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
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
with the 23.1% prevalence of learning disorders reported in an unselected sample of children in Finland.⁷²