Seizure Disorders

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Chapter 102

Seizure Disorders

Perspective

A seizure is the clinical manifestation of excessive, abnormal cortical neuron activity. The physical manifestation depends on the area of brain cortex involved and, to a lesser extent, on the specific underlying abnormality. Ictal event is the more general term used to describe the seizure or seizure-like episode. Patients who have recurring seizures without consistent provocation have epilepsy, a term that encompasses many disparate clinical syndromes. Seizures may also occur as a predictable response to certain toxic, pathophysiologic, or environmental stresses; these are reactive or secondary seizures, and patients who experience these do not have epilepsy. In the United States, 10% of people experience at least one seizure in their lifetime; the cumulative incidence of epilepsy is 3%.1

More than 1 million patients visit U.S. emergency departments (EDs) every year for seizure care.2 The evaluation of patients with seizures in the ED can be complex and difficult. A careful history must be elicited to determine the presence of ictal events that represent epilepsy, exposure to ictogenic stimuli (e.g., alcohol, cocaine), significant underlying illness (e.g., meningitis, hypoxemia, hypoglycemia, intracranial mass), or provocative stimuli (e.g., sleep deprivation in an epileptic). The physical examination focuses on the identification of focal neurologic abnormalities, systemic illness, and signs of toxic exposure. If the patient continues to experience seizure activity, airway protection and abortive therapy must be provided.3 Laboratory and radiographic evaluation are guided by historical and physical findings and may be limited or unnecessary in some cases. Finally, the appropriate disposition of a patient in the ED with a seizure or with a history of a recent seizure requires an understanding of the underlying illness, likelihood of recurrence, indications for maintenance pharmacologic therapy, and state reporting regulations.

In addition to the distinction between primary (epileptic) and secondary (reactive) seizures, many other classifications of ictal events have been proposed.48 Seizures are termed generalized or focal (partial) depending on the clinical manifestations. Generalized seizures result from an abnormal electrical event that simultaneously involves both cerebral hemispheres and is accompanied by loss of consciousness; in partial seizures, abnormal activity is limited to part of one cerebral hemisphere only. Generalized seizures usually are characterized by rhythmic, tonic-clonic muscle contractions, or convulsions, although nonconvulsive generalized seizures also occur. Partial seizures can be differentiated further into seizures during which cognition is maintained (simple partial) and seizures during which cognition is impaired (complex partial). The term cognition refers to involvement of at least two of five features—perception, attention, emotion, memory, and executive function—and replaces the previously used term consciousness, which is difficult to define and difficult to document.9,10 Finally, partial seizures may become generalized (partial with secondary generalization).

Inexperienced witnesses may provide histories that are insufficient for accurate categorization of seizures. However, when an accurate history is available, secondary (reactive) seizures typically are generalized, not partial, in nature. The definitive differentiation among these classifications may require electroencephalogram (EEG) recording during the seizure, sometimes in association with simultaneous video recording.11,12

Seizures in children, as in adults, are classified as primary (idiopathic) and secondary (symptomatic or reactive). The term cryptogenic is used sometimes when seizures are thought to be secondary but no cause has been identified. The history is a vital diagnostic tool in evaluating seizures in children, as the actual seizure activity is usually not observed.

Other important terms to describe ictal events include status epilepticus, in which seizures are prolonged or occur serially without an intervening return to a normal neurologic condition; spasm, which is a specific, debilitating seizure syndrome that occurs in infants; and myoclonus, which refers to rhythmic, shocklike muscle contractions also typical for specific seizure syndromes. The postictal period is an interval after a seizure, of variable duration, usually characterized by impaired cognition but sometimes also marked by such diverse physiologic manifestations as self-limited focal motor paralysis (Todd’s paralysis) or neurogenic pulmonary edema.

Principles of Disease

The pathophysiology of seizures at the neuronal level is incompletely understood, with most of what is known coming from animal studies in which either electrical or pharmacologic stimulation is applied directly to brain cortex. To produce generalized ictus, stimuli must be simultaneously applied to both hemispheres. Some studies show the concept of recruitment, which occurs when the initiating neurons’ abnormal, increased electrical activity activates adjacent neurons and propagates until the thalamus and other subcortical structures are recruited. The clinical seizure activity typically, but not always, reflects the focus of initiation.10,13

What prompts such initiation is unclear. Proposed mechanisms include disruption of normal structure, whether congenital, maturational, or acquired (as with scar tissue), and disruption of local metabolic or biochemical function. The latter mechanism is better understood because the roles of two neurotransmitters—acetylcholine, which is excitatory to cortical neurons, and γ-aminobutyric acid (GABA), which is inhibitory—have been more fully characterized. In sensitive neurons, such as those at an ictogenic focus, subtle changes in the local concentrations of these neurotransmitters can produce sustained membrane depolarization, ultimately followed by local hyperpolarization and recruitment. Recruitment may follow contiguous paths or extend along diverse integrated circuits that are deep and cross the midline.10,13

When the ictal discharge extends below the cortex to deeper structures, the reticular activating system in the brainstem may be affected, altering consciousness. In generalized seizures, the focus often is subcortical and midline, which explains the prompt loss of consciousness and bilateral involvement. Seizures typically are self-limited; at some point, the hyperpolarization subsides and the electrical discharges from the focus terminate. This termination may be related to reflex inhibition, loss of synchrony, neuronal exhaustion, or alteration of the local balance of acetylcholine and GABA in favor of inhibition.10

The systemic manifestations of convulsive ictal activity include hypertension, tachycardia, tachypnea, and hyperglycemia from sympathetic stimulation. With more prolonged convulsions, skeletal muscle damage, lactic acidosis, and, rarely, frank rhabdomyolysis may ensue.10,14,15 Autonomic discharge and bulbar muscle involvement may result in urinary or fecal incontinence, vomiting (with significant aspiration risk), tongue biting, and airway impairment.

Clinical Features

Primary Seizures in Adults

Primary ictal events in adults may have a genetic origin or may be idiopathic. Onset is typically during childhood or adolescence, but occasionally idiopathic seizures may begin de novo in adulthood. Because idiopathic seizures are rare, a first-time seizure in an adult requires a thorough evaluation.

Focal seizures in adults may be classified as simple partial or complex partial. Simple partial seizures are limited in electrical focus to one cerebral hemisphere and do not cause loss of cognition. Although the specific function of the initiating neurons determines the clinical manifestation of the ictal event (i.e., motor, somatosensory, special sensory, autonomic, or psychic), such clinical manifestations are not sufficiently specific for anatomic localization without an EEG. Typical features of simple partial seizures include focal clonic movements; paresthesias; visual, auditory, olfactory, or gustatory experiences; sweating and flushing; dysphasia; a sense of déjà vu; or a sense of unwarranted fear.10,13 Motor signs, which by definition remain ipsilateral in simple partial seizures, may spread contiguously in a stepwise fashion (Jacksonian march) as neuron recruitment occurs in the motor cortex. There is generally no postictal state after a simple partial seizure.

Complex partial seizures are ictal events that involve impairment of cognition, either at onset or evolving from focal activity. Amnesia for the ictal event is a consistent feature of complex partial seizures, although during the episode the patient may remain responsive to the surroundings. Complex partial seizures typically involve automatisms that are specific to the affected person, such as lip smacking, repeated swallowing or uttering verbal phrases, or picking at clothing. Complex partial seizures generally are associated with an aura, such as a specific smell, taste, visual hallucination, or intense emotional feeling. In contrast with those experiencing generalized seizures, these patients may continue with ongoing motor activity, such as driving an automobile, riding a bicycle, or playing a musical instrument (reactive automatisms), and they may react to their surroundings in a semi-appropriate manner.10 Partial seizures may progress rapidly to generalized seizures. A postictal state is common after complex partial seizures and may persist for hours.13

Generalized seizures in adults may be convulsive or nonconvulsive. By definition, patients lose consciousness in a generalized seizure, and no aura is present. Some patients may experience a brief, vague prodrome or dysphoric state just before the ictal event. Convulsive generalized seizures are typified by the tonic-clonic, or grand mal, seizure, in which the patient loses consciousness, stiffens with generalized muscular hypertonus, and then rhythmically and violently contracts multiple, bilateral, and usually symmetrical muscle groups. The muscular force may be sufficiently vigorous to result in posterior shoulder dislocation or fractures of thoracic spine vertebral bodies; significant tongue and buccal injuries also may be incurred from biting with repeated jaw muscle contractions. Dysautonomia, including transient apnea, is a potential manifestation of convulsive generalized seizures; urinary incontinence is more common than fecal incontinence. A generalized convulsive seizure generally lasts 1 to 2 minutes and is followed by a postictal state, headache, and drowsiness that may persist for hours. This state must be differentiated from altered consciousness attributable to other causes.

Nonconvulsive generalized seizures include absence, or petit mal, seizures; myoclonic seizures; tonic seizures; and atonic seizures. Absence seizures in adults are subclassified further as typical or atypical. Typical absence ictus is characterized by the sudden cessation of normal, conscious activity, followed by a nonconvulsive, dissociative state that persists for a few seconds to several minutes before suddenly terminating. Eye movements, blinking, or automatisms may be present. There is no aura and no postictal state. If the seizure occurs midsentence, then the patient typically will resume speaking at precisely the point of interruption without awareness of the intervening event. Absence seizures typically begin in childhood but occasionally develop in adults. Atypical absence seizures are marked by more complicated motor signs, coexistence with other forms of generalized seizures, inconsistent postictal confusion, and irregular EEG abnormalities.13

Atonic seizures are characterized by focal diminution of muscle tone (limb or head) or generalized loss of postural tone in which the head falls forward and then the body slumps to the ground (“drop attack”), usually landing buttocks first (although this can vary depending on the axis of gravity at the time of the fall). Recovery occurs immediately, and there is either no loss or an extremely brief loss of consciousness. In myoclonic-atonic seizures, a brief (less than 100 msec) myoclonic jerk of muscle groups of variable anatomy occurs before the episode of atonia.10 Because typically no postictal state is associated with these episodes, an altered level of consciousness in a patient after an atonic or myoclonic-atonic seizure should prompt an investigation for head trauma or a toxic or metabolic abnormality.

Status epilepticus is defined as serial seizure activity without interictal recovery or prolonged, continuous seizure activity. Traditionally, status epilepticus was defined as seizure activity lasting longer than 30 minutes, which is the estimated duration necessary for neuronal injury.16,17 However, because an isolated tonic-clonic seizure rarely lasts more than a few minutes, an operational definition of status epilepticus as either a continuous seizure lasting more than 5 minutes or more than two discrete seizures without intervening recovery of consciousness has been advocated.18 Although it is recognized that the underlying cause of status epilepticus is the predominant factor determining morbidity and mortality, prolonged seizure activity does cause neuronal injury and therefore warrants prompt abortive therapy. Furthermore, status epilepticus may become refractory to treatment over time.17,19,20

In some cases a patient’s first seizure episode will manifest as status epilepticus. The most common cause of status epilepticus is discontinuation of anticonvulsant medication. This situation may be compounded by barbiturate withdrawal when phenobarbital therapy is abruptly discontinued. Many other causes of status epilepticus have been documented (Box 102-1).14,16,21,22 After prolonged status epilepticus or after incomplete treatment, the patient may exhibit very subtle manifestations of continued seizure activity, such as small-amplitude twitching of the extremities or jerking of the eyes, or any visible motor activity may cease while seizure activity detectable on the EEG continues.2325 Recognition of the latter scenario, termed nonconvulsive status epilepticus, requires a high index of clinical suspicion. Prompt treatment is essential to prevent neuronal damage; mortality approaches 30% if the seizure lasts more than an hour.26 Nonconvulsive status epilepticus may be present in more than 9% of hospitalized patients with prolonged decreased mental status.27

All classes of primary seizures may recur sporadically, randomly, or predictably. Cyclic recurrence has been reported with awakening, sleep deprivation, emotional or physical stress, alcohol, and menses, among other factors. Seizures also may be triggered by specific sensory stimuli, the most common of which is visual stimulation in the form of flashing lights, such as strobe lights, television, and video games.10,28 Seizures also can be caused by auditory, gustatory, tactile, or startle triggers that are specific to the affected person. The most common cause of recurrent primary seizures is medication noncompliance.13,29

Reactive Seizures in Adults

Reactive or secondary seizures do not result from genetic or idiopathic causes. The conditions that cause reactive seizures may be static (e.g., anatomic scarring), progressive (e.g., degenerative cortical disorders), or transient (e.g., acute electrolyte derangements).

Seizures Caused by Metabolic Derangements

Hypoglycemia is a common metabolic cause of reactive seizures. Ictal activity can occur when the plasma glucose level is less than 45 mg/dL, although some patients may manifest neurologic disturbances even at higher levels.30 A rapid bedside glucose test is an integral part of the evaluation of the patient exhibiting seizure activity. Convulsive and nonconvulsive seizures and generalized and partial seizures all may occur during hypoglycemia.3134 Patients at the extremes of age are particularly susceptible to glucose stress during acute illness. Hypoglycemia also may result from insulin reaction, a deliberate insulin or hypoglycemic agent overdose, alcoholism, poor nutrition, and sepsis. Hypoglycemic seizures respond to glucose therapy; anticonvulsants and benzodiazepines are unnecessary. At times, however, prolonged seizures may cause hypoglycemia. Seizures that do not cease after correction of low blood glucose deserve further evaluation and treatment.

Cation derangements, notably hypernatremia and hyponatremia, hypomagnesemia, and hypocalcemia, are other common metabolic causes of ictal activity.35,36 Hypo-osmolar and hyperosmolar states can precipitate seizures. Disorders of sodium, the primary cation in the extracellular fluid compartment and the primary determinant of serum osmolarity, are most common. Hyponatremia is the most frequently identified electrolyte disorder in hospitalized patients, and sodium levels less than 120 mEq/L often are associated with seizures.37,38 The rate at which the sodium level decreases, and not the absolute magnitude of the decrease, determines the risk for neurologic manifestation.37 Correcting hyponatremia should be undertaken slowly to avoid osmotic demyelination. If seizures are persistent, administration of hypertonic (3%) saline may be indicated.37 Hypernatremia will result in cerebral edema and seizures in the setting of rapid elevation of serum sodium to greater than 160 mEq/L or during aggressive correction of subacute hyponatremia.36,39

Hypercalcemia reduces neuronal excitability and rarely causes seizures; significant hypocalcemia (below 7.5 mEq/L), however, is associated with ictal activity. Hypocalcemia may result from hypoparathyroidism, renal failure, or acute pancreatitis and typically is associated with hypomagnesemia, which also can precipitate seizures, particularly at serum levels less than 1 mEq/L. Hypomagnesemia is seen most often as a result of poor nutrition, especially in alcoholic patients. Patients with significant hypomagnesemia or hypocalcemia are treated empirically for both disorders.35,36

Nonketotic hyperosmolar hyperglycemia can be associated with seizure activity. Partial seizures, including partial status, predominate. These seizures do not respond to anticonvulsants; rather, they are best managed with gradual correction of fluid deficits and glucose excess.4042

Seizures may complicate the course and treatment of renal failure.43 Ictal activity occasionally complicates uremic encephalopathy, more commonly occurs as a result of acute fluid and electrolyte shifts during dialysis (dialysis disequilibrium syndrome), and can be a complication of immunosuppressive therapy after renal transplantation.

Thyroid hormones lower seizure threshold, and consequently Graves’ disease and thyrotoxicosis may occasionally manifest as seizures, including status epilepticus.44 Seizures also occur with hypoparathyroidism as a result of secondary hypocalcemia.14

Seizures Caused by Infectious Diseases

Infectious diseases can cause seizures independent of a purely febrile mechanism. These seizures generally result from primary central nervous system (CNS) infections but occasionally arise from other septic sources. The most important ictogenic infections are meningitis, encephalitis, cerebral abscess, cerebral parasitosis, and human immunodeficiency virus (HIV) disease and associated opportunistic infections, with their protean CNS manifestations. Cerebral malaria is a common cause in developing countries.45

Seizures may result from the acute inflammatory response that occurs with bacterial or viral meningitis. During the acute course of illness, 15% of patients with bacterial meningitis will have at least one seizure,46 and surviving patients have an increased risk of epilepsy.47 Viral meningoencephalitides, the most common of which are caused by the herpes simplex virus, also are associated with seizures. These seizures may be generalized or partial, often recur during the acute phase of the illness, and may persist after the illness has resolved.48

The parasitic CNS infection neurocysticercosis is relatively common in areas of the United States where there is a population of immigrants from Latin America. Seizures complicate 50 to 90% of neurocysticercosis cases.49 Latent syphilis can cause adult-onset seizures. Primary HIV disease of the CNS with its attendant infectious and mass lesion complications constitutes a significant cause of generalized and partial seizures. Common HIV-associated infections and conditions include toxoplasmosis, lymphoma, and the demyelinating infection progressive multifocal leukoencephalopathy.50 Choosing an antiepileptic drug (AED) for an HIV-infected patient with seizures is done in consultation with infectious disease and neurology specialists because of the well-recognized increase in adverse effects of AEDs and the interactions between AEDs and antiviral medications.

Seizures Caused by Drugs and Toxins

The list of substances reported to cause seizures either as an idiosyncratic side effect of therapeutic use or as a manifestation of toxic overdose is extensive.22,51 The recognition of this etiologic category is crucial in the ED setting. Seizure activity is a dire sign of toxicity and may herald the onset of life-threatening instability.

Seizures may occur after therapeutic doses of antimicrobials, cardiovascular agents, neuroleptics, and sympathomimetics.52 Seizures also may result from exposure to plant toxins, insecticides, rodenticides, and hydrocarbons. Certain over-the-counter supplements also have been associated with seizures, either alone or through adverse interactions with prescription medications.53,54 The most common drug-associated and toxin-associated seizures occur, however, in conjunction with illicit drugs, such as cocaine, amphetamines, and phencyclidine; with overdoses of anticholinergic agents, such as cyclic antidepressants and antihistamines; as a manifestation of withdrawal from ethyl alcohol and sedative-hypnotics; and with toxic levels and deliberate overdoses of diverse medications, including aspirin, theophylline, meperidine, isoniazid, lithium, and anticonvulsants, including phenytoin, carbamazepine, lamotrigine, and topiramate.51,55 Standard ED therapeutic measures are usually effective for management of toxic seizures. In some cases, specific antidotal therapy is available, such as alkalinization for cyclic antidepressant and salicylate overdoses, and pyridoxine (vitamin B6) for isoniazid overdose. Hemodialysis is the treatment of choice for serious salicylate and lithium toxicity. Dilantin administration is contraindicated in cases of ingestion because its sodium channel blocking actions can worsen the hemodynamic impact of the ingestion.3

Because of its prevalence in urban ED patient populations, cocaine toxicity warrants special mention. Seizures may occur after isolated recreational use or chronic abuse, after overdose, and in “body packers” and “body stuffers.”56 Cocaine-related seizures may be a manifestation of direct CNS toxicity or an indirect result of hypoxemia from cardiac toxicity.57 Seizures in cocaine-intoxicated patients are managed as part of the overall toxic reaction, which often includes high fever, rhabdomyolysis, and cardiac arrhythmias. A benzodiazepine is the appropriate initial therapeutic agent.

Ethyl alcohol use and abuse are additional common toxic causes of seizures; up to 40% of seizure patients in the ED have alcohol-related seizures.58 Ictal events may occur with acute inebriation but are more common during withdrawal from alcohol.59 Withdrawal seizures are typically generalized and recurrent and begin within 6 hours of cessation of or decrease in alcohol consumption. Through a phenomenon termed kindling, the risk and severity of seizures increase with each episode of withdrawal. Kindling means that with each episode of alcohol withdrawal, the seizure threshold is lower. Alcoholic patients with seizures should also be evaluated for related, concomitant ictogenic problems (e.g., hypoglycemia, electrolyte derangements, head trauma, coingestion of other toxins, pregnancy). The preferred treatment for alcohol-associated seizures is with benzodiazepines, as these drugs substitute for the GABA-enhancing effect of ethanol in the CNS.

Seizures Caused by Trauma

Post-traumatic seizures can occur acutely as a result of blunt or penetrating head trauma or as a post-traumatic sequela. Immediate post-traumatic seizures occur within 24 hours of injury. Epidural, subdural, and intracerebral hematomas and traumatic subarachnoid hemorrhages all can be acutely ictogenic, particularly as intracranial pressure rises. More often, however, the onset of seizure activity is delayed for at least several hours. Early post-traumatic seizures occur within 1 week of injury, whereas late post-traumatic seizures occur after 1 week. Immediate and early post-traumatic seizures are more common in children than in adults, and children also are more likely than adults to be presented in status epilepticus in the immediate or early post-traumatic phase.60

The severity of head injury correlates with the likelihood of post-traumatic seizures. Although seizures rarely occur after mild traumatic brain injury, the incidence approaches 30% in patients with depressed skull fracture.60,61 Antiepileptic drugs are recommended for prophylaxis against post-traumatic seizures occurring within the first 7 days after severe brain injury in adults; however, they have not been shown to be effective in preventing late post-traumatic seizures.62,63

Seizures Associated with Malignancy or Vasculitis

Seizures are a common manifestation of primary and metastatic CNS neoplasms. They also may complicate cancer treatment as a result of postsurgical scarring or chemotherapy-related electrolyte derangements, hematologic abnormalities, or immunosuppression. Although any CNS tumor can be ictogenic, low-grade and slow-growing primary neoplasms (e.g., well-differentiated gliomas and oligodendrogliomas) are implicated most commonly.64 In such cases, seizures, which most often are partial with secondary generalization, may be the initial clinical manifestation. A new-onset seizure in a patient with a non-CNS primary malignancy, such as melanoma and tumors of the lung, breast, colon, germ cells, or renal cells, prompts consideration of CNS metastasis and warrants neuroimaging.

Seizures also may be the presenting manifestation of CNS vasculitis in patients with systemic lupus erythematosus and polyarteritis nodosa and are usually complex partial seizures that give a general indication of the acute inflammatory focus. Secondary generalization may also occur.65

Seizures Caused by Strokes, Arteriovenous Malformations, Aneurysms, and Migraines

Ischemic or hemorrhagic stroke is the cause of new-onset seizures in 40 to 54% of elderly patients.66 The overall incidence of seizures with stroke ranges from 4 to 15%; more than one half occur within the first week after stroke. The incidence of epilepsy after stroke is 4 to 9%.67,68 Seizures that occur acutely with stroke are thought to result from local metabolic alterations in the CNS; these events are transient, and the seizures often are focal and self-limited. Seizures that develop later are more likely to be generalized.

Convulsive seizures occur in 6 to 26% of patients with subarachnoid hemorrhage after aneurysmal rupture; 8 to 15% of patients will experience nonconvulsive seizures.69 Seizures also occur in conjunction with unruptured cerebrovascular aneurysms and arteriovenous malformations.70 Arteriography may be required to confirm the diagnosis; unruptured arteriovenous malformations are easier to detect on an enhanced cranial computed tomography (CT) scan than are smaller, unruptured aneurysms.

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