Stroke is defined as a neurologic deficit caused by a focal injury to the central nervous system secondary to vascular disease, and includes ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH).1 Each year, approximately 800,000 new people develop a stroke in the United States.2 Stroke is the fifth leading cause of death in the United States and a leading cause of major disability in adults.2 Furthermore, the risk of recurrent stroke is as high as 20% at 5 years.3 There are 2 major types of stroke: ischemic and hemorrhagic stroke. Approximately, 87% of stroke in the United States is ischemic and the remaining is hemorrhagic.3 Hemorrhagic stroke can be further divided into ICH and SAH.4 This chapter aims to outline the current understanding of common stroke presentations, risk factors, pathophysiology, complications, and treatment.
Acute stroke should be suspected in a presentation of acute neurologic deficits that could be attributed to a vascular distribution. The knowledge of stroke is intertwined with typical clinical presentation syndromes associated with large or small vessel occlusions. Anterior cerebral artery (ACA) lesions typically present with leg weakness or numbness, aphasia, and apraxia, while middle cerebral artery (MCA) lesions manifest as face or arm weakness more than leg weakness, with aphasia (left side involvement) and, at times, neglect (right side involvement). Posterior circulation strokes present with cranial nerve deficits such as diplopia and often with cerebellar features such as ataxia, nausea, and nystagmus. Presence of alteration in mental status, headache, nausea, and vomiting is usually more indicative of increased intracranial pressure (ICP) and hemorrhagic strokes.5
Modifiable risk factors and nonmodifiable vascular risk factors result in disparities in ischemic stroke risk factors between different populations. Age and sex are known to be strong nonmodifiable indicators of ischemic stroke risk. The risk of stroke increases by 9% every year for men and 10% for women.6 Men are at higher risk of ischemic strokes in the young and middle-aged groups; however, women have a higher ischemic stroke risk in their lifetime and tend to have worse mortality and morbidity outcomes.7
Ethnicity is another significant nonmodifiable risk factor for ischemic stroke. Blacks have a higher risk of ischemic stroke risk, especially in the young middle-aged group (between 45 and 54 years of age) with a black-to-white incidence ratio of 4.02.8 The risk remains higher in the older age group but becomes more attenuated. Another nonmodifiable risk factor is a family history of strokes. The Framingham study showed that history of parental stroke before the age of 65 increases risk 3-fold.9 Other hypercoagulable conditions have been linked to increased risk of ischemic stroke, including hereditary diseases such as sickle cell disease, Fabry disease, and homocystinuria,10 and acquired hypercoagulable conditions such as the antiphospholipid syndrome.11
Modifiable stroke risk factors include hypertension, physical activity, obesity, diet and nutrition, diabetes, dyslipidemia, smoking, drug use, atrial fibrillation (AF), congestive heart failure, valvular disease, chronic obstructive pulmonary disease (COPD), and peripheral vascular disease.
Several different stroke etiological systems exist. The TOAST criteria (Trial of Org 10172 in Acute Stroke Treatment) includes 5 different ischemic stroke subtypes: large-artery atherosclerosis including large artery thrombosis and artery-to-artery embolization, cardioembolism, small-vessel occlusion, stroke of other determined cause, and stroke of undetermined cause.12 Outlined below are the subtypes of ischemic strokes commonly utilized in clinical practice.
Large-artery atherosclerosis refers to disease of the common and internal carotid arteries, the vertebral artery, and the major vessels of the circle of Willis. Typically, atherosclerosis leads to either extracranial stenosis at the proximal cervical internal carotid artery or intracranial atherosclerosis within the circle of Willis. Large vessel disease accounts for around 30% of all strokes.13
Cardioembolic stroke refers to an arterial embolism originating from the heart. The most common cause of cardioembolism is AF, although other causes include bacteria (infective endocarditis), tumor cells (marantic endocarditis), congestive heart failure, recent myocardial infarction, atrial myxoma, or mechanical heart valve. Cardioembolic sources of stroke account for 20% to 30% of total strokes.14
Occlusion of small penetrating vessels is another common stroke mechanism accounting for approximately 25% of all strokes.12 This mechanism results in lacunar stroke syndromes. It is pathologically associated with hypertension, diabetes, and hyperlipidemia. All three lead to lipohyalinosis and microatheroma formation.
Other determined cause refers to other known stroke mechanism not able to be categorized into cardioembolism, large-artery disease, or small-vessel disease. Examples of other mechanisms of stroke include arterial dissection, vasculitis, sickle cell disease, or mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
Cryptogenic stroke refers to stroke without any known mechanism or stroke with more than 1 potential mechanism and accounts for up to 23% to 40% of all strokes. They occur more frequently in younger patients and have a higher risk of recurrence.15 Cryptogenic strokes represent a diagnostic dilemma, as a more detailed and technologically advanced workup is recommended to identify an underlying mechanism.
Types of lacunar syndromes and large vessel stroke syndromes are seen in Tables 15-1 and 15-2.16,17
| Syndrome/Signs | Vessel | Localization |
|---|---|---|
| Pure motor/contralateral hemiparesis | Lenticulostriate vessels from MCA or perforating arteries from basilar artery | Posterior limb of internal capsule or corona radiata or basis pontis |
| Pure sensory/contralateral hemisensory loss | Lenticulostriate vessels from MCA or thalamoperforators off the posterior cerebral artery | Ventroposterior lateral nucleus of the thalamus |
| Sensorimotor/contralateral weakness and sensory loss | Lenticulostriate vessels from MCA | Thalamus and adjacent posterior limb of internal capsule |
| Dysarthria-clumsy hand syndrome | Slurred speech and fine motor weakness of the contralateral hand |
| Large Vessel | Symptoms |
|---|---|
| Internal carotid artery | Combined anterior and middle cerebral artery ischemic symptoms, intermittent ipsilateral visual disturbances due to central retinal artery occlusion (amaurosis fugax) |
| Anterior cerebral artery | Contralateral leg weakness and numbness, transcortical aphasia (left), ipsilateral or contralateral ideomotor apraxia |
| Middle cerebral artery | Contralateral face/arm > leg weakness and numbness, aphasia (left), gaze preference toward side of lesion, contralateral neglect (right), agraphesthesia/astereognosis (right) |
| Posterior cerebral artery (PCA) | Contralateral partial or complete homonymous hemianopia, alexia without agraphia, Weber syndrome if with midbrain involvementa |
| Superior cerebellar artery | Ipsilateral limb and gait ataxia |
| Anterior inferior cerebellar artery | Vertigo, ipsilateral deafness, facial weakness, and ataxia |
| Posterior inferior cerebellar artery/lateral medulla | Wallenberg syndrome: ipsilateral face and contralateral body pain and temperature sensory loss; ipsilateral seventh nerve palsy; ipsilateral palatal weakness; dysphagia; dysarthria; nystagmus; vomiting/nausea; ipsilateral Horner syndrome; skew deviation |
| Basilar artery | Locked-in syndrome with bilateral pontine infarcts: intact vertical eye movement, anarthria, quadriplegia |
| Brainstem stroke syndromes | |
| Deep penetrating arteries from PCA/medial midbrain | Weber syndrome: ipsilateral III nerve palsy, contralateral hemiparesis (including face) |
| Deep penetrating arteries from PCA/ventral midbrain | Benedikt syndrome: ipsilateral III nerve palsy, contralateral involuntary movements |
| Deep penetrating arteries from PCA/superior cerebellar peduncle | Nothnagel syndrome: ipsilateral III nerve palsy, contralateral dysmetria |
| Pontine perforators off the basilar artery/caudal pons | Foville syndrome: ipsilateral III and VI nerve palsy with or without contralateral hemiparesis |
| Paramedian pontine perforators off the basilar artery/paramedian pons | One-and-a-half syndrome: ipsilateral VI nerve palsy, bilateral intranuclear ophthalmoplegia |
| Vertebral artery or anterior spinal artery/medial medulla | Dejerine syndrome: ipsilateral tongue weakness and contralateral hemiparesis ± contralateral loss of vibration and position sensation |
Ischemia within affected neurons occurs through a series of complex cellular processes. Neuronal cell death occurs predominantly through necrosis, or nonprogrammed cell death, and apoptosis, or programmed cell death. In conjunction with cell death, cytotoxic edema plays an important role in evolution of disease. Water influx intracellularly occurs as a result of calcium buildup in the cytoplasm, as well as buildup of sodium and chloride. Delayed edema results in increased intracranial pressure, herniation, and vascular compression. Other pathological processes that further exacerbate cerebral ischemia include acidosis, peri-infarct depolarization, and free radical formations.18
On a macrocellular scale, ischemia results in compartmentalization of brain tissue, with 1 compartment irreversibly affected (the ischemic core) and another that is structurally intact but becomes functionally impaired and is thus potentially salvageable (the penumbra). The extent of ischemia depends not only on duration of vessel occlusion, but also on cerebral perfusion pressure, which relies on multiple factors including extent of collaterals and systemic arterial pressure. Evidence suggests that there is temporal evolution of the ischemic stroke on the expense of the penumbra, thus warranting intervention within a certain time period.18
Identification of an ischemic stroke event requires an acute neurologic deficit that could correlate to a vascular territory, small or large. The first step in diagnosis includes identifying a last known normal and performing a physical exam. The physical exam should focus on establishing a National Institute of Health Stroke Scale (NIHSS) score, which is an approximation of stroke severity. The scale must be used with caution, as it is biased toward dominant—often left-sided—MCA strokes, thus underestimating posterior circulation and cerebellar strokes. The scale contains 11 items including level of consciousness, orientation, visual fields, gaze preference, language fluency and comprehension, speech, motor strength, ataxia, neglect, and sensory loss.19
A noncontrast computed tomography (CT) scan then is obtained to primarily rule out intracranial hemorrhage, but it can also help identify early signs of ischemia (hypoattenuation or loss of gray white differentiation) (Class of Recommendation [COR] I, Level of Evidence [LOE] A). Findings may influence decision to administer thrombolytic medications, namely intravenous (IV) tissue plasminogen activator (tPA), and may denote a certain hemorrhagic risk of administration depending on presence and size of visualized early hypoattenuation. The most sensitive and specific modality for ischemic stroke remains the diffusion-weighted imaging (DWI) sequence in magnetic resonance imaging (MRI), with a sensitivity ranging between 88% and 100% and a specificity ranging between 95% and 100%, within minutes of symptom onset. However, there are limiting factors to obtaining an MRI within the acute clinical presentation: high cost, prolonged duration of the test, and limited availability.20
In the acute setting, CT angiography (CTA) can be used to detect a large-vessel occlusion with an accuracy approaching that of angiography. A CTA has a high positive predictive value for large-vessel occlusions (91–100%), with a sensitivity raging between 92% and 100% and a specificity ranging between 82% and 100%.21
Time-of-flight magnetic resonance (MR) angiography can also be obtained; however, it remains limited by availability and duration and has a lower sensitivity for occlusions, ranging from 60% and 85% for stenoses and from 80% to 90% for occlusions.21
The first step in the management of acute stroke is prompt recognition of the event followed by a decision regarding emergent therapies, including IV tPA and mechanical thrombectomy. Thrombolysis using IV tPA has been shown to improve functional outcomes at 3 months with a number needed to treat of 3.22 The more quickly a patient receives IV tPA, the greater chance is of functional improvement.23 Once clinical stroke is suspected, a quick history and examination, including the NIHSS, should be performed. A noncontrast head CT is necessary to rule out hemorrhage and large completed areas of infarction. Once hemorrhage is ruled out, IV tPA should be administered if the last known well time is within 4.5 hours (COR I, LOE A). Beyond this time window, IV tPA is not effective and the risk of causing hemorrhage increases. Intravenous tPA was approved following a landmark National Institute of Neurological Disorders and Stroke (NINDS) trial in 1995 in which neurologic recovery or NIHSS improvement by more than 4 points was achieved within 24 hours following IV tPA therapy.24 The major risk of treatment with IV tPA remains intracerebral hemorrhage with a risk of 6.4% when compared to 0.6% in patients who received placebo.24
Recently, 5 randomized clinical trials have proven the effectiveness of mechanical thrombectomy in cases of large-vessel occlusion. In any patient with suspected stroke due to large-vessel occlusion (typically NIHSS > 6), vessel imaging, preferably with CTA should be obtained (COR I, LOE A).
Perfusion imaging, MR or CT, can also be obtained to delineate penumbral tissue that can be potentially salvaged with intervention.25
For patients with proximal middle cereral artery or internal carotid artery occlusion and a region of tissue that is ischemic and not infarcted, or there is a mismatch between clinical deficit and infarct, mechanical thrombectomy is an option up to 24 hours from the time the patient was known to be well (COR I, LOE A).25-27 Endovascular therapy should be offered to patients with basilar occlusion despite these guidelines, given the catastrophic outcomes if left untreated. Patients eligible for IV tPA should be given IV tPA regardless of consideration for endovascular therapy (COR I, LOE A).25 Mechanical thrombectomy leads to greater chance of functional recovery at 3 months. Success is dependent upon multiple factors, including time to recanalization, extent of recanalization, and amount of salvageable tissue.25
Up to 10% of ischemic strokes are large enough to lead to significant cerebral edema resulting in herniation, which, if left untreated, is associated with a mortality rate of up to 78%.28 Hemicraniectomy involves removal of the skull and dura of the side of the large ischemic stroke in order to allow for external rather than internal herniation. A pooled analysis of 3 landmark European studies including Decompressive craniectomy in malignant middle cerebral artery infarcts (DECIMAL), Decompressive surgery for the treatment of malignant infarction of middle cerebral artery (DESTINY), and Hemicraniectomy after middle cerebral artery infarction with life-threatening edema trial (HAMLET) showed that patients who underwent surgical intervention had improved survival and functional outcomes. The number needed to treat for an outcome with a modified Rankin Scale (mRS) of 4 or less was 2 and the number needed to treat for an outcome with an mRS of 3 or less was 4.29 However, a favorable functional outcome in these studies was defined by an mRS of 3, which indicates moderate disability and may be viewed differently by patients and families.
Follow-up studies have included patients over 60 years of age and indicated that hemicraniectomy was associated with better survival, but all patients were left with at least moderate disability (defined as an mRS of 3 or higher).30 Given the above data, hemicraniectomy is typically reserved for patients less than 60 years of age and within 48 hours of presentation (COR I, LOE B).31
Following acute presentation and the decision-making process regarding thrombolytic and mechanical thrombectomy, further workup is warranted to identify the stroke mechanism. Vascular imaging, including MR or CT angiography, can be utilized to identify carotid artery disease and intracranial disease. Decision regarding secondary prevention with single or dual antiplatelet therapy (aspirin and clopidogrel) can be based on vascular imaging findings and whether the current event can be attributed to stenosis or occlusion.
The remaining workup includes echocardiography and telemetry to investigate a cardioembolic mechanism. Cryptogenic strokes require monitoring for a longer period of time than standard telemetry. Two large randomized trials have shown that prolonged cardiac monitoring is most beneficial in cryptogenic strokes. The Cryptogenic Stroke and Underlying AF (CRYSTAL AF) trial identified the underlying mechanism to be AF in 8.9% of stroke patients at 6 months and 30% of patients at 3 years.32 The 30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation after a Cerebral Ischemic Event (EMBRACE) trial showed that longer monitoring with an event monitor for 30 days was superior to the standard 24-hour telemetry, with a detection rate of 16.1% versus 3.2% in the control group.33
Secondary stroke prevention with antiplatelets for ischemic stroke and transient ischemic attack (TIA) has long shown benefit in preventing recurrent events. Aspirin was found to have a minimal but real reduction of death and recurrent stroke when administered within 24 to 48 hours of symptoms (COR I; LOE A).34 A combination of other antiplatelet agents (eg, clopidogrel) plus aspirin has mostly shown benefit in patients with intracranial atherosclerosis as concluded by recent trials, including SAMMPRIS35 and VISSIT,36 which revealed superiority of medical management over stenting for recurrent strokes in patients with intracranial atherosclerosis. Guidelines recommend dual antiplatelets for TIAs and minor strokes secondary to large-artery stenosis identified on vessel imaging (COR IIb, LOE B). For TIAs or minor ischemic strokes occurring due to severe stenosis, treatment with aspirin/clopidogrel for 90 days has shown to decrease risk of recurrent stroke by 32%.37
Hypertension is the most common modifiable risk factor in the United States, affecting blacks more than whites and men more than women. Recent Joint National Committee (JNC) guidelines recommended patients over the age of 60 years be treated for a blood pressure (BP) goal of less than 150/90 mmHg, while patients less than 60 years of age be treated for a BP goal of less than 140/90 mmHg. Patients with diabetes mellitus or chronic kidney disease should be treated for a BP goal of less than 130/80 mmHg, regardless of age (COR IIb, LOE B).38 It should be noted that the Systolic Blood Pressure Intervention Trial (SPRINT), which investigated outcomes in patients with tight systolic BP control below 120 mmHg, rather than the commonly set goal of less than 140 mmHg, was stopped prematurely due to the significantly reduced risk of cardiovascular events and stroke in patients with strict control of systolic BP below 120 mmHg.39 However, since that trial excluded patients with prior strokes and showed no difference in stroke events at follow-up, most neurologists follow American Heart Association (AHA)/American Stroke Association (ASA) guidelines, which recommend lowering the BP to below 140/90 mmHg in stroke patients without diabetes (COR I, LOE B).1
Management of dyslipidemia is also critical in secondary prevention with a goal low-density lipoprotein (LDL) of less than 70 mg/dL. In addition to their lipid lowering potential, statins have been found to exert a neuroprotective effect on the endothelium and cerebral blood flow.40 A large randomized prospective controlled trial showed that 80 mg of atorvastatin, a high-dose statin, reduces the risk of recurrent strokes and cardiac events in patients with coronary artery disease or an LDL of 100 to 190 mg/dL.41 Thus, ASA/AHA guidelines recommend initiating moderate to high statin therapy in patients with stroke and an LDL over 190 mg/dL, an LDL over 70 mg/dL and diabetes mellitus, an LDL less than 70 mg/dL and a 10-year atherosclerotic cardiovascular risk of 7.5% or higher, or atherosclerotic disease (COR I, LOE B). Metabolic syndrome, diabetes, and prediabetes (hemoglobin A1c, 5.7–6.4%) are independently associated with approximately a 60% risk of recurrent stroke in the elderly.42
Smoking has been identified to have a double risk of stroke within the general population, with the risk being dose dependent. This risk seems to be even higher when coupled with hypertension and returns back to baseline with abstinence in 10 years.43 Smoking cessation should be encouraged in any patients with a stroke (COR I, LOE C).
Atrial fibrillation is a common cause of ischemic stroke and is the most common cause of cardioembolic stroke. Patients with AF face a heightened stroke risk, and an estimated 15% of all ischemic strokes are attributed to AF.44 The CHA2DS2-VASc can be used as a stroke risk predictive tool in patients with AF, with higher scores indicative of a higher stroke risk.45 Given the elevated associated risk, AF management has been an important topic in secondary stroke prevention, and multiple studies have indicated a risk reduction for stroke of approximately two-thirds in patients taking anticoagulation.46 AHA/ASA guidelines recommend anticoagulation for patients with AF with the choice of agents tailored depending on age, medical history, and other associated risk factors (COR IIa, LOE B).
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