Erik Saetre

An International Multicenter Randomized Double‐Blind Controlled Trial of Lamotrigine and Sustained‐Release Carbamazepine in the Treatment of Newly Diagnosed Epilepsy in the Elderly

Summary:  Purpose: To assess the comparative effectiveness, efficacy, and tolerability of lamotrigine (LTG) and sustained‐release carbamazepine (CBZ) in the treatment of newly diagnosed epilepsy in the elderly.

Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy

Disturbances of reproductive endocrine hormones are more often found in men with epilepsy than in the general population. There is an ongoing debate whether this can be attributed to chronic use of antiepileptic drugs or to the epilepsy itself. The aim of the present study was to evaluate the degree of endocrine disturbances in men with epilepsy compared with healthy controls, and to investigate whether there was a drug‐specific effect of valproate (VPA) or carbamazepine (CBZ). Men with epilepsy, 20–40 years old, having used either VPA (n = 16) or CBZ (n = 19) as monotherapy for >2 years were included and compared with age‐matched controls. Men with epilepsy (VPA + CBZ) had significantly lower FSH values and higher C‐peptide values compared with controls. Regarding possible drug‐specific effects, the VPA treated patients had significantly higher dehydroepiandrosterone (DHEAS) levels and lower FSH and LH concentrations compared with the controls, whereas there were no differences in testosterone, testosterone/sexhormone‐binding globulin (SHBG) ratio or androstenedione levels. Men on VPA also had significantly lower free carnitine/total carnitine, which may have implications for sperm motility, and also higher insulin and C‐peptide concentrations. The CBZ treated patients had significantly lower testosterone/SHBG ratio than the controls. Compared with the CBZ treated patients, men on VPA had significantly higher DHEAS concentrations and lower levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) as well as a lower free carnitine/total carnitine ratio. A marked age dependency was found in all three groups regarding several of the endocrine hormones. In conclusion, drug‐specific endocrine effects of VPA and CBZ were found in men with epilepsy. Long‐term VPA treatment leads to significant changes in DHEAS, FSH, LH, insulin, C‐peptide and carnitine ratio. Long‐term CBZ treatment leads to significant lower testosterone/SHBG ratio. A strict age matching were found to be of importance in the evaluation of endocrine function in men.

Alterations in semen parameters in men with epilepsy treated with valproate or carbamazepine monotherapy

Men with epilepsy are known to have reduced fertility. Whether this is drug‐induced or a result of the epilepsy itself is still under debate. Few studies have been carried out on semen from men with epilepsy. The aim of the present study was first to investigate possible drug‐specific effects of long‐term treatment with either valproate or carbamazepine on semen quality and testicular size, and secondly to see whether the results in epilepsy patients differed from healthy fertile males. Men with epilepsy, 20–40 years old, having used either valproate (n = 16) or carbamazepine (n = 20) for >2 years, were included. The semen data of healthy fertile men without epilepsy in the same age group (n = 90) were used as controls. The semen was examined according to WHO (1999). No significant differences in semen quality were seen between men receiving either valproate or carbamazepine. However, semen from the valproate‐treated, as opposed to the carbamazepine‐treated, differed from controls with regard to tail abnormalities. Absolute testicular size was not significantly different between the two treatment groups. However, after correcting for changes in body mass index (BMI), the testicular size/BMI ratio was lower in the valproate‐treated patients. The valproate‐treated patients gained significantly more weight than the carbamazepine‐treated patients after start of current medication. No differences between the patient groups were found in terms of libido/potency or number of pregnancies fathered. When comparing all epilepsy patients with healthy fertile males, there was a significant reduction in the percentage of rapidly progressive motile sperms in the semen from epileptic patients. The semen from men with epilepsy also showed significant differences from the controls regarding neck and head abnormalities of the spermatozoa.

Do women with epilepsy have increased frequency of menstrual disturbances

PROBLEM Menstrual disorders, reduced fertility and sexual problems seem to be more frequent in women with epilepsy than in the general population. Most investigations concerning menstrual disturbances in epilepsy patients, however, are small and based on selected materials. We therefore wanted to investigate the frequency of menstrual disturbances in a large, unselected population of epilepsy patients. METHODS A retrospective, questionnaire study of a cohort of female outpatients, aged 18-45 was conducted. Each patient chose a close female friend who served as control, to optimise matching regarding age and lifestyle. RESULTS Answers were received from 265 patients and 142 controls. Menstrual disturbances were more frequent in patients with epilepsy (48.0%) than in controls (30.7%) (P=0.004). Menstrual disturbances were more frequent in patients on polytherapy versus monotherapy (P=0.049) and more frequent in patients with high seizure frequency (>5seizures/year) compared to patients with a lower seizure frequency or those seizure free (P=0.006). The frequency of menstrual disturbances was higher in patients on valproate compared to carbamazepine monotherapy (P=0.045). CONCLUSION This investigation confirms that women with epilepsy have an increased frequency of menstrual disturbances compared to women without epilepsy. In women with high seizure frequency and in those on polytherapy, the frequency of menstrual disturbances are further increased. The highest frequency of menstrual disturbances occurred in women using valproate.

Cardiac function and antiepileptic drug treatment in the elderly: A comparison between lamotrigine and sustained-release carbamazepine

Purpose:  To investigate the comparative effects of carbamazepine (CBZ) and lamotrigine (LTG) on electrocardiography (ECG) parameters in elderly patients with newly diagnosed epilepsy.

Antiepileptic drugs and quality of life in the elderly: Results from a randomized double-blind trial of carbamazepine and lamotrigine in patients with onset of epilepsy in old age

During an international double-blind trial evaluating the efficacy and tolerability of lamotrigine and carbamazepine in patients aged >or=65 with newly diagnosed epilepsy, the comparative effects of the drugs on health-related quality of life were investigated based on screening and 12-, 28-, and 40-week data, using the modified Side Effect and Life Satisfaction (SEALS) Inventory and the Liverpool Adverse Event Profile. Of 167 patients, 29 discontinued before first follow-up, and data were incomplete for 13. In 125 eligible subjects (62 taking carbamazepine, 63 taking lamotrigine), comparable baseline data did not change significantly during medication, within or across treatments. A borderline difference in the SEALS Dysphoria subscores favored lamotrigine. No difference between completers and noncompleters was identified. Twelve-week data for noncompleters were comparable across treatments. Changes in the inventories up to 40 weeks correlated moderately. Neither lamotrigine nor carbamazepine seems likely to cause significant changes in health-related quality of life measures after 40 weeks at therapeutic doses.

Onset of epilepsy and menarche—Is there any relationship?

PURPOSE Women with epilepsy have increased frequency of reproductive health problems compared to women without epilepsy. In puberty, reproductive hormonal changes during sexual maturation may affect epilepsy and induce the debut of seizures as indicated in some studies. On the other hand, epileptic activity affects sex hormone function, which may induce alterations in pubertal endocrine maturation and thereby menarche age. We wanted to investigate the relation between epilepsy and menarche age in a larger population of female epilepsy patients. METHODS A retrospective, questionnaire study of a cohort of 265 female outpatients from three Norwegian hospitals and 142 controls, aged 18-45 years was conducted. Parameters regarding epilepsy and reproductive health issues were registered. Perimenarche was defined as 2 years before and 2 years after the year of menarche. RESULTS There was a significantly higher frequency of patients with epilepsy debut between 10 and 18 year compared to 0-9 years (p<0.01). There was, however, no significant difference in occurrence of epilepsy debut in the perimenarche period compared to the 5 year periods before and after perimenarche, and no significant difference in epilepsy debut in the year of menarche compared to the 5 years before or after. Menarche age was not significantly different in those with epilepsy debut before or after menarche. Epilepsy type (idiopathic generalised or partial) did not influence the menarche age. CONCLUSIONS The study did not confirm the former observations of clustering of epilepsy debut at menarche or in the perimenarche period or alterations in menarche age in girls with epilepsy. However, onset of epilepsy is more frequent in the adolescent years (10-18), than in childhood (0-9).

Utilisation and polypharmacy aspects of antiepileptic drugs in elderly versus younger patients with epilepsy: A pharmacoepidemiological study of CNS-active drugs in Norway, 2004-2015

BACKGROUND AND PURPOSE Many patients with epilepsy use antiepileptic drugs (AEDs) in combination. The elderly is a vulnerable group regarding polypharmacy. The purpose of this study was to investigate changes in utilisation of AEDs, and the extent of polypharmacy with other CNS-active drugs in elderly versus younger patients in Norway. METHODS This pharmacoepidemiological study included all prescriptions of antiepileptic, antidepressant and antipsychotic drugs from Norwegian pharmacies in the Norwegian Prescription Database (NorPD) (2004-2015). Variables included number of patients, utilisation in defined daily doses, age, gender, and diagnosis specific reimbursement codes for AEDs. RESULTS The use of AEDs has increased in all age groups in this population-based study in Norway. In the elderly, AEDs used in neuropathic pain (mainly gabapentin and pregabalin) have increased more than 10-fold (from 0.7 to 9.6 DDDs/1000 elderly/day, 2004-2015), while the prevalence of users is four times more than in younger patients. Polypharmacy between antiepileptic, antidepressant and antipsychotic drugs occurred in 35% of elderly and 38% of younger patients with epilepsy. The use of enzyme-inducers was common, and occurred more often in elderly patients. A total of 42 different interactions that may have clinical implications were identified among these drugs. CONCLUSION The use of AEDs in elderly compared to younger patients is increasing, especially in neuropathic pain. Polypharmacy with antiepileptic, antidepressant and/or antipsychotic drugs was documented in more than one third of the patients. Awareness of increased drug utilisation, polypharmacy with potential drug interactions, and focus on elderly patients are important for increased patient safety.

Pharmacokinetic variability, efficacy and tolerability of eslicarbazepine acetate-A national approach to the evaluation of therapeutic drug monitoring data and clinical outcome.

BACKGROUND Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED), still insufficiently studied regarding pharmacokinetic variability, efficacy and tolerability. The purpose of this study was to evaluate therapeutic drug monitoring (TDM) data in Norway and relate pharmacokinetic variability to clinical efficacy and tolerability in a long-term clinical setting in patients with refractory epilepsy. METHODS This retrospective observational study included TDM-data from the main laboratories and population data from the Norwegian Prescription Database in Norway, in addition to clinical data from medical records of adult patients using ESL for up to three years, whenever possible. RESULTS TDM-data from 168 patients were utilized for assessment of pharmacokinetic variability, consisting of 71% of the total number of patients in Norway using ESL, 2011-14. Median daily dose of ESL was 800mg (range 400-1600mg), and median serum concentration of ESL was 53μmol/L (range 13-132μmol/L). Inter-patient variability of ESL was extensive, with 25-fold variability in concentration/dose ratios. Additional clinical data were available from 104 adult patients out of the 168, all with drug resistant focal epilepsy. After 1, 2 and 3 years follow-up, the retention rate of ESL was 83%, 72% and 64%, respectively. ESL was generally well tolerated as add-on treatment, but sedation, cognitive impairment and hyponatremia were reported. Hyponatremia (sodium <137mmol/L) was present in 36% of the patients, and lead to discontinuation in three. CONCLUSION Pharmacokinetic variability of ESL was extensive and the demonstration of usefulness of TDM requires further studies. In patients with drug resistant focal Epilepsy, the high retention rate indicated good efficacy and tolerability. Hyponatremia was observed in one third of the patients. The present results point to a need for individualization of treatment and TDM may be useful.