The Epilepsies

Incidence and Prevalence

Seizures are common in the general population, and about 1 in 10 people will experience a seizure in their lifetime. Most of these seizures are provoked by acute events and are not related to epilepsy. The overall annual incidence of acute symptomatic seizures, excluding febrile seizures, in developed countries is about 39 per 100,000 people. The incidence is higher in men and follows a bimodal age distribution, with its highest peak in the first year of life (up to 300 per 100,000), a nadir of 15 per 100,000 in the third and fourth decades of life, and a second peak rising to 123 per 100,000 after 75 years of age. These differences are attributable to the high incidence of acute symptomatic seizures associated with metabolic, infectious, and encephalopathic causes during the neonatal period and of cerebrovascular, neoplastic, and degenerative diseases in elderly persons.

After headache, the epilepsies are the most frequent chronic neurologic condition seen in general practice worldwide. In developed countries, the prevalence of active epilepsy ranges from 5 to 7 per 1000 persons, and the median annual incidence is 45 per 100,000 (range, 30 to 67), varying by age and socioeconomic status. One in 26 people will develop epilepsy during their lifetime (1 in 21 males and 1 in 28 females). The incidence of epilepsy peaks in children younger than 5 years at 60 to 70 per 100,000, decreases throughout adolescence to 30 per 100,000 in early adulthood, and rises again after the sixth decade, reaching a peak of 150 to 200 per 100,000 persons older than 75 years. The overall incidence of epilepsy appears to be increasing in recent decades because of a larger proportion of elderly persons in the population and an increasing incidence rate of epilepsy within the elderly population. Overall, the incidence and prevalence of the epilepsies are higher in developing countries, largely owing to a higher frequency of perinatal insults, trauma, and infectious disorders of the brain and to suboptimal treatment. In these countries, the median prevalence of active epilepsy is 12.5 per 1000 (range, 5 to 57 per 1000), and the annual incidence ranges from 78 to 190 per 100,000. Furthermore, the patterns of age-specific incidence are quite different in developing countries, where incidence peaks in young adults, not in elderly persons.

Risk Factors

Among all age groups, the top five risk factors for developing acute symptomatic seizures are head trauma (16%), stroke (16%), infectious disorders (15%), toxic-metabolic disorders (15%), and drug and alcohol withdrawal (14%) ( Table 372-1 ).

The risk factors for developing epilepsy differ in adults and children. In childhood, excluding inherited epilepsies, the risk is increased by febrile seizures, head trauma, infections of the brain, intellectual disability, cerebral palsy, brain malformations, and attention-deficit/hyperactivity disorder. Perinatal insults do not carry an increased risk for epilepsy unless they are accompanied by intellectual disability or cerebral palsy.

In adults, risk factors for developing epilepsy can be identified in about one third of patients, in whom head trauma, brain infections, stroke, brain tumor, and dementia are the most common causes. In surgical specimens, the most common causes are mesial temporal sclerosis, cortical dysplasias, low-grade tumors, and vascular malformations. The risk of developing epilepsy is increased more than 500-fold by a history of a military head injury; 30-fold by a severe civilian head injury ( Chapter 368 ); 20-fold each by stroke ( Chapter 376 ) and brain infection ( Chapter 381 to 383 ); and 10-fold each for Alzheimer disease ( Chapter 371 ), migraine ( Chapter 367 ), and hypertension. In Latin America, the most frequently identified risk factor is brain infection. In endemic areas, neurocysticercosis ( Chapter 325 ) accounts for about 10% of all newly diagnosed cases of epilepsy.

Pathobiology

Pathogenesis

The pathologic substrates and mechanisms underpinning initiation and propagation differ for focal and generalized seizures. In focal seizures, an aggregate of cortical or subcortical neurons develop high-frequency bursts of sodium-dependent action potentials caused by a shift in calcium conductance, thereby resulting in the typical EEG spike discharge ( Fig. 372-1 ). Spread of bursting activity to other neurons is normally prevented by surrounding inhibitory mechanisms, such as hyperpolarization and inhibitory interneurons. When a sufficient number of neurons are engaged in sustained bursting, further excitatory phenomena ensue, including the increased release of excitatory neurotransmitters owing to presynaptic accumulation of Ca ²⁺ , depolarization of surrounding neurons owing to increased extracellular K ⁺ , and further neuronal activation caused by depolarization-induced activation of N -methyl- d -aspartate (NMDA) receptors. As excitation increases and inhibition decreases, additional neurons are recruited regionally and distantly, thereby resulting in seizure propagation. The mechanisms by which neurons develop a tendency toward anomalous bursting activity include alterations in neurotransmitters, membrane receptors, ion channels, second-messenger systems, and gene expression of various proteins.

Considerably less is known about the basic mechanisms underlying generalized seizures, which depend prominently on thalamocortical circuits. In absence seizures, the classic generalized spike-and-wave discharges seen on EEG ( Video 372-1 ) are related to alterations in oscillatory rhythms generated by circuits that connect the thalamus and cortex and that involve T-type Ca ²⁺ channels, which are located in the reticular nucleus of the thalamus. In generalized convulsive seizures, cortical neurons exhibit prolonged depolarization during the tonic phase, followed by rhythmic depolarization and repolarization during the clonic phase. Activation of NMDA receptors increases calcium Ca ²⁺ influx, thereby leading to further neuronal excitation. The initiation and modulation of generalized convulsive seizures involve cholinergic, noradrenergic, serotonergic, and histaminergic afferents from the brain stem and basal forebrain structures, which modulate excitability of hemispheric motor mechanisms.

Focal Seizures

The seizure warning often consists of sensory, autonomic, or emotional symptoms that are experienced at the start of an observable seizure. The warning symptom is a focal seizure itself, and it is often missed because patients and clinicians focus on the more dramatic aspects of awareness or convulsion that follow. Careful inquiry about the occurrence of a warning is of crucial importance for three reasons. First, it points to a focal as opposed to a generalized onset, thereby implying an underlying focal structural or functional brain abnormality (e.g., a tumor) that requires further investigation. Second, focal seizures have important implications for therapy and for prognosis (see later). Third, the nature of the symptoms points to the area of the brain that gives rise to the seizure and that could be a target for surgical treatment ( Table 372-2 ).

The neuronal discharge causing the focal seizure may remain confined to the region where it began (as a warning symptom or more objective focal event), or it may spread to involve additional brain areas. Thus a focal seizure originating in the cortical area that represents sensation of the hand (rolandic area) may begin with contralateral hand tingling and then progress to involve additional cortical regions ipsilaterally, producing more extensive sensory symptoms as well as clonic motor signs. Seizures of rolandic origin in particular exhibit a peculiar type of propagation, in which the seizure activity “marches” from hand to arm to leg area ipsilaterally, a process referred to as a jacksonian march. After the clonic motor activity ends, patients are often weak; a postictal or Todd paralysis may last hours or even a day or two, with gradual resolution ( Video 372-2 ). The seizure may also propagate to distant ipsilateral or contralateral regions along known anatomic pathways.

In focal impaired awareness seizures, the person is not aware of self or environment during the seizure because of sufficient propagation of seizure activity to limbic and bilateral structures to cause alteration of awareness ( Videos 372-3 and 372-4 ). Focal seizures originating from any region can impair awareness, and unilateral focal seizures can progress to involve bilateral brain areas and cause a bilateral convulsive seizure ( Video 372-5 ). Such convulsive seizures usually take the form of bilateral tonic-clonic events rather than another type of generalized seizure ( Table 372-3 ).

The evolution of the focal clinical seizure reflects the evolution of the EEG changes, which in turn reflects the pathophysiology of the process. A simultaneous rhythmic, localized discharge (often in the 4- to 7-Hz range) becomes higher in amplitude and lower in frequency as the seizure continues (see Video 372-5 ). Some seizures that begin in the association cortex (e.g., frontal or parietal lobes) have bizarre or extremely brief clinical manifestations without postictal deficits and create diagnostic challenges ( Videos 372-6 , 372-7 , and 372-8 ). The stereotyped nature of the clinical events, with identification of EEG changes if present, may be the only way to make an appropriate diagnosis. The diagnosis can be even more challenging if the seizure spreads to different cortical regions during different seizure episodes, thereby producing variable constellations of clinical findings at different times.

Focal seizures with or without impaired awareness can also occur as a series of single events without intervening normal behavior, thereby resulting in focal status epilepticus. Focal status epilepticus with impaired awareness seizures is characterized by prolonged confused behavior. EEG findings may be normal in a focal seizure without altered awareness, even in patients with status epilepticus, but the diagnosis is usually evident from the clinical features. In status epilepticus of focal impaired awareness seizures, EEG recordings show continuous abnormalities that are different than those seen in single seizures in that individual. The most common are a slow background with superimposed rhythmic high-amplitude sharp waves or repetitive rhythmic seizure discharges ( Fig. 372-3 ). This type of status epilepticus is most frequent with frontal lobe seizures but can occur in temporal lobe or other seizures as well. The factors that precipitate status epilepticus are not well defined, nor are the implications for treatment or prognosis.

Nonconvulsive status epilepticus consists of a state of confusion or impaired mental status in patients with various neurologic diagnoses (e.g., trauma, stroke) in the acute intensive care unit setting ( Video 372-9 ). It also denotes a condition that can occur de novo in older adults without a precipitating cause and that is characterized by prolonged confusional episodes, which are caused by generalized slow spike-and-wave status epilepticus. Clinical suspicion should prompt an EEG study, which is essential for diagnosis.

Generalized Seizures

Generalized seizures rapidly affect both cerebral hemispheres, and their clinical expression is consistent with substantial involvement of both sides of the brain (see Table 372-3 ). Convulsive seizures, which were previously termed grand mal seizures, consist of excessive abnormal muscle contractions that may be sustained or interrupted and usually are a combination of tonic and clonic phases (generalized tonic-clonic seizures). This type of seizure may involve both hemispheres at the onset or may result from propagation of a focal seizure. These dramatic seizures often frighten witnesses and cause severe disruption of social interaction and development. They may begin with a “cry” as a result of abrupt air movement across the glottis from sudden tonic muscle contraction. The patient becomes diffusely stiff, usually with limb and body extension ( Video 372-10 ). Breathing is suspended, cyanosis occurs, and urinary incontinence is common. After 15 to 45 seconds, the tonic activity gives way to clonic, rhythmic, sometimes asymmetrical jerking of all four extremities ( Video 372-11 ). The rhythmic contractions gradually become slower in frequency until the event stops; the patient is apneic, comatose, and diaphoretic, but breathing with stridor and gasping begins within 60 seconds. Patients who have generalized tonic-clonic seizures in public often prompt bystanders to initiate resuscitation efforts, although such patients begin spontaneous respiration within 1 minute or so. Postictal stupor persists for a variable length of time. The patient generally sleeps for 2 to 8 hours and then complains of severe headache, sore muscles, a bitten tongue, and the inability to concentrate for a day or more. After generalized tonic-clonic seizures, some individuals have severe memory loss that gradually improves, sometimes over a period of weeks. Generalized tonic-clonic seizures also are a common expression of many metabolic, toxic, traumatic, or ischemic insults (see Table 372-1 ), but these provoked seizures do not qualify for the diagnosis of epilepsy.

Absence seizures, which are the second most common type of generalized seizure, are classified as typical or atypical (see Table 372-3 ). In typical absence seizures, patients experience an abrupt onset and termination of a momentary lapse of awareness. Patients have no perception of any aspect of the event and may or may not realize that some time was lost, although individuals often lose their train of thought. Because consciousness is abruptly lost and immediately regained, there is neither an initial symptom nor residual postictal symptoms. These seizures begin in childhood, and school teachers are often the first to notice them. In absence seizures, patients stop abruptly, stare vacantly, may have brief eye blinking or myoclonic movements, particularly if the event extends beyond 10 seconds (as judged by EEG), and regain function instantly (see Video 372-1 ). These seizures can occur many times a day but are not associated with progressive neurologic disease. Absences can also occur in a more continuous form as nonconvulsive status epilepticus with resultant confusion.

Atypical absence seizures occur in patients with extensive bilateral brain disease. The events are similar to typical absence seizures in terms of loss of contact, but the onset and termination are gradual instead of abrupt; the duration is longer; and there is more motor, autonomic, or automatic activity.

Myoclonic seizures consist of brief, irregular, unsustained episodes of sudden motor contraction (see Table 372-3 ) that can be focal ( Video 372-12 ), with one limb involved, or bilateral and massive, with involvement of the face, both upper extremities, and the trunk. Consciousness may be preserved but can be difficult to evaluate because of the brevity of these seizures. Myoclonic seizures form part of three main clinical entities: juvenile myoclonic epilepsy, which starts in childhood or adolescence and often persists into adulthood; epilepsy with various combinations of absence and myoclonic seizures; and progressive myoclonic epilepsy, which occurs in the setting of degenerative or inherited syndromes with bilateral cerebral involvement and abnormal cerebral function. Myoclonic seizures most commonly occur in the morning after awakening and often increase in frequency to culminate in a generalized tonic-clonic seizure.

Atonic and tonic seizures are brief but extremely disabling motor events that are characterized by a sudden increase or decrease in muscle tone. They can result in falls and injuries with variable impairment of awareness. Such seizures frequently begin in children with diffuse central nervous system (CNS) disease and multiple types of seizures, but they persist during adulthood ( Videos 372-13 and 372-14 ).

Differential Diagnosis

The first question facing clinicians is whether the episodes under consideration are indeed seizures. The diverse clinical expression of seizures encompasses a large differential diagnosis among conditions that produce episodic neurologic dysfunction ( Table 372-4 ). Common conditions resembling seizures include syncope ( Chapters 39 and 49 ), transient ischemic attacks ( Chapter 376 ), migraine ( Chapter 367 ), movement disorders ( Chapter 379 ), and psychogenic nonepileptic seizures (see Table 372-4 ).

A number of historical elements dramatically change the likelihood of this diagnosis. Three essential elements help determine whether an episode is a seizure ( Table 372-5 ) and distinguish seizures from other causes of temporary loss of consciousness, especially syncope ( Chapters 39 and 49 ).

• 1.

  The clinical context, including medical and family history and circumstances under which the episode occurred. For example, a strong family history of seizures and an event after sleep deprivation support a diagnosis of epileptic seizures. Conversely, a family history of syncope and an event occurring upon standing or with painful stimuli support a diagnosis of syncope.

• 2.

  Specific triggers or provoking factors. For example, events occurring with exposure to bright or flashing lights support a diagnosis of epileptic seizures.

• 3.

  A stereotypical evolution of the event, including four key components:

  • What is the first symptom or sign (presence and type of warning symptom, evidence of focal seizure at onset)?

  • How does it evolve after onset (what happens during the seizure proper, what are the signs or symptoms, how long does it last)?

  • How does it end (gradually or abruptly)?

  • Are there any neurologic deficits after the seizure ends?

Because patients have limited or no recall, the history from others is crucial. Observers can contribute important information about the patient’s activity, responses, and appearance, including changes in color, diaphoresis, respirations, vocalization, and muscle tone. Cell-phone videos obtained by witnesses can be very helpful in this regard. This information is required to characterize the type of seizure and to distinguish seizures from conditions that resemble seizures.

Migraine ( Chapter 367 ) and focal seizures not only resemble each other but also coexist as comorbid conditions and share genetic susceptibility loci. Features that favor a diagnosis of seizures over classic migraine include an inconsistent occurrence of headache during the event, a brief duration, and the occurrence of more severe seizures. Myoclonus ( Chapter 379 ) occurs in a variety of settings (e.g., metabolic encephalopathies) without any association with epilepsy or the EEG changes seen in myoclonic epilepsy.

Frontal lobe seizures arise predominantly during sleep and can have dramatic motor expression. They can be confused with nonepileptic psychogenic seizures, sleep disorders ( Chapter 374 ), or movement disorders ( Chapters 378 and 379 ). Video EEG monitoring may be necessary for diagnosis (see Videos 372-7 and 372-8 ).

Patients with panic attacks ( Chapter 362 ) can experience events that mimic focal seizures with autonomic and emotional features. However, panic attacks usually have a longer duration, do not progress to more severe seizures, and can be linked to specific circumstances. Nevertheless, focal seizures with emotional symptoms are often misdiagnosed as panic attacks.

Psychogenic nonepileptic seizures are behaviors that resemble seizures and are part of a functional neurologic disorder ( Chapter 362 ) that often leads to misdiagnosis. Psychogenic seizures can be difficult to diagnose because they can mimic almost any type of epileptic seizure, and they often coexist with epilepsy in the same patient. An erroneous diagnosis of nonepileptic seizures poses a risk for inappropriate discontinuation of medication, resulting in status epilepticus. Conversely, an erroneous diagnosis of epileptic seizures in a patient with psychogenic seizures can result in complications of unnecessary therapy, excessive sedation, and consequent cardiorespiratory depression, often requiring intubation and respiratory support. Features suggesting nonepileptic psychogenic seizures include variable clinical manifestations across episodes, frequent and prolonged episodes, lack of response to antiseizure medication, out-of-phase upper and lower body movements, prominent pelvic thrusting, eye closure during convulsive movements, and lack of rigidity. Patients may have a history of sexual or physical abuse. Nevertheless, the peculiarities of these attacks may require continuous video EEG monitoring for diagnosis.

Diagnostic Investigations

A detailed history, EEG recordings, and magnetic resonance imaging (MRI) can lead to a definitive diagnosis of epilepsy and can identify a cause in up to 50% of patients. In other patients, the information is insufficient or inconsistent, but the physiologic and CNS abnormalities surrounding the actual event allow it to be placed provisionally into a specific diagnostic category in about another 30% of patients. Continuous video EEG monitoring in an inpatient epilepsy unit can increase diagnostic accuracy.