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.

Ulster Medical Society Junior Members Forum Thursday 12th December 2013 Whitla Medical Building, Queen’s University Belfast. ASPIRIN THERAPY IS ASSOCIATED WITH REDUCED MORTALITY IN PATIENTS WITH ACUTE LUNG INJURY Boyle AJ, Digangi A, Mottram LJ, Hamid U, McNamee L, White G, Cross LJM, McNamee J, O’Kane C, McAuley DM. Introduction: Platelet activation has a role in the pathogenesis of acute lung injury (ALI). Observational data suggests aspirin treatment may prevent the development of ALI in critically ill patients. However, it is unknown if aspirin usage alters outcomes in patients with established ALI. Methods: All patients with ALI were identified prospectively in a single large regional medical and surgical Intensive Care Unit (ICU) between December 2010 and July 2012. Demographic, clinical, and laboratory variables were recorded. Aspirin usage, both pre-hospital and during Intensive Care Unit (ICU) stay, was included. The primary outcome was ICU mortality. We used univariate and multivariate analyses to assess the impact of these variables on ICU mortality. Results: Two hundred and two patients with ALI were included. 56 (28%) of these received aspirin either prehospital, in ICU, or both. Using multivariate logistic regression analysis, aspirin was found to be protective for ICU mortality. Conclusion: Aspirin usage is associated with reduced mortality in patients with ALI. Whilst trials are ongoing to assess if aspirin can prevent ALI, these new data support the need for a clinical trial to investigate if aspirin improves outcomes in patients with established ALI. MALFORMATION RISKS OF ANTIEPILEPTIC DRUG MONOTHERAPIES IN PREGNANCY: AN UPDATE FROM THE UK AND IRELAND EPILEPSY AND PREGNANCY REGISTERS Campbell E, Kennedy F, Russell A, Smithson WH, Parsons L, Robertson I, Irwin B, Liggan B, Delanty N, Morrison PJ, Hunt SJ, Craig J, Morrow J. Aim: To assess risk of major congenital malformations (MCMs) from exposure to anti-epileptic drugs (AEDs) during pregnancy. Methods: Fifteen-year prospective observational study from 1996 until 2012. Outcomes are reported for valproate, carbamazepine, lamotrigine and levetiracetam monotherapy exposures. Main outcome measure is the MCM rate. Results: Informative outcomes were available for 5510 cases. 1290 women were exposed to valproate monotherapy, 1718 to carbamazepine monotherapy, 2198 to lamotrigine monotherapy and 304 to levetiracetam monotherapy. The MCM risk with valproate monotherapy exposure in-utero is 6.7% (95% CI 5.5%-8.3%), compared to 2.6% with carbamazepine (95% CI 1.9%-3.5%), 2.3% with lamotrigine (95% CI 1.8%-3.1%) and 0.70% (95% CI 0.2%-2.5%) with levetiracetam. A significant dose effect is seen with valproate (p= 0.0006) and carbamazepine (p=0.03) exposed pregnancies, but not with exposure to lamotrigine (p=0.26) or levetiracetam (p=0.09). MCM rate for even the highest doses of lamotrigine (>400mg daily) were lower than the MCM rate observed in pregnancies exposed to less than 600mg daily of valproate (3.4% compared to 5.0%, p=0.35). Conclusions: AED exposure during pregnancy increases the risk of MCM in the infants of women with epilepsy. In utero exposure to valproate carries a significantly higher MCM risk than lamotrigine (p=0.0001), levetiracetam (p=0.0001) or carbamazepine (p=0.0001) monotherapy. Our results are in contrast to previous suggestions that the MCM risk with exposure to low doses of valproate is preferable to that seen with exposure to high doses of lamotrigine. Together with recently published neurodevelopmental data, this data suggests that either lamotrigine or levetiracetam should be used as drugs of choice over valproate, even at low dose, in women of childbearing age with epilepsy. THE USE OF HIGHLY CONCENTRATED HYPERTONIC SALINE IN THE TREATMENT OF TRAUMATIC BRAIN INJURY RELATED REFRACTORY INTRACRANIAL HYPERTENSION. Major EH, O’Connor P, Mullan B. Background: In recent years hypertonic saline has attracted increasing interest in the treatment of traumatic intracranial hypertension, and has a number of documented and theoretical advantages over other hyperosmolar agents. To date, no consensus has been achieved on the safest and most effective HTS concentration for administration. Aims: The purpose of this paper was to evaluate the efficacy of intravenous bolus administration of highly concentrated

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.

Introduction Coeliac disease is an immune-medicated, gluten sensitive enteropathy affecting 1% of the UK population.1 Early diagnosis is important due to the potential long-term complications. Histological analysis along with serum biomarkers are used in diagnosis.1 British Society of Gastroenterology (BSG) guidelines recommend a minimum of 4 duodenal biopsies in order to maximise detection rates.2,3 Objectives To determine the current practice relating to the number of duodenal biopsy specimens taken at endoscopy in Belfast HSCT compared to national guidelines, and to assess the correlation between serology results and subsequent diagnosis of coeliac disease. Methods Retrospective review of the first 500 duodenal biopsy histology reports processed by Belfast Trust pathology laboratory in 2012. Positive/equivocal histological features based on criteria in BSG guidelines.2Serology results were checked via the Link Labs© system on all patients with pathology submitted. Results 481 duodenal histology records were included in the study with 19 excluded. 225 specimens (46.7%) had less than the 4 recommended individual biopsy fragments. 26 patients were diagnosed with Coeliac disease based on histological findings, and a further 30 had ‘equivocal’ results. Patients with positive or equivocal coeliac histology had a higher percentage of 4 or more biopsies as compared to the whole group (80.7% and 77.3% respectively vs 53.3%). Overall 96% with histological evidence of coeliac disease also had positive serology (n = 23). For those with ‘equivocal’ histology, serology was positive in 55% and negative in 45%. 2% of patients with negative histology had strongly positive serology. Conclusion The number of duodenal biopsy specimens taken at endoscopy is below recommended guidelines in 46.7% of cases. There is a higher number of biopsy specimens taken in those with subsequently positive or equivocal histological features. 96% of cases where histology was diagnostic also demonstrated positive serology. 2% of patients with subsequently negative histology had strongly positive serology prior to endoscopy, and in these cases almost all had 4 or more individual pathology specimens. This suggests that where strong clinical suspicion and positive biochemistry indicate a higher probability of coeliac disease, the endoscopist is inclined to take more biopsy specimens. References Richey R, et al. Recognition and assessment of coeliac disease in children and adults: summary of NICE guidance. BMJ 2009 May 27;338:b1684 Ciclitira PJ, et al. The Management of Adults with Coeliac Disease. BSG Guidelines Rubio-Tapia A, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013;108:656–676 Disclosure of Interest None Declared.

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 women9s preferred choice of antiepileptic drug.

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 women's preferred choice of antiepileptic drug.

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.

Background Emerging data on the teratogenic potential of valproate and topiramate have resulted in a prescribing shift towards lamotrigine and levetiracetam in women of childbearing age with epilepsy. However use of these AEDs during pregnancy is associated with new difficulties. It is widely documented that lamotrigine clearance increases by up to 330% in pregnancy, with associated increase in seizure frequency in 39–45% of women. Early studies show that levetiracetam serum levels also fall by 40–62% during pregnancy, but in contrast to lamotrigine very little is known about the clinical effect of this observation. Methods Retrospective chart review was performed for women in Northern Ireland taking levetiracetam monotherapy during pregnancy from 2003 to 2011. Results Forty four women taking levetiracetam during pregnancy were identified. Deterioration or relapse of seizures was observed in 30.8% of women, improvement in seizure control in 17.9% and no change in 51.3%. Conclusion Seizure control deteriorated in over 30% of women in this study, towards the upper end of the expected range of 14–32%. This is the largest study to date of seizure control in women taking levetiracetam during pregnancy. These preliminary findings, together with the paucity of evidence in this area, highlight that further research is clearly needed to guide clinicians on the potential clinical impact of this phenomenon.

Background Use of valproate in pregnancy, especially in doses over 1000mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs. We sought to investigate whether the increased risk could be minimised by using controlled release or divided daily doses of valproate. Methods The UK Epilepsy and Pregnancy Register is a prospective, observational and follow-up study set up to determine the risks of major congenital malformations for infants exposed to antiepileptic drugs in-utero. In this study we have extracted data for those pregnancies exposed to valproate in monotherapy. We have calculated malformation rates and relative risks as a function of valproate exposure. Results Outcome data were available for 1109 pregnancies exposed to valproate in monotherapy. Exposure to over 1000 mg a day of valproate was associated with almost double the risk of major congenital malformation compared with daily valproate doses below 1000mg daily (8.86% vs 4.88%, RR: 1.7; 95% CI 1.1 to 2.9). There were no differences in the risks for malformations between standard release valproate and controlled release valproate preparations (RR: 1.11; 95% CI 0.67 to 1.83) or for those exposed to single or multiple daily administrations (RR: 0.99, 95% CI 0.58 to 1.70). Conclusion Prescribing controlled release valproate or multiple daily administrations in pregnancy did not reduce the risk for malformations. Higher malformation rates observed with in utero exposure to valproate are more likely related to total daily dose, rather than peak serum levels.

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.

Aim To assess the relative risk of major congenital malformations (MCM) from exposure to anti-epileptic drugs (AEDs) during pregnancy. Methods 15 year prospective observational study from 1996 until 2009. The outcome measure is the MCM rate. Results Informative outcomes were available for 5802 cases. The risk of MCM was significantly higher in women on AEDs during pregnancy (n=5376) in comparison to those on no treatment (n=426), RR: 1.55 (95% CI 1.13 to 2.14), and significantly higher in polytherapy (n=1183) than monotherapy (n=4193), RR: 1.60 (95% CI 1.19 to 2.15). The risk to those on valproate monotherapy was more than double that for those on either carbamazepine (RR 2.35, 95% CI 1.55 to 3.57) or lamotrigene (RR 2.40, 95% CI 1.57 to 3.68). 245 and 362 informative outcomes were obtained for topiramate and levetiracetam respectively, with MCM rates of 7.1% (95% CI 4.5 to 11.0%) and 2.5% (95% CI 1.3 to 4.7%). There were 3/83 cases of MCM in Topiramate monotherapy and 14/162 cases in polytherapy. There were no cases of MCMs in levetiracetam monotherapy and 9/229 cases levetiracetam polytherapy. Conclusions AED exposure during pregnancy increases the risk of MCM in the babies of women with epilepsy. Polytherapy exposure has a higher risk than monotherapy. Valproate exposure carries higher MCM risk than any other AED. Lowest risk is associated with carbamazepine or lamotrigene monotherapy. Results for levetiracetam, although numbers are small, look promising.