Treatment of Single and Infrequent Seizures

Ettore Beghi

Anne T. Berg

Shlomo Shinnar

W. Allen Hauser

Introduction

Epilepsy is a treatable condition characterized by the occurrence of repeated unprovoked seizures. Thus, the patient who presents with an isolated first unprovoked seizure (or cluster of seizures within 24 hours) does not yet qualify for the diagnosis of epilepsy. In the past, it was believed that almost all individuals coming to medical attention for a first seizure would inevitably have additional episodes; such individuals were usually treated with antiepileptic drugs (AEDs).²²^,⁵² In addition, based on studies from tertiary referral centers, there was the perception that epilepsy was a chronic, progressive, unremitting disease.³⁰^,⁵⁴ Thus, early aggressive treatment with antiepileptic drugs was presumed to be beneficial through suppression or control of the evolving process of the disorder. The results of recent epidemiologic studies and randomized clinical trials have greatly changed our understanding of the nature and natural history of seizures and of epilepsy. For the most part, it is clear that epilepsy is a relatively benign condition with an excellent prognosis for seizure control and, ultimately, discontinuation of AEDs. In light of these changes, the clinical management of a single seizure has to be reconsidered. In this chapter, we will address several issues pertaining to the diagnosis and management of the patient who presents with a single unprovoked seizure, including (a) the diagnosis of epileptic seizures, first unprovoked seizures, and epilepsy; (b) the influence of seizure recurrence and early treatment on the prognosis of epilepsy, based on earlier and present views; (c) the risk of recurrence of a given seizure; (d) the impact of treatment on that risk and on the long-term prognosis of epilepsy; (e) the risk:benefit ratio of pharmacologic treatment; and (f) the sociocultural and legal implications of seizure recurrence compared with the tolerability and acceptance of chronic therapy.

Diagnosis of Epileptic Seizures, First Unprovoked Seizures, and Epilepsy

The diagnosis of epileptic seizures and epilepsy is beyond the scope of this chapter and is being covered elsewhere in this book. Briefly, in any newly presenting patient a series of questions must be addressed: (a) did the individual have an epileptic seizure? (b) Is there an acute cause for the seizure, perhaps one requiring immediate treatment itself? (c) If this is an unprovoked seizure, is it the first ever this person has had or, upon history, is there convincing evidence of previous events?

According to the International League Against Epilepsy and the International Bureau for Epilepsy, an epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.²⁵ Although the occurrence of at least one epileptic seizure as a prerequisite for the diagnosis of epilepsy is still a matter of debate,⁶ a first epileptic seizure has an inherent susceptibility to relapse. A first seizure may present as status epilepticus. Status epilepticus is a seizure showing no clinical signs of arresting after a duration encompassing the great majority of seizures of that type in most patients or recurrent seizures without interictal resumption of baseline central nervous system function.¹¹

Seizures should also be characterized as acute symptomatic or unprovoked, with reference to the presence or absence of known precipitants.¹⁹ Seizure definitions are discussed more extensively in Chapter 67. Although acute symptomatic seizures are a risk factor for unprovoked seizures and epilepsy, they may not necessarily recur, provided that the underlying epileptogenic condition is properly diagnosed and treated.

Another aspect of diagnosis that can be particularly difficult in an individual with a history of nonconvulsive ictal events is the determination of whether the event is really the first seizure. Not all forms of epilepsy are equally likely to present with a single seizure.³ This is frequently an issue in syndromes such as juvenile myoclonic epilepsy, where the patient may come to medical attention for a generalized tonic–clonic seizure but, upon careful questioning, is found to have a history of myo-clonic events that were never recognized as seizures. Similar scenarios are often seen with patients who are found to have a history consistent with complex partial seizures, or absence seizures. Some patients may have had one or more nocturnal episodes that are recognized only in retrospect. Such patients may present with a first seizure requiring medical attention; however, they already have epilepsy.³⁶ The issue of the diagnosis of the first seizure is further complicated by the high variability of clinical interpretation among neurologists. This variability seems to be reduced only by the use of simple diagnostic criteria and a discussion among the treating physicians.⁶⁵

Changing Views on the Early Prognosis of Epilepsy and the Effects of Early Treatment

Views on the prognosis of epilepsy have changed in the last 40 years. Until the late 1960s it was believed that less than a third of patients with epilepsy would achieve a complete remission from seizures, and the majority (up to 85%) would be likely to have a chronic seizure disorder.⁵⁴ Further, it was believed that seizures beget seizures. As Gowers wrote³⁰:

“When one attack has occurred, whether in apparent consequence of an immediate excitant or not, others usually follow without any immediate traceable cause. The effect of a convulsion on the nerve centres is such as to render the occurrence of another more easy, to intensify the predisposition that already exists. Thus, every fit may be said to be, in part, the result of those that have preceded it, the cause of those which follow it.”

In contrast to previous studies, community surveys and prospective studies on referral patients done in the last 30 years have reported that up to 90% of newly diagnosed patients with epilepsy tend to achieve prolonged seizure remission, and about 40% to 60% of these enter remission as soon as treatment is initiated.³⁹ Likewise, well-conducted, unbiased studies of prognosis following a first unprovoked seizure have also demonstrated that a significant percentage of patients do not have further seizures.²^,³¹ Although it has been maintained that the better prognoses observed in more recent studies can be attributed to improved treatment,⁵² epidemiologic evidence indicates that the poor prognoses observed in earlier studies were largely the result of selection bias: Patients in these studies were from tertiary referral centers where those with poor outcomes are overrepresented.⁷ In contrast, recent studies have been conducted on newly diagnosed patients. Given the changes in our understanding of the nature of seizures and epilepsy and the prognosis following a first unprovoked seizure, there are now many considerations that must be made in approaching the management and treatment of the patient who presents with a first unprovoked seizure.

It has been suggested in the past that AEDs should be initiated promptly in newly diagnosed patients under the assumption that epilepsy is an evolving process that, if left untreated, tends to be accompanied by reduced drug response.⁵² This assumption was supported by experimental findings in kindled animals.⁵³ However, the concept that early AED treatment can influence the prognosis of epilepsy is not unanimously accepted. An alternative view is that the outcome of epilepsy is determined largely by the underlying substratum upon which the epilepsy is superimposed and that treatment does not influence the course of the disease.³⁷^,⁵⁵^,⁶¹ Epilepsy is a heterogeneous clinical condition and many different forms have been recognized. The outcome to some extent is determined by the type of epilepsy. These contrasting opinions may still greatly affect the decision to treat a patient at the time of his or her first medical contact for unprovoked seizures, which for some individuals may be the first epileptic seizure.

Treatment of a single epileptic seizure is a therapeutic option. Knowledge of the clinical pharmacology of AEDs has led to a more precise outline of the efficacy and tolerability of the available drugs (see Chapter 109). Consequences of recurrence of epileptic seizures must be balanced against the consequences of treatment (Chapters 95 and 108). This chapter will mostly focus on prophylaxis following a single unprovoked seizure. Although a more detailed overview of the epidemiology of isolated seizures has been provided elsewhere in this book (see Chapters 5 and 7), this issue will be summarized briefly here.

Risk of Recurrence of a First Seizure

In patients coming to medical attention with a first unprovoked seizure, the risk of recurrence has been reported to range from 23% to 71%.⁴^,⁸ This large range reflects considerable differences among studies with respect to length of follow-up, target population, definition of first seizure, and study design.⁷^,⁸ Population-based studies²^,³¹ provide more homogeneous relapse rates at 1 (36% to 37%) and 2 years (43% to 45%). In a systematic review of 16 reports,⁸ the average recurrence risk was 51% (95% confidence interval [CI], 49% to 53%). The risk of recurrence of a first seizure at 2 years ranged from 25% to 52%, with a median of 38%. Numerous prognostic factors have been examined in the literature. These can be divided into three groups: (a) those clearly identifying patients at high and low risk, (b) those clearly considered of no prognostic significance, and (c) those for which available data are insufficient or conflicting.

The two most consistent predictors of recurrence are an abnormal electroencephalogram (EEG) and the presence of an underlying etiology.⁸ The EEG is a useful predictor of relapse of a first unprovoked seizure in both children and adults.⁸ Children with a cryptogenic first seizure and EEG epileptiform abnormalities have recurrence rates doubling those with nonepileptiform abnormalities. The results are less conclusive in adults, but also suggest that an EEG with epileptiform abnormalities is associated with a significantly increased risk of relapse.⁸^,⁵⁷^,⁶⁷ When a first seizure is associated with an underlying neurologic condition or event to which the occurrence of the seizure can be attributed, the risk of recurrence is roughly double that of an idiopathic or cryptogenic first seizure.⁸ The 2-year risk of recurrence seems to vary significantly according to the presence of a recognized etiology of the seizure and of an abnormal (not necessarily epileptiform) EEG. The risk is lowest (24%) in patients with idiopathic or cryptogenic seizures and normal EEGs, intermediate (48%) in those with symptomatic seizures or abnormal EEGs, and highest (65%) in those with symptomatic seizures and abnormal EEGs.⁸ In three of the four studies that examined the sleep state at the time of the first seizure,¹⁴^,³⁸^,⁵⁹^,⁶⁶ the risk of recurrence was doubled in patients who were asleep at the time of the index event compared with those who were awake. In one study,⁵⁹ sleep state was a strong predictor of recurrence, even among lowest-risk patients (i.e., those with cryptogenic first seizures and normal EEGs).

Most studies find a small to moderate increase in risk of recurrence associated with a family history of unprovoked seizures. This association appears to be greater among patients with cryptogenic first seizures than among those with a first remote symptomatic seizure. Partial-onset seizures are associated with remote symptomatic etiology and an abnormal EEG. This is particularly the case in patients with remote symptomatic first seizures but less so in those with cryptogenic first seizures. However, in studies controlling for etiology and EEG,²^,¹⁴ partial seizures still may be associated with a higher recurrence risk than are generalized-onset seizures.

Some factors were fairly consistently found not to be predictive of recurrence after a first unprovoked seizure. These include gender and status epilepticus. Although the evidence is still limited, the risk of recurrence does not appear to be greater in patients whose first unprovoked seizure was an episode of cryptogenic status epilepticus.³³^,⁶⁰^,⁶³ whereas an increased risk of recurrence has been observed in those with a first episode of remote symptomatic status epilepticus.

Factors for which the evidence of seizure recurrence is inconclusive include age and a history of prior provoked seizures. Although developmental factors associated with age play an important role in the occurrence and prognosis of epilepsy, it is not clear whether they play a role in predicting recurrence in patients with a first unprovoked seizure.

Contrary to other reports, two studies²⁴^,⁶⁶ have found substantial differences in recurrence risk across age groups. In both studies, children and adolescents had higher recurrence risks than did adults. The results for older adults were contradictory in these studies, one reporting a further decrease in risk⁶⁶ and the other reporting an increase.²⁴ Most studies have focused on a history of prior febrile seizures, primarily in patients with cryptogenic first seizures. In studies of children,¹⁴^,⁵⁸ a prior history of febrile seizures does not appear to be associated with the risk of recurrent febrile seizures. In a study primarily of adults,³² a history of prior provoked seizures (most of which were febrile) was associated with recurrence. Information is insufficient regarding the prognostic significance of neonatal or other prior provoked seizures.

In summary, the overall risk of recurrence after a recognized first unprovoked seizure is about 38% after 2 years. Factors increasing risk of recurrence by 2 years include an antecedent condition associated with an increased risk for epilepsy, an
abnormal EEG (particularly one with epileptiform abnormalities), and, probably, sleep state. In addition, most evidence suggests that family history of epilepsy and partial seizures are associated with a somewhat higher recurrence risk. Either such factors as sex, age at first seizure, status epilepticus, and history of prior provoked seizures were not associated with higher recurrence risk or the available information was inconclusive.

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