Status epilepticus: what's new for the intensivist.

PURPOSE OF REVIEW: Status epilepticus (SE) is a common neurologic emergency affecting about 36.1/100 000 person-years that frequently requires intensive care unit (ICU) admission. There have been advances in our understanding of epidemiology, pathophysiology, and EEG monitoring of SE, and there have been large-scale treatment trials, discussed in this review. RECENT FINDINGS: Recent changes in the definitions of SE have helped guide management protocols and we have much better predictors of outcome. Observational studies have confirmed the efficacy of benzodiazepines and large treatment trials indicate that all routinely used second line treatments (i.e., levetiracetam, valproate and fosphenytoin) are equally effective. Better understanding of the pathophysiology has indicated that nonanti-seizure medications aimed at underlying pathological processes should perhaps be considered in the treatment of SE; already immunosuppressant treatments are being more widely used in particular for new onset refractory status epilepticus (NORSE) and Febrile infection-related epilepsy syndrome (FIRES) that sometimes revealed autoimmune or paraneoplastic encephalitis. Growing evidence for ICU EEG monitoring and major advances in automated analysis of the EEG could help intensivist to assess the control of electrographic seizures. SUMMARY: Research into the morbi-mortality of SE has highlighted the potential devastating effects of this condition, emphasizing the need for rapid and aggressive treatment, with particular attention to cardiorespiratory and neurological complications. Although we now have a good evidence-base for the initial status epilepticus management, the best treatments for the later stages are still unclear and clinical trials of potentially disease-modifying therapies are long overdue.

Cryptococcal meningoencephalitis in multiple sclerosis treated with fingolimod.

A 21-year-old woman with multiple sclerosis (taking regular fingolimod) developed sudden-onset severe headache with nausea and malaise. Neurological examination was normal and she was afebrile. Blood results showed lymphocytes 0.53 x 109/L and C reactive protein 19 mg/L. CT scan of head and venogram were normal. CSF showed an opening pressure of 33 cm H2O and an incidental light growth of Cryptococcus neoformans, confirmed with positive India Ink stain and a positive cryptococcal antigen (1:100). She was treated for cryptococcal meningoencephalitis with amphotericin and flucytosine. Her presenting symptoms had closely mimicked subarachnoid haemorrhage. This atypical presentation of cryptococcal CNS infection highlights the need for vigilance in immunosuppressed patients.

What are the chances of having a second epileptic seizure?

The studyNeligan A, Adan G, Nevitt SJ, et al. Prognosis of adults and children following a first unprovoked seizure. Cochrane Database Syst Rev 2023;1:1-75.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/epilepsy-what-are-the-chances-of-having-a-second-seizure/.

Early and established status epilepticus: The impact of timing of intervention, treatment escalation and dosing on outcome.

OBJECTIVE: We investigated the management and outcome of early and established status epilepticus including timing, dosing and selection of benzodiazepines along with the timing and efficacy of second line treatments. METHODS: Retrospective single tertiary centre observational cohort study to identify all cases of SE between January 2019 and February 2022. RESULTS: 252 cases were identified. Seizures terminated spontaneously in 136 (54%) cases. 116 (46%) were given benzodiazepines, of which 29 (25%) were given at least one benzodiazepine by family/carers, and 72 (62.1%) received benzodiazepines by ambulance services. Benzodiazepines terminated seizures in 83 (71.6%) cases. The commonest benzodiazepine used was buccal midazolam (35.5%). Median time to first benzodiazepine was 14.5 (6-27) minutes. There was a positive correlation between time to first benzodiazepine and time to seizure cessation, progression to second- and third-line treatment, and respiratory complications (p<0.05). 73 (62.9%) cases received a correct benzodiazepine dose. Benzodiazepine underdosing was associated with longer seizure duration (p<0.05). 33 (28.4%) cases progressed to second-line treatment where mean time to treatment was 59.4 min (±32.3 min). The commonest second-line treatment was Levetiracetam (53.8%), followed by Phenytoin (43.6%) with SE termination in 57.5% cases. 14 (12.1%) cases progressed to third-line treatment; mean time to treatment was 60.6 min (±22.24 min). Respiratory complications occurred in 17 (6.75%) cases; none due to benzodiazepines. There were two deaths in refractory SE. CONCLUSION: Early administration of benzodiazepines and optimal dosing is associated with a higher rate of SE termination. Levetiracetam was the most commonly used second line treatment.

The etiology and mortality of new-onset refractory status epilepticus (NORSE) in adults: A systematic review and meta-analysis.

New-onset refractory status epilepticus (NORSE) is a devastating neurological presentation. There is a paucity of large studies on NORSE as it is a relatively new clinical syndrome. The aim of this review was to summarize the etiologies and establish a mortality rate for NORSE. Two independent authors systematically searched the following electronic databases from January 1, 2005 April 20, 2021: PubMed, Embase, OVID, Scopus, Web of Science, "Clinicaltrials.gov," and the International Standard Randomised Controlled Trial Number (ISRCTN) registry. We included all primary research studies of NORSE in adults and excluded commentaries, reviews, pre-clinical studies, and pediatric populations. Etiology was extracted from all studies meeting eligibility criteria, whereas data relating to treatments, hospital stay, functional outcomes, and mortality were extracted from studies with sample size ≥5. We conducted a random-effects meta-analysis of mortality rate with meta-regression testing for significant covariates. Of 1482 studies, 109 case reports and case series met our criteria, comprising 395 cases of NORSE. The most common etiology was cryptogenic in 197 cases (49.9%), followed by autoimmune in 143 cases (36.2%). The pooled mortality rate was 22% (95% confidence interval 17%-27%; N studies  = 15), with low heterogeneity ( I 2  = 0%). Meta-regression revealed that year of study, treatment with ketogenic diet or immunotherapy, percentage of cryptogenic cases, and length of intensive care unit stay were not significant covariates for mortality. Common treatments included antiseizure medications (median 5), general anesthesia, and immunotherapy such as corticosteroids, intravenous immunoglobulin, and plasma exchange. Mean length of intensive care admission was 33.4 days, with 52% of cases diagnosed with epilepsy on discharge. Neurocognitive impairment was a common sequela of NORSE. NORSE is associated with a high mortality. Half of cases remain cryptogenic, which presents a diagnostic challenge. Future focus should be on elucidating the underlying neurobiology and determining the most effective therapeutic interventions.

Prognosis of adults and children following a first unprovoked seizure.

BACKGROUND: Epilepsy is clinically defined as two or more unprovoked epileptic seizures more than 24 hours apart. Given that, a diagnosis of epilepsy can be associated with significant morbidity and mortality, it is imperative that clinicians (and people with seizures and their relatives) have access to accurate and reliable prognostic estimates, to guide clinical practice on the risks of developing further unprovoked seizures (and by definition, a diagnosis of epilepsy) following single unprovoked epileptic seizure. OBJECTIVES: 1. To provide an accurate estimate of the proportion of individuals going on to have further unprovoked seizures at subsequent time points following a single unprovoked epileptic seizure (or cluster of epileptic seizures within a 24-hour period, or a first episode of status epilepticus), of any seizure type (overall prognosis). 2. To evaluate the mortality rate following a first unprovoked epileptic seizure. SEARCH METHODS: We searched the following databases on 19 September 2019 and again on 30 March 2021, with no language restrictions. The Cochrane Register of Studies (CRS Web), MEDLINE Ovid (1946 to March 29, 2021), SCOPUS (1823 onwards), ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). CRS Web includes randomized or quasi-randomized, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. In MEDLINE (Ovid) the coverage end date always lags a few days behind the search date. SELECTION CRITERIA: We included studies, both retrospective and prospective, of all age groups (except those in the neonatal period (< 1 month of age)), of people with a single unprovoked seizure, followed up for a minimum of six months, with no upper limit of follow-up, with the study end point being seizure recurrence, death, or loss to follow-up. To be included, studies must have included at least 30 participants. We excluded studies that involved people with seizures that occur as a result of an acute precipitant or provoking factor, or in close temporal proximity to an acute neurological insult, since these are not considered epileptic in aetiology (acute symptomatic seizures). We also excluded people with situational seizures, such as febrile convulsions. DATA COLLECTION AND ANALYSIS: Two review authors conducted the initial screening of titles and abstracts identified through the electronic searches, and removed non-relevant articles. We obtained the full-text articles of all remaining potentially relevant studies, or those whose relevance could not be determined from the abstract alone and two authors independently assessed for eligibility. All disagreements were resolved through discussion with no need to defer to a third review author. We extracted data from included studies using a data extraction form based on the checklist for critical appraisal and data extraction for systematicreviews of prediction modelling studies (CHARMS). Two review authors then appraised the included studies, using a standardised approach based on the quality in prognostic studies (QUIPS) tool, which was adapted for overall prognosis (seizure recurrence). We conducted a meta-analysis using Review Manager 2014, with a random-effects generic inverse variance meta-analysis model, which accounted for any between-study heterogeneity in the prognostic effect. We then summarised the meta-analysis by the pooled estimate (the average prognostic factor effect), its 95% confidence interval (CI), the estimates of I² and Tau² (heterogeneity), and a 95% prediction interval for the prognostic effect in a single population at three various time points, 6 months, 12 months and 24 months. Subgroup analysis was performed according to the ages of the cohorts included; studies involving all ages, studies that recruited adult only and those that were purely paediatric. MAIN RESULTS: Fifty-eight studies (involving 54 cohorts), with a total of 12,160 participants (median 147, range 31 to 1443), met the inclusion criteria for the review. Of the 58 studies, 26 studies were paediatric studies, 16 were adult and the remaining 16 studies were a combination of paediatric and adult populations. Most included studies had a cohort study design with two case-control studies and one nested case-control study. Thirty-two studies (29 cohorts) reported a prospective longitudinal design whilst 15 studies had a retrospective design whilst the remaining studies were randomised controlled trials. Nine of the studies included presented mortality data following a first unprovoked seizure. For a mortality study to be included, a proportional mortality ratio (PMR) or a standardised mortality ratio (SMR) had to be given at a specific time point following a first unprovoked seizure. To be included in the meta-analysis a study had to present clear seizure recurrence data at 6 months, 12 months or 24 months. Forty-six studies were included in the meta-analysis, of which 23 were paediatric, 13 were adult, and 10 were a combination of paediatric and adult populations. A meta-analysis was performed at three time points; six months, one year and two years for all ages combined, paediatric and adult studies, respectively. We found an estimated overall seizure recurrence of all included studies at six months of 27% (95% CI 24% to 31%), 36% (95% CI 33% to 40%) at one year and 43% (95% CI 37% to 44%) at two years, with slightly lower estimates for adult subgroup analysis and slightly higher estimates for paediatric subgroup analysis. It was not possible to provide a summary estimate of the risk of seizure recurrence beyond these time points as most of the included studies were of short follow-up and too few studies presented recurrence rates at a single time point beyond two years. The evidence presented was found to be of moderate certainty. AUTHORS' CONCLUSIONS: Despite the limitations of the data (moderate-certainty of evidence), mainly relating to clinical and methodological heterogeneity we have provided summary estimates for the likely risk of seizure recurrence at six months, one year and two years for both children and adults. This provides information that is likely to be useful for the clinician counselling patients (or their parents) on the probable risk of further seizures in the short-term whilst acknowledging the paucity of long-term recurrence data, particularly beyond 10 years.

Educational inequalities in epilepsy mortality in the Baltic countries and Finland in 2000-2015.

Little is known about socioeconomic differences in epilepsy mortality. This study examined educational inequalities in epilepsy mortality in the general population in the Baltic countries and Finland in 2000-2015. Education-specific mortality estimates for individuals aged 30-74 in Estonia, Latvia and Lithuania were obtained from census-linked mortality datasets while data for Finland came from the register-based population and death data file of Statistics Finland. Trends and educational inequalities in epilepsy mortality were assessed using age-standardised mortality rates (ASMRs) per 100,000 person years and age-adjusted mortality rate ratios (RRs) calculated using Poisson regression. ASMRs were higher in men than women in all countries. ASMRs reduced in 2000-2015 among all men and women except for Finnish women. Among men, an inverse educational gradient in epilepsy mortality in 2000-2007 widened in 2008-2015 with ASMRs falling among high and mid educated men in all countries but increasing among low educated men in three countries. An inverse educational gradient in female mortality remained in all countries throughout 2000-2015. Although epilepsy mortality fell in the Baltic countries and Finland (men only) in 2000-2015, this masked a clear inverse educational gradient in mortality that became steeper across the period.

New-Onset Refractory Status Epilepticus (NORSE): The Queen Square Neuro-ICU experience.

The introduction and widespread adoption of the term 'NORSE' - new-onset refractory status epilepticus - raises both fundamental conceptual and pragmatic questions. We studied a cohort of patients with 'NORSE' at the National Hospital for Neurology and Neurosurgery to investigate the clinical features, treatment responses, and outcomes with a focus on sub-group analysis. We identified 26 cases of 'NORSE'. There was no difference in prognosis between 'NORSE' and non-'NORSE' RSE, nor in any sub-analysis in the 'NORSE' cohort. We discuss the utility and validity of the term NORSE as a descriptor for a subgroup with RSE in whom the underlying etiologies are heterogeneous and pathophysiological mechanisms are unknown.

Advances in the management of generalized convulsive status epilepticus: what have we learned?

Convulsive status epilepticus is the most serious manifestation of an epileptic diathesis. In the early stages (5-30 min), there exists class A evidence to support the efficacy of benzodiazepines as first-line treatment. As status epilepticus progresses into the later stages, the evidence for treatment becomes less robust until we are depending upon short case series and case reports for the treatment of refractory status epilepticus. However, the past year saw the publication of three randomized controlled trials in the setting of benzodiazepine-resistant established convulsive status epilepticus: the EcLiPSE and ConSEPT studies, compared levetiracetam to phenytoin in children; and the ESETT study compared fosphenytoin, levetiracetam and sodium valproate in adults and children. In addition, the emergence of data from the SENSE study, a multicentre multinational prospective cohort study and the publication of a systematic review and meta-analysis of the mortality of status epilepticus over the past 30 years, has brought the treatment of status epilepticus into sharp focus. In this update we provide a detailed analysis of these studies and their impact on clinical practice. We review contentious areas of management in status epilepticus where a consensus is lacking and advance the case for more research on existing and alternative treatment strategies.

The Influence of Socioeconomic Deprivation on Dementia Mortality, Age at Death, and Quality of Diagnosis: A Nationwide Death Records Study in England and Wales 2001-2017.

BACKGROUND: Socioeconomic deprivation may be an important determinant of dementia risk, mortality, and access to diagnostic services. Premature mortality from other causes and under-representation of deprived individuals in research may lead to this effect being overlooked. OBJECTIVE: We assessed the relationship between deprivation and dementia mortality using comprehensive death certificate data for England and Wales from 2001 to 2017. METHODS: We used standardized mortality ratios (SMR) and a Poisson model to compare likelihood of dying from dementia in each deprivation decile. We also examined the associations of deprivation with age at death from dementia, and with likelihood of receiving a diagnosis of unspecified dementia. RESULTS: Risk of dying from dementia was higher in more deprived deciles (Mean SMR [95% CI] in decile 1 : 0.528 [0.506 to 0.550], decile 10:0.369 [0.338 to 0.400]). In 2017, 14,837 excess dementia deaths were attributable to deprivation (21.5% of all dementia deaths that year). There were dose-response associations of deprivation with likelihood of being older at death with dementia (odds ratio [95% CI] for decile 10 (least deprived): 1.31 [1.28 to 1.33] relative to decile 1), and with likelihood of receiving a diagnosis of unspecified dementia (odds ratio [95% CI] for decile 10:0.78 [0.76 to 0.80] relative to decile 1). CONCLUSION: Socioeconomic deprivation in England and Wales is associated with increased dementia mortality, younger age at death with dementia, and poorer access to specialist diagnosis. Reducing social inequality may have a role in the prevention of dementia mortality.

A retrospective cohort study of super-refractory status epilepticus in a tertiary neuro-ICU setting.

PURPOSE: Over the last decade, the range of treatments available for the management of super-refractory status epilepticus (SRSE) has expanded. However, it is unclear whether this has had an impact on its high mortality and morbidity. The aim of this study was to investigate whether there has been a change in the outcome of SRSE over time in a neurological intensive care unit (ICU) within a tertiary centre. METHODS: Analysis of a retrospective cohort of 53 admissions from 45 patients to the neurological ICU at the National Hospital for Neurology and Neurosurgery, Queen Square, London, between January 2004 and September 2018. RESULTS: Significant reductions were observed in both duration of SRSE over time and in the time spent in ICU, suggesting that treatment quality has improved over time. A median of four antiseizure drugs (ASDs) were given prior to seizure resolution. In 23 % resolution of SRSE occurred following optimisation of current treatment rather than introduction of a new ASD. The mortality rate was very low at 11 % by 6 months; however, there was no indication of improvement in outcome as all surviving patients had a modified Rankin scale score of 3-5 upon discharge from ICU, classified as moderate-to-severe disability. CONCLUSION: Neither the survival rate nor the outcome score changed significantly over time, suggesting that changes in the treatment of SRSE have had no impact on patient outcome.

The association between alcohol consumption and sleep disorders among older people in the general population.

The relationship between alcohol consumption and sleep disturbance is complex. The association of alcohol dependence with insomnia is likely to be bidirectional in nature. Alcohol use is common among older people in many societies and the prevalence of insomnia tends to increase with age, therefore this group warrants particular consideration. We explored the cross sectional and long term (30 years) associations between alcohol drinking (volume and hazardous drinking) and sleep duration and insomnia in a general population study of older adults (6,117 male and female civil servants followed for 30 years). For men, drinking more than 21 units (approximately 168 grams) of alcohol per week, compared with not drinking, was associated with waking several times a night (odds ratio 1.30, confidence intervals 1.02-1.66). Men who maintained a heavy volume of drinking over the three decades of observation, or who had an unstable consumption pattern, tended to have worse sleep profiles in terms of waking tired and waking several times. Sustained male hazardous drinking (as measured by the AUDIT-C scale) was also associated with worse sleep profiles. Findings for women were not so clear. In this population based setting, drinking high volumes of alcohol may contribute to the prevalence of sleep problems in older age, particularly for men. People in this age group should be discouraged from using alcohol as a sleep aid.

Sleep disturbance and recovery during rehabilitation after traumatic brain injury: a systematic review.

Purpose: Sleep disturbance is well recognized following traumatic brain injury, but less is known about the potential effects of this on patients and their recovery. We review the recent literature that investigates the relationship between sleep disturbance in adult patients following a traumatic brain injury and their functioning, disability, and health.Materials and methods: The PRISMA statement was used as a guide to report the systematic review. Embase, PubMed, and the Cochrane library were searched for all research articles published (or in press) in the 10 y prior to 25 May 2018 that investigated the relationship between the development (or treatment) of sleep disturbance of adult patients with a history of traumatic brain injury and patient outcomes, according to the domains of the International Classification of Functioning, Disability, and Health Core Sets for persons with sleep disorders. Two authors independently assessed all identified studies by title and abstract and were included following article review and discussion. Study quality was assessed using the evidence-based library and information practice critical appraisal checklist.Results: Our search identified 27 studies with a wide range in patient populations and assessment measures. Results suggested that sleep disturbance in patients with a history of traumatic brain injury may be associated with the resolution of post-traumatic amnesia and specific impairments of cognition, affective disorders, fatigue, and pain. Some studies indicated that sleep disturbance could be related to an impaired functional ability and reduced quality of life. Limitations of the systematic review included strict inclusion and exclusion criteria and reporting of secondary outcome measures.Conclusions: These findings highlight the relationship between sleep disturbance and patient rehabilitation and outcomes, and therefore the importance of assessing sleep in patients following a traumatic brain injury. Further research is required with more focused patient populations that combine both subjective and objective assessments of sleep to help clarify this relationship.Implications for rehabilitationSleep disturbance following traumatic brain injury may be related to the resolution of post-traumatic amnesia, cognitive and affective disorders, fatigue, and pain.Those with a history of traumatic brain injury and sleep disturbance may demonstrate a worse functional ability and report a poorer satisfaction with life.It is important for rehabilitation professionals to take sleep disturbance into account in those patients with a history of traumatic brain injury.

First evidence of the clinical impact of a general practitioner with a special interest in epilepsy.

PURPOSE: The purpose of the study was to review the clinical outcomes of people with epilepsy (PWE) attending a primary care-based specialist epilepsy service. METHOD: The case notes of 355 people attending the service and subsequent follow-up from 2005 to 2013 were reviewed. RESULTS: There had been 37 deaths (all nonattributable to epilepsy), and 38 people had left the area, leaving 280 people who completed the audit. Positive outcomes could be attributed in 94% still attending the service at the end of follow-up. Seventy-five percent of people on treatment, referred with poor seizure control, achieved seizure remission with antiepilepsy drug (AED) changes initiated by the service. CONCLUSION: This study suggests that the majority of people who attended the service had a positive outcome and provides the first evidence for the clinical effectiveness of a general practitioner (GP) with special interest in epilepsy (GPwSIe) and provides support for the recommendations in earlier government reports to promote the use of such a service. Clinical Commissioning Groups (CCGs) and Government should consider investment in this intermediate tier of care as a means to both improving the quality of care and potentially reducing costs.

Change in Mortality of Generalized Convulsive Status Epilepticus in High-Income Countries Over Time: A Systematic Review and Meta-analysis.

IMPORTANCE: Status epilepticus (SE) is associated with significant morbidity and mortality. Since the late 1990s, a more aggressive management of prolonged convulsive seizures lasting longer than 5 minutes has been advocated. OBJECTIVE: To determine if convulsive SE mortality has decreased during a time of increasing advocacy for out-of-hospital treatment and escalating and earlier treatment protocols for prolonged seizures and SE. DATA SOURCE: This systemic review and meta-analysis on studies focused on the mortality of convulsive status epilepticus was conducted by searching MEDLINE, Embase, PsychINFO, CINAHL Plus, and the Cochrane Database of Systematic Reviews between January 1, 1990, and June 30, 2017. STUDY SELECTION: Studies were excluded if they had fewer than 30 participants (<20 for refractory SE), were limited to SE of single specific etiology or an evaluation of a single treatment modality, or were studies of nonconvulsive SE. DATA EXTRACTION AND SYNTHESIS: Data were abstracted and their quality was assessed via a modified Newcastle-Ottawa scale independently by 2 reviewers (A.N. and T.D.G.) using the Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES: The main outcome measure was in-hospital mortality or 30-day case fatality expressed as proportional mortality. RESULTS: Sixty-one studies were included in the analysis. The pooled mortality ratios were 15.9% (95% CI, 12.7-19.2) for adult studies, 13.0% (95% CI, 7.2-19.0) for all-age population studies, 3.6% (95% CI, 2.0%-5.2%) for pediatric studies, and 17.3% (95% CI, 9.8-24.7) for refractory SE studies, with very high between-study heterogeneity. We found no evidence of a change in prognosis over time nor by the definition of SE used. CONCLUSIONS AND RELEVANCE: The mortality of convulsive SE is higher in adults than in children and there was no evidence for improved survival over time. Although there are many explanations for these findings, they can be explained by aetiology of SE being the major determinant of mortality. However, there are potential confounders, including differences in case ascertainment and study heterogeneity. This meta-analysis highlights the need for strict international guidelines for the study of this condition.

Epilepsy mortality trends in Cuba compared with England and Wales: 1987-2010.

There are limited epilepsy mortality data from developing countries and Latin America in particular. We examined national epilepsy mortality data from Cuba and contrasted them with comparable data from England and Wales. National epilepsy mortality data for Cuba between the years 1987 and 2010 were obtained from the Medical Records and Health Statistics Bureau of the Cuban Public Health Ministry (www.sld.cu/sitios/dne/) with the corresponding mortality data from England and Wales obtained from the UK Office of National Statistics (ONS, www.ons.gov.uk). Indirect standardization with calculation of a standardized mortality ratio (SMR) was used to compare trends. The overall trend was of a slight decrease in mortality rates over the 23 years in Cuba, with higher mortality rates primarily occurring in young people. Annual age-adjusted rates were consistently lower in Cuba than those seen in England and Wales, with the SMR ranging from 0.35 (95% confidence interval (CI): 0.30 to 0.48) in 2007 to 1.00 (95% CI: 0.85 to 1.15) in 1994. Cuban epilepsy mortality rates are consistently lower than those of England and Wales. Reasons for this disparity in mortality rates are not immediately apparent but are likely to be multifactorial.

Genetic biomarkers of posttraumatic epilepsy: A systematic review.

INTRODUCTION: Posttraumatic epilepsy (PTE) is caused by traumatic brain injury (TBI) and is an important contributor to the overall social and economic burden of epilepsy. Epidemiological studies suggest that there is a genetic contribution to the development of PTE. Identification of clinically useful genetic biomarkers is important for advancements in diagnosis and treatment of PTE. METHODS: A systematic review was performed on the existing literature of genetic biomarkers of posttraumatic epilepsy (PTE). A multi-database search yielded 4 articles deemed suitable for review. Potential genetic biomarkers were identified and critically evaluated. RESULTS & DISCUSSION: Biomarkers identified included single nucleotide polymorphism (SNP) rs1143634 of the interkeukin-1ß (IL-1ß) gene, SNPs rs3828275, rs3791878, and rs769391 of the glutamic acid decarboxylase 1 (GAD1) gene, SNPs rs3766553 and rs10920573 of the adenosine A1 receptor (A1AR) gene, and the functional variant C677T of the methylenetetrahydrofolate reductase (MTHFR) enzyme. The most promising biomarkers identified were IL-1ß rs1143634 and A1AR rs10920573. Both had heterogenous at risk genotypes (CT). Those with IL-1ß rs1143634 CT genotype developed PTE in 47.7% of cases (p=0.008) and those with A1AR rs10920573 CT genotype developed PTE in 19.2% of cases (p=0.022). CONCLUSION: The majority of articles were preliminary with a need for validation of results. There is a need for continued high calibre research in order to validate the currently identified genetic biomarkers as well as to discover new genetic biomarkers in PTE.