Epidemiology of Acute Symptomatic Seizures

Chapter 8

W. Allen Hauser

Introduction

What condition looks like epilepsy, is frequently called “epilepsy,” is frequently counted as epilepsy in epidemiologic studies, but in general has a different basis from that of epilepsy and is seldom treated as epilepsy? The answer is acute symptomatic seizures, also referred to as reactive seizures, provoked seizures, or situation-related seizures. Acute symptomatic seizures are seizures that occur at the time of a systemic insult or in close temporal association with a documented brain insult.⁷^,⁸^,¹⁶ This class of seizure falls into the category of situation-related seizures in the Revised Classification of Epilepsies and Epileptic syndromes suggested by the International League Against Epilepsy.⁷

Acute symptomatic seizures differ from epilepsy in several important aspects: First, unlike epilepsy, these seizures have a clearly identifiable proximate cause, to the extent that one can never be certain of a causal association. When one considers the temporal sequence of acute symptomatic seizures (e.g., uremia, head injury, or stroke immediately preceding a seizure), the biologic plausibility (acute disruption of brain integrity or metabolic homeostasis) and in many cases the dose effect (severity of injury correlated with the risk for seizures) all quite compellingly indicate causation. Although a risk ratio for the immediate association between cause and effect has not been calculated, it must be enormous. Second, unlike epilepsy, acute symptomatic seizures are not characterized by a tendency to recur. The risk for subsequent epilepsy may be increased in individuals experiencing such insults; in general, one does not expect seizures to recur unless the underlying condition recurs. As a corollary, such individuals usually do not need to be treated with antiseizure medication on a long-term basis, although such treatment may be warranted on a short-term basis until the acute condition is resolved.³⁴

Few epidemiologic studies report the frequency of acute symptomatic seizures. This may be caused in part by the difficulties involved in identification. Such seizures are seldom indexed as acute symptomatic seizures; rather, the underlying condition is likely to be diagnosed and coded. This makes a study design relying on medical record review inefficient and probably leads to gross underenumeration. Individuals with acute symptomatic seizures are seldom referred to neurologists for long-term follow-up, and given the acute nature of the condition, an electroencephalographic evaluation may not be warranted or appropriate. These important sources of patient identification are thus eliminated. In studies relying on field surveys, a moderate amount of sophistication is necessary to distinguish acute symptomatic seizures from unprovoked seizures. Thus, even though causation and prognosis of acute symptomatic seizures are quite different from those of epilepsy, some recent epidemiologic studies have categorized individuals with such seizures as having “epilepsy,”³¹ have failed to distinguish between unprovoked and acute symptomatic seizures,²⁸ or have not provided detailed information on cause, age, or gender.¹³^,²⁰^,²¹ To study acute symptomatic seizures properly, it is more efficient to study the associated conditions, such as head injury or stroke. This procedure is not usually undertaken by most epileptologists, and seizures are not a major interest to specialists treating underlying conditions such as stroke or hyponatremia. Nonetheless, in aggregate, acute symptomatic seizures account for more than half, and in some geographic areas as much as 80%, of all newly occurring seizures. Failure to consider these conditions separately will greatly modify the apparent epidemiologic characteristics of what is called “epilepsy.” In addition to greatly increasing the apparent incidence of “epilepsy” mortality, age and gender structure of those affected is quite different if such cases were included as epilepsy, as has been suggested by some.¹⁴^,¹⁸^,²⁷ At present, acute symptomatic seizures continue to be a useful concept for classification and prognosis, and the suggestions by some that the term (and presumably the concept) be abolished seems inappropriate.

FIGURE 1. Age-specific incidence of acute symptomatic seizures (excludes childhood febrile seizures). CVD, cerebrovascular disease.

A major difficulty with acute symptomatic seizures remains their definition. For conditions such as stroke or brain trauma, seizures occurring in the first week of an insult have generally been classified as acute symptomatic. This is clearly an artificial cut-point of convenience and would better include all seizures occurring until the point of clinical stabilization. For metabolic conditions, it is frequently unclear for systemic metabolic derangements how severe a derangement must be or for what duration it must persist. For some conditions (e.g., neurocysticercosis), the acute insult may persist for weeks or months, defying a strict temporal definition.¹¹ This chapter reviews the incidence of acute symptomatic seizures and the incidence of seizures in conditions associated with acute symptomatic seizures. Although febrile seizures in childhood are by definition acute symptomatic seizures, they differ from other acute symptomatic seizures in their unique age specificity, high frequency in the population (up to 9%), and universality of exposure. It therefore seems appropriate that they be discussed separately.

Incidence of Acute Symptomatic Seizures

Overall Incidence

Only two studies provide detailed information regarding the incidence of acute symptomatic seizures.⁵^,²⁴^,²⁶ The incidence of seizures occurring at the time of systemic metabolic insults or temporally associated with an insult to the central nervous system (CNS) was determined for the residents of Rochester, Minnesota. The age-adjusted incidence rates for 1955 to 1984, the period of most complete case ascertainment, was 39 per

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100,000 person-years (U.S. 1970 population). This represents about 40% of all cases of afebrile seizures identified in the community during the study period and underscores the overall importance of this class of seizure disorder in population-based incidence surveys.

This rate is somewhat higher than that reported in Gironde, Bordeaux, France, which was 29 per 100,000 person-years. In this community-based study, acute symptomatic seizures also accounted for about 40% of all newly identified cases of afebrile seizures. The difference in absolute incidence of acute symptomatic seizures in these two communities may reflect a difference in the completeness of case ascertainment or a difference in the frequency of underlying conditions rather than any true difference in the epidemiologic characteristics. In any case, the similarities in the patterns and causes reported in the two studies are considerable.

Other studies provide some concept of frequency, but do not provide additional detail about age, etiology, or gender. In Switzerland, incidence was 25.2 per 100,000, accounting for 35% of all new cases of unprovoked seizures (Jallon). In Martinique, the incidence was 17 per 100,000, accounting for about 20% of all incident cases; in a study in children in Tunis, about 10% of all new cases were acute symptomatic. Although not specifically population based, a study from a British general practice survey³³ reported 21% of newly occurring seizures to fall into the category of acute symptomatic seizures.

Gender

From what we know about the conditions associated with acute symptomatic seizures, men seem to be at higher risk than women. In both the French study and the U.S. study, the age-adjusted incidence in men was considerably higher than that in women. Sex-specific incidence in the French study, adjusted to the U.S. 1970 population, was 33 for men and 17 for women. In contrast, the adjusted incidence in the United States during a similar time interval was 56 for men and 33 for women. These differences would seem to reflect gender-related differences in incidence of underlying conditions associated with acute asymptomatic seizures rather than any specific biologic phenomena.

Age

The age-specific incidence of acute asymptomatic seizures in the U.S. study was by far the highest during the first year of life (Fig. 1). This is attributable to the high incidence of acute symptomatic seizures associated with metabolic, infectious, and encephalopathic causes during the neonatal period. Incidence declined in childhood and the early adult years and reached a nadir of 15 per 100,000 person-years among those 25 to 34 years of age. After 35 years of age, the incidence increased progressively, and reached 123 per 100,000 among those older than 75 years of age. Cerebrovascular disease accounted for about half of all acute symptomatic seizures in persons older than 65 years of age.

As mentioned previously, age-adjusted incidence is considerably higher in men than women. The sex difference was greatest at the extremes of age. Between the ages of 15 and 44, there were few differences among all causes of acute symptomatic seizures. Seizures associated with eclampsia in women of childbearing age offset a lower incidence of seizures among women associated with other causes.

The age-specific incidence rates of acute symptomatic seizures in the French and U.S. studies were similar in middle-aged men, but the U.S. rates were higher in children younger than 15 years of age and in the elderly. Because incidence rates by etiologic groups were not provided in the French study, it is not possible to contrast the rates by etiology or to judge whether the differences in overall incidence might be attributable to differing distributions of the underlying insults associated with acute asymptomatic seizures.

Causes of Acute Symptomatic Seizures

The major causes of acute symptomatic seizures in both the French and U.S. studies were traumatic brain injury, cerebrovascular disease, drug withdrawal, and CNS infection. The underlying causes of the seizures are reflected in patterns of age, sex, and time period. Although the overall proportional distribution by cause was similar in the United States and France, no age- or etiology-specific data are available for the latter study. Cause-specific data from the U.S. study are presented in FIGURE 2.

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FIGURE 2. Acute symptomatic seizure precipitating causes.

Acute Symptomatic Seizures Associated with Primary Brain Insults

Central Nervous System Infection

Acute symptomatic seizures in infections of the central nervous system are those occurring during the acute phase of infection. About 5% of people with CNS infection can be expected to experience an acute symptomatic seizure.⁴ Infections of the CNS accounted for about 15% of all acute symptomatic seizures in both Bordeaux, France, and Rochester, Minnesota. In the latter study, the age-specific trends of acute symptomatic seizures associated with CNS infection followed the pattern of incidence of CNS infection.²⁹ The highest incidence was during the first year of life and in children younger than 15 years of age; the incidence was lower in adults. The age-adjusted incidence of 5.2 per 100,000 person-years has been relatively constant over time. Overall, the age-adjusted incidence in men is twice that in women.

Neurocysticercosis (NC) represents a special category of CNS infection and also a special category of acute symptomatic seizures. Seizures are second only to headache as a presenting symptom of NC. It is assumed that most of these seizures are acute symptomatic and are associated with the response to the acute inflammatory response associated with transitional cyst degeneration.¹⁰ Unlike most time-delimited insults associated with acute symptomatic seizures, the inflammatory response may last from weeks to months, thus requiring a modification of some of the usual concepts of acute symptomatic seizures.¹¹

Brain Trauma

Seizures occurring within the first week of a traumatic brain injury are generally assumed to be acute symptomatic. Seizures occurring after that time are generally considered late or unprovoked, although it would certainly be more appropriate to include the concept of stabilization in such definitions. In civilian studies of traumatic brain injuries, about 6% of all cases are associated with acute symptomatic seizures.²^,³² The frequency of early seizures increases with severity of injury and probably represents a surrogate for severity. Acute symptomatic seizures associated with head trauma accounted for about 15% of all acute symptomatic seizures occurring in Rochester and only about 5% of all cases in Bordeaux. The higher frequency in Rochester reflects the fact that all cases of head injury in the community were reviewed, whereas the French study depended on identification of only those people with seizures. Traumatic acute symptomatic seizures in Rochester were more common in men (age-adjusted rate, 8.6) than in women (age-adjusted rate, 4.8) at all ages. The age-specific incidence of head trauma is trimodal.³^,⁹ Given similar levels of severity of injury, children are at higher risk for acute symptomatic seizures than adults.²

Cerebrovascular Disease

Following the example of brain injury, acute symptomatic seizures associated with cerebrovascular disease are generally limited to seizures occurring within 1 week of the acute ictus. Between 5% and 10% of individuals with a cerebrovascular insult experience a seizure at the time of stroke.²²^,³⁰^,³⁵ The frequency varies with the nature of the insult and is probably highest in those with intracerebral hemorrhage. In Bordeaux, cerebrovascular disease accounted for about one third of all cases of acute symptomatic seizures, compared with only 15% of all cases in Rochester.

Paralleling the incidence of cerebrovascular disease,⁶ acute symptomatic seizures associated with stroke are rare in persons younger than 55 years of age; the incidence rises rapidly with increasing age, reaching 54.6 per 100,000 among persons older than 75 years of age. The age-adjusted incidence of acute symptomatic seizures is higher in men than in women (9.4 vs. 4.7 per 100,000 cases).⁶ The sex-specific difference is particularly dramatic in those 65 to 74 years of age: 55.1 per 100,000 in men versus 15.5 per 100,000 in women.

In Rochester, the age-specific incidence of acute symptomatic seizures associated with cerebrovascular disease was stable from 1945 through 1974 but fell in the final decade along with the incidence of stroke.⁶ The age-adjusted incidence fell through the years from 8.6 in the decade 1955 to 1964 to 6.5 in the decade 1964 to 1974 to 5.1 in the decade 1975 to 1984.

Brain Tumor

There is debate about how to classify seizures associated with brain tumors. A high proportion of individuals with brain tumors may experience acute symptomatic seizures.¹⁵ In Rochester, acute symptomatic seizures associated with primary or secondary brain tumors occurred at all ages but were rare in persons younger than 45 years of age. The age-specific incidence rates in persons older than 45 years of age were constant at 6 to 8 per 100,000 person-years. Unlike most other acute symptomatic seizures, seizures associated with neoplasm were equally common in men and women.

Acute Symptomatic Seizures Associated with Systemic Disturbances

Seizures occurring in association with systemic insults are easy to identify, although strict operational definitions are elusive. The severity of a systemic insult or the timing of the seizures from the start of the insult is seldom specified.¹² Nonetheless, this category accounts for a substantial proportion of all acute symptomatic seizures.

Eclampsia

In the Rochester studies, 15 women had seizures attributed to eclampsia during a 50-year period; this accounted for about 3% of acute symptomatic seizures in women, an incidence of 2.8 per 100,000 women ages 15 to 44 years. The incidence of eclampsia may more appropriately be expressed as a proportion of deliveries. The risk per 1,000 deliveries was 1.1 in the decade 1934 to 1944, 0.6 during 1945 to 1954, 0.4 during 1955 to 1964, 0.2 during 1965 to 1974, and 0.1 during 1975

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to 1984. Because a higher proportion of deliveries occurred at home during the 1930s and 1940s, cases of eclampsia have been missed during this period, leading to an underestimation in the true decline in incidence in this community. The progressive decline of the incidence of eclampsia since 1935 probably reflects better management of toxemia in pregnancy.

Socioeconomic factors probably play a role in incidence rates of eclampsia. In Houston, Texas, the incidence of eclampsia in two inner-city hospitals from 1982 to 1992 was 0.7 per 1,000 deliveries,¹ a frequency similar to that in Rochester, Minnesota, in the 1940s. Seizures associated with eclampsia were not separately reported in the Bordeaux study.

Toxic Insults

Seizures may occur in association with a variety of toxic insults (e.g., carbon monoxide poisoning or acetylsalicylic acid overdose). Toxic insults accounted for about 5% of all acute symptomatic seizures in Rochester, but only a small proportion of cases in Bordeaux. This may be a consequence of differences between these two studies in inclusion criteria for this category. In Rochester, the overall incidence of acute symptomatic seizures associated with toxic insults was 2.2 per 100,000 cases, with the highest incidence in the elderly (older than 75 years of age).

Drug Withdrawal

Most drug withdrawal seizures are associated with abuse of ethanol and, less frequently, barbiturates or other substances. This category of acute symptomatic seizures accounted for about 15% of cases in Rochester and about one third of cases in Bordeaux. Incidence for this group of acute symptomatic seizures peaked in the 35- to 54-year-old age group, and the age-adjusted incidence was considerably higher in men than women (10.5 per 100,000 person-years vs. 3.4 per 100,000 person-years). Withdrawal seizures were the primary cause of acute symptomatic seizures for those 25 to 55 years of age. The incidence of seizures attributed to this cause progressively increased during the study period. Seizures associated with alcohol or drug abuse or withdrawal may be less completely ascertained than seizures associated with other causes because, unlike evaluations of stroke, head trauma, CNS infection, and brain tumors, each alcohol-related patient evaluation is not systematically reviewed for seizures.

Metabolic Insults

Systemic metabolic illness accounted for about 10% of all acute symptomatic seizures in Rochester and about 15% of cases in Bordeaux. In Rochester, the incidence of acute symptomatic seizures attributed to metabolic insults was highest during the first year of life. This was largely caused by hypocalcemia or hypoglycemia in newborns. These cases were identified primarily before 1960; they are virtually nonexistent at the present time in this community, although it is conceivable that they continue to account for a substantial proportion of newborn cases in less medically sophisticated areas. Seizures associated with metabolic disturbances were rare between the second week of life and 55 years of age. There was a slight rise in incidence after this age. The incidence of seizures attributed to metabolic causes among newborns fell from 105 per 100,000 cases during the decade 1945 to 1954 to 50 per 100,000 in the decade 1975 to 1984.

Cumulative Incidence of Acute Symptomatic Seizures

In Rochester, the risk for experiencing an acute symptomatic seizure during an 80-year life span is 3.6%; this approaches the risk for epilepsy. The risk for any type of acute symptomatic seizure from birth through 80 years of age is almost 5% in men and a little more than 2.5% in women. The prevalence of history of acute symptomatic seizures is somewhat lower than the cumulative incidence because of the high mortality rate associated with many of the causes of acute symptomatic seizures.

Prognosis of Acute Symptomatic Seizures

In general, acute symptomatic seizures are a reflection of disease severity and, as such, are associated with a relatively high mortality rate.¹⁸^,²³^,²⁷ However, prognosis obviously varies with the underlying condition. No studies address the influence of acute symptomatic seizures on risk for mortality within given conditions, so it is impossible to assess the contribution of seizures per se on mortality. In survivors of neurologic insults, those with acute symptomatic seizures seem to be consistently at increased risk for subsequent epilepsy compared with those without acute symptomatic seizures.²^,⁴^,¹⁹ This is probably not related to a kindling phenomenon but rather to the increased severity of initial insult in those with acute symptomatic seizures. Acute symptomatic seizures associated with metabolic insults are not associated with a similar increase in risk for subsequent epilepsy. None of the cases of eclampsia in the Rochester cohort had subsequent seizures. There has been no systemic study of the risk for epilepsy in people with other metabolic conditions.

Summary and Conclusions

Acute symptomatic seizures account for a substantial proportion of all newly occurring seizures, even when febrile seizures are excluded. Acute symptomatic seizures continue to be a useful concept for classification and prognosis, and the suggestions by some that the term (and presumably the concept) be abolished seems inappropriate. The causes and prognosis of acute symptomatic seizures require further systematic study and greater consideration when the total picture of the epilepsies is considered.

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	Epilepsy: A Comprehensive Textbook 2nd Edition
	© 2008 Lippincott Williams & Wilkins

Epilepsy: A Comprehensive Textbook2nd Edition

Epilepsy: A Comprehensive Textbook
2nd Edition