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Stroke in Young
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Stroke in Young

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Stroke in people under 45 years of age is less frequent than in older populations but has a major impact on the individual and society. In this article we provide an overview of the epidemiology and etiology of young stroke.

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Stroke in Young

  1. 1. Stroke in Young
  2. 2. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 6 5 e2 6 9 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/apme Review Article Stroke in young Pushpendra Nath Renjen* Sr. Consultant Neurologist & Academic Coordinator, Institute of Neurosciences, Indraprastha Apollo Hospitals, New Delhi 110076, India article info abstract Article history: Stroke in people under 45 years of age is less frequent than in older populations but has a Received 8 August 2013 major impact on the individual and society. In this article we provide an overview of the Accepted 17 October 2013 epidemiology and etiology of young stroke. Available online 20 November 2013 Cerebral ischemia in young adults occurs at an annual incidence rate of about 6/100,000. Although it represents only about 1% of all strokes, it has a relevant impact on years of Keywords: potential life lost and on socioeconomic costs, considering the long life expectancy at these Cerebral ischemia ages. There is general agreement on the role of atherosclerosis in men over age 35 and of Prognosis cardiac diseases, migraine, and oral contraceptive use in women under age 35 as patho- Young adult genic determinants for cerebral ischemia. Whether the early onset of stroke in young Stroke adults might reflect severity of underlying pathology is still an open question. The shortterm prognosis of stroke in young adults is considered favorable, despite its relationship with the presence and severity of complications at the time of the first event. Long-term prognosis of young patients with transient ischemic attack is reported to be even more favorable, although the risk of new ischemic events depends on the presence of vascular risk factors. The available prospective studies report annual incidence rates of death and recurrent stroke ranging from 1% to 2.6%, with higher long-term mortality in patients who had large-vessel stroke. The prognosis has been reported to be severe in patients with carotid stenosis and mild in patients with coexisting stroke and migraine. Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. 1. Introduction Stroke in people under 45 years of age is less frequent than in older populations but has a major impact on the individual and society. In this article we provide an overview of the epidemiology and etiology of young stroke. Cerebral ischemia in young adults occurs at an annual incidence rate of about 6/100,000. Although it represents only about 1% of all strokes, it has a relevant impact on years of potential life lost and on socioeconomic costs, considering the long life expectancy at these ages.1 There is general agreement on the role of atherosclerosis in men over age 35 and of cardiac diseases, migraine, and oral contraceptive use in women under age 35 as pathogenic determinants for cerebral ischemia.2,3 Whether the early onset of stroke in young adults might reflect severity of underlying pathology is still an open question.3 The short-term prognosis of stroke in young adults is considered favorable, despite its relationship with the presence and severity of complications at the time of the first event.4,5 Long-term prognosis of young patients with transient ischemic attack (TIA) is reported to be even more favorable, * Tel.: þ91 11 29871016, þ91 9810059614 (mobile). E-mail address: pnrenjen@hotmail.com. 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2013.10.008
  3. 3. 266 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 6 5 e2 6 9 although the risk of new ischemic events depends on the presence of vascular risk factors.6,7 The available prospective studies report annual incidence rates of death and recurrent stroke ranging from 1% to 2.6%, with higher long-term mortality in patients who had a large-vessel stroke.5,8,9 The prognosis has been reported to be severe in patients with carotid stenosis and mild in patients with coexisting stroke and migraine.10 2. Etiologies The range of potential etiologies for stroke in young adults is broader than that for older adults (Table 1). Like in older adults, stroke in younger adults is typically categorized as primarily ischemic or hemorrhagic. Ischemic etiologies include cardioembolic, atherosclerotic disease, and nonatherosclerotic cerebral vasculopathies. Hemorrhagic strokes include subarachnoid and intraparenchymal types. Of particular note in young adults are stroke causes such as hematologic disorders, substance abuse, trauma, dissections, oral contraceptive use, pregnancy and postpartum states, and migraine. 3. Clinical manifestations The clinical presentations for stroke in young adults are not unique to this age group. Sudden or subacute onset of neurologic symptoms referable to the brain should suggest stroke as a potential explanation. The presence of a given stroke risk factor does not assure that it is causative. Many young patients have multiple risk factors. Detailed history and examination, oriented toward common and uncommon etiologies, are especially important. Stroke mimics in the young adult population include multiple sclerosis and malignancy. The physical exam should include neurologic, cardiovascular, ophthalmologic and dermatologic assessments. Relevant ocular findings include corneal arcus (hypercholesterolemia) or corneal opacity (Fabry’s disease); Lisch nodules, optic atrophy (neurofibromatosis); lens subluxation (Marfan’s syndrome, homocystinuria); and retinal perivasculitis (sickle-cell disease, syphilis, connective tissue diseases, inflammatory bowel disease), occlusions (emboli), angioma (cavernous malformation), or hamartoma (tuberous sclerosis). Among dermatologic associations are splinter hemorrhages or needle tracks (endocarditis); xanthoma Table 1 e Differential diagnosis of stroke in young adults. Ischemic Cardiac disease (including congenital, rheumatic valve disease, mitral valve prolapse, patent foramen ovale, endocarditis, atrial myxoma, arrhythmias, cardiac surgery) Large vessel disease Premature atherosclerosis. Dissection (spontaneous or traumatic). Inherited metabolic diseases (homocystinuria, Fabry’s, pseudoxanthoma elasticum, MELAS syndrome). Fibromuscular dysplasia. Infection (bacterial, fungal, tuberculosis, syphilis, Lyme). Vasculitis (collagen vascular diseases e systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, polyarteritis nodosa; ¨ Takayasu’s disease, Wegener’s syndrome, cryoglobulinemia, sarcoidosis, inflammatory bowel disease, isolated central nervous system angiitis). Moyamoya disease. Radiation. Toxic (illicit drugs e cocaine, heroin, phencyclidine; therapeutic drugs e l-asparaginase, cytosine arabinoside). Small vessel disease Vasculopathy (infectious, noninfectious, microangiopathy). Hematologic disease Sickle-cell disease. Leukemia. Hypercoagulable states (antiphospholipid antibody syndromes, deficiency of antithrombin III or protein S or C, resistance to activated protein C, increased factor VIII). Disseminated intravascular coagulation. Thrombocytosis. Polycythemia vera. Thrombotic thrombocytopenic purpura. Venous occlusion (dehydration, parameningeal infection, meningitis, neoplasm, polycythemia, leukemia, inflammatory bowel disease). Migraine Hemorrhagic Subarachnoid hemorrhage (cerebral aneurysm) Intraparenchymal hemorrhage Arteriovenous malformation. Neoplasm (primary central nervous system, metastatic, leukemia). Hematologic (sickle-cell disease, neoplasm, thrombocytopenia), moyamoya disease. Drug use (warfarin, amphetamines, cocaine, phenylpropanolamine). Iatrogenic (peri-procedural).
  4. 4. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 6 5 e2 6 9 ´ (hyperlipidemia); cafe-au-lait spots, neurofibromas (neurofibromatosis); purpura (coagulopathy); and capillary angioma (cavernous malformation).11 One-fifth to one-third of strokes in the young may be caused by cardioembolic phenomena. Transesophageal echocardiography (TEE) is usually indicated. Causes include congenital heart disease, valvular disease (including endocarditis) and arrhythmias. Mitral valve prolapse and patent foramen ovale are common but are typically not causes of stroke when present. An atrial septal aneurysm is less likely to be associated with stroke when found in isolation than when it occurs with other cardiac abnormalities. Premature atherosclerotic cerebrovascular disease can be symptomatic in young adults, just as atherosclerosis can begin in childhood. The symptoms and signs are similar to those for older adults. Cervicocephalic arterial dissections can involve the extracranial internal carotid, the vertebrobasilar system, or, less commonly, the intracranial carotid system. They are associated with major or minimal trauma, chiropractic manipulation, or can occur spontaneously. Other associations include fibromuscular dysplasia, Marfan syndrome, EhlerseDanlos syndrome type IV, moyamoya and sympathomimetic drug abuse. Symptoms and signs may include neck pain, transient or lasting ischemia of retina, cerebral hemispheres, or posterior fossa, Horner’s syndrome, hemicranial pain, or subarachnoid hemorrhage. Extracranial ultrasound or magnetic resonance angiography (MRA) may confirm the clinical impression. Often catheter angiography is required for diagnosis. Cerebral vasculitis should be considered for cases of ischemic or hemorrhagic stroke, recurrent strokes, stroke with encephalopathy, and stroke with fever, multifocal symptoms, skin abnormalities, or abnormal renal function or sedimentation rate. Infectious vasculitis (eg, with syphilis, tuberculosis, purulent meningitis), necrotizing vasculitis (eg, polyarteritis nodosa), vasculitis with collagen vascular disease (eg, lupus, rheumatoid arthritis), giant cell arteritis, and hypersensitivity vasculitis (eg, drug-induced) are seen much more often than primary central nervous system vasculitis. Moyamoya is a noninflammatory vasculopathy associated with extensive collateral vasculature. It can present with transient ischemic attacks, headaches, hemiparesis, seizures, cerebral infarction, or hemorrhage. MRA screening is useful. Angiographic findings are distinctive and resemble in part a “puff of smoke”.12 Hypercoagulable states may be responsible for 2%e7% of cases in young adults. Inherited (primary) thrombophilic disorders include entities that are recently described (hyperhomocysteinemia, factor V Leiden, prothrombin G20210A), well-established (deficiencies of antithrombin, protein S or protein C), and extremely rare (dysfibrinogenemia, thrombomodulin deficiency, heparin cofactor II deficiency).13 Acquired (secondary) causes include malignancy, pregnancy/postpartum states, oral contraceptive use and sickle-cell disease. Prior thromboembolic disease in a young patient or in family members should raise suspicion.12 Cerebral venous thrombosis can cause ischemic or hemorrhagic strokes. Septic thrombosis usually occurs at the cavernous sinus as a complication of facial infection. Signs include proptosis, chemosis, and gaze palsies. Aseptic 267 thromboses are seen disproportionately in women during pregnancy or postpartum periods, or while taking oral contraceptives. Presenting symptoms include headache, emesis, lethargy, and seizures. Papilledema may accompany focal signs.12,14 Strokes induced by migraines are rare, considering that perhaps 20% of US adults may suffer migraines. Symptoms include persistent visual, motor, sensory or aphasic deficits, which began in the course of a typical migraine attack, where other causes are excluded. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are inherited causes of stroke which can include migraine as part of the clinical presentation.11,12 Up to 45% of strokes in young adults are due to spontaneous intracerebral hemorrhage.12 Approximately half are lobar; one-quarter are in basal ganglia or internal capsule.15 Vascular malformations, aneurysms, hypertension, and illicit drug use are the main causes.12,15 4. Investigations The initial work-up should be as expeditious as possible to allow consideration of acute therapies, such as tissue plasminogen activator (t-PA).16 Brain computed tomography (CT) is usually the initial imaging study of choice as it is readily available and is highly sensitive for acute hemorrhage. Blood work should include a complete blood count with differential and platelet count, prothrombin time (international normalized ratio), activated partial thromboplastin time, glucose, chemistries, electrolytes, serology for syphilis, and an erythrocyte sedimentation rate. A more detailed coagulation profile (anticardiolipin antibodies, lupus anticoagulants, protein S, protein C, activated protein C resistance, antithrombin III) is requested in patients without a firmly identified cause of stroke or if the patient or family members have a history of thromboses. It is advantageous to send such a profile prior to initiating anticoagulation, as heparin can alter interpretation of some of those assays. Therefore, consider ordering these assays at the beginning of the work-up. Most patients should have high-quality brain magnetic resonance imaging (MRI) and often MRA.12,17 Where available, MRI with diffusion-weighted imaging (DWI) and perfusion imaging (PI) is becoming standard. DWI-PI has the potential to distinguish irreversibly injured tissue from that which may be salvageable.18 Additional studies in initial screening include pregnancy testing, a chest roentgenogram, and an electrocardiogram. An echocardiogram (consider transesophageal), and extracranial (carotid-vertebral) Doppler ultrasound are routinely obtained, although often after initial antiplatelet or anticoagulation therapy is started. Keep in mind the limitations of studies performed. CT will miss a minority of acute bleeds. MRI with DWI, quite sensitive for acute stroke, has an occasional false negative result (17 out of 782 patients in a recent study).19 Also, MRA’s resolution is not yet on par with conventional angiography.
  5. 5. 268 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 6 5 e2 6 9 Consider conventional angiography of cerebral and neck vessels for patients in whom dissection is suspected or in whom no other cause is found. Transcranial Doppler ultrasound can be helpful. Toxicologic studies are often productive, even when drug use is not acknowledged. Other blood tests may include homocysteine, fibrinogen, antinuclear antibody, lipid panel, lipoprotein (a), serum protein electrophoresis, hemoglobin electrophoresis, and sicklecell assay. Cerebrospinal fluid analysis is indicated for cases suspicious for infectious, vasculitic, or occult hemorrhage origins. Telemetry monitoring for arrhythmias is occasionally revealing.12 Prothrombin mutation G20210A testing is of uncertain utility in cerebrovascular disease, but may be appropriate for patients with a personal history of thromboembolic disease or family history of thrombophilia. A patient with one or more risk factors, such as migraine or diabetes, should be thoroughly investigated for other possibilities. The cause of stroke in young patients may remain undetermined in 20%e30% of cases, even after a detailed work-up.12 5. and intracranial vessels. Whilst the commonest cause of cardioembolic stroke in the elderly is atrial fibrillation, in a young patient transesophageal echocardiography looking for the presence of a patent foramen ovale Æ an atrial septal aneurysm will have a higher yield. One must not forget, however, that atherosclerosis still contributes to a large proportion of stroke in young patients and likely explains at least some of the ethnic differences noted in the incidence of stroke, emphasizing the need for aggressive risk factor management. This, as well as differences in the prevalence of other causative etiologies, such as rheumatic fever and infection, combined with a younger background population age distribution, may contribute to an increased incidence of young stroke in developing countries. Finally, the incidence of stroke appears greater in women than men under the age of 30, and women are at increased risk of hemorrhage and infarction in the puerperium. Additional history, including use of the oral contraceptive pill, and testing for antiphospholipid antibodies is important in young women. There is a need for further research in young stroke, particularly population-based studies utilizing standardized methodology. These will provide clarity by enabling comparison of incidence rates between countries and trends overtime, and insights into underlying etiological mechanisms. Management General management of ischemic and hemorrhagic strokes is similar to that for older adults and is beyond the scope of this article. Additional specific measures are oriented toward any underlying etiology found. Conflicts of interest The author has none to declare. references 6. Prognosis The outcome of stroke in young adults is better than that for older adults. In a recent study of 330 patients with first stroke or transient ischemic attack, followed for an average of 96 months, 8% died, 3% had another stroke, and 3% had a myocardial infarction. Approximately 16% were dependent, but 56% had returned to work. Unfortunately, only a minority of those who smoked at the time of their stroke subsequently stopped using tobacco. The overall annual recurrence rate is less than 1%. Prognosis is often closely associated with the underlying cause. A relatively good outcome may be found after many cases of arterial dissection. Risk of stroke recurrence is low (2% over 5 years) in women whose first stroke occurred in pregnancy. 7. Conclusion In summary, stroke in the young requires a different approach to investigation and management than stroke in the elderly given differences in the relative frequencies of possible underlying causes. Haemorrhagic stroke is common, and vascular imaging is recommended given a high frequency of underlying vascular anomalies. It is also important to explore the possibility of illicit drug use in these cases. With regard to ischemic stroke, the increased frequency of dissection mandates a high index of suspicion for imaging the extracranial 1. Carolei A, Marini C, Di Napoli M, et al. High stroke incidence in the prospective community-based L’Aquila registry (1994e1998): first year’s results. Stroke. 1997;28:2500e2506. ´ 2. Tzourio C, Tehindrazanarivelo A, Iglesias S, et al. Casecontrol study of migraine and risk of ischaemic stroke in young women. BMJ. 1995;310:830e833. 3. Carolei A, Marini C, Ferranti E, Frontoni M, Prencipe M, Fieschi C, The National Research Council Study Group. A prospective study of cerebral ischemia in the young: analysis of pathogenic determinants. Stroke. 1993;24:362e367. 4. Chancellor AM, Glasgow GL, Ockelford PA, Johns A, Smith J. Etiology, prognosis and hemostatic function after cerebral infarction in young adults. Stroke. 1989;20:477e482. 5. Hindfelt B, Nilsson O. Long-term prognosis of ischemic stroke in young adults. Acta Neurol Scand. 1992;86:440e445. 6. Johnson S, Skre H. Transient cerebral ischemic attacks in the young and middle aged: a population study. Stroke. 1986;17:662e666. 7. Larsen BH, Sorenson PS, Marquardsen J. Transient ischaemic attacks in young patients: a thromboembolic or migrainous manifestation? A 10 year follow-up study of 46 patients. J Neurol Neurosurg Psychiatr. 1990;53:1029e1033. 8. Bogousslavsky J, Regli F. Ischemic strokes in adults younger than 30 years of age: cause and prognosis. Arch Neurol. 1987;44:479e482. 9. Kappelle LJ, Adams HP, Heffner ML, Torner JC, Gomez F, Biller J. Prognosis of young adults with ischemic stroke: a long-term follow-up study assessing recurrent vascular events and functional outcome in the Iowa Registry of Stroke in Young Adults. Stroke. 1994;25:1360e1365.
  6. 6. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 6 5 e2 6 9 10. Carolei A, Marini C, Nencini P, et al, The National Research Council Study Group. Prevalence and outcome of symptomatic carotid lesions in young adults. BMJ. 1995;311:1363e1366. 11. Stern BJ, Wityk RJ. Stroke in the young. In: Feldmann E, ed. Current Diagnosis in Neurology. St. Louis, MO: Mosby; 1994:34e40. 12. Biller J. Strokes in the young. In: Toole JF, ed. Cerebrovascular Disorders. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 1999:283e316. 13. Nguyen A. Prothrombin G20210A polymorphism and thrombophilia. Mayo Clin Proc. 2000;75:595e604. 14. Ameri A, Bousser MG. Cerebral venous thrombosis. Neurol Clin. 1992;10:87e111. 269 15. Ruız-Sandoval JL, Cantu C, Barinagarrementeria F. Intracerebral ´ ´ hemorrhage in young people: analysis of risk factors, location, causes and prognosis. Stroke. 1999;30:537e541. 16. Brott T, Bogousslavsky J. Drug therapy: treatment of acute ischemic stroke. N Engl J Med. 2000;343:710e722. 17. Provenzale JM, Barboriak DP. Brain infarction in young adults: etiology and imaging findings. Am J Roentgenol. 1997;169:1161e1168. 18. Fisher M, Albers GW. Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke. Neurology. 1999;52:1750e1756. 19. Ay H, Buonanno FS, Rordorf G, et al. Normal diffusionweighted MRI during stroke-like deficits. Neurology. 1999;52:1784e1792.
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