Aline Russell

Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register

Objective: To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AEDs). Methods: Prospective data collected by the UK Epilepsy and Pregnancy Register were analysed. The presence of MCMs recorded within the first three months of life was the main outcome measure. Results: Full outcome data were collected on 3607 cases. The overall MCM rate for all AED exposed cases was 4.2% (95% confidence interval (CI), 3.6% to 5.0%). The MCM rate was higher for polytherapy (6.0%) (n = 770) than for monotherapy (3.7%) (n = 2598) (crude odds ratio (OR) = 1.63 (p = 0.010), adjusted OR = 1.83 (p = 0.002)). The MCM rate for women with epilepsy who had not taken AEDs during pregnancy (n = 239) was 3.5% (1.8% to 6.8%). The MCM rate was greater for pregnancies exposed only to valproate (6.2% (95% CI, 4.6% to 8.2%) than only to carbamazepine (2.2% (1.4% to 3.4%) (OR = 2.78 (p<0.001); adjusted OR = 2.97 (p<0.001)). There were fewer MCMs for pregnancies exposed only to lamotrigine than only to valproate. A positive dose response for MCMs was found for lamotrigine (p = 0.006). Polytherapy combinations containing valproate carried a higher risk of MCM than combinations not containing valproate (OR = 2.49 (1.31 to 4.70)). Conclusions: Only 4.2% of live births to women with epilepsy had an MCM. The MCM rate for polytherapy exposure was greater than for monotherapy exposure. Polytherapy regimens containing valproate had significantly more MCMs than those not containing valproate. For monotherapy exposures, carbamazepine was associated with the lowest risk of MCM.

Topiramate in pregnancy - Preliminary experience from the UK epilepsy and pregnancy register

Objectives: Topiramate (Topamax®) is licensed to be used, either in monotherapy or as adjunctive treatment, for generalized tonic clonic seizures or partial seizures with or without secondary generalization and for prevention of migraine. The safety of topiramate in human pregnancy is largely unknown. Here we report on our experience of pregnancies exposed to topiramate. Methods: This study is part of a prospective, observational, registration and follow-up study. Suitable cases are women with epilepsy who become pregnant while taking topiramate either singly or along with other antiepileptic drugs (AEDs), and who are referred before outcome of the pregnancy is known. The main outcome measure is the major congenital malformation (MCM) rate. Secondary outcomes include risk of specific MCM, minor malformation rate, birthweight, and gestational age at delivery. Results: Full outcome data are available on 203 pregnancies. Of these, 178 resulted in live birth; 16 had an MCM (9.0%; 95% CI 5.6% to 14.1%). Three MCMs were observed in 70 monotherapy exposures (4.8%; 95% CI 1.7% to 13.3%) and 13 in cases exposed to topiramate as part of a polytherapy regimen (11.2%; 95% CI 6.7% to 18.2%). Four of the MCMs were oral clefts (2.2%; 95% CI 0.9% to 5.6%). Four cases of hypospadias were reported (5.1%; 95% CI 0.2% to 10.1%) among 78 known live male births of which two were classified as major malformations. Conclusions: The number of outcomes of human pregnancies exposed to topiramate is low, but the major congenital malformation rate for topiramate polytherapy raises some concerns. Overall, the rate of oral clefts observed was 11 times the background rate. Although the present data provide new information, they should be interpreted with caution due to the sample size and wide confidence intervals.

Early outcomes and predictors in 260 patients with psychogenic nonepileptic attacks

Objective: To determine short-term outcome and its predictors in patients with psychogenic nonepileptic attacks (PNEA). Methods: Retrospective cohort study of outcomes relating to attendance at follow-up, spells, use of emergency services, employment, and social security payments recorded at 6 and 12 months post diagnosis in 260 consecutive patients. Results: A total of 187 patients (71.9%) attended at least 1 follow-up visit, and 105 patients (40.4%) attended 2. A total of 71/187 patients (38.0%) were spell-free at last follow-up. In contrast, 35/187 patients (18.7%) had marked increase in spell frequency postdiagnosis. Delay to diagnosis had no relationship to outcome. Patients with anxiety or depression were 2.32 times less likely to become spell-free (p = 0.012), and patients drawing social security payments at baseline were 2.34 times less likely to become spell-free (p = 0.014), than patients without those factors. Men were 2.46 times more likely to become spell-free than women (p = 0.016). While 93/187 patients (49.7%) were using emergency medical services at baseline, only 29/187 (15.5%) were using them at follow-up (p < 0.001). This was independent of whether or not the patient became spell-free. Conclusion: A substantial minority of our patients became spell-free with communication of the diagnosis the only intervention. Previous psychiatric diagnoses, social security payments, and gender were important predictors of outcome. Most patients stopped using emergency services, irrespective of whether or not spells continued. Outcomes other than spell frequency may be important in patients with psychogenic nonepileptic attacks.

Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers

Objectives Antiepileptic drug (AED) exposure during pregnancy increases the risk of major congenital malformations (MCMs). The magnitude of this risk varies by AED exposure. Here we provide updated results from the UK Epilepsy and Pregnancy Register of the risk of MCMs after monotherapy exposure to valproate, carbamazepine and lamotrigine. Methods Fifteen-year prospective observational study from 1996 until 2012. The main outcome measure is the MCM rate. Results Informative outcomes were available for 5206 cases. 1290 women were exposed to valproate monotherapy, 1718 to carbamazepine monotherapy and 2198 to lamotrigine monotherapy. The MCM risk with valproate monotherapy exposure in utero was 6.7% (95% CI 5.5% to 8.3%) compared with 2.6% with carbamazepine (95% CI 1.9% to 3.5%) and 2.3% with lamotrigine (95% CI 1.8% to 3.1%). A significant dose effect was seen with valproate (p=0.0006) and carbamazepine (p=0.03) exposed pregnancies. A non-significant trend towards higher MCM rate with increasing dose was found with lamotrigine. MCM rate for high-dose lamotrigine (>400 mg daily) was lower than the MCM rate for pregnancies exposed to <600 mg daily of valproate, but this was not significant (3.4% vs 5.0%, p=0.31). Conclusions In utero exposure to valproate carries a significantly higher MCM risk than lamotrigine (p=0.0001) and carbamazepine (p=0.0001) monotherapy. In contrast to prior findings, high-dose lamotrigine was associated with fewer MCMs than all doses of valproate. While lamotrigine has a favourable profile compared with valproate for adverse pregnancy outcomes, the requirements for seizure control should not be overlooked.

Outpatient video EEG recording in the diagnosis of non-epileptic seizures: a randomised controlled trial of simple suggestion techniques

Objective: To assess the yield of recorded habitual non-epileptic seizures during outpatient video EEG, using simple suggestion techniques based on hyperventilation and photic stimulation. Design: Randomised controlled trial of “suggestion” v “no suggestion” during outpatient video EEG recording. Setting: Regional epilepsy service (tertiary care; single centre). Participants: 30 patients (22 female, 8 male), aged over 16 years, with a probable clinical diagnosis of non-epileptic seizures; 15 were randomised to each group. Main outcome measures: Yield of habitual non-epileptic seizures recorded, and requirement for additional inpatient video EEG. Results: 10/15 patients had habitual non-epileptic seizures with suggestion; 5/15 had non-epileptic seizures with no suggestion (p = 0.058; NS); 8/9 patients with a history of previous events in medical settings had non-epileptic seizures recorded during study. Logistic regression analysis with an interaction clause showed a significant effect of suggestion in patients with a history of previous events in medical settings (p = 0.003). An additional inpatient video-EEG was avoided in 14 of the 30 patients (47%). Conclusions: Habitual non-epileptic seizures can be recorded reliably during short outpatient video EEG in selected patients. Simple (non-invasive) suggestion techniques increase the yield at least in the subgroup with a history of previous events in medical settings. Inpatient video EEG can be avoided in some patients.

Levetiracetam in pregnancy Results from the UK and Ireland epilepsy and pregnancy registers

Objectives: Levetiracetam is a broad-spectrum antiepileptic drug (AED) which is currently licensed in the United States and the United Kingdom and Ireland for use as adjunctive treatment of focal-onset seizures and myoclonic seizures or generalized tonic-clonic seizures, occurring as part of generalized epilepsy syndromes. In the United Kingdom and Ireland, it is also licensed as monotherapy treatment for focal-onset seizures. Previous small studies have suggested a low risk for major congenital malformations (MCM) with levetiracetam use in pregnancy. Methods: The UK and Ireland Epilepsy and Pregnancy Registers are prospective, observational registration and follow-up studies that were set up to determine the relative safety of all AEDs taken in pregnancy. Here we report our combined results for first-trimester exposures to levetiracetam from October 2000 to August 2011. Results: Outcome data were available for 671 pregnancies. Of these, 304 had been exposed to levetiracetam in monotherapy, and 367 had been exposed to levetiracetam in combination with at least one other AED. There were 2 MCM in the monotherapy group (0.70%; 95% confidence interval [CI] 0.19%–2.51%) and 19 in the polytherapy group (6.47%; 4.31%–9.60%). The MCM rate in the polytherapy group varied by AED regimen, with lower rates when levetiracetam was given with lamotrigine (1.77%; 95% CI 0.49%–6.22%) than when given with valproate (6.90%; 95% CI 1.91%–21.96%) or carbamazepine (9.38%; 95% CI 4.37%–18.98%). Conclusion: This study, in a meaningful number of exposed pregnancies, confirms a low risk for MCM with levetiracetam monotherapy use in pregnancy. MCM risk is higher when levetiracetam is taken as part of a polytherapy regimen, although further work is required to determine the risks of particular combinations. With respect to MCM, levetiracetam taken in monotherapy can be considered a safer alternative to valproate for women with epilepsy of childbearing age.

Folic acid use and major congenital malformations in offspring of women with epilepsy. A prospective study from the UK Epilepsy and Pregnancy Register.

Objective: In the general population, folic acid supplementation during pregnancy has been demonstrated to reduce the frequency of neural tube defects (NTDs) and other major congenital malformations (MCMs). It is recommended that women with epilepsy contemplating pregnancy take supplemental folic acid because of the known antifolate effect of some antiepileptic drugs (AEDs). Here the aim was to determine the effectiveness of this practice. Methods: This study is part of a prospective, observational, registration and follow-up study. Suitable cases are women with epilepsy who become pregnant and who are referred before outcome of the pregnancy is known. The main outcome measure is the MCM rate. Outcomes were analysed against folic acid exposure, malformation type and drug group for the most commonly used monotherapy AEDs. Results: In 1935 cases reported to have received preconceptual folic acid, 76 MCMs (3.9%; 95% CI 3.1 to 4.9) and eight NTDs (0.4%; 95% CI 0.2 to 0.8) were identified. For 2375 women who were reported to have received folic acid but not until later in the pregnancy (n = 1825) or not at all (n = 550), there were 53 outcomes with an MCM (2.2%; 95% CI 1.7 to 2.9) and eight NTDs (0.34%; 95% CI 0.2 to 0.7). Conclusions: The study supports the view that extrapolation from studies carried out in the general population to groups of women with epilepsy may be questionable. It may be that the increased risk of MCM recorded in this group occurs through mechanisms other than that of folic acid metabolism.

Gender differences in psychogenic non-epileptic seizures

PURPOSE To determine whether male and female populations of patients with psychogenic non-epileptic seizures (PNES) are similar, in terms of demographic and social factors, aetiological factors, the clinical characteristics of events and path to diagnosis. METHODS Prospective study by semi-structured interview of 160 consecutive patients (117 female and 43 male) with video EEG confirmed diagnosis of PNES + epileptic seizures (ES). RESULTS Most parameters showed no significant differences. Males were, however, more likely to be unemployed (P = 0.028), and females were six times more likely to self-harm (P = 0.050), though the numbers were small in these categories. Men were more likely to attribute their PNES to a predisposing factor for epilepsy (P = 0.001), and women were over eight times more likely to report sexual abuse (P = 0.001). Event semiology was similar, but women were more likely to weep after events (P = 0.017). The carers and family of men with PNES were three times less likely to accept the diagnosis of PNES (P = 0.017). CONCLUSIONS Our samples showed few significant gender differences, suggesting that other male and female populations of patients with PNES are likely to be similar also. Some of the differences we found may give insight into causation of PNES.

Pseudosleep events in patients with psychogenic non-epileptic seizures: prevalence and associations

Objectives: To determine the prevalence and clinical associations of a history of events during sleep in patients with psychogenic non-epileptic seizures (PNES, pseudoseizures), and to compare the prevalence of a history of sleep events with that in poorly controlled epilepsy. Methods: Prospective study by semistructured interview of the history of event patterns and their clinical associations in 142 patients with video EEG confirmed PNES, and 100 patients with poorly controlled epilepsy. Results: 84/142 patients with PNES (59%) and 47/100 with epilepsy (47%) gave a history of events during sleep (p = 0.062). In patients with PNES, significant associations were found between a history of sleep events and: convulsive clinical semiology, antiepileptic drug treatment, fatigue, suicide attempts, mood disorder, and physical abuse. A particularly strong association with social security benefit was also found (odds ratio 4.0, p<0.001). Conclusions: The prevalence of a history of sleep events is similar in PNES and epilepsy, and is of no value in discriminating between the two, although a history of events occurring exclusively during sleep does suggest epileptic seizures. The clinical associations found indicate that a combination of psychopathological and external influences may be important in determining whether or not a patient with PNES gives a history of events during sleep.

Spatiotemporal patterns of electrocorticographic very fast oscillations (>80 Hz) consistent with a network model based on electrical coupling between principal neurons

Purpose:  We sought to characterize spatial and temporal patterns of electrocorticography (ECoG) very fast oscillations (> ∼80 Hz, VFOs) prior to seizures in human frontotemporal neocortex, and to develop a testable network model of these patterns.