A retrospective review of changes and challenges in the use of antiseizure medicines in Dravet syndrome in Norway.

OBJECTIVE: Dravet syndrome is a developmental and epileptic encephalopathy characterized by severe and drug-resistant seizures in early childhood, followed by developmental delay. The purpose of this study was to investigate aspects of pharmacological treatment of Norwegian patients with Dravet syndrome, focusing on the use of antiseizure medicines (ASMs) and identifying treatment challenges. METHODS: Patients were identified through medical registries at the National Center for Epilepsy in Norway and National Center for Rare Epilepsy Related Disorders during 2008-2018. Additional clinical data were obtained from medical records and laboratory request forms. RESULTS: We identified 53 patients with Dravet syndrome, 30/23 males/females, aged 2-50 years. The majority of patients with known seizure frequency experienced frequent seizures, 80% (n = 35/44). Only two patients were seizure-free. Valproate (n = 48), clobazam (n = 45), levetiracetam (n = 30), and stiripentol (n = 38) were most commonly used, previous or current use. More than one-third (n = 20) had tried sodium channel blockers (including lamotrigine), but these drugs were used less during the last decade. Polytherapy was common, 81% (n = 43) used two or more ASMs, and eight of these patients used 4-5 drugs (15%). Several challenges were identified: high seizure frequency, comorbidities, treatment changes with a wide range of ASMs, common use of oral gastro-tubes, extensive polypharmacy, and drug interactions. SIGNIFICANCE: The use of ASMs has changed over the last decade, in accordance with updated international recommendations. Various treatment challenges were identified. This vulnerable group of patients needs close follow-up for an optimal treatment outcome.

Pharmacokinetic Variability During Long-Term Therapeutic Drug Monitoring of Valproate, Clobazam, and Levetiracetam in Patients With Dravet Syndrome.

BACKGROUND: The use of therapeutic drug monitoring (TDM) for antiseizure medications (ASMs) may contribute to treatment optimization in individual patients. This study included patients with Dravet syndrome as they often require close monitoring because of polypharmacy with various ASMs. The aim was to use long-term TDM to investigate pharmacokinetic variability of ASMs in these patients. METHODS: Retrospective data from patients with Dravet syndrome were collected from the TDM database at the Section for Clinical Pharmacology, National Center for Epilepsy in Norway (2008-2018). Concentration/(dose/kg)ratios (C/D ratios) were calculated for the ASMs and the concentration (C/C ratio) for N-desmethylclobazam. In patients with at least 3 measurements, the CV for C/D ratios for intrapatient and interpatient variability was calculated. RESULTS: Fifty-three patients (30 male patients/23 female patients) between 2 and 50 years of age (mean, 16 years) were included. Pharmacokinetic variability of the total number of measurements of valproate (n = 417), clobazam and N-desmethylclobazam (n = 328), and levetiracetam (n = 238) was determined. Interpatient variability was more pronounced than intrapatient variability (coefficient of variations: valproate, 65% vs. 24%; levetiracetam, 71% vs. 27%; and clobazam/N-desmethylclobazam, 47%/77% vs. 35%/55%) (P < 0.01). Comedication with stiripentol (n = 16) increased the C/D ratio of valproate by 63% and of clobazam by 133% and the C/C ratio of N-desmethylclobazam/clobazam by 104% (P < 0.05). Younger age also contributed to pharmacokinetic variability. CONCLUSIONS: Long-term TDM revealed extensive variability in serum concentrations over time; the variability was lowest for levetiracetam, moderate for valproate, and highest for clobazam. Pharmacokinetic variability and interactions can thus be identified and adjusted to facilitate decision making to achieve the optimal treatment outcome.

Incidence rate of sudden death in epilepsy: A systematic review and meta-analysis.

OBJECTIVE: The aim of the study was to summarize the pooled incidence rate of sudden unexpected death in epilepsy (SUDEP) in patients. Meta-regression analysis was applied to identify factors influencing the incidence rate. DESIGN: The study was a systematic review and critical appraisal with a meta-analysis of cohort studies, both prospective and retrospective. MATERIAL AND METHOD: In a literature search, a total of 45 cohort studies were identified. A random effect model was used to synthesize the results. Heterogeneity between studies was examined by subgroup and meta-regression analysis. The small-study effect was evaluated and not corrected for by the "trim and fill" method because of great heterogeneity. RESULTS: A substantial heterogeneity was present. The pooled estimated incidence rate for SUDEP was 1.4/1000 patient years. A meta-regression pinpointed a negative association between the incidence rate of SUDEP and the mean follow-up time and a positive association with the mean age of the patient. The definition of epilepsy showed statistical significance, with a higher incidence rate of SUDEP in studies where the definition of epilepsy was described and clear (p = 0.019) compared with studies having an inadequate or failing epilepsy definition. CONCLUSION: Evidence from this study suggests a high incidence rate of sudden death in epilepsy. Its incidence rate was 23 times the incidence rate of sudden death in the total population of the same age. There was heterogeneity and variability of incidence rate depending on the quality of the study and on the definition of epilepsy and the mean age of the patients.

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.

[Epilepsy in the elderly]. / Epilepsi hos eldre.

BACKGROUND: Diagnostic work-up and treatment of patients who have developed epilepsy after the age of 65 can both be difficult. Epilepsy is one of the most common neurological conditions in the elderly, and the incidence of de novo geriatric epilepsy is rising. The aim of this review is to provide guidance on the management of epilepsy in this patient group. METHOD: The review is based on a discretionary selection of original articles and reviews found in PubMed using the search term combination 'epilepsy' and 'elderly', and the authors' personal experience. RESULTS: The seizures, which are most commonly of the focal type, are not infrequently overlooked or misdiagnosed. Cerebrovascular disease is the underlying cause of about half of the cases. When selecting an anticonvulsant, it is important to take age-related physiological changes and comorbidities into consideration. Because elderly patients have a narrower therapeutic window than younger persons and greater susceptibility to cognitive and other side effects, a low starting dose and slower dose titration are particularly important. INTERPRETATION: The results of studies of young epilepsy patients cannot be extrapolated to apply to elderly patients. More studies directly targeting this patient population are therefore needed. As a general rule, we do not recommend starting on enzyme-inducing drugs such as phenytoin, phenobarbital and carbamazepine, partly because of their high interaction potential.

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.

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. METHODS: The study was conducted in the Norwegian subcohort (n = 108) of an international randomized double-blind 40-week trial, which compared the efficacy and tolerability of LTG and sustained-release CBZ in patients aged 65 and older with newly diagnosed epilepsy. Target maintenance doses were 400 mg/day for CBZ and 100 mg/day for LTG, with adjustments based on clinical response. Patients with significant unpaced atrioventricular (AV) conduction defect were excluded. Resting 12-lead ECG recordings were made under standardized conditions at pretreatment (baseline) and at the 40-week study visit (treatment visit). Changes in QRS interval (primary endpoint), heart rate (HR), PQ, and QTc (HR-corrected QT) intervals were assessed and compared between groups. RESULTS: Of the 108 patients randomized, 33 discontinued prematurely because of adverse events (n = 24, none of which was cardiac) or other reasons (n = 9), and 15 were nonevaluable due to incomplete ECG data. None of the assessed ECG parameters differed significantly between groups at baseline. No significant ECG changes were recorded between baseline and treatment visit for QRS duration and QTc intervals, whereas HR fell and PQ intervals increased slightly on both treatments. However, there were no differences between groups in changes from baseline to treatment visit. There were no significant relationships between individual ECG changes and serum drug concentrations, except for QTc intervals, which decreased slightly with increasing CBZ concentrations. The proportion of patients with ECG parameters outside the normal range at treatment visit was similar to that recorded at baseline. DISCUSSION: Clinically significant ECG changes are not common during treatment with CBZ or LTG in elderly patients with no preexisting significant AV conduction defects.

An international multicenter randomized double-blind controlled trial of lamotrigine and sustained-release carbamazepine in the treatment of newly diagnosed epilepsy in the elderly.

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. METHODS: Patients aged 65 years or older, who had experienced at least two unprovoked partial and/or generalized tonic-clonic seizures, were randomized to receive LTG (n=93) or CBZ (n=92) according to a multicenter double-blind, parallel-group design. Trial duration was 40 weeks and included a 4-week dose escalation followed by a maintenance phase during which dosages could be adjusted according to response. Initial, maintenance and maximum dosages were 25 mg, 100 mg, and 500 mg per day for LTG, and 100 mg, 400 mg, and 2,000 mg per day for CBZ, respectively. The primary end point was retention in the trial. RESULTS: In the LTG group, 68 patients (73%) completed the 40-week study period compared with 61 (67%) in the CBZ group, a nonsignificant difference. Time to withdrawal from any cause did not differ between groups (p=0.34). The number of subjects who completed the 40-week period and were seizure free in the last 20 weeks was 48 (52%) in the LTG group and 52 (57%) in the CBZ group. Adverse events leading to withdrawal occurred in 13 (14%) subjects in the LTG group and 23 (25%) subjects in the CBZ group. CONCLUSION: LTG and CBZ showed comparable effectiveness, with a trend for higher seizure-free rates for CBZ and better tolerability for LTG. Differences in outcome compared with previous trials may be related to different dosing rates and use of a sustained-release formulation for CBZ.

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).

Outcomes research: clinical trials in the elderly.

Very few clinical trials have been done in the elderly. This report reviews results of two completed studies and describes one in progress. The largest published study was a United States Veterans Affairs Administration study in newly diagnosed patients with epilepsy. It compared carbamazepine to gabapentin and lamotrigine, and found that, although equivalent in efficacy, the newer antiepileptic drugs (AEDs) were better tolerated. This study also highlighted many of the difficulties in recruiting and retaining elderly patients in studies, the large number of comorbidities, and the problems of distinguishing seizures in the elderly from other symptoms. Another study of new-onset epilepsy suggested that a large percentage of elderly patients respond to initial AED therapy, but side effect profiles differ. More studies are needed to better define the risk/benefit relationships in elderly patients.

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.