First unprovoked seizure: workup and management …

Epilepsy & Seizures

Updated 06.14.2023
Released 02.10.2014
Expires For CME 06.14.2026

First unprovoked seizure: workup and management

Authors: Susan Duberstein Coad MD, Shlomo Shinnar MD PhD

See Contributor Disclosures

Editor: Jerome Engel Jr MD PhD

First unprovoked seizure: workup and management

In This Article

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Introduction

Overview

Seizures are dramatic and frightening occurrences for the patient and those who witness them. Clinicians should be familiar with and reassuring about the workup and approach to management for a pediatric or adult patient presenting with a first seizure.

Key points

	• First seizure (single or multiple events within 24 hours) represents a frequent presentation of new-onset seizures, accounting for up to a third of such presentations. However, most of these patients will not go on to have recurrent seizures (ie, epilepsy).
	• An electroencephalogram (EEG) is a standard of care in children and adults. MRI is indicated except in those cases with an EEG diagnostic of a known self-limited pediatric syndrome, such as benign epilepsy of childhood with centrotemporal spikes or primary generalized epilepsy. A toxicology screen is useful in the emergency department but not in the office setting. Without a relevant history (eg, vomiting and diarrhea), other blood work is generally not helpful. A careful history will guide both investigation and treatment options.
	• Although pharmacologic treatment reduces recurrence risk, it does not alter long-term prognosis. Therefore, reserving treatment until the occurrence of the second seizure is appropriate in most cases, especially in children and adolescents.
	• Education and counseling for patients with a first seizure is important for treatment choices and safety considerations.

Historical note and terminology

Seizure (or epileptic seizure) is defined as "a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain" (15). The manifestation of a seizure can range from physical thrashing in a tonic-clonic event to the brief loss of awareness seen in a typical absence seizure. Epilepsy is "a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures" (15). The diagnosis of epilepsy requires the occurrence of at least one epileptic seizure, and even a single seizure is frightening to the patient and family. However, the psychosocial and practical ramifications of the diagnosis of epilepsy are significant, making the diagnosis of epilepsy a momentous step.

Seizures and epilepsy have long shared a hidden and stigmatized history. From ancient times, the "falling sickness" was recognized but often associated with evil and supernatural causes such as demonic possession. As recently as the 20thcentury, patients with seizures were routinely segregated and treated alongside those with psychiatric disturbances and neurodegenerative disorders such as neurosyphilis. To this day, the diagnosis of seizure is fraught with emotional, financial, and social ramifications; the diagnosis of epilepsy even more so. Therefore, the clinician addressing the diagnosis and workup of a first seizure, whether in a child or in an adult, should address the task with a comprehensive and directed approach. The primary requirement is a complete history and physical and neurologic examination. Further testing should be guided by the information thus obtained and limited to those tests indicated by the clinical presentation (22; 02; 29).

Up to 30% of first seizures are defined as “acute symptomatic” or “provoked immediate” (01). These are seizures caused either by a direct trauma or insult to the brain or by some metabolic or toxic disturbance with an effect on the brain. These seizures, especially when caused by a reversible factor, lead to only a small risk of subsequent seizures or epilepsy and are not the focus of our discussion.

Approximately 10% of the population will have at least one unprovoked seizure during their lifetime, and as much as 4% of the population carries a diagnosis of epilepsy at some point (20; 29). Up to 50% of patients presenting with an apparent first seizure prove, on careful history, to have had previous events suspicious enough for seizure to warrant the diagnosis of epilepsy (22; 29). But for those who truly present with an isolated event, the approach to diagnosis and management has changed considerably over the past few decades.

For the past few decades, the assumption was that the vast majority of people who presented with a single seizure would go on to have more seizures unless treated with medication. This view changed with the landmark paper by Hauser and colleagues, which demonstrated that only a minority of adolescents and adults with a single seizure would experience a seizure recurrence (19). Similar results were subsequently obtained in children and adolescents using the same methodology (41). Subsequently, several large landmark randomized clinical trials, including children and adults in Italy and the United Kingdom, showed that although treatment after an initial seizure reduces recurrence risk, it does not change long-term outcomes (08; 13; 36; 32). In general, our medications, although often called “antiepileptic drugs (AEDs),” are really anti-seizure medicines (ASMs), as they do not alter the natural history of epilepsy (42). Based on these studies, there was an evolving movement to not automatically initiate pharmacologic treatment after a first unprovoked seizure, but generally to wait until after a second (22; 32). This practice was first applied in children, in whom the risk-benefit ratio in favor of not treating was more clear-cut, but has since evolved to include adults (with some exceptions) (18; 13; 32). A recent Cochrane review of available studies supported this practice, confirming less than 50% seizure recurrence rates as late as 2 years (37). This review will summarize the available data.

Clinical manifestations

Presentation and course

	• First seizure usually manifests as either generalized tonic-clonic or focal onset with secondary generalization.
	• A careful history is required to elicit possible prior events that may not have been recognized as seizures.
	• Neonatal seizures, febrile seizures, and status epilepticus require separate parameters for workup and carry different prognoses from other first seizures.

In patients who present with a single seizure, including multiple events in one day, the range of seizure manifestations is fairly limited. Generalized tonic-clonic seizure is, by far, the most common (41). Seizures of focal onset with secondary generalization are also common (41). Less common are complex partial seizures and atypical prolonged absence seizures. Although patients with these seizure types can present after a single episode, they rarely do so. More commonly, on careful history, there is a several-month history of events often not identified as seizures by the patient or family, with ultimate presentation to medical attention with a convulsive event. Typical absence seizures, myoclonic seizures, and atonic seizures almost never present with a single episode and are, thus, not part of the spectrum of a single seizure presentation (22). Febrile seizures are a common seizure type in children but are considered a form of acute symptomatic or provoked seizure and, therefore, are not part of this discussion. Neonatal seizures, defined as those occurring in the first month of life, are more difficult to classify as unprovoked, require a more extensive evaluation, and are managed differently. They are, therefore, also excluded from the category of first unprovoked seizures.

First seizures can be prolonged and fit the diagnostic criteria for status epilepticus (lasting 30 minutes or more). The diagnostic evaluation of these patients is more extensive; therefore, they are excluded from most parameters addressing diagnostic evaluation of a first unprovoked seizure, which is fairly limited (22; 38; 29). It should be noted, however, that recurrence frequency and long-term prognosis are similar in such patients, and it is unclear if management is significantly different than in those presenting with a brief initial seizure (18; 39).

Prognosis and complications

The long-term prognosis of both children and adults who present with a first unprovoked seizure is favorable. Fewer than half will have a recurrence (37). Of those that do, most have very mild epilepsy with only occasional seizures; the vast majority of these are in 2-year remission within 5 years of diagnosis (08; 36; 51; 03; 32). Initial seizure frequency strongly predicts future intractability, and a single seizure is at the extreme low end of that spectrum. In addition, the epilepsy syndromes that tend to be intractable, such as Lennox-Gastaut in children and mesial temporal lobe epilepsy in adolescents and adults, rarely present with a first unprovoked seizure but usually first present to medical attention with a clear history of multiple events over the prior months.

In more than half of these patients, although the first unprovoked seizure is frightening, it is an isolated incident, and no further episodes will occur. Recurrent seizures occur in 40% to 50% (19; 41; 05; 32; 40; 37). When recurrences do occur, they occur early, with 50% occurring in the first 6 months and 80% in the first 2 years. Late recurrences are uncommon (43; 18).

First unprovoked seizures can be classified etiologically as remote symptomatic (involving a structural or metabolic abnormality), or as of unknown cause (previously cryptogenic/idiopathic) (10; 11; 04; 50). Determination of etiology may depend on workup and does affect prognosis, though it often won’t alter immediate management.

Risk factors for recurrence include a remote symptomatic etiology (including known brain lesion or insult or a new significant brain imaging abnormality), an abnormal EEG, and the occurrence of the first seizure in sleep (28). Age is not an important risk factor for recurrence, though age is clearly relevant when assessing the potential consequences of a recurrent seizure and making treatment decisions. The number of seizures in 24 hours, family history of seizures, duration of seizure, and prior history of febrile seizures also have not been proven to increase recurrence risk (05; 43; 26).

Remote symptomatic etiology has consistently been shown to increase the risk for subsequent seizures, with one meta-analysis suggesting a recurrence rate of 57% for patients with this etiology compared with 32% for those without (05). Other analyses have generally confirmed this finding (42; 49; 32; 27).

Similarly, abnormal findings on EEG indicate an increased risk of recurrence (19; 20; 05; 22; 27; 40). Distinction between types of abnormalities is of interest to the epileptologist, but in the initial assessment, the important point is that any abnormality, particularly an epileptiform one, confers additional risk (05; 27; 40).

In studies of first seizures that occur out of sleep, even after controlling for the initial presentation of syndromes that typically include such events (eg, benign epilepsy of childhood with centrotemporal spikes), recurrence is increased (24; 40). However, in these cases, recurrences also tend to occur in sleep, reducing the likelihood of patient injury (40).

A focal seizure is associated with a higher recurrence risk but is also more common in those with a remote symptomatic etiology and those with an abnormal EEG. Once we adjust for etiology and EEG, there are no clear differences on multivariate analysis in recurrence risk for those who present with a focal seizure compared to those who present with a generalized seizure. Therefore, a first focal seizure does not need to be approached differently, except for the need for imaging studies (22; 23; 29; 18).

Initiation of ongoing treatment with antiseizure medications following a first unprovoked seizure reduces seizure recurrence risk by approximately half but has no effect on long-term prognosis. This very significant statement will be discussed at greater length in the Management section below.

Although most patients with a first unprovoked seizure will never have another seizure, the first seizure is the initial presentation of a seizure disorder or epilepsy in a substantial minority. The question arises: at what point should we classify someone as having epilepsy? The traditional definition has been two or more unprovoked seizures more than 24 hours apart (10; 11; 04). In 2014, an ILAE report proposed a new and controversial definition that would include patients with a single unprovoked seizure and a high (> 60%) risk of seizure recurrence within 10 years (14). From a practical standpoint, this in no way alters the management of a first seizure. The difficulty continues to lie in appropriately assessing this statistical risk. The ILAE report concedes that “no formula can be applied for additive risks since data are lacking on how such risks combine; such risks will have to be decided by individualized considerations.” Therefore, management choices, including the use of antiseizure medications, must be individualized as well.

Following a second seizure, the risk of further seizures in both children and adults is approximately 70% (21; 43); in other words, after a second seizure, there is no group with a low recurrence risk of additional seizures, and both the diagnosis of epilepsy and the recommendation for treatment is clear. Apart from children with some of the age-dependent self-limited epilepsy syndromes, such as benign epilepsy of childhood with centrotemporal spikes, treatment is generally indicated following a second seizure. These patients now meet the diagnostic criteria for epilepsy.

Independent risk factors for subsequent seizures include remote symptomatic etiology and the occurrence of the second seizure within 6 months of the first seizure. Again, treatment reduces recurrence risk by approximately 50%, similar to the effect following a first seizure; there is little evidence that it alters long-term prognosis.

The population with a single seizure has a much lower frequency of comorbidities than patients with newly diagnosed epilepsy. To address perhaps the most common concern, there is no convincing evidence that brief seizures cause brain damage (16; 06; 23). Patients and their families should be reassured on this point.

Other comorbidities are also less frequent in this population. For example, in a cohort of children who presented with a first unprovoked seizure and were assessed 10 years later, those with two or more seizures had more school difficulties and cognitive and behavioral problems than those with a single seizure. The group with an isolated seizure did not appear different from their siblings (47).

Another major concern today is the risk of sudden unexplained death in epilepsy (SUDEP). The first seizure population is not high risk for SUDEP. A few cases of SUDEP have been reported in studies of first seizures. All have occurred in patients with established epilepsy following at least three seizures (32; 45; 46). Thus, concern about SUDEP, although influencing treatment decisions in patients with newly diagnosed epilepsy and supporting the importance of a thorough and thoughtful history, should not affect the decision of whether or not to treat following the true first seizure.

Clinical vignette

All of the following cases are fictitious.

Clinical vignette 1. Marie D. was a 5-year-old girl with no significant medical history. She was in her usual state of good health until one evening when her parents awoke to noises coming from her room. Her mother found her thrashing in bed and thought she was having a nightmare, but when she uncovered the child, she saw jerking movements of her whole body and foam coming from her mouth. Marie did not respond to her mother calling her name or touching her for 2 minutes, and then the child stopped moving and “woke up” but was confused. Marie’s father called an ambulance while her mother was watching her.

By the time the family arrived in the emergency room, Marie was awake and crying but was easily consoled with a coloring book. However, her mother told the emergency room physician that Marie was sleepy during the ambulance ride and did not seem “herself” for several minutes after the event. At this point, Marie’s parents were more upset than she was. After a careful examination in the emergency department, the physician explained to the parents that immediate workup beyond basic blood work was unnecessary. The physician referred the child for an outpatient EEG, which revealed spikes over the centrotemporal regions of the head that increased during sleep. After the syndrome of childhood epilepsy with centrotemporal spikes was explained to the parents, they were reassured. Medication was not started. When Marie had a second and similar seizure 8 months later, her parents did not call the ambulance and instead took her to her pediatrician in the morning, who reassured the family that she was well. Marie had no other medical issues and went on to have a total of four brief seizures at night over the next 3 years before “outgrowing” her epilepsy syndrome, as expected.

This is an example of how recognition of the pattern of onset of a syndrome can prevent unnecessary testing and allow reassurance and a reliable prognosis for the family.

Clinical vignette 2. Joe, a 17-year-old man, presented to the emergency department with a tonic-clonic seizure. He had been out late at a party the night before and was sleep deprived. No prior history of seizure was obtained, and he was referred to clinic as a first unprovoked seizure. Outpatient EEG and MRI were normal. On evaluation in the office, he denied a history of prior seizures. However, on careful questioning, he gave an excellent description of what were best described as déjà vu phenomena, with sensations that he had been experiencing the same situation over and over, that had been occurring for the past 6 months. When asked if his friends could tell he was having these symptoms, he replied that they told him that he looked “spacey.” Although Joe was referred as a first unprovoked seizure, he had, in fact, had epilepsy for the past 6 months and finally presented to medical attention when, in the context of sleep deprivation, he had a convulsive event. Over time, his syndrome was determined to be temporal lobe epilepsy based on subsequent EEGs.

Distinguishing a case like Joe’s from a true first unprovoked seizure is very important; a careful history is crucial.

Clinical vignette 3. Ms. Smith, a 25-year-old woman living in Manhattan, had a generalized tonic-clonic seizure lasting 1 minute. Neurologic and physical evaluation in the emergency department was unremarkable. Subsequent EEG and MRI were normal. At her follow-up visit in the office, she wanted to know whether she needed to be on antiepileptic drugs. She did not drive or operate heavy machinery. She was in graduate school and in a relationship, planned to marrry soon, and was considering having children in a few years. A careful history elicited no prior suspicious events.

In this young woman, the risk-benefit ratio clearly favored no treatment unless a second event occurred. She was counseled to take seizure precautions, but no treatment was started. She did not have a second event in the next few years, and the burdens of taking medication and repeated testing were thus avoided.

Clinical vignette 4. Mrs. Jones, a 70-year-old woman with osteoporosis, hypertension, and heart disease who lived in an assisted living residence, had a generalized tonic-clonic seizure. On arrival at the emergency department, she was somewhat confused. EEG was normal. MRI showed diffuse atrophy and a small, old infarct in the right anterior cerebral artery distribution. Neurologic examination when she returned to baseline showed mild dementia. No clear history of prior events was elicited. In this patient, the recurrence risk was high, and, more importantly, the potential morbidity of another seizure in a patient with heart disease and osteoporosis was significant. This justified treatment after only one seizure, although, given all the other medications she was taking, a drug with minimal enzyme induction and drug-drug interactions was preferred, if effective.

Biological basis

Localization

Brain imaging is usually normal, and EEG is either normal or nonlocalizing (22; 29). Therefore, it is frequently difficult to definitively localize the seizure onset.

In patients who go on to have recurrent seizures, more definitive localization is often made, sometimes with the help of serial EEGs. But with the exception of centrotemporal seizures or cases in which localization is well defined by EEG or MRI, one cannot accurately localize seizure onset in patients who present with a single seizure.

Pathophysiology

Normal neuronal electrical activity is nonsynchronous. In seizures, a group of neurons begin firing in an abnormal, excessive, and synchronized manner. This results in a wave of depolarization, or paroxysmal depolarizing shift. The manifestation of the seizures depends on the location of the abnormally functioning neurons.

An excitatory neuron normally becomes more resistant to firing for a period of time (refractory period) after depolarization; this results from a combination of the effect of inhibitory neurons, electrical changes within the excitatory neuron, and the negative effects of inhibitory inotropes. In epilepsy, this refractory period is decreased. The pathophysiology of the changes involved is not perfectly understood but may result in a specific area from which seizures may develop, known as a "seizure focus." Possible mechanisms include dysfunction of ion channels or inhibitory neurons, upregulation of excitatory circuits, or downregulation of inhibitory circuits (12).

The pathophysiology of a first unprovoked seizure is, as far as we know, not different than that of a seizure occurring in the context of an established epilepsy. In support of this, the clinical semiology is the same, and the list of causes is also the same. Furthermore, when the EEG is abnormal, the abnormalities (such as centrotemporal spikes or generalized spike-and-wave) are identical to those seen in patients with epilepsy syndromes defined by these abnormalities. Indeed, if the patient has an additional seizure, he would meet the criteria for those syndromes. We do not at this point fully understand why some patients who have the EEG characteristic of an epilepsy syndrome never have a clinical seizure, some have only one, and some go on to have recurrent unprovoked seizures or epilepsy. Presumably, both genetic factors and environmental influences are involved.

Differential diagnosis

Confusing conditions

The differential diagnosis of first seizure focuses on three issues:

1. Was the event a seizure?

2. If yes, was it unprovoked?

3. If yes, was it really the first event, or was it the first presentation to medical attention of someone who turned out to have had prior seizures?

Was the event a seizure? Episodes of loss of consciousness or syncope are often associated with some myoclonic or even frank convulsive movements, but the primary event may not be a seizure. In both pediatric and adult series of syncope (33; 34), approximately 5% of cases turn out to be seizures, and these are often not correctly diagnosed until there have been multiple events. The evaluation of syncope is different from that of a clear seizure and is outside the scope of this review.

In children, adolescents, and young adults, forms of complex migraine (including basilar artery migraine, acute confusional migraine, hemiplegic migraine, and Alice in Wonderland syndrome) may be misdiagnosed as seizures. Many patients with these migraines have an abnormal EEG, which further confuses the differential. A careful history will help to differentiate the two entities. In adults, particularly older ones, events such as transient global amnesia and transient ischemic attacks may be confused with complex partial seizures. Acute drug intoxication can also mimic a complex partial seizure. Nonepileptic events are in the differential but rarely present with a single event. For a review of events that can mimic a seizure, the reader is referred to the monograph by Kaplan and Fisher (25).

If a seizure, was it unprovoked? The key differential is between unprovoked seizures (which include those with a remote cause, such as head trauma or stroke) and acute symptomatic seizures due to a direct or ongoing insult (including infection, stroke, hemorrhage, drug ingestion, and other acute causes). As noted in the section on diagnostic management, the focus of the immediate evaluation is to exclude acute abnormalities that may need immediate therapy; this can usually be done based on history and examination. The patient with a brief seizure who quickly and fully returns to baseline is unlikely to have had an acute symptomatic event. Failure to return to baseline within 30 minutes should prompt a more extensive and urgent evaluation of possible causes; the possibility of ongoing seizure activity, including nonconvulsive status epilepticus, should not be overlooked.

In young children, febrile seizures, which are a specific age-related and benign form of acute symptomatic seizures, are very common. Approximately 20% will not have a recognized fever at the time of the seizure; instead, the fever develops later. It is important to recognize that fever developing up to 24 hours after the seizure still meets the criteria for a febrile seizure, and these events should not be classified as unprovoked seizures (07; 40).

If an unprovoked seizure, is it truly the first? As noted above, a substantial percentage of cases who present with an apparent first unprovoked seizure turn out, on careful history, to have had prior events that are likely or definitely seizures (22; 02; 29). Clinical vignette 2 provides a typical example of such a case. In the past, when anyone with even a single seizure was presumptively treated, this was not as critical a part of the diagnostic evaluation. However, now that patients with a first unprovoked seizure are frequently untreated, making this distinction is a crucial part of the diagnostic history. Clearly, the young man described in Clinical vignette 2 would be treated, whereas many neurologists, including the authors, would not treat him after the initial event if no such history was elicited.

Associated and underlying disorders

By definition, children and adults who present with a single seizure, as distinct from those who first present to medical attention and already have a history of prior events that are felt to be seizures, do not have epilepsy. In fact, an isolated unprovoked seizure was recognized as a distinct entity in the prior classification of epilepsy syndromes (10).

However, one can analyze which epilepsy syndromes initially present as a single unprovoked seizure. Most will have a normal EEG and MRI and, thus, not fit into any recognized syndrome. In children with a single unprovoked seizure, the most common syndrome is self-limited epilepsy with centrotemporal spikes (SeLECTS), formerly termed Rolandic epilepsy (48); these children may present with either a focal onset or generalized seizure. The next most common is children who present with a tonic-clonic seizure and prove to have an EEG with generalized spike-and-wave, meeting criteria for primary generalized epilepsy (44).

Identifiable syndromes are far less common in adults with a first unprovoked seizure. The most common identifiable syndrome is a tonic-clonic seizure with an EEG demonstrating generalized spike-and-wave. Adult-onset idiopathic generalized epilepsy is not thought to be significantly different from the more common childhood-onset syndromes in pathophysiology or genetics, but frequently the history elicits a precipitant of alcohol use or sleep deprivation (31). These are considered “triggers,” but the seizures are still unprovoked; the term “provoked” is reserved for events (stroke, head trauma, fever in a child) that can cause a seizure even in someone without an underlying seizure disorder. If such precipitants are a clear trigger for that patient, then the patient can be counseled to avoid them; they are common enough that it is good practice to preemptively provide counseling even if the patient does not report them.

Although temporal lobe epilepsy can present with a single seizure, this is uncommon (17). The more common presentation is after 6 months to 2 years of complex partial seizures (eg, clinical vignette 2). The common epilepsy syndromes of childhood absence and juvenile myoclonic epilepsy do not present with a single seizure; neither do developmental epileptic encephalopathy syndromes, such as infantile spasms syndrome (formerly West syndrome), epilepsy with myoclonic astatic seizures (EMAts, formerly Doose syndrome), and Lennox-Gastaut syndrome.

Diagnostic workup

	• Diagnostic evaluation begins with emergent workup to rule out acute provoking factors and also to rule out ongoing seizure activity.
	• A careful history will help clarify the event and whether it is an isolated phenomenon.
	• Emergent laboratory testing in patients with no signs of illness and who have returned to baseline is of limited utility.
	• Electroencephalogram is recommended in the evaluation of both children and adults with first unprovoked seizure. Magnetic resonance imaging is pursued in adults but may not be needed in pediatric patients.

The diagnostic evaluation of the patient who presents with an apparent first unprovoked seizure consists of two parts: emergent workup and subsequent outpatient evaluation. In the emergency department, workup should begin with verification that the patient has normal vital signs and adequate oxygenation and that there is no further seizure activity. Following this, a careful history and physical examination should determine imaging and laboratory testing decisions (22; 02; 29). Once the patient is stable, the focus is on establishing that the event was a seizure and, once that is done, on excluding acute symptomatic causes, which may require immediate medical attention.

The history should initially focus on determining whether a seizure actually occurred and evaluating the circumstances and characteristics of the event. The patient’s memory of the event, and the time immediately preceding it, should be carefully investigated even if compromised by ictal amnesia or by possible historical inaccuracy (ie, due to young age or dementia). If the event was witnessed, the patient’s behaviors during the event and evidence of partial onset may be important in identifying a specific form of epilepsy. A history of trauma or symptoms of infection (eg, stiff neck, fever, headache) may raise the likelihood of a provoked seizure requiring a directed workup or treatment. The patient should be asked about medications, illicit drug use, and alcohol use; this history should be elicited even in pediatric patients. A history of neurologic or developmental disorders or a family history of epilepsy may also provide guidance. The physical examination should include a thorough neurologic and mental status evaluation to rule out the possibility of neurologic deficits or ongoing events.

If the event is deemed an unprovoked seizure, laboratory tests and imaging are of limited acute utility in treatment or diagnosis. It is important to distinguish the acute workup from nonemergent testing. The acute workup is fairly brief in the patient who has returned to baseline. A toxicology screen is appropriate in the emergent setting but not in the nonacute or office setting. In patients who have returned to baseline and who have no neurologic deficits on examination, an emergency CT scan, which has a lower diagnostic yield than nonemergent MRI, is generally unnecessary.

The use of serum prolactin measurement has been investigated in distinguishing an epileptic seizure from a nonepileptic event; however, it should be noted that the sensitivity of this test, which must be obtained within 10 to 20 minutes of the event, is approximately 60% for generalized tonic-clonic seizures and 46% for complex partial seizures (09). Additionally, because serum prolactin levels can be elevated in cases of syncope, it is not useful in distinguishing between syncopal episodes and seizures (09). Therefore, current practice parameters do not recommend the routine use of this test in this setting (22; 29). Similar results have been reported in the use of creatine kinase levels (30). Other laboratory testing results, including blood counts, blood glucose, electrolytes, and lumbar puncture, should be considered as the clinical picture warrants.

The elective evaluation of the patient with a first unprovoked seizure includes, in addition to a careful history and examination by the neurologist, an EEG, and an MRI. The EEG is considered a standard of care in evaluating children and adults with a first unprovoked seizure (22; 29). It is abnormal in approximately half the children and one quarter of adults. In addition to providing prognostic information about the risk of recurrence, which may influence treatment decisions, it also provides additional information about the underlying syndrome and potentially long-term prognosis.

Imaging abnormalities are present in approximately 10% to 20% of children and adults with a first unprovoked seizure (22; 29). These abnormalities, when found, generally do not require acute intervention but may alter recurrence risk. Particularly in adults, they may also offer valuable information as to the cause of the seizure, which may require other medical therapy. For example, if there is a remote symptomatic stroke, such as in clinical vignette 4, treatment of the vascular disease may be indicated.

In adults, imaging with MRI is routinely recommended following a first unprovoked seizure, except in those cases where the cause is already known based on prior evaluation for a neurologic disorder. In children, the story is more complex. Imaging is not necessary in what were previously called the idiopathic focal epilepsies (self-limited epilepsy with centrotemporal spikes/SeLECTS and self-limited epilepsy with autonomic symptoms/SeLEAS) or in the primary generalized epilepsies (childhood absence epilepsy, juvenile absence epilepsy, and juvenile myoclonic epilepsy). In other cases, MRI is recommended, though one must weigh the risk and benefits in younger children if sedation is needed to obtain an adequate study (22).

Management

A number of randomized clinical trials in both children and adults have convincingly demonstrated that following a first unprovoked seizure, treatment with chronic antiseizure medication therapy reduces recurrence risk by approximately 50% but has no impact on long-term prognosis (08; 36; 23; 32; 28). Therefore, treatment is indicated in those cases where the risk of a second seizure outweighs the risks of chronic antiseizure medication therapy.

In children, the consensus as of 2023 is that treatment is not usually initiated after a first unprovoked seizure. In adults, the statistical risks of recurrence are the same, but the risk-benefit calculation is different. The publication of guidelines on the management of unprovoked first seizure in adults (28) do not substantially change the previous management standard. The updated guideline is in consensus with previous recommendations regarding the recurrence risk within the first 2 years and with the risk factors increasing the rate of recurrence. It does treat more explicitly the question of initiation of antiseizure medications pending a second seizure, suggesting that patients be advised that treatment “will not improve the long-term prognosis but will reduce seizure risk over the subsequent two years,” further noting that most adverse events associated with the use of antiseizure medications are “mild and reversible.” However, the guideline also states that no objective improvement in quality of life is associated with earlier use of antiseizure medications, an important outcome measure that is often not fully considered when analyzing risks and benefits (14). It is also worth noting that in the MESS study, one of the larger multicenter studies to include quality of life as an outcome measure, adults who were not immediately started on an antiseizure medication reported equivalent satisfaction with their treatment as those who were. Furthermore, those who were randomized to immediate treatment were more likely, in follow-up, to prefer the alternative (ie, deferred treatment) (32).

Statistical risks alone can never give the whole picture. Refer to clinical vignette 3, which discussed a 25-year-old woman with a single generalized tonic-clonic seizure who intends to have children soon, takes public transportation, and worked in an office setting. Contrast this with an alternate example of a 30-year-old man with the same first seizure and clinical workup but who drives a truck for his job and lives in the country. The practical effect of a second seizure on this patient may be vastly more serious, although the theoretical risk of recurrence may be identical.

Ultimately, there is no clear generalized management plan and no formula that can accurately stratify risks and benefits, so the clinician must approach each case individually. Nevertheless, the evolving view is that although more adults with a first seizure will be treated than children, this decision should be case-based, and often no treatment is needed. Although the statistical risks are also similar in the elderly, the potential severe consequences, such as a broken hip or stress on a fragile individual, usually argue in favor of treatment.

In those cases in which the clinician, after discussing risk and benefits with the patient and family, decides to initiate antiseizure medication therapy, the choice of medication should be based on seizure type, EEG and imaging findings, age, gender, and comorbidity. Medication choices do not differ from those for newly diagnosed epilepsy. A detailed discussion of first-line antiseizure medications for different seizure types is outside the scope of this discussion.

In cases where the first seizure was prolonged or consisted of a flurry of seizures in one day, consideration should be given to providing an abortive agent (typically some form of a benzodiazepine), whether or not chronic antiseizure medication therapy is initiated. Although FDA-approved only as adjunct therapy to chronic antiseizure medication therapy, these agents appear to be equally effective in the setting of a first unprovoked seizure without concomitant antiseizure medication therapy.

Regardless of whether treatment with antiseizure medications is initiated, the patient should be instructed not to drive for a period, which varies in different jurisdictions. Proper counseling on this topic is significant for patient safety and medicolegal protection for the physician; clinicians should be aware of local statutes regarding driving prohibition and reporting standards and should document this discussion carefully. Patients should also be instructed about seizure precautions in situations such as swimming or engaging in activities such as scuba diving or skydiving. Treatment reduces but does not eliminate recurrence risk and, thus, does not alter the need for seizure precautions. In addition, though risk is low after a first seizure, there are increasing recommendations for early discussion of SUDEP in patients whose history suggests the development of an epilepsy syndrome (35; 52).

Ultimately, treatment decisions and management need to be individualized based not just on the statistical risk of further seizures but also on the potential consequence of another seizure, which needs to be weighed against the morbidity of chronic antiseizure medication therapy. Fortunately, patients who present with a first unprovoked seizure very rarely go on to have medically refractory epilepsy and have a favorable long-term prognosis regardless of the choice of treatment or watchful waiting.

References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Susan Duberstein Coad MD

Dr. Duberstein of the Montefiore Medical Center and Albert Einstein College of Medicine has no relevant financial relationships to disclose.
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Shlomo Shinnar MD PhD

Dr. Shinnar of the Montefiore Medical Center and Albert Einstein College of Medicine received consulting fees for service on drug safety monitoring boards from UCB and Eisai.
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Editor

Jerome Engel Jr MD PhD

Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, has no relevant financial relationships to disclose.
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First unprovoked seizure: workup and management

Associated Disorders

Epilepsy
Status epilepticus

Differential Diagnosis

basilar artery migraine
acute confusional migraine
hemiplegic migraine
Alice in Wonderland syndrome
transient global amnesia
- transient ischemic attacks
- acute drug intoxication
- nonepileptic events
- acute symptomatic seizures due to an acute insult
- febrile seizures

Also Relevant

Absence status epilepticus
Epilepsy
Epilepsy with myoclonic-atonic seizures
Febrile seizures
Focal clonic seizures
- Generalized onset tonic-clonic seizures
- Juvenile myoclonic epilepsy
- Myoclonic-atonic seizures
- Self-limited epilepsy with centrotemporal spikes
- West syndrome

First unprovoked seizure: workup and management …

First unprovoked seizure: workup and management

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Localization

Pathophysiology

Differential diagnosis

Confusing conditions

Associated and underlying disorders

Diagnostic workup

Management

References

Contributors

Authors

Editor

Patient Profile

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Photosensitive occipital lobe epilepsy

Intermittent explosive disorder

Pyridoxine/P5P-dependent developmental epileptic encephalopathy

Reflex seizures

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Epilepsy with auditory features

Alcohol withdrawal seizures

First unprovoked seizure: workup and management

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Localization

Pathophysiology

Differential diagnosis

Confusing conditions

Associated and underlying disorders

Diagnostic workup

Management

References

Contributors

Authors

Editor

Patient Profile

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Photosensitive occipital lobe epilepsy

Intermittent explosive disorder

Pyridoxine/P5P-dependent developmental epileptic encephalopathy

Reflex seizures

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Epilepsy with auditory features

Alcohol withdrawal seizures

This is an article preview.
Start a Free Account
to access the full version.