Purpose: To examine the risk of undergoing an epileptic seizure as a function of differing levels of occupational stress (physical and mental) in new military recruits with no previous history of epilepsy or with epilepsy in remission for over 2 years.
Methods: The medical records of over 300,000 18-year-old men recruited to the Israeli army between mid-eighties and mid-nineties were used to assemble a cohort, which was followed for a period of 30 months. The severity of epilepsy at recruitment was determined according to four categories, 0 (no history of seizures) and 1–3 (history of seizures with different relapse-free periods, with or without treatment). The soldiers were subdivided according to their occupational categories to: combat units (CU), maintenance units (MU), and administrative units (AU).
Results: The annual incidence rates per 100,000 in category 0 were 317, 298, and 401 in AU, MU, and CU, respectively. The incidence of seizures in category 0 was higher (relative risk [RR]= 1.29, CI = 1.03–1.62) in CU compared to AU and MU. No differences were found for seizure recurrence among various occupational groups.
Conclusion: The increased risk of seizures in CU compared to AU and MU may indicate contribution of service conditions in CU, like physical and mental stress. The equivalent rates of seizure relapse, regardless of the type of occupation, suggests the need for minimal occupational restrictions for epilepsy patients who have been free of seizures for long periods.
The prevalence of epilepsy is 0.5–1% worldwide, with the highest incidence occurring in early childhood and late adulthood (Hauser et al., 1991). Studies on the risk for recurrent seizures show that between 27% and 81% of patients will suffer a second seizure within 3–5 years (Shinnar et al., 1990, 1996; Hauser et al., 1998; MacDonald, 2001). Extensive research on epilepsy found several factors associated with recurrent seizures (MacDonald, 2001) including young age (<16 years; Beghi & Tognoni, 1988; Hart et al., 1990), an abnormal neurological examination (Camfield et al., 1985a, 1985b; Elwes et al., 1985), the presence of EEG abnormalities (Beghi & Tognoni, 1988; Shinnar et al., 1990; Burn et al., 1997; Stroink et al., 1998), and a history of head injury (Jennett & Lewin, 1960; Annegers et al., 1980).
The association between stress and seizure frequency has been reported anecdotally. Stress is commonly believed to precipitate seizures in some patients with epilepsy, but direct examination of this assumption is problematic because of the difficulty in defining vague factors such as emotional stress (Neufeld et al., 1994). Stress itself may also be associated with other seizure-provoking factors such as alcohol and sleep deprivation and there may be a reporting bias as people search for an explanation for their seizures (Brown & Prevett, 2007).
The aim of the present study was to determine the relative risk (RR) for development of first ever seizure and relapse in those with established epilepsy in remission among young adults serving in three types of military units differentiated by their nature of duty, and their physical and mental stressors.
Materials and Methods
The Israel Defense Forces (IDF) draft is mandated by law and includes all 18-year-old male citizens of the State of Israel, excepting only certain minority populations, the extreme Jewish religious population and candidates who are medically unfit for military service.
The military service is 3 years long. At the age of 17-years all Jewish citizens are required to attend the IDF's recruiting office for a medical evaluation. The present study involved all male recruits between mid-eighties and mid-nineties (over 95% of the eligible Jewish male population). The inductee's medical history was obtained, in most cases, from his family physician. During the initial examination, each was asked specifically whether he was ever diagnosed as having epilepsy or seizures. If the inductee (or the family physician) gave a positive reply, implying the possibility of past or present epilepsy or seizures, he was referred to an evaluation by a certified neurologist. The inductee was asked to provide medical information about the seizures including medications, EEG, and brain imaging studies. The diagnosis of epilepsy was based on the definition of recurrent unprovoked seizures according to criteria recommended by the International League Against Epilepsy (Guidelines for epidemiologic studies on epilepsy).
During 30 months of obligatory military service, any newly diagnosed epilepsy or seizures and any relapse or exacerbation of known epilepsy that necessitated a change in epilepsy category and/or a change in duty assignment were recorded. The exact figures of the number of soldiers cannot be given, as this information is classified. The follow-up was limited to 30 months in order to avoid loss to follow-up due to personal, nonmedical reasons (like upcoming early release within a month or two in order to start academic studies). The study was approved by the military ethics committee.
Population medical categories
The subjects were divided into the following categories according to criteria written in the IDF's list of medical profiles: (0) no evidence of past or present seizures; (1) diagnosed epilepsy in complete clinical remission for at least 6 years with a normal EEG and no use of antiepileptic drugs (AED); (2) diagnosed epilepsy, in complete clinical remission, last seizure 2–6 years ago, with normal EEG and no current use of AED; (3) diagnosed epilepsy, in complete clinical remission for at least 2 years, receiving AED or with abnormal EEG; and (4) diagnosed epilepsy with recurrent seizures during service (with or without AED) and with abnormal EEG recorded in the last 2 years. Post-traumatic seizures have a different medical profile and therefore these patients are not included in the study.
If any symptoms suggestive of seizures developed during the follow-up period, the subjects were reevaluated by a certified neurologist in accordance with the medical parameters defined in the military medical list of profiles. The medical status was then reassessed by a military medical committee comprised of two senior physicians. If necessary, the medical profile was adjusted in light of the new evidence and the soldier was reassigned to a suitable post. The study endpoint per subject was defined as a change in the medical profile from the preliminary category (0–3) to category 4. This process was supervised and monitored by a trained physician stationed at the headquarters of the IDF medical corps.
The soldiers' assignments were categorized into combat units (CU), maintenance units (MU), and administrative units (AU). The CU included service in infantry CU with high mental stress and strenuous physical activity as well as mobile CU with high mental stress, but less strenuous physical activity and shorter trainings. The service in MU is characterized by a more moderate physical activity and moderate mental stress. The service in AU is predominantly characterized by sedentary office work and low mental stress. We used these categories as markers of occupational stress.
Soldiers in category 0 were posted in all CU. Soldiers in category 1 could be posted in CU, but only in less demanding tasks. Soldiers in categories 2 and 3 were posted either in MU or AU only and those in category 4 were assigned to AU as volunteers or dismissed from military service altogether. There are no rotations in job assignment in the army as long as the soldiers are fit for their assignment.
The RR for new onset seizures during the study period was estimated by comparing incidence rates using stratified analysis, according to disease categories. The significance of point estimates was assessed using a chi-square-test with correction for continuity. A p < 0.05 in two tailed tests was considered to be significant. RR and 95% confidence intervals (CIs) were calculated using a standard statistical package (Compare 2 version 1.28; Abramson, 2000–2002).
Table 1 summarizes the annual incidence rates of seizures during the study period according to the subject's epilepsy status at recruitment. The RR for developing seizures was significantly higher among subjects in category 0 who were assigned to CU as compared to AU and MU (RR = 1.29 and 1.37, respectively, p < 0.05). The average annual incidence rate during 30 months of follow-up was 0.034%, 1%, 2.7%, and 8.2% in categories 0–3, respectively.
Table 1. Relative risk (RR) and 95% confidence interval (CI) for new onset or recurrent seizures among young male soldiers (18–21 years), by severity of disease at recruitment for the follow-up period and per year
|0 (No history of seizures)||AU (n > 120,000)||0.08%||0.03%||1a||NS|
|MU (n > 80,000)||0.07%||0.03%||0.94 (0.71–1.25)||NS|
|CU (n > 100,000)||0.1% ||0.04%||1.29 (1.03–1.62)||0.03|
|Total||n > 300,000||0.08%|| 0.034%|| |
|1 (≥6 years without seizures and normal EEG)||AU (n = 258)||7 (2.7%)||2.8 (1.1%)||1a|| |
|MU (n = 158)||4 (2.5%)||1.6 (1.0%)||0.93 (0.28–3.14)||NS|
|CU (n = 161)|| 4 (2.48%)||1.6 (1.0%)||0.92 (0.27–3.08)||NS|
|Total||n = 577||15 (2.6%) ||6 (1%)|| |
|2† (2–6 years without seizures and normal EEG)||AU (n = 241)||17 (7.1%) ||6.8 (2.8%)||1a|| |
|MU (n = 109)||7 (6.4%)||2.8 (2.6%)||0.91 (0.39–2.13)||NS|
|Total||n = 350||24 (6.8%) ||9.6 (2.7%)|| |
|3† (no seizures for 2–6 years, abnormal EEG, or receiving AED)||AU (n = 531)||108 (20.3%) ||43.2 (8.1%) ||1a|| |
|MU (n = 100)||22 (22.0%)||8.8 (8.8%)|| 1.1 (0.72–1.62)||NS|
|Total||n = 831||130 (20.6%) ||52 (8.2%)|| |
The RR for development of a first seizure or relapse of epilepsy in remission during military service is calculated in Table 2. The RR comparing soldiers in categories 0 and 1 was 24.8 (16.1–171.8). The RR for recurrence of seizures comparing categories 2 and 3 was 3.4 (CI = 1.77–4.7) and 2.9 (CI = 1.53–7.67) in MU and AU, respectively. The relapse rates for recruits with a history of epilepsy in remission were higher than the rates of a first seizure in those without a history of epilepsy, and further increase if the last seizures had occurred closer to recruitment. The rates for relapse, however, did not vary as a function of occupational category.
Table 2. The RR and confidence interval of developing or worsening epilepsy or seizures within the types of military duty
|1/0||24.8 (16.1–171.8)||34.1 (12.7–92.4)||34.3 (16.1–73.1) |
|2/0||–|| 86.4 (40.8–183.4)||89.3 (53.7–148.5) |
|3/0||–|| 296 (192.2–456.8)||256 (197.7–333.9)|
|2/1||–||2.53 (0.76–8.46)||2.6 (1.1–6.2) |
|3/1||–|| 8.7 (3.09–24.5)||7.5 (3.5–15.9) |
|3/2||–|| 3.4 (1.53–7.67)||2.9 (1.8–4.7) |
With more than one million person-years of follow-up and 1558 male subjects with a history of epileptic seizures, the current study clearly shows that CU soldiers with no history of epilepsy at recruitment are at a significantly elevated risk (RR = 1.29 CI = 1.03–1.62) for epileptic seizures during their military service as compared to noncombat unit soldiers. A direct association was found between the category of disease at recruitment and the risk for seizure recurrence. The annual incidence rates during 30 months of follow-up were 0.034%, 1%, 2.7%, and 8.2% in categories 0–3, respectively.
The crude annual incidence rate for first seizures calculated in our study (34/100,000) is lower than previous rates reported for young adolescents in the U.K. (53.8/100,000; Wallace et al., 1998) and in Iceland (64.1/100,000; Olafsson et al., 2005). An earlier study that documented first seizures in 67 general practices found an overall annual incidence rate of 63/100,000 (Sander & Shorvon, 1987). Studies in other countries have reported similar rates. Throughout a working lifetime, from 16 to 65 years of age, the annual rate of first seizures is approximately 40/1,000 (Wallace et al., 1998). The lower rate in the current research can be explained by restricting the analysis only to preselected inductees who were considered fit for military service; subjects diagnosed with severe medical conditions were not recruited and thus were beyond the scope of this study.
The incidence rate of new onset or recurrent seizure in the different categories is demonstrated in Table 1. The RR for new onset seizures (category 0) was higher for soldiers assigned to CU than AU (RR = 1.29 CI = 1.03–1.62). The soldiers' service in CU is characterized by highly intensive physical activity, inhabitance in field conditions, working night shifts, sleep deprivation, and mental stress. Our findings are consistent with other reports linking stress and sleep deprivation to seizures. As many as two-thirds of persons with epilepsy identify stress as a potential trigger factor for seizures (Spector et al., 2000; Haut et al., 2003). Prospective diary studies have reported associations between seizure occurrence and stressful or major life events (Webster & Mawer, 1989; Neugebauer et al., 1994). A recent study demonstrated association between high anxiety scores and a doubling of the risk of seizure the next day compared to low anxiety scores (Haut et al., 2007). Sleep deprivation is considered the most common seizure threshold-lowering factor and affects approximately 30–40% of patients with seizure disorders (Brown & Prevett, 2007). The increased risk in CU compared to AU and MU in category 0 may indicate that any one or all the factors associated with CU service conditions could contribute to this increased risk.
The annual rate of recurrent seizures among soldiers in category 1 (1% annually) is similar to the results obtained by Shinnar et al. (1996) (0.66%); however, their study group included children after a first unprovoked afebrile seizure while our study also included young adults previously diagnosed with epilepsy who were seizure free for at least 6 years (but probably longer). We did not find any difference in the recurrence of seizures between CU to MU and AU in category 1 although a small but significant difference in new onset seizures was found in category 0. We think the difference might stem from different tasks in CU in those categories, because soldiers in category 1 were only posted to less strenuous and demanding assignments.
We compared the annual incidence rates of seizures in categories 2 and 3 (2.7% and 8.2%, respectively) to other studies. Two studies (Shinnar et al., 1990, 1996) evaluated childhood populations. Shinnar et al. (1990) estimated the risks of seizure relapse following a first unprovoked seizure in childhood. The cumulative risk of relapse in 81 children with abnormal EEG were 41%, 54%, and 56% at 12, 24, and 36 months, respectively, but only 15%, 23%, and 26% at 12, 24, and 36 months, respectively, in 138 children with normal EEG. Most recurrent seizures took place within the first 2 years of follow-up, and only a small difference was found between the two populations in the third year (2% vs. 3%). The results of seizure relapse in these 138 children are similar to results in our category 2 subjects (3% vs. 2.7%), yet the results from the 81 children differ from our study results in category 3 subjects (3% vs. 8%). In another study (Shinnar et al., 1996), 407 children with mean age of 6.8 years were evaluated for a mean follow-up of 6.3 years. In children with cryptogenic first seizure and epileptiform EEG, the risk of relapse was 52% and 59% at 2 and 5 years, respectively (2.33% annual incidence compared to 8.2% in our study). These differences could be due to the younger age of the subjects in the studies of Shinnar et al. (1990, 1996).
We found three different studies concerning seizure relapse of adult population. In the first study, which included 208 patients (Hauser et al., 1990) the relapse rates were estimated to be 14%, 29%, and 34% at 1, 3, and 5 years, respectively, following the first episode. The annual incidence compared to category 2 was 2.7%, the same as in our study. In the second study (Hauser et al., 1998), 204 patients with mean age of 36 years, who were seizure free for at least 24 months, were followed. The relapse rate was 7% for 3 years (2.33% annually), similar to category 2 in our study. However, in the analysis, EEG findings were not associated with the risk of relapse. Lindsten et al. (2001) followed 107 patients aged ≥17 years with a newly diagnosed unprovoked epileptic seizure for 10.3 years. At 750 days after the index seizure, the relapse was 58%, beyond which no events occurred. Nevertheless, 78% of the patients received AED after the index seizure, which could probably explain lower relapse rates.
To summarize, most studies found relapse rates of 2.5% in the parallel follow-up period as characterized in our category 2, but lower relapse rates compared to category 3. Our study shows that categories 2 and 3 have different risks for recurrent seizures, even after a 2 years of seizure-free period. Unfortunately, in our study, we could not distinguish between the effect of EEG and AED as a prognostic parameter because, category 3 includes subjects classified according to either or both parameters.
As expected, the risk for recurrent seizures increased from groups 0 to 3 with direct association to the severity of disease at recruitment. In a multicenter study (First Seizure Trial Group, 1993), having epileptiform abnormalities in EEG, was associated with 1.7-fold increased risk for recurrent seizures. In another study (Hauser et al., 1990), only a generalized spike and wave pattern was associated with an increased recurrence risk (RR = 2.69). The risk of relapse was 2.8 times higher for untreated subjects. In our study, we found a higher risk in group 3 subjects compared to other studies (3.4 and 2.9 in MU and AU, respectively), most probably for two main reasons: (1) we used a complete database and (2) we could not separate the effect of EEG and AED because category 3 included subjects classified according to either or both parameters.
One of the drawbacks of our study is the possibility that some individuals took advantage of the medical military policy, and falsely reported having seizures. We assume that the minute incidence of malingering is probably similar to the minute incidence of the false negative diagnosis (highly motivated individuals). The low incidence of new seizures in category 0 proves that over-reporting was probably very low.
Determining fitness for work for a person with a disease that may cause rapid loss of control, such as epilepsy, is fraught with difficulty (Donoghue, 2001). First, there is a paucity of epidemiological studies. Many of the studies that have been reported, investigated motor vehicle accidents (Laks & Korczyn, 1978; Bener et al., 1996; Taylor et al., 1996), but very few evaluated industrial accidents (Gilmore et al., 1996; Zwerling et al., 1998). Methodological limitations of these studies include small size groups and nondifferentiation of high-risk subgroups (Bener et al., 1996; Gilmore et al., 1996; Taylor et al., 1996; Zwerling et al., 1998). Second, there are wide variations in the frequency with which loss of control occurs in individuals with the same disease. Third, the likelihood that loss of control will result in damage to property or injury to person varies greatly (Dasgupta et al., 1982; Neufeld et al., 2000; Van den Broek & Beghi, 2004).
The increased risk in CU compared to AU and MU in category 0 may indicate that service conditions in CU like physical and mental stress could be plausible contributing factors for new onset seizure in these young male subjects. On the other hand, the fact that assignment type did not affect the risk of seizure recurrence in those with a history of seizures suggests that the need for occupational restrictions could be minimized in subjects with a long-term remission in their seizures without subjecting them to serious risk of recurrence.