AED Polytherapy Research Articles

Factors associated with alexithymia in adults with epilepsy

PurposeThe relationship between epilepsy and alexithymia, characterized by the inability to feel or express emotion, remains incompletely understood. We investigated alexithymia and its association with epilepsy-related factors in patients with epilepsy (PWE). MethodsIn this cross-sectional study, PWE and healthy control subjects were recruited. Alexithymia was assessed using the Toronto Alexithymia Scale-20 (TAS-20). The Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7) were also administered to assess depression and anxiety, respectively. Mediation analysis was conducted using a two-stage regression method. ResultsNinety adult PWE and 161 healthy control subjects were included in the study. PWE had significantly higher TAS-20 scores (B = 2.445, p = 0.014) than controls, but the prevalence of alexithymia, defined as TAS-20≥61, did not differ between PWE and control subjects after controlling for confounders (15.6% vs. 6.2%, respectively; p = 0.873). Uncontrolled seizures significantly increased alexithymia through depression (B = 3.536, p = 0.006), and this effect was responsible for 61.2% of the total effect on alexithymia. The direct effects of uncontrolled seizures on alexithymia were not significant. In contrast, AED polytherapy had significant direct effects on alexithymia (B = 4.489, p = 0.037) independent of depression. The indirect effects of AED polytherapy via depression did not reach statistical significance (B = 2.371, p = 0.066). ConclusionsAlexithymia was more severe, but not more prevalent, in PWE than in healthy controls. AED polytherapy was directly associated with alexithymia, while uncontrolled seizures were indirectly related to alexithymia through depressive symptoms.

Gelastic seizures not associated with hypothalamic hamartoma: A long-term follow-up study

ObjectiveThe objective of the study was to describe the electroclinical features, seizure semiology, and the long-term evolution of gelastic seizures (GS) not associated with hypothalamic hamartoma (HH). MethodsWe reviewed video-electroencephalogram (video-EEG) recordings from pediatric patients with GS without HH admitted to 14 Italian epilepsy centers from 1994 to 2013. We collected information about age at onset, seizures semiology, EEG and magnetic resonance imaging (MRI) findings, treatment, and clinical outcome in terms of seizure control after a long-term follow-up. ResultsA total of 30 pediatric patients were stratified into two groups according to neuroimaging findings: group 1 including 19 children (63.3%) with unremarkable neuroimaging and group 2 including 11 children with structural brain abnormalities (36.7%). At the follow-up, patients of group 1 showed better clinical outcome both in terms of seizure control and use of AED polytherapy. Our patients showed remarkable clinical heterogeneity, including seizure semiology and epilepsy severity. Electroencephalogram recordings showed abnormalities mainly in the frontal, temporal, and frontotemporal regions without relevant differences between the two groups. Overall, carbamazepine showed good efficacy to control GS. ConclusionsPatients with nonlesional GS have a more favorable outcome with better drug response, less need of polytherapy, and good long-term prognosis, both in terms of seizure control and EEG findings.

Antiepileptic drugs and foetal malformation: analysis of 20 years of data in a pregnancy register

PurposeThis paper reports additional data supplementing earlier publications based on Australian Pregnancy Register (APR) data. MethodOver 20 years, the APR has collected Information on pregnancies in Australian women with epilepsy (WWE), untreated WWE and those taking AEDs for other indications. Contact is by telephone, at set intervals. Treatment is not interfered with. Data are analysed using conventional statistical techniques, confidence interval methods, and logistic regression. ResultsBy 2018, the APR contained details of 2148 pregnancies. AEDs were taken throughout 1972 of the pregnancies (91.8%). The remaining 176 (8.2%) did not receive AEDs, at least early in pregnancy.There were (i) dose-related increased incidences of pregnancies carrying foetal malformations associated with maternal intake of valproate and topiramate when topiramate was a component of AED polytherapy (P < .05), (ii) a similar dose-related trend in relation to carbamazepine intake, (iii) no evidence that levetiracetam and lamotrigine were unsafe from the foetal standpoint, (iv) insufficient data to permit conclusions regarding teratogenicity in relation to other AEDs, and (v) no evidence that pre-conception folate supplementation reduced the hazard of AED-associated foetal malformation. AED polytherapy did not increase foetal hazard unless valproate or topiramate was involved in the AED combination. Genetic factors probably contributed to the malformation hazard. Seizures occurring in earlier pregnancy probably did not contribute to the malformation hazard. ConclusionsIf it were not for the importance of maintaining seizure control, the above findings suggest that it would be better to avoid using certain AEDs, particularly valproate and topiramate, during pregnancy.

Effect of valproic acid on perampanel pharmacokinetics in patients with epilepsy.

We prospectively examined the effect of antiepileptic (AED) cotherapy on steady state plasma concentrations of perampanel (PMP) in epileptic patients. We classified AEDs as strong enzyme inducers (carbamazepine, phenobarbital, phenytoin, oxcarbazepine), not strong enzyme inducers/not inhibitors (levetiracetam, lamotrigine, topiramate, rufinamide, lacosamide, zonisamide, clobazam), and enzyme inhibitors (valproic acid [VPA]). The main outcome was the comparison of PMP plasma concentration to weight-adjusted dose ratio (C/D; [μg/mL]/mgkg-1 d-1 ) among comedication subgroups. From 79 patients (42 females, 37 males) aged (mean± standard deviation) 33±13years (range = 12-66years), 114 plasma samples were collected. Twenty-eight patients (44 samples) were cotreated with enzyme inducers (group A), 21 (27 samples) with not strong enzyme inducers/not inhibitors (group B), 21 (31 samples) with not strong enzyme inducers/not inhibitors + VPA (group C), and 9 (12 samples) with enzyme inducers + VPA (group D). PMP C/D was reduced (-56%, P<.001) in group A (1.79±0.80) versus group B (4.05±2.16) and increased (P<.001) in group C (6.72±4.04) compared with groups A (+275%), B (+66%), and D (2.76±2.00, +143%). Our study documents the unpublished higher PMP C/D in patients cotreated with VPA. These findings have both theoretical relevance, suggesting better characterization of PMP metabolic pathways with ad hoc studies, and clinical usefulness in managing patients on AED polytherapy.

Anti-epileptic drug exposure and risk of foetal death in utero.

To clarify whether anti-epileptic drug exposure during pregnancy is associated with an increased risk of intrauterine foetal death. Analysis of data from 2064 pregnancies with known outcomes included in the Australian Register of Antiepileptic Drugs in Pregnancy, 170 of the pregnancies being unexposed to the drugs in at least the first half of pregnancy. The relative risk (6.46; 95% C.I. 0.90, 46.22) of intrauterine death appeared higher, though not statistically significantly higher, in drug-exposed pregnancies compared with unexposed ones (3.44% vs 0.59%). There was no statistically significantly increased hazard associated with AED polytherapy as compared with monotherapy. Logistic regression analysis showed a statistically significantly increased and dose-related hazard of intrauterine death in relation to carbamazepine exposure. Intrauterine exposure to anti-epileptic drugs, particularly carbamazepine, may be associated with an increased risk of foetal death during pregnancy.

Severity of self-reported insomnia in adults with epilepsy is related to comorbid medical disorders and depressive symptoms.

Few studies have systematically investigated insomnia in adults with epilepsy. We performed a prospective cross-sectional investigation of the prevalence, severity, and comorbidities of insomnia in 90 adults with epilepsy using a battery of self-reported instruments and polysomnography. We quantified insomnia severity using the Insomnia Severity Index (ISI). Fifty-nine of 90 (65.5%) adults with epilepsy reported insomnia (ISI≥8), moderate or severe (ISI≥15) in 28.9%. Good agreement between standard clinical diagnostic criteria and ISI was found for patients with ISI scores <8 and ≥15. Scores on the modified Beck Depression Inventory (mBDI) (r=0.25, p=0.021), the original BDI (r=0.32, p=0.002), and self-reported total sleep duration (TSD) (r=-0.3, p=0.006) were significantly related to ISI score. A multiple regression model found that decreased TSD (ß=-0.93, p=0.007), head trauma (ß=4.37, p=0.003), sedative-hypnotic use (ß=4.86, p=0.002), AED polytherapy (ß=3.52, p=0.005), and asthma/COPD (ß=3.75, p=0.014) were predictors of a higher ISI score. For 63 patients with focal epilepsy, an increased mBDI (ß=0.24, p=0.015), decreased TSD (ß=-1.11, p=0.008), asthma/COPD (ß=4.19, p=0.02), and epilepsy surgery (ß=5.33, p=0.006) were significant predictors of an increased ISI score. Patients with temporal lobe epilepsy (TLE) showed a trend for greater severity compared with those with extra-TLE (ß=-2.92, p=0.054). Our findings indicate that severity of insomnia in adults with epilepsy is more likely to be associated with comorbid medical and depressive symptoms and less likely to be directly related to epilepsy. Good agreement between standard clinical diagnostic criteria for insomnia and the ISI for subjects without insomnia symptoms and for those with moderate-to-severe symptoms supports the use of this instrument in epilepsy research.

8. Evaluation of counselling received by women with epilepsy in their reproductive years and management in pregnancy

Objective The primary outcome of the study was to evaluate whether women with epilepsy (WWE) of reproductive age received counselling before conception, including issues such as folate supplementation, antiepileptic drug selection (AED) and their potential teratogenic risks. Background WWE of reproductive age should be counselled regarding their condition and the potential complications of pregnancy associated with epilepsy and AEDs, considering that 50% of pregnancies are unplanned. Design/methods We retrospectively reviewed 64 consecutive medical charts of WWE between the ages of 13 and 50, who were followed prior to conception, and managed during pregnancy at the Centre Hospitalier Universitaire de Sherbrooke (CHUS) between July 1, 2003 to June 30, 2013. Twenty patients were excluded primarily due to referral to the CHUS only after conception. Forty-two patients, encompassing 62 pregnancies were included. Maternal and neonatal charts were thoroughly reviewed and information was collected on an Excel spreadsheet. The protocol was approved by the Ethics review Board of the CHUS. We described our population regarding pre-conception counselling, dose of folate supplementation taken, type, dose and quantity of AEDs, control of seizure in the year preceding pregnancy as well as throughout pregnancy, maternal and neonatal complications or malformations. We evaluated whether those who received counselling before pregnancy were less likely to be taking Valproic acid (VPA) during pregnancy, have less seizures during pregnancy and less complications during pregnancy and delivery. Results Counselling before conception was documented in 45/62 (72.6%) of medical charts. Folate supplementation before pregnancy was prescribed in 44/62 (71%) pregnancies. Risks of complications were formally documented in 27/62 (43%) of charts. There were no statistically significant differences between those receiving counselling and those that did not, in terms of seizure frequency during pregnancy, and VPA use. Interestingly, of the 15 (100%) women on an AED polytherapy, all received counselling compared to those who did not ( p = 0.006). There were no statistically significant differences regarding maternal and neonatal complications for women on polytherapy, those on VPA or women with seizure during pregnancy, compared to their counterparts. Two cases of malformations were detected and one woman died unexpectedly at 18 weeks of pregnancy. Between 2003 and 2008 there were 11/34 (32%) women on VPA compared to 2/26 (7%) between 2009 and 2013, p = 0.026. Conclusion This study has shown that the rate of counselling received by WWE at our centre was satisfactory, but remains an area that can be improved. Physicians should more actively be prescribing folate supplementation to this population due to the high rate of unexpected pregnancies. More attention should be placed in formally documenting important discussions about risks of epilepsy and AED. We plan to raise awareness of these issues to the healthcare professionals at our center who are involved in the care of WWE during their reproductive years.

SAFETY AND EFFICACY OF ESLICARBAZEPINE ACETATE (ZEBINIX) IN EVERYDAY CLINICAL PRACTICE USING A RETROSPECTIVE MULTICENTRE AUDIT

Purpose We report on the safety and efficacy of eslicarbazepine acetate (ESL) in routine clinical practice. Method Retrospective multicentre audit of outcomes following ESL treatment for localisation-related epilepsy across 7 UK sites (2009–2013). Results 201 patients with median values for age 43.0 (18–83) years; duration of epilepsy 17.0 (0–65) years; 2 (0–4) concomitant AEDs, 12 months (2 days-53 months) duration of ESL treatment and 0–12 (87.1% ≥2) previous AED exposures. ESL dosage ranged from 400–1600 mg/day. Baseline seizure types comprised secondarily generalised tonic-clonic seizures (78.1%), complex partial seizures (74.1%) and simple partial seizures (23.4%). Psychiatric comorbidity was reported in 29.9% of patients, most commonly mood disorders. 101 patients (50.2%) experienced ≥50% seizure frequency reduction. 39 subjects (19.4%) became seizure free, of whom 11 (28.2%) had 0–1 previous AED exposures. ESL was discontinued in 70 patients (34.8%) for reasons related to tolerability (n=43), efficacy (n=7), both (n=4) or other (n=16). Adverse events (AEs) were fatigue (18.9%), dizziness (10.0%) and disturbance in attention/concentration (9.0%); most were observed with AED polytherapy. Psychiatric and behavioural AEs (n=6, 3.0%) included suicidal ideation (n=1) and led to ESL withdrawal in 2 patients (1.0%). Hyponatraemia was reported (n=14, 7.0%) and led to discontinuation in 4 patients (2.0%). Conclusion ESL has comparable efficacy to other AEDs for partial-onset seizures with or without secondary generalisation. Discontinuation due to tolerability was mainly related to AED polytherapy. Reported AEs were consistent with ESL9s known safety profile. The benign neuropsychiatric profile with once-daily dosing may convey some advantage in AED selection.

Antiepileptic drug use during pregnancy: Perinatal outcomes

Purpose This study was undertaken to (1) measure the frequency of AED monotherapy or polytherapy during pregnancy and AED discontinuation prior to pregnancy in a cohort of women with treated epilepsy; and (2) describe the frequency of major congenital malformations according to maternal use of AED during pregnancy. Methods A cohort of epileptic pregnant women was identified within the Quebec Pregnancy Registry and was divided into three groups based on maternal AED use during pregnancy: AED monotherapy, AED polytherapy and no AED use. Results Of the 349 pregnancies meeting eligibility criteria, 79.6% were exposed to AED monotherapy and 5.8% to polytherapy during pregnancy; 14.6% discontinued AED prior to pregnancy. The most commonly used AEDs were carbamazepine (29.9%) and valproic acid (19.7%); the most common AED polytherapy combination was carbamazepine combined with clobazam (2.5%). Of 111 deliveries in the group of women on monotherapy during pregnancy, 9.9% ( n = 11) were born with major congenital malformations; in the group of women treated with polytherapy, 19.0% ( n = 8 over 42) of babies had major congenital malformations compared to 20.0% in women who discontinued AEDs prior to pregnancy. Conclusion This study demonstrates that the majority of women suffering from epilepsy were treated with monotherapy rather than polytherapy during pregnancy. While most used other agents, an important number of women continued to use valproate in pregnancy despite the long standing evidence of its teratogenicity and increasing evidence of its neuro-toxicity to the fetus.

AED polytherapy a significant factor in infertility

AED polytherapy a significant factor in infertility

Population-based study of antiepileptic drug exposure in utero—Influence on head circumference in newborns

Purpose To study the effect of AED exposure on head circumference in the newborn. Methods Data on all Swedish singletons births between 1995 and 2005, over 900,000 births, were obtained from the Swedish Medical Birth Registry. The effects of AEDs on birth-weight-adjusted mean head circumference (bw-adj-HC) were estimated by comparison with data from all births in an analysis which was adjusted for year of birth, maternal age, parity, maternal smoking, and maternal body mass index. Results A significant reduction of mean bw-adj-HC was seen after both carbamazepine (CBZ) (standard deviation scores (SDS) = 0.15, p < 0.001) and valproic acid (VPA) (SDS = 0.10, p = 0.04) in monotherapy. No effect on mean bw-adj-HC was seen for phenytoin, clonazepam, lamotrigine and gabapentin. There was a significant increase in the occurrence of microcephaly (bw-adj-HC smaller than 2 SD below the mean) after any AED polytherapy (OR = 2.85, 95% CI: 1.74–4.78) but not after AED monotherapy or monotherapy with CBZ or VPA. CBZ or VPA was taken by 71% of the pregnant mothers on AED, and the usage increased over time. Conclusions CBZ and VPA in monotherapy during pregnancy reduce mean bw-adj-HC. AED polytherapy increases the rate of microcephaly but no significant effect is seen of AED monotherapy. The possible significance for the further development of the child is uncertain but should be explored.

Truly "rational" polytherapy: maximizing efficacy and minimizing drug interactions, drug load, and adverse effects.

While several newer AEDs have study data that support monotherapy usage, most possess FDA indications for adjunctive treatment of partial onset seizures, leading to their initial (and often persistent) clinical use as adjunctive polytherapy for patients with refractory epilepsy. This review considers a practical approach to the appropriate role for polytherapy in epilepsy, presents the evidence for AED polytherapy, reviews the mythic but practically reasonable concept of “rational polytherapy,” and concludes with practical strategies for avoiding and employing polytherapy in clinical practice. The appropriate indications for AED polytherapy include transitional polytherapy during titration of a new adjunctive AED toward monotherapy or long-term maintenance AED polytherapy in medically refractory epilepsy.

Pattern of adverse drug reactions to anti‐epileptic drugs: a cross‐sectional one‐year survey at a tertiary care hospital

To investigate pattern and extent of adverse drug reactions (ADRs) associated with AEDs and to identify safer options for treatment of epilepsy. Study was a retrospective, cross-sectional survey. Data from patients with epilepsy at the out-patient and in-patient of Neurology Department was collected in a specially designed proforma. Causality and severity of ADRs was categorized as per WHO guidelines. Among 788 patients with epilepsy, 80 (10.27%) had ADRs. ADRs with AED monotherapy were 9.18% and with polytherapy were 11.56%. ADRs with conventional and newer AED monotherapy was 10.24% and 6.84%, respectively, and were maximum with phenytoin and clobazam (14.28% and 12.5%). ADRs were mild in 4.16%, moderate in 70.83% and severe in 25% patients. Causality was probable in 65.62%, possible in 13.54% and definite in 20.83%. Patients (15/80) were hospitalized due to ADRs. Age and gender distribution showed statistically significant difference in occurrence of ADRs (p < 0.05). Chi-square test for poly versus monotherapy and conventional versus newer AEDs did not show any significant difference. Study showed maximum ADRs with AED polytherapy with no significant difference in frequency and severity of ADRs between conventional versus newer AEDs. This finding needs further investigation in larger number of patients to identify safer treatment options for epilepsy.

2005 AES Annual Course: Evidence Used to Treat Women with Epilepsy

Although most female-specific considerations for treatment of epilepsy cannot be answered by Class I evidence, significant progress in our knowledge base has occurred in the past few years. Open-label studies of progesterone supplementation showed promising results; an ongoing randomized trial may provide definitive evidence for therapeutic use of progesterone in women. A randomized trial of hormone replacement therapy demonstrated a dose-related increase in seizure frequency in postmenopausal women with epilepsy. The use of different AED regimens during pregnancy cannot be explored with randomized, controlled trials; we must rely on the best available evidence from ongoing observational studies. The consistent findings of large prospective pregnancy registries reveal a consistent pattern of amplified risk for major congenital malformations in pregnancies exposed to valproate. These registries have also highlighted the concern for the effect of shifting hormones on AED concentrations. An increased frequency of seizures during pregnancy has been noted with lamotrigine (LTG) and oxcarabazepine, both of which undergo glucuronidation. Other studies have demonstrated an increased clearance of LTG during pregnancy and with exogenous estrogen use. It may be prudent to closely monitor serum concentrations of these AEDs with hormonal changes. An increased risk for neurodevelopmental consequences has been demonstrated for the fetus exposed to AED polytherapy, valproic acid, or frequent maternal convulsive seizures. Preliminary information about breastfeeding with LTG and levetiracetam is available. These newly released findings provide the tools to begin to practice evidence-based medicine when treating our female patients during their reproductive and postmenopausal years.

Cognitive profile of topiramate as compared with lamotrigine in epilepsy patients on antiepileptic drug polytherapy: relationships to blood serum levels and comedication

Rationale This retrospective study was conducted to identify cognitive domains affected by topiramate (TPM), and to evaluate the role of blood serum levels of TPM and comedication in the etiology of TPM-induced cognitive impairment. Methods Forty-two patients on AED polytherapy containing topiramate and a random sample of 42 patients with lamotrigine as the corresponding agent underwent extensive neuropsychological testing. Current blood serum levels of TPM were correlated with test scores. Results Patients on TPM scored significantly worse in phonematic verbal fluency, memory spans, and working memory; language and memory function were not affected per se. In few cognitive domains, serum levels of TPM and performance were correlated before correction for multiple testing. Drug load of additional medication did not account for differences between or within groups. Discussion Consistent with previous reports, patients on AED polytherapy including TPM display a cognitive pattern with specific impairment in executive functions. The severity of the cognitive side effects of TPM may be related to dosing to a certain extent, but this relationship may be disclosed only with larger sample sizes. Accordingly, TPM dosage does not appear to be a good indicator of TPM-related cognitive side effects in the individual patient.

Choreoathetosis with Gabapentin

A 37-year-old man with severe mental retardation since birth and intractable epilepsy treated with AED polytherapy developed choreoathetosis and orofacial dyskinesia within 5 days of introducing gabapentin (GBP) at the Department of Neurology, West Virginia University, Morgantown, WV.