Section 2: Diseases of the Central Nervous System

INTRODUCTION

A seizure (from the Latin sacire, “to take possession of”) is a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Depending on the distribution of discharges, this abnormal brain activity can have various manifestations, ranging from dramatic convulsive activity to experiential phenomena not readily discernible by an observer. Although a variety of factors influence the incidence and prevalence of seizures, ~5–10% of the population will have at least one seizure, with the highest incidence occurring in early childhood and late adulthood.

The meaning of the term seizure needs to be carefully distinguished from that of epilepsy. Epilepsy describes a condition in which a person has a risk of recurrent seizures due to a chronic, underlying process. This definition implies that a person with a single seizure, or recurrent seizures due to correctable or avoidable circumstances, does not necessarily have epilepsy (although a single seizure associated with particular clinical or electroencephalographic features may establish the diagnosis of epilepsy). Epilepsy refers to a clinical phenomenon rather than a single disease entity, because there are many forms and causes of epilepsy. However, among the many causes of epilepsy there are various epilepsy syndromes in which the clinical and pathologic characteristics are distinctive and suggest a specific underlying etiology.

Using the definition of epilepsy as two or more unprovoked seizures, the incidence of epilepsy is ~0.3–0.5% in different populations throughout the world, and the prevalence of epilepsy has been estimated at 5–30 persons per 1000.

CLASSIFICATION OF SEIZURES

Determining the type of seizure that has occurred is essential for focusing the diagnostic approach on particular etiologies, selecting the appropriate therapy, and providing potentially vital information regarding prognosis. The International League Against Epilepsy (ILAE) Commission on Classification and Terminology provided an updated approach to classification of seizures in 2017 (Table 418-1). This system is based on the clinical features of seizures and associated electroencephalographic findings. Other potentially distinctive features such as etiology or cellular substrate are not considered in this classification system, although this will undoubtedly change in the future as more is learned about the pathophysiologic mechanisms that underlie specific seizure types.

A fundamental principle is that seizures may be either focal or generalized. Focal seizures originate within networks limited to one brain region (note that the term partial seizures is no longer used). Generalized seizures arise within and rapidly engage networks distributed across both cerebral hemispheres. Focal seizures are usually associated with structural abnormalities of the brain. In contrast, generalized seizures may result from cellular, biochemical, or structural abnormalities that have a more widespread distribution. There are clear exceptions in both cases, however.

FOCAL ONSET SEIZURES

Focal seizures arise from a neuronal network either discretely localized within one brain region or more broadly distributed but still within a cerebral hemisphere. With the new classification system, the subcategories of “simple focal seizures” and “complex focal seizures” have been eliminated. Instead, the classification emphasizes the effect on awareness (intact or impaired) and nature of the onset (motor or nonmotor). Focal seizures can also evolve into generalized seizures. In the past this was referred to as focal seizures with secondary generalization, but the new system relies on descriptions of the type of generalized seizures that evolve from the focal seizure.

The routine interictal (i.e., between seizures) electroencephalogram (EEG) in patients with focal seizures is often normal or may show brief discharges termed epileptiform spikes, or sharp waves. Because focal seizures can arise from the medial temporal lobe or inferior frontal lobe (i.e., regions distant from the scalp), the EEG recorded during the seizure may be nonlocalizing. However, the region of seizure onset may be detected using surgically placed intracranial electrodes.

Focal Seizures with Intact Awareness

Focal seizures can have motor manifestations (such as tonic, clonic, or myoclonic movements) or nonmotor manifestations (such as sensory, autonomic, or emotional symptoms) without impairment of awareness. For example, a patient having a focal motor seizure arising from the right primary motor cortex near the area controlling hand movement will note the onset of involuntary movements of the contralateral, left hand. Since the cortical region controlling hand movement is immediately adjacent to the region for facial expression, the seizure may also cause abnormal movements of the face synchronous with the movements of the hand. The EEG recorded with scalp electrodes during the seizure (i.e., an ictal EEG) may show abnormal discharges in a very limited region over the appropriate area of cerebral cortex if the seizure focus involves the cerebral convexity.

Three additional features of focal motor seizures are worth noting. First, in some patients, the abnormal motor movements may begin in a very restricted region such as the fingers and gradually progress (over seconds to minutes) to include a larger portion of the extremity. This phenomenon, described by Hughlings Jackson and known as a “Jacksonian march,” represents the spread of seizure activity over a progressively larger region of motor cortex. Second, patients may experience a localized paresis (Todd’s paralysis) for minutes to many hours in the involved region following the seizure. Third, in rare instances, the seizure may continue for hours or days. This condition, termed epilepsia partialis continua, is often refractory to medical therapy.

Focal seizures may also manifest as changes in somatic sensation (e.g., paresthesias), vision (flashing lights or formed hallucinations), equilibrium (sensation of falling or vertigo), or autonomic function (flushing, sweating, piloerection). Focal seizures arising from the temporal or frontal cortex may also cause alterations in hearing, olfaction, or emotional state. This includes the sensation of unusual, intense odors (e.g., burning rubber or kerosene) or sounds (crude or highly complex sounds), or an epigastric sensation that rises from the stomach or chest to the head. Some patients describe odd, internal feelings such as fear, a sense of impending change, detachment, depersonalization, déjá vu, or illusions that objects are growing smaller (micropsia) or larger (macropsia). These subjective, “internal” events that are not directly observable by someone else are referred to as auras.

Focal Seizures with Impaired Awareness

Focal seizures may also be accompanied by a transient impairment of the patient’s ability to maintain normal contact with the environment. The patient is unable to respond appropriately to visual or verbal commands during the seizure and has impaired recollection or awareness of the ictal phase. The seizures frequently begin with an aura (i.e., a focal seizure without cognitive disturbance) that is stereotypic for the patient. The start of the ictal phase is often a motionless stare, which marks the onset of the period of impaired awareness. The impaired awareness is usually accompanied by automatisms, which are involuntary, automatic behaviors that have a wide range of manifestations. Automatisms may consist of very basic behaviors such as chewing, lip smacking, swallowing, or “picking” movements of the hands, or more elaborate behaviors such as a display of emotion or running. The patient is typically confused following the seizure, and the transition to full recovery of consciousness may range from seconds up to an hour or longer. Examination immediately following the seizure may show an anterograde amnesia or transient neurological deficits (such as aphasia, hemi-neglect, or visual loss) caused by postictal inhibition of the cortical regions most involved in the seizure itself.

The range of potential clinical behaviors linked to focal seizures is so broad that extreme caution is advised before concluding that stereotypic episodes of bizarre or atypical behavior are not due to seizure activity. In such cases additional, detailed EEG studies may be helpful.

EVOLUTION OF FOCAL SEIZURES TO GENERALIZED SEIZURES

Focal seizures can spread to involve both cerebral hemispheres and produce a generalized seizure, usually of the tonic-clonic variety (discussed below). This evolution is observed frequently following focal seizures arising from a region in the frontal lobe, but may also be associated with focal seizures occurring elsewhere in the brain. A focal seizure that evolves into a generalized seizure is often difficult to distinguish from a primary generalized onset tonic-clonic seizure, because bystanders tend to emphasize the more dramatic, generalized convulsive phase of the seizure and overlook the more subtle, focal symptoms present at onset. In some cases, the focal onset of the seizure becomes apparent only when a careful history identifies a preceding aura. Often, however, the focal onset is not clinically evident and may be established only through careful EEG analysis. Nonetheless, distinguishing between these two entities is extremely important, because there may be substantial differences in the evaluation and treatment of epilepsies characterized by focal versus generalized onset seizures.

GENERALIZED ONSET SEIZURES

Generalized seizures arise at some point in the brain but immediately and rapidly engage neuronal networks in both cerebral hemispheres. Several types of generalized seizures have features that place them in distinctive categories and facilitate clinical diagnosis.

Typical Absence Seizures

Typical absence seizures are characterized by sudden, brief lapses of consciousness without loss of postural control. The seizure usually lasts for only seconds, consciousness returns as suddenly as it was lost, and there is no postictal confusion. Although the brief loss of consciousness may be clinically inapparent or the sole manifestation of the seizure discharge, absence seizures are usually accompanied by subtle, bilateral motor signs such as rapid blinking of the eyelids, chewing movements, or small-amplitude, clonic movements of the hands.

Typical absence seizures are associated with a group of genetically determined epilepsies with onset usually in childhood (ages 4–10 years) or early adolescence and are the main seizure type in 15–20% of children with epilepsy. The seizures can occur hundreds of times per day, but the child may be unaware of or unable to convey their existence. Because the clinical signs of the seizures are subtle, especially to parents who may not have had previous experience with seizures, it is not surprising that the first clue to absence epilepsy is often unexplained “daydreaming” and a decline in school performance recognized by a teacher.

The electrophysiologic hallmark of typical absence seizures is a generalized, symmetric, 3-Hz spike-and-slow-wave discharges that begins and ends suddenly, superimposed on a normal EEG background. Periods of spike-and-slow-wave discharges lasting more than a few seconds usually correlate with clinical signs, but the EEG often shows many more brief bursts of abnormal cortical activity than were suspected clinically. Hyperventilation tends to provoke these electrographic discharges and even the seizures themselves and is routinely used when recording the EEG.

Atypical Absence Seizures

Atypical absence seizures have features that deviate both clinically and electrophysiologically from typical absence seizures. For example, the lapse of consciousness is usually of longer duration and less abrupt in onset and cessation, and the seizure is accompanied by more obvious motor signs that may include focal or lateralizing features. The EEG shows a generalized, slow spike-and-slow-wave pattern with a frequency of ≤2.5 per second, as well as other abnormal activity. Atypical absence seizures are usually associated with diffuse or multifocal structural abnormalities of the brain and therefore may accompany other signs of neurologic dysfunction such as mental retardation. Furthermore, the seizures are less responsive to anticonvulsants compared to typical absence seizures.

Generalized, Tonic-Clonic Seizures

Generalized onset tonic-clonic seizures are the main seizure type in ~10% of all persons with epilepsy. They are also the most common seizure type resulting from metabolic derangements and are therefore frequently encountered in many different clinical settings. The seizure usually begins abruptly without warning, although some patients describe vague premonitory symptoms in the hours leading up to the seizure. This prodrome is distinct from the stereotypic auras associated with focal seizures that generalize. The initial phase of the seizure is usually tonic contraction of muscles throughout the body, accounting for a number of the classic features of the event. Tonic contraction of the muscles of expiration and the larynx at the onset will produce a loud moan or “ictal cry.” Respirations are impaired, secretions pool in the oropharynx, and cyanosis develops. Contraction of the jaw muscles may cause biting of the tongue. A marked enhancement of sympathetic tone leads to increases in heart rate, blood pressure, and pupillary size. After 10–20 s, the tonic phase of the seizure typically evolves into the clonic phase, produced by the superimposition of periods of muscle relaxation on the tonic muscle contraction. The periods of relaxation progressively increase until the end of the ictal phase, which usually lasts no more than 1 min. The postictal phase is characterized by unresponsiveness, muscular flaccidity, and excessive salivation that can cause stridorous breathing and partial airway obstruction. Bladder or bowel incontinence may occur at this point. Patients gradually regain consciousness over minutes to hours, and during this transition, there is typically a period of postictal confusion. Patients subsequently complain of headache, fatigue, and muscle ache that can last for many hours. The duration of impaired consciousness in the postictal phase can be extremely long (i.e., many hours) in patients with prolonged seizures or underlying central nervous system (CNS) diseases such as alcoholic cerebral atrophy.

The EEG during the tonic phase of the seizure shows a progressive increase in generalized low-voltage fast activity, followed by generalized high-amplitude, polyspike discharges. In the clonic phase, the high-amplitude activity is typically interrupted by slow waves to create a spike-and-slow-wave pattern. The postictal EEG shows diffuse suppression of all cerebral activity, then slowing that gradually recovers as the patient awakens.

There are a number of variants of generalized motor seizures, including pure tonic and pure clonic seizures. Brief tonic seizures lasting only a few seconds are especially noteworthy since they are usually associated with specific epilepsy syndromes having mixed seizure phenotypes, such as the Lennox-Gastaut syndrome (discussed below).

Atonic Seizures

Atonic seizures are characterized by sudden loss of postural muscle tone lasting 1–2 s. Consciousness is briefly impaired, but there is usually no postictal confusion. A very brief seizure may cause only a quick head drop or nodding movement, whereas a longer seizure will cause the patient to collapse. This can be extremely dangerous, because there is a substantial risk of direct head injury with the fall. The EEG shows brief, generalized spike-and-wave discharges followed immediately by diffuse slow waves that correlate with the loss of muscle tone. Similar to pure tonic seizures, atonic seizures are usually seen in association with known epilepsy syndromes.

Myoclonic Seizures

Myoclonus is a sudden and brief muscle contraction that may involve one part of the body or the entire body. A normal, common physiologic form of myoclonus is the sudden jerking movement observed while falling asleep. Pathologic myoclonus is most commonly seen in association with metabolic disorders, degenerative CNS diseases, or anoxic brain injury (Chap. 301). Although the distinction from other forms of myoclonus is imprecise, myoclonic seizures are considered to be true epileptic events because they are caused by cortical (versus subcortical or spinal) dysfunction. The EEG shows bilaterally synchronous spike-and-slow-wave discharges immediately prior to the movement and muscle artifact associated with the myoclonus. Myoclonic seizures usually coexist with other forms of generalized seizures but are the predominant feature of juvenile myoclonic epilepsy (JME) (discussed below).

Epileptic Spasms

Epileptic spasms are characterized by a briefly sustained flexion or extension of predominantly proximal muscles, including truncal muscles. The EEG usually shows hypsarrhythmia, which consist of diffuse, giant slow waves with a chaotic background of irregular, multifocal spikes and sharp waves. During the clinical spasm, there is a marked suppression of the EEG background (the “electrodecremental response”). The electromyogram (EMG) also reveals a characteristic rhomboid pattern that may help distinguish spasms from brief tonic and myoclonic seizures. Epileptic spasms occur predominantly in infants and likely result from differences in neuronal function and connectivity in the immature versus mature CNS.

EPILEPSY SYNDROMES

Epilepsy syndromes are disorders in which epilepsy is a predominant feature, and there is sufficient evidence (e.g., through clinical, EEG, radiologic, or genetic observations) to suggest a common underlying mechanism. Three important epilepsy syndromes are listed below; additional examples with a known genetic basis are shown in Table 418-2.

JUVENILE MYOCLONIC EPILEPSY

JME is a generalized seizure disorder of unknown cause that appears in early adolescence and is usually characterized by bilateral myoclonic jerks that may be single or repetitive. The myoclonic seizures are most frequent in the morning after awakening and can be provoked by sleep deprivation. Consciousness is preserved unless the myoclonus is especially severe. Many patients also experience generalized tonic-clonic seizures, and up to one-third have absence seizures. Although complete remission is relatively uncommon, the seizures usually respond well to appropriate anticonvulsant medication. There is often a family history of epilepsy, and genetic linkage studies suggest a polygenic cause.

LENNOX-GASTAUT SYNDROME

Lennox-Gastaut syndrome occurs in children and is defined by the following triad: (1) multiple seizure types (usually including generalized tonic-clonic, atonic, and atypical absence seizures); (2) an EEG showing slow (<3 Hz) spike-and-wave discharges and a variety of other abnormalities; and (3) impaired cognitive function in most but not all cases. Lennox-Gastaut syndrome is associated with CNS disease or dysfunction from a variety of causes, including de novo mutations, developmental abnormalities, perinatal hypoxia/ischemia, trauma, infection, and other acquired lesions. The multifactorial nature of this syndrome suggests that it is a nonspecific response of the brain to diffuse neuronal dysfunction. Unfortunately, many patients have a poor prognosis due to the underlying CNS disease and the physical and psychosocial consequences of severe, poorly controlled epilepsy.

MESIAL TEMPORAL LOBE EPILEPSY SYNDROME

Mesial temporal lobe epilepsy (MTLE) is the most common syndrome associated with focal seizures with impairment of consciousness and is an example of an epilepsy syndrome with distinctive clinical, electroencephalographic, and pathologic features (Table 418-3). High-resolution magnetic resonance imaging (MRI) can detect the characteristic hippocampal sclerosis that appears to be essential in the pathophysiology of MTLE for many patients (Fig. 418-1). Recognition of this syndrome is especially important because it tends to be refractory to treatment with anticonvulsants but responds well to surgical intervention. Advances in the understanding of basic mechanisms of epilepsy have come through studies of experimental models of MTLE, discussed below.

THE CAUSES OF SEIZURES AND EPILEPSY

Seizures are a result of a shift in the normal balance of excitation and inhibition within the CNS. Given the numerous properties that control neuronal excitability, it is not surprising that there are many different ways to perturb this normal balance, and therefore many different causes of both seizures and epilepsy. Three clinical observations emphasize how a variety of factors determine why certain conditions may cause seizures or epilepsy in a given patient.

1. The normal brain is capable of having a seizure under the appropriate circumstances, and there are differences between individuals in the susceptibility or threshold for seizures. For example, seizures may be induced by high fevers in children who are otherwise normal and who never develop other neurologic problems, including epilepsy. However, febrile seizures occur only in a relatively small proportion of children. This implies there are various underlying endogenous factors that influence the threshold for having a seizure. Some of these factors are genetic, as a family history of epilepsy has a clear influence on the likelihood of seizures occurring in otherwise normal individuals. Normal development also plays an important role, because the brain appears to have different seizure thresholds at different maturational stages.

2. There are a variety of conditions that have an extremely high likelihood of resulting in a chronic seizure disorder. One of the best examples of this is severe, penetrating head trauma, which is associated with up to a 45% risk of subsequent epilepsy. The high propensity for severe traumatic brain injury to lead to epilepsy suggests that the injury results in a long-lasting pathologic change in the CNS that transforms a presumably normal neural network into one that is abnormally hyperexcitable. This process is known as epileptogenesis, and the specific changes that result in a lowered seizure threshold can be considered epileptogenic factors. Other processes associated with epileptogenesis include stroke, infections, and abnormalities of CNS development. Likewise, the genetic abnormalities associated with epilepsy likely involve processes that trigger the appearance of specific sets of epileptogenic factors.

3. Seizures are episodic. Patients with epilepsy have seizures intermittently and, depending on the underlying cause, many patients are completely normal for months or even years between seizures. This implies there are important provocative or precipitating factors that induce seizures in patients with epilepsy. Similarly, precipitating factors are responsible for causing the single seizure in someone without epilepsy. Precipitants include those due to intrinsic physiologic processes such as psychological or physical stress, sleep deprivation, or hormonal changes. They also include exogenous factors such as exposure to toxic substances and certain medications.

These observations emphasize the concept that the many causes of seizures and epilepsy result from a dynamic interplay between endogenous factors, epileptogenic factors, and precipitating factors. The potential role of each needs to be carefully considered when determining the appropriate management of a patient with seizures. For example, the identification of predisposing factors (e.g., family history of epilepsy) in a patient with febrile seizures may increase the necessity for closer follow-up and a more aggressive diagnostic evaluation. Finding an epileptogenic lesion may help in the estimation of seizure recurrence and duration of therapy. Finally, removal or modification of a precipitating factor may be an effective and safer method for preventing further seizures than the prophylactic use of anticonvulsant drugs.

CAUSES ACCORDING TO AGE

In practice, it is useful to consider the etiologies of seizures based on the age of the patient, because age is one of the most important factors determining both the incidence and the likely causes of seizures or epilepsy (Table 418-4). During the neonatal period and early infancy, potential causes include hypoxic-ischemic encephalopathy, trauma, CNS infection, congenital CNS abnormalities, and metabolic disorders. Babies born to mothers using neurotoxic drugs such as cocaine, heroin, or ethanol are susceptible to drug-withdrawal seizures in the first few days after delivery. Hypoglycemia and hypocalcemia, which can occur as secondary complications of perinatal injury, are also causes of seizures early after delivery. Seizures due to inborn errors of metabolism usually present once regular feeding begins, typically 2–3 days after birth. Pyridoxine (vitamin B₆) deficiency, an important cause of neonatal seizures, can be effectively treated with pyridoxine replacement. The idiopathic or inherited forms of benign neonatal seizures are also seen during this time period.

The most common seizures arising in late infancy and early childhood are febrile seizures, which are seizures associated with fevers but without evidence of CNS infection or other defined causes. The overall prevalence is 3–5% and even higher in some parts of the world such as Asia. Patients often have a family history of febrile seizures or epilepsy. Febrile seizures usually occur between 3 months and 5 years of age and have a peak incidence between 18 and 24 months. The typical scenario is a child who has a generalized, tonic-clonic seizure during a febrile illness in the setting of a common childhood infection such as otitis media, respiratory infection, or gastroenteritis. The seizure is likely to occur during the rising phase of the temperature curve (i.e., during the first day) rather than well into the course of the illness. A simple febrile seizure is a single, isolated event, brief, and symmetric in appearance. Complex febrile seizures are characterized by repeated seizure activity, duration >15 minutes, or by focal features. Approximately one-third of patients with febrile seizures will have a recurrence, but <10% have three or more episodes. Recurrences are much more likely when the febrile seizure occurs in the first year of life. Simple febrile seizures are not associated with an increase in the risk of developing epilepsy, while complex febrile seizures have a risk of 2–5%; other risk factors include the presence of preexisting neurologic deficits and a family history of nonfebrile seizures.

Childhood marks the age at which many of the well-defined epilepsy syndromes present. Some children who are otherwise normal develop idiopathic, generalized tonic-clonic seizures without other features that fit into specific syndromes. Temporal lobe epilepsy usually presents in childhood and may be related to mesial temporal lobe sclerosis (as part of the MTLE syndrome) or other focal abnormalities such as cortical dysgenesis. Other types of focal seizures, including those that evolve into generalized seizures, may be the relatively late manifestation of a developmental disorder, an acquired lesion such as head trauma, CNS infection (especially viral encephalitis), or very rarely a CNS tumor.

The period of adolescence and early adulthood is one of transition during which the idiopathic or genetically based epilepsy syndromes, including JME and juvenile absence epilepsy, become less common, while epilepsies secondary to acquired CNS lesions begin to predominate. Seizures that arise in patients in this age range may be associated with head trauma, CNS infections (including parasitic infections such as cysticercosis), brain tumors, congenital CNS abnormalities, illicit drug use, or alcohol withdrawal. Autoantibodies directed against CNS antigens such as potassium channels or glutamate receptors are a newly recognized cause of epilepsy that also begins to appear in this age group (although cases of autoimmunity are being increasingly described in the pediatric population), including patients without an identifiable cancer. This etiology should be suspected when a previously normal individual presents with a particularly aggressive seizure pattern developing over weeks to months and characterized by increasingly frequent and prolonged seizures, especially when combined with psychiatric symptoms and changes in cognitive function (Chap. 90).

Head trauma is a common cause of epilepsy in adolescents and adults. The head injury can be caused by a variety of mechanisms, and the likelihood of developing epilepsy is strongly correlated with the severity of the injury. A patient with a penetrating head wound, depressed skull fracture, intracranial hemorrhage, or prolonged posttraumatic coma or amnesia has a 30–50% risk of developing epilepsy, whereas a patient with a closed head injury and cerebral contusion has a 5–25% risk. Recurrent seizures usually develop within 1 year after head trauma, although intervals of >10 years are well known. In controlled studies, mild head injury, defined as a concussion with amnesia or loss of consciousness of <30 min, was found to be associated with only a slightly increased likelihood of epilepsy. Nonetheless, most epileptologists know of patients who have focal seizures within hours or days of a mild head injury and subsequently develop chronic seizures of the same type; such cases may represent rare examples of chronic epilepsy resulting from mild head injury.

The causes of seizures in older adults include cerebrovascular disease, trauma (including subdural hematoma), CNS tumors, and degenerative diseases. Cerebrovascular disease may account for ~50% of new cases of epilepsy in patients >65 years. Acute seizures (i.e., occurring at the time of the stroke) are seen more often with embolic rather than hemorrhagic or thrombotic stroke. Chronic seizures typically appear months to years after the initial event and are associated with all forms of stroke.

Metabolic disturbances such as electrolyte imbalance, hypo- or hyperglycemia, renal failure, and hepatic failure may cause seizures at any age. Similarly, endocrine disorders, hematologic disorders, vasculitides, and many other systemic diseases may cause seizures over a broad age range. A wide variety of medications and abused substances are known to precipitate seizures as well (Table 418-5).

BASIC MECHANISMS

MECHANISMS OF SEIZURE INITIATION AND PROPAGATION

Focal seizure activity can begin in a very discrete region of cortex and then slowly invade the surrounding regions. The hallmark of an established seizure is typically an electrographic “spike” due to intense near-simultaneous firing of a large number of local excitatory neurons, resulting in an apparent hypersynchronization of the excitatory bursts across a relatively large cortical region. The bursting activity in individual neurons (the “paroxysmal depolarization shift”) is caused by a relatively long-lasting depolarization of the neuronal membrane due to influx of extracellular calcium (Ca²⁺), which leads to the opening of voltage-dependent sodium (Na⁺) channels, influx of Na⁺, and generation of repetitive action potentials. This is followed by a hyperpolarizing afterpotential mediated by γ-aminobutyric acid (GABA) receptors or potassium (K⁺) channels, depending on the cell type. The synchronized bursts from a sufficient number of neurons result in a so-called spike discharge on the EEG.

The spreading seizure wavefront is thought to slow and ultimately halt by intact hyperpolarization and a “surround” inhibition created by feedforward activation of inhibitory neurons. With sufficient activation, there is a recruitment of surrounding neurons via a number of synaptic and nonsynaptic mechanisms, including: (1) an increase in extracellular K⁺, which blunts hyperpolarization and depolarizes neighboring neurons; (2) accumulation of Ca²⁺ in presynaptic terminals, leading to enhanced neurotransmitter release; (3) depolarization-induced activation of the N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptor, which causes additional Ca²⁺ influx and neuronal activation; and (4) ephaptic interactions related to changes in tissue osmolarity and cell swelling. The recruitment of a sufficient number of neurons leads to the propagation of excitatory currents into contiguous areas via local cortical connections and to more distant areas via long commissural pathways such as the corpus callosum.

Many factors control neuronal excitability, and thus there are many potential mechanisms for altering a neuron’s propensity to have bursting activity. Mechanisms intrinsic to the neuron include changes in the conductance of ion channels, response characteristics of membrane receptors, cytoplasmic buffering, second-messenger systems, and protein expression as determined by gene transcription, translation, and posttranslational modification. Mechanisms extrinsic to the neuron include changes in the amount or type of neurotransmitters present at the synapse, modulation of receptors by extracellular ions and other molecules, and temporal and spatial properties of synaptic and nonsynaptic input. Nonneural cells, such as astrocytes and oligodendrocytes, have an important role in many of these mechanisms as well.

Certain recognized causes of seizures are explained by these mechanisms. For example, accidental ingestion of domoic acid, which is an analogue of glutamate (the principal excitatory neurotransmitter in the brain), causes profound seizures via direct activation of excitatory amino acid receptors throughout the CNS. Penicillin, which can lower the seizure threshold in humans and is a potent convulsant in experimental models, reduces inhibition by antagonizing the effects of GABA at its receptor. The basic mechanisms of other precipitating factors of seizures, such as sleep deprivation, fever, alcohol withdrawal, hypoxia, and infection, are not as well understood but presumably involve analogous perturbations in neuronal excitability. Similarly, the endogenous factors that determine an individual’s seizure threshold may relate to these properties as well.

Knowledge of the mechanisms responsible for initiation and propagation of most generalized seizures (including tonic-clonic, myoclonic, and atonic types) remains rudimentary and reflects the limited understanding of the connectivity of the brain at a systems level. Much more is understood about the origin of generalized spike-and-wave discharges in absence seizures. These appear to be related to oscillatory rhythms normally generated during sleep by circuits connecting the thalamus and cortex. This oscillatory behavior involves an interaction between GABA_B receptors, T-type Ca²⁺ channels, and K⁺ channels located within the thalamus. Pharmacologic studies indicate that modulation of these receptors and channels can induce absence seizures, and there is good evidence that the genetic forms of absence epilepsy may be associated with mutations of components of this system.

MECHANISMS OF EPILEPTOGENESIS

Epileptogenesis refers to the transformation of a normal neuronal network into one that is chronically hyperexcitable. There is often a delay of months to years between an initial CNS injury such as trauma, stroke, or infection and the first clinically evident seizure. The injury appears to initiate a process that gradually lowers the seizure threshold in the affected region until a spontaneous seizure occurs. In many genetic and idiopathic forms of epilepsy, epileptogenesis is presumably determined by developmentally regulated events.

Pathologic studies of the hippocampus from patients with temporal lobe epilepsy have led to the suggestion that some forms of epileptogenesis are related to structural changes in neuronal networks. For example, many patients with MTLE have a highly selective loss of neurons that normally contribute to inhibition of the main excitatory neurons within the dentate gyrus. There is also evidence that, in response to the loss of neurons, there is reorganization of surviving neurons in a way that affects the excitability of the network. Some of these changes can be seen in experimental models of prolonged electrical seizures or traumatic brain injury. Thus, an initial injury such as head injury may lead to a very focal, confined region of structural change that causes local hyperexcitability. The local hyperexcitability leads to further structural changes that evolve over time until the focal lesion produces clinically evident seizures. Similar models have provided strong evidence for long-term alterations in intrinsic, biochemical properties of cells within the network such as chronic changes in glutamate or GABA receptor function. Induction of inflammatory cascades may be a critical factor in these processes as well.

GENETIC CAUSES OF EPILEPSY

The most important recent progress in epilepsy research has been the identification of genetic mutations associated with a variety of epilepsy syndromes (Table 418-2). Although most of the mutations identified to date cause rare forms of epilepsy, their discovery has led to extremely important conceptual advances. For example, it appears that many of the inherited epilepsies are due to mutations affecting ion channel function. These syndromes are therefore part of the larger group of channelopathies causing paroxysmal disorders such as cardiac arrhythmias, episodic ataxia, periodic weakness, and familial hemiplegic migraine. Other gene mutations are proving to be associated with pathways influencing CNS development or neuronal homeostasis. De novo mutations may explain a significant proportion of these syndromes, especially those with onset in early childhood. A current challenge is to identify the multiple susceptibility genes that underlie the more common forms of idiopathic epilepsies. Recent studies suggest that ion channel mutations and copy number variants may contribute to causation in a subset of these patients.

MECHANISMS OF ACTION OF ANTIEPILEPTIC DRUGS

Antiepileptic drugs appear to act primarily by blocking the initiation or spread of seizures. This occurs through a variety of mechanisms that modify the activity of ion channels or neurotransmitters, and in most cases, the drugs have pleiotropic effects. The mechanisms include inhibition of Na⁺-dependent action potentials in a frequency-dependent manner (e.g., phenytoin, carbamazepine, lamotrigine, topiramate, zonisamide, lacosamide, rufinamide), inhibition of voltage-gated Ca²⁺ channels (phenytoin, gabapentin, pregabalin), facilitating the opening of potassium channels (ezogabine), attenuation of glutamate activity (lamotrigine, topiramate, felbamate), potentiation of GABA receptor function (benzodiazepines and barbiturates), increase in the availability of GABA (valproic acid, gabapentin, tiagabine), and modulation of release of synaptic vesicles (levetiracetam, brivaracetam). Two of the effective drugs for absence seizures, ethosuximide and valproic acid, probably act by inhibiting T-type Ca²⁺ channels in thalamic neurons.

In contrast to the relatively large number of antiepileptic drugs that can attenuate seizure activity, there are currently no drugs known to prevent the formation of a seizure focus following CNS injury. The eventual development of such “antiepileptogenic” drugs will provide an important means of preventing the emergence of epilepsy following injuries such as head trauma, stroke, and CNS infection.

APPROACH TO THE PATIENT

HISTORY AND EXAMINATION

The first goal is to determine whether the event was truly a seizure. An in-depth history is essential, because in many cases the diagnosis of a seizure is based solely on clinical grounds—the examination and laboratory studies are often normal. Questions should focus on the symptoms before, during, and after the episode in order to differentiate a seizure from other paroxysmal events (see “Differential Diagnosis of Seizures” below). Seizures frequently occur out-of-hospital, and the patient may be unaware of the ictal and immediate postictal phases; thus, witnesses to the event should be interviewed carefully.

The history should also focus on risk factors and predisposing events. Clues for a predisposition to seizures include a history of febrile seizures, a family history of seizures, and, of particular importance, earlier auras or brief seizures not recognized as such. Epileptogenic factors such as prior head trauma, stroke, tumor, or CNS infection should be identified. In children, a careful assessment of developmental milestones may provide evidence for underlying CNS disease. Precipitating factors such as sleep deprivation, systemic diseases, electrolyte or metabolic derangements, acute infection, drugs that lower the seizure threshold (Table 418-5), or alcohol or illicit drug use should also be identified.

The general physical examination includes a search for signs of infection or systemic illness. Careful examination of the skin may reveal signs of neurocutaneous disorders such as tuberous sclerosis or neurofibromatosis, or chronic liver or renal disease. A finding of organomegaly may indicate a metabolic storage disease, and limb asymmetry may provide a clue to brain injury early in development. Signs of head trauma and use of alcohol or illicit drugs should be sought. Auscultation of the heart and carotid arteries may identify an abnormality that predisposes to cerebrovascular disease.

All patients require a complete neurologic examination, with particular emphasis on eliciting signs of cerebral hemispheric disease (Chap. 415). Careful assessment of mental status (including memory, language function, and abstract thinking) may suggest lesions in the anterior frontal, parietal, or temporal lobes. Testing of visual fields will help screen for lesions in the optic pathways and occipital lobes. Screening tests of motor function such as pronator drift, deep tendon reflexes, gait, and coordination may suggest lesions in motor (frontal) cortex, and cortical sensory testing (e.g., double simultaneous stimulation) may detect lesions in the parietal cortex.

LABORATORY STUDIES

Routine blood studies are indicated to identify the more common metabolic causes of seizures such as abnormalities in electrolytes, glucose, calcium, or magnesium, and hepatic or renal disease. A screen for toxins in blood and urine should also be obtained from all patients in appropriate risk groups, especially when no clear precipitating factor has been identified. A lumbar puncture is indicated if there is any suspicion of meningitis or encephalitis, and it is mandatory in all patients infected with HIV, even in the absence of symptoms or signs suggesting infection. Testing for autoantibodies in the serum and cerebrospinal fluid (CSF) should be considered in patients presenting with a seemingly aggressive form of epilepsy associated with other abnormalities such as psychiatric symptoms or cognitive disturbances.

ELECTROPHYSIOLOGIC STUDIES

The electrical activity of the brain (the EEG) is easily recorded from electrodes placed on the scalp. The potential difference between pairs of electrodes on the scalp (bipolar derivation) or between individual scalp electrodes and a relatively inactive common reference point (referential derivation) is amplified and displayed on a computer monitor, oscilloscope, or paper. Digital systems allow the EEG to be reconstructed and displayed with any desired format and to be manipulated for more detailed analysis and also permit computerized techniques to be used to detect certain abnormalities. The characteristics of the normal EEG depend on the patient’s age and level of arousal. The rhythmic activity normally recorded represents the postsynaptic potentials of vertically oriented pyramidal cells of the cerebral cortex and is characterized by its frequency. In normal awake adults lying quietly with the eyes closed, an 8- to 13-Hz alpha rhythm is seen posteriorly in the EEG, intermixed with a variable amount of generalized faster (beta) activity (>13 Hz); the alpha rhythm is attenuated when the eyes are opened (Fig. 418-3). During drowsiness, the alpha rhythm is also attenuated; with light sleep, slower activity in the theta (4–7 Hz) and delta (<4 Hz) ranges becomes more conspicuous.

All patients who have a possible seizure disorder should be evaluated with an EEG as soon as possible. In the evaluation of a patient with suspected epilepsy, the presence of electrographic seizure activity during the clinically evident event (i.e., abnormal, repetitive, rhythmic activity having a discrete onset and termination) clearly establishes the diagnosis. The absence of electrographic seizure activity does not exclude a seizure disorder, however, because focal seizures may originate from a region of the cortex that cannot be detected by standard scalp electrodes. The EEG is always abnormal during generalized tonic-clonic seizures. Because seizures are typically infrequent and unpredictable, it is often not possible to obtain the EEG during a clinical event. In such situations, activating procedures are generally undertaken while the EEG is recorded in an attempt to provoke abnormalities. These procedures commonly include hyperventilation (for 3 or 4 min), photic stimulation, sleep, and sleep deprivation on the night prior to the recording. Continuous monitoring for prolonged periods in video-EEG telemetry units for hospitalized patients or the use of portable equipment to record the EEG continuously for ≥24 h in ambulatory patients has made it easier to capture the electrophysiologic accompaniments of clinical events. In particular, video-EEG telemetry is now a routine approach for the accurate diagnosis of epilepsy in patients with poorly characterized events or seizures that are difficult to control.

The EEG may also be helpful in the interictal period by showing certain abnormalities that are highly supportive of the diagnosis of epilepsy. Such epileptiform activity consists of bursts of abnormal discharges containing spikes or sharp waves. The presence of epileptiform activity is not entirely specific for epilepsy, but it has a much greater prevalence in patients with epilepsy than in normal individuals. However, even in an individual who is known to have epilepsy, the initial routine interictal EEG may be normal up to 60% of the time. Thus, the EEG cannot establish the diagnosis of epilepsy in many cases.

The EEG is also used for classifying seizure disorders and aiding in the selection of anticonvulsant medications (Fig. 418-4). For example, episodic generalized spike-wave activity is usually seen in patients with typical absence epilepsy and may be seen with other generalized epilepsy syndromes. Focal interictal epileptiform discharges would support the diagnosis of a focal seizure disorder such as temporal lobe epilepsy or frontal lobe seizures, depending on the location of the discharges.

The routine scalp-recorded EEG may also be used to assess the prognosis of seizure disorders; in general, a normal EEG implies a better prognosis, whereas an abnormal background or profuse epileptiform activity suggests a worse outcome. Unfortunately, the EEG has not proved to be useful in predicting which patients with predisposing conditions such as head injury or brain tumor will go on to develop epilepsy, because in such circumstances epileptiform activity is commonly encountered regardless of whether seizures occur.

Magnetoencephalography (MEG) provides another way of looking noninvasively at cortical activity. Instead of measuring electrical activity of the brain, it measures the small magnetic fields that are generated by this activity. The source of epileptiform activity seen on MEG can be analyzed, and its source in the brain can be estimated using a variety of mathematical techniques. These source estimates can then be plotted on an anatomic image of the brain such as an MRI (discussed below) to generate a magnetic source image (MSI). MSI can be useful to localize potential seizure foci.

BRAIN IMAGING

Almost all patients with new-onset seizures should have a brain imaging study to determine whether there is an underlying structural abnormality that is responsible. The only potential exception to this rule is children who have an unambiguous history and examination suggestive of a benign, generalized seizure disorder such as absence epilepsy. MRI has been shown to be superior to computed tomography (CT) for the detection of cerebral lesions associated with epilepsy. In some cases, MRI will identify lesions such as tumors, vascular malformations, or other pathologies that need urgent therapy. The availability of newer MRI methods such as 3-tesla scanners, parallel imaging with multichannel head coils, three-dimensional structural imaging at submillimeter resolution, and widespread use of pulse sequences such as fluid-attenuated inversion recovery (FLAIR), has increased the sensitivity for detection of abnormalities of cortical architecture, including hippocampal atrophy associated with mesial temporal sclerosis, as well as abnormalities of cortical neuronal migration. In such cases, the findings may not lead to immediate therapy, but they do provide an explanation for the patient’s seizures and point to the need for chronic antiepileptic drug therapy or possible surgical resection.

In the patient with a suspected CNS infection or mass lesion, CT scanning should be performed emergently when MRI is not immediately available. Otherwise, it is usually appropriate to obtain an MRI study within a few days of the initial evaluation. Functional imaging procedures such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are also used to evaluate certain patients with medically refractory seizures (discussed below).

GENETIC TESTING

With the increasing recognition of specific gene mutations causing epilepsy, genetic testing is beginning to emerge as part of the diagnostic evaluation of patients with epilepsy. In addition to providing a definitive diagnosis (which may be of great benefit to the patient and family members, and curtail the pursuit of additional, unrevealing laboratory testing), genetic testing may offer a guide for therapeutic options (see section “Selection of Antiepileptic Drugs” below). Presently, genetic testing is being done mainly in infants and children with epilepsy syndromes thought to have a genetic cause. However, genetic testing should also be considered in older patients with a history suggesting an undiagnosed genetic epilepsy syndrome that began early in life.

DIFFERENTIAL DIAGNOSIS OF SEIZURES

Disorders that may mimic seizures are listed in Table 418-6. In most cases, seizures can be distinguished from other conditions by meticulous attention to the history and relevant laboratory studies. On occasion, additional studies such as video-EEG monitoring, sleep studies, tilt-table analysis, or cardiac electrophysiology may be required to reach a correct diagnosis. Two of the more common nonepileptic syndromes in the differential diagnosis are detailed below.

SYNCOPE

(See also Chap. 18) The diagnostic dilemma encountered most frequently is the distinction between a generalized seizure and syncope. Observations by the patient and bystanders that can help differentiate between the two are listed in Table 418-7. Characteristics of a seizure include the presence of an aura, cyanosis, unconsciousness, motor manifestations lasting >15 s, postictal disorientation, muscle soreness, and sleepiness. In contrast, a syncopal episode is more likely if the event was provoked by acute pain or emotional stress or occurred immediately after arising from the lying or sitting position. Patients with syncope often describe a stereotyped transition from consciousness to unconsciousness that includes tiredness, sweating, nausea, and tunneling of vision, and they experience a relatively brief loss of consciousness. Headache or incontinence usually suggests a seizure but may on occasion also occur with syncope. A brief period (i.e., 1–10 s) of convulsive motor activity is frequently seen immediately at the onset of a syncopal episode, especially if the patient remains in an upright posture after fainting (e.g., in a dentist’s chair) and therefore has a sustained decrease in cerebral perfusion. Rarely, a syncopal episode can induce a full tonic-clonic seizure. In such cases, the evaluation must focus on both the cause of the syncopal event as well as the possibility that the patient has a propensity for recurrent seizures.

PSYCHOGENIC SEIZURES

Psychogenic seizures are nonepileptic behaviors that resemble seizures. They are often part of a conversion reaction precipitated by underlying psychological distress. Certain behaviors such as side-to-side turning of the head, asymmetric and large-amplitude shaking movements of the limbs, twitching of all four extremities without loss of consciousness, and pelvic thrusting are more commonly associated with psychogenic rather than epileptic seizures. Psychogenic seizures often last longer than epileptic seizures and may wax and wane over minutes to hours. However, the distinction is sometimes difficult on clinical grounds alone, and there are many examples of diagnostic errors made by experienced epileptologists. This is especially true for psychogenic seizures that resemble focal seizures, because the behavioral manifestations of focal seizures (especially of frontal lobe origin) can be extremely unusual, and in both cases, the routine surface EEG may be normal. Video-EEG monitoring is very useful when historic features are nondiagnostic. Generalized tonic-clonic seizures always produce marked EEG abnormalities during and after the seizure. For suspected focal seizures of temporal lobe origin, the use of additional electrodes may help to localize a seizure focus. Measurement of serum prolactin levels may also help to distinguish between epileptic and psychogenic seizures, because most generalized seizures and some focal seizures are accompanied by rises in serum prolactin (during the immediate 30-min postictal period), whereas psychogenic seizures are not. The diagnosis of psychogenic seizures does not exclude a concurrent diagnosis of epilepsy, because the two may coexist.

TREATMENT

STATUS EPILEPTICUS

Status epilepticus refers to continuous seizures or repetitive, discrete seizures with impaired consciousness in the interictal period. Status epilepticus has numerous subtypes, including generalized convulsive status epilepticus (GCSE) (e.g., persistent, generalized electrographic seizures, coma, and tonic-clonic movements) and nonconvulsive status epilepticus (e.g., persistent absence seizures or focal seizures with confusion or partially impaired consciousness, and minimal motor abnormalities). The duration of seizure activity sufficient to meet the definition of status epilepticus has traditionally been specified as 15–30 min. However, a more practical definition is to consider status epilepticus as a situation in which the duration of seizures prompts the acute use of anticonvulsant therapy. For GCSE, this is typically when seizures last beyond 5 min.

GCSE is an emergency and must be treated immediately, because cardiorespiratory dysfunction, hyperthermia, and metabolic derangements can develop as a consequence of prolonged seizures, and these can lead to irreversible neuronal injury. Furthermore, CNS injury can occur even when the patient is paralyzed with neuromuscular blockade but continues to have electrographic seizures. The most common causes of GCSE are anticonvulsant withdrawal or noncompliance, metabolic disturbances, drug toxicity, CNS infection, CNS tumors, refractory epilepsy, and head trauma.

GCSE is obvious when the patient is having overt seizures. However, after 30–45 min of uninterrupted seizures, the signs may become increasingly subtle. Patients may have mild clonic movements of only the fingers or fine, rapid movements of the eyes. There may be paroxysmal episodes of tachycardia, hypertension, and pupillary dilation. In such cases, the EEG may be the only method of establishing the diagnosis. Thus, if the patient stops having overt seizures, yet remains comatose, an EEG should be performed to rule out ongoing status epilepticus. This is obviously also essential when a patient with GCSE has been paralyzed with neuromuscular blockade in the process of protecting the airway.

The first steps in the management of a patient in GCSE are to attend to any acute cardiorespiratory problems or hyperthermia, perform a brief medical and neurologic examination, establish venous access, and send samples for laboratory studies to identify metabolic abnormalities. Anticonvulsant therapy should then begin without delay; a treatment approach is shown in Fig. 418-5. A recent large trial of patients with benzodiazepine-refractory convulsive status epilepticus demonstrated similar efficacy and side effects with fosphenytoin, valproate, and levetiracetam.

The treatment of nonconvulsive status epilepticus is thought to be less urgent than GCSE, because the ongoing seizures are not accompanied by the severe metabolic disturbances seen with GCSE. However, evidence suggests that nonconvulsive status epilepticus, especially that caused by ongoing, focal seizure activity, is associated with cellular injury in the region of the seizure focus; therefore, this condition should be treated as promptly as possible using the general approach described for GCSE.

BEYOND SEIZURES: OTHER MANAGEMENT ISSUES

EPILEPSY COMORBIDITIES

The adverse effects of epilepsy often go beyond clinical seizures. Many epilepsy patients are completely normal between seizures and live highly successful and productive lives. However, a significant proportion of patients suffer from varying degrees of cognitive dysfunction, including psychiatric disease, and it has become increasingly clear that the network dysfunction underlying epilepsy can have effects well beyond the occurrence of seizures. For example, patients with seizures secondary to developmental abnormalities or acquired brain injury may have impaired cognitive function and other neurologic deficits due to abnormal brain structure. Frequent interictal EEG abnormalities are associated with subtle dysfunction of memory and attention. Patients with many seizures, especially those emanating from the temporal lobe, often note an impairment of short-term memory that may progress over time.

The psychiatric problems associated with epilepsy include depression, anxiety, and psychosis. This risk varies considerably depending on many factors, including the etiology, frequency, and severity of seizures and the patient’s age and previous personal or family history of psychiatric disorder. Depression occurs in ~20% of patients, and the incidence of suicide is higher in patients with epilepsy than in the general population. Depression should be treated through counseling or medication. The selective serotonin reuptake inhibitors (SSRIs) typically have minimal effect on seizures, whereas tricyclic antidepressants may lower the seizure threshold. Anxiety can be a seizure symptom, and anxious or psychotic behavior can occur during a postictal delirium. Postictal psychosis is a rare phenomenon that typically occurs after a period of increased seizure frequency. There is usually a brief lucid interval lasting up to a week, followed by days to weeks of agitated, psychotic behavior. The psychosis usually resolves spontaneously but frequently will require short-term treatment with antipsychotic or anxiolytic medications.

MORTALITY OF EPILEPSY

Patients with epilepsy have a risk of death that is roughly two to three times greater than expected in a matched population without epilepsy. Most of the increased mortality is due to the underlying etiology of epilepsy (e.g., tumors or strokes in older adults). However, a significant number of patients die from accidents, status epilepticus, and a syndrome known as sudden unexpected death in epilepsy (SUDEP), which usually affects young people with convulsive seizures and tends to occur at night. The cause of SUDEP is unknown; it may result from brainstem-mediated effects of seizures on pulmonary, cardiac, and arousal functions. Recent studies suggest that, in some cases, a genetic mutation may be the cause of both epilepsy and a cardiac conduction defect that gives rise to sudden death. Some measures of heart rate variability are also associated with SUDEP, further implicating an cardiac arrhythmic contribution.

PSYCHOSOCIAL ISSUES

There continues to be a cultural stigma about epilepsy, although it is slowly declining in societies with effective health education programs. Many patients with epilepsy harbor fears such as the fear of becoming mentally retarded or dying during a seizure. These issues need to be carefully addressed by educating the patient about epilepsy and by ensuring that family members, teachers, fellow employees, and other associates are equally well informed. A useful source of educational material is the website www.epilepsy.com.

EMPLOYMENT, DRIVING, AND OTHER ACTIVITIES

Many patients with epilepsy face difficulty in obtaining or maintaining employment, even when their seizures are well controlled. Federal and state legislation is designed to prevent employers from discriminating against patients with epilepsy, and patients should be encouraged to understand and claim their legal rights. Patients in these circumstances also benefit greatly from the assistance of health providers who act as strong patient advocates.

Loss of driving privileges is one of the most disruptive social consequences of epilepsy. Physicians should be very clear about local regulations concerning driving and epilepsy, because the laws vary considerably among states and countries. In all cases, it is the physician’s responsibility to warn patients of the danger imposed on themselves and others while driving if their seizures are uncontrolled (unless the seizures are not associated with impairment of consciousness or motor control). In general, most states allow patients to drive after a seizure-free interval (on or off medications) of between 3 months and 2 years.

Patients with incompletely controlled seizures must also contend with the risk of being in other situations where an impairment of consciousness or loss of motor control could lead to major injury or death. Thus, depending on the type and frequency of seizures, many patients need to be instructed to avoid working at heights or with machinery or to have someone close by for activities such as bathing and swimming.

SPECIAL ISSUES RELATED TO WOMEN AND EPILEPSY

CATAMENIAL EPILEPSY

Some women experience a marked increase in seizure frequency around the time of menses. This is believed to be mediated by either the effects of estrogen and progesterone on neuronal excitability or changes in antiepileptic drug levels due to altered protein binding or metabolism. Some patients may benefit from increases in antiepileptic drug dosages during menses. Natural progestins or intramuscular medroxyprogesterone may be of benefit to a subset of women.

PREGNANCY

Most women with epilepsy who become pregnant will have an uncomplicated gestation and deliver a normal baby. However, epilepsy poses some important risks to a pregnancy. Seizure frequency during pregnancy will remain unchanged in ~50% of women, increase in ~30%, and decrease in ~20%. A recent observational study demonstrated no difference between convulsive seizures during pregnancy in women with epilepsy compared with those who were not pregnant, although dose adjustments of antiepileptic medications were more common in the pregnant group. Changes in seizure frequency are attributed to endocrine effects on the CNS, variations in antiepileptic drug pharmacokinetics (such as acceleration of hepatic drug metabolism or effects on plasma protein binding), and changes in medication compliance. It is useful to see patients at frequent intervals during pregnancy and monitor serum antiepileptic drug levels. Measurement of the unbound drug concentrations may be useful if there is an increase in seizure frequency or worsening of side effects of antiepileptic drugs.

The overall incidence of fetal abnormalities in children born to mothers with epilepsy is 5–6%, compared to 2–3% in healthy women. Part of the higher incidence is due to teratogenic effects of antiepileptic drugs, and the risk increases with the number of medications used (e.g., 10–20% risk of malformations with three drugs) and possibly with higher doses. A meta-analysis of published pregnancy registries and cohorts found that the most common malformations were defects in the cardiovascular and musculoskeletal system (1.4–1.8%). Valproic acid is strongly associated with an increased risk of adverse fetal outcomes (7–20%). Findings from a large pregnancy registry suggest that, other than topiramate, the newer antiepileptic drugs are far safer than valproic acid.

Because the potential harm of uncontrolled convulsive seizures on the mother and fetus is considered greater than the teratogenic effects of antiepileptic drugs, it is currently recommended that pregnant women be maintained on effective drug therapy. When possible, it seems prudent to have the patient on monotherapy at the lowest effective dose, especially during the first trimester. For some women, however, the type and frequency of their seizures may allow for them to safely wean off antiepileptic drugs prior to conception. Patients should also take folate (1–4 mg/d), because the antifolate effects of anticonvulsants are thought to play a role in the development of neural tube defects, although the benefits of this treatment remain unproved in this setting.

Enzyme-inducing drugs such as phenytoin, carbamazepine, oxcarbazepine, topiramate, phenobarbital, and primidone cause a transient and reversible deficiency of vitamin K–dependent clotting factors in ~50% of newborn infants. Although neonatal hemorrhage is uncommon, the mother should be treated with oral vitamin K (20 mg/d, phylloquinone) in the last 2 weeks of pregnancy, and the infant should receive intramuscular vitamin K (1 mg) at birth.

CONTRACEPTION

Special care should be taken when prescribing antiepileptic medications for women who are taking oral contraceptive agents. Drugs such as carbamazepine, phenytoin, phenobarbital, and topiramate can significantly decrease the efficacy of oral contraceptives via enzyme induction and other mechanisms. Patients should be advised to consider alternative forms of contraception, or their contraceptive medications should be modified to offset the effects of the antiepileptic medications.

BREAST-FEEDING

Antiepileptic medications are excreted into breast milk to a variable degree. The ratio of drug concentration in breast milk relative to serum ranges from ~5% (valproic acid) to 300% (levetiracetam). Given the overall benefits of breast-feeding and the lack of evidence for long-term harm to the infant by being exposed to antiepileptic drugs, mothers with epilepsy can be encouraged to breast-feed. This should be reconsidered, however, if there is any evidence of drug effects on the infant such as lethargy or poor feeding.

ACKNOWLEDGMENT

Dr. Michael J. Aminoff contributed to the section on EEG interpretation in earlier editions.

FURTHER READING

Additional Online Reference

INTRODUCTION

Cerebrovascular diseases include some of the most common and devastating disorders: ischemic stroke and hemorrhagic stroke. Stroke is the second leading cause of death worldwide, with 6.2 million dying from stroke in 2015, an increase of 830,000 since the year 2000. In 2016, the lifetime global risk of stroke from age 25 years onward was 24.9%, an increase of 8.9% from 1990. While stroke has grown in incidence worldwide, it is declining among the affluent and rising among those with less access to medical care. In the United States, the incidence of stroke has declined steadily since at least 1958, and stroke is currently the fifth leading cause of death with 133,000 dying in 2014. Despite this progress, however, stroke remains the most common disabling disease in the United States and in many forms is preventable.

A stroke, or cerebrovascular accident, is defined as an abrupt onset of a neurologic deficit that is attributable to a focal vascular cause. Thus, the definition of stroke is clinical, and laboratory studies including brain imaging are used to support the diagnosis. The clinical manifestations of stroke are highly variable because of the complex anatomy of the brain and its vasculature. Cerebral ischemia is caused by a reduction in blood flow that lasts longer than several seconds. Neurologic symptoms are manifest within seconds because neurons lack glycogen, so energy failure is rapid. If the cessation of flow lasts for more than a few minutes, infarction or death of brain tissue results. When blood flow is quickly restored, brain tissue can recover fully and the patient’s symptoms are only transient: this is called a transient ischemic attack (TIA). The definition of TIA requires that all neurologic signs and symptoms resolve within 24 h without evidence of brain infarction on brain imaging. Stroke has occurred if the neurologic signs and symptoms last for >24 h or brain infarction is demonstrated. A generalized reduction in cerebral blood flow due to systemic hypotension (e.g., cardiac arrhythmia, myocardial infarction, or hemorrhagic shock) usually produces syncope (Chap. 18). If low cerebral blood flow persists for a longer duration, then infarction in the border zones between the major cerebral artery distributions may develop. In more severe instances, global hypoxia-ischemia causes widespread brain injury; the constellation of cognitive sequelae that ensues is called hypoxic-ischemic encephalopathy (Chap. 301). Focal ischemia or infarction, conversely, is usually caused by thrombosis of the cerebral vessels themselves or by emboli from a proximal arterial source or the heart (Chap. 420). Intracranial hemorrhage is caused by bleeding directly into or around the brain; it produces neurologic symptoms by producing a mass effect on neural structures, from the toxic effects of blood itself, or by increasing intracranial pressure (Chap. 421).

APPROACH TO THE PATIENT

STROKE SYNDROMES

A careful history and neurologic examination can often localize the region of brain dysfunction; if this region corresponds to an arterial distribution, the possible causes responsible for the syndrome can be narrowed. This is of particular importance when the patient presents with a TIA and a normal examination. For example, if a patient develops language loss and a right homonymous hemianopia, a search for causes of left middle cerebral emboli should be performed. A finding of an isolated stenosis of the right internal carotid artery in that patient, for example, suggests an asymptomatic carotid stenosis, and the search for other causes of stroke should continue. The following sections describe the clinical findings of cerebral ischemia associated with cerebral vascular territories depicted in Figs. 419-2, 419-3, 419-4, 419-5, 419-6, 419-7, 419-8, 419-9, 419-10, 419-11. Stroke syndromes are divided into: (1) large-vessel stroke within the anterior circulation, (2) large-vessel stroke within the posterior circulation, and (3) small-vessel disease of either vascular bed.

Stroke within the Anterior Circulation

The internal carotid artery and its branches comprise the anterior circulation of the brain. These vessels can be occluded by intrinsic disease of the vessel (e.g., atherosclerosis or dissection) or by embolic occlusion from a proximal source as discussed above. Occlusion of each major intracranial vessel has distinct clinical manifestations.

MIDDLE CEREBRAL ARTERY

Occlusion of the proximal middle cerebral artery (MCA) or one of its major branches is most often due to an embolus (artery-to-artery, cardiac, or of unknown source) rather than intracranial atherothrombosis. Atherosclerosis of the proximal MCA may cause distal emboli to the middle cerebral territory or, less commonly, may produce low-flow TIAs. Collateral formation via leptomeningeal vessels often prevents MCA stenosis from becoming symptomatic.

The cortical branches of the MCA supply the lateral surface of the hemisphere except for (1) the frontal pole and a strip along the superomedial border of the frontal and parietal lobes supplied by the anterior cerebral artery (ACA) and (2) the lower temporal and occipital pole convolutions supplied by the posterior cerebral artery (PCA) (Figs. 419-2, Figs. 419-3, Figs. 419-4, 419-5).

The proximal MCA (M1 segment) gives rise to penetrating branches (termed lenticulostriate arteries) that supply the putamen, outer globus pallidus, posterior limb of the internal capsule, adjacent corona radiata, and most of the caudate nucleus (Fig. 419-2). In the sylvian fissure, the MCA in most patients divides into superior and inferior divisions (M2 branches). Branches of the inferior division supply the inferior parietal and temporal cortex, and those from the superior division supply the frontal and superior parietal cortex (Fig. 419-3).

If the entire MCA is occluded at its origin (blocking both its penetrating and cortical branches) and the distal collaterals are limited, the clinical findings are contralateral hemiplegia, hemianesthesia, homonymous hemianopia, and a day or two of gaze preference to the ipsilateral side. Dysarthria is common because of facial weakness. When the dominant hemisphere is involved, global aphasia is present also, and when the nondominant hemisphere is affected, anosognosia, constructional apraxia, and neglect are found (Chap. 26).

Complete MCA syndromes occur most often when an embolus occludes the stem of the artery. Cortical collateral blood flow and differing arterial configurations are probably responsible for the development of many partial syndromes. Partial syndromes may also be due to emboli that enter the proximal MCA without complete occlusion, occlude distal MCA branches, or fragment and move distally.

Partial syndromes due to embolic occlusion of a single branch include hand, or arm and hand, weakness alone (brachial syndrome) or facial weakness with nonfluent (Broca) aphasia (Chap. 26), with or without arm weakness (frontal opercular syndrome). A combination of sensory disturbance, motor weakness, and nonfluent aphasia suggests that an embolus has occluded the proximal superior division and infarcted large portions of the frontal and parietal cortices (Fig. 419-3). If a fluent (Wernicke’s) aphasia occurs without weakness, the inferior division of the MCA supplying the posterior part (temporal cortex) of the dominant hemisphere is probably involved. Jargon speech and an inability to comprehend written and spoken language are prominent features, often accompanied by a contralateral, homonymous superior quadrantanopia. Hemineglect or spatial agnosia without weakness indicates that the inferior division of the MCA in the nondominant hemisphere is involved.

Occlusion of a lenticulostriate vessel produces small-vessel (lacunar) stroke within the internal capsule (Fig. 419-2). This produces pure motor stroke or sensory-motor stroke contralateral to the lesion. Ischemia within the genu of the internal capsule causes primarily facial weakness followed by arm and then leg weakness as the ischemia moves posterior within the capsule. Alternatively, the contralateral hand may become ataxic, and dysarthria will be prominent (clumsy hand, dysarthria lacunar syndrome). Lacunar infarction affecting the globus pallidus and putamen often has few clinical signs, but parkinsonism and hemiballismus have been reported.

ANTERIOR CEREBRAL ARTERY

The ACA is divided into two segments: the precommunal (A1) circle of Willis, or stem, which connects the internal carotid artery to the anterior communicating artery, and the postcommunal (A2) segment distal to the anterior communicating artery (Figs. 419-2 and 419-4). The A1 segment gives rise to several deep penetrating branches that supply the anterior limb of the internal capsule, the anterior perforate substance, amygdala, anterior hypothalamus, and the inferior part of the head of the caudate nucleus.

Occlusion of the proximal ACA is usually well tolerated because of collateral flow through the anterior communicating artery and collaterals through the MCA and PCA. Occlusion of a single A2 segment results in the contralateral symptoms noted in Fig. 419-4. If both A2 segments arise from a single anterior cerebral stem (contralateral A1 segment atresia), the occlusion may affect both hemispheres. Profound abulia (a delay in verbal and motor response) and bilateral pyramidal signs with paraparesis or quadriparesis and urinary incontinence result.

ANTERIOR CHOROIDAL ARTERY

This artery arises from the internal carotid artery and supplies the posterior limb of the internal capsule and the white matter posterolateral to it, through which pass some of the geniculocalcarine fibers (Fig. 419-5). The complete syndrome of anterior choroidal artery occlusion consists of contralateral hemiplegia, hemianesthesia (hypesthesia), and homonymous hemianopia. However, because this territory is also supplied by penetrating vessels of the proximal MCA and the posterior communicating and posterior choroidal arteries, minimal deficits may occur, and patients frequently recover substantially. Anterior choroidal strokes are usually the result of in situ thrombosis of the vessel, and the vessel is particularly vulnerable to iatrogenic occlusion during surgical clipping of aneurysms arising from the internal carotid artery.

INTERNAL CAROTID ARTERY

The clinical picture of internal carotid occlusion varies depending on whether the cause of ischemia is propagated thrombus, embolism, or low flow. The cortex supplied by the MCA territory is affected most often. With a competent circle of Willis, occlusion may go unnoticed. If the thrombus propagates up the internal carotid artery into the MCA or embolizes it, symptoms are identical to proximal MCA occlusion (see above). Sometimes there is massive infarction of the entire deep white matter and cortical surface. When the origins of both the ACA and MCA are occluded at the top of the carotid artery, abulia or stupor occurs with hemiplegia, hemianesthesia, and aphasia or anosognosia. When the PCA arises from the internal carotid artery (a configuration called a fetal PCA), it may also become occluded and give rise to symptoms referable to its peripheral territory (Figs. 419-4 and 419-5).

In addition to supplying the ipsilateral brain, the internal carotid artery perfuses the optic nerve and retina via the ophthalmic artery. In ~25% of symptomatic internal carotid disease, recurrent transient monocular blindness (amaurosis fugax) warns of the lesion. Patients typically describe a horizontal shade that sweeps down or up across the field of vision. They may also complain that their vision was blurred in that eye or that the upper or lower half of vision disappeared. In most cases, these symptoms last only a few minutes. Rarely, ischemia or infarction of the ophthalmic artery or central retinal arteries occurs at the time of cerebral TIA or infarction.

A high-pitched prolonged carotid bruit fading into diastole is often associated with tightly stenotic lesions. As the stenosis grows tighter and flow distal to the stenosis becomes reduced, the bruit becomes fainter and may disappear when occlusion is imminent.

COMMON CAROTID ARTERY

All symptoms and signs of internal carotid occlusion may also be present with occlusion of the common carotid artery. Jaw claudication may result from low flow in the external carotid branches. Bilateral common carotid artery occlusions at their origin may occur in Takayasu’s arteritis (Chap. 356).

Stroke within the Posterior Circulation

The posterior circulation is composed of the paired vertebral arteries, the basilar artery, and the paired PCAs. The vertebral arteries join to form the basilar artery at the pontomedullary junction. The basilar artery divides into two PCAs in the interpeduncular fossa (Figs. 419-4, 419-5, 419-6). These major arteries give rise to long and short circumferential branches and to smaller deep penetrating branches that supply the cerebellum, medulla, pons, midbrain, subthalamus, thalamus, hippocampus, and medial temporal and occipital lobes. Occlusion of each vessel produces its own distinctive syndrome.

POSTERIOR CEREBRAL ARTERY

In 75% of cases, both PCAs arise from the bifurcation of the basilar artery; in 20%, one has its origin from the ipsilateral internal carotid artery via the posterior communicating artery; in 5%, both originate from the respective ipsilateral internal carotid arteries (Figs. 419-4, 419-5, 419-6). The precommunal, or P1, segment of the true PCA is atretic in such cases.

PCA syndromes usually result from atheroma formation or emboli that lodge at the top of the basilar artery; posterior circulation disease may also be caused by dissection of either vertebral artery or fibromuscular dysplasia.

Two clinical syndromes are commonly observed with occlusion of the PCA: (1) P1 syndrome: midbrain, subthalamic, and thalamic signs, which are due to disease of the proximal P1 segment of the PCA or its penetrating branches (thalamogeniculate, Percheron, and posterior choroidal arteries); and (2) P2 syndrome: cortical temporal and occipital lobe signs, due to occlusion of the P2 segment distal to the junction of the PCA with the posterior communicating artery.

P1 SYNDROMES

Infarction usually occurs in the ipsilateral subthalamus and medial thalamus and in the ipsilateral cerebral peduncle and midbrain (Figs. 419-5 and 419-11). A third nerve palsy with contralateral ataxia (Claude’s syndrome) or with contralateral hemiplegia (Weber’s syndrome) may result. The ataxia indicates involvement of the red nucleus or dentatorubrothalamic tract; the hemiplegia is localized to the cerebral peduncle (Fig. 419-11). If the subthalamic nucleus is involved, contralateral hemiballismus may occur. Occlusion of the artery of Percheron produces paresis of upward gaze and drowsiness and often abulia. Extensive infarction in the midbrain and subthalamus occurring with bilateral proximal PCA occlusion presents as coma, unreactive pupils, bilateral pyramidal signs, and decerebrate rigidity.

Occlusion of the penetrating branches of thalamic and thalamogeniculate arteries produces less extensive thalamic and thalamocapsular lacunar syndromes. The thalamic Déjérine-Roussy syndrome consists of contralateral hemisensory loss followed later by an agonizing, searing, or burning pain in the affected areas. It is persistent and responds poorly to analgesics. Anticonvulsants (carbamazepine or gabapentin) or tricyclic antidepressants may be beneficial.

P2 SYNDROMES

(Figs. 419-4 and 419-5) Occlusion of the distal PCA causes infarction of the medial temporal and occipital lobes. Contralateral homonymous hemianopia without macula sparing is the usual manifestation. (MCA strokes often produce hemianopia but typically spare the macula as calcarine cortex is perfused by the P2 segment). Occasionally, only the upper quadrant of visual field is involved or the macula vision is spared. If the visual association areas are spared and only the calcarine cortex is involved, the patient may be aware of visual defects. Medial temporal lobe and hippocampal involvement may cause an acute disturbance in memory, particularly if it occurs in the dominant hemisphere. The defect usually clears because memory has bilateral representation. If the dominant hemisphere is affected and the infarct extends to involve the splenium of the corpus callosum, the patient may demonstrate alexia without agraphia. Visual agnosia for faces, objects, mathematical symbols, and colors and anomia with paraphasic errors (amnestic aphasia) may also occur, even without callosal involvement. Occlusion of the PCA can produce peduncular hallucinosis (visual hallucinations of brightly colored scenes and objects).

Bilateral infarction in the distal PCAs produces cortical blindness (blindness with preserved pupillary light reaction). The patient is often unaware of the blindness or may even deny it (Anton’s syndrome). Tiny islands of vision may persist, and the patient may report that vision fluctuates as images are captured in the preserved portions. Rarely, only peripheral vision is lost and central vision is spared, resulting in “gun-barrel” vision. Bilateral visual association area lesions may result in Balint’s syndrome, a disorder of the orderly visual scanning of the environment (Chap. 26), usually resulting from infarctions secondary to low flow in the “watershed” between the distal PCA and MCA territories, as occurs after cardiac arrest. Patients may experience persistence of a visual image for several minutes despite gazing at another scene (palinopsia) or an inability to synthesize the whole of an image (asimultanagnosia). Embolic occlusion of the top of the basilar artery can produce any or all the central or peripheral territory symptoms. The hallmark is the sudden onset of bilateral signs, including ptosis, pupillary asymmetry or lack of reaction to light, and somnolence. Patients will often have posturing and myoclonic jerking that simulates seizure. Interrogation of the noncontrast CT scan for a hyperdense basilar artery sign (indicating thrombus in the basilar artery), or CT angiography (CTA) establishes this diagnosis. Physicians should be suspicious of this rare, but potentially treatable stroke syndrome in the setting of presumed new onset seizure and cranial nerve deficits.

VERTEBRAL AND POSTERIOR INFERIOR CEREBELLAR ARTERIES

The vertebral artery, which arises from the innominate artery on the right and the subclavian artery on the left, consists of four segments. The first (V1) extends from its origin to its entrance into the sixth or fifth transverse vertebral foramen. The second segment (V2) traverses the vertebral foramina from C6 to C2. The third (V3) passes through the transverse foramen and circles around the arch of the atlas to pierce the dura at the foramen magnum. The fourth (V4) segment courses upward to join the other vertebral artery to form the basilar artery (Fig. 419-6); only the fourth segment gives rise to branches that supply the brainstem and cerebellum. The posterior inferior cerebellar artery (PICA) in its proximal segment supplies the lateral medulla and, in its distal branches, the inferior surface of the cerebellum.

Atherothrombotic lesions have a predilection for V1 and V4 segments of the vertebral artery. The first segment may become diseased at the origin of the vessel and may produce posterior circulation emboli; collateral flow from the contralateral vertebral artery or the ascending cervical, thyrocervical, or occipital arteries is usually sufficient to prevent low-flow TIAs or stroke. When one vertebral artery is atretic and an atherothrombotic lesion threatens the origin of the other, the collateral circulation, which may also include retrograde flow down the basilar artery, is often insufficient (Figs. 419-5 and 419-6). In this setting, low-flow TIAs may occur, consisting of syncope, vertigo, and alternating hemiplegia; this state also sets the stage for thrombosis. Disease of the distal fourth segment of the vertebral artery can promote thrombus formation manifest as embolism or with propagation as basilar artery thrombosis. Stenosis proximal to the origin of the PICA can threaten the lateral medulla and posterior inferior surface of the cerebellum.

If the subclavian artery is occluded proximal to the origin of the vertebral artery, there is a reversal in the direction of blood flow in the ipsilateral vertebral artery. Exercise of the ipsilateral arm may increase demand on vertebral flow, producing posterior circulation TIAs, or “subclavian steal.”

Although atheromatous disease rarely narrows the second and third segments of the vertebral artery, this region is subject to dissection, fibromuscular dysplasia, and, rarely, encroachment by osteophytic spurs within the vertebral foramina.

Embolic occlusion or thrombosis of a V4 segment causes ischemia of the lateral medulla. The constellation of vertigo, numbness of the ipsilateral face and contralateral limbs, diplopia, hoarseness, dysarthria, dysphagia, and ipsilateral Horner’s syndrome is called the lateral medullary (or Wallenberg’s) syndrome (Fig. 419-7). Ipsilateral upper motor neuron facial weakness can also occur. Most cases result from ipsilateral vertebral artery occlusion; in the remainder, PICA occlusion is responsible. Occlusion of the medullary penetrating branches of the vertebral artery or PICA results in partial syndromes. Hemiparesis is not a typical feature of vertebral artery occlusion; however, quadriparesis may result from occlusion of the anterior spinal artery.

Rarely, a medial medullary syndrome occurs with infarction of the pyramid and contralateral hemiparesis of the arm and leg, sparing the face. If the medial lemniscus and emerging hypoglossal nerve fibers are involved, contralateral loss of joint position sense and ipsilateral tongue weakness occur.

Cerebellar infarction can lead to respiratory arrest due to raised intracranial pressure from cerebellar swelling, closure of the aqueduct of Silvius or fourth ventricle, followed by hydrocephalus and central herniation. Displacement of the brainstem from cerebellar edema will also cause respiratory and hemodynamic instability. Drowsiness, Babinski signs, dysarthria, and bifacial weakness may be absent, or present only briefly, before respiratory arrest ensues. Gait unsteadiness, headache, dizziness, nausea, and vomiting may be the only early symptoms and signs and should arouse suspicion of this impending complication, which may require neurosurgical decompression, often with an excellent outcome. Separating these symptoms from those of viral labyrinthitis can be a challenge, but headache, neck stiffness, and unilateral dysmetria favor stroke.

BASILAR ARTERY

Branches of the basilar artery (Fig. 419-6) supply the base of the pons and superior cerebellum and fall into three groups: (1) paramedian, 7–10 in number, which supply a wedge of pons on either side of the midline; (2) short circumferential, 5–7 in number, that supply the lateral two-thirds of the pons and middle and superior cerebellar peduncles; and (3) bilateral long circumferential (superior cerebellar and anterior inferior cerebellar arteries), which course around the pons to supply the cerebellar hemispheres.

Atheromatous lesions can occur anywhere along the basilar trunk but are most frequent in the proximal basilar and distal vertebral segments. Typically, lesions occlude either the proximal basilar and one or both vertebral arteries. The clinical picture varies depending on the availability of retrograde collateral flow from the posterior communicating arteries. Rarely, dissection of a vertebral artery may involve the basilar artery and, depending on the location of true and false lumen, may produce multiple penetrating artery strokes.

Although atherothrombosis occasionally occludes the distal portion of the basilar artery, emboli from the heart or proximal vertebral or basilar segments are more commonly responsible for “top of the basilar” syndromes.

Because the brainstem contains many structures in close apposition, a diversity of clinical syndromes may emerge with ischemia, reflecting involvement of the corticospinal and corticobulbar tracts, ascending sensory tracts, and cranial nerve nuclei (Figs. 419-7, 419-8, 419-9, 419-10, 419-11).

The symptoms of transient ischemia or infarction in the territory of the basilar artery often do not indicate whether the basilar artery itself or one of its branches is diseased, yet this distinction has important implications for therapy. The picture of complete basilar occlusion, however, is easy to recognize as a constellation of bilateral long tract signs (sensory and motor) with signs of cranial nerve and cerebellar dysfunction. Patients may have spontaneous posturing movements that are myoclonic in nature and simulate seizure activity. A “locked-in” state of preserved consciousness with quadriplegia and cranial nerve signs suggests complete pontine and lower midbrain infarction. The therapeutic goal is to identify impending basilar occlusion before devastating infarction occurs. A series of TIAs and a slowly progressive, fluctuating stroke are extremely significant, because they often herald an atherothrombotic occlusion of the distal vertebral or proximal basilar artery.

TIAs in the proximal basilar distribution may produce vertigo (often described by patients as “swimming,” “swaying,” “moving,” “unsteadiness,” or “light-headedness”). Other symptoms that warn of basilar thrombosis include diplopia, dysarthria, facial or circumoral numbness, and hemisensory symptoms. In general, symptoms of basilar branch TIAs affect one side of the brainstem, whereas symptoms of basilar artery TIAs usually affect both sides, although a “herald” hemiparesis has been emphasized as an initial symptom of basilar occlusion. Most often, TIAs, whether due to impending occlusion of the basilar artery or a basilar branch, are short lived (5–30 min) and repetitive, occurring several times a day. The pattern suggests intermittent reduction of flow. Although treatment with intravenous heparin or various combinations of antiplatelet agents have been used to prevent clot propagation there is no specific evidence to support any one approach, and endovascular intervention is also an option.

Atherothrombotic occlusion of the basilar artery with infarction usually causes bilateral brainstem signs. A gaze paresis or internuclear ophthalmoplegia associated with ipsilateral hemiparesis may be the only manifestation of bilateral brainstem ischemia. More often, unequivocal signs of bilateral pontine disease are present. Complete basilar thrombosis carries a high mortality.

Occlusion of a branch of the basilar artery usually causes unilateral symptoms and signs involving motor, sensory, and cranial nerves. If symptoms remain unilateral, concern over pending basilar occlusion should be reduced.

Occlusion of the superior cerebellar artery results in severe ipsilateral cerebellar ataxia, nausea and vomiting, dysarthria, and contralateral loss of pain and temperature sensation over the extremities, body, and face (spino- and trigeminothalamic tract). Partial deafness, ataxic tremor of the ipsilateral upper extremity, Horner’s syndrome, and palatal myoclonus may occur rarely. Partial syndromes occur frequently (Fig. 419-10). With large strokes, swelling and mass effects may compress the midbrain or produce hydrocephalus; these symptoms may evolve rapidly. Neurosurgical intervention may be lifesaving in such cases.

Occlusion of the anterior inferior cerebellar artery produces variable degrees of infarction because the size of this artery and the territory it supplies vary inversely with those of the PICA. The principal symptoms include: (1) ipsilateral deafness, facial weakness, vertigo, nausea and vomiting, nystagmus, tinnitus, cerebellar ataxia, Horner’s syndrome, and paresis of conjugate lateral gaze; and (2) contralateral loss of pain and temperature sensation. An occlusion close to the origin of the artery may cause corticospinal tract signs (Fig. 419-8).

Occlusion of one of the short circumferential branches of the basilar artery affects the lateral two-thirds of the pons and middle or superior cerebellar peduncle, whereas occlusion of one of the paramedian branches affects a wedge-shaped area on either side of the medial pons (Figs. 419-8, 419-9, 419-10).

IMAGING STUDIES

See also Chap. 416.

CT Scans

CT radiographic images identify or exclude hemorrhage as the cause of stroke, and they identify extraparenchymal hemorrhages, neoplasms, abscesses, and other conditions masquerading as stroke. Brain CT scans obtained in the first several hours after an infarction generally show no abnormality, and the infarct may not be seen reliably for 24–48 h. CT may fail to show small ischemic strokes in the posterior fossa because of bone artifact; small infarcts on the cortical surface may also be missed.

Contrast-enhanced CT scans add specificity by showing contrast enhancement of subacute infarcts and allow visualization of venous structures. Coupled with multidetector scanners, CT angiography can be performed with administration of IV iodinated contrast allowing visualization of the cervical and intracranial arteries, intracranial veins, aortic arch, and even the coronary arteries in one imaging session. Carotid disease and intracranial vascular occlusions are readily identified with this method (see Fig. 420-2). After an IV bolus of contrast, deficits in brain perfusion produced by vascular occlusion can also be demonstrated (Fig. 419-12) and used to predict the region of infarcted brain and the brain at risk of further infarction (i.e., the ischemic penumbra, see “Pathophysiology of Ischemic Stroke” in Chap. 420). CT imaging is also sensitive for detecting SAH (although by itself does not rule it out), and CTA can readily identify intracranial aneurysms (Chap. 301). Because of its speed and wide availability, noncontrast head CT is the imaging modality of choice in patients with acute stroke (Fig. 419-1), and CTA and CT perfusion imaging may also be useful and convenient adjuncts.

MRI

MRI reliably documents the extent and location of infarction in all areas of the brain, including the posterior fossa and cortical surface. It also identifies intracranial hemorrhage and other abnormalities and, using special sequences, can be as sensitive as CT for detecting acute intracerebral hemorrhage. MRI scanners with magnets of higher field strength produce more reliable and precise images. Diffusion-weighted imaging is more sensitive for early brain infarction than standard MR sequences or CT (Fig. 419-13), as is fluid-attenuated inversion recovery (FLAIR) imaging (Chap. 416). Using IV administration of gadolinium contrast, MR perfusion studies can be performed. Brain regions showing poor perfusion but no abnormality on diffusion provide, compared to CT, an equivalent measure of the ischemic penumbra. MR angiography is highly sensitive for stenosis of extracranial internal carotid arteries and of large intracranial vessels. With higher degrees of stenosis, MR angiography tends to overestimate the degree of stenosis when compared to conventional x-ray angiography. MRI with fat saturation is an imaging sequence used to visualize extra or intracranial arterial dissection. This sensitive technique images clotted blood within the dissected vessel wall. Iron-sensitive imaging (ISI) is helpful to detect cerebral microbleeds that may be present in cerebral amyloid angiopathy and other hemorrhagic disorders.

MRI is more expensive and time consuming than CT and less readily available. Claustrophobia and the logistics of imaging acutely critically ill patients also limit its application. Most acute stroke protocols use CT because of these limitations. However, MRI is useful outside the acute period by more clearly defining the extent of tissue injury and discriminating new from old regions of brain infarction. MRI may have utility in patients with TIA, because it is also more likely to identify new infarction, which is a strong predictor of subsequent stroke.

Cerebral Angiography

Conventional x-ray cerebral angiography is the gold standard for identifying and quantifying atherosclerotic stenoses of the cerebral arteries and for identifying and characterizing other pathologies, including aneurysms, vasospasm, intraluminal thrombi, fibromuscular dysplasia, arteriovenous fistulae, vasculitis, and collateral channels of blood flow. Conventional angiography carries risks of arterial damage, groin hemorrhage, embolic stroke, and renal failure from contrast nephropathy, so it should be reserved for situations where less invasive means are inadequate. Acute stroke treatment with endovascular thrombectomy has proven effective in ischemic strokes caused by internal carotid terminus or MCA occlusions and has now part of routine clinical practice at centers that have this capability (see Chap. 420).

Ultrasound Techniques

Stenosis at the origin of the internal carotid artery can be identified and quantified reliably by ultrasonography that combines a B-mode ultrasound image with a Doppler ultrasound assessment of flow velocity (“duplex” ultrasound). Transcranial Doppler (TCD) assessment of MCA, ACA, and PCA flow and of vertebrobasilar flow is also useful. This latter technique can detect stenotic lesions in the large intracranial arteries because such lesions increase systolic flow velocity. TCD can also detect microemboli from otherwise asymptomatic carotid plaques. In many cases, MR angiography combined with carotid and transcranial ultrasound studies eliminates the need for conventional x-ray angiography in evaluating vascular stenosis. Alternatively, CTA of the entire head and neck can be performed during the initial imaging of acute stroke. Because this images the entire arterial system relevant to stroke, with the exception of the heart, much of the clinician’s stroke workup can be completed with this single imaging study.

Perfusion Techniques

Both xenon techniques (principally xenon-CT) and positron emission tomography (PET) can quantify cerebral blood flow. These tools are generally used for research (Chap. 416) but can be useful for determining the significance of arterial stenosis and planning for revascularization surgery. Single-photon emission computed tomography (SPECT) and MR perfusion techniques report relative cerebral blood flow. As noted above, CT imaging is used as the initial imaging modality for acute stroke, and some centers combine both CTA and CT perfusion imaging together with the noncontrast CT scan. CT perfusion imaging increases the sensitivity for detecting ischemia and can measure the ischemic penumbra (Fig. 419-12). Alternatively, MR perfusion can be combined with MR diffusion imaging to identify the ischemic penumbra as the mismatch between these two imaging sequences (Fig. 419-13).

FURTHER READING

Additional Online References

INTRODUCTION

The clinical diagnosis of stroke is discussed in Chap. 419. Once this diagnosis is made, and either a non-contrast CT scan or MRI has been performed, rapid reversal of ischemia is paramount. This chapter will focus on the stroke treatment timeline and subsequent secondary stroke prevention.

PATHOPHYSIOLOGY OF ISCHEMIC STROKE

Acute occlusion of an intracranial vessel causes reduction in blood flow to the brain region it supplies. The magnitude of flow reduction is a function of collateral blood flow, and this depends on individual vascular anatomy (which may be altered by disease), the site of occlusion, and systemic blood pressure. A decrease in cerebral blood flow to zero causes death of brain tissue within 4–10 min; values <16–18 mL/100 g tissue per minute cause infarction within an hour; and values <20 mL/100 g tissue per minute cause ischemia without infarction unless prolonged for several hours or days. If blood flow is restored to ischemic tissue before significant infarction develops, the patient may experience only transient symptoms, and the clinical syndrome is called a transient ischemic attack (TIA). Another important concept is the ischemic penumbra, defined as the ischemic but reversibly dysfunctional tissue surrounding a core area of infarction. The penumbra can be imaged by perfusion imaging using MRI or CT (see below and Figs. 419-12 and 419-13). The ischemic penumbra will eventually progress to infarction if no change in flow occurs, and hence saving the ischemic penumbra is the goal of revascularization therapies.

Focal cerebral infarction occurs via two distinct pathways (Fig. 420-1): (1) a necrotic pathway in which cellular cytoskeletal breakdown is rapid, due principally to energy failure of the cell; and (2) an apoptotic pathway in which cells become programmed to die. Ischemia produces necrosis by starving neurons of glucose and oxygen, which in turn results in failure of mitochondria to produce ATP. Without ATP, membrane ion pumps stop functioning and neurons depolarize, allowing intracellular calcium to rise. Cellular depolarization also causes glutamate release from synaptic terminals; excess extracellular glutamate produces neurotoxicity by activating postsynaptic glutamate receptors that increase neuronal calcium influx. Free radicals are produced by degradation of membrane lipids and mitochondrial dysfunction. Free radicals cause catalytic destruction of membranes and likely damage other vital functions of cells. Lesser degrees of ischemia, as are seen within the ischemic penumbra, favor apoptotic cellular death causing cells to die days to weeks later. Fever dramatically worsens brain injury during ischemia, as does hyperglycemia (glucose >11.1 mmol/L [200 mg/dL]), so it is reasonable to suppress fever and prevent hyperglycemia as much as possible. The value of induced mild hypothermia to improve stroke outcomes is the subject of continuing clinical research.

TREATMENT

ETIOLOGY OF ISCHEMIC STROKE

(Fig. 420-2 and Table 420-2) Although the initial management of AIS often does not depend on the etiology, establishing a cause is essential to reduce the risk of recurrence. Focus should be on atrial fibrillation and carotid atherosclerosis, because these etiologies have proven secondary prevention strategies. The clinical presentation and examination findings often establish the cause of stroke or narrow the possibilities to a few. Judicious use of laboratory testing and imaging studies completes the initial evaluation. Nevertheless, nearly 30% of strokes remain unexplained despite extensive evaluation.

Clinical examination should focus on the peripheral and cervical vascular system (carotid auscultation for bruits and blood pressure), the heart (dysrhythmia, murmurs), extremities (peripheral emboli), and retina (effects of hypertension and cholesterol emboli [Hollenhorst plaques]). A complete neurologic examination is performed to localize the anatomic site of stroke. An imaging study of the brain is nearly always indicated and is required for patients being considered for thrombolysis; it may be combined with CT- or MRI-based angiography to visualize the vasculature of the neck and intracranial vessels (see “Imaging Studies,” Chap. 419). A chest x-ray, electrocardiogram (ECG), urinalysis, complete blood count, erythrocyte sedimentation rate (ESR), serum electrolytes, blood urea nitrogen (BUN), creatinine, blood glucose, serum lipid profile, prothrombin time (PT), and partial thromboplastin time (PTT) are often useful and should be considered in all patients. An ECG, and subsequent cardiac telemetry, may demonstrate arrhythmias or reveal evidence of recent myocardial infarction (MI). Of all these studies, only brain imaging and capillary blood glucose are necessary prior to IV rtPA; the results of other studies should not delay the rapid administration of IV rtPA if the patient is eligible.

Cardioembolic Stroke

Cardioembolism is responsible for ~20% of all ischemic strokes. Stroke caused by heart disease is primarily due to embolism of thrombotic material forming on the atrial or ventricular wall or the left heart valves. These thrombi then detach and embolize into the arterial circulation. The thrombus may fragment or lyse quickly, producing only a TIA. Alternatively, the arterial occlusion may last longer, producing stroke. Embolic strokes tend to occur suddenly with maximum neurologic deficit present at onset. With reperfusion following more prolonged ischemia, petechial hemorrhages can occur within the ischemic territory. These are usually of no clinical significance and should be distinguished from frank intracranial hemorrhage into a region of ischemic stroke where the mass effect from the hemorrhage can cause a significant decline in neurologic function.

Emboli from the heart most often lodge in the intracranial internal carotid artery, the MCA, the posterior cerebral artery (PCA), or one of their branches; infrequently, the anterior cerebral artery (ACA) is involved. Emboli large enough to occlude the stem of the MCA (3–4 mm) or internal carotid terminus lead to large infarcts that involve both deep gray and white matter and some portions of the cortical surface and its underlying white matter. A smaller embolus may occlude a small cortical or penetrating arterial branch. The location and size of an infarct within a vascular territory depend on the extent of the collateral circulation.

The most significant cause of cardioembolic stroke in most of the world is nonrheumatic (often called nonvalvular) atrial fibrillation. MI, prosthetic valves, rheumatic heart disease, and ischemic cardiomyopathy are other considerations (Table 420-2). Cardiac disorders causing brain embolism are discussed in the chapters on heart diseases, but a few pertinent aspects are highlighted here.

Nonrheumatic atrial fibrillation is the most common cause of cerebral embolism overall. The presumed stroke mechanism is thrombus formation in the fibrillating atrium or atrial appendage, with subsequent embolization. Patients with atrial fibrillation have an average annual risk of stroke of ~5%. The risk of stroke can be estimated by calculating the CHA₂DS₂-VASc score (Table 420-3). Detection of atrial fibrillation following stroke is typically accomplished with a 30-day cardiac event monitor, but recent data shows even more cases of occult atrial fibrillation are discovered with implantable electrocardiographic devices kept in place for 12 months. Left atrial enlargement is an additional risk factor for formation of atrial thrombi. Rheumatic heart disease usually causes ischemic stroke when there is prominent mitral stenosis or atrial fibrillation. Recent MI may be a source of emboli, especially when transmural and involving the anteroapical ventricular wall, and prophylactic anticoagulation following MI has been shown to reduce stroke risk. Mitral valve prolapse is not usually a source of emboli unless the prolapse is severe.

Paradoxical embolization occurs when venous thrombi migrate to the arterial circulation, usually via a patent foramen ovale (PFO) or atrial septal defect. Bubble-contrast echocardiography (IV injection of agitated saline coupled with either transthoracic or transesophageal echocardiography) can demonstrate a right-to-left cardiac shunt, revealing the conduit for paradoxical embolization. Alternatively, a right-to-left shunt is implied if immediately following IV injection of agitated saline, the ultrasound signature of bubbles is observed during transcranial Doppler insonation of the MCA; pulmonary arteriovenous malformations should be considered if this test is positive yet an echocardiogram fails to reveal an intracardiac shunt. Both techniques are highly sensitive for detection of right-to-left shunts. Besides venous clot, fat and tumor emboli, bacterial endocarditis, IV air, and amniotic fluid emboli at childbirth may occasionally be responsible for paradoxical embolization. The importance of a PFO as a cause of stroke is debated, particularly because they are present in ~15% of the general population. Some studies have suggested that the risk is only elevated in the presence of a coexisting atrial septal aneurysm. The presence of a venous source of embolus, most commonly a deep-venous thrombus, may provide confirmation of the importance of a PFO with an accompanying right-to-left shunt in a particular case. Two recent trials found about a 1% per year absolute reduction in stroke risk using percutaneous occlusion devices in patients with no other explanation for their stroke.

Bacterial endocarditis can be a source of valvular vegetations that give rise to septic emboli. The appearance of multifocal symptoms and signs in a patient with stroke makes bacterial endocarditis more likely. Infarcts of microscopic size occur, and large septic infarcts may evolve into brain abscesses or cause hemorrhage into the infarct, which generally precludes use of anticoagulation or thrombolytics. Mycotic aneurysms caused by septic emboli may also present as subarachnoid hemorrhage (SAH) or intracerebral hemorrhage.

Artery-to-Artery Embolic Stroke

Thrombus formation on atherosclerotic plaques may embolize to intracranial arteries producing an artery-to-artery embolic stroke. Less commonly, a diseased vessel may acutely thrombose. Unlike the myocardial vessels, artery-to-artery embolism, rather than local thrombosis, appears to be the dominant vascular mechanism causing large-vessel brain ischemia. Any diseased vessel may be an embolic source, including the aortic arch, common carotid, internal carotid, vertebral, and basilar arteries.

CAROTID ATHEROSCLEROSIS

Atherosclerosis within the carotid artery occurs most frequently within the common carotid bifurcation and proximal internal carotid artery; the carotid siphon (portion within the cavernous sinus) is also vulnerable to atherosclerosis. Male gender, older age, smoking, hypertension, diabetes, and hypercholesterolemia are risk factors for carotid disease, as they are for stroke in general (Table 420-4). Carotid atherosclerosis produces an estimated 10% of ischemic stroke. For further discussion of the pathogenesis of atherosclerosis, see Chap. 232.

Carotid disease can be classified by whether the stenosis is symptomatic or asymptomatic and by the degree of stenosis (percent narrowing of the narrowest segment compared to a nondiseased segment). Symptomatic carotid disease implies that the patient has experienced a stroke or TIA within the vascular distribution of the artery, and it is associated with a greater risk of subsequent stroke than asymptomatic stenosis, in which the patient is symptom free and the stenosis is detected through screening, although such asymptomatic screening is not currently recommended. Greater degrees of arterial narrowing are generally associated with a higher risk of stroke, except that those with near occlusions are at lower risk of stroke.

OTHER CAUSES OF ARTERY-TO-ARTERY EMBOLIC STROKE

Intracranial atherosclerosis produces stroke either by an embolic mechanism or by in situ thrombosis of a diseased vessel. It is more common in patients of Asian and African-American descent. Recurrent stroke risk is ~15% per year, similar to untreated symptomatic carotid atherosclerosis.

Dissection of the internal carotid or vertebral arteries or even vessels beyond the circle of Willis is a common source of embolic stroke in young (age <60 years) patients. The dissection is usually painful and precedes the stroke by several hours or days. Extracranial dissections do not cause hemorrhage, presumably because of the tough adventitia of these vessels. Intracranial dissections, conversely, may produce SAH because the adventitia of intracranial vessels is thin and pseudoaneurysms may form, requiring urgent treatment to prevent rerupture. Treating asymptomatic pseudoaneurysms following dissection is likely not necessary. The cause of dissection is usually unknown, and recurrence is rare. Ehlers-Danlos type IV, Marfan’s disease, cystic medial necrosis, and fibromuscular dysplasia are associated with dissections. Trauma (usually a motor vehicle accident or a sports injury) can cause carotid and vertebral artery dissections. Spinal manipulative therapy is associated with vertebral artery dissection and stroke. Most dissections heal spontaneously, and stroke or TIA is uncommon beyond 2 weeks. A recent trial showed no difference in stroke prevention with aspirin compared to anticoagulation, with a low recurrent stroke rate of 2%.

SMALL-VESSEL STROKE

The term lacunar infarction refers to infarction following atherothrombotic or lipohyalinotic occlusion of a small artery in the brain. The term small-vessel stroke denotes occlusion of such a small penetrating artery and is now the preferred term. Small-vessel strokes account for ~20% of all strokes.

Pathophysiology

The MCA stem, the arteries comprising the circle of Willis (A1 segment, anterior and posterior communicating arteries, and P1 segment), and the basilar and vertebral arteries all give rise to 30- to 300-μm branches that penetrate the deep gray and white matter of the cerebrum or brainstem (Fig. 420-3). Each of these small branches can occlude either by atherothrombotic disease at its origin or by the development of lipohyalinotic thickening. Thrombosis of these vessels causes small infarcts that are referred to as lacunes (Latin for “lake” of fluid noted at autopsy). These infarcts range in size from 3 mm to 2 cm in diameter. Hypertension and age are the principal risk factors.

Clinical Manifestations

The most common small-vessel stroke syndromes are the following: (1) Pure motor hemiparesis from an infarct in the posterior limb of the internal capsule or the pons; the face, arm, and leg are almost always involved; (2) pure sensory stroke from an infarct in the ventral thalamus; (3) ataxic hemiparesis from an infarct in the ventral pons or internal capsule; (4) and dysarthria and a clumsy hand or arm due to infarction in the ventral pons or in the genu of the internal capsule.

Transient symptoms (small-vessel TIAs) may herald a small-vessel infarct; they may occur several times a day and last only a few minutes. Recovery from small-vessel strokes tends to be more rapid and complete than recovery from large-vessel strokes; in some cases, however, there is severe permanent disability.

A large-vessel source (either thrombosis or embolism) may manifest initially as a small-vessel infarction. Therefore, the search for embolic sources (carotid and heart) should not be completely abandoned in the evaluation of these patients. Secondary prevention of small-vessel stroke involves risk factor modification, specifically reduction in blood pressure (see “Treatment: Primary and Secondary Prevention of Stroke and TIA,” below).

LESS COMMON CAUSES OF STROKE

(Table 420-2) Hypercoagulable disorders (Chap. 61) primarily increase the risk of cortical vein or cerebral venous sinus thrombosis. Systemic lupus erythematosus with Libman-Sacks endocarditis can be a cause of embolic stroke. These conditions overlap with the antiphospholipid syndrome, which probably requires long-term anticoagulation to prevent further stroke. Homocysteinemia may cause arterial thromboses as well; this disorder is caused by various mutations in the homocysteine pathways and responds to different forms of cobalamin depending on the mutation.

Venous sinus thrombosis of the lateral or sagittal sinus or of small cortical veins (cortical vein thrombosis) occurs as a complication of oral contraceptive use, pregnancy and the postpartum period, inflammatory bowel disease, intracranial infections (meningitis), and dehydration. It is also seen in patients with laboratory-confirmed thrombophilia including antiphospholipid syndrome, polycythemia, sickle cell anemia, deficiencies of proteins C and S, factor V Leiden mutation (resistance to activated protein C), antithrombin III deficiency, homocysteinemia, and the prothrombin G20210 mutation. Women who take oral contraceptives and have the prothrombin G20210 mutation may be at particularly high risk for sinus thrombosis. Patients present with headache and may also have focal neurologic signs (especially paraparesis) and seizures. Often, CT imaging is normal unless an intracranial venous hemorrhage has occurred, but the venous sinus occlusion is readily visualized using magnetic resonance (MR) or CT venography or conventional x-ray angiography. With greater degrees of sinus thrombosis, the patient may develop signs of increased ICP and coma. Intravenous heparin, regardless of the presence of intracranial hemorrhage, reduces morbidity and mortality, and the long-term outcome is generally good. Heparin prevents further thrombosis and reduces venous hypertension and ischemia. If an underlying hypercoagulable state is not found, many physicians treat with vitamin K antagonists (VKAs) for 3–6 months and then convert to aspirin, depending on the degree of resolution of the venous sinus thrombus. Anticoagulation is often continued indefinitely if thrombophilia is diagnosed. Endovascular treatment strategies to augment anticoagulation, even in severe cases, have not been proven to be effective.

Sickle cell anemia (SS disease) is a common cause of stroke in children. A subset of homozygous carriers of this hemoglobin mutation develop stroke in childhood, and this may be predicted by documenting high-velocity blood flow within the MCAs using transcranial Doppler ultrasonography. In children who are identified to have high velocities, treatment with aggressive exchange transfusion dramatically reduces risk of stroke, and if exchange transfusion is ceased, their stroke rate increases again along with MCA velocities.

Fibromuscular dysplasia affects the cervical arteries and occurs mainly in women. The carotid or vertebral arteries show multiple rings of segmental narrowing alternating with dilatation. Vascular occlusion is usually incomplete. The process is often asymptomatic but occasionally is associated with an audible bruit, TIAs, or stroke. Involvement of the renal arteries is common and may cause hypertension. The cause and natural history of fibromuscular dysplasia are unknown (Chap. 275). TIA or stroke generally occurs only when the artery is severely narrowed or dissects. Anticoagulation or antiplatelet therapy may be helpful.

Temporal (giant cell) arteritis (Chap. 356) is a relatively common affliction of elderly individuals in which the external carotid system, particularly the temporal arteries, undergo subacute granulomatous inflammation with giant cells. Occlusion of posterior ciliary arteries derived from the ophthalmic artery results in blindness in one or both eyes and can be prevented with glucocorticoids. It rarely causes stroke because the internal carotid artery is usually not inflamed. Idiopathic giant cell arteritis involving the great vessels arising from the aortic arch (Takayasu’s arteritis) may cause carotid or vertebral thrombosis; it is rare in the Western Hemisphere.

Necrotizing (or granulomatous) arteritis, occurring alone or in association with generalized polyarteritis nodosa or granulomatosis with polyangiitis (Wegener’s), involves the distal small branches (<2 mm diameter) of the main intracranial arteries and produces small ischemic infarcts in the brain, optic nerve, and spinal cord. The CSF often shows pleocytosis, and the protein level is elevated. Primary central nervous system vasculitis is rare; small or medium-sized vessels are usually affected, without apparent systemic vasculitis. The differential diagnosis includes other inflammatory vasculopathies including infection (tuberculous, fungal), sarcoidosis, angiocentric lymphoma, carcinomatous meningitis, and noninflammatory causes such as atherosclerosis, emboli, connective tissue disease, vasospasm, migraine-associated vasculopathy, and drug-associated causes. Some cases develop in the postpartum period and are self-limited.

Patients with any form of vasculopathy may present with insidious progression of combined white and gray matter infarctions, prominent headache, and cognitive decline. Brain biopsy or high-resolution conventional x-ray angiography is usually required to make the diagnosis (Fig. 420-4). An inflammatory profile (elevated WBCs, elevated IgG index, bands on electrophoresis) found on lumbar puncture favors an inflammatory cause. In cases where inflammation is confirmed, aggressive immunosuppression with glucocorticoids, and often cyclophosphamide, is usually necessary to prevent progression; a diligent investigation for infectious causes such as tuberculosis is essential prior to immunosuppression. With prompt recognition and treatment, many patients can make an excellent recovery.

Drugs, in particular amphetamines and perhaps cocaine, may cause stroke on the basis of acute hypertension or drug-induced vasculopathy. This vasculopathy is commonly due to vasospasm or atherosclerosis but cases of inflammatory vasculitis have also been reported. No data exist on the value of any treatment, but cessation of stimulants is prudent. Phenylpropanolamine has been linked with intracranial hemorrhage, as has cocaine and methamphetamine, perhaps related to a drug-induced vasculopathy. Moyamoya disease is a poorly understood occlusive disease involving large intracranial arteries, especially the distal internal carotid artery and the stem of the MCA and ACA. Vascular inflammation is absent. The lenticulostriate arteries develop a rich collateral circulation around the occlusive lesion, which gives the impression of a “puff of smoke” (moyamoya in Japanese) on conventional x-ray angiography. Other collaterals include transdural anastomoses between the cortical surface branches of the meningeal and scalp arteries. The disease occurs mainly in Asian children or young adults, but the appearance may be identical in adults who have atherosclerosis, particularly in association with diabetes. Intracranial hemorrhage may result from rupture of the moyamoya collaterals; thus, anticoagulation is risky. Progressive occlusion of large surface arteries can occur, producing large-artery distribution strokes. Surgical bypass of extracranial carotid arteries to the dura or MCAs may prevent stroke and hemorrhage.

Posterior reversible encephalopathy syndrome (PRES) can occur with head injury, seizure, migraine, sympathomimetic drug use, eclampsia, and in the postpartum period. The pathophysiology is uncertain but likely involves a hyperperfusion state where blood pressure exceeds the upper limit of cerebral autoregulation resulting in cerebral edema (Chap. 301). Patients complain of headache and manifest fluctuating neurologic symptoms and signs, especially visual symptoms. Sometimes cerebral infarction ensues, but typically the clinical and imaging findings reverse completely. MRI findings are characteristic with the edema present within the occipital lobes but can be generalized and do not respect any single vascular territory. A closely related reversible cerebral vasoconstriction syndrome (RCVS) typically presents with sudden, severe headache closely mimicking SAH. Patients may experience ischemic infarction and intracerebral hemorrhage and typically have new-onset, severe hypertension. Conventional x-ray angiography reveals changes in the vascular caliber throughout the hemispheres resembling vasculitis, but the process is noninflammatory. Oral calcium channel blockers may be effective in producing remission, and recurrence is rare.

Leukoaraiosis, or periventricular white matter disease, is the result of multiple small-vessel infarcts within the subcortical white matter. It is readily seen on CT or MRI scans as areas of white matter injury surrounding the ventricles and within the corona radiata. The pathophysiologic basis of the disease is lipohyalinosis of small penetrating arteries within the white matter, likely produced by chronic hypertension. Patients with periventricular white matter disease may develop a subcortical dementia syndrome, and it is likely that this common form of dementia may be delayed or prevented with antihypertensive medications (Chap. 425).

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an inherited disorder that presents as small-vessel strokes, progressive dementia, and extensive symmetric white matter changes often including the anterior temporal lobes visualized by MRI. Approximately 40% of patients have migraine with aura, often manifest as transient motor or sensory deficits. Onset is usually in the fourth or fifth decade of life. This autosomal dominant condition is caused by one of several mutations in Notch-3, a member of a highly conserved gene family characterized by epidermal growth factor repeats in its extracellular domain. Other monogenic ischemic stroke syndromes include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) and hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS). Fabry’s disease also produces both a large-vessel arteriopathy and small-vessel infarctions. The COL4A1 mutation is associated with multiple small vessel strokes with hemorrhagic transformation.

TRANSIENT ISCHEMIC ATTACKS

TIAs are episodes of stroke symptoms that last only briefly; the standard definition of duration is <24 h, but most TIAs last <1 h. If a relevant brain infarction is identified on brain imaging, the clinical entity is now classified as stroke regardless of the duration of symptoms. A normal brain imaging study following a TIA does not rule-out TIA; rather, the clinical syndrome is diagnostic. The causes of TIA are similar to the causes of ischemic stroke, but because TIAs may herald stroke, they are an important risk factor that should be considered separately and urgently. TIAs may arise from emboli to the brain or from in situ thrombosis of an intracranial vessel. With a TIA, the occluded blood vessel reopens and neurologic function is restored.

The risk of stroke after a TIA is ~10–15% in the first 3 months, with most events occurring in the first 2 days. This risk can be directly estimated using the well-validated ABCD² score (Table 420-5). Therefore, urgent evaluation and treatment are justified. Because etiologies for stroke and TIA are identical, evaluation for TIA should parallel that of stroke (Fig. 420-2). The improvement characteristic of TIA is a contraindication to thrombolysis. However, because the risk of subsequent stroke in the first few days after a TIA is high, the opportunity to give rtPA rapidly if a subsequent stroke occurs may justify hospital admission for most patients. The combination of aspirin and clopidogrel was found to prevent stroke following TIA better than aspirin alone in a large Chinese randomized trial and is undergoing similar evaluation in an ongoing National Institutes of Health (NIH)-sponsored trial (POINT study). Failure to respond to the combination of aspirin and clopidogrel is linked to carriage of a common CYP2C19 polymorphism that leads to poor metabolism of clopidogrel into its active form. This mutation is common, particularly in Asians. An aggressive strategy of treating TIA with secondary prevention rapidly has led to a decrease in the high risk of subsequent stroke in the last two decades.

TREATMENT

TREATMENT

FURTHER READING

Additional Online References

INTRODUCTION

Intracranial hemorrhage is a form of stroke (see Chap. 419). Compared to ischemic stroke, patients with intracranial hemorrhage are more likely to present with headache; however, brain imaging is required to distinguish these entities. CT imaging of the head is highly sensitive and specific for intracranial hemorrhage and determines the location(s) of bleeding. Hemorrhages are classified by their location and the underlying vascular pathology. Hemorrhage directly into the brain parenchyma, also known as intracerebral hemorrhage (ICH), and arteriovenous malformations (AVMs) of the brain will be considered here. Other categories of hemorrhage include bleeding into subdural and epidural spaces, usually caused by trauma (Chap 435), and subarachnoid hemorrhage due to trauma or the rupture of an intracranial aneurysm (Chap. 302).

DIAGNOSIS

Intracranial hemorrhage is often identified on noncontrast CT imaging of the brain during the acute evaluation of stroke. Because CT is more widely available and may be logistically easier to perform than MRI, CT imaging is generally the preferred method for acute stroke evaluation (Fig. 421-1). The location of the hemorrhage narrows the differential diagnosis to a few entities. Table 421-1 lists the causes and anatomic spaces involved in hemorrhages.

EMERGENCY MANAGEMENT

Close attention should be paid to airway management because a reduction in the level of consciousness is common and often progressive. The initial blood pressure should be maintained until the results of the CT scan are reviewed and demonstrate ICH. In theory, a higher blood pressure should promote hematoma expansion, but it remains unclear if lowering of blood pressure reduces hematoma growth. Recent clinical trials have shown that systolic blood pressure (SBP) can be safely lowered acutely and rapidly to <140 mmHg in patients with spontaneous ICH whose initial SBP was 150–220 mmHg. The INTERACT2 trial was a large phase 3 clinical trial to address the effect of acute blood pressure lowering on ICH functional outcome. INTERACT2 randomized patients with spontaneous ICH within 6 h of onset and a baseline SBP of 150–220 mmHg to two different SBP targets (<140 and <180 mmHg). In those with the target SBP <140 mmHg, 52% had an outcome of death or major disability at 90 days compared with 55.6% of those with a target SBP <180 mmHg (p = .06). There was a significant shift to improved outcomes in the lower blood pressure arm, whereas both groups had a similar mortality. ATACH2 was a similarly designed clinical trial that assessed the same blood pressure targets but demonstrated no difference in outcome between groups. Current U.S. and European guidelines emphasize that blood pressure lowering to a target SBP is likely safe and possibly beneficial. However, these guidelines were completed prior to publication of the ATACH2 results, thus the specific optimal target remains a point of debate. In patients who have higher SBP on presentation or who are deeply comatose with possible elevated intracranial pressure (ICP), it is unclear whether these clinical trial results apply. In patients who have ICP monitors in place, current recommendations are that maintaining the cerebral perfusion pressure (mean arterial pressure [MAP] minus ICP) at 50–70 mmHg is reasonable, depending on the individual patient’s cerebral autoregulation status (Chap. 301). Blood pressure should be lowered with nonvasodilating IV drugs such as nicardipine, labetalol, or esmolol. Patients with cerebellar hemorrhages with depressed mental status or radiographic evidence of hydrocephalus should undergo urgent neurosurgical evaluation; these patients require close monitoring because they can deteriorate rapidly. Based on the clinical examination and CT findings, further imaging studies may be necessary, including MRI or conventional x-ray angiography. Stuporous or comatose patients with clinical and imaging signs of herniation are generally treated presumptively for elevated ICP with tracheal intubation and sedation, administration of osmotic diuretics such as mannitol or hypertonic saline, and elevation of the head of the bed while surgical consultation is obtained (Chap. 301). Reversal of coagulopathy and consideration of surgical evacuation of the hematoma (detailed below) are two other principal aspects of initial emergency management.

INTRACEREBRAL HEMORRHAGE

ICH accounts for ~10% of all strokes, and about 35–45% of patients die within the first month. Incidence rates are particularly high in Asians and blacks. Hypertension, coagulopathy, sympathomimetic drugs (cocaine, methamphetamine), and cerebral amyloid angiopathy (CAA) cause most of these hemorrhages. Advanced age, heavy alcohol, and low-dose aspirin use in those without symptomatic cardiovascular disease increase the risk, and cocaine and methamphetamine use is one of the most important causes in the young.

Hypertensive ICH

PATHOPHYSIOLOGY

Hypertensive ICH usually results from spontaneous rupture of a small penetrating artery deep in the brain. The most common sites are the basal ganglia (especially the putamen), thalamus, cerebellum, and pons. The small arteries in these areas seem most prone to hypertension-induced vascular injury. When hemorrhages occur in other brain areas or in nonhypertensive patients, greater consideration should be given to other causes such as hemorrhagic disorders, neoplasms, vascular malformations, vasculitis, and CAA. The hemorrhage may be small, or a large clot may form and compress adjacent tissue, causing herniation and death. Blood may also dissect into the ventricular space, which substantially increases morbidity and may cause hydrocephalus.

Most hypertensive ICHs initially develop over 30–90 min, whereas those associated with anticoagulant therapy may evolve for as long as 24–48 h. However, it is now recognized that about a third of patients even with no coagulopathy may have significant hematoma expansion with the first day. Within 48 h, macrophages begin to phagocytize the hemorrhage at its outer surface. After 1–6 months, the hemorrhage is generally resolved to a slitlike cavity lined with a glial scar and hemosiderin-laden macrophages.

CLINICAL MANIFESTATIONS

ICH generally presents as the abrupt onset of a focal neurologic deficit. Seizures are uncommon. Although clinical symptoms may be maximal at onset, commonly the focal deficit worsens over 30–90 min and is associated with a diminishing level of consciousness and signs of increased ICP such as headache and vomiting.

The putamen is the most common site for hypertensive hemorrhage, and the adjacent internal capsule is usually damaged (Fig. 421-1). Contralateral hemiparesis is therefore the sentinel sign. When mild, the face sags on one side over 5–30 min, speech becomes slurred, the arm and leg gradually weaken, and the eyes deviate away from the side of the hemiparesis. The paralysis may worsen until the affected limbs become flaccid or extend rigidly. When hemorrhages are large, drowsiness gives way to stupor as signs of upper brainstem compression appear. Coma ensues, accompanied by deep, irregular, or intermittent respiration, a dilated and fixed ipsilateral pupil, and decerebrate rigidity. In milder cases, edema in adjacent brain tissue may cause progressive deterioration over 12–72 h.

Thalamic hemorrhages also produce a contralateral hemiplegia or hemiparesis from pressure on, or dissection into, the adjacent internal capsule. A prominent sensory deficit involving all modalities is usually present. Aphasia, often with preserved verbal repetition, may occur after hemorrhage into the dominant thalamus, and constructional apraxia or mutism occurs in some cases of nondominant hemorrhage. There may also be a homonymous visual field defect. Thalamic hemorrhages cause several typical ocular disturbances by extension inferiorly into the upper midbrain. These include deviation of the eyes downward and inward so that they appear to be looking at the nose, unequal pupils with absence of light reaction, skew deviation with the eye opposite the hemorrhage displaced downward and medially, ipsilateral Horner’s syndrome, absence of convergence, paralysis of vertical gaze, and retraction nystagmus. Patients may later develop a chronic, contralateral pain syndrome (Déjérine-Roussy syndrome).

In pontine hemorrhages, deep coma with quadriplegia often occurs over a few minutes. Typically, there is prominent decerebrate rigidity and “pinpoint” (1 mm) pupils that react to light. There is impairment of reflex horizontal eye movements evoked by head turning (doll’s-head or oculocephalic maneuver) or by irrigation of the ears with ice water (Chap. 300). Hyperpnea, severe hypertension, and hyperhidrosis are common. Most patients with deep coma from pontine hemorrhage ultimately die, or develop a locked-in state, but small hemorrhages are compatible with survival and significant recovery.

Cerebellar hemorrhages usually develop over several hours and are characterized by occipital headache, repeated vomiting, and ataxia of gait. In mild cases, there may be no other neurologic signs except for gait ataxia. Dizziness or vertigo may be prominent. There is often paresis of conjugate lateral gaze toward the side of the hemorrhage, forced deviation of the eyes to the opposite side, or an ipsilateral sixth nerve palsy. Less frequent ocular signs include blepharospasm, involuntary closure of one eye, ocular bobbing, and skew deviation. Dysarthria and dysphagia may occur. As the hours pass, the patient often becomes stuporous and then comatose from brainstem compression or obstructive hydrocephalus; immediate surgical evacuation before severe brainstem compression occurs may be lifesaving. Hydrocephalus from fourth ventricle compression can be relieved by external ventricular drainage; however, in this situation definitive hematoma evacuation is recommended rather than treatment with ventricular drainage alone. If the deep cerebellar nuclei are spared, full recovery is common.

Lobar Hemorrhage

The major neurologic deficit with an occipital hemorrhage is hemianopsia; with a left temporal hemorrhage, aphasia and delirium; with a parietal hemorrhage, hemisensory loss; and with frontal hemorrhage, arm weakness. Large hemorrhages may be associated with stupor or coma if they compress the thalamus or midbrain. Most patients with lobar hemorrhages have focal headaches, and more than one-half vomit or are drowsy. Stiff neck and seizures are uncommon.

Other Causes of ICH

CAA is a disease of the elderly in which arteriolar degeneration occurs and amyloid is deposited in the walls of the cerebral arteries. Amyloid angiopathy causes both single and recurrent lobar hemorrhages and is probably the most common cause of lobar hemorrhage in the elderly. It accounts for some intracranial hemorrhages associated with IV thrombolysis given for myocardial infarction. This disorder can be suspected in patients who present with multiple hemorrhages (and infarcts) over several months or years or in patients with “microbleeds” in the cortex, seen on brain MRI sequences sensitive for hemosiderin (iron-sensitive imaging), but it is definitively diagnosed by pathologic demonstration of Congo red staining of amyloid in cerebral vessels. The ε2 and ε4 allelic variations of the apolipoprotein E gene are associated with increased risk of recurrent lobar hemorrhage and may therefore be markers of amyloid angiopathy. Positron emission tomography imaging can image amyloid-beta deposits in CAA using specific antibody labels and may be helpful in diagnosing CAA noninvasively. Although cerebral biopsy is the most definitive method of diagnosis, evidence of inflammation on lumbar puncture should prompt consideration of CAA-associated vasculitis as an underlying cause and oral glucocorticoids may be beneficial. Non-inflammatory CAA has no specific treatment. Oral anticoagulants are typically avoided.

Cocaine and methamphetamine are frequent causes of stroke in young (age <45 years) patients. ICH, ischemic stroke, and subarachnoid hemorrhage (SAH) are all associated with stimulant use. Angiographic findings vary from completely normal arteries to large-vessel occlusion or stenosis, vasospasm, or changes consistent with vasculopathy. The mechanism of sympathomimetic-related stroke is not known, but cocaine enhances sympathetic activity causing acute, sometimes severe, hypertension, and this may lead to hemorrhage. Slightly more than one-half of stimulant-related intracranial hemorrhages are intracerebral and the rest are subarachnoid. In cases of SAH, a saccular aneurysm is usually identified. Presumably, acute hypertension causes aneurysmal rupture.

Head injury often causes intracranial bleeding. The common sites are intraparenchymal (especially temporal and inferior frontal lobes) and into the subarachnoid, subdural, and epidural spaces. Trauma must be considered in any patient with an unexplained acute neurologic deficit (hemiparesis, stupor, or confusion), particularly if the deficit occurred in the context of a fall (Chap. 435).

Intracranial hemorrhages associated with anticoagulant therapy can occur at any location; they are often lobar or subdural. Anticoagulant-related ICHs may continue to evolve over 24–48 h, especially if coagulopathy is insufficiently reversed. Coagulopathy and thrombocytopenia should be reversed rapidly, as discussed below. ICH associated with hematologic disorders (leukemia, aplastic anemia, thrombocytopenic purpura) can occur at any site and may present as multiple ICHs. Skin and mucous membrane bleeding may be evident and offers a diagnostic clue.

Hemorrhage into a brain tumor may be the first manifestation of neoplasm. Choriocarcinoma, malignant melanoma, renal cell carcinoma, and bronchogenic carcinoma are among the most common metastatic tumors associated with ICH. Glioblastoma multiforme in adults and medulloblastoma in children may also have areas of ICH.

Hypertensive encephalopathy is a complication of malignant hypertension. In this acute syndrome, severe hypertension is associated with headache, nausea, vomiting, convulsions, confusion, stupor, and coma. Focal or lateralizing neurologic signs, either transitory or permanent, may occur but are infrequent and therefore suggest some other vascular disease (hemorrhage, embolism, or atherosclerotic thrombosis). There are retinal hemorrhages, exudates, papilledema (hypertensive retinopathy), and evidence of renal and cardiac disease. In most cases, ICP and CSF protein levels are elevated. MRI brain imaging shows a pattern of typically posterior (occipital > frontal) brain edema that is reversible and termed reversible posterior leukoencephalopathy. The hypertension may be essential or due to chronic renal disease, acute glomerulonephritis, acute toxemia of pregnancy, pheochromocytoma, or other causes. Lowering the blood pressure reverses the process, but stroke can occur, especially if blood pressure is lowered too rapidly. Neuropathologic examination reveals multifocal to diffuse cerebral edema and hemorrhages of various sizes from petechial to massive. Microscopically, there is necrosis of arterioles, minute cerebral infarcts, and hemorrhages. The term hypertensive encephalopathy should be reserved for this syndrome and not for chronic recurrent headaches, dizziness, recurrent transient ischemic attacks, or small strokes that often occur in association with high blood pressure. Distinguishing hypertensive encephalopathy with ICH from hypertensive ICH is important since aggressive lowering of SBP to 140–180 mmHg acutely is usually considered in hypertensive ICH but less aggressive measures should be used in hypertensive encephalopathy. Having no alteration in mental status or other prodrome prior to the ICH favors hypertensive ICH as the disease.

Primary intraventricular hemorrhage is rare and should prompt investigation for an underlying vascular anomaly. Sometimes bleeding begins within the periventricular substance of the brain and dissects into the ventricular system without leaving signs of intraparenchymal hemorrhage. Alternatively, bleeding can arise from periependymal veins. Vasculitis, usually polyarteritis nodosa or lupus erythematosus, can produce hemorrhage in any region of the central nervous system; most hemorrhages are associated with hypertension, but the arteritis itself may cause bleeding by disrupting the vessel wall. Nearly one-half of patients with primary intraventricular hemorrhage have identifiable bleeding sources seen using conventional angiography.

Sepsis can cause small petechial hemorrhages throughout the cerebral white matter. Moyamoya disease (Chap. 421), mainly an occlusive arterial disease that causes ischemic symptoms, may on occasion produce ICH, particularly in the young. Hemorrhages into the spinal cord are usually the result of an AVM, cavernous malformation, or metastatic tumor. Epidural spinal hemorrhage produces a rapidly evolving syndrome of spinal cord or nerve root compression (Chap. 434). Spinal hemorrhages usually present with sudden back pain and some manifestation of myelopathy.

Laboratory and Imaging Evaluation

Patients should have routine blood chemistries and hematologic studies. Specific attention to the platelet count and PT/PTT/INR is important to identify coagulopathy. CT imaging reliably detects acute focal hemorrhages in the supratentorial space. Rarely very small pontine or medullary hemorrhages may not be well delineated because of motion and bone-induced artifact that obscure structures in the posterior fossa. After the first 2 weeks, x-ray attenuation values of clotted blood diminish until they become isodense with surrounding brain. Mass effect and edema may remain. In some cases, a surrounding rim of contrast enhancement appears after 2–4 weeks and may persist for months. MRI, although more sensitive for delineating posterior fossa lesions, is generally not necessary for primary diagnosis in most instances. Images of flowing blood on MRI scan may identify AVMs as the cause of the hemorrhage. MRI, CT angiography (CTA), and conventional x-ray angiography are used when the cause of intracranial hemorrhage is uncertain, particularly if the patient is young or not hypertensive and the hematoma is not in one of the usual sites for hypertensive hemorrhage. CTA or postcontrast CT imaging may reveal one or more small areas of enhancement within a hematoma; this “spot sign” is thought to represent ongoing bleeding. The presence of a spot sign is associated with an increased risk of hematoma expansion, increased mortality, and lower likelihood of favorable functional outcome. Because patients typically have focal neurologic signs and obtundation and often show signs of increased ICP, a lumbar puncture is generally unnecessary and should usually be avoided because it may induce cerebral herniation.

TREATMENT

VASCULAR ANOMALIES

Vascular anomalies can be divided into congenital vascular malformations and acquired vascular lesions.

CONGENITAL VASCULAR MALFORMATIONS

True AVMs, venous anomalies, and capillary telangiectasias are lesions that usually remain clinically silent through life. AVMs are probably congenital, but cases of acquired lesions have been reported.

True AVMs are congenital shunts between the arterial and venous systems that may present with headache, seizures, and intracranial hemorrhage. AVMs consist of a tangle of abnormal vessels across the cortical surface or deep within the brain substance. AVMs vary in size from a small blemish a few millimeters in diameter to a large mass of tortuous channels composing an arteriovenous shunt of sufficient magnitude to raise cardiac output and precipitate heart failure. Blood vessels forming the tangle interposed between arteries and veins are usually abnormally thin and histologically resemble both arteries and veins. AVMs occur in all parts of the cerebral hemispheres, brainstem, and spinal cord, but the largest ones are most frequently located in the posterior half of the hemispheres, commonly forming a wedge-shaped lesion extending from the cortex to the ventricle.

Bleeding, headache, and seizures are most common between the ages of 10 and 30, occasionally as late as the fifties. AVMs are more frequent in men, and rare familial cases have been described. Familial AVM may be a part of the autosomal dominant syndrome of hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber) syndrome due to mutations in either endoglin or activin receptor-like kinase 1, both involved in transforming growth factor (TGF) signaling and angiogenesis.

Headache (without bleeding) may be hemicranial and throbbing, like migraine, or diffuse. Focal seizures, with or without generalization, occur in ~30% of cases. One-half of AVMs become evident as ICHs. In most, the hemorrhage is mainly intraparenchymal with extension into the subarachnoid space in some cases. Unlike primary subarachnoid hemorrhages (Chap. 302), blood from a ruptured AVM is usually not deposited in the basal cisterns, and symptomatic cerebral vasospasm is rare. The risk of AVM rupture is strongly influenced by a history of prior rupture. Although unruptured AVMs have a hemorrhage rate of ~2–4% per year, previously ruptured AVMs may have a rate as high as 17% a year, at least for the first year. Hemorrhages may be massive, leading to death, or may be as small as 1 cm in diameter, leading to minor focal symptoms or no deficit. The AVM may be large enough to steal blood away from adjacent normal brain tissue or to increase venous pressure significantly to produce venous ischemia locally and in remote areas of the brain. This is seen most often with large AVMs in the territory of the middle cerebral artery.

Large AVMs of the anterior circulation may be associated with a systolic and diastolic bruit (sometimes self-audible) over the eye, forehead, or neck and a bounding carotid pulse. Headache at the onset of AVM rupture is generally not as explosive as with aneurysmal rupture. MRI is better than CT for diagnosis, although noncontrast CT scanning sometimes detects calcification of the AVM and contrast may demonstrate the abnormal blood vessels. Once identified, conventional x-ray angiography is the gold standard for evaluating the precise anatomy of the AVM.

Surgical treatment of AVMs presenting with hemorrhage often done in conjunction with preoperative embolization to reduce operative bleeding is usually indicated for accessible lesions. Stereotactic radiosurgery, an alternative to conventional surgery, can produce a slow sclerosis of the AVM over 2–3 years.

Several angiographic features can be used to help predict future bleeding risk. Paradoxically, smaller lesions seem to have a higher hemorrhage rate. The presence of deep venous drainage, venous outflow stenosis, and intranidal aneurysms may increase rupture risk. Because of the relatively low annual rate of hemorrhage and the risk of complications due to surgical or endovascular treatment, the indication for surgery in asymptomatic AVMs is debated. The ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) trial randomized patients to medical management versus intervention (surgery, endovascular embolization, combination embolization and surgery, or gamma-knife). The trial was stopped prematurely for harm, with the medical arm achieving the combined endpoint of death or symptomatic stroke in 10.1% of patients compared to 30.7% in the intervention group at an average follow-up time of 33 months. This highly significant finding, now confirmed in longer follow-up averaging over 4 years, argues against routine intervention for patients presenting without hemorrhage, although debate ensues regarding the generalizability of these results.

Venous anomalies are the result of development of anomalous cerebral, cerebellar, or brainstem venous drainage. These structures, unlike AVMs, are functional venous channels. They are of little clinical significance and should be ignored if found incidentally on brain imaging studies. Surgical resection of these anomalies may result in venous infarction and hemorrhage. Venous anomalies may be associated with cavernous malformations (see below), which do carry some bleeding risk.

Capillary telangiectasias are true capillary malformations that often form extensive vascular networks through an otherwise normal brain structure. The pons and deep cerebral white matter are typical locations, and these capillary malformations can be seen in patients with hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber) syndrome. If bleeding does occur, it rarely produces mass effect or significant symptoms. No treatment options exist.

ACQUIRED VASCULAR LESIONS

Cavernous angiomas are tufts of capillary sinusoids that form within the deep hemispheric white matter and brainstem with no normal intervening neural structures. The pathogenesis is unclear. Familial cavernous angiomas have been mapped to several different genes: KRIT1, CCM2, and PDCD10. Both KRIT1 and CCM2 have roles in blood vessel formation, whereas PDCD10 is an apoptotic gene. Cavernous angiomas are typically <1 cm in diameter and are often associated with a venous anomaly. Bleeding is usually of small volume, causing slight mass effect only. The bleeding risk for single cavernous malformations is 0.7–1.5% per year and may be higher for patients with prior clinical hemorrhage or multiple malformations. Antithrombotic medications should not be withheld when indicated as they do not increase the risk of recurrent hemorrhage. Seizures may occur if the malformation is located near the cerebral cortex. Surgical resection eliminates bleeding risk and may reduce seizure risk, but it is usually reserved for those malformations that form near the brain surface. Radiation treatment has not been shown to be of benefit.

Dural arteriovenous fistulas are acquired connections usually from a dural artery to a dural sinus. Patients may complain of a pulse-synchronous cephalic bruit (“pulsatile tinnitus”) and headache. Depending on the magnitude of the shunt, venous pressures may rise high enough to cause cortical ischemia or venous hypertension and hemorrhage, particularly SAH. Surgical and endovascular techniques are usually curative. These fistulas may form because of trauma, but most are idiopathic. There is an association between fistulas and dural sinus thrombosis. Fistulas have been observed to appear months to years following venous sinus thrombosis, suggesting that angiogenesis factors elaborated from the thrombotic process may cause these anomalous connections to form. Alternatively, dural arteriovenous fistulas can produce venous sinus occlusion over time, perhaps from the high pressure and high flow through a venous structure.

FURTHER READING

Additional Online References

INTRODUCTION

The general approach to headache as a cardinal symptom are covered elsewhere (Chap. 13); here, disorders in which headache and associated features occur in the absence of any exogenous cause are discussed. The most common are migraine, tension-type headache (TTH), and the trigeminal autonomic cephalalgias (TACs), notably cluster headache; the complete list is summarized in Table 422-1.

MIGRAINE

Migraine, the second most common cause of headache, and the most common headache-related, and indeed neurologic, cause of disability in the world, afflicts ~15% of women and 6% of men over a 1-year period. It is usually an episodic headache associated with certain features such as sensitivity to light, sound, or movement; nausea and vomiting often accompany the headache. A useful description of migraine is a recurring syndrome of headache associated with other symptoms of neurologic dysfunction in varying admixtures (Table 422-2). A migraine attack has three phases: premonitory (prodrome), headache phase, and postdrome; each has distinct and sometimes disabling symptoms. About 20–25% of migraine patients have a fourth, aura, phase. Migraine can often be recognized by its activators, referred to as triggers.

Migraineurs are particularly sensitive to environmental and sensory stimuli; migraine-prone patients do not habituate easily to sensory stimuli. This sensitivity is amplified in females during the menstrual cycle. Headache can be initiated or amplified by various triggers, including glare, bright lights, sounds, or other types of afferent stimulation; hunger; let-down from stress; physical exertion; stormy weather or barometric pressure changes; hormonal fluctuations during menses; lack of or excess sleep; and alcohol or other chemical stimulation, such as with nitrates. Knowledge of a patient’s susceptibility to specific triggers can be useful in management strategies involving lifestyle adjustments, although it is becoming recognized that some apparent triggers may in fact be part of the initial phase of the attack; i.e., the premonitory phase or prodrome. For reasons that remain unclear, migraine patients with aura have an increased risk of incident cardiovascular and cerebrovascular disease; clinicians should remain vigilant for these problems in these patients.

Pathogenesis

The sensory sensitivity that is characteristic of migraine is probably due to dysfunction of monoaminergic sensory control systems located in the brainstem and hypothalamus (Fig. 422-1).

Activation of cells in the trigeminal nucleus results in the release of vasoactive neuropeptides, particularly calcitonin gene–related peptide (CGRP), at vascular terminals of the trigeminal nerve and within the trigeminal nucleus. Six CGRP receptor antagonists, gepants, have now been shown to be effective in the acute treatment of migraine, and four monoclonal antibodies to CGRP or its receptor have been shown to be effective in migraine prevention. Centrally, the second-order trigeminal neurons cross the midline and project to ventrobasal and posterior nuclei of the thalamus for further processing. Additionally, there are projections to the periaqueductal gray and hypothalamus, from which reciprocal descending systems have established antinociceptive effects. Other brainstem regions likely to be involved in descending modulation of trigeminal pain include the nucleus locus coeruleus in the pons and the rostroventromedial medulla.

Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also known as serotonin) in migraine. In the late 1950s methysergide was found to antagonize certain peripheral actions of 5-HT and was introduced, based on its anti-inflammation properties, as the first drug capable of preventing migraine attacks. The triptans were designed to stimulate selectively subpopulations of 5-HT receptors; at least 14 different 5-HT receptors exist in humans. The triptans are potent agonists of 5-HT_1B and 5-HT_1D receptors, and some are active at the 5-HT_1F receptor; the latter’s exclusive agonists are called ditans. Triptans arrest nerve signaling in the nociceptive pathways of the trigeminovascular system, at least in the trigeminal nucleus caudalis and trigeminal sensory thalamus, in addition to promoting cranial vasoconstriction, while ditans, now shown conclusively to be effective in acute migraine, act only at neural and not vascular targets. A range of neural targets are currently under investigation for the acute and preventive management of migraine.

Data also support a role for dopamine in the pathophysiology of migraine. Most migraine symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Dopamine receptor antagonists are effective therapeutic agents in migraine, especially when given parenterally or concurrently with other antimigraine agents. Moreover, hypothalamic activation, anterior to that seen in cluster headache, has now been shown in the premonitory (prodromal) phase of migraine using functional imaging, and this may hold a key to understanding some part of the role of dopamine in the disorder. In addition, there appears to be a lower risk of developing type 2 diabetes mellitus in women with active migraine suggesting a potential role of hyperglycemia and hyperinsulinism on migraine occurrence.

Migraine genes identified by studying families with familial hemiplegic migraine (FHM) reveal involvement of ion channels, suggesting that alterations in membrane excitability can predispose to migraine. Mutations involving the Ca_v2.1 (P/Q)–type voltage-gated calcium channel CACNA1A gene are now known to cause FHM 1; this mutation is responsible for about 50% of FHM cases. Mutations in the Na⁺-K⁺ATPase ATP1A2 gene, designated FHM 2, are responsible for about 20% of FHMs. Mutations in the neuronal voltage-gated sodium channel SCN1A cause FHM 3. Functional neuroimaging has suggested that brainstem regions in migraine (Fig. 422-2) and the posterior hypothalamic gray matter region close to the human circadian pacemaker cells of the suprachiasmatic nucleus in cluster headache (Fig. 422-3) are good candidates for specific involvement in these primary headaches.

Diagnosis and Clinical Features

Diagnostic criteria for migraine headache are listed in Table 422-3. A high index of suspicion is required to diagnose migraine: the migraine aura, consisting of visual disturbances with flashing lights or zigzag lines moving across the visual field or of other neurologic symptoms, is reported in only 20–25% of patients. It should be distinguished from the pan-field television static-like disturbance now recognized as the visual snow syndrome. The first phase of a migraine attack for most patients is the premonitory (prodromal) phase consisting of some or all of the following: yawning, tiredness, cognitive dysfunction, mood change, neck discomfort, polyuria, and food cravings; this can last from a few hours to days. Typically, the headache phase follows with its associated features, such as nausea, photophobia, and phonophobia as well as allodynia. When questioned, these typical migraine symptoms also emerge in the premonitory phase, and typical premonitory symptoms also continue into the headache phase. As the headache lessens many patients enter a postdrome, most commonly feeling tired/weary, having problems concentrating, and experiencing mild neck discomfort that can last for hours and sometimes up to a day. A headache diary can often be helpful in making the diagnosis; this is also helpful in assessing disability and the frequency of treatment for acute attacks. Patients with episodes of migraine on eight or more days per month and with at least 15 total days of headache per month are considered to have chronic migraine (see “Chronic Daily Headache” in Chap. 13). Migraine must be differentiated from TTH (discussed below), which is reported to be the most common primary headache syndrome. Migraine has several forms that have been defined (Table 422-1): migraine with and without aura and chronic migraine are the most important. Migraine at its most basic level is headache with associated features, and tension-type headache is headache that is featureless. Most patients with disabling headache probably have migraine.

Patients with acephalgic migraine (typical aura without headache, 1.2.1.2 in Table 422-1) experience recurrent neurologic symptoms, often with nausea or vomiting, but with little or no headache. Vertigo can be prominent; it has been estimated that one-third of patients referred for vertigo or dizziness have a primary diagnosis of migraine. Migraine aura can have prominent brainstem symptoms, and the terms basilar artery and basilar-type migraine have now been replaced by migraine with brainstem aura (Table 422-1).

TREATMENT