The diagnosis of acute ischemic stroke is often straight forward. The sudden onset of a focal neurologic deficit, such as hemiparesis, focal weakness, and aphasia, in a recognizable vascular pattern identifies a common syndrome of acute stroke. However, differential diagnostic problems remain because there are several subtypes of stroke and also because some nonvascular disorders may have clinical features identical to those of strokes.
8.1 Cerebral Infarction in Young Adults
Stroke affects mainly people aged over 65 years and atherosclerosis predominates as the main etiologic factor in ischemic stroke. On the other hand, cardiac embolism and arterial dissection are the most frequent causes of ischemic stroke in patients aged less than 45 years. However, inappropriate control of traditional vascular risk factors in young people may be causing a significant increase of atherosclerosis-related ischemic stroke. In endemic regions, neurocysticercosis and Chagas disease deserve consideration. Undetermined cause has been still reported in as many as one-third of young stroke patients.
Cerebrovascular atherosclerosis (thrombotic or embolic)
i. Valvular (mitral stenosis, prosthetic valve, infective endocarditis, marantic endocarditis, Libman–Sacks endocarditis, mitral annulus calcification, mitral valve prolapse, calcific aortic stenosis)
ii. Atrial fibrillation and sick sinus syndrome
iii. Acute myocardial infarction and/or left ventricular aneurysm
Paradoxical embolism or pulmonary source
i. Pulmonary arteriovenous malformation (including Osler–Weber–Rendu disease)
ii. Atrial and ventricular septal defects with right to left shunt
iii. Patent foramen ovale (PFO) with shunt
Inflammatory (see also vasculitis classification discussed later in the chapter)
ii. Allergic (Churg–Strauss syndrome) and granulomatous
iv. Associated with drug use (e.g., amphetamine, cocaine, phenylpropanolamine)
v. Associated with systemic disease (lupus, Wegener’s granulomatosis, polyarteritis nodosa, rheumatoid arthritis, Sjogren’s syndrome, scleroderma, Degos disease, Behcet’s syndrome, acute rheumatic fever, inflammatory bowel disease)
Hematological disease and coagulopathy
i. Polycythemia and myeloproliferative dysproteinemia myeloma, Waldenstrom’s macroglobulinemia, cryoglobulinemia
i. Thrombotic thrombocytopenia purpura
ii. Chronic diffuse intravascular coagulation
iii. Paroxysmal nocturnal hemoglobinuria
iv. Oral contraceptive use/peripartum/pregnancy
vi. Sickle cell and hemoglobin C disease
ix. C2 complement deficiency (familial)
8.1.1 Causes of infarction in young adults
Hart RG, Miller VT. Cerebral infarction in young adults: a practical approach. Stroke 1983;14(1):110–114
Hindfelt B, Nilsson O. Brain infarction in young adults (with particular reference to pathogenesis). Acta Neurol Scand 1977;55(2):145–157
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Adams HP Jr, Butler MJ, Biller J, Toffol GJ. Nonhemorrhagic cerebral infarction in young adults. Arch Neurol 1986;43(8):793–796
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Yew KS, Cheng EM. Diagnosis of acute stroke. Am Fam Physician 2015;91(8):528–536
Jordan LC, Hillis AE. Challenges in the diagnosis and treatment of pediatric stroke. Nat Rev Neurol 2011;7(4):199–208
8.2 Stroke Differential Diagnosis
Stroke mimics: Nonvascular conditions that simulate stroke are as follows:
i. Complicated migraine (especially younger women)
ii. Hemorrhagic stroke (intracerebral hemorrhage)
iv. Hypertensive encephalopathy
v. Seizures (postictal paralysis or Todd’s paralysis)
vi. Small vessel stroke/penetrating vessel stroke (comprise 20–25% of all strokes)
Generalized convulsive with postictal confusion or focal neurologic signs
Nonconvulsive status epilepticus
Hemiplegic migraine (Todd’s paralysis)
Intracranial tumors (primary CNS, metastatic) – Hypertensive encephalopathy
Susac’s syndrome (small vessel disease of brain, retina, and inner ear)
Nonketotic hyperosmolar coma (hyperglycemia) – Postcardiac arrest ischemia
Venous infarction (accounts for 1% of all strokes)
Mitochondrial encephalopathy, lactic acidosis, and stroke-like events (MELAS)
Stroke “chameleons”: Strokes with atypical presentations that take on the appearance of other diseases.
Confusional states, agitation, and delirium have all been reported as a consequence of focal neurologic injury, involving the limbic cortex of the temporal lobes and the orbitofrontal regions. These states must be distinguished from the neglect syndromes and fluent aphasias, but careful examination demonstrates a clear focal deficit (e.g., in syndromes of visual neglect, visual field testing will reveal a dramatic field cut).
Any witnesses that suggest a convulsive episode should raise suspicion of the presence of an ictal or postictal phenomena.
Sensory complaints of either unusual sensations or loss of sensation are common in parietal and thalamic strokes. They may take on a characteristic of another clinical condition, e.g., chest pain and limb pain that mimicked that of a myocardial infarction. Cortical involvement is usually accompanied by other neurological deficits such as hemiparesis, aphasia, hemineglect, or visual field abnormalities. Cortical blindness (Anton’s syndrome) is unusual but may occur and may be distinguished from bilateral ocular disease by the normal pupillary light response and normal optic disks.
Uncommonly, movement disorders will present from a focal lesion such as ischemic stroke or hemorrhage. Acute hemiballismus or unilateral dyskinesis often result from acute vascular lesions in the subthalamic nucleus or connections. The key to diagnosis is an abrupt onset of symptoms and risk factors for cerebrovascular disease.
8.2.1 Radiology (CT/MRI) characteristics of stroke mimics
See ▶Fig. 8.1 for radiological characteristics of stroke mimics.
Fig. 8.1 Stroke radiological differential diagnosis and mimics. (a) Seizures: Restricted diffusion and edema in left parieto-occipital area. (b) HSV encephalitis: Initially diagnosed with bilateral anterior cerebral artery (ACA) and middle cerebral artery (MCA) infarction. Ultimately diagnosed with HSV encephalitis. MRI showed asymmetric multifocal regions of restricted diffusion in the bilateral temporal lobes, frontal lobes, insula, cingulate gyri, and thalamus. (c) Anaplastic astrocytoma: (i, ii) Plain and enhanced CT initially interpreted as an infarction with left MCA territory hypodensity and a hyperdensity. (iii, iv) MRI showed a nonenhancing expansible lesion with elevated diffusion. (d) Transient global amnesia: The diffusion-weighted imaging 4 days after the ictus shows punctate foci of restricted diffusion in bilateral hippocampi. (e) Mitochondrial encephalopathy, lactic acidosis, and stroke-like events (MELAS). FLAIR imaging showed nonvascular distribution of cortical swelling in the left posterior parieto-temporal-occipital region with areas of both restricted and increased diffusion. (f) Global hypoxic injury: Hypoxic-ischemic encephalopathy following pulseless electrical activity (PEA) arrest. MRI demonstrated diffuse restricted diffusion with associated T2-FLAIR hyperintensity in the bilateral parieto-occipital and frontal lobes, bilateral thalami. The cerebellum is usually spared. (g) Creutzfeldt–Jakob disease: MRI showed restricted diffusion (i) and T2-FLAIR (ii) hyperintensity in the bilateral basal ganglia, thalami, and cortex. (h) Wernicke’s encephalopathy: Diagnosis of Wernicke’s disease was made due to malnutrition with a thiamine level of 35 nmol (normal 70–180 nmol). MRI showed variable diffusion with FLAIR hyperintensity in quadrigeminal plate, periaqueductal gray matter, hypothalamus, and bilateral superior colliculi. (i) Carbon monoxide poisoning: Camper found awake, staring, and foaming at the mouth with a respiratory rate of 6/min and a carboxy hemoglobin level of 22.9. MRI demonstrates symmetric restricted diffusion (i, ii) and T2-FLAIR hyperintensity (iii, iv) in the bilateral globus pallidi. (j) Osmotic myelinolysis: Alcoholic with severe hyponatremia who developed seizures and poor swallowing after correction of hyponatremia. MRI demonstrates T2 hyperintensity within the central pons, sparing the periphery and cortico-spinal tracts and bilateral putamen, caudate nuclei, thalami, external capsules, and central pons. (k) Nonketotic hyperglycemia: MRI revealed restricted diffusion (i) and T1 hyperintensity (ii) within the lentiform nucleus. CT shows hyperintensity of the left lentiform nucleus and caudate head (iii).
8.3 Stroke Risk Factors
Most important stroke risk factor is age. About 30% of strokes occur before the age of 65; 70% occur in those over 65 years of age. Stroke risk approximately doubles for every decade of age greater than 55 years.
The risk of stroke relates to the level of systolic hypertension. This applies to both sexes, to all ages, and to risk for hemorrhagic, atherothrombotic, and lacunar stroke. Interestingly, the risk of stroke at a given level of systolic hypertension is less with advancing age, so it becomes a less powerful, albeit still important and treatable, risk factor in the elderly.
Brain infarcts and stroke occur some 30% more frequently in men than women; the gender differential is even greater before age 65.
A fivefold increase in stroke prevalence among monozygotic compared to dizygotic male twin pairs suggests a genetic predisposition to stroke. The 1913 Swedish birth cohort study demonstrated a threefold increase in the incidence of stroke in men whose mothers died of stroke compared with men without such a maternal history. Family history also seems to play a role in stroke mortality among the upper middle-class Caucasian population in California.
After controlling for other stroke risk factors, diabetes increases the risk of thromboembolic stroke by approximately two- to threefold relative to persons without diabetes. Diabetes may predispose an individual to cerebral ischemia via acceleration of atherosclerosis of the large vessels such as coronary artery, carotid tree or by local effects on the cerebral microcirculation.
Individuals with heart disease of any type have more than twice the risk of stroke compared to those with normal cardiac function. Coronary artery disease is a strong indicator of both the presence of diffuse atherosclerotic vascular disease, and a potential source of emboli from mural thrombi due to myocardial infarction. Congestive heart failure and hypertensive heart disease are associated with increased stroke. Atrial fibrillation is strongly associated with embolic stroke and atrial fibrillation due to rheumatic valvular disease greatly increases the stroke risk by 17 times. Various other cardiac lesions have been associated with stroke, such as mitral valve prolapse, PFO, atrial septal defect, atrial septal aneurysm, and atherosclerotic/thrombotic lesions of the ascending aorta.
A carotid bruit does indicate an increased risk of a future stroke, although the risk is for stroke in general, and not for stroke specifically in the distribution of the artery with the bruit.
Several reports including a meta-analysis of a number of studies have shown that cigarette smoking clearly confers an increased risk for stroke off all ages and both sexes, that the degree of risk correlates with the number of cigarettes smoked, and that smoking cessation decreases the risk and reverts to the risk of nonsmokers by 5 years after smoking cessation.
Heightened viscosity causes stroke symptoms when hematocrit exceeds 55%. The major determinant of whole blood viscosity is the red blood cell content; plasma proteins, particularly fibrinogen, play a contributing role. When heightened viscosity results from polycythemia, hyperfibrinogenemia, or paraproteinemia, it usually causes generalized symptoms, such as headache, lethargy, tinnitus, and blurred vision. Focal cerebral infarction and retinal vein occlusion is much less common and may follow platelet dysfunction due to thrombocytosis. Intracerebral and subarachnoid hemorrhages may occur occasionally.
Elevated fibrinogen level and other clotting system abnormalities
A hypercoagulable state accounts for 1–2% of all strokes and 2–7% of stroke in younger patients, less than 50 years. The inherited thrombophilia i.e., protein C, S, and antithrombin deficiencies are relatively common at 1:200 to 1:2000 in the heterozygous form. Similarly, activated protein C resistance, including, but not limited to factor V Leiden mutation, are important genetic risk factors for venous thromboembolic disease. Elevated fibrinogen level constitutes a risk factor for thrombotic stroke. Rare abnormalities of the blood clotting system have also been noted, such as antithrombin III deficiency, and deficiencies of protein C and protein S and are associated with venous thrombotic events. Also, heparin is lowering antithrombin levels, and warfarin lowers functional levels of protein C and S.
Sickle cell disease can cause ischemic/hemorrhagic infarction, intracerebral and subarachnoid hemorrhages, venous sinus, and cortical vein thrombosis. The overall incidence of stroke in sickle cell disease is 6–15%. Paroxysmal nocturnal hemoglobinuria may result in cerebral venous thrombosis.
Up to 14% of ischemic and hemorrhagic brain infarcts in individuals aged 18–44 years were caused by substance abuse. Drugs that have been associated with stroke include methamphetamines, norepinephrine, lysergic acid diethylamide (LSD), heroin, and cocaine; also, over-the-counter sympatheticomimetics (phenylpropanolamine, ephedrine, and pseudoephedrine), phencyclidine, marijuana have been associated with stroke. The amphetamines induce a necrotizing vasculitis that may result in diffuse petechial hemorrhages or focal areas of ischemia and infarction. The heroin may produce allergic vascular hypersensitivity leading to infarction. Subarachnoid hemorrhage and cerebral infarction have been reported after the use of cocaine.
Although elevated cholesterol clearly has been related to coronary heart disease, its relation to stroke has been less clear. Elevated cholesterol does appear to be a risk factor for carotid atherosclerosis, especially in males under 55 years of age. The significance of hypercholesterolemia diminishes as age advances. Cholesterol below 160 is related to intracerebral hemorrhage or subarachnoid hemorrhage. There is no apparent relationship of cholesterol level to lacunar infarction.
The early high-estrogen oral contraceptives were reported to increase the risk of stroke in young women. Lowering the estrogen content has decreased this problem but not eliminated it altogether. This risk factor is strongest in women over 35 years who are also smokers. The presumed mechanism is an increased coagulation by estrogen stimulation of liver protein production or rarely an autoimmune one.
Increased risk of cerebral infarction and subarachnoid hemorrhage has been associated with alcohol abuse in young adults. Mechanisms by which ethanol may produce stroke include effects on blood pressure, platelets, plasma osmolality, hematocrit, and red blood cells. Furthermore, alcohol-induced myocardiopathy, arrhythmias, changes in cerebral blood flow and autoregulation are also some of the effects of alcohol.
Obesity (measured as relative weight or body mass index) consistently predicted subsequent strokes. Its association with stroke could be explained partly by the presence of hypertension and diabetes. Relative weight more than 30% above average was an independent contributor to a subsequent atherosclerotic brain infarction.
Infection (particularly chlamydia pneumonia and HIV) and acute and chronic inflammation have been attributed to raising stroke risk in younger patients. The relative risk was higher in the injection-drug abuse, HIV-infected individuals, particularly for hemorrhagic stroke. High stroke risk was associated with low CD4 cell count before antiviral treatment. Meningeal infection can result in cerebral infarction through the development of inflammatory changes in vessel walls. Diagnostic considerations in the infection setting include meningovascular syphilis; nonbacterial thrombotic endocarditis with cardiogenic embolism; vasculopathies associated with cryptococcal, tuberculous, and lymphomatous meningitis; toxoplasmosis; and herpes zoster. Mucormycosis may cause cerebral arteritis and infarction.
Homocysteinemia or homocystinuria (homozygous form)
It predisposes to cerebral arterial or venous thromboses. The estimated risk of stroke at a young age is 10–16%.
Migrainous infarction accounts for 13.7% of ischemia in young adults, especially women with a long standing (mean of 13 years) history of severe migraine and prolonged aura symptoms persisting for more than 60 minutes, visual and cortical symptoms, cigarette smoking, use of oral contraceptives, and posterior circulation infarct on brain imaging are factors that raise suspicion for migrainous stroke.
African-Americans have disproportionately higher stroke rates than other ethnic or racial groups.
In the United States and most European countries, stroke is the third most frequent cause of death after heart diseases and cancers. Most often strokes are caused by atherosclerotic changes rather than by hemorrhage. Middle-aged black women are exception, in whom hemorrhage leads the list. In Japan, stroke is the leading cause of death in adults and hemorrhage is more common than atherosclerosis.
Circadian and seasonal factors
The circadian variation of ischemic strokes peaking between 10:00 a.m. and 12:00 noon has led to hypothesis that diurnal changes in platelet function and fibrinolysis may be relevant to stroke. A relationship between seasonal climatic variation and ischemic stroke occurrence has been postulated. An increase in referral for cerebral infarction was observed during the warmer months in Iowa. The mean ambient temperature negatively correlated with the incidence of cerebral infarction in Japan. Seasonality has been correlated with a higher risk of cerebral infarction in 40 to 64-year-old individuals who are nonhypertensive and individuals with serum cholesterol below 160 mg/dl.
Conditions with hematologic changes leading to stroke
Include pregnancy, cancer, nephrotic syndrome, leukemia, inflammatory bowel disease, acute infection, paroxysmal nocturnal hemoglobinuria, and Bechet’s syndrome.
Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285(18):2370–2375
Hughes M, Lip GY. Stroke and thromboembolism in atrial fibrillation: A systematic review of stroke risk factors, stratification schema and cost effectiveness data Molecules to Medicine (Part 1). Stuttgart: Schattauer GmbH; 2008:295–304
Duken ML. Stroke risk factors. Chapter 6. In: JW Norris, et al. eds. Prevention of stroke Springer Science 1991:83
Feigin VL, Roth GA, Naghavi M, et al; Global Burden of Diseases, Injuries and Risk Factors Study 2013 and Stroke Experts Writing Group. Global burden of stroke and risk factors in 188 countries, during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet Neurol 2016;15(9):913–924
8.4 Common Cardiac Disorders Associated with Cerebral Infarction
Cerebral embolism arising from the heart and leading to infarction may be the presenting symptom of previously unidentified cardiac disease. Most cerebral emboli, including those of cardiac origin, will lodge in the branches of the middle cerebral artery; no more than 6.8% will affect the anterior cerebral artery, and 10% of emboli occlude the vertebral or basilar arteries and their branches.
Chronic nonvalvular atrial fibrillation (CNVAF)
It is recognized as a frequent cause of embolic cerebral ischemia, and is associated with some 15% of all ischemic strokes. Patients with NVAF have a fivefold risk of ischemic stroke compared with age-matched individuals, facing a 35% lifetime risk of ischemic stroke and a yearly stroke risk of 5%. NVAF with comorbid states can further increase the risk of embolic stroke. Risk of cerebral embolism in thyrotoxic NVAF averages 12% yearly, while associated congestive heart failure or coronary heart disease will increase the stroke risk slightly above the baseline. Other cardiac dysrhythmias carry a higher stroke rate than NVAF but are less common and do not pose the same challenge to population-based disease management. Patients with NVAF associated with rheumatic heart disease have a 17-fold increased risk of stroke compared with age-matched controls, but constitute no more than 25% of the entire atrial fibrillation population.
A common disorder observed in 6–8% of the general population that could be associated with embolic infarction involving the brain or the retina. The incidence of cerebral infarction associated with this disorder is low—approximately 1 in 6,000 known cases.
The most common neurological complication of infective endocarditis was cerebral embolism, occurring in 17% of patients in a study. Cerebral embolism was associated with a high mortality rate killing 30 of the 37 patients of the study; brain abscess was discovered in 4.1% and mycotic aneurysm was detected in 1.8% cases.
Streptococcus viridans (acute or subacute bacterial endocarditis) – Typically seen in elderly individuals who had rheumatic heart disease and were infected with S. viridans.
Patients are more typically younger individuals, most frequently intravenous drug abusers, and the organism is the more virulent S. aureus.
It is a clinical disorder consisting of aseptic cardiac valvular vegetations that may cause cerebral or systemic emboli. Abnormal coagulation profiles in cancer patients with cerebral ischemia should prompt consideration not only of embolic arterial occlusion observed in thrombotic endocarditis, but also of microvascular thrombosis associated with disseminated intravascular coagulation (DIC).
Abnormalities of the myocardial wall
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Wolf PA, Dawbar TR, Thomas E, et al. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology 1978;28(10):973
Arboix A, Alió J. Cardioembolic stroke: clinical features, specific cardiac disorders and prognosis. Curr Cardiol Rev 2010;6(3):150–161
8.5 Transient Ischemic Attack
A transient ischemic attack (TIA) is a temporary inadequacy of the circulation in part of the brain (a cerebral or retinal deficit) that gives a clinical picture similar to a stroke except that it is transient and reversible. Hence, TIA is a retrospective diagnosis. The duration is no more than 24 hours, and the majority of TIAs last for less than 30 minutes. Features that do not fully fit for TIA are called transient neurological attacks (TNAs); the risk of subsequent stroke is not as high as for TIA.
8.5.1 Incidence
TIAs affect 35 people per 100,000 of the population each year; they affect men more than women and black races are at greater risk. About 15% of first stroke victims have had a preceding TIA.
8.5.2 Differential diagnosis (the “three Bs”)
Beware of diagnosing TIA if there has been loss of consciousness, or convulsion. Todd’s paralysis follows a seizure and is characterized by a temporary, usually unilateral, paralysis. It may also affect speech or vision and usually resolves within 48 hours.
Before there is full recovery it is impossible to differentiate from a stroke. It is usually embolic, may be thrombotic, and occasionally hemorrhagic (unlikely to produce a reversible lesion). It affects the carotid area in about 80% and the vertebrobasilar area in about 20% of the cases. The most common source of emboli is the carotid bifurcation. They can originate in the heart with atrial fibrillation particularly, with mitral valve disease, or aortic valve disease, or from a mural thrombus forming on a myocardial infarct or a cardiac tumor, usually atrial myxoma.
Atherosclerotic disease (extracranial, intracranial, aorta)
Arteritides (giant cell arteritis, CNS angiitis, polyarteritis nodosa, etc.)
Erythrocyte disorders (polycythemia vera, sickle cell disease)
Platelet dysfunction (thrombocytosis)
Protein abnormalities (anticardiolipin/antiphospholipid antibodies, protein C and S deficiency, lupus anticoagulant)
Emboli (cardiogenic sources, infective endocarditis, atrial myxoma, mitral valve prolapse, lupus, paradoxical emboli etc.)
Easton JD, Sarer JL, Albers GW, et al. Definition and evaluation of transient ischemic attack Stroke 2009;40:2276–2293
Wu CM, McLaughlin K, Lorenzetti DL, et al. Early risk of stroke after TIA: A systematic review and Meta-analysis. Arc Intern Med 2007;67(22):2417–2422
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