Pure Motor Hemiparesis

This is the most common manifestation of a lacunar stroke. In this syndrome, there is motor involvement of the face, arm, and leg, sometimes with more involvement of one than the other, but with absence of sensory, visual, language, or other cortical symptoms. There are often varying degrees of dysarthria and dysphagia, as a result of involvement of corticobulbar tracts. Structures commonly involved in this syndrome reflect the descending course of the corticospinal tract: the corona radiata, the posterior limb of the internal capsule (Fig. 42-3), and the basis pontis. Less often, a midbrain peduncular or medullary pyramidal infarct (with sparing of the face) can also cause this syndrome. The diagnosis of brainstem pure motor hemiparesis requires the absence of all the following: vertigo, deafness, tinnitus, diplopia, nystagmus, and ataxia. Traditionally, it has been taught that isolated monoparesis, usually brachial, is rarely caused by lacunar infarct but instead indicates a cortical or centrum semiovale lesion, regions where the motor homunculus is more spatially separated. However, with the advent of MRI, this has been shown not to be the case. Isolated monoparesis is compatible with small-vessel disease: for example, in the corona radiata and pons.³³

Figure 42-3 Diffusion-weighted MR image revealing a lacunar infarction in the posterior limb of the internal capsule on the right.

Pure Sensory Syndrome

Although this is considered the sensory analogue of pure motor hemiparesis, it occurs far less frequently than pure motor hemiparesis. It is usually caused by infarction of the ventro posteromedial and ventroposterolateral nuclei of the thalamus as a result of involvement of the inferolateral artery off the P2 segment of the PCA, but it can also result from corona radiata infarction through interruption of thalamocortical projections. Both spinothalamic and lemniscal modalities are usually affected, but selective sensory impairment can also occur. Perfect splitting of the midline on sensory testing can be observed, and involvement of midline structures such as tongue and genitalia may also be present. The hemisensory deficits may be complete or incomplete with a cheiro-oral predominance. Some patients may develop a chronic pain syndrome, especially with right thalamic lesions, with pronounced dysesthesias and paresthesias on the side contralateral to the thalamic involvement (Dejerine-Roussy syndrome). This syndrome usually appears in the subacute or chronic period and can be difficult to manage.

Sensorimotor Syndrome

This condition is a combination of sensory and motor deficits. Although single penetrator disease can probably cause this syndrome, there have been only a few autopsy studies, and the specificity of this syndrome for a lacunar mechanism is probably lower than for the other four syndromes. Nevertheless, most authors postulate predominant involvement of the thalamus with impingement on the adjacent posterior limb of the internal capsule. An alternative explanation, however, is that both the sensory loss and hemiparesis result from thalamic involvement alone, inasmuch as the inferolateral artery also supplies the ventrolateral nucleus, which projects to motor cortex.³⁴ It is likely that MRI will help to better define the anatomical basis of this syndrome.

Dysarthria–Clumsy Hand Syndrome

In this uncommon syndrome, there is a predominance of dysarthria and upper limb ataxia over the other clinical features. Less pronounced findings are mild to moderate facial, hand, and leg weakness. The usual stroke locations are the anterior limb or genu of the internal capsule and the basis pontis.

Ataxic Hemiparesis

The classic syndrome, caused by basis pontis infarction, was described as limb ataxia ipsilateral to distal leg paresis with minimal or no facial or arm weakness. This diagnosis can be difficult to establish, because limb dysmetria must be out of proportion to the hemiparesis. Other typical locations of infarction are the corona radiata, the anterior or posterior limb of the internal capsule, and the thalamus. The cerebellum has been implicated in some cases. Larger cortical strokes involving the ACA territory may manifest in a similar way, but the more pronounced leg involvement and the many behavioral abnormalities occurring with ACA-distribution strokes may help differentiate the two (see Table 42-1).

Anterior Circulation

Middle Cerebral Arteries

The MCAs account for about 80% of the blood flow to the cerebral hemispheres and are the arteries most commonly involved in hemispherical strokes. Also, because of the key structures supplied by them, they give rise to some of the most florid and dramatic ischemic stroke syndromes found in clinical practice.

The mechanisms by which the MCAs can be affected are multiple but most commonly involve either an embolism from a more proximal source such as the heart, aorta, or the large cervical vessels (i.e., cardioembolic and large-artery strokes, progressive intracranial disease from atherosclerosis) or other less common conditions such as sickle cell disease, postirradiation changes, moyamoya syndrome, primary CNS angiitis, and focal intracranial dissection.

The location in which embolic material can lodge is variable and includes the proximal MCA stem (usually associated with a more severe syndrome due to involvement of lenticulostriate arteries), its bifurcation (in which case the deep lenticulostriate branches are spared), or at one of the more distal branches beyond the bifurcation (the superior or inferior division and their smaller distal branches). The site of vessel occlusion and the extent of the collateral supply in a given individual determine the amount of tissue damage and therefore the clinical presentation. Individuals with limited collateral supply (from distal branches of the large vessels in the circle of Willis or from extracranial to intracranial anastomoses) are the more severely affected and have the worst prognosis. These patients usually have very large hemispherical strokes affecting the cortical and subcortical territories and are prone to massive hemispherical swelling and subsequent herniation (the “malignant MCA syndrome”).

Middle Cerebral Artery Stem Occlusion

The proximal syndrome is usually dramatic and reflects damage to the basal ganglia and internal capsule, supplied by the medial and lateral lenticulostriate branches that arise from the dorsal surface of the MCA stem, as well as large areas of cortical infarction in the territories of the superior and inferior divisions of the MCA (Fig. 42-4). The typical patient presents with contralateral hemiplegia with equal involvement of the arm and leg, variable degrees of primary sensory abnormality, dysphagia, and hemianopia. There is forced eye deviation toward the side of the affected hemisphere, sometimes with accompanying ipsilateral head deviation. With dominant hemispherical involvement, there is usually global aphasia, buccofacial apraxia, and ideomotor apraxia. In the first few days there may be frank mutism. With nondominant hemispherical involvement, there is usually contralateral hemineglect, contralateral anosognosia, and delirium. Less frequently, syndromes more often associated with bilateral hemispherical damage, such as prosopagnosia and the reduplicative paramnesias, can be present with unilateral nondominant hemisphere damage. Individuals with an MCA stem occlusion are the most likely to develop massive hemispherical swelling with midline shift, and subfalcine and transtentorial herniation. The prognosis for these patients is guarded, and in complete MCA-distribution strokes, the mortality rate can be as high as 80% despite neurointensive care efforts.

Figure 42-4 Diffusion-weighted MR image showing a large right hemispherical infarction from a right middle cerebral artery stem occlusion.

Middle Cerebral Artery Upper Division Occlusion

Isolated involvement is uncommon because the superior trunk is short, but when it occurs, it is usually caused by ICA or MCA atherosclerosis (Fig. 42-5). This division supplies most of the frontal convexity and anterior parietal lobe, and the syndrome resembles stem occlusion with a contralateral hemiparesis, forced eye and head deviation toward the side of the lesion, and variable degrees of aphasia and hemineglect. In contrast to stem occlusion, motor deficits are characterized by a gradient of weakness with the contralateral side of the face and arm (brachiofacial pattern) more severely affected than the leg, reflecting the involvement of the corresponding cortical structures rather than the internal capsule. A visual field defect is usually absent.

Figure 42-5 Angiogram after left internal carotid artery injection. Left middle cerebral artery shows a blockage distal to the origin of the lenticulostriate vessels, predominantly affecting the middle cerebral artery superior division.

With dominant hemispherical involvement, there is language disturbance characterized in the acute phase by global aphasia, which tends to reduce to predominantly Broca’s aphasia and speech apraxia. This highlights the fact that in the acute stroke setting, vascular aphasias are often global and nonclassic in their presentation.³⁵ With nondominant involvement, there may be some degree of visuospatial neglect but usually not as pronounced as with a larger territorial infarct. Acute agitated delirium is usually not present, because this requires infarction of the right middle temporal gyrus and inferior parietal lobule, supplied by the inferior division of the MCA (see later discussion). Because of the smaller volume of tissue infarction, upper-division MCA-distribution strokes do not cause the same high rate of mortality observed with holo-MCA strokes but carry a significant degree of long-term disability that necessitates intensive rehabilitation.

Middle Cerebral Artery Lower Division Occlusion

This condition is usually caused by cardiac embolism. In this syndrome, hemiparesis and forced eye-head deviation are usually absent, because there is sparing of perirolandic structures. Hemianopia can be present from involvement of the optic radiations, but the most obvious abnormalities are in the domains of language and behavior. With involvement of the dominant hemisphere, a predominantly fluent (sensory or Wernicke’s) or a conduction-type aphasia (inability to repeat spoken language) can be present in isolation, although an initial global aphasia can also be present. When the nondominant hemisphere is affected, behavioral abnormalities predominate with confusion/delirium and mild degrees of visuospatial inattention. Sensory aprosody may also occur in the acute state. The prognosis after such a stroke is relatively good, and the potential for rehabilitation can be greater than for other types of MCA-distribution strokes, because of the smaller territory involved and the absence of significant motor or sensory deficits.

There are syndromes associated with occlusion of each of the 12 vessels that branch off the two main MCA trunks. Space precludes description of MCA branch syndromes, but suffice to say that subcomponents of the trunk syndromes are observed and more subtle behavioral abnormalities may be apparent, because they are not obscured by more global abnormalities present with stem and trunk occlusions.

Anterior Cerebral Arteries

In comparison with strokes in the MCA distribution, ACA-distribution strokes are uncommon and are most often secondary to embolism from a proximal source such as the carotid artery or the heart. Less frequent causes of an ACA-distribution stroke include vasospasm from a ruptured saccular aneurysm (anterior communicating artery), in which case the strokes may be bilateral, and inflammatory vasculopathy involving the intracranial vessels. The most common manifestations of an infarct in the distal territory of the ACA are a function of the territories supplied: anterior and medial frontal lobes, including the motor-sensory cortex for the contralateral foot and leg; the supplementary motor area; and the central bladder representation, and also of lesion side³⁶ (Fig. 42-6).

Figure 42-6 Diffusion-weighted MR image showing a right parasagittal infarction in the distribution of the right anterior cerebral artery.

Left-sided infarction causes transient akinetic mutism (abulia), transcortical motor aphasia, contralateral leg and shoulder weakness with sparing of the distal upper extremity and face, and contralateral deficits in higher order sensory functions such as stereognosis (ability to discriminate two simultaneous stimuli) and joint-position sense discrimination. Right-sided infarction causes acute confusional state, motor hemineglect, transient akinetic mutism, contralateral hemiparesis, and sensory deficits in the pattern described for left-sided infarction. Predominant leg weakness is not unique to ACA infarction; it is also present with MCA-territory cortical infarction. It can also be present with capsular and pontine infarcts. In general, lesions that affect the medial premotor cortex, the supplementary motor area, and the rear portion of the medial part of the precentral gyrus, or their projections, can cause leg-predominant hemiparesis.³⁷

Bilateral ACA infarction causes persistent akinetic mutism, sphincter dysfunction (urinary more than defecatory incontinence) and paraplegia or tetraplegia. Bilateral ACA strokes can occur when both ACAs originate from the same carotid system, when only one ACA supplies both medial hemispheres (azygous ACA), in vasospasm from subarachnoid hemorrhage, or in the setting of an extrinsic lesion compressing both the ACAs (intraparenchymal hemorrhage, head trauma, subfalcine herniation).

In addition to abulia and predominant leg weakness, callosal disconnection syndromes can help distinguish ACA from MCA infarcts. The three main syndromes are left unilateral ideomotor apraxia, agraphia, and tactile anomia. All three syndromes affect the left hand in right-handed patients. Left unilateral ideomotor apraxia, also called the anterior disconnection syndrome, is the inability to perform overlearned skilled movements in response to verbal command. Patients with left-hand agraphia have severely impaired handwriting with their left hands but not their right. Patients with unilateral tactile anomia are unable to name objects placed in their left hands. All three syndromes are probably caused by interruption of transcallosal information to or from the language areas in the left hemisphere. They usually result from infarcts in different regions of the corpus callosum caused by interruption of pericallosal branches of the ACA. However, these syndromes, although of phenomenological interest, are overemphasized, in view of their low frequency of occurrence. They are relatively rare probably because the anterior corpus callosum is supplied by both ACAs.

The two to four recurrent arteries of Heubner arise near the junction of the anterior communicating artery and the ACA and supply the inferior part of the head of the caudate nucleus, the adjacent anterior limb of the internal capsule, and the subfrontal white matter. Caudate infarcts cause prominent behavioral abnormalities, including abulia, agitation, aphasia, and hemineglect. Extension of the infarct into the anterior limb of the internal capsule and anterior putamen can lead to dysarthria, movement disorders, and mild hemiparesis. However, the only study to associate symptomatic caudate infarcts with their culprit vascular territory showed that only one infarct was in the territory of Heubner’s arteries; the rest were in the territory of lenticulostriate vessels off the MCA.

Posterior Circulation

Twenty percent of ischemic events involve areas supplied by the posterior circulation, but they are often incorrectly diagnosed. For example, isolated lightheadedness, syncope, and vertigo are frequently blamed on a posterior circulation process even though it is almost never the cause of these symptoms. Conversely, a patient with multiple stroke risk factors may present with vertigo and gait ataxia resulting from brainstem ischemia, but vestibular neuronitis may be diagnosed. The term vertebrobasilar insufficiency, although popular, is vague with regard to mechanism and should be avoided. Overall, in patients with posterior circulation TIA and minor stroke, the risk of subsequent stroke or death is similar to that in patients presenting with carotid disease, although their risk is probably slightly higher than that of carotid patients in the acute phase. Posterior circulation TIAs carry a higher risk of recurrence than do anterior circulation TIAs.

Vertebrobasilar Territory Strokes

Extracranial Vertebral Arteries

The extracranial vertebral arteries (ECVAs) are frequently affected by atherosclerosis and this condition is a relatively common cause of posterior circulation strokes. The most common sites for atherosclerosis are at or near their origin from the subclavian arteries, analogous to atherosclerosis at the ICA origin, and at their entry point into the skull. The ECVAs are also susceptible to traumatic or spontaneous dissection (see “Stroke of Other Determined Causes” section). Progressive narrowing at the vertebral artery origin can eventually lead to total occlusion or serve as a nidus for thrombosis and distal embolization. Occlusion of one vertebral artery is usually well tolerated when the contralateral artery is patent and of sufficient caliber. In addition, the ECVA, unlike the ICA, gives off muscular branches and therefore can be reconstituted distally in the setting of origin stenosis. Thus, TIAs and strokes caused by ECVA stenosis result from embolism rather than from flow failure. The most common recipient sites for emboli from the ECVAs are the ipsilateral intracranial vertebral artery (ICVAs) and the top of the basilar artery.

Intracranial Vertebral Arteries

The most common site for ICVA atherosclerosis is the distal segment of the artery near the vertebrobasilar junction, after takeoff of the PICA and lateral medullary penetrators. The most common stroke syndrome associated with focal ICVA disease is the lateral medullary syndrome (Wallenberg’s syndrome), and it usually represents involvement of vertebral artery branches directly supplying the lateral medulla. In contrast, involvement of PICA itself usually causes cerebellar rather than medullary infarction and results from cardiac or ECVA embolism. Lateral medullary syndrome manifests with a subset of the following symptoms and signs: vertigo, dysphagia, hoarseness, ipsilateral facial and contralateral trunk and limb thermoanalgesia, ipsilateral oculosympathetic dysfunction, ipsilateral limb ataxia, gait ataxia, nausea, and vomiting. The specific constellation of symptoms depends on the rostrocaudal and horizontal extent of the medullary lesion. Occlusion of the medial PICA branch causes infarction of the dorsal medulla and the inferior cerebellar vermis. Involvement of the lateral PICA branch causes infarction of the posteroinferior cerebellar hemisphere, with truncal ataxia and ipsilateral limb ataxia. Brainstem signs such as vertigo and dysarthria are usually not present. Full PICA territory infarction causes vomiting, gait and ipsilateral limb ataxia, and truncal lateral pulsion. Multidirectional nystagmus may also be present. A full PICA infarction can lead to considerable edema, usually within 24 to 48 hours, with “pseudotumoral” mass effect. This can be rapidly fatal as a result of progressive pontine and medullary compression. Surgical decompression is necessary. Clues to brainstem compression include headache, vomiting, drowsiness, ipsilateral gaze preference, and ipsilateral hemiparesis.

Basilar Artery Branches

The basilar artery originates from the confluence of the two vertebral arteries at the pontomedullary junction and represents the main vascular supply to the brainstem and rostral cerebellum. Atherosclerosis is by far the most important pathology of the basilar artery, strokes are usually preceded by TIAs, and the paramedian pontine base is the most common site of infarction.

The main branches off the basilar artery arise in pairs: the anterior inferior cerebellar artery, the superior cerebellar artery, and the PCA. Throughout its course, the basilar artery gives rise to multiple penetrating and circumferential branches that supply the brainstem; it is responsible for the whole blood supply of the pons and much of the distal brainstem.

Anterior Inferior Cerebellar Arteries.

Infarction in this territory, usually resulting from in situ atherosclerosis unless there is bilateral involvement, is dominated by brainstem (the caudolateral pontine syndrome) rather than cerebellar symptoms. The mid-pons and middle cerebellar peduncle are the areas most often involved. The typical manifestation is ipsilateral peripheral facial weakness, Horner’s syndrome, deafness, limb ataxia, and contralateral hemiparesis with limb and trunk hypesthesia. In very rare cases, and only in patients with diabetes, isolated involvement of the internal auditory artery can manifest with isolated vertigo and/or hearing loss. This is mentioned to emphasize the fact that, apart from this exception, isolated vertigo is almost never caused by ischemic vertebrobasilar disease.

Superior Cerebellar Arteries.

Traditionally, it was thought that isolated superior cerebellar artery territory infarcts were rare but instead occurred in combination with midbrain, thalamic, and PCA territory infarcts, as a result of embolism to the top of the basilar artery. However, modern MRI suggests that the occurrence of isolated superior cerebellar artery infarcts has been underestimated.³⁸ These infarcts can be small or territorial, both most commonly caused by embolism. The superior cerebellar artery supplies most of the cerebellar cortex, the cerebellar nuclei, and the superior cerebellar peduncle. Superior cerebellar artery infarcts result in a combination of the following signs and symptoms: vertigo and dizziness, nystagmus, limb ataxia, gait ataxia, and mild hemiparesis. Clinical brainstem signs are usually absent.

Basilar Artery and Its Penetrators.

The posterior wall of the basilar artery gives rise to small paramedian and short circumferential arteries that supply the paramedian and lateral pontine regions. These arteries can be affected by either microatheroma at their origins or lipohyalinosis along their length. These are believed to be distinct pathological processes. Stroke from basilar artery disease is very variable and can range from a mild lacunar stroke, resulting from a small penetrator disease, to a large, devastating syndrome with extensive destruction of the brainstem from complete or almost complete basilar occlusion (Fig. 42-7). Pontine syndromes reflect the particular structures affected, with a basic division between strokes that predominantly affect the anterior pons and those that affect predominantly the pontine tegmentum. Anterior pontine infarctions can manifest as classic lacunar syndromes with pure motor hemiparesis or ataxic hemiparesis/dysarthria–clumsy hand syndrome, as a result of damage to the corticospinal tract and crossing corticopontocerebellar fibers. Strokes that predominantly affect the pontine tegmentum manifest with a constellation of brainstem signs as a result of involvement of the medial lemniscus, the medial longitudinal fasciculus, the cerebellar peduncles, the abducens nucleus, and the vestibular nuclei.

Figure 42-7 A, Extensive infarction of brainstem, occipital lobes, temporal lobes, and bilateral thalamus, resulting from acute basilar occlusion. B, Angiographic lateral view in the same patient, demonstrating midbasilar and distal basilar occlusion with distal reconstitution through superficial cerebellar collateral vessels.

Locked-in Syndrome.

One of the most devastating conditions in clinical neurology is observed after basilar artery occlusion with extensive infarction of the ventral pons (basis pontis) and is commonly referred to as locked-in syndrome. Because of infarction of key motor structures in the basis pontis (pontine nuclei, corticospinal tract, and corticobulbar tract), the patients present with tetraparesis evolving to tetraplegia, pronounced dysphagia, and anarthria. Extraocular movements are affected, most notably with bilateral gaze paresis, often with preserved vertical gaze. Vertical gaze, as well as normal alertness, is intact because of preservation of the rostral structures in the midbrain and pontine tegmentum, respectively. Blinking may be spared, and in these cases patients can communicate only with vertical eye movements or blinking of the eyes. With a more extensive damage and rostral midbrain involvement, blinking can also be affected, and patients may have bilateral ptosis, a situation difficult to differentiate from a comatose state. The locked-in syndrome usually results from extensive in situ thrombosis of the basilar artery and carries a poor prognosis.

Top-of-the-Basilar Syndrome.

When an embolic particle arises either from the heart or from the proximal vertebral arteries, it travels all the way downstream until it lodges in a vessel with a diameter equal to or less than that of the particle size. Because of the relatively large diameter of the basilar artery, this usually occurs at the distal segment, where it gives rise to both superior cerebellar arteries and PCAs and leads to a constellation of signs and symptoms commonly referred to as the “top-of-the-basilar” syndrome. Infarction of the rostral midbrain (tectum, posterior commissure, red nucleus) leads to oculomotor abnormalities such as vertical gaze palsies, convergence retractive nystagmus, bilateral hyperconvergence (“pseudo-sixth” nerve palsy), and eyelid retraction. The involvement of the more caudal midbrain results in damage to the cranial nerve III nucleus and fascicle and is responsible for cranial nerve III palsy with bilateral ptosis, midposition and poorly reactive pupils, and internuclear ophthalmoparesis. Midbrain involvement also includes damage to the ascending reticular activating system with consequent somnolence or stupor.

In rare cases, patients may present with vivid, well-formed visual hallucinations after strokes in the distal basilar territory, a phenomenon called peduncular hallucinosis. There exist few pathological studies of the usual location and nature of the lesions causing such a syndrome, but it is thought to occur from rostral midbrain or thalamic involvement.

Other structures that can be affected by an embolus to the distal basilar artery include the occipital lobes, medial temporal lobes, and thalami (Fig. 42-8). Their involvement can be either unilateral or bilateral and gives rise to multiple signs or symptoms referable to the involvement of the PCA territory (see next section).³⁹

Figure 42-8 Computed tomographic scan demonstrating bilateral thalamic strokes secondary to embolization to the top of the basilar artery (“top-of-basilar” syndrome) from a cardiac source.

Posterior Cerebral Arteries.

The PCAs are the terminal branches arising from the basilar artery. In about 30% of patients, one PCA arises from the ipsilateral ICA; this is a so-called fetal PCA. Infarcts in the PCA territory are mainly caused by emboli, which is perhaps not surprising because the PCAs are the end territory of the posterior circulation. The first, P1, segment of the PCA courses posteriorly around the midbrain and gives off small branches to the midbrain and medial thalamus before it becomes the P2 segment, which supplies the ventral and lateral thalamus, the occipital lobe, and the medial temporal lobe. The three most prominent symptoms and signs after PCA territory infarction are headache, positive and negative visual field defects, and hemisensory disturbances. The most common visual field abnormality is a hemianopia from infarction of the optic radiations or calcarine cortex. If the field cut is transient, release hallucinations can occur at its edges as it clears. Involvement of the lateral thalamus and surrounding afferent white matter tracts is responsible for hemisensory disturbances, which can range from hemibody tingling to frank hemianesthesia in all sensory modalities. Sometimes the sensory complaints are accompanied by clumsiness and ataxia, also probably attributable to thalamic involvement, whereas dense hemiparesis results from infarction of the cerebral peduncle.

In addition to the common symptoms and signs described previously, there are unique neuropsychological deficits in up to 60% of patients with visual field defects. These neuropsychological deficits are hemisphere specific or hemisphere predominant. Some of the neuropsychological deficits are more florid when there is bilateral PCA infarction. Infarction in the territory of the left PCA that extends to the splenium of the corpus callosum or to its neighboring parieto-occipital white matter leads to alexia without agraphia. Visual perception is normal in the preserved left hemifield, but the information cannot reach language areas of the left hemisphere. In addition, there is color anomia because color percepts are purely visual and therefore no other sensory modality can be evoked to provide a clue to the left language region. In addition to alexia without agraphia and color anomia, some patients have visual object agnosia. Alexia with agraphia, along with some anomia, occurs with infarcts in the left temporo-occipital junction. Infarction of the left medial temporal lobe can lead to anterograde and retrograde amnesia, which can last months. Presumably, the contralateral hippocampus can take over with time. It follows that permanent anterograde amnesia can result from bilateral PCA infarcts.

Prosopagnosia can occur with right inferior occipitotemporal lesions. Other behavioral syndromes associated with right PCA infarction are less specific and probably reflect right parietal syndromes, inasmuch as the PCA sometimes supplies parts of the right posterior parietal lobe.

Balint’s syndrome can arise after unilateral or bilateral infarction of the superior parietal lobule at the parieto-occipital junction, supplied by the MCA-PCA watershed. The syndrome, also known as optic ataxia, is characterized by defective directional control of visually guided reaching movements, but motor execution is normal when other sensory modalities are used. On-line control is more impaired than feedforward planning, and errors in reaching are variable with no appreciable constant errors. Anton’s syndrome is denial of blindness despite clear physiological evidence for it after bilateral occipital infarction. This syndrome can be accompanied by agitation/delirium, possibly from the decreased visual input or concomitant involvement of the temporal lobes.

Duplex Doppler and Transcranial Doppler Imaging

The Doppler effect is noted through detection of flow velocity of a moving object, determined by the time between insonation and reflection of ultrasound waves through a given medium. In the case of duplex Doppler study, anatomical imaging is determined through the B-mode gray scale whereas Doppler shift values are determined through the reflection of the ultrasound waves by the moving red blood cells in the extracranial and intracranial vessels. When the intracranial vasculature is studied, both technologies can be used, but the use of Doppler studies, without the anatomical definition provided by the B-mode gray scale, is the most widely available.

Duplex study of the extracranial circulation is most useful in the determination of the degree of stenosis of the ICA (Fig. 42-9). This determination is crucial because of the difference in the approach to patients with a recent ischemic stroke related to an ipsilateral ICA stenosis (see later discussion). Analysis of the ECVAs also provides valuable information in patients with posterior circulation strokes.

Figure 42-9 Duplex Doppler image of the extracranial carotid system, demonstrating high-degree stenosis at the origin of the internal carotid artery (ICA). CCA, common carotid artery.

When duplex Doppler imaging is compared with the “gold standard” for anatomical definition (digital subtraction angiog raphy), the sensitivity and specificity for hemodynamically significant (>70% diameter narrowing) extracranial ICA stenosis varies between 85% to 90% and 75% to 80%, respectively.⁴⁴ On the basis of these numbers, the best approach is to combine duplex Doppler study with another noninvasive imaging modality, such as MRA, because both tests, when concordant, have been shown to accurately predict significant extracranial ICA stenosis in more than 90% of the cases.^45,46 Nonconcordance most often occurs because ultrasonography and MRA can differ in the degree of stenosis they reveal, with a tendency for MRA to overcall degree of stenosis. Another concern is whether noninvasive techniques can reliably differentiate high-grade stenosis from occlusion, a critical factor in surgical decision making. For example, Doppler imaging might demonstrate total ICA occlusion, whereas, in fact, a string sign is present; conversely, an ascending pharyngeal artery or muscular branch may be mistaken for residual flow through an occluded ICA. In such a situation, conventional angiography, CTA, or gadolinium-enhanced MRA should be considered.

Transcranial Doppler (TCD) imaging is used to determine the blood flow velocities of the large and medium-sized intracranial arteries, and indirectly, estimate flow. The approaches used when TCD imaging is performed can be the transtemporal approach (ACA, MCA, and PCA), the transforaminal approach (vertebrobasilar system), and the transorbital approach (ophthalmic vessels and carotid siphons). Flow velocities can help identify a focal stenosis, proximal occlusion with decreased distal flow, or complete occlusion of one of the three cerebral arteries. TCD imaging is particularly helpful in cases of stenosis of the intracranial arteries, such as those in atherosclerotic or inflammatory vasculopathies, and is a test of proven utility in helping determine the need for exchange transfusion in patients with sickle cell disease.

TCD imaging is a valuable tool in the assessment of the intracranial consequences of cervical carotid or vertebral stenosis. Specifically, TCD imaging can detect blunted waveforms and recruitment of collateral pathways (e.g., cross-filling from the anterior communicating artery) (Fig. 42-10). TCD imaging can also provide information on adequacy of collateral flow through the use of vasodilatory challenges such as carbon dioxide inhalation (see later discussion). Also, TCD imaging can be used to monitor the MCAs for evidence of intermittent embolization from a proximal arterial or cardiac (PFO, atrial fibrillation) source (Fig. 42-11).

Figure 42-10 Transcranial Doppler image after bilateral middle cerebral artery insonation, demonstrating blunted waveform on the right in comparison with the left. This appearance is compatible with a proximal internal carotid artery high-grade stenosis.

Figure 42-11 Transcranial Doppler image after agitated saline injection, demonstrating multiple microembolic signals (MES) compatible with a right-to-left cardiac shunting from a patent foramen ovale (PFO). PI, pulsatility index.

Computed Tomographic Angiography

This technique combines injection of intravenous contrast as a bolus, with high-speed continuous CT scanning of a volume of interest, followed by three-dimensional reconstruction of the extracranial and intracranial vasculature from the original cross-sectional images. CTA is of great potential benefit for evaluation of patients for acute thrombolytic treatment, because these patients must obtain a CT scan anyway to rule out hemorrhage, and CT scanning is still much more available than MRI in the emergency setting. If occlusion and high-grade stenosis of intracranial vessels off the circle of Willis are not identified, perhaps because of spontaneous recanalization, then mobilization of an interventional radiology team may not be justified. CTA has some important limitations, however. First, CTA cannot always reliably distinguish between moderate and high-grade stenosis. This is especially true when mural calcification is present. Second, patients undergoing CTA must ingest an intravenous contrast agent, which can be toxic to the kidneys in patients with preexisting renal insufficiency, dehydration, and poorly controlled diabetes.

Magnetic Resonance Angiography

Like CTA, this is a noninvasive modality to study the intracranial and extracranial circulation. The objective of any MRA technique is to maximize signal coming from the vessel while minimizing background signal. The most popular sequences are two- and three-dimensional time-of-flight (TOF) MRA. TOF MRA is based on flow-related enhancement of blood signal, which allows blood to be differentiated from stationary tissues. The data may be acquired as single slices (two-dimensional) or as a thick slab that is subsequently reconstructed into thin sections (three-dimensional). In the case of three-dimensional imaging, blood flow must be more rapid in order to traverse the whole slab before saturation occurs with attendant loss of signal. Thus, three-dimensional TOF is usually better for vessels in which flow velocity is high (i.e., cervical arteries and the circle of Willis), whereas two-dimensional TOF is better for assessing cerebral veins and sinuses. Phase-contrast MRA is another technique that is time-consuming and has not had much application in the workup of ischemic stroke so far. One scenario in which phase-contrast MRA can be helpful is when an arterial lumen is stenosed by subacute thrombus, which is bright on T1 images. Thus, a TOF MRA might misread a bright vessel as patent when it is in fact occupied by subacute thrombus. This high signal is subtracted out in phase-contrast imaging.

TOF MRA is helpful as a screening test for significant (>70% diameter reduction) ICA stenosis because it has comparable sensitivity to digital subtraction angiography. However, TOF images can be contaminated by artifacts in the presence of slow flow or turbulence. This is a problem mainly when slow flow caused by ICA stenosis leads to signal dropout, which is mistaken for very high-grade stenosis or complete ICA occlusion. Therefore, when no ICA stenosis is identified on MRA, no further testing is necessary, but when significant stenosis is detected, imaging with another noninvasive modality should be obtained (duplex Doppler imaging or CTA).⁴⁶ In the case when MRA suggests complete occlusion, CTA, gadolinium-enhanced three-dimensional MRA, or conventional angiography should be used as confirmatory tests, despite the high sensitivity and specificity of MRA in complete ICA occlusion reported in some studies.⁴⁷ MRA also has utility in detecting intracranial atherostenotic disease but, again, tends to overestimate the degree of stenosis and should be followed by digital subtraction angiography for better spatial definition and determination of whether the lesion is amenable to interventional radiological approaches. Other pathologies detectable by MRA are extracranial dissection, Takayasu’s arteritis, and moyamoya syndrome. MRA is usually followed by digital subtraction angiography when intervention is planned.

Workup for a Cardioembolic Source

Ischemic stroke is a vascular disease and is frequently caused by cardiac embolism. Thus, investigation of the cardiovascular system is an integral part of the diagnostic workup. Electrocardiography is helpful in determining the baseline rhythm, as well as identifying markers of cardiovascular risk factors such as ventricular or atrial enlargement and evidence of a prior myocardial infarction. When the initial electrocardiogram yields little information, 24-hour Holter monitoring should be considered, especially when the presentation, neurological examination findings, and pattern of infarction are suggestive of embolus. TTE should also be performed in patients after stroke to rule out mechanical abnormalities of the cardiac chambers or valves predisposing to thrombus formation. TTE is especially important in patients with prior large myocardial infarction, to rule out ventricular aneurysm with superimposed thrombus.

When TTE does not reveal a potential embolic source, TEE should be considered. With the exception of the patient with an otherwise obvious source of distal embolism such as tight ipsilateral ICA stenosis or known atrial fibrillation, all other patients should undergo evaluation with TEE to definitely rule out a cardiac embolic source. TEE has considerably higher sensitivity and specificity than TTE for valvular abnormalities, including vegetations; left atrial and atrial appendage thrombus; atrial myxoma and other cardiac tumors; presence of spontaneous echo contrast in the atrium; and PFO with associated ASA. TTE, because of the close proximity of the left ventricle to the thoracic wall, has a higher yield than does TEE for left ventricular thrombus.

Adequate Oxygenation

Despite promising results with animal models^52,53 and anecdotal reports of clinical efficacy, there is currently no definitive evidence to support the use of supplemental oxygen therapy, despite its widespread use in victims of acute stroke.⁵⁴ When hypoxemia is present, it should be treated aggressively because it is extremely detrimental to penumbral brain tissue. All efforts in the emergency room should be geared toward avoiding further neuronal loss through transformation of the ischemic penumbra into infarct.

Blood Pressure Management

Many patients with acute stroke have an elevated blood pressure in the first few hours to days after the ictus. The levels may be above 200 mm Hg for systolic blood pressure but usually normalize without treatment within a few days. In view of the current notion of a viable ischemic penumbra and loss of local vessel tone in the area surrounding an acute infarction (where cerebral vascular resistance is less responsive to changes in CPP), it is imperative that no attempt is made to reduce the blood pressure in the acute peristroke period. Moreover, in chronically hypertensive individuals, the upper and lower limits of the autoregulatory curve are shifted upward, and therefore blood pressure reduction to within the normal range may extend infarction into penumbral regions. Two important exceptions are made: (1) for patients eligible for intravenous tissue-type plasminogen (tPA), because current guidelines require that systolic blood pressure be less than 185 mm Hg and diastolic pressure less than 110 mm Hg, and (2) patients with evidence of ongoing or imminent end-organ damage, such as pulmonary edema, acute myocardial infarction, acute aortic dissection, or acute renal insufficiency.⁵⁵ In such patients, careful gradual blood pressure lowering can be attempted with parenteral medications such as β blockers (labetalol) or calcium channel blockers (nicardipine). When possible, these agents are preferred over direct venodilators such as nitroprusside or nitroglycerin. Research has focused on the dependence of peri-infarct brain perfusion on systemic blood pressure and its relevance for short- and long-term recovery. Investigators using SPECT found a negative relationship between blood pressure reduction and improvement in CBF,⁵⁶ but the sample size was too small to extrapolate the results to the general stroke population. In two prospective studies, investigators found deleterious effects of acute blood pressure lowering on outcomes at 21 days⁵⁷ and at 3 months, respectively.⁵⁸

In the debate on how to better manage blood pressure in the peristroke period, a new concept has arisen: pharmacologically induced hypertension in patients in whom acute, reversible flow failure is suspected on clinical grounds or from perfusion MRI/CT scan. The approach seems most plausible for patients with acute large-vessel stenosis or occlusion, in whom penumbral tissue would benefit from increased perfusion and further recruitment of collateral channels. However, except for small pilot studies,⁵⁹ no universally accepted protocol is in place, and this strategy cannot be recommended outside of a clinical trial.

Glycemic Control

The notion that hyperglycemia is detrimental to ischemic brain tissue is not new.⁶⁰ Only since 2000, however, have the concepts of neuronal damage and infarct expansion been demonstrated for hyperglyamia in humans by neuroimaging⁶¹ and functional outcomes studies.⁶² In the National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rt-PA) trial, hyperglycemia was identified as an independent predictor of worse outcomes as well as a risk factor for ICH complicating treatment with thrombolytics.⁶³ Hyperglycemia also seems to reduce the effect of thrombolysis, probably by making the ischemic penumbra less amenable to the benefits of reperfusion.⁶⁴ The effects of hyperglycemia are likely to predispose to acute clinical worsening⁶⁵ and possibly play a significant role in long-term recovery and mortality.⁶⁶ Although there is nearly consensus on the detrimental effects of hyperglycemia in the acute stroke period, more studies are needed to determine its optimal management. The only large multicenter trial to date to address the safety of aggressive glycemic control was the United Kingdom Glucose Insulin Trial (GIST-UK). The investigators concluded that continuous infusion of glucose/potassium/insulin solutions is feasible and safe in the peristroke period.⁶⁷ A smaller group of patients has been reported in whom tight glycemic control was maintained with a continuous insulin infusion, but symptomatic, readily reversible hypoglycemia occurred in 20% of the patients.⁶⁸ It is currently not known whether aggressive control of blood glucose translates into short- or long-term benefits or whether there is increased risk of hypoglycemic episodes. Despite the lack of current guidelines and formal recommendations, it seems reasonable that the patients with acute stroke, particularly those eligible for thrombolytic treatment, should undergo aggressive correction of hyperglycemia.

Temperature Control

Although hypothermia seems plausible as a neuroprotective strategy, studies are still scarce, and no clear recommendations can be made at this point. Animal studies have reliably demonstrated adverse outcomes associated with hyperthermia in the peristroke period, but only as recently as 2000 have objective data in humans shown an effect of elevated temperature on clinical outcomes.⁶⁹ Two large studies demonstrated the benefit of induced hypothermia in hypoxic-ischemic brain damage after cardiac arrest, but there are no comparable studies on the effects of hypothermia on focal ischemic lesions.^70,71 It is reasonable to recommend control of peristroke pyrexia with the usual measures available in current clinical practice, acetaminophen and cooling blankets, until more data become available.

Recanalization Strategies

aPTT, activated partial thromboplastin time; CT, computed tomography; INR, international normalized ratio; rt-PA, recombinant tissue plasmin activator.

Adapted from Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333:1581-1587.

The dose of rt-PA chosen was lower than that for ECASS, and the blood pressure exclusion criteria were stricter (systolic blood pressure <185 mm Hg and diastolic blood pressure <110 mm Hg) (Table 42-5). Endpoints were defined in two parts: Part 1 required an improvement in the first 24 hours of more than 4 points in the National Institutes of Health Stroke Score (NIHSS) scale. Part 2 required improvement at 3 months on the Barthel Index (score = 95 to 100), the modified Rankin Scale (score = 1), and the Glasgow Outcome Scale (score = 1). The results of part 1 did not show a significant difference between the two groups. In part 2, benefit from tPA was observed in all outcome measures: Patients treated with tPA were 30% to 50% more likely to have no or minimal disability at 3 months than were those treated with placebo.⁷⁶ The benefit was maintained regardless of stroke subtype and was still present 6 months and 1 year after stroke.⁷⁷ The rate of symptomatic ICH was 6.4% in the tPA-treated individuals, in comparison with 0.6% in the placebo arm, but the mortality rates at 3 months and 1 year were not different between the two groups. Predictors of better outcome were treatment within 90 minutes⁷⁸ (Fig. 42-12) and decrease in NIHSS score at 24 hours.⁷⁹

TABLE 42-5 National Institute of Neurological Disorders and Stroke rt-PA Study Protocol for Intravenous Thrombolysis in Acute Ischemic Stroke

Rights were not granted to include this table in electronic media. Please refer to the printed book.

From Adams, HP, Adams RJ, Brott T, et al: Guidelines for the early management of patients with ischemic stroke. Stroke 2003; 34:1056-1083.

Figure 42-12 Graph of model estimating odds ratio for favorable outcome at 3 months in patients treated with recombinant tissue plasminogen activator (rt-PA) in comparison with those treated with placebo by time from stroke onset to treatment. Odds ratio > 1 indicates greater odds that rt-PA treated patients will have a favorable outcome at 3 months in comparison with the placebo-treated patients.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(From Marler JR, Tilley BC, Lu M, et al: Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology 2000; 55:1649-1655).

Independent risk factors for symptomatic ICH were the severity of the stroke (measured by the NIHSS score), brain edema, or mass effect at baseline CT scan.⁸⁰ Later studies showed that elevated blood glucose level at the time of treatment was also independently associated with higher risk of ICH.⁶³ In 1996, on the basis of these favorable results, the U.S. Food and Drug Administration (FDA) approved the use of intra venous tPA for acute ischemic stroke within 3 hours of onset in patients who met inclusion/exclusion criteria.

After a post hoc analysis of ECASS demonstrated benefit in patients treated within 3 hours of stroke onset, a second trial (ECASS II) was conducted. The changes in the original protocol included a lower dose of tPA (0.9 mg/kg) and the exclusion of patients with CT evidence of large infarction (more than one third of the MCA territory involved, diffuse swelling). Other exclusion criteria were similar to those in the NINDS trial. The final analysis showed no significant difference between the treatment and the placebo recipients when the favorable outcome of a modified Rankin Scale score of 0 or 1 was considered (minimal or no disability). However, a post hoc analysis dichotomizing patients as either functionally dependent (modified Rankin Scale score > 2) or independent (modified Rankin Scale score = 2) found a significant 8.3% absolute difference in favor of the treatment recipients.⁴¹ As observed in the NINDS trial, the rate of symptomatic ICH was higher in the treatment recipients (8.8%) than in the placebo recipients (3.4%), but the 3-month mortality rates were similar.

The FDA approval of intravenous tPA for acute stroke, along with subsequent favorable reanalyses and meta-analyses of existing intravenous tPA trials, has led to a broad consensus that it is an effective treatment for acute stroke. However, there have been many criticisms of the NINDS trial, and there remain many questions that will be answered only by further trials, not by reanalyzing old data. It is notable that the American Heart Association/American Stroke Association guidelines for intravenous tPA did not change from 2003 to 2005; which reflects the absence of new information.

Some of the major concerns with the extant tPA trials and meta-analyses, along with questions that remain, are as follows: (1) The efficacy of intravenous tPA is small and available to only a very limited group of patients. (2) The NINDS trial is the only one to show benefit based on prespecified outcome measures. The other trials required post hoc analysis to show a benefit. (3) There was a statistically significant difference between the treatment groups in the NINDS study. Of note, in the 91- to 180-minute time window within which most patients receive intravenous tPA, there were over four times more patients in the mildest stroke severity category who received intravenous tPA than patients who received placebo. (4) Information on stroke etiology was inadequate, and therefore it is still not known which stroke subtypes are best treated with intravenous tPA. For example, it is unclear whether lacunar infarcts in the absence of large vessel disease are really ameliorated with intravenous tPA. (5) The effects of age, prior aspirin use, white matter disease, and stroke subtype on hemorrhage risk are unknown. (6) It is not known whether there are systematic differences in recanalization rates for ICA, MCA stem, basilar, and branch occlusions. (7) Recent data suggest that patients with rapidly improving or mild symptoms should still receive tPA. (8) Patients with very high NIHSS scores show only minimal benefit from tPA.

Intravenous Thrombolysis Beyond the 3-Hour Period

The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study was designed in an attempt to expand the narrow window for intravenous tPA use.⁸¹ The study tested the safety and effectiveness of intravenous tPA (0.9 mg/kg) within 5 hours of stroke onset. The primary endpoint was excellent neurological recovery (NIHSS score = 1) at day 90. The tPA dose and the other inclusion and exclusion criteria were similar to those of the NINDS trial. The result was negative; tPA treated patients had higher rates of symptomatic ICH and mortality at 90 days. The delayed time window drove the negative result, as only 15% of patients were treated within 3 hours of onset.

A metaanalysis of pooled data from the NINDS, ATLANTIS, and ECASS trials has been performed. A total of 2775 patients treated with either placebo or intravenous thrombolysis within 360 minutes of stroke onset were analyzed. The odds ratios of a favorable outcome at 3 months were 2.81 for the patients treated within 90 minutes and 1.55 for those treated within 91 to180 minutes. There was no significant difference in mortality between patients treated within 270 minutes, but the mortality rate among patients given thrombolytics more than 270 minutes after stroke onset was in excess of 45%. Hemorrhage rate did not appear to be related to the time for thrombolysis but was related to age and the use of thrombolytics as opposed to placebo.⁸² Of note, this metaanalysis, like a Cochrane review,^82a also suggested some benefit in patients treated between 180 and 270 minutes after stroke onset (odds ratio, 1.4). Nevertheless, intravenous thrombolysis is currently not recommended more than 3 hours after stroke onset. It is clear that 3 hours is not a magic number, and more physiological measures are sorely needed to optimally select patients for recanalization therapy. There are almost certainly patients in whom recanalization and completion of infarction have occurred within 3 hours and who would therefore not benefit from intravenous tPA and only be placed at unnecessary risk for hemorrhage. Conversely, there may be other patients, with persistent occlusion and large areas of misery perfusion, who could still benefit from recanalization more than 3 hours after stroke onset. The critical measures are likely to be the demonstration of both large-artery occlusion and the presence of a substantial volume of penumbral tissue beyond the infarct core.

A way forward is to use the combination of DWI, PWI, and MRA to provide a rapid assessment of the ischemic infarct core (DWI), the presence of arterial occlusion (MRA), and tissue at risk, defined as an area of reduced perfusion that extends beyond the boundaries of the diffusion abnormality. This is known as PWI-DWI mismatch. The concept of PWI-DWI mismatch has recently been modified for two reasons. First, as noted in the “Ischemic stroke” section, there is a spectrum of reversible ischemia from benign oligemia to impending necrosis. Second, DWI abnormalities are not always indicative of irreversible ischemia. Thus, the new definition of the penumbra (tissue at risk) excludes a rim of benign oligemia and includes some of the DWI core with high ADC values.⁸³

A recent magnetic resonance study of the evolution of DWI- and PWI-observed lesion volumes, from acute to subacute time points, showed a contraction of the PWI-observed lesion by 85% and an expansion of the DWI-observed lesion by 136%.⁸⁴ The Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) pilot study showed improved recanalization, reduced DWI expansion, and penumbral salvage in patients who received intravenous tPA within 6 hours.⁶¹ The magnetic resonance surrogate measures were correlated with clinical outcome measures. These theoretical considerations, observational studies, and pilot studies have led to five ongoing studies (EPITHET; Diffusion-weighted imaging Evaluation For Understanding Stroke Evolution [DEFUSE]; Desmoteplase in Acute Ischemic Stroke Trial [DIAS]; MR and Recanalization of Stroke Clots Using Embolectomy [MR RESCUE]; and ReoPro Retavase Reperfusion of Stroke Safety Study [ROSIE]) evaluating tPA or mechanical thrombolysis on the basis of penumbral dynamics. Preliminary data are favorable,⁸⁵ but it is necessary to wait until the trials are completed because many intuitively appealing ideas for stroke treatment have been shown to be untenable after completion of properly randomized trials.

Thrombolysis in the Community

With the approval of intravenous tPA for acute stroke treatment, multiple groups tried to ascertain whether the benefits observed in the NINDS trial were reproducible at the community care level. In 2000, Katzan and colleagues published the experience at 29 hospitals in the Cleveland area and determined the rate of use of thrombolytics, related complications, and protocol violations.⁸⁶ Their results showed that only 1.8% of all patients admitted with a diagnosis of ischemic stroke received intravenous tPA. Moreover, of the treated patients, 15.7% had symptomatic ICH, and the NINDS protocol was violated in 50% of the cases. The analysis also showed higher in-hospital mortality rates in the tPA-treated patients than in the placebo-treated patients.⁸⁶ Protocol violations were also high in another community-based study⁸⁷; not surprisingly, there was a higher rate of symptomatic ICH than in the original NINDS trial.

With increased awareness of its indications and the importance to adhere strictly to the published protocol, tPA use was reanalyzed in the Cleveland area 2 years after the first study. A higher percentage (2.7%) of patients received treatment; they represented 18.8% of all eligible patients. Protocol violations occurred for 19% of patients, and symptomatic ICH occurred in 6.4%,⁸⁸ a significant improvement from the original study. Familiarity with the use of thrombolytics and better adherence to published guidelines were likely reasons for the observed improvement. However, the overall tPA usage rates were not impressive, and this raises the possibility that specialized centers, analogous to designated trauma centers, might be a better option.

In 2001 Grotta and associates published the Houston experience with tPA for acute stroke. In a period of 4 years, 15% of all patients presenting with an acute ischemic stroke were treated with intravenous tPA; almost a third of those were treated within 2 hours after onset. The rate of symptomatic ICH was 4.5%, and protocol violations occurred for 13% of all treated patients. This study proved that a well-organized team approach and adherence to currently accepted protocols are key to successful implementation of intravenous thrombolysis.⁸⁹

In 2002, a group from Canada evaluated their experience with over 1000 patients treated with intravenous tPA over a period of 30 months. Their results were similar to the NINDS trial, in which 30% of the treated patients had no or minimal deficits at 90 days. The ICH rate was 4.6%, and protocol violations were observed in 15% of cases.⁹⁰ Other studies have yielded similar results.

Intra-Arterial Thrombolysis

For more than a decade, small case series were published on the feasibility and angiographic efficacy of intra-arterial delivery of thrombolytics. There has since been great improvement in angiographic catheter technology, as well as an increase in the experience of interventionalists. In many academic settings, intra-arterial thrombolysis is commonly employed in patients for whom the 3-hour window for intravenous thrombolysis is past or in those with an absolute contraindication to systemic thrombolysis. The potential advantages are the higher rates of recanalization achieved by delivering the drug locally at the site of the occlusive thrombus/embolus and fewer systemic side effects. It is unclear whether any particular agent is more effective, but those that are more fibrin selective might have a theoretical advantage (tPA, recombinant tPA, recombinant prourokinase) over less selective agents, such as urokinase.

Despite the inherent plausibility of an intra-arterial approach, only one placebo-controlled, double-blind multicenter trial has been completed. The Prolyse in Acute Cerebral Thromboembolism Trial (PROACT) was published in two parts. In PROACT I, recombinant prourokinase, a highly fibrin-selective agent, was administered intra-arterially, and its effects were compared with those of placebo in patients with an angiographically documented MCA (M1 or M2) occlusion within 6 hours of stroke onset. Inclusion criteria included a NIHSS score of at least 4, as well as the other NINDS tPA trial inclusion/exclusion criteria, including those for blood pressure. Heparin was administered concomitantly for 4 hours in both groups, and mechanical clot disruption was not allowed in either group. Forty patients were enrolled, and the rate of angiographically proven recanalization was 57.7% for the treatment recipients and 14.3% for the placebo recipients. Among patients who received higher doses of intravenous heparin together with the intra-arterial recombinant prourokinase, recanalization and symptomatic ICH rates were higher (81.8% and 27%, respectively). The recanalization rate was lower in the patients given lower dose heparin (40%), but the rate of symptomatic ICH was also significantly lower (6%). Overall, the rate of ICH was 15.4% among patients receiving thrombolytics and 14.3% among those receiving placebo. The trend toward effectiveness in this phase 2 trial prompted the second part of the trial (PROACT II), which tested clinical efficacy. The inclusion criteria in PROACT II were similar to those of PROACT I except, as in to ECASS, patients with CT hypodensity representing involvement of more than a third of the MCA territory were excluded. The baseline severity of strokes was higher than in the NINDS tPA trial (mean NIHSS scores = 17 versus 14) and the median time from onset to treatment was 5.3 hours. The primary outcome was the proportion of patients with a modified Rankin Scale score of 2 or less (independent) at 90 days. The study found a 15% absolute benefit in the patients who received treatment (intra-arterial recombinant prourokinase followed by intravenous heparin for 4 hours) in comparison with those who received placebo (only intravenous heparin for 4 hours). This translates into a number-needed-to-treat of seven. Symptomatic ICH occurred in 10% of recombinant prourokinase recipients and 2% of the control group, and recanalization rates at 2 hours were 66% for the treatment recipients and 18% for the control group. No difference in mortality rates was observed between the two groups.^91,92

Data from the PROACT suggest that patients outside the currently accepted treatment window for intravenous tPA could benefit from an aggressive interventional approach. However, the results of PROACT II did not suffice for FDA approval. Nevertheless, this approach is likely to be particularly useful for those patients with either ICA or MCA occlusion (Fig. 42-13A and B), in whom the rate of recanalization with systemic thrombolysis appears to be much lower than that with locally delivered thrombolytics.

Figure 42-13 A, Complete occlusion of the left middle cerebral artery stem. B, Recanalization of the middle cerebral artery stem and its branches after intra-arterial tissue plasminogen activator was administered to a patient with onset of a stroke 2 hours earlier, who was not a candidate for intravenous thrombolysis.

The existence of a sizable subgroup of patients who cannot receive systemic thrombolysis (because of recent surgery, recent nonhead trauma, previous stroke) is a strong incentive for development of intra-arterial therapies. Areas under active investigation include the use of mechanical extraction devices that remove an obstructing clot without many of the attendant risks of a thrombolytic agent. Several such devices are currently under investigation. The use of PWI-DWI mismatch, as previously discussed, is certain to be used in the future to select patients most likely to benefit from intra-arterial therapy.

Vertebrobasilar thrombosis has extremely high overall morbidity and mortality rates (approximately 70% to 80%), whereas successful recanalization is associated with a survival rate of 55% to 75%. Thus, basilar thrombosis is another situation in which intra-arterial thrombolysis may prove more efficacious than systemic thrombolysis. Despite the absence of a large randomized study to prove its safety and efficacy, the potential longer window (up to 24 or even 72 hours in selected cases) for therapy, based on multiple case series, makes acute basilar thrombosis a compelling scenario for use of intra-arterial thrombolysis or mechanical clot extraction.

Combined Intravenous and Intra-Arterial Thrombolysis

The rate of complete recanalization of ICA or MCA occlusion after intravenous tPA appears to be low, ranging from 10% to 30%. Moreover, in many instances, recanalization is followed by reocclusion and neurological worsening. The Emergency Management of Stroke (EMS) pilot study aimed at establishing the safety and feasibility of lower dose intravenous thrombolysis (0.6 mg/kg) within 3 hours, followed by intra-arterial tPA for presumed MCA or ICA occlusion (NIHSS score > 5). The rationale behind this approach is to combine speed of delivery of intravenous tPA with the higher recanalization rate and extended time window of intra-arterial tPA. The study results showed that the combination of intravenous and intra-arterial thrombolysis led to higher recanalization rates and more bleeding complications, without appreciable effect on overall outcome.⁹³ A follow-up study, the Interventional Management of Stroke (IMS) trial, enrolled 44 patients to the intravenous/intra-arterial tPA treatment group. The rate of symptomatic ICH was 6.3%. In comparison with the historical data from the NINDS intravenous tPA trial, in which 36% of patients with a NIHSS score higher than 10 achieved a good outcome, 56% of such patients in the IMS study had a good outcome, which is suggestive of added benefit from intra-arterial therapy in patients with probable large-vessel occlusion.⁹⁴ Currently, however, such an approach is experimental and is not recommended outside a clinical trial setting.

Aspirin

Aspirin use is a time-honored strategy for secondary prevention of ischemic stroke in both the acute and chronic settings. Multiple clinical trials have been conducted, the most important being the French, British, European, and Canadian trials. They revealed a benefit ranging from 20% to 30% relative risk reduction for stroke and vascular death. The Antithrombotic Trialists Collaboration addressed the role of aspirin among patients at high risk for vascular events, including those with a prior ischemic stroke. The benefit of aspirin was modest, with a 22% relative risk reduction for vascular events (stroke, myocardial infarction, vascular death) in patients with a prior TIA/stroke. The absolute benefit of aspirin, across all doses, was a modest 2.5% (Fig. 42-14).⁹⁵

Figure 42-14 Absolute effects of antiplatelet therapy on various outcomes in patients with previous stroke or transient ischemic attack (21 trials). In the “any death” columns, nonvascular deaths are represented by lower horizontal lines (and may be calculated by subtracting vascular deaths from any deaths).

(From Antithrombotic Trialists’ Collaboration: Collaborative metaanalysis of randomized trials of antiplatelet therapy for the prevention of death, MI, and stroke in high risk patients. BMJ 2002; 324:71-86.)

Whereas most studies agree on the benefit of aspirin, its optimal dose has been a matter of some controversy. The Dutch trial showed equal benefit for very low and moderate doses of salicylates (30 mg/day versus 283 mg/day),^95a a finding similar to that in the British trial,^95b in which very different dosing schedules were used (300 mg/day versus 1200 mg/day). In view of the potential side effects, mainly from gastrointestinal bleeding and ulceration, it is reasonable to prescribe low-dose aspirin (81 mg/day) for long-term secondary stroke prevention, although efficacy at this low dose of aspirin for long-term stroke prevention has not been determined. The International Stroke Trial (IST) evaluated patients within 48 hours of an acute stroke and established the benefit of 300 mg/day of aspirin in reducing recurrent strokes at 14 days and death or dependency at 6 months.⁹⁶ The Chinese Acute Stroke Trial (CAST) evaluated the use of 160 mg/day of aspirin within 48 hours of suspected ischemic stroke (13% of patients had no confirmatory CT scan before randomization).⁹⁷ Analysis of the results showed a 12% relative risk reduction of death or recurrent stroke within 4 weeks for the aspirin recipients. Together, the IST and CAST trials showed an improved outcome for patients receiving aspirin within 48 hours of a stroke, with 13 fewer dead or dependent patients in the months after the event.^96,97

Aspirin is often discontinued for elective surgery or bleeding complications. There have been concerns for some time that discontinuation of aspirin, and other antiplatelet agents, might lead to a transient prothrombotic “rebound” effect that increases the risk of ischemic stroke. This concern is supported by a case-control study whose results suggest that aspirin discontinuation can increaset the risk of ischemic stroke, especially in patients with multiple cardiovascular risk factors.^97a

Clopidogrel

Clopidogrel inhibits adenosine diphosphate–induced platelet aggregation. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study investigated its use for the prevention of ischemic strokes. Patients with nondisabling ischemic strokes, patients with recent myocardial infarction, and patients with symptomatic peripheral arterial disease were randomly assigned to receive aspirin (325 mg/day) or clopidogrel (75 mg/day). The primary outcome was an aggregate of myocardial infarction, ischemic stroke, and vascular death. Overall, events occurred in 5.3% of patients receiving clopidogrel and 5.8% in those receiving aspirin; this represented a relative risk reduction of 8.7% in favor of clopidogrel. This benefit was achieved mainly from a relative risk reduction of 23.8% in the patients with peripheral arterial disease and was not observed in the patients with a prior ischemic stroke, in whom a nonsignificant relative risk reduction of 7.3% in favor of clopidogrel was observed. The rate of gastrointestinal hemorrhage was lower in the clopidogrel recipients (1.99%) than in those taking aspirin (2.66%), but the rates of ICH were similar. These results suggest that in patients with a prior ischemic stroke, clopidogrel is no more effective than aspirin. Its use is justified in patients with aspirin intolerance and in patients with symptomatic peripheral arterial disease. The history of a prior gastrointestinal bleeding episode during aspirin therapy would, in theory, also justify using clopidogrel. Thrombotic thrombocytopenic purpura is a concern with clopidogrel, but CAPRIE did not show a higher risk of fatal thrombocytopenia than with the use of aspirin.

Combination Antiplatelet Therapy

Heparin and Heparinoids

The debate over the use of anticoagulants in the acute stroke setting continues relentlessly. Proponents of anticoagulation favor its use on the basis of biologically plausible arguments:

However, despite these arguments, the use of unfractionated or low-molecular-weight heparin (LMWH) in the acute stroke setting is not supported by current evidence. In 1997, the IST evaluated the use of subcutaneous unfractionated heparin in the acute stroke setting. Chosen outcomes measures were death at 14 days and death and dependency at 6 months. The investigators used a factorial design in which patients were given subcutaneous unfractionated heparin (5000 IU or 12,500 IU twice a day), placebo in addition to aspirin (300 mg/day), or placebo. Treatment was started within 48 hours of an acute stroke and continued for 14 days. Among heparin-treated patients, there were nonsignificantly fewer deaths within 14 days than among patients who received no heparin (9.0% versus 9.3%, respectively), corresponding to 3 fewer deaths for every 1000 patients treated. Also, there was no difference between the groups in dead or dependent patients at 6 months. Patients receiving heparin had significantly fewer recurrent ischemic strokes within 14 days (2.9% versus 3.8%), a finding offset by a similar increase in hemorrhagic strokes (1.2% versus 0.4%). Heparin use was also associated with a greater risk of any extracranial hemorrhage and hemorrhages necessitating transfusion; the higher risks were present with higher heparin doses. The nonsignificant decrease in deaths at 14 days was similar to that observed with the use of aspirin alone. Indeed, the reduction at 6 months in death or nonfatal recurrent stroke was greater in the aspirin group than in the heparin group, predominantly because of lower rates of ICH in the aspirin-treated group. The conclusion drawn from this study was that heparin is of no obvious benefit in the prevention of either stroke recurrence, death, or disability, and therefore there is no support for the use of high-dose subcutaneous heparin (exceeding 5000 IU twice daily) in the acute stroke setting.⁹⁶ The major limitations of the IST study were the open-label nature of the study, absence of initial CT scan in up to one third of all patients, lack of anticoagulation parameter control in the heparin-treated patients, and lack of weight adjustment of the heparin dose.

In the late 1980s, Duke and colleagues investigated the role of intravenous unfractionated heparin or placebo up to 24 hours after an acute, stable, noncardioembolic ischemic stroke. Rates of stroke progression, death, and recovery were similar in the two groups.⁹⁹ Many smaller studies and case series have been published since, with most results suggesting no benefit from acute use of intravenous unfractionated heparin.

The use of LMWH in acute ischemic stroke has also been investigated in small studies, the majority of which revealed no significant benefit of subcutaneous LMWH in the prevention of recurrence or death after an acute ischemic stroke. Most notable, the Tinzaparin in Acute Ischemic Stroke Trial (TAIST) evaluated the efficacy of two different doses of subcutaneous LMWH (tinzaparin), in comparison with aspirin, for 10 days after an acute ischemic stroke. The results revealed no differences in outcome of clinical deterioration and stroke recurrence in 15 days or in modified Rankin Scale score at 6 months between the two groups, in all subtypes of ischemic stroke, including cardioembolic stroke. There was a higher rate of symptomatic intracranial hemorrhage in the tinzaparin-treated patients and a higher rate of venous thromboembolism in the aspirin-treated patients.¹⁰⁰

The Trial of ORG 10172 in Acute Stroke Treatment (TOAST) enrolled approximately 1300 patients to receive either placebo or intravenous danaparoid (LMWH) for 7 days after an acute ischemic stroke.¹⁰¹ The primary endpoint was a favorable outcome (based on scores on the Glasgow Outcome Scale and the Barthel index) at 3 months. The level of anticoagulation was corrected according to anti–factor Xa levels. The outcomes of neurological worsening and recurrent ischemic stroke at 7 days and the 3-month outcomes were similar in the two groups. When the subgroups were evaluated according to stroke subtype, the early recurrence rates for patients with cardioembolic stroke were similar in the two treatment groups. However, in contrast to the TAIST trial, the only patients who showed a trend toward benefit from intravenous danaparoid were those with LAA.

When embolic stroke subtypes are considered, the results of the Heparin in Acute Embolic Stroke (HAEST) trial provide some insight.¹⁰² It was a double-blind, randomized investigation of the effectiveness of LMWH (dalteparin) given subcutaneously in comparison with aspirin (160 mg/day) in patients with an acute stroke presumably secondary to atrial fibrillation. The patients were assigned to receive either dalteparin or aspirin within 30 hours of the ischemic stroke and were treated for 10 days. The primary outcome of recurrent stroke within 14 days occurred in 7.5% of the aspirin-treated patients and 8.5% of the dalteparin-treated patients, with a trend toward more ICH in the dalteparin-treated group. This study emphasizes that the recurrence after a cardioembolic stroke is lower than previously thought and that emergency anticoagulation may be more harmful than helpful.

In summary, the role for acute heparin use after an ischemic stroke, including those with a cardioembolic mechanism, is not supported by current evidence.¹⁰³ In some cases, however, scenarios may arise that were not systematically investigated by existing trials. In such scenarios, the underlying pathophysiology (arterial dissection, “stuttering” TIAs, acutely symptomatic critical arterial stenosis, large left ventricular thrombus) might nonetheless justify anticoagulation. In these circumstances, a careful weighing of the (at best theoretical) benefit of acute anticoagulation against its risks should be the rule.

Oral Anticoagulation

Noncardioembolic Stroke

Traditionally, neurologists used long-term anticoagulation in patients with noncardioembolic stroke in whom secondary prevention with aspirin was deemed ineffective (“aspirin failure”). The poor prognosis associated with strokes secondary to intracranial atherosclerosis despite the use of antiplatelet agents has also been a common justification for long-term anticoagulation. Two studies have shed light onto these two issues. The WARSS was the first large trial to investigate whether warfarin was superior to aspirin for the secondary prevention of noncardioembolic ischemic stroke. It was a multicenter, double-blind, randomized trial that enrolled more than 2200 patients to receive either aspirin (325 mg/day) or warfarin for a target INR of 1.4 to 2.8. At the 2-year follow up, the primary endpoint of recurrent stroke or death was observed in 16% of patients receiving aspirin and 17.8% of those receiving warfarin; these percentages represented a statistically insignificant difference. The beneficial effects of warfarin seemed to be mostly in the INR range of 1.5 without significant additive benefits above that range. The endpoint was achieved in a similar proportion of patients in both groups regardless of the underlying stroke etiology, with a comparable rate of bleeding complications in the two groups (2.22%/year for warfarin and 1.49%/year for aspirin). The WARSS investigators concluded that aspirin and warfarin are equivalent in efficacy in the secondary prevention of noncardioembolic strokes, with a comparable relatively low risk of bleeding complications.¹⁰⁸

The risk of recurrent stroke in large-vessel intracranial atherosclerosis can be as high as 10% per year. The retrospective portion of the Warfarin Aspirin for Symptomatic Intracranial Disease (WASID) trial evaluated the efficacy of anticoagulation in comparison with antiplatelet therapy for the secondary prevention of strokes attributable to posterior circulation intracranial atherosclerosis.¹⁰⁹ The results of the retrospective analysis, showing recurrence rates of 10.4% per year in the aspirin recipients and 3.6%/year in the warfarin recipients, led to a prospective trial. The prospective part of the WASID study was a double-blind randomized trial that enrolled patients with symptomatic, angiographically proven, high-degree (>50% diameter reduction) intracranial stenosis. Patients were assigned to receive either warfarin (INR goal of 2.0 to 3.0) or aspirin (1300 mg/day). Determination of recurrent stroke or vascular death at 3-year follow-up was planned, but the study was prematurely interrupted after a mean follow-up of only 1.8 years because interim analysis showed higher rates of major hemorrhagic complications in the warfarin-treated group (8.3% for warfarin versus 3.2% for aspirin). The rates for all strokes or vascular death were similar in both groups (21.8% for warfarin versus 22.1% for aspirin). These results argue against the widespread practice of chronic anticoagulation for patients with symptomatic intracranial atherosclerosis.¹⁸ However, they also attest to the inadequacy of either medication.

Further evidence for the nonsuperiority of warfarin over aspirin was provided by a Cochrane review.¹¹⁰ A metaanalysis of five trials (>4000 patients) that compared anticoagulation with antiplatelet therapy for the secondary prevention of noncardioembolic strokes showed similar rates of recurrent stroke at all levels of anticoagulation (INR ranges 1.4 to 2.8, 2.1 to 3.6, and 3.0 to 4.5) in comparison with antiplatelet therapy. Major bleeding rates were significantly higher in patients receiving high-intensity anticoagulation but similar in the patients receiving low- and medium-intensity anticoagulation in comparison with antiplatelet therapy.

Strokes Associated with Antiphospholipid Antibodies

The best therapy, antiplatelet or anticoagulation, for patients with stroke who also have positive results on tests for antiphospholipid antibody is still a matter of debate. A WARSS substudy, the Antiphospholipid Antibodies and Stroke Study (APASS), sought to answer this question. Of the 1770 patients from WARSS who had blood tests for antiphospholipid antibodies, 41% were found to have positive results. These patients showed no differences in the rates of death or thrombotic events in comparison with those who had negative results for antibodies. Of more importance, there was no difference in outcome of recurrent stroke or death when the treatment with either aspirin or warfarin was considered.¹¹¹ However, the WARSS population had an average age of more than 50, and the study was not powered to answer questions of antibody titer or subtype. It remains possible that patients younger than 45 with high titers of immunoglobulin G antiphospholipid antibody, who evidence suggests are at risk for arterial stroke as well as venous thrombosis, might benefit from anticoagulation.

Stroke Associated with a Patent Foramen Ovale

In patients with a cryptogenic stroke and a documented PFO, the best strategy for secondary prevention has been a matter of intense debate. The results of a prospective study evaluating young patients (<55 years old) with cryptogenic stroke and a PFO found the risk of recurrent stroke to be 15% over 4 years, with aspirin, when the PFO was associated with an ASA. This recurrence rate was dramatically higher than for isolated PFO¹¹² and suggested that aspirin is inadequate. The Patent foramen ovale In Cryptogenic Stroke Study (PICSS), another substudy of WARSS, is the only randomized, double-blind study to investigate the best medical management of PFO.¹¹³ Six hundred and thirty patients from WARSS underwent a transesophageal examination; a PFO was found in 39% of patients with cryptogenic strokes and in 29.9% of patients with other known causes. Besides reinforcement of the notion of a PFO being a risk factor for a first-ever stroke, other aspects of the PICSS results are worth noting:

These results do not support long-term anticoagulation for unselected patients with a cryptogenic stroke and a PFO, without a known underlying venous thrombosis or a hypercoagulable state. Unfortunately, the average age of the patients in WARSS was 59, and so the applicability of these results to the population younger than 45 without conventional risk factors is highly questionable. The role for endovascular or surgical closure of such a defect is currently being investigated by a clinical trial and cannot be routinely recommended at this point; however, closure might be appropriate in a young patient with stroke who is found to have a large PFO and associated ASA.

Elevated Homocysteine Level

Elevated blood homocysteine levels have been observed in patients with coronary artery disease, as well as in patients with a prior TIA/stroke. Whether these represent a marker of advanced atherosclerosis or have a causal role in the pathogenesis of vascular disease remains to be determined. Blood homocysteine levels are inversely related to the dietary intake of folic acid, vitamin B₆, and vitamin B₁₂. However, whether dietary supplementation with these vitamins to lower homocysteine levels decreases cardiovascular risk is uncertain. In the Vitamin Intervention for Stroke Prevention (VISP) trial, in which more than 10,000 patients with a prior TIA/stroke were given vitamin supplementation (folate, vitamin B₆, and vitamin B₁₂) or placebo, results showed that vitamin supplementation did not reduce the risk of recurrent stroke over 2 years.¹¹⁸ The Vitamins To Prevent Stroke (VITATOPS) study was also an evaluation of the effect of vitamin supplementation on a large population of patients with prior TIA/stroke. Preliminary results revealed no significant reduction in markers of vascular inflammation (C-reactive protein) or hypercoagulability (prothrombin fragments, D-dimer), despite reduction in total homocysteine levels.^119,120 The benefits, if any, on stroke recurrence will be known only after completion of the study. Routine use of folic acid, cobalamin, and pyridoxine supplementation is not currently recommended for secondary stroke prevention.

Hormone Replacement Therapy

The use of hormone replacement therapy, with either estrogen or a combination of estrogen and progesterone, has increased dramatically since the mid-1990s. The main indication is prevention of postmenopausal osteoporosis. Accumulating evidence, however, points to an increased risk of cardiovascular disease. In the Women’s Estrogen for Stroke Trial (WEST), estrogen replacement was compared with placebo in more than 600 menopausal women with a history of a prior TIA/stroke. After a mean follow-up period of 2.8 years, estrogen was not shown to provide any protection against minor strokes (odds ratio = 1.0) but was shown to be associated with increased risk of fatal strokes in comparison with placebo (odds ratio = 2.8). Even though the numbers of minor strokes were comparable in both groups, strokes in the estrogen recipients were associated with slightly worse neurological and functional deficits.¹²¹ Those results were reinforced by the Women’s Health Initiative (WHI) study. The main goal of the WHI study was to investigate primary prevention of cardiovascular disease in postmenopausal women and hormone replacement therapy. Nevertheless, it demonstrated an odds ratio for ischemic stroke of 1.5, independent of all other stroke risk factors.¹²² On the basis of these results, hormone replacement therapy is not recommended as primary prevention for stroke and certainly should not be used in women with a history of prior TIA/stroke. In postmenopausal women without cardiovascular risk factors, its use may be considered if truly indicated.

Carotid Endarterectomy

In the early 1980s, resection of the stenotic portion of the ICA, or carotid endarterectomy (CEA), was a common surgical procedure. The conviction that CEA was an optimal form of secondary stroke prevention arose from recognition of the fact that large-artery atherosclerotic strokes are associated with a high rate of early recurrence. However, in the middle to late 1980s, the uncertainty about the efficacy of CEA in comparison with optimal medical therapy and the failure of the extracranial-intracranial bypass trial led to a decrease in enthusiasm for the CEA. However, in 1991, the North American Symptomatic Carotid Endarterectomy (NASCET) trial published its results.¹²³ There was an absolute risk reduction in the incidence of recurrent stroke of 17% for CEA in comparison with medical treatment in symptomatic patients with ICA stenosis of more than 70% diameter reduction. In absolute numbers, strokes recurred within 2 years in 26% of the medically treated patients and 9% of the surgically treated patients; this was a 66% relative risk reduction for CEA. The risks of major or fatal ipsilateral stroke in the surgically and medically treated patients were 2.5% and 13.1%, respectively.¹⁶ When all centers were considered, the overall surgical morbidity and mortality rate was 5.8%. In their latest results, the NASCET investigators found that in patients with a moderate degree of ICA stenosis (50% to 69% diameter reduction), the benefit was more modest, with a 5-year rate of stroke in the surgically and medically treated patients of 15.7% and 22.2%, respectively.¹²⁴

The Veterans Affairs Cooperative Study yielded similar results, with an absolute risk reduction of 11.7% for surgery versus medical therapy at 1 year of follow-up. Patients had ICA stenosis that ranged from 50% to 99% diameter reduction, and, as in the NASCET trial, the results showed greater benefit for patients with higher degrees of stenosis. The perioperative morbidity and mortality rate was approximately 5%.¹²⁵ The European Carotid Surgery Trial (ECST) was conducted around the same time as the two other CEA trials. There were some important differences between ECST and NASCET, which led to slightly different results. The main methodological differences were in the angiographic measurement of the degree of stenosis (the ECST method overestimated degree of stenosis in comparison with the NASCET method) and in the definition of the stroke outcome (ECST defined stroke as a deficit persistent for >7 days, and NASCET defined stroke as a neurological deficit persisting for >24 hours). The final ECST results for 3-year risk of stroke or death showed a 26.5% risk in medically treated patients with a symptomatic ICA stenosis of more than 80% diameter reduction, and a 14.9% risk for patients undergoing CEA; the absolute benefit for surgery was 11.6%. The risk of major stroke or death complicating surgery was 7%.^126–128 Reanalysis of the ECST results, with degree of stenosis recalculated with the NASCET method, revealed an absolute risk reduction of 21.2% for 5-year risk of stroke or death after CEA in comparison with medical treatment in patients with ICA stenosis of 70% to 99% diameter reduction.¹²⁸

Various post hoc analyses have been performed to further stratify recurrent stroke and surgical risk in patients with symptomatic high-degree ICA stenosis in order to better select patients who will maximally benefit from CEA. In medically treated patients, certain features other than the degree of stenosis are associated with a higher risk of stroke. These include absence of adequate collateral circulation on angiogram, ulcerated plaque or intraluminal thrombus, contralateral occlusion, male gender, hemispherical as opposed to retinal symptoms, and stroke as opposed to TIA as the presenting syndrome. Similarly, for patients treated with CEA, certain features are predictive of higher risk of perioperative stroke. These include female gender, age older than 75, contralateral occlusion, intraluminal thrombus, ulcerated plaque, peripheral vascular disease, and neurological instability.

Traditionally, CEA was delayed for 4 to 6 weeks after an acute stroke to reduce the risk of ICH, perhaps caused by reperfusion at higher pressure than the hemisphere was used to. However, an analysis of pooled NASCET and ECST data showed maximal benefit from CEA if it was performed within 2 weeks of nondisabling stroke. Similar information on timing of CEA after TIA is not available, but in view of data that show a greater risk of stroke after TIA than after stroke, it is likely that these patients should also undergo CEA within a week or two, as long as they are stable. The smallest benefit of CEA was observed in patients undergoing operation after 12 weeks. To qualify for these trials, patients had to have had an ipsilateral event within 6 months of random assignment. At 2 years, the annual stroke risk never exceeded 3%. Another reanalysis showed a small benefit for CEA with stenosis of 50% to 69% diameter reduction and no benefit for 30% to 49% diameter reduction.

Symptomatic complete ICA occlusion is a special case that is not amenable to CEA. No benefit was observed for extracranial-intracranial bypass surgery in unselected patients in a trial in 1985,¹²⁹ which failed to show a benefit from the surgical procedure as a result of high complication rates. However, the elevated risks of recurrent stroke in this patient population (as high as 14% per year in some studies), justifies another trial with better selection of candidates based on preoperative evaluation of hemodynamic reserve, because it is thought that recurrent stroke in these patients is caused by flow failure rather than embolus. The Carotid Occlusion Surgery Study is currently under way and aims to determine whether extracranial-intracranial bypass is superior to medical therapy in patients with recently symptomatic unilateral ICA occlusion and with evidence on PET scan for misery perfusion with increased OEF. Although these results are not available, risk factor modification, antiplatelet medications, and aggressive cholesterol control are the recommended treatment modalities for these patients.

Angioplasty and Stenting

Angioplasty and stenting are currently considered preferable to surgery in cases of ICA stenosis secondary to prior radiation therapy in the neck, previous CEA with recurrent stenosis, contralateral ICA occlusion, and surgically inaccessible high bifurcation of the common carotid artery.¹³⁰ In addition, angioplasty and stenting might be preferable in patients with multiple comorbid conditions who might not be ideal surgical candidates. The efficacy of angioplasty and stenting in comparison with CEA remains to be determined by ongoing trials (Carotid Revascularization Endarterectomy versus Stent Trial [CREST]; Stent-protected Percutaneous Angioplasty of the Carotid vs. Endarterectomy [SPACE]; International Carotid Stenting Study of the Carotid and Vertebral Artery Transluminal Angioplasty Study [CAVATAS-2]).

The first large study to compare the safety and efficacy of CEA and angioplasty was the Carotid and Vertebral artery Transluminal and Angioplasty Study (CAVATAS). About 500 patients were randomly assigned to undergo either CEA or angioplasty (with or without stent implantation) and were monitored for 1 year. Major perioperative morbidity, mortality, and stroke rates were similar in the two groups at 30 days, and stroke rates were similar at 1 year, although the rate of restenosis was greater for the patients who underwent angioplasty. Of importance, angioplasty was followed by stent implantation, a procedure thought necessary to maintain vessel patency, in only 26% of the patients undergoing endovascular treatment. In addition, no distal protection device to minimize embolization was used in this trial.¹³¹ CAVATAS-2 is currently under way and should answer some questions with regard to equivalency to CEA, when both stent deployment and distal protection devices are used during the endovascular procedure.

The recent Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial was designed to determine the noninferiority of angioplasty with stent implantation with ICA stenosis in comparison with CEA. The SAPPHIRE study showed a 7.9% absolute benefit in the outcome of stroke/myocardial infarction/death at 30 days and ipsilateral stroke or death at 1 year in favor of angioplasty with stent implantation over CEA in patients considered to be at high risk (with associated medical comorbid conditions). For the patients undergoing angioplasty and stent implantation, the perioperative morbidity and mortality rate was about half of that observed after CEA. However, a major problem with this study is that almost 70% of the patients were asymptomatic. It is already known from the CEA trials for high-grade asymptomatic carotid stenosis (see Chapter 46) that patients with medical comorbid conditions should not undergo operation because they need to be alive at 5 years to show the modest benefit. Thus, it is not clear why asymptomatic patients with associated medical comorbid conditions should undergo angioplasty and stent implantation at all. What are needed are studies of angioplasty with stent implantation versus CEA as a secondary prevention strategy in patients without comorbid conditions and those at high risk. The ongoing CREST should answer the former question.

Angioplasty and stent implantation for symptomatic intracranial stenoses remain investigational and controversial. The seriousness of intracranial atherosclerosis was made plain by the WASID study (discussed previously), which showed, over a 1.8-year follow-up period, that ischemic stroke recurrence rate for intracranial stenoses of more than 50% diameter reduction ranged from 17% to 20%, almost half being fatal or disabling strokes. In view of this poor prognosis and the lack of better secondary prevention strategies, small studies have been performed to investigate safety, feasibility, and efficacy of interventional procedures in patients with symptomatic intracranial atherosclerosis. A review of a single center’s experience with intracranial stent implantation over a 6-year period revealed a very high overall periprocedural complication rate of 28% for patients in whom the procedure was deemed a last resort.¹³² Unfortunately, the idea of last resort assumes good natural history data for medically treated symptomatic intracranial stenoses; however, such data are not available. There have been two studies of elective stent implantation with symptomatic M1 stenosis. The rationale for pursuing this treatment is that symptomatic M1 stenosis carries an annual stroke recurrence rate of about 8%. One study enrolled 14 patients, and the other enrolled 40. The former had morbidity and mortality rates of 33.3% and 8.3%, respectively; the latter, 10% and 2.5%. In the larger study, M1 lesions were classified on the basis of their location, morphology, and access. All three factors were relevant to periprocedural complication rates and efficacy at 10-month median follow-up.

The Stenting for Symptomatic Atherosclerotic Lesions in the Vertebral and Intracranial Arteries (SSYLVIA) trial, the only prospective multicenter trial of intracranial angioplasty and stent implantation to date, investigated the feasibility of intracranial stent implantation for patients with symptomatic intracranial LAA. In 95% of the patients, a stent was successfully deployed with a 30-day stroke rate of 6.6%. All strokes were observed in the posterior circulation, but no deaths occurred. At 6 months, one third of the patients after intracranial stent implantation experienced restenosis involving more than 50% diameter reduction, about 40% of these stenoses being symptomatic. SSYLVIA had important limitations. First, patients who entered this trial were not “medication failures”; that is, they had not necessarily received currently accepted maximal medical therapy (antiplatelets, statins, and aggressive risk factor modification). Second, it was not a randomized study; therefore, it could not answer the questions of whether intracranial angioplasty is superior to currently accepted medical therapy. These few studies indicate that angioplasty and stent implantation for symptomatic intracranial stenoses carry relatively high morbidity and mortality rates. However, the disease itself seems to have a poor natural history, according to existing data. Prospective randomized trials with a maximal medical therapy condition are needed.