J Head Trauma Rehabil Vol. 30, No. 1, pp. 29–37 c 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright 

The Prevalence of Epilepsy and Association With Traumatic Brain Injury in Veterans of the Afghanistan and Iraq Wars Mary Jo V. Pugh, PhD; Jean A. Orman, ScD, MPH; Carlos A. Jaramillo, MD, PhD; Martin C. Salinsky, MD; Blessen C. Eapen, MD; Alan R. Towne, MD, MPH; Megan E. Amuan, MPH; Gustavo Roman, MD; Shane D. McNamee, MD; Thomas A. Kent, MD; Katharine K. McMillan, PhD; Hamada Hamid, MD, MPH; Jordan H. Grafman, PhD Objective: To examine the association of epilepsy with traumatic brain injury (TBI) in Afghanistan and Iraq (Operation Enduring Freedom [OEF]/Operation Iraqi Freedom [OIF]) Veterans. Design: Cross-sectional observational study. Participants: A total 256 284 OEF/OIF Veterans who received inpatient and outpatient care in the Veterans Health Administration in fiscal years 2009-2010. Main Outcome Measures: We used algorithms developed for use with International Classification of Diseases, Ninth Revision, Clinical Modification, codes to identify epilepsy, TBI (penetrating TBI [pTBI]/other TBI), and other risk factors for epilepsy (eg, stroke). TBI and other risk factors were identified prior to the index date (first date of seizure or October 1, 2009) for primary analyses. Results: Epilepsy prevalence was 10.6 per 1000 (N = 2719) in fiscal year 2010; age-adjusted prevalence was 6.1. Of 37 718 individuals with a diagnosis of TBI, 29 297 Veterans had a diagnosis of TBI prior to the index date. Statistically significant associations were found between epilepsy and prior TBI diagnosis (pTBI: adjusted odds ratio = 18.77 [95% confidence interval, 9.21-38.23]; other TBI: adjusted odds ratio = 1.64 [1.43–1.89]). Conclusions: Among OEF/OIF Veterans, epilepsy was associated with previous TBI diagnosis, with pTBI having the strongest association. Because war-related epilepsy in Vietnam War Veterans with TBI continued 35 years postwar, a detailed, prospective study is needed to understand the relationship between epilepsy and TBI severity in OEF/OIF Veterans. Key words: epidemiology, epilepsy, traumatic brain injury, Veterans

Author Affiliations: South Texas Veterans Health Care System (VERDICT), San Antonio (Drs Pugh and McMillan); Department of Epidemiology & Biostatistics, University of Texas Health Science Center at San Antonio (Drs Pugh, Orman, and McMillan); Department of Medicine, Texas A&M University School of Medicine (Dr Pugh); Statistics and Epidemiology US Army Institute of Surgical Research, Fort Sam, Houston, Texas and University of Texas School of Public Health, San Antonio Regional Campus, San Antonio (Dr Orman); Department of Rehabilitation Medicine, Polytrauma Rehabilitation Center South Texas Veterans Health Care System (STVHCS), U.T. Health Science Center San Antonio, San Antonio (Drs Jaramillo and Eapen); Portland Veterans Affairs Medical Center, Portland, Oregon (Dr Salinsky); Oregon Health & Sciences University, Portland (Dr Salinsky); Epidemiology and Community Health, Virginia Commonwealth University, Richmond (Dr Towne); Epilepsy Center of Excellence, McGuire Veterans Administration Hospital, Richmond, Virginia (Dr Towne); Edith Nourse Rogers Memorial Hospital (The Center for Health Quality, Outcomes and Economic Research [CHQOER]), Bedford, Massachusetts (Dr Amuan); Nantz National Alzheimer Center, Methodist Neurological Institute, Houston, Texas (Dr Roman); Physical Medicine & Rehabilitation Service, Hunter Holmes McGuire Veterans Administration Hospital, Richmond, Virginia (Dr McNamee); Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas (Dr Kent); Baylor College of Medicine, Houston, Texas (Dr Kent); West Haven VA Medical Center, West Haven, Connecticut (Dr Hamid); and Brain Injury Research, Rehabilitation Institute of Chicago, Chicago, Illinois (Dr Grafman).

Findings were presented at the American Academy of Neurology in April 2012 and VA HSR&D Annual Research Meeting in July 2012. The study was funded by VA Health Services Research and Development (DHI 09-237). Administrative, technical, or material support was provided by Kathleen Franklin, South Texas Veterans Healthcare System. Data analysis was conducted by Ms Amuan. The content of this article is solely the responsibility of the authors and does not necessarily reflect the official views of the Veterans’ Health Administration. The funding organizations had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.headtraumarehab.com). Corresponding Author: Mary Jo V. Pugh, PhD, South Texas Veterans Health Care System (ALMD), 7400 Merton Minter Blvd (11C6), San Antonio, TX 78229 ([email protected]). DOI: 10.1097/HTR.0000000000000045

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VER the past 12 years, many service members deployed to Afghanistan and Iraq during Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) have experienced a traumatic brain injury (TBI),1–3 with approximately 15% to 19% of returning OEF/OIF troops reporting a TBI with either loss of consciousness or altered mental status4 and nearly 7% of Veterans receiving care in the Veterans Health Administration (VHA) being identified as having a TBI.5 While primarily mild TBI (mTBI),1 the high prevalence of TBI has raised concern for the long-term consequences of neurotrauma in this population.6 Based on data from previous wars, there is a particular concern for the risk of posttraumatic epilepsy (PTE). Studies of Veterans from World War II and the Korean War identified the link between combat-related head injury and epilepsy, with penetrating head injuries being more strongly associated with the development of epilepsy.7–11 Among those World War II Veterans who developed seizures, half did so within 9 months of injury and 80% developed seizures within 5 years, and development of seizures continued at a rate of 1% per year over the next 5 to 10 years.7 The Vietnam Head Injury Study (VHIS) extended this research, comparing individuals with head injuries, 92% of which were penetrating, with normal controls. Consistent with prior war cohorts, penetrating TBI (pTBI) conferred the highest risk of epilepsy, with more than 50% of those with pTBI experiencing epilepsy within a year of the TBI and about half of that group continuing to experience seizures 15 years later.12–14 Because prior military assessments focused on pTBI, without examining other levels of TBI severity,7–14 the association of mTBI related to the current military on the development of PTE is unknown.15 In a civilian population-based study, Annegers and colleagues16 examined the risk of epilepsy by TBI severity level in a civilian population and found a 50% increase in the incidence of epilepsy (standardized incidence ratio [SIR] = 1.5; 95% confidence interval [CI], 1.0-2.2) among individuals with mTBI compared with those with no TBI and a significantly higher SIR (17.2; 95% CI, 12.3-23.6) among those with severe TBI. These data led Chen and colleagues15 to hypothesize that the high prevalence of mTBI in this population may result into substantial numbers of individuals with epilepsy. In fact, recent investigation by the Department of Defense indicated that epilepsy incidence increased by 52% from 2006 to 2010, with approximately 8% of those with epilepsy having a previous diagnosis of TBI.17 One identified limitation of that analysis was that those with more severe and penetrating TBI, who are at a highest risk of PTE and more frequently discharged from the military, were underrepresented in that active-duty population.17

To our knowledge, no previous studies have investigated the association between TBI and epilepsy in the population of OEF/OIF Veterans enrolled in the VHA. The purpose of this study was to examine the epidemiology of epilepsy in the OEF/OIF population of Veterans enrolled in the VHA by identifying the prevalence of epilepsy and the association of previously diagnosed TBI controlling for other medical and psychiatric risk factors. Because of strong evidence for the link between pTBI and epilepsy in prior military war cohorts,13,14 our primary analyses distinguished penetrating from other TBI; secondary analyses examined the broader array of TBI severity. METHODS Sample and data sources We conducted a retrospective database analysis of healthcare system data from OEF/OIF Veterans receiving VHA care at least once each year between the beginning of fiscal year 2009 (FY09; October 1, 2008) and the end of FY10 (September 30, 2010). We obtained all national VHA inpatient, outpatient, and pharmacy data for these individuals from FY02 to FY10 and linked those data sources for each individual using an encrypted identifier. Inpatient and outpatient data included demographic characteristics and diagnosis codes (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM], codes) for each clinic visit; ancillary and telephone clinic data were excluded from analysis. Pharmacy data included names of medications prescribed. For our primary analysis, we identified the first day of FY10 as the index date for those who did not meet criteria for epilepsy and the date of the first seizure (ICD-9CM codes 345 [epilepsy] or 780.39 [other convulsion]) in VHA care as the index date for those individuals who met epilepsy criteria (see later).18,19 Primary analyses included TBI and other comorbid risk factors identified prior to the index date. Permission This retrospective data study received approval including a waiver of informed consent and HIPAA (Health Insurance Portability and Accountability Act) authorization by the institutional review boards of the South Texas Veterans Health Care System and the Edith Nourse Rogers Memorial Hospital. Measures Epilepsy We used an adaptation of our previously validated algorithm to identify individuals who met epilepsy criteria

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Epilepsy and Its Association With TBI in War Veterans based on having diagnoses indicative of epilepsy (ICD-9CM codes 780.39 [other convulsions] and 345 [epilepsy and recurrent seizures]) and concomitant or subsequent use of antiepileptic drugs in pharmacy data FY09FY10.20 A prior study using this algorithm found a positive predictive value of 0.94 to 0.98 in a geriatric population.20 However, our examination of 100 medical records of OEF/OIF Veterans who met criteria for epilepsy taking gabapentin or pregabalin as the only antiepileptic drug found that more than 75% of gabapentin or pregabalin use was for pain. Accordingly, we used a conservative algorithm including only the following antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, valproate, lamotrigine, topiramate, tiagabine, zonisamide, oxcarbazepine, levetiracetam, and lacosamide. TBI classification We used the algorithm from the Armed Forces Health Surveillance Center to identify TBI using ICD-9-CM codes diagnosed prior to the index date (see Supplemental Digital Content Appendix 1, available at: http://links.lww.com/JHTR/A101). Individuals having diagnoses identified as pTBI by this classification system were further identified as pTBI1 (see Supplemental Digital Content Appendix 1, available at: http://links.lww.com/JHTR/A101). All other individuals with a diagnosis of TBI (that did not include pTBI) were initially classified as “other TBI.” Because of several concerns regarding TBI status, we also conducted sensitivity analyses using TBI variables. First, combining all non-pTBIs may possibly distort the relationships between pTBI and other TBI, suggesting the possibility of a relationship among those with mTBI when it may not actually exist. Therefore, we used the Armed Forces Health Surveillance Center algorithm to disaggregate “other TBI” into mild, moderate, severe, and unclassifiable TBIs for further analysis. Because individuals may have received more than 1 type of TBI diagnosis, we created a hierarchy of mutually exclusive categories, beginning with penetrating, followed by the most severe when more than 1 level of severity was indicated during the study period. Second, because the VHA TBI screening process may lead to identification of TBI long after it occurred, it is possible that individuals who experienced TBI prior to epilepsy diagnosis may have received a diagnosis of TBI in VHA data after their epilepsy diagnosis. Therefore, we conducted another secondary analysis including all individuals with a TBI diagnosis during the study period, providing a range for the strength of association between TBI and epilepsy.

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Demographic characteristics Epilepsy is more common in minorities, men, and older adults,19,21,22 so we used VHA data to identify age, sex, race/ethnicity, and marital status and controlled for these variables in our analysis. Our prior work found that those without race/ethnicity identified in the VHA data tend to be healthier and seen less frequently at VHA healthcare facilities (data available upon request); thus, we included individuals with missing race data in the analyses, categorizing them as “unclassified,” to avoid further biasing our findings toward the population with high disease burden. Other conditions associated with epilepsy In addition to TBI, a number of other conditions have been demonstrated to be risk factors for newonset epilepsy in adults. Studies in the civilian and VHA populations have identified cerebrovascular disease/stroke, cardiovascular disease, dementia, hypertension, neuropathic pain, and headache as epilepsy risk factors.13,19,21,23–27 We used algorithms validated for research using administrative data (eg, Charlson, Elixhauser, Selim28–31 ) to identify these conditions (see Supplemental Digital Content Appendix 2, available at: http://links.lww.com/JHTR/A102). Consistent with studies identifying chronic conditions, we required individuals to have either diagnoses (ICD-9-CM codes) from 2 outpatient clinical encounters at least 7 days apart or a single diagnosis in an inpatient setting.29,32–34 A number of psychiatric conditions have also been associated with an epilepsy risk. In fact, studies suggest a potentially bidirectional relationship with epilepsy, in which individuals with schizophrenia, depression, and bipolar disorder are more likely than others to subsequently receive a diagnosis of epilepsy and persons with epilepsy are more often to receive a diagnosis of these conditions than are similar individuals without epilepsy.35–38 Individuals with substance use disorder have also been found to be at a higher risk for epilepsy most likely because of the increased risk of serious injury, including TBI, among substance abusers.39 Accordingly, we identified individuals with the following psychiatric conditions: schizophrenia, bipolar disorder, depression, anxiety, and substance abuse, using previously validated algorithms requiring 2 outpatient or 1 inpatient diagnosis.29 In addition, posttraumatic stress disorder (PTSD) is a common comorbidity in Veterans with TBI.40 A PTSD is of particular interest to the present research in that the combination of TBI and PTSD is also strongly associated with psychogenic nonepileptic seizures (PNES) in studies of Veterans undergoing inpatient videoelectroencephalographic monitoring.41,42 This suggests the need to investigate whether the association between www.headtraumarehab.com

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TBI and epilepsy is different for individuals with and without PTSD. Statistical analysis After identifying individuals who met criteria for epilepsy in FY10, we first calculated the unadjusted prevalence per 1000 population. We then calculated the age-adjusted prevalence to the US Census population using the direct method. Descriptive statistics were used to summarize the demographic and clinical characteristics for the study population; differences between those with and without epilepsy were tested for statistical significance using the χ 2 statistic. Next, we used logistic regression analyses to calculate unadjusted odds ratios (ORs) for (a) any TBI and (b) pTBI/other TBI. We then used multivariable logistic regression analyses to calculate the adjusted odds ratios (AORs) for pTBI/other TBI controlling for the other potential risk factors described earlier43 including a TBI-PTSD interaction term. Secondary analyses included a similar multivariable analy-

sis, first, using all categories of TBI severity diagnosed prior to epilepsy and then all TBI severity diagnosed during the study period. All statistical analyses were performed using the SAS software (version 9.2; SAS Institute, Inc, Cary, North Carolina). RESULTS Of the 256 284 Veterans who received VHA care in FY09-FY10, 2719 (mean age = 33.36, SD = 8.40) met criteria for epilepsy in FY10 (1.1%) and 253 565 (mean age = 35.45, SD = 9.85) did not. The prevalence of epilepsy in FY10 was 10.6 per 1000, and the age-adjusted prevalence was 6.1 (95% CI, 5.8-6.6) per 1000. We also identified 37 718 Veterans (14.7%) who had a diagnosis of TBI in FY09-FY10; of those, only 29 297 had a diagnosis prior to the index date. Descriptive statistics for the study population by epilepsy status are shown in Table 1. Veterans with epilepsy were more likely to be younger than 50 years, white, and have a previous TBI diagnosis. Individuals

Demographic characteristics for Afghanistan and Iraq Veterans with and without epilepsy TABLE 1

Variable

Age groups 17- 49 y 50-64 y 65+ y Race/ethnicity White African American Hispanic Other Unknown Married Women Any TBI before Penetrating TBI Other TBI Conditions associated with epilepsy Psychiatric comorbidity PTSD Depression Anxiety Bipolar disorder Schizophrenia Substance use disorder Other clinical covariates Cardiac conditions Cerebrovascular disease Dementia/cognitive impairment Hypertension Headache Neuropathic pain

Epilepsy (n = 2719), n (%)

No epilepsy (n = 253 565), n (%)

2602 (95.7) 112 (4.1) 5 (0.2)

230 536 (90.9) 22 564 (8.9) 465 (0.2)

1936 (71.2) 385 (14.2) 261 (9.6) 80 (2.9) 57 (2.1) 1185 (43.6) 305 (11.2) 661 (24.3) 18 (0.6) 643 (23.7)

160 406 (63.3) 43 701 (17.2) 30 429 (12.0) 10 264 (4.1) 8765 (3.5) 115 271 (45.5) 33 300 (13.1) 28 636 (11.3) 68 (0.0) 28 568 (11.2)

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