Catastrophic Neurologic Disorders in the Emergency Department , 2nd Edition

Chapter 15. Major Ischemic Stroke Syndromes

The causes of ischemic stroke are numerous, but only a few are common. The benefits of therapy in most instances so far are small. Treatment of acute ischemic stroke with thrombolytics has become a staple of care in the emergency department. However, clot retrieval and thrombus obliteration devices have come into existence.1 Controversies and uncertainties remain about the use of thrombolytic agents, and some skeptics do not take the results at face value, alleging baseline imbalances in trials and comparatively small numbers of patients.2,3,4,5 In addition, many patients still do not qualify for intravenous or intra-arterial thrombolysis, mostly due to prehospital delay time6,7 (in one study, only 0.06% of all stroke admissions in 16 Connecticut hospitals8). In addition, the time window for intravenous administration of tissue-type plasminogen activator (tPA) remains within 3 hours and cannot be extended to 6 hours.3,9,10,11 To complicate matters further, there is also documented evidence of increased mortality partly due to increased hemorrhage risk in routine practice outside the rigor of clinical trials.8

Patients with an ischemic stroke and candidates for such aggressive management usually present with a major neurologic deficit, often involving the entire function of an arm and a leg, speech, perception of the left side of the body, and, if the lesion is localized in the brain stem or cerebellum, stance, swallowing, and vision. These deficits can be quantified by use of the National Institutes of Health (NIH) Stroke Scale (Table 15.1),12,13 and grading is practical when interventional therapies are under consideration.

This chapter discusses the most commonly encountered clinical presentations and the difficulties in management of major ischemic stroke syndromes. Some of the less frequently encountered disorders are mentioned, particularly when different therapies are recommended. The approach to this vast diagnostic field is by the arterial system.

Large Vessel Occlusions

Ischemic stroke embodies a diverse group of patients with different modes of onset, progression, and outcome. Over time, more complete evaluation of ischemic stroke has resulted in a better definition of its mechanism.

Clinical Presentation

Characteristic clinical presentations should be familiar to any physician managing acute stroke, but the fine points can be addressed by neurologists. The essence is combining the clinical features found through neurologic evaluation with findings of neuroimaging studies to allow quick triage. The role of the emergency physician in this respect has become substantial and reduces unnecessary delays.14

Table 15.1. Stroke Scale of the National Institutes of Health and National Institute of Neurological Disorders and Stroke (the NIH Stroke Scale)*

Level of consciousness









Level of consciousness, questions

   Answers both correctly


   Answers one correctly




Level of consciousness, commands

   Obeys both correctly


   Obeys one correctly







   Partial gaze palsy


   Forced deviation



   No loss


   Partial hemianopsia


   Complete hemianopsia


   Partial hemianopsia


Facial palsy









Motor, right arm

   No drift




   Cannot resist gravity


   No effort against gravity


   No movement


Motor, left arm

   No drift




   Cannot resist gravity


   No effort against gravity


   No movement


Motor, right leg

   No drift




   Cannot resist gravity


   No effort against gravity


No movement


Motor, left leg

   No drift




   Cannot resist gravity


   No effort against gravity


   No movement


      Limb ataxia



   Present in either upper or lower


   Present in both upper and lower





   Partial loss


   Dense loss



   No neglect


   Partial neglect


   No neglect



   Normal articulation


   Mild to moderate dysarthria


   Nearly unintelligible or worse



   No aphasia


   Mild to moderate aphasia


   Severe aphasia




*A sum score of 10 or greater is strongly indicative of a large vessel occlusion, predominantly in the middle cerebral artery. Examination may take only 5 minutes.
Source: Modified from Brott T, Adams HP Jr, Olinger CP, et al.: Measurements of acute cerebral infarctions: a clinical examination scale. 
Stroke 20:864, 1989. By permission of the American Heart Association.

Middle Cerebral Artery Occlusion

Catastrophic cerebral infarction often is caused by an occlusion of the middle cerebral artery (MCA). Its arterial system can be occluded at the Ml segment (proximal MCA), proximal to the lateral lenticulostriatal arteries, and at the M2 segment. The M2 segment is further divided by the superior and inferior trunks, which supply the perisylvian area of the frontal and temporal lobes, respectively. The M2 MCA segment then is divided into the M3, or operculum, segment and the M4, or cortical, branches.

The most devastating MCA occlusion is at M1 or the stem, with a thrombus possibly extending into the carotid artery. Occlusion at the origin of the MCA may lead to gaze preference, hemianopsia, and flaccid hemiplegia of the arm, with some sparing of movement in the leg. Global aphasia and speech apraxia occur if the left MCA is involved and left body neglect, aprosodia (lack of affection or pitch in speech), and bilateral ptosis (see Chapter 3) if the right MCA is involved. Hemisensory loss with no grimacing or withdrawal to pinprick is typical. A multimodulary speech deficit is common in left MCA occlusion. The patient has eyes open and may look about but is unable to follow any command or does so in an inappropriate manner. There is an inability to move the lips and tongue and to blow out the cheeks. Speech may be characterized by repetitive stopping and starting and fumbling words.15 Other patients are mute. Occlusion of the superior trunk of the left MCA produces exactly the same characteristics and therefore cannot be differentiated clinically. However, occlusion of the inferior trunk of the left MCA produces a Wernicke-type aphasia and a superior homonymous quadrantanopsia (“pie in the sky”).

An infarct may preferentially involve the perforating arteries of the MCA (lenticulostriate arteries) when the collateral supply from the anterior circulation and posterior cerebral artery (PCA) is sufficient to protect the remainder of the hemisphere from infarction. A comma-shaped infarct, or so-called striatocapsular infarct, occurs with hemiplegia equally severe in the arm and leg and with fairly mild sensory symptoms.

In many patients, the defect may further evolve or fluctuate and, in some, surprisingly, may disappear. Decrease in deficit may occur in patients with large territorial MCA occlusions (“spectacular shrinking deficit”).16 It is explained by fragmentation of the obstructing clot. In 13% of patients, deterioration occurs after initial dramatic improvement and is attributed to reocclusion.17,18

Anterior Cerebral Artery Occlusion

Most anterior cerebral artery (ACA) distribution infarctions are caused by a cardioembolic source or by artery-to-artery embolization from internal carotid artery stenosis with a diameter reduction of more than 70%.19 The clinical symptoms of acute ACA occlusion are complex and may not be obvious. Usually, occlusion involves severe weakness of the leg in combination with other frontal lobe symptoms, such as abulia, loss of vitality, and incontinence. Transcortical motor and sensory aphasia, characterized by lack of spontaneous speech and comprehension but the ability to repeat phrases, has been reported in an infarction involving the ACA territory. Apraxia of the left arm with normal use of the right arm is typical, and this dissociation can be explained by corpus callosum infarction interrupting connecting fibers and can occur irrespective of occlusion of the right or left ACA. The disorder is revealed when patients can name objects placed in the right hand but are unable to recognize and name objects in the left hand.

An important artery that may become occluded is the recurrent artery of Heubner. Infarction of this territory produces weakness in the contralateral arm and side of the face, with dysarthria and hemichorea. If bilateral occlusions occur, a syndrome of akinetic mutism may evolve.

Vertebrobasilar Artery Occlusion

The basilar artery contributes several paramedian vessels to the pons, as well as short circumference vessels, and two major cerebellar arteries, the proximal anterior inferior cerebellar artery (AICA) and, more distally, the superior cerebellar artery (SCA). The basilar artery divides into both posterior cerebellar arteries. Occlusions are possible at several levels, most often from artery-to-artery embolization. Occlusion of the basilar artery or its branches may produce several ischemic syndromes. Lodging of an embolus at the tip of the basilar artery results in infarction of the brain stem, thalamus, and occipital and medial temporal lobes. Cerebellar infarction may involve each or all of the feeding arteries to the cerebellum with propagation of clot to the cerebral artery (posterior inferior cerebellar artery [PICA], AICA, and SCA). Less dramatic syndromes of brain stem infarction, many carrying French eponyms, are shown in Table 15.2for easy reference, but they are rarely complete at presentation. (These syndromes are interesting exercises in localization and, thus, are favorites of neurologists.) Occlusion of the basilar artery results in a profound neurologic deficit but may start with any of these brain stem syndromes. However, a study of patients with basilar artery occlusion and thromboembolization found that sudden disturbance of consciousness was a predominant clinical symptom and was followed by brain stem signs without a clear unifying syndrome. In many patients, ophthalmoparesis and bulbar weakness develop early after onset.20Sudden vertigo, dysarthria, and quadriparesis are presenting features. Intranuclear ophthalmoplegia is common, explained by interruption of the intranuclear connections through the medial lemniscus fasciculus; cold water irrigation may bring this on in a comatose patient (see Chapter 8). Patients may have hemiparesis mimicking a hemispheric lesion. Brief rhythmical shaking movements, most likely a forme fruste of extensor posturing, can be observed and are commonly misinterpreted as seizures, again leading to false localization in the hemisphere. An occluding embolus at the junction of the basilar artery and PCA may further interrupt the thalamic perforating artery and result in infarction of the thalamus bilaterally, midbrain, and occipital lobes. Vertical gaze palsy, abnormal convergence, skew deviation, behavioral disturbances, and visual hallucinations are common combinations and have been named “top-of-the-basilar syndrome.” Cortical blindness or polyopia (multiple images stacked up) due to bilateral occipital lobe ischemia may be a prominent presenting feature.

Table 15.2. The Classic Brain Stem Syndromes






Cerebral peduncle

Ipsilateral III nerve palsy
Contralateral hemiparesis


Tegmentum red nucleus

Ipsilateral III nerve palsy
Contralateral tremor, chorea


Quadrigeminal plate

Paralysis of upward gaze



Decreased vibration and proprioception
Arm and leg weakness with or without facial weakness



Paramedian area

Ipsilateral lateral rectus muscle paresis, contralateral hemiplegia


Medial lower

Ipsilateral facial palsy with contralateral hemiplegia (often also VI palsy)


Medial lower

Ipsilateral VII
Ipsilateral paralysis of lateral gaze
Contralateral hemiparesis






Ipsilateral facial spasm
Contralateral hemiparesis

Medulla Oblongata



Horner syndrome (ipsilateral), IX, X palsy
Crossed hemianesthesia


Nucleus ambiguus tractus solitarius

X, XI palsy (ipsilateral face, contralateral body)

Spinothalamic tract

Contralateral dissociated hemianesthesia


Vagal nuclei
Bulbar and spinal nuclei of accessory fibers



Nuclear vagus, accessory, hypoglossus nerve



Motor Nuclei vagus, and hypoglossue


Many patients have progression to coma, with quadriplegia and pathologic withdrawal or extensor motor responses to pain. In our series of 25 patients with basilar artery occlusion who required mechanical ventilation, one-third lost most brain stem reflexes within the first 24 hours.21 Failure to trigger the ventilator does occur and may remain the only intact clinical sign.

Locked-in syndrome is the result of occlusion of the perforating arteries of the paramedian basilar artery, leading to dysfunction of the corticospinal tract, corticobulbar tract, and exiting sixth nerve fibers. The level of consciousness is normal, and the patient can communicate only with vertical eye movements and blinking (see Chapter 8). Thalamic involvement or extension to the dorsal mesencephalon, thus affecting the reticular formation, may cause intermittent drowsiness and failure to consistently answer questions.

Cerebellar infarctions may involve the PICA, SCA, and, much less commonly, AICA. PICA occlusions may have different clinical presentations depending on the area of involvement, which may include the lateral medulla. Mainly, these occlusions are manifested by acute headache, vertigo, ataxia of gait, or limb ataxia, but isolated vertigo due to involvement of the vestibular portion of the vermis may be seen.

SCA occlusions may be the most frequent cerebellar infarct, and acute dysarthria and ipsilateral dysmetria may be very prominent. This type of occlusion may closely mimic dysarthria-clumsy hand-lacunar syndrome. Vertigo is much less apparent.

AICA occlusions are manifested by a characteristic acute deafness or profound unilateral hearing loss, but facial paralysis, Homer's syndrome, facial numbness, and loss of sensitivity to pain and temperature may occur as well.

Evolving cerebellar swelling may displace the pons or compress the medulla from tonsillar herniation (see Chapter 8). Impairment of consciousness occurs after a delay of 2–4 days, but patients may have cerebellar swelling at the time of admission to the emergency department.

Posterior Cerebral Artery

The PCA produces characteristic neurobehavioral syndromes that can be easily recognized in the emergency department. A proximal PCA occlusion involving the dominant hemisphere (most often the left side) leads to alexia without agraphia. This dissociation syndrome is caused by an infarction of the splenium of the corpus callosum; patients are unable to read, but the ability to write is preserved because of intact language centers. Color agnosia may accompany a dominant hemispheric lesion. This color-naming disturbance should be tested in patients with right homonymous hemianopsia. Infarction of the dominant angular gyrus results in Gerstmann's syndrome, which involves finger agnosia (inability to name the fingers), inability to calculate, rightleft disorientation, and agraphia. Right nondominant PCA occlusion may lead to prosopagnosia (inability to recognize familiar faces, such as those of family members or celebrities), in addition to a visual field defect.

Bilateral PCA occlusion can lead to two relatively rare syndromes, such as cortical blindness, in which patients may not recognize that they are blind and may relate vivid descriptions of the emergency room and persons surrounding them, all untrue, and Balint's syndrome, with bilateral involvement in the border zone areas between ACA and PCA territories, often occurring after an episode of severe hypotension. Patients complain of “blindness,” are unable to describe a full scene, and cannot describe more than two components of a visual field at the same time (simultanagnosia). In this syndrome, ocular apraxia may be observed, that is, lack of quick focusing on a new stimulus, previously called spasm of fixation. When a stimulus is entering a visual field and even when told this is occurring, patients are not immediately alert to the stimulus. In addition, there is optic ataxia, referring to difficulty pointing accurately at a target under visual guidance. This can be brought about with the simple finger-pointing test. Distal occlusion of the PCA produces only a visual defect, usually with sparing of the macula due to collateral supply from the MCA.

Interpretation of Diagnostic Tests

Computed Tomographic Scanning and Magnetic Resonance Imaging

Before third-generation computed tomographic (CT) scanners, CT scanning in a patient with possible ischemic stroke was performed only to “exclude a hemorrhage.” The definition of brain structures has improved with the newer generation of CT scanners, and the signs of early ischemia can be recognized. The vascular territories should be known when one views CT scans (Fig. 15.1). If no obvious hypodensity is present, the CT scan should be carefully scrutinized for early signs of cerebral infarction: sulci effacement and an obscured outline of the lentiform nucleus or decrease in tissue attenuation (Fig. 15.2). The subtle differences between gray and white matter are more easily detected when several CT window settings are used. Obscuration of the lentiform nucleus is the most frequent earliest sign22 and may appear within the first hour of infarction (Fig. 15.2A). In a small study of 25 patients, it appeared in one of two patients within an hour of the ictus, in seven of eight patients in the second hour, in all three patients in the third hour, in seven of eight patients in the fourth hour, and in all four patients scanned thereafter.22 Early abnormalities on the CT scan also involve the parenchyma, with loss of the precise delineation between gray and white matter and, particularly, loss of the insular ribbon.23 The insular segment of the MCA supplies the insular ribbon, and with complete occlusion of the MCA, the insular region becomes a watershed arterial zone.24 In addition, the insular cortex is the region most distant from the collateral flow from the ACA and PCA (Fig. 15.2B).

Figure 15.1 Vascular territories of the brain (computed tomographic scans and corresponding arterial territories). ACA, anterior cerebral artery; AChA, anterior choroidal artery; AICA, anterior inferior cerebellar artery; BA, basilar artery; LSA, lenticulostriate artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; SCA, superior cerebellar artery.

In some patients, the extent of the ischemic territory is noted by eye deviation on CT (Fig. 15.3).25 Hypodensity may involve the entire MCA territory (Fig. 15.4A) but is usually evident days after onset. Hypodensity on CT scans may involve only the M2 territory (Fig. 15.4B) or the lenticulostriate arteries (Fig. 15.4C). A hypodensity can be seen within hours after MCA trunk occlusion.26 Transferred patients seen several hours after onset who had CT scanning during previous hospitalization at the time of the ictus should have a repeat CT scan, which may show a developing hypodensity.

Figure 15.2 A: Normal definition of the caudate nucleus, lentiform nucleus (arrows), and insular ribbon (arrowhead) in the left hemisphere has disappeared in the right hemisphere. B: One day later, a CT scan shows a hypodensity in that area (arrows).

A hyperdense MCA sign27 actually indicates the clot in the MCA and has been recognized as a prognostic feature. In our studies, a hyperdense MCA together with early swelling (sulci effacement) predicted deterioration from further brain swelling.28,29,30 In other reports, hemorrhagic transformation was deemed more likely in patients who had a hyperdense MCA sign.27,31,32 When the clot fragments and breaks up, the hyperdense MCA sign disappears, often spontaneously or, at times, after intravenous administration of tPA (Fig. 15.5A,B).33 Swelling from MCA infarction often involves shift of the septum pellucidum followed by early trapping of the temporal horn. Involvement of the ACA circulation indicates a carotid occlusion (Fig. 15.6).

Figure 15.3 Note eye deviation on computed tomo-graphic (CT) exam.

Cerebral infarction is better visualized on magnetic resonance imaging (MRI) than on CT scanning.34 Additional findings on MRI include lack of normal flow voids, representing die occluded vessel.35 Arterial enhancement of the T1-weighted images in die ischemic zone after administration of gadolinium contrast material is caused by slow flow in an otherwise high-flow arterial system distal to the obstructing lesion.36 This finding is seen in approximately 50% of patients with acute cortical infarcts.35

Newer MRI techniques using diffusion-weighted imaging (DWI) or fluid-attenuated inversion recovery (FLAIR) are extremely sensitive for early infarction.37 In DWI, areas of hyperintensity (bright areas) indicate decreased movement of water,38,39 and the study is superior within 6 hours of presentation when compared with CT or MRI alone (Fig. 15.7A and B).40 Several studies have shown that early infarction underlies the high signal intensity. It most likely reflects failure of water movement in tissue in this zone of infarction. When these areas of restricted diffusion are quantified using the apparent diffusion coefficient, they are seen as a hypodense area (Fig. 15.8). The size of the lesion with this abnormality predicts future outcome; however, the critical size for possible improvement is not known, and DWI cannot distinguish which lesions may be reversible after specific treatment (particularly thrombolytic therapy). Practical use of DWI in acute situations remains undefined, and most currently published studies on these MR sequences represent a fraction of the admitted patients with acute stroke. FLAIR sequences are also superior to routine MR sequences, and a recent study comparing multimodality MR techniques found a sensitivity of 98% for DWI and 91% for FLAIR for detecting ischemic brain lesions within hours of the ictus.41 The accuracy of DWI for subcortical infarcts is 95%.42 An important recent development is the potential value of MRI diffusion (DWI) and perfusion (PWI) to assess salvageability of tissue when considering thrombolysis. It seems from preliminary studies that a mismatch between DWI and PWI (hypoperfusion lesion more than diffusion lesion) may be present in a considerable proportion of patients and could suggest the presence of a reversible penumbra after thrombolysis.43These evolving but not established techniques could be used to assess patients who may be eligible outside the accepted clinical windows, assuming that DWI abnormalities would indicate cell injury.44

Figure 15.4 Computed tomographic scans. A: Middle cerebral artery stem occlusion. B: Superior division occlusion. C: Striatocapsular infarct.

Figure 15.5 A,B: Hyperdense middle cerebral artery tissue-type sign. The sign disappeared after administration of developed.

Figure 15.6 Signs of late swelling of middle cerebral artery infarct on computed tomography. Note sparing of the anterior cerebral artery and posterior cerebral artery territories (black arrows), shift, and contralateral hydrocephalus (white arrows).

Currently, CT scanning remains the most important initial study and, in most institutions without immediate 24-hour MRI services, is not likely to be replaced soon by these more sensitive, and undoubtedly superb, tests for the diagnosis of ischemic stroke. Until then, it is therefore of utmost importance that physicians treating ischemic stroke be familiar with the early signs on high-definition CT scans.45

Using MRI and MRA, vertebrobasilar artery occlusion is diagnostic in virtually all cases, although the extent of the infarction may take some time to mature (Fig. 15.9). A marked discrepancy between the initial CT scan (which may show only a hyperdense basilar artery sign) and the MRIs may be seen. CT scanning of cerebellar infarcts may be characterized by only a faintly developed hypodensity and distortion of the fourth ventricle. MRI is also the preferred test in cerebellar infarcts because it defines the degree of compression and herniation (Fig. 15.10).

Figure 15.7 A,B: Fluid-attenuated inversion recovery (FLAIR) image of evolving right middle cerebral artery stroke compared with virtually normal computed tomographic scan.

Computed Tomographic Scan Angiography

CT scan angiography with a high dose of contrast medium is beginning to replace MR angiographic studies.46 It immediately provides the site of arterial occlusion and an estimate of the capacity of the collaterals. However, the introduction of a large amount of contrast material remains of concern in patients with increased serum creatinine levels, and the additional acquisition time may have an effect on the first 3-hour period in which intravenous tPA is used, particularly in institutions not yet equipped for the study.47,48 In addition, observer agreement among neuroradiologists may be marginal in acute occlusion of the MCA, particularly in the assessment of symmetrical arterial enhancement.49 Thus, the study may be less practical when used to assess vascular occlusion before the use of intravenous tPA.47,48

Figure 15.8 DWI showing (A) restricted diffusion (arrow) and (B) reduced ADC (arrows). ADC, apparent diffusion coefficient.

Figure 15.9 Examples of vertebrobasilar occlusive disease on magnetic resonance imaging. A: Study with fluid attenuation inversion recovery shows infarction in temporal lobe, pons-mesencephalon, thalamus, and occipital lobe very consistent with occlusion of the top of the basilar artery. B: Midbasilar stenosis on magnetic resonance angiography and cerebellar and occipital infarct (arrows).

Figure 15.10 Cerebellar stroke with swelling and early hydrocephalus (left) from fourth ventricle obstruction on computed tomographic scan and magnetic resonance imaging (middle, right).

The role of CT scan angiography in basilar artery occlusion has not been determined, but the study may be useful in patients with fluctuating symptoms, to assess whether occlusion is imminent, a finding that only then may lead to conventional cerebral angiography. It may also resolve problems with localization in patients with predominant hemiplegia.

Cerebral Angiography

Cerebral angiography remains the standard means of determining the extent of occlusion and collateral circulation. Its use in acute situations is defined by whether intra-arterial thrombolysis is considered and thus requires a certified interventional neuroradiologist. However, in approximately one-third of patients, cerebral angiography done immediately after an ischemic stroke yields normal findings or shows a distal branch occlusion or a carotid occlusion unsuitable for thrombolysis.

First Priority in Management

Initial management should involve supportive stabilizing measures and consideration of thrombolysis. The contraindications for thrombolysis are shown in Table 15.3. Although CT scan findings should be normal, it is not known whether very early signs of infarction (effacement of the lentiform nucleus) preclude the use of tPA; but current practice is to accept early changes and only defer thrombolysis with large hypodensity (more than one-third of the territory), sulci effacement, and other signs of brain swelling. These signs may reduce the chance of recovery (are indicators of permanent ischemia) or perhaps increase the risk of intracerebral hematoma.

There is concern about possible unnecessary exclusion of patients eligible for intravenous tPA, tPA has been inappropriately deferred in patients with “mild deficits,” prior use of aspirin, prior strokes, or old age. In some instances, the physician allows a few more minutes to observe improvement, followed by deferral of tPA after crossing the 3-hour limit.50 The exclusion criteria of seizure onset are debatable, as is “major surgery preceding 14 days.” When surgery involves body areas that can be amenable to homeostasis, thrombolysis should not be automatically deferred. Cervical arterial dissection is not an absolute contraindication.51

Table 15.3. Eligibility Criteria for Using Intravenous Recombinant Tissue-type Plasminogen Activator for the Treatment of Acute Ischemic Stroke

   Clinical indication
   Ischemic stroke within 3 hours of onset of symptoms (the last time patient was noted to be at baseline neurologic status before the stroke)
Clinical contraindications
   Any history of intracranial hemorrhage
   Pretreatment of systolic blood pressure > 185 mm Hg
   Diastolic blood pressure >110 mm Hg
   Mild neurologic signs (e.g., isolated sensory deficit)
   Symptoms suggesting subarachnoid hemorrhage
   Stroke or serious head trauma within the preceding 3 months
   Gastrointestinal or urinary hemorrhage within the preceding 21 days
   Major surgery within the preceding 14 days
   Arterial puncture at a noncompressible site within the preceding 7 days
   Seizure at the onset of stroke
   Taking oral anticoagulants
   Received heparin within previous 48 hours
Radiographic contraindications
   Evidence of intracranial hemorrhage on computed tomography of the brain
   Laboratory contraindications
   Prothrombin time >15 seconds (international normalized ratio >1.7)
   Platelet count < 100 × 10
   Elevated partial thromboplastin time
   Blood glucose level <50 mg/dL

Intravenous thrombolysis with tPA can be started if symptoms have not abated within 3 hours after onset. A reasonable, albeit arbitrary, guideline is an NIH Stroke Scale score of more than 4. This could reduce the chance of significantly worsening a minimal deficit with an intracerebral hematoma. The ictus should be precisely known and not estimated. It is typically not known when patients have awakened from a night's sleep. Administration of tPA is intravenous, in a dose of 0.9 mg/kg (maximum 90 mg), with 10% of the total dose given in a 1- to 2-minute bolus and 90% in a 1-hour infusion (Box 15.1).52

Box 15.1. Recombinant Tissue-type Plasminogen Activator (tPA)

Currently used fibrinolytic agents ate plasminogen activators. tPA catalyzes plasmin formation from plasminogen. Plasmin degrades circulatory fibrinogen and the fibrin lattice of thrombi into soluble end products. Heparin enhances plasmin generation and, thus, enhances the tPA effect, which has a biologic half-life of 3–8 minutes. The major source of tPA is vascular endothelium; tPA has a high affinity for fibrin-bound plasminogen. It results in a less severe systemic thrombolytic state than that seen with urokinase. In clinical use, tPA causes a marked decrease in or depletion of measurable circulating plasminogen and fibrinogen, resulting in prolongation of the partial thromboplastin time.

When patients are seen between 3 and 6 hours after onset, intra-arterial administration of tPA should be considered.53,54 This requires expertise available in tertiary centers. A randomized study showed efficacy of clot lysis in patients eligible for this procedure.55,56

Fluctuation often occurs in patients with an MCA (Ml) occlusion, and some improvement may be related to improved collateral flow and partial dissolution of the thrombus. Cerebral angiography, however, should not be deferred for that reason; and in many patients, an occluding thrombus is present that is suitable for thrombolysis. Combined “bridging” therapy is cerebral angiography after a reduced (usually half) dose of intravenous tPA and no improvement clinically. This is followed by intra-arterial lysis of the clot, if still present. This approach has been studied in a very small series of patients, but no improved outcome was observed.57 Intravenous heparin is not used 24 hours after intravenous tPA but is recommended after intra-arterial tPA. A summary of current practice recommendations for thrombolysis (intra-arterial or intravenous) is shown in Figure 15.11. Deviation from this protocol may be considered in extreme circumstances. For example, the presence of a hyperdense MCA sign in an elderly patient (>80 years) with a high NIH Stroke Scale score may indicate a poor outcome and a comparatively high rate of hemorrhagic conversion. In young patients (arbitrarily defined as less than 40 years), we believe a cerebral angiogram is warranted to define the occlusion. Because many of these occlusions represent less organized venous clots due to a high prevalence of patent foramen ovale in this population, we consider mechanical disruption first before proceeding with intra-arterial tPA.58,59

Figure 15.11 Algorithm for use of intravenous (IV) or intra-arterial (IA) thrombolysis, tPA, tissue plasminogen activator; NIH, National Institutes of Health.

Table 15.4. Initial Management of Acute Ischemic Stroke in Anterior Circulation

Protect airway, endotracheal intubation if desaturation is noted on pulse oximeter
No antihypertensive medication, accept mean arterial pressure of ≤130 mm Hg, use of 5 mg of labetalol intravenously if pressure is continuously elevated and no other cause is apparent
Rehydrate with 0.9% NaCl, 2 L/24 hours
Correct hyperglycemia (glucose 100–150 mg/dL) with insulin
Correct hyperthermia with a cooling blanket
If computed tomographic scans show swelling and coma is rapidly deepening, give mannitol 20%–25%, 1g/kg, and consider decompressive hemicraniectomy

Management of a massive ischemic stroke remains complex. Many therapeutic measures are unproved. The initial guidelines for stabilization are shown in Table 15.4. Options are intravenous heparin, blood pressure augmentation, and rehydration. The use of intravenous heparin is an unresolved issue and has many opponents. Proponents use intravenous heparin in patients with large artery occlusions due to a cardiogenic source.60 It should not be used in patients with a large territorial infarction to reduce the chance of early significant hemorrhagic conditions. It is important not to aggressively manage hypertension because cerebral perfusion is marginal in the area of infarction. We discontinue any antihypertensive agent and accept any mean arterial blood pressure less than 130 mm Hg in the first 24 hours. Patients should remain normovolemic, normoglycemic,61 and normothermic. Mannitol can be considered when swelling leads to clinical deterioration, but decompressive hemicraniectomy to relieve intracranial pressure and reduce brain stem shift may be indicated (Box 15.2). The procedure may still result in profound disability.63,64,65 Early preemptive decompressive hemicraniectomy in patients at risk is not justified. Some patients with mass effect on CT scan recover spontaneously.65

The outcome of untreated basilar artery occlusion is poor. Many series without the use of intra-arterial thrombolysis have reported 80%–90% mortality or poor outcome. The management of basilar artery occlusion has been revolutionized by the use of intra-arterial thrombolysis within 12 hours of presentation.54,66MRI abnormalities showing early infarction in the cerebellum and pons probably should not preclude the use of intra-arterial thrombolysis because they may indicate ischemia rather than permanent infarction.54 Recanalization can be demonstrated in approximately 60% of patients, with clinical improvement in a similar proportion. However, the selection of patients potentially eligible for intra-arterial thrombolysis is not well defined. (Some centers have used thrombolysis in patients 14–79 hours after onset of symptoms, but most of these patients had fluctuating clinical courses interrupted by a sudden, more severe deficit.66) Initial stabilization of acute stroke in the posterior circulation is shown in Table 15.5.

Predictors of Outcome

Large hemispheric infarcts have a worse prognosis when early swelling and mass effect are evident on CT scans. Overall, mortality is 50%, but if clinical signs of herniation occur, mortality approaches 80%. Indicators of poor prognosis are use of mechanical ventilation to protect the airway and coma. Basilar artery occlusion is associated with major fluctuations in neurologic findings; thus, outcome remains difficult to predict early in the clinical course, certainly in the emergency department. The involvement of the thalamus in top-of-the-basilar artery occlusions can cause a devastating loss of memory despite frequent recovery from ataxia. Locked-in syndrome at presentation or coma virtually never is associated with a functional outcome, but an incomplete clinical picture may improve substantially. Outcome in patients with acute basilar artery occlusion who have apnea is poor, and we and others rarely have found survivors.21However, dramatic reversals of coma and locked-in syndrome have been reported after urokinase injected intra-arterially but only within an ictus and treatment interval of 12–15 hours.54

The cerebral angiogram has important prognostic features in basilar artery occlusion. Occlusion of a short restricted portion of the basilar artery has a higher probability of recanalization after intra-arterial thrombolysis than that of longer segments. In addition, collateral circulation has predicted a better outcome after recanalization.66

Box 15.2. Decompressive Hemicraniectomy

Large hemispheric infarcts maybe caused by carotid artery or MCA occlusion. Swelling may occur after an interval of several days and cause a herniation syndrome.62 Supportive therapies, such as hyper-ventilation and administration of mannitol, glycerol, barbiturates, and corticosteroids, have been unsuccessful. A large craniectomy with duraplasty to allow swelling outside the skull may be considered. There is some anecdotal evidence that this procedure has increased survival and resulted in 30%–50% functional outcome. The surgical procedure should be offered to patients irrespective of the involved hemisphere. Alternative therapies, such as moderate hypothermia (32°C or 33°C) or combined hypothermia and decompressive surgery, have appeared successful. Large randomized trials are needed to resolve many uncertainties about the outcome in patients with these interventions.63

Cerebellar infarcts may cause sudden deterioration from swelling and pontine compression. Outcome remains good, including in patients who have emergency surgical evacuation. Many patients of all ages may be able to ambulate with minimal assistance. Early withdrawal of care is not appropriate.


·     If intra-arterial administration of tPA is considered, cerebral angiography suite.

·     Neurologic intensive care unit for monitoring brain swelling, hemorrhagic conversion, and possibly intracranial pressure.

·     Patients with cerebellar infarcts who have normal Glasgow coma scores and early CT scan findings may not necessarily have to be admitted to the intensive care unit, but a repeat CT scan is needed within 12 hours to monitor early swelling.

·     Operating room for suboccipital craniectomy or ventriculostomy, or both, in cerebellar infarcts when brain stem compression causes upward-gaze palsy, deteriorating motor responses, and pupillary changes.

Table 15.5. Initial Management of Acute Ischemic Stroke in Posterior Circulation

Protect airway and intubate early if patient has marked bulbar symptoms
Maintain flat body position to optimize blood pressure
Perform immediate cerebral angiography of posterior circulation if intra-arterial administration of tissue plasminogen activator is possible (<12 hours from onset)
Consider ventriculostomy or suboccipital craniectomy with cerebellar swelling from infarction

Arterial Dissection

A tear in the intima permits blood to dissect its way more distally into the muscular arterial wall and create a double lumen into the artery.67,68 It occurs most commonly in the supraclinoid segment of the internal carotid artery.69,70 The vast majority of vertebral artery dissections are at the level of the C1 and C2 vertebral bodies or at the intradural segment. The clot may dissect under the intima (subintimal) or throughout the media (subadventitial), causing distention of the vessel wall inward, producing occlusion, or outward, creating a pseudoaneurysm (Fig. 15.12).68 A false luminal channel can be created when intramural hemorrhage exits at a more distal site, but this is uncommon. Intracranial dissections may perforate the thin media and adventitia, causing sub-arachnoid hemorrhage, with CT scan patterns similar to those of aneurysmal subarachnoid hemorrhage (Chapter 13).71 A pseudoaneurysm does not rupture but may become a nidus for emboli and thus may need surgical therapy if antiplatelet agents are ineffective.

Dissection of the internal carotid vertebral artery is mostly spontaneous and may represent 10%–25% of ischemic strokes in adults aged 35–5069,70Predisposing factors have been reported, and they may be more common in vertebral artery dissection than in carotid artery dissection. The dissection can be the result of a direct force to the artery, possibly triggered by strenuous activity, head turning, or chiropractic maneuvers but also by seemingly trivial insults, such as a brief Valsalva maneuver.67 There is a seasonal predilection for autumn.72 An increased incidence of upper respiratory infection during this period may suggest an inflammatory cause or insults from repeated coughing. Dissections have been associated with congenital abnormalities of the wall of the artery, such as cystic medial necrosis, fibro-muscular dysplasia,73 Marfan's syndrome, Ehlers-Danlos syndrome type IV, α1-antitrypsin deficiency, autosomal-dominant polycystic kidney disease, and familial lentiginosis.74 In a prospective study of dissections at the Mayo Clinic, joint and skin laxity and facial stigmata of an underlying vasculopathy were found but could not be characterized as typical arteriopathy.75

Figure 15.12 Process of arterial dissection (A) leading to occlusion (B), rupture (C), and pseudoaneurysm (D) or healing (E).

Dissection of the carotid or vertebral artery may be associated with head injury,76 but in a report on five patients with traumatic dissections of the internal carotid arteries, cystic medial necrosis and marked lack of elastic fibers were found, suggesting a primary arteriopathy that increased the vulnerability of the arteries to trauma.77

Clinical Presentation

Headache or neck pain is present in approximately 60% of patients. The headache can be sudden but infrequently is a typical “thunderclap headache” (see Chapter 6). Thunderclap headache should suggest subarachnoid hemorrhage from dissection through the entire wall in the intracranial portion. Headache may precede an ischemic stroke by several days and may not be clearly remembered or vocalized by the patient. The character of the headache is dull and seldom throbbing. Retroorbital headache of sudden onset should point to carotid artery dissection. Carotid artery dissection might be associated with a new presentation of Homer's syndrome, pulsatile tinnitus, and lower cranial nerve involvement, particularly the twelfth cranial nerve, causing weakness of the tongue. Other lower cranial nerves can become compressed in the cervical parapharyngeal space.69 The ninth to twelfth cranial nerves are in close proximity to the internal carotid artery and alone or in combination can become involved, producing dysarthria, dysphasia, dysphonia, and dysgeusia (metallic or bad taste). Less common are a decreased sensation of the frontal division of the trigeminal nerve, oculomotor palsy, and abducens palsy.78 Carotid dissection may be almost completely without any clinical neurologic deficits except for a new carotid bruit. This finding in a young patient with sudden facial or occipital headache should point to a dissection and prompt immediate neuroimaging studies.

Cerebral infarction involves MCA branch occlusions from propagated emboli. The interval between dissection and cerebral infarction varies widely, from minutes to 1 month, but is less than a week in most patients.79 Low-flow (“misery”) infarction involving watershed areas is an uncommon mechanism80,81despite trickle flow with poor collateral compensation in some patients. Carotid occlusion may result in a malignant infarct with massive swelling involving the ACA and MCA territories.

Dissection of the extracranial vertebral artery is manifested almost immediately by signs of an ischemic stroke in the cerebellum involving, as expected, the territory of the PICA. Severe vertigo, vomiting, and appendicular ataxia might be presenting symptoms. In patients with vertebral artery dissection, the lateral medulla may become involved, causing typical Wallenberg's syndrome (see Table 15.2).82 Swelling of the infarcted cerebellar tissue might cause considerable mass effect, displacement of the pons, and obstructive hydrocephalus.

Interpretation of Diagnostic Tests

Magnetic Resonance Imaging and Magnetic Resonance Angiography

MRI may replace conventional cerebral angiography as the first diagnostic test because it provides a definitive diagnosis in a large proportion of cases. Magnetic resonance angiography (MRA) is highly sensitive and specific in the diagnosis of internal carotid artery dissection but much less sensitive for a diagnosis of vertebral artery dissection.83,84 Combined MRI and MRA compared with conventional arteriography has a sensitivity of 84% and a specificity of 99% for the diagnosis of carotid dissection.85 MRI also may show the typical dense “crescent” or “double-lumen” sign, which reflects an intramural thrombus, often found at lower slices (Fig. 15.13).

Figure 15.13 Magnetic resonance image showing double-lumen sign (arrows) in bilateral carotid dissections.

Cerebral Angiography

Cerebral angiography remains the standard procedure. The most typical angiographic finding is relatively smooth, irregularly tapered luminal narrowing, often producing a very high stenosis (string sign) (Fig. 15.15).84 Dissections may occur in both vertebral arteries, in the carotid and vertebral arteries, or in all four arteries at the same time. A pseudoaneurysm might be found later, with typical fusiform appearance.

First Priority in Management

Carotid dissections might resolve within 6 weeks but reconstitution to a normal lumen after 6 months is uncommon (Fig. 15.14). Many physicians favor anticoagulation with intravenous heparin followed by warfarin (aiming at an international normalized ratio between 2 and 3) until MRI and MRA show recanalization, but this is deferred if the dissection involves the intracranial portion because of the risk of causing subarachnoid hemorrhage (although very low [10%] in patients with intracranial dissection).86 Antithrombotic therapy with aspirin 325 mg daily or clopidogrel 75 mg daily can be continued for another 3 months, but this period is arbitrary. Aneurysmal dilatation also may disappear spontaneously. However, it might become a source of recurrent transient ischemic attacks. If embolization occurs despite antiplatelet therapy, aneurysmal dilatation warrants surgical therapy or coil embolization of the artery with stenting of the occluded artery.87 Endovascular treatment may be considered in patients with intracranial vertebral artery dissections and possibly tailored to those with large or growing aneurysmal dilations and certainly when associated with sub-arachnoid hemorrhage (see Chapter 13).88

Predictors of Outcome

Permanent stenosis of the carotid artery remains associated with a low incidence of recurrent stroke (0.7%), and ischemic strokes have occurred despite aspirin or warfarin.89 Dissection may recur in 1% per year (2% in the first month).90 Patients with associated hereditary disorders do not have a higher incidence of recurrence of dissection, and a history of dissection in a family member does increase the incidence of recurrence. Outcome from infarction due to dissection appears more favorable in younger patients than in older patients with similar infarcts; the explanation is not known. Massive swelling may occur because of involvement of the anterior circulation; mortality is high without decompressive craniectomy.

Figure 15.14 Magnetic resonance angiography shows a right vertebral artery dissection and cerebellar and thalamic infarcts (arrows). Recanalization of the right vertebral artery occurred in 3 months.


·     Admission to the ward for intravenous administration of heparin in patients with extracranial dissections.

·     Admission to the neurologic-neurosurgical intensive care unit when early hemispheric brain swelling is evident on CT scans.

·     Admission to the neurologic-neurosurgical intensive care unit for patients who have vertebral artery dissections with cerebellar infarct.

Multiple Small Vessel Occlusion

Multiple cerebral infarctions represent a separate entity but with different causes. The differential diagnosis is particularly complex in younger persons, and extensive evaluation of underlying coagulopathies or intrinsic vasculopathies is needed.

The diagnostic considerations in these patients seen in the emergency department are shown in Table 15.6. Only the disorders that are clinically the most relevant are discussed here.

Figure 15.15 Cerebral angiogram of distal carotid artery dissection (arrows).

Vasculitis of the Central Nervous System

Granulomatous vasculitis or isolated angiitis of the central nervous system (CNS) is an emergency and may rapidly lead to permanent devastating ischemic strokes or, less commonly, to intracranial hematomas or subarachnoid hemorrhage.91,92 Progressive or recurrent neurologic symptoms are common, but because of the infrequent occurrence of this disorder, they may not be recognized as typical features of CNS vasculitis until the destruction is permanent. Delay in diagnosis has been established as an unfortunate fact.93

The presentation of CNS vasculitis as sub-arachnoid hemorrhage is mentioned in Chapter 13 and as a consequence of herpes zoster encephalitis in Chapter 17.

Clinical Presentation

Two-thirds of patients present with severe, persistent headache overriding any other symptom. Profound aphasia, apraxia, or hemiparesis may occur, but acute confusion and, most typically, emotional lability with crying or bizarre hysterical or childish behavior are more common. Some patients become dull and abulic, particularly with preferential involvement of the anterior cerebral circulation. Multifocal neurologic findings can be expected because the pattern involves scattered inflammation of the medium- and small-sized arteries.93

Table 15.6. Diagnostic Considerations in Patients with Multiple Cerebral Infarctions

Cerebral Infarctions

Primary isolated angiitis (granulomatous) of the central nervous system

Giant cell arteritis

Associated systemic or collagen vascular disease (sarcoidosis, Behcet's disease, polyarteritis nodosa, Wegener's granulomatosis, systemic lupus erythematosus, Sneddon's syndrome)

Associated infections (herpes zoster, cytomegalovirus, neurosyphilis)

Drug-induced (amphetamines, heroin)


Malignant angioendotheliomatosis (intravascular lymphomatosis)

Moyamoya disease

Hereditary endotheliopathies

Nonatherosclerotic vasculopathy with skin abnormalities (e.g., Fabry's disease, Degos' disease)


Subacute bacterial infections

Nonbacterial thrombotic (marantic) in advanced cancer


Protein C deficiency

Antiphospholipid antibody syndrome

Protein S deficiencies

Antithrombin III deficiencies

Hemoglobin disorders

Sickle-cell syndromes

Platelet disorders

Thrombotic thrombocytopenic purpura

Antiphospholipid antibody syndrome

Hemolytic-uremic syndrome

CNS vasculitis may be secondary to a systemic illness or drug abuse. Skin lesions, joint swelling, or additional evidence of mononeuritis multiplex or progressive polyneuropathy may point to a connective tissue disorder or systemic vasculitis. The use of an amphetamine often can be inferred only from a careful history of drug use, which is not volunteered by most patients with strokes.94,95,96

Infectious causes can produce CNS vasculitis, but other localizations should be evident (e.g., retina for cytomegalovirus, painful crusty skin lesions for herpes zoster, pulmonary manifestations associated with Histoplasma or Coccidioides immitis, or systemic manifestations of human immunodeficiency virus infection). Finally, lymphoproliferative disorders (Hodgkin's lymphoma) may be associated with vasculitis.97

Moore's criteria for the diagnosis of isolated angiitis of the CNS are (1) recent severe onset of headaches, confusion, or multifocal neurologic deficits that are recurrent or progressive; (2) typical angiographic findings; (3) exclusion of systemic disease or infection; and (4) leptomeningeal and parenchymal biopsy findings that confirm vascular inflammation and exclude infection, neoplasia, and noninflammatory vascular disease.92,98,99

Interpretation of Diagnostic Tests

Computed Tomographic Scanning and Magnetic Resonance Imaging

The sensitivity of CT scanning in isolated angiitis is low, but occasionally subarachnoid hemorrhage due to rupture of involved sulcal arteries can be found (see Chapter 13).100 CT scanning may help diagnose Wegener's granulomatosis, characterized by bone thickening and focal erosive changes of the nasal septum and soft tissue masses in the sinuses. MRI abnormalities should reveal infarction involving several vascular territories, producing effacement of sulci and hyperintense signals following the gyri (Fig. 15.16). In some patients, the initial predilection sites are the parieto-occipital lobes, mimicking reversible posterior leukoencephalopathy.101 Lesions deep in the white matter that spare the overlying cortex are less common.102 Conversely, it can be generally stated that normal MRI findings, certainly with FLAIR sequences, virtually exclude widespread CNS vasculitis.103 MRA may be useful as an initial screening test; but it overestimates narrowing, may not visualize abnormalities in medium-sized or smaller arteries due to current poor resolution, and therefore does not match cerebral angiography.

Cerebral Angiography

The sensitivity of cerebral angiography in CNS vasculitis is high, approximately 95%–99%. A cerebral angiogram with negative findings has been described in biopsy-proven CNS vasculitis. Suggestive findings are changed vessel caliber, with constriction, occlusion (“cutoffs”), irregularities, and dilatation showing a characteristic beading pattern (Fig. 15.16D). Alternative explanations for the angiographic findings include cerebral vasospasm (very unusual on the day of onset of hemorrhage), advanced atherosclerosis (proximal carotid artery abnormalities or irregularities in the proximal vertebrobasilar system may be suggestive of atheromatous disease), and radiation-induced occlusive vasculopathy (abnormalities inside the radiation field).104,105 The inflammatory changes in the wall eventually lead to fibrosis and may lead to fixed angiographic narrowing.106

Blood and Serology

It is important to exclude a connective tissue disorder by measurement of antinuclear antibody, rheumatoid factor, antineutrophil cytoplasmic antibodies, sedimentation rate, and serology against human immunodeficiency virus, herpes zoster virus, cytomegalovirus, syphilis, and Toxoplasma. It is also important to obtain a urine sample for amphetamines.

Cerebrospinal Fluid

A profound inflammatory response is usually absent, including in patients with progressive disease. Mildly increased protein may be the only sign. Mild pleocytosis (≤20 lymphocytes/mm3) has been found in fewer than 50% of cases.107

Brain Biopsy

Biopsy should involve the area that is abnormal on MRI, and available series claim 70% sensitivity. Random brain biopsy has a very low yield and probably should be deferred if angiographic findings are diagnostic and the cerebrospinal fluid is normal. The biopsy specimen, which should include the dura, leptomeninges, cortex, and white matter, is fixed in 10% buffered formalin for light microscopy.108 Tissue samples should be frozen or stored with dry ice for later interpretation by electron microscopy. The pathologic hallmark is an infiltrate consisting of lymphocytes, histiocytes, and plasma cells involving the intima or media, with occasional necrosis of both leptomeningeal and intracerebral vessels.109 Giant cells may be seen in areas of fragmented internal elastic lamina. Prominent necrosis should suggest polyarteritis nodosa. (Unfortunately, less characteristic or ambiguous pathologic findings may be the only result after a brain biopsy.)

Figure 15.16 Computed tomography (A,B) and magnetic resonance imaging (C) show multiple infarcts associated with central nervous system vasculitis. D: Cerebral angiographic findings of segmental stenosis and beading are typical.

First Priority in Management

Administration of corticosteroids in patients with presumed clinical CNS vasculitis is advised, and it should begin if no other causes are evident and if the patient is known to have collagen vascular disease. Brain biopsy within days in cortico-steroid-treated patients should not mask inflammation and certainly not necrosis. Methylprednisolone 1 gram for 3 days and cyclophosphamide 15 mg/kg using slow infusion should be started with active disease, and there is a reasonable consensus among experts that only such an aggressive treatment can reverse CNS inflammation. It is followed by corticosteroids 1.5 mg/kg daily, and cyclophosphamide 2 mg/kg daily orally. Cortico-steroid administration can be tapered to a lower dose after 4 weeks, but cyclophosphamide, which has very low side effects with this dose, should be given for 1 year. The patient should be familiar with a 20% risk of infertility from cyclophosphamide, and egg or sperm harvesting should be offered. Proton pump inhibitors should be added for stomach ulcer protection and possibly cotrimoxazole for Pneumacystis cariniipneumonia prophylaxis. Adequate hydration with intravenous fluids and frequent monitoring of the white blood cell count are needed to reduce the risk of hemorrhagic cystitis, and one should change the dose in case of neutropenia.

Predictors of Outcome

Recurrence is more common when patients are treated with corticosteroids alone. Outcome can be very good after aggressive combination therapy with administration of cyclophosphamide for at least 1 year (the estimated relapse rate then is <10%). Corticosteroid doses can be tapered after 6 months. Mortality is uncommon, but functional outcome can be quite severely impacted when cerebral infarcts are widespread or located in both frontal lobes.


·     Urgent cerebral angiography and neurosurgical consultation for possible cerebral biopsy

·     Neurology ward

Hematologic Disorders

Albeit unusual, disorders of coagulation, disorders of the structure of red blood cells, and platelet dysfunction may cause multiple cerebral infarcts in rapid succession.110,111 These disorders may not be apparent with routine automated laboratory evaluation in the emergency department, which measures only white blood cell count, platelet count, and sedimentation rate. Both small and large arteries may become occluded, and neurologic deficits may vary. Noteworthy clinical features of these hematologic disorders are discussed in this section.

Clinical Presentation

Red Blood Cell Disorders

Sickle-cell syndromes are rather prevalent, in most instances caused by a single amino acid substitution in the globin βchains (valine instead of glutamic acid). Sickle-cell disease or sickle-cell trait (heterozygotic state) is more prevalent in African-American patients, often manifested after a hypoxemic trigger, cold, or excessive alcohol consumption. Sickled masses of red blood cells occlude the arterial and venous systems, but other mechanisms, such as vasculopathy or fat embolization from infarcted bone marrow, may be operative. Stroke as a first presentation of sickle-cell disease has rarely been documented, but earlier ischemic strokes, predominantly those localized in the subcortical white matter, may be silent. One should inquire about previous episodes of Streptococcus pneumoniae infections, osteomyelitis by Salmonella species, painless hematuria, painful priapism, retinal-vitreous hemorrhage, or crises resulting in chest and abdominal pain.

Polycythemia vera, a more complex disorder of increased erythrocytes and platelets, causes increased viscosity. It should be considered in patients with generalized pruritus, splenomegaly, headaches, and paresthesias. With a prevalence of five cases per one million persons, it is very uncommon.

Polycythemia may occur as a consequence of hypoxemia with cyanotic heart disease or obstructive pulmonary disease, but its association with is-chemic stroke is less evident also, because precise understanding of the mechanism is lacking.

Platelet Disorders

Thrombotic thrombocytopenic purpura should be considered in multiple strokes of undetermined cause when patients present with a documented gradual decrease in platelet count. Middle-aged women are predominantly affected. Characteristic additional clinical signs are hematuria, myalgia, bloody diarrhea, fever, and, in some patients, rapidly developing renal failure. These symptoms, caused by platelet microthrombi, may not appear in 25% of cases, and ischemic stroke may be the defining illness. Seizures are comparatively frequent, and non-convulsive status epilepticus may be a presenting feature. Headache, acute confusional episodes, and hemiparesis may progress to coma if not aggressively treated with plasma exchange.

Thrombocytosis may occur in many underlying disorders, often chronic myeloid leukemia and myelofibrosis, or as a myeloproliferative disorder itself. Cerebrovascular manifestations, although recognized as a complication of myeloproliferative disorders, are not well characterized.

Antiphospholipid Antibody Syndrome

This increasingly recognized syndrome associated with antiphospholipid antibodies is a common manifestation in younger patients.112,113,114,115 Both anticardiolipin antibodies and lupus anticoagulants can be demonstrated, but they may not be linked to each other. Evidence of arterial occlusions (ocular, peripheral artery, pulmonary, or mesenteric artery) or venous occlusions (deep venous thrombosis or jugular venous thrombosis113), miscarriages, and prior unexplained pulmonary hypertension are clues to the diagnosis. In 20% of patients, ischemic stroke is part of this syndrome. Inappropriate treatment results in a high rate of recurrence of cerebral infarction.112,113,116 Clinical features may include cardiac bruit (from associated mitral valve lesions or, possibly, Libman-Sacks endocarditis) and livedo reticularis.116 Blotchy hands and feet should point to the diagnosis (see Color Fig. 15.17 in separate color insert). Multiorgan failure may be a presenting feature.117

Interpretations of Laboratory Tests

Blood and Serum

Hemoglobin electrophoresis yields the diagnosis in sickle cell disease. Associated findings are increased leukocyte count, recent decrease in hemoglobin concentration (hemolytic anemia), and hyperbilirubinemia.

Polycythemia vera is diagnosed by increases in hematocrit and white cell count and, at later stages, bone marrow metaplasia. Laboratory criteria (minor criteria) are platelets >400,000/µL, leukocytes >12,000/µL, leukocyte alkaline phosphatase score >100, and vitamin B12 >900 pg/mL.

Thrombotic thrombocytopenic purpura is considered when the following laboratory findings are present: fragmented red blood cells (schistocytes, or helmet cells), increased reticulocytes, unconjugated bilirubinemia with normal prothrombin time and partial thromboplastin time, and normal fibrin degradation products (differentiating it from disseminated intravascular coagulation and antiphospholipid antibody syndrome.) Lactate dehydrogenase is greatly increased. Haptoglobin should be low or even unmeasurable.

Anticardiolipin antibodies can be determined, but only a high titer of immunoglobulin G (IgG) is diagnostic117,118 (many laboratories define high titer as 20–100 IgG phospholipid units or more). IgM titers may vary significantly and can be increased by nonspecific stimuli, such as fever, infection, and pharmaceutical agents. Activated partial thromboplastin time (PTT) is a good screening test. Prolonged PTT may occur in one-third of patients with antiphospholipid antibody syndrome.

Magnetic Resonance Imaging

Multiple cerebral infarcts, often involving branches of the ACA and MCA territory, are nonspecific but can be visualized on MRI with much higher sensitivity. The study is particularly diagnostic in thrombotic thrombocytopenic purpura and antiphospholipid antibody syndrome (Fig. 15.18).

Figure 15.18 Magnetic resonance images showing multiple ischemic infarcts (arrows) in antiphospholipid antibody syndrome.

First Priority in Management

The recommended management options for specific hematologic disorders are summarized in Table 15.7. Specific treatment in these disorders is seldom started immediately in the emergency department because of the necessary delay for diagnostic tests.

Predictors of Outcome

Outcome is difficult to predict because of the rarity of the disorders; thus, general rules apply. Multiple small vessel occlusions may result in full recovery. Untreated, the disorders may lead to multi-infarct dementia, disabling hemiplegia, and speech and language disorders.


·     Neurology ward.

·     Intensive care unit in life-threatening thrombotic thrombocytopenic purpura, sickle-cell crises, and evidence of other sites of vascular occlusion.

·     Concomitant medical illnesses may warrant admission to a medical or surgical intensive care unit.

·     Hematology consultation and consideration of bone marrow biopsy.

Table 15.7. Management of Stroke in Unusual Hematologic Disorders



Sickle-cell disease

Exchange transfusion

Oral folate

Polycythemia vera

Phlebotomy, 500 mL (aim at hematocrit ≤42%)

Hydroxyurea, 500 mg twice daily

Thrombotic thrombocytopenic purpura

Plasma exchange (up to three exchanges)

Prednisone, 60 mg

Alternatively, intravenous immunoglobulin (e.g., Gammagard S/D), 1 g/kg

Thrombocytosis (any cause)


Avoid anticoagulation

Antiphospholipid antibody syndrome

Heparin and long-term warfarin (international normalized ratio 3 or 4)

Cyclophosphamide (when associated with systemic lupus erythematosus)

Cerebral Venous Sinus Thrombosis

Cerebral Venous Sinus thrombosis is rare, equally distributed in males and females; however, the incidence rises steeply in the second and third decades in women because of its association with the use of oral contraceptives. The clinical spectrum of cerebral venous sinus thrombosis varies from a mild headache to progressive papilledema with rapidly deteriorating multiple hemorrhagic infarcts. The disorder is an acute neurologic emergency that may have a catastrophic outcome if not timely treated with intravenous heparin and, if available, endovascular lysis of the propagating thrombus within the cerebral venous system. Many conditions can be associated with cerebral venous thrombosis; however, despite extensive laboratory tests and increasingly sophisticated evaluation of coagulopathies, up to one-third of cases remain entirely unexplained. Causes associated with cerebral venous thrombosis are oral contraceptive use, pregnancy, the puerperium, anti-phospholipid antibody syndrome and lupus anticoagulant, congenital coagulopathies, and damage to the jugular vein associated with surgical trauma or sacrifice, or due to direct cannulation. Infectious causes, such as acute sinusitis, mastoiditis, infections involving the facial skin, and dental abscesses, need immediate recognition and treatment.

Clinical Presentation

The common early feature is headache refractory to commonly prescribed pain medication. The headache is related to increased intracranial pressure, which in turn is associated with venous hypertension. Venous hypertension reduces the reabsorption of cerebrospinal fluid and results in papilledema. The progression of headache, seizures, and focal neurologic deficits is rapid, in days; but in approximately one-third of patients, the course may be protracted.119 Cerebral infarction is typically hemorrhagic and may involve multiple territories. When multiple cerebral infarcts cause substantial swelling, herniation can occur.120 A large intracranial temporal hematoma may progress to uncal herniation syndrome. Involvement of a cortical vein alone is rare. Commonly, the vein of Labbé is involved in these types of cortical infarct, which are located in the parietotemporal region. (This is the largest superficial vein and mostly drains the posterior temporal region.) Cortical vein thrombosis may be manifested by focal or generalized seizures evolving into focal neurologic findings such as aphasia and hemiparesis.121

Figure 15.19 Computed tomographic scan with “string sign” (transverse sinus). Note hyperdensity in sigmoid sinus (left), transverse sinus (middle), and vein of Galen and straight sinus (right, arrows).

Figure 15.20 Hemorrhagic infarct from sagittal sinus thrombosis (A) and cortical venous thrombosis (B).

Figure 15.21 Magnetic resonance imaging and magnetic resonance angiography diagnosis of sagittal sinus (A) and left transverse sinus (B) thrombosis.


Interpretation of Diagnostic Tests


A typical CT scan feature is the cord or string sign, representing clot in the transverse sinus (Fig. 15.19). CT scanning may show multiple hemorrhagic infarcts with early swelling (Fig. 15.20). MRI and MRA usually are diagnostic and reveal the extent of venous thrombosis. Flow void is absent, and thrombus appears hyperintense on T1-weighted and hypointense on T2-weighted images (Fig. 15.21).122,123 In a study of transcranial Doppler ultrasonography, increased flow velocities or asymmetries in venous flow velocities were noted;124 however, the practical value of the technique in the emergency department is not known, and extent can be better defined by MRI and magnetic resonance venography.125


A propensity toward thrombosis should be examined by measuring antithrombin III, protein C and protein S for deficiencies126 and lupus anticoagulant or antiphospholipid antibodies. Factor V Leiden and the recently discovered 20210A allele mutation of the prothrombin gene may increase the risk of cerebral venous thrombosis.119,127,128

First Priority in Management

Currently, there is a shift in the management of cerebral venous thrombosis. Intravenous heparin has substantially reduced morbidity and mortality, even in patients with already developed hemorrhagic infarcts.129 Low-molecular-weight heparin was not more effective in a randomized trial.130 Nonetheless, thrombosis may progress despite adequate anticoagulation. Recanalization with thrombolytic agents through a catheter in the thrombosed vein has been successful in some case series.131

Predictors of Outcome

In a large group of patients, 86% had good recovery and those with involvement of only a portion of the venous system had even better recovery.119 Absence of associated cancer, common in many published series, is a predictor of good out-come.132 However, coma at presentation, seizures, and intracerebral hematomas do not predict poor outcome. A major discrepancy exists between the devastation seen on MRI and the outcome, and neuroimaging should not be a major factor in deciding on future care. Blindness from papilledema or seizures may become persistent sequelae.


·     Patients receiving intravenous heparin who have progression: to the neurointerventional suite for endovascular lysis of the clot

·     Neurosurgical intensive care unit to consider evacuation of hemorrhagic mass.

·     Treatment of increased intracranial pressure if multiple hemorrhagic infarcts and edema occur.


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