Evaluation of First Seizure and Newly Diagnosed Epilepsy

Elaine Wirrell, MD, FRCP(C), FAAN Epilepsy p. 230-260 April 2022, Vol.28, No.2 doi: 10.1212/CON.0000000000001074
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KEY POINTS

Epilepsy is defined as any of the following: (1) at least two unprovoked (or reflex) seizures occurring more than 24 hours apart, (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years, or (3) diagnosis of an epilepsy syndrome.

A careful history taken from both the patient as well as any witnesses to the event(s) is the most critical aspect in distinguishing a seizure from a nonepileptic paroxysmal event.

It is the first convulsive seizure that typically brings the patient to medical attention. Many people presenting with a “first seizure” have a history of prior seizures, which may not have been recognized, and thus have epilepsy.

A diagnosis of an epilepsy syndrome is possible in approximately one-quarter of epilepsy cases beginning in infancy and childhood but is less frequently found in adults. Diagnosis of a specific syndrome provides key information to assist with choosing optimal investigations and treatment and for providing accurate prognosis.

Genetic causes of epilepsy are increasingly recognized. In some cases, such as the idiopathic generalized epilepsies, inheritance is polygenic, and pathogenic variants are typically not found on gene panels. In other cases, particularly in early-onset developmental epileptic encephalopathies, inheritance is monogenic, and pathogenic variants are identified on epilepsy gene panels or whole-exome sequencing.

Increasingly, specific antibodies are being detected in people with autoimmune encephalitis that result in acute symptomatic seizures. These should be distinguished from immune-mediated epilepsies in which an enduring predisposition to seizures is present.

Despite advances in neuroimaging and genetics, approximately 40% of people with new-onset epilepsy have no known etiology found.

Cognitive and psychiatric comorbidities are common in people with epilepsy and often predate seizure onset. The causes are multifactorial, but they are critical to diagnose and treat as they often have an even greater impact than seizures on quality of life.

An EEG is indicated in all patients with new-onset, unprovoked seizures. Care must be taken to avoid misinterpreting normal variants as epileptogenic. The EEG assists with determination of seizure and epilepsy type, choice of further investigations, and prognosis regarding the risk for seizure recurrence.

Neuroimaging is recommended for all patients with new-onset, unprovoked seizures, except those with a well-defined, drug-responsive idiopathic generalized epilepsy or self-limited focal epilepsy of childhood. In patients who have returned to their neurologic baseline and for whom there are no concerns for an acute neurologic process, urgent CT is not needed. Rather, MRI can be obtained on an outpatient basis.

Routine blood and urine studies are commonly obtained but of low yield in patients with new-onset, unprovoked seizures.

A lumbar puncture should be considered if the clinical picture is suggestive of possible meningitis, encephalitis, or subarachnoid hemorrhage but is otherwise is of low yield.

All patients with new-onset, unprovoked seizures must be counseled about lifestyle issues, seizure safety, and what to do if further seizures occur. Water safety is of utmost importance. Showers are safe; however, bathing or swimming alone is not recommended.

Although immediate initiation of antiseizure medication after a first unprovoked seizure does reduce the risk of recurrence, it does not impact long-term epilepsy outcome or quality of life.

PURPOSE OF REVIEW This article focuses on the evaluation of children and adults who present with new-onset seizures, with an emphasis on differential diagnosis, classification, evaluation, and management.

RECENT FINDINGS New-onset seizures are a common presentation in neurologic practice, affecting approximately 8% to 10% of the population. Accurate diagnosis relies on a careful history to exclude nonepileptic paroxysmal events. A new classification system was accepted in 2017 by the International League Against Epilepsy, which evaluates seizure type(s), epilepsy type, epilepsy syndrome, etiology, and comorbidities. Accurate classification informs the choice of investigations, treatment, and prognosis. Guidelines for neuroimaging and laboratory and genetic testing are summarized.

SUMMARY Accurate diagnosis and classification of first seizures and new-onset epilepsy are key to choosing optimal therapy to maximize seizure control and minimize comorbidities.

Address correspondence to Dr Elaine Wirrell, Mayo Clinic, 200 First St SW, Rochester MN 55905, [email protected].

RELATIONSHIP DISCLOSURE: Dr Wirrell has received personal compensation in the range of $500 to $4999 for serving as a Consultant for BioMarin and Eisai Co, Ltd, and for serving on a scientific advisory or data safety monitoring board for Amicus Therapeutics, Inc, Encoded Therapeutics, Inc, and Neurocrine Biosciences, Inc, and has received publishing royalties from UpToDate, Inc.

UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Dr Wirrell reports no disclosure.

INTRODUCTION

Approximately 8% to 10% of the population will experience a seizure, and approximately 1 in 26 people will develop epilepsy in their lifetime, making seizures one of the most common neurologic problems. The epilepsies are a diverse group of conditions that share a predisposition to recurrent, unprovoked seizures. In addition to seizures, the majority of patients have cognitive, psychiatric, or medical comorbidities, which must be appropriately diagnosed and treated. Correctly identifying the epilepsy type and syndrome, as well as the underlying etiology, is critical for choosing cost-effective, yet high-yield investigations, optimizing therapy, and understanding long-term prognosis.

What Is a Seizure?

An epileptic seizure was defined by the International League Against Epilepsy (ILAE) as “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.”

What Is Epilepsy?

Epilepsy was defined in 2005 as “a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition.” In 2014, the ILAE proposed a practical clinical definition for epilepsy that included any of the following: (1) at least two unprovoked (or reflex) seizures occurring more than 24 hours apart, (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years, or (3) diagnosis of an epilepsy syndrome.

APPROACH TO DIAGNOSIS

A careful clinical history taken from both the patient as well as any witnesses to the clinical event(s) is the most critical aspect of making an accurate diagnosis. The questions that follow must be answered.

Is This a Seizure or a Nonepileptic Event?

Multiple, nonepileptic paroxysmal events can mimic seizures, and thus, a careful clinical assessment is required to reach an accurate diagnosis. Some of these epilepsy mimics require prompt diagnosis to prevent adverse outcomes (ie, prolonged QT syndrome). The patient should be asked to describe the event from onset, including any auras or postictal symptoms. A history of incontinence, tongue biting, or carpet burn is more suggestive of a seizure. Terminology should be clarified; for example, the term dizziness may reflect lightheadedness or vertigo, and an abnormal sensation in the abdomen could reflect either nausea or an abnormal rising sensation. The physician should ask about what the patient was doing at the onset, as well as possible triggers, intercurrent illnesses, or medications. It is immensely helpful to speak directly to the witness of the clinical event also, and this can be done by phone while the patient is in the office. Observers should be asked about skin color change, motor findings (ie, was the patient abnormally limp or stiff), types of abnormal movement (ie, rhythmic clonic versus irregular shaking), response to voice or touch during the event, and any postictal confusion, sleepiness, focal weakness, or language difficulties. If the diagnosis is suggestive of a generalized tonic-clonic seizure, one should ask carefully about any focal features (ie, deviation of the eyes or head) or confusion before onset. A thorough physical examination done immediately after the seizure may show evidence of lateral tongue bites, bruises, or other injury due to a fall or convulsive activity, and transient neurologic signs or focal weakness suggestive of a Todd paralysis, which may provide important information on the likely seizure localization.

Studies carried out in multiple settings have reported misdiagnosis rates ranging from 4.6% to 30%. In adults, the misdiagnosis rate was higher for patients diagnosed by nonspecialists than neurologists (19.3% versus 5.6%), and the most common final diagnoses in misdiagnosed patients are cardiovascular syncope and psychogenic nonepileptic events. Approximately 24% of children referred with a first seizure were found to have had a nonepileptic event, and in one study, 39% of children who were admitted to a tertiary epilepsy center were found to not have epilepsy. Common final diagnoses in children included nonepileptic staring spells (eg, daydreaming), psychogenic nonepileptic events, syncope, parasomnias, and breath-holding spells. In many cases, incomplete history taking and overinterpretation of the EEG contribute to misdiagnosis. Common seizure mimics, typical ages at their presentation, and clinical characteristics are listed in table 1-1.

case 1-1 illustrates the importance of relying on a careful history and avoiding overinterpretation of EEG.

CASE 1-1

A 13-year-old girl presented with recurrent spells of lightheadedness without vertigo. These occurred more commonly when she stood up too quickly. She had two more severe events, one during a discussion on frog dissection in biology class and another while she was getting her blood drawn. Her examination was normal.

Her EEG was interpreted as showing independent bitemporal sharp waves in drowsiness and sleep. She was diagnosed with focal epilepsy and was started on oxcarbazepine. Her lightheadedness persisted, and she had two more spells; one was just before a subsequent EEG when the EEG technician was rubbing the girl’s head, and the other was after she skinned her knee. During these spells, she was said to feel “woozy,” look pale, and drop slowly to the ground. She lost consciousness and remained limp for about 30 seconds, then gradually recovered over about 2 to 5 minutes.

She underwent video-EEG monitoring, during which time the EEG technician rubbed the girl’s head to induce her spell. The EEG (figure 1-1) was found to be consistent with syncope, due to a cardiac cause, as opposed to seizure. Careful review of her initial EEG showed 14 and 6 positive spikes as opposed to bitemporal sharp waves, which are a normal variant and not epileptiform.

COMMENT

This case exemplifies that a careful history taken from both the patient as well as any witness to the event is the most critical aspect in distinguishing a seizure from a nonepileptic paroxysmal event. A diagnosis of epilepsy cannot be made solely by relying on EEG findings.

In some cases, confident differentiation of a seizure from a nonepileptic event may not be possible as specific historical details may be lacking. In the absence of other compelling data, careful follow-up to clarify the diagnosis before initiation of antiseizure medication is recommended.

If a Seizure, Is This Provoked or an Acute Symptomatic Seizure Versus an Unprovoked Seizure?

Provoked seizures are due to identifiable causes such as toxins, drugs, or metabolic factors. Most people with provoked seizures have a history of confusion or behavior change that precedes the seizure and often persists beyond the typical postictal phase. Additionally, provoked seizures are usually generalized convulsive events, as opposed to focal seizures. Details of use or abrupt cessation of any prescription medication or drug of abuse, including alcohol, should be queried. Abrupt withdrawal of benzodiazepines, barbiturates, or alcohol may lead to seizures. Young children may accidentally ingest medications or toxins in the home, and thus, a careful inventory of all such agents in the home is critical. Details of any chronic medical condition that could lead to metabolic disturbances, such as diabetes or kidney disease, should be sought. Careful assessment of vital signs and other clinical findings may point to a specific toxidrome. Laboratory screening including serum glucose, electrolytes, renal and liver function, and urine toxicology should be considered as patients with provoked seizures may require urgent therapy to address the underlying cause and prevent further brain injury (eg, hypoglycemia). In most cases of provoked seizures, prophylactic antiseizure medication is not required. The basic mechanisms by which toxins lead to provoked seizures are (1) increased excitation, (2) decreased inhibition, or (3) withdrawal of central nervous system depressants, and these categories are outlined in table 1-2.

Acute symptomatic seizures result from an acute brain process such as encephalitis, stroke, or traumatic brain injury. The history and physical examination often provide important clues to the underlying diagnosis, and these patients typically present with other neurologic findings consistent with their brain injury, such as focal deficits and abnormal vital signs including fever. Seizure symptomatology often reflects the location of the acute brain process, and seizures usually are focal in onset. With acute symptomatic seizures, specific treatment targeted to the underlying brain process may be required; however, patients may additionally need short-term antiseizure medication

If This Is an Unprovoked Seizure, Does This Person Have Epilepsy?

Several studies have shown that a significant minority of patients presenting with an alleged first, unprovoked seizure have actually experienced prior seizures. It is typically the first convulsive seizure that brings the patient to medical attention, whereas other seizures including absence, myoclonic, or focal seizures without motor manifestations may have previously occurred but have not been recognized. Correctly identifying these events is critical to making a correct diagnosis of epilepsy. Thus, patients and their families should be carefully questioned about any episodes of unresponsive staring, isolated quick body jerks, and symptoms of nocturnal seizures such as unexplained tongue biting or incontinence. Confirming a diagnosis of epilepsy as opposed to a single seizure may have implications for the initiation of prophylactic antiseizure medication.

case 1-2 illustrates how the EEG can sometimes confirm a diagnosis of epilepsy, as opposed to a single unprovoked seizure, and thus alter recommendations for treatment.

CASE 1-2

A 19-year-old woman presented with her first generalized convulsive seizure. She had been up late the night before and had a 3-minute generalized tonic-clonic seizure, which was witnessed by her roommate, approximately 10 minutes after getting up for work the next day. She denied any aura. During the seizure, she lost bladder continence and bit the side of her tongue. Her examination 2 hours after the seizure was unremarkable, and her basic metabolic panel was normal.

Her paternal aunt had epilepsy as a young adult, which was well controlled with medication.

On EEG (figure 1-2), she was found to have generalized polyspike-and-wave discharge and had several myoclonic jerks with clinical correlate occurring spontaneously as well as with photic stimulation.

She admitted to episodes of hand-twitching in the morning that caused her to spill her tea but had attributed that to nervousness. Based on the history and EEG, she was diagnosed with juvenile myoclonic epilepsy, and antiseizure medication was initiated.

COMMENT

This case emphasizes that it is the first convulsive seizure that typically brings the patient to medical attention. Many patients presenting with a “first seizure” have a history of prior seizures that may not have been recognized and, thus, have epilepsy. In this case, the patient described hand-twitching in the morning, which was consistent with early-morning myoclonus.

If This Is Epilepsy, What Type Is This?

The ILAE published a revised classification of seizure types (figure 1-3) and epilepsies (figure 1-4) in 2017. These frameworks provide a mechanism to understand the possible seizures patients have, what other seizure types they may develop, potential triggers, underlying etiology, and prognosis. Furthermore, classification also informs the risk of important comorbidities, including learning disorders, intellectual disability, psychiatric disorders, and mortality.

Seizure type

The first level of classification is the seizure type, which is divided into focal, generalized, and unknown onset. A generalized-onset seizure engages bilateral brain networks from onset, whereas a focal seizure begins within one region or hemisphere. Generalized-onset seizures are classified into motor or nonmotor types, the latter comprising various subtypes of absence seizures. Focal seizures are subdivided based on awareness (aware versus impaired awareness) and motor symptoms (motor: tonic, clonic, atonic, or myoclonic activity; nonmotor: behavior arrest, cognitive, emotional, sensory, or autonomic features). Importantly, a focal seizure may evolve to bilateral convulsive activity, and thus, one must carefully probe for auras or other focal features that preceded a generalized tonic-clonic seizure.

Both focal impaired-awareness seizures, as well as absence seizures, may present with staring spells. Important distinguishing features between these seizure types are shown in table 1-3.

Epilepsy type

The second level of classification focuses on epilepsy type, which is based on the type(s) of seizures the patient is having. Epilepsy types are divided into generalized, focal, combined generalized and focal, or unknown. A diagnosis of generalized epilepsy would be made in a patient who has one or more types of generalized seizures, which would include tonic, tonic-clonic, absence, myoclonic, or atonic as well as generalized spike-and-wave discharge on EEG. One needs to be cautious with a patient with a generalized tonic-clonic seizure and normal EEG as it is unclear if that seizure was truly generalized in onset or evolved to a bilateral tonic-clonic seizure.

Conversely, a diagnosis of focal epilepsy would be made if a patient has had one or more types of focal-onset seizures, which could include focal to bilateral tonic-clonic seizures. In most cases of focal epilepsy, the interictal EEG will show focal epileptiform discharge; however, this EEG finding is not required to make a diagnosis of focal epilepsy.

Less commonly but importantly, there are some patients who have both generalized and focal seizures who have generalized and focal epilepsy. This subgroup is most common in some of the early-onset, drug-resistant epilepsies such as Lennox-Gastaut syndrome or Dravet syndrome. These patients have a history of both generalized and focal seizure types, and their interictal EEG may show both generalized and focal discharges; however, epileptiform activity is not required for this diagnosis and is made on clinical grounds.

The term unknown is used if information is inadequate to determine the epilepsy type.

Epilepsy syndrome

An epilepsy syndrome is a characteristic cluster of clinical and EEG features that may be supported by specific etiologic findings. Syndromes often have age-dependent presentations and specific comorbidities. Many carry important implications for the choice of specific therapy and prognosis, and we are seeing an increased focus on drug trials in defined syndromes.

The ILAE has convened a task force to provide definitions for the various syndromes, and their educational website provides an excellent resource for the diagnosis of epilepsy syndromes. An epilepsy syndrome is identifiable in approximately one-quarter of epilepsy cases beginning in infants and children but is less frequent in adult-onset epilepsy. table 1-4 provides an overview of some of the more common epilepsy syndromes, along with their clinical and EEG features and long-term prognosis.

The 2017 classification defined the term developmental and epileptic encephalopathy to describe epilepsies that are associated with underlying encephalopathy, where both the underlying etiology (developmental) and the frequent seizures and epileptiform discharges (epileptic) are felt to contribute to the encephalopathy. Although this term can be applied to people at any age, the developmental and epileptic encephalopathies most commonly have an onset early in life. Developmental and epileptic encephalopathies can be defined by epilepsy syndrome (ie, infantile epileptic spasms syndrome, Dravet syndrome, Lennox-Gastaut syndrome) or by etiology. In most cases, developmental and epileptic encephalopathies are correlated with a high risk of lifelong, drug-resistant seizures, variable degrees of intellectual disability (often severe), and multiple other medical and behavioral comorbidities.

The idiopathic generalized epilepsies collectively account for approximately 15% to 20% of all epilepsies and are made up of four syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic-clonic seizures alone, with juvenile myoclonic epilepsy being the most prevalent among this group. These epilepsies typically affect developmentally normal children and young adults and present with varied types of generalized seizures. The main seizure type(s) and typical age at presentation vary among the syndromes. In many cases, complete seizure control may be achieved with medication, and in childhood absence epilepsy, remission often occurs by adolescence.

Another important syndrome group is the self-limited focal epilepsies of childhood, which comprise self-limited neonatal epilepsy, self-limited infantile epilepsy, self-limited epilepsy with autonomic seizures, and self-limited epilepsy with centrotemporal spikes. Depending on the syndrome, seizures have an onset anywhere from the neonatal period through late childhood but remit with time.

case 1-3 illustrates how defining the epilepsy syndrome can help choose cost-effective investigations and therapies and provide an accurate prognosis.

CASE 1-3

A 9-year-old boy, who was previously well, presented to the emergency department with his first witnessed generalized tonic-clonic seizure that occurred around 6:30 am. His mother was getting ready for work and heard a choking sound from her son’s room. She found him having a generalized convulsive seizure that lasted approximately 3 minutes. He had bitten his tongue. An ambulance was called, and he was taken to the emergency department. His neurologic examination on arrival showed paresis of the left arm and face, which rapidly resolved within 30 minutes. Brain MRI was normal.

He had no significant medical history and was an excellent student. He did admit to having two brief episodes over the past 6 months where he woke up in the early morning and felt that he was drooling, his left mouth was numb, and he could not speak clearly, although he was otherwise alert. These resolved within 1 minute, and the family had attributed these to a normal sleep variant.

His EEG in wakefulness showed occasional right centrotemporal discharges; however, these became significantly more frequent in sleep (figure 1-5).

Based on the clinical history and EEG, he was diagnosed with self-limited epilepsy with centrotemporal spikes. The family was reassured that he would outgrow this seizure disorder, typically in the next 1 to 2 years. They were provided teaching on seizure safety and counseled on the low risk of sudden unexpected death in epilepsy (SUDEP) and associated cognitive concerns. They elected to withhold daily medication. He had no further seizures over the subsequent 2 years and continued to do well in school.

COMMENT

This case illustrates how the accurate diagnosis of a specific syndrome provides key information to assist with choosing optimal investigations and treatment and for providing accurate prognosis.

What Is the Etiology?

One of the main questions people with new-onset seizures have is “What has caused this?” The range of possible etiologies for seizures is diverse, and a careful investigation to determine the underlying cause is needed.

The causes of epilepsy are defined in the six following groups.

Structural

Epilepsy is said to have a structural cause if a structural brain change is present that results in epilepsy. Structural causes may be developmental abnormalities, such as focal cortical dysplasia or polymicrogyria, or acquired brain processes, such as infection, stroke, trauma, or tumor. In most cases, structural abnormalities will be visible on MRI but may require specific epilepsy protocols.

Genetic

Epilepsy is considered genetic if it is caused by a known or presumed genetic variant. In some cases of genetic epilepsy, a clear pathogenic variant in a single gene can be identified, such as KCNQ2, CDKL5, or STXBP1. These single-gene disorders are often, but not always, associated with drug-resistant, early-onset developmental and epileptic encephalopathies. Some of these genes may lead to structural brain changes (ie, ARX, TSC1, or TSC2) whereas others can result in metabolic alterations that contribute to seizures (ie, SLC2A1 or ALDH7A1).

Another large group of genetic epilepsies includes the idiopathic generalized epilepsies. In these conditions, family studies have documented a strong genetic predisposition, although a single causal gene is typically not found. Rather, the underlying etiology is felt to be polygenic, with or without environmental factors.

Infectious

Infectious etiologies are the most common worldwide cause of epilepsy but are more prevalent in developing nations. An infectious etiology implies that epilepsy and seizures are core symptoms of the disorder, and examples include neurocysticercosis, human immunodeficiency virus (HIV), cerebral malaria, or congenital infections such as Zika virus or cytomegalovirus. Infectious etiology should not be used to describe acute symptomatic seizures that occur during brain infection, such as encephalitis or meningitis.

Metabolic

A metabolic etiology implies that epilepsy and seizures are the result of biochemical changes that result from a known metabolic disorder. Some metabolic disorders are critical to identify early because they have a specific therapy that will stop seizures and often prevent further developmental decline. Examples are glucose transporter disorder, which is treatable with a ketogenic diet, or a disorder of creatine metabolism, which is often treatable with high-dose supplemental creatine. Many metabolic disorders also have an underlying genetic etiology.

Immune

An immune epilepsy implies that epilepsy directly results from the underlying immune disorder. A recent report by the ILAE Autoimmune and Inflammation Task Force distinguishes immune-mediated epilepsy, where an enduring predisposition to seizures is present, from acute symptomatic seizures secondary to autoimmune encephalitis. Examples of immune epilepsy include Rasmussen syndrome or glutamic acid decarboxylase 65 (GAD65)-associated epilepsy.

Unknown

The more extensive the investigations, the more likely a cause is to be found. However, even after exhaustive investigations, no clear etiology can be found in approximately one-third to one-half of patients with new-onset unprovoked seizures.

Some causes will fit into more than one etiologic category, and these should be combined if needed. For example, tuberous sclerosis complex results in structural brain changes leading to epilepsy but is caused by a pathogenic variant in TSC1 or TSC2. Thus, it would be considered to have a structural-genetic etiology. Glucose transporter deficiency results in hypoglycorrhachia but, in most cases, is caused by a pathogenic variant of SLC2A1 and, thus, should be considered to have genetic-metabolic etiology.

What Are the Associated Comorbidities?

The ILAE has recognized the importance of comorbidities in its core definition of epilepsy as “a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition.” Thus, management of people with epilepsy must address cognitive and psychological comorbidities in addition to seizures. It is increasingly recognized that such comorbidities are the rule, rather than the exception, and they can have an even greater impact on quality of life than seizures.

Cognitive disorders are common and often precede seizure onset. Their etiology is multifactorial and may include the underlying pathology that has led to epilepsy, the impact of frequent seizures and epileptiform discharges, or treatment-related effects (side effects of antiseizure medications or epilepsy surgery). Furthermore, other neuropsychiatric disorders such as attention deficit hyperactivity disorder and mood disorders are also more prevalent and often precede seizure onset. These are critical to identify early, as they are treatable and can significantly worsen cognitive function if left untreated.

FURTHER INVESTIGATIONS

The diagnosis of a first seizure and epilepsy is a clinical one in nearly all cases. While the clinical history is the most critical piece of the puzzle, other investigations may provide supportive data to confirm epilepsy or may yield information on the underlying cause.

The American Academy of Neurology has developed an evidence-based guideline for the management of a first seizure in adults and a practice parameter for evaluating a first nonfebrile seizure in children.

EEG

Studies have shown that between 18% and 56% of children and 12% and 50% of adults presenting with new-onset seizures have an epileptiform abnormality found on routine EEG. An EEG is recommended as part of the neurodiagnostic evaluation in both children and adults with an apparent first unprovoked seizure because it may impact management decisions.

The diagnostic yield appears highest if the EEG can be done in the first 24 hours; however, background findings such as focal slowing may be seen transiently after a seizure as postictal phenomena and then resolve. Thus, the presence of focal slowing in that time frame should not be assumed to be due to an underlying structural change. Most studies have also shown that the yield of EEG after a period of sleep deprivation is higher, particularly for those with focal discharges. In patients presenting to the emergency department with a first seizure who fully recover to neurologic baseline and are otherwise well, an EEG can typically be performed on an outpatient basis.

Interpretation of EEG must be done in the context of the clinical history because approximately 3% of people without epilepsy may show epileptiform discharges, and thus, an abnormal EEG does not equate to epilepsy. Additionally, caution must be taken to not overinterpret normal variants as pathogenic (figure 1-6). In young children, vertex sharp waves may appear spiky and lead to misdiagnosis of central spikes, and hypnagogic hypersynchrony may be misinterpreted as generalized spike and wave. In adolescents and adults, wicket waves and rhythmic temporal theta of drowsiness are often miscalled as temporal epileptiform discharges. Thus, interpretation by a qualified electroencephalographer is key.

Although it is relatively uncommon to detect clinical events during recording of routine EEG, both epileptic and nonepileptic events may be captured. In most laboratories, one channel is dedicated to ECG, which allows screening for potential cardiac arrhythmias. Psychogenic nonepileptic events may also be seen on routine EEG; video recording during routine recordings can be helpful in appreciating their symptomatology. Activation parameters done during the routine EEG typically involve both hyperventilation, which often triggers absence seizures in those with untreated childhood or juvenile absence epilepsy, and photic stimulation, which may trigger myoclonic seizures in someone with juvenile myoclonic epilepsy. Detection of these more subtle seizure types often points to a specific syndrome and typically would mandate initiation of prophylactic antiseizure medication.

The EEG may also help with determining the epilepsy type. Focal epilepsy is suggested if the EEG shows focal epileptiform discharges or focal slowing. In contrast, generalized spike-and-wave discharges would be consistent with a generalized epilepsy. Some epilepsy syndromes have a unique EEG signature. For example, finding independent, high-amplitude centrotemporal spikes, which are activated in sleep, in a neurotypical, school-aged child with a history of early-morning convulsive seizures would support a diagnosis of self-limited epilepsy with centrotemporal spikes. Conversely, an otherwise well 18-year-old woman who presents with a single, early-morning generalized tonic-clonic seizure, and who has generalized polyspike and wave triggered by photic stimulation, most likely has juvenile myoclonic epilepsy.

The EEG may also help guide the need for other investigations. In most cases, focal epileptiform discharges and/or focal slowing may suggest a diagnosis of an underlying lesion.

Finally, the EEG provides information on the risk of seizure recurrence. Approximately 40% to 50% of people who have a first unprovoked seizure will experience a recurrence within the next 2 years. A systematic review in adults with a first seizure reported that an EEG with epileptiform abnormalities was associated with a relative rate increase for seizure recurrence at 1 to 5 years of 2.16 (95% confidence interval [CI], 1.07 to 4.38) compared with that in patients without EEG abnormalities. Studies in children with a first seizure have shown the risk of recurrence increases from 27% to 42% if the EEG is normal to 60% to 71% if the EEG shows epileptiform abnormalities.

Prolonged video-EEG monitoring is rarely required after a first seizure. However, such monitoring should be considered to exclude frequent subtle seizures or status epilepticus in those who do not show recovery to baseline neurologic function within 60 minutes, have fluctuating levels of consciousness, or have unexplained focal neurologic findings.

Neuroimaging

The Commission on Neuroimaging of the ILAE has recommended that all patients with epilepsy should undergo MRI, except those with a clearly defined, drug-responsive idiopathic generalized epilepsy syndrome (childhood absence epilepsy, juvenile absence epilepsy, or juvenile myoclonic epilepsy) or self-limited focal epilepsy of childhood (self-limited epilepsy with centrotemporal spikes or self-limited epilepsy with autonomic seizures).

Patients with new-onset seizures with associated focal neurologic deficits, fever, persistent headache, cognitive changes, or a recent history of head trauma should be considered for urgent imaging, which is more commonly done by CT given its ease of access. However, imaging with MRI is preferable to CT because MRI avoids radiation exposure and enhances the detection of lesions. CT has low sensitivity for detecting many small cortical epileptogenic lesions including focal cortical dysplasia, mesial temporal sclerosis, low-grade gliomas, or cavernous malformations, as well as lesions in the base of the skull such as the orbitofrontal or mesial temporal regions. However, CT is more sensitive than MRI for calcified lesions or bone lesions. Approximately 10% of adults with new-onset, unprovoked seizures are found to have a clinically relevant structural lesion on neuroimaging, and these individuals have a higher risk of seizure recurrence than those without imaging abnormalities (relative risk, 2.44; 95% CI, 1.09 to 5.44).

In patients who have returned to their neurologic baseline, who have no focal neurologic deficits and for whom no other concern is present, MRI can be obtained on an outpatient basis. An epilepsy protocol MRI with adequate spatial resolution and multiplanar reformatting will enhance the yield of detection of lesions. Other functional neuroimaging methods, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), and magnetoencephalography (MEG) are often considered in cases of drug-resistant, focal epilepsy and have little role in the evaluation of new-onset seizures.

If a lesion is found on MRI, one must establish, using both clinical and electrophysiologic data, whether it is indeed the underlying etiology for the seizures. Small T2 hyperintensities, arachnoid cysts, or small meningiomas are often coincidental as opposed to causal.

In children younger than 3 years of age, ongoing brain myelination often limits the detection of lesions such as cortical dysplasia. In such cases, MRI studies should be reviewed by a pediatric neuroradiologist, and consideration should be given to repeating the MRI after the age of 3 years if seizures persist.

Laboratory Studies

Other laboratory studies may be indicated in a person with new-onset seizures.

Routine blood and urine studies

Routine laboratory screening of patients with new-onset seizures, with complete blood cell count, glucose, electrolytes including calcium and magnesium, blood urea nitrogen, and creatinine, is commonly done to exclude provoked seizures but has an overall low yield. Clinical circumstances that may suggest a higher likelihood of underlying provoked seizures include failure to return to baseline alertness, vomiting, diarrhea, dehydration, failure to thrive, certain underlying medical conditions (eg, diabetes), or medication exposures. More detailed screening for inborn errors of metabolism should be considered in children who have concerning clinical features, in addition to the seizures, including developmental plateauing or regression, paroxysmal decompensation with altered consciousness, vomiting or unusual odors with minor infectious illnesses, or unexplained organomegaly. Such testing could include glucose, bicarbonate, alanine transaminase (ALT), aspartate transaminase (AST), serum for amino acids, ammonia, lactate, pyruvate, carbohydrate-deficient transferrin, very long chain fatty acids, and urine for organic acids, mucopolysaccharides, oligosaccharides, and creatine metabolites.

Toxicology

Toxicology screening is not mandated in all cases but should be strongly considered if toxin exposure or substance abuse is a concern or if the clinical findings are suggestive of a possible exposure (table 1-2).

Lumbar puncture

Lumbar puncture should be considered if the clinical picture is suggestive of possible meningitis, encephalitis, or subarachnoid hemorrhage but is of limited value otherwise. A lumbar puncture should be considered in the presence of new, unexplained fever with seizures, encephalopathy, or meningeal signs such as nuchal rigidity. Patients who are immunocompromised may also have abnormal CSF results without overt clinical evidence of a brain infection.

Febrile seizures are relatively common, affecting 2% to 5% of children between the ages of 6 months and 5 years. Recommendations regarding the need for lumbar puncture have been published by the American Academy of Pediatrics. In children aged 6 months to 5 years presenting with a simple febrile seizure, defined as a duration of less than 15 minutes, without focal features and without recurrence within a 24-hour period, a lumbar puncture should be performed if meningeal signs are present or if the history or examination suggests central nervous system infection. It should be considered an option for infants aged 6 to 12 months who are deficient in either Haemophilus influenzae or Streptococcus pneumonia immunization (or if immunization status cannot be determined) or in children who have received antibiotics, which may mask clinical symptoms of intracranial infection. Although no guidelines have been determined for children with complex febrile seizures, in the absence of febrile status epilepticus, the risk of brain infection is low, and lumbar punctures should be performed selectively. However, in children presenting with convulsive febrile status epilepticus, a lumbar puncture should be performed because the risk of meningitis is approximately 17%.

In the presence of possible increased intracranial pressure or new focal neurologic symptoms or signs, a brain imaging study should precede the lumbar puncture.

Autoimmune testing

Neuronal antibodies may be associated with acute symptomatic seizures because of an autoimmune encephalitis but are exceedingly rare in new-onset epilepsy. A recent review of this topic noted several clinical features that should suggest an autoimmune etiology, including a characteristic onset (frequent, drug-resistant seizures), other associated features (cognitive and/or behavioral dysfunction, dysautonomia, movement disorders such as orofacial dyskinesias), and specific seizure types (faciobrachial dystonic seizures). Serum and CSF autoimmune studies should be strongly considered in the presence of suggestive clinical features but are of low yield in their absence.

Genetic testing

Understanding of the genetic contributions to epilepsy has markedly expanded over the past 20 years, with large-scale molecular genetic studies leading to identification of an increasing number of novel epilepsy genes (figure 1-7). Although genetic testing should be selectively considered, it is not recommended for most patients with new-onset epilepsy.

The report of the ILAE Genetics Commission suggests that the clinical utility of testing should be evaluated before genetic testing. Testing should be considered if the result will likely lead to a change in the procedures used for evaluation or a change in the optimal treatment choice or prognosis and if it will likely influence a decision about reproduction. Additionally, the social or psychological impact on the patient must be considered.

Genetic testing is of the highest yield in infants and young children with developmental and epileptic encephalopathies of unknown cause, with approximately one-third to one-half of these patients having a pathogenic variant found. Genetic testing should also be considered in patients whose examination or other investigations point to a probable genetic cause. This includes individuals with findings on neuroimaging suggestive of a genetic-structural cause (ie, tuberous sclerosis complex or double cortex) or those with imaging or laboratory findings suggestive of a genetic-metabolic etiology (eg, mitochondrial disorders, Batten disease, or glucose transporter deficiency).

The implications of genetic testing may be significant and should be discussed with the family by a genetic counselor or other knowledgeable health care provider before initiation of testing. These include the following:

  • Medical implications: some genes may have implications for symptoms other than epilepsy, and these implications may also extend to relatives of the person being tested
  • Reproductive implications: the risk of passing on an abnormal variant
  • Psychological implications: the impact of potentially carrying an abnormal variant that could result in disease in oneself or increase risk of disease in one’s child
  • Insurance and financial implications

Several possible genetic investigations, including karyotype, chromosomal microarray, single-gene sequencing, epilepsy gene panel, and whole-exome or whole-genome sequencing, and, in certain cases, specific clinical features, may drive the choice for a particular test. For example, in a 3-year-old child with global developmental delay, absent speech, disrupted sleep, a happy demeanor, and new-onset epilepsy, whose EEG is found to have a notched delta appearance, focused testing for Angelman syndrome will likely be pursued. However, in many cases, the phenotype does not suggest a specific gene. A recent meta-analysis that assessed cost-effectiveness of various genetic tests commonly used in patients with epilepsy suggested that either an epilepsy gene panel or whole-exome sequencing study should be the initial test ordered in such cases.

Management

In any individual presenting with a first unprovoked seizure or new-onset epilepsy, counseling on lifestyle issues, seizure safety, and what to do if further seizures occur must be provided. Although the risk of recurrence will depend on several factors, including underlying cause and EEG findings, in general, the highest risk of recurrence is in the first 1 to 2 years after the seizure.

The most important lifestyle modification that is indicated for all patients with new-onset, unprovoked seizures pertains to safety around water. Although showers are generally safe, being in a bathtub or swimming alone is not recommended. Patients should also be counseled about other safety issues such as avoiding excessive heights. Other potential restrictions may be required based on their occupation or participation in certain sports.

For people who have had seizures that alter their awareness, guidance regarding driving varies depending on the place of residence. The Epilepsy Foundation website has a list of updated driving laws for each state.

Patients should also understand the importance of managing seizure triggers. Sleep deprivation is a common trigger for many epilepsy types, and thus, regulating sleep hygiene is important. Overall, patients benefit from regular mealtimes and a healthy diet, regular exercise, and management of emotional stress and mood disorders. Other triggers can be specific for certain epilepsies, such as flashing lights, or, in some cases, even eating or reading. Some women have a catamenial pattern to seizures, and fever or intercurrent illness may also trigger seizures in susceptible individuals.

Some patients may benefit from having a seizure rescue medication that could be used if they have a prolonged seizure or cluster of seizures. This is particularly important in those who live a considerable distance from emergency medical services or those with a history of a previous seizure emergency. Patients and their families should understand when and how to administer such therapy, as well as other aspects of seizure first aid (rolling the patient on their side, avoiding placing objects in the mouth, and when to call emergency medical services).

Finally, patients must be informed of the potential risks of recurrent seizures, including status epilepticus, aspiration, and sudden unexpected death in epilepsy (SUDEP).

In deciding whether to initiate a prophylactic antiseizure drug, one must consider the recurrence risk for further seizures, the seizure severity, and the potential impact of further seizures on the individual patient and balance this against potential adverse effects of medication. Patient and family preferences must be considered. Antiseizure medication is typically started in cases of new-onset epilepsy but not in most cases of first unprovoked seizure with normal EEG and imaging.

In adults presenting with a first unprovoked seizure, immediate antiseizure medication treatment compared with treatment delayed until a second seizure occurs was found to reduce the absolute risk of recurrence by about 35% for a subsequent seizure within the next 2 years, but it did not alter quality of life or improve the chance of obtaining sustained seizure remission over the longer term. In children, a similar consensus was reached; however, few data are available from studies limited to children.

CONCLUSION

New-onset seizures are a common presentation to the neurologist. A careful clinical history is key to excluding seizure mimics and provoked or acute symptomatic seizures. Accurate classification of epilepsy assists with the choice of cost-effective investigations, optimal treatment, and accurate prognosis. Counseling regarding seizure safety and first aid should be addressed in all cases of new-onset seizures.

KEY POINTS

  • Epilepsy is defined as any of the following: (1) at least two unprovoked (or reflex) seizures occurring more than 24 hours apart, (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years, or (3) diagnosis of an epilepsy syndrome.
  • A careful history taken from both the patient as well as any witnesses to the event(s) is the most critical aspect in distinguishing a seizure from a nonepileptic paroxysmal event.
  • It is the first convulsive seizure that typically brings the patient to medical attention. Many people presenting with a “first seizure” have a history of prior seizures, which may not have been recognized, and thus have epilepsy.
  • A diagnosis of an epilepsy syndrome is possible in approximately one-quarter of epilepsy cases beginning in infancy and childhood but is less frequently found in adults. Diagnosis of a specific syndrome provides key information to assist with choosing optimal investigations and treatment and for providing accurate prognosis.
  • Genetic causes of epilepsy are increasingly recognized. In some cases, such as the idiopathic generalized epilepsies, inheritance is polygenic, and pathogenic variants are typically not found on gene panels. In other cases, particularly in early-onset developmental epileptic encephalopathies, inheritance is monogenic, and pathogenic variants are identified on epilepsy gene panels or whole-exome sequencing.
  • Increasingly, specific antibodies are being detected in people with autoimmune encephalitis that result in acute symptomatic seizures. These should be distinguished from immune-mediated epilepsies in which an enduring predisposition to seizures is present.
  • Despite advances in neuroimaging and genetics, approximately 40% of people with new-onset epilepsy have no known etiology found.
  • Cognitive and psychiatric comorbidities are common in people with epilepsy and often predate seizure onset. The causes are multifactorial, but they are critical to diagnose and treat as they often have an even greater impact than seizures on quality of life.
  • An EEG is indicated in all patients with new-onset, unprovoked seizures. Care must be taken to avoid misinterpreting normal variants as epileptogenic. The EEG assists with determination of seizure and epilepsy type, choice of further investigations, and prognosis regarding the risk for seizure recurrence.
  • Neuroimaging is recommended for all patients with new-onset, unprovoked seizures, except those with a well-defined, drug-responsive idiopathic generalized epilepsy or self-limited focal epilepsy of childhood. In patients who have returned to their neurologic baseline and for whom there are no concerns for an acute neurologic process, urgent CT is not needed. Rather, MRI can be obtained on an outpatient basis.
  • Routine blood and urine studies are commonly obtained but of low yield in patients with new-onset, unprovoked seizures.
  • A lumbar puncture should be considered if the clinical picture is suggestive of possible meningitis, encephalitis, or subarachnoid hemorrhage but is otherwise is of low yield.
  • All patients with new-onset, unprovoked seizures must be counseled about lifestyle issues, seizure safety, and what to do if further seizures occur. Water safety is of utmost importance. Showers are safe; however, bathing or swimming alone is not recommended.
  • Although immediate initiation of antiseizure medication after a first unprovoked seizure does reduce the risk of recurrence, it does not impact long-term epilepsy outcome or quality of life.

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USEFUL WEBSITES

EPILEPSY FOUNDATION STATE DRIVING LAWS DATABASE

This is a database of state driving laws related to epilepsy.

epilepsy.com/driving-laws/2008806

INTERNATIONAL LEAGUE AGAINST EPILEPSY

This website provides an online diagnostic manual of the epilepsies.

epilepsydiagnosis.org

© 2022 American Academy of Neurology.