerebellar degeneration, especially after clinical intoxication. Magnetic resonance provides the diagnosis of anatomical structures in the posterior fossa without the limitation of beam hardening artefacts. The aim of this study was to evaluate the relationship of phenytoin medication and cerebellar atrophy in 11 patients with increased serum levels (21.4 micrograms/ml-95.6 micrograms/ml). Five patients had normal cerebellar structures, although three of them had a history of clinical intoxication and all had at least one episode of increased serum level of DPH. The remaining six patients had moderate severe cerebellar atrophy (n = 4) and atrophy of the vermis cerebelli (n = 5). Two of them had never experienced clinical intoxication. There was no correlation between the degree of atrophy and severity of clinical symptoms and evaluation of serum DPH levels (up to four times normal values). There was also no correlation between cerebellar atrophy, duration of epilepsy and frequency of seizures. We conclude that phenytoin overdosage does not necessarily result in cerebellar atrophy and it is unlikely that phenytoin medication was the only cause of cerebellar atrophy in the remaining patients.

The incidence of epileptic seizures is high in childhood, but shows regression during adult life until the age of 65 when there is again a marked, age-dependent increase in frequency. The specific problems of anticonvulsive therapy in the elderly are discussed in the light of the sparse literature on this subject. Pathophysiological influences of aging on the pharmacodynamics and pharmacokinetics of antiepileptic drugs have to be taken into account, such as changes in the renal, hepatic and intestinal functions as well as increased neuronal receptor sensitivity, among other factors. The optimal time to start therapy is controversial. In selecting the antiepileptic drug, particular attention must be paid on cognitive dysfunction and impairment of impulse conduction. Moreover, age-dependent side effects, as well as possible additive effects due to interaction with other medication have to be taken into consideration. In view of the high rate of relapses great caution has to be taken to withdraw the antiepileptic drugs in completion of the therapeutic regimen.

In recent years potassium bromide has again been used with increasing frequency in the treatment of epilepsy. A 3-year-old girl with bromoderma tuberosum following such treatment is described; the symptoms disappeared after reduction of the bromide dose.

In a prospective study we investigated the serum concentrations and frequency of seizures in 38 women with epilepsy in a total of 44 pregnancies. Monthly follow-up examinations were carried out in cooperation with the risk outpatient unit of the Department of Gynecology. Antiepileptic serum concentrations were determined using the technique of fluorescence polarisation. At constant dosage, a decrease in serum concentration occurred in most cases with a maximum at the 5th and 6th month of gestation, regardless of the kind of antiepileptic medication. No changes in seizure frequency have been observed. The treatment of epilepsy during pregnancy should in any case depend on the course of the illness, rather than on laboratory parameters.

We report on 79 pregnancies in 66 female outpatients with epilepsy. An increase of seizure frequency was significantly more frequent in complex partial seizures than in grand mal seizures and in absences. The reason for these disparities are not clear. In most patients a raised frequency of seizures during pregnancy decreased again after delivery. Carbamazepine was the antiepileptic drug prescribed most frequently followed by valproic acid. The course of the blood levels of carbamazepine and valproic acid was nonuniform during pregnancy. Total concentrations of carbamazepine in cord blood were on average 84.5% of those in maternal blood (n = 22). Valproic acid blood levels were on average 183% of those in maternal blood (n = 15). It is still unclear whether these differences are clinically relevant. During the last weeks of pregnancy we found an increase of the free fraction of carbamazepine and valproic acid. Simultaneously the total protein concentration decreased. Until now these findings are without clinical relevance. The course of labor did not differ from normal population concerning the ratios of spontaneous labor, cesarean section and delivery by forceps. Miscarriage and perinatal mortality were 2.7% each and outnumbered the risk in the general population. In 42.8% of the neonates one to three perinatal complications were observed. The ratio of perinatal complications is not different between patients with monotherapy and combined therapy respectively. There was a tendency to lower values of length, weight and head circumference in the male neonates but not in the female neonates. The risk of minor malformations was 26%, the risk of major malformations was 14% (including one case of suspected malformation) without a discernible correlation with a specific antiepileptic drug.

Epilepsy affects almost 1% of all pregnant women. The effect of pregnancy upon epilepsy is unpredictable for the individual patient. In one third to one half of the patients epilepsy had no effect on seizure frequency, in one fourth to one third of the patients seizure frequency increased, and in one third to one fourth it improved. Several reasons are discussed for a frequently observed tendency to a drop in plasma concentration of antiepileptic drugs during pregnancy where the daily dose was kept unchanged. For unknown reasons, perinatal lethality is up to twice as high as in controls. The risk of bearing children with malformations is approximately 1.5-3 times higher for mothers with epilepsy than in non-epileptic mothers. Apart from antiepileptic drugs the role of genetic factors, the type and severity of epilepsy and the possible influence of grand-mal seizures during pregnancy must be considered to be involved in congenital anomalies. Polypharmacy produces more frequent anomalies than monotherapy. Valproate should be avoided in the pregnant women due to the increased incidence of neural tube defects. At this time there is no reason to discourage a mother on antiepileptic drug therapy from breast feeding.