Seizure-related Injury and Death

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1 Seizure-related Injury and Death Maromi Nei, MD, and Ritu Bagla, MD Corresponding author Maromi Nei, MD Jefferson Comprehensive Epilepsy Center, Department of Neurology, Jefferson Medical College, 900 Walnut Street, Suite 200, Philadelphia, PA 19107, USA. Current Neurology and Neuroscience Reports 2007, 7: Current Medicine Group LLC ISSN Copyright 2007 by Current Medicine Group LLC Epilepsy is associated with significantly increased morbidity and mortality from a variety of causes. Patients with epilepsy have approximately two to three times the risk of death from any cause compared with persons without epilepsy. Seizures may cause significant trauma, drowning, and accidental injury. Many of the deaths in persons with epilepsy are directly related to seizures, accidents and injuries arising from seizures, and the underlying condition resulting in seizures. This review focuses on recent data regarding seizure-related injury and mortality. Introduction Epilepsy affects 50 million people worldwide [1]. In the United States, the prevalence of active epilepsy is estimated as approximately 2.7 million. Patients with epilepsy have approximately two to three times the risk of death from any cause as compared with those individuals without epilepsy. Due to uncontrolled seizures, there is also an increased risk for seizure-related injury. These injuries are often burns, fractures, and soft tissue injury but may also include more severe injuries such as intracranial hemorrhages, spine fractures, and drowning. This review focuses on the mortality and injury associated with seizures, with particular emphasis on more recent studies in the field. Mortality Although overall mortality rates for patients with epilepsy are increased, the causes of death are numerous and include direct seizure-related causes, such as trauma and status epilepticus, as well as sudden unexplained death in epilepsy (SUDEP), suicide, and deaths related to complications of treatment for epilepsy. The mortality rate also varies from country to country, which is likely at least partially related to the availability of specific types of medical treatment available. According to the World Health Organization [1], 80% of individuals with epilepsy live in developing countries, where in some regions 80% to 90% of people receive no specific treatment for their epilepsy. Most deaths in patients with epilepsy are not related to the epilepsy or underlying cause of epilepsy [2]. Although it has been noted that deaths from any cause may be increased in persons with uncontrolled epilepsy, this review focuses specifically on the types of death and injury that are directly related to the condition of epilepsy. The mortality related to epilepsy is largely dependent upon the population of epilepsy patients that is studied. Lower rates of mortality are seen in well-controlled individuals as compared with uncontrolled individuals. Mortality is highly linked to the underlying etiology of epilepsy, as well as to seizure control. Overall mortality There is increased overall mortality from all causes in patients with epilepsy. In developed countries, the standardized mortality ratio (SMR) in patients with epilepsy is generally reported to be in the range of 1.6 to 4.1 [3,4]. This variability in SMR is related to differences between populations, including variable durations of patient follow-up and source differences. In developing countries as well, most studies report an increase in SMR, with generally higher rates than those noted in developed countries. There are often significant limitations in many of these studies because there are often source limitations for accurate data acquisition. In one prospective study from Ecuador [5], the SMR was 6.2. In a study in rural China, the SMR was 3.9 [6], with a particularly high SMR of 23.3 in the group 15 to 19 years of age. Of note, this study did exclude individuals with progressive neurologic disorders, learning disabilities, psychiatric disorders, and other medical problems, and thus likely underestimates the mortality rate in this population. Increased SMRs in other countries, ranging from 2.45 in Argentina [7] to 5.7 in Mali [5], have also been reported. The higher mortality in developing countries is likely related directly to decreased access to treatment. Mortality after a single seizure Mortality is increased after a first seizure, particularly during the first 2 years after the seizure occurs [8,9]. There are differences in SMRs for death, largely dependent upon

2 336 Epilepsy the underlying etiology for the seizure. Hauser et al. [8] reported an SMR of 2.3 (with half of the deaths occurring the first year) for those with a single unprovoked seizure in a population of children and adults in Rochester, MN. Loiseau et al. [10] reported an increased SMR during the first year after a single afebrile seizure in a pediatric and adult population. Mortality depended highly upon the seizure etiology. Patients with idiopathic or cryptogenic seizures were not at increased risk of death. However, for those with remote symptomatic seizures the SMR was 6.4, and in those with acute symptomatic seizures the SMR was The increased risk seen in these groups was largely related to the underlying pathology. Shinnar et al. [11] reported data from a cohort of 407 children followed for a mean of 14.2 years after a first unprovoked seizure. Of the nine children who died in follow-up, five died due to non seizure-related causes after having had no further seizures, and four died due to a possible or likely epilepsy-related cause. Most deaths occurred in patients with neurologic impairment. Only one of the probable seizurerelated deaths occurred in a neurologically normal patient with idiopathic epilepsy. Studies consistently find a close relationship between the severity of underlying etiology for the seizure and mortality. Age of epilepsy onset and etiology of epilepsy Younger age of epilepsy onset has generally been associated with increased risk for premature death. Berg et al. [12] found that children with age of epilepsy onset at less than 2 years were at significantly higher risk for death as compared with children older than 2 years of age at epilepsy onset. This risk appears to be closely related to the etiology of the epilepsy. Those with remote symptomatic etiology or epileptic encephalopathy in this cohort were both independently associated with an increased risk for death. This study supports earlier studies [13,14] that found the underlying etiology for the epilepsy appears to be more highly related to the increased risk of death rather than the seizures themselves. Camfield et al. [13] found that of 686 children evaluated over an average of 13 years, 26 patients had died. The majority (n = 22) of these deaths were likely related to the underlying severe neurologic disorder. They found that children with severe neurologic disorders were 22.2 times more likely to die than those who were neurologically normal. In only one of these 22 patients was the cause of death directly related to seizures (status epilepticus). Another two patients in this series had potentially seizure-related deaths (one suicide and one probable SUDEP). Similarly, Callenbach et al. [14] found that all nine of 472 children who died during the study period had symptomatic epilepsy and that their mortality risk was 22.9 times the expected rate of death. Children who are neurologically normal (or have idiopathic partial or generalized epilepsy) appear to be at lower risk of premature death [12,15]. In adults as well, the etiology for the epilepsy is highly linked to risk for mortality. Mohanraj et al. [16] reported significantly reduced survival in newly diagnosed adult epilepsy patients with symptomatic epilepsy as compared with those with idiopathic or cryptogenic epilepsy. Many of the deaths seen early after the diagnosis of epilepsy are related to the underlying etiology of the epilepsy; however, many of the later deaths are due to the consequences of uncontrolled seizures. In a mixed-age group (ages 5 to 69 years) of individuals with remote symptomatic epilepsy, the leading causes of death were seizures, aspiration pneumonia, and drowning [17], with an overall SMR for all causes of 4.0 as compared with the general population of California. The greatest excess of deaths was due to seizures, with an SMR of Because these data were obtained from a computer database, details were not available regarding how epilepsy caused deaths. Thus, many of these deaths, as well as those whose causes of death were not determined, may be related to SUDEP. This study again underscores the significant problem of increased mortality in individuals with symptomatic epilepsy. Mortality rate and epilepsy control Mortality is linked to epilepsy control, particularly in cases of SUDEP. Patients with refractory epilepsy are at higher risk for mortality, which is partly related to the association of uncontrolled seizures with the patient s underlying neurologic disorder, as seen in the case of children. Mohanraj et al. [16] found that in an adult epilepsy service population, increased mortality from all causes occurred in those who were not seizure free, with no increase in mortality in those who were seizure free. In case-control studies of SUDEP, the risk for SUDEP has been closely associated with seizure control [18,19 ]. With increased seizure frequency, the SUDEP rate increased significantly. Surgical data also support this finding. Seizure-freedom achieved by successful epilepsy surgery reduces the risk of mortality from all causes [20,21]. Specific Causes of Mortality and Morbidity Status epilepticus Most studies define status epilepticus as continuous seizure activity of at least 30 minutes in duration or repetitive seizures without return to baseline interictal neurologic status for at least 30 minutes. Status epilepticus continues to be associated with significant morbidity and mortality. A short-term mortality of 7% to 46% has been reported in adults, and an incidence between 9.9 and 41 per 100,000 people per year has been reported in developed countries [22]. Poor prognostic factors include older age and acute symptomatic etiology [23,24]. More recently, marked impairment of consciousness has also been shown to be independently predictive of poor outcome [25,26]. The aggressive treatment used in status epilepticus may

3 Seizure-related Injury and Death Nei and Bagla 337 also impact upon mortality. Electroencephalogram (EEG) data suggest a burst-suppression pattern after resolution of status epilepticus, and periodic lateralized epileptiform discharges (PLEDs) may be indicative of a poor prognosis [27,28]. Rosetti et al. [29] recently proposed clinical criteria to determine prognosis in status epilepticus. A score determined by age greater than or less than 65 years, presence or absence of acute symptomatic etiology, level of impairment of consciousness, and type of seizure was found to be highly predictive of mortality in their retrospective analysis. In children, status epilepticus has an estimated incidence of 17 to 23 per 100,000 people per year [30 ]. In a recent review of pediatric convulsive status epilepticus, short-term mortality was 2.7% to 5.2%, and morbidity, other than epilepsy, was less than 15% [31]. Higher mortality was associated with a younger age and acute symptomatic etiology. There are few studies evaluating nonconvulsive status epilepticus in children. Tay et al. [32] reported 26% mortality in a retrospective study of 19 patients with nonconvulsive status epilepticus between the ages of 1 month and 17 years. Mortality was due to the underlying acute symptomatic etiology in these patients, and, as seen in adults, PLEDs on the EEG were associated with increased risk of mortality. SUDEP SUDEP is a major cause of mortality in patients with epilepsy, accounting for approximately 1% to 17% of deaths. Studies use various definitions for SUDEP, which may impact upon the differences in incidence seen. The incidence of SUDEP varies greatly depending on the population that is studied. Risk factors for SUDEP include having refractory epilepsy, generalized tonic-clonic seizures, mental retardation, low antiepileptic drug (AED) levels, young age (20 40 years), and AED polytherapy. Patients often die in their sleep and may be found in the prone position. Rates are lowest in population-based studies, in mixed groups of patients of varying seizure control, and in children. The etiology for SUDEP is still uncertain, but accumulating data suggest that respiratory and/or cardiac dysfunction contributes. A seizure just prior to death is also commonly reported in witnessed cases and may trigger acute cardiopulmonary dysfunction resulting in death. So et al. [33] reported a case of near SUDEP in which a patient had a postictal apnea and responded to cardiopulmonary resuscitation. Stimulation at the time of seizures might reduce risk for SUDEP, possibly by preventing respiratory compromise associated with the seizures [19,34]. Recent animal data also reveal intriguing evidence that oxygenation can prevent sudden death in a strain of seizure-prone mice that generally demonstrate respiratory arrest after audiogenic seizures [35]. In a subsequent study in the same mice strain, a serotonin reuptake inhibitor reduced respiratory arrest at doses that did not reduce seizure severity [36]. This was thought to be due to the ability of serotonin to modulate respiratory mechanisms. Additional investigation will be needed to assess whether such data may be pertinent to humans. Patients with epilepsy also have increased cardiac autonomic dysfunction [37] that may result in an increased risk of sudden cardiac death. In patients who subsequently died due to SUDEP, inpatient video-eeg/ electrocardiogram (ECG) recordings have not revealed any specific interictal cardiac abnormalities to suggest that these individuals who have died due to SUDEP have underlying cardiac arrhythmias that contribute to death [38]. However, these data did reveal that heart rate increases associated with seizures were greater, particularly in sleep and during seizure clusters, in the SUDEP patients as compared with a general refractory localization-related epilepsy control population, suggesting that excessive autonomic stimulation associated with seizures may be involved in the mechanism of death in SUDEP. Long-term cardiac data in patients with refractory partial seizures revealed that seven of 19 patients had ictal bradycardia and/or asystole, resulting in pacemaker placement in four individuals [39 ]. However, at this time the clinical utility of pacemakers in the potential prevention of SUDEP is unknown and needs to be evaluated with larger studies. Although cardiac asystole may be directly a result of the seizure itself, it is possible that the asystole may be a secondary event following an initial respiratory trigger [40]. Multiple factors might have an additive effect on an individual s risk for asystole and other cardiac arrhythmias. Obstructive sleep apnea may also cause sinus arrest and has been linked to an increased risk for sudden cardiac death, particularly in sleep [41], as seen in SUDEP. Of note, early morning bradycardia unassociated with a seizure was noted in three of 19 patients in the Rugg- Gunn et al. study [39 ] and early morning asystole in one of 14 patients with refractory epilepsy in another study [42]. It is possible that the combined effects of epilepsy and sleep-related cardiac changes may have an additive effect in affecting cardiac rhythm. Such a process could potentially account for the increased SUDEP occurring in sleep. Additional investigation is needed in this area to determine the relationship between cardiac and respiratory abnormalities, as well as the possible effect that sleep and sleep disorders may have on cardiac and respiratory function in patients with epilepsy. Data have also emerged recently regarding the possible effect of specific anticonvulsant medications on the risk for SUDEP and for cardiac arrhythmias. A higher percentage of SUDEP victims were taking carbamazepine as compared with a control epilepsy population, suggesting that carbamazepine might increase risk for SUDEP [43,44]. Cardiac autonomic data also suggest that carbamazepine might alter autonomic function [45]. However, additional investigation is needed to further evaluate the clinical significance of these findings.

4 338 Epilepsy Suicide Risk for suicide appears to be elevated in persons with epilepsy. Most studies report that approximately 5% to 7% of deaths in people with epilepsy are due to suicides, although the reported rates vary widely. A recent meta-analysis study by Pompili et al. [46] suggests that suicide rates in persons with epilepsy may be significantly underestimated in the literature. A history of psychiatric illness, early onset of epilepsy (especially during adolescence), and inadequate neurologic follow-up are often reported in individuals with epilepsy who commit suicide [47]. Recently, Nilsson et al. [48] performed a case-control study evaluating for specific risk factors for suicide. They evaluated 26 cases of suicide and 23 cases of suspected suicide in persons with epilepsy with 171 control patients with epilepsy and found that there was a ninefold increase in risk of suicide with mental illness and 10-fold relative risk with the use of antipsychotic drugs. Onset of epilepsy at age before 18 years was associated with a relative risk of suicide of 16. They found no association between risk of suicide and any specific type of epilepsy or localization or lateralization of epileptogenic focus. In contrast, Fukuchi et al. [49] found in their casecontrolled study of 43 cases of death in epilepsy (including six suicides) compared with 1722 epilepsy control patients that temporal lobe epilepsy was significantly associated with increased risk for suicide. Additionally, they found that a history of psychotic episodes was also more frequently found in suicide cases than in the controls, and that half of the cases of suicide occurred in the midst of an episode of postictal psychosis. Seizure-related injury and accident-related mortality Patients with epilepsy have an increased risk of accidental injury and morbidity than the general population. This is often the direct result of a seizure from a fall or other comorbid condition, such as learning disabilities or psychiatric disorders, which may increase risk for injury. As a consequence, patients with epilepsy are often subject to restrictions of daily activities, which could also cause impaired social interaction and lead to significant emotional distress. There are conflicting results regarding the risk of accidents in patients with epilepsy. As seen in the mortality data, the rates of injury published are highly dependent upon the population studied, with higher rates of injury found in multi-handicapped patients as well as patients evaluated in the emergency department, and lower rates found in population studies. Risk factors for seizurerelated injuries include a seizure frequency of greater than once per month, generalized tonic-clonic, atonic, and myoclonic seizures, and unsteadiness from AED side effects. In a prospective European cohort study by Beghi and Cornaggia [50] of 951 children and adults with idiopathic, cryptogenic, or remote symptomatic epilepsy and 909 age- and sex-matched controls, patients with epilepsy had a significantly higher probability of having an accident compared with controls. Seventeen percent and 27% of patients (and 12% and 17% of controls; P < ) had accidents by 1 and 2 years, respectively. Among the patients with epilepsy, 24% of accidents were seizure related. When these events were excluded, the risk of injury was significantly reduced and similar to matched controls. Most accidental injuries were minor, but concussions and abrasions were significantly higher in patients compared with controls. In another population-based study of 247 patients with epilepsy, 16% (equivalent to one injury in 44 person-years) of the cohort had seizure-related injuries [51]. In the emergency room setting, injuries were reported in 13.8% of seizures [52]. In general, most seizure-related injuries are minor, with head trauma being the most common type of injury, the majority occurring during convulsive seizures. About 1% to 12% of deaths in patients with epilepsy may be due to accidents [4]. Based on visits to emergency rooms, the incidence of seizure-related injury is estimated at 29.5 per 100,000 per year [52]. Individuals with remote symptomatic epilepsy from developmental disabilities or identified brain lesions had an increased risk of death, with drowning being the most common accidental cause of death [17]. These usually occur while bathing or swimming without direct supervision. Maintaining adequate precautionary measures, including swimming only when supervised by qualified personnel, is important in preventing these deaths. Fractures Several retrospective studies have found a nearly twofold increased risk of fractures in patients with epilepsy, particularly for hip and femur fractures. Risk factors for injury include age over 45 years, recent diagnosis of epilepsy, poor control of generalized tonic-clonic seizures, and possibly AED polytherapy [53]. The increased risk of fractures may also partially be due to clumsiness related to AED usage and AED-related reduction in bone mineral density [54]. Souverein et al. [55 ] evaluated the risk of fracture in 1018 patients with epilepsy and 1842 matched controls. The risk for fractures was higher in epilepsy patients and women, and increased with cumulative duration of AED usage, particularly for more than 12 years of use. Contrary to prior studies, they did not find an increased risk for fractures with cytochrome P450 enzyme-inducing AEDs compared with non-enzyme inducers. A recent retrospective study found that patients with refractory epilepsy were 30 to 40 times more likely to suffer a cervical spinal cord injury after a seizure-related fall than in the normal population [56]. Contrary to retrospective studies, the study by Beghi and Cornaggia [50] found no increased risk of fractures in persons with epilepsy (3% vs 2% in patients with epilepsy and controls, respectively), although fractures did account for 11% of accidents in the epilepsy cohort. Additional long-term prospective studies may further help to define the risk

5 Seizure-related Injury and Death Nei and Bagla 339 and identify specific contributing risk factors for fractures over time in persons with epilepsy. Head trauma Most seizure-related head traumas are minor; however, prior studies suggest that seizures may increase the severity of head injury, increase mortality, and account for 1.7% to 3.8% of inpatient head trauma admissions. More recently, Neidlinger et al. [57] found that 10% of patients with epilepsy and a seizure-related head injury and Glascow Coma Scale score of 15 had an acute intracranial hemorrhage or skull fracture on head CT, revealing that even a normal neurologic examination in this situation is not predictive of a negative CT scan. In a prospective study over a 12-month period of 255 resident patients with chronic long-term epilepsy, 45.2% of 27,934 seizures were associated with falls, causing 766 head injuries [58]. Thus, 2.7% of all seizures resulted in head injury, of which 422 were minor, 341 required sutures, and three were more serious and included a skull fracture and intracranial hematoma. Beghi et al. [50] found that most injuries were minor, with concussion occurring in 2% of the cohort as compared with 1% of the control group (P < 0.05). As with other injuries, the risk of head trauma is increased with generalized tonic-clonic seizures. Burns In the study by Beghi and Cornaggia [50], patients with epilepsy did not have a significantly greater risk of burns. In a questionnaire-based study, 10.2% of 244 patients with epilepsy reported a seizure-related burn severe enough to require medical attention [59]. The major risk factor for burns is the total number of seizures. Burns were more likely in patients with more seizures and in those individuals with interictal neurologic impairment. In a retrospective study of 4690 inpatient and 2250 outpatient admissions to a regional burn unit, 111 burns were secondary to a seizure [60]. Most were due to scald injuries and contact burns and were relatively small, with a mean percentage of total body surface area burn of 2.2%, but most (65%) required surgery. Jang et al. [61] found that 39 of 9522 burns in a burn unit were seizure-related in a Korean population, and scald injuries were again most common. The median total body surface area burn was 6%, resulting in a median hospital length of 38 days. Improved safety measures, including use of fire and radiator guards, flame-retardant clothing, shower thermostats, self-sealing deep fryers, insulated kettles, anti-spill mugs, and cooker guards can help prevent burns. As in other types of injuries, degree of seizure control is likely the most important factor in determining burn risk. Driving-related injury There is strong evidence from retrospective studies that patients with epilepsy have a higher risk of motor vehicle accidents compared with the general population. In a retrospective study of 159 persons with epilepsy and 559 controls matched for age, gender, place of residence, and exposure period in Denmark, drivers with epilepsy were seven times more likely than a healthy control to be treated at a casualty department after a motor vehicle accident [62]. In a large epidemiologic study of driving fatalities, seizure-related fatalities were rare, accounting for 0.2% of the total annual driving fatalities from 1995 to 1997 in the United States, but drivers with epilepsy had an increased risk of fatal crashes [63]. Factors that significantly correlated with lower rates of crashes include longer period of seizure freedom, reliable auras with every seizure, and a history of fewer total non seizure-related accidents in the past [64]. Patients who had a seizure-free interval of 12 months had a 93% reduced chance of a motor vehicle accident compared with patients with shorter intervals of seizure freedom. Over half of the patients who crashed were driving illegally. Of concern is the finding that nearly one third of patients with refractory partial epilepsy presenting for surgical evaluation in one multicenter study were driving, with 26% reporting at least one accident due to a seizure [65]. Conclusions Seizure-related injury and death are closely linked to the severity of the underlying neurologic disorder and severity of epilepsy. Acute symptomatic etiologies for epilepsy and severe underlying neurologic impairment account for most early deaths related to seizures and epilepsy. Seizure severity accounts for many of the later deaths associated with epilepsy. Most people with epilepsy do not die due to a seizure-related etiology, and those with well-controlled seizures and an idiopathic or cryptogenic etiology are at relatively low risk for mortality and injury. In addition to aggressive seizure control and minimizing drug-related side effects, supervision when swimming and bathing, protective measures, and measures to maintain bone health may help reduce risk for injuries. Rates for injury and mortality vary widely depending on the source population. Additional large-scale and longer-duration prospective studies with improved methods of case ascertainment are needed in different populations to determine accurate data regarding specific risk factors. Additional studies are also needed to identify specific effective preventive measures that may reduce risk for injury and death. SUDEP is a major cause of mortality, and although specific risk factors have been identified, additional data are needed to determine its potential causes. Accumulating data suggest that there may be a cardiac and/or respiratory etiology. Additional data regarding the effects of specific AEDs and multidisciplinary data assessing simultaneous neurologic, cardiac, and pulmonary function are needed as well. At this time, the best method to prevent SUDEP

6 340 Epilepsy and other seizure-related injuries and death appears to be improved seizure control with a minimum of side effects. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Epilepsy Atlas. Geneva, Switzerland: World Health Organization; Lhatoo SD, Sander JW: Cause-specific mortality in epilepsy. Epilepsia 2005, 46: Shackleton DP, Westendorp RG, Kasteleinj-Noist Trenite DG, et al.: Survival of patients with epilepsy: an estimate of the mortality risk. Epilepsia 2002, 43: Forsgren L, Hauser WA, Olafsson E, et al.: Mortality of epilepsy in developed countries: a review. Epilepsia 2005, 46: Carpio A, Bharucha NE, Jallon P, et al.: Mortality of epilepsy in developing countries. Epilepsia 2005, 46: Ding D, Want W, Wu J, et al.: Premature mortality in people with epilepsy in rural China. Lancet Neurol 2006, 5: Kochen S, Melcon MO: Prognosis of epilepsy in a community-based study: 8 years of follow-up in an Argentine community. Acta Neurol Scand 2005, 112: Hauser WA, Annegers JF, Elveback LR: Mortality in patients with epilepsy. Epilepsia 1980, 21: Lindsten H, Nystrom L, Forsgren L: Mortality risk in an adult cohort with newly diagnosed unprovoked epileptic seizure. A population-based study. Epilepsia 2000, 41: Loiseau J, Picot MC, Loiseau P: Short-term mortality after a first epileptic seizure: A population-based study. Epilepsia 1999, 40: Shinnar S, O Dell C, Berg AT: Mortality following a first unprovoked seizure in children: a prospective study. Neurology 2005, 64: Berg AT, Shinnar S, Testa FM, et al.: Mortality in childhood-onset epilepsy. Arch Pediatr Adolesc Med 2004, 158: Camfield CS, Camfield PR, Veugelers PJ: Death in children with epilepsy: a population-based study. Lancet 2002, 359: Callenbach PM, Westendorp RG, Geerts AT, et al.: Mortality risk in children with epilepsy: the Dutch study of epilepsy in childhood. Pediatrics 2001, 107: Sillanpaa M, Jalava M, Kaleva O, Shinnar S: Long-term prognosis of seizures with onset in childhood. N Engl J Med 1998, 338: Mohanraj R, Norrie R, Stephen LJ, et al.: Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study. Lancet Neurol 2006, 5: Day, SM, Wu YW, Strauss DJ, et al.: Causes of death in remote symptomatic epilepsy. Neurology 2005, 65: Nilsson L, Farahmand BY, Persson PG, et al.: Risk factors for sudden unexpected death in epilepsy: a case-control study. Lancet 1999, 353: Langan Y, Nashef L, Sander JW: Case-control study of SUDEP. Neurology 2005, 64: This study evaluated 154 cases of SUDEP and compared clinical factors with four controls per case. The risk of SUDEP was found to be elevated when there was a history of a generalized tonic-clonic seizure during the preceding 3 months, suggesting that SUDEP is a seizure-related phenomenon and that seizure control is important in reducing risk for SUDEP. Additionally, nocturnal supervision appeared to protect against SUDEP. 20. Sperling MR, Feldman H, Kinman J, et al.: Seizure control and mortality in epilepsy Ann Neurol 1999, Hennessy MJ, Langan Y, Elwes RD, et al.: A study of mortality after temporal lobe epilepsy surgery. Neurology 1999, 53: Logroscino G, Hesdorffer DC, Cascino G, et al.: Mortality after a first episode of status epilepticus in the United States and Europe. Epilepsia 2005, 46: Logroscino G, Hesdorffer DC, Cascino GD, et al.: Shortterm mortality after a first episode of status epilepticus. Epilepsia 1997, 38: Towne AR, Pellock JM, Ko D, De Lorenzo RJ: Determinants of mortality in status epilepticus. Epilepsia 1994, 35: Shneker B, Fountain NB: Assessment of acute morbidity and mortality in nonconvulsive status epilepticus. Neurology 2003, 61: Rossetti AO, Hurwitz R, Logroscino G, Bromfield EB: Prognosis of status epilepticus: role of aetiology, age, and consciousness impairment at presentation. J Neurol Neurosug Psychiatry 2006, 77: Jaitly R, Sgro JA, Towne AR, et al.: Prognostic value of EEG monitoring after status epilepticus: A prospective adult study. J Clin Neurophysiol 1997, 14: Nei M, Lee J, Shanker VL, Sperling MR: The EEG and prognosis in status epilepticus. Epilepsia 1999, 40: Rosetti AO, Logroscino G, Bromfield EB: A clinical score for prognosis of status epilepticus in adults. Neurology 2006, 66: Chin RF, Neville BG, Peckham C, et al.: Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006, 368: This prospective study is one of a few evaluating exclusively pediatric convulsive status epilepticus. The mortality (3%) was lower than that seen in the adult population, and the causes of status epilepticus, most commonly prolonged febrile convulsions, are very different from those seen in adults. 31. Raspall-Chaure M, Chin RF, Neville BG, Scott RC: Outcome of paediatric convulsive status epilepticus: a systematic review. Lancet Neurol 2006, 5: Tay SK, Hirsch LJ, Leary L, et al.: Nonconvulsive status epilepticus in children: clinical and EEG characteristics. Epilepsia 2006, 47: So EL, Sam MC, Lagerlund TL: Postictal central apnea as a cause of SUDEP: evidence from near-sudep incident. Epilepsia 2000, 41: Nashef L, Fish DR, Garner S, et al.: Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995, 36: Venit EL, Shepard BD, Seyfried TN: Oxygenation prevents sudden death in seizure-prone mice. 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