management of post traumatic epilepsy pte an evidence review over the last 5 years and future directions

Accepted Date : 07-Feb-2017 Accepted Article Article type : Critical Review Title page: Management of Post-Traumatic Epilepsy (PTE): an evidence review over the last years and future directions Running title –Post-Traumatic Epilepsy (PTE) management Keywords – traumatic brain injury, epilepsy, late seizures, management, community Loretta Piccenna BSc (Hons) PhD1,2, Graeme Shears1, Terence J O’Brien MBBS, MD, FRACP, FRCPE3 The Epilepsy Foundation, Melbourne, Victoria, Australia Department of Medicine, The University of Melbourne, Victoria, Australia James Stewart Professor of Medicine, Department of Medicine, The University of Melbourne, The Royal Melbourne Hospital Victoria, Australia Corresponding Author: Loretta Piccenna, Epilepsy Foundation, 587 Canterbury Road, Surrey Hills, Victoria 3127 Phone: +61 8809 0670 Fax: +61 9836 2124 Email: lpiccenna@epilepsyfoundation.org.au This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record Please cite this article as doi: 10.1002/epi4.12049 This article is protected by copyright All rights reserved Accepted Article Key points  There is no evidence for the effectiveness of pharmacological treatments in the prevention or treatment of symptomatic seizures in adults  Limited high level evidence for the effectiveness of levetiracetam was identified for children with PTE  Promising low-level evidence was shown for the use of a psychoeducational intervention in assisting the management of PTE to improve quality of life  More effective therapeutic targets are necessary for the management of PTE Abstract Post-traumatic epilepsy (PTE) is a relatively underappreciated condition that can develop as a secondary consequence following traumatic brain injury (TBI) The aim of this rapid evidence review is to provide a synthesis of existing evidence on the effectiveness of treatment interventions for the prevention of PTE in people who have suffered a moderate/severe TBI to increase awareness and understanding among consumers Electronic medical databases (n=5) and grey literature published between January 2010 and April 2015 were searched for studies on the management of PTE Twenty-two eligible studies were identified which met the inclusion criteria No evidence was found for the effectiveness of any pharmacological treatments in the prevention or treatment of symptomatic seizures in adults with PTE However, limited high-level evidence for the effectiveness of the anti-epileptic drug levetiracetam was identified for PTE in children Low-level evidence was identified for non-pharmacological interventions in significantly reducing seizures in patients with PTE, but only in a minority of cases, requiring further high-level studies to confirm the results This review provides an opportunity for researchers and health service professionals to better understand the underlying pathophysiology of PTE to develop novel, more effective therapeutic targets and to improve the quality of life of people with this condition This article is protected by copyright All rights reserved Introduction Accepted Article Post-Traumatic Epilepsy (PTE) is a serious and disabling delayed consequence of a traumatic brain injury (TBI) PTE is one of the most common types of acquired (or secondary) epilepsies, which are due to a brain insult, e.g trauma, tumours, stroke, and infections, accounting for 20% of acquired epilepsy in the general population 1; People with PTE commonly experience a latent or silent period of at least months, and sometimes up to 20 years, between the causative injury and the onset of seizures, providing a potential time window for intervention (Figure 1) Due to this latency, it is essential that there is an understanding of the associated risk factors, the person’s natural history and clinical heterogeneity for appropriate treatment to be provided at the right time Insert PiccennaFigure here Incidence and Risk Factors PTE has been described as a particularly heterogeneous condition, in particular due to the heterogeneity associated with TBI The types of seizures experienced by people with PTE are focal onset seizures with or without secondary generalisation to bilateral tonic-clonic convulsive activity, with some experiencing focal non-convulsive seizures only Early seizures are often of the generalised tonic-clonic convulsive type, in comparison to late seizures which are mostly nonconvulsive in nature It is well-established that the incidence of PTE increases with the severity of TBI For example, an analysis of the relative risk (RR) for unproved seizures by Herman (2002) reported that severe TBI confers a RR 29 times that of the general population, whilst for mild and moderate TBI it was 1.5 and 4, respectively Within the first years following TBI, it has been found that the risk of PTE is the highest However, the risk of developing PTE is still high >10 years in people with moderate TBI and >20 years in people with severe TBI Hence, it is not unusual for cases of PTE to occur 30-35 years This article is protected by copyright All rights reserved following TBI, and it is important that people with TBI who live in the community undergo “vigilant Accepted Article long-term neurologic follow-ups” Over the last decade, there have been numerous hospital (mostly) and population-based studies to identify the incidence of PTE (Table 1)7-17 There are studies for PTE in children only (3 from the USA) with incidence rates ranging from 11% to 19%; studies in adults only with varying incidence rates; and studies involving adults and children with PTE with studies from China reporting similar rates (5 and 9%) Adults referring to people aged 18 years and above Insert PiccennaTable here Several risk factors have also been studied and documented for PTE, and include  Personal factors – young age or increasing age from 15 years, family history, depression, and premorbid alcohol abuse 18  Injury factors - markers of increasing injury severity such as penetrating injuries and depressed skull fracture, seizures occurring within the first week following TBI (early seizures) 18 Another risk factor which has recently been identified is the disruption of the blood-brain barrier (BBB) which has been observed by significant electroencephalography (EEG) slowing in the region of blood-brain barrier breakdown 19 There is some controversy as to whether early seizures increase the risk of developing PTE Annegers et al (1998) have reported that early seizures are not an independent risk factor for late seizures However, there is stronger evidence for a high risk of seizure recurrence subsequent to the first late seizure of 47% within a month after TBI and after years 86% following TBI 20 This article is protected by copyright All rights reserved Recently, it has been identified that people with a history of depression, epilepsy and/or who Accepted Article experience three or more chronic medical conditions at discharge are at high risk of developing PTE 11 Also, genetic polymorphisms have been reported to increase the person’s susceptibility to developing PTE including variability in the glutamic acid decarboxylase (GAD) gene 21 and the C677T variant in the methylenetetrahydrofolate reductase (MTHFR) enzyme 22 A recent study has found an association with genetic variants in the gene for the inflammatory cytokine, IL-1β 23 However, further studies are needed to confirm these findings Pathophysiology The pathogenic mechanisms underlying PTE are still poorly understood However, what is known is that the pathophysiology following TBI differs depending on the type of injury Closed head injuries result in diffuse axonal injury, edema, ischemia and a cascade of secondary damage including the release of toxic mediators, excitatory amino acids and cytokines 1; 24 Non-penetrating head injury has been described as producing focal contusions and intracranial haemorrhage whilst penetrating head injury results in “a cicatrix in the cortex” or scar tissue 25 There is evidence to suggest that the underlying pathological processes that result in PTE are multifactorial, including the release of excitotoxins, blood-barrier deterioration with vascular changes, parenchymal haemorrhage, and free radical damage Currently, there are also no reliable molecular biomarkers that have been identified in people with TBI that can predict the development of PTE, or its outcome It is clear that further understanding the pathophysiological mechanisms underlying PTE will assist greatly in identifying better therapeutic targets and clinically applicable biomarkers This article is protected by copyright All rights reserved Management of Post-traumatic Epilepsy – Assessment/Diagnosis Accepted Article The utilisation of diagnostic testing is to assist in the assessment of PTE for appropriate treatments to be provided to people with PTE Electroencephalography (EEG), which is usually used as a short (1 week post-injury) not attributable to another obvious cause in patients following TBI Although the term post-traumatic epilepsy commonly has designated single or multiple seizures including early seizures (within the first week of injury), the term should be reserved for recurrent, late post-traumatic seizures (>1 week post-injury).”18; 32 Exclusion – Neonates, infants, people with brain tumours, encephalitis, or sub-arachnoid or traumatic haemorrhage, stroke, cardiac arrest or people with epilepsy who suffer head injury due to an accident, in-vivo (animal) studies, in-vitro studies Intervention: Any type of management (pharmacological, non-pharmacological or surgical and assessment tools) Phase of care: Any Exclusion - None Study type: Inclusion - Systematic reviews, evidence-based reviews, primary studies not included in systematic reviews (RCTs, observational, pre-post studies) Exclusion – Case series, case study, conference proceedings, literature reviews Steps and - Narrative synthesis of included studies and Report production Data was extracted from the systematic reviews and evidence-based reviews using the following headings – 1) number of included studies, 2) type of intervention, and 3) conclusion/key findings and level of evidence They were also categorised according to adult or children focused studies and pharmacological and non-pharmacological studies Data was also extracted from the primary included studies using the following headings – 1) country, 2) type of injury, 3) number of This article is protected by copyright All rights reserved ccepted Articl randomised phase placebo) trial hours post injury with year up The most common severe adverse prevention study in an at- follow-up events in treatment subjects were risk traumatic brain injury headache, fatigue, drowsiness, and population Levetiracetam irritability There was no higher was safe and well tolerated incidence of infection, mood changes, in this population This study or behaviour problems among sets the stage for treatment subjects compared to implementation of a observation subjects Only (2.5%) of prospective study to prevent 40 subjects developed posttraumatic posttraumatic epilepsy in an epilepsy (defined as seizures >7 days at-risk population.” (page after trauma).” e135) USA Klein, P et al., 20126 Adults and children with Levetiracetam (LEV) 55 “Of the 66 participants treated with “Treatment with 55 mg/kg/d TBI and PTE mg/kg/day, twice daily., for levetiracetam, (3%) stopped of levetiracetam 30 days, starting within treatment owing to toxicity (a dose with an hours post injury with year (somnolence) The most common antiepileptogenic effect on Open-label nonrandomised phase (n=66 participants LEV This article is protected by copyright All rights reserved ccepted Articl trial USA (46 adults follow-up adverse events were fatigue, headache, animals) for patients with and 20 children), and 60 and somnolence Mood scores and TBI at risk for PTE is safe and observation group (40 number of infections did not differ well tolerated, with plasma adults and 20 children) between the treatment and levels similar to those in observation groups Mean trough levels animal studies The findings of levetiracetam on days to 30 ranged support further evaluation from 19.6 to 26.7 μg/ of levetiracetam treatment mL At years, 13 of 86 adults (15.1%) for the prevention of and of 40 children (2.5%) developed PTE.” (page 1290) l Pieracci, F et al., 20127 Cost minimisation PTE At years, of 46 treated adults (10.9%) and of 40 untreated adults (20.0%) developed PTE (relative risk, 0.47; P=.18).” Decision tree using data Phenytoin (PHT) versus “The PHT strategy was superior to the “From both institutional and from literature review Levetiracetam (LEV) LEV strategy from both the institutional patient perspectives, PHT is (mean cost per patient $151.24 vs less expensive than LEV for with costs and charges This article is protected by copyright All rights reserved ccepted Articl analysis and Monte Carlo $411.85, respectively) and patient routine simulation (mean charge per patient $2,302.58 vs pharmacoprophylaxis of $3,498.40, respectively) perspectives early seizures among Varying both baseline adverse event traumatic brain injury probabilities and frequency of patients Pending compelling laboratory testing did not alter the efficacy data, LEV should not superiority of the PHT strategy LEV replace PHT as a first-line replaced PHT as the dominant strategy agent for this indication.” only when the cost/charge of treating (page 276) USA Cotton, B et al., 20118 mental status deterioration was increased markedly above baseline.” Cost effectiveness Phenytoin patients receive “The cost of a 7-day course of “Phenytoin is more cost- analysis 1.0 g fosphenytoin load + fosphenytoin, phenytoin, and free effective than levetiracetam Cost effectiveness days of 100 mg three times a phenytoin level was $37.50, whereas at all reasonable prices and analysis day (TID), have level drawn the cost of a 7-day course of at all clinically plausible on day 3, "therapeutic" levetiracetam was $480.00 reductions in post-TBI This article is protected by copyright All rights reserved ccepted Articl USA patients receive 100 mg TID … on days to 7, and “Quality-adjusted life years (QALY) "subtherapeutic" patients were 23.6 for phenytoin and 23.2 for receive 200 mg TID on days levetiracetam As a result, the to 7; (2) levetiracetam cost/effectiveness ratios were patients receive 500 mg load $1.58/QALY for phenytoin and + days of 500 mg two times $20.72/QALY for levetiracetam All a day sensitivity analyses favored phenytoin seizure potential.” unless levetiracetam prevented 100% of seizures and cost