Acute Ischemic Stroke

Evaluation and Treatment

Damien Fair, PA-C, Daryl Story, MD

Damien Fair is an Associate Clinical Instructor in the Yale University Department of Neurology, New Haven, Connecticut. Daryl Story practices at Neurology Associates of Norwalk in Connecticut; he is Director of the Acute Stroke Team at Norwalk Hospital and an Associate Clinical Instructor at the Yale University Department of Neurology.

Stroke ranks as the number one cause of long-term disability and as the third leading cause of death in the United States. About 700,000 Americans experience new or recurrent strokes each year. ¹ Despite recent progress in treatment options for acute ischemic stroke and the declining death rate among stroke patients, actual numbers of stroke deaths continue to rise. In 2004 alone, the direct and indirect costs of stroke have been forecast at $53.6 billion.¹

New therapeutic interventions (most notably, thrombolysis with recombinant tissue plasminogen activator [rt-PA]) have led to improved outcomes after acute stroke. However, the efficacy of these interventions is dependent on the interval from symptom onset until treatment, which necessitates a rapid diagnosis. Because patients do not often have immediate access to a stroke specialist, a neurologist, or a hospital with a stroke team, it is es!= sential for primary care providers and emergency department personnel (and even the general public) to have the most current information about acute stroke.

This article will briefly review stroke pathophysiology, evaluation, and early stroke management, as well as use of rt-PA and other acute therapies.

Pathophysiology

The pathophysiology of acute ischemic stroke is not yet fully understood. However, new concepts, such as the role of the ischemic penumbra in stroke progression, have greatly influenced the philosophy of stroke treatment.

The ischemic penumbra

According to a theory introduced in 1981 by Astrup et al,² the ischemic penumbra is the zone that surrounds the ischemic core of nonviable tissue after ischemic insult. This inactive area can progress to infarction but is salvageable if blood flow is restored. Subsequent research has confirmed this concept, and now the ischemic penumbra is a major focus in the treatment of acute stroke.^3,4

When normal cerebral blood flow is stopped abruptly, autoregulatory mechanisms attempt to restore flow and normal metabolism. If these mechanisms are overcome, irreversible damage occurs, leaving a region of nonsalvageable tissue--the ischemic core. The surrounding viable tissue forms the ischemic penumbra. The ischemic penumbra, supplied by residual cerebral blood flow, is both dependent on autoregulatory mechanisms and affected by the degree of obstruction.^3,4

For a brief period, the reduced flow remains sufficient to maintain viable tissue and energy metabolism; however, autoregulation is at its maximum and viability is perfusion dependent. For this reason, any reduction in blood pressure (BP)--in theory--will extend ischemic injury and promote cell death. Thus, in acute stroke, it is often recommended to avoid BP lowering unless critically high (ie, systolic pressure, > 220 mm Hg; diastolic pressure, > 120 mm Hg).^5,6

Early Assessment

Once the patient is deemed stable, a detailed history is taken and a neurologic examination performed. If the patient is unable to communicate effectively, family members or witnesses of the episode can often provide helpful information. See Table 1⁷ for symptoms of ischemic stroke and Table 2^5,8 for the differential diagnosis.

For the patient who may be experiencing an ischemic event, it is crucial to establish the time of symptom onset. If the onset was not witnessed (the patient woke with symptoms, for example), then time of onset is established as the last time the patient was symptom free. This information will help the clinician determine whether to pursue use of rt-PA (see "Acute Treatment of Ischemic Stroke," below).

The patient or a family member should also be asked about recent medical or neurologic occurrences: trauma, hemorrhage, surgery, myocardial infarction, previous stroke, and use of oral anticoagulants, antiplatelet agents, and other medications.⁵

Examination

The neurologic examination--although it should be brief when thrombolysis is being considered--is irreplaceable as a potential means to identify the cause of the event, localize the lesion, and determine the extent of dysfunction. When time allows, the examiner should include a detailed mental status evaluation and assessment of speech and language, cranial nerves, motor and sensory function, reflexes, cerebellar function, and gait performance. A pure numbness or dysarthria without aphasia may justify withholding thrombolytics.

Though not essential for thrombolytic treatment, administering the National Institutes of Health Stroke Scale (NIHSS) is recommended. In this validated, reproducible 42-point scale, numbers assigned to each deficit are totaled to reflect the patient's neurologic state; higher scores reflect a worse deficit. A changing NIHSS can be used to quantify the patient's evolving status. A significant improvement during assessment may justify withholding treatment with intravenous rt-PA. ⁹

The neurovascular and cardiac assessment should include auscultation of the heart and neck for murmurs and bruits, palpation of the peripheral pulses, and close BP monitoring.

Fever may suggest an infectious cause of stroke or another infection presenting with stroke-like symptoms.⁵

Diagnostic tests

While the patient is being stabilized, an emergent head CT scan should be ordered to differentiate between ischemic and hemorrhagic stroke. The evaluation should also include other basic diagnostic tests (see Table 3¹⁰) to help rule out conditions that may mimic stroke, to help determine the etiology of a suspected stroke, and possibly to reveal potential complications.⁵

CT scanning

CT scanning is a quick, widely available technique that can be useful for detecting both ischemic stroke and intracerebral hemorrhage (see Figure 1), which can present with a focal deficit identical to that resulting from ischemic infarction. Abnormal hyperdensity in brain tissue is suggestive of blood.

It is important to note that a negative CT scan does not rule out subarachnoid hemorrhage (see Figure 2) if clinical suspicion is strong. In these cases, lumbar puncture should be performed.

During acute ischemic processes, signs on CT may include effacement of the sulci, loss of the gray-white junction, ventricular compression, midline shift, and (later) hypodense tissue (see Figure 3). Usually, these findings are absent or subtle in the early stages of assessment. Thus, a negative CT does not rule out ischemic stroke, but its importance lies in ruling out hemorrhage.

The finding of a hyperdense middle cerebral artery (the "dense MCA sign"; see Figure 4A) is a marker of occlusion. This is often associated with larger infarcts and severe neurologic deficits; it carries a poor prognosis.¹¹

Magnetic resonance imaging

MRI has become increasingly valuable in the acute stroke setting. In particular, diffusion-weighted and perfusion-weighted imaging (DWI, PWI) have hyperacute sensitivities to detect ischemic brain tissue (see Figure 4B). DWI can afford accurate, reliable diagnosis of stroke within hours of symptom onset; PWI, which requires intravenous contrast, can quickly detect perfusion abnormalities.¹²

PWI images may disclose a larger area of jeopardized blood flow than does DWI. This "perfusion-diffusion mismatch," which usually equalizes after two to four days, is thought to represent tissue that is threatened yet still viable.¹³

Compared with CT, MRI more accurately detects lesions in the brainstem and posterior fossa¹⁴; magnetic resonance angiography allows clinicians to detect evidence of large vessel disease and anatomic abnormalities that were previously visible only on cerebral angiography. Recent study results suggest that MRI detects intracranial blood as accurately as CT.¹⁵ Because ordering both tests is very costly, ¹⁶ some facilities have modified their protocol to rely on MRI alone for acute stroke work-up and rt-PA administration.¹⁷

Disadvantages to MRI, however, include cost, time to obtain the study, its contraindication in patients with metallic implants, and its lack of widespread availability. Additionally, few data are available to support MRI use to detect subarachnoid hemorrhage. Consequently, CT scanning remains the standard.

Acute Treatment of Ischemic Stroke

Acute stroke treatment encompasses four main goals: lysing the clot (if possible) to restore blood flow to ischemic tissue, limiting the ultimate size of the stroke, preventing complications of stroke, and reducing the likelihood of early recurrence.

Recombinant tissue-type p lasminogen activator

In 1996, rt-PA was approved by the FDA for thrombolysis in selected patients experiencing acute ischemic stroke. Now the sole approved treatment choice, rt-PA is endorsed by the American Academy of Neurology, the American Heart Association, and the American College of Chest Physicians.^5,18,19 However, some controversy persists regarding the quantity of data from the clinical trials and treatment safety in clinical practice.²⁰ Hospitals that provide treatment with rt-PA should observe a formal protocol, based on published recommendations ^5,18,19 and designed by a staff neurologist.

The two-part trial conducted by the NINDS (National Institute of Neurologic Diseases and Stroke)²¹ showed that patients treated with rt-PA within three hours had a 31% chance of having a highly favorable outcome (defined as independent and practically deficit free) at three months, compared with 20% in patients who received placebo. Based on this, the FDA approved rt-PA use, but only within this strict three-hour time window. A more detailed analysis of this trial has revealed that the benefit of rt-PA steadily diminishes beyond this three-hour time frame. Therefore, the sooner the patient is treated, the greater the likelihood of a very favorable outcome.²² (The use of rt-PA increases the risk of hemorrhagic transformation. Patient selection criteria are designed to limit this risk and are based on the NINDS clinical trial protocol shown in Table 4.²¹)

On the CT scan, presence of blood is the most important contraindication to thrombolysis.²¹ Subtle early ischemic changes have been presumed to indicate a higher likelihood of hemorrhage²³ (a source of concern when no neuroradiologist is accessible). Data have emerged, however, suggesting that these changes are not independently predictive of treatment-related hemorrhage but may be a marker for a time of onset close to or greater than three hours.²⁴ Thus, early ischemic changes should not necessarily exclude a patient from treatment; instead, they should prompt a redetermination of time of onset from all available sources.

Meanwhile, it is important to monitor BP. Although lowering BP during an acute stroke is not generally advocated, BP must be below 185/110 mm Hg before thrombolysis is initiated. ⁵ Intra!= venous labetalol (10 mg over one to two minutes, which may be repeated or doubled after 10 minutes to a maximum of 150 mg) is the usual choice in this setting. If two doses fail to achieve the target range, rt-PA should be withheld, as difficult-to-control pressures may lead to parenchymal hemorrhage.^5,24

For patients who receive rt-PA, postthrombolysis care should be provided in the ICU over the succeeding 24 hours with careful monitoring of vital signs and neurologic status. Invasive procedures and use of aspirin or heparin are avoided and BP is controlled. ⁵ Any headache or decline in status warrants a CT head scan to rule out hemorrhage.

Patients not receiving rt-PA

In the community setting, only about 15% of stroke patients arrive within the recommended three-hour window, and only about 20% of those patients receive rt-PA.⁹ For stroke patients who are not treated with rt-PA, acute stroke care centers on limiting stroke-induced damage and preventing complications and recurrence.

Neuroprotection. In the future, it may be possible to limit the extent of damage with neuroprotective agents, but none have yet been shown beneficial in clinical trials.⁵ Agents like citicoline, however, appear promising.²⁵

Blood pressure control. Optimizing BP may be one way to limit ischemic damage. In acute stroke, BP is almost always elevated--probably a physiologic response to brain ischemia and possibly a mechanism to promote blood flow to jeopardized tissue; BP usually normalizes within a week.²⁶ Hypotension, on the other hand, is unusual; it should prompt immediate treatment and a search for an underlying cause.²⁷

According to current guidelines, lowering BP should be avoided unless systolic pressure is greater than 220 mm Hg⁵ or cardiac ischemia, congestive heart failure, renal failure, suspicion of aortic aneurysm, or another compelling reason exists.^5,28

Controlling hyperglycemia. Hyperglycemia is considered a poor prognostic indicator for both diabetic and nondiabetic patients.^29,30 Use of intravenous solutions that contain dextrose should be avoided. The potential benefits of insulin therapy to control hyperglycemia in human stroke patients are under investigation. ²⁹

Controlling temperature. Fever (especially within 24 hours of stroke) is also associated with increased morbidity and mortality.³¹ Thus, use of antipyretics is important, as is the search for a source of fever (eg, pneumonia, to which aspiration and other factors make stroke patients particularly susceptible).

Other Complications of Stroke

Preventing complications of acute stroke can be challenging. Aspiration is common in those with dysarthria and aphasia, and patients should be evaluated for swallowing ability before they take food by mouth. Early mobilization can help minimize the risk of pneumonia, deep venous thrombosis, and decubitus ulcers.

Though less likely to occur after ischemic stroke than hemorrhagic stroke, poststroke seizures are a potential concern.³² They usually present with symptoms relating to the focal lesion. Other causes for seizure, however, should be considered and signs of drug withdrawal, metabolic disturbances, and glucose abnormalities ruled out. ³³

Early management should be approached as with any other seizure. Electroencephalography should be performed, and benzodiazepines can be administered acutely. Poststroke seizures are usually managed well with a single, patient-appropriate anticonvulsant.³³

Preventive measures

Unless the patient is treated with rt-PA or cannot take aspirin, aspirin should be administered acutely for its small but consistent benefit in reducing stroke morbidity and mortality. ^34,35

Any reduction in stroke recurrence and/or systemic thrombotic complications through use of full anticoagulation has been shown to be offset by a higher rate of hemorrhage. However, low-dose subcutaneous heparin has been deemed safe, even in the face of hemorrhagic stroke, and it helps prevent deep venous thrombosis (though not pulmonary embolism).²⁸

On the Horizon

The future for acute stroke care is encouraging. Neuroimaging techniques that will provide information valuable for thrombolysis decisions and patient selection are advancing rapidly. Promising developments for stroke prevention and treatment include the possible benefits for intravenous rt-PA past the three-hour window,³⁶ neuroprotective agents,^5,25 intra-arterial thrombolysis (with a six-hour treatment window), use of therapeutic hypothermia (ie, external or endovascular cooling),^37,38 modalities that promote neuronal recovery and growth, and new mechanical interventions for embolus retrieval. ^39,40 Until the risks and benefits of these interventions are fully explored in randomized controlled trials, the focus must remain on what is available now.†

Conclusion

Through increased professional and public awareness, it is hoped that the near future will see greater numbers of patients presenting quickly after stroke symptom onset and thus being eligible for thrombolysis with rt-PA. The Brain Attack Coalition has issued guidelines for the establishment of primary stroke centers⁴¹ that can be implemented by many community hospitals. Lowering the risk of first and recurrent stroke, of course, is an equally important area of stroke care.

We are indebted to Mark Gorman, MD, and Larry Brass, MD, for their helpful editorial comments.

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