Harrison Neurology in Clinical Medicine Second Edition

SECTION III Diseases of the Central Nervous System232 genes that underlie the more common forms of idiopathic HISTORY AND EXAMINATION epilepsies. The first goal is to determine whether the event was MECHANISMS OF ACTION OF truly a seizure. An in-depth history is essential, for in ANTIEPILEPTIC DRUGS many cases the diagnosis of a seizure is based solely on clinical grounds—the examination and laboratory studies are often Antiepileptic drugs appear to act primarily by blocking normal. Questions should focus on the symptoms before, the initiation or spread of seizures.This occurs through a during, and after the episode in order to differentiate a variety of mechanisms that modify the activity of ion seizure from other paroxysmal events (see Differential channels or neurotransmitters, and in most cases the Diagnosis of Seizures later). Seizures frequently occur drugs have pleiotropic effects. The mechanisms include out-of-hospital, and the patient may be unaware of the inhibition of Na+-dependent action potentials in a ictal and immediate postictal phases; thus, witnesses to frequency-dependent manner (e.g., phenytoin, carba- the event should be interviewed carefully. mazepine, lamotrigine, topiramate, zonisamide), inhibi- tion of voltage-gated Ca2+ channels (phenytoin), decrease The history should also focus on risk factors and pre- of glutamate release (lamotrigine), potentiation of GABA disposing events. Clues for a predisposition to seizures receptor function (benzodiazepines and barbiturates), include a history of febrile seizures, earlier auras or brief increase in the availability of GABA (valproic acid, seizures not recognized as such, and a family history of gabapentin, tiagabine), and modulation of release of seizures. Epileptogenic factors such as prior head trauma, synaptic vesicles (levetiracetam). The two most effective stroke, tumor, or infection of the nervous system should drugs for absence seizures, ethosuximide and valproic be identified. In children, a careful assessment of devel- acid, probably act by inhibiting T-type Ca2+ channels in opmental milestones may provide evidence for underly- thalamic neurons. ing CNS disease. Precipitating factors such as sleep deprivation, systemic diseases, electrolyte or metabolic In contrast to the relatively large number of antiepileptic derangements, acute infection, drugs that lower the drugs that can attenuate seizure activity, there are currently seizure threshold (Table 20-5), or alcohol or illicit drug no drugs known to prevent the formation of a seizure use should also be identified. focus following CNS injury.The eventual development of such “antiepileptogenic” drugs will provide an important The general physical examination includes a search for means of preventing the emergence of epilepsy following signs of infection or systemic illness. Careful examina- injuries such as head trauma, stroke, and CNS infection. tion of the skin may reveal signs of neurocutaneous dis- orders, such as tuberous sclerosis or neurofibromatosis, or Approach to the Patient: chronic liver or renal disease. A finding of organomegaly SEIZURE may indicate a metabolic storage disease, and limb asym- metry may provide a clue to brain injury early in devel- When a patient presents shortly after a seizure, the opment. Signs of head trauma and use of alcohol or first priorities are attention to vital signs, respiratory illicit drugs should be sought. Auscultation of the heart and cardiovascular support, and treatment of seizures and carotid arteries may identify an abnormality that if they resume (see Rx: Seizures and Epilepsy). Life- predisposes to cerebrovascular disease. threatening conditions such as CNS infection, meta- bolic derangement, or drug toxicity must be recognized All patients require a complete neurologic examina- and managed appropriately. tion, with particular emphasis on eliciting signs of cere- bral hemispheric disease (Chap. 1). Careful assessment of When the patient is not acutely ill, the evaluation mental status (including memory, language function, and will initially focus on whether there is a history of ear- abstract thinking) may suggest lesions in the anterior lier seizures (Fig. 20-2). If this is the first seizure, then frontal, parietal, or temporal lobes.Testing of visual fields the emphasis will be to (1) establish whether the will help screen for lesions in the optic pathways and reported episode was a seizure rather than another occipital lobes. Screening tests of motor function such as paroxysmal event, (2) determine the cause of the seizure pronator drift, deep tendon reflexes, gait, and coordina- by identifying risk factors and precipitating events, and tion may suggest lesions in motor (frontal) cortex, and (3) decide whether anticonvulsant therapy is required in cortical sensory testing (e.g., double simultaneous stimu- addition to treatment for any underlying illness. lation) may detect lesions in the parietal cortex. In the patient with prior seizures or a known his- LABORATORY STUDIES tory of epilepsy, the evaluation is directed toward (1) identification of the underlying cause and precipi- Routine blood studies are indicated to identify the more tating factors, and (2) determination of the adequacy common metabolic causes of seizures, such as abnormali- of the patient’s current therapy. ties in electrolytes, glucose, calcium, or magnesium, and hepatic or renal disease. A screen for toxins in blood and

Adult Patient with a Seizure 233 History Physical examination Exclude Syncope Transient ischemic attack Migraine Acute psychosis Other causes of episodic cerebral dysfunction History of epilepsy; currently treated No history of epilepsy with antiepileptics Assess: adequacy of antiepileptic therapy Laboratory studies Side effects CBC Serum levels Electrolytes, calcium, magnesium Serum glucose Consider Liver and renal function tests CHAPTER 20 Seizures and Epilepsy Electrolytes Urinalysis CBC Toxicology screen Liver and renal function tests Toxicology screen Positive metabolic screen Negative or symptoms/signs metabolic screen Normal Abnormal or change in suggesting a metabolic neurologic exam or infectious disorder MRI scan or EEG Subtherapeutic Therapeutic Treat identifiable Further work-up Focal features of antiepileptic antiepileptic metabolic abnormalities Lumbar puncture seizures levels levels Cultures Focal abnormalities Assess cause of Endocrine studies on clinical or lab neurologic change CT examination MRI if focal Other evidence of Appropriate Increase antiepileptic features present neurologic increase or therapy to maximum dysfunction resumption tolerated dose; Treat underlying of dose consider alternative metabolic abnormality antiepileptic drugs Consider: Antiepileptic therapy Yes No Consider: Mass lesion; stroke; CNS infection; Idiopathic seizures trauma; degenerative disease Consider: Antiepileptic therapy Treat underlying disorder Consider: Antiepileptic therapy FIGURE 20-2 resonance imaging; EEG, electroencephalogram; CNS, Evaluation of the adult patient with a seizure. CBC, com- central nervous system. plete blood count; CT, computed tomography; MRI, magnetic urine should also be obtained from all patients in appro- ELECTROPHYSIOLOGIC STUDIES priate risk groups, especially when no clear precipitating factor has been identified. A lumbar puncture is indicated All patients who have a possible seizure disorder should if there is any suspicion of meningitis or encephalitis, and be evaluated with an EEG as soon as possible. Details it is mandatory in all patients infected with HIV, even in about the EEG are covered in Chap. 3. the absence of symptoms or signs suggesting infection. In the evaluation of a patient with suspected epilepsy, the presence of electrographic seizure activity during the

SECTION III Diseases of the Central Nervous System234 clinically evident event—i.e., abnormal, repetitive, rhyth- conditions, such as head injury or brain tumor, will go mic activity having an abrupt onset and termination— on to develop epilepsy, because in such circumstances clearly establishes the diagnosis. The absence of electro- epileptiform activity is commonly encountered regardless graphic seizure activity does not exclude a seizure disorder, of whether seizures occur. however, because simple or complex seizures may origi- nate from a region of the cortex that is not within range BRAIN IMAGING of the scalp electrodes. The EEG is always abnormal during generalized tonic-clonic seizures. Since seizures Almost all patients with new-onset seizures should have a are typically infrequent and unpredictable, it is often not brain imaging study to determine whether there is an possible to obtain the EEG during a clinical event. underlying structural abnormality that is responsible. The Continuous monitoring for prolonged periods in video- only potential exception to this rule is children who have EEG telemetry units for hospitalized patients or the use an unambiguous history and examination suggestive of a of portable equipment to record the EEG continuously benign, generalized seizure disorder such as absence on cassettes for Ն24 h in ambulatory patients has made it epilepsy. MRI has been shown to be superior to CT for easier to capture the electrophysiologic accompaniments the detection of cerebral lesions associated with epilepsy. of clinical events. In particular, video-EEG telemetry is In some cases MRI will identify lesions such as tumors, now a routine approach for the accurate diagnosis of vascular malformations, or other pathologies that need epilepsy in patients with poorly characterized events or immediate therapy.The use of newer MRI methods, such seizures that are difficult to control. as fluid-attenuated inversion recovery (FLAIR), has Magnetoencephalography (MEG) provides another increased the sensitivity for detection of abnormalities of way of looking noninvasively at cortical activity. Instead cortical architecture, including hippocampal atrophy asso- of measuring electrical activity of the brain, it measures ciated with mesial temporal sclerosis, as well as abnormal- the small magnetic fields that are generated by this ities of cortical neuronal migration. In such cases the activity. Epileptiform activity seen on the MEG can be findings may not lead to immediate therapy, but they do analyzed, and its source in the brain can be estimated provide an explanation for the patient’s seizures and point using a variety of mathematical techniques.These source to the need for chronic anticonvulsant therapy or possible estimates can then be plotted on an anatomic image of surgical resection. the brain, such as an MRI (discussed later), to generate a magnetic source image (MSI). MSI can be useful to In the patient with a suspected CNS infection or mass localize potential seizure foci. lesion, CT scanning should be performed emergently The EEG may also be helpful in the interictal period when MRI is not immediately available. Otherwise, it is by showing certain abnormalities that are highly support- usually appropriate to obtain an MRI study within a few ive of the diagnosis of epilepsy. Such epileptiform activity days of the initial evaluation. Functional imaging proce- consists of bursts of abnormal discharges containing spikes dures such as positron emission tomography (PET) and or sharp waves. The presence of epileptiform activity is single photon emission computed tomography (SPECT) not specific for epilepsy, but it has a much greater preva- are also used to evaluate certain patients with medically lence in patients with epilepsy than in normal individuals. refractory seizures (discussed below). However, even in an individual who is known to have epilepsy, the initial routine interictal EEG may be normal DIFFERENTIAL DIAGNOSIS up to 60% of the time. Thus, the EEG cannot establish OF SEIZURES the diagnosis of epilepsy in many cases. The EEG is also used for classifying seizure disorders Disorders that may mimic seizures are listed in Table 20-6. and aiding in the selection of anticonvulsant medications. In most cases seizures can be distinguished from other For example, episodic generalized spike-wave activity is conditions by meticulous attention to the history and usually seen in patients with typical absence epilepsy and relevant laboratory studies. On occasion, additional stud- may be seen with other generalized epilepsy syndromes. ies, such as video-EEG monitoring, sleep studies, tilt- Focal interictal epileptiform discharges would support table analysis, or cardiac electrophysiology, may be required the diagnosis of a partial seizure disorder such as tempo- to reach a correct diagnosis. Two of the more common ral lobe epilepsy or frontal lobe seizures, depending on nonepileptic syndromes in the differential diagnosis are the location of the discharges. detailed below. The routine scalp-recorded EEG may also be used to assess the prognosis of seizure disorders; in general, a nor- SYNCOPE mal EEG implies a better prognosis, whereas an abnormal background or profuse epileptiform activity suggests a (See also Chap. 8) The diagnostic dilemma encountered poor outlook. Unfortunately, the EEG has not proved to most frequently is the distinction between a generalized be useful in predicting which patients with predisposing seizure and syncope. Observations by the patient and

TABLE 20-6 syncopal episode can induce a full tonic-clonic seizure. In 235CHAPTER 20 Seizures and Epilepsy such cases the evaluation must focus on both the cause of DIFFERENTIAL DIAGNOSIS OF SEIZURES the syncopal event as well as the possibility that the patient has a propensity for recurrent seizures. Syncope Vasovagal syncope PSYCHOGENIC SEIZURES Cardiac arrhythmia Valvular heart disease Psychogenic seizures are nonepileptic behaviors that resem- Cardiac failure ble seizures. They are often part of a conversion reaction Orthostatic hypotension precipitated by underlying psychological distress. Certain behaviors, such as side-to-side turning of the head, asym- Psychological disorders metric and large-amplitude shaking movements of the Psychogenic seizure limbs, twitching of all four extremities without loss of Hyperventilation consciousness, and pelvic thrusting are more commonly Panic attack associated with psychogenic rather than epileptic seizures. Psychogenic seizures often last longer than epileptic Metabolic disturbances seizures and may wax and wane over minutes to hours. Alcoholic blackouts However, the distinction is sometimes difficult on clinical Delirium tremens grounds alone, and there are many examples of diagnostic Hypoglycemia errors made by experienced epileptologists. This is espe- Hypoxia cially true for psychogenic seizures that resemble complex Psychoactive drugs (e.g., hallucinogens) partial seizures, since the behavioral manifestations of complex partial seizures (especially of frontal lobe origin) Migraine can be extremely unusual, and in both cases the routine Confusional migraine surface EEG may be normal. Video-EEG monitoring is Basilar migraine very useful when historic features are nondiagnostic. Gen- eralized tonic-clonic seizures always produce marked EEG Transient ischemic attack (TIA) abnormalities during and after the seizure. For suspected Basilar artery TIA complex partial seizures of temporal lobe origin, the use of additional electrodes beyond the standard scalp locations Sleep disorders (e.g., sphenoidal electrodes) may be required to localize a Narcolepsy/cataplexy seizure focus. Measurement of serum prolactin levels may Benign sleep myoclonus also help to distinguish between organic and psychogenic seizures, since most generalized seizures and many com- Movement disorders plex partial seizures are accompanied by rises in serum Tics prolactin (during the immediate 30-min postictal period), Nonepileptic myoclonus whereas psychogenic seizures are not. The diagnosis of Paroxysmal choreoathetosis psychogenic seizures does not exclude a concurrent diag- nosis of epilepsy, since the two often coexist. Special considerations in children Breath-holding spells Treatment: Migraine with recurrent abdominal pain and cyclic SEIZURES AND EPILEPSY vomiting Benign paroxysmal vertigo Therapy for a patient with a seizure disorder is almost Apnea always multimodal and includes treatment of underly- Night terrors ing conditions that cause or contribute to the seizures, Sleepwalking avoidance of precipitating factors, suppression of recur- rent seizures by prophylactic therapy with antiepileptic bystanders that can help differentiate between the two are medications or surgery, and addressing a variety of psy- listed in Table 20-7. Characteristics of a seizure include chological and social issues. Treatment plans must be the presence of an aura, cyanosis, unconsciousness, motor individualized, given the many different types and manifestations lasting >30 s, postictal disorientation, mus- causes of seizures as well as the differences in efficacy cle soreness, and sleepiness. In contrast, a syncopal episode and toxicity of antiepileptic medications for each is more likely if the event was provoked by acute pain or patient. In almost all cases a neurologist with experience anxiety or occurred immediately after arising from the lying or sitting position. Patients with syncope often describe a stereotyped transition from consciousness to unconscious- ness 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 pos- ture after fainting (e.g., in a dentist’s chair) and therefore has a sustained decrease in cerebral perfusion. Rarely, a

236 TABLE 20-7 FEATURES THAT DISTINGUISH GENERALIZED TONIC-CLONIC SEIZURE FROM SYNCOPE SECTION III Diseases of the Central Nervous System FEATURES SEIZURE SYNCOPE Immediate precipitating factors Usually none Emotional stress, Valsalva, orthostatic hypotension, cardiac etiologies Premonitory symptoms None or aura Tiredness, nausea, diaphoresis, (e.g., odd odor) tunneling of vision Posture at onset Variable Usually erect Transition to unconsciousness Often immediate Gradual over secondsa Duration of unconsciousness Minutes Seconds Duration of tonic or clonic 30–60 s Never more than 15 s movements Cyanosis, frothing Pallor Facial appearance during event at mouth Many minutes <5 min Disorientation and sleepiness to hours after event Often Sometimes Sometimes Rarely Aching of muscles after event Sometimes Sometimes Biting of tongue Sometimes Rarely Incontinence Headache aMay be sudden with certain cardiac arrhythmias. in the treatment of epilepsy should design and oversee benefit from surgical removal of the epileptic brain implementation of the treatment strategy. Furthermore, region (see later). patients with refractory epilepsy or those who require polypharmacy with antiepileptic drugs should remain AVOIDANCE OF PRECIPITATING FACTORS under the regular care of a neurologist. Unfortunately, little is known about the specific factors that determine precisely when a seizure will occur in a TREATMENT OF UNDERLYING CONDITIONS patient with epilepsy. Some patients can identify partic- If the sole cause of a seizure is a metabolic disturbance ular situations that appear to lower their seizure thresh- such as an abnormality of serum electrolytes or glucose, old; these situations should be avoided. For example, a then treatment is aimed at reversing the metabolic patient who has seizures in the setting of sleep depriva- problem and preventing its recurrence. Therapy with tion should obviously be advised to maintain a normal antiepileptic drugs is usually unnecessary unless the sleep schedule. Many patients note an association metabolic disorder cannot be corrected promptly and between alcohol intake and seizures, and they should the patient is at risk of having further seizures. If the be encouraged to modify their drinking habits accord- apparent cause of a seizure was a medication (e.g., theo- ingly. There are also relatively rare cases of patients with phylline) or illicit drug use (e.g., cocaine), then appropri- seizures that are induced by highly specific stimuli such ate therapy is avoidance of the drug; there is usually no as a video game monitor, music, or an individual’s voice need for antiepileptic medications unless subsequent (“reflex epilepsy”). If there is an association between seizures occur in the absence of these precipitants. stress and seizures, stress reduction techniques such as physical exercise, meditation, or counseling may be Seizures caused by a structural CNS lesion such as a helpful. brain tumor, vascular malformation, or brain abscess may not recur after appropriate treatment of the under- ANTIEPILEPTIC DRUG THERAPY Antiepilep- lying lesion. However, despite removal of the structural tic drug therapy is the mainstay of treatment for most lesion, there is a risk that the seizure focus will remain in patients with epilepsy. The overall goal is to completely the surrounding tissue or develop de novo as a result of prevent seizures without causing any untoward side gliosis and other processes induced by surgery, radia- effects, preferably with a single medication and a dosing tion, or other therapies. Most patients are therefore schedule that is easy for the patient to follow. Seizure maintained on an antiepileptic medication for at least classification is an important element in designing the 1 year, and an attempt is made to withdraw medications treatment plan, since some antiepileptic drugs have dif- only if the patient has been completely seizure-free. If ferent activities against various seizure types. However, seizures are refractory to medication, the patient may

there is considerable overlap between many antiepilep- Selection of Antiepileptic Drugs Antiepileptic 237 tic drugs, such that the choice of therapy is often deter- drugs available in the United States are shown in mined more by the patient’s specific needs, especially Table 20-8, and the main pharmacologic characteristics CHAPTER 20 Seizures and Epilepsy his/her assessment of side effects. of commonly used drugs are listed in Table 20-9. World- wide, older medications such as phenytoin, valproic When to Initiate Antiepileptic Drug Therapy acid, carbamazepine, and ethosuximide are generally Antiepileptic drug therapy should be started in any used as first-line therapy for most seizure disorders patient with recurrent seizures of unknown etiology or a since, overall, they are as effective as recently marketed known cause that cannot be reversed.Whether to initiate drugs and significantly less expensive. Most of the new therapy in a patient with a single seizure is controversial. drugs that have become available in the past decade are Patients with a single seizure due to an identified lesion used as add-on or alternative therapy, although some such as a CNS tumor, infection, or trauma, in which there are now being used as first-line monotherapy. is strong evidence that the lesion is epileptogenic, should be treated. The risk of seizure recurrence in a In addition to efficacy, factors influencing the choice patient with an apparently unprovoked or idiopathic of an initial medication include the convenience of dos- seizure is uncertain, with estimates ranging from 31 to ing (e.g., once daily versus three or four times daily) and 71% in the first 12 months after the initial seizure. This potential side effects. In this regard, a number of the uncertainty arises from differences in the underlying newer drugs have the advantage of a relative lack of seizure types and etiologies in various published epi- drug-drug interactions and easier dosing. Almost all of demiologic studies. Generally accepted risk factors asso- the commonly used antiepileptic drugs can cause simi- ciated with recurrent seizures include the following: lar, dose-related side effects such as sedation, ataxia, and (1) an abnormal neurologic examination, (2) seizures pre- diplopia. Close follow-up is required to ensure these are senting as status epilepticus, (3) postictal Todd’s paraly- promptly recognized and reversed. Most of the older sis, (4) a strong family history of seizures, or (5) an abnor- drugs and some of the newer ones can also cause idio- mal EEG. Most patients with one or more of these risk syncratic toxicity such as rash, bone marrow suppres- factors should be treated. Issues such as employment or sion, or hepatotoxicity. Although rare, these side effects driving may influence the decision whether to start med- should be considered during drug selection, and ications as well. For example, a patient with a single, idio- patients must be instructed about symptoms or signs pathic seizure whose job depends on driving may prefer that should signal the need to alert their health care taking antiepileptic drugs rather than risk a seizure recur- provider. For some drugs, laboratory tests (e.g., com- rence and the potential loss of driving privileges. plete blood count and liver function tests) are recom- mended prior to the institution of therapy (to establish TABLE 20-8 SELECTION OF ANTIEPILEPTIC DRUGS PRIMARY PARTIALa ABSENCE ATYPICAL GENERALIZED ABSENCE, TONIC-CLONIC MYOCLONIC, ATONIC First-Line Carbamazepine Valproic acid Valproic acid Phenytoin Ethosuximide Lamotrigine Valproic acid Lamotrigine Topiramate Lamotrigine Oxcarbazepine Lamotrigine Topiramate Valproic acid Clonazepam Clonazepam Felbamate Alternatives Levetiracetamb Topiramate Zonisamideb Tiagabineb Phenytoin Zonisamideb Carbamazepine Gabapentinb Oxcarbazepine Phenobarbital Phenobarbital Primidone Primidone Felbamate Felbamate aIncludes simple partial, complex partial, and secondarily generalized seizures. bAs adjunctive therapy.

238 TABLE 20-9 DOSAGE AND ADVERSE EFFECTS OF COMMONLY USED ANTIEPILEPTIC DRUGS GENERIC TRADE PRINCIPAL TYPICAL DOSE; HALF-LIFE THERAPEUTIC ADVERSE EFFECTS DRUG NAME NAME USES DOSE INTERVAL RANGE NEUROLOGIC SYSTEMIC INTERACTIONS Phenytoin Dilantin Tonic-clonic 300–400 mg/d 24 h (wide 10–20 μg/mL Dizziness Gum Level increased (diphenyl- (grand (3–6 mg/kg, variation, Diplopia hyperplasia by isoniazid, hydantoin mal) adult; 4–8 mg/kg, dose- Ataxia sulfonamides, Focal-onset child); qd-bid dependent) Incoordination Lymphade- fluoxetine Confusion nopathy Carba Tegretol Tonic-clonic 600–1800 mg/d 10–17 h 6–12 μg/mL Level decreased (15–35 mg/kg, Ataxia Hirsutism by enzyme- mazepine Carbatrol Focal-onset child); bid-qid Dizziness Osteomalacia inducing drugsa Diplopia Facial SECTION III Diseases of the Central Nervous System Valproic Depakene Tonic-clonic 750–2000 mg/d 15 h 50–125 μg/mL Vertigo Altered folate acid Depakote Absence (20–60 mg/kg); coarsening metabolism Depakote Atypical bid-qid Ataxia Skin rash ER absence Sedation Aplastic Level decreased Myoclonic Tremor by enzyme- Focal-onset anemia inducing drugsa Dizziness Leukopenia Lamotrigine Lamictal Focal-onset 150–500 mg/d; 25 h Not established Diplopia Gastrointesti- Level increased Tonic-clonic bid Sedation nal irritation by erythromycin, Atypical 14 h (with Ataxia Hepatotoxicity propoxyphene, Headache Hyponatremia isoniazid, cimeti- absence enzyme- dine, fluoxetine Myoclonic Hepatotoxicity Level decreased Lennox- inducers) Thrombocyto- by enzyme- Gastaut penia inducing drugsa syndrome Gastrointesti- Absence nal irritation Level decreased Weight gain by enzyme- (petit mal) Transient inducing drugsa alopecia and oral Hyperamm- contraceptives onemia Level increased Skin rash by valproic acid Stevens- Johnson syndrome 59 h (with val- proic acid) Ethosuxi Zarontin 750–1250 mg/d 60 h, adult 40–100 μg/mL Ataxia Gastrointesti- mide (20-40 mg/kg); 30 h, child Lethargy nal irritation qd-bid Headache Skin rash Gabapentin Neurontin Focal-onset 900–2400 mg/d; 5–9 h Not established Sedation Bone marrow No known tid-qid Dizziness significant Ataxia suppression interactions Topiramate Topamax Focal-onset 200–400 mg/d; 20–30 h Not established Fatigue Gastrointesti- Tonic-clonic bid Psychomotor nal irritation Level decreased Lennox- slowing Weight gain by enzyme- Sedation Edema inducing Gastaut Speech or Renal stones drugsa syndrome language (avoid use problems with other Level decreased Tiagabine Gabitril Focal-onset 32–56 mg/d; 7–9 h Not established Fatigue carbonic by enzyme- Tonic-clonic bid-qid Paresthesias anhydrase inducing inhibitors) drugsa Confusion Glaucoma Sedation Weight loss Depression Hypohydrosis Dizziness Gastrointesti- Speech or nal irritation language problems Paresthesias Psychosis

TABLE 20-9 (CONTINUED) 239 DOSAGE AND ADVERSE EFFECTS OF COMMONLY USED ANTIEPILEPTIC DRUGS ADVERSE EFFECTS GENERIC TRADE PRINCIPAL TYPICAL DOSE; HALF-LIFE THERAPEUTIC NEUROLOGIC SYSTEMIC DRUG NAME NAME USES DOSE INTERVAL RANGE Skin rash INTERACTIONS Sedation Phenobar Luminol Tonic-clonic 60–180 mg/d 90 h (70 h in 10–40 μg/mL Ataxia Level increased bital Focal-onset Confusion by valproic acid, (1–4 mg/kg, children) Dizziness phenytoin Decreased adult); (3–6 mg/kg, libido Depression child); qd Same as phenobarbital Primidone Mysoline Tonic-clonic 750–1000 mg/d Primidone, Primidone, Clonazepam Klonopin Focal-onset (10–25 mg/kg); Felbamate Felbatol bid-tid 8–15 h 4–12 μg/mL Absence Atypical 1–12 mg/d Phenobarbital, Phenobarbital, absence (0.1–0.2 mg/kg); Myoclonic qd-tid 90 h 10–40 μg/mL Focal-onset Lennox- 24–48 h 10–70 ng/mL Ataxia Anorexia Level decreased Sedation by enzyme- Gastaut 2400–3600 mg/d, 16–22 h Not Lethargy Aplastic inducing CHAPTER 20 Seizures and Epilepsy syndrome (45 mg/kg, child); established anemia drugsa tid-qid Insomnia Hepatic Increases Dizziness failure phenytoin, Levetirace- Keppra Focal-onset 1000–3000 6–8 h Not Sedation Weight loss valproic acid, tam mg/d; bid established Headache Gastrointesti- active nal irritation carbamazepine Sedation Anemia metabolite Fatigue Leukopenia Incoordination None known Psychosis Zonisamide Zonegran Focal-onset 200–400 mg/d; 50–68 h Not Sedation Anorexia Level decreased qd-bid established Dizziness Renal stones by enzyme- Confusion Hypohydrosis inducing Headache drugsa Psychosis Oxcarbaz- Trileptal Focal-onset 900–2400 mg/d 10–17 h (for Not Fatigue epine (30–45 mg/kg, active established Ataxia child); bid metabolite) Dizziness See carba- Level decreased Diplopia mazepine by enzyme- Vertigo inducing Headache drugsa May increase phenytoin aPhenytoin, carbamazepine, phenobarbital. baseline values) and during initial dosing and titration other drugs. However, phenytoin shows properties of of the agent. saturation kinetics, such that small increases in pheny- toin doses above a standard maintenance dose can pre- Antiepileptic Drug Selection for Partial cipitate marked side effects. This is one of the main Seizures Carbamazepine (or a related drug, oxcar- causes of acute phenytoin toxicity. Long-term use of bazepine), phenytoin, lamotrigine and topiramate are phenytoin is associated with untoward cosmetic effects currently the drugs of choice approved for the initial (e.g., hirsutism, coarsening of facial features, and gingival treatment of partial seizures, including those that secon- hypertrophy), and effects on bone metabolism, so it is darily generalize. Overall they have very similar efficacy, often avoided in young patients who are likely to but differences in pharmacokinetics and toxicity are the require the drug for many years. An advantage of carba- main determinants for use in a given patient. For exam- mazepine (which is also available in an extended- ple, phenytoin has a relatively long half-life and offers release form) is that its metabolism follows first-order the advantage of once or twice daily dosing in compari- pharmacokinetics, and the relationship between drug son with two or three times daily dosing for many of the dose, serum levels, and toxicity is linear. Carbamazepine

SECTION III Diseases of the Central Nervous System240 can cause leukopenia, aplastic anemia, or hepatotoxicity treatment of primary generalized, tonic-clonic seizures. Phenytoin, followed by topiramate, carbamazepine, and and would therefore be contraindicated in patients with zonisamide are suitable alternatives. Valproic acid is also predispositions to these problems. Asian individuals car- particularly effective in absence, myoclonic, and atonic rying the HLA allele HLA-B*1502 are at particularly high seizures and is therefore the drug of choice in patients risk of developing fatal skin reactions including Stevens with generalized epilepsy syndromes having mixed Johnson syndrome and should be tested for this allele seizure types. Importantly, both carbamazepine and prior to initiation of carbamazepine. Oxcarbazepine has phenytoin can worsen certain types of generalized the advantage of being metabolized in a way that seizures, including absence, myoclonic, tonic, and atonic avoids an intermediate metabolite associated with seizures. Ethosuximide is a particularly effective drug for some of the side effects of carbamazepine. Oxcar- the treatment of uncomplicated absence seizures, but it bazepine also has fewer drug interactions than carba- is not useful for tonic-clonic or partial seizures. Ethosux- mazepine. Lamotrigine tends to be well-tolerated in imide rarely causes bone marrow suppression, so that terms of side effects. However, patients need to be par- periodic monitoring of blood cell counts is required. ticularly vigilant about the possibility of a skin rash dur- Lamotrigine appears to be particularly effective in ing the initiation of therapy. This can be extremely epilepsy syndromes with mixed, generalized seizure severe and lead to Stevens-Johnson syndrome if unrec- types such as JME and Lennox-Gastaut syndrome. Topi- ognized and if the medication is not discontinued ramate, zonisamide, and felbamate may have similar immediately. This risk can be reduced by slow introduc- broad efficacy. tion and titration. Lamotrigine must be started slowly when used as add-on therapy with valproic acid, since Initiation and Monitoring of Therapy Because valproic acid inhibits lamotrigine metabolism, thereby the response to any antiepileptic drug is unpredictable, substantially prolonging its half-life. Topiramate has patients should be carefully educated about the recently been approved as monotherapy for partial and approach to therapy. The goal is to prevent seizures and primary generalized seizures. Similar to some of the minimize the side effects of therapy; determination of other antiepileptic drugs, topiramate can cause signifi- the optimal dose is often a matter of trial and error. This cant psychomotor slowing and other cognitive prob- process may take months or longer if the baseline lems, and it should not be used in patients at risk for the seizure frequency is low. Most anticonvulsant drugs development of glaucoma or renal stones. need to be introduced relatively slowly to minimize side effects, and patients should expect that minor side Valproic acid is an effective alternative for some effects such as mild sedation, slight changes in cogni- patients with partial seizures, especially when the seizures tion, or imbalance will typically resolve within a few secondarily generalize. Gastrointestinal side effects are days. Starting doses are usually the lowest value listed fewer when using the valproate semisodium formulation under the dosage column in Table 20-9. Subsequent (Depakote). Valproic acid also rarely causes reversible increases should be made only after achieving a steady bone marrow suppression and hepatotoxicity, and labora- state with the previous dose (i.e., after an interval of five tory testing is required to monitor toxicity. This drug or more half-lives). should generally be avoided in patients with preexisting bone marrow or liver disease. Irreversible, fatal hepatic fail- Monitoring of serum antiepileptic drug levels can be ure appearing as an idiosyncratic rather than dose-related very useful for establishing the initial dosing schedule. side effect is a relatively rare complication; its risk is high- However, the published therapeutic ranges of serum est in children <2 years, especially those taking other drug concentrations are only an approximate guide for antiepileptic drugs or with inborn errors of metabolism. determining the proper dose for a given patient. The key determinants are the clinical measures of seizure Levetiracetam, tiagabine, zonisamide, and gabapentin frequency and presence of side effects, not the labora- are additional drugs currently used for the treatment of tory values. Conventional assays of serum drug levels partial seizures with or without secondary generaliza- measure the total drug (i.e., both free and protein- tion. Phenobarbital and other barbiturate compounds bound). However, it is the concentration of free drug were commonly used in the past as first-line therapy for that reflects extracellular levels in the brain and corre- many forms of epilepsy. However, the barbiturates fre- lates best with efficacy. Thus, patients with decreased quently cause sedation in adults, hyperactivity in chil- levels of serum proteins (e.g., decreased serum albumin dren, and other more subtle cognitive changes; thus, due to impaired liver or renal function) may have an their use should be limited to situations in which no increased ratio of free to bound drug, yet the concentra- other suitable treatment alternatives exist. tion of free drug may be adequate for seizure control. These patients may have a “subtherapeutic” drug level, Antiepileptic Drug Selection for General- but the dose should be changed only if seizures remain ized Seizures Valproic acid and lamotrigine are currently considered the best initial choice for the

uncontrolled, not just to achieve a “therapeutic” level. It of clonazepam, and those with absence seizures may 241 is also useful to monitor free drug levels in such respond to a combination of valproic acid and ethosux- patients. In practice, other than during the initiation or imide. The same principles concerning the monitoring modification of therapy, monitoring of antiepileptic of therapeutic response, toxicity, and serum levels for drug levels is most useful for documenting compliance. monotherapy apply to polypharmacy, and potential drug interactions need to be recognized. If there is no If seizures continue despite gradual increases to the improvement, a third drug can be added while the first maximum tolerated dose and documented compliance, two are maintained. If there is a response, the less effec- then it becomes necessary to switch to another tive or less well-tolerated of the first two drugs should antiepileptic drug. This is usually done by maintaining be gradually withdrawn. the patient on the first drug while a second drug is added. The dose of the second drug should be adjusted SURGICAL TREATMENT OF REFRACTORY CHAPTER 20 Seizures and Epilepsy to decrease seizure frequency without causing toxicity. EPILEPSY Approximately 20–30% of patients with Once this is achieved, the first drug can be gradually epilepsy are resistant to medical therapy despite efforts withdrawn (usually over weeks unless there is significant to find an effective combination of antiepileptic drugs. toxicity). The dose of the second drug is then further For some, surgery can be extremely effective in substan- optimized based on seizure response and side effects. tially reducing seizure frequency and even providing Monotherapy should be the goal whenever possible. complete seizure control. Understanding the potential value of surgery is especially important when, at the time When to Discontinue Therapy Overall, about of diagnosis, a patient has an epilepsy syndrome that is 70% of children and 60% of adults who have their considered likely to be drug-resistant. Rather than sub- seizures completely controlled with antiepileptic drugs mitting the patient to years of unsuccessful medical ther- can eventually discontinue therapy. The following patient apy and the psychosocial trauma and increased mortal- profile yields the greatest chance of remaining seizure- ity associated with ongoing seizures, the patient should free after drug withdrawal: (1) complete medical control have an efficient but relatively brief attempt at medical of seizures for 1–5 years; (2) single seizure type, either par- therapy and then be referred for surgical evaluation. tial or generalized; (3) normal neurologic examination, including intelligence; and (4) normal EEG. The appropri- The most common surgical procedure for patients ate seizure-free interval is unknown and undoubtedly with temporal lobe epilepsy involves resection of the varies for different forms of epilepsy. However, it seems anteromedial temporal lobe (temporal lobectomy) or a reasonable to attempt withdrawal of therapy after 2 years more limited removal of the underlying hippocampus in a patient who meets all of the above criteria, is moti- and amygdala (amygdalohippocampectomy). Focal vated to discontinue the medication, and clearly under- seizures arising from extratemporal regions may be stands the potential risks and benefits. In most cases it is abolished by a focal neocortical resection with precise preferable to reduce the dose of the drug gradually over removal of an identified lesion (lesionectomy). When 2–3 months. Most recurrences occur in the first 3 months the cortical region cannot be removed, multiple subpial after discontinuing therapy, and patients should be transection, which disrupts intracortical connections, is advised to avoid potentially dangerous situations such as sometimes used to prevent seizure spread. Hemi- driving or swimming during this period. spherectomy or multilobar resection is useful for some patients with severe seizures due to hemispheric abnor- Treatment of Refractory Epilepsy Approxi- malities such as hemimegalencephaly or other dysplas- mately one-third of patients with epilepsy do not tic abnormalities, and corpus callosotomy has been respond to treatment with a single antiepileptic drug, shown to be effective for disabling tonic or atonic and it becomes necessary to try a combination of drugs seizures, usually when they are part of a mixed-seizure to control seizures. Patients who have focal epilepsy syndrome (e.g., Lennox-Gastaut syndrome). related to an underlying structural lesion or those with multiple seizure types and developmental delay are par- Presurgical evaluation is designed to identify the ticularly likely to require multiple drugs. There are cur- functional and structural basis of the patient’s seizure rently no clear guidelines for rational polypharmacy, disorder. Inpatient video-EEG monitoring is used to although in theory a combination of drugs with differ- define the anatomic location of the seizure focus and to ent mechanisms of action may be most useful. In most correlate the abnormal electrophysiologic activity with cases the initial combination therapy combines first-line behavioral manifestations of the seizure. Routine scalp drugs, i.e., carbamazepine, phenytoin, valproic acid, and or scalp-sphenoidal recordings are usually sufficient for lamotrigine. If these drugs are unsuccessful, then the localization, and advances in neuroimaging have made addition of a newer drug such as levetiracetam or topi- the use of invasive electrophysiologic monitoring such ramate is indicated. Patients with myoclonic seizures as implanted depth electrodes or subdural electrodes resistant to valproic acid may benefit from the addition less common. A high-resolution MRI scan is routinely

SECTION III Diseases of the Central Nervous System242 used to identify structural lesions, and this is sometimes associated increased seizure threshold. Adverse effects of the surgery are rare, and stimulation-induced side augmented with MEG. Functional imaging studies such effects, including transient hoarseness, cough, and dysp- as SPECT and PET are adjunctive tests that may help ver- nea, are usually mild. ify the localization of an apparent epileptogenic region. Once the presumed location of the seizure onset is Although still in development, there are some addi- identified, additional studies, including neuropsycho- tional therapies that will likely be of benefit to patients logical testing and the intracarotid amobarbital test with medically refractory epilepsy. Preliminary studies (Wada test) may be used to assess language and mem- suggest that stereotactic radiosurgery may be effective ory localization and to determine the possible func- in certain partial seizure disorders. There has also been tional consequences of surgical removal of the epilepto- great interest in the development of implantable genic region. In some cases, the exact extent of the devices that can detect the onset of a seizure (in some resection to be undertaken is determined by perform- instances, before the seizure becomes clinically appar- ing cortical mapping at the time of the surgical proce- ent) and deliver either an electrical stimulation or drug dure, allowing for a tailored resection. This involves elec- directly to the seizure focus to abort the event. trocorticographic recordings made with electrodes on the surface of the brain to identify the extent of epilep- STATUS EPILEPTICUS tiform disturbances. If the region to be resected is within or near brain regions suspected of having senso- Status epilepticus refers to continuous seizures or repeti- rimotor or language function, electrical cortical stimula- tive, discrete seizures with impaired consciousness in the tion mapping is performed on the awake patient to interictal period. Status epilepticus has numerous sub- determine the function of cortical regions in question in types, including generalized convulsive status epilepticus order to avoid resection of so-called eloquent cortex (GCSE) (e.g., persistent, generalized electrographic and thereby minimize postsurgical deficits. seizures, coma, and tonic-clonic movements), and non- convulsive status epilepticus (e.g., persistent absence Advances in presurgical evaluation and microsurgical seizures or partial seizures, confusion or partially impaired techniques have led to a steady increase in the success consciousness, and minimal motor abnormalities). The of epilepsy surgery. Clinically significant complications duration of seizure activity sufficient to meet the defini- of surgery are <5%, and the use of functional mapping tion of status epilepticus has traditionally been specified procedures has markedly reduced the neurologic as 15–30 min. However, a more practical definition is to sequelae due to removal or sectioning of brain tissue. consider status epilepticus as a situation in which the For example, about 70% of patients treated with tempo- duration of seizures prompts the acute use of anticon- ral lobectomy will become seizure-free, and another vulsant therapy. For GCSE, this is typically when 15–25% will have at least a 90% reduction in seizure fre- seizures last beyond 5 min. quency. Marked improvement is also usually seen in patients treated with hemispherectomy for catastrophic GCSE is an emergency and must be treated immediately, seizure disorders due to large hemispheric abnormali- since cardiorespiratory dysfunction, hyperthermia, and ties. Postoperatively, patients generally need to remain metabolic derangements can develop as a consequence on antiepileptic drug therapy, but the marked reduction of prolonged seizures, and these can lead to irreversible of seizures following resective surgery can have a very neuronal injury. Furthermore, CNS injury can occur beneficial effect on quality of life. Recently, focal radio- even when the patient is paralyzed with neuromuscular surgery as emerged as a potential alternative to resec- blockade but continues to have electrographic seizures. tive procedures. The most common causes of GCSE are anticonvulsant withdrawal or noncompliance, metabolic disturbances, Not all medically refractory patients are suitable can- drug toxicity, CNS infection, CNS tumors, refractory didates for resective surgery. For example, some epilepsy, and head trauma. patients have seizures arising from more than one site, making the risk of ongoing seizures or potential harm GCSE is obvious when the patient is having overt from the surgery unacceptably high. Vagus nerve stimu- convulsions. However, after 30–45 min of uninterrupted lation (VNS) may be useful in some of these cases, seizures, the signs may become increasingly subtle. although the benefit for most patients seems to be very Patients may have mild clonic movements of only the limited; i.e., the efficacy of VNS appears to be no greater fingers or fine, rapid movements of the eyes. There may than trying another drug, which rarely works if a patient be paroxysmal episodes of tachycardia, hypertension, and has proved to be refractory to the first two to three pupillary dilation. In such cases, the EEG may be the drugs. The precise mechanism of action of VNS is only method of establishing the diagnosis. Thus, if the unknown, although experimental studies have shown patient stops having overt seizures, yet remains comatose, that stimulation of vagal nuclei leads to widespread an EEG should be performed to rule out ongoing status activation of cortical and subcortical pathways and an

Lorazepam 0.1–0.15 mg/kg IV over 1–2 min Additional emergent drug therapy 243 (repeat x 1 if no response after 5 min) may not be required if seizures stop and the etiology of status FIGURE 20-3 epilepticus is rapidly corrected Pharmacologic treatment of generalized tonic-clonic status epilepticus in adults. Fosphenytoin 20 mg/kg PE IV @ 150 mg/min The horizontal bars indicate the approximate or Phenytoin 20 mg/kg IV @ 50 mg/min duration of drug infusions. IV, intravenous; PE, phenytoin equivalents. Seizures continuing Consider valproate Fosphenytoin 7–10 mg/kg PE IV @ 150 mg/min 25 mg/kg IV in pts. or Phenytoin 7–10 mg/kg IV @ 50 mg/min normally taking Seizures continuing Consider valproate valproate and who may No immediate access to ICU 25 mg/kg IV be subtherapeutic Admit Phenobarbital 20 mg/kg IV @ 60 mg/min CHAPTER 20 Seizures and Epilepsy to ICU Seizures continuing Phenobarbital 10 mg/kg IV @ 60 mg/min IV anesthesia with propofol or midazolam or pentobarbital epilepticus.This is obviously also essential when a patient productive lives. In contrast, patients with seizures sec- with GCSE has been paralyzed with neuromuscular ondary to developmental abnormalities or acquired blockade in the process of protecting the airway. brain injury may have impaired cognitive function and other neurologic deficits. Frequent interictal EEG The first step in the management of a patient in GCSE abnormalities have been shown to be associated with is to attend to any acute cardiorespiratory problems or subtle dysfunction of memory and attention. Patients hyperthermia, perform a brief medical and neurologic with many seizures, especially those emanating from the examination, establish venous access, and send samples for temporal lobe, often note an impairment of short-term laboratory studies to identify metabolic abnormalities. memory that may progress over time. Anticonvulsant therapy should then begin without delay; a treatment approach is shown in Fig. 20-3. Patients with epilepsy are at risk of developing a vari- ety of psychiatric problems, including depression, anxiety, The treatment of nonconvulsive status epilepticus is and psychosis.This risk varies considerably depending on somewhat less urgent than GCSE, since the ongoing many factors, including the etiology, frequency, and seizures are not accompanied by the severe metabolic severity of seizures and the patient’s age and previous disturbances seen with GCSE. However, evidence sug- history. Depression occurs in ~20% of patients, and the gests that nonconvulsive status epilepticus, especially that incidence of suicide is higher in epileptic patients than caused by ongoing, focal seizure activity, is associated in the general population. Depression should be treated with cellular injury in the region of the seizure focus, so through counseling or medication. The selective sero- that the condition should be treated as promptly as pos- tonin reuptake inhibitors typically have no effect on sible using the general approach described for GCSE. seizures, while the tricyclic antidepressants may lower the seizure threshold. Anxiety can appear as a manifesta- BEYOND SEIZURES: OTHER tion of a seizure, and anxious or psychotic behavior can MANAGEMENT ISSUES sometimes be observed as part of a postictal delirium. Postictal psychosis is a rare phenomenon that typically INTERICTAL BEHAVIOR occurs after a period of increased seizure frequency. There is usually a brief lucid interval lasting up to a The adverse effects of epilepsy often go beyond the week, followed by days to weeks of agitated, psychotic occurrence of clinical seizures, and the extent of these behavior. The psychosis will usually resolve sponta- effects largely depends on the etiology of the seizure neously but may require treatment with antipsychotic or disorder, the degree to which the seizures are controlled, anxiolytic medications. and the presence of side effects from antiepileptic ther- apy. Many patients with epilepsy are completely normal There is ongoing controversy as to whether some between seizures and able to live highly successful and patients with epilepsy (especially temporal lobe epilepsy)

SECTION III Diseases of the Central Nervous System244 have a stereotypical “interictal personality.” The predomi- (unless the seizures are not associated with impairment of nant view is that the unusual or abnormal personality consciousness or motor control). In general, most states traits observed in such patients are, in most cases, not due allow patients to drive after a seizure-free interval (on or to epilepsy but result from an underlying structural brain off medications) of between 3 months and 2 years. lesion, the effects of antiepileptic drugs, or psychosocial factors related to suffering from a chronic disease. Patients with incompletely controlled seizures must also contend with the risk of being in situations where MORTALITY OF EPILEPSY an impairment of consciousness or loss of motor control could lead to major injury or death.Thus, depending on Patients with epilepsy have a risk of death that is the type and frequency of seizures, many patients need roughly two to three times greater than expected in a to be instructed to avoid working at heights or with matched population without epilepsy. Most of the machinery, or to have someone close by for activities increased mortality is due to the underlying etiology of such as bathing and swimming. epilepsy, e.g., tumors or strokes in older adults. However, a significant number of patients die from accidents, sta- SPECIAL ISSUES RELATED tus epilepticus, and a syndrome known as sudden unex- TO WOMEN AND EPILEPSY pected death in epileptic patients (SUDEP), which usually affects young people with convulsive seizures and tends CATAMENIAL EPILEPSY to occur at night. The cause of SUDEP is unknown; it may result from brainstem-mediated effects of seizures Some women experience a marked increase in seizure on cardiac rhythms or pulmonary function. frequency around the time of menses.This is thought to reflect either the effects of estrogen and progesterone PSYCHOSOCIAL ISSUES on neuronal excitability or changes in antiepileptic drug levels due to altered protein binding. Acetazo- There continues to be a cultural stigma about epilepsy, lamide (250–500 mg/d) may be effective as adjunctive although it is slowly declining in societies with effective therapy in some cases when started 7–10 days prior to health education programs. Many patients with epilepsy the onset of menses and continued until bleeding stops. harbor fears, such as the fear of becoming mentally Some patients may benefit from increases in antiepilep- retarded or dying during a seizure. These issues need to tic drug dosages during this time or from control of the be carefully addressed by educating the patient about menstrual cycle through the use of oral contraceptives. epilepsy and by ensuring that family members, teachers, Natural progestins may be of benefit to a subset of fellow employees, and other associates are equally well women. informed. The Epilepsy Foundation of America (1-800- EFA-1000) is a patient advocacy organization and a use- PREGNANCY ful source of educational material. Most women with epilepsy who become pregnant will EMPLOYMENT, DRIVING, AND OTHER have an uncomplicated gestation and deliver a normal ACTIVITIES baby. However, epilepsy poses some important risks to a pregnancy. Seizure frequency during pregnancy will Many patients with epilepsy face difficulty in obtaining or remain unchanged in ~50% of women, increase in 30%, maintaining employment, even when their seizures are and decrease in 20%. Changes in seizure frequency are well controlled. Federal and state legislation is designed to attributed to endocrine effects on the CNS, variations in prevent employers from discriminating against patients antiepileptic drug pharmacokinetics (such as acceleration with epilepsy, and patients should be encouraged to of hepatic drug metabolism or effects on plasma protein understand and claim their legal rights. Patients in these binding), and changes in medication compliance. It is use- circumstances also benefit greatly from the assistance of ful to see patients at frequent intervals during pregnancy health providers who act as strong patient advocates. and monitor serum antiepileptic drug levels. Measure- ment of the unbound drug concentrations may be useful Loss of driving privileges is one of the most disruptive if there is an increase in seizure frequency or worsening social consequences of epilepsy. Physicians should be very of side effects of antiepileptic drugs. clear about local regulations concerning driving and epilepsy, since the laws vary considerably among states The overall incidence of fetal abnormalities in children and countries. In all cases, it is the physician’s responsibil- born to mothers with epilepsy is 5–6%, in comparison ity to warn patients of the danger imposed on themselves with 2–3% in healthy women. Part of the higher inci- and others while driving if their seizures are uncontrolled dence is due to teratogenic effects of antiepileptic drugs, and the risk increases with the number of medications

used (e.g., 10% risk of malformations with three drugs).A BREAST-FEEDING 245 syndrome comprising facial dysmorphism, cleft lip, cleft palate, cardiac defects, digital hypoplasia, and nail dysplasia Antiepileptic medications are excreted into breast milk to was originally ascribed to phenytoin therapy, but it is now a variable degree. The ratio of drug concentration in known to occur with other first-line antiepileptic drugs breast milk relative to serum is ~80% for ethosuximide, (i.e., valproic acid and carbamazepine) as well. Also, val- 40–60% for phenobarbital, 40% for carbamazepine, 15% proic acid and carbamazepine are associated with a 1–2% for phenytoin, and 5% for valproic acid. Given the overall incidence of neural tube defects compared with a baseline benefits of breast-feeding and the lack of evidence for of 0.5–1%. Little is currently known about the safety of long-term harm to the infant by being exposed to newer drugs, although very recent reports suggest a antiepileptic drugs, mothers with epilepsy can be encour- higher than expected incidence of cleft lip with the use of aged to breast-feed.This should be reconsidered, however, lamotrigine during pregnancy. if there is any evidence of drug effects on the infant, such as lethargy or poor feeding. Because the potential harm of uncontrolled seizures on the mother and fetus is considered greater than the ter- FURTHER READINGS CHAPTER 20 Seizures and Epilepsy atogenic effects of antiepileptic drugs, it is currently rec- ommended that pregnant women be maintained on BARBARO NM et al: A multicenter, prospective pilot study of gamma effective drug therapy.When possible, it seems prudent to knife radiosurgery for mesial temporal lobe epilepsy: Seizure response, have the patient on monotherapy at the lowest effective adverse events, and verbal memory.Ann Neurol 65:167, 2009. dose, especially during the first trimester. Patients should also take folate (1–4 mg/d), since the antifolate effects of CHANG B, LOWENSTEIN DH: Mechanisms of disease: Epilepsy. N anticonvulsants are thought to play a role in the develop- Engl J Med 349:1257, 2003 ment of neural tube defects, although the benefits of this treatment remain unproved in this setting. CHOI H et al: Epilepsy surgery for pharmacoresistant temporal lobe epilepsy:A decision analysis. JAMA 300:2497, 2008 Enzyme-inducing drugs such as phenytoin, phenobar- bital, and primidone cause a transient and reversible defi- DUNCAN JS et al: Adult epilepsy. Lancet 367:1087, 2006 ciency of vitamin K–dependent clotting factors in ~50% ENSRUD KE et al: Antiepileptic drug use and rates of hip bone loss in of newborn infants. Although neonatal hemorrhage is uncommon, the mother should be treated with oral vita- older men: A prospective study. Neurology 71:723, 2008 min K (20 mg/d) in the last 2 weeks of pregnancy, and FRENCH JA, PEDLEY TA: Clinical practice. Initial management of the infant should receive vitamin K (1 mg) at birth. epilepsy. 359:166, 2008 CONTRACEPTION HARDEN CL et al: Management issues for women with epilepsy- Special care should be taken when prescribing antiepilep- Focus on pregnancy (an evidence-based review): I-III. Teratoge- tic medications for women who are taking oral contracep- nesis and perinatal outcomes: Report of the Quality Standards tive agents. Drugs such as carbamazepine, phenytoin, phe- Subcommittee and Therapeutics and Technology Subcommittee nobarbital, and topiramate can significantly antagonize the of the American Academy of Neurology and the American effects of oral contraceptives via enzyme induction and Epilepsy Society. Epilepsia 50:1229, 2009 other mechanisms. Patients should be advised to consider KARCESKI S et al: Treatment of epilepsy in adults: Expert opinion, alternative forms of contraception, or their contraceptive 2005. Epilepsy Behav 7(Suppl 1):S1, 2005 medications should be modified to offset the effects of the LOCHARERNKUL C et al: Carbamazepine- and phenytoin-induced antiepileptic medications. Stevens-Johnson syndrome is associated with HLA-B∗1502 allele in Thai population. Epilepsia 49:2087, 2008 LOWENSTEIN DH: Treatment options for status epilepticus. Curr Opin Pharmocol 5:334, 2005 LUCIANO AL, SHORVON SD: Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol 62:375, 2007 TAN NC et al: Genetic dissection of the common epilepsies. Curr Opin Neurol 19:157, 2006

CHAPTER 21 CEREBROVASCULAR DISEASES Wade S. Smith I Joey D. English I S. Claiborne Johnston I Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 I Intracranial Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Pathophysiology of Ischemic Stroke . . . . . . . . . . . . . . . . . . . 247 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Etiology of Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Emergency Management . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 Less Common Causes of Stroke . . . . . . . . . . . . . . . . . . . . . 258 Intraparenchymal Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . 276 Transient Ischemic Attacks . . . . . . . . . . . . . . . . . . . . . . . . . . 259 Risk Factors for Ischemic Stroke and TIA . . . . . . . . . . . . . . . 260 I Vascular Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 Primary and Secondary Prevention of Stroke and TIA . . . . . . 260 Congenital Vascular Malformations . . . . . . . . . . . . . . . . . . . . 280 Stroke Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Acquired Vascular Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Imaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Cerebrovascular diseases include some of the most com- and the patient’s symptoms are only transient: this is mon and devastating disorders: ischemic stroke, hemor- called a transient ischemic attack (TIA).The standard defin- rhagic stroke, and cerebrovascular anomalies such as ition of TIA requires that all neurologic signs and symp- intracranial aneurysms and arteriovenous malformations toms resolve within 24 h regardless of whether there is (AVMs). They cause ~200,000 deaths each year in the imaging evidence of new permanent brain injury; stroke United States and are a major cause of disability. The has occurred if the neurologic signs and symptoms last incidence of cerebrovascular diseases increases with age, for >24 h. However, a newly proposed definition classi- and the number of strokes is projected to increase as the fies those with new brain infarction as ischemic strokes elderly population grows, with a doubling in stroke regardless of whether symptoms persist. A generalized deaths in the United States by 2030. Most cerebrovascu- reduction in cerebral blood flow due to systemic lar diseases are manifest by the abrupt onset of a focal hypotension (e.g., cardiac arrhythmia, myocardial infarc- neurologic deficit, as if the patient was “struck by the tion, or hemorrhagic shock) usually produces syncope hand of God.” A stroke, or cerebrovascular accident, is (Chap. 8). If low cerebral blood flow persists for a longer defined by this abrupt onset of a neurologic deficit that duration, then infarction in the border zones between is attributable to a focal vascular cause. Thus, the defini- the major cerebral artery distributions may develop. In tion of stroke is clinical, and laboratory studies including more severe instances, global hypoxia-ischemia causes brain imaging are used to support the diagnosis. The widespread brain injury; the constellation of cognitive clinical manifestations of stroke are highly variable sequelae that ensues is called hypoxic-ischemic encephalopa- because of the complex anatomy of the brain and its thy (Chap. 22). Focal ischemia or infarction, on the other vasculature. Cerebral ischemia is caused by a reduction in hand, is usually caused by thrombosis of the cerebral blood flow that lasts longer than several seconds. Neuro- vessels themselves or by emboli from a proximal arterial logic symptoms are manifest within seconds because source or the heart. Intracranial hemorrhage is caused by neurons lack glycogen, so energy failure is rapid. If the bleeding directly into or around the brain; it produces cessation of flow lasts for more than a few minutes, neurologic symptoms by producing a mass effect on infarction or death of brain tissue results. When blood neural structures, from the toxic effects of blood itself, or flow is quickly restored, brain tissue can recover fully by increasing intracranial pressure. 246

Approach to the Patient: ALGORITHM FOR STROKE AND TIA MANAGEMENT 247 CEREBROVASCULAR DISEASE Stroke or TIA Rapid evaluation is essential for use of time-sensitive ABCs, glucose treatments such as thrombolysis. However, nearly half of patients with acute stroke often do not seek medical Ischemic stroke/ Obtain brain Hemorrhage assistance on their own, both because they are rarely in TIA, 85% imaging 15% pain, as well as because they may lose the appreciation that something is wrong (anosognosia); it is often a Consider thrombolysis/ Consider BP family member or a bystander who calls for help. thrombectomy lowering Therefore, patients and their family members should be counseled to call emergency medical services Establish cause Establish cause immediately if they experience or witness the sudden onset of any of the following: loss of sensory and/or Atrial Carotid Other, Aneurysmal Hyperten- Other, motor function on one side of the body (nearly 85% fibrillation, disease, of ischemic stroke patients have hemiparesis); change in 64% SAH, 4% sive ICH, 7% 4% vision, gait, or ability to speak or understand; or if they 17% 4% experience a sudden, severe headache. Consider Consider Treat Clip or coil Consider Treat CHAPTER 21 Cerebrovascular Diseases There are several common causes of sudden-onset warfarin CEA or specific (Chap. 22) surgery specific neurologic symptoms that may mimic stroke, including cause cause seizure, intracranial tumor, migraine, and metabolic stent encephalopathy. An adequate history from an observer that no convulsive activity occurred at the onset reason- Deep venous thrombosis prophylaxis ably excludes seizure. Tumors may present with acute Physical, occupational, speech therapy neurologic symptoms due to hemorrhage, seizure, or Evaluate for rehab, discharge planning hydrocephalus. Surprisingly, migraine can mimic stroke, Secondary prevention based on disease even in patients without a significant migraine history. When it develops without head pain (acephalgic migraine), FIGURE 21-1 the diagnosis may remain elusive. Patients without any Medical management of stroke and TIA. Rounded boxes prior history of migraine may develop acephalgic are diagnoses; rectangles are interventions. Numbers are migraine even older than 65 years.A sensory disturbance percentages of stroke overall. TIA, transient ischemic attack; is often prominent, and the sensory deficit, as well as any ABCs, airway, breathing, circulation; BP, blood pressure; motor deficits, tends to migrate slowly across a limb over CEA, carotid endarterectomy, SAH, subarachnoid hemor- minutes rather than seconds as with stroke.The diagno- rhage; ICH, intracerebral hemorrhage. sis of migraine becomes more secure as the cortical dis- turbance begins to cross vascular boundaries or if typical endovascular mechanical thrombectomy may be benefi- visual symptoms are present, such as scintillating sco- cial in restoring cerebral perfusion (see Rx: Acute tomata (Chap. 6). At times it may be difficult to make Ischemic Stroke). Medical management to reduce the the diagnosis until multiple episodes have occurred leav- risk of complications becomes the next priority, followed ing behind no residual symptoms and with a normal by plans for secondary prevention. For ischemic stroke, MRI study of the brain. Classically, metabolic several strategies can reduce the risk of subsequent stroke encephalopathies produce fluctuating mental status in all patients, while other strategies are effective for without focal neurologic findings. However, in the set- patients with specific causes of stroke such as cardiac ting of prior stroke or brain injury, a patient with fever embolus and carotid atherosclerosis. For hemorrhagic or sepsis may manifest hemiparesis, which clears rapidly stroke, aneurysmal subarachnoid hemorrhage (SAH) and when the infection is remedied. The metabolic process hypertensive intracranial hemorrhage are two important serves to “unmask” a prior deficit. causes. The treatment and prevention of hypertensive intracranial hemorrhage are discussed later in this Once the diagnosis of stroke is made, a brain imaging chapter. SAH is discussed in Chap. 22. study is necessary to determine if the cause of stroke is ischemia or hemorrhage (Fig. 21-1). CT imaging of the ISCHEMIC STROKE brain is the standard imaging modality to detect the pres- ence or absence of intracranial hemorrhage (see Imaging PATHOPHYSIOLOGY OF ISCHEMIC STROKE Studies, later). If the stroke is ischemic, administration of recombinant tissue plasminogen activator (rtPA) or Acute occlusion of an intracranial vessel causes reduction in blood flow to the brain region it supplies.The magni- tude of flow reduction is a function of collateral blood

248 CASCADE OF CEREBRAL ISCHEMIA Arterial occlusion Ischemia Thrombolysis Reperfusion Energy failure Thrombectomy Glutamate PARP Inflammatory release response Mitochondrial damage Leukocyte adhesion Glutamate Ca2+/Na+ influx Apoptosis Arachidonic acid receptors production Proteolysis Lipolysis iNOS Free radical formation Membrane and Phospholipase FIGURE 21-2 cytoskeletal breakdown Major steps in the cascade of cerebral ischemia. See text for details. PARP, poly-A SECTION III Diseases of the Central Nervous System Cell death ribose polymerase; iNOS, inducible nitric oxide synthase. flow and this depends on individual vascular anatomy as are seen within the ischemic penumbra, favor apop- and the site of occlusion. A fall in cerebral blood flow to totic cellular death causing cells to die days to weeks zero causes death of brain tissue within 4–10 min; values later. Fever dramatically worsens ischemia, as does hyper- <16–18 mL/100 g tissue per min cause infarction within glycemia [glucose >11.1 mmol/L (200 mg/dL)], so it is an hour; and values <20 mL/100 g tissue per min cause reasonable to suppress fever and prevent hyperglycemia as ischemia without infarction unless prolonged for several much as possible. Induced moderate hypothermia to mit- hours or days. If blood flow is restored prior to a signifi- igate stroke is the subject of continuing clinical research. cant amount of cell death, the patient may experience only transient symptoms, i.e., a TIA. Tissue surrounding Treatment: the core region of infarction is ischemic but reversibly ACUTE ISCHEMIC STROKE dysfunctional and is referred to as the ischemic penumbra. The penumbra may be imaged by using perfusion- After the clinical diagnosis of stroke is made, an orderly diffusion imaging with MRI (see later and Fig. 21-16). process of evaluation and treatment should follow The ischemic penumbra will eventually infarct if no (Fig. 21-1). The first goal is to prevent or reverse brain change in flow occurs, and hence saving the ischemic injury. Attend to the patient’s airway, breathing, circula- penumbra is the goal of revascularization therapies. tion, and treat hypoglycemia or hyperglycemia if identi- fied. Perform an emergency noncontrast head CT scan in Focal cerebral infarction occurs via two distinct path- order to differentiate between ischemic stroke and hem- ways (Fig. 21-2): (1) a necrotic pathway in which cellu- orrhagic stroke; there are no reliable clinical findings that lar cytoskeletal breakdown is rapid, due principally to conclusively separate ischemia from hemorrhage, energy failure of the cell; and (2) an apoptotic pathway in although a more depressed level of consciousness, which cells become programmed to die. Ischemia pro- higher initial blood pressure, or worsening of symptoms duces necrosis by starving neurons of glucose, which in after onset favor hemorrhage, and a deficit that remits turn results in failure of mitochondria to produce ATP. suggests ischemia. Treatments designed to reverse or Without ATP, membrane ion pumps stop functioning lessen the amount of tissue infarction and improve clini- and neurons depolarize, allowing intracellular calcium to cal outcome fall within six categories: (1) medical sup- rise. Cellular depolarization also causes glutamate release port (2) intravenous thrombolysis, (3) endovascular from synaptic terminals; excess extracellular glutamate techniques, (4) antithrombotic treatment, (5) neuropro- produces neurotoxicity by activating postsynaptic gluta- tection, and (6) stroke centers and rehabilitation. mate receptors that increase neuronal calcium influx. Free radicals are produced by membrane lipid degrada- MEDICAL SUPPORT When ischemic stroke occurs, tion and mitochondrial dysfunction. Free radicals cause the immediate goal is to optimize cerebral perfusion in catalytic destruction of membranes and likely damage the surrounding ischemic penumbra. Attention is also other vital functions of cells. Lesser degrees of ischemia,

directed toward preventing the common complications 60 min) vs. placebo in patients with ischemic stroke 249 of bedridden patients—infections (pneumonia, urinary within 3 h of onset. Half of the patients were treated tract, and skin) and deep venous thrombosis (DVT) with within 90 min. Symptomatic intracerebral hemorrhage CHAPTER 21 Cerebrovascular Diseases pulmonary embolism. Many physicians use pneumatic occurred in 6.4% of patients on rtPA and 0.6% on compression stockings to prevent DVT; subcutaneous placebo. There was a nonsignificant 4% reduction in heparin appears to be safe as well and can be used mortality in patients on rtPA (21% on placebo and concomitantly. 17% on rtPA); there was a significant 12% absolute increase in the number of patients with only minimal Because collateral blood flow within the ischemic disability (32% on placebo and 44% on rtPA.) Thus, brain is blood pressure dependent, there is controversy despite an increased incidence of symptomatic about whether blood pressure should be lowered intracerebral hemorrhage, treatment with IV rtPA acutely. Blood pressure should be lowered if there is within 3 h of the onset of ischemic stroke improved malignant hypertension or concomitant myocardial clinical outcome. ischemia or if blood pressure is >185/110 mmHg and thrombolytic therapy is anticipated. When faced with Results of other trials of rtPA have been negative, per- the competing demands of myocardium and brain, low- haps because of the dose of rtPA and timing of its deliv- ering the heart rate with a β1-adrenergic blocker (such ery. The European Cooperative Acute Stroke Study as esmolol) can be a first step to decrease cardiac work (ECASS) I used a higher dose of rtPA (1.2 mg/kg), and and maintain blood pressure. Fever is detrimental and ECASS-II tested the NINDS dose of rtPA (0.9 mg/kg; max- should be treated with antipyretics and surface cooling. imum dose, 90 mg) but allowed patients to receive drug Serum glucose should be monitored and kept at <6.1 up to the sixth hour. No significant benefit was found, mmol/L (110 mg/dL) using an insulin infusion. but improvement was found in post hoc analyses. ATLANTIS tested the NINDS dosing of rtPA between 3 Between 5 and 10% of patients develop enough and 5 h and found no benefit. Because of the marked cerebral edema to cause obtundation or brain hernia- differences in trial design, including drug and dose used, tion. Edema peaks on the second or third day but can time to thrombolysis, and severity of stroke, the precise cause mass effect for ~10 days. The larger the infarct, the efficacy of IV thrombolytics for acute ischemic stroke greater the likelihood that clinically significant edema remains unclear. The risk of intracranial hemorrhage will develop. Water restriction and IV mannitol may be appears to rise with larger strokes, longer times from used to raise the serum osmolarity, but hypovolemia onset of symptoms, and higher doses of rtPA adminis- should be avoided as this may contribute to hypoten- tered. The established dose of 0.9 mg/kg administered sion and worsening infarction. Combined analysis of IV within 3 h of stroke onset appears safe. The ECASS-III three randomized European trials of hemicraniectomy trial established efficacy of IV tPA in a 4.5-h window, (craniotomy and temporary removal of part of the skull) although with less robust results compared to 3-hour shows that this procedure markedly reduces mortality, trials. When data from all randomized IV rtPA trails are and the clinical outcomes of survivors are acceptable. combined, efficacy is confirmed in the <3-h time win- dow, and efficacy likely extends to 4.5 h. One may be Special vigilance is warranted for patients with cere- able to select patients beyond the usual time windows bellar infarction. Such strokes may mimic labyrinthitis who will benefit from thrombolysis using advanced because of prominent vertigo and vomiting; the pres- neuroimaging (see neuroimaging section later), but this ence of head or neck pain should alert the physician to is currently investigational. The drug is now approved in consider cerebellar stroke from vertebral artery dissec- the United States, Canada, and Europe for acute stroke tion. Even small amounts of cerebellar edema can when given within 3 h from the time the stroke symp- acutely increase intracranial pressure (ICP) or directly toms began, and efforts should be made to give it as compress the brainstem. The resulting brainstem com- early in this 3-h window as possible. The time of stroke pression can result in coma and respiratory arrest and onset is defined as the time the patient’s symptoms require emergency surgical decompression. Prophylac- began or the time the patient was last seen as normal. tic suboccipital decompression of large cerebellar Patients who awaken with stroke have the onset infarcts before brainstem compression, although not defined as when they went to bed. Table 21-1 summa- tested rigorously in a clinical trial, is practiced at most rizes eligibility criteria and instructions for administra- stroke centers. tion of IV rtPA. INTRAVENOUS THROMBOLYSIS The National ENDOVASCULAR TECHNIQUES Ischemic stroke Institute of Neurological Disorders and Stroke (NINDS) from large-vessel intracranial occlusion results in high recombinant tPA (rtPA) Stroke Study showed a clear rates of mortality and morbidity. Occlusions in such benefit for IV rtPA in selected patients with acute large vessels [middle cerebral artery (MCA), internal stroke. The NINDS study used IV rtPA (0.9 mg/kg to a 90-mg max; 10% as a bolus, then the remainder over

250 TABLE 21-1 ADMINISTRATION OF INTRAVENOUS RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR (rtPA) FOR ACUTE ISCHEMIC STROKEa INDICATION CONTRAINDICATION Clinical diagnosis of stroke Sustained BP >185/110 despite treatment Onset of symptoms to time Platelets <100,000; HCT <25%; glucose <50 or of drug administration Յ3 h >400 mg/dL CT scan showing no hemorrhage Use of heparin within 48 h and prolonged PTT, or edema of >1/3 of the MCA territory Age Ն18 years or elevated INR Consent by patient or surrogate Rapidly improving symptoms Prior stroke or head injury within 3 months; prior Administration of rtPA intracranial hemorrhage Major surgery in preceding 14 days Minor stroke symptoms Gastrointestinal bleeding in preceding 21 days Recent myocardial infarction Coma or stupor SECTION III Diseases of the Central Nervous System Intravenous access with two peripheral IV lines (avoid arterial or central line placement) Review eligibility for rtPA Administer 0.9 mg/kg intravenously (maximum 90 mg) IV as 10% of total dose by bolus, followed by remainder of total dose over 1 h Frequent cuff blood pressure monitoring No other antithrombotic treatment for 24 h For decline in neurologic status or uncontrolled blood pressure, stop infusion, give cryoprecipitate, and reimage brain emergently Avoid urethral catheterization for Ն2 h aSee Activase (tissue plasminogen activator) package insert for complete list of contraindications and dosing. Note: BP, blood pressure; HCT, hematocrit; INR, international normalized ratio; MCA, middle cerebral artery; PTT, partial thromboplastin time. carotid artery, and the basilar artery] generally involve a device to restore patency of occluded intracranial ves- large clot volume and often fail to open with IV rtPA sels within 8 h of ischemic stroke symptoms. Recanal- alone. Therefore, there is growing interest in using ization of the target vessel occurred in 48% of treated thrombolytics via an intraarterial route to increase the patients and in 60% following use of adjuvant endovas- concentration of drug at the clot and minimize systemic cular methods, and successful recanalization at 90 days bleeding complications. The Prolyse in Acute Cerebral correlated well with favorable outcome. Based upon Thromboembolism (PROACT) II trial found benefit for these nonrandomized data, the FDA approved this intraarterial pro-urokinase for acute MCA occlusions up device for revascularization of occluded vessels in acute to the sixth hour following onset of stroke. Intra-arterial ischemic stroke within 8 h of symptom onset. Recent treatment of basilar artery occlusions may also be trials have shown that it is safe to use this technique beneficial for selected patients. Intra-arterial administration even in patients who have been given IV rtPA yet have of a thrombolytic agent for acute ischemic stroke is not failed to recanalize. Such a strategy allows primary approved by the U.S. Food and Drug Administration stroke centers to administer rtPA to eligible patients, (FDA); however, many stroke centers offer this treatment then rapidly refer such patients to comprehensive based on these data. stroke centers that have endovascular capability. Endovascular mechanical thrombectomy has ANTITHROMBOTIC TREATMENT recently shown promise as an alternative treatment of Platelet Inhibition Aspirin is the only antiplatelet acute stroke in patients who are ineligible for, or have agent that has been proven effective for the acute contraindications to, thrombolytics or in those who have treatment of ischemic stroke; there are several failed to have vascular recanalization with IV throm- antiplatelet agents proven for the secondary prevention bolytics (Fig. 21-15). The MERCI (Mechanical Embolus of stroke (see later). Two large trials, the International Removal in Cerebral Ischemia) single-arm trial investi- Stroke Trial (IST) and the Chinese Acute Stroke Trial gated the ability of a novel endovascular thrombectomy

(CAST), found that the use of aspirin within 48 h of STROKE CENTERS AND REHABILITATION 251 stroke onset reduced both stroke recurrence risk and Patient care in comprehensive stroke units followed by mortality minimally. Among 19,435 patients in IST, those rehabilitation services improves neurologic outcomes CHAPTER 21 Cerebrovascular Diseases allocated to aspirin, 300 mg/d, had slightly fewer deaths and reduces mortality. Use of clinical pathways and staff within 14 days (9.0 vs. 9.4%), significantly fewer dedicated to the stroke patient can improve care. Stroke recurrent ischemic strokes (2.8 vs. 3.9%), no excess of teams that provide emergency 24-h evaluation of acute hemorrhagic strokes (0.9 vs. 0.8%), and a trend toward stroke patients for acute medical management and a reduction in death or dependence at 6 months (61.2 consideration of thrombolysis or endovascular treatments vs. 63.5%). In CAST, 21,106 patients with ischemic stroke are important. received 160 mg/d of aspirin or a placebo for up to 4 weeks. There were very small reductions in the aspirin Proper rehabilitation of the stroke patient includes group in early mortality (3.3 vs. 3.9%), recurrent ischemic early physical, occupational, and speech therapy. It is strokes (1.6 vs. 2.1%), and dependency at discharge or directed toward educating the patient and family about death (30.5 vs. 31.6%). These trials demonstrate that the the patient’s neurologic deficit, preventing the compli- use of aspirin in the treatment of acute ischemic stroke cations of immobility (e.g., pneumonia, DVT and pulmonary is safe and produces a small net benefit. For every 1000 embolism, pressure sores of the skin, and muscle con- acute strokes treated with aspirin, about 9 deaths or tractures), and providing encouragement and instruc- nonfatal stroke recurrences will be prevented in the first tion in overcoming the deficit. The goal of rehabilitation few weeks and ~13 fewer patients will be dead or is to return the patient to home and to maximize recov- dependent at 6 months. ery by providing a safe, progressive regimen suited to the individual patient. Additionally, the use of restraint The glycoprotein IIb/IIIa receptor inhibitor abciximab therapy (immobilizing the unaffected side) has been held promise as an acute treatment, but a recent clinical shown to improve hemiparesis following stroke, even trial was stopped because of excess intracranial hemor- years following the stroke, suggesting that physical ther- rhage. apy can recruit unused neural pathways. This finding suggests that the human nervous system is more adapt- Anticoagulation Numerous clinical trials have able than originally thought and has stimulated active failed to demonstrate any benefit of anticoagulation in research into physical and pharmacologic strategies the primary treatment of atherothrombotic cerebral that can enhance long-term neural recovery. ischemia. Several trials have investigated antiplatelet versus anticoagulant medications given within 12–24 h ETIOLOGY OF ISCHEMIC STROKE of the initial event. The U.S. Trial of Organon 10172 in Acute Stroke Treatment (TOAST), an investigational low- (Figs. 21-1 and 21-3 and Table 21-2) Although the molecular-weight heparin, failed to show any benefit initial management of acute ischemic stroke often does over aspirin. Use of SC unfractionated heparin versus not depend on the etiology, establishing a cause is essen- aspirin was tested in IST. Heparin given SC afforded no tial in reducing the risk of recurrence. Particular focus additional benefit over aspirin and increased bleeding should be on atrial fibrillation and carotid atherosclero- rates. Several trials of low-molecular-weight heparins sis, as these etiologies have proved secondary prevention have also shown no consistent benefit in acute ischemic strategies. The clinical presentation and examination stroke. Furthermore, trials generally have shown an findings often establish the cause of stroke or narrow the excess risk of brain and systemic hemorrhage with acute possibilities to a few. Judicious use of laboratory testing anticoagulation. Therefore, trials do not support the use and imaging studies completes the initial evaluation. of heparin or other anticoagulants for patients with Nevertheless, nearly 30% of strokes remain unexplained atherothrombotic stroke. despite extensive evaluation. NEUROPROTECTION Neuroprotection is the con- Clinical examination should focus on the peripheral cept of providing a treatment that prolongs the brain’s and cervical vascular system (carotid auscultation for tolerance to ischemia. Drugs that block the excitatory bruits, blood pressure, and pressure comparison between amino acid pathways have been shown to protect arms), the heart (dysrhythmia, murmurs), extremities neurons and glia in animals, but despite multiple clinical (peripheral emboli), and retina [effects of hypertension trials, they have not yet been proven to be beneficial in and cholesterol emboli (Hollenhorst plaques)]. A com- humans. Hypothermia is a powerful neuroprotective plete neurologic examination is performed to localize treatment in patients with cardiac arrest (Chap. 22) and the site of stroke. An imaging study of the brain is nearly is neuroprotective in animal models of stroke, but it has always indicated and is required for patients being con- not been adequately studied in patients with ischemic sidered for thrombolysis; it may be combined with CT- stroke. or MRI-based angiography to interrogate the neck and

252 Intracranial Penetrating atherosclerosis artery disease Carotid Flow Internal plaque with reducing carotid arteriogenic carotid emboli stenosis External carotid Cardiogenic Atrial fibrillation emboli Common Valve disease carotid SECTION III Diseases of the Central Nervous System AB C Left ventricular thrombi major intracranial arteries; (3) hypoperfusion caused by flow- limiting stenosis of a major extracranial (e.g., internal carotid) FIGURE 21-3 or intracranial vessel, often producing “watershed” ischemia. Pathophysiology of ischemic stroke. A. Diagram illustrat- B and C. Diagram and reformatted CT angiogram of the ing the three major mechanisms that underlie ischemic common, internal, and external carotid arteries. High-grade stroke: (1) occlusion of an intracranial vessel by an embolus stenosis of the internal carotid artery, which may be associ- that arises at a distant site (e.g., cardiogenic sources such as ated with either cerebral emboli or flow-limiting ischemia, atrial fibrillation or artery-to-artery emboli from carotid ather- was identified in this patient. osclerotic plaque), often affecting the large intracranial ves- sels; (2) in situ thrombosis of an intracranial vessel, typically affecting the small penetrating arteries that arise from the intracranial vessels (see Imaging Studies, later). A chest the ischemic territory. This is usually of no clinical sig- x-ray, electrocardiogram (ECG), urinalysis, complete nificance and should be distinguished from frank blood count, erythrocyte sedimentation rate, serum intracranial hemorrhage into a region of ischemic stroke electrolytes, blood urea nitrogen, creatinine, blood sugar, where the mass effect from the hemorrhage can cause a serologic test for syphilis, serum lipid profile, prothrom- decline in neurologic function. bin time, and partial thromboplastin time (PTT) are often useful and should be considered in all patients. An Emboli from the heart most often lodge in the MCA, ECG may demonstrate arrhythmias or reveal evidence the posterior cerebral artery (PCA), or one of their of recent myocardial infarction (MI). branches; infrequently, the anterior cerebral artery (ACA) territory is involved. Emboli large enough to occlude the Cardioembolic Stroke stem of the MCA (3–4 mm) lead to large infarcts that involve both deep gray and white matter and some por- Cardioembolism is responsible for ~20% of all ischemic tions of the cortical surface and its underlying white strokes. Stroke caused by heart disease is primarily due matter.A smaller embolus may occlude a small cortical or to embolism of thrombotic material forming on the penetrating arterial branch. The location and size of an atrial or ventricular wall or the left heart valves. These infarct within a vascular territory depend on the extent thrombi then detach and embolize into the arterial cir- of the collateral circulation. culation. The thrombus may fragment or lyse quickly, producing only a TIA. Alternatively, the arterial occlu- The most significant causes of cardioembolic stroke sion may last longer, producing stroke. Embolic strokes in most of the world are nonrheumatic (often called tend to be sudden in onset, with maximum neurologic nonvalvular) atrial fibrillation, MI, prosthetic valves, deficit at once. With reperfusion following more pro- rheumatic heart disease, and ischemic cardiomyopathy longed ischemia, petechial hemorrhage can occur within (Table 21-2). Cardiac disorders causing brain embolism are discussed in the respective chapters on heart diseases. A few pertinent aspects are highlighted here.

TABLE 21-2 253 CAUSES OF ISCHEMIC STROKE UNCOMMON CAUSES CHAPTER 21 Cerebrovascular Diseases COMMON CAUSES Hypercoagulable disorders Protein C deficiency Thrombosis Protein S deficiency Lacunar stroke (small vessel) Antithrombin III deficiency Large vessel thrombosis Antiphospholipid syndrome Dehydration Factor V Leiden mutationa Prothrombin G20210 mutationa Embolic occlusion Systemic malignancy Artery-to-artery Sickle cell anemia Carotid bifurcation β-Thalassemia Aortic arch Polycythemia vera Arterial dissection Systemic lupus erythematosus Cardioembolic Homocysteinemia Atrial fibrillation Thrombotic thrombocytopenic purpura Mural thrombus Disseminated intravascular coagulation Myocardial infarction Dysproteinemias Dilated cardiomyopathy Nephrotic syndrome Valvular lesions Inflammatory bowel disease Mitral stenosis Oral contraceptives Mechanical valve Bacterial endocarditis Venous sinous thrombosisb Paradoxical embolus Fibromuscular dysplasia Atrial septal defect Vasculitis Patent foramen ovale Atrial septal aneurysm Systemic vasculitis (PAN, Wegener’s, Spontaneous echo contrast Takayasu’s, giant cell arteritis) Primary CNS vasculitis Meningitis (syphilis, tuberculosis, fungal, bacterial, zoster) Cardiogenic Mitral valve calcification Atrial myxoma Intracardiac tumor Marantic endocarditis Libman-Sacks endocarditis Subarachnoid hemorrhage vasospasm Drugs: cocaine, amphetamine Moyamoya disease Eclampsia aChiefly cause venous sinus thrombosis. bMay be associated with any hypercoagulable disorder. Note: CNS, central nervous system; PAN, polyarteritis nodosa. Nonrheumatic atrial fibrillation is the most common formation of atrial thrombi. Rheumatic heart disease usu- cause of cerebral embolism overall. The presumed stroke ally causes ischemic stroke when there is prominent mitral mechanism is thrombus formation in the fibrillating stenosis or atrial fibrillation. Guidelines for the use of war- atrium or atrial appendage, with subsequent embolization. farin and aspirin for secondary prevention are based on Patients with atrial fibrillation have an average annual risk risk factors (Table 21-3). of stroke of ~5%.The risk varies according to the presence of certain risk factors, including older age, hypertension, Recent MI may be a source of emboli, especially poor left ventricular function, prior cardioembolism, mitral when transmural and involving the anteroapical ventric- stenosis, prosthetic heart valve, or diabetes. Patients <65 ular wall, and prophylactic anticoagulation following MI years with none of these risk factors have an annual risk has been shown to reduce stroke risk. Mitral valve pro- for stroke of ~0.5%, while those with most of the factors lapse is not usually a source of emboli unless the prolapse have a rate of ~15% per year. Left atrial enlargement and is severe. congestive heart failure are additional risk factors for Paradoxical embolization occurs when venous thrombi migrate to the arterial circulation, usually via a patent

254 TABLE 21-3 acutely thrombose; the resulting blockage causes stroke by producing ischemia within the region of brain it sup- CONSENSUS RECOMMENDATION FOR ANTITHROMBOTIC plied. Unlike the myocardial vessels, artery-to-artery PROPHYLAXIS IN ATRIAL FIBRILLATION embolism, rather than local thrombosis, appears to be the dominant vascular mechanism causing ischemia. Any AGE RISK FACTORSa RECOMMENDATION diseased vessel may be a source, including the aortic arch, common carotid, internal carotid, vertebral, and Յ65 years Ն1 Warfarin INR 2–3 basilar arteries. Carotid bifurcation atherosclerosis is the 65–75 years 0 Aspirin most common source of artery-to-artery embolus, and >75 years Ն1 Warfarin INR 2–3 specific treatments have proven efficacy in reducing risk. 0 Warfarin INR 2–3 or aspirin Warfarin INR 2–3 Carotid Atherosclerosis Atherosclerosis within the carotid artery occurs most aRisk factors include previous transient ischemic attack or stroke, frequently within the common carotid bifurcation and hypertension, heart failure, diabetes, systemic embolism, mitral steno- proximal internal carotid artery. Additionally, the carotid sis, or prosthetic heart valve. siphon (portion within the cavernous sinus) is also vul- Source: Modified from DE Singer et al: Antithrombotic therapy in nerable to atherosclerosis. Male gender, older age, smok- atrial fibrillation. Chest 126:429S, 2004; with permission. ing, hypertension, diabetes, and hypercholesterolemia are risk factors for carotid disease, as they are for stroke in SECTION III Diseases of the Central Nervous System foramen ovale or atrial septal defect. Bubble-contrast general (Table 21-4). Carotid atherosclerosis produces echocardiography (IV injection of agitated saline coupled an estimated 10% of ischemic stroke. with either transthoracic or transesophageal echocardiog- raphy) can demonstrate a right-to-left cardiac shunt, Carotid disease can be classified by whether the revealing the conduit for paradoxical embolization. Alter- stenosis is symptomatic or asymptomatic and by the natively, a right-to-left shunt is implied if immediately degree of stenosis (percent narrowing of the narrowest following IV injection of agitated saline, the ultrasound segment compared to a more distal internal carotid seg- signature of bubbles is observed during transcranial ment). Symptomatic carotid disease implies that the Doppler insonation of the MCA; pulmonary AVMs patient has experienced a stroke or TIA within the vas- should be considered if this test is positive yet an echocar- cular distribution of the artery, and it is associated with a diogram fails to reveal an intracardiac shunt. Both tech- greater risk of subsequent stroke than asymptomatic niques are highly sensitive for detection of right-to-left stenosis, in which the patient is symptom free and the shunts. Besides venous clot, fat and tumor emboli, bacte- stenosis is detected through screening. Greater degrees rial endocarditis, IV air, and amniotic fluid emboli at of arterial narrowing are generally associated with a childbirth may occasionally be responsible for paradoxi- greater risk of stroke, except that those with near occlu- cal embolization. The importance of right-to-left shunt sions are at lower risk of stroke. as a cause of stroke is debated, particularly because such shunts are present in ~15% of the general population. Treatment: Some studies have suggested that the risk is only ele- CAROTID ATHEROSCLEROSIS vated in the presence of a coexisting atrial septal aneurysm. The presence of a venous source of embolus, Carotid atherosclerosis can be removed surgically most commonly a deep venous thrombus, may provide (endarterectomy) or mitigated with endovascular stent- confirmation of the importance of a right-to-left shunt ing with or without balloon angioplasty. in a particular case. SURGICAL THERAPY Symptomatic carotid stenosis Bacterial endocarditis can cause valvular vegetations was studied in the North American Symptomatic that can give rise to septic emboli. The appearance of Carotid Endarterectomy Trial (NASCET) and the multifocal symptoms and signs in a patient with stroke European Carotid Surgery Trial (ECST). Both showed a makes bacterial endocarditis more likely. Infarcts of substantial benefit for surgery in patients with a stenosis microscopic size occur, and large septic infarcts may of Ն70%. In NASCET, the average cumulative ipsilateral evolve into brain abscesses or cause hemorrhage into the stroke risk at 2 years was 26% for patients treated infarct, which generally precludes use of anticoagulation medically and 9% for those receiving the same medical or thrombolytics. Mycotic aneurysms caused by septic treatment plus a carotid endarterectomy. This 17% emboli give rise to SAH or intracerebral hemorrhage. absolute reduction in the surgical group is a 65% relative risk reduction favoring surgery (Table 21-4). NASCET also Artery-to-Artery Embolic Stroke showed a significant, although less robust, benefit for Thrombus formation on atherosclerotic plaques may embolize to intracranial arteries producing an artery-to- artery embolic stroke. Alternatively, a diseased vessel may

TABLE 21-4 255 RISK FACTORS FOR STROKE NUMBER NEEDED TO TREATa RISK FACTOR RELATIVE RISK RELATIVE RISK REDUCTION PRIMARY SECONDARY WITH TREATMENT PREVENTION PREVENTION Hypertension 2–5 Atrial fibrillation 1.8–2.9 38% 100–300 50–100 Diabetes 1.8–6 68% warfarin, 21% aspirin 20–83 13 Smoking 1.8 No proven effect 50% at 1 year, baseline risk at 560 230 Hyperlipidemia 1.8–2.6 5 years post cessation 85 N/A Asymptomatic carotid 2.0 16–30% 53% N/A 12 stenosis Symptomatic carotid 65% at 2 years N/A 77 stenosis (70–99%) 29% at 5 years Symptomatic carotid stenosis (50–69%) CHAPTER 21 Cerebrovascular Diseases aNumber needed to treat to prevent one stroke annually. Prevention of other cardiovascular outcomes is not considered here. Note: N/A, not applicable. patients with 50–70% stenosis. ECST found harm for risk reduction is only 5.9% over 5 years, or 1.2% annually patients with stenosis <30% treated surgically. (Table 21-4). Nearly half of the strokes in the surgery group were caused by preoperative angiograms. The A patient’s risk of stroke and possible benefit from recently published ACST randomized 3120 asympto- surgery are related to the presence of retinal versus matic patients with >60% carotid stenosis to hemispheric symptoms, degree of arterial stenosis, endarterectomy or medical therapy. The 5-year risk of extent of associated medical conditions (of note, stroke in the surgical group (including perioperative NASCET and ECST excluded “high-risk” patients with stroke or death) was 6.4%, in comparison with 11.8% in significant cardiac, pulmonary, or renal disease), institu- the medically treated group (46% relative risk reduction tional surgical morbidity and mortality, timing of and 5.4% absolute risk reduction). surgery relative to symptoms, and other factors. A recent meta-analysis of the NASCET and ECST trials demon- In both ACAS and ACST, the perioperative complication strated that endarterectomy is most beneficial when rate was higher in women, perhaps negating any benefit performed within 2 weeks of symptom onset. In addi- in the reduction of stroke risk within 5 years. It is possible tion, benefit is more pronounced in patients >75 years, that with longer follow-up, a clear benefit in women will and men appear to benefit more than women. emerge. At present, carotid endarterectomy in asympto- matic women remains particularly controversial. In summary, a patient with recent symptomatic hemi- spheric ischemia, high-grade stenosis in the appropriate In summary, the natural history of asymptomatic internal carotid artery, and an institutional perioperative stenosis is a ~2% per year stroke rate, while sympto- morbidity and mortality rate of Յ6% generally should matic patients experience a 13% per year risk of stroke. undergo carotid endarterectomy. If the perioperative Whether to recommend carotid revascularization for an stroke rate is >6% for any particular surgeon, however, asymptomatic patient is somewhat controversial and the benefits of carotid endarterectomy are questionable. depends on many factors, including patient preference, degree of stenosis, age, gender, and comorbidities. Med- The indications for surgical treatment of asympto- ical therapy for reduction of atherosclerosis risk factors, matic carotid disease have been clarified by the results of including cholesterol-lowering agents and antiplatelet the Asymptomatic Carotid Atherosclerosis Study (ACAS) medications, is generally recommended for patients and the Asymptomatic Carotid Surgery Trial (ACST). with asymptomatic carotid stenosis. As with atrial fibril- ACAS randomized asymptomatic patients with Ն60% lation, it is imperative to counsel the patient about TIAs stenosis to medical treatment with aspirin or the same so that therapy can be revised if symptoms develop. medical treatment plus carotid endarterectomy. The sur- gical group had a risk over 5 years for ipsilateral stroke ENDOVASCULAR THERAPY Balloon angioplasty (and any perioperative stroke or death) of 5.1%, com- coupled with stenting is being used with increasing pared to a risk in the medical group of 11%. While this frequency to open stenotic carotid arteries and maintain demonstrates a 53% relative risk reduction, the absolute

SECTION III Diseases of the Central Nervous System256 their patency. These techniques can treat carotid of patients on aspirin experienced major hemorrhage, compared to 8.3% of patients taking warfarin. stenosis not only at the bifurcation but also near the skull base and in the intracranial segments.The SAPPHIRE Given the worrisome natural history of symptomatic trial (Stenting and Angioplasty with Protection in intracranial atherosclerosis (in the aspirin arm of the Patients at High Risk for Endarterectomy) randomized WASID trial, 15% of patients experienced a stroke high-risk patients (defined as patients with clinically within the first year, despite current standard aggressive significant coronary or pulmonary disease, contralateral medical therapy), some centers treat symptomatic lesions carotid occlusion, restenosis after endarterectomy, with intracranial angioplasty and stenting.This interven- contralateral laryngeal-nerve palsy, prior radical neck tion has not been compared with medical therapy for surgery or radiation, or age >80) with symptomatic stroke prevention in this patient population, but such carotid stenosis >50% or asymptomatic stenosis >80% clinical trials will likely be conducted in the near future. to either stenting combined with a distal emboli- Likewise, it is unclear whether EC-IC bypass, or other protection device or endarterectomy. The risk of death, grafting procedures of extracranial blood supply to the stroke, or MI within 30 days and ipsilateral stroke or pial arteries, is of value in such patients. death within 1 year was 12.2% in the stenting group and 20.1% in the endarterectomy group (p = .055), Dissection of the internal carotid or vertebral arteries suggesting that stenting is at the very least comparable or even vessels beyond the circle of Willis is a common to endarterectomy as a treatment option for this patient source of embolic stroke in young (<60 years) patients. group at high risk of surgery. However, the outcomes The dissection is usually painful and precedes the stroke with both interventions may not have been better than by several hours or days. Extracranial dissections do not leaving the carotid stenoses untreated, particularly for cause hemorrhage because of the tough adventitia of the asymptomatic patients, and much of the benefit these vessels. Intracranial dissections, on the other hand, seen in the stenting group was due to a reduction in may produce SAH because the adventitia of intracranial peri-procedure MI. Multicenter trials are currently vessels is thin and pseudoaneurysms may form, requiring underway comparing stenting with endarterectomy in treatment to prevent rerupture. Treating asymptomatic lower-risk patients, the population previously studied in pseudoaneurysms following dissection is controversial. the NASCET, ECST, ACAS, and ACST trials (see above). The cause of dissection is usually unknown and recur- rence is rare. Ehlers-Danlos type IV, Marfan’s disease, BYPASS SURGERY Extracranial-to-intracranial (EC-IC) cystic medial necrosis, and fibromuscular dysplasia are bypass surgery has been proven ineffective for atheroscle- associated with dissections. Trauma (usually a motor rotic stenoses that are inaccessible to conven-tional vehicle accident or a sports injury) can cause carotid and carotid endarterectomy. However, a trial is underway to vertebral artery dissections. Spinal manipulative therapy evaluate whether patients with decreased brain is independently associated with vertebral artery dissec- perfusion based on positron emission tomography (PET) tion and stroke. Most dissections heal spontaneously, and imaging will benefit from EC-IC bypass. stroke or TIA is uncommon beyond 2 weeks. Although there are no trials comparing anticoagulation to Other Causes of Artery-to-Artery antiplatelet agents, many physicians treat acutely with Embolic Stroke anticoagulants for 3–6 months then convert to 6–9 Intracranial atherosclerosis produces stroke either by an months of antiplatelet therapy after demonstration of embolic mechanism or by in situ thrombosis of a diseased vascular recanalization; a recent observational study ques- vessel. It is more common in patients of Asian and tioned the superiority of anticoagulants versus antiplatelets African-American descent. The WASID (Warfarin- in carotid dissection. Aspirin Symptomatic Intracranial Disease) trial random- ized patients with symptomatic stenosis (50–99%) of a Small-Vessel Stroke major intracranial vessel to either high-dose aspirin (1300 mg/d) or warfarin (target INR, 2.0–3.0), with a com- The term lacunar infarction refers to infarction following bined primary endpoint of ischemic stroke, brain hemor- atherothrombotic or lipohyalinotic occlusion of a small rhage, or death from vascular cause other than stroke.The artery (30–300 μm) in the brain. The term small-vessel trial was terminated early because of an increased risk of stroke denotes occlusion of such a small penetrating adverse events related to warfarin anticoagulation. With a artery and is now the preferred term. Small-vessel mean follow-up of 1.8 years, the primary endpoint was strokes account for ~20% of all strokes. seen in 22.1% in the aspirin group and 21.8% of the war- farin group. Death from any cause was seen in 4.3% of Pathophysiology the aspirin group and 9.7% of the warfarin group; 3.2% The MCA stem, the arteries comprising the circle of Willis (A1 segment, anterior and posterior communicat- ing arteries, and P1 segment), and the basilar and vertebral arteries all give rise to 30- to 300-μm branches that

Anterior cerebral a. Deep branches of the 257 middle cerebral a. Anterior cerebral a. Internal carotid a. Middle cerebral a. Internal carotid a. Middle cerebral a. Basilar a. Vertebral a. CHAPTER 21 Cerebrovascular Diseases Basilar a. Deep branches Vertebral a. of the basilar a. FIGURE 21-4 posterior circulation, similar arteries arise directly from the Diagrams and reformatted CT angiograms in the coronal vertebral and basilar arteries to supply the brainstem (lower section illustrating the deep penetrating arteries involved in panels). Occlusion of a single penetrating artery gives rise to small-vessel strokes. In the anterior circulation, small pene- a discrete area of infarct (pathologically termed a “lacune,” or trating arteries called lenticulostriates arise from the proximal lake). Note that these vessels are too small to be visualized portion of the anterior and middle cerebral arteries and on CT angiography. supply deep subcortical structures (upper panels). In the penetrate the deep gray and white matter of the cere- stroke from an infarct in the ventral thalamus; (3) ataxic brum or brainstem (Fig. 21-4). Each of these small hemiparesis from an infarct in the ventral pons or internal branches can occlude either by atherothrombotic disease capsule; (4) and dysarthria and a clumsy hand or arm due at its origin or by the development of lipohyalinotic to infarction in the ventral pons or in the genu of the thickening. Thrombosis of these vessels causes small internal capsule. infarcts that are referred to as lacunes (Latin for “lake” of fluid noted at autopsy).These infarcts range in size from Transient symptoms (small vessel TIAs) may herald a 3 mm to 2 cm in diameter. Hypertension and age are small-vessel infarct; they may occur several times a day the principal risk factors. and last only a few minutes. Recovery from small-vessel strokes tends to be more rapid and complete than recov- Clinical Manifestations ery from large-vessel strokes; in some cases, however, The most common lacunar syndromes are the following: there is severe permanent disability. Often, institution of (1) Pure motor hemiparesis from an infarct in the posterior combined antithrombotic treatments does not prevent limb of the internal capsule or basis pontis; the face, eventual stroke in “stuttering lacunes.” arm, and leg are almost always involved; (2) pure sensory A large-vessel source (either thrombosis or embolism) may manifest initially as a lacunar syndrome with

SECTION III Diseases of the Central Nervous System258 small-vessel infarction. Therefore, the search for embolic Doppler ultrasonography. In children who are identified sources (carotid and heart) should not be completely to have high velocities, treatment with aggressive exchange abandoned in the evaluation of these patients. Secondary transfusion dramatically reduces risk of stroke, and if prevention of lacunar stroke involves risk factor modifi- exchange transfusion is ceased, their stroke rate increases cation, specifically reduction in blood pressure (see Primary again along with MCA velocities. and Secondary Prevention, later). Fibromuscular dysplasia affects the cervical arteries and LESS COMMON CAUSES OF STROKE occurs mainly in women.The carotid or vertebral arter- ies show multiple rings of segmental narrowing alter- (Table 21-2) Hypercoagulable disorders primarily cause nating with dilatation. Occlusion is usually incomplete. increased risk of venous thrombosis and therefore may The process is often asymptomatic but occasionally is cause venous sinus thrombosis. Protein S deficiency and associated with an audible bruit, TIAs, or stroke. homocysteinemia may cause arterial thromboses as Involvement of the renal arteries is common and may well. Systemic lupus erythematosus with Libman-Sacks result in hypertension. The cause and natural history of endocarditis can be a cause of embolic stroke. These fibromuscular dysplasia are unknown. TIA or stroke conditions overlap with the antiphospholipid syndrome, generally occurs only when the artery is severely nar- which probably requires long-term anticoagulation to rowed or dissects. Anticoagulation or antiplatelet ther- prevent further stroke. apy may be helpful. Venous sinus thrombosis of the lateral or sagittal sinus or Temporal (giant cell) arteritis is a relatively common of small cortical veins (cortical vein thrombosis) occurs affliction of elderly persons in which the external as a complication of oral contraceptive use, pregnancy carotid system, particularly the temporal arteries, and the postpartum period, inflammatory bowel disease, becomes the site of a subacute granulomatous inflam- intracranial infections (meningitis), and dehydration. It is mation with giant cells. Occlusion of posterior ciliary also seen with increased incidence in patients with labo- arteries derived from the ophthalmic artery results in ratory-confirmed thrombophilia (Table 21-2) including blindness in one or both eyes and can be prevented with polycythemia, sickle cell anemia, deficiencies of proteins glucocorticoids. It rarely causes stroke as the internal C and S, factor V Leiden mutation (resistance to acti- carotid artery is usually not inflamed. Idiopathic giant vated protein C), antithrombin III deficiency, homocys- cell arteritis involving the great vessels arising from the teinemia, and the prothrombin G20210 mutation. aortic arch (Takayasu’s arteritis) may cause carotid or ver- Women who take oral contraceptives and have the pro- tebral thrombosis; it is rare in the western hemisphere. thrombin G20210 mutation may be at particularly high risk for sinus thrombosis. Patients present with headache Necrotizing (or granulomatous) arteritis, occurring alone and may also have focal neurologic signs (especially or in association with generalized polyarteritis nodosa or paraparesis) and seizures. Often, CT imaging is normal Wegener’s granulomatosis, involves the distal small unless an intracranial venous hemorrhage has occurred, branches (<2 mm diameter) of the main intracranial but the venous sinus occlusion is readily visualized using arteries and produces small ischemic infarcts in the brain, magnetic resonance (MR) venography or conventional optic nerve, and spinal cord. The cerebrospinal fluid x-ray angiography. With greater degrees of sinus throm- (CSF) often shows pleocytosis, and the protein level is bosis, the patient may develop signs of increased ICP elevated. Primary central nervous system vasculitis is rare; small and coma. Intravenous heparin, regardless of the pres- or medium-sized vessels are usually affected, without ence of intracranial hemorrhage, has been shown to apparent systemic vasculitis. Brain biopsy or high-resolution reduce morbidity and mortality, and the long-term out- conventional x-ray angiography is usually required to make come is generally good. Heparin prevents further the diagnosis (Fig. 21-5).The differential diagnosis includes thrombosis and reduces venous hypertension and infection (tubercular, fungal), atherosclerosis, emboli, ischemia. If an underlying hypercoagulable state is not connective tissue disease, sarcoidosis, angiocentric lym- found, many physicians treat with warfarin sodium for phoma, carcinomatous meningitis, vasospasm, and drug- 3–6 months then convert to aspirin, depending on the associated causes. Some cases follow the postpartum degree of resolution of the venous sinus thrombus. Anti- period and are self-limited. Patients with any form of coagulation is often continued indefinitely if throm- vasculitis may present with insidious progression of com- bophilia is diagnosed. bined white and gray matter infarctions, prominent headache, and cognitive decline. Aggressive immunosup- Sickle cell anemia (SS disease) is a common cause of pression with glucocorticoids, and often cyclophos- stroke in children. A subset of homozygous carriers of phamide, is usually necessary to prevent progression; a this hemoglobin mutation develop stroke in childhood diligent investigation for infectious causes such as tuber- and this may be predicted by documenting high- culosis is essential prior to immunosuppression. Depend- velocity blood flow within the MCAs using transcranial ing upon the duration of the disease, many patients can make an excellent recovery.

FIGURE 21-5 Reversible posterior leukoencephalopathy can occur in 259 CHAPTER 21 Cerebrovascular Diseases Cerebral angiogram from a 32-year-old male with central head injury, migraine, sympathomimetic drug use, nervous system vasculitis. Dramatic beading (arrow) typical eclampsia, and the postpartum period. The etiology is of vasculitis is seen. unclear but likely involves widespread cerebral segmen- tal vasoconstriction and cerebral edema. Patients com- Drugs, in particular amphetamines and perhaps plain of headache and manifest fluctuating neurologic cocaine, may cause stroke on the basis of acute hyper- symptoms and signs, especially visual symptoms. Some- tension or drug-induced vasculitis. Abstinence appears times cerebral infarction ensues, but typically the clinical to be the best treatment, as no data exist on use of any and imaging findings suggest that ischemia reverses treatment. Phenylpropanolamine has been linked with completely. Conventional x-ray angiography is the only intracranial hemorrhage, as has cocaine, perhaps related means of establishing the diagnosis, but MRI findings to a drug-induced vasculitis. Arteritis can also occur as a are characteristic. consequence of bacterial, tuberculous, and syphilitic meningitis. Leukoariosis, or periventricular white matter disease, is the result of multiple small-vessel infarcts within the subcor- Moyamoya disease is a poorly understood occlusive dis- tical white matter. It is readily seen on CT or MRI ease involving large intracranial arteries, especially the dis- scans as areas of white matter injury surrounding the tal internal carotid artery and the stem of the MCA and ventricles and within the corona radiata. Areas of lacunar ACA.Vascular inflammation is absent. The lenticulostriate infarction are often seen also.The pathophysiologic basis arteries develop a rich collateral circulation around the of the disease is lipohyalinosis of small penetrating arter- occlusive lesion, which gives the impression of a “puff of ies within the white matter, likely produced by chronic smoke” (moyamoya in Japanese) on conventional x-ray hypertension. Patients with periventricular white matter angiography. Other collaterals include transdural anasto- disease may develop a subcortical dementia syndrome, moses between the cortical surface branches of the depending on the amount of white matter infarction. meningeal and scalp arteries.The disease occurs mainly in Asian children or young adults, but the appearance may be CADASIL (cerebral autosomal dominant arteriopathy identical in adults who have atherosclerosis, particularly with subcortical infarcts and leukoencephalopathy) is an in association with diabetes.The etiology of the childhood inherited disorder that presents as small-vessel strokes, form is unknown. Because of the occurrence of intracra- progressive dementia, and extensive symmetric white nial hemorrhage from rupture of the transdural and pial matter changes visualized by MRI.Approximately 40% of anastomotic channels, anticoagulation is risky. Breakdown patients have migraine with aura, often manifest as tran- of dilated lenticulostriate arteries may produce parenchy- sient motor or sensory deficits. Onset is usually in the mal hemorrhage, and progressive occlusion of large surface fourth or fifth decade of life. This autosomal dominant arteries can occur, producing large-artery distribution condition is caused by one of several mutations in Notch- strokes. Bypass of extracranial carotid arteries to the dura 3, a member of a highly conserved gene family character- or MCAs may prevent stroke and hemorrhage. ized 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 large-vessel arteriopathy and small-vessel infarcts by an unknown mechanism. 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.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.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 neu- rologic function is restored. However, infarcts of the brain do occur in 15–50% of TIAs even though neuro- logic signs and symptoms are absent. Newer definitions

SECTION III Diseases of the Central Nervous System260 of TIA categorize those with new infarct as having thrombotic stroke, diabetes mellitus, hypertension, ischemic stroke rather than TIA regardless of symptom tobacco smoking, abnormal blood cholesterol [particu- duration, but the vast majority of studies have used the larly, low high-density lipoprotein (HDL) and/or high standard, time-based definition. low-density lipoprotein (LDL)], and other factors are In addition to the stroke syndromes discussed later, either proven or probable risk factors for ischemic one specific TIA symptom should receive special notice. stroke, largely by their link to atherosclerosis. Risk of Amaurosis fugax, or transient monocular blindness, occurs stroke is much greater in those with prior stroke or TIA. from emboli to the central retinal artery of one eye.This Many cardiac conditions predispose to stroke, including may indicate carotid stenosis as the cause or local oph- atrial fibrillation and recent MI. Oral contraceptives and thalmic artery disease. hormone replacement therapy increase stroke risk, and The risk of stroke after a TIA is ~10–15% in the first certain inherited and acquired hypercoagulable states 3 months, with most events occurring in the first 2 days. predispose to stroke. Hypertension is the most signifi- Therefore, urgent evaluation and treatment are justified. cant of the risk factors; in general, all hypertension Since etiologies for stroke and TIA are identical, evalua- should be treated.The presence of known cerebrovascu- tion for TIA should parallel that of stroke (Figs. 21-1 lar disease is not a contraindication to treatment aimed and 21-3). The improvement characteristic of TIA is a at achieving normotension. Also, the value of treating contraindication to thrombolysis. However, since the systolic hypertension in older patients has been clearly risk of subsequent stroke in the first few days after a TIA established. Lowering blood pressure to levels below is high, the opportunity to give rtPA more frequently those traditionally defining hypertension appears to and rapidly if a stroke occurs probably justifies hospital reduce the risk of stroke even further. Data are particu- admission for most patients. Acute antiplatelet therapy larly strong in support of thiazide diuretics, angiotensin- has not been tested specifically after TIA but is likely to converting enzyme inhibitors, and angiotensin receptor be effective and is recommended. No large-scale trial blockers. has evaluated acute anticoagulation after TIA, a setting in which the risk of hemorrhage may be lower than for Several trials have confirmed that statin drugs reduce other categories of stroke. the risk of stroke even in patients without elevated LDL or low HDL. The recently reported SPARCL (Stroke RISK FACTORS FOR ISCHEMIC Prevention by Aggressive Reduction in Cholesterol STROKE AND TIA Levels) trial showed benefit in secondary stroke reduc- tion for patients with recent stroke or TIA who were Identification and control of modifiable risk factors is prescribed atorvastatin, 80 mg/d. Although studies the best strategy to reduce the burden of stroke, and the specifically targeting primary prevention of stroke are total number of strokes could be reduced substantially still underway, results for patients with cardiovascular by these means (Table 21-4). risk factors or dyslipidemia have been compelling, with a 16–30% relative risk reduction for stroke. Therefore, a PRIMARY AND SECONDARY PREVENTION statin should be considered in all patients with prior OF STROKE AND TIA ischemic stroke.Tobacco smoking should be discouraged in all patients. Whether tight control of blood sugar in General Principles patients with diabetes lowers stroke risk is uncertain, but statins, more aggressive blood pressure control, and piogli- A number of medical and surgical interventions, as well tazone (an agonist of peroxisome proliferator-activated as lifestyle modifications, are available for preventing receptor gamma) are effective. stroke. Some of these can be widely applied because of their low cost and minimal risk; others are expensive Antiplatelet Agents and carry substantial risk but may be valuable for selected high-risk patients. Platelet antiaggregation agents can prevent atherothrom- botic events, including TIA and stroke, by inhibiting the Evaluation of a patient’s clinical risk profile can help formation of intraarterial platelet aggregates. These can determine which preventive treatments to offer. In addi- form on diseased arteries, induce thrombus formation, tion to known risk factors for ischemic stroke (above), and occlude the artery or embolize into the distal circu- certain clinical characteristics also contribute to an lation. Aspirin, clopidogrel, and the combination of aspirin increased risk of stroke (Table 21-4). plus extended-release dipyridamole are the antiplatelet agents most commonly used for this purpose. Ticlopi- Atherosclerosis Risk Factors dine has been largely abandoned because of its adverse effects. There are a number of factors that are associated with the risk of atherosclerosis. Older age, family history of Aspirin is the most widely studied antiplatelet agent. Aspirin acetylates platelet cyclooxygenase, which

irreversibly inhibits the formation in platelets of phosphodiesterases, dipyridamole also potentiates the 261 CHAPTER 21 Cerebrovascular Diseases thromboxane A2, a platelet aggregating and vasocon- antiaggregatory effects of prostacyclin and nitric oxide stricting prostaglandin. This effect is permanent and produced by the endothelium and acts by inhibiting lasts for the usual 8-day life of the platelet. Paradoxi- platelet phosphodiesterase, which is responsible for the cally, aspirin also inhibits the formation in endothelial breakdown of cyclic AMP. The resulting elevation in cells of prostacyclin, an antiaggregating and vasodilat- cyclic AMP inhibits aggregation of platelets. Dipyri- ing prostaglandin. This effect is transient. As soon as damole is erratically absorbed depending on stomach aspirin is cleared from the blood, the nucleated pH, but a newer formulation combines timed-release endothelial cells again produce prostacyclin. Aspirin in dipyridamole, 200 mg, with aspirin, 25 mg, and has better low doses given once daily inhibits the production of oral bioavailability. This combination drug was studied thromboxane A2 in platelets without substantially in two trials. The European Stroke Prevention Study inhibiting prostacyclin formation. Higher doses of (ESPS) II showed efficacy of both 50 mg/d of aspirin aspirin have not been proven to be more effective than and extended-release dipyridamole in preventing lower doses, and 50–325 mg/d of aspirin is generally stroke, and a significantly better risk reduction when recommended for stroke prevention. the two agents were combined. The ESPRIT (Euro- pean/Australasian Stroke Prevention in Reversible Ticlopidine and clopidogrel block the ADP receptor Ischaemia Trial) trial confirmed the ESPS-II results. on platelets and thus prevent the cascade resulting in This was an open-label, academic trial in which 2739 activation of the glycoprotein IIb/IIIa receptor that patients with stroke or TIA treated with aspirin were leads to fibrinogen binding to the platelet and conse- randomized to dipyridamole, 200 mg twice daily, or no quent platelet aggregation. Ticlopidine is more effective dipyridamole. Primary outcome was the composite of than aspirin; however, it has the disadvantage of causing death from all vascular causes, non-fatal stroke, non-fatal diarrhea, skin rash, and, in rare instances, neutropenia MI, or major bleeding complication. After 3.5 years of and thrombotic thrombocytopenic purpura. Clopidogrel follow-up, 13% patients on aspirin and dipyridamole is not associated with these important side effects. How- and 16% on aspirin alone (hazard ratio 0.80, 95% CI ever, the CAPRIE (Clopidogrel versus Aspirin in 0.66–0.98) met the primary outcome. A meta-analysis Patients at Risk of Ischemic Events) trial, which led to of all dypridamole data on secondary stroke prevention FDA approval, found that it was only marginally more found an overall risk ratio for the composite of vascular effective than aspirin in reducing risk of stroke. The death, stroke, or MI of 0.82 (95% CI 0.74–0.91). The MATCH (Management of Atherothrombosis with principal side effect of the drug is headache. A combina- Clopidogrel in High-Risk Patients) trial was a large tion capsule of extended-release dipyridamole and aspirin multicenter, randomized double-blind study that com- is approved for prevention of stroke. pared clopidogrel in combination with aspirin to clopi- dogrel alone in the secondary prevention of TIA or Many large clinical trials have demonstrated clearly stroke.The MATCH trial found no difference in TIA or that most antiplatelet agents reduce the risk of all impor- stroke prevention with this combination, but did show a tant vascular atherothrombotic events (i.e., ischemic small but significant increase in major bleeding compli- stroke, MI, and death due to all vascular causes) in patients cations (3% vs. 1%). In the CHARISMA (Clopidogrel at risk for these events. The overall relative reduction in for High Atherothrombotic Risk and Ischemic Stabiliza- risk of nonfatal stroke is about 25–30% and of all vascular tion, Management, and Avoidance) trial, which included events is about 25%.The absolute reduction varies consid- a subgroup of patients with prior stroke or TIA along erably, depending on the particular patient’s risk. Individ- with other groups at high risk of cardiovascular events, uals at very low risk for stroke seem to experience the there was no benefit of clopidogrel combined with same relative reduction, but their risk may be so low that aspirin compared to aspirin alone. Thus, the use of the “benefit” is meaningless. On the other hand, individ- clopidogrel in combination with aspirin is not generally uals with a 10–15% risk of vascular events per year expe- recommended for stroke prevention. However, these tri- rience a reduction to about 7.5–11%. als did not enroll patients immediately after the stroke or TIA, and the benefits of combination therapy were Aspirin is inexpensive, can be given in low doses, and greater among those treated earlier, so it is possible that could be recommended for all adults to prevent both clopidogrel combined with aspirin may be beneficial in stroke and MI. However, it causes epigastric discomfort, this acute period. Ongoing studies are currently address- gastric ulceration, and gastrointestinal hemorrhage, ing this question. which may be asymptomatic or life-threatening. Con- sequently, not every 40- or 50-year-old should be Dipyridamole is an antiplatelet agent that inhibits the advised to take aspirin regularly because the risk of uptake of adenosine by a variety of cells, including atherothrombotic stroke is extremely low and is out- those of the vascular endothelium. The accumulated weighed by the risk of adverse side effects. Conversely, adenosine is an inhibitor of aggregation. At least in every patient who has experienced an atherothrom- part through its effects on platelet and vessel wall botic stroke or TIA and has no contraindication should

SECTION III Diseases of the Central Nervous System262 be taking an antiplatelet agent regularly because the persists. Warfarin is currently being studied in patients average annual risk of another stroke is 8–10%; another with congestive heart failure. few percent will experience a MI or vascular death. Clearly, the likelihood of benefit far outweighs the risks Stroke secondary to thromboembolism is one of the of treatment. most serious complications of prosthetic heart valve The choice of antiplatelet agent and dose must bal- implantation. The intensity of anticoagulation and/or ance the risk of stroke, the expected benefit, and the risk antiplatelet therapy is dictated by the type of prosthetic and cost of treatment. However, there are no definitive valve and its location. The Seventh American College of data, and opinions vary. Many authorities believe low- Chest Physicians Conference on Antithrombotic Therapy dose (30–75 mg/d) and high-dose (650–1300 mg/d) for Valvular Heart Disease published the following guide- aspirin are about equally effective. Some advocate very lines in 2004: (1) for St. Jude Medical bileaflet valves in low doses to avoid adverse effects, and still others advo- the aortic position, long-term warfarin with a target INR cate very high doses to be sure the benefit is maximal. of 2.5 (range 2.0–3.0), (2) for tilting disk valves and Most physicians in North America recommend 81–325 bileaflet mechanical valves in the mitral position, long- mg/d, while most in Europe recommend 50–100 mg. term warfarin with a target INR of 3.0; (range 2.5–3.5); Similarly, the choice of aspirin, clopidogrel, or dipyri- (3) for caged ball or caged disk valves, long-term warfarin damole plus aspirin must balance the fact that the latter with target INR of 3.0 (range 2.5–3.5) in combination are more effective than aspirin but the cost is higher, and with aspirin (75–100 mg/d); (4) for bioprosthetic valves, this is likely to affect long-term patient adherence. The warfarin anticoagulation with target INR 2.5 for 3 Prevention Regimen for Effectively Avoiding Second months, followed by long-term aspirin alone (75–100 Strokes (PRoFESS) study was a large randomized sec- mg/d), assuming there is no history of atrial fibrillation. ondary prevention trial of over 20,000 patients that demonstrated equal efficacy of clopidogrel and the If the embolic source cannot be eliminated, anticoag- combination of low-dose aspirin and extended-release ulation should in most cases be continued indefinitely. dipyridamole, suggesting that either is a reasonable Many neurologists recommend combining antiplatelet choice for secondary stroke prevention. agents with anticoagulants for patients who “fail” anti- coagulation (i.e., have another stroke or TIA). Anticoagulation Therapy and Embolic Stroke Anticoagulation Therapy and Noncardiogenic Stroke Several trials have shown that anticoagulation (INR range, 2–3) in patients with chronic nonvalvular (non- Data do not support the use of long-term warfarin for rheumatic) atrial fibrillation prevents cerebral embolism preventing atherothrombotic stroke, for either intracra- and is safe. For primary prevention and for patients who nial or extracranial cerebrovascular disease. The WARSS have experienced stroke or TIA, anticoagulation with (Warfarin-Aspirin Reinfarction Stroke Study) study warfarin reduces the risk by about 67%, which clearly found no benefit of warfarin sodium (INR, 1.4–2.8) outweighs the 1% risk per year of a major bleeding over aspirin, 325 mg, for secondary prevention of stroke complication. In those patients who cannot tolerate but did find a slightly higher bleeding rate in the war- warfarin, the combination of aspirin and clopidogrel farin group. A recent European study confirmed this appears superior to aspirin alone. finding.The WASID study (see earlier) demonstrated no benefit of warfarin (INR, 2–3) over aspirin in patients The decision to use anticoagulation for primary pre- with symptomatic intracranial atherosclerosis, and also vention is based primarily on risk factors (Table 21-3). found higher bleeding complications. The presence of any risk factor tips the balance in favor of anticoagulation. Other Causes of Stroke Because of the high annual stroke risk in untreated Carotid Disease rheumatic heart disease, primary prophylaxis against Surgical or endovascular repair of carotid atherosclerosis stroke has not been studied in a double-blind fashion. is preferred over medical therapy for symptomatic These patients generally should receive long-term anti- carotid artery disease (see earlier section). Anticoagula- coagulation. tion has not been directly compared with antiplatelet therapy for carotid disease. Anticoagulation also reduces the risk of embolism in acute MI. Most clinicians recommend a 3-month course Dural Sinus Thrombosis of anticoagulation when there is anterior Q-wave infarc- Limited evidence exists to support short-term usage of tion, substantial left ventricular dysfunction, congestive anticoagulants, regardless of the presence of intracranial heart failure, mural thrombosis, or atrial fibrillation. Warfarin is recommended long-term if atrial fibrillation

hemorrhage for venous infarction following sinus 263 thrombosis. STROKE SYNDROMES Internal capsule A careful history and neurologic examination can often localize the region of brain dysfunction; if this region Caudate Claustrum corresponds to a particular arterial distribution, the pos- sible causes responsible for the syndrome can be nar- Anterior Putamen rowed.This is of particular importance when the patient cerebral a. presents with a TIA and a normal examination. For example, if a patient develops language loss and a right Internal carotid a. Uncus homonymous hemianopia, a search for causes of left middle cerebral emboli should be performed. A finding Middle cerebral a. CHAPTER 21 Cerebrovascular Diseases of an isolated stenosis of the right internal carotid artery in that patient, for example, suggests an asymptomatic KEY carotid stenosis, and the search for other causes of stroke should continue. The following sections describe the Ant. cerebral a. clinical findings of cerebral ischemia associated with Middle cerebral a. cerebral vascular territories depicted in Figs. 21-4, and Deep branches of middle cerebral a. 21-6 through 21-14. Stroke syndromes are divided into: Post cerebral a. (1) large-vessel stroke within the anterior circulation, (2) Deep branches of ant. cerebral a. large-vessel stroke within the posterior circulation, and (3) small-vessel disease of either vascular bed. FIGURE 21-6 Diagram of a cerebral hemisphere in coronal section Stroke within the Anterior Circulation showing the territories of the major cerebral vessels that branch from the internal carotid arteries. The internal carotid artery and its branches comprise the anterior circulation of the brain. These vessels can be and inferior divisions (M2 branches). Branches of the occluded by intrinsic disease of the vessel (e.g., atheroscle- inferior division supply the inferior parietal and tempo- rosis or dissection) or by embolic occlusion from a proxi- ral cortex, and those from the superior division supply mal source as discussed earlier. Occlusion of each major the frontal and superior parietal cortex (Fig. 21-7). intracranial vessel has distinct clinical manifestations. If the entire MCA is occluded at its origin (blocking Middle Cerebral Artery both its penetrating and cortical branches) and the distal Occlusion of the proximal MCA or one of its major collaterals are limited, the clinical findings are contralat- branches is most often due to an embolus (artery-to- eral hemiplegia, hemianesthesia, homonymous hemianopia, artery, cardiac, or of unknown source) rather than and a day or two of gaze preference to the ipsilateral side. intracranial atherothrombosis.Atherosclerosis of the proxi- Dysarthria is common because of facial weakness. When mal MCA may cause distal emboli to the middle cerebral the dominant hemisphere is involved, global aphasia is territory or, less commonly, may produce low-flow TIAs. present also, and when the nondominant hemisphere is Collateral formation via leptomeningeal vessels often pre- affected, anosognosia, constructional apraxia, and neglect vents MCA stenosis from becoming symptomatic. are found (Chap. 15). The cortical branches of the MCA supply the lateral Complete MCA syndromes occur most often when surface of the hemisphere except for (1) the frontal pole an embolus occludes the stem of the artery. Cortical and a strip along the superomedial border of the frontal collateral blood flow and differing arterial configurations and parietal lobes supplied by the ACA, and (2) the are probably responsible for the development of many lower temporal and occipital pole convolutions supplied partial syndromes. Partial syndromes may also be due to by the PCA (Figs. 21-6, 21-7, 21-8, and 21-9). emboli that enter the proximal MCA without complete occlusion, occlude distal MCA branches, or fragment The proximal MCA (M1 segment) gives rise to pen- and move distally. etrating branches (termed lenticulostriate arteries) that sup- ply the putamen, outer globus pallidus, posterior limb of the internal capsule, the adjacent corona radiata, and most of the caudate nucleus (Fig. 21-6). In the sylvian fissure, the MCA in most patients divides into superior

264 Ant. parietal a. Rolandic a. Prerolandic a. Post. parietal a. Angular a. Lateral orbitofrontal a. Sup. division Post. temporal a. middle cerebral a. Temporopolar a. SECTION III Diseases of the Central Nervous System Inf. division Visual radiation middle cerebral a. Ant. temporal a. KEY Sensory cortex Auditory area Motor cortex Broca's area Contraversive Wernicke's Visual cortex eye center aphasia area FIGURE 21-7 Conduction aphasia: Central speech area (parietal Diagram of a cerebral hemisphere, lateral aspect, showing operculum) the branches and distribution of the middle cerebral artery and the principal regions of cerebral localization. Note the bifurcation Apractognosia of the nondominant hemisphere, anosog- of the middle cerebral artery into a superior and inferior division. nosia, hemiasomatognosia, unilateral neglect, agnosia for the left half of external space, dressing “apraxia,” construc- Signs and symptoms: Structures involved tional “apraxia,” distortion of visual coordinates, inaccurate Paralysis of the contralateral face, arm, and leg; sensory localization in the half field, impaired ability to judge dis- impairment over the same area (pinprick, cotton touch, tance, upside-down reading, visual illusions (e.g., it may vibration, position, two-point discrimination, stereognosis, appear that another person walks through a table): Non- tactile localization, barognosis, cutaneographia): Somatic dominant parietal lobe (area corresponding to speech area motor area for face and arm and the fibers descending from in dominant hemisphere); loss of topographic memory is the leg area to enter the corona radiata and corresponding usually due to a nondominant lesion, occasionally to a domi- somatic sensory system nant one Motor aphasia: Motor speech area of the dominant hemi- sphere Homonymous hemianopia (often homonymous inferior Central aphasia, word deafness, anomia, jargon speech, quadrantanopia): Optic radiation deep to second temporal sensory agraphia, acalculia, alexia, finger agnosia, right-left convolution confusion (the last four comprise the Gerstmann syndrome): Central, suprasylvian speech area and parietooccipital cortex Paralysis of conjugate gaze to the opposite side: Frontal of the dominant hemisphere contraversive eye field or projecting fibers Partial syndromes due to embolic occlusion of a single the dominant hemisphere is probably involved. Jargon branch include hand, or arm and hand, weakness alone speech and an inability to comprehend written and spo- (brachial syndrome) or facial weakness with nonfluent ken language are prominent features, often accompanied (Broca) aphasia (Chap. 15), with or without arm weakness by a contralateral, homonymous superior quadrantanopia. (frontal opercular syndrome). A combination of sensory Hemineglect or spatial agnosia without weakness indi- disturbance, motor weakness, and nonfluent aphasia sug- cates that the inferior division of the MCA in the non- gests that an embolus has occluded the proximal superior dominant hemisphere is involved. division and infarcted large portions of the frontal and parietal cortices (Fig. 21-7). If a fluent (Wernicke’s) apha- Occlusion of a lenticulostriate vessel produces small-ves- sia occurs without weakness, the inferior division of the sel (lacunar) stroke within the internal capsule (Fig. 21-6). MCA supplying the posterior part (temporal cortex) of 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 fol- hypothalamus, and the inferior part of the head of the 265 CHAPTER 21 Cerebrovascular Diseases lowed by arm then leg weakness as the ischemia moves caudate nucleus (Fig. 21-6). posterior within the capsule. Alternatively, the contralat- eral hand may become ataxic and dysarthria will be Occlusion of the proximal ACA is usually well toler- prominent (clumsy hand, dysarthria lacunar syndrome). ated because of collateral flow through the anterior Lacunar infarction affecting the globus pallidus and communicating artery and collaterals through the MCA putamen often has few clinical signs, but parkinsonism and PCA. Occlusion of a single A2 segment results in and hemiballismus have been reported. the contralateral symptoms noted in Fig. 21-8. If both A2 segments arise from a single anterior cerebral stem Anterior Cerebral Artery (contralateral A1 segment atresia), the occlusion may The ACA is divided into two segments: the precommunal affect both hemispheres. Profound abulia (a delay in ver- (A1) circle of Willis, or stem, which connects the internal bal and motor response) and bilateral pyramidal signs carotid artery to the anterior communicating artery, and with paraparesis and urinary incontinence result. the postcommunal (A2) segment distal to the anterior communicating artery (Figs. 21-4, 21-6, and 21-8). The Anterior Choroidal Artery A1 segment gives rise to several deep penetrating branches This artery arises from the internal carotid artery and that supply the anterior limb of the internal capsule, supplies the posterior limb of the internal capsule and the anterior perforate substance, amygdala, anterior the white matter posterolateral to it, through which pass some of the geniculocalcarine fibers (Fig. 21-9). The Secondary Motor Medial Post. cortex rolandic a. parietal a. motor area Medial Pericallosal a. Sensory Splenial a. cortex prerolandic a. Lateral posterior choroidal a. Callosomarginal a. Post. thalamic a. Frontopolar a. Parietooccipital a. Ant. cerebral a. Visual cortex Medial orbitofrontal a. Post. communicating a. Striate area along calcarine sulcus Calcarine a. Post. temporal a. Penetrating Post. Medial posterior choroidal a. thalamosubthalamic cerebral paramedian As. stem Ant. Hippocampal As. temporal a. FIGURE 21-8 Contralateral grasp reflex, sucking reflex, gegenhalten Diagram of a cerebral hemisphere, medial aspect, (paratonic rigidity): Medial surface of the posterior frontal lobe; likely supplemental motor area showing the branches and distribution of the anterior Abulia (akinetic mutism), slowness, delay, intermittent cerebral artery and the principal regions of cerebral interruption, lack of spontaneity, whispering, reflex distrac- tion to sights and sounds: Uncertain localization—probably localization. cingulate gyrus and medial inferior portion of frontal, pari- etal, and temporal lobes Signs and symptoms: Structures involved Impairment of gait and stance (gait apraxia): Frontal Paralysis of opposite foot and leg: Motor leg area cortex near leg motor area A lesser degree of paresis of opposite arm: Arm area of Dyspraxia of left limbs, tactile aphasia in left limbs: Corpus callosum cortex or fibers descending to corona radiata Cortical sensory loss over toes, foot, and leg: Sensory area for foot and leg Urinary incontinence: Sensorimotor area in paracentral lobule

266 Internal Ant. cerebral a. carotid a. Post. communicating a. Ant. Post. cerebral a. choroidal a. Medial posterior Mesencephalic choroidal a. paramedian As. Splenial a. Ant. temporal a. Parietooccipital a. Calcarine a. Hippocampal a. Post. temporal a. SECTION III Diseases of the Central Nervous System Visual Post. thalamic a. cortex Lateral posterior choroidal a. FIGURE 21-9 visual spread, palinopsia, distortion of outlines, central pho- Inferior aspect of the brain with the branches and distribu- tophobia: Calcarine cortex. Complex hallucinations: Usually tion of the posterior cerebral artery and the principal nondominant hemisphere. anatomic structures shown. Central territory. Thalamic syndrome: sensory loss (all Signs and symptoms: Structures involved modalities), spontaneous pain and dysesthesias, choreoa- Peripheral territory (see also Fig. 21-12). Homonymous thetosis, intention tremor, spasms of hand, mild hemipare- hemianopia (often upper quadrantic): Calcarine cortex or sis: Posteroventral nucleus of thalamus; involvement of the optic radiation nearby. Bilateral homonymous hemianopia, adjacent subthalamus body or its afferent tracts. Thalamop- cortical blindness, awareness or denial of blindness; tactile erforate syndrome: crossed cerebellar ataxia with ipsilateral naming, achromatopia (color blindness), failure to see third nerve palsy (Claude’s syndrome): Dentatothalamic to-and-fro movements, inability to perceive objects not tract and issuing third nerve. Weber’s syndrome: Third nerve centrally located, apraxia of ocular movements, inability to palsy and contralateral hemiplegia: Third nerve and cere- count or enumerate objects, tendency to run into things bral peduncle. Contralateral hemiplegia: Cerebral peduncle. that the patient sees and tries to avoid: Bilateral occipital Paralysis or paresis of vertical eye movement, skew devia- lobe with possibly the parietal lobe involved. Verbal dyslexia tion, sluggish pupillary responses to light, slight miosis and without agraphia, color anomia: Dominant calcarine lesion ptosis (retraction nystagmus and “tucking” of the eyelids and posterior part of corpus callosum. Memory defect: may be associated): Supranuclear fibers to third nerve, Hippocampal lesion bilaterally or on the dominant side only. interstitial nucleus of Cajal, nucleus of Darkschewitsch, and Topographic disorientation and prosopagnosia: Usually with posterior commissure. Contralateral rhythmic, ataxic action lesions of nondominant, calcarine, and lingual gyrus. Simul- tremor; rhythmic postural or “holding” tremor (rubral tanagnosia, hemivisual neglect: Dominant visual cortex, tremor): Dentatothalamic tract. contralateral hemisphere. Unformed visual hallucinations, peduncular hallucinosis, metamorphopsia, teleopsia, illusory complete syndrome of anterior choroidal artery occlu- Internal Carotid Artery sion consists of contralateral hemiplegia, hemianesthesia (hypesthesia), and homonymous hemianopia. However, The clinical picture of internal carotid occlusion varies because this territory is also supplied by penetrating ves- depending on whether the cause of ischemia is propagated sels of the proximal MCA and the posterior communi- thrombus, embolism, or low flow. The cortex supplied cating and posterior choroidal arteries, minimal deficits by the MCA territory is affected most often. With a may occur, and patients frequently recover substantially. competent circle of Willis, occlusion may go unnoticed. Anterior choroidal strokes are usually the result of in situ If the thrombus propagates up the internal carotid artery thrombosis of the vessel, and the vessel is particularly vul- into the MCA or embolizes it, symptoms are identical nerable to iatrogenic occlusion during surgical clipping to proximal MCA occlusion (see earlier). Sometimes of aneurysms arising from the internal carotid artery. there is massive infarction of the entire deep white mat- ter and cortical surface. When the origins of both the

ACA and MCA are occluded at the top of the carotid PCA syndromes usually result from atheroma forma- 267 CHAPTER 21 Cerebrovascular Diseases artery, abulia or stupor occurs with hemiplegia, hemi- tion or emboli that lodge at the top of the basilar anesthesia, and aphasia or anosognosia. When the PCA artery; posterior circulation disease may also be caused arises from the internal carotid artery (a configuration by dissection of either vertebral artery and fibromuscu- called a fetal posterior cerebral artery), it may also become lar dysplasia. occluded and give rise to symptoms referable to its peripheral territory (Figs. 21-8 and 21-9). Two clinical syndromes are commonly observed with occlusion of the PCA: (1) P1 syndrome: midbrain, sub- In addition to supplying the ipsilateral brain, the inter- thalamic, and thalamic signs, which are due to disease of nal carotid artery perfuses the optic nerve and retina via the proximal P1 segment of the PCA or its penetrating the ophthalmic artery. In ~25% of symptomatic internal branches (thalamogeniculate, Percheron, and posterior carotid disease, recurrent transient monocular blindness choroidal arteries); and (2) P2 syndrome: cortical tempo- (amaurosis fugax) warns of the lesion. Patients typically ral and occipital lobe signs, due to occlusion of the P2 describe a horizontal shade that sweeps down or up across segment distal to the junction of the PCA with the pos- the field of vision. They may also complain that their terior communicating artery. vision was blurred in that eye or that the upper or lower half of vision disappeared. In most cases, these symptoms P1 Syndromes last only a few minutes. Rarely, ischemia or infarction of Infarction usually occurs in the ipsilateral subthalamus the ophthalmic artery or central retinal arteries occurs at and medial thalamus and in the ipsilateral cerebral the time of cerebral TIA or infarction. peduncle and midbrain (Figs. 21-9 and 21-14). A third nerve palsy with contralateral ataxia (Claude’s syn- A high-pitched prolonged carotid bruit fading into drome) or with contralateral hemiplegia (Weber’s syn- diastole is often associated with tightly stenotic lesions. drome) may result. The ataxia indicates involvement of As the stenosis grows tighter and flow distal to the the red nucleus or dentatorubrothalamic tract; the hemi- stenosis becomes reduced, the bruit becomes fainter and plegia is localized to the cerebral peduncle (Fig. 21-14). may disappear when occlusion is imminent. If the subthalamic nucleus is involved, contralateral hemiballismus may occur. Occlusion of the artery of Common Carotid Artery Percheron produces paresis of upward gaze and drowsi- All symptoms and signs of internal carotid occlusion ness, and often abulia. Extensive infarction in the mid- may also be present with occlusion of the common brain and subthalamus occurring with bilateral proximal carotid artery. Bilateral common carotid artery occlu- PCA occlusion presents as coma, unreactive pupils, bilat- sions at their origin may occur in Takayasu’s arteritis. eral pyramidal signs, and decerebrate rigidity. Stroke within the Posterior Circulation Occlusion of the penetrating branches of thalamic and thalamogeniculate arteries produces less extensive The posterior circulation is composed of the paired ver- thalamic and thalamocapsular lacunar syndromes. The tebral arteries, the basilar artery, and the paired posterior thalamic Déjerine-Roussy syndrome consists of contralateral cerebral arteries. The vertebral arteries join to form the hemisensory loss followed later by an agonizing, searing basilar artery at the pontomedullary junction.The basilar or burning pain in the affected areas. It is persistent and artery divides into two posterior cerebral arteries in the responds poorly to analgesics. Anticonvulsants (carba- interpeduncular fossa (Figs. 21-4, 21-8, and 21-9).These mazepine or gabapentin) or tricyclic antidepressants may major arteries give rise to long and short circumferential be beneficial. branches and to smaller deep penetrating branches that supply the cerebellum, medulla, pons, midbrain, subthal- P2 Syndromes amus, thalamus, hippocampus, and medial temporal and (See also Figs. 21-8 and 21-9) Occlusion of the distal occipital lobes. Occlusion of each vessel produces its PCA causes infarction of the medial temporal and own distinctive syndrome. occipital lobes. Contralateral homonymous hemianopia with macula sparing is the usual manifestation. Occa- Posterior Cerebral Artery sionally, only the upper quadrant of visual field is In 75% of cases, both PCAs arise from the bifurcation of involved. If the visual association areas are spared and the basilar artery; in 20%, one has its origin from the only the calcarine cortex is involved, the patient may be ipsilateral internal carotid artery via the posterior com- aware of visual defects. Medial temporal lobe and hip- municating artery; in 5%, both originate from the pocampal involvement may cause an acute disturbance respective ipsilateral internal carotid arteries (Figs. 21-8 in memory, particularly if it occurs in the dominant and 21-9).The precommunal, or P1, segment of the true hemisphere. The defect usually clears because memory posterior cerebral artery is atretic in such cases. has bilateral representation. If the dominant hemisphere is affected and the infarct extends to involve the splenium

SECTION III Diseases of the Central Nervous System268 of the corpus callosum, the patient may demonstrate threatens the origin of the other, the collateral circulation, alexia without agraphia.Visual agnosia for faces, objects, which may also include retrograde flow down the basilar mathematical symbols, and colors and anomia with artery, is often insufficient (Figs. 21-4 and 21-9). In this paraphasic errors (amnestic aphasia) may also occur in setting, low-flow TIAs may occur, consisting of syncope, this setting, even without callosal involvement. Occlu- vertigo, and alternating hemiplegia; this state also sets sion of the posterior cerebral artery can produce pedun- the stage for thrombosis. Disease of the distal fourth seg- cular hallucinosis (visual hallucinations of brightly colored ment of the vertebral artery can promote thrombus for- scenes and objects). mation manifest as embolism or with propagation as Bilateral infarction in the distal PCAs produces corti- basilar artery thrombosis. Stenosis proximal to the origin cal blindness (blindness with preserved pupillary light of the PICA can threaten the lateral medulla and poste- reaction). The patient is often unaware of the blindness rior inferior surface of the cerebellum. or may even deny it (Anton’s syndrome). Tiny islands of vision may persist, and the patient may report that vision If the subclavian artery is occluded proximal to the fluctuates as images are captured in the preserved por- origin of the vertebral artery, there is a reversal in the tions. Rarely, only peripheral vision is lost and central direction of blood flow in the ipsilateral vertebral artery. vision is spared, resulting in “gun-barrel” vision. Bilateral Exercise of the ipsilateral arm may increase demand on visual association area lesions may result in Balint’s syn- vertebral flow, producing posterior circulation TIAs, or drome, a disorder of the orderly visual scanning of the “subclavian steal.” environment (Chap. 15), usually resulting from infarc- tions secondary to low flow in the “watershed” between Although atheromatous disease rarely narrows the the distal PCA and MCA territories, as occurs after car- second and third segments of the vertebral artery, this diac arrest. Patients may experience persistence of a region is subject to dissection, fibromuscular dysplasia, visual image for several minutes despite gazing at and, rarely, encroachment by osteophytic spurs within another scene (palinopia) or an inability to synthesize the the vertebral foramina. whole of an image (asimultanagnosia). Embolic occlusion of the top of the basilar artery can produce any or all of Embolic occlusion or thrombosis of a V4 segment the central or peripheral territory symptoms. The hall- causes ischemia of the lateral medulla. The constellation mark is the sudden onset of bilateral signs, including of vertigo, numbness of the ipsilateral face and contralat- ptosis, pupillary asymmetry or lack of reaction to light, eral limbs, diplopia, hoarseness, dysarthria, dysphagia, and somnolence. and ipsilateral Horner’s syndrome is called the lateral medullary (or Wallenberg’s) syndrome (Fig. 21-10). Most Vertebral and Posterior Inferior cases result from ipsilateral vertebral artery occlusion; in Cerebellar Arteries the remainder, PICA occlusion is responsible. Occlusion The vertebral artery, which arises from the innominate of the medullary penetrating branches of the vertebral artery on the right and the subclavian artery on the left, artery or PICA results in partial syndromes. Hemiparesis consists of four segments.The first (V1) extends from its is not a feature of vertebral artery occlusion, however, quadri- origin to its entrance into the sixth or fifth transverse paresis may result from occlusion of the anterior spinal artery. vertebral foramen. The second segment (V2) traverses the vertebral foramina from C6 to C2. The third (V3) Rarely, a medial medullary syndrome occurs with infarc- passes through the transverse foramen and circles around tion of the pyramid and contralateral hemiparesis of the the arch of the atlas to pierce the dura at the foramen arm and leg, sparing the face. If the medial lemniscus magnum. The fourth (V4) segment courses upward to and emerging hypoglossal nerve fibers are involved, join the other vertebral artery to form the basilar artery; contralateral loss of joint position sense and ipsilateral only the fourth segment gives rise to branches that sup- tongue weakness occur. ply the brainstem and cerebellum.The posterior inferior cerebellar artery (PICA) in its proximal segment supplies Cerebellar infarction with edema can lead to sudden the lateral medulla and, in its distal branches, the inferior respiratory arrest due to raised ICP in the posterior fossa. surface of the cerebellum. Drowsiness, Babinski signs, dysarthria, and bifacial weak- Atherothrombotic lesions have a predilection for V1 ness may be absent, or present only briefly, before respi- and V4 segments of the vertebral artery. The first seg- ratory arrest ensues. Gait unsteadiness, headache, dizziness, ment may become diseased at the origin of the vessel nausea, and vomiting may be the only early symptoms and may produce posterior circulation emboli; collateral and signs and should arouse suspicion of this impending flow from the contralateral vertebral artery or the ascend- complication, which may require neurosurgical decom- ing cervical, thyrocervical, or occipital arteries is usually pression, often with an excellent outcome. Separating sufficient to prevent low-flow TIAs or stroke. When one these symptoms from those of viral labrynthitis can be a vertebral artery is atretic and an atherothrombotic lesion challenge, but headache, neck stiffness, and unilateral dysmetria favor stroke. Basilar Artery Branches of the basilar artery supply the base of the pons and superior cerebellum and fall into three groups:

Medial lemniscus Pyramid 269 Spinothalamic tract 12th n. Inferior olive Ventral spinocerebellar tract 10th n. Medulla Cerebellum Dorsal Descending spinocerebellar tract sympathetic tract Nucleus ambiguus – motor 9 +10 Restiform body Descending nucleus Olivocerebellar and tract - 5th n. fibers Tractus solitarus 12th n. Medial longitudinal fasciculus with nucleus nucleus Vestibular nucleus Medullary syndrome: Lateral Medial CHAPTER 21 Cerebrovascular Diseases FIGURE 21-10 Horner’s syndrome (miosis, ptosis, decreased Axial section at the level of the medulla, depicted sweating): Descending sympathetic tract schematically on the left, with a corresponding MR image on the right. Note that in Figs. 21-10 through 21-14, all drawings Dysphagia, hoarseness, paralysis of palate, paraly- are oriented with the dorsal surface at the bottom, matching sis of vocal cord, diminished gag reflex: Issuing the orientation of the brainstem that is commonly seen in all fibers ninth and tenth nerves modern neuroimaging studies. Approximate regions involved in medial and lateral medullary stroke syndromes are shown. Loss of taste: Nucleus and tractus solitarius Numbness of ipsilateral arm, trunk, or leg: Cuneate Signs and symptoms: Structures involved 1. Medial medullary syndrome (occlusion of vertebral and gracile nuclei Weakness of lower face: Genuflected upper motor artery or of branch of vertebral or lower basilar artery) On side of lesion neuron fibers to ipsilateral facial nucleus On side opposite lesion Paralysis with atrophy of half the tongue: Ipsilateral Impaired pain and thermal sense over half the body, twelfth nerve sometimes face: Spinothalamic tract On side opposite lesion 3. Total unilateral medullary syndrome (occlusion of ver- Paralysis of arm and leg, sparing face; impaired tac- tile and proprioceptive sense over half the body: tebral artery): Combination of medial and lateral syn- Contralateral pyramidal tract and medial lemnis- dromes cus 4. Lateral pontomedullary syndrome (occlusion of verte- bral artery): Combination of lateral medullary and lat- 2. Lateral medullary syndrome (occlusion of any of five eral inferior pontine syndrome vessels may be responsible—vertebral, posterior inferior 5. Basilar artery syndrome (the syndrome of the lone ver- cerebellar, superior, middle, or inferior lateral medullary tebral artery is equivalent): A combination of the vari- arteries) ous brainstem syndromes plus those arising in the On side of lesion posterior cerebral artery distribution. Pain, numbness, impaired sensation over half the Bilateral long tract signs (sensory and motor; cerebel- face: Descending tract and nucleus fifth nerve Ataxia of limbs, falling to side of lesion: Uncertain— lar and peripheral cranial nerve abnormalities): Bilat- restiform body, cerebellar hemisphere, cerebellar eral long tract; cerebellar and peripheral cranial fibers, spinocerebellar tract (?) nerves Nystagmus, diplopia, oscillopsia, vertigo, nausea, Paralysis or weakness of all extremities, plus all bulbar vomiting: Vestibular nucleus musculature: Corticobulbar and corticospinal tracts bilaterally (1) paramedian, 7–10 in number, which supply a wedge rior cerebellar and anterior inferior cerebellar arteries), of pons on either side of the midline; (2) short circum- which course around the pons to supply the cerebellar ferential, 5–7 in number, which supply the lateral two- hemispheres. thirds of the pons and middle and superior cerebellar peduncles; and (3) bilateral long circumferential (supe- Atheromatous lesions can occur anywhere along the basilar trunk but are most frequent in the proximal

270 basilar and distal vertebral segments. Typically, lesions emerge with ischemia, reflecting involvement of the occlude either the proximal basilar and one or both ver- corticospinal and corticobulbar tracts, ascending sensory tebral arteries. The clinical picture varies depending on tracts, and cranial nerve nuclei (Figs. 21-11, 21-12, the availability of retrograde collateral flow from the 21-13, and 21-14). posterior communicating arteries. Rarely, dissection of a vertebral artery may involve the basilar artery and, The symptoms of transient ischemia or infarction in depending on the location of true and false lumen, may the territory of the basilar artery often do not indicate produce multiple penetrating artery strokes. whether the basilar artery itself or one of its branches is Although atherothrombosis occasionally occludes the diseased, yet this distinction has important implications distal portion of the basilar artery, emboli from the heart for therapy. The picture of complete basilar occlusion, however, or proximal vertebral or basilar segments are more com- is easy to recognize as a constellation of bilateral long tract signs monly responsible for “top of the basilar” syndromes. (sensory and motor) with signs of cranial nerve and cerebellar Because the brainstem contains many structures in dysfunction. A “locked-in” state of preserved conscious- close apposition, a diversity of clinical syndromes may ness with quadriplegia and cranial nerve signs suggests complete pontine and lower midbrain infarction. The SECTION III Diseases of the Central Nervous System Spinothalamic Corticospinal and Medial lemniscus 7th and 8th tract corticobulbar tract cranial Middle cerebellar nerves Descending tract 6th n. peduncle and nucleus of 5th n. Inferior pons 7th n. 8th n. Dorsal Medial longitudinal Cerebellum cochlear fasciculus nucleus Impaired tactile and proprioceptive sense over half 6th n. nucleus of the body: Medial lemniscus 7th n. nucleus complex Restiform body 2. Lateral inferior pontine syndrome (occlusion of anterior Vestibular nucleus inferior cerebellar artery) On side of lesion Inferior pontine syndrome: Horizontal and vertical nystagmus, vertigo, nausea, vomiting, oscillopia: Vestibular nerve or nucleus Lateral Medial Facial paralysis: Seventh nerve Paralysis of conjugate gaze to side of lesion: Center FIGURE 21-11 for conjugate lateral gaze Axial section at the level of the inferior pons, depicted Deafness, tinnitus: Auditory nerve or cochlear nucleus schematically on the left, with a corresponding MR image on Ataxia: Middle cerebellar peduncle and cerebellar the right. Approximate regions involved in medial and lateral hemisphere inferior pontine stroke syndromes are shown. Impaired sensation over face: Descending tract and nucleus fifth nerve Signs and symptoms: Structures involved On side opposite lesion 1. Medial inferior pontine syndrome (occlusion of para- Impaired pain and thermal sense over half the body (may include face): Spinothalamic tract median branch of basilar artery) On side of lesion Paralysis of conjugate gaze to side of lesion (preser- vation of convergence): Center for conjugate lat- eral gaze Nystagmus: Vestibular nucleus Ataxia of limbs and gait: Likely middle cerebellar peduncle Diplopia on lateral gaze: Abducens nerve On side opposite lesion Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract in lower pons

Corticospinal and 271 corticopontine tracts Medial lemniscus Temporal lobe Mid-pons 5th n. 5th cranial Lateral nerve lemniscus Cerebellum Middle cerebellar Medial longitudinal CHAPTER 21 Cerebrovascular Diseases peduncle fasciculus Spinothalamic tract 5th n. motor nucleus 5th n. sensory nucleus Superior cerebellar peduncle Midpontine syndrome: Lateral Medial FIGURE 21-12 Variable impaired touch and proprioception when Axial section at the level of the mid pons, depicted schemati- lesion extends posteriorly: Medial lemniscus cally on the left, with a corresponding MR image on the right. Approximate regions involved in medial and lateral midpon- 2. Lateral midpontine syndrome (short circumferential tine stroke syndromes are shown. artery) On side of lesion Signs and symptoms: Structures involved Ataxia of limbs: Middle cerebellar peduncle 1. Medial midpontine syndrome (paramedian branch of Paralysis of muscles of mastication: Motor fibers or nucleus of fifth nerve midbasilar artery) Impaired sensation over side of face: Sensory fibers On side of lesion or nucleus of fifth nerve On side opposite lesion Ataxia of limbs and gait (more prominent in bilateral Impaired pain and thermal sense on limbs and involvement): Pontine nuclei trunk: Spinothalamic tract On side opposite lesion Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract therapeutic goal is to identify impending basilar occlusion suggests intermittent reduction of flow. Many neurolo- before devastating infarction occurs. A series of TIAs and gists treat with heparin to prevent clot propagation. a slowly progressive, fluctuating stroke are extremely sig- nificant, as they often herald an atherothrombotic occlu- Atherothrombotic occlusion of the basilar artery with sion of the distal vertebral or proximal basilar artery. infarction usually causes bilateral brainstem signs. A gaze paresis or internuclear ophthalmoplegia associated with TIAs in the proximal basilar distribution may produce ipsilateral hemiparesis may be the only manifestation of vertigo (often described by patients as “swimming,”“sway- bilateral brainstem ischemia. More often, unequivocal ing,” “moving,” “unsteadiness,” or “light-headedness”). signs of bilateral pontine disease are present. Complete Other symptoms that warn of basilar thrombosis include basilar thrombosis carries a high mortality. diplopia, dysarthria, facial or circumoral numbness, and hemisensory symptoms. In general, symptoms of basilar Occlusion of a branch of the basilar artery usually branch TIAs affect one side of the brainstem, whereas causes unilateral symptoms and signs involving motor, symptoms of basilar artery TIAs usually affect both sides, sensory, and cranial nerves. As long as symptoms remain though a “herald” hemiparesis has been emphasized as unilateral, concern over pending basilar occlusion should an initial symptom of basilar occlusion. Most often TIAs, be reduced. whether due to impending occlusion of the basilar artery or a basilar branch, are short-lived (5–30 min) and Occlusion of the superior cerebellar artery results in repetitive, occurring several times a day. The pattern severe ipsilateral cerebellar ataxia, nausea and vomiting, dysarthria, and contralateral loss of pain and temperature sensation over the extremities, body, and face (spino- and

272 Pontine nuclei and Corticospinal tract pontocerebellar fibers Medial lemniscus Temporal lobe Basilar artery Central tegmental bundle Lateral Superior lemniscus pons Medial longitudinal Spinothalamic fasciculus tract Superior cerebellar peduncle SECTION III Diseases of the Central Nervous System Superior pontine syndrome: Lateral Medial FIGURE 21-13 2. Lateral superior pontine syndrome (syndrome of supe- Axial section at the level of the superior pons, depicted rior cerebellar artery) schematically on the left, with a corresponding MR image on On side of lesion the right. Approximate regions involved in medial and lateral Ataxia of limbs and gait, falling to side of lesion: superior pontine stroke syndromes are shown. Middle and superior cerebellar peduncles, supe- rior surface of cerebellum, dentate nucleus Signs and symptoms: Structures involved Dizziness, nausea, vomiting; horizontal nystagmus: 1. Medial superior pontine syndrome (paramedian Vestibular nucleus Paresis of conjugate gaze (ipsilateral): Pontine con- branches of upper basilar artery) tralateral gaze On side of lesion Skew deviation: Uncertain Miosis, ptosis, decreased sweating over face (Horner’s Cerebellar ataxia (probably): Superior and/or middle syndrome): Descending sympathetic fibers cerebellar peduncle Tremor: Localization unclear—Dentate nucleus, superior cerebellar peduncle Internuclear ophthalmoplegia: Medial longitudinal On side opposite lesion fasciculus Impaired pain and thermal sense on face, limbs, and trunk: Spinothalamic tract Myoclonic syndrome, palate, pharynx, vocal cords, Impaired touch, vibration, and position sense, more respiratory apparatus, face, oculomotor appara- in leg than arm (there is a tendency to incongruity tus, etc.: Localization uncertain—central tegmen- of pain and touch deficits): Medial lemniscus tal bundle, dentate projection, inferior olivary (lateral portion) nucleus On side opposite lesion Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract Rarely touch, vibration, and position are affected: Medial lemniscus trigeminothalamic tract). Partial deafness, ataxic tremor vertigo, nausea and vomiting, nystagmus, tinnitus, of the ipsilateral upper extremity, Horner’s syndrome, and cerebellar ataxia, Horner’s syndrome, and paresis of palatal myoclonus may occur rarely. Partial syndromes conjugate lateral gaze; and (2) contralateral loss of pain occur frequently (Fig. 21-13).With large strokes, swelling and temperature sensation. An occlusion close to the and mass effects may compress the midbrain or produce origin of the artery may cause corticospinal tract signs hydrocephalus; these symptoms may evolve rapidly. Neu- (Fig. 21-11). rosurgical intervention may be lifesaving in such cases. Occlusion of one of the short circumferential Occlusion of the anterior inferior cerebellar artery branches of the basilar artery affects the lateral two-thirds produces variable degrees of infarction because the of the pons and middle or superior cerebellar peduncle, size of this artery and the territory it supplies vary whereas occlusion of one of the paramedian branches inversely with those of the PICA.The principal symp- affects a wedge-shaped area on either side of the medial toms include: (1) ipsilateral deafness, facial weakness, pons (Figs. 21-11 through 21-13).

3rd n. 273 Crus cerebri Red nucleus Basilar artery Internal carotid artery Substantia nigra Medial lemniscus 3rd nerve Spinothalamic Midbrain nucleus tract Cerebral aqueduct Periaqueductal gray matter Superior colliculus Midbrain syndrome: CHAPTER 21 Cerebrovascular Diseases Lateral Medial FIGURE 21-14 Paralysis of face, arm, and leg: Corticobulbar and Axial section at the level of the midbrain, depicted corticospinal tract descending in crus cerebri schematically on the left, with a corresponding MR image on the right. Approximate regions involved in medial and lateral 2. Lateral midbrain syndrome (syndrome of small pene- midbrain stroke syndromes are shown. trating arteries arising from posterior cerebral artery) On side of lesion Signs and symptoms: Structures involved Eye “down and out” secondary to unopposed 1. Medial midbrain syndrome (paramedian branches of action of fourth and sixth cranial nerves, with dilated and unresponsive pupil: Third nerve fibers upper basilar and proximal posterior cerebral arteries) and/or third nerve nucleus On side of lesion On side opposite lesion Hemiataxia, hyperkinesias, tremor: Red nucleus, Eye “down and out” secondary to unopposed dentatorubrothalamic pathway action of fourth and sixth cranial nerves, with dilated and unresponsive pupil: Third nerve fibers On side opposite lesion IMAGING STUDIES the coronary arteries in one imaging session. Carotid dis- ease and intracranial vascular occlusions are readily identi- See also Chap. 2. fied with this method (Fig. 21-3). After an IV bolus of contrast, deficits in brain perfusion produced by vascular CT Scans occlusion can also be demonstrated (Fig. 21-15) and used to predict the region of infarcted brain and the brain at CT radiographic images identify or exclude hemor- risk of further infarction (i.e., the ischemic penumbra). CT rhage as the cause of stroke, and they identify extra- imaging is also sensitive for detecting SAH (though by parenchymal hemorrhages, neoplasms, abscesses, and itself does not rule it out), and CTA can readily identify other conditions masquerading as stroke. Scans obtained intracranial aneurysms (Chap. 22). Because of its speed and in the first several hours after an infarction generally wide availability, noncontrast head CT is the imaging show no abnormality, and the infarct may not be seen modality of choice in patients with acute stroke (Fig. 21-1), reliably for 24–48 h. CT may fail to show small ischemic and CTA and CT perfusion imaging may also be useful strokes in the posterior fossa because of bone artifact; and convenient adjuncts. small infarcts on the cortical surface may also be missed. MRI Contrast-enhanced CT scans add specificity by show- ing contrast enhancement of subacute infarcts and allow MRI reliably documents the extent and location of visualization of venous structures. Coupled with newer infarction in all areas of the brain, including the posterior generation multi-detector scanners, CT angiography fossa and cortical surface. It also identifies intracranial (CTA) can be performed with administration of IV iodi- hemorrhage and other abnormalities but is less sensitive nated contrast allowing visualization of the cervical and than CT for detecting acute blood. MRI scanners with intracranial arteries, intracranial veins, aortic arch, and even

274 FIGURE 21-15 Acute left middle cerebral artery (MCA) A B stroke with right hemiplegia but preserved language. A. CT perfusion mean-transit time map showing delayed perfusion of the left MCA distribution (blue). B. Pre- SECTION III Diseases of the Central Nervous System dicted region of infarct (red) and penumbra (green) based on CT perfusion data. C. Conventional angiogram showing occlu- sion of the left internal carotid–MCA bifur- cation (left panel), and revascularization of C the vessels following successful thrombec- tomy 8 h after stroke symptom onset (right panel). D. The clot removed with a thrombec- tomy device (L5, Concentric Medical, Inc). E. CT scan of the brain 2 days later; note infarction in the region predicted in B but DE preservation of the penumbral region by suc- cessful revascularization. magnets of higher field strength produce more reliable limitations. However, MRI may be useful outside the and precise images. Diffusion-weighted imaging is more acute period by more clearly defining the extent of tissue sensitive for early brain infarction than standard MR injury and discriminating new from old regions of brain sequences or CT (Fig. 21-16), as is FLAIR (fluid- infarction. MRI may have particular utility in patients attenuated inversion recovery) imaging (Chap. 2). Using with TIA: it is also more likely to identify new infarction, IV administration of gadolinium contrast, MR perfusion which is a strong predictor of subsequent stroke. studies can be performed. Brain regions showing poor perfusion but no abnormality on diffusion are considered Cerebral Angiography equivalent to the ischemic penumbra (see Pathophysiol- ogy of Ischemic Stroke, earlier and Fig. 21-16), and Conventional x-ray cerebral angiography is the “gold patients showing large regions of mismatch may be standard” for identifying and quantifying atherosclerotic better candidates for acute revascularization. MR angiog- stenoses of the cerebral arteries and for identifying and raphy is highly sensitive for stenosis of extracranial inter- characterizing other pathologies, including aneurysms, nal carotid arteries and of large intracranial vessels. With vasospasm, intraluminal thrombi, fibromuscular dysplasia, higher degrees of stenosis, MR angiography tends to arteriovenous fistula, vasculitis, and collateral channels of overestimate the degree of stenosis when compared to blood flow. Endovascular techniques, which are evolving conventional x-ray angiography. MRI with fat saturation rapidly, can be used to deploy stents within delicate intracra- is an imaging sequence used to visualize extra- or nial vessels, to perform balloon angioplasty of stenotic intracranial arterial dissection. This sensitive technique lesions, to treat intracranial aneurysms by embolization, and images clotted blood within the dissected vessel wall. to open occluded vessels in acute stroke with mechanical thrombectomy devices. Recent studies have also docu- MRI is less sensitive for acute blood products than CT mented that intraarterial delivery of thrombolytic agents and is more expensive and time consuming and less read- to patients with acute MCA stroke can effectively recanal- ily available. Claustrophobia also limits its application. ize vessels and improve clinical outcomes.Although its use Most acute stroke protocols use CT because of these

AB that combines a B-mode ultrasound image with a 275 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. In many cases, MR angiography combined with carotid and transcranial ultrasound studies eliminates the need for conventional x-ray angiography in evaluating vascular stenosis. Alter- natively, CT angiography of the entire head and neck can be performed during the initial imaging of acute stroke. Because this images the entire arterial system rel- evant to stroke, with the exception of the heart, much of the clinician’s stroke workup can be completed with one imaging study. CD Perfusion Techniques CHAPTER 21 Cerebrovascular Diseases FIGURE 21-16 Both xenon techniques (principally xenon-CT) and PET MRI of acute stroke. A. Perfusion defect within the right can quantify cerebral blood flow. These tools are gener- hemisphere (bright signal) imaged after administration of an ally used for research (Chap. 2) but can be useful for IV bolus of gadolinium contrast. B. Cerebral blood flow mea- determining the significance of arterial stenosis and sured at the same time as in A; darker signal reflects planning for revascularization surgery. Single photon emis- decreased blood flow. C. Diffusion-weighted image obtained sion tomography (SPECT) and MR perfusion techniques 5 h after onset of a right middle cerebral artery stroke; bright report relative cerebral blood flow. Since CT imaging is signal indicates regions of restricted diffusion that will used as the initial imaging modality for acute stroke, progress to infarction. The discrepancy between the region of some centers now combine both CT angiography and poor perfusion shown in A and B and the diffusion deficit is CT perfusion imaging together with the noncontrast CT called diffusion-perfusion mismatch and is a measure of the scan. CT perfusion imaging increases the sensitivity for ischemic penumbra. Without specific therapy (as shown in detecting ischemia, and can measure the ischemic Fig. 21-15) the region of infarction will expand to match the penumbra (Fig. 21-15). Alternatively, MR perfusion can perfusion deficit, as shown in the diffusion weighted image in be combined with MR diffusion imaging to identify the D obtained 5 days later. (Courtesy of Gregory Albers and ischemic penumbra as the mismatch between these two Vincent Thijs, MD, Stanford University; with permission.) imaging sequences (Fig. 21-16).The ability to image the ischemic penumbra allows more judicious selection of patients who may or may not benefit from acute inter- ventions such as thrombolysis, thrombectomy, or investi- gational neuroprotective strategies. is investigational in many centers, cerebral angiography INTRACRANIAL HEMORRHAGE coupled with endovascular techniques for cerebral revas- cularization may become routine in the near future. Hemorrhages are classified by their location and the Centers capable of these techniques are termed compre- underlying vascular pathology. Bleeding into subdural hensive stroke centers to distinguish them from primary and epidural spaces is principally produced by trauma. stroke centers that can administer IV rtPA but not per- SAHs are produced by trauma and rupture of intracra- form endovascular therapy. Conventional angiography nial aneurysms (Chap. 22). Intraparenchymal and intra- carries risks of arterial damage, groin hemorrhage, ventricular hemorrhage will be considered here. embolic stroke, and renal failure from contrast nephropa- thy, so it should be reserved for situations where less DIAGNOSIS invasive means are inadequate. Intracranial hemorrhage is often discovered on noncon- Ultrasound Techniques trast CT imaging of the brain during the acute evalua- tion of stroke. Since CT is more sensitive than routine Stenosis at the origin of the internal carotid artery can MRI for acute blood, CT imaging is the preferred be identified and quantified reliably by ultrasonography

276 TABLE 21-5 CAUSES OF INTRACRANIAL HEMORRHAGE CAUSE LOCATION COMMENTS Head trauma Intraparenchymal: frontal lobes, Coup and contracoup injury during brain Hypertensive hemorrhage anterior temporal lobes; subarachnoid deceleration Putamen, globus pallidus, thalamus, Chronic hypertension produces cerebellar hemisphere, pons hemorrhage from small (~100 μm) vessels in these regions Transformation of prior Basal ganglion, subcortical Occurs in 1–6% of ischemic strokes with ischemic infarction regions, lobar predilection for large hemispheric infarctions Metastatic brain tumor Lobar Lung, choriocarcinoma, melanoma, renal cell carcinoma, thyroid, atrial myxoma Coagulopathy Any Uncommon cause; often associated with prior stroke or underlying vascular anomaly Drug Lobar, subarachnoid Cocaine, amphetamine, phenylpropranolamine SECTION III Diseases of the Central Nervous System Arteriovenous malformation Lobar, intraventricular, subarachnoid Risk is ~2–4% per year for bleeding Aneurysm Subarachnoid, intraparenchymal, Mycotic and nonmycotic forms of aneurysms rarely subdural Amyloid angiopathy Lobar Degenerative disease of intracranial vessels; linkage to Alzheimer’s disease, rare in Cavernous angioma Intraparenchymal patients <60 Multiple cavernous angiomas linked to Dural arteriovenous fistula Lobar, subarachnoid mutations in KRIT1, CCM2, and PDCD10 Capillary telangiectasias Usually brainstem genes Produces bleeding by venous hypertension Rare cause of hemorrhage method for acute stroke evaluation (Fig. 21-1). The elevation of the head of the bed while surgical consulta- location of the hemorrhage narrows the differential tion is obtained (Chap. 22). diagnosis to a few entities. Table 21-5 lists the causes and anatomic spaces involved in hemorrhages. INTRAPARENCHYMAL HEMORRHAGE EMERGENCY MANAGEMENT Intraparenchymal hemorrhage is the most common type of intracranial hemorrhage. It accounts for ~10% of all Close attention should be paid to airway management strokes and is associated with a 50% case fatality rate. since a reduction in the level of consciousness is com- Incidence rates are particularly high in Asians and mon and often progressive. The initial blood pressure African Americans. Hypertension, trauma, and cerebral should be maintained until the results of the CT scan amyloid angiopathy cause the majority of these hemor- are reviewed. There is growing evidence that intra- rhages. Advanced age and heavy alcohol consumption parenchymal hemorrhage may be exacerbated by increase the risk, and cocaine use is one of the most acutely elevated blood pressure, and current recommen- important causes in the young. dations are to lower mean arterial blood pressure to <130 mmHg. Blood pressure should be lowered with Hypertensive Intraparenchymal Hemorrhage nonvasodilating IV drugs such as nicardipine, labetalol, or esmolol. Patients with cerebellar hemorrhages or Pathophysiology with depressed mental status and radiographic evidence Hypertensive intraparenchymal hemorrhage (hyperten- of hydrocephalus should undergo urgent neurosurgical sive hemorrhage or hypertensive intracerebral hemor- evaluation. Based on the clinical examination and CT rhage) usually results from spontaneous rupture of a small findings, further imaging studies may be necessary, penetrating artery deep in the brain. The most common including MRI or conventional x-ray angiography. Stu- sites are the basal ganglia (especially the putamen), thala- porous or comatose patients generally are treated pre- mus, cerebellum, and pons. When hemorrhages occur in sumptively for elevated ICP, with tracheal intubation other brain areas or in nonhypertensive patients, greater and hyperventilation, mannitol administration, and consideration should be given to hemorrhagic disorders,

neoplasms, vascular malformations, and other causes. worsen until the affected limbs become flaccid or 277 CHAPTER 21 Cerebrovascular Diseases The small arteries in these areas seem most prone to extend rigidly. When hemorrhages are large, drowsiness hypertension-induced vascular injury. The hemorrhage gives way to stupor as signs of upper brainstem com- may be small or a large clot may form and compress adja- pression appear. Coma ensues, accompanied by deep, cent tissue, causing herniation and death. Blood may dissect irregular, or intermittent respiration, a dilated and fixed into the ventricular space, which substantially increases ipsilateral pupil, and decerebrate rigidity. In milder cases, morbidity and may cause hydrocephalus. edema in adjacent brain tissue may cause progressive deterioration over 12–72 h. Most hypertensive intraparenchymal hemorrhages develop over 30–90 min, whereas those associated with Thalamic hemorrhages also produce a contralateral anticoagulant therapy may evolve for as long as 24–48 h. hemiplegia or hemiparesis from pressure on, or dissection Within 48 h macrophages begin to phagocytize the hem- into, the adjacent internal capsule. A prominent sensory orrhage at its outer surface.After 1–6 months, the hemor- deficit involving all modalities is usually present. Aphasia, rhage is generally resolved to a slitlike orange cavity lined often with preserved verbal repetition, may occur after with glial scar and hemosiderin-laden macrophages. hemorrhage into the dominant thalamus, and construc- tional apraxia or mutism occurs in some cases of non- Clinical Manifestations dominant hemorrhage.There may also be a homonymous Although not particularly associated with exertion, visual field defect. Thalamic hemorrhages cause several intracerebral hemorrhages almost always occur while the typical ocular disturbances by virtue of extension inferi- patient is awake and sometimes when stressed.The hem- orly into the upper midbrain.These include deviation of orrhage generally presents as the abrupt onset of focal the eyes downward and inward so that they appear to be neurologic deficit. Seizures are uncommon. The focal looking at the nose, unequal pupils with absence of light deficit typically worsens steadily over 30–90 min and is reaction, skew deviation with the eye opposite the hem- associated with a diminishing level of consciousness and orrhage displaced downward and medially, ipsilateral signs of increased ICP, such as headache and vomiting. Horner’s syndrome, absence of convergence, paralysis of vertical gaze, and retraction nystagmus. Patients may later The putamen is the most common site for hyperten- develop a chronic, contralateral pain syndrome (Déjerine- sive hemorrhage, and the adjacent internal capsule is Roussy syndrome). usually damaged (Fig. 21-17). Contralateral hemiparesis is therefore the sentinel sign. When mild, the face sags In pontine hemorrhages, deep coma with quadriple- on one side over 5–30 min, speech becomes slurred, the gia usually occurs over a few minutes. There is often arm and leg gradually weaken, and the eyes deviate away prominent decerebrate rigidity and “pin-point” (1 mm) from the side of the hemiparesis. The paralysis may pupils that react to light. There is impairment of reflex horizontal eye movements evoked by head turning FIGURE 21-17 (doll’s-head or oculocephalic maneuver) or by irrigation Hypertensive hemorrhage. Transaxial noncontrast CT scan of the ears with ice water (Chap. 14). Hyperpnea, severe through the region of the basal ganglia reveals a hematoma hypertension, and hyperhidrosis are common. Death involving the left putamen in a patient with rapidly progres- often occurs within a few hours, but small hemorrhages sive onset of right hemiparesis. are compatible with survival. 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 other than 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 ocu- lar 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 brain- stem compression or obstructive hydrocephalus; imme- diate surgical evacuation before brainstem compression occurs may be lifesaving. Hydrocephalus from fourth ventricle compression can be relieved by external ven- tricular drainage, but definitive hematoma evacuation is essential for survival. If the deep cerebellar nuclei are spared, full recovery is common.

SECTION III Diseases of the Central Nervous System278 Lobar Hemorrhage Intracranial hemorrhages associated with anticoagulant therapy can occur at any location; they are often lobar or Symptoms and signs appear over several minutes. Most subdural. Anticoagulant-related intracerebral hemor- lobar hemorrhages are small and cause a restricted clinical rhages may evolve slowly, over 24–48 h. Coagulopathy syndrome that simulates an embolus to an artery supply- and thrombocytopenia should be reversed rapidly, as dis- ing one lobe. For example, the major neurologic deficit cussed below. Intracerebral hemorrhage associated with with an occipital hemorrhage is hemianopia; with a left hematologic disorders (leukemia, aplastic anemia, thrombo- temporal hemorrhage, aphasia and delirium; with a parietal cytopenic purpura) can occur at any site and may pre- hemorrhage, hemisensory loss; and with frontal hemor- sent as multiple intracerebral hemorrhages. Skin and rhage, arm weakness. Large hemorrhages may be associ- mucous membrane bleeding is usually evident and offers ated with stupor or coma if they compress the thalamus a diagnostic clue. or midbrain. Most patients with lobar hemorrhages have focal headaches, and more than half vomit or are drowsy. Hemorrhage into a brain tumor may be the first mani- Stiff neck and seizures are uncommon. festation of neoplasm. Choriocarcinoma, malignant melanoma, renal cell carcinoma, and bronchogenic car- Other Causes of Intracerebral Hemorrhage cinoma are among the most common metastatic tumors associated with intracerebral hemorrhage. Glioblastoma Cerebral amyloid angiopathy is a disease of the elderly in multiforme in adults and medulloblastoma in children which arteriolar degeneration occurs and amyloid is may also have areas of intracerebral hemorrhage. deposited in the walls of the cerebral arteries. Amyloid angiopathy causes both single and recurrent lobar hem- Hypertensive encephalopathy is a complication of malig- orrhages and is probably the most common cause of nant hypertension. In this acute syndrome, severe hyper- lobar hemorrhage in the elderly. It accounts for some tension is associated with headache, nausea, vomiting, intracranial hemorrhages associated with IV thromboly- convulsions, confusion, stupor, and coma. Focal or later- sis given for MI. This disorder can be suspected in alizing neurologic signs, either transitory or permanent, patients who present with multiple hemorrhages (and may occur but are infrequent and therefore suggest infarcts) over several months or years, or in patients with some other vascular disease (hemorrhage, embolism, or “micro-bleeds” seen on brain MRI sequences sensitive atherosclerotic thrombosis). There are retinal hemor- for hemosiderin, but it is definitively diagnosed by rhages, exudates, papilledema (hypertensive retinopathy), pathologic demonstration of Congo red staining of and evidence of renal and cardiac disease. In most cases amyloid in cerebral vessels. The ε2 and ε4 allelic varia- ICP and CSF protein levels are elevated. The hyperten- tions of the apolipoprotein E gene are associated with sion may be essential or due to chronic renal disease, increased risk of recurrent lobar hemorrhage and may acute glomerulonephritis, acute toxemia of pregnancy, therefore be markers of amyloid angiopathy. Currently, pheochromocytoma, or other causes. Lowering the there is no specific therapy, though antiplatelet and anti- blood pressure reverses the process, but stroke can occur, coagulating agents are typically avoided. especially if blood pressure is lowered too rapidly. Neu- ropathologic examination reveals multifocal to diffuse Cocaine is a frequent cause of stroke in young (<45 cerebral edema and hemorrhages of various sizes from years) patients. Intracerebral hemorrhage, ischemic stroke, petechial to massive. Microscopically, there are necrosis and SAH are all associated with cocaine use.Angiographic of arterioles, minute cerebral infarcts, and hemorrhages. findings vary from completely normal arteries to large- The term hypertensive encephalopathy should be reserved vessel occlusion or stenosis, vasospasm, or changes consis- for this syndrome and not for chronic recurrent tent with vasculitis. The mechanism of cocaine-related headaches, dizziness, recurrent TIAs, or small strokes that stroke is not known, but cocaine enhances sympathetic often occur in association with high blood pressure. activity causing acute, sometimes severe, hypertension, and this may lead to hemorrhage. Slightly more than half Primary intraventricular hemorrhage is rare. It usually of cocaine-related intracranial hemorrhages are intracere- begins within the substance of the brain and dissects bral, and the rest are subarachnoid. In cases of SAH, a into the ventricular system without leaving signs of saccular aneurysm is usually identified. Presumably, acute intraparenchymal hemorrhage. Alternatively, bleeding hypertension causes aneurysmal rupture. can arise from periependymal veins. Vasculitis, usually polyarteritis nodosa or lupus erythematosus, can pro- Head injury often causes intracranial bleeding. The duce hemorrhage into any region of the central nervous common sites are intracerebral (especially temporal and system; most hemorrhages are associated with hyperten- inferior frontal lobes) and into the subarachnoid, sub- sion, but the arteritis itself may cause bleeding by dis- dural, and epidural spaces.Trauma must be considered in rupting the vessel wall. Sepsis can cause small petechial any patient with an unexplained acute neurologic deficit hemorrhages throughout the cerebral white matter. (hemiparesis, stupor, or confusion), particularly if the Moyamoya disease, mainly an occlusive arterial disease deficit occurred in the context of a fall (Chap. 31). that causes ischemic symptoms, may on occasion pro- duce intraparenchymal hemorrhage, particularly in the

young. Hemorrhages into the spinal cord are usually the warfarin sodium, more rapid reversal of coagulopathy 279 result of an AVM or metastatic tumor. Epidural spinal can be achieved by infusing prothrombin complex hemorrhage produces a rapidly evolving syndrome of concentrates followed by fresh-frozen plasma and CHAPTER 21 Cerebrovascular Diseases spinal cord or nerve root compression (Chap. 30). Spinal vitamin K. When intracerebral hemorrhage is associated hemorrhages usually present with sudden back pain and with thrombocytopenia (platelet count <50,000/μL), some manifestation of myelopathy. transfusion of fresh platelets is indicated. At present, little can be done about the hemorrhage itself. Hematomas Laboratory and Imaging Evaluation may expand for several hours following the initial hemorrhage, so treating severe hypertension seems Patients should have routine blood chemistries and hema- reasonable to prevent hematoma progression. Preliminary tologic studies. Specific attention to the platelet count data suggested that treatment with recombinant factor and PT/PTT are important to identify coagulopathy. VIIa, even in patients without coagulopathy, may decrease CT imaging reliably detects acute focal hemorrhages in risk of hematoma expansion and improve clinical the supratentorial space. Small pontine hemorrhages may outcome; however, a multicenter randomized trial of this not be identified because of motion and bone-induced approach did not show clinical benefit despite a decrease artifact that obscure structures in the posterior fossa. in hematoma expansion. After the first 2 weeks, x-ray attenuation values of clot- ted blood diminish until they become isodense with Evacuation of supratentorial hematomas does not surrounding brain. Mass effect and edema may remain. appear to improve outcome. The International Surgical In some cases, a surrounding rim of contrast enhance- Trial in Intracerebral Hemorrhage (STICH) randomized ment appears after 2–4 weeks and may persist for 1033 patients with supratentorial intracerebral hemor- months. MRI, though more sensitive for delineating rhage to either early surgical evacuation or initial med- posterior fossa lesions, is generally not necessary in most ical management. No benefit was found in the early instances. Images of flowing blood on MRI scan may surgery arm, though analysis was complicated by the identify AVMs as the cause of the hemorrhage. MRI, fact that 26% of patients in the initial medical manage- CT angiography, and conventional x-ray angiography ment group ultimately had surgery for neurologic deteri- are used when the cause of intracranial hemorrhage is oration. Overall, these data do not support routine surgi- uncertain, particularly if the patient is young or not cal evacuation of supratentorial hemorrhages; however, hypertensive and the hematoma is not in one of the many centers operate on patients with progressive neu- four usual sites for hypertensive hemorrhage. For exam- rologic deterioration. Surgical techniques continue to ple, hemorrhage into the temporal lobe suggests rupture evolve, and minimally invasive endoscopic hematoma of a MCA saccular aneurysm. evacuation may prove beneficial in future trials. Since patients typically have focal neurologic signs For cerebellar hemorrhages, a neurosurgeon should and obtundation, and often show signs of increased ICP, be consulted immediately to assist with the evaluation; a lumbar puncture should be avoided as it may induce most cerebellar hematomas >3 cm in diameter will cerebral herniation. require surgical evacuation. If the patient is alert without focal brainstem signs and if the hematoma is <1 cm in Treatment: diameter, surgical removal is usually unnecessary. INTRACRANIAL HEMORRHAGE Patients with hematomas between 1 and 3 cm require careful observation for signs of impaired consciousness ACUTE MANAGEMENT Nearly 50% of patients and precipitous respiratory failure. with a hypertensive intracerebral hemorrhage die, but others may have a good to complete recovery if they Tissue surrounding hematomas is displaced and survive the initial hemorrhage. The volume and location compressed but not necessarily infarcted. Hence, in sur- of the hematoma determine the prognosis. In general, vivors, major improvement commonly occurs as the supratentorial hematomas with volumes <30 mL have a hematoma is reabsorbed and the adjacent tissue good prognosis; 30–60 mL, an intermediate prognosis; regains its function. Careful management of the patient and >60 mL, a poor prognosis during initial hospitalization. during the acute phase of the hemorrhage can lead to Extension into the ventricular system worsens the considerable recovery. prognosis, as does advanced age, location within the posterior fossa, and depressed level of consciousness at Surprisingly, ICP is often normal even with large intra- initial presentation. Any identified coagulopathy should parenchymal hemorrhages. However, if the hematoma be reversed as soon as possible. For patients taking causes marked midline shift of structures with conse- quent obtundation, coma, or hydrocephalus, osmotic agents coupled with induced hyperventilation can be instituted to lower ICP (Chap. 22). These maneuvers will provide enough time to place a ventriculostomy or ICP monitor. Once ICP is recorded, further hyperventilation

SECTION III Diseases of the Central Nervous System280 and osmotic therapy can be tailored to the individual Headache (without bleeding) may be hemicranial and throbbing, like migraine, or diffuse. Focal seizures, with patient. For example, if ICP is found to be high, CSF can or without generalization, occur in ~30% of cases. Half be drained from the ventricular space and osmotic ther- of AVMs become evident as intracerebral hemorrhages. apy continued; persistent or progressive elevation in ICP In most, the hemorrhage is mainly intraparenchymal may prompt surgical evacuation of the clot or with- with extension into the subarachnoid space in some drawal of support. Alternately, if ICP is normal or only cases. Blood is usually not deposited in the basal cisterns, mildly elevated, induced hyperventilation can be and symptomatic cerebral vasospasm is rare. The risk of reversed and osmotic therapy tapered. Since hyperven- rerupture is ~2–4% per year and is particularly high in tilation may actually produce ischemia by cerebral vaso- the first few weeks. Hemorrhages may be massive, lead- constriction, induced hyperventilation should be limited ing to death, or may be as small as 1 cm in diameter, to acute resuscitation of the patient with presumptive leading to minor focal symptoms or no deficit. The high ICP and eliminated once other treatments (osmotic AVM may be large enough to steal blood away from therapy or surgical treatments) have been instituted. adjacent normal brain tissue or to increase venous pres- Glucocorticoids are not helpful for the edema from sure significantly to produce venous ischemia locally and intracerebral hematoma. in remote areas of the brain.This is seen most often with large AVMs in the territory of the MCA. PREVENTION Hypertension is the leading cause of primary intracerebral hemorrhage. Prevention is aimed Large AVMs of the anterior circulation may be associ- at reducing hypertension, excessive alcohol use, and use ated with a systolic and diastolic bruit (sometimes self-audi- of illicit drugs such as cocaine and amphetamines. ble) over the eye, forehead, or neck and a bounding carotid pulse. Headache at the onset of AVM rupture is not gener- VASCULAR ANOMALIES ally as explosive as with aneurysmal rupture. MRI is better than CT for diagnosis, although noncontrast CT scanning Vascular anomalies can be divided into congenital vascu- sometimes detects calcification of the AVM and contrast lar malformations and acquired vascular lesions. may demonstrate the abnormal blood vessels. Once identi- fied, conventional x-ray angiography is the gold standard CONGENITAL VASCULAR MALFORMATIONS for evaluating the precise anatomy of the AVM. True arteriovenous malformations (AVMs), venous anom- Surgical treatment of symptomatic AVMs, often with alies, and capillary telangiectasias are lesions that usually preoperative embolization to reduce operative bleeding, remain clinically silent through life. Although most is usually indicated for accessible lesions. Stereotaxic AVMs are congenital, cases of acquired lesions have been radiation, an alternative to surgery, can produce a slow reported. sclerosis of arterial channels over 2–3 years. True AVMs are congenital shunts between the arterial Patients with asymptomatic AVMs have about a ~2–4% and venous systems that may present as headache, per year risk for hemorrhage. Several angiographic features seizures, and intracranial hemorrhage. AVMs consist of a of the AVM can be used to help predict future bleeding tangle of abnormal vessels across the cortical surface or risk. Paradoxically, smaller lesions seem to have a higher deep within the brain substance. AVMs vary in size from hemorrhage rate.The impact of recurrent hemorrhage on a small blemish a few millimeters in diameter to a large disability is relatively modest, so the indication for surgery mass of tortuous channels composing an arteriovenous in asymptomatic AVMs is debated. A large-scale random- shunt of sufficient magnitude to raise cardiac output. ized trial is currently addressing this question. The blood vessels forming the tangle interposed between arteries and veins are usually abnormally thin and do Venous anomalies are the result of development of not have a normal structure. AVMs occur in all parts of anomalous cerebral, cerebellar, or brainstem drainage. the cerebral hemispheres, brainstem, and spinal cord, but These structures, unlike AVMs, are functional venous the largest ones are most frequently in the posterior half channels. They are of little clinical significance and of the hemispheres, commonly forming a wedge-shaped should be ignored if found incidentally on brain imag- lesion extending from the cortex to the ventricle. ing studies. Surgical resection of these anomalies may result in venous infarction and hemorrhage. Venous Although the lesion is thought to be present from anomalies may be associated with cavernous malforma- birth in most patients, bleeding or other symptoms are tions (see below), which do carry some bleeding risk. If most common between 10 and 30 years of age, occa- resection of a cavernous malformation is attempted, the sionally as late as the 50s. AVMs are more frequent in venous anomaly should not be disturbed. men, and rare familial cases have been described. 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 capil- lary malformations can be seen in patients with hereditary

hemorrhagic telangiectasia (Osler-Rendu-Weber) syn- Cardiology Council, Cardiovascular Radiology and Intervention 281 CHAPTER 21 Cerebrovascular Diseases drome. If bleeding does occur, it rarely produces mass effect or significant symptoms. No treatment options exist. Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Work- ACQUIRED VASCULAR LESIONS ing Groups. The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Cavernous angiomas are tufts of capillary sinusoids that form Stroke 38:1655, 2007 within the deep hemispheric white matter and brainstem ALBERTS MJ et al: Recommendations for comprehensive stroke centers: with no normal intervening neural structures.The patho- A consensus statement from the Brain Attack Coalition. Stroke genesis is unclear. Familial cavernous angiomas have been 36:1597, 2005 mapped to several different chromosomal loci: KRIT1 CHOI JH, MOHR JP: Brain arteriovenous malformations in adults. (7q21-q22), CCM2 (7p13), and PDCD10 (3q26.1). Both Lancet Neurol 4:299, 2005 KRIT1 and CCM2 are instrumental in blood vessel for- CONNOLLY SJ et al: Effect of clopidogrel added to aspirin in patients mation while PDCD10 is an apoptotic gene. Cavernous with atrial fibrillation. N Engl J Med. 360:2066, 2009 angiomas are typically <1 cm in diameter and are often GEORGIADIS D et al: Aspirin vs anticoagulation in carotid artery associated with a venous anomaly. Bleeding is usually of dissection. Neurology 72:1810, 2009 small volume, causing slight mass effect only.The bleeding GOLDSTEIN LB et al: Primary prevention of ischemic stroke: A risk for single cavernous malformations is 0.7–1.5% per guideline from the American Heart Association/American year and may be higher for patients with prior clinical Stroke Association Stroke Council: cosponsored by the Ather- hemorrhage or multiple malformations. Seizures may osclerotic Peripheral Vascular Disease Interdisciplinary Work- occur if the malformation is located near the cerebral cor- ing Group; Cardiovascular Nursing Council; Clinical Cardiol- tex. Surgical resection eliminates bleeding risk and may ogy Council; Nutrition, Physical Activity, and Metabolism reduce seizure risk, but it is reserved for those malforma- Council; and the Quality of Care and Outcomes Research tions that form near the brain surface. Radiation treatment Interdisciplinary Working Group: The American Academy of has not been shown to be of benefit. Neurology affirms the value of this guideline. Stroke 37:1583, 2006 Dural arteriovenous fistulas are acquired connections HACKE W et al: Thrombolysis with Alteplase 3 to 4.5 Hours after usually from a dural artery to a dural sinus. Patients may Acute Ischemic Stroke. N Engl J Med 359:1317, 2008 complain of a pulse-synchronous cephalic bruit (“pul- HOWARD VJ et al: Care seeking after stroke symptoms. Ann Neurol satile tinnitus”) and headache. Depending on the magni- 63:466, 2008 tude of the shunt, venous pressures may rise high Ikram MA et al: Genome-wide association studies of stroke. N Engl J enough to cause cortical ischemia or venous hyperten- Med 360:1718, 2009 sion and hemorrhage, particularly subarachnoid hemor- JOHNSTON SC et al: National Stroke Association guidelines for the rhage. Surgical and endovascular techniques are usually management of transient ischemic attacks. Ann Neurol 60:301, curative. These fistulas may form because of trauma, but 2006 most are idiopathic. There is an association between fis- MAYER SA et al: Efficacy and safety of recombinant activated factor tulas and dural sinus thrombosis. Fistulas have been VII for acute intracerebral hemorrhage. N Engl J Med 358:2127, observed to appear months to years following venous 2008 sinus thrombosis, suggesting that angiogenesis factors MENDELOW AD et al: Early surgery versus initial conservative treat- elaborated from the thrombotic process may cause these ment in patients with spontaneous supratentorial intracerebral anomalous connections to form. Alternatively, dural haematomas in the International Surgical Trial in Intracerebral arteriovenous fistulas can produce venous sinus occlu- Haemorrhage (STICH): A randomised trial. Lancet 365:387, sion over time, perhaps from the high pressure and high 2005 flow through a venous structure. MOHR JP et al: A comparison of warfarin and aspirin for the preven- tion of recurrent ischemic stroke. N Engl J Med. 345:1444, 2001 FURTHER READINGS ROTHWELL PM et al: Endarterectomy for symptomatic carotid steno- sis in relation to clinical subgroups and timing of surgery. Lancet ADAMS HP JR. et al: Guidelines for the Early Management of Adults 363:915, 2004 with Ischemic Stroke. A Guideline from the American Heart SACCO RL et al: Guidelines for Prevention of Stroke in Patients with Association/American Stroke Association Stroke Council, Clinical Ischemic Stroke and Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/ American Stroke Association Council on Stroke. Stroke 37:577, 2006 _______ et al: Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 359:1317, 2008