Medical risks in epilepsy: a review with focus on physical injuries, mortality, traffic accidents and their prevention

Epilepsy Research 60 (2004) 1–16

Review

Medical risks in epilepsy: a review with focus on physical injuries, mortality, traffic accidents and their prevention Torbjörn Tomson a,∗ , Ettore Beghi b , Anders Sundqvist a , Svein I. Johannessen c a

Department of Clinical Neuroscience, Karolinska Institute, SE-171 76 Stockholm, Sweden b Mario Negri Institute, Milan, Italy c National Center for Epilepsy, Sandvika, Norway Received 31 March 2004; received in revised form 20 May 2004; accepted 21 May 2004 Available online 4 July 2004

Abstract The present review aims at highlighting selective aspects of the medical risks in epilepsy and their prevention. Emphasis is put on accidents and physical injuries, including risk factors and effectiveness of prevention; mortality, its causes, risk factors and prevention of seizure-related deaths, as well as traffic accidents, their risk factors and the effectiveness of prevention. Accidents and injuries are slightly more frequent among people with epilepsy than in the general population. This increased risk is probably most prevalent in patients with symptomatic epilepsy and frequent seizures, most often in combination with associated handicaps. The majority of accidents are trivial and occur at home. The most frequent injuries among patients with epilepsy are contusions, wounds, fractures, abrasions and brain concussions. The standardised mortality ratio (SMR; the ratio of observed number of deaths in a population with epilepsy to that expected, based on age and sex-specific mortality rates in a reference population) in population-based studies of epilepsy is 2–3 compared to the general population. This increased mortality is largely related to the etiology of the epilepsy and is probably not influenced by the treatment of the epilepsy. On the other hand, most fatalities in patients with chronic, therapy resistant epilepsy seem to be seizure-related and often sudden unexpected deaths (SUDEP). The frequency of such seizure-related deaths is most likely to be reduced by intensified treatment aiming at early seizure control, although appropriate studies for definitive evidence are still lacking. Apparently, there is an increased rate of traffic accidents in drivers with epilepsy, even if population-based prospective data are lacking. Many of these accidents are seizure-related. Probably, the extent to which physicians report their patients with uncontrolled epilepsy to the authorities is too low, but this has not yet been explored. Moreover, the preventive measures in legislation may be ignored by many people with epilepsy. © 2004 Elsevier B.V. All rights reserved. Keywords: Epilepsy; Injuries; Accidents; Mortality; Prevention

1. Introduction

∗

Corresponding author. Tel.: +46 8 51773705; fax: +46 8 51773757. E-mail address: [email protected] (T. Tomson).

Currently, there is intense research into various aspects of the medical risks relating to epilepsy, including total and cause-specific mortality, accidents and injuries in patients with epilepsy, mortality

0920-1211/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2004.05.004

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relating to seizures, fatal and other side-effects of various antiepileptic drugs (AEDs). The overall objective of this research is to assess risk factors for the medical consequences of epilepsy in terms of both existence and magnitude. This information will help to prevent or reduce such risks and is needed in order to evaluate the risk/benefit ratio for AED therapy and other treatments (Perucca et al., 2000). Epilepsy is associated with a wide spectrum of medical and other risks. In the present review, we will concentrate on some of the most apparent and extensively studied physical risks and their prevention, including accidents and physical injuries, mortality and traffic accidents. Other topics like psychosocial consequences, psychiatric comorbidity in epilepsy, fatal adverse reactions to AEDs, risks associated with epilepsy in everyday life and their prevention are equally important but have been dealt with elsewhere (Johannessen et al., 2001).While describing these various risks, one major objective of the review is to discuss the potential for reducing the medical risks associated with epilepsy. Emphasis will therefore be on potentially preventable risks.

2. Accidents and physical injuries 2.1. Methodological issues Epilepsy is thought to carry a high risk of accidents and injuries. This assumption is mostly based on clinical observations (Beghi, 2001). However, these reports provide conflicting evidence, which is mostly explained by the type of study population (population-based sample versus referral patients), the definition of the disease (idiopathic, cryptogenic or symptomatic epilepsy), the accuracy of injury reports (types, circumstances and severity), the study design (retrospective versus prospective), and the length of the observation period. Compared to an unselected sample of people with epilepsy, referral patients may include an increased proportion of cases with uncontrolled seizures and/or comorbid conditions. A documented etiology is present in about one-third of patients with epilepsy (Beghi, 2004). Mental retardation and cerebral palsy are important sources of comorbidity (Hauser and Hesdorffer, 1990). In many of these cases, the underlying disease may be responsible

for several complications. The risk of injuries may be higher in symptomatic than in idiopathic/cryptogenic epilepsies because seizure control may be less frequent and the underlying epileptogenic condition may be responsible per se for non-seizure-related accidents. Accidents and injuries also require a precise definition. An accident is any non-spontaneous unintended event secondary to a sudden unexpected cause leading to physical damage and occasionally to death. Type, severity and circumstances of the accidents may affect reports. The completeness of reporting may be higher in prospective than in retrospective studies due to a systematic search of the complications of epilepsy and seizures. Finally, the risk of accidents tends to increase with time in any population at risk. A cause–effect relationship between epilepsy and an accident can be proved only when an injury is related to a witnessed seizure or there is strong indirect evidence based on the type and circumstances of the accident. However, few seizures are witnessed and most injuries cannot be unequivocally attributed to a seizure, the disease or its treatment. Accidents and injuries can be expected to occur in patients with epilepsy as in any other individual as a consequence of several independent factors. For these reasons, the calculation of the risk of accidents and injuries attributable to epilepsy must be based on the difference between the rate observed and that expected by chance in the same population, which can be obtained using population statistics. However, the use of non-concurrent controls limits the validity of the results because they may not be comparable to patients with epilepsy for baseline characteristics and modalities of ascertainment of accidents and injuries. For a correct risk assessment, concurrent controls and prospective observation are preferred to assure comparability between groups. In that sense, compared to the case-control study, the cohort study is the best investigational design. 2.2. Studies on non-fatal seizure-related injuries and fractures Neufeld et al. (1999) studied the lifelong history of seizure-related injuries and fractures in 298 patients attending an outpatient referral clinic and calculated the ratio of the reported events to the total number of patient-years in their population. They reported

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three injuries and 0.5 fractures per 100 patient-years. These numbers were significantly lower than those of Nakken and Lossius (1993) who reported 120 injuries and 13 fractures per 100 patient-years in a sample of multi-handicapped patients with poorly controlled epilepsy. A higher number of injuries (300 per 100 patient-years) was also observed by Russell-Jones and Shorvon (1989) among 255 resident patients with long-term epilepsy. Eleven percent of 177 adults attending an outpatient clinic in Sweden sustained one or more fractures (2.4/100 person-years) (Persson et al., 2002). In this population, the overall standardized morbidity ratio was 2.4 (95% confidence interval, CI 1.5–3.6). In a well-defined US population, Annegers et al. (1989) found one fracture per 100 patient-years. This marked difference in the number of injuries or fractures per unit population is mainly explained by differing populations at risk. Based on a mail survey of patients with active epilepsy (i.e., a history of seizures in the past 2 years or currently receiving AEDs) identified in one UK health region, Buck et al. (1997) reported that 65% of 344 cases having at least one seizure in the previous 12 months sustained no injuries, 24% had at least one head injury, 16% a burn or scald, 10% a dental injury, and 6% other fractures. In studies comparing patients with documented epilepsy to different control populations, the relative risk (RR) of fractures (whether or not seizure-related) also tends to vary with the characteristics of the target population. Desai et al. (1996) found a seven-fold risk of seizure-related femur fractures and a five-fold risk of non-seizure-related femur fractures in 202 institutionalized patients with epilepsy compared to an age and sex-matched normal population. In contrast, non-institutionalized outpatients with epilepsy have a two-fold risk of fractures compared to randomly selected controls (Seeley et al., 1996). Similarly, while children with attention-deficit hyperactivity disorder with or without epilepsy have a higher injury rate, cognitively normal children with epilepsy do not have a higher injury rate than their peers without epilepsy (Kirsch and Wirrell, 2001). Young people with intellectual disability are also at higher risk of injuries, the risk factors being psychopathology (odds ratio, OR 3.4; 95% CI 1.8–6.4), epilepsy (OR 2.4; 95% CI 1.4–4.0), and sociability (OR 2.2; 95% CI 1.1–4.1) (Sherrand et al., 2001).

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Admission rates in burn units attributable to epilepsy decreased from 5–10% to 1–2% in more recent years (Josty et al., 2000). In parallel, the size of seizure-related burns decreased from 15 to 2%. Burns caused by domestic accidents have become the most common cause of burn unit admissions in patients with epilepsy (Josty et al., 2000). The largest investigation on epilepsy and the risk of accidents is a multicenter cohort study undertaken in nine European countries (England, Estonia, Germany, Holland, Italy, Portugal, Russia, Slovenia and Spain) (Beghi and Cornaggia, 1997). In this study, 951 children and adults with early epilepsy and 909 matched controls were followed prospectively for 17,484 and 17,206 person-months, respectively (Beghi and Cornaggia, 2002). Two hundred and seventy accidents were reported by 199 patients compared to 149 accidents reported by 124 controls. The cumulative time-dependent probability of accidents in the patient cohort was 17 and 27% at 12 and 24 months, respectively (controls, 12 and 17%; P < 0.0001). About one fourth of accidents in patients with epilepsy were seizure-related. Contusions and wounds were the most common complaints (6 and 5%), followed by abrasions and fractures (3% each), and brain concussions (2%). Contusions (4%), followed by wounds (3%) and sprains or strains (2%) predominated in the controls. The RR of accidents varied by type, being highest for concussions (RR 2.6; 95% CI 1.2–5.8) followed by abrasions (RR 2.1; 95% CI 1.1–4.0), and wounds (RR 1.9; 95% CI 1.2–3.1). Most accidents occurred at home and about one half of domestic accidents were seizure-related. The second most common site for accidents was the road, followed by leisure-related locations, work and school. Complications after an accident were reported by 21% of patients with epilepsy and 14% of controls (P < 0.0001). An accident requiring hospital admission occurred in 3% of cases and 1% of controls (P < 0.05). Except for brain concussion, accidents occurring in patients with epilepsy and controls were mostly trivial and tended to decrease significantly after exclusion of seizure-related events. 2.3. Risk factors Seizure type (atonic and tonic–clonic) and severity were repeatedly found to be risk factors for

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Table 1 Factors predicting epilepsy-related injuries Injury/factor

Odds ratioa

95% confidence intervalb

Burn/scald Seizure severity (ictal) At least one seizure a month Sex (F)

1.3 3.3 2.2

1.1–1.4 1.4–10.0 1.1–4.6

Head injury Seizure severity (ictal) Type of seizure (other only)

1.3 2.5

1.2–1.4 1.2–5.3

Dental injury Seizure severity (ictal)

1.4

1.2–1.7

Other fracture Seizure severity (percept) Duration of epilepsy No. of adverse effects (3+)

2.3 1.1 4.1

1.4–3.8 1.1–1.2 1.2–14.3

Any injury Seizure severity (ictal) Seizure type (other only) At least one seizure per month

1.4 2.7 2.0

1.3–1.6 1.3–5.5 1.3–3.3

Seizure while bathing/swimming At least one seizure a month No. of adverse effects (3+)

3.3 2.0

1.4–10.0 1.1–4.1

Source: Buck et al. (1997) (with permission). a Odds ratios >1 indicate that subjects with a given characteristic are more likely to experience an injury. b When 95% confidence intervals exclude 1, there was a statistically significant association (P < 0.05) by a conventional chi-square test.

seizure-related injuries. In one study (Buck et al., 1997), risk factors for injuries included gender (female), tonic–clonic seizures, and at least one seizure per month (Table 1). Multivariate analysis indicated seizure severity, type and frequency as the best predictors of all types of injuries, and seizure frequency and number of drug-related adverse events as the best predictors of injuries occurring while bathing or swimming. In the multicenter European study, except for concussion, which was found to vary with epilepsy syndrome, none of the clinical features of the disease were significantly correlated to the risk of accidents (van den Broek and Beghi (2004)). After adjusting for age, sex, disability and country, concussions were most common in patients with generalized epilepsy (hazard ratio, HR 6.8; 95% CI 1.1–42.6). Abrasions were less

common in patients with inactive epilepsy (HR 0.3; 95% CI 0.1–0.9) or with rare seizures (HR 0.4; 95% CI 0.2–1.0). The risk of accidents and deaths dropped, becoming non-significant after excluding seizure-related events. 2.3.1. Risk factors for head injuries Head injuries, mostly trivial, have been reported as a common complication of seizures (Russell-Jones and Shorvon, 1989; Nakken and Lossius, 1993; Zwimpfer et al., 1997; Neufeld et al., 1999). As with other injuries, the risk of head trauma is mostly related to having a major seizure (generalized tonic–clonic or myoclonic), although childhood absence seizures may also be implicated (Wirrell et al., 1996). 2.3.2. Risk factors for burns The number of lifetime seizures and the absence of neurological impairment increase the likelihood of seizure-related burns (Spitz et al., 1994), suggesting that people with controlled seizures and disabled individuals with close supervision are at lower risk of burns associated with seizures. Burns are significantly more common in patients with complex partial seizures, with or without generalized tonic–clonic seizures, than in patients with only generalized tonic–clonic seizures (Hampton et al., 1988). 2.3.3. Risk factors for fractures In the only population-based study (Annegers et al., 1989), disease and treatment duration were found to affect the incidence of hip and Colles’ fractures, respectively. In this study, hip fracture incidence was increased during the first 10 years after diagnosis (standardized morbidity ratio for years 0–4, 4.1 with 95% CI 2.3–6.6, and for years 5–9, 3.2 with 95% CI 1.2–7.0). By contrast, an increase in Colles’ fracture incidence was associated with duration of therapy (standardized morbidity ratio for 10+ years of drug use, 2.4 with 95% CI 1.0–5.0). In the Swedish study (Persson et al., 2002), men 45 years or older were at higher risk of fractures. The risk was higher in the first 2 years after diagnosis compared to longer disease duration (RR 3.7; 95% CI 1.2–11.5). Anticonvulsant treatment has been reported to affect the risk of complications of an accident in patients with epilepsy. A six-fold risk of fractures was reported by Lidgren and Walloe (1977) in adults on chronic

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phenytoin treatment compared to the general population. In another study (Vestergaard et al., 1999), epilepsy type (symptomatic with tonic–clonic seizures), a family history of epilepsy, and phenytoin use were more frequently reported in patients with fractures. Women 65 years and older on AEDs have a two- to three-fold risk of fractures compared to women without epilepsy of similar age (Cummings et al., 1995; Seeley et al., 1996). Based on these studies, the risk of non-fatal injuries or fractures seems high only in selected study populations. These mostly include patients with uncontrolled seizures and/or multiple handicaps. The role of AEDs as a putative cause of fractures is still debatable, as impairment of bone metabolism (Morrell, 2003) is mostly sub-clinical when institutionalized patients on poor diets and with limited sunlight exposure are excluded (Bono et al., 1993) and it cannot be excluded that AEDs serve as surrogate marker of severity of epilepsy. These findings must have significant implications for the social life of patients with epilepsy. In particular, with reference to risks of accidents, a reappraisal of all the data is needed, including those of the insurance companies. In addition, as there appears to be no significant increase in risk in relation to serious accidents, being a person with epilepsy should no more be considered per se a reason for discrimination. Today, it is difficult for people with epilepsy to be accepted by insurance companies under normal conditions. However, although having epilepsy may imply a more cautious lifestyle, on the basis of the above findings more people with epilepsy should be included in the normal risk group.

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epilepsy and seizure-related accidents the commonest sources of injuries. In the multicenter European study, the RR of accidents fell from 1.5 to 1.3 in patients with idiopathic/cryptogenic epilepsy, and from 1.2 to 1.0 in patients with symptomatic epilepsy when seizure-related events were excluded (Beghi and Cornaggia, 2002). For this reason, preventive measures should be adopted more strictly for patients with uncontrolled seizures. Risk assessment should thus be adapted to the patient’s individual situation, considering the extent of seizure control as a reference to define the limits of one’s restrictions of daily living activities. Since many high-risk activities are governed by national laws, efforts should be made to harmonize the rules, at least in countries with similar socio-cultural settings. The use of AEDs has also been associated with the occurrence of traumatic injuries complicated by fractures. However, in the absence of data comparing patients with epilepsy on chronic treatment with untreated individuals and for the lack of data comparing different AEDs, the possibility cannot be excluded that the drugs act as surrogate markers of active epilepsy. A significant correlation was also found between wounds and number of AEDs (Beghi and Cornaggia, 2002). As compared to monotherapy, polytherapy can be seen as a surrogate marker of a more severe disease, which may be per se the real risk factor for injuries. Although, in the absence of comparative studies, insufficient data are available on the risk of accidents related to the type of AED, drugs with a strong impact on alertness and cognitive functions should be used with caution in the light of the risk of traumatic events caused by impaired vigilance.

2.4. Prevention 3. Mortality Understanding the inherent risk of a particular activity, the risk of seizure recurrence, seizure type, and the risk of adverse treatment events will contribute greatly to decision-making and help develop valuable preventive measures (Drazkowski et al., 2003). People with epilepsy experience restrictions in many areas of daily life. Relatives, school and workmates should be informed of the potential hazards imposed by recurring seizures for every patient with epilepsy. Seizure recurrence is by and large the most significant cause of accidental injuries in patients with

3.1. Overall mortality A major concern for most people with epilepsy and their families is that seizures may have fatal consequences. Community-based studies as well as reports from more selected epilepsy populations have indeed consistently revealed that people with epilepsy have an increased mortality rate. In studies based on populations from hospitals or epilepsy centers, standardised mortaility ratios (SMR; the ratio of observed

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number of deaths in a population with epilepsy to that expected, based on the age and sex-specific mortality rates in a reference population) range from 1.9 to 3.6 (Alström, 1950; White et al., 1979; Klenerman et al., 1993; Nilsson et al., 1997; Shackleton et al., 1999). Such studies suffer from selection bias towards more chronic, severe epilepsy, which is likely to affect the cause-specific mortality. A further limitation is the small numbers of observed deaths. However, there are two large-scale hospital-based studies. One comprised all adults who were admitted and discharged from any hospital in Stockholm, Sweden with a diagnosis of epilepsy during the years 1980–1989. These were followed until the end of 1992 (53,520 person-years) and an SMR of 3.6 (3.5–3.7) was reported (Nilsson et al., 1997). Shackleton et al. (1999) made a retrospective analysis of mortality in 1355 patients with epilepsy diagnosed at a Dutch epilepsy center between 1953 and 1967 and followed until 1994. The mean follow-up of these incident cases was 28 years, 38,665 person-years were surveyed, and SMR was 3.2 (2.9–3.5). Population-based studies provide death rates and SMRs that are more representative of the epilepsy population in general. Six such studies with adults and mixed age populations have been published (Zielinski, 1974; Hauser et al., 1980; Cockerell et al., 1994; Olafsson et al., 1998; Loiseau et al., 1999; Lindsten et al., 2000). One is based on a prevalence cohort from Warsaw, Poland (Zielinski, 1974), while the others are studies of incident cohorts. The SMRs in these population-based studies range from 1.6 to 4.1 (Table 2). A study from the US is a retrospective analysis of 618 patients with a first diagnosis of epilepsy between 1935 and 1974 in Rochester, and is based on a follow-up time of up to more than 30 years (Hauser et al., 1980). A prospective follow-up study from the UK of 1091 patients with newly diagnosed

or suspected epilepsy, who had been identified from general practices throughout the country revealed that there were 564 patients who had a definite diagnosis of epilepsy, which included people with single unprovoked seizures. For the confirmed epilepsy group the SMR was 3.0 (2.5–3.7; 95% CI) after a median follow-up of 6.9 years (Cockerell et al., 1994) and 2.6 (2.1–3.0) after 11.9 years (Lhatoo et al., 2001). The SMR was 1.6 (1.2–2.2) in a 30-year follow-up of 224 incident cases of unprovoked seizures diagnosed from 1960 through 1964 in Iceland (Olafsson et al., 1998). The short-term, 1-year, mortality of 804 patients with a first seizure, provoked or unprovoked, was assessed in the region of Gironde, France (Loiseau et al., 1999). SMR in the 459 patients with unprovoked seizures was 4.1 (2.5–6.2), higher than in other population-based studies. This is largely explained by the short follow-up period. The SMR was 2.5 (1.6–3.8) by the end of follow-up in 1996 in a study comprising 107 adult residents of the County of Västerbotten, Sweden, with unprovoked seizures diagnosed between 1985 and 1987 (Lindsten et al., 2000). There are three additional population-based studies of children with epilepsy (Kurtz et al., 1998; Sillanpää et al., 1998; Camfield et al., 2002). In a retrospective analysis of a cohort of 686 children with epilepsy from Nova Scotia, SMR was 5.3 (2.3–8.3) during the first 10 years and 8.8 (4.2–13.4) the following 10 years after diagnosis (Camfield et al., 2002). The comparatively high SMR is mainly caused by high mortality among children with neurological comorbidity but also the low expected mortality in children. In a prospective study by Kurtz et al. (1998), following 124 children with epilepsy from the UK, nine (7%) had died by age 28. Sillanpää et al. (1998) studied prospectively the long-term prognosis of 245 (61%

Table 2 Community-based studies of mortality in epilepsy Country and reference

Method and study population

SMR (95% confidence interval)

Poland (Zielinski, 1974) US (Hauser et al., 1980) UK (Lhatoo et al., 2001) Iceland (Olafsson et al., 1998) France (Loiseau et al., 1999) Sweden (Lindsten et al., 2000)

Retrospective analysis of prevalence cohort Retrospective analysis of incidence cohort Prospective analysis of incidence cohort Retrospective analysis of incidence cohort Prospective analysis of incidence cohort Prospective analysis of incidence cohort

1.8 2.3 2.6 1.6 4.1 2.5

SMR: standardised mortality ratio.

(not available) (1.9–2.6) (2.1–3.0) (1.2–2.2) (2.5–6.2) (1.6–3.8)

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incident, 39% prevalent) children with epilepsy in Finland. Forty-four (20%) of the 220 patients with available data 30 years after diagnosis had died, yielding a mortality rate of 6.2 per 1000 patient-years (95% CI 5.7–6.7).Hence, despite differences in the methodology in existing studies, it is clear that epilepsy is associated with an increased mortality, two to three times higher than the general population and probably even more so in children. 3.2. Causes of mortality The causes of death among people with epilepsy may be (1) completely independent of the epilepsy, (2) related to the underlying etiology of epilepsy or to comorbidities, (3) caused by the treatment, or (4) directly (e.g., status epilepticus and SUDEP) or indirectly caused by seizures (e.g., accidents). Fatalities caused by the treatment are rare (Askmark and Pettersson, 2001; Arroyo and de la Morena, 2001). In contrast, the major cause of the higher mortality in people with newly diagnosed epilepsy is the underlying etiology of which epilepsy is a symptom. Consequently, population-based studies of incident cohorts report higher mortality in patients with remote symptomatic epilepsy compared with idiopathic cases (Hauser et al., 1980; Cockerell et al., 1994; Olafsson et al., 1998). Although SMRs range from 1.1 to 1.8 among patients with idiopathic epilepsy, it was increased significantly only in the Rochester and UK studies, 1.8 (1.4–2.3) and 1.6 (1.0–2.4), respectively (Hauser et al., 1980; Cockerell et al., 1994). In the extended follow-up of the UK cohort, SMR for idiopathic epilepsy was no longer significantly increased, 1.3 (0.9–1.9) in contrast to the first report after 6.9 years follow-up (Lhatoo et al., 2001). These data highlight the importance of the underlying disease for the increased mortality in new-onset patients. The observation that the high mortality rate is most pronounced during the first few years after diagnosis (Hauser et al., 1980; Olafsson et al., 1998; Lindsten et al., 2000; Lhatoo et al., 2001) provides further evidence for the influence of the etiology, which is likely to be most important early in the course of epilepsy. A detailed evaluation of specific causes of death in people with epilepsy is complicated, since large cohorts are needed and also because it may be difficult to determine accurately the cause of death in each indi-

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vidual case. The cause-specific mortality will depend on the patient population and, as indicated above, the duration of epilepsy may also have an impact. Proportionate mortality ratio describes the proportion of deaths due to specific causes and compares the relative contribution of different causes to the overall mortality in a specific population. Proportionate mortality has been reported in some of the community-based studies of new-onset epilepsy (Hauser et al., 1980; Cockerell et al., 1994; Lindsten et al., 2000; Rafnsson et al., 2001). In these, neoplasms have accounted for 18–34% of deaths, on average about one-third of these being due to brain tumours. Cerebrovascular disorders account for 14–17% of deaths, heart disease 11–26% and pneumonia for 8–18%. The proportionate mortality in suicide varies considerably. Most recent population-based studies report low figures, none in the Swedish study (Lindsten et al., 2000), 1% in the Rochester study and in the UK cohort (Hauser et al., 1980; Lhatoo et al., 2001). The study from Iceland is an exception with 9% of deaths being suicide (Rafnsson et al., 2001). Since a major objective of this review is to discuss the potential to reduce the medical risks associated with epilepsy, the seizure-related causes of death rather than deaths related to the etiology of epilepsy are most relevant. Seizure-related deaths seem to be rare in population-based cohorts of incident cases. Lindsten et al. (2000) reported none among 39 fatalities. It is not clear if there were any SUDEPs or fatalities from status epilepticus in the study from Iceland, although the numbers must be low (Rafnsson et al., 2001). Only two deaths (3% of all fatalities) occurred during a seizure in the French study (Loiseau et al., 1999). Five deaths (3%) in the UK cohort were considered directly related to epilepsy (Lhatoo et al., 2001). Hauser et al. (1980) reported 12 deaths (6%) from accidents, but it is not clear to what extent these were seizure-related. While seizure-related mortality is rare in new-onset epilepsy, the situation is completely different in patients with chronic epilepsy, where the majority of deaths appear to be seizure-related (Table 3) (Lip and Brodie, 1992; Kloster and Engelskjön, 1999; Nashef et al., 1995a, 1995b; Derby et al., 1996; Annegers et al., 1998; Racoosin et al., 2001). In these populations, SUDEP accounts for 24–67% of all deaths and it is by far the most common cause of seizure-related

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Table 3 Seizure-related causes of death (proportionate mortality ratios, percent of all deaths) in cohorts with chronic epilepsy Reference

Population

Total deaths (n)

SUDEP (%)

Status epilepticus (%)

Accidents (%)a

Lip and Brodie (1992) Nashef et al. (1995a) Nashef et al. (1995b) Derby et al. (1996) Leestma et al. (1997) Annegers et al. (1998) Kloster and Engelskjön (1999) Racoosin et al. (2001)

Referral center Severe epilepsy and learning difficulties Tertiary referral center Refractory epilepsy Lamotrigine clinical trials database Vagal nerve stimulation database Tertiary referral center Add-on trials in AED development programs

18 28 24 63 45 15 140 124

67 50 46 24 53b 53 26 42

6 14 4 n.a. 7 n.a. n.a. 4

6 11 13 n.a. 2 n.a. n.a. 16

SUDEP: sudden unexpected death in epilepsy; n.a., data not available in the publications. a In general, no clear distinction is made between accidents that are seizure-related, and those that are not. b Also includes two drowning deaths.

mortality in patients with chronic epilepsy (Pedley and Hauser, 2002). SUDEP will therefore be in focus for the further discussions. 3.3. Risk factors for SUDEP In the absence of a clear understanding of the mechanisms behind SUDEP, a rational approach to its prevention could at best be based on identification of groups at high risk and in particular of risk factors that might be amenable to intervention. Earlier studies are often based on selected series of SUDEP cases from the Medical Examiner or Coroner’s Office and lack appropriate controls (Hirsch and Martin, 1971; Terrence et al., 1975; Leestma et al., 1984, 1989; Earnest et al., 1992). The most appropriate method for the analysis of risk factors is by case-control studies where SUDEP cases are compared with non-SUDEP cases from the same source population of epilepsy patients. A community-based study (Jick et al., 1992) included patients presumed to have “chronic primary epilepsy” identified through AED prescription registers. Eleven SUDEP cases were identified and, for each case, four controls were selected that were presumed to have epilepsy, had not died, and were taken from the same cohort receiving AED prescriptions. Derby et al. (1996) focused on patients with refractory epilepsy. Subjects from an AED prescription register receiving two or more AEDs concurrently were included in the study population. Fifteen of those were considered to be definite, probable or possible SUDEP cases and, for each case, four controls were selected from the

source population. Another study reviewed retrospectively all deaths among epilepsy out-patients who had attended a tertiary referral center in Norway (Kloster and Engelskjön, 1999). Forty-two SUDEP cases were identified and compared with 37 non-SUDEP deaths from the same source population of refractory epilepsy. In a Swedish retrospective, nested, case-control study (Nilsson et al., 1999), 57 SUDEP cases were identified from a large cohort of adult patients with a diagnosis of epilepsy. For each case, three controls, who were living epilepsy patients were selected from the same cohort. In a prospective study from Minnesota (Walczak et al., 2001) 20 cases with definite or probable SUDEP were identified. For each case, four controls were randomly selected from non-SUDEP epilepsy patients enrolled during the same month at the same epilepsy center as the index case. A recent prospective Australian study, based on coroners cases, identified 50 SUDEP and compared clinical data with 50 control epilepsy cases who died of other causes (Opeskin and Berkovic, 2003). SUDEP can occur at any age although the mean age at death in most studies is between 25 and 40 years (Hirsch and Martin, 1971; Terrence et al., 1975; Leestma et al., 1984, 1989; Earnest et al., 1992; Lip and Brodie, 1992; Timmings, 1993, 1998; Tennis et al., 1995; Nashef et al., 1995b; Derby et al., 1996; Leestma et al., 1997; Langan et al., 1998, 2000; Ficker et al., 1998; Kloster and Engelskjön, 1999). Somewhat higher ages were reported in two case-control studies, a mean of 44 years in the Swedish study (Nilsson et al., 1999) and the highest risk between 50

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and 59 years in the prospective study from Minnesota (Walczak et al., 2001). Early reports of drug and alcohol abuse as risk factors and a higher incidence among black people and a preponderance of men are probably due to selection bias. However, mental retardation may be a risk factor for SUDEP (Jick et al., 1992; Walczak et al., 2001). SUDEP appears to be an issue mainly in patients with chronic epilepsy. The incidence is low in community-based studies, estimated to 0.35 per 1000 person-years in an unselected US cohort of epilepsy patients (Ficker et al., 1998) or even as low as 0.09 per 1000 person-years (Lhatoo et al., 2001). The highest risk is observed in patients with severe chronic epilepsy and in particular among epilepsy surgery candidates, where the incidence was found to be 9.3 per 1000 patient-years (Dasheiff, 1991). Most studies report a mean duration of the seizure disorder at the time of the event between 15 and 20 years, and SUDEP is rarer during the first year after seizure onset (Terrence et al., 1975; Leestma et al., 1984, 1989; Earnest et al., 1992; Timmings, 1993; Nashef et al., 1995a, 1995b; Kloster and Engelskjön, 1999; Nilsson et al., 1999; Walczak et al., 2001). The duration of epilepsy was significantly longer among SUDEP cases than among the non-deceased controls in the Swedish case-control study (Nilsson et al., 1999), and long duration was also identified as a risk factor in the prospective US case-control study (Walczak et al., 2001). In the study by Nilsson et al. (1999), cases and controls were matched for age. Hence, the longer duration among SUDEP cases reflects an earlier onset of epilepsy. In fact, the relative risk (RR) of SUDEP was 7.7 (2.1–28) with epilepsy onset at 0–15 years compared with onset after 45 years of age. This risk remained significantly increased after adjustment for seizure frequency, RR 5.0 (1.3–20). Kloster and Engelskjön (1999) likewise observed a significantly earlier onset of epilepsy among their SUDEP cases than in the controls who died from other causes. Information on age of onset as a risk factor is sparse in other studies. Although SUDEP does not seem to be associated with any particular type of epilepsy (Derby et al., 1996; Nilsson et al., 1999), the seizure type appears to be important. A history of primary or secondary generalized tonic–clonic seizures is reported in at

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least 90% of SUDEP cases (Hirsch and Martin, 1971; Terrence et al., 1975; Leestma et al., 1984, 1989; Earnest et al., 1992; Timmings, 1993; Langan et al., 1998, 2000; Kloster and Engelskjön, 1999; Walczak et al., 2001). Most studies including information on seizure control report moderate or high seizure frequency among SUDEP cases. SUDEP is rare in patients in remission and only few such cases have been reported (MRC, 1991; Ficker et al., 1998; Lhatoo et al., 1999). Seizure frequency may be the strongest risk factor, the relative risk of SUDEP being 23 (3.2–170) times higher in those who had experienced at least one seizure during the year of observation compared with seizure free patients (Nilsson et al., 1999). Similarly, Walczak et al. (2001) found a progressive increase in risk for SUDEP with increasing seizure frequency and concluded that the occurrence of as few as 1–3 such seizures per year was associated with an increased risk. Neither Kloster and Engelskjön (1999) nor Opeskin and Berkovic (2003) found an association between seizure control and SUDEP risk, which may be due the selection of their control groups. In fact, both these studies reported post-mortem evidence of terminal seizures in a high proportion of SUDEP cases and significantly more often than among the controls. More sophisticated post-mortem analyses have provided further evidence for recent seizures prior to death in SUDEP cases (Thom et al., 2003). This corroborates the clinical observations that, when witnessed, most SUDEP cases occur in association with a convulsive seizure (Langan et al., 2000). Of particular interest is the potential role of treatment as a risk factor. The number of concomitantly taken AEDs was the second strongest risk factor in one case-control study (Nilsson et al., 1999). Taking three AEDs was associated with an RR for SUDEP of 8 (2.3–28) compared with monotherapy, even after adjustment for seizure frequency. Polytherapy was also found to be an independent risk factor in the US study (Walczak et al., 2001). Racoosin et al. (2001) also noted a trend toward a higher SUDEP rate in patients with two or more concomitant AEDs in add-on trials, compared with patients taking only one concomitant AED. Kloster and Engelskjön (1999) and Opeskin and Berkovic (2003) failed to find an association between polytherapy and SUDEP risk, which

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again may be related to their selection of control groups. The only study suggesting an association with a specific AED is that of Timmings (1993, 1998). Carbamazepine was found to be used more often among SUDEP cases than among the general patients attending an epilepsy clinic. However, no attempts were made to control for other potential confounding risk factors. The Swedish case-control study found no difference between monotherapy with carbamazepine and phenytoin with respect to SUDEP incidence (Nilsson et al., 1999). However, in a further analysis of therapeutic monitoring data, carbamazepine plasma levels above 40 ␮mol/l at the last visit were associated with an increased risk, even when adjusted for seizure frequency (Nilsson et al., 2001). Such an association was not confirmed in the US study, where only one SUDEP case and two controls had carbamazepine levels exceeding 40 ␮mol/l (Walczak et al., 2001). Lip and Brodie (1992) observed that death was preceded by a change in dose or treatment in 5 of 12 cases and indeed frequent dose changes were also identified as a risk factor in the Swedish study (Nilsson et al., 1999). This issue has not been addressed systematically in many other investigations and further analysis is warranted. Non-compliance with the prescribed AED therapy has also previously been proposed as a precipitating factor for SUDEP, which however has not been confirmed in controlled studies (Opeskin et al., 1999; Walczak et al., 2001; Nilsson et al., 2001; Opeskin and Berkovic, 2003). In summary, the patient at risk for SUDEP is a young or middle-aged person with chronic refractory epilepsy, in particular with generalised tonic–clonic seizures and a complicated and unstable treatment. The available data strongly suggest that SUDEP in most cases is triggered by a seizure, and the prevailing hypothesis is that SUDEP is caused by seizure-induced cardio-respiratory alterations (Nashef et al., 1996). Although the treatment-related risk factors may just be surrogate markers of severe epilepsy or insufficiencies in the epilepsy care, it has also been hypothesized that drugs under certain circumstances may make some patients more susceptible to the fatal seizure-related events by direct effects on the heart (Danielsson et al., 2003) or via effects on autonomic cardiac control (Tomson et al., 1998; Persson et al., 2003).

3.4. Prevention of seizure-related mortality In contrast to the situation in other therapeutic areas, e.g., hypertension and cancer, death has not been a primary endpoint in randomised clinical trials in epilepsy. Furthermore, we lack randomised placebo-controlled long-term studies to assess the effects of intervention on the natural course of epilepsy. Consequently, as is the case with accidents, any discussion on prevention and effectiveness of interventions aiming at reducing mortality in patients with epilepsy will be specualtive rather than evidence-based and at best rely on observational studies and circumstantial evidence. Given these circumstances, and the fact that only a small fraction of the mortality in population-based cohorts is directly epilepsy-related, it is hardly surprising that AED treatment did not seem to influence mortality rate in the large prospective epidemiological study of newly diagnosed epilepsy in the UK (Lhatoo et al., 2001). Treatment with AEDs can only be expected to affect seizure-related mortality, which is more prevalent among patients with chronic epilepsy, where SUDEP is the dominating cause of death. Interestingly, in the review of double-blind placebo-controlled lamotrigine trials, the incidence of SUDEP and possible SUDEP seemed to be lower among patients randomised to lamotrigine (0/312 patient-years) as compared with placebo (2/175 patient-years) (Leestma et al., 1997). However, as pointed out by the authors, the numbers were too small for a formal statistical comparison. Unfortunately, Racoosin et al. (2001) do not provide SUDEP rates on placebo in their analysis of the pooled data from randomised add-on trials of four different AEDs. Data from epilepsy surgery programs may also give some clues as to the effectiveness of seizure control in prevention of seizure-related mortality and in particular SUDEP. There were six cases of SUDEP on follow-up among 305 patients from the UK who had temporal lobe epilepsy surgery. Only two of these were reported to be seizure-free post-operatively (Hennessy et al., 1999). A follow-up of 393 patients who had epilepsy surgery in the US identified 11 deaths, of which seven were epilepsy-related (six SUDEPs) (Sperling et al., 1999). None of the 199 patients who became seizure-free after surgery died. In a study from another US center, there were eleven deaths in a follow-up of 215 patients treated

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surgically for refractory temporal lobe epilepsy (Salanova et al., 2002). Three died during seizures, another three were SUDEP, and two patients died in accidents. Mortality was lower (2%) among patients rendered seizure-free compared with those who continued to have seizures after the operation (11.9%). In a population-based Swedish cohort of 596 patients who had undergone epilepsy surgery, none of the six cases of SUDEP were seizure-free (Nilsson et al., 2003). It thus appears that patients who become seizure-free after surgery have a reduced mortality and in particular a lower risk of SUDEP. This is in line with the observation that SUDEP is rare among patients in remission (MRC, 1991). It should, however, be emphasised that although a lower mortality in patients with successful outcome of surgery is encouraging, we lack conclusive evidence that the lower mortality is a direct consequence of surgery. As pointed out in a recent comprehensive review on this issue, there may be pre-existing differences between responders and non-responders to epilepsy surgery that theoretically also could be related to the risk of death (Ryvlin and Kahane, 2003). Although seizure control for obvious reasons seems crucial in attempts to prevent SUDEP and other seizure-related mortality, the supervision and management of the person who has a seizure may be important as well. None of the 14 SUDEP deaths among pupils with epilepsy and learning difficulties occurred while they were supervised at their residential school, but rather when they were on leave and less closely monitored during holidays (Nashef et al., 1995a, 1995b). Preliminary observations from a large ongoing case-control study also suggest that attention to recovery following a seizure and positioning or stimulation may be important in the prevention of SUDEP (Langan, 2000). 3.5. Conclusions: mortality While the mortality in population-based studies is two to three times higher than in the general population, this is largely related to the etiology of the epilepsy and can thus not be expected to be affected by treatment or management of the epilepsy as would seizure-related causes of death. In contrast, it appears that most fatalities in patients with chronic, refractory epilepsy are seizure-related and in most cases SUDEP.

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It is therefore reasonable to assume that treatment resulting in improved seizure-control would reduce the mortality in this population. However, while clinical observations suggest that this might be correct, we still lack the appropriate studies for definitive evidence of the effectiveness of these interventions in the reduction of the mortality rate among people with epilepsy.

4. Traffic accidents 4.1. Traffic accidents attributable to epilepsy There are no prospective population-based studies concerning the road traffic accident (RTA) rate in drivers with epilepsy. The methodological problems start with defining and finding the study population. The estimation of seizure frequency is, with few exceptions, based on the patient’s reported seizures. A study from the UK (Dalrymple and Appleby, 2000) compared the seizure frequency that the patients reported to their general practitioner with what they stated in a linked anonymous questionnaire. According to the questionnaire, 40% had had a seizure in the past year, but only 10% reported that to their doctor. In the UK all drivers are required to inform the driving licence authority about any symptom or diagnosis that may relate to their medical fitness to drive. However, Taylor et al. (1995) found that less than one-third of the patients with newly diagnosed epilepsy or other unexplained episodes of loss of consciousness returned the compulsory notification slip to the authorities. In other countries, the responsibility to inform the authorities lies primarily with the treating physician. There are no studies concerned with how physicians fulfill this obligation. The under-reporting of epilepsy or seizure frequency from patients and physicians creates a possible selection bias in studies of RTA rates in epilepsy. In a population-based retrospective cohort study of 30,420 subjects, including all the licensed drivers in seven contiguous ZIP Code areas in Wisconsin, USA, with and without epilepsy or diabetes mellitus (Hansotia and Broste, 1991), the RTA ratio was 1.33 (P = 0.04) for epilepsy and 1.32 (P = 0.01) for diabetes. A retrospective study from the UK (Taylor et al., 1996) compared self-completed questionnaires from 8888 normal drivers and 16,958 drivers who

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had notified the authorities about a single seizure or diagnosed epilepsy. No overall differences in total RTA rate was found, but serious injuries were 40% higher in the epilepsy cohort and there was evidence of a two-fold increase in non-driver fatalities. Ling carried out a 10-year historical cohort register study of 159 subjects with epilepsy and 559 matched controls in Denmark (Lings, 2001). Persons with recorded diagnoses of other neurologic diseases, diabetes, psychoses, or abuse, were excluded. The outcome measure was treatment at the casualty department after an accident as a car driver. The treatment rate was seven times higher (CI 2.18–26.13) in those with epilepsy compared to the control cohort. The author concluded that drivers with epilepsy are more likely than healthy controls to be treated at a casualty department after having a motor vehicle accident. 4.2. Risk factors Few studies are concerned with RTA risk as a direct consequence of a seizure. Gastaut and Zifkin (1987) reported 97 patients who had had 109 seizures while driving. It was found that 55% of all the seizures had led to a RTA. Complex partial seizures without aura and tonic–clonic seizures were associated with a 75% risk while complex partial seizure with aura had a 33% risk. A retrospective case-control study of RTA rate in outpatients attending an epilepsy clinic (Krauss et al., 1999) identified risk factors for seizure-related motor vehicle crashes. Both case and control patients had epilepsy, drove, and were from the same clinic, but the cases differed from controls in having had seizure-related crashes. Fifty patients with epilepsy who crashed during seizures and 50 matched control patients were compared. Factors that significantly decreased the chances of patients with epilepsy having motor vehicle crashes due to seizures were: long seizure-free intervals, reliable auras, few prior non-seizure-related accidents, and having had their AEDs reduced or switched. The latter finding is explained by the authors as a consequence of an ambition to find better drug treatment. Patients who had a seizure-free interval 12 months had a 93% reduced chance of crashing compared to patients with shorter intervals.

An important factor is the risk of having a relapse after a given seizure-free interval. In meta-analysis of 16 prospective studies (Berg and Shinnar, 1991), the authors found a relapse rate of 40%, 1 year after a first seizure. The relapse rate after a first seizure with patients randomized to AEDs or no treatment (First Seizure Trial Group, 1993) was 55% by 2 years in the no-treatment group compared to 25% in the treatment group. A different angle was taken in the UK MRC withdrawal study (1991) in which the relapse rate was studied in 1013 epilepsy patients. The cohort was randomised to continuation of drug treatment or tapering off after at least 2 years of seizure freedom. After 1 year, 78% of the patients who continued medication were still seizure-free compared to 59% in the patients who had stopped their AED treatment. A subsequent study of 409 patients from this cohort who had had at least one recurring seizure (Chadwick et al., 1996) showed a further 1-year remission for 95% of the cohort in the 3 years after the initial seizure recurrence, and 90% of the cohort had experienced a 2-year remission after 5 years. There was no evidence of a difference in long-term outcome between the treatment and the withdrawal groups from the study from 1991. A reasonable conclusion from these two important studies is that, even in a successfully treated group of epilepsy patients, occasional seizures may recur with long intervals. Epileptiform discharges seen in the EEG and not accompanied by obvious clinical events are generally regarded as subclinical or interictal. However, in about 50% of patients who show discharges during psychological testing, brief episodes of impaired cognitive function are noted during such discharges (Binnie, 2003). The precise role of this phenomenon in road traffic safety is not known. 4.3. Prevention Current legislation in most countries permit people with epilepsy who have controlled seizures to obtain a driving licence. These laws attempt to balance the important economic and social value of driving with the risk to public safety from seizure-related crashes. Various clinical factors are considered in these laws, but the length of the prescribed seizure-free interval is the dominating factor. Driving restrictions vary

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considerably between countries and even between states in the US and states in the European Union (EU). The EU regulatory body prescribes observation of the progress of epilepsy and other disturbances of consciousness and states 2 years without seizures as an example for group 1 driving licences (motorcycles and private cars). Regarding group 2 driving licences (heavy trucks, buses and taxi) the directive is that driving licences shall not be issued or renewed for applicants suffering or liable to suffer from epileptic seizures or other sudden disturbances of consciousness (European Union Council Directive, 1991). EU members are currently involved in a process aiming at harmonisation of the member states’ national legislations. 4.4. Effectiveness of prevention In a US study (Berg et al., 2000), patients with refractory localization-related epilepsy were interviewed when they presented for epilepsy surgery evaluation. Of 367 eligible participants, 115 (31.3%) had driven in the last year, most on at least a weekly basis. In a multivariable analysis, factors associated with an increased likelihood of driving were having a current license (OR = 10.71, P < 0.001) and ever having had a license (OR = 3.86, P = 0.003). Younger individuals were also more likely to drive. Lower levels of driving were found in women (OR = 0.31, P < 0.001), individuals who were self-described as disabled (OR = 0.20, P < 0.001), and those who were employed full-time (OR = 0.43, P = 0.03) or part-time (OR = 0.15, P = 0.005). One hundred and forty-four individuals had experienced seizures while driving, and 98 at least one accident because of a seizure. Of those who had accidents, 94% reported property damage, 32% had an injury, and 20% caused injury to others. The authors conclude that, despite legal restrictions, almost one-third of individuals with refractory epilepsy drive. Drazkowski et al. (2003) performed a time trend study with analysis of motor vehicle crash reports in the state of Arizona 3 years before (1991–1993) and 3 years after (1994–1996) the required seizure-free interval was decreased from 12 to 3 months. The number of motor vehicle crashes related to seizures increased, but the difference was not found to be statistically significant. However, it is not clear whether driving habits changed when the law did.

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4.5. Conclusions: traffic accidents Despite the lack of population-based prospective data, there is strong evidence of an increase in RTA in people with epilepsy. The preventive measures in legislation, especially a prescribed seizure-free period before driving, is probably not observed by a substantial proportion of people with epilepsy, and the extent to which physicians report their patients with uncontrolled epilepsy to the authorities has not yet been elucidated.

5. General conclusions We have discussed three important aspects of medical risks that people with epilepsy may face. Although there are significant methodological problems, there are data to describe and to some extent quantify these risks. Thus, accidents and injuries are slightly more frequent among people with epilepsy than in the general population. The majority of accidents are trivial and occur at home. The most frequent injuries among patients with epilepsy are contusions, wounds, fractures, abrasions and brain concussions. Also, there is overwhelming evidence of an increase in traffic accidents involving people with epilepsy as drivers. Furthermore, mortality is two to three times higher among people with epilepsy compared with the general population. The underlying cause of the epilepsy is the main reason for the high mortality rate in population-based studies of new-onset cases, whereas seizure-related fatalities are much more important in chronic epilepsy. We have tried to put emphasis on causes that could potentially be prevented. Risk factors have been identified for such physical injuries, traffic accidents and death. This increased risk for injuries is most prevalent in a subgroup of patients with symptomatic epilepsy and frequent seizures, usually in combination with associated handicaps. Poor seizure control has also been identified as the strongest risk factor for SUDEP. Although it may seem obvious that intensified treatment aiming at early seizure control would reduce these seizure-related risks, appropriate studies providing definitive evidence are still lacking. Future large-scale intervention studies should therefore consider including outcome measures reflecting possible risk reduction along with

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the more conventional endpoints related to efficacy and tolerability.

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