Erik Taubøll

Effect of Antiepileptic Drugs on Reproductive Endocrine Function in Individuals with Epilepsy

It is well known that epilepsy, antiepileptic drugs (AEDs), and the reproductive system have complex interactions. Fertility is lower in both men and women with epilepsy than in the general population. Moreover, reproductive endocrine disorders are more common among patients with epilepsy than among the population in general. These disorders have been attributed both to epilepsy itself and to use of AEDs.The use of the liver enzyme-inducing AEDs phenobarbital, phenytoin and carbamazepine increases serum sex hormone-binding globulin (SHBG) concentrations in both men and women with epilepsy. Over time, the increase in serum SHBG levels leads to diminished bioactivity of testosterone and estradiol, which may result in diminished potency in men and menstrual disorders in some women, and thus to reduced fertility. Liver enzyme-inducing AEDs also reduce the efficacy of oral contraceptives.Valproic acid medication may have effects on serum androgen concentrations and it reduces serum follicle stimulating hormone levels in men with epilepsy. However, the clinical significance of valproic acid-related reproductive endocrine changes in men is unknown. On the other hand, in women, use of valproic acid appears to be associated with a frequent occurrence of reproductive endocrine disorders characterised by polycystic changes in the ovaries, high serum testosterone concentrations (hyperandrogenism) and menstrual disorders. These disorders are especially common among women who have gained weight during valproic acid treatment. There are some discrepancies regarding the reported occurrence of reproductive endocrine disorders in women taking valproic acid for epilepsy. However, most studies also including patients receiving valproic acid for other reasons than epilepsy, and studies in different non-epileptic animal models, have shown an association between valproic acid medication and hyperandrogenism and related reproductive endocrine disorders.From a practical point of view, the length of the menstrual cycles and body weight should be monitored in women with epilepsy after commencement of treatment with valproic acid. A serum testosterone assay is helpful in following the possible biochemical endocrine changes. Ultrasonography of the ovaries (preferably transvaginal) is indicated if clinical assessment and serum testosterone measurement imply that there is a clinically significant valproic acid-related reproductive endocrine problem. That would be the case if the menstrual cycles were irregular or prolonged (usually >35 days) and serum testosterone levels elevated, especially with associated weight gain.The endocrine effects of the new AEDs have not been widely studied. However, it seems they may offer an alternative if reproductive endocrine problems emerge during treatment with the older AEDs.

Altered ovarian function and cardiovascular risk factors in valproate-treated women.

PURPOSE Polycystic ovaries and menstrual disturbances seem to be common among women taking valproate for epilepsy. The purpose of the present study was to assess the frequency of valproate-related metabolic and endocrine disorders in different groups of women with epilepsy. SUBJECTS AND METHODS Seventy-two women with epilepsy and 52 control subjects from centers in three European countries (Finland, Norway, and the Netherlands) participated in the study. Thirty-seven of the women with epilepsy were taking valproate monotherapy and 35 carbamazepine monotherapy. RESULTS The frequency of polycystic ovaries or hyperandrogenism, or both, among valproate-treated women with epilepsy was 70% (26 of 37) compared with 19% (10 of 52) among control subjects (P <0.001). They were found in 79% (11 of 14) of obese and 65% (15 of 23) of lean women on valproate, and in 20% (7 of 35) of carbamazepine-treated women. The obese valproate-treated women with polycystic ovaries or hyperandrogenism, or both, had hyperinsulinemia and associated unfavorable changes in serum lipid levels consistent with insulin resistance. CONCLUSIONS Polycystic ovaries and related hyperandrogenism are frequently encountered in both obese and lean women taking valproate for epilepsy. The use of valproate is associated with risk factors for cardiovascular disease in obese women.

Psychiatric comorbidity and hostility in patients with psychogenic nonepileptic seizures compared with somatoform disorders and healthy controls.

Summary:  Purpose: To investigate the prevalence of psychiatric comorbidity and level of anxiety, depression, and aggression in patients with psychogenic nonepileptic seizures compared with those in patients with somatoform disorders and healthy controls.

Reproductive dysfunction in women with epilepsy: recommendations for evaluation and management

Background: Epilepsy is commonly associated with reproductive endocrine disorders. These include polycystic ovary syndrome (PCOS), isolated components of this syndrome such as polycystic ovaries, hyperandrogenaemia, hypothalamic amenorrhoea, and functional hyperprolactinaemia. Objective: To summarise the currently known relations between epilepsy and reproductive endocrine disorders. Methods: A review of clinical experience and published reports. Results: The most likely explanations for endocrine disorders related to epilepsy or antiepileptic drugs are: (1) a direct influence of the epileptogenic lesion, epilepsy, or antiepileptic drugs on the endocrine control centres in the brain; (2) the effects of antiepileptic drugs on peripheral endocrine glands; (3) the effects of antiepileptic drugs on the metabolism of hormones and binding proteins; and (4) secondary endocrine complications of antiepileptic drug related weight changes or changes of insulin sensitivity. Regular monitoring of reproductive function at visits is recommended, including questioning about menstrual disorders, fertility, weight, hirsutism, and galactorrhoea. Particular attention should be paid to patients on valproate and obese patients or those experiencing significant weight gain. Single abnormal laboratory or imaging findings without symptoms may not constitute a clinically relevant endocrine disorder. However, patients with these kinds of abnormalities should be monitored to detect the possible development of a symptomatic disorder associated with, for example, menstrual disorders or fertility problems. Conclusions: If a reproductive endocrine disorder is found, antiepileptic drug treatment should be reviewed to ensure that it is correct for the particular seizure type and that it is not contributing to the endocrine problem. The possible benefits of a change in treatment must be balanced against seizure control and the cumulative side effect of alternative agents.

New SCN5A mutation in a SUDEP victim with idiopathic epilepsy

Many idiopathic epilepsies have been shown to be caused by ion channel dysfunction. Channelopathies also cause the long QT syndrome (LQTS) which is associated with syncopes and sudden cardiac death. It has been postulated that the same channelopathy may be associated with both epilepsy and LQTS. We report a patient with idiopathic epilepsy who died in sudden unexpected death in epilepsy (SUDEP) at the age of 25. A post mortem DNA sequencing of the LQTS-associated genes revealed a novel missense mutation in the SCN5A gene coding for the cardiac sodium channel, voltage gated, type V, alpha subunit. The possibility that the mutation may explain both the epilepsy and the sudden death is discussed. However, the patient was treated with lamotrigine which may interfere with cardiac ion channels and may also have played a part in inducing a terminal cardiac arrhythmia.

Temporal distribution of seizures in epilepsy

A major problem in epileptology is why a seizure occurs at a particular moment in time. An initial step in solving this problem is a detailed analysis of the temporal distribution of seizures. Using methods and theories of stochastic processes, seizure patterns in a group of epileptic outpatients were examined for stationarity, randomness, dependency and periodicity in a prospective study. Sixteen of the 21 seizure diaries included in the study showed stationarity; 2 were non-stationary and 3 inconclusive. Eleven of the 16 stationary diaries were non-Poisson (P less than 0.005), indicating that in the majority of patients seizures did not occur randomly. The most frequently encountered phenomenon was seizure clustering. Clustering was considered when the diaries fulfilled all three criteria: (1) a positive R-test (P less than 0.001); (2) deviation from the fitted Poisson distribution towards clustering; and (3) the feature of an autoregressive process in the autocorrelogram plot. Dependency between seizure events was demonstrated in 8 of the 16 stationary diaries, computing first order transition probabilities. A detailed analysis of seizure occurrence is a major step towards a better understanding of the mechanisms underlying seizure precipitation. This is exemplified by our finding of a relation between seizure frequency and the menstrual cycle.

Levetiracetam, Phenytoin, and Valproate Act Differently on Rat Bone Mass, Structure, and Metabolism

Summary:  Purpose: Long‐term treatment with antiepileptic drugs (AEDs) is associated with increased risk of fractures. Phenytoin (PHT) and valproate (VPA) have both been suggested to influence bone health, whereas levetiracetam (LEV) is scarcely studied. The present study compares the effect of these AEDs on bone mass, biomechanical strength, and bone turnover in rats.

Up-regulation of hippocampal glutamate transport during chronic treatment with sodium valproate

Excessive glutamatergic neurotransmission has been implicated in some neurodegenerative disorders. It would be of value to know whether glutamate transport, which terminates the glutamate signal, can be up‐regulated pharmacologically. Here we show that chronic treatment of rats with the anti‐epileptic drug sodium valproate (200 mg or 400 mg/kg bodyweight, twice per day for 90 days) leads to a dose‐dependent increase in hippocampal glutamate uptake capacity as measured by uptake of [3H]glutamate into proteoliposomes. The level of glutamate transporters EAAT1 and EAAT2 in hippocampus also increased dose‐dependently. No effect of sodium valproate on glutamate transport was seen in frontal or parietal cortices or in cerebellum. The hippocampal levels of glial fibrillary acidic protein and glutamine synthetase were unaffected by valproate treatment, whereas the levels of synapsin I and phosphate‐activated glutaminase were reduced by valproate treatment, suggesting that the increase in glutamate transporters was not caused by astrocytosis or increased synaptogenesis. A direct effect of sodium valproate on the glutamate transporters could be excluded. The results show that hippocampal glutamate transport is an accessible target for pharmacological intervention and that sodium valproate may have a role in the treatment of excitotoxic states in the hippocampus.

Variants of the genes encoding AQP4 and Kir4.1 are associated with subgroups of patients with temporal lobe epilepsy

OBJECTIVE The etiopathogenesis of temporal lobe epilepsy (TLE) and its subgroups - mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and TLE with antecedent febrile seizures (TLE-FS) - is poorly understood. It has been proposed that the water channel aquaporin-4 (AQP4) and the potassium channel Kir4.1 (KCNJ10 gene) act in concert to regulate extracellular K(+) homeostasis and that functional alterations of these channels influence neuronal excitability. The current study was designed to identify variants of the AQP4 and KCNJ10 genes associated with TLE and subgroups of this condition. MATERIAL AND METHODS We included 218 Norwegian patients with TLE and 181 ethnically matched healthy controls. An association study was established in which all TLE patients were compared with healthy controls. Additionally, subgroups of 56 MTLE-HS patients were compared with 162 TLE patients without HS, and 102 TLE-FS patients were compared with 105 TLE without FS. RESULTS We found eight single SNPs, seven in KCNJ10 and one between KCNJ10 and KCNJ9, associated with TLE-FS (nominal p-values from 0.009 to 0.041). Seven of the SNPs segregate into one large haplotype block expanding from KCNJ10 to KCNJ9, including the region interposed those genes. One haplotype was overrepresented in the TLE-FS cases (nominal p-value 0.014). These results were confirmed by explorative multivariate analysis indicating that a combination of SNPs from KCNJ10, the region between KCNJ10 and KCNJ9, and the AQP4 gene is associated with TLE-FS. For the TLE cohort as a whole, explorative multivariate analysis indicated a combination of SNPs from the KCNJ10 and AQP4 genes in association with TLE. CONCLUSION Variations in the AQP4 and the KCNJ10/KCNJ9 region are likely to be associated with TLE, particularly TLE-FS, supporting the suggestion that perturbations of water and K(+) transport are involved in the etiopathogenesis of TLE.

Effects of chronic valproate treatment on reproductive endocrine hormones in female and male Wistar rats

Valproate (VPA) has been claimed to induce endocrine disorders in both sexes in humans. There is sparse information regarding the mechanisms behind these disturbances. By using an animal model, we wanted to study the effect of valproate on hormonal function in non-epileptic rats. Female rats were given 0 (vehicle control, n=15), 200mg/kg (n=15), or 300 mg/kg (n=20) valproate twice daily by gavage for 90 days, resulting in mean valproate concentrations within the therapeutic range 4-6h after the last dose given. Serum testosterone concentrations remained unchanged, while estradiol levels were significantly reduced in both treatment groups, leading to significantly increased testosterone/estradiol ratios. Follicle stimulating hormone (FSH) levels remained unaltered in valproate treated rats, whereas the luteinizing hormone (LH) concentrations were reduced at the lowest valproate dose. Male rats received 0 (vehicle control, n=15), 200mg/kg (n=15), or 400mg/kg (n=20) valproate twice daily by gavage for 90 days, resulting in mean valproate concentrations within the therapeutic range 4-6h after the last dose. Serum testosterone levels were not significantly changed, but there was a highly significant increase in FSH and LH concentrations at the high dose. In conclusion, the study demonstrates a drug-induced effect of valproate on endocrine function in both male and female rats. The results indicate that the drug exerts its effect primarily at the gonadal level, although a centrally mediated effect cannot be ruled out.