Chapter 12: Seizures & Syncope

Consciousness is lost when the function of both cerebral hemispheres or the brainstem reticular activating system is compromised. Episodic dysfunction of these anatomic regions produces transient, and often recurrent, loss of consciousness. There are two major causes of episodic loss of consciousness: seizures and syncope.

SEIZURES

Seizures are disorders characterized by temporary neurologic signs or symptoms resulting from abnormal, paroxysmal, and hypersynchronous electrical neuronal activity in the brain.

SYNCOPE

Syncope is loss of consciousness due to reduced blood flow to both cerebral hemispheres or the brainstem. It can result from pancerebral hypoperfusion caused by vasovagal reflexes, orthostatic hypotension, or decreased cardiac output, or from selective hypoperfusion of the brainstem resulting from vertebrobasilar ischemia.

APPROACH TO DIAGNOSIS

Seizures and syncope have different causes, diagnostic approaches, and treatment.

First determine whether the setting in which the event occurred, or associated symptoms or signs, suggests a direct result of a disease requiring prompt attention, such as hypoglycemia, meningitis, head trauma, cardiac arrhythmia, or acute pulmonary embolism. Assess the number of spells and their similarity or dissimilarity. If all spells are identical, then a single pathophysiologic process can be assumed. Major differential features should be ascertained as discussed below.

EVENTS AT ONSET OF SPELL

Prodromal Symptoms (Aura)

Inquire about prodromal and initial symptoms. A witness may be critical. The often brief, stereotyped premonitory symptoms (aura) at the onset of some seizures may localize the central nervous system (CNS) abnormality responsible for seizures. Note that more than one type of aura may occur in an individual patient. A sensation of fear, olfactory or gustatory hallucinations, or visceral or déjà vu sensations are commonly associated with seizures originating in the temporal lobe. Progressive light-headedness, dimming of vision, and faintness suggest decreased cerebral blood flow (eg, simple faints, cardiac arrhythmias, orthostatic hypotension).

Posture When Loss of Consciousness Occurs

Orthostatic hypotension and simple faints occur in the upright or sitting position. Episodes that also or only occur in the recumbent position suggest seizure or cardiac arrhythmia as a likely cause, although syncope induced by strong emotional stimuli (eg, phlebotomy) can also occur in recumbency.

Relationship to Physical Exertion

Syncope induced by exertion is usually due to cardiac arrhythmias or outflow obstruction (eg, aortic stenosis, obstructive hypertrophic cardiomyopathy, or atrial myxoma).

Focal Symptoms

Focal motor or sensory phenomena (eg, involuntary jerking of one hand, hemifacial paresthesias, or forced head turning) suggest a seizure originating in the contralateral frontoparietal cortex. A sensation of fear, olfactory or gustatory hallucinations, or visceral or déjà vu sensations are commonly associated with seizures originating in the temporal lobe.

EVENTS DURING THE SPELL

Tonic Stiffening & Clonic Movement

Generalized tonic–clonic (grand mal, or major motor) seizures are characterized by loss of consciousness, accompanied initially by tonic stiffening and subsequently by clonic (jerking) movements of the extremities (see Figure 12-2).

Flaccidity

Cerebral hypoperfusion usually produces flaccid unresponsiveness.

Brief Stiffening or Jerking

Loss of consciousness from hypoperfusion rarely lasts more than 10 to 20 seconds and is not followed by postictal confusion unless severe and protracted brain ischemia has occurred. Cerebral hypoperfusion can also result in stiffening or jerking movements, especially if hypoperfusion is prolonged, for example, because the patient is prevented from falling or otherwise assuming a recumbent posture. This phenomenon, sometimes referred to as convulsive syncope, is self-limited and does not require anticonvulsant treatment.

EVENTS AFTER THE SPELL

Prompt Recovery of Consciousness

Recovery from a simple faint is characterized by a prompt return to consciousness, with full lucidity, within 20 to 30 seconds.

Postictal Confusion

A period of confusion, disorientation, or agitation (postictal state) follows a generalized tonic–clonic seizure. The period of confusion usually lasts minutes. Although such behavior is often strikingly evident to witnesses, it may not be recalled by the patient.

Prolonged Confusion

Prolonged alteration of consciousness (prolonged postictal state) may follow status epilepticus. It may also occur after a single seizure in patients with diffuse structural cerebral disease (eg, dementia, other cognitive impairment, head trauma, or encephalitis), metabolic encephalopathy, or continuing nonconvulsive seizures.

Tongue Biting

Biting of the lateral aspect of the tongue is highly specific for generalized tonic–clonic seizure and may be noted by the patient after such a spell.

Urinary Incontinence

Incontinence of urine can occur during either seizure or syncope. Fecal incontinence is an uncommon result of a seizure.

A seizure is a transient disturbance of cerebral function caused by an abnormal neuronal discharge. Epilepsy, a group of disorders characterized by recurrent seizures, is a common cause of episodic loss of consciousness defined as two unprovoked seizures or as a single seizure when clinical factors or investigations suggest an above average risk of recurrence. The prevalence of epilepsy in the general population is about 2-3%, but the lifetime probability of experiencing a seizure is approximately 10%.

An actively convulsing patient or a reported seizure in a known epileptic usually poses no diagnostic difficulty. However, because most seizures occur outside the hospital and are unobserved by medical personnel, the diagnosis most often must be established retrospectively. The two historic features most suggestive of a seizure are the aura associated with seizures of focal onset and the postictal confusional state that follows generalized tonic–clonic seizures.

ETIOLOGY

Seizures can result from either primary CNS dysfunction, an underlying metabolic derangement, or systemic disease. This distinction is critical, because therapy must be directed at the underlying disorder as well as at seizure control. A list of common neurologic and systemic disorders that produce seizures is presented in Table 12-1. The age of the patient may help in establishing the cause of seizures (Figure 12-1).

The genetic contribution to epilepsy and its response to treatment is complex. A single epileptic syndrome (eg, juvenile myoclonic epilepsy) can result from mutations in several different genes; conversely, mutations in a single gene (eg, SCN1A sodium channel subunit) can cause several epilepsy phenotypes. Genes implicated in susceptibility to epilepsy include those coding for sodium, calcium, potassium, and chloride channels; nicotinic cholinergic, GABA, and G protein-coupled receptors; and enzymes.

PRIMARY NEUROLOGIC DISORDERS

Benign Febrile Convulsions

Benign febrile convulsions occur in 2% to 5% of children aged 6 months to 5 years, usually during the first day of a febrile illness (temperature > 100.4°F or 38°C), and in the absence of CNS infection (meningitis or encephalitis). There may be a family history of benign febrile convulsions or other types of seizures. Mutations in several genes have been linked to febrile convulsions, including the G protein-coupled receptor MASS1; the inositol monophosphatase IMPA2; SCN1A, SCN1B, and SCN2A sodium channel subunits; KCNQ2, KCNQ3, and KCNA1 potassium channel subunits; and GABRG2 and GABRD GABA receptor subunits.

Benign febrile convulsions usually last for less than 10 to 15 minutes and lack focal features. Approximately two-thirds of patients experience a single seizure, and fewer than one-tenth have more than three. Seizures occurring during the first hour of fever in children younger than 18 months or in children with a family history of febrile seizures are associated with an increased risk for recurrence; 90% of recurrences occur within 2 years of the initial episode. Any MRI abnormality increases the risk of subsequent febrile status. The differential diagnosis includes meningitis and encephalitis (see Chapter 4, Confusional States); if present, these entities should be treated as described elsewhere in this volume.

Because benign febrile convulsions are usually self-limited, treatment is often unnecessary; prolonged convulsions (≥15 minutes) can be aborted with diazepam 0.3 mg/kg orally, intramuscularly, or intravenously or 0.6 mg/kg rectally, or by buccal midazolam (0.5 mg/kg; maximum, 10 mg). Such treatment may decrease the risk of recurrence. When recurrence does occur and parents are particularly anxious, intermittent oral diazepam at the onset of febrile illness may prevent further recurrences. The probability of developing a chronic seizure disorder is 2% to 6% and is highest in patients with persistent neurologic abnormalities; prolonged, focal, or multiple seizures; or a family history of nonfebrile seizures. Long-term administration of phenobarbital or valproic acid to reduce the risk of subsequent afebrile seizures is generally not indicated, as the risk of nonfebrile seizures is unaltered and anticonvulsant drug use is associated with significant morbidity.

Idiopathic (Cryptogenic) Seizures

These account for two-thirds of new-onset seizures in the general population. The age range of onset is broad, from the second to the seventh decade (see Figure 12-1). The risk of recurrence in the next 5 years is approximately 35% after a first unprovoked seizure. A second seizure increases the risk of recurrence to approximately 75%. Most recurrences occur in the first year. Genes implicated in idiopathic generalized epilepsy include the mitochondrial NAD-dependent malic enzyme ME2 and the CACNA1A and CACNB4 calcium channel subunits.

Head Trauma

Head trauma is a common cause of epilepsy, particularly when it occurs perinatally or is associated with a depressed skull fracture or intracerebral or subdural hematoma. Seizures that occur within the first week after nonpenetrating head injuries are not predictive of a chronic seizure disorder, however. Although patients with serious head injuries are often treated prophylactically with anticonvulsant drugs, a resultant reduction in the incidence of posttraumatic seizures in patients so treated has not been consistently observed.

Stroke

Stroke affecting the cerebral cortex produces seizures in 5% to 15% of patients and can occur after thrombotic or embolic infarction or intracerebral hemorrhage (see Chapter 13, Stroke). As in head trauma, early seizures are not necessarily indicative of chronic epilepsy, and long-term anticonvulsant therapy may not be required. Even without rupturing, vascular malformations may be associated with seizures, presumably as a result of their irritative effects on adjacent brain tissue.

Mass Lesions

Mass lesions, such as brain tumors (Table 6-4) or abscesses (Table 3-7), can present with seizures. Glioblastomas, astrocytomas, and meningiomas are the most common tumors associated with seizures, reflecting their high prevalence among tumors that affect the cerebral hemispheres.

Meningitis or Encephalitis

Bacterial (eg, Haemophilus influenzae or tuberculous), viral (eg, herpes simplex), fungal, or parasitic (eg, cysticercosis) infections (see Chapter 4, Confusional States) can also cause seizures. Seizures in patients with AIDS are most often related to HIV-associated dementia, but also occur with toxoplasmosis or cryptococcal meningitis.

Developmental Anomalies

Cortical dysgenesis and neuronal migration disorders can predispose to epilepsy.

SYSTEMIC DISORDERS

Metabolic and other systemic disorders, including drug-overdose and drug-withdrawal syndromes, may be associated with seizures that abate with correction of the underlying abnormality. In these cases, the patient is not considered to have epilepsy. Many of these disorders are discussed in detail in Chapter 4, Confusional States.

1. Hypoglycemia can produce seizures, especially with serum glucose levels of 20 to 30 mg/dL, but neurologic manifestations of hypoglycemia are also related to the rate at which serum glucose levels fall.

2. Hyponatremia may be associated with seizures at serum sodium levels less than 120 mEq/L (mean 110mEq/L) or at higher levels after a rapid decline.

3. Hyperosmolar states, including both hyperosmolar nonketotic hyperglycemia and hypernatremia, may lead to seizures when serum osmolality rises above approximately 330 mOsm/L.

4. Hypocalcemia with serum calcium levels in the range of 4.3 to 9.2 mg/dL can produce seizures with or without tetany.

5. Uremia can cause seizures, especially when it develops rapidly, but this tendency correlates poorly with absolute serum urea nitrogen levels.

6. Hepatic encephalopathy is sometimes accompanied by generalized or multifocal seizures.

7. Porphyria is a disorder of heme biosynthesis that produces both neuropathy (see Chapter 9, Motor Disorders) and seizures. The latter may be difficult to treat because most anticonvulsants can exacerbate the metabolic abnormalities. Case reports attest to the safety and efficacy of gabapentin, lorazepam, and levetiracetam in porphyria.

8. Drug overdose can exacerbate epilepsy or cause seizures in nonepileptic patients. Generalized tonic–clonic seizures are most common, but focal or multifocal partial seizures can also occur. The drugs most frequently associated with seizures are antidepressants, antipsychotics, cocaine, insulin, isoniazid, lidocaine, and methylxanthines (Table 12-2).

9. Drug withdrawal, especially withdrawal from ethanol or sedative drugs, may be accompanied by one or more generalized tonic–clonic seizures that usually resolve spontaneously. Alcohol withdrawal seizures occur within 48 hours after cessation or reduction of ethanol intake in 90% of cases and are characterized by brief flurries of one to six attacks that resolve within 12 hours. Acute abstinence from sedative drugs can also produce seizures in patients habituated to more than 600 to 800 mg/d of secobarbital or equivalent doses of other short-acting sedatives. Seizures from sedative drug withdrawal typically occur 2 to 4 days after abstinence but may be delayed for up to 1 week. Focal seizures are rarely due to alcohol or sedative drug withdrawal alone; such occurrences suggest an additional focal cerebral lesion that requires evaluation.

10. Global cerebral ischemia (see Chapter 13, Stroke) from cardiac arrest, cardiac arrhythmias, or hypotension may produce, at onset, a few tonic or tonic–clonic movements that resemble seizures, but they probably reflect abnormal brainstem activity instead. Global ischemia may also be associated with spontaneous myoclonus (see Chapter 11, Movement Disorders) or, after consciousness returns, with myoclonus precipitated by movement (action myoclonus). Partial or generalized tonic–clonic seizures also occur; these may be manifested only by subtle movements of the face or eyes and must be recognized and treated. Nonetheless, isolated seizures after global cerebral ischemia do not necessarily indicate a poor outcome.

11. Hypertensive encephalopathy (see Chapter 4, Confusional States) may be accompanied by generalized tonic–clonic or partial seizures.

12. Eclampsia refers to the occurrence of seizures or coma in a pregnant woman with hypertension, proteinuria, and edema (preeclampsia). As in hypertensive encephalopathy in nonpregnant patients, cerebral edema, ischemia, and hemorrhage may contribute to neurologic complications. Magnesium sulfate has been widely used to treat eclamptic seizures and for this purpose may be superior to anticonvulsants such as phenytoin.

13. Hyperthermia can result from infection, exposure (heat stroke), hypothalamic lesions, or drugs such as phencyclidine, as well as anticholinergics or neuroleptics (neuroleptic malignant syndrome; see Chapter 11, Movement Disorders) and inhalational anesthetics or neuromuscular blocking agents (malignant hyperthermia; see Chapter 9, Motor Disorders). Clinical features of severe hyperthermia (42°C, or 107°F) include seizures, confusional states or coma, shock, and renal failure. Treatment is with antipyretics and artificial cooling to reduce body temperature immediately to 39°C (102°F) and anticonvulsants and more specific therapy (eg, antibiotics for infection, dantrolene for malignant hyperthermia) where indicated. Patients who survive may be left with ataxia as a result of the special vulnerability of cerebellar neurons to hyperthermia.

NONEPILEPTIC SEIZURES

Attacks that resemble seizures (nonepileptic seizures or psychogenic seizures) may be manifestations of a psychiatric disturbance such as conversion disorder, somatization disorder, factitious disorder with physical symptoms, or malingering.

Nonepileptic seizures usually can be distinguished both clinically and by the electroencephalographic (EEG) findings. In patients with nonepileptic seizures resembling tonic–clonic attacks, there may be warning and preparation before the attack; there is usually no tonic phase, and the clonic phase consists of wild thrashing movements during which the patient rarely comes to harm or is incontinent. Ictal eye closure is common. In some instances, there are abnormal movements of all extremities without loss of consciousness; in others, there is shouting, uttering of obscenities, or goal-directed behavior during apparent loss of consciousness. There is no postictal confusion after the attack, nor are there abnormal clinical signs. The EEG, if recorded during an episode, does not show organized seizure activity, and postictal slowing does not occur. The differential diagnosis should include frontal lobe seizures, which may be marked by unusual midline movements (eg, pelvic thrusting or bicycling) and by very brief postictal states. Ictal EEG abnormalities may escape detection as well.

It is important to appreciate that many patients with nonepileptic seizures also have genuine epileptic attacks that require anticonvulsant medications, but these should be prescribed at an empirically appropriate dose. Psychiatric referral may be helpful.

CLASSIFICATION & CLINICAL FINDINGS

CLASSIFICATION

Seizures are classified as follows:

Generalized Seizures

1. Tonic–clonic (grand mal)

2. Absence (petit mal)

3. Other types (tonic, clonic, myoclonic, atonic)

Partial (Focal) Seizures

1. Simple partial (with preservation of consciousness; focal onset aware seizure)

2. Complex partial (focal impaired awareness seizure, temporal lobe, psychomotor, or focal seizures with dyscognitive features)

3. Partial seizures with secondary generalization (focal to bilateral tonic clonic)

GENERALIZED SEIZURES

Generalized Tonic–Clonic Seizures

Generalized tonic–clonic seizures are attacks in which consciousness is lost, usually without aura or other warning. When a warning does occur, it usually consists of nonspecific symptoms.

1. Tonic phase—The initial manifestations are unconsciousness and tonic contraction of limb muscles for 10 to 30 seconds, producing first flexion and then extension, particularly of the back and neck (Figure 12-2). Tonic contraction of the muscles of respiration may produce an expiration-induced vocalization (cry or moan) and cyanosis, and contraction of masticatory muscles may cause tongue trauma. The patient falls to the ground and may be injured.

2. Clonic phase—The tonic phase is followed by a clonic (alternating muscle contraction and relaxation) phase of symmetric limb jerking that persists for an additional 30 to 60 seconds or longer. Ventilatory efforts return immediately after cessation of the tonic phase, and cyanosis clears. The mouth may froth with saliva. With time, the jerking becomes less frequent, until finally all movements cease and the muscles are flaccid. Sphincteric relaxation or detrusor muscle contraction may produce urinary incontinence.

3. Recovery—As the patient regains consciousness, there is postictal confusion and often headache. Full orientation commonly takes 10 to 30 minutes or even longer in patients with status epilepticus (see next section) or preexisting structural or metabolic brain disorders. Physical examination during the postictal state is usually otherwise normal in idiopathic epilepsy or seizures of metabolic origin, except that plantar responses may be transiently extensor (Babinski sign). The pupils always react to light, even when the patient is unconscious.

4. Status epilepticus—Status epilepticus is defined arbitrarily as a seizure continuing for 5 to 30 minutes or more without ceasing spontaneously or as seizures recurring so frequently that full consciousness is not restored between successive episodes. Status epilepticus is a medical emergency because it can lead to permanent brain damage from hyperpyrexia, circulatory collapse, or excitotoxic neuronal damage if untreated.

Absence (Petit Mal) Seizures

These are genetically transmitted seizures that always begin in childhood and rarely persist into adolescence. Genes linked to childhood absence epilepsy include the voltage-gated calcium channel and GABA_A receptor subunits, malic enzyme 2, and inhibin alpha precursor. The spells are characterized by brief loss of consciousness (for 5-10 seconds) without loss of postural tone. Subtle motor manifestations, such as eye blinking or a slight head turning, are common. More complex automatic movements (automatisms) are uncommon. Full orientation is present immediately after seizure cessation.

There may be as many as several hundred spells daily, leading to impaired school performance or social interactions, so that children may be mistakenly thought to be mentally retarded. The spells are characteristically inducible by hyperventilation or by intermittent photic stimulation. The EEG pattern during a seizure is that of 3-Hz spike-wave activity (Figure 12-3). In most patients with normal intelligence and normal background activity on EEG, absence spells occur only during childhood; uncommonly, the attacks continue into adult life, either alone or in association with other types of seizures.

Other Types of Generalized Seizures

These include tonic seizures (not followed by a clonic phase), clonic seizures (not preceded by a tonic phase), and myoclonic seizures.

1. Tonic seizures are characterized by continuous muscle contraction that can lead to fixation of the limbs and axial musculature in flexion or extension; they are a cause of drop attacks. The accompanying arrest of ventilatory movements leads to cyanosis. Consciousness is lost, and there is no clonic phase to these seizures.

2. Clonic seizures are characterized by repetitive clonic jerking accompanied by loss of consciousness. There is no initial tonic component.

3. Myoclonic seizures are characterized by sudden, brief, shock-like contractions that may be localized to a few muscles or one or more extremities or may have a more generalized distribution causing falls. Juvenile myoclonic epilepsy is the most common cause, with onset usually in adolescence. Not all myoclonic jerks have an epileptic basis, however, as discussed in Chapter 11, Movement Disorders. There is a family history of seizures in one-third of patients with myoclonic seizures. The disorder is genetically heterogeneous, with linkage in different families to the calcium channel beta4 subunit, CASR calcium channel sensor receptor, GABA_A receptor alpha one and delta subunits, and myoclonin1. Myoclonic seizures may also be associated with a variety of rare hereditary neurodegenerative disorders, including Unverricht-Lundborg disease (cystatin B mutations), Lafora body disease (laforin mutations), neuronal ceroid lipofuscinosis, and mitochondrial encephalomyopathy (myoclonus epilepsy with ragged red fibers on skeletal muscle biopsy).

4. Atonic seizures result from loss of postural tone, sometimes after a myoclonic jerk, leading to a fall or drop attack. They are most common in developmental disorders such as the Lennox–Gastaut syndrome.

PARTIAL SEIZURES

Focal Onset Aware Seizures (Simple Partial Seizures)

Focal seizures begin with motor, sensory, or autonomic phenomena, depending on the cortical region affected. For example, clonic movements of a single muscle group in the face, a limb, or the pharynx may occur and may be self-limited; they may be recurrent or continuous or may spread to involve contiguous regions of the motor cortex (Jacksonian march).

Autonomic symptoms may consist of pallor, flushing, sweating, piloerection, pupillary dilatation, vomiting, borborygmi, or hypersalivation. Psychic symptoms include distortions of memory (eg, déjà vu, the sensation that a new experience is familiar), forced thinking or labored thought processes, cognitive deficits, affective disturbances (eg, fear, depression, an inappropriate sense of pleasure), hallucinations, or illusions. During focal onset aware seizure, consciousness is preserved unless and until the seizure discharge spreads to other areas of the brain, producing tonic–clonic seizures (focal to bilateral tonic–clonic seizures; secondary generalization). The aura is the portion of the seizure that precedes loss of consciousness and of which the patient retains some memory. The aura is sometimes the sole manifestation of the epileptic discharge.

In the postictal state, a focal neurologic deficit such as hemiparesis (Todd paralysis) may persist for 30 minutes to 36 hours and indicates an underlying focal brain lesion.

Focal Impaired Awareness Seizures (Complex Partial Seizures)

Seizures formerly called complex partial, temporal lobe, limbic, or psychomotor seizures are now descriptively referred to as focal impaired awareness seizures. These are partial seizures in which consciousness, responsiveness, or memory is impaired. Risk factors include prolonged febrile seizures of childhood, head trauma, or brain infections. Many causes are unknown. The seizure discharge usually arises from the temporal lobe or medial frontal lobe but can originate elsewhere. The symptoms take many forms but are usually stereotyped for the individual patient. Seizures may begin with an aura. Epigastric sensations are most common, but affective (fear), psychic (déjà vu), and sensory (olfactory hallucinations) symptoms also occur. Consciousness is then impaired. Seizures generally persist for 1 to 3 minutes; those originating in the frontal lobe are briefer. The motor manifestations are characterized by coordinated involuntary motor activity, termed automatisms, which take the form of orobuccolingual movements in approximately 75% of patients and other facial or neck or hand movements in approximately 50%. Sitting up or standing, fumbling with objects, and bilateral limb movements are less common. With frontal lobe origin, bicycling movement or pelvic thrusting can occur. Involvement of both sides of the brain, previously called secondary generalization, is now termed focal to bilateral tonic-clinic seizure. A postictal confusional state of approximately 15 minutes follows, but the patient may not be completely normal for hours.

DIAGNOSIS

The diagnosis of seizures is based on clinical recognition of one of the seizure types described previously. The EEG can be a helpful confirmatory test in distinguishing seizures from other causes of loss of consciousness (Figure 12-4). However, a normal or nonspecifically abnormal interictal EEG never excludes the diagnosis of epilepsy. Specific EEG features that suggest epilepsy include abnormal spikes, polyspike discharges, and spike-wave complexes.

A standard diagnostic evaluation of patients with recent onset of seizures is presented in Table 12-3. Metabolic and toxic disorders that can cause seizures (see Table 12-1) should be excluded because they do not require anticonvulsants.

Seizures with a clearly focal onset or those that begin after the age of 25 years require prompt evaluation to exclude the presence of a structural brain lesion. Magnetic resonance imaging (MRI) is essential for this purpose (computed tomography [CT] scan is not adequate). If no cause is found, the decision to begin chronic anticonvulsant therapy should be based on the probability of recurrence. After a single generalized tonic–clonic seizure, recurrence of one or more seizures can be expected within 3 to 4 years in 30% of untreated adult patients (Figure 12-5).

TREATMENT

PRINCIPLES OF TREATMENT

Therapy should be directed toward the cause of the seizures, if known (see Table 12-1). Seizures associated with metabolic and systemic disorders usually respond poorly to anticonvulsants but cease with correction of the underlying abnormality. Acute withdrawal from alcohol and other sedative drugs produces self-limited seizures that, in general, require no anticonvulsant drug therapy. Acute head trauma and other structural brain lesions that result in seizures must be diagnosed and treated appropriately, and the associated seizures controlled by anticonvulsant drug therapy. Idiopathic epilepsy is treated with anticonvulsant medications.

There are four key principles of management:

1. Establish the diagnosis of epilepsy before starting drug therapy—Therapeutic trials of anticonvulsant drugs intended to establish or reject a diagnosis of epilepsy may yield incorrect diagnoses.

2. Choose the right drug for the seizure type—Absence seizures, for example, do not respond to most drugs used for focal onset or generalized seizures.

3. Modulate treatment according to seizure control, rather than the serum drug levels—Control of seizures is achieved at different drug levels in different patients.

4. Evaluate one drug at a time—In most cases, seizures can be controlled with a single drug. Therefore, beginning therapy with multiple drugs may expose patients to increased drug toxicity without added therapeutic benefit.

ANTICONVULSANT DRUGS

Most anticonvulsant drugs act by potentiating inhibitory (GABAergic) synaptic transmission, inhibiting excitatory (glutamatergic) synaptic transmission, or attenuating postsynaptic propagation of action potentials through sodium channel blockade. Drugs acting at GABAergic synapses and their molecular targets are illustrated in Figure 12-6; those acting at glutamatergic synapses and their molecular targets are illustrated in Figure 12-7.

Commonly used anticonvulsant drugs and their dosages and methods of administration are listed in Table 12-4.

TREATMENT STRATEGIES

Most patients with epilepsy fall into one of the following treatment categories.

New Seizures

Most epileptologists do not recommend chronic anticonvulsant drug treatment after a single seizure unless an underlying cause is found that is not correctable and is likely to produce recurrent seizures (eg, primary or metastatic brain tumor). However, recurrent seizures (two or more, greater than two hours apart) do require anticonvulsant treatment; if such therapy is to be administered, the oral loading schedules presented in Table 12-4 can be used. Note that starting a drug at its daily maintenance dose produces stable serum drug levels only after approximately five half-lives have elapsed. Therefore, loading doses should only be given to achieve therapeutic drug levels promptly in patients with frequent seizures.

1. Focal seizures with impaired consciousness or focal to bilateral tonic–clonic seizures—As appropriate drugs of first choice for treating these seizure types, levetiracetam, lamotrigine, or sodium valproate are preferred; phenytoin, carbamazepine, oxcarbazepine, topiramate, or zonisamide are also appropriate. Aside from ethosuximide (and perhaps rufinamide), all currently available seizure medications have demonstrated efficacy in treating partial seizures. As none of the newest medications (including lacosamide, perampanel, and eslicarbazepine) have demonstrated superior efficacy or side-effect profiles, they should not be used for initial therapy. Gabapentin is usually not used for initial seizure treatment because its short half-life is a significant limitation. Tiagabine, vigabatrin, barbiturates, and benzodiazepines are not used for initial treatment because of their side-effect profiles. In limited comparative trials, lamotrigine is superior to carbamazepine.

2. Generalized seizures—Valproic acid is effective for all types of primary generalized seizures, but is not recommended as the initial treatment in women of childbearing age because of its potential teratogenicity. However, in comparative trials, valproate is better tolerated than topiramate and more effective than lamotrigine. Levetiracetam, topiramate, lamotrigine, and zonisamide can also be used successfully in generalized epilepsies.

3. Absence seizures—Absence attacks of the petit mal variety are treated with sodium valproate or ethosuximide. The former has the advantage of also providing protection against tonic–clonic seizures but has caused fatalities from hepatic damage in children younger than 10 (usually <2) years of age. Levetiracetam, topiramate, zonisamide, and lamotrigine may also be used for absence seizures. As with valproate, they provide protection against tonic–clonic seizures as well.

4. Myoclonic seizures—These are treated with sodium valproate, levetiracetam, zonisamide, or clonazepam.

Recurrent Seizures on Drug Therapy

1. Determining serum levels of drugs—Blood levels of anticonvulsant drugs the patient has been taking should be measured in samples taken just before a scheduled dose. For a single breakthrough seizure, no acute change in medication is mandated, even if there has been no interruption of drug therapy and anticonvulsant drug levels are in the therapeutic range, but a slight increase in prescribed dose may be considered. If the history or serum drug levels suggest that treatment has been interrupted, the prescribed drug should be started again as for new seizures.

2. Changing to a different drug—A different anticonvulsant should be introduced only if seizures continue to occur after maximum therapeutic benefit has been achieved with the initial drug. This means that blood levels of the drug are in the therapeutic range and that drug toxicity precludes further dosage increments. An anticonvulsant that has failed to alter seizure frequency should be discontinued gradually once therapeutic levels of the new drug have been achieved. Transition to monotherapy with a different drug is recommended twice before trials of two-drug combination therapy. As second monotherapy or combination therapeutic agents, lamotrigine or sodium valproate (alone or in combination) are preferred; levetiracetam, zonisamide, or topiramate are also appropriate. After failure of two appropriate anticonvulsants at therapeutic plasma concentrations, patients are deemed medically refractory. Drug recommendations in special circumstances are addressed below (Table 12-5).

3. Treating refractory seizures—In some patients, disabling seizures persist despite trials of major anticonvulsants, alone and in combination, at the highest doses the patient can tolerate. When no treatable cause can be found, seizures are not due to a progressive neurodegenerative disease, and medical treatment has been unsuccessful for at least 2 years, evaluation for possible surgical therapy should be considered.

Presurgical evaluation begins with a detailed history and neurologic examination to explore the cause of seizures and their site of origin within the brain and to document the adequacy of prior attempts at medical treatment. MRI and electrophysiologic studies are performed to identify the epileptogenic zone within the brain. Several electrophysiologic techniques can be used: EEG, in which cerebral electrical activity is recorded noninvasively from the scalp; intracranial or invasive EEG, in which activity is recorded from electrodes inserted into the brain (depth electrodes) or placed over the brain surface (subdural electrodes); and electrocorticography, which involves intraoperative recording from the surface of the brain. When an epileptogenic zone can be identified in this manner and its removal is not expected to produce undue neurologic impairment, surgical excision may be indicated.

Patients with focal impaired awareness seizure (complex partial seizures) arising from a single temporal lobe are the most frequent surgical candidates; unilateral anterior temporal lobectomy or stereotaxic laser interstitial thermal therapy (with fewer neurocognitive effects) abolishes seizures and auras in approximately 50% of these patients and significantly reduces their frequency in another 25%. Hemispherectomy and corpus callosum section are also sometimes used to treat intractable epilepsy.

Left vagal (X) nerve stimulation has been shown to reduce seizure frequency by as much as 50% in adults and children with refractory epilepsy. Response rates increase over 12-18 months. The mechanism of action is unknown, but afferent responses from the vagus are received in the nucleus tractus solitarius in the medulla and project widely.

Transcranial magnetic stimulation and deep brain stimulation are evolving experimental treatments.

As diet therapy, the ketogenic diet (4:1 fat/carbohydrate) has been used for a century in the pediatric epileptic population. Resultant ketone bodies may affect GABA synthesis or glutamate release. The diet is difficult to maintain but the Atkins diet may produce a similar reduction in seizure frequency (50% seizure reduction in one-third of patients).

Multiple Seizures or Status Epilepticus

1. Early management—Status epilepticus is a medical emergency because of its potential for causing irreversible brain injury and death.

   1. Immediate attention should be given to ensure that the airway is patent and the patient is positioned to prevent aspiration of stomach contents.

   2. The laboratory studies listed in Table 12-6 should be ordered without delay.

   3. Dextrose (50 mL of 50% solution) should be given intravenously.

   4. Meningitis and encephalitis should be considered, especially if fever and meningeal signs are present, and a lumbar puncture performed if indicated. Note that postictal pleocytosis is detectable in cerebrospinal fluid (CSF) in approximately 2% of patients with single generalized tonic–clonic seizures (and approximately 15% of those with status epilepticus) in the absence of infection. The white blood cell count may be as high as 80/μL, with either polymorphonuclear or mononuclear predominance. Serum protein content may be slightly elevated, but glucose concentration is normal, and Gram stain is negative. The postictal pleocytosis resolves in 2 to 5 days.

2. Drug therapy to control seizures—Every effort must be made to establish a precise etiologic diagnosis so that treatment of the underlying disorder can be started. Because generalized seizure activity per se damages the brain if it persists for more than 2 hours, drug therapy to terminate seizures should be instituted immediately. An outline for rapid pharmacologic control of multiple seizures is presented in Table 12-7.

3. Management of hyperthermia—The systemic physiologic consequences of status epilepticus are related to increased motor activity and high levels of circulating catecholamines; they include hyperthermia (temperature elevation to 42-43°C [108-109°F] in the absence of infection), lactic acidosis (pH < 7.00), and peripheral blood leukocytosis (elevation to 30,000 cells/μL). These derangements resolve after cessation of the seizures. Only hyperthermia, which is known to increase the risk of brain damage from status epilepticus, requires specific attention. Severe hyperthermia must be treated with a cooling blanket and, if necessary, the induction of motor paralysis with a neuromuscular blocking agent. Mild or moderate hyperthermia (101-102°F), not requiring specific intervention, may persist for 24 to 48 hours after seizure cessation. Lactic acidosis resolves spontaneously over 1 hour and should not be treated. Infection should, of course, be excluded.

DISCONTINUING ANTICONVULSANTS

Patients (usually children) with epilepsy who are seizure-free on medication for 2 to 5 years may wish to discontinue anticonvulsant drugs. In patients with normal intelligence and a normal neurologic examination, the risk of seizure recurrence may be as low as 25%. Risk factors for recurrence include slowing or spikes (maximum risk with both present) on EEG. When anticonvulsants are to be withdrawn, one drug is eliminated at a time by tapering the dose slowly over approximately 6 weeks. Recurrence of seizures has been reported in approximately 20% of children and 40% of adults after medication withdrawal, in which case prior medication should be reinstituted at the previously effective levels.

COMPLICATIONS OF EPILEPSY & ANTICONVULSANT THERAPY

Complications of Epilepsy

When the diagnosis of epilepsy is made, the patient should be warned against working around moving machinery or at heights and reminded of the risks of swimming alone. The issue of driving must also be addressed. Many state governments have notification requirements when a diagnosis of epilepsy is made.

Sudden unexpected death in epilepsy (SUDEP) affects 1 in 1000 epileptic patients yearly; if seizures are uncontrolled, the risk of death after a generalized seizure is 1 in 150. SUDEP accounts for 8-17% of all deaths in patients with epilepsy. The cause is uncertain but appears to be seizure related and caused by either a heart rhythm abnormality or an abnormality in breathing.

Decreased bone mineral density, which may lead to osteoporosis, occurs with use of P450-inducing anticonvulsants (phenobarbital, phenytoin, carbamazepine, and primidone) and probably with valproate as well. The newer anticonvulsants are safer. The need for periodic assessment of bone mineral density in the setting of these agents is controversial.

Side Effects of Anticonvulsant Drugs

The side effects of anticonvulsant drug therapy are summarized in Table 12-8. Nearly all anticonvulsant drugs may lead to blood dyscrasias, and some have hepatic toxicity. For this reason, a complete blood count and liver function tests should be obtained before initiating administration of these drugs and at intervals during the course of treatment. The authors recommend performing these tests twice in the first weeks to months and every 6 to 12 months thereafter. Lamotrigine has a 1:1000 incidence of Stevens–Johnson syndrome in the first 8 weeks. Most anticonvulsant drugs (especially barbiturates) affect cognitive function to some degree, even in therapeutic doses.

Drug Interactions

A variety of drugs alter the absorption or metabolism of anticonvulsants when given concomitantly. The changes in anticonvulsant levels are summarized in Table 12-9. Some anticonvulsants (carbamazepine, primidone, phenytoin, phenobarbital, topiramate, felbamate, and oxcarbazepine) that induce the cytochrome P450 system may lead to reduced effectiveness of oral contraceptives. Oral contraceptive medications may decrease the plasma concentration of lamotrigine.

Epilepsy & Anticonvulsant Therapy in Pregnancy (Oral contraceptives have greater failure rate than non oral)

1. Teratogenic effects of epilepsy—The incidence of stillbirth, microcephaly, mental retardation, and seizure disorders is increased in children born to epileptic mothers.

2. Teratogenic effects of anticonvulsant treatment—Anticonvulsant therapy during pregnancy is also associated with a greater than normal frequency of congenital malformations, especially cleft palate, cleft lip, and cardiac anomalies. Such malformations are about twice as common in the offspring of medicated than of unmedicated epileptic mothers, but because patients with more severe epilepsy are more likely to be treated, it is difficult to know whether epilepsy or its treatment is the more important risk factor.

3. Differences in teratogenesis among anticonvulsants—In women unexposed to anticonvulsant drugs, congenital malformations occur in 1.1%. Among women using common anticonvulsants, malformations occur in 2.2-9% of births. The relative risk (highest to lowest) is associated with valproic acid, phenobarbital, topiramate, carbamazepine, phenytoin, levetiracetam, and lamotrigine. Topiramate exposure in the first trimester is associated with oral cleft malformations. From current data, the safest anticonvulsants in pregnancy are lamotrigine and levetiracetam.

4. Folate deficiency—Several anticonvulsants can lower serum folate levels. As dietary deficiency of folic acid is associated with neural tube defects, folate supplementation (1 mg/d) should be provided for all women of childbearing age who take antiepileptic drugs.

5. Withdrawing anticonvulsants before pregnancy—When an epileptic patient who has been seizure free for several years is contemplating pregnancy, an attempt should be made to assess whether anticonvulsant drugs can be safely withdrawn before conception. In contrast to generalized tonic–clonic seizures, partial and absence seizures present little risk to the fetus, and it may be possible to tolerate imperfect control of these seizures during pregnancy to avoid fetal drug exposure. If anticonvulsant therapy is continued during pregnancy, it is best to maintain treatment with a single drug that has been shown effective for the patient’s seizures, using a dose that avoids clinical toxicity. Status epilepticus is treated as described previously for nonpregnant patients.

6. Anticonvulsant levels in pregnancy—Plasma levels of anticonvulsant drugs may decrease during pregnancy because of the patient’s enhanced drug metabolism, and higher doses may be required to maintain control of seizures. It is therefore important to monitor drug levels closely in this setting. This is particularly important with lamotrigine as the dose often needs to be doubled or tripled during a pregnancy to maintain adequate blood levels.

PROGNOSIS

After a single unprovoked seizure, less than half of patients will have a recurrence over 3 to 5 years (ie, develop epilepsy). If a second seizure occurs, however, the subsequent recurrence rate approaches 75%, and anticonvulsants therefore should be started. In prospective assessment, 47% are seizure free on the first agent, 13% with a second drug added, and 4% with a third or multiple drugs. At the onset of treatment, patients should be seen every few months to monitor seizure frequency and make dose adjustments.

Syncope is episodic loss of consciousness associated with loss of postural tone. The pathophysiology, involving global hypoperfusion of the brain or brainstem, is distinct from that of seizures. The most common causes of syncope are given in Table 12-10.

VASOVAGAL SYNCOPE (SIMPLE FAINTS)

Vasovagal syncope occurs in all age groups. Genetic factors may be relevant. Precipitating factors include emotional stimulation, pain, the sight of blood, fatigue, medical instrumentation, blood loss, or prolonged motionless standing. Vagally mediated decreases in arterial blood pressure and heart rate combine to produce CNS hypoperfusion and subsequent syncope. Cerebral ischemia resulting in brief tonic–clonic movements can occur.

Vasovagal episodes generally begin while the patient is in a standing or seated position and only rarely in a horizontal position (eg, with phlebotomy or intrauterine device insertion). A prodrome lasting 30 to 60 seconds usually precedes syncope and can include marked facial pallor, lassitude, yawning, light-headedness, nausea, diaphoresis, salivation, blurred vision, and tachycardia.

The patient, who then loses consciousness and falls to the ground, is pale and diaphoretic and has dilated pupils. Breathing continues. The eyes remain open and there is an upward turning of the globes. Bradycardia replaces tachycardia as consciousness is lost. During unconsciousness, abnormal movements may occur, particularly if the patient remains relatively vertical; these are mainly tonic or opisthotonic, but seizure-like tonic–clonic activity is occasionally seen, which can lead to a misdiagnosis of epilepsy. Urinary incontinence may also occur.

The patient recovers consciousness very rapidly (20-30 seconds) after assuming the horizontal position, but residual nervousness, dizziness, headache, nausea, pallor, diaphoresis, and an urge to defecate may be noted. A postictal confusional state, characteristic of seizures, with disorientation and agitation either does not occur or is very brief (<30 seconds). Syncope may recur, especially if the patient stands within the next 30 minutes.

Reassurance and a recommendation to avoid precipitating factors are usually the only treatment necessary.

Recurrent vasovagal syncope (also termed neurally mediated or neurocardiogenic syncope) can be diagnosed by inducing syncope during head-up tilt-testing. The bradycardia and hypotension of syncope can be ameliorated by the alpha-agonist midodrine (2.5 to 10 mg three times daily) or with the alpha-beta adrenergic agonist droxidopa (100 mg three times daily initially). Tilt-training may have benefit. Artificial pacing is ineffective.

CARDIOVASCULAR SYNCOPE

A cardiovascular cause is suggested when syncope occurs in a recumbent position, during or after physical exertion, or in a patient with known heart disease. Loss of consciousness related to cardiac disease is most often due to an abrupt decrease in cardiac output with resultant cerebral hypoperfusion. Such cardiac dysfunction can result from cardiac arrest, rhythm disturbances (either brady- or tachyarrhythmias), cardiac inflow or outflow obstruction, intracardiac right-to-left shunts, leaking or dissecting aortic aneurysms, or acute pulmonary embolism (Table 12-11). The diagnosis is established by electrophysiologic study and/or long-term event recording. Event monitors triggered by the patient at the onset of symptoms may be helpful; implantable loop recorders, providing continuous EKG recording for up to 3 years, have a high diagnostic yield in unexplained syncope.

CARDIAC ARREST

Cardiac arrest (ventricular fibrillation or asystole) from any cause will result in loss of consciousness in 3 to 5 seconds if the patient is standing or within 15 seconds if the patient is recumbent. Seizure like activity and urinary and fecal incontinence may be seen as the duration of cerebral hypoperfusion increases.

TACHYARRHYTHMIAS

Supraventricular Tachyarrhythmias

Supraventricular tachyarrhythmias (atrial or junctional tachycardia, atrial flutter, or atrial fibrillation) may be paroxysmal or chronic. Syncope is preceded most often by sudden brief palpitations or less often by dizziness or dyspnea.

Heart rates faster than 160 to 200/min reduce cardiac output by decreasing the ventricular filling period or inducing myocardial ischemia. Prolonged tachycardia of 180 to 200 beats or more per minute will produce syncope in 50% of normal persons in the upright posture; in patients with underlying heart disease, a heart rate of 135/min may impair cardiac output enough to induce loss of consciousness. Patients with sinus node dysfunction may develop profound bradycardia or even asystole on termination of their tachyarrhythmias. The diagnosis is established when arrhythmias are demonstrated during a symptomatic episode.

The postural tachycardia syndrome (POTS) is a systemic disorder that occurs predominantly in women 15-45 years old. Its major symptom is an orthostatic increase in heart rate of 30 or more beats per minute, generally without significant change in blood pressure, occurring on standing from a supine position. Associated symptoms include palpitation, tremulousness, gastrointestinal symptoms, fatigue, sleep disturbances, and migraine. Symptoms are accentuated by dehydration, alcohol, and exercise. The induced heart rate increase diminishes with age.

Ventricular Tachyarrhythmias

Ventricular tachyarrhythmias (idiopathic ventricular tachycardia or multiform, frequent, or paired premature ventricular contractions) are found on prolonged ECG monitoring in some patients with syncope. The syncope associated with ventricular tachycardia is characterized by a very brief prodrome (<5 seconds). The duration of syncope and of the arrhythmia are closely linked. Frequent or repetitive premature ventricular contractions alone do not often coincide with syncopal symptoms but are predictive of sudden death. Elevation of the ST segment in the right precordium of young adults, without structural heart disease (Brugada syndrome), predisposes to ventricular arrhythmias and sudden death. Multiple genes, particularly involving sodium channels, have been implicated.

Mitral Valve Prolapse

Mitral valve prolapse (click-murmur syndrome) is a common disorder that can be associated with ventricular tachyarrhythmias and resultant syncope in a small number of patients. Other symptoms include nonexertional chest pain, dyspnea, and fatigue. The ECG may be normal or show nonspecific ST-T wave changes or frequent premature ventricular contractions. Diagnosis is by echocardiography.

Prolonged QT Syndrome

The congenital prolonged QT-interval syndrome consists of paroxysmal ventricular arrhythmias (often torsades de pointes), syncope (usually during exercise), and sudden death. It is inherited as an autosomal recessive condition associated with deafness or as an autosomal dominant form without deafness. Cardiac events are most common during the early teenage years to the mid-twenties. Genes implicated in prolonged QT syndrome include potassium channels (KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1), sodium channels (SCN4B, SCN5A), calcium channels (CACNA13), A kinase anchor protein 9 (AKAP9), ankyrin 2 (ANK2), caveolin 3 (CAV3), and α-1 syntrophin (SNTA1). Sporadic cases also occur. Antiarrhythmic drugs and electrolyte disorders (hypomagnesemia, hypocalcemia, hypokalemia) can also produce QT prolongation. Hereditary cases may respond to β-blockers.

BRADYARRHYTHMIAS

Sinoatrial Node Disease

Sinoatrial node disease (ie, sick sinus syndrome), a disorder of older adults, is commonly associated with syncope caused by profound sinus bradycardia, prolonged sinus pauses, or sinus arrest with a slow atrial, junctional, or idioventricular escape rhythm. The diagnosis is by electrocardiographic rhythm identification. Sick sinus syndrome may be inherited as an autosomal recessive or dominant disorder, caused by mutations in the type V voltage-gated sodium channel alpha subunit (SCN5A) or hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) genes, respectively. Patients should be evaluated promptly by a cardiologist, as a permanent pacemaker is necessary in many cases. In tachycardia-bradycardia syndrome, a form of sick sinus syndrome, both types of arrhythmias occur.

Complete Heart Block

Complete heart block (third-degree atrioventricular block) is a common cause of bradyarrhythmia producing recurrent syncope without prodrome. Permanent atrioventricular conduction abnormalities are easily noted on a routine ECG, but intermittent (paroxysmal) conduction abnormalities may not be present on a random tracing. A normal PR interval on an ECG obtained after the episode does not exclude the diagnosis of transient complete heart block.

Patients with syncope and documented or suspected complete heart block should be hospitalized promptly. Patients with acute inferior myocardial infarctions are at high risk for atrioventricular block.

CARDIAC INFLOW OBSTRUCTION

Atrial or ventricular myxomas and atrial thrombi usually present with embolic events, but they may also produce a left ventricular inflow or outflow obstruction that results in a sudden decrease in cardiac output, followed by syncope. A history of syncope occurring with change in position is classic but uncommon. Echocardiography can confirm the diagnosis. Surgical removal of the myxoma is indicated.

Constrictive pericarditis or pericardial tamponade presents with dyspnea, thoracic pain, and signs of cardiac failure. Here, any maneuver or drug that decreases heart rate or venous return can result in suddenly inadequate cardiac output and syncope.

CARDIAC OUTFLOW OBSTRUCTION

Aortic Stenosis

Loss of consciousness from congenital or acquired severe aortic stenosis usually occurs after exercise and is often associated with dyspnea, angina, and diaphoresis. The pathophysiology may involve acute left ventricular failure resulting in coronary hypoperfusion and subsequent ventricular fibrillation, or abrupt increases in left ventricular pressure that stimulate baroreceptors, leading to peripheral vasodilation. Echocardiography can help confirm the diagnosis.

Symptomatic aortic stenosis requires valve replacement; without treatment, survival after syncope from aortic stenosis is 18 months to 3 years.

Pulmonary Stenosis

Most pulmonic valve disorders are congenital. Severe pulmonary stenosis can produce syncope, associated with dyspnea and angina, especially after exertion. A hemodynamic process similar to that occurring in aortic stenosis is responsible. Diagnosis is by echocardiology.

HYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy comprises a group of congenital cardiomyopathies inherited as autosomal dominant disorders of variable severity. Many different genes have been implicated. Symptoms usually begin between the second and fourth decades. Dyspnea is the most common presenting complaint and can be associated with chest pain and palpitations. Syncope occurs in 30% of patients, is the presenting complaint in 10% of patients, and characteristically develops during or after exercise, but orthostatic and posttussive episodes also occur. Syncope may be due to left ventricular outflow obstruction, inflow obstruction, or transient arrhythmias. The diagnosis can be confirmed by echocardiography. Propranolol may control symptoms; an implantable cardioverter defibrillator may terminate potentially fatal ventricular arrhythmias.

DISSECTING AORTIC ANEURYSM

Although acute onset of severe chest or back pain is the most common presenting symptom, approximately 5% to 10% of patients with acute aortic dissections (usually proximal dissection) present with isolated syncope. In 15% of patients, the dissection is painless. Other neurologic abnormalities (stroke, coma, spinal cord ischemia) may or may not be present. Cardiac tamponade is present and may be etiologic in the majority of patients presenting with syncope. A transthoracic echocardiogram is diagnostic.

PULMONARY HYPERTENSION & PULMONARY EMBOLUS

Syncope, often exertional, may be the presenting symptom of pulmonary hypertension. A history of exertional dyspnea is usual, and blood gas analysis shows hypoxemia, even at rest. Syncope is the presenting symptom in approximately 20% of patients experiencing massive pulmonary embolism. The mechanism of syncope is pulmonary vascular occlusion with attenuated cardiac output resulting in reduced cerebral perfusion. Tachy- and bradyarrhythmias may be associated. Upon recovery, such patients are hypotensive, often complain of pleuritic chest pain, dyspnea, and apprehension. Hypotension, tachycardia, tachypnea, hemoptysis, and arterial hypoxemia (O₂ saturations are an inadequate screen) frequently accompany these large emboli. Venous thrombosis is a common embolic source; in some cases, embolization may be induced by defecation.

CEREBROVASCULAR SYNCOPE

Cerebrovascular disease (Chapter 13, Stroke) is an often suspected but actually uncommon cause of episodic unconsciousness.

BASILAR ARTERY INSUFFICIENCY

Basilar artery transient ischemic attacks usually occur after the sixth decade; males with ischemic heart disease and hypertension are most commonly affected. Syncopal attacks occur in about 10% and occur among other symptoms of brainstem ischemia: diplopia, vertigo, ataxia, dysphagia, dysarthria, paresthesias, and drop attacks. Syncopal episodes are typically sudden in onset and brief in duration (seconds to minutes), but when consciousness is lost, recovery is frequently prolonged (30-60 minutes or longer). Isolated unconsciousness without other symptoms of brainstem ischemia is rarely due to basilar artery insufficiency. Two-thirds of patients have recurrent attacks, and strokes eventually occur in approximately one-fifth of all cases. Basilar artery symptoms can also be due to associated subclavian steal. Treatment is discussed in Chapter 13, Stroke.

SUBCLAVIAN STEAL SYNDROME

The subclavian steal syndrome results from subclavian or innominate artery stenosis that causes retrograde blood flow in the vertebral artery, diverting flow from the brainstem and producing hypoperfusion. Sudden turning of the head in the direction of the affected side can induce symptoms of vertigo, syncope, and intermittent claudication of the upper extremity. The degree of subclavian artery stenosis that produces symptoms is variable, but even minor (~40%) stenosis may sometimes do so. A difference between blood pressures measured in the two arms is nearly always found, the average difference being a 45 mm Hg decrease in systolic pressure in the arm supplied by the stenotic vessel. Cerebrovascular risk factors should be modified; stroke is rare. Arteriography and revascularization procedures may be considered.

MIGRAINE

In ~10% of patients with migraine, syncope occurs during the headache, often on rapid rising to a standing position, suggesting that loss of consciousness is due to orthostatic hypotension; autonomic neuropathy may coexist. The headache can precede or follow the syncopal spell. Migraine without syncope occurs in the majority. Syncopal migraine has both more prolonged unconsciousness and more prolonged recovery than syncope alone. A familial association between migraine and syncope occurs. In some patients, basilar migraine produces symptoms similar to those of basilar artery transient ischemic attacks. Antimigraine prophylactic agents (see Chapter 6, Headache & Facial Pain) are often effective in preventing attacks.

TAKAYASU DISEASE

Takayasu disease, sometimes referred to as pulseless arteritis, is a panarteritis of the aorta and its major branches that is most prevalent in young Asian women. Symptoms of claudication are most common, followed by fatigue, headache, visual disturbances, and dyspnea. Syncope occurs in 10%; precipitating factors include exercise, standing, or head movement. Vascular examination shows an absent or diminished pulse, a blood pressure difference between extremities, bruits, hypertension, stroke, heart failure, and aortic regurgitation. The erythrocyte sedimentation rate and C reactive protein may be elevated. Angioplasty is the treatment of choice although medical approaches include corticosteroids or methotrexate.

CAROTID SINUS SYNCOPE

Carotid sinus syncope is uncommon. Men are affected twice as often as women, and most affected individuals are more than 60 years old. Drugs known to predispose to carotid sinus syncope include propranolol, digitalis, and methyldopa. Carotid sinus syncope is diagnosed when carotid sinus massage for 10 seconds (on either side and in supine and upright postures) results in a mixture of bradycardia/hypotension (carotid sinus hypersensitivity) and reproduces spontaneous syncope. Carotid sinus hypersensitivity without syncope is common in older men. Treatment for symptomatic patients is with pacing.

Carotid sinus syncope may be mistakenly diagnosed when symptoms result from compression of a normal carotid artery contralateral to an occluded internal carotid artery. Carotid sinus massage should not be performed in patients with recent TIA or stroke or with carotid bruit.

ORTHOSTATIC HYPOTENSION

Orthostatic hypotension patients represent approximately 15% of syncope patients. Symptomatic orthostasis occurs more often in men than in women, is most common in the sixth and seventh decades, but may appear even in teenagers. Loss of consciousness usually occurs upon rapidly rising to a standing position, standing motionless for a prolonged period (especially after exercise), or standing after prolonged recumbency (especially in the elderly).

Numerous conditions can produce orthostatic hypotension (Table 12-12), which generally results from either hypovolemia or autonomic dysfunction. The latter may be due to drugs, autonomic neuropathy, or CNS disorders affecting sympathetic pathways in the hypothalamus, brainstem, or spinal cord.

Orthostatic hypotension may also be a feature of neurodegenerative disorders. Idiopathic orthostatic hypotension is associated with isolated degeneration of postganglionic sympathetic neurons. In multisystem atrophy (Shy-Drager syndrome), degeneration of preganglionic sympathetic neurons occurs in combination with parkinsonian, pyramidal, cerebellar, or lower motor neuron signs. These disorders are discussed in Chapter 11, Movement Disorders.

The diagnosis of classic orthostatic hypotension is established by demonstrating a decline in blood pressure of at least 20 mm Hg systolic or 10 mm Hg diastolic within 3 minutes of the patient standing from a lying position. Severe orthostatic intolerance associated with heart rate increases (>120/min) without significant hypotension or syncope is termed postural orthostatic tachycardia syndrome (POTS) and is most common in young women (see above).

A detailed general physical and neurologic examination and laboratory studies (hematocrit, stool occult blood, serum glucose and electrolytes, FTA-ABS, nerve conduction studies) should be directed toward establishing the cause of the disorder. Any medication (particularly diuretics, venodilators such as nitrates, and vasodilators such as α-agonists) that might be responsible for orthostatic hypotension should be discontinued if possible. The patient should be instructed to stand up gradually, to elevate the head of the bed on blocks, and to use waist-high elasticized support hosiery. Rapid ingestion of 500 mL of water on awakening prior to getting out of bed increases blood pressure for an hour. Other therapy is dictated by the specific cause of hypotension.

After discontinuing hypotension-inducing medications, enhancing hydration, and adding dietary salt, patients with continued symptoms can be treated with regimens that include midodrine (starting at 2.5 mg two or three times daily increasing to 10 mg tid as needed) and droxidopa as blood pressure enhancers. Pyridostigmine and fludrocortisone are next-line agents, and low-dose atomoxetine may be effective with central autonomic failure.

MISCELLANEOUS CAUSES OF SYNCOPE

COUGH SYNCOPE

Cough (tussive) syncope occurs chiefly in middle-aged men with chronic obstructive pulmonary disease but has also been reported in children. Coughing, which need not be prolonged, immediately precedes unconsciousness. Cough syncope may occur while the patient is supine. Prodromal symptoms are absent, and the duration of unconsciousness is brief—often only a few seconds. Full recovery of consciousness occurs promptly. A history of similar episodes is common, and symptoms may be reproduced by having the patient cough on request. The cause may be a decrease in cerebral blood flow from increased intracranial pressure, which results from the transmission of cough-induced, markedly increased intrathoracic pressure to the intracranial compartment via the spinal fluid or venous connections. Other data support a baroreflex-mediated fall in total peripheral resistance induced by coughing.

The condition is usually benign, and there is no specific treatment except for antitussive drugs such as dextromethorphan. Syncopal spells with a pathophysiology similar to that of coughing include laughter-induced syncope and syncope induced by sneezing or weightlifting.

MICTURITION & DEFECATION SYNCOPE

Micturition syncope is a cerebral hypoperfusion event occurring almost exclusively in men, probably because of the standing position for urination, and is due to peripheral pooling of blood plus vagally induced bradycardia. Episodes can occur immediately before, during, or after micturition. They are more likely to occur at night after the prolonged recumbency of sleep. Urination in a sitting position usually eliminates the symptoms. Syncope during defecation occurs most often in older women and at night, but it can occur throughout the day. The etiology is speculative, but vasodilation and bradycardia following distension of the rectum has been suggested. Border-zone cerebral ischemia has been reported.

GLOSSOPHARYNGEAL NEURALGIA

Glossopharyngeal neuralgia (see Chapter 6, Headache & Facial Pain) is a rare syndrome characterized by intermittent, agonizing, paroxysmal pain localized to the tonsillar pillar or occasionally to the external auditory meatus. The pain is triggered by contact with or movement of the tonsillar pillars, especially during swallowing or talking. Syncope results from activation of a glossopharyngeal-vagal reflex arc, producing transient bradyarrhythmia leading to cerebral hypoperfusion. Carbamazepine 400 to 1000 mg/d orally will prevent pain and bradycardia in most patients. Microvascular decompression of cranial nerve IX or X has been suggested.

PSYCHOGENIC SYNCOPE

Psychogenic syncope is a diagnosis of exclusion and is often made erroneously. Recording an episode with an implantable loop recorder may be required. Suggestive clinical features are lack of any prodrome, possible secondary gain, bizarre postures and movements, lack of pallor, frequent spells, and a prolonged period of apparent unresponsiveness. Eyes are closed during episodes. Psychogenic spells rarely occur when the patient is alone and are rarely associated with incontinence or injury. Most patients are young or have a well-documented history of conversion disorder. Without such a history, diagnosis after the third decade is suspect.

The EEG during psychogenic unconsciousness is normal, without the slowing that typically occurs with cerebral hypoperfusion and follows unconsciousness from a seizure. Caloric testing (see Chapter 3, Coma), which produces nystagmus in conscious patients and tonic eye deviation in unconscious patients, can distinguish psychogenic unresponsiveness from coma caused by a metabolic or structural lesion. Establishing a diagnosis of psychogenic pseudosyncope has been associated with a decrease in frequency of episodes.

NARCOLEPSY

Severe episodes of daytime sleepiness, occurring in the setting of adequate nighttime sleep, can mimic syncope. In narcolepsy, a sporadic disorder with an onset between ages 10 and 20, induced sleep episodes are brief and follow a fixed pattern in a given patient. REM sleep is disordered, and REM elements occur during wakefulness. These elements include sleep paralysis and hypnogogic hallucinations-described as dreaming while awake (both occurring at the transition between sleep and waking), as well as motor paralysis of cataplexy (evolving over many seconds, lasting 1-2 minutes, affecting the face and neck before trunk and limbs, and induced by emotion, usually laughing). A decrease in hypocretin neurons of the lateral hypothalamus and a decrease in CSF hypocretin are found in most narcolepsy and all cataplectic patients. A narcolepsy diagnosis is made by history and nocturnal polysomnography to exclude nocturnal sleep disorders, document two or more sleep onset REM periods, and show brief sleep latencies (less than eight minutes). Narcolepsy treatment begins with brief naps in the morning and afternoon. Modafinil (100-400 mg each morning or 200 mg bid) is the first-line pharmacologic therapy. Cataplexy can be attenuated by tricyclic antidepressants (clomipramine 10-150 mg/d). Sleep paralysis and hypnogogic hallucinations are usually addressed by education.