Cryptogenic Stroke—The Appropriate Diagnostic Evaluation Authors
Cerebrovascular Disease and Stroke (D Greer, Section Editor)
First Online: 19 December 2013 DOI:
Cite this article as: Amin, H. & Greer, D.M. Curr Treat Options Cardio Med (2014) 16: 280. doi:10.1007/s11936-013-0280-3 Opinion statement
Ischemic strokes are a significant cause of morbidity and mortality in the United States. They may be due to large artery atherosclerosis, small vessel occlusion, cardioembolism, or other less common mechanisms such as toxins, hypercoagulable disorders, and vasospasm. Each mechanism carries its own risk of recurrence and prognosis. Strokes without an identifiable cause despite a complete work-up are described as cryptogenic. Cryptogenic stroke therefore is a diagnosis of exclusion, and one that should not be arrived at haphazardly. One must complete a thorough, and frequently challenging, stroke work-up prior to this diagnosis. Challenges in determining stroke etiology include the transient nature of precipitating events such as vasospasm or cardiac arrhythmias, variable durations of cardiac monitoring, and unclear significance of certain cardiac structural anomalies. Many consider cryptogenic stroke to be a heterogeneous combination of paroxysmal and occult conditions that create such diagnostic difficulties. The diagnosis of cryptogenic stroke itself carries with it specific outcomes and prognosis. This article will provide an overview of the definition and epidemiology, recommendations for diagnostic evaluation, and risks of recurrence of cryptogenic stroke.
Keywords Cryptogenic stroke Cardioembolism Atrial fibrillation Large vessel Small vessel disease Hypercoagulable Patent foramen ovale Cardiac monitoring
This article is part of the Topical Collection on
Cerebrovascular Disease and Stroke References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: •• Of major importance
Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6–245. An excellent resource for data on morbidity, mortality, quality of care and costs of work-up and management related to cerebrovascular disease.
Agency for Healthcare Research and Quality. total expenses and percent distribution for selected conditions by type of service: United States, 2010. Medical expenditure panel survey household component data. Generated interactively. Accessed May 13, 2013.
(CDC) CfDCaP. Prevalence of stroke--United States, 2006-2010. MMWR Morb Mortal Wkly Rep. 2012;61(20):379–82.
Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multi-center clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):35–41.
Jacobs BS, Boden-Albala B, Lin IF, Sacco RL. Stroke in the young in the northern Manhattan stroke study. Stroke. 2002;33(12):2789–93.
Towfighi A, Saver JL, Engelhardt R, Ovbiagele B. A midlife stroke surge among women in the United States. Neurology. 2007;69(20):1898–904.
Seshadri S, Beiser A, Kelly-Hayes M, et al. The lifetime risk of stroke: estimates from the Framingham Study. Stroke. 2006;37(2):345–50.
White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study. Circulation. 2005;111(10):1327–31.
Schneider AT, Kissela B, Woo D, et al. Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites. Stroke. 2004;35(7):1552–6.
Zweifler RM, Lyden PD, Taft B, Kelly N, Rothrock JF. Impact of race and ethnicity on ischemic stroke. The University of California at San Diego Stroke Data Bank. Stroke. 1995;26(2):245–8.
Romano JG, Arauz A, Koch S, et al. Disparities in stroke type and vascular risk factors between 2 Hispanic populations in Miami and Mexico City. J Stroke Cerebrovasc Dis. 2012.
Sacco RL, Ellenberg JH, Mohr JP, et al. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol. 1989;25(4):382–90.
Schulz UG, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke. 2003;34(8):2050–9.
Guercini F, Acciarresi M, Agnelli G, Paciaroni M. Cryptogenic stroke: time to determine aetiology. J Thromb Haemost. 2008;6(4):549–54.
Köhrmann M, Schellinger PD. Acute stroke triage to intravenous thrombolysis and other therapies with advanced CT or MR imaging: pro MR imaging. Radiology. 2009;251(3):627–33.
Latchaw RE, Alberts MJ, Lev MH, et al. Recommendations for imaging of acute ischemic stroke: a scientific statement from the American Heart Association. Stroke. 2009;40(11):3646–78.
Vertinsky AT, Schwartz NE, Fischbein NJ, Rosenberg J, Albers GW, Zaharchuk G. Comparison of multidetector CT angiography and MR imaging of cervical artery dissection. Am J Neuroradiol. 2008;29(9):1753–60.
Carroll BA. Carotid sonography. Radiology. 1991;178(2):303–13.
Zwiebel WJ. Duplex sonography of the cerebral arteries: efficacy, limitations, and indications. Am J Roentgenol. 1992;158(1):29–36.
Fujitani RM, Mills JL, Wang LM, Taylor SM. The effect of unilateral internal carotid arterial occlusion upon contralateral duplex study: criteria for accurate interpretation. J Vasc Surg. 1992;16(3):459–67. discussion 467–58.
Saqqur M, Shuaib A, Alexandrov AV, et al. Derivation of transcranial Doppler criteria for rescue intra-arterial thrombolysis: multi-center experience from the Interventional Management of Stroke study. Stroke. 2005;36(4):865–8.
Saqqur M, Zygun D, Demchuk A. Role of transcranial Doppler in neurocritical care. Crit Care Med. 2007;35(5 Suppl):S216–23.
Alexandrov AV, Demchuk AM, Wein TH, Grotta JC. Yield of transcranial Doppler in acute cerebral ischemia. Stroke. 1999;30(8):1604–9.
Fisher M. Occlusion of the internal carotid artery. AMA Arch Neurol Psychiatr. 1951;65(3):346–77.
Ducrocq X, Lacour JC, Debouverie M, Bracard S, Girard F, Weber M. Cerebral ischemic accidents in young subjects. A prospective study of 296 patients aged 16 to 45 years. Rev Neurol (Paris). 1999;155(8):575–82.
Schievink WI. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med. 2001;344(12):898–906.
de Bray JM, Marc G, Pautot V, et al. Fibromuscular dysplasia may herald symptomatic recurrence of cervical artery dissection. Cerebrovasc Dis. 2007;23(5–6):448–52.
Gdynia HJ, Kühnlein P, Ludolph AC, Huber R. Connective tissue disorders in dissections of the carotid or vertebral arteries. J Clin Neurosci. 2008;15(5):489–94.
Provenzale JM, Sarikaya B. Comparison of test performance characteristics of MRI, MR angiography, and CT angiography in the diagnosis of carotid and vertebral artery dissection: a review of the medical literature. Am J Roentgenol. 2009;193(4):1167–74.
Ozdoba C, Sturzenegger M, Schroth G. Internal carotid artery dissection: MR imaging features and clinical-radiologic correlation. Radiology. 1996;199(1):191–8.
Lévy C, Laissy JP, Raveau V, et al. Carotid and vertebral artery dissections: three-dimensional time-of-flight MR angiography and MR imaging vs conventional angiography. Radiology. 1994;190(1):97–103.
Lazzaro MA, Krishnan K, Prabhakaran S. Detection of atrial fibrillation with concurrent holter monitoring and continuous cardiac telemetry following ischemic stroke and transient ischemic attack. J Stroke Cerebrovasc Dis. 2012;21(2):89–93.
Liao J, Khalid Z, Scallan C, Morillo C, O'Donnell M. Noninvasive cardiac monitoring for detecting paroxysmal atrial fibrillation or flutter after acute ischemic stroke: a systematic review. Stroke. 2007;38(11):2935–40.
Tayal AH, Tian M, Kelly KM, et al. Atrial fibrillation detected by mobile cardiac outpatient telemetry in cryptogenic TIA or stroke. Neurology. 2008;71(21):1696–701.
Jabaudon D, Sztajzel J, Sievert K, Landis T, Sztajzel R. Usefulness of ambulatory 7-day ECG monitoring for the detection of atrial fibrillation and flutter after acute stroke and transient ischemic attack. Stroke. 2004;35(7):1647–51.
Fisher CM. Lacunar strokes and infarcts: a review. Neurology. 1982;32(8):871–6.
Caplan LR. Intracranial branch atheromatous disease: a neglected, understudied, and underused concept. Neurology. 1989;39(9):1246–50.
Lee DK, Kim JS, Kwon SU, Yoo SH, Kang DW. Lesion patterns and stroke mechanism in atherosclerotic middle cerebral artery disease: early diffusion-weighted imaging study. Stroke. 2005;36(12):2583–8.
Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353(19):2034–41.
Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med. 2010;182(2):269–77.
Arzt M, Young T, Finn L, Skatrud JB, Bradley TD. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med. 2005;172(11):1447–51.
Kurth T, Kase CS, Berger K, Gaziano JM, Cook NR, Buring JE. Smoking and risk of hemorrhagic stroke in women. Stroke. 2003;34(12):2792–5.
Kurth T, Kase CS, Berger K, Schaeffner ES, Buring JE, Gaziano JM. Smoking and the risk of hemorrhagic stroke in men. Stroke. 2003;34(5):1151–5.
Reynolds K, Lewis B, Nolen JD, et al. Alcohol consumption and risk of stroke: a meta-analysis. JAMA. 2003;289(5):579–88.
Sacco RL, Elkind M, Boden-Albala B, et al. The protective effect of moderate alcohol consumption on ischemic stroke. JAMA. 1999;281(1):53–60.
Rist PM, Berger K, Buring JE, Kase CS, Gaziano JM, Kurth T. Alcohol consumption and functional outcome after stroke in men. Stroke. 2010;41(1):141–6.
PubMedCentral PubMed CrossRef
Brust JC, Richter RW. Stroke associated with cocaine abuse–? N Y State J Med. 1977;77(9):1473–5.
Gold MS, Washton AM, Dackis CA. Cocaine abuse: neurochemistry, phenomenology, and treatment. NIDA Res Monogr. 1985;61:130–50.
Kaufman MJ, Levin JM, Ross MH, et al. Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA. 1998;279(5):376–80.
Westover AN, McBride S, Haley RW. Stroke in young adults who abuse amphetamines or cocaine: a population-based study of hospitalized patients. Arch Gen Psychiatry. 2007;64(4):495–502.
Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). Circulation. 2003;108(9):1146–62.
Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Coll Cardiol. 1991;17(1):66–72.
Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc. 1984;59(1):17–20.
Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc. 1999;74(9):862–9.
Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case–control studies. Neurology. 2000;55(8):1172–9.
Berthet K, Lavergne T, Cohen A, et al. Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke. 2000;31(2):398–403.
Meacham RR, Headley AS, Bronze MS, Lewis JB, Rester MM. Impending paradoxical embolism. Arch Intern Med. 1998;158(5):438–48.
Stöllberger C, Slany J, Schuster I, Leitner H, Winkler WB, Karnik R. The prevalence of deep venous thrombosis in patients with suspected paradoxical embolism. Ann Intern Med. 1993;119(6):461–5.
Cramer SC, Rordorf G, Maki JH, et al. Increased pelvic vein thrombi in cryptogenic stroke: results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) study. Stroke. 2004;35(1):46–50.
Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale vs medical therapy after cryptogenic stroke. N Engl J Med. 2013;368(12):1092–100.
Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366(11):991–9.
Thaler DE, Wahl A. Critique of closure or medical therapy for cryptogenic stroke with patent foramen ovale: the hole truth? Stroke. 2012;43(11):3147–9.
Krumsdorf U, Ostermayer S, Billinger K, et al. Incidence and clinical course of thrombus formation on atrial septal defect and patient foramen ovale closure devices in 1,000 consecutive patients. J Am Coll Cardiol. 2004;43(2):302–9.
Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368(12):1083–91.
Messé SR, Kent DM. Still no closure on the question of PFO closure. N Engl J Med. 2013;368(12):1152–3.
Silver MD, Dorsey JS. Aneurysms of the septum primum in adults. Arch Pathol Lab Med. 1978;102(2):62–5.
Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke. 1993;24(12):1865–73.
Pearson AC, Nagelhout D, Castello R, Gomez CR, Labovitz AJ. Atrial septal aneurysm and stroke: a transesophageal echocardiographic study. J Am Coll Cardiol. 1991;18(5):1223–9.
Belkin RN, Kisslo J. Atrial septal aneurysm: recognition and clinical relevance. Am Heart J. 1990;120(4):948–57.
Cujec B, Polasek P, Voll C, Shuaib A. Transesophageal echocardiography in the detection of potential cardiac source of embolism in stroke patients. Stroke. 1991;22(6):727–33.
Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med. 1994;331(22):1474–9.
Harloff A, Strecker C, Dudler P, et al. Retrograde embolism from the descending aorta: visualization by multidirectional 3D velocity mapping in cryptogenic stroke. Stroke. 2009;40(4):1505–8.
Harloff A, Simon J, Brendecke S, et al. Complex plaques in the proximal descending aorta: an underestimated embolic source of stroke. Stroke. 2010;41(6):1145–50.
Waddy SP. Disorders of coagulation in stroke. Semin Neurol. 2006;26(1):57–64.
Fullerton HJ, Wu YW, Zhao S, Johnston SC. Risk of stroke in children: ethnic and gender disparities. Neurology. 2003;61(2):189–94.
Fullerton HJ, Adams RJ, Zhao S, Johnston SC. Declining stroke rates in Californian children with sickle cell disease. Blood. 2004;104(2):336–9.
Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91(1):288–94.
Kenet G, Lütkhoff LK, Albisetti M, et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation. 2010;121(16):1838–47.
Harmon DL, Woodside JV, Yarnell JW, et al. The common 'thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM. 1996;89(8):571–7.
Kohara K, Fujisawa M, Ando F, et al. MTHFR gene polymorphism as a risk factor for silent brain infarcts and white matter lesions in the Japanese general population: The NILS-LSA Study. Stroke. 2003;34(5):1130–5.
Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46(4):1019–27.
Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295–306.
Caplan LR. Stroke. New York: Demos Medical Publishing; 2006.
Roach ES, Golomb MR, Adams R, et al. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke. 2008;39(9):2644–91.
Flemming KD, Brown RD, Petty GW, Huston J, Kallmes DF, Piepgras DG. Evaluation and management of transient ischemic attack and minor cerebral infarction. Mayo Clin Proc. 2004;79(8):1071–86.
Petty GW, Brown RD, Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO. Ischemic stroke subtypes: a population-based study of functional outcome, survival, and recurrence. Stroke. 2000;31(5):1062–8.
Murat Sumer M, Erturk O. Ischemic stroke subtypes: risk factors, functional outcome and recurrence. Neurol Sci. 2002;22(6):449–54.
Sacco RL, Foulkes MA, Mohr JP, Wolf PA, Hier DB, Price TR. Determinants of early recurrence of cerebral infarction. The Stroke Data Bank. Stroke. 1989;20(8):983–9.
Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology. 2004;62(4):569–73.
Moroney JT, Bagiella E, Paik MC, Sacco RL, Desmond DW. Risk factors for early recurrence after ischemic stroke: the role of stroke syndrome and subtype. Stroke. 1998;29(10):2118–24.
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