Stroke in young adults

Differential diagnosis
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By Bartlomiej Piechowski-Jozwiak MD, Jorge Moncayo-Gaete MD, and Julien Bogousslavsky MD

Conditions that can simulate stroke include focal seizures, migraine with prolonged aura, and migraine variants such as basilar and hemiplegic migraines, acute vestibular syndrome, hypo- and hyperglycemia, periodic paralysis, multiple sclerosis, brain tumor, subdural hematoma, cerebral contusion, encephalitis, radiculopathy, neuromuscular junction disorders, neuropathy, Wernicke encephalopathy, and conversion disorder (Singhal et al 2013). A detailed history, physical exam, and appropriate laboratory or neuroimaging tests should be performed to further evaluate for these stroke mimics.

Defining the cause of stroke in a 15- to 45-year-old patient is often challenging because of the broad spectrum of etiologies to be considered. Published studies of ischemic stroke in the young attribute variable percentages to several stroke etiologies. An overview suggests that the cause of stroke is large artery atherosclerosis in 0% to 63% of patients, nonatherosclerotic disease in 3% to 33%, small vessel disease in 2% to 21%, cardiac embolism in 5% to 37%, hematologic disease in 3% to 28%, oral contraceptives in 3% to 24%, drug abuse in 2% to 11%, and migraine in 2% to 18% of patients. In 4% to 56% of patients, the etiology remains undefined. Significant variability in the proportion of strokes attributed to any one cause is related to the population used to collect the data (community-based vs. tertiary care center) as well as the extent and availability of diagnostic evaluation. Multiple stroke etiologies may coexist.

A report including cases from both community and referral hospitals determined etiology percentages from Baltimore City and regional counties: cardiac 15.4%, small vessel disease 9.8%, hematologic 8.9%, nonatherosclerotic vasculopathy 5.6%, substance abuse 4.7%, oral contraceptive use 2.6%, large artery atherosclerosis 1.9%, migraine 0.7%, and cryptogenic 31.8% (Kittner et al 1998). Transesophageal echocardiography was not readily available, possibly accounting for the relatively high percentage of strokes without a definable cause. A Swedish population-based epidemiological survey of stroke in the young found the following frequencies of etiologies: cardiac 33%, nonatherosclerotic vasculopathy 19%, atherosclerotic 11%, hematologic 7%, oral contraceptive use 3%, migraine 1%, and cryptogenic 21%. Transesophageal echocardiography was more available in this study (Kristensen et al 1997). Cardioembolism, mainly from patent foramen ovale and cardiomyopathy, accounted for approximately half of cerebral infarcts in 215 patients 18 to 45 years of age who were evaluated in a tertiary stroke center. One third of the patients had “other determined causes,” according to TOAST criteria, mainly comprising arterial dissection (13%), reversible cerebral vasoconstriction syndromes (5%), moyamoya disease (3%), and hypercoagulable state (2.8%). Atherosclerotic small-vessel and large-vessel disease were found in 7% and 2% of the patients, respectively, and occurred exclusively in patients older than 36 years of age. Probably because of extensive diagnostic workup, the cause remained undetermined in only 9% of the patients in this cohort (Ji et al 2012).

Atherosclerosis occurs in patients with predisposing risk factors and increases in a linear fashion with advancing age (7% to 30% incidence in patients younger than 50 years). Atherosclerosis as a cause of stroke is less prominent from the 15- to 30-year age group (2%) and more prominent in the 30- to 45-year age group (30% to 35%) (Bogousslavsky and Regli 1987; Carolei et al 1993).

Physicians should avoid attributing atherosclerosis as the etiology of stroke in young patients simply because risk factors are present; nevertheless, with the growing prevalence of obesity, diabetes, and metabolic syndrome, atherosclerosis is increasingly being recognized as the cause of stroke in children and young adults. In fact, large artery atherosclerosis (mostly diagnosed by angiography and ultrasound examination) was the most common cause of stroke in 197 Chinese young adults with cerebral infarct (mean age of 39), accounting for 41% of all stroke etiology, followed by other causes in a quarter of those patients (Niu et al 2014). Intracranial atherosclerotic disease predominated in the same young patients with large artery atherosclerosis, which involves the carotid circulation (middle cerebral artery and intracranial internal carotid artery) in approximately 70% of cases. Almost all patients with intracranial atherosclerotic disease had multiple modifiable stroke risk factors, with stroke due to large artery atherosclerosis increasing in proportion to the number of stroke risk factors (Niu et al 2014). Nonatherosclerotic vasculopathy is a heterogeneous category that may account for 14% to 25% of stroke in younger patients (Biller et al 1991; Rasura et al 2006). Disorders in this category include focal cerebral arteriopathy (FCA) of childhood, Takayasu disease, fibromuscular dysplasia, cervical carotid and vertebral dissections, idiopathic or secondary forms of moyamoya disease, peripartum angiopathy, reversible vasoconstrictive syndromes, radiation-induced arteriopathy, non-amyloid vasculopathy, hyperhomocysteinemia, and others. In the International Pediatric Stroke Study, arteriopathy was identified on neurovascular imaging in 53% of children with arterial ischemic stroke (Amlie-Lefond et al 2009). FCA was the most common type (25%), followed by moyamoya disease and syndrome, and arterial dissection. Recent upper respiratory tract infection was found to be a predictor for FCA, especially in children 5 to 9 years of age. The clinical-imaging features of primary cerebral vasculitis in young adults appear similar to the features of primary cerebral vasculitis in children, which have been described (Aviv et al 2006; Benseler et al 2006).

Fibromuscular dysplasia is the most frequent arterial dysplasia of the vertebral and carotid vasculature, typically affecting medium-sized arteries of young Caucasian females, most frequently the distal cervical and vertical petrous internal carotid arteries, V3 segments of the vertebral arteries, and the renal arteries (Mettinger and Ericson 1982). Fibromuscular dysplasia may lead to arterial dissection, aneurysm or fistula formation, thromboembolic phenomena, and hemodynamic failure in the affected arterial territory (Piechowski-Jozwiak and Bogousslavsky 2004). The pathologic process results in rings of fibrous tissue and smooth muscle segments, producing the classical "string of beads" appearance on angiogram and arterial dissections and, less commonly, tubular stenosis and fusiform dilation (Furie and Tien 1994). Stroke can result from dissection as well as progressive arterial occlusion. In the Lausanne Stroke Registry, fibromuscular dysplasia accounted for 4% of strokes in patients 16 to 30 years old and 1% of strokes in patients 31 to 45 years (Bogousslavsky and Pierre 1992).

Cervical arterial dissection accounts for 10% to 20% of ischemic strokes in young adults (Schievink 2001). Dissection may occur spontaneously or follow mild or severe trauma, chiropractic manipulation, surgical procedures, sudden head version, or neck hyperextension (Schievink 2001; Schwartz et al 2009). An underlying connective tissue disorder has been postulated in some cases (Brandt et al 2001). Dissection is associated with fibromuscular dysplasia, Marfan syndrome, Ehlers-Danlos syndrome type IV (North et al 1995; Schievink 2004), cystic medial necrosis, osteogenesis imperfecta, pseudoxanthoma elasticum, autosomal dominant polycystic kidney disease, alpha1-antitrypsin deficiency, redundancy of the internal carotid artery, lentiginosis, and infection (Rubinstein et al 2005; Schwartz et al 2009). A multicenter observational study assessed the relationship between the subtypes of migraine and cervical artery dissection (carotid or vertebral artery) in younger patients with stroke. Migraine--particularly without aura--was more frequent in patients with cervical artery dissection presenting with ischemic stroke (35%) than in patients with cerebral infarct not due to cervical artery dissection (27%). Both groups of patients had mild strokes (mean NIHSS score of 6; mean age of 44 years). The pathophysiology and causative relationship between migraine and cervical artery dissection remains to be fully understood (Metso et al 2012).

The gold standard diagnostic modality remains cerebral angiography. Less invasive alternatives include CTA and MRI/MRA. CTA may demonstrate a filling defect suggestive of thrombus or intimal flap. A T1-fat-suppressed sequence should be requested on MRI to assess for extraluminal T1-hyperintense material suggestive of methemoglobin in the dissection flap. Level I evidence has not yet proven the sensitivity or specificity for these techniques. The overall prognosis for carotid dissections is better than that of vertebral dissections. In one group of patients, 76% of carotid dissections completely recovered neurologic function (Mokri et al 1986; 1988), and less than 5% suffered fatal stroke or hemorrhage. Ten percent of patients with vertebral artery dissection die in the acute phase secondary to massive stroke or intracranial extension. The latter is usually associated with a dissecting pseudoaneurysm and has a worse prognosis than extracranial dissection (Hart and Easton 1985; Blunt and Galton 1997) due to a fulminant presentation with posterior fossa subarachnoid hemorrhage and a high rate of rebleeding. Pseudoaneurysm formation was more frequent in internal carotid dissections (22%) than in the vertebral artery (14%) in a series of 177 cervical artery dissection patients with a mean age of 44 (Schwartz et al 2009). With the exception of dissecting vertebrobasilar pseudoaneurysms, recurrent dissection is rare: less than 2% in studies from academic centers and even lower in epidemiological studies (Lee et al 2006; Schwartz et al 2009).

Moyamoya disease is a noninflammatory vasculopathy most prominent in Asia (annual incidence is 0.35 per 100,000 Japanese inhabitants) (Kuroda and Houkin 2008) that usually affects children older than 6 years of age. Ratio of females to males affected is 1.8 to 1. Moyamoya disease is characterized by initially asymmetric, progressive, steno-occlusion of both supraclinoid internal carotid arteries and the circle of Willis that may result in recurrent ischemic or hemorrhagic strokes or seizures. Ischemic infarcts are more common in children; hemorrhagic infarcts are more common in patients older than 30 years of age (Love and Biller 2009). Six angiographic stages are described: stage I consists of supraclinoid internal carotid artery stenosis; stages II through V consist of progressive appearance then disappearance of moyamoya vessels; and stage VI consists of external carotid artery branches supplying the intracranial circulation due to occlusion of the major intracranial vessels (Suzuki and Kodama 1983). The posterior cerebral arteries are spared until late in the disease. The classic angiographic appearance is a faint blush of contrast akin to "a puff of smoke" secondary to the development of multiple, fragile collateral vessels in the basal ganglia and thalami that are prone to hemorrhage. Two additional subtypes of moyamoya may manifest late in the disease: ethmoidal (Suzuki and Kodama 1971) and vault (Kodama et al 1980). The former is primarily supplied by the ophthalmic artery and posterior and anterior ethmoidal arteries. The latter is supplied by transdural anastomoses from the middle meningeal or superficial temporal arteries. Moyamoya disease is associated with a number of systemic conditions, including sickle cell disease, Down syndrome, neurofibromatosis type I, radiation therapy, neonatal anoxia, coarctation of the aorta, and certain infections such as tuberculosis (Yamashiro et al 1984; Yilmaz et al 2001). Surgical revascularization procedures include superficial temporal artery-middle cerebral artery (STA-MCA) bypass or rarely, superficial temporal artery-anterior cerebral artery (STA-ACA) bypass, occipital artery-middle cerebral artery (OA-MCA) bypass, encephaloduroarteriosynangiosis (EDAS), or encephaloduroarteriomyosynangiosis (EDAMS) (Yilmaz et al 2001; Kuroda and Houkin 2008).

Stroke from reversible cerebral arterial vasoconstriction or Call-Fleming syndrome, is gaining recognition (Singhal et al 2002; Singhal 2004a; 2004b; Calabrese et al 2007). It has been described in a variety of conditions, including pregnancy and the puerperium (postpartum angiopathy), migraine, use of vasoconstrictive drugs, reversible posterior leukoencephalopathy, blood transfusions, tumors (eg, phaeochromocytoma), medical conditions (hemolysis, antiphospholipid syndrome, thrombotic thrombocytopenic purpura), and benign angiopathy of the central nervous system (Miller et al 2015). In a retrospective analysis of 139 patients at 2 academic centers that included cases of “probable” reversible arterial vasoconstriction syndrome, the patients were predominantly female (80%) and had a mean age of 42 (Singhal et al 2011). One third of these patients had a history of vasoconstrictive drug exposure and 6% were recent postpartum patients. Forty-three percent of patients had focal neurologic deficits. Brain ischemia (often watershed rather than territorial infarcts) was documented in around 40% of patients. Subarachnoid hemorrhage overlying the hemispheric convexity was found in 34%; and 20% of patients had lobar hemorrhage. Arterial narrowing (most often by transfemoral or CT angiography) was severe in nearly all patients, even in the absence of cerebral lesions on brain imaging, and complete resolution of the stenosis in the angiographic follow-up occurred in around 70% of patients. A good outcome was observed in 90% of patients, and only 2% of patients died. Out of 159 patients aged 18 to 45 years who were admitted in a stroke unit with acute cerebral infarct found on brain MRI, 21 patients (13%) had multifocal segmental stenosis (mean of 4.52 per patient) in at least 2 different intracranial arteries on 3D-TOF-MRA or CTA performed on the day of admission, and ended up with proven spontaneous reversibility of all segmental stenosis within 3 to 6 months. This finding was the only abnormality observed, despite an extensive etiological investigation, and was considered by the authors to be a variant of a reversible vasoconstriction syndrome (Wolff et al 2015). These patients had a number of differences compared with others reported in large series of reversible arterial vasoconstriction syndrome: they were younger (mean age of 32) and predominantly male; they showed a higher frequency of traditional stroke risk factors; 74% of them had unusually severe headaches during a mean of 9 days before the onset of stroke; and none of them had the classically recurrent thunderclap headache. A precipitating factor (mostly cannabis use) was identified in 81% of these patients and cerebral infarcts were found in all of them upon neuroimaging studies, with territorial infarcts predominating in the posterior circulation. At 3 months all patients showed a good outcome (Wolff et al 2015).

Misdiagnosis is common because clinical and radiological features may overlap with primary cerebral vasculitis. The preeminent factors for distinguishing between reversible cerebral vasoconstriction syndrome and primary angiitis of the central nervous system can be an explosive onset or worst-ever headache with recurrent thunderclap headaches in the next few days, the clinical setting, the type and location of brain lesions, and normal cerebrospinal fluid results (Singhal et al 2011).

Common causes of cardiac emboli in the young include prosthetic heart valves, rheumatic valvular disease, bacterial endocarditis, atrial septal aneurysm, patent foramen ovale, dilated cardiomyopathy, ischemic dyskinetic segments, atrial myxomas, and mitral valve prolapse. Less common sources of cardiac emboli are nonbacterial thrombotic (marantic) and Libman-Sacks endocarditis. Marantic endocarditis is characterized by multiple, sterile, fibrin or platelet thrombi adherent to the mitral and aortic valves, usually in patients with mucin-secreting malignancies. Libman-Sacks endocarditis occurs in patients with systemic lupus erythematosus and is characterized by verrucous, fibrinous lesions of the mitral and aortic valves, leading to valvular insufficiency.

Rheumatic fever remains the most common cause worldwide of acquired heart conditions in the young and an eminently preventable etiology of stroke. The mitral valve is most frequently affected, followed by the aortic valve. The lifetime risk of embolism with rheumatic mitral stenosis is 20%; cerebral embolism is present in 60% of these cases and is more likely if atrial fibrillation, left atrial enlargement, low cardiac output, or severe mitral stenosis is present (Biller et al 2009). Rheumatic fever should be suspected with clinical manifestations such as fever, arthralgia or arthritis, painless subcutaneous nodules, chorea, or erythema marginatum following tonsillopharyngitis. Pharyngeal cultures growing beta-hemolytic streptococcus or serum streptococcal antibody titers are diagnostic. Less commonly, ischemic stroke may be associated with the tetralogy of Fallot, Eisenmenger complex, patent ductus arteriosus, or other cardiac valvular anomalies. The prevalence of cardiac abnormalities in the asymptomatic population must be considered when attributing cause to stroke in a younger population. This is particularly true for a high-prevalence condition such as mitral valve prolapse, which may be no more common in stroke patients (1.9%) than in controls (2.7%) (Gilon et al 1999). One referral center study reported a 24% to 29% proportion of ischemic strokes attributed to cardiac embolism (Adams et al 1986). A population-based study reported a 28% to 31% proportion of ischemic strokes attributed to cardiac embolism (Hart and Miller 1983). The variability in estimates (from 10% to 40%) may be due to extent of cardiac evaluation. Transesophageal echocardiography may be superior to transthoracic echocardiography for the detection of a cardiac source of cerebral embolism (Mas et al 2001; Musolino et al 2003) due to improved visualization of left atrial appendage thrombi, valvular vegetations, atrial septal aneurysms, and patent foramen ovale with the latter. The addition of Doppler color flow studies is especially useful to assess structural features and flow characteristics of prosthetic heart valves.

Paradoxical embolization is a presumed cause of so-called cryptogenic stroke in the young. Patent foramen ovale is more frequently found in patients with cryptogenic stroke than in those with known etiology or in healthy control patients. A thorough work-up should be undertaken to identify a venous source of emboli to traverse the shunt; if absent, the presence of a patent foramen ovale should only be considered a possible cause for the stroke (Cramer et al 2004). Patients with both a patent foramen ovale and atrial septal aneurysm have a much higher stroke risk than patients with either 1 of these conditions (OR 23.93; 95% CI: 3.09-185.42) (Mas et al 2001; Piechowski-Jozwiak and Bogousslavsky 2013). Spontaneous echo contrast is found in up to 9% of transesophageal echocardiograms in young stroke patients (DiTullio et al 1993). Although its significance is unclear, it is caused by sluggish left atrial blood flow and is more common in atrial fibrillation.

Characteristics of cardioembolic stroke include abrupt onset of neurologic deficit maximal at onset that is often triggered by activity. Association with Valsalva maneuver or acute pulmonary hypertension may also suggest paradoxical embolism (Biller et al 2009). Prior transient ischemic attacks in the same arterial territory are unlikely. A good history should evaluate for episodic palpitations, lightheadedness, or a history of sick sinus syndrome or atrial fibrillation (Cohen et al 1993). Although nearly half of cardioembolic strokes are related to atrial fibrillation, the latter is found in only 0.4% of adults younger than 60 years of age (Biller et al 2009). In the last few months, after prolonged cardiac monitoring, the prevalence of previous or de novo atrial fibrillation was found to be 9% (14 patients, 8 with paroxysmal atrial fibrillation and 5 with permanent atrial fibrillation) among 157 young adults with brain infarction (mean age of 43, 60% males). In this series, atrial fibrillation was more commonly associated with valvulopathy or cardiomyopathy (Prefasi et al 2013). In another study which included long-term ECG Holter monitoring performed after a median of 39 days from admission for the index event, a 10% rate of atrial fibrillation was found in 98 patients aged 18 to 49 with acute cerebral infarct. The mean time from start of long-term ECG Holter monitoring to detection of arrhythmia (mainly in paroxysmal form) was 11.5 days. In contrast to Prefasi’s series, structural heart disease was found in only 10% of the atrial fibrillation patients. These patients had an elevated level of acute serum cardiac markers (N-terminal probrain natriuretic peptide and high sensitive troponin T). N-terminal probrain natriuretic peptide may be a predictor of atrial fibrillation (Sanak et al 2015).

Table 2. Conditions Associated with Cardiac Emboli

Probable source

  • Endocarditis
  • Atrial fibrillation
  • Recent myocardial infarction
  • Akinetic segment
  • Dilated cardiomyopathy
  • Intracardiac thrombus
  • Cardiac tumors
    - Atrial myxoma
    - Cardiac rhabdomyoma
    - Cardiac papillary fibroelastoma
  • Sick sinus syndrome
  • Valvular vegetations including nonbacterial thrombotic endocarditis
    - Nonbacterial thrombotic endocarditis
    - - Libman-Sacks endocarditis
  • Rheumatic valvular disease
  • Prosthetic valve
  • Right-to-left shunt with associated venous thrombosis
  • Spontaneous atrial contrast echo
  • Atrial septal aneurysm
  • Intracardiac tumors
  • Recent cardiac procedures
    - Bypass graft
    - Valvular surgery
    - Heart transplantation
    - Extracorporeal membrane oxygenation (ECMO)

Possible source

  • Mitral valve prolapse
  • Atrial flutter
  • Remote myocardial infarction
  • Left ventricular hypertrophy
  • Hypokinetic segment
  • Atrial septal aneurysm
  • Isolated atrial septal defect or patent foramen ovale (without associated venous thrombosis)
  • Mitral annular calcification
  • Calcific aortic stenosis
  • Coarctation of the aorta
  • Mitral valve strands
  • Aneurysm of the sinus of Valsalva
  • Left ventricular aneurysm

Adapted from (Stern and Wityk 1994).

The spectrum of hematologic causes of stroke includes primary hypercoagulable syndromes and secondary hypercoagulable states. Primary hypercoagulable states are caused by quantitative or qualitative abnormalities of specific coagulation proteins leading to a lifelong predisposition to thrombosis. Secondary hypercoagulable states, a diverse group of mostly acquired conditions, cause a prothrombotic state by complex mechanisms (Nachman and Silverstein 1993). Ischemic stroke can be the presenting feature of a hematologic disorder (Table 3). A hypercoagulable state accounts for 1% to 2% of all stroke and 2% to 7% of stroke in patients younger than 50 years. The inherited thrombophilias (ie, protein C, S, and antithrombin deficiencies) are relatively common at 1:200 to 1:2000 in the heterozygous form, but the frequency of symptomatic deficiency is only 1:36000 (Greaves 1993; Martin et al 1997). Symptomatic episodes are usually venous thromboses; hereditary deficiencies of proteins C, S, or antithrombin III are rare in ischemic stroke patients younger than 45 years (Douay et al 1998). Resistance to activated protein C due to a mutation in factor V (factor V Leiden) and a mutation in the prothrombin gene (20210A) have been shown to be important genetic risk factors for venous thromboembolic disease, including cerebral venous thrombosis (Martinelli et al 1998), but less likely for arterial ischemic stroke (Zunker et al 2001). One study determined the odds ratio for carriers of factor V Leiden mutation compared to noncarriers to be 2.56. Relationship with the factor V Leiden mutation was greater in women (odds ratio 3.95), and the combined presence of factor V Leiden mutation plus at least one vascular risk factor increased the odds ratio to 10.72 (Margaglione et al 1999). An important note is that acute thrombosis itself may cause transient decreases in proteins C, S, and antithrombin. The acute evaluation for these deficiencies, therefore, may yield inaccurate results. Also, heparin has been found to lower antithrombin levels, and warfarin lowers functional levels of protein C and S. Conditions with hematologic changes possibly leading to stroke include pregnancy, cancer, nephrotic syndrome, leukemia, inflammatory bowel disease, acute infection, paroxysmal nocturnal hemoglobinuria, and Behçet syndrome. Finally, antiphospholipid antibodies have been associated with ischemic stroke in some studies; however, their causative role in stroke is not entirely clear (Brey et al 2002). To estimate the frequency of any antiphospholipid antibodies (aPL) in patients with stroke between 16 and 50 years of age (median age of 37), Sciascia and coworkers identified 5217 patients (3349 stroke patients and 1868 controls) included in 43 studies (6 prospective studies with 408 patients) in a systematic review of available relevant papers in electronic databases from 1970 to 2013 (Sciascia et al 2014). In young stroke patients, the frequency of any antiphospholipid antibody was 17%; anticardiolipin antibodies (aCL), lupus anticoagulant, and anti-β2 glycoprotein 1 antibodies were found in 22%, 16%, and 14% of these patients, respectively. Despite significant heterogeneity and methodological flaws observed in the studies included, the authors maintain that the results suggest a robust association between antiphospholipid antibody and stroke when compared with young control individuals. Accordingly, an antiphospholipid antibody positivity test may be associated with a 5-fold higher risk for cerebrovascular event (ischemic stroke or transient ischemic attack). A hypercoagulable screen is warranted when venous thrombosis with paradoxical embolism is suspected, when there is a family history of recurrent thrombosis, or when there is a personal or family history of recurrent miscarriage.

Table 3. Selected Hematologic Disorders Associated with Stroke

  • Sickle cell disease
  • Hemoglobin SC disease
  • Polycythemia
  • Hyperviscosity state
  • Thrombocytosis
  • Heparin-induced thrombocytopenia
  • Iron deficiency anemia
  • Thrombotic thrombocytopenic purpura
  • Paroxysmal nocturnal hemoglobinuria
  • Hyperhomocysteinemia and homocystinuria
  • Disseminated intravascular coagulation
  • Antiphospholipid antibodies
    - Lupus anticoagulant
    - Anticardiolipin antibodies
  • Antithrombin deficiency
  • Protein C deficiency
  • (Free) Protein S deficiency
  • Activated protein C resistance (including, but not limited to, Factor V Leiden mutation)
  • Disorders of fibrinolysis
  • Methylene tetrahydrofolate reductase (MTHFR) mutation C677T
  • Plasminogen activator promoter polymorphism (PAI-1)
  • Prothrombin gene 20210A mutation

Adapted from (Stern and Wityk 1994).

Multiple illicit drugs, including heroin, amphetamine, cocaine, over-the-counter sympathomimetics such as phenylpropanolamine, ephedrine and pseudoephedrine, phencyclidine, lysergic acid diethylamide, marijuana, and alcohol, have been associated with stroke (Kernan et al 2000). Up to 14% of ischemic and hemorrhagic infarcts in individuals aged 18 to 44 years were caused by substance abuse in a study (Westover 2007). Patients may not provide an accurate history regarding substance abuse; therefore, a complete physical examination, including skin exam for presence of needle marks, should raise suspicion for drug abuse. Blood and urine toxicology should also be obtained. The possibility of septic endocarditis should also be considered in the intravenous drug abuser.

Stroke is a rare complication of migraine (Tzourio et al 1995; Chang et al 1999). The overall incidence of migraine-associated stroke is 3.36 per 100,000 per year. In individuals without other stroke risk factors, the incidence decreases to 1.44 per 100,000 per year. Migraine with aura and the subtypes of migraine, such as familial hemiplegic migraine, and basilar, retinal, and ophthalmoplegic migraine have a higher stroke risk. Several case-control studies have demonstrated an approximately 4-fold higher stroke risk in women with migraine under age 45 years; within this population, the risk increases to 10-fold in smokers and 14-fold in those taking oral contraceptive pills. The risk is highest (odds ratio of 34) in young women with migraine who smoke and take oral contraceptive pills. This association is inconsistent in older women and men. Given the high prevalence and incidence rates of migraine (10% to 25%) and ischemic stroke and the high prevalence of headache in patients with stroke, it is important to distinguish between (1) stroke of another cause coexisting with migraine, (2) stroke of another cause (eg, carotid artery dissection) presenting with clinical features of migraine with aura, and (3) stroke occurring during the course of a typical attack of migraine with aura (Welch 1994). The aura of migraine is a key risk factor for cerebral ischemia. Stang and colleagues found that migraine with aura was strongly associated with verified stroke (O.R. 2.81) as well as symptoms of stroke (O.R. 5.46) and symptoms of TIA (OR 4.28); the association was not significant in patients with headache without aura (Stang et al 2005). The mechanisms underlying the relationship between migraine and cerebral ischemia are not yet well understood. Migraine-specific mechanisms, potential common biological mechanisms (endothelial dysfunction, patent foramen ovale, and hypercoagulability), atherosclerotic mediated mechanisms, and genetic influence –likely all acting synergistically– might be operating to increase the propensity of cerebral ischemia in migraine (Pezzini et al 2011). Young age, female sex, a history of “high-risk” migraine subtypes (eg, familial hemiplegic migraine), cigarette smoking, use of oral contraceptives, onset with typical but perhaps more severe migrainous headache, prolonged aura, spreading or marching symptoms, visual and cortical symptoms, and posterior circulation infarct on brain imaging are factors that raise suspicion for migrainous stroke. Criteria for the diagnosis of migraine-induced stroke include: (1) previously established diagnosis of migraine with aura, (2) onset of infarction occurring during the course of a typical migraine aura attack, (3) persistent aura symptoms for more than 60 minutes, (4) evidence of ischemic infarction in relevant location by neuroimaging, and (5) no other obvious cause of infarction (The International Classification of Headache Disorders 2004).

Migrainous infarction accounts for 13.7% of ischemia in young adults (Arboix 2003). Migraine-associated acute cerebral ischemia was identified in 17 individuals (11 having migraine with aura) in a prospectively collected data set of 8137 stroke patients over an 11-year period, amounting to an estimated frequency of around 2 cases per 1000 strokes per year (Wolf et al 2011). These patients were younger women with a longstanding (mean of 13 years) history of migraine and prolonged aura symptoms. Moreover, a high prevalence of patent foramen ovale was identified and lesions were small, most often involving the posterior circulation. The overall outcome was favorable (Wolf et al 2011). Therefore, migrainous infarction is a diagnosis of exclusion. Because migraine is a clinical diagnosis without a diagnostic marker or unique radiographic features, alternative etiologies such as arteriovenous malformation, cervical arterial dissection, antiphospholipid syndrome, MELAS, or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) should be pursued if the presentation is not highly consistent.

Infection (particularly chlamydia and HIV) and acute and chronic inflammation have been attributed to raising stroke risk in younger patients (Bova et al 1996; Macko et al 1996; Pinto 1996; Qureshi et al 1997; Madre et al 2002; Anzini et al 2004; Cole et al 2004). A population-based study found AIDS to be a major risk factor for ischemic as well as hemorrhagic stroke (Cole et al 2004). In a nationwide population-based cohort study, HIV-infected individuals had an increased risk of stroke compared to their controls (Rasmussen et al 2011). The relative risk was substantially higher in the injection-drug-abuse HIV-infected individuals (35.6 median years), particularly for intracerebral and subarachnoid hemorrhage. High stroke risk was further associated with low CD4 cell count before the start of HAART, and also with abacavir treatment, although not with HAART, in general. 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.

Stroke can result from inherited disorders such as MELAS and CADASIL. MELAS is a disorder of mitochondrial metabolism resulting from a point mutation in mitochondrial DNA encoded transfer RNA for leucine. The pathology of stroke remains unclear. Patients typically present with ischemic-appearing lesions that are not restricted to a single arterial vascular territory, migraine-like headaches, seizures, emesis, and lactic acidosis and may have myopathy, ataxia, cardiomyopathy, diabetes, retinitis pigmentosa, or renal abnormalities. Muscle biopsy reveals ragged red fibers. Patients with CADASIL typically present with recurrent subcortical strokes (Joutel et al 1996; Markus et al 2002). Specific mutations in the notch 3 gene on chromosome 19 have been identified in patients with CADASIL. Brain MRI typically reveals a diffuse leukoencephalopathy with infarcts in the basal ganglia and white matter bilaterally, extending into the anterior temporal lobes and external capsules. Cerebral microhemorrhages are common (Viswanathan and Chabriat 2006). Imaging abnormalities can precede stroke-like symptoms by several years. Diagnosis is made by skin biopsy. Another condition associated with stroke is Hashimoto encephalopathy with cerebral vasculitis. Clinical presentation includes relapsing and remitting neurologic symptoms and signs of seizures, myoclonus, stroke-like episodes, cognitive decline, and neuropsychiatric manifestations (Mocellin 2007). Some migraine patients may present with headache, reversible neurologic deficits, and recurrent cerebrospinal fluid lymphocytosis (HaNDL) syndrome; their neuroimaging studies are normal (Fumal et al 2005).

Fabry disease, or Anderson-Fabry disease, is an X-linked recessive lysosomal storage disorder due to alpha-galactosidase-A deficiency (mutation of the gene at Xq22.1) leading to a glycosphingolipid accumulation in neurons and vascular endothelial and smooth muscle cells. Men and women are similarly affected, with a wide range of clinical manifestations from asymptomatic states to irreversible organ failure.

Fabry disease affects the peripheral and central nervous systems, as well as the myocardium, kidney, and the gastrointestinal system. Nonneurologic clinical manifestations on the skin (angiokeratoma corporis diffusum), corneal opacity (cornea verticillata), subcapsular cataracts, hypohidrosis, and acroparesthesias often develop in childhood or adolescence, although they may occasionally be absent in young adults, making the diagnosis of Fabry disease a challenge. Stroke is the leading complication of Fabry disease in the central nervous system. The leading complication of Fabry disease is stroke (Shi et al 2014). Cerebral infarcts and transient ischemic attacks are the most prevalent stroke subtypes, sometimes presenting as the first manifestation of this disease, thus leading to its diagnosis. Large vessel and small vessel symptomatic infarcts are most common, although chronic white matter hyperintensities, usually asymptomatic, may also be found on neuroimaging studies. Intracerebral or subarachnoid hemorrhages, microbleeds, and cerebral venous thrombosis are less common occurrences in Fabry disease (Kolodny et al 2015).

Fabry disease is considered an uncommon, though treatable, cause of stroke. The stroke pathogenesis associated with Fabry disease is incompletely understood, despite its association with arterial ectasia, endothelial dysfunction, premature atherosclerosis, and cardiopathy (hypertrophic and restrictive cardiomyopathies, valvular and conduction-system abnormalities). In a metaanalysis of 9 studies (8 ranked moderate to high quality by a designed assessment tool; 4 studies focusing on cryptogenic stroke and the remainder on all stroke etiologies) comprising around 8000 patients with a mean age range between 38 to 51 years, the prevalence of Fabry disease was higher in patients with cryptogenic stroke (0.6% to 11%), whereas it ranged from 0.4% to 2.6% in stroke of any etiology. A male predominance in the prevalence of Fabry disease was observed in cryptogenic stroke (4.5% vs. 3.4% in women), but no gender difference in the prevalence of Fabry disease was observed when stroke of any etiology was considered.

Moreover, the incidence of definite or probable Fabry disease was estimated in a prospective multicenter observational study (47 centers in 15 European countries) which included 5023 patients from 18 to 55 years of age (median age of 46) presenting a recent cerebrovascular event (within 3 months; brain infarct in 71% of patients; transient ischemic attack in 22%; intracerebral hemorrhage in 5%) (Rolfs et al 2013). In this largest cohort of young stroke patients, Fabry disease was present in 1% (0.5% definite and 0.4% probable diagnosis). Females, younger patients, and ischemic stroke predominated in both diagnostic categories. Territory infarcts were found in 40% and 33% of definite and probable Fabry disease patients, respectively. Interestingly, no association was found between Fabry disease with cardiopathy (congestive heart failure or arrhythmia), and family history of cardiac, renal, or cerebrovascular disease (Rolfs et al 2013).

Many other disorders have been associated with cerebral infarction in the young. Some possible entities are listed in Table 4.

Table 4. Other Conditions Associated with Stroke

Inflammatory diseases:

  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Scleroderma
  • Sjögren syndrome
  • Polymyositis
  • Proximal myotonic myopathy
  • Henoch-Schönlein purpura
  • Polyarteritis nodosa
  • Churg-Strauss syndrome
  • Wegener granulomatosis
  • Lymphomatoid granulomatosis
  • Sarcoidosis
  • Primary vasculitis of the central nervous system
  • Behçet disease

Infectious diseases:

  • Neuroborreliosis
  • Neurocysticercosis
  • Varicella zoster
  • HIV
  • Bacterial (pyogenic) meningitis
  • Chlamydia pneumonia
  • Hepatitis C virus and mixed cryoglobulinemia
  • Hydatid cyst embolism
  • Leptospirosis

Cancer:

  • Tumor emboli
  • Malignant angioendotheliomatosis

Hereditary disorders:

  • Neurofibromatosis
  • Epidermal nevus syndrome
  • CADASIL
  • Sneddon syndrome
  • Williams syndrome

Medication-related:

  • Ovarian hyperstimulation syndrome or high-dose female sex hormone therapy
  • L-asparaginase
  • High-dose intravenous immunoglobulin
  • Methotrexate
  • Interferons

Other:

  • Fibrocartilaginous embolism
  • Childhood cerebral arteriopathies
  • Dysplastic arteriopathies/arterial abnormalities (PHACES syndrome, Alagille syndrome, Williams Syndrome, Noonan syndrome, and trisomy 21)
  • Hashimoto encephalopathy with vasculitis
  • Headache, neurologic deficits, and cerebrospinal fluid lymphocytosis (HaNDL) syndrome

Adapted from (Stern and Wityk 1994).

The majority of intraparenchymal hemorrhages are lobar; they may also occur in deep subcortical structures (basal ganglia, internal capsule), brainstem, or cerebellum, depending on etiology (Del Brutto et al 1999; Ruiz-Sandoval et al 1999). In a study of intracerebral hemorrhage in young adults, ruptured arteriovenous malformations were found in 29%; hypertension in 15%; ruptured aneurysms in 10%; miscellaneous conditions in 22%; and undetermined causes in 24% (Toffol et al 1987). Another study of intracerebral hemorrhage in young people noted vascular malformations in 49% of patients; hypertension in 11%; cerebral venous thrombosis in 5%; sympathomimetic drug use in 4%; toxemia of pregnancy in 4%; and cryptogenic cause in 15% (Ruiz-Sandoval et al 1999). Excluded from this study were primary subarachnoid hemorrhage, trauma, past evidence of vascular malformation, and brain tumor. The importance of repeat vascular imaging (ideally catheter angiography) after an interval of 8 to 12 weeks to allow for resolution of intracranial blood products cannot be overstated as repeat workup of intraparenchymal hemorrhages in young adults without vascular risk factors often yields a previously occult vascular malformation.

Selected causes of hemorrhagic events are listed in Table 5. Normotensive patients with lobar hemorrhages are especially likely to have an underlying vascular lesion. Patients with cavernous malformations occasionally have a familial history, as do 20% to 30% of individuals with an aneurysm (Gunel et al 1996). Familial aneurysms are more common in women below the age of 50 years (Leblanc 1996). Disorders associated with intracranial saccular aneurysms include autosomal dominant polycystic renal disease, pseudoxanthoma elasticum, Ehlers-Danlos type IV, Marfan syndrome (possibly), neurofibromatosis, coarctation of the aorta, arteriovenous malformations, and moyamoya disease. Mycotic aneurysms represent 4% of all intracranial aneurysms and occur in 3% of patients with infective endocarditis (Frazee et al 1980). They may be saccular or fusiform and frequently occur in distal branches of the middle and posterior more than anterior cerebral arteries. Due to the peripheral location, mycotic aneurysm rupture frequently results in intraparenchymal, not subarachnoid, hemorrhage.

Table 5. Selected Causes of Spontaneous Intracranial Hemorrhage

  • Trauma
  • Aneurysm
    - Berry
    - Mycotic
    - Dissecting pseudoaneurysm
  • Vascular malformation
    - Arteriovenous malformation (AVM)
    - Dural arteriovenous fistula (dAVF)
    - Cavernous malformation
  • Hypertension
  • Coagulopathy
  • Arteritis
    - sterile
    - infectious
  • Sympathomimetic drugs
    - cocaine and crack cocaine
    - fenfluramine and phentermine
    - phenylpropanolamine, ephedrine/ephedra
  • Hemorrhage into a tumor
  • Moyamoya disease or syndrome
  • Hereditary intracerebral hemorrhage
    - Dutch type (mutation in amyloid precursor protein gene)
    - Icelandic type (mutation in cystatin C)

Adapted from (Stern and Wityk 1994).

Unfortunately, even after an exhaustive evaluation for etiology of stroke in the younger patient, up to 40% of cases remain without a known etiology. In a survey of ischemic stroke in the young, 44% of patients had known cause of stroke, although 1 in 5 of these patients may have been inadequately investigated, resulting in a spuriously high percentage of cryptogenic cases (Chan et al 2000). A complete diagnostic evaluation is, therefore, critical in order to determine potential causes and effective secondary stroke-prevention strategies.

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Pregnancy
Anesthesia
References cited
Contributors