Zonisamide safety in pregnancy: Data from the UK and Ireland epilepsy and pregnancy register.

BACKGROUND: Animal data suggest teratogenic effects with zonisamide use and risk of pregnancy losses. Human data following zonisamide exposure are presently limited, but suggest low risk of malformation with elevated risk of low birth weight. OBJECTIVE: To calculate the major congenital malformation (MCM) rate of zonisamide in human pregnancy and assess for a signal of any specific malformation pattern and associations with birth weight. METHODS AND MATERIALS: Data were obtained from the UK and Ireland Epilepsy and Pregnancy register (UKIEPR) which is an observational, registration, and follow up study from December 1996 to July 2020. Eligibility criteria were use of zonisamide and to have been referred to the UKIEPR before the outcome of the pregnancy was known. Primary outcome was evidence of MCM. RESULTS: From December 1996 through July 2020 there were 112 cases of first trimester exposure to zonisamide, including 26 monotherapy cases. There were 3 MCM for monotherapy cases (MCM rate 13.0% (95% confidence interval 4.5-32.1)), and 5 MCM for polytherapy cases (MCM rate 6.9% (95% confidence interval 3.0-15.2)). While the median birth weight was on 71st and 44th centile for monotherapy and polytherapy cases respectively, there was a high rate of infants born small for gestational age (21% for both). CONCLUSION: These data raise concerns about a signal for potential teratogenicity with zonisamide in human pregnancy. Given the low numbers reported, further data will be required to adequately counsel women who use zonisamide in pregnancy.

Sensitivity of the UK Clinical Practice Research Datalink to Detect Neurodevelopmental Effects of Medicine Exposure in Utero: Comparative Analysis of an Antiepileptic Drug-Exposed Cohort.

INTRODUCTION: Electronic healthcare data have several advantages over prospective observational studies, but the sensitivity of data on neurodevelopmental outcomes and its comparability with data generated through other methodologies is unknown. OBJECTIVES: The objectives of this study were to determine whether data from the UK Clinical Practice Research Datalink (CPRD) produces similar risk estimates to a prospective cohort study in relation to the risk of neurodevelopmental disorders (NDDs) following prenatal antiepileptic drug (AED) exposure. METHODS: A cohort of mother-child pairs of women with epilepsy (WWE) was identified in the CPRD and matched to a cohort without epilepsy. The study period ran from 1 January 2000 to 31 March 2007 and children were required to be in the CPRD at age 6 years. AED exposure during pregnancy was determined from prescription data and children with an NDD diagnosis by 6 years were identified from Read clinical codes. The prevalence and risk of NDDs was calculated for mother-child pairs in WWE stratified by AED regimen and for those without epilepsy. Comparisons were made with the results of the prospective Liverpool and Manchester Neurodevelopment Group study which completed assessment on 201 WWE and 214 without epilepsy at age 6 years. RESULTS: In the CPRD, 1018 mother-child pairs to WWE and 6048 to women without epilepsy were identified. The CPRD identified a lower prevalence of NDDs than the prospective study. In both studies, NDDs were more frequently reported in children of WWE than women without epilepsy, although the CPRD risk estimate was lower (2.16 vs. 0.96%, p < 0.001 and 7.46 vs. 1.87%, p = 0.0128). NDD prevalence differed across AED regimens but the CPRD data did not replicate the significantly higher risk of NDDs following in utero monotherapy valproate exposure (adjusted odds ratio [ORadj] 2.02, 95% confidence interval [CI] 0.52-7.86) observed in the prospective study (ORadj 6.05, 95% CI 1.65-24.53). CONCLUSION: It was possible to identify NDDs in the CPRD; however, the CPRD appears to under-record these outcomes. Larger studies are required to investigate further.

Who gains clinical benefit from using insulin pump therapy? A qualitative study of the perceptions and views of health professionals involved in the Relative Effectiveness of Pumps over MDI and Structured Education (REPOSE) trial.

AIMS: To explore health professionals' views about insulin pump therapy [continuous subcutaneous insulin infusion (CSII)] and the types of individuals they thought would gain greatest clinical benefit from using this treatment. METHODS: In-depth interviews with staff (n = 18) who delivered the Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial. Data were analysed thematically. RESULTS: Staff perceived insulin pumps as offering a better self-management tool to some individuals due to the drip feed of insulin, the ability to alter basal rates and other advanced features. However, staff also noted that, because of the diversity of features on offer, CSII is a more technically complex therapy to execute than multiple daily injections. For this reason, staff described how, alongside clinical criteria, they had tended to select individuals for CSII in routine clinical practice based on their perceptions about whether they possessed the personal and psychological attributes needed to make optimal use of pump technology. Staff also described how their assumptions about personal and psychological suitability had been challenged by working on the REPOSE trial and observing individuals make effective use of CSII who they would not have recommended for this type of therapy in routine clinical practice. CONCLUSIONS: Our findings add to those studies that highlight the difficulties of using patient characteristics and variables to predict clinical success using CSII. To promote equitable access to CSII, attitudinal barriers and prejudicial assumptions amongst staff about who is able to make effective use of CSII may need to be addressed.

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.

Patients' perspectives on antiepileptic medication: relationships between beliefs about medicines and adherence among patients with epilepsy in UK primary care.

BACKGROUND: Nonadherence to antiepileptic drugs (AEDs) can result in suboptimal outcomes for patients. AIM: This study aimed to assess the utility of a theory-based approach to understanding patient perspectives on AEDs and adherence. METHOD: Patients with epilepsy, identified by a GP case note review, were mailed validated questionnaires assessing their perceptions of AEDs and their adherence to them. RESULTS: Most (84.9%) of the 398 AED-treated respondents accepted the necessity of AEDs, but over half expressed doubts, with 55% disagreeing or uncertain about the statement 'I would prefer to take epilepsy medication than risk a seizure'. Over a third (36.4%) expressed strong concerns about the potential negative effects of AEDs. We used self-report and medication possession ratio to classify 36.4% of patients as nonadherent. Nonadherence was related to beliefs about medicines and implicit attitudes toward AEDs (p<0.05). Adherence-related attitudes toward AEDs were correlated with general beliefs about pharmaceuticals (BMQ General: General Harm, General Overuse, and General Benefit scales) and perceptions of personal sensitivity to medicines (PSM scale). CONCLUSION: We identified salient, adherence-related beliefs about AEDs. Patient-centered interventions to support medicine optimization for people with epilepsy should take account of these beliefs.

The effect of socioeconomic status on treatment and pregnancy outcomes in women with epilepsy in Scotland.

Compared to the background population, people with epilepsy tend to have lower rates of education and employment, lower rates of marriage and childbearing, and lower overall socioeconomic status (SES). Disparities in epilepsy care based on sociodemographic factors have been observed in the literature, but it is not known whether any such disparities exist in the UK. The UK Epilepsy and Pregnancy Register is a prospective, observational, registration and follow-up study that was set up to determine the relative safety of all AEDs taken in pregnancy. Here, we report outcomes of registered pregnancies to women with epilepsy living in Scotland from December 1996 to June 2012, based on the degree of socioeconomic deprivation of their postcode area. The Scottish Index of Multiple Deprivation (SIMD) quintile scores from 2006 were used to determine degree of socioeconomic deprivation, and group 1 (most deprived) and group 5 (least deprived) were compared. There were 1526 pregnancies with complete outcome data to women living in Scotland. Of these, 1453 (95.1%) resulted in a live birth and 68 (4.7%) had a major congenital malformation (MCM). Postcodes could not be reliably identified or verified for an additional three women, who have been excluded from SIMD group analysis. Of all women included in this study, 32.4% were in group 1 and 13.2% in group 5. No difference in MCM rate was observed between the two groups (4.4% in group 1 compared to 4.7% in group 5, p=0.84). Women in group 5 were more likely to take preconceptual folic acid (56.8% compared to 14.0%, relative risk: 4.1; 95% CI: 3.1-5.2) and less likely to have generalized tonic-clonic seizures in pregnancy (13.0% compared to 29.2%, relative risk: 0.4; 95% CI: 0.3-0.7) than those in group 1. Women in group 5 were more likely to be on monotherapy regimens (80.2% compared to 65.9%, relative risk: 1.2; 95% CI: 1.1-1.3), less likely to be on valproate (19.5% compared to 28.0%, p=0.05), and more likely to be on lower doses of the drug (825.9mg/day compared to 1012.0mg/day, p=0.05) compared to those in group 1. Although no change in MCM rate was seen based on SES, differences in treatment between socioeconomic groups do exist, particularly for preconceptual folic acid consumption, AED regimen, and seizure frequency. Greater emphasis on the importance of preconceptual counseling, both to discuss AED choice and folic acid intake, would be of benefit, particularly to those living in areas of high socioeconomic deprivation, to improve equity of healthcare delivery for women with epilepsy in Scotland.

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.

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.

Integrating the algorithm into community practice.

The success of integrating an algorithm of care for amyotrophic lateral sclerosis (ALS) into community practice depends on highlighting the benefits to patients and families and demonstrating those benefits to clinicians and service providers. The key issues in providing care for patients with ALS are the delay in establishing a diagnosis, variable access to necessary multidisciplinary services in health and social care, the need for further research to improve the prognosis, and increasing the level of information about ALS among professionals. Achieving an accurate diagnosis as soon as possible can enable focused services to be available earlier and can enable a management plan to be drawn up in anticipation of clinical deterioration. In view of the low incidence of the condition, it may be prudent to include ALS education as part of a broader neurologic educational initiative. Voluntary organizations, patients and their families, specialist liaison nurses, and pressure groups can all be powerful influences on the provision of health care and public/professional education. Adoption of the algorithm into community practice is likely to be a gradual process, involving a number of different approaches. The only general guidance is to carefully consider the key messages and their intended target audiences.

Patient views on primary care services for epilepsy and areas where additional professional knowledge would be welcome.

In the past decade there has been increasing interest in the part that general practice can play in the care of people with epilepsy. Primary care services for epilepsy vary from practice to practice. Some studies have suggested that people with epilepsy prefer secondary care services and are not keen for their epilepsy to be managed in general practice, but much of the data were collected in secondary care. This study collected data from various sources about present provision of services, patient satisfaction with services, views about service development, areas where GP knowledge may be improved and whether the site of data collection influenced the results. A questionnaire was piloted, then distributed and collected through branches of the British Epilepsy Association, general practice and secondary care clinics. Data collected were both quantitative and qualitative. One hundred and seventy-eight questionnaires were collected from three sources. The responders were a severe seizure group. Structured care in general practice was uncommon with 54% being seen only when needed. Dose and type of antiepileptic medication was rarely altered in general practice. Information about their condition was given to 44% of the responders by their GP. Sixty-one percent would prefer their epilepsy care to be 'shared' between primary and secondary services. The majority of patients were satisfied with GP services, felt they could easily discuss their epilepsy, but 58% felt they 'rarely' or 'never' received enough information about their condition in general practice. Satisfaction with GP care varied, dependent on where the data were collected. Patients would value more information and more time to discuss the effects of their epilepsy. In conclusion general practice care for epilepsy is still reactive. Patients value more information and more time to discuss implications. The data collection point affects the results; any conclusions about the organisation of epilepsy care should draw data from community patient samples.

'Red'flu': a study of an epidemic in a girls' boarding school in February 1978.

All the girls at a boarding school who presented with symptoms of influenza were interviewed and examined. Their symptoms and signs were recorded and related to age, date of last menstrual period, and previous influenza immunization.The age of the girls had no influence on the incidence of disease, nor did the number of girls in each form. However, the attack rate among those not immunized was 61 per cent and those not immunized 71 per cent. There was a highly significant variation in the incidence of influenza in relation to the menstrual cycle.