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.

Safety at The William Quarrier Scottish Epilepsy Centre.

PURPOSE: We examined the yield from EMFIT bed alarms and staff response time to generalised seizure in a medium term residential assessment unit for epilepsy. METHODS: The Scottish Epilpesy Centre (SEC) has a Video Observation System (VOS) that provides continuous recording of all patient spaces (external and internal) and allows retention of clinically relevant events. A retrospective audit of daily EMFIT test records, nursing seizure record sheets (seizure type and EMFIT alert status), clinical incident reporting systems and the VOS database of retained clinical events was conducted for an 9 month period from April 1st 2016 till December 31st 2016. All generalized tonic clonic seizures (GTCS) were noted by patient, time and location and staff response time to GTCS was calculated. RESULTS: There were 85 people admitted during the audit period who had 61 GTCS. 50 events were in bed and EMFIT alert status was recorded. On 8 occasions the EMFIT did not alert: 5 events were not of sufficient duration or frequency, in 2 the patient fell from the bed early and 1 event the alarm did not trigger. The average response time to GTCS was 23s. The longest response time was 69s (range, 0-69s, sd 15.76.). CONCLUSIONS: The EMFIT bed alarm appears to be a valuable adjunct to safety systems. Within the novel environment of the SEC it is possible to maintain a response time to GTCS that is comparable to hospital based UK video telemetry units.

Healthcare resource utilization after medium-term residential assessment for epilepsy and psychogenic nonepileptic seizures.

INTRODUCTION: Epilepsy and epilepsy mimics may lead to high healthcare resource utilization (HRU) including diagnostic resources. The William Quarrier Scottish Epilepsy Centre (SEC) provides medium-term residential assessment (MTRA; average length of stay: 28days) and treatment for complex presentations of epilepsy and related conditions (principally psychogenic nonepileptic seizures, PNES). We studied the effect of MTRA on HRU in a defined health board area in Scotland. METHODS: A retrospective audit of individuals admitted to the SEC from a defined health board area using SEC and health board medical records. Neurological HRU assessed included emergency department visits, hospital admissions, outpatient clinic appointments, and brain imaging prior to and post-MTRA. Healthcare resource utilization was also compared with individuals referred but not admitted to the SEC because of individual circumstances and choice. RESULTS: Seventy-three individuals (51 female, average age: 37.51; 22 men, average age: 43.72) were identified from three years of admissions (1st April 2010 to 31st March 2013). Final diagnosis was epilepsy (ES), 32; ES and psychogenic nonepileptic seizures (ES+PNES), 17; and PNES alone, 24. Twenty-two individuals were identified as a comparison group (8 men, 14 women; average age: 37.21 and 43.90, respectively). Total average contacts per patient per year (CPY) was significantly different pre- and post-MTRA (4.16 vs. 1.32; t(72)=6.11, p<.0001, d=.72). Comparison of HRU in the first year of baseline and last full year of follow-up showed a post-MTRA reduction in HRU for PNES of 92.28%, for ES of 46.81%, and for ES+PNES of 28.3%. During the course of follow-up, PNES CPY continued to drop (1.13 first year vs. 0.10 at 3years post-MTRA). For individuals with epilepsy (with or without PNES), HRU use dropped significantly in the year after admission, and these gains remained stable (total first vs. third postdischarge CPY, 1.74 vs. 1.29). The participants in the comparison group, who were not admitted, had no comparable drop across the study period and were using significantly more resources at each follow-up point than those in the admitted group (F (1, 48)=44.45, p<.01, ηp(2)=.49). CONCLUSION: Medium-term residential assessment is associated with sustained reduction in HRU especially in patients with PNES. Overall HRU reduction was 68.27% following admission (d=.72). This suggests benefit from the MTRA model for people with complex presentations.

Primary and secondary care attendance, anticonvulsant and antidepressant use and psychiatric contact 5-10 years after diagnosis in 188 patients with psychogenic non-epileptic seizures.

BACKGROUND AND OBJECTIVES: There have been few studies of long-term outcome in psychogenic non-epileptic seizures (PNES), and none of long-term healthcare utilization. METHODS: We studied attendance with seizures, healthcare use and employment over a 6-month period from the family doctors of 260 consecutive patients with psychogenic non-epileptic seizures (PNES), 5-10 years after diagnosis. RESULTS: We obtained clinical data in 188/260 patients (72.3%), of whom 60 (31.9%) had attended primary or secondary care with seizures in the previous 6 months. Predictors of attendance with seizures included a diagnosis of epilepsy+PNES (OR 5.7, p=0.009), work status (OR 3.9, p=0.027) and social security payments (OR 6.3, p=0.003). Latency to diagnosis was not predictive. Emergency admission data were available in 187 patients, of whom 25 (13.4%) had emergency hospital attendances. Prescription data were available for 172 patients, of whom 154 had 'PNES only'. Of these, 17 (11.0%) remained on antiepileptic medication (AED). 68/172 patients (39.5%) were prescribed antidepressant (AD) drugs. We had psychiatric contact data in 185 patients, of whom 49 (26.5%) had accessed psychiatric services in the last 6 months. CONCLUSIONS: Surprisingly few of our patients had presented with seizures during the study period. Early reductions in both AED use and healthcare use were sustained long term. Although psychiatric and employment outcomes were less encouraging, some aspects of PNES outcome may be better than previously thought.

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 5.56% (3.54%­8.56%) [corrected]. 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.

Recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero.

PURPOSE: Use of antiepileptic drugs in pregnancy is associated with congenital malformations and developmental delay. Previous studies have suggested that women who have had one child with a congenital malformation are at increased risk of having other children with malformations. We sought to confirm the magnitude of risk in a large cohort drawn from the United Kingdom Epilepsy and Pregnancy Register. METHODS: The United Kingdom Epilepsy and Pregnancy Register is a prospective, observational registration and follow-up study set up to determine the relative safety of antiepileptic drugs in pregnancy. We have extracted data for those women who prospectively registered more than one pregnancy and calculated the recurrence risks for fetal malformations. KEY FINDINGS: Outcome data were available for 1,534 pregnancies born to 719 mothers. For women whose first child had a congenital malformation there was a 16.8% risk of having another child with a congenital malformation, compared with 9.8% for women whose first child did not have a malformation (relative risk 1.73, 95% confidence interval [CI] 1.01-2.96). The risk for recurrence was 50% for women who had had two previous children with a congenital malformation. There was a trend toward a higher risk for recurrent malformations in pregnancies exposed to valproate (21.9%, relative risk 1.47, 95% CI 0.68-3.20) and topiramate (50%, relative risk 4.50, 95% CI 0.97-20.82), but not for other drugs such as carbamazepine and lamotrigine. Recurrence risks were also higher for pregnancies exposed to polytherapy regimens and for those where the dose of antiepileptic drug treatment had been increased after the first pregnancy. SIGNIFICANCE: Women who have had a child with a malformation are at increased risk of having other children with malformations. This is in keeping with previous reports that have suggested that genetic influences may be one of the factors determining the teratogenic risk of antiepileptic drugs.

Glissandi: transient fast electrocorticographic oscillations of steadily increasing frequency, explained by temporally increasing gap junction conductance.

PURPOSE: We describe a form of very fast oscillation (VFO) in patient electrocorticography (ECoG) recordings, that can occur prior to ictal events, in which the frequency increases steadily from ≈ 30-40 to >120 Hz, over a period of seconds. We dub these events "glissandi" and describe a possible model for them. METHODS: Four patients with epilepsy had presurgical evaluations (with ECoG obtained in two of them), and excised tissue was studied in vitro, from three of the patients. Glissandi were seen spontaneously in vitro, associated with ictal events-using acute slices of rat neocortex-and they were simulated using a network model of 15,000 detailed layer V pyramidal neurons, coupled by gap junctions. KEY FINDINGS: Glissandi were observed to arise from human temporal neocortex. In vitro, they lasted 0.2-4.1 s, prior to ictal onset. Similar events were observed in the rat in vitro in layer V of frontal neocortex when alkaline solution was pressure-ejected; glissandi persisted when γ-aminobutyric acid A (GABA(A)), GABA(B), and N-methyl-d-aspartate (NMDA), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were blocked. Nonalkaline conditions prevented glissando generation. In network simulations it was found that steadily increasing gap junction conductance would lead to the observed steady increase in VFO field frequency. This occurred because increasing gap junction conductance shortened the time required for an action potential to cross from cell to cell. SIGNIFICANCE: The in vitro and modeling data are consistent with the hypothesis that glissandi arise when pyramidal cell gap junction conductances rise over time, possibly as a result of an alkaline fluctuation in brain pH.

Reading epilepsy.

Reading epilepsy is a rare epilepsy syndrome triggered by language related activity, in particular reading. Here we describe a patient with reflex seizures brought on specifically by reading in Arabic. The types of reading epilepsy, their typical clinical features, probable pathophysiology and management are discussed.

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. METHODS: ECoG data were recorded with subdural grids from two preoperative patients with seizures of frontal lobe onset in an epilepsy monitoring unit. VFOs were recorded from rat neocortical slices. A "cellular automaton" model of network oscillations was developed, extending ideas of Traub et al. (Neuroscience, 92, 1999, 407) and Lewis & Rinzel (Network: Comput Neural Syst, 11, 2000, 299); this model is based on postulated electrical coupling between pyramidal cell axons. RESULTS: Layer 5 of rat neocortex, in vitro, can generate VFOs when chemical synapses are blocked. Human epileptic neocortex, in situ, produces preseizure VFOs characterized by the sudden appearance of "blobs" of activity that evolve into spreading wavefronts. When wavefronts meet, they coalesce and propagate perpendicularly but never pass through each other. This type of pattern has been described by Lewis & Rinzel in cellular automaton models with spatially localized connectivity, and is demonstrated here with 120,000- to 5,760,000-cell models. We provide a formula for estimating VFO period from structural parameters and estimate the spatial scale of the connectivity. DISCUSSION: These data provide further evidence, albeit indirect, that preseizure VFOs are generated by networks of pyramidal neurons coupled by gap junctions, each predominantly confined to pairs of neurons having somata separated by < ∼1-2 mm. Plausible antiepileptic targets are tissue mechanisms, such as pH regulation, that influence gap-junction conductance.

The movement disorders of Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS) is an X-linked semi-dominant condition with learning difficulties and dysmorphism caused by mutations in the gene RSK2. Originally, epilepsy was reported as a feature. We and others have since described predominantly sound-startle induced drop attacks that have been labelled 'cataplexy', abnormal startle response and hyperekplexia. We sought to clarify why there should be controversy over the type of paroxysmal events. Review of the literature and our patients confirmed that each centre had studied only a small numbers of individuals (mean = 2). The type of movement disorder varied both with age and between individuals. One individual might have more than one movement disorder. One of our adult patients had several types of movement disorder and epilepsy that merged seamlessly: there was true cataplexy triggered by telling a joke, something close to cataplexy ('cataplexy') triggered by sound-startle, a predominantly hypertonic reaction varying from hyperekplexia to a more prolonged tonic reaction resembling startle epilepsy, and true unprovoked epileptic seizures. In the large database of the Coffin-Lowry Syndrome Foundation family support group, 34 of 170 (20%) individuals with CLS and known age had 'drop attacks' and an additional 9 (5%) of these had additional epileptic seizures. The onset of such events was usually after age 5 years, prevalence peaking at 15-20 years (27%). Many became wheelchair bound as a result. This unique combination of more than one non-epileptic movement disorder and epilepsy deserves further semiological and genetic study both for the patients with CLS and for the wider implications.