David J. Thurman

Objective: In order to more appropriately apply and understand the “epilepsy treatment gap” (ETG) concept in current health systems, revised conceptual and operational definitions of ETG are timely and necessary. This article therefore systematically reviews worldwide studies of the ETG, distinguishing high‐, middle‐, and low‐income regions, and provides recommendations for an updated International League Against Epilepsy (ILAE) definition of ETG.Methods: A systematic review of the ETG was performed using Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) standards. The search was conducted from January 1990 to July 2019, in the online databases of Ovid MEDLINE and Embase. Identified abstracts were reviewed in duplicate and data independently extracted using a standard proforma. Data describing treatment gap information including both diagnostic and therapeutic aspects of access to epilepsy treatment were recorded. Descriptive statistics are presented.Results: The treatment gap reported in the 45 distinctive populations represented 33 countries. Treatment gap definitions varied widely. The reported ETGs ranged broadly from 5.6% in Norway to 100% in parts of Tibet, Togo, and Uganda. The wide range of reported ETGs was multifactorial in origin including true differences in the availability and utilization of health care among study populations, variations in operational definitions of the epilepsy treatment gap, and methodological differences in sampling and identifying representative epilepsy cases in populations.Significance and recommendations: For the ETG to be a useful metric to compare levels of unmet epilepsy care across different countries and regions, a standardized definition must be adapted, recognizing some of the limitations of the current definitions. Our proposed definition takes into account the lack of effective health care insurance, the diagnostic gap, the therapeutic gap, quality‐of‐care, and other unmet health care needs.”

Importance Limited population-based data are available on antiepileptic drug (AED) treatment patterns in women of childbearing age with epilepsy; the current population risk is not clear. Objectives To examine the AED treatment patterns and identify differences in use of valproate sodium and topiramate by comorbidities among women of childbearing age with epilepsy. Design, Setting, and Participants A retrospective cohort study used a nationwide commercial database and supplemental Medicare as well as Medicaid insurance claims data to identify 46 767 women with epilepsy aged 15 to 44 years. The eligible study cohort was enrolled between January 1, 2009, and December 31, 2013. Data analysis was conducted from January 1, 2017, to February 22, 2018. Exposures Cases required anInternational Classification of Diseases, Ninth Revision, Clinical Modification–coded epilepsy diagnosis with continuous medical and pharmacy enrollment. Incident cases required a baseline of 2 or more years without an epilepsy diagnosis or AED prescription before the index date. For both incident and prevalent cases, focal and generalized epilepsy cohorts were matched by age, payer type, and enrollment period and then compared. Main Outcomes and Measures Antiepileptic drug treatment pattern according to seizure type and comorbidities. Results Of the 46 767 patients identified, there were 8003 incident cases (mean [SD] age, 27.3 [9.4] years) and 38 764 prevalent cases (mean [SD] age, 29.7 [9.0] years). Among 3219 women in the incident epilepsy group who received AEDs for 90 days or more, 3173 (98.6%) received monotherapy as first-line treatment; among 28 239 treated prevalent cases, 18 987 (67.2%) received monotherapy. In 3544 (44.3%) incident cases and 9480 (24.5%) prevalent cases, AED treatment was not documented during 180 days or more of follow-up after diagnosis. Valproate (incident: 35 [5.81%]; prevalent: 514 [13.1%]) and phenytoin (incident: 33 [5.48%]; prevalent: 178 [4.53%]) were more commonly used for generalized epilepsy and oxcarbazepine (incident: 53 [8.03%]; prevalent: 386 [9.89%]) was more often used for focal epilepsy. Levetiracetam (incident: focal, 267 [40.5%]; generalized, 271 [45.0%]; prevalent: focal, 794 [20.3%]; generalized, 871 [22.2%]), lamotrigine (incident: focal, 123 [18.6%]; generalized, 106 [17.6%]; prevalent: focal, 968 [24.8%]; generalized, 871 [22.2%]), and topiramate (incident: focal, 102 [15.5%]; generalized, 64 [10.6%]; prevalent: focal, 499 [12.8%]; generalized, 470 [12.0%]) were leading AEDs prescribed for both focal and generalized epilepsy. Valproate was more commonly prescribed for women with comorbid headache or migraine (incident: 53 of 1251 [4.2%]; prevalent: 839 of 8046 [10.4%]), mood disorder (incident: 63 of 860 [7.3%]; prevalent: 1110 of 6995 [15.9%]), and anxiety and dissociative disorders (incident: 57 of 881 [6.5%]; prevalent: 798 of 5912 [13.5%]). Topiramate was more likely prescribed for those with comorbid headache or migraine (incident: 335 of 1251 [26.8%]; prevalent: 2322 of 8046 [28.9%]). Conclusions and Relevance Many women appear to be treated with valproate and topiramate despite known teratogenicity risks. Comorbidities may affect selecting certain AEDs despite their teratogenicity risks.

Objective To estimate the treatment gap between a new epilepsy diagnosis and antiepileptic drug (AED) initiation in the United States. Methods Retrospective claims-based cohort study using Truven Health MarketScan databases (commercial and supplemental Medicare, calendar years 2010–2015; Medicaid, 2010–2014) and a validation study using PharMetrics Plus Database linked to LRx claims database (2009–2014). Persons met epilepsy diagnostic criteria, had an index date (first epilepsy diagnosis) with a preceding 2-year baseline (1 year for persons aged 1 to <2 years; none for persons <1 year), and continuous medical and pharmacy enrollment without epilepsy/seizure diagnosis or AED prescription during baseline. Outcomes included percentage of untreated persons (no AED prescription) up to 3 years9 follow-up and comparative outcomes (incidence rate ratio: untreated persons/treated persons), including medical events and health care resource utilization. Results In the primary study, 59,970 persons met selection (or inclusion) criteria; 36.7% of persons with newly diagnosed epilepsy remained untreated up to 3 years after diagnosis. In the validation study (N = 30,890), 31.8% of persons remained untreated up to 3 years after diagnosis. Lack of AED treatment was associated with an adjusted incidence rate ratio (95% confidence interval) of 1.2 (1.2–1.3) for medical events, 2.3 (2.2–2.3) for hospitalizations, and 2.8 (2.7–2.9) for emergency department visits. Conclusions One-third of newly diagnosed persons remain untreated up to 3 years after epilepsy diagnosis. The increased risk of medical events and health care utilization highlights the consequences of delayed treatment after epilepsy diagnosis, which might be preventable.

Aim: This population‐based study aimed to estimate the impact of neonatal seizures on subsequent neurological outcomes, regardless of underlying etiology.Method: We performed a retrospective cohort study (1st January 2009–31st December 2014), using a USA nationwide claims database. Newborn infants enrolled in 2009 were followed for up to 6 years. Neonatal seizures were identified by combining the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code of 779.0 (convulsions in newborn), procedure codes of electroencephalogram and brain imaging, and antiepileptic drugs claims. Cox regression models were built to estimate the independent impact of neonatal seizures on developing epilepsy, intellectual disability, psychiatric/behavioral disorders, and headache.Results: Out of 490 071 newborn infants (251 850 males [51.4%], 238 221 females [48.6%]), 800 neonatal seizure cases were identified. After controlling for sex, birthweight, preterm birth status, and underlying etiology, neonates with seizures were more likely to have epilepsy (hazard ratio=32.7; 95% confidence interval [CI]=27.7−38.7; ppp=0.013) than those without seizures.Interpretation: Observed covariates being equal, seizures in neonates appeared to play a significant role in developing epilepsy, intellectual disability, and headache. The findings showed a detrimental impact of the event in the very early life on neurological outcomes in later life.What this paper adds: Seizures had their own impact on the development of adverse neurological outcomes. The magnitude of impact was quite large in epilepsy.

Summary: Among the causes of epilepsy are several that are currently preventable. In this review, we summarize the public health burden of epilepsy arising from such causes and suggest priorities for primary epilepsy prevention. We conducted a systematic review of published epidemiologic studies of epilepsy of 4 preventable etiologic categories—perinatal insults, traumatic brain injury (TBI), central nervous system (CNS) infection, and stroke. Applying consistent criteria, we assessed the quality of each study and extracted data on measures of risk from those with adequate quality ratings, summarizing findings across studies as medians and interquartile ranges. Among higher‐quality population‐based studies, the median prevalence of active epilepsy across all ages was 11.1 per 1000 population in lower‐ and middle‐income countries (LMIC) and 7.0 per 1000 in high‐income countries (HIC). Perinatal brain insults were the largest attributable fraction of preventable etiologies in children, with median estimated fractions of 17% inLMICand 15% inHIC. Stroke was the most common preventable etiology among older adults with epilepsy, both inLMICand inHIC, accounting for half or more of all new onset cases.TBIwas the attributed cause in nearly 5% of epilepsy cases inHICandLMIC.CNSinfections were a more common attributed cause inLMIC, accounting for about 5% of all epilepsy cases. Among some ruralLMICcommunities, the median proportion of epilepsy cases attributable to endemic neurocysticercosis was 34%. A large proportion of the overall public health burden of epilepsy is attributable to preventable causes. The attributable fraction for perinatal causes, infections,TBI, and stroke in sum reaches nearly 25% in bothLMICandHIC. Public health interventions addressing maternal and child health care, immunizations, public sanitation, brain injury prevention, and stroke prevention have the potential to significantly reduce the burden of epilepsy.