Predicting seizures in pregnant women with epilepsy: Development and external validation of a prognostic model.

BACKGROUND: Seizures are the main cause of maternal death in women with epilepsy, but there are no tools for predicting seizures in pregnancy. We set out to develop and validate a prognostic model, using information collected during the antenatal booking visit, to predict seizure risk at any time in pregnancy and until 6 weeks postpartum in women with epilepsy on antiepileptic drugs. METHODS AND FINDINGS: We used datasets of a prospective cohort study (EMPiRE) of 527 pregnant women with epilepsy on medication recruited from 50 hospitals in the UK (4 November 2011-17 August 2014). The model development cohort comprised 399 women whose antiepileptic drug doses were adjusted based on clinical features only; the validation cohort comprised 128 women whose drug dose adjustments were informed by serum drug levels. The outcome was epileptic (non-eclamptic) seizure captured using diary records. We fitted the model using LASSO (least absolute shrinkage and selection operator) regression, and reported the performance using C-statistic (scale 0-1, values > 0.5 show discrimination) and calibration slope (scale 0-1, values near 1 show accuracy) with 95% confidence intervals (CIs). We determined the net benefit (a weighted sum of true positive and false positive classifications) of using the model, with various probability thresholds, to aid clinicians in making individualised decisions regarding, for example, referral to tertiary care, frequency and intensity of monitoring, and changes in antiepileptic medication. Seizures occurred in 183 women (46%, 183/399) in the model development cohort and in 57 women (45%, 57/128) in the validation cohort. The model included age at first seizure, baseline seizure classification, history of mental health disorder or learning difficulty, occurrence of tonic-clonic and non-tonic-clonic seizures in the 3 months before pregnancy, previous admission to hospital for seizures during pregnancy, and baseline dose of lamotrigine and levetiracetam. The C-statistic was 0.79 (95% CI 0.75, 0.84). On external validation, the model showed good performance (C-statistic 0.76, 95% CI 0.66, 0.85; calibration slope 0.93, 95% CI 0.44, 1.41) but with imprecise estimates. The EMPiRE model showed the highest net proportional benefit for predicted probability thresholds between 12% and 99%. Limitations of this study include the varied gestational ages of women at recruitment, retrospective patient recall of seizure history, potential variations in seizure classification, the small number of events in the validation cohort, and the clinical utility restricted to decision-making thresholds above 12%. The model findings may not be generalisable to low- and middle-income countries, or when information on all predictors is not available. CONCLUSIONS: The EMPiRE model showed good performance in predicting the risk of seizures in pregnant women with epilepsy who are prescribed antiepileptic drugs. Integration of the tool within the antenatal booking visit, deployed as a simple nomogram, can help to optimise care in women with epilepsy.

Clinical outcomes of VNS therapy with AspireSR® (including cardiac-based seizure detection) at a large complex epilepsy and surgery centre.

PURPOSE: To compare the efficacy of AspireSR® to preceding VNS battery models for battery replacements, and to determine the efficacy of the AspireSR® for new implants. METHODS: Data were collected retrospectively from patients with epilepsy who had VNS AspireSR® implanted over a three-year period between June 2014 and June 2017 by a single surgeon. Cases were divided into two cohorts, those in whom the VNS was a new insertion, and those in whom the VNS battery was changed from a previous model to AspireSR®. Within each group, the seizure burden was compared between the periods before and after insertion of AspireSR®. RESULTS: Fifty-one patients with a newly inserted AspireSR® VNS model had a significant reduction in seizure frequency (p < 0.001), with 59% (n = 30) reporting ≥50% reduction. Of the 62 patients who had an existing VNS, 53% (n = 33) reported ≥50% reduction in seizure burden when the original VNS was inserted. After the battery was changed to the AspireSR®, 71% (n = 44) reported a further reduction of ≥50% in their seizure burden. The size of this reduction was at least as large as that resulting from the insertion of their existing VNS in 98% (61/62) of patients. CONCLUSION: The results suggest that approximately 70% of patients with existing VNS insertions could have significant additional benefit from cardiac based seizure detection and closed loop stimulation from the AspireSR® device. For new insertions, the AspireSR® device has efficacy in 59% of patients. The 'rule of thirds' used in counseling patients may need to be modified accordingly.

Type 1 diabetes mellitus and risk of incident epilepsy: a population-based, open-cohort study.

AIMS/HYPOTHESIS: The aim of this research was to explore the relationship between incident epilepsy and type 1 diabetes in British participants. METHODS: Using The Health Improvement Network database, we conducted a retrospective, open-cohort study. Patients who were newly diagnosed with type 1 diabetes mellitus at the age of ≤40 years were identified and followed-up from 1 January 1990 to 15 September 2015. These patients, identified as not suffering from epilepsy at the time of diagnosis, were randomly matched with up to four individuals without type 1 diabetes mellitus, based on age, sex and participating general practice. A Cox regression analysis was subsequently performed using Townsend deprivation index, cerebral palsy, head injury and learning disabilities as model covariates. RESULTS: The study population consisted of a total of 24,610 individuals (4922 with type 1 diabetes and 19,688 controls). These individuals were followed up for a mean of 5.4 years (approximately 132,000 person-years of follow up). Patients with type 1 diabetes were significantly more likely to be diagnosed with epilepsy during the observation period compared with controls (crude HR [95% CI]: 3.02 [1.95, 4.69]). The incidence rate was estimated to be 132 and 44 per 100,000 person-years in patients and controls, respectively. This finding persisted after adjusting for model covariates (adjusted HR [95% CI]: 3.01 [1.93, 4.68]) and was also robust to sensitivity analysis, excluding adult-onset type 1 diabetes mellitus. CONCLUSIONS/INTERPRETATION: Patients with type 1 diabetes are at approximately three-times greater risk of developing epilepsy compared with matched controls without type 1 diabetes. This should be considered when investigating seizure-related disorders in patients with type 1 diabetes mellitus.

Early haemodynamic changes observed in patients with epilepsy, in a visual experiment and in simulations.

OBJECTIVE: The objective of this study was to investigate whether previously reported early blood oxygen level dependent (BOLD) changes in epilepsy could occur as a result of the modelling techniques rather than physiological changes. METHODS: EEG-fMRI data were analysed from seven patients with focal epilepsy, six control subjects undergoing a visual experiment, in addition to simulations. In six separate analyses the event timing was shifted by either -9,-6,-3,+3,+6 or +9 s relative to the onset of the interictal epileptiform discharge (IED) or stimulus. RESULTS: The visual dataset and simulations demonstrated an overlap between modelled haemodynamic response function (HRF) at event onset and at ± 3 s relative to onset, which diminished at ± 6s. Pre-spike analysis at -6s improved concordance with the assumed IED generating lobe relative to the standard HRF in 43% of patients. CONCLUSION: The visual and simulated dataset findings indicate a form of "temporal bleeding", an overlap between the modelled HRF at time 0 and at ± 3s which attenuated at ± 6s. Pre-spike analysis at -6s may improve concordance. SIGNIFICANCE: This form of analysis should be performed at 6s prior to onset of IED to minimise temporal bleeding effect. The results support the presence of relevant BOLD responses occurring prior to IEDs.

Variation in the reporting of outcomes among pregnant women with epilepsy: a systematic review.

Studies on pregnant women with epilepsy should evaluate both neurological and pregnancy outcomes. We undertook a systematic review of the literature of studies on pregnant women with epilepsy to collate the outcomes reported, and the quality of outcomes report in these studies. We searched major electronic databases (from 1999 until January 2015). Two independent reviewers selected studies and extracted data on study design, the risk of bias of the studies, journal impact factor and the quality of reported outcomes. We assessed the quality outcomes report using a six items standardised tool (score range 0-6). There were 70 different outcomes reported in 232 studies (maternal neurological (13/70, 19%), fetal and neonatal (28/70, 40%), and obstetric outcomes (29/70, 41%)). Most studies reported on major congenital fetal abnormalities (103/232, 44%), followed by live birth (60/232, 26%). Quality of the reported outcomes was poor (mean 1.54, SD 1.36). It was associated with journal impact factor (p=0.007), but not with study design (p=0.60), or risk of bias (p=0.17). The outcomes reported in studies on pregnant women with epilepsy varied widely, and the quality of the outcomes report was poor. There is a need to identify a set of core outcome to harmonise reporting in future clinical studies.

Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis.

BACKGROUND: Antenatal care of women with epilepsy is varied. The association of epilepsy and antiepileptic drug exposure with pregnancy outcomes needs to be quantified to guide management. We did a systematic review and meta-analysis to investigate the association between epilepsy and reproductive outcomes, with or without exposure to antiepileptic drugs. METHODS: We searched MEDLINE, Embase, Cochrane, AMED, and CINAHL between Jan 1, 1990, and Jan 21, 2015, with no language or regional restrictions, for observational studies of pregnant women with epilepsy, which assessed the risk of obstetric complications in the antenatal, intrapartum, or postnatal period, and any neonatal complications. We used the Newcastle-Ottawa Scale to assess the methodological quality of the included studies, risk of bias in the selection and comparability of cohorts, and outcome. We assessed the odds of maternal and fetal complications (excluding congenital malformations) by comparing pregnant women with and without epilepsy and undertook subgroup analysis based on antiepileptic drug exposure in women with epilepsy. We summarised the association as odds ratio (OR; 95% CI) using random effects meta-analysis. The PROSPERO ID of this Systematic Review's protocol is CRD42014007547. FINDINGS: Of 7050 citations identified, 38 studies from low-income and high-income countries met our inclusion criteria (39 articles including 2,837,325 pregnancies). Women with epilepsy versus those without (2,809,984 pregnancies) had increased odds of spontaneous miscarriage (OR 1·54, 95% CI 1·02-2·32; I(2)=67%), antepartum haemorrhage (1·49, 1·01-2·20; I(2)=37%), post-partum haemorrhage (1·29, 1·13-1·49; I(2)=41%), hypertensive disorders (1·37, 1·21-1·55; I(2)=23%), induction of labour (1·67, 1·31-2·11; I(2)=64%), caesarean section (1·40, 1·23-1·58; I(2)=66%), any preterm birth (<37 weeks of gestation; 1·16, 1·01-1·34; I(2)=64%), and fetal growth restriction (1·26, 1·20-1·33; I(2)=1%). The odds of early preterm birth, gestational diabetes, fetal death or stillbirth, perinatal death, or admission to neonatal intensive care unit did not differ between women with epilepsy and those without the disorder. INTERPRETATION: A small but significant association of epilepsy, exposure to antiepileptic drugs, and adverse outcomes exists in pregnancy. This increased risk should be taken into account when counselling women with epilepsy. FUNDING: EBM CONNECT Collaboration.

'The great imitator': Neurosyphilis and new-onset refractory status epilepticus (NORSE) syndrome.

New-onset refractory status epilepticus (NORSE) is a syndrome of new-onset drug resistant status epilepticus that often has a catastrophic outcome. A 30-year-old man of Somali origin presented with refractory status to a district general hospital. A clinical diagnosis of NORSE syndrome was made, and he was transferred to the regional epilepsy center for immunomodulatory treatment and consideration for cyclophosphamide treatment. After transfer to the regional epilepsy center, his repeat cerebrospinal fluid tested strongly positive for syphilis, indicating a diagnosis of neurosyphilis, and the patient was treated with high-dose intravenous (IV) benzylpenicillin. His status epilepticus abated 24 h later. New-onset refractory status epilepticus syndrome is a diagnosis of exclusion. Before instigation of potentially harmful neuromodulatory therapies, treatable causes such as neurosyphilis should be considered. We advocate the early transfer of refractory status patients to a specialist epilepsy center for both seizure management and cause determination.

The management of Convulsive Refractory Status Epilepticus in adults in the UK: No consistency in practice and little access to continuous EEG monitoring.

PURPOSE: Convulsive Status Epilepticus (CSE) is a common neurological emergency with patients presenting with prolonged epileptic activity. Sub-optimal management is coupled with high morbidity and mortality. Continuous electroencephalogram (EEG) monitoring is considered essential by the National Institute for Health and Care Excellence (NICE) in the management of Convulsive Refractory Status Epilepticus (CRSE). The aim of this research was to determine current clinical practice in the management of CRSE amongst adults in intensive care units (ICU) in the UK and establish if the use of a standardised protocol requires re-enforcement within trusts. METHODS: 75 randomly selected UK NHS Trusts were contacted and asked to complete a questionnaire in addition to providing their protocol for CRSE management in ICU. RESULTS: 55 (73%) trusts responded. While 31 (56% of responders) had a protocol available in ICU for early stages of CSE, just 21 (38%) trusts had specific guidelines if CRSE occurred. Only 23 (42%) trusts involved neurologists at any stage of management and just 18 (33%) have access to continuous EEG monitoring. CONCLUSION: This study identifies significant inconsistency in the management of CSE in ICU's across the UK. A minority of ICU units have a protocol for CRSE or access to continuous EEG monitoring despite it being considered fundamental for management and supported by NICE guidance.

Effects of monitoring strategies on seizures in pregnant women on lamotrigine: a meta-analysis.

OBJECTIVES: Pregnant women with epilepsy have a significantly increased risk of mortality and morbidity compared to non-pregnant women. At least one in 250 pregnancies is exposed to anti-epileptic drugs (AED). Seizure deterioration occurs in up to a third of pregnant women. AED levels fall in most pregnant women, although it is uncertain that this is responsible for seizure deterioration rather than a hormonal effect. Current practice of AED monitoring is either therapeutic drug monitoring (TDM) or clinical features monitoring (CFM) to adjust the AED dose. We have systematically reviewed the effectiveness of the two monitoring regimens for AEDs, especially lamotrigine, the most commonly used AED in pregnancy on maternal and fetal outcomes. STUDY DESIGN: We searched MEDLINE (1966-2012), EMBASE (1980-2012) and Cochrane, for relevant citations on the effectiveness of different monitoring strategies on seizure deterioration in pregnant women with epilepsy on lamotrigine. Study selection, quality assessment and data extraction were carried out by two independent reviewers. We calculated the rates of deterioration in seizures with the two strategies and pooled the estimates with random effects meta-analysis. RESULTS: Six observational studies (n=132) evaluated the effectiveness of the two monitoring strategies on pregnant women with epilepsy on lamotrigine. There were no randomised controlled trials. The rate of seizure deterioration was 0.30 (95% CI 0.21-0.41) in women monitored by therapeutic drug monitoring (TDM) compared to 0.73 (95% CI 0.56-0.86) in those receiving clinical feature monitoring (CFM) alone. CONCLUSION: Evidence based on observational data suggests that monitoring of AED levels in pregnancy reduces seizure deterioration, although the included studies have numerous sources of bias. There is paucity of evidence to make firm recommendations on optimal monitoring of AED drugs in pregnancy. Further research is needed to advise on the best clinical practice in managing AED in pregnancy.

Behavioral and cognitive effects of anti-epileptic drugs.

Anti-epileptic drugs (AEDs) have a variety of mechanisms of action which are reflected through different anticonvulsant activities and behavioral effects. Two categories of AEDs are considered based on psychotropic profile. The first group is characterized by potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission, and comprises of agents such as vigabatrin, tiagabine, and gabapentin. These agents are noted to have sedating effects ranging from cognitive slowing to anti-manic effects. On the other hand, the second group is typified by attenuation of glutamate excitatory neurotransmission and has activating effects including anxiogenic and antidepressant actions. Lamotrigine and felbamate feature in this latter group. Mechanisms of action, chief clinical indications, as well as behavioral profile including comment on chief cognitive effects of the newer AEDs are reviewed in accordance with this dual categorization. In clinical practice, assessment of an individual patient alongside consideration of AED behavioral profile primes for appropriate prescription according to patient mood profile, also permitting exposure of AED-induced behavioral disturbance.

The neural correlates of altered consciousness during epileptic seizures.

Epileptic seizures are characterized by a multifaceted spectrum of alterations in the general level of awareness and/or the subjective contents of consciousness. Complete loss of consciousness occurs when epileptic activity involves both cortical and subcortical structures, as in generalized seizures. On the other hand, simple partial seizures can spare both the level and contents of consciousness. Finally, complex partial seizures associated with medial temporal lobe discharges can selectively impair the patient's subjective experiences with variable degrees of responsiveness. The differences in ictal semiology between patients with epilepsy offer unique avenues for understanding the relationship between pathological brain function and altered conscious states.

Understanding routine antiepileptic drug decisions: a qualitative analysis of patients' accounts of hospital consultations.

OBJECTIVE: We sought to understand how antiepileptic drug (AED) decisions, similar to those that occur in observational studies on AEDs, were made between doctors and patients in the hospital clinic. We could find no previous research that focused specifically on understanding AED decision making in epilepsy. METHODS: In-depth interviews were conducted with patients who carried a secure diagnosis of epilepsy and who had recently attended a follow-up appointment with a consultant with a special interest in epilepsy. Interviews were digitally recorded and professionally transcribed. A "grounded theory" approach was used for analysis; the Nvivo (QRS release 2.0) computer package was used to manage the data effectively and transparently. No new important themes emerged by the final 10 transcripts, suggesting theoretical data saturation had been reached. RESULTS: Five major themes emerged: preappointment treatment considerations; preconsultation feelings and hopes; acceptance of prognosis and disillusionment; hypothetical change; and decisional ownership. Our interviewees appeared highly susceptible to the doctor's suggestions. All those with active epilepsy and seizures that impacted their life appeared happy to follow the doctor's advice-whatever that may be. This highlights both the desperation many patients have to be free of epilepsy and also the doctor's authority; the perceived authority of the doctor seemed to explain why even patients who were seizure free said they would follow the advice to change treatment, were it suggested. CONCLUSION: Our findings describe decision making from the patients' perspective and support a dominant role for the doctor in the decision making process. There may be factors specific to intractable epilepsy that may be disempowering to involvement in decision making. However, whether patients wish for greater involvement in decision making remains unanswered as stated by one patient "But you're there to take their [the doctor's] advice, that's what you go for don't you?".

An association between type 1 diabetes and idiopathic generalized epilepsy.

OBJECTIVE: Idiopathic generalized epilepsies (IGEs) account for approximately 30% of all patients with epilepsy. Both the IGEs and type 1 diabetes mellitus (T1D) represent serious worldwide problems, because of related medical and social management costs. Clinical experience suggested the two conditions were seen in individuals more frequently than might be expected by chance. METHODS: We compared the population prevalence of T1D in 15- to 30-year-olds to a cohort of 518 15- to 30-year-olds with IGE. RESULTS: We found a highly significant excess of T1D in our IGE cohort, with an odds ratio of 4.4 (95% confidence interval, 2.1-9.2). INTERPRETATION: Our results suggest that the prevalence of T1D is increased by a factor of four in young adults with IGE. To our knowledge, this is the first published association between the two conditions and expands the diseases known to be associated with T1D.

Current drug treatment of epilepsy in adults.

The choice of antiepileptic drugs (AEDs) is rapidly increasing. This review looks at the evidence that guides the decision of which AED to start as monotherapy and aims to aid the choice of treatment if monotherapy fails. Unfortunately, the evidence supporting the prescribing of new drugs is sparse, because most randomised controlled trials answer questions focused on regulatory requirements rather than on clinical use. Ultimately, the choice of one AED will be determined by an individual risk-benefit assessment in which the most effective drug for an individual patient is chosen, and one that would have the lowest risk of significant harm. It is the risk of chronic toxic effects and issues of teratogenicity for women that may affect the choice of drug therapy to the greatest degree. In the future there is a need to improve the quality of clinical data on efficacy and harmful effects of AEDs.