James Morrow

The development of a seizure severity scale as an outcome measure in epilepsy

In controlled trials of antiepileptic drugs (AEDs) seizure frequency is often the only variable considered. With little prospect of improving assessment of AEDs, using seizure counts as the only end-point, there is a need for the development of new outcome measures. Clinical experience indicates that seizure severity is equally important to the patient and, by preventing seizure spread, AEDs can influence seizure severity without necessarily reducing seizure frequency. A scale capable of measuring seizure severity and change of severity attributable to treatment could be a useful additional outcome measure. Such a scale should exhibit the basic properties of validity and reliability. An easily administrable 16-point scale, containing 2 subscales--perception of control and ictal/post-ictal effects--has been developed. This scale has been tested on a patient population (n = 159) representative of that seen in trials of novel AEDs. Using standardised statistical methods, the scale has been shown to be both reliable and valid.

Best practice guidelines for the management of women with epilepsy

Clinical guidelines for the treatment of epilepsy have been published. A statement on management issues for women with epilepsy has recently been produced by the American Academy of Neurology which has raised awareness of the issues facing women with epilepsy. The communication presented here aims to review current literature on specific issues relating to women with epilepsy, and proposes graded recommendations for its management within a UK health care framework.

Child development following in utero exposure Levetiracetam vs sodium valproate

Objective: Children born to women with epilepsy (WWE), exposed in utero to levetiracetam (LEV, n = 51), were assessed for early cognitive development and compared to children exposed to sodium valproate in utero (VPA, n = 44) and a group of children representative of the general population (n = 97). Methods: Children were recruited prospectively from 2 cohorts in the United Kingdom and assessed using the Griffiths Mental Development Scale (1996), aged <24 months. Information regarding maternal demographics were collected and controlled for. This is an observational study with researchers not involved in the clinical management of the WWE. Results: On overall developmental ability, children exposed to LEV obtained higher developmental scores when compared to children exposed to VPA (p < 0.001). When compared, children exposed to LEV did not differ from control children (p = 0.62) on overall development. Eight percent of children exposed to LEV in utero fell within the below average range (DQ score of <84), compared with 40% of children exposed to VPA. After controlling for maternal epilepsy and demographic factors using linear regression analysis, exposure to LEV in utero was not associated with outcome (p = 0.67). Conversely, when compared with VPA exposure, LEV exposure was associated with higher scores for the overall developmental quotient (p < 0.001). Conclusion: Children exposed to LEV in utero are not at an increased risk of delayed early cognitive development under the age of 24 months. LEV may therefore be a preferable drug choice, where appropriate, for WWE prior to and of childbearing age.

Adjunctive treatment of partial seizures with tiagabine: A placebo-controlled trial

Tiagabine is a new antiepileptic drug which acts by a novel mechanism, inhibiting the reuptake of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into neurons and glia. A double-blind, placebo-controlled, crossover trial was undertaken, based upon a response-dependent design. Ninety-four patients with complex partial seizures with or without secondary generalised tonic-clonic seizures were recruited into an open screening phase and tiagabine was added to their existing drug therapy in doses titrated to reduce seizure frequency by > or = 25% or to the limit of tolerance. Forty-six responders were subsequently randomised to a double-blind crossover trial in which tiagabine was compared with placebo. Forty-two patients completed the trial. A significant reduction in the frequency of complex partial and secondary generalised tonic clonic seizures was seen. Twenty-six percent had a reduction of > or = 50% in the frequency of their complex partial seizures, and of the 27 patients who also had secondary generalised tonic clonic seizures, 63% experienced a reduction of > or = 50%. No interactions with baseline antiepileptic drugs were detected and no serious adverse reactions occurred. The commonest adverse events were tiredness, dizziness and headache. We conclude that tiagabine has promising antiepileptic effects. Further trials are underway.

In utero exposure to levetiracetam vs valproate Development and language at 3 years of age

Objective: To compare the cognitive and language development of children born to women with epilepsy (WWE) exposed in utero to levetiracetam (LEV) or sodium valproate (VPA) and control children born to women without epilepsy not taking medication during pregnancy. Methods: The children, aged between 36 and 54 months, were recruited from the United Kingdom and assessed using the Griffiths Mental Development Scales and the Reynell Language Development Scale. Maternal demographic and epilepsy information was also collected for use in statistical regression. This is an observational study with researchers not involved in the clinical management of the mothers enrolled. Results: After controlling for confounding variables, children exposed to LEV in utero (n = 53) did not differ from unexposed control children (n = 131) on any scale administered. Children exposed to VPA (n = 44) in utero scored, on average, 15.8 points below children exposed to LEV on measures of gross motor skills (95% confidence interval [CI] −24.5 to −7.1, p < 0.001), 6.4 points below on comprehension language abilities (95% CI −11.0 to −1.8, p = 0.005), and 9.5 points below on expressive language abilities (95% CI −14.7 to −4.4, p < 0.001). Conclusion: The current study indicates that children exposed to LEV in utero were superior in their language and motor development in comparison to children exposed to VPA. This information should be used collaboratively between health care professionals and WWE when deciding on womens preferred choice of antiepileptic drug.

Anti-epileptic drugs in pregnancy: current safety and other issues.

Women with epilepsy of child-bearing years have their own considerations, which must be taken into account if management of their epilepsy is to be optimised. The main issues to consider include the effects of: female hormones on seizure control, anti-epileptic drugs (AEDs) on hormonal methods of contraception, epilepsy and AEDs on fertility, epilepsy and AEDs on pregnancy itself, pregnancy on AEDs and seizure control and epilepsy, seizures and AEDs on the developing embryo/fetus. Whereas previous studies have concentrated on the increased risk of major congenital malformations from prenatal AED exposure, the effects on cognitive and behavioural development are increasingly being explored. This article looks at the evidence currently available for all of the above issues, taking into account the increased number of AEDs which are now available.

Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate

Objective: To investigate the effects of prenatal exposure to monotherapy levetiracetam, topiramate, and valproate on child cognitive functioning. Methods: This was a cross-sectional observational study. Children exposed to monotherapy levetiracetam (n = 42), topiramate (n = 27), or valproate (n = 47) and a group of children born to women who had untreated epilepsy (n = 55) were enrolled retrospectively from the UK Epilepsy and Pregnancy Register. Assessor-blinded neuropsychological assessments were conducted between 5 and 9 years of age. Information was collected on demographic and health variables and adjusted for in multiple regression analyses. Results: In the adjusted analyses, prenatal exposure to levetiracetam and topiramate were not found to be associated with reductions in child cognitive abilities, and adverse outcomes were not associated with increasing dose. Increasing dose of valproate, however, was associated with poorer full-scale IQ (−10.6, 95% confidence interval [CI] −16.3 to −5.0, p < 0.001), verbal abilities (−11.2, 95% CI −16.8 to −5.5, p < 0.001), nonverbal abilities (−11.1, 95% CI −17.3 to −4.9, p < 0.001), and expressive language ability (−2.3, 95% CI −3.4 to −1.6, p < 0.001). Comparisons across medications revealed poorer performance for children exposed to higher doses of valproate in comparison to children exposed to higher doses of levetiracetam or topiramate. Conclusions: Preconception counseling should include discussion of neurodevelopmental outcomes for specific treatments and their doses and women should be made aware of the limited nature of the evidence base for newer antiepileptic drugs.

In utero exposure to valproate increases the risk of isolated cleft palate

Introduction Orofacial clefting (OFC) has been described in infants exposed to valproic acid (VPA) prenatally, but often no distinction is made between cleft lip and palate (CLP) and isolated cleft palate (ICP). This distinction is important as these conditions have different management implications and the distinction has implications too for understanding the teratogenic mechanisms. Methods We searched EMBASE, Medline and Web of Science for observational studies describing OFC in association with VPA exposure. Searches for similarly exposed patients referred to a regional genetic centre and those recorded in the UK Epilepsy and Pregnancy Register (UKEPR) were undertaken. Cleft type and, where available, VPA doses prescribed were recorded. Results A total of 4459 cases of VPA exposure were reported in the literature in nine separate studies with 50 cases of OFC, the majority of which did not differentiate the cleft type. Eight patients ascertained through the regional genetic centre had ICP. Thirteen cases of OFC occurred in 1282 VPA monotherapy-exposed pregnancies in the UKEPR; nine had ICP and four had CLP, representing an 11.3-fold and 3.5-fold increase risk in ICP and CLP, respectively, over general population risk. Doses ranged from 200 to 2500 mg VPA daily with 73% of monotherapy ICP cases from the local cohort and UKEPR occurring at doses over 1000 mg. Conclusion ICP is the predominant cleft type seen in prenatal VPA exposure. Parents should be counselled appropriately and infants should undergo review after delivery for ICP. Pregnancy registers collecting information on congenital anomalies should make the distinction between CLP and ICP as the risk differs across the two conditions.

Changing antiepilepsy drug-prescribing trends in women with epilepsy in the UK and Ireland and the impact on major congenital malformations

Objectives After 20 years of data collection, pregnancy registers have informed prescribing practice. Various populations show trends for a reduction in valproate prescribing, which is associated with an increased risk of anatomical teratogenesis and neurodevelopmental effects in those exposed in utero. Our aim was to determine if any shifts in prescribing trends have occurred in the UK and Ireland Epilepsy and Pregnancy Register cohort and to assess if there had been any change in the overall major congenital malformation (MCM) rate over time. Methods The UK and Ireland Epilepsy and Pregnancy Register, a prospective, observational, registration and follow-up study established in 1996, was used to determine the changes in antiepileptic drugs (AEDs) utilised during pregnancy and the MCM rate between 1996 and 2016. Linear regression analysis was used to assess changes in AED utilisation, and Poisson regression was used for the analysis of trends in the MCM rates. Results Outcome data for 9247 pregnancies showed a stable percentage of monotherapy to polytherapy prescribing habits over time. After Bonferroni correction, statistically significant (p<0.003) changes were found in monotherapy prescribing with increases in lamotrigine and levetiracetam and decreases in valproate and carbamazepine use. Between 1996 and 2016, the total MCM rate showed a 2.1% reduction per year (incidence risk ratio 0.979 (95% CIs 0.956 to 1.002) but Poisson regression analysis showed that this was not statistically significant p=0.08). Conclusion Significant changes are seen in the prescribing habits in this cohort over 20 years, but a statistically significant change in the MCM rate was not detected. This work should be replicated on a larger scale to determine if significant changes are occurring in the MCM rate, which would allow a robust economic estimate of the benefits of improvements in prescribing practice and the personal effect of such changes.