Keywords

FormalPara Key Points

  • The diagnosis of acute ischemic stroke in the emergency room is a clinical diagnosis based on history, physical exam, and neuroimaging.

  • Intravenous recombinant tissue plasminogen activator (tPA) is recommended for acute ischemic stroke within 4.5 h after onset. Intra-arterial therapy is also recommended for patients with a large vessel occlusion within 6 h of onset.

  • Hypoxia, fever, hypotension, hypertension, and hyperglycemia are associated with worse outcomes after ischemic stroke and should be managed appropriately.

  • The inpatient evaluation consists of vascular imaging, echocardiography, and risk factor identification/management.

  • Decompressive hemicraniectomy is a lifesaving procedure and should be considered in younger patients with large strokes involving greater than 2/3 of the cerebral hemisphere.

  • The first line of secondary stroke prevention is antiplatelet therapy.

  • Management of risk factors such as hypertension, diabetes, cholesterol, and smoking is necessary to reduce the risk of recurrent cardiovascular events.

  • Patients with intracranial atherosclerotic disease are treated with aspirin, clopidogrel, antihypertensives, and high-dose statin therapy.

  • Carotid revascularization should be considered in patients with symptomatic and asymptomatic disease who meet certain criteria.

  • Stroke patients with atrial fibrillation should be anticoagulated; if warfarin is contraindicated, then antiplatelets should be utilized.

1 Introduction

Until 1995, ischemic stroke management was a classic example of “diagnose and adios.” Care of patients presenting to the hospital or clinic with symptoms of stroke consisted of aspirin followed by rehabilitation, with few disease-specific strategies directed toward optimal treatment and outcomes. The past two decades have witnessed an explosion of research into ischemic stroke. We now have specific therapies and management strategies to reduce morbidity and mortality. This chapter will first discuss the identification of patients with ischemic stroke, followed by acute treatment, inpatient management, and secondary stroke prevention.

2 Diagnosis

The clinical assessment remains the most efficient method to diagnose ischemic stroke in the emergency room. The history, general examination, and neurologic examination can almost always reliably determine the location of the infarct, even without the aid of neuroimaging. The goal of the initial evaluation is to diagnose an ischemic stroke and evaluate for any emergency treatments.

The first component of the clinical assessment is the history. The deficits are usually sudden in onset, during normal daily activities or upon awakening from sleep. Progression of symptoms over days or weeks is less common. Since patients presenting within the first few hours after onset can be eligible for acute reperfusion therapies, the time of onset is critical. Many times the patient can identify when the symptoms began. If the patient suffers from aphasia or woke up from sleep with symptoms, then determining the exact time of onset can be difficult. In this setting the time of onset is considered the time the patient was last seen normal. For example, if the symptoms were present upon awakening from sleep, then the time the patient went to sleep the night before is considered the time of onset. Additional components of the history should focus on concurrent medical problems and medications, particularly the use of anticoagulants.

The general examination is similar to other patients and begins with the “ABCs” of airway, breathing, and circulation. Vital signs including temperature and oxygen saturation are important. Examination of the head and neck can reveal signs of trauma, seizure, or carotid artery disease. The cardiac examination should focus on identifying acute MI, atrial fibrillation, or aortic dissection. The skin exam can elucidate significant systemic disease, such as a coagulopathy or hepatic dysfunction [1].

The main purpose of the neurologic examination is to localize the lesion. Patients with ischemic stroke usually present with focal neurologic signs and symptoms that fit a recognized neuroanatomic pattern. Physicians can utilize the pattern of deficits to localize the lesion and determine appropriate testing.

Common patterns of deficits in patients with ischemic stroke appear in List 1. Since the left side of the brain controls the right side of the body, the stroke in the brain is typically on the opposite side of the deficits on the body. The left hemisphere is the dominant hemisphere; even left-handed people are left hemisphere dominant 2/3 of the time. Brainstem strokes often cause “crossed findings” – i.e., deficits involving the left face and right side of the body. This is because almost all cranial nerves are ipsilateral, whereas the descending motor and sensory tracts are contralateral. For instance, a lesion in the left pons may cause left facial weakness (due to impairment of the left seventh cranial nerve) but right-sided weakness.

List 1 Common Patterns of Neurologic Deficits in Ischemic Stroke

  • Left Hemisphere (Dominant Hemisphere)

    • Aphasia

    • Right-sided weakness

    • Right-sided numbness

    • Right homonymous hemianopsia

    • Left gaze preference

  • Right Hemisphere (Non-dominant Hemisphere)

    • Neglect or extinction

    • Left-sided weakness

    • Left-sided numbness

    • Left homonymous hemianopsia

    • Right gaze preference

  • Brainstem

    • Impaired consciousness

    • Ataxia/incoordination

    • Vertigo or dizziness

    • Double vision (diplopia)

    • Trouble swallowing (dysphagia)

    • Slurred speech (dysarthria)

    • Nystagmus

The National Institutes of Health Stroke Scale (NIHSS) score (List 2) is commonly employed by stroke neurologists to describe the deficits and determine the size of the stroke: the larger the stroke, the higher the NIHSS. The customary orientation questions are person and place. The routine commands are “Close your eyes” and “Show me 2 fingers.” It is important for the examiner to not perform the tasks themselves to prevent aphasic patients from mimicking. Technically, the NIHSS score should reflect the patient’s total deficits, regardless of acuity. However, in clinical use the NIHSS score is often scored to reflect the patient’s new deficits. When used properly, the NIHSS not only serves to describe deficits but also helps identify the occluded vessel and determine prognosis [2]. For example, a patient with an NIHSS of 20 likely has a carotid occlusion and poor prognosis.

List 2 NIH Stroke Scale

  • 1A. Level of Consciousness

    • 0 = alert

    • 1 = arousable with minor stimulation

    • 2 = arousable with repeated stimulation

    • 3 = unresponsive or coma

  • 1B. Orientation Questions (Two Questions)

    • 0 = answers both correctly

    • 1 = one question correct

    • 2 = neither question correct

  • 1C. Commands (Two Commands)

    • 0 = follows both

    • 1 = follows one command

    • 2 = follows neither command

  • 2. Lateral Gaze

    • 0 = normal horizontal eye movements

    • 1 = partial horizontal gaze palsy

    • 2 = complete gaze palsy or forced deviation

  • 3. Visual Fields

    • 0 = intact to confrontation

    • 1 = partial hemianopsia

    • 2 = complete hemianopsia

    • 3 = bilateral hemianopsia or blind

  • 4. Facial Movement

    • 0 = normal

    • 1 = minor facial weakness

    • 2 = paralysis of the lower face or significant weakness

    • 3 = complete unilateral facial palsy

  • 5. Motor Function in the Arm (A = Left, B = Right)

    • 0 = able to raise the arm for 10 s without drift

    • 1 = the arm drifts but does not touch the bed

    • 2 = the arm drifts down to the bed before 10 s

    • 3 = no movement against gravity, unable to raise

    • 4 = no movement

  • 6. Motor Function in the Leg (A = Left, B = Right)

    • 0 = able to raise for 5 s without drift

    • 1 = the leg drifts but does not touch the bed

    • 2 = the leg drifts down to the bed before 5 s

    • 3 = no movement against gravity, unable to raise

    • 4 = no movement

  • 7. Limb Ataxia

    • 0 = no ataxia

    • 1 = ataxia in one limb

    • 2 = ataxia in two or more limbs

  • 8. Sensory

    • 0 = normal

    • 1 = mild sensory loss

    • 2 = severe or total sensory loss

  • 9. Language

    • 0 = normal

    • 1 = mild aphasia, mild loss of fluency

    • 2 = severe aphasia, fragmented speech

    • 3 = mute of global aphasia

  • 10. Dysarthria

    • 0 = normal

    • 1 = mild dysarthria, but able to be understood

    • 2 = moderate dysarthria, unintelligible, or mute

  • 11. Extinction or Neglect

    • 0 = absent

    • 1 = mild, extinction

    • 2 = severe neglect or inattention

It is also important to differentiate ischemic stroke from common mimics. Processes that can mimic acute stroke symptoms include seizures, migraines, encephalopathy, positional vertigo, and hypo- or hyperglycemia. In the setting on aphasia, it can become particularly difficult to distinguish between focal language impairment and other causes of altered mental status, such as delirium. Often, the aphasic patient will be awake and alert, regarding the examiner, but unable to follow commands, compared to the delirious patient who often is agitated or somnolent/lethargic [3]. Headaches are uncommon in the setting of acute ischemic stroke because the brain itself is not sensitive to pain [4]. Yet another common scenario is patients who present with serious medical comorbidities such as acute kidney injury or infection/sepsis that can cause altered mental status. Often there is confusion and decreased level of consciousness without focal neurologic deficits as described above. The absence of focal symptoms should prompt a thorough medical evaluation for possible causes of toxic/metabolic encephalopathies [5,6,7]. Isolated dysarthria is another presentation that often makes physicians suspicious for stroke. It is important to remember that isolated dysarthria (without other focal deficits) is usually not an ischemic stroke sign. Avoiding tunnel vision and keeping other causes such as alcohol intoxication or lack of dentures in mind helps avoid unnecessary tests and consultations.

The diagnosis of stroke can often be made on the basis of history and clinical exam alone. Neuroimaging is critical to differentiate ischemic from hemorrhagic stroke [8]. The most commonly employed modality is CT scanning. A simple non-contrast CT of the head can consistently determine the presence of intracranial hemorrhage and diagnose some nonvascular causes such as malignancy [9]. CT has important limitations. First, CT is relatively insensitive in detecting acute ischemic infarcts, as well as small cortical or subcortical strokes [10]. The inability of CT to determine acute infarcts is significant; therefore, the main utility of CT is to exclude hemorrhage and other causes. The diagnosis of acute ischemic stroke in the ED remains a largely clinical diagnosis. Magnetic resonance imaging (MRI) is increasingly utilized in the ER as the initial neuroimaging modality and is discussed later.

  • The diagnosis of stroke is based on the clinical exam and history.

  • Often conditions such as acute kidney injury, sepsis, or alcohol intoxication can mimic strokes. Altered mental status without focal deficits should prompt a workup for toxic/metabolic etiologies.

  • The CT scan is used to distinguish between ischemic and hemorrhagic stroke since CT can often miss ischemic strokes early on.

3 Acute Thrombolysis and Treatment

Thrombolysis has redefined the acute management of stroke. The FDA approved recombinant tissue plasminogen activator (tPA) in 1995 based upon the results of the pivotal National Institute of Neurological Disorders and Stroke (NINDS) trial . In this study, 624,000 patients presenting within 3 h of symptom onset were randomized to treatment with IV tPA (0.9 mg/kg) or placebo. Patients treated with tPA were 30% more likely to have a favorable outcome at 3 months compared to placebo [11]. It is interesting to note that there was no significant decrease in the NIHSS scores at 24 h. So even if patients do not immediately improve, they are still more likely to have a favorable outcome at 3 months if treated with tPA . The most significant adverse effect of tPA was intracerebral hemorrhage, which occurred in 6.4% of treated patients. The number of patients needed to treat with tPA to cause benefit is 3; whereas the number needed to harm is 30 [12]. Proper selection of patients is critical. Criteria to select patients for treatment with tPA are listed in List 3 [13]. Deviations from published guidelines may increase the rate of intracranial hemorrhage [14, 15].

List 3 Inclusion and Exclusion Criteria of Patients with Acute Ischemic Stroke Who Could Be Treated Within 3 h from Symptom Onset

  • Inclusion Criteria

    • Diagnosis of ischemic stroke with measurable neurologic deficit

    • Last seen normal <3 h before beginning treatment

    • Age 18 ≥ years

  • Exclusion Criteria

    • Any acute hemorrhage on neuroimaging

    • Significant head trauma or prior stroke in past 3 months

    • Symptoms suggest subarachnoid hemorrhage

    • Arterial puncture at non-compressible site in past 7 days

    • History of intracranial hemorrhage (not including cerebral microhemorrhages)

    • Intracranial neoplasm or arteriovenous malformation

    • Recent intracranial or spinal surgery

    • Blood pressure > 185/110 mmHg

    • Active internal bleeding

    • Serum glucose <50 mg/dL

    • CT evidence of hypodensity >1/3 cerebral hemisphere

    • Acute bleeding diathesis, including but not limited to

      • Platelet count <100 k/mm3

      • Heparin received in past 48 h with elevated PTT

      • INR > 1.7 or PT > 15 s

      • Current use of direct thrombin or factor Xa inhibitors

  • Relative Exclusion Criteria (Consider Risk vs. Benefit Carefully if One or More Are Present)

    • Minor or rapidly spontaneously improving symptoms

    • Pregnancy

    • Seizure at onset of symptoms with postictal neurologic impairments

    • Major surgery or previous trauma in past 14 days

    • GI or urinary tract hemorrhage in past 21 days

    • Acute MI in past 3 months

    • Unruptured cerebral aneurysm

    • History of hemorrhagic diabetic retinopathy

Despite the approval of tPA for acute ischemic stroke, only a small percentage of patients nationwide receive the drug. The most common exclusion is presentation outside the 3 h window [16]. Early trials of tPA beyond 3 h failed to show a benefit. However, a meta-analysis suggested a benefit to IV tPA beyond 3 h [17], and a large US trial showed a benefit of IV tPA up to 4.5 h after symptom onset [18]. As a result of this data, IV tPA has been recommended in 3–4.5 h with additional inclusion and relative exclusion criteria [19, 20].

Another rapidly expanding area of acute stroke treatment is intra-arterial therapy (IAT) . IAT is attractive because of the added benefit of mechanical clot lysis via a plethora of specialized catheters and devices (Fig. 18.1). IAT also enables the administration of thrombolytic medications directly into the clot, leading to higher recanalization rates [21]. Problems with IAT include availability and time. Typically, only large centers have experienced neuro-interventionalists and a specialized treatment team.

Fig. 18.1
figure 1

(a) Examples of intra-arterial stent retrievers . Trevo Retriever (Stryker Neurovascular). A stent is deployed across the thrombus and then withdrawn slowly to remove the thrombus and recanalize the vessel. (b) Actual Solitaire revascularization device (Medtronic) after removal with the clot still entrapped in the mesh stent [129]

Full size image

Three early studies with either primary IAT or first-generation mechanical thrombectomy devices failed to a benefit over conventional IV tPA , despite better recanalization rates [22,23,24]. With the advent of more experience and stent retrievers (Fig. 18.1), studies now show improved recanalization and, most importantly, outcomes [25,26,27,28,29]. Based upon these trials, IAT is now recommend for patients with acute ischemic stroke who have received IV tPA and have a large stroke with large artery occlusion on vascular imaging, and treatment can be initiated (groin puncture) within 6 h of symptom onset [30]. Observing the patient after IV tPA to assess for clinical response before pursuing endovascular therapy is not required nor recommended. The use of IAT in patients who are not eligible for IV tPA , or with smaller vessel occlusions, is of unproven benefit. However, it is common practice to refer patients with large vessel occlusions who are not candidates for IV tPA for IAT because there is no other acute therapy to offer.

Because of this opportunity to help select patients, many EDs now obtain emergent vascular imaging with CT angiography when an acute ischemic stroke patient is eligible for IV tPA. The exact timing of the imaging is an area of debate. Some prefer to get the CTA along with the initial head CT done in the first few minutes. The main advantage of this approach is that patients who are eligible for IAT can be identified sooner. The major disadvantage is the delay in treatment with IV tPA . The additional imaging takes extra time (on average about 15 min) and can unnecessarily delay IV tPA treatment for all patients. Time is brain, and this delay in IV treatment could lead to worse outcomes. Therefore, many EDs will get the initial head CT, make a decision about IV tPA , and then send the patient back for CT angiography while the IV tPA is being administered. This can sometimes delay IAT, but only some IV tPA patients are eligible for IAT .

  • IV tPA is approved for ischemic stroke, if used within 4.5 h of symptom onset.

  • Intra-arterial thrombolysis is indicated for patients with large vessel occlusions within 6 h of symptom onset.

4 Inpatient General Medical Care

The inpatient care of stroke patients focuses on controlling risk factors and rehabilitation. Hypoxia can occur in patients with acute ischemic stroke, due to partial airway obstruction, hypoventilation, aspiration pneumonia, or atelectasis. Hypoxia should be treated to limit additional ischemic brain injury. Stroke patients with brainstem dysfunction or depressed consciousness are at particular risk of hypoxia due to impaired airway-protective reflexes [31]. Many times stroke patients are routinely placed on supplemental oxygen, but the benefit has not been proven [32]. The target blood oxygen saturation should be greater than or equal to 92% [33]. Endotracheal intubation should be performed if the airway is threatened. Hyperbaric oxygen has been studied in acute ischemic stroke; however, trials do not reveal improved outcomes [34].

Fever is also associated with poor neurological outcomes after stroke. Possible mechanisms include increased metabolic demands, release of neurotransmitters, and free radical production [35, 36]. Treating fever may improve prognosis [37]. Fever may be secondary to a cause of stroke, such as endocarditis, or from a complication, such as deep venous thrombosis.

Hypothermia is a promising therapy for acute ischemic stroke. Hypothermia has already been shown to improve neurological outcomes after cardiac arrest [38, 39]. Small studies have evaluated the feasibility of hypothermia in acute ischemic stroke [40,41,42]. Patients can be cooled with external cooling devices, such as helmets, or internal catheters. Hypothermia is also being tested in combination with other potential neuroprotective agents, such as caffeinol (a combination of caffeine and alcohol) [43]. Although promising, hypothermia is associated with significant complications, such as hypotension, pneumonia, and cardiac arrhythmias [44]. Hypothermia in acute ischemic stroke is an active area of research, but at this time, hypothermia is not recommended outside the setting of a clinical trial.

Cardiac arrhythmias and myocardial ischemia are potential complications of acute ischemic stroke [45]. Interestingly , strokes in the right hemisphere, particularly the insula, may have an increased risk of cardiac complications. The etiology is unknown but thought to involve autonomic disturbances [46, 47]. In addition, stroke itself can cause ST segment depression, QT dispersion, inverted T waves, and prominent U waves [48, 49]. Cardiac monitoring is recommended for the first 24 h after admission, but it is usually continued for the duration of the inpatient stay. The most common arrhythmia in ischemic stroke patients is atrial fibrillation [50].

The optimal management of blood pressure in ischemic stroke patients is controversial. Both hyper and hypotension on admission are associated with increased mortality [51]. Theoretically, blood pressure lowering may reduce cerebral edema, lower the risk of hemorrhagic transformation, and prevent further vascular damage [1]. On the other hand, lowering the blood pressure may also lead to neurologic worsening by decreasing cerebral perfusion [52, 53]. One randomized, controlled trial suggests that blood pressure can be acutely lowered safely, but further study is needed [54, 55].

In the acute setting, elevated blood pressure is associated with an increased risk of hemorrhagic transformation after IV tPA [56, 57]. Outside of thrombolysis, the general consensus is to allow permissive hypertension. Guidelines for acute BP management are summarized in Table 18.1 [13]. Many experienced centers discontinue antihypertensive medications upon admission, and then blood pressure is gradually lowered during the inpatient stay.

Table 18.1 Blood pressure management in acute ischemic stroke
Full size table

Hyperglycemia is often seen in ischemic stroke patients. The presence of hyperglycemia and diabetes is associated with worse outcomes and neurologic deterioration [58,59,60]. It is unclear if hyperglycemia causes worse outcomes or is merely a marker for more severe strokes. Treatment of blood glucose levels greater than 200 mg/dL is recommended [1]. Intensive glucose control does not seem to affect mortality and increases the incidence of hypoglycemia [61, 62]. Despite the lack of good data to guide clinical decisions, it is generally agreed that hyperglycemia after stroke should be controlled [63].

5 Inpatient Ischemic Stroke Evaluation

The primary goals of the inpatient evaluation are to determine the etiology of the stroke, manage neurologic complications, and prevent future events. The first goal is to determine the size of the ischemic stroke and determine the etiology. Non-contrast CT scans can determine stroke size after the acute period has passed. Because the CT scan looks at the brain structure, once 48 h has passed, the infarct is much better defined on CT. The CT scan can also identify hemorrhagic transformation, which can affect the use of antiplatelets or anticoagulants. However, it is difficult to distinguish new from old areas of infarction on CT. In addition, small lacunar or brainstem strokes may be missed [10].

Because of the limitations of CT, many centers employ MRI to evaluate stroke patients. The first important sequence is diffusion-weighted imaging (DWI), often called the “stroke sequence ” (Fig. 18.2). Acute strokes will appear bright on DWI within an hour of ischemia and remain bright for approximately 2 weeks [64]. The companion image to the DWI is the ADC (apparent diffusion coefficient); acute strokes appear dark on ADC and then normalize in 5–10 days [65]. After a few hours of ischemia, FLAIR (fluid-attenuated inversion recovery) sequences identify areas of vasogenic edema, consistent with acute ischemic stroke [65]. FLAIR sequences also identify old areas of ischemia. Although CT reliably detects hemorrhage, GRE (gradient echo) images on MRI are much more sensitive for areas of small petechial and old hemorrhages [66, 67]. Because of its many advantages over CT, MRI is the imaging modality of choice in stroke patients.

Fig. 18.2
figure 2

DWI in ischemic stroke: in acute ischemic stroke, the CT scan is often normal (a), but the stroke can easily be seen on DWI (b)

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After determining the size and extent of the stroke, the next step is to determine the etiology of the vascular occlusion. Clots can be divided into two basic classes. A thrombus forms at the site of the occlusion, whereas an embolus forms in one place and then travels to occlude the artery. Because ischemic stroke can be due to either process, it is important to obtain vascular imaging to evaluate the arteries and cardiac imaging to evaluate for emboli.

Carotid ultrasound (CUS) is a common technique to image the vessels of the neck. CUS is based on Doppler imaging of velocity in the carotid arteries. The advantages of CUS are that it is noninvasive, quick, and does not require contrast. As the diameter of the vessel decreases, the velocity must increase to maintain consistent flow. The degree of stenosis can be determined using velocity criteria [68]. Disadvantages of ultrasound are that it cannot image the entire length of the carotid or vertebral arteries and provides no information about the intracranial vessels.

A technique to image the arterial circulation of the entire head and neck is CT angiography (CTA). This is done in the CT scanner. IV contrast is injected and allows for visualization of the vessel lumen. CTA of the neck can identify areas of stenosis or occlusion anywhere along the carotid or vertebral arteries [69]. CTA of the head can be performed at the same time and provides valuable information about the intracranial circulation. The main drawback of CTA is that it requires contrast, which is nephrotoxic, and must be used with caution in patients with renal insufficiency.

Because many stroke patients undergo an MRI while in the hospital, magnetic resonance angiography (MRA) has become a convenient noninvasive method of vascular imaging. MRA is based on the flow of blood through the vessel [70]. An MRA of the head and neck will provide similar information to a CTA (Fig. 18.3).

Fig. 18.3
figure 3

MRA of the head and neck reveals a smooth narrowing of the left internal carotid artery (arrow)

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The gold standard imaging technique remains invasive cerebral angiography. This is done in the angiography suite by direct arterial injection. Because of its invasive nature, the complications of angiography can be serious – arterial dissection, creation of emboli to cause further strokes, and even death. However, complication rates are low in the hands of experienced interventionalists [70]. Ultimately, the choice of vascular imaging is personal; different centers prefer different imaging modalities.

Since emboli leading to stroke are often cardiac in origin, echocardiography is done in almost every patient with ischemic stroke. Transthoracic echocardiography (TTE) provides information about the structure and function of the heart. Transesophageal echocardiography (TEE) provides better visualization of the atrial chambers, and particularly the left atrial appendage, where many clots form. TEE also provides information about atherosclerotic disease in the arch, which may be an additional source of emboli. TEE is preferred over TTE [71]. Most centers routinely employ TTE, with selected patients undergoing TEE. In patients with a PFO, a Doppler venous ultrasound of the lower extremities is recommended to evaluate for a paradoxical embolus. An MRV of the pelvis can also be considered.

  • Ischemic stroke patient should have vascular imaging to evaluate the vessels of the head and neck for areas of stenosis or occlusion.

  • CT or MR angiography provides noninvasive imaging of the vasculature.

  • Invasive cerebral angiography remains the gold standard vascular imaging technique.

  • Echocardiography aids in the identification of causes of cardiogenic emboli.

6 Inpatient Management of Neurologic Complications

There are three significant acute neurologic complications of ischemic stroke. First is cerebral edema. Second is hemorrhagic transformation. Third is seizures. Consultation with a neurologist or neurosurgeon is recommended for management of acute neurologic complications.

Signs of increased intracranial pressure due to cerebral edema include depressed consciousness or worsening neurologic deficits. In some patients, cerebral edema can be severe enough to cause a shift of the intracranial structures. A particularly ominous sign is a fixed dilated pupil; this occurs with compression of the third cranial nerve.

Cerebral edema typically peaks about 4 days after stroke onset [72]. Although most strokes will have some degree of edema, relatively few have significant enough edema to warrant intervention [73]. Initial management of cerebral edema involves avoiding hypo-osmolar fluid (which theoretically may worsen edema). In addition, hypoxemia, hypercarbia, and hyperthermia may exacerbate swelling and should be managed appropriately. Antihypertensives should be avoided to maximize cerebral perfusion [1].

Large middle cerebral artery strokes may cause significant intracranial shift. The definitive treatment is decompressive hemicraniectomy . This involves removing half of the skull and cutting the dura on the side of the stroke to allow room for the damaged brain to swell outward. The bone is saved and can be reinserted later, after the edema has resolved. We now know that early hemicraniectomy (within 48 h of stroke onset) improves survival and outcomes, whereas delaying hemicraniectomy beyond 48 h improves survival but has little effect on outcomes [74, 75]. Hemicraniectomy should be considered in patients under the age of 60, with large hemispheric stroke involving greater than 2/3 of the middle cerebral artery territory [75]. However, surviving patients often have significant neurologic deficits, and quality of life after hemicraniectomy remains a topic of debate.

Management of hemorrhagic transformation depends upon the amount of bleeding and symptoms. Small petechial hemorrhages are usually asymptomatic. Large confluent hematomas can increase intracranial pressure and cause neurologic deterioration. Although hemorrhagic transformation is a well-known complication of ischemic stroke, optimal treatment strategies have not been defined. If a patient recently received tPA , the tPA should be reversed by administration of cryoprecipitate and platelets [3]. In late hemorrhagic transformation, antiplatelets and anticoagulants should be temporarily held.

Seizures are uncommon after ischemic stroke, occurring in about 5% of patients. They usually occur within 48 h of infarction. Most seizures are focal and do not generalize. Interestingly, seizures do not appear to be associated with worse outcome [76]. Little data exists about the management of seizures in ischemic stroke ; therefore management is similar to seizures in other neurological illnesses.

7 Stroke Prevention

The key component of stroke prevention is risk factor management. The section will begin by discussing risk factor management applicable to most ischemic stroke patients, such as hypertension, diabetes, cholesterol, etc. This is followed by a discussion of antiplatelet agents, indications for anticoagulation, and the treatment for other disease states that may be discovered during the inpatient evaluation, such as carotid artery disease and intracranial stenosis.

The association between blood pressure reduction and primary stroke prevention is well established [77]. Antihypertensive medications also decrease recurrent stroke rates, regardless of whether the patient has hypertension or not [78]. Based on the current data, specific recommendations about choice of antihypertensive agents cannot be made, but antihypertensive therapy is recommended to prevent recurrent stroke and vascular events [50].

As mentioned previously, hyperglycemia has been associated with worse outcomes in ischemic stroke patients. Glycemic control reduces the occurrence of microvascular complications [79]. Conventional reasoning would argue that glycemic control should therefore also prevent macrovascular complications and reduce vascular mortality in patients with diabetes. Interestingly, multiple studies now reveal the tight glycemic control in patients with type 2 diabetes does not reduce cardiovascular events and may actually increase mortality [80,81,82]. While glycemic control is probably still important in stroke prevention, aggressive glycemic control may not be the best strategy. The optimum blood glucose and hemoglobin A1c concentrations to prevent recurrent strokes and cardiovascular events have not been established.

The association between hyperlipidemia and stroke risk has been to topic of much study and discussion. Prior studies have shown a weak correlation between lipid levels and stroke [83]. The pivotal study to prove that statin therapy reduced recurrent stroke patients with stroke or TIA was the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels ) trial. This study proved that atorvastatin reduced the overall incidence of strokes and cardiovascular events [84]. Patients with stroke should be treated according to the updated guidelines with lifestyle modification, dietary guidelines, and medications [85]. The new guidelines have moved away from the target LDL goals and instead focus on cardiovascular risk. The current recommendation is that patients with stroke or TIA thought to be due to atherosclerotic disease are candidates for statin therapy . Statins are suspected to have beneficial effects on the vascular endothelium, beyond cholesterol lowering. Therefore, patients with atherosclerotic ischemic stroke are reasonable candidates for statin therapy [50].

In many patients, smoking cessation is the single most effective way to decrease the risk of recurrent vascular events. Smoking approximately doubles the risk of stroke compared to non-smokers [86]. In addition, secondhand smoke may also increase the risk of cardiovascular disease [87,88,89]. A combination of nicotine therapy, social support, and skills training is the most effective approach to quitting smoking [90]. The increased risk of stroke disappears 5 years after smoking cessation [91, 92].

Most studies suggest a J-shaped relationship between alcohol consumption and ischemic stroke. Consumption of one or two drinks per day appears to decrease the risk of stroke. Consumption of 0 or > 5 drinks per day had an increased stroke risk [93]. The current recommendations state that light to moderate levels of alcohol consumption (two drinks/day for men, one drink/day for women who are not pregnant) may be beneficial [1]. Heavy drinkers should reduce their consumption [50].

An increasing body mass index (BMI) increases stroke risk in men [94], but the effect in women is unclear [95]. Although losing weight has not been shown to decrease stroke risk, losing weight improves blood pressure, glucose levels, and cholesterol [96]. The goal BMI is 18.5–24.9 kg/m2 [50].

Much attention is focused on the choice of antiplatelet agents to reduce recurrent stroke. At present there are three different agents that are commonly utilized – aspirin, dipyridamole+aspirin (Aggrenox), and clopidogrel (Plavix). Aspirin has been consistently shown to reduce the risk of recurrent stroke. The dose range varies from 50 to 1300 mg/day. Both high- and low-dose aspirin have similar efficacy [97, 98]. However, higher doses of aspirin increase the risk of GI bleeding [99]. Clopidogrel is considered similar to aspirin for stroke prevention [100]. The combination of aspirin plus clopidogrel offers further benefit for stroke prevention, but this benefit is offset by an increase of intracranial hemorrhage in stroke patients and is not recommended for long-term secondary prevention [101]. In one study, dipyridamole+aspirin was shown superior to aspirin or dipyridamole alone [102].

If dipyridamole+aspirin is superior to aspirin, and clopidogrel is equivalent to aspirin, therefore dipyridamole+aspirin must be superior to both aspirin and clopidogrel . Based upon this logic, for years, stroke neurologists considered dipyridamole+aspirin (Aggrenox) the antiplatelet of choice for secondary stroke prevention. Then in 2008, the results of a trial comparing dipyridamole+aspirin to clopidogrel (the largest stroke prevention trial to date) were released. Surprisingly, there was no significant difference [103]. The decision of which antiplatelet to use should be individualized. Patients who are unable to tolerate aspirin because of GI side effect may benefit from clopidogrel . Patients suffering headaches because of dipyridamole may benefit from aspirin or clopidogrel .

Many stroke patients presenting to the hospital are often already prescribed and taking an antiplatelet agent. A common practice is to change the antiplatelet prior to discharge, on the assumption that the current antiplatelet was ineffective. For example, if a patient has a stroke on aspirin, they are changed to clopidogrel on discharge, because they have “failed” aspirin therapy. If antiplatelet agents prevented 100% of recurrent strokes, then this would be acceptable. But just because a patient was taking aspirin and has a vascular event, this does not mean that the patient did not benefit from antiplatelet therapy. There is no clear data to support the common practice of changing antiplatelet therapy in patients presenting with ischemic stroke [104]. Platelet function testing can determine the aggregation responses to arachidonic acid (aspirin mediated) or ADP (clopidogrel mediated). In one study, 43% of patients were found to be nonresponders to aspirin and 35% for clopidogrel . A subset of patients had their antiplatelet therapy modified, and interestingly these patients had higher morbidity compared to patients in which the treatment was not modified [105]. Because the clinical significance of platelet aggregation testing is uncertain, it is not recommended at this time [104].

Dissections of the carotid and vertebral arteries are common causes of stroke or TIA in the young. Often they are due to trauma but can also occur spontaneously or with minor injuries such as vomiting or coughing [106]. Despite the prevalence, the optimal strategy for prevention is unknown. Either antiplatelet agents or anticoagulation is reasonable. Patient with recurrent events despite medical therapy should be considered for endovascular or surgical treatment [104]. Dissections usually heal over time, and most neurologists will repeat vascular imaging in 3–6 months and re-evaluate treatment. Long-term treatment is not typical.

During the inpatient evaluation, extracranial carotid artery disease is frequently found in stroke patients. Atherosclerotic disease of the carotid artery tends to affect the internal carotid artery (ICA) near the bifurcation of the common carotid into the internal and external carotid arteries. A lesion is considered symptomatic if the stroke or TIA is on ipsilateral hemisphere. If there is no stroke on the side of the stenosis, then the lesion is considered asymptomatic. The decision to potentially intervene is based upon three factors: (1) degree of stenosis, (2) symptomatic vs. asymptomatic, and (3) sex of the patient. If the ICA stenosis is less than 50%, there is no benefit to intervention, and nothing further is required. Consultation with a vascular surgeon is recommended if the following criteria are met – men with symptomatic stenosis of 50–99%, women with symptomatic stenosis of 70–99%, and men with asymptomatic stenosis of 60–99% [107]. No studies have shown a clear benefit for women with asymptomatic stenosis. Revascularization is also not recommended when the carotid is completely occluded. However, even patients who are not candidates for revascularization may benefit from additional counseling by a specialist.

Two main options exist for carotid revascularization , carotid endarterectomy (CEA) and carotid artery stenting (CAS) . In a CEA, an incision is made in the neck exposing the ICA. The artery is opened and the plaque cleaned out by hand. In recent years carotid artery stenting (CAS) has become another available option. This is done endovascularly, similar to cardiac stenting. The procedures are essentially equivalent. There is some evidence that patients over the age of 70 may benefit more from CEA and younger patient from CAS [108]. The choice of intervention is mainly dependent upon referral patterns and physician preference. No intervention is of proven benefit in extracranial vertebrobasilar disease. Patient with recurrent events despite medical management should be considered for endovascular stenting or other surgical procedures even though the data is lacking [104]. Routine preventive therapy as discussed elsewhere is still recommended for all patients with atherosclerotic disease. The timing of revascularization is dependent upon multiple factors such as the size of the stroke, presence of hemorrhage, and degree of stenosis. In general, the recommendation is that revascularization be performed within 2 weeks of the stroke [30].

Intracranial atherosclerotic disease is also frequently encountered in ischemic stroke patients. Patients with >50% symptomatic intracranial stenosis should be treated with aspirin, antihypertensives with goal SBP < 140 mmHg, and high-intensity statin treatment. Clopidogrel 75 mg daily is often added as well [104]. Dual antiplatelet therapy is continued for about 90 days at which point the patient is switched to a single agent. Intracranial stenting is not recommended because of a higher risk of stroke and death [109]. Intracranial stenting or angioplasty is considered investigational in patients with recurrent symptoms despite maximal medical therapy. Anticoagulation is no longer recommended for intracranial atherosclerotic disease [110].

Occasionally, stroke patients admitted to the hospital are started on heparin to decrease the risk of neurologic deterioration and recurrent stroke. Several studies have shown no benefit of routine anticoagulation [3]. Antiplatelet therapy remains preferred over anticoagulation to prevent recurrent stroke, except in certain circumstances.

The most common indication for anticoagulation in ischemic stroke patients is atrial fibrillation (AF) . AF is the most common cardiac arrhythmia in the elderly [50]. Clinical trials have consistently shown a benefit to anticoagulation over placebo, aspirin, and aspirin plus clopidogrel in ischemic stroke patients [111,112,113]. The goal INR is 2.0–3.0. In patients not eligible for warfarin, antiplatelet therapy still reduces stroke risk. Approximately 10% of stroke patients will have new-onset AF detected during their hospital admission, but longer outpatient monitoring protocols have uncovered even more cases of occult AF [114,115,116]. In patients with acute ischemic stroke or TIA without a clear cause, prolonged rhythm monitoring is very reasonable [104].

Other indications for anticoagulation in ischemic stroke patients are acute MI with LV thrombus, rheumatic mitral valve disease, mechanical prosthetic heart valves, or bioprosthetic heart valves. Cardiac conditions in which anticoagulation or antiplatelet therapy is appropriate are dilated cardiomyopathy with a low EF and mitral regurgitation due to mitral annular calcification [50]. In addition, patients with arterial dissection are often placed on warfarin for 3–6 months, although data to support this practice is lacking [50].

The choice of medication to achieve therapeutic anticoagulation should be individualized. Warfarin, apixaban, dabigatran, rivaroxaban, etc. are all reasonable choices. Cost, tolerability, patient preference, drug interactions, and renal function should all be incorporated into the decision. Often we run into similar issues with anticoagulation as we do with antiplatelets. Patients can present with ischemic stroke despite therapeutic anticoagulation with warfarin or a newer agent. Options in this situation would be to either add antiplatelet therapy to anticoagulation or switch the anticoagulant. The addition of aspirin to warfarin has been shown to increase risk of major bleeding with no significant reduction in ischemic events [117]. An exception would be patient with AF and coronary artery disease, where antiplatelet therapy may be beneficial [99]. No studies that show a benefit to switching the anticoagulation in patients with ischemic events despite therapeutic anticoagulation, although this is often done as an emotional decision with good intentions. Such patients may be candidates for left atrial appendage closure.

The timing of when to start anticoagulation is an important but understudied part of poststroke care. The secondary prevention benefits of anticoagulation should be weighed against the increased risk of hemorrhagic conversion. Based upon available evidence, the ACCP recommends starting anticoagulation within 14 days of acute ischemic stroke [118]. In patients with a high risk of hemorrhagic conversion, it is reasonable to delay anticoagulation beyond 14 days. More studies are needed to identify subgroups of patients who may benefit from urgent anticoagulation.

Recently multiple trials have shown that percutaneous closure of the left atrial appendage with the Watchman™ device may be superior to warfarin to prevent ischemic strokes with a lower risk of hemorrhage [119,120,121]. The device may also be beneficial in patients with AF who are not candidates for anticoagulation [122]. Further study is ongoing, and patients with AF should be evaluated by cardiology to determine if the patient is a candidate.

Anticoagulation with warfarin has been shown to be superior to antiplatelet therapy (aspirin alone and aspirin+clopidogrel ) in AF [123, 124]. However, patients with AF who are not candidates for anticoagulation should be treated with antiplatelet therapy. Aspirin has been shown to reduce the risk of strokes in AF [125, 126]. The combination of aspirin and clopidogrel further lowers the risk of ischemic events, but there is increased risk of hemorrhage, and therefore there is no significant difference between the two options [127, 128].

  • Control of risk factors such as hypertension, hyperglycemia, hyperlipidemia , smoking, alcohol, and obesity is the most effective method to prevent recurrent stroke.

  • Antiplatelet therapy is indicated in most patients with ischemic stroke.

  • Carotid revascularization with CEA or CAS should be considered in men with symptomatic stenosis of 50–99% and women with 70–99% stenosis.

  • Patient with intracranial atherosclerotic disease should be treated with aspirin, clopidogrel , antihypertensives, and high-dose statin therapy.

  • Indications for anticoagulation include atrial fibrillation and prosthetic heart valves.

8 Summary

Ischemic stroke patients typically present with sudden onset of focal neurologic symptoms that follow a recognized neuroanatomic pattern. Every patient should get neuroimaging in the ER, usually a non-contrast CT, mainly to exclude hemorrhage. Ischemic strokes will appear on CT a few hours after symptom onset.

In patients with acute ischemic stroke, the time of onset is critical. IV tPA is recommended for acute ischemic stroke within 4.5 h of symptom onset. Intra-arterial therapy is beneficial in patients with large vessel occlusion within 6 h of onset.

The management of hypoxia, fever, and hyperglycemia is important and should not be overlooked. Permissive hypertension for the first few days may help optimize cerebral perfusion. Neuroimaging during the inpatient stay provides valuable information about stroke size and location. CT is often used. MRI has many advantages over CT, as it can distinguish acute from chronic infarcts and small strokes that are often missed by CT. Stroke patients should receive vascular imaging. Carotid ultrasound is a minimum, but CTA or MRA is preferred since these modalities allow for noninvasive imaging of the entire vasculature of the head and neck. The gold standard remains invasive cerebral angiography. Echocardiography is recommended to evaluate for cardiac sources of emboli.

Significant inpatient complications of ischemic stroke are cerebral edema, hemorrhagic transformation, and seizures. Decompressive hemicraniectomy improves morbidity and mortality in large hemispheric strokes when done within 48 h of large ischemic strokes.

Management of blood pressure, glucose, cholesterol, smoking, and obesity is much more effective than antiplatelet therapy for stroke prevention. Antiplatelets are generally indicated for ischemic stroke prevention. Carotid revascularization should be considered in men with symptomatic stenosis (50–99%) and women with symptomatic (70–99%) stenosis. Anticoagulation should be reserved for patients with conditions such as atrial fibrillation and mechanical heart valves.

List 4 Additional Inclusion and Exclusion Criteria of Patients with Acute Ischemic Stroke Who Could Be Treated Within 3–4.5 h from Symptom Onset

  • Inclusion Criteria

    • Diagnosis of ischemic stroke with measurable neurologic deficit

    • Last seen normal within 3–4.5 h before beginning treatment

  • Relative Exclusion Criteria

    • Age > 80 years

    • Severe stroke (NIHSS > 25)

    • Taking oral anticoagulant regardless of INR

    • History of both diabetes and ischemic stroke

9 Case Studies

9.1 Case Study #1

A 60-year-old African-American male presents to the emergency room with acute onset of left-sided weakness and numbness upon awakening at about 6 am. He has a past medical history of diabetes and hypertension. Medications are aspirin, HCTZ, and metformin. Vital signs are unremarkable except for a BP of 170/95. On examination he has a left facial droop and dysarthria. Cranial nerves are otherwise intact. He is able to raise his left arm and leg off the bed, but they drift to the bed in a few seconds. He has impaired sensation too on the left (NIHSS 7). CT of the head shows a hypodensity in the right internal capsule suspicious for acute stroke. Laboratory studies are normal. He is outside the window for IV tPA because he was last seen normal at 10 pm the night before when he went to bed.

He is admitted for further workup and treatment. His total cholesterol is 180 mg/dL, and LDL is 110 mg/dL. He has an MRI and MRA, which reveal an acute infarct in the right internal capsule and 60% stenosis of his right internal carotid artery. Transthoracic echocardiography reveals an EF of 55% and mild mitral regurgitation. During the next few days in the hospital, his sensation returns to normal, and his strength improves to only subtle weakness on his left side. He is started on antihypertensives. Since he is thought to have an atherosclerosis-related stroke, he is started on statin therapy.

Because the RICA stenosis meets the criteria (>50% symptomatic stenosis), he consult a vascular surgeon, who feels he is a candidate for CEA. He undergoes the CEA next week without complications.

9.2 Case Study #2

An 80-year-old Caucasian female has acute onset of aphasia and right-sided weakness at 6 pm while eating dinner. The onset is witnessed by the family. Her past medical history is hypertension and hyperlipidemia . Medications are aspirin, atorvastatin , and metoprolol. Upon examination her vital signs are normal except for BP 180/100. She has a left gaze deviation, right homonymous hemianopsia, and right facial droop. She is alert and follows commands but is unable to speak. She has no movement or response to pain on his right side (NIHSS 18). CT of the head shows small vessel ischemic disease but no acute intracranial abnormality.

She is a candidate for IV tPA and treatment is started at 7:30 pm. She is then sent for a CTA that shows an occlusion of the LMCA. The neuro-interventionalist on call is notified, and she is taken to cerebral angiography, which confirms the thrombus, and it is removed successfully with a stent retriever. She is admitted to the ICU; her metoprolol and aspirin are held. Overnight telemetry shows paroxysmal atrial fibrillation. MRI and MRA the next day show patchy areas of acute infarction in the left hemisphere.

During her hospital stay, her visual fields improve, and she is able to raise her right arm and leg off the bed. She is discharged to inpatient rehabilitation. Two weeks after the stroke, she is started on anticoagulation for atrial fibrillation.

9.3 Case Study #3

A 64-year-old female presents with acute onset of left-sided weakness. Past medical history is type 2 diabetes, hypertension, and hyperlipidemia . She presents outside the window for IV tPA . MRI confirmed a stroke in the subcortical white matter in the right hemisphere. MRA revealed a stenosis in the right middle cerebral artery estimated to be about 70%. She was started on aspirin 81 mg daily, clopidogrel 75 mf daily, and Lipitor 80 mg daily. She was discharged to acute rehab.

She comes back in to the office in 1 month and is doing well. She follows up again in about 2 months, and she is switched to single antiplatelet therapy with clopidogrel alone since she has completed 90 days of dual antiplatelet therapy for intracranial atherosclerotic disease.