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VIEWPOINTS Produced in association with ACNR

Wednesday / Thursday / London Lecture – Friday / Expert-led 23 Refractory Epilepsy 24 what’s new in status epilepticus? 25 poster session Improving the treatment of refractory In The London Lecture, Professor Simon Highlights included the latest research epilepsy was a key focus of this meeting, Shorvon reviewed progress in our into SUDEP, hospitalisation rates, with topics ranging from dietary treatments, understanding of status epilepticus and AED use in clinical practice, and new to new surgical techniques and outcomes, highlighted some of the most promising data with , and recent developments in AED treatment. new treatment approaches in development. perampanel, and other drug treatments.

The 2015 Annual Scientific Meeting of the epilepticus (see page 6) and Professor Ingmar report of this well-attended symposium can be ILAE British Chapter, held in London on 23–25 Blümcke reviewing the latest analysis of surgical found on pages 4 and 5 of this newsletter. September 2015, brought together more than 300 outcomes in adults and children from the European We hope you enjoy this issue of VIEWPOINTS, epilepsy researchers and healthcare professionals Epilepsy Brain Bank (see page 2). Dr Jim Morrow which offers a selection of meeting highlights, and from across the British Isles. In a varied and from the Belfast Health and Social Care Trust was provides an update on some of the latest and most busy programme that included plenary sessions, awarded this year’s ILAE Excellence in Epilepsy exciting research underway across the country. sponsored satellite symposia, a debate, and an Award at the meeting and, in his award lecture, expert-led poster session, delegates heard news he presented encouraging new data on the risk of of the latest research from across the country in major congenital malformations associated with ILAE meetings give a chance a broad range of epilepsy topics. Opening the some of the newer antiepileptic drugs (AEDs) “ for all the groups in the epilepsy meeting, President of the ILAE British Chapter, (see page 3). community to come together, Dr John Paul Leach, described the annual event To mark the granting of a new indication in the UK including neurologists, nurses, as ‘one of my favourite meetings’, encouraging for the novel AED, perampanel (Fycompa®) as everyone to get involved in the discussions and psychologists, psychiatrists and an adjunctive treatment for primary generalised take an active part in the event. basic scientists. It is important tonic-clonic (PGTC) seizures in adults and that we all have a Several keynote presentations were made at the meeting by world-renowned epilepsy experts, generalised epilepsy (IGE), Eisai sponsored a broad outlook… with Professor Simon Shorvon delivering The satellite symposium entitled, ‘Do we need a new ” Dr John Paul Leach, London Lecture, focusing on what’s new in status therapeutic approach for our IGE patients?’. A President of the ILAE British Chapter

Produced in association with Advances in Clinical Neuroscience & Rehabilitation (ACNR). Initiated and funded by Eisai Ltd. Prescribing information can be found on the last page. Epilepsy surgery continues to offer hope to patients with medically- Also new refractory epilepsy: new European and UK data presented at this Epilepsy surgery remains an important treatment Surgical outcomes data from 6899 adults and option for adults and children with medically- 2707 children were presented demonstrating refractory epilepsy, achieving seizure freedom in overall seizure-freedom rates at 12 months of meeting… many individuals. In the ILAE 2015 British Chapter 64.1% (Table 1). Rates were reported to be Annual International Lecture, Professor Ingmar similar in adults (74.0%) and children (65.1%). Walton Centre study suggests many patients Blümcke from the University Hospital Erlangen do not remain seizure-free in the long term in Germany presented the latest analysis of Table 1: 12-month seizure-freedom rates data from the European Epilepsy Brain Bank, reported in a recent (unpublished) analysis of A new study by The Walton Centre for to which three UK centres have contributed. data from the European Epilepsy Brain Bank Neurology and Neurosurgery and Liverpool University reported similarly good initial Onset of Age of outcomes of epilepsy surgery in 284 % patients Neuropathological spontaneous patients n (%) seizure-free at patients with medically-refractory epilepsy findings seizure activity at surgery 12 months (Wieshmann et al., 2015). In this study, a (years) (years) seizure freedom rate of 45% at 12 months Hippocampal sclerosis 3405 (35.4) 9 34 64.7 after surgery was reported, however, this

Tumours 2189 (22.8) 13 25 71.3 reduced to 42% at 2 years, 29% at 5 years and 19% at 10 years post-surgery. In Malformations of 1873 (19.5) 3 15 63.5 cortical development his presentation to the meeting, Dr Udo Wieshmann from The Walton Centre said No lesions 739 (7.7) 11 28 51.7 that although surgery resulted in a dramatic Vascular malformation 564 (5.9) 21 35 65.8 reduction of seizures in many patients, long- Glial scars 473 (4.9) 8 25 52.0 term outcomes appeared less favourable. He proposed that surgery could potentially Dual pathology 223 (2.3) 6 28 61.3 convert a medically-refractory epilepsy to Encephalitis 135 (1.4) 5 12 60.4 a medically-treatable form and that better patient selection and new surgical techniques Double pathology 5 (0.1) 20 32 100 might improve outcomes in the future. Total 9606 12 28 64.1

According to Prof. Blümcke, the decision to operate tended to come sooner after seizure onset in Low complication rates reported by the children than in adults, with earlier surgery delivering better outcomes. He reported that epilepsy duration, localisation and histopathological diagnosis appeared to predict surgical outcomes, however, National Hospital for Neurology and he said, this had not yet been confirmed statistically due to the relatively small sample size. Neurosurgery A team from the National Hospital for Neurology Encouraging results with RTG RUF and Neurosurgery in London reported the ESL 2% the use of newer AEDs in 5% 2% results from a 25-year retrospective study of physical complications in 911 epilepsy a nurse-led community PER surgical procedures (Gooneratne et al., 17% epilepsy service ZNS 2015). Most (84%) procedures reviewed 48% were temporal lobe surgeries. No peri- LAC operative deaths were reported. A total of Newer AEDs are being used more frequently with 26% encouraging results, according to the findings of 131 (14%) of surgeries were complicated a recent audit of a nurse-led community epilepsy by persistent neurological complications; the service in mid-Staffordshire (Tittensor et al., 2015). most persistent anticipated complication was ESL, eslicarbazepine acetate; LAC, ; The audit included data from approximately 800 PER, perampanel; RTG, ; RUF, ru!namide; a quadrantanopia (77 patients; 8%), which ZNS, . patients under regular review by the service and occurred in 10% of patients who had temporal reported that 133 of these patients had been offered Figure 1: Percentage of treatment-refractory patients lobe surgery. Surgical complications occurred receiving one of the six newer AEDs (n=133) in a nurse-led treatment with one of the newer AEDs (Figure 1). community epilepsy service in mid-Staffordshire (Tittensor in 83 patients (9%). The group concluded Most patients trying these drugs had failed to have et al., 2015) that complication rates in their study were their epilepsy controlled with older . became seizure free in this study) despite being the similar to those reported in the literature and Zonisamide (n=63), lacosamide (n=35) and most treatment refractory (Tittensor et al., 2015). The that the risk of physical, neuropsychiatric and perampanel (n=22) were reported to have reduced research group from the Royal Wolverhampton NHS neuropsychological complications needed to seizure frequency by at least 50% in 62%, 76% and Trust and Keele University reported ‘encouraging be made clear to individuals considering this 65% of patients, respectively. Patients receiving statistics’ that, they concluded, supported the use treatment option. perampanel were most likely to achieve seizure of the newer AEDs in the treatment-refractory freedom of at least 6 months (18% of patients population being studied.

2 Produced in association with ACNR High rates of unscheduled admissions and readmissions in epilepsy cost the NHS millions

al., 2015). A total of 177 1 year and one-third reattending five or more 350000 318768 admission episodes were times. The group called for further research to 300000 captured belonging to 120 characterise the clinical features of this cohort of 250000 200000 patients. These patients patients and to design alternative care pathways 146801 150000 were hospitalised for a total aimed at reducing costs and improving the quality 95758 100000 of 548 days and 13 patients of care.

39581 38666 35457 50000 28403 25576 24801 21039 7098 6445 6016 5232 4970 4506 4072 2483 2038 (10.8%) were admitted to Number of admissions 0 ITU. The length of

disorders Ataxias h o s p i t a l i s a t i o n Meningitis Stroke or TIA Encephalitis Sleep disorders Multiple sclerosis ranged from 1 to 25 Cranial nerve disorders 25 Migraine and headaches Nervous system atrophy days (mean 4.55

Parkinson’s disease and dystonia Intracranial abscess or phlebitis Other disorders of nervous system Epilepsy including !t or seizure NOS Myopathies and myoneural disorders days) (Figure 3). Cerebral palsy and paralyticNerve syndromes root disorders and neuropathies Hydrocephalus and toxic encephalopathy Disorders of the autonomic nervous system Thirty-one patients 20 Alzheimer’s disease and other degenerative had a further 57 Figure 2: Neurological diagnoses ranked by number of emergency hospital r e a d m i s s i o n s 15 admissions between 31 April 2007 and 31 March 2013 (Hick et al., 2015) (Figure 4) – the Percent High rates of unscheduled admissions for adults majority due to 10 with suspected seizures are costing the NHS uncontrolled epilepsy. Drug compliance, systemic illness and AED in England an average of £93 million per year 5 according to the results of a new study (Hick et al., changes were common provocative factors for admissions. There was 2015). Researchers from the Royal Hallamshire 0 Hospital and the University of Sheffield presented a significant readmission risk with a 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 19 21 25 Days n=177 new data collected between 2007 and 2013 recent admission (p=0.006), use of (p=0.012) and partial showing that 38.9% of all unscheduled/emergency Figure 3: Distribution of length of stay for all current admission episodes neurological admissions in England were for seizures (p=0.042). Most readmissions epilepsy/seizure/convulsion (Figure 2), making were within 2 months (Figure 4). this the largest neurological cause for admission A high risk of hospital readmission for and accounting for 0.75% of all emergency epilepsy was also found by researchers admissions. The median cost per admission was 10 from the University of Sheffield and 9 reported to be £1650 (range 0 to £217,998) and the Royal Hallamshire Hospital in a 8 the mean total cost to the NHS in England was £93 recent literature review (Dudhill et al., 7 million per year. 6 2015). These researchers reported 5 4 In a second study, which was conducted by that there are, on average, 37,000 Frequency hospital admissions for epilepsy each 3 the Abertawe Bro Morgannwyg (ABM) University 2 Health Board (UHB) and Swansea University, year in England and Wales – the 1 0 895 patients with suspected seizures visited the majority of which are readmissions. Up to 1m 1-2 m 2-3 m 3-4 m 4-5 m 5-6 m >6 m emergency department of ABM UHB hospitals Patients with epilepsy frequently Time interval for !rst readmission (months) n=31 between January 2013 and May 2014 and attended emergency departments, with over 60% reattending within 349 (39.0%) of these were admitted (Khan et Figure 4:

Latest analysis from the UK Epilepsy and Pregnancy Also new at this meeting… Register shows low risk of major congenital Dr Rebecca Bromley from the University of Manchester presented a meta-analysis of published data evaluating the risk associated malformations with and with in-utero exposure to lamotrigine or levetiracetam monotherapy and confirmed a low risk relative to other AEDs evaluated (Bromley Winner of this outcome data available in almost 9000 et al., 2015). According to her analysis, there was no evidence of year’s ILAE pregnancies. As expected, the risk of major a difference in overall malformation rate between lamotrigine- and Excellence in malformations was highest with levetiracetam-exposed children. Epilepsy Award, 5.7% (74/1302), with the lowest risk A recent audit on the use of sodium valproate (VPA) in women of Dr Jim Morrow, reported with lamotrigine (2.0%; 46/2343) child-bearing age (aged 16–45 years) with epilepsy undertaken at Cardiff University and the University Hospital Wales, and from the Belfast Health and levetiracetam (1.3%; 7/558). The risk presented in a poster by Jessica Lock and colleagues, has and Social Care Trust focused his plenary associated with carbamazepine (2.4%; revealed that VPA is still being prescribed to many young women lecture on the latest evidence of major 43/1806) was identical to the background with epilepsy (Lock et al., 2015). Valproate was prescribed as the congenital malformations associated rate reported with no AED use (2.4%; first-choice AED in 32% of the women, however, the rationale for choosing VPA was documented in only one-third of patients’ notes. with exposure to AEDs during pregnancy 14/587). According to Dr Morrow, these Pre-conception counselling was documented in 70% of case notes from the UK Epilepsy and Pregnancy encouraging rates are similar, if not slightly and in 40% of notes on more than one encounter. Although the Register. This latest analysis, presented lower, than those reported in other national researchers found general compliance with current guidelines, for the first time at the meeting, included or international registries. they highlighted continued follow-up of women taking VPA and clear documentation as key areas for improvement. data from 10,625 registrations, with full

Produced in association with ACNR 3 Delegates welcome perampanel (Fycompa®) as a new therapeutic approach for patients with idiopathic generalised epilepsy (IGE)

The summer of 2015 heralded the arrival of a undertaken that inform new therapeutic approach for IGE, an advance clinical decision-making. New clinical evidence for management of PGTCS that has been widely welcomed by the epilepsy According to Prof. 332 study: 50% and 100% responder rate (PGTCS) ® community. Perampanel (Fycompa , Eisai Ltd) Marson, the available 90 p=0.0019 Placebo (n=81) – a convenient, once-daily epilepsy treatment – evidence indicates that 80 64.2 Perampanel (n=81) became available in the UK in July 2015 for the sodium valproate (VPA) is 70 (n=52) adjunctive treatment of primary generalised tonic- the most effective first-line 60 50 39.5 clonic (PGTC) seizures in adults and adolescents treatment for IGE (Marson (n=32) 40 30.9 ® SmPC 2015), et al., 2007a; Marson et (n=25) 30 a condition with only limited licensed treatment al., 2007b; Bonnett et 12.3 Responder rate (%) Responder rate 20 options (Rheims et al., 2014). In an Eisai- al., 2014), however, the (n=10) 10 sponsored satellite symposium, Professor John worrying risk of major 0 Duncan from the National Hospital for Neurology congenital malformations 50% 100% French JA et al. Neurology 2015;85:1-8. Responder rates

and Neurosurgery in London explained why a and developmental PGTCS, primary generalised tonic-clonic seizures. Full Analysis Set; secondary endpoint. new therapeutic approach is needed, outlining problems associated with Responder: ≥50% reduction and 100% reduction in seizure frequency per 28 days during the Maintenance Period vs Baseline. The values have not been adjusted for multiplicity. the major consequences of uncontrolled epilepsy its use in pregnancy has in terms of mortality, morbidity and psychosocial recently led the European Figure 6: consequences (Figure 5) (Laxer et al., 2014). Medicines Agency (EMA) (adapted from French et al., 2015) to recommend that VPA is The burden of IGE eligible to participate, patients were required to only initiated in women or girls who can become have experienced three or more PGTC seizures pregnant if other treatments are ineffective or not Generalised tonic-clonic seizures occur in many during the 8-week baseline period and have a tolerated (EMA, 2014). IGE syndromes, which are now referred to as prior EEG consistent with primary generalised genetic generalised epilepsies (GGE) (Berg et al., Perampanel (Fycompa®) now licensed in epilepsy. The patient population enrolled in 2010). It has been estimated that approximately PGTC seizures the study was treatment refractory, with 66% one-third of individuals with GGEs are inadequately of all study participants receiving two or three ® controlled with antiepileptic drugs (AEDs) (Brodie Perampanel (Fycompa ) is the first (and only) concomitant AEDs at study baseline. The mean et al., 2013), and these patients are at significant licensed AED to selectively target the initiation time since the diagnosis of IGE was 17.2 years. risk of physical injury, sudden unexpected death and spread of seizures through selective, from epilepsy (SUDEP) and a poor quality of life non-competitive inhibition of AMPA receptors The results from this clinical trial provided Class (Rogawski et al., 2011). It I evidence of the efficacy and tolerability of perampanel at doses up to 8 mg/day in patients Consequences of uncontrolled epilepsy is the first new treatment for PGTC seizures in 8 years with PGTC seizures associated with IGE (French (Eisai data on file, 2015). et al., 2015). Sixty-four percent of patients treated 1 Mortality 6OQSFEJDUBCJMJUZ t46%&1 Perampanel has been t"DDJEFOUT available for the adjunctive reduction in PGTC seizure frequency per 28 t4VJDJEF treatment of partial-onset days during the maintenance period compared seizures with or without to baseline (the primary efficacy endpoint) versus secondary generalisation 39.5% of patients receiving placebo (p=0.0019) (Figure 6). During the 13-week maintenance .PSCJEJUZ1 t*OKVSJFT 1TZDIPTPDJBMDPOTFRVFODFT1 since 2012, and more period, 30.9% of patients became free from t#VSOT t%SJWJOH than 30,000 patients have PGTC seizures when treated with perampanel t$PHOJUJPO t7PDBUJPOBM t4PDJBM received the treatment as an adjunctive therapy, compared with 12.3% 46%&1 TVEEFOVOFYQMBJOFEEFBUIJOFQJMFQTZ t%FQSFTTJPOBOEBOYJFUZ since its launch worldwide of patients in the placebo group (Figure 6). No -BYFS,%FUBM&QJMFQTZ#FIBW (Eisai data on file, 2015). aggravation of absence (n=60) or myoclonic The approval of perampanel (n=47) seizures was observed with adjunctive Figure 5: The consequences of uncontrolled epilepsy (adapted from Laxer et al., 2014) for the treatment of PGTC perampanel treatment compared with placebo in resulting from their seizures (Laxer et al., 2014). a sub-analysis of data from this study, which was Differentiating between focal and generalised with IGE was based on the results of a landmark presented in a poster at the meeting (O-Brien et epilepsies can be challenging in clinical practice, randomised controlled trial (RCT) (French et al., al., 2015). as illustrated by Dr Mar Carreño from the Hospital 2015) – the results of which were presented at According to Prof. Reuber, adjunctive perampanel Clinic of Barcelona in Spain, however, she the ILAE 2015 meeting by Professor Markus was generally well tolerated, with low rates of stressed, reaching a correct diagnosis is vital to Reuber from the Royal Hallamshire Hospital and discontinuation due to treatment-emergent ensure the appropriate treatment is initiated with the University of Sheffield. adverse events (TEAEs) observed in the the aim of improving clinical and quality of life Pivotal phase 3 clinical study perampanel treatment group (11.1% vs. 6.1% outcomes for these patients. in the placebo group) (French et al., 2015). This pivotal, global, phase 3 clinical study Unfortunately, as delegates heard from Professor Prof. Reuber concluded that adjunctive treatment (Study 332) assessed the safety and efficacy of Tony Marson from The Walton Centre and the with perampanel has demonstrated a favourable adjunctive perampanel compared with placebo in University of Liverpool, few AEDs have been risk:benefit profile in an adolescent and adult 164 patients aged 12 years or older with PGTC shown to be effective in generalised epilepsies population with inadequately controlled PGTC seizures and IGE (French et al., 2015). To be and few randomised controlled trials have been seizures.

4 Produced in association with ACNR Also new at this meeting… Precision therapies in Perampanel use in clinical practice: epilepsy evolve latest study results Several new studies of perampanel use in clinical practice were as genomic presented at the meeting. In brief: technologies NHS Trust presented the findings from a UK London reported the results from a multicentre, and Ireland multicentre study involving 18 prospective audit involving 104 patients who advance hospitals, who pooled their case note data for had received perampanel treatment at six UK adult outpatients with refractory epilepsy and centres (Theocari et al., 2015).* Forty-seven New genetic sequencing technologies and learning disability (LD) treated with perampanel of these patients had learning disability; an evolving information on genomic architecture (Shah et al., 2015).* Eighty-six patients with average of six previous and three other current and epilepsy aetiology may one day lead to LD (mean age 34 years) and 177 patients AEDs were being used. The mean follow-up more patients receiving targeted treatment based without LD (mean age 43 years) were included was >1 year for 75 patients and the mean in the analysis; >96% and 89% of these patients, duration on perampanel treatment was 9.7 on their unique molecular profile, according to respectively, were receiving two or more AEDs months. Perampanel treatment retention was several speakers at the meeting. Professor at the time of perampanel treatment initiation. reported to be 62% at 12 months and the Tony Marson from The Walton Centre and the Retention rates were reported to be in-line with cumulative probability of improved seizure control University of Liverpool and Dr Michael Johnson other newer AEDs and similar between the two was 37% at 12 months. Most patients responded from Imperial College London described several early to perampanel doses of 2–4 mg, however, examples of drugs that could potentially be seizure frequency was reported in 46%/55% of improvements occurred with longer follow-up. ‘repurposed’ as epilepsy treatments based on LD/non-LD patients with tonic-clonic seizures Side-effects were reported in 62% of patients, and 49%/41% of patients with complex partial with the most common being irritability/mood the results of gene mutation analysis. Examples seizures. Two LD patients (2.3%) and eight changes. According to the authors, the study described included in the treatment of non-LD patients (4.5%) became seizure free. confirmed the results of the short-term RCTs, with KCTN1-positive epilepsies (Mikati et al., 2015), The most commonly-observed adverse effects high treatment retention rates and many patients riboflavin for patients with SLC52A2 mutations, in LD/non-LD patients were behaviour/mood having significant and sustained improvements and bepridil for patients with SCN1A disease disturbance (29%/20%), sedation (29%/20%) with perampanel treatment. (Dravet syndrome). For a recent review of the and dizziness (8%/18%). The research group state-of-the-art in precision medicine in epilepsy, concluded that perampanel was well tolerated *These studies were supported by research grants and effective in the treatment of partial and please see September’s issues of Lancet from Eisai Ltd. generalised seizures in patients with difficult-to- Neurology (EpiPM Consortium, 2015). treat epilepsy and learning disability.

Epilepsy Passport now Epilepsy Passport launched in Communicating my condition the UK

The UK’s first Epilepsy Passport, which is designed the project and ensure that every young person to contain essential information about a child or has a current passport in place containing up-to- young person’s epilepsy, was launched in September date information on their epilepsy, emergency care 2015 with the aim of improving communication plan, medications and emergency contact details. and continuity of care across services. In the first The project is being led by the Royal College of presentation of the meeting, Dr Richard Appleton Paediatrics and Child Health, with funding from the from Alder Hey Children’s NHS Foundation Trust in Healthcare Quality Improvement Partnership. Liverpool urged the epilepsy community to support

For more information, please visit www.epilepsypassport.org.uk.

Produced in association with ACNR 5 What’s new in status epilepticus?

The London Lecture by Professor Simon Shorvon, University College London, Institute of Neurology and National Hospital for Neurology and Neurosurgery

Professor Simon Shorvon presented The diazepam and all showed considerable SE (Ilvento et al., 2015), with a recent systematic London Lecture and reviewed some of the latest promise for the Stage 1 treatment of SE, with review of the literature reporting good response findings relating to the causes and treatment of several major clinical trials currently underway rates in both adults and children and low rates status epilepticus (SE), based on discussions (Kälviäinen, 2015). of complications (Zeiler, 2015). Finally, Prof. held earlier in the year at the 5th International Shorvon discussed the potential use of deep Turning to the issue of refractory and super- Colloquium on Status Epilepticus and Acute hypothermia, which has proved to be a powerful refractory SE (SRSE), Prof. Shorvon presented Seizures in London. The proceedings of this method of controlling seizures in animal models new, high-quality epidemiological evidence meeting were published in the August 2015 of SE (Niquet et al., 2015), suggesting its use in suggesting that approximately 20% of patients with issue of Epilepsy & Behaviour (volume 49). patients with refractory SE should be more fully refractory SE being treated in intensive care units Prof. Shorvon presented preliminary results from explored. may progress to SRSE, with 1-year mortality rates a new global audit of 488 cases of SE drawn approaching 40% (Kantanen et al., 2015). He also from 44 different countries demonstrating that reviewed evidence suggesting that prolonged use Take part in a global audit of cerebrovascular disease remains a common of intravenous anaesthetics in SRSE worsens the treatment of refractory SE cause of SE (responsible for 13% of cases), outcomes (Sutter et al., 2015) which, he said, with acute CNS infections (13%), acute CNS Prof. Shorvon urged delegates to register needed urgent further investigation. anoxia (11%), /drug/toxin/metabolic (9%) and participate in a new, on-line audit of the treatment and outcomes of SE. and drug reduction or withdrawal (9%) other Looking to the future, Prof. Shorvon suggested For more information, please visit: frequent causes (Ferlisi et al., 2015). In terms of that may well prove to be a useful www.status-epilepticus.net. new treatments, he said intranasal midazolam, alternative first-line anaesthetic in the treatment of

New data on early outcomes in super- Modified refractory NORSE ketogenic diet Early outcomes in six consecutive patients with All patients received at least three AEDs and ‘super-refractory’ new-onset refractory status were sedated with propofol or thiopentone; shows promise epilepticus (NORSE) were reported at the five patients received plasma exchange. At 6 meeting by a team from the University Hospital months, three patients had only mild-to-moderate in adults with Birmingham (Paul et al., 2015). The mean age of cognitive impairment and were able to live in the presentation of the patients was 29.5 years (range community. One patient was living in a nursing resistant 15–49 years). All patients had acute or sub-acute home and two patients died on ITU. The group onset of behavioural or cognitive difficulties prior called for a multicentre collaboration to investigate epilepsy to the onset of status. The median length of this rare but serious condition in order to help stay on ITU (intensive care unit) was reported identify possible immunological markers and Dr Manny Bagary from the Queen to be 41 days (range 7–167 days). The cause of develop management guidelines. Elizabeth Hospital in Birmingham NORSE was unknown in five of the six patients; presented encouraging initial results from neurosyphillis was the underlying cause in the a small cohort of adult patients (n=11) with remaining patient. pharmacoresistant, non-lesional epilepsy initiated on a modified ketogenic diet (Bagary Does AMPA receptor inhibition explain et al., 2015). The diet was carefully phased in over a 4-week period, with efficacy assessed how ketogenic diets work in epilepsy? at 3 months. Of the 11 patients who have completed the study so far, two patients Researchers from the University College of Sophie Williams from UCL demonstrated that DA (18%) became seizure-free, eight patients London’s (UCL) Institute of Neurology and the reduces the intrinsic excitability of neurons and (73%) experienced a 50% improvement in Royal Holloway University of London have recently that novel branch derivatives of other medium seizure frequency and one patient reported demonstrated that decanoic acid (DA), which is a chain fatty acid associated with the ketogenic no change in seizure frequency. The diet key component of the medium chain triglyceride diet can block epileptiform activity in vitro (Chang was generally well tolerated and there were ketogenic diet, acts as a non-competitive AMPA et al., 2015). The hope is that, in the future, the no drop-outs due to treatment-emergent receptor antagonist (Williams et al., 2015), which clinical benefits associated with the ketogenic diet adverse events. may help to explain how ketogenic diets work in can be reproduced using novel compounds with epilepsy. Studies presented at the meeting by similar mechanisms that are easier to tolerate.

6 Produced in association with ACNR Selecting AEDs based on their A B 100 100 clinical ‘effectiveness’: why both 3 months 6 months 90 90 81.8% (153/187) 78.6% (81/103) safety and efficacy matter 80 80 69.9% (146/209) 68.1% (77/113) AEDs should be selected based on the composite Clinical effectiveness of 70 70 61.8% of clinical ‘effectiveness’, which takes into account eslicarbazepine acetate: (76/123) 60 60 both their safety and efficacy (Figure 7). This was the new real-world data 48.5% 46.8% (65/134) (66/141) 50 50 conclusion reached in a BIAL and Eisai co-sponsored presented 39.2% 37.5% (74/189) (60/160) satellite symposium entitled, ‘Optimising epilepsy 40 40 In terms of clinical 25.9% Responder rate (%) Responder rate (55/212)

effectiveness, new 30 (%) rate freedom Seizure 30 real-world data on Treatment concepts in epilepsy 20 20 eslicarbazepine acetate (Zebinix®/ESL, BIAL) were 10 10 presented in two posters Maintenance of 0 0 at the meeting, confirming 3 months 6 months Total Simple Complex Secondarily “normal life” seizures partial partial generalised that the treatment is seizures seizures seizures “E!ectiveness” both effective and well CI, con!dence intervals tolerated in clinical practice (Holtkamp et al., Figure 8: (A) Responder rates for total seizures and (B) seizure freedom rates for total 2015; Kerr et al., 2015). seizures and by seizure type (with 95% CI) after 3 and 6 months (Holtkamp et al., 2015) Favourable No or minimal AED Eslicarbazepine acetate is seizure control + adverse e!ects a once-daily AED that is High ESL treatment retention rates (>80% “E"cacy” “Tolerability” approved in the UK as adjunctive therapy in adults of patients over 6 months) were observed with partial-onset seizures, with or without secondary (Holtkamp et al., 2015). Figure 7: The concept of treatment effectiveness in epilepsy generalisation (Zebinix® SmPC, 2015). The treatment has been extensively investigated in a series of RCTs Additional beneficial effects of ESL adjunctive (Elger et al., 2009; Ben-Menachem et al., 2010; Gil- therapy were observed in patient-rated quality therapy: searching for the evidence, looking beyond Nagel et al., 2009; Sperling et al., 2015). These latest of life (QOLIE-10) and clinician-rated global the data’. During the symposium, Dr Rajiv Mohanraj data have been generated from the prospective, improvement (CGI-GI) (Kerr et al., 2015). from the Greater Manchester Neuroscience Centre in non-interventional Eslicarbazepine acetate in Partial- Salford presented compelling evidence that adverse The author concludes: Onset Seizures (EPOS) study, which investigated the events may be more important than seizure frequency effectiveness and safety/tolerability of ESL as add-on in determining quality of life in treatment-resistant monotherapy in everyday clinical practice to treat to AED monotherapy in everyday clinical practice epilepsy (Gilliam et al., 2004), emphasising that safety adult patients with partial seizures, ESL was generally across eight European countries.* considerations were paramount in determining choice of well tolerated as >80% of the patients were retained AED – especially in the adjunctive setting where there over six months.” is no conclusive evidence that any one AED is more meeting included: *This study was supported by a research grant from Eisai. effective than another. Professor Norman Delanty from the Beaumont Hospital in Dublin explained why ESL adjunctive therapy was generally well tolerated and very effective, with high responder frequency during the previous 3 months compared with the seizure good quality clinical practice involved a common sense frequency during the 3 months prior to starting ESL treatment. approach in which clinical trial data were unified with rates (82%) and seizure freedom rates (39%) at Seizure freedom was defined as no seizures during the previous real-life issues and experience. He stressed that there 6 months after ESL was added to monotherapy 3 months. could be no ‘one-size-fits-all’ approach when choosing in patients with insufficient seizure control AEDs, since every patient is unique. (Figure 8) (Holtkamp et al., 2015).** The SUDEP and Seizure Lack of awareness of SUDEP may Safety Checklist leads to be putting patients at risk: how can step-up care and greater communication be improved? risk awareness: could this help patients to stay A lack of awareness of SUDEP may be putting patients at risk, according to the results of several studies presented at safe in the future? the meeting. Researchers at Cardiff University and University A team from the Cornwall Partnership NHS Foundation Trust, in association with Hospital Wales investigated the opinions of people with epilepsy SUDEP Action, Plymouth University and Royal Cornwall Hospital, has pioneered the about how SUDEP information is provided and reported that development of a SUDEP and Seizure Safety Checklist and a mobile application that only 39% of patients they questioned claimed to have any has generated considerable interest across the epilepsy community. The Checklist is knowledge about SUDEP, and only 10% of patients showed a practical, evidence-based tool that is quickly completed in the clinic and designed a good understanding of SUDEP (Drew et al., 2015). Patients to communicate and highlight risk. It was introduced into routine clinical practice in were overwhelmingly in favour of being told about SUDEP, Cornwall in 2013, and a telehealth project used the checklist on a quarterly basis to and subsequent provision of information led to encouraging monitor 15 high-risk but stable patients with epilepsy and 90 patients with epilepsy behaviour modifications such as improved registered in a community-based general practice (Shankar et al., 2015). compliance, improved sleep and a reduction in alcohol intake. In a prize-winning poster, Dr Rohit Shankar presented the findings from his studies, Another study conducted by teams at the Royal Free Hospital, demonstrating that, over a 2-year period, 80% of people with epilepsy accessing the National Hospital for Neurology and Neurosurgery, and Kings Cornwall’s epilepsy services had their SUDEP risk assessed and recorded using the College Hospital in London found that only 50% of patients were checklist and 98% of patients and caregivers responded positively to its use (Shankar aware of SUDEP and only 38% were aware of status epilepticus et al., 2015). The telehealth project reported that 17% of patients with epilepsy using (Keddie et al., 2015). Provision of SUDEP information resulted the Checklist received a step-up of care with interventions that would not have in positive consequences in 48% of patients. happened otherwise. The checklist has since formed the basis of a self-monitoring app called EpSMon (funded by Kt’s Fund via SUDEP Action), which prompts patients According to these researchers, both studies support a change to assess their risk factors and engage with services regularly and appropriately. For in the way SUDEP is discussed with patients, with information more information about these initiatives, please visit: www.sudep.org provided on the risks and positive steps that can be taken to modify those risks. “This meeting had something of interest for everyone, and I think we all learnt something that will help us provide better care for our patients in the future.” Dr John Paul Leach, President of the ILAE British Chapter

Produced in association with ACNR 7 References

Bagary M, Keogh S, Hughes D, et al. Modified ketogenic diet in Fycompa® (perampanel) Summary of Product Characteristics. Eisai Ltd. adults with resistant epilepsy. Platform presentation at the ILAE British Revision dated 22 June 2015. Available at: https://www.medicines.org. Chapter 2015 Annual Scientific Meeting. uk/emc/medicine/26951. Accessed 28 September 2015. Ben-Menachem E, Gabbai AA, Hufnagel A, et al. Eslicarbazepine Gil-Nagel A, Lopes-Lima J, Almeida L, et al. Efficacy and safety acetate as adjunctive therapy in adult patients with partial epilepsy. of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment Epilepsy Res 2010;89(2-3):278-85. in adults with refractory partial-onset seizures. Acta Neurol Scand Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and 2009;120(5):281-7. concepts for organization of seizures and epilepsies: report of the ILAE Gilliam FG, Fessler AJ, Baker G, et al. Systematic screening allows Commission on Classification and Terminology, 2005-2009. Epilepsia reduction of adverse antiepileptic drug effects: a randomized trial. 2010;51(4):676-85. Neurology 2004;62(1):23-7. Bonnett LJ, Tudur Smith C, Smith D, et al. Time to 12-month Gooneratne IK, Mannan S, de Tisi J, et al. Physical complications remission and treatment failure for generalised and unclassified of epilepsy surgery at the National Hospital for Neurology and epilepsy. J Neurol Neurosurg Psychiatry 2014;85(6):603-10. Neurosurgery – a 25-year prospective from 1990 to 2014. Poster Brodie MJ. Road to refractory epilepsy: the Glasgow story. Epilepsia presentation at the ILAE British Chapter 2015 Annual Scientific 2013;54 (Suppl 2):5-8. Meeting. Abstract EL04. Bromley R, Weston J, Jackson C, et al. Malformation risk following in Hick J, Jacques R, Grünewald R, et al. Unscheduled admissions for utero exposure to lamotrigine or levetiracetam in comparison to other adults with suspected seizures in the NHS in England 2007–2013 using antiepileptic drugs: a meta-analysis. Platform presentation at the ILAE Hospital Episode Statistics. Poster presentation at the ILAE British British Chapter 2015 Annual Scientific Meeting. Chapter 2015 Annual Scientific Meeting. Abstract EL02. Chang P, Zuckermann AM, Williams S, et al. Seizure control by Holtkamp M, McMurray R, Sousa R, et al. Real-world data on derivatives of medium chain fatty acids associated with the ketogenic eslicarbazepine acetate as add-on treatment to antiepileptic diet show novel branching-point structure for enhanced potency. J monotherapy in adults with partial-onset seizures: the EPOS study. Pharmacol Exp Ther 2015;352(1):43-52. Poster presentation at the ILAE British Chapter 2015 Annual Scientific Meeting. Abstract 021. Drew C, Elwakil S, O’Neill C, et al. Discussing Sudden Unexpected Death in Epilepsy (SUDEP). Do patients want to know? Does Ilvento L, Rosati A, Marini C, et al. Ketamine in refractory convulsive knowledge change behaviour? Poster presentation at the ILAE British status epilepticus in children avoids endotracheal intubation. Epilepsy Chapter 2015 Annual Scientific Meeting. Abstract EL03. Behav 2015;49:343-6. Dudhill H, Reuber M, Grünewald R, et al. The potential for community- Kälviäinen R. Intranasal therapies for acute seizures. Epilepsy Behav based alternative care pathways for patients after suspected seizures: a 2015;49:303-6. literature review. Poster presentation at the ILAE British Chapter 2015 Kantanen AM, Reinikainen M, Parviainen I, et al. Incidence and Annual Scientific Meeting. Abstract 014. mortality of super-refractory status epilepticus in adults. Epilepsy Behav Eisai Ltd. Data on file, 2015. 2015;49:131-4. Elger C, Halász P, Maia J, et al. Efficacy and safety of eslicarbazepine Keddie S, Angus-Leppan H, Parker T, et al. Discussing Sudden acetate as adjunctive treatment in adults with refractory partial-onset Unexpected Death in Epilepsy: where are we going wrong? Poster seizures: a randomized, double-blind, placebo-controlled, parallel- presentation at the ILAE British Chapter 2015 Annual Scientific group phase III study. Epilepsia 2009;50(3):454-63. Meeting. Abstract 019. EpiPM Consortium. A roadmap for precision medicine in the epilepsies. Kerr M, McMurray R, Sousa R, et al. Impact on quality of life and Lancet Neurol. 2015 Sep 18. pii: S1474-4422(15)00199-4. doi: 10.1016/ clinician-rated global improvement with eslicarbazepine acetate as add- S1474-4422(15)00199-4. [Epub ahead of print] on treatment to antiepileptic monotherapy in adults with partial-onset seizures. Poster presentation at the ILAE British Chapter 2015 Annual European Medicines Agency (EMA). CMDh agrees to strengthen Scientific Meeting. Abstract 020. warnings on the use of valproate medicines in women and girls. Press release EMA/709243/2014. Issued 21 November 2014. Available Khan NA, Sawhney IMS, Malik G, et al. Review of hospitalised patients at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_ with epilepsy to prevent further admissions. Poster presentation at the release/2014/11/WC500177638.pdf. Accessed 28 September 2015. ILAE British Chapter 2015 Annual Scientific Meeting. Abstract 022. Ferlisi M, Hocker S, Grade M, et al. Preliminary results of the global Laxer KD, Trinka E, Hirsch LJ, et al. The consequences of refractory audit of treatment of refractory status epilepticus. Epilepsy Behav epilepsy and its treatment. Epilepsy Behav 2014;37:59-70. 2015;49:318-24. Lock J, Hamandi K. An audit of sodium valproate use in women. French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic- Poster presentation at the ILAE British Chapter 2015 Annual Scientific clonic seizures in idiopathic generalized epilepsy: A randomized trial. Meeting. Abstract 027. Neurology 2015 Aug 21. pii: 10.1212/WNL.0000000000001930. [Epub ahead of print] Abbreviations used in this publication:

AED: antiepileptic LAC: lacosamide SE: status epilepticus DA: decanoic acid LD: learning disability SRSE: super-refractory status epilepticus EEG: electroencephalogram NORSE: new-onset refractory status SUDEP: sudden unexpected death from EMA: European Medicines Agency epilepticus epilepsy ESL: eslicarbazepine acetate PER: perampanel TEAE: treatment-emergent adverse event GGE: genetic generalised epilepsy PGTC: primary generalised tonic-clonic VPA: valproate IGE: idiopathic generalised epilepsy RCT: randomised controlled trial ZNS: zonisamide ILAE: International League Against Epilepsy RTG: retigabine ITU: intensive care unit RUF:

Produced in association with ACNR 8 PRESCRIBING INFORMATION Cont. Zonegran® (zonisamide) References Please refer to the SPC before prescribing. Presentation: Hard capsules: 25 mg, 50 mg, 100 mg zonisamide. Indication: Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy. Adjunctive therapy in the treatment of partial Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of seizures, with or without secondary generalisation, in adults, adolescents, and children aged 6 years and above. effectiveness of valproate, lamotrigine, or for generalised Dose and administration: Adults: Monotherapy: Starting dose is 100 mg once a day. After two weeks, and unclassifiable epilepsy: an unblinded randomised controlled trial. increase to 200 mg once a day. Then increase at two-weekly intervals in 100 mg increments. Withdraw gradually. Adjunctive therapy: Starting dose is 50 mg in two divided doses. After one week, increase to Lancet 2007a;369(9566):1016-26. 100 mg daily. Then increase at one weekly intervals in 100 mg increments. Can be taken once or twice daily after titration. In renal or hepatic impairment and patients not receiving CYP3A4-inducing agents Marson AG, Appleton R, Baker GA, et al. A randomised controlled consider two weekly intervals. Paediatric population (aged 6 years and above): Adjunctive therapy: starting dose is 1 mg/kg once a day. After one week, increase at weekly intervals in increments of 1 mg/kg. trial examining the longer-term outcomes of standard versus new In patients not receiving CYP3A4-inducing agents consider two weekly intervals in increments of 1 mg/kg. antiepileptic drugs. The SANAD trial. Health Technol Assess For patients weighing 20 to 55 kg a maintenance dose of 6 to 8 mg/kg once a day is recommended. For patients weighing above 55 kg a maintenance dose of 300 to 500 mg once a day is recommended. 2007b;11(37):iii-iv, ix-x, 1-134. Withdraw gradually. Elderly and patients with renal or hepatic impairment: Caution. Not recommended in severe hepatic impairment. Contra-Indications: Hypersensitivity to zonisamide, sulphonamide or any Mikati MA, Jiang YH, Carboni M, et al. Quinidine in the treatment excipient. Pregnancy: of KCNT1 positive epilepsies. Ann Neurol 2015 Sep 15. doi: 10.1002/ childbearing potential must use contraception during treatment and for one month after discontinuation. Lactation: Excreted into breast milk. Either discontinue Zonegran or stop breast-feeding. Warnings and ana.24520. [Epub ahead of print] Precautions: Serious rashes occur, including cases of Stevens-Johnson syndrome. Closely supervise and consider discontinuation in patients with unexplained rash. Zonegran contains a sulphonamide group Niquet J, Baldwin R, Gezalian M, et al. Deep hypothermia for the which is associated with serious immune based adverse reactions. Cases of agranulocytosis, treatment of refractory status epilepticus. Epilepsy Behav 2015;49:313- thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and leucocytosis have been reported. Monitor for signs of suicidal ideation and behaviours and consider appropriate treatment. Use with caution 7. in patients with risk factors for nephrolithiasis, including prior stone formation, family history of nephrolithiasis and hypercalcuria. In the event kidney stones occur in paediatric patients, Zonegran should O’Brien T, Steinhoff B, Yang H, et al. Efficacy of adjunctive be discontinued. If a hepatic event is suspected, liver function should be evaluated and discontinuation perampanel in idiopathic generalised epilepsy: subgroup analysis should be considered. Evaluate and monitor serum bicarbonate levels in patients who are at risk of metabolic acidosis. If metabolic acidosis develops and persists, consider reducing Zonegran dose, of patients with absence and myoclonic seizures in a double-blind discontinuing Zonegran treatment or adding alkali treatment with Zonegran as osteopenia may develop. Use with caution in adult patients treated with carbonic anhydrase inhibitors, e.g. topiramate or placebo-controlled Phase 3 trial. Poster presentation at the ILAE British acetazolamide. Not recommended for use in paediatric patients with other carbonic anhydrase inhibitors. Chapter 2015 Annual Scientific Meeting. Abstract 008. Monitoring of serum bicarbonate levels should be carried out in the paediatric population. Decreased sweating, elevated body temperature and heat stroke have been reported. Patients should maintain Paul NLM, Kumari S, Sivaguru A, et al. Early outcomes in super- hydration; avoid excessive temperatures and strenuous physical exercise. Prescribers should draw the refractory NORSE: case-series of 6 patients seen in a specialist heatstroke and overheating. Discontinuation should be considered in the event of signs or symptoms of epilepsy service. Poster presentation at the ILAE British Chapter 2015 dehydration, oligohydrosis, or elevated body temperature. Co-medication in paediatric patients with other medicinal products that predispose patients to heat related disorders; these include carbonic anhydrase Annual Scientific Meeting. Abstract EL06. inhibitors and medicinal products with anticholinergic activity are not recommended. Monitor pancreatic lipase and amylase levels in patients taking Zonegran who develop clinical signs and symptoms of Rheims S, Ryvlin P. Pharmacotherapy for tonic-clonic seizures. Expert pancreatitis, consider discontinuation. In cases of severe muscle pain/weakness with or without fever, Opin Pharmacother 2014;15(10):1417-26. assess markers of muscle damage and consider discontinuation. Not recommended in paediatric patients who are underweight or have decreased appetite. Weight should be monitored in paediatric patients. In Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug patients with weight loss consider dietary supplement, increased food intake or discontinuation. There are limited data from clinical studies in patients with a body weight of less than 20 kg. Therefore children aged target. Epilepsy Curr 2011;11(2):56-63. 6 years and above with a body weight of less than 20 kg should be treated with caution. The long term effect of weight loss in the paediatric population on growth and development is unknown. Zonegran 100 mg Shah E, Reuber M, Goulding P, et al. Clinical use of perampanel in capsules contain E110. Drug Interactions: No clinically relevant pharmacokinetic effects on adult patients with uncontrolled epilepsy and learning disability: a UK carbamazepine, lamotrigine, , sodium valproate, oral contraceptives (ethinylestradiol or and Ireland multicentre study. Poster presentation at the ILAE British Zonegran was not affected by lamotrigine or CYP3A4 inhibitors. Caution with drugs which are P-gp substrates. Avoid concomitant administration with drugs causing urolithiasis. Zonisamide is metabolised Chapter 2015 Annual Scientific Meeting. Abstract 045. partly by CYP3A4, N-acetyl-transferases and conjugation with glucuronic acid; therefore caution with substances that can induce or inhibit these enzymes. Interaction studies have only been performed in Shankar R, Newman C, Hanna J, et al. The SUDEP and Seizure adults. Side effects: The most common adverse reactions in a randomised, controlled monotherapy trial Safety Checklist List and mobile application (EpsMon) Project: steps comparing zonisamide with carbamazepine prolonged release were decreased bicarbonate, decreased towards self-management of risk for Patients with Epilepsy (PWE). Poster presentation at the ILAE British Chapter 2015 Annual Scientific dizziness, memory impairment, somnolence, bradyphrenia, disturbance in attention, paraesthesia, diplopia, constipation, diarrhoea, dyspepsia, nausea, vomiting, rash, fatigue, pyrexia, irritability, weight Meeting. Abstract EL09. decreased, blood creatinine phosphokinase increased, alanine aminotransferase increased, aspartate aminotransferase increased. Isolated cases of Sudden Unexplained Death in Epilepsy Patients (SUDEP). Sperling MR, Abou-Khalil B, Harvey J, et al. Eslicarbazepine A pooled analysis of safety data on 95 elderly subjects has shown a relatively higher reporting frequency of acetate as adjunctive therapy in patients with uncontrolled partial-onset oedema peripheral and pruritus compared to the adult population. Post-marketing data suggests patients seizures: Results of a phase III, double-blind, randomized, placebo- syndrome. Most common adverse reactions in controlled adjunctive-therapy studies were somnolence, controlled trial. Epilepsia 2015;56(2):244-53. irritability, confusional state, depression, ataxia, dizziness, memory impairment, somnolence, diplopia, Sutter R, Kaplan PW. Can anesthetic treatment worsen outcome in anxiety, insomnia, psychotic disorder, bradyphrenia, disturbance in attention, nystagmus, paraesthesia, status epilepticus? Epilepsy Behav 2015;49:294-7. speech disorder, tremor, abdominal pain, constipation, diarrhoea, dyspepsia, nausea, rash, pruritis, Theocari E, Slaght S, Louden W, et al. Perampanel in the treatment Serious effects: pneumonia, suicidal attempt, convulsion, cholecystitis, calculus urinary, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms, hypersensitivity-type of epilepsy. Poster presentation at the ILAE British Chapter 2015 Annual Scientific Meeting. Abstract 016. controlled clinical studies was consistent with that of adults. A pooled analysis of safety data on 420 paediatric subjects has shown a relatively higher reporting frequency of pneumonia, dehydration, Tittensor P, Whitehurst J, George R. Audit of newer antiepileptic decreased sweating, abnormal liver function tests, otitis media, pharyngitis, sinusitis and upper respiratory tract infection, cough, epistaxis and rhinitis, abdominal pain, vomiting, rash and eczema, and fever drugs in a nurse led community epilepsy service. Poster presentation at compared to the adult population (particularly in subjects aged below 12 years) and, at a low incidence, the ILAE British Chapter 2015 Annual Scientific Meeting. Abstract 052. amnesia, creatinine increased, lymphadenopathy, and thrombocytopenia. The incidence of a decrease in body weight of 10% or more was 10.7%. In some cases of weight decrease there was a delay in transition Wieshmann U, Mohan M, Nicolson A, et al. The long-term outcome to the next Tanner stage and in bone maturation. Legal Category: POM Basic UK NHS cost: Zonegran 25 mg: packs of 14 £8.82, Zonegran 50 mg: packs of 56 £47.04, Zonegran 100 mg: packs of 56 £62.72. of epilepsy surgery. Platform presentation at the ILAE British Chapter Irish price to wholesaler: Zonegran 25 mg: packs of 14 €9.20, Zonegran 50 mg: packs of 56 €48.78, 2015 Annual Scientific Meeting. Zonegran 100 mg: packs of 56 €65.18. Marketing authorisation numbers: Zonegran 25 mg 14 capsules: EU/1/04/307/001, Zonegran 50 mg 56 capsules: EU/1/04/307/003, Zonegran 100 mg 56 capsules: Williams S, Pavlov I, Williams R, et al. The role of AMPA receptors EU/1/04/307/004. Marketing authorisation holder: Eisai Ltd. Further Information from/Marketed by: Date of in the treatment of epilepsy. Platform presentation at the ILAE British preparation: November 2013.

Chapter 2015 Annual Scientific Meeting. Adverse events should be reported. Reporting forms and Information can be found at Zebinix® (eslicarbazepine acetate) Summary of Product Characteristics. www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Eisai Ltd on 0208 600 1400/0845 676 1400 or [email protected] Eisai Ltd and BIAL. Revision dated 22 January 2014. Available at: https://www.medicines.org.uk/emc/medicine/22376. Accessed 28 PRESCRIBING INFORMATION September 2015. Fycompa® (perampanel) Please refer to the SPC before prescribing. Zeiler FA. Early Use of the NMDA Receptor Antagonist Ketamine in Presentation: Film-coated tablets: 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg perampanel. Indication: Adjunctive treatment of partial-onset seizures with or without secondarily generalised seizures in adult and Refractory and Superrefractory Status Epilepticus. Crit Care Res Pract adolescent patients from 12 years of age with epilepsy. 2015;2015:831260. Adjunctive treatment of primary generalised tonic-clonic seizures in adult and adolescent patients from 12 years of age with idiopathic generalised epilepsy. Acknowledgements: This newsletter was initiated, supported and Dose and administration: Adults and Adolescents: Doses of 4 mg/day to 12 mg/day have been shown to be effective therapy in partial onset seizures. A dose up to 8 mg/day has been shown to be effective in funded by Eisai Ltd and is based on presentations and posters at the primary generalised tonic-clonic seizures. Starting dose is 2 mg daily. Dose may be increased based on ILAE British Chapter 2015 Annual Scientific Meeting held in London, clinical response and tolerability by increments of 2 mg (either weekly or every 2 weeks, as per half-life considerations described below) to a maintenance dose of up to 8 mg/day. Depending upon individual 23–25 September 2015. Medical writing was provided by Ali Jordan clinical response and tolerability at a dose of 8 mg/day, the dose may be increased up to 12 mg/day. Dose and was funded by Eisai Ltd. should be taken orally once daily at bedtime. Patients who are taking concomitant medicinal products that do not shorten the half-life of perampanel should be titrated no more frequently than at 2-week intervals.

9 Produced in association with ACNR Patients who are taking concomitant medicinal products that shorten the half-life of perampanel should be titrated no more frequently than at 1-week intervals. Withdraw gradually. Elderly and patients with renal or hepatic impairment: Dosage adjustments not required in elderly patients. Dosage adjustments not shown to induce the CYP3A4 enzyme. Carefully monitor patients on drugs metabolised by the CYP3A required in mild renal impairment. Fycompa not recommended in patients with moderate or severe renal enzyme for two weeks at start of, or after the end of treatment with Inovelon, or after a marked change impairment or patients undergoing haemodialysis. Caution in mild or moderate hepatic impairment, titration should not be faster than every 2 weeks and maximum daily dosage not exceeding 8mg. Not recommended narrow therapeutic window such as warfarin and digoxin. No effects on the of olanzapine. in severe hepatic impairment. Children and adolescents under 12 years: No data available. Contra- No interaction data with alcohol. Adverse effects: The most common adverse reactions in the clinical Indications: Hypersensitivity to perampanel or any excipient. Pregnancy: Not recommended. Lactation: development program were headache, dizziness, fatigue, and somnolence. Adverse reactions associated Unknown if excreted into breast milk. A decision whether to discontinue breastfeeding or to discontinue/ therapy for the woman. Warnings and Precautions: Patient and their carer should monitor for signs sinusitis, rhinitis, anorexia, eating disorder, decreased appetite, anxiety, insomnia, status epilepticus, of suicidal ideation and behaviours and seek medical advice should such signs emerge. Perampanel convulsion, coordination abnormal, nystagmus, psychomotor hyperactivity, tremor, diplopia, vision blurred, vertigo, epistaxis, abdominal pain upper, constipation, dyspepsia, diarrhoea, rash, acne, back pain, At doses of 12 mg/day Fycompa may decrease the effectiveness of progestative-containing hormonal contraceptives. There appears to be an increased risk of falls, particularly in the elderly. Aggressive and hypersensitivity and hepatic enzyme increase. Legal Category: POM Presentation: Aluminium/aluminium hostile behaviour has been reported; patients and caregivers should be counselled to alert a healthcare blisters. Basic UK NHS cost: Inovelon 100 mg: packs of 10 £5.15, Inovelon 200 mg: packs of 60 £61.77, Inovelon 400 mg: packs of 60 £102.96. Oral Suspension 40mg/ml: 460ml bottle £94.71 Irish price to of perampanel should be reduced if such symptoms occur and should be discontinued immediately if wholesaler: Inovelon 100 mg: packs of 10 €5.32, Inovelon 200 mg: packs of 60 €63.30, Inovelon 400 symptoms are severe. Caution in patients with a history of substance abuse and the patient should be mg: packs of 60 €120.15. Oral Suspension 40mg/ml: 460ml bottle €103.56. Marketing authorisation monitored for symptoms of perampanel abuse. Patients should be closely monitored for tolerability and numbers: Inovelon 100 mg: packs of 10 EU/1/06/378/001, Inovelon 200 mg: packs of 60 EU/1/06/378/009, clinical response when adding or removing cytochrome P450 inducers or inhibitors, or switching from Inovelon 400 mg: packs of 60 EU/1/06/378/014. Oral Suspension 40mg/ml: EU/1/06/378/017 Marketing concomitant non-inducer anti-epileptic medicinal products to enzyme inducing medicinal products and vice authorisation holder: Eisai Ltd. Further Information from/Marketed by: Eisai Limited, European versa, since perampanel plasma levels can be decreased or increased; the dose of perampanel may need Date of preparation: October 2015. to be adjusted accordingly. Fycompa contains lactose, therefore patients with rare hereditary problems of Adverse events should be reported. Reporting forms and information can be found at perampanel. Drug Interactions: www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Eisai Ltd on contraceptives should be considered for women needing Fycompa 12 mg/day and an additional reliable 0208 600 1400/0845 676 1400 or [email protected] method (intra-uterine device (IUD), condom) is to be used. Carbamazepine, phenytoin, and topiramate have been shown to increase perampanel clearance and consequently to decrease plasma PRESCRIBING INFORMATION concentrations of perampanel. Fycompa did not affect in a clinically relevant manner the clearance of Zebinix® (eslicarbazepine acetate) clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, zonisamide, carbamazepine, clobazam, Please refer to the SPC before prescribing. Presentation: Tablets containing 800 mg eslicarbazepine lamotrigine and valproic acid. Fycompa was found to decrease the clearance of oxcarbazepine by 26%. acetate. Indication: Adjunctive therapy in adults with partial-onset seizures with or without secondary Fycompa (6 mg once daily for 20 days) decreased midazolam AUC by 13% in healthy subjects (CYP3A generalisation Dose and administration: May be taken with or without food. Starting dose is 400 mg substrate effect). Strong inducers of cytochrome P450 such as rifampicin and hypericum are expected once daily, increased to 800 mg once daily after one or two weeks. Dose may be increased to 1200 to decrease perampanel concentrations. , a CYP3A4 inhibitor, increased perampanel mg once daily. Withdraw gradually to minimise the potential of increased seizure frequency. Elderly AUC by 20% and prolonged perampanel half-life by 15%. Strong inhibitors of other cytochrome P450 patients >65 years: No dose adjustment is needed in the elderly population provided that the renal isoforms could potentially also increase perampanel concentrations. Fycompa used in combination with function is not disturbed. Children and adolescents <18years of age: Not recommended. Patients other central nervous system (CNS) depressants such as alcohol can increase levels of anger, confusion, with renal impairment: Adjust dose according to creatinine clearance (CLCR) and use with caution. Not and depression. The effects of perampanel on tasks involving alertness and vigilance such as driving recommended in severe impairment. Patients with hepatic impairment: No dose adjustment in mild to ability were additive or supra-additive to the effects of alcohol. Adverse events: Adverse reactions most moderate impairment and use with caution in these patients. Not recommended in severe impairment. commonly leading to discontinuation of perampanel were dizziness and somnolence. Refer to SPC for Contra-Indications: Hypersensitivity to the active substance, other carboxamide derivatives (e.g. carbamazepine, oxcarbazepine) or any excipients. Second or third degree AV block. Contraceptives: decreased appetite, increased appetite, aggression, anger, anxiety, confusional state, ataxia, dysarthria, Interacts with oral contraceptives. Use an alternative method of contraception during treatment and up balance disorder, irritability, diplopia, vision blurred, vertigo, nausea, back pain, gait disturbance, fatigue, to the end of the current menstrual cycle after treatment has been stopped. Pregnancy: No data on the use of Zebinix in pregnant women. Carefully re-evaluate treatment if women become pregnant or plan to on the clinical trial database of 165 adolescents, the frequency, type and severity of adverse reactions become pregnant. Refer to the SPC for further information. Lactation: Excretion in human breast milk in adolescents are expected to be the same as in adults. Legal Category: POM Basic UK NHS cost: is unknown. Breastfeeding should be discontinued during treatment. Warnings and precautions: May Fycompa 2 mg: packs of 7 £35.00, Fycompa 2 mg: packs of 28 £140.00, Fycompa 4 mg: packs of 28 cause some CNS reactions such as dizziness and somnolence. Do not use with oxcarbazepine. Rash has £140.00, Fycompa 6 mg: packs of 28 £140.00, Fycompa 8 mg: packs of 28 £140.00, Fycompa 10 mg: been reported. Discontinue if signs or symptoms of hypersensitivity develop. Screen for allele HLA-B*1502 packs of 28 £140.00, Fycompa 12 mg: packs of 28 £140.00 Irish price to wholesaler: Fycompa 2 mg: in individuals of Han Chinese, and Thai origin and consider screening in other Asian populations as this packs of 7 €40.95, Fycompa 4 mg: packs of 28 €163.80, Fycompa 6 mg: packs of 28 €163.80, Fycompa has been shown to be strongly associated with the risk of developing Stevens-Johnson syndrome (SJS) 8 mg: packs of 28 €163.80, Fycompa 10 mg: packs of 28 €163.80, Fycompa 12 mg: packs of 28 €163.80 when treated with carbamazepine. Allele HLA-A*3101 has been shown to increase the risk of developing Marketing authorisation numbers: Fycompa 2 mg 7 tablets: EU/1/12/776/001, Fycompa 2 mg 28 tablets: carbamazepine induced cutaneous adverse reactions including SJS, TEN, drug rash with eosinophilia EU/1/12/776/017, Fycompa 4 mg 28 tablets: EU/1/12/776/003, Fycompa 6 mg 28 tablets: EU/1/12/776/006, (DRESS) or less severe acute generalised exanthematous pustulosis (AGEP) and maculopapular rash in Fycompa 8 mg 28 tablets: EU/1/12/776/009, Fycompa 10mg 28 tablets: EU/1/12/776/012, Fycompa 12 patients of European descent and Japanese population. Hyponatraemia was reported by 1.2% of patients in mg 28 tablets: EU/1/12/776/015. Marketing authorisation holder: Eisai Ltd. Further Information from/ trials. Examine serum sodium levels before and during treatment in patients with pre-existing renal disease Marketed by: or who are treated with medicinal products which may lead to hyponatraemia. Determine sodium serum Date of preparation: June 2015 levels if clinical signs of hyponatraemia occur. Discontinue if clinically relevant hyponatraemia develops. Prolongations in PR interval have been observed. Caution in patients with medical conditions or when taking For UK healthcare professionals: concomitant medicinal products associated with PR prolongation. Monitor for signs of suicidal ideation and Adverse events should be reported. Reporting forms and Information can be found at behaviours and advise patients (and caregivers) to seek medical advice if these occur. May affect ability www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Eisai Ltd on to drive and use machines. Drug interactions: Has an inducing effect on the metabolism of medicinal 0208 600 1400/0845 676 1400 or [email protected] products mainly eliminated by CYP3A4 (e.g. Simvastatin), therefore the dose of these products may need to be increased when used concomitantly with Zebinix. May have an inducing effect on the metabolism of PRESCRIBING INFORMATION medicinal products mainly eliminated by UDP- glucuronyl transferases. May take 2 to 3 weeks to reach Inovelon® the new level of enzyme activity when initiating, discontinuing or changing dose of Zebinix, therefore Please refer to the SPC before prescribing. Presentation: Film coated tablets containing 100 mg, 200 take time delay into account when using with other medicines that require dose adjustment. Interactions Indication: Adjunctive therapy in the treatment can arise when co-administering high doses with medicinal products mainly metabolised by CYP2C19 of seizures associated with Lennox-Gastaut syndrome in patients 4 years and older. Dose and (e.g. phenytoin). Carbamazepine: Zebinix dose may need to be increased if used concomitantly with administration: For oral use. Inovelon should be administered twice daily in two equally divided doses carbamazepine. Concomitant treatment with carbamazepine increased the risk of the diplopia, abnormal with water and with food in the morning and in the evening. Inovelon can be crushed and administered coordination and dizziness. An increase in other adverse reactions cannot be excluded. Phenytoin: An increase of Zebinix dose and a decrease of phenytoin dose may be required. Lamotrigine and topiramate: at equal doses. Patients should be monitored during the switch over period. Children 4 years of age or No dose adjustments are required. Valproate and levetiracetam: Concomitant administration appeared Initial daily dose is 200 mg in two divided doses (or 5 ml dosing suspension given as two 2.5 ml doses, one in the morning and one in the evening) and may be Oral contraceptives: Interacts with the oral contraceptive. Simvastatin: An increase of the simvastatin increased by 200 mg/day increments, as frequently as every two days, up to a maximum dose of 1000 dose may be required when used concomitantly with Zebinix. Rosuvastatin: concomitant administration reduced exposure to rosuvastatin. Monitor response to therapy (e.g. levels). Warfarin: Can dose is 200 mg in two divided doses and may be increased by 200 mg/day after a minimum of 2 days, decrease exposure to S-warfarin. No effects on R-warfarin or coagulation. Monitoring of INR should be Initial daily dose is 400 mg in two divided doses and may be increased by 400 mg/day increments, as an interaction between eslicarbazepine acetate and MAOIs is theoretically possible. Adverse events: frequently as every two days, up to a maximum of 3200 mg/day (or 80 ml/day) based on patient’s weight (see SPC). Elderly and patients with renal or hepatic impairment: No dosage adjustment required in elderly and renal impairment. Not recommended in severe hepatic impairment. Contra-Indications: Pregnancy: Inovelon should not be disturbance in attention, tremor, ataxia, balance disorder, diplopia, vision blurred, vertigo, nausea, vomiting, used during pregnancy unless clearly necessary. Lactation: Excretion into human breast milk unknown. diarrhoea, rash, fatigue, gait disturbance, asthenia. Serious side effects: anaemia, hypersensitivity, Lactation should be avoided during maternal treatment with Inovelon. Warnings and Precautions: Cases hypothyroidism, aphasia, peripheral neuropathy, depression, psychomotor retardation, psychotic disorder, amnesia, convulsion, nystagmus, peripheral oedema, dehydration, visual impairment, ocular hyperaemia, palpitations, bradycardia, hypertension, hypotension, chest pain, alopecia, liver disorder, hypoacusis seizure types and/or experience an increased frequency of status epilepticus. Withdraw gradually to reduce possibility of seizures on withdrawal and reduce dose by approximately 25% every two days. Inovelon has been associated with dizziness, somnolence, ataxia and gait disturbances which could increase the frequency i.e. frequency cannot be estimated from available data). Some rare adverse reactions such occurrence of accidental falls in this population, therefore patients and carers should exercise caution until as bone marrow depression, anaphylactic reactions, severe cutaneous reactions (e.g. SJS), systemic they are familiar with the potential effects of Inovelon. Serious antiepileptic drug hypersensitivity syndrome lupus erythematosus or serious cardiac arrhythmias did not occur during Zebinix clinical studies but have including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) and Stevens-Johnson been reported with oxcarbazepine. Their occurrence during treatment with Zebinix cannot be excluded. Decrease in bone mineral density, osteopenia, osteoporosis and fractures were reported in patients on associated with other organ system involvement, lymphadenopathy, liver function tests abnormalities and long-term therapy with structurally related oxcarbazepine and carbamazepine. Legal Category: POM. Basic UK NHS cost: Zebinix 800mg pack of 30 £136.00. Irish price to wholesaler: Zebinix 800mg pack of 30 €143.19. Marketing authorisation numbers: EU/1/09/514/012-020. Marketing authorisation holder: Bial-Portela & Cª., S.A. À Av. da Siderurgia Nacional 4745-457 S. Mamede do Coronado – the underlying mechanism and safety relevance is not known. Clinicians should use clinical judgment Portugal. Further Information from: Herts, AL10 9SN, UK. Date of preparation: June 2015 duration. Women of childbearing potential must use contraceptive measures during treatment with Inovelon. Inovelon tablets contain lactose, therefore patients with rare hereditary problems of galactose Adverse events should be reported. For UK healthcare professionals: reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should Inovelon oral suspension contains parahydroxybenzoates which may cause allergic reactions (possibly also be reported to Eisai Ltd on 0845 676 1400 or [email protected] delayed). It also contains sorbitol and, therefore, should not be administered to patients with rare hereditary ® problems of fructose intolerance. Monitor patients for signs of suicidal ideation and behaviour and consider Zebinix : Pregnancy Registry appropriate treatment. Patients and carers should also be advised to see medical advice should such signs To provide information regarding the effects of in utero exposure to Zebinix® physicians are occur. Drug Interactions: advised to enrol pregnant patients taking Zebinix® in the International Registry of Antiepileptic Drugs and Pregnancy (EURAP). More information can be found at the website http://www. eurapinternational.org/. BIAL-Portela and Ca appears to have no clinically relevant effect on carbamazepine, lamotrigine, phenobarbital, topiramate, knowledge about safety and outcomes in pregnant women being treated with antiepileptic drugs including eslicarbazepine acetate (Zebinix®) and to respond to a requirement of the Committee for Medicinal Products for Human Use (CHMP) to address missing information on safety in pregnancy.

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