Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 6
Risk Factors
Dale C. Hesdorffer
Introduction
Well-established risk factors for unprovoked seizures include head trauma, central nervous system (CNS) infection, Alzheimer disease, clinically detected stroke, febrile seizures, cerebral palsy, and mental retardation. Each of these increases the risk for unprovoked seizures at least 10-fold. Several other risk factors for unprovoked seizures are less well described; these include consumption of alcohol, use of heroin or marijuana, low socioeconomic status, attention deficit hyperactivity disorder, major depression, multiple sclerosis, dementia other than Alzheimer disease, and risk factors for stroke in the absence of clinically detected stroke. Additionally, current diuretic use has been shown to protect against the development of a first unprovoked seizure.
Epidemiologic Study Designs
Epidemiologic studies of risk factors for epilepsy or unprovoked seizures employ one of three study designs: Case control, retrospective cohort, or prospective cohort. These study designs are reviewed briefly before the discussion of risk factors for epilepsy in children and adults.
In case-control studies, potential predisposing factors are compared between patients with epilepsy and control patients without epilepsy. The odds ratio (OR) derived from these studies indicates the extent to which a given factor increases or decreases the risk for epilepsy. Case-control studies are best done with new-onset cases of epilepsy; identification of factors preceding the occurrence of seizures that might increase the risk for developing seizures supersedes investigation of factors that are a consequence of seizures. Population-based case-control studies have advantages over hospital-based studies because they include all cases of epilepsy in a population rather than the select group of patients who seek care at a particular hospital.
Both retrospective and prospective cohort studies begin with people who do not have epilepsy. These people are categorized according to whether or not they were exposed to a factor thought to predispose to epilepsy. Exposed and unexposed people are then followed chronologically to determine risk for epilepsy among people exposed to the predisposing factor relative to the risk among unexposed people. The measure that quantifies this risk is called the relative risk (the risk for disease in exposed subjects compared with the risk for disease in unexposed subjects).
The stronger the association is between a risk factor and a disease, the less likely the association can be explained by another, potentially confounding, factor. For example, it is harder to explain away a relative risk or of 10 than of 2. Associations of 10 or greater are strong enough to be considered clinically detectable by most physicians who see patients with epilepsy. Examples of these include, but are not limited to, head injury and clinically detected stroke.
Risk Factors for Childhood Epilepsy
The risk factors for childhood epilepsy are different from those for epilepsy later in life.1 Inherited epilepsy is discussed elsewhere (see Chapters 15,16,17,18,19); consequently, this discussion is limited to nongenetic factors. The risk for epilepsy beginning in childhood is increased by febrile seizures, head trauma, CNS infection, mental retardation, cerebral palsy, and attention deficit hyperactivity disorder. Age itself seems to be a risk factor independent of other factors.23 Adverse events during the prenatal and perinatal period do not influence seizure risk when children with mental retardation and cerebral palsy are excluded. Pertussis vaccination does not appear to alter the risk for unprovoked seizures; nor does low socioeconomic status.
Febrile Seizures
Febrile seizures can be regarded as distinct from childhood epilepsy (Chapter 57). Berg9 summarizes the epidemiologic evidence for this assertion as follows: The risk of recurrent febrile seizures is far greater than the risk of unprovoked seizures after a febrile seizure; and risk factors for recurrent febrile seizures differ from risk factors for subsequent unprovoked seizures. Large cohort studies demonstrate that following a first febrile seizure, 2% to 4% of children experience a subsequent unprovoked seizure,6,52,76 a risk four times the risk for unprovoked seizure in the general population. The increased risk for unprovoked seizures after febrile seizure is substantially greater among children with neurologic abnormalities present from birth than among children without such abnormalities. For most children with febrile seizures (i.e., those with simple febrile seizures), the risk of unprovoked seizure is only increased slightly.
Risk factors for unprovoked seizures following a first febrile seizure include a family history of epilepsy, complex features of the febrile seizure (i.e., multiple or focal and lasting longer than 15 minutes), and the presence of neurodevelopmental abnormalities present from birth.6,10,52,76 Increasing duration of fever prior to the first febrile seizure and high temperature are associated with a reduced risk of developing subsequent unprovoked seizures,10 suggesting that some children may have a low overall seizure threshold.
The type of febrile seizure influences the type of unprovoked seizure that may develop.6,47 Repeated simple febrile seizures increase the risk for generalized-onset unprovoked seizures. Additionally, there is an association between complex febrile seizures and partial-onset unprovoked seizures. The suggestion of an underlying brain pathology common to both complex febrile seizure and partial-onset unprovoked seizure has led to the question of whether some febrile seizures lead to the development of mesial temporal sclerosis and subsequent intractable temporal lobe epilepsy. One study of 107 patients with drug-resistant epilepsy46 showed that 45 (42%) had
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focal or diffuse hippocampal volume loss on high-resolution volumetric magnetic resonance imaging (MRI) and most of these had a history of febrile seizures during childhood. If febrile seizures do predispose to some cases of hippocampal sclerosis, this cannot be the only mechanism involved, as 64% of the patients46 with hippocampal volume loss had no history of febrile seizures. Further insight into this potential association comes from a prospective study75 in which MRI examinations were performed within days of a prolonged febrile seizure. Among 15 children with focal prolonged febrile seizures, two had chronic hippocampal abnormalities and four had increased T2-weighted signal intensity and increased hippocampal volume associated with a mean seizure duration of 41 minutes: Two of the four with acute injury developed hippocampal atrophy on the follow-up MRI. In contrast, none of the 12 children with generalized prolonged febrile seizures had a definite abnormality on MRI. These data suggest that extremely prolonged focal febrile seizures can cause acute hippocampal injury, leading to later atrophy. Still unanswered is whether or not this atrophy is associated with the development of temporal lobe epilepsy.
Prenatal and Perinatal Risk Factors
Prenatal and perinatal adverse events do not appear to be associated with the occurrence of childhood epilepsy when children with cerebral palsy and mental retardation are excluded. In an early case-control study,15 100 children with epilepsy born in four hospitals in a large town in Germany were compared with 100 healthy children of the same age who had been born “at virtually the same time.” The study indicates that higher age of the mother at birth, toxemia of pregnancy, premature birth, and heavy birth weight were associated with later epilepsy; many other factors were not. This study had methodologic weaknesses: Medical records were reviewed retrospectively, a select group of patients was studied, and children with cerebral palsy and mental retardation were included. It is therefore interesting to compare the results with other, better designed studies.
In a review of large studies of defined populations, including the National Collaborative Perinatal Project (NCPP) cohort, Nelson and Ellenberg53 concluded that among the hundreds of prenatal and perinatal factors studied, the main predictors of childhood seizure disorders were congenital malformations of the fetus (cerebral and noncerebral), family history of certain neurologic disorders, and neonatal seizures. In agreement with the British National Child Development Study,67 labor and delivery factors in the NCPP did not appear to contribute to childhood seizure disorders. It seems that maldevelopment, rather than damage at birth to an intact nervous system, is the more common mechanism. In a prospective 1-year birth cohort study performed in northern Finland61 that included 12,058 children, 208 had epilepsy. Of these children, 8.7% had a prenatal risk factor, 18.2% a perinatal risk factor, 15.9% a postnatal risk factor, and 57.2% no identifiable risk factor. This study included seizures in the neonatal period; some cohort studies, such as the British Child Health and Education Study (CHES),77 have not included neonatal seizures.
Postnatal Causes
The British CHES cohort77 has demonstrated that the causes of epilepsy in children, when known or suspected, are heterogeneous. No single cause predominates.
Traumatic Brain Injury
Jennett42 found that the incidence of posttraumatic epilepsy in children was not markedly different from that in adults (Chapter 253). The risk for later epilepsy after depressed fractures ranged from <30% to 70%. Jennett also drew attention to “early” epilepsy after head injury; in about 5% of all patients admitted to the hospital, seizures occurred within a week of the head injury. The incidence in children <5 years of age was almost double this. First-week seizures were quite distinct, occurring 30 times more frequently in the first week than the average of any of the 7 succeeding weeks. Fewer than a third of the patients with one or more seizures in the first week had any further epilepsy in the next 4 years.
Vaccination
It is unlikely that a relationship exists between vaccination, in particular pertussis immunization, and serious acute neurologic illness in children2; however, diphtheria-tetanus-pertussis (DPT) vaccination appears to increase the risk for fever, resulting in an earlier onset of febrile seizures among children predisposed to such seizures.37,70 The possibility of an association between DPT vaccination and afebrile seizures was addressed in Great Britain by the National Childhood Encephalopathy Study.50 In a review of the relationship between pertussis immunization and seizures,8 Bellman suggested that pertussis vaccination was not associated with a convulsive disorder and instead might act as a nonspecific trigger for the onset of symptoms in children who were already predisposed to the development of infantile spasms. The one study to address this question20 found no statistically significant increased risk in young children for any type of afebrile seizure in the 7 days after DPT vaccine exposure. Thus, it appears that the only adverse neurologic consequence significantly associated with DPT vaccination is febrile seizure in children who are already predisposed to such seizures.
Attention Deficit Hyperactivity Disorder
Clinically, there is a perception that attention deficit hyperactivity disorder (ADHD) is more common among children with epilepsy, due to the seizure disorder or its treatment.7,16 When time order is examined, ADHD is associated with increased risk for developing epilepsy. This has been shown in case-control studies of children with epilepsy7,16,34 and in cohort studies of select populations of children with ADHD.28,40,41,79 In two prior case-control studies of children with incident unprovoked seizure,7,16 behavioral disturbances before the onset of first seizure were more frequent than among controls. In one study of 148 children with first unprovoked seizure and 89 seizure-free sibling controls, attention problems as assessed by the Child Behavior Checklist were 2.4-fold more common prior to identification of the first seizure (8.1%) than in controls (3.4%).7 In a population-based case-control study conducted among Icelandic children,34 children with incident unprovoked seizure were 2.5-fold more likely than age- and gender-matched controls to have a history of ADHD (95% confidence interval [CI] = 1.1 to 5.5), meeting Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria prior to seizure onset. The association was restricted to ADHD-predominantly inattentive type (OR = 3.7; 95% CI = 1.1 to 13). When the occurrence of new-onset seizures is examined in selected samples with ADHD,28,40,41,79 the percentage of children who develop unprovoked seizures (0.2% to 2%) is greater than the expected rate, because the average annual incidence of seizures is approximately 0.0470 per year in children aged 5 to 16 years.24 Thus, there is an increased risk for developing seizures in children with ADHD, and the reported increased risk is smaller in case-control studies than in cohort studies, which were limited by small numbers of ensuing unprovoked seizures during short follow-up periods in selected populations. This is consistent
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with the 23.1% prevalence of learning disorders reported in an unselected sample of children in Finland.72
Other Neurologic Problems
Mental retardation and cerebral palsy both predispose to the development of epilepsy (see Chapter 263). In a cohort of 221 children identified with mental retardation and born between 1951 and 1955 in Aberdeen, Scotland,21 the cumulative risk for epilepsy was 15% by 22 years of age. In children with mental retardation and no associated disabilities, the cumulative risk at 22 years of age was 5%; in those with mental retardation and cerebral palsy, it was 38%; and in those with a postnatal injury associated with mental retardation, cumulative risk 15 years after the injury was 66%. Interestingly, epilepsy often remitted in mentally retarded individuals. In Rochester, Minnesota, neurologic deficits from birth, mental retardation, and/or cerebral palsy were important antecedents of epilepsy.24 Thus, in the absence of associated disability or postnatal injury, the incidence of epilepsy in those with mental retardation alone was more than three times that of the general population of Rochester, Minnesota. Additionally, there appears to be an interaction between mental retardation and cerebral palsy on the risk for epilepsy.
Association of Different Risk Factors with Different Types of Epilepsy
Most published works examine risk factors for epilepsy as if epilepsy were a single condition rather than a heterogeneous group of seizure types and syndromes. Rocca et al.63,64,65 addressed this issue in several articles, using the Rochester data to identify risk factors for different types of epilepsy. The risk for absence seizures was significantly increased by a history of febrile convulsions.63 For generalized tonic–clonic seizures, the following were significantly more common in cases than controls: A history of epilepsy or febrile seizures in the mother, febrile convulsions, and a history of head trauma.64 For complex partial seizures, the following were significantly more common in cases than controls: A history of epilepsy or febrile convulsions in the mother, febrile convulsions, neonatal convulsions, cerebral palsy, head trauma, and viral encephalitis.65 This work emphasizes the importance of accurately identifying seizure types and epilepsy syndromes when considering etiology.
Risk Factors for Epilepsy in Adults
There are several established risk factors for epilepsy in adults: Head trauma, CNS infections, CNS malignancies, occlusive cerebrovascular disease, and Alzheimer disease (Fig. 1). Several other factors have been associated with epilepsy but await confirmation in future studies. These potential risk factors include multiple sclerosis, hypertension, left ventricular hypertrophy, risk factors for embolic stroke, dementia other than Alzheimer disease, major depression, alcohol abuse, use of illicit drugs, and low socioeconomic status (Fig. 1). Acute symptomatic seizures also appear to increase the risk for subsequent epilepsy. There is evidence that diuretic therapy may be protective for the development of epilepsy.
Head Injury
Head injury increases the risk for later unprovoked seizure, with the greatest risk occurring among survivors of severe injury (Chapter 253). Analogous to seizures after penetrating head injuries, unprovoked seizures may be a consequence of neurosurgical procedures to the head.
In a study of Vietnam veterans who survived penetrating head wounds caused by missile injury, risk for remote symptomatic seizures increased 580-fold during the first 12 months after the injury and 25-fold after 10 to 15 years.11,68 Among those veterans with epilepsy, persistence of epilepsy was associated with features related to the wound and not to functional consequences of the injury.
Penetrating head injuries sustained during war are more severe than all but 17% of cases of head trauma accompanied by loss of consciousness or posttraumatic amnesia in nonmilitary populations.3 In civilian populations, case-control studies64,65 and retrospective cohort studies3 report an increased risk for unprovoked seizure after head trauma. In a retrospective cohort study from Rochester, Minnesota, that excluded people with seizures before head injury, the increased risk for subsequent unprovoked seizure was related to the severity of the injury.3 Among residents of Rochester with mild injury, defined as unconsciousness or posttraumatic amnesia of less than 30 minutes’ duration, risk for unprovoked seizure was increased 1.5-fold, which was not statistically significant. The risk for unprovoked seizure was increased fourfold for residents with moderate injury, defined as skull fracture or 30 minutes to 24 hours of unconsciousness or posttraumatic amnesia. Similar to the risk for seizures among Vietnam veterans 10 to 15 years after head injury, the risk for unprovoked seizure was increased 29-fold after severe injury, defined as more than 24 hours of unconsciousness or posttraumatic amnesia, brain contusion, or intracerebral hematoma. Severity of head injury may be a proxy for the amount of permanent epileptogenic damage inflicted by the injury.
Studies of unprovoked seizures after neurosurgery are complicated by the nature of the underlying disease, the presence of seizures before surgery, and the select nature of the populations studied. In one study, the risk for unprovoked seizures after surgery increased with increasing severity of preoperative neurologic deficit,43 providing evidence that preoperative neurologic function alters postoperative seizure risk. Data also suggest an increased risk for seizure from the neurosurgical procedure itself. Using life table methodology18 to study 877 consecutive neurosurgical patients, unprovoked seizures developed in 17% within 5 years of surgery. This cumulative incidence far exceeds the risk for seizures in the general population.24 Further large and carefully designed studies are needed to untangle the effects of preoperative conditions and neurosurgical procedures in increasing the risk for seizures.
FIGURE 1. Risk factors for seizures in adults.
Central Nervous System Infection
Infections of the CNS—encephalitis and meningitis—are associated with an increased risk for subsequent unprovoked seizures. Among children with complex partial seizures, there is a 31-fold increased risk associated with viral encephalitis.65 In a retrospective cohort study from Rochester, Minnesota, that followed people of all ages for the development of unprovoked seizure, CNS infections increased seizure risk 11-fold.4 The risk for seizures varied by type of CNS infection. A 16-fold increased risk was associated with encephalitis, a fourfold increased risk with bacterial meningitis, and a twofold increased risk with aseptic meningitis. Almost all unprovoked seizures occurred during the first 5 years after infection (see Chapter 265 for further discussion).
Central Nervous System Malignancies
Case series have been used to evaluate the risk for epilepsy among patients with brain tumors or the prevalence of brain
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tumors in newly diagnosed cases of epilepsy. Series of the former type report that 28% of patients undergoing surgery for brain tumors have seizures,18,19 a risk far exceeding the incidence in Rochester, Minnesota.24 Series of the latter type reveal that 12% to 16.3% of adults with newly diagnosed epilepsy have brain tumors13,49,62; indeed, seizures are often the first sign of brain tumors (see Chapter 264 for further discussion).
Occlusive Cerebrovascular Disease
A chronic epileptogenic lesion at the stroke site may account for unprovoked seizures that occur more than 1 to 2 weeks after a clinical stroke.14 Such unprovoked seizures occur after a clinically detected stroke in 2.7% to 35% of patients.26,38,45,51,59,78 This variability can be attributed to several factors in study design: Variation in length of follow-up, inclusion of only patients with computed tomographic confirmation of stroke, or inclusion of patients with subarachnoid hemorrhage only if they survived long enough to have surgery. Regardless of the selection factors or length of follow-up, the risk for unprovoked seizure after stroke is at least three times that expected based on the incidence among adults in Rochester, Minnesota.24
Because stroke produces a focal brain injury that serves as a substrate focus for seizure development, it has been hypothesized that only unprovoked partial seizures should occur after stroke. Generalized seizures are, however, not uncommon after stroke, although some investigators include secondary generalized seizures in this category.22 Researchers who distinguish primary from secondary generalized seizures find that primary generalized seizures account for 4% to 69% of all unprovoked seizures after stroke.38,39,45,48,59,74 Undetected onset of partial seizures may account for this variability. Nonetheless, true primary generalized seizures do occur after stroke, perhaps as a result of persistent global alterations in neurotransmitter function after stroke or of factors that alter cerebral autoregulation in people with risk factors for stroke.
Seizure prevalence is greater than expected before the occurrence of a first clinical stroke. In a case-control study of acute cerebrovascular accidents,71 the prevalence of epilepsy preceding stroke was 4.55%, compared with 0.6% among controls selected from patients hospitalized for routine surgery and matched to cases by age, race, and sex. Potential controls were
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excluded if they had a history of undefined cerebrovascular disease or if their surgery was related to disseminated carcinoma or alcohol excess, not formally defined abuse. These results have recently been replicated using the UK General Practice Research Database.12 The cumulative risk for stroke was 10.0% in people with seizures compared with 4.4% in those without seizures (p <0.0001).
This increased prevalence of epilepsy before a first clinically detected stroke has led to the study of risk factors for stroke in the absence of stroke as risk factors for unprovoked seizures. Data from three studies suggest that if hypertension, measured by a physician’s diagnosis or blood pressure reading, increases seizure risk, the magnitude of the increased risk is small (OR ranging from 1.0 to 1.7).29,56,69 Additionally, left ventricular hypertrophy untreated with diuretics is associated with a sevenfold increased risk for developing unprovoked seizures29 with a 20-fold increased risk for generalized-onset seizures and a threefold increased risk for partial-onset seizures. Thus, risk factors for stroke may increase the risk for unprovoked seizures.
Dementia
The underlying pathology of Alzheimer disease may be associated with an increased susceptibility for seizures. In patients in whom Alzheimer disease was later confirmed by autopsy,25 there was a 10-fold increased risk for unprovoked seizures compared with the expected risk derived from data from Rochester, Minnesota. In a comparison of the risk for unprovoked seizures in patients with mild probable Alzheimer disease to the risk in cognitively normal controls over a 7.5-year follow-up period,66 new-onset seizures developed in 16% of patients with probable Alzheimer disease after they became severely demented; no control developed seizures. All seizures in this study were generalized tonic–clonic seizures. In a population-based case-control study30 there was a sixfold increased risk for unprovoked seizure associated with Alzheimer disease. In contrast with an earlier study,66 which may have missed partial-onset seizures, this population-based study found an increased risk for both generalized- and partial-onset seizures.
Hesdorffer et al.30 also evaluated the risk for seizures associated with dementia other than Alzheimer disease determined by ad hoc criteria based on DSM-III. They found that dementia increased the risk for unprovoked seizure eightfold overall; risk was increased for both generalized- and partial-onset seizure. This result suggests that any disease sufficiently severe to result in a dementing process may increase seizure risk.
Multiple Sclerosis
Several studies now suggest that multiple sclerosis is associated with an increased risk for epilepsy,44,57,60,73 suggesting an epileptogenic role for white matter lesions. In these retrospective cohort studies of people with multiple sclerosis, 1.8% to 4.8% had seizures at the time of diagnosis or developed seizures after diagnosis. Across studies, this risk is more than three times the risk for unprovoked seizures over a similar time period.
Depression and Treatment for Depression
Depression diagnosed according to DSM-III-R criteria, treatment with tricyclic antidepressants, and use of phenothiazine and electroconvulsive shock therapy were studied as risk factors for unprovoked seizures in a population-based case-control study.31 Only depression increased the risk for seizures after controlling for the other risk factors (OR = 3.7). Additionally, attempted suicide has been shown to increase the risk for first unprovoked seizure,32 adjusting for depression, alcohol consumption, age, and gender. These associations may be caused by disturbances in neurotransmitter function common to depression, suicide attempt, and seizures (see Chapter 205 for further discussion).
Alcohol
Alcohol intake appears to be associated with seizure occurrence (Chapter 268). A case-control study in Harlem in New York City compared individuals admitted for a first seizure with controls admitted for the first time for an acute surgical procedure.54 Controls were excluded if they had a condition related to alcohol abuse or had experienced a seizure. Controlling for age, sex, history of hypertension, history of head injury, history of stroke, and heroin use for more than 6 months, there was a dose response between alcohol consumption and the risk for seizure, particularly among male patients (OR = 1.3 to 19.5, depending on the amount of alcohol consumed). Seizure occurrence was not associated with time since last drink. A case-control study from Nigeria also associated alcohol consumption with seizures; however, these authors did not define alcohol use.58
Illicit Drugs
The association between heroin and marijuana use and seizures was investigated in the Harlem case-control study.55 Controlling for age, history of head trauma, history of stroke, and alcohol use, these investigators found that heroin increased the risk for unprovoked seizures threefold and the risk for provoked seizures fourfold. Marijuana use conferred 82% protection against provoked seizures and 64% protection against unprovoked seizures. These interesting results require confirmation in other studies (see Chapter 268 for further discussion).
Acute Symptomatic Seizures
Acute symptomatic seizures typically occur within the first week of an insult known to predispose to seizures (e.g., head trauma) and are not regarded as epilepsy (Chapter 8). In Rochester, Minnesota, the cumulative incidence of acute symptomatic seizures in patients up to 80 years of age is 3.7%.5 Across many causes of acute symptomatic seizures, studies suggest that such seizures increase the risk for later epilepsy at least threefold, perhaps because their occurrence is a marker for severity of brain injury.36
Among Rochester adults with moderate or severe head trauma, early seizures increased the risk for later unprovoked seizures ninefold3; children with early seizures were not at increased risk for unprovoked seizures. In military populations with penetrating missile wounds to the head, 50% of men with early seizures experienced later unprovoked seizures.11 Early postoperative seizures are associated with unprovoked seizures.18 The magnitude of this increased risk appears related to the underlying disease requiring surgery; patients with vascular or ventricular disease before surgery have the greatest risk (increased fourfold) for unprovoked seizure. Among stroke patients without early seizures, the risk for unprovoked seizure is 19%; for those with early seizures, the risk is even greater.26 If early seizures occur, the risk for unprovoked seizures after encephalitis is increased threefold, and after bacterial meningitis fourfold.4
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The Protective Effect of Diuretics
Current diuretic use has been shown to be protective for the development of idiopathic/cryptogenic unprovoked seizures in a population-based case-control study in the elderly.33 The protective effect was 46% for thiazide use and 39% for furosemide; Aldactazide was not associated with a protective effect for seizure development.
Socioeconomic Status
Indices of low socioeconomic status (SES) are associated with many established risk factors for epilepsy, including cerebrovascular disease, head trauma, congenital malformations, central nervous system infection (meningitis, encephalitis), alcohol intake or abuse, brain neoplasms, and Alzheimer disease. This complicates studies designed to examine the association between low socioeconomic status and the development of epilepsy.
Two studies now show that low socioeconomic status is associated with an increased risk for developing epilepsy,27,35 and one study fails to find an association.17 These studies are either community based or population based. A prospective study in England,27 using a composite measure of SES, concluded that low SES is a risk factor for the development of epilepsy. A case-control study in Iceland35 found that low education increased the risk for unprovoked seizure twofold, whereas home ownership was protective. When analyses were repeated by seizure etiology, the association persisted only in the idiopathic/cryptogenic group even after adjusting for cumulative alcohol intake. Interestingly, there was no effect of low SES in children, suggesting that there is a cumulative effect of social deprivation associated with the development of epilepsy.
Future Research
Much is known about factors that appear to increase the risk for unprovoked seizures, particularly for risk factors that produce clear structural brain damage. Recently, studies have suggested associations between factors that are not known to lead to such brain damage (e.g., major depression) and unprovoked seizures. Thus, the challenge for future studies of unprovoked seizures is to elucidate risk factors that increase risk in people whose seizures have no established cause. Such studies have the potential to identify novel mechanisms for seizure occurrence or to identify shared genetic susceptibility between a risk factor and unprovoked seizures.
Few studies exist concerning risk factors for seizures in older adults, in whom the incidence of seizures is increased. New studies elucidating novel factors associated with seizures in this population and confirming those already suggested are needed.
Summary and Conclusions
Studies suggest that febrile seizures, mental retardation, and cerebral palsy are risk factors for epilepsy unique to children. Prenatal and perinatal adverse events are not associated with the occurrence of epilepsy when investigators exclude children with mental retardation and cerebral palsy. Among children and adults, established risk factors for epilepsy include CNS infection, head injury, and CNS malignancies. Attention deficit hyperactivity disorder also increases seizure risk in children. In adult populations, cerebrovascular disease and Alzheimer disease are established risk factors for epilepsy. Multiple sclerosis, risk factors for stroke, major depression, alcohol intake, illicit drug use, and low socioeconomic status appear to increase the risk for epilepsy, but further studies are needed to confirm these findings.
References
1. Aicardi J. Epilepsy and other seizure disorders. In: Aicardi J, ed. Diseases of the Nervous System in Childhood. London: Mac Keith Press; 1992:911–1001.
2. Aicardi J. Para-infectious and other inflammatory disorders of immunological origin. In: Aicardi J, ed. Diseases of the Nervous System in Childhood. London: Mac Keith Press; 1992:697–731.
3. Annegers JF, Grabow JD, Groover RV, et al. Seizures after head trauma: a population study. Neurology. 1980;30:683–689.
4. Annegers JF, Hauser WA, Beghai E, et al. The risk of unprovoked seizures after encephalitis and meningitis. Neurology. 1988;38:1407–1410.
5. Annegers JF, Hauser WA, Lee JR-J, et al. Incidence of acute symptomatic seizures in Rochester, Minnesota, 1935–1984. Epilepsia. 1995;36:327–333.
6. Annegers JF, Hauser WA, Shirts SB, et al. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med. 1987;316:493–498.
7. Austin JK, Harezlak J, Dunn DW, et al. Behavior problems in children before first recognized seizure. Pediatrics. 2001;107:115–122.
8. Bellman MH, Ross EM, Miller DL. Infantile spasms and pertussis immunization. Lancet. 1983;1:1031–1034.
9. Berg AT. Febrile seizures and epilepsy: the contributions of epidemiology. Paediatr Perinat Epidemiol. 1992;6:145–152.
10. Berg AT, Shinnar S. Unprovoked seizures in children with febrile seizures: short-term outcome. Neurology. 1996;47:562–568.
11. Caverness WF, Meirowsky Am, Rish BL, et al. The nature of posttraumatic epilepsy. J Neurosurg. 1979;50:545–553.
12. Cleary P, Shorvon S, Tallis R. Late-onset seizures as a predictor of subsequent stroke. Lancet. 2004;363:1184–1186.
13. Dam AM, Fuglsang-Frederiksen A, Svarre-Olsen U, et al. Late onset epilepsy: etiologies, types of seizures, and value of clinical investigation, EEG, and computerized tomography scan. Epilepsia. 1985;26:227–231.
14. De Carolis P, D’Alessandro R, Ferrara R, et al. Late seizures in patients with internal carotid and middle cerebral artery occlusive disease following ischemic events. J Neurol Neurosurg Psychiatry. 1984;47:1345–1347.
15. Degen R. Epilepsy in children: an etiological study based on their obstetrical records. J Neurol. 1978;217:145–158.
16. Dunn DW, Austin JK, Huster GA. Behavior problems in children with new-onset epilepsy. Seizure. 1997;6:283–287.
17. Forsgren L, Nystrom L. An incident case-referent study of epileptic seizures in adults. Epilepsy Res. 1990;6:66–81.
18. Foy PM, Copeland GP, Shaw MDM. The natural history of postoperative seizures. Acta Neurochir (Wien). 1981;57:15–22.
19. Franceschetti S, Battagha G, Lodrini S, et al. Relationship between tumors and epilepsy. In: Broggi G, ed. The Rational Basis of the Surgical Treatment of Epilepsies. London: John Libbey; 1988.
20. Gale JL, Thapa PB, Wassilak SG, et al. Risk of serious acute neurological illness after immunization with diphtheria-tetanus-pertussis vaccine. A population-based case-control study. JAMA. 1994;271:37–41.
21. Goulden KJ, Shinnar S, Koller H, et al. Epilepsy in children with mental retardation: a cohort study. Epilepsia. 1991;32:690–697.
22. Gupta SR, Naheedy MH, Elias D, et al. Postinfarction seizures: a clinical study. Stroke. 1981;19:1477–1481.
23. Hauser WA. Seizure disorders: the changes with age [Review]. Epilepsia. 1992;33(Suppl 4):S6–14.
24. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia. 1993;34:453–468.
25. Hauser WA, Morris ML, Heston LL, et al. Seizures and myoclonus in patients with Alzheimer’s disease. Neurology. 1986;36:1226–1230.
26. Hauser WA, Ramirez-Lassepas M, Rosenstein R. Risk for seizures and epilepsy following cerebrovascular insults. Epilepsia. 1984;25:666.
27. Heaney DC, MacDonald BK, Everitt A, et al. Socioeconomic variation in incidence of epilepsy: prospective community based study in south east England. BMJ. 2002;325:1013–1016.
28. Hemmer SA, Pasternak JF, Zecker SG, et al. Stimulant therapy and seizure risk in children with ADHD. Pediatr Neurol. 2001;24:99–102.
29. Hesdorffer DC, Hauser WA, Annegers JF, et al. Severe, uncontrolled hypertension and adult-onset seizures: a case-control study in Rochester, Minnesota. Epilepsia. 1996;37:736–741.
30. Hesdorffer DC, Hauser WA, Annegers JF, et al. Dementia and adult-onset unprovoked seizures. Neurology. 1996;46:727–730.
31. Hesdorffer DC, Hauser WA, Annegers JF, et al. Major depression is a risk factor for seizures in older adults. Ann Neurol. 2000;47:246–249.
32. Hesdorffer DC, Hauser WA, Ludvigsson P, et al. Depression and attempted suicide as risk factors for incident unprovoked seizures and epilepsy. Ann Neurol. 2006;59:35–41.
33. Hesdorffer DC, Stables JP, Hauser WA, et al. Are certain diuretics also anticonvulsants? Ann Neurol. 2001;50:458–462.
P.63

34. Hesdorffer DC, Ludvigsson P, Olafsson E, et al. ADHD as a risk factor for incident unprovoked seizures and epilepsy in children. Arch Gen Psychiatry. 2004;61:731–736.
35. Hesdorffer DC, Tian H, Anand K, et al. Socioeconomic status is a risk factor for epilepsy in Icelandic adults but not in children. Epilepsia. 2005;46:1297–1303.
36. Hesdorffer DC, Logroscino G, Cascino G, et al. Risk of unprovoked seizure after acute symptomatic seizure: effect of status epilepticus. Ann Neurol. 1998;44:908–913.
37. Hirtz DG, Nelson KB, Ellenberg JH. Seizures following childhood immunization. J Pediatr. 1983;102;14–18.
38. Holmes GL. The electroencephalogram as a predictor of seizures following cerebral infarction. Clin Electroencephalogr. 1980;11:83–86.
39. Hornig CR, Buttner T, Hufnagel A, et al. Epileptic seizures following ischemic cerebral infarction: clinical picture, CT findings and prognosis. Eur Arch Psychiatry Clin Neurosci. 1990;239:379–383.
40. Holtmann M, Becker K, Kentner-Figura B, et al. Increased frequency of rolandic spikes in ADHD children. Epilepsia. 2003;44:1241–1244.
41. Hughes JR, DeLeo AJ, Melyn MA. The electroencephalogram in attention deficit-hyperactivity disorder: emphasis on epileptiform discharges. Epilepsy Behav. 2000;1:271–277.
42. Jennett B. Trauma as a cause of epilepsy in childhood. Dev Med Child Neurol. 1973;15:56–62.
43. Keranen T, Tapaninako A, Hernasniemi J, et al. Late epilepsy after aneurysm operations. Neurosurgery. 1985;17:897–900.
44. Kinnunen E, Wikstrom J. Prevalence and prognosis of epilepsy in patients with multiple sclerosis. Epilepsia. 1986;27:729–733.
45. Kotila M, Waltimo O. Epilepsy after stroke. Epilepsia. 1992;33:495–498.
46. Kuks JB, Cook MJ, Fish DR, et al. Hippocampal sclerosis in epilepsy and childhood febrile seizures. Lancet. 1993;342:1391–1394.
47. Leviton A, Cowan LD. Do febrile seizures increase the risk of complex partial seizures? An epidemiological assessment. In: Nelson KB, Ellenberg JH, eds. Febrile Seizures. New York: Raven Press; 1981:65–74.
48. Louis S, Mcdowell F. Epileptic seizures in nonembolic cerebral infarction. Arch Neurol. 1967;17:414–418.
49. Luhdorf K, Jensen LK, Plesner AM. Etiology of seizures in the elderly. Epilepsia. 1986;27:458–463.
50. Miller DL, Ross EM, Alderslade R, et al. Pertussis immunization and serious acute neurological illness in childhood. BMJ. 1981;1:1595–1599.
51. Moskowitz E, Lightbody FEM, Freitag NS. Long-term follow-up of the poststroke patient. Arch Phys Med Rehabil. 1972;53:167–172.
52. Nelson KB, Ellenberg JH. Predictors of epilepsy in children who have experienced febrile seizures. N Engl J Med. 1976;295:1029–1033.
53. Nelson KB, Ellenberg JH. Predisposing and causative factors in childhood epilepsy. Epilepsia. 1987;28(Suppl 1):S16–24.
54. Ng SKC, Hauser WA, Brust JCM, et al. Alcohol consumption and withdrawal in new-onset seizures. N Engl J Med. 1988;19:666–673.
55. Ng SKC, Hauser WA, Brust JCM, et al. Illicit drug use and first onset seizures. Am J Epidemiol. 1990;132:47–57.
56. Ng SKC, Hauser WA, Brust JCM, et al. Hypertension and the risk of new onset unprovoked seizures. Neurology. 1993;43:425–428.
57. Nicoletti A, Sofia V, Biondi R, et al. Epilepsy and multiple sclerosis in Sicily: a population-based study. Epilepsia. 2003;44:1445–1448.
58. Ogunniyi A, Osuntokun BO, Bademosi O, et al. Risk factors for epilepsy: case-control study in Nigeria. Epilepsia. 1987;28:280–285.
59. Ohman J. Hypertension as a risk factor for epilepsy after aneurysmal subarachnoid hemorrhage and surgery. Neurosurgery. 1990;27:578–581.
60. Olafsson E, Benedikz J, Hauser WA. Risk of epilepsy in patients with multiple sclerosis: a population-based study in Iceland. Epilepsia. 1999;40:745–747.
61. Rantakallio P, von Wendt L. A prospective comparative study of the aetiology of cerebral palsy and epilepsy in a one-year birth cohort from northern Finland. Acta Paediatr Scand. 1986;75:586–592.
62. Roberts MA, Godfrey JW, Caird FI. Epileptic seizures in the elderly. I. Aetiology and type of seizure. Age Ageing. 1982;11:24–28.
63. Rocca WA, Sharbrough FW, Hauser WA, et al. Risk factors for absence seizures: a population-based case-control study in Rochester, Minnesota. Neurology. 1987;37:1309–1314.
64. Rocca WA, Sharbrough FW, Hauser WA, et al. Risk factors for generalized tonic-clonic seizures—a population-based case-control study in Rochester, Minnesota. Neurology. 1987;37:1315–1322.
65. Rocca WA, Sharbrough FW, Hauser WA, et al. Risk factors for complex partial seizures: a population-based case-control study. Ann Neurol. 1987;21:22–31.
66. Romanelli MF, Morris JC, Ashkin K, et al. Advanced Alzheimer’s disease is a risk factor for late-onset seizures. Arch Neurol. 1990;47:847–850.
67. Ross EM, Peckham CS, West PB, et al. Epilepsy in childhood: findings from the National Child Development Study. BMJ. 1980;280:207–210.
68. Salazar AM, Jabbari B, Vance SC, et al. Epilepsy after penetrating head injury. I. Clinical correlates: a report of the Vietnam Head Injury Study. Neurology. 1985;35:1406–1414.
69. Shapiro IM, Neufeld MY, Korczyn AD. Seizures of unknown origin after the age of 50: vascular risk factors. Acta Neurol Scand. 1990;82:78–80.
70. Shields WD, Neilsen C, Buch D, et al. Relationship of pertussis immunization to the onset of neurologic disorders: a retrospective epidemiologic study. Pediatrics. 1988;113:801–805.
71. Shinton RA, Zezulka AV, Gill JS, et al. The frequency of epilepsy preceding stroke. Case-control study in 230 patients. Lancet. 1987;1:11–13.
72. Sillanpää M. Epilepsy in children: prevalence, disability and handicap. Epilepsia. 1992;33:444–449.
73. Striano P, Orefice G, Morra VB, et al. Epileptic seizures in multiple sclerosis: clinical and EEG correlations. Neurol Sci. 2003;23:322–328.
74. Sung C-Y, Chu NS. Epileptic seizures in thrombotic stroke. J Neurol. 1990;237:166–170.
75. VanLandignham KE, Heinz ER, Cavazos JE, et al. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions. Ann Neurol. 1998;43:413–426.
76. Verity CM, Golding J. Risk of epilepsy after febrile convulsion: a national cohort study. BMJ. 1991;303:1373–1376.
77. Verity CM, Ross EM, Golding J. Epilepsy in the first 10 years of life: findings of the Child Health and Education Study. BMJ. 1992;205:857–861.
78. Viitanen M, Ericksson S, Asplund K. Risk of recurrent stroke, myocardial infarction and epilepsy during long-term follow-up after stroke. Eur Neurol. 1988;28:227–231.
79. Williams J, Schultz EG, Griebel ML. Seizure occurrence in children diagnosed with ADHD. Clin Pediatr. 2001;40:221–224.
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