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Cryptogenic Stroke

Learning objectives

  • Defining cryptogenic stroke
  • Appropriate investigations
  • Managing the patient with cryptogenic stroke


Cryptogenic stroke (CS) is defined as brain infarction that is not attributable to a source of definite cardioembolism, large artery atherosclerosis, or small artery disease despite extensive vascular, cardiac, and serologic evaluation. No cause is found in 30-40%. This figure decreases with age. The cause of stroke in young adults (18-45 years old) can remain unknown despite multiple investigations. A standard protocol would involve working through commonest to least common causes to reduce the risks of false positives. The following is a list of possible causes of stroke in young adults. Is cryptogenic stroke the result of a perfect storm. A disastrous combination of events and risk factors that sum up to form a clot. The absence of one of which may have changed everything. Post-partum Pregnant smoker with migraine crosses some clotting threshold. The reason that we don't see more strokes is due to the balance between clot formation and breakdown in the systemic circulation and brain is vulnerable as it has a very high arterial perfusion for its size.

Ischaemic stroke - Affecting large or small vessels

  • Premature atherosclerosis
  • Dissection (spontaneous or traumatic)
  • Inherited metabolic diseases (Fabry's, homocystinuria, pseudoxanthoma elasticum, Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke (MELAS) syndrome)
  • Inherited due to gene mutation (e.g. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL))
  • Fibromuscular dysplasia
  • Infection (Zoster, tuberculosis, syphilis, Lyme)
  • Moyamoya disease
  • Toxic of illicit drugs (e.g. cocaine, heroin, phencyclidine) or therapeutic drugs (e.g. L-asparaginase, cytosine arabinoside)
  • Vasculitis (systemic lupus erythematosus, Takayasu's disease, Wegener's syndrome, etc.)
  • Radiation vasculopathy
  • Iatrogenic
  • Reversible vasoconstriction syndrome


  • Non contrast CT/MRI/MRA/MRV
  • Transoesophgeal Echo + Bubble study : Cardiomyopathy, Patent Foramen ovale, Endocarditis, Atrial myxoma, Occult mitral stenosis, Dilated Cardiomyopathy
  • Actively exclude carotid/vertebral dissection which may be clinically silent with MR
  • Thrombophilia screen
  • 24 hr tape (may need several)to look for AF
  • ESR and CRP / Vasculitis
  • LP - CSF pressure, protein, cells, lactate (MELAS)
  • Skin biopsy for CADASIL
  • Screen for Fabry's disease
  • Autoimmune screen
  • Haemorrhagic stroke : MRI/MRA - look for AVM, Cavernoma, Coagulation screen, platelets, Cocaine toxicology, MRV to exclude haemorrhagic venous infarcts, Screen for Sickle cell

Cardiac source

  • High risk: atrial fibrillation or more challenging Paroxysmal AF, recent anterior myocardial infarction, rheumatic valve disease, mechanical valve, endocardiac thrombus, tumour, endocarditis
  • Medium risk: left ventricular hypokinesis/aneurysm, bioprosthetic valve, congestive heart failure, myxomathous mitral valve prolapse, etc.
  • Low/unclear risk: patent foramen oval (PFO), spontaneous echo contrast, Prothrombotic states


  • High risk: antiphospholipid syndrome, antithrombin III, protein C or S deficiency
  • Moderate risk: Factor V Leiden, Prothrombin 20210A mutation, High FVIII
  • Sickle cell, thalassemia major
  • Myeloproliferative syndromes (e.g. polycythaemia vera, essential thrombocythaemia, etc.) Other (e.g. cancer, MTHFR methylenetetrahydrofolate reductase (NAD(P)H) mutation)

Haemorrhagic stroke

  • Aneurysmal
  • Arteriovenous malformation
  • Neoplasm (e.g. primary central nervous system, metastatic, leukaemia)
  • Haematologic (e.g. neoplasm, thrombocytopenia)
  • Moyamoya disease
  • Inherited metabolic diseases (e.g. Fabry disease)
  • Drug use (e.g. warfarin, amphetamines, cocaine, phenypropanolamine, etc.)
  • Hereditary (CADASIL)
  • Iatrogenic (peri-procedural)

*Adapted from Makris M, Blood 2009; 113:5314-532.

Young Person Ischaemic Stroke

In all younger strokes I have my own personal acronym - VIVID and ask myself is this Venous, Infectious, Vasculitis, Inflammatory, Dissection. I will actively look to exclude these in a young person with a large vessel stroke. They have very distinct and different treatments. Don't send of all tests at once but work through logically. Stop once you find the cause.

Summary of Rare Causes and Investigations in Young adults [Adapted from Ferro JM et al. 2010]

FindingClinical signsConfirmatory tests
Carotid/Vertebral dissectionMinor head/neck trauma, headache, facial pain, Horner's syndrome, XII palsyCervical MRI with fat suppression, angiography
Atherosclerotic large vesselMultiple vascular risk factors, TIA, Carotid bruitCarotid/vertebral doppler, MRA
Small Vessel diseaseHTN, DM, LACI syndrome, Capsular warning syndromeMRI DWI
Patent Foramen OvaleStroke during valsalva, Stroke with DVT/ImmobilisationTOE or TCD with microbubbles
Other cardioembolic diseaseHistory, large vessel cortical stroke, haemorrhagic transformation, multiple infarcts in different vascular territoriesECG, Holter, TTE, TOE, Holter
Pulmonary FistulaeR to L shunt, no PFO, Osler-weber-rendu syndromeChest CT
SLEAnaemia, arthralgia, Low platelets, high ESR, renal diseaseAnti dsDNA, ANA, sm
Antiphospholipid syndromeMiscarriages, Venous thrombosis, prolonged APTT Lupus anticoagulant, anticardiolipin, beta-2, glycoprotein antibodies
Sneddon's syndromeLivedo reticularis, Ischaemic and Haem strokesSkin biopsy, digital artery biopsy
Takayasu's diseaseAbsent radial, brachial pulses. Blood pressure differenceCT/MRA thorax, aortic PET
Primary CNS VasculitisMultiple strokes, encephalopathy, feverLP, DSA or MRA, meningeal brain biopsy
Moyamoya syndromeMultiple strokes ischaemic and haemorrhagic, cognitive declineAngiography (MRA/CTA/DSA)
Retinopathy and retinocochlearcerebral arteriopathyVisual loss, progressive deafnessENT/Ophthalmological review
Sickle Cell DiseaseAfrican originHB electrophoresis, genetic testing, TCD
Inherited thrombophiliaVenous mainly but and possibly arterial strokesAT3, FVL, Protein C/S testing, genetic testing
CADASILMigraine with aura, small vessel strokes, dementia, psychosisSkin biopsy, genetic testing
HANAC syndrome (COL4a1) Small vessel disease, cerebral aneurysms, porencephaly, retinal artery tortuosity, kidney disease, muscle crampsGenetic testing
Fabry's diseaseSkin, ocular, renal disease, vertebrobasilar dolicooectasiaGenetic testing, a-galactosidase activity
MELASMigraine, seizures, deafness , short statureEMG, muscle biopsy, Genetic testing
Homocysteine levels
Reversible Cerebral Vasoconstriction SyndromeRepeated thunderclap headaches and stroke in middle aged femalesReversible vasoconstriction on angiography
Infections causing stroke
Serum levels for syphilis, borrelia, zoster, Hepatitis B, Hepatitis C (also cryoglobulins), HIV
Infective endocarditisEmbolic stroke, HaemorrhageBlood cultures, CRP, TOE
TB meningitisHeadache, coma, meningismLP, CXR, Cultures, HIV, TCD test
HIV vasculopathySmall vessel vasculopathyHIV test, CD4, Viral load, LP
CysticercosisAffects MCA and PCA zones. Lacunar infarctions can occur as a result of inflammation of small penetrating arteries. Ischaemic strokes are less frequent in patients with parenchymal neurocysticercosis and usually arise in the vicinity of cysts.CT, LP, TCD


Is finding no cause a good thing or not. It often suggests a low risk of stroke recurrence. Each situation must be carefully assessed and risks hedged to try to reduce any theoretical risk of recurrence balanced with potential harm from preventative therapies. The history is key. Is it a dissection that is mild enough not to be seen on MRA but sufficient to have led to artery to artery embolism. It is wise to d-dimer and look for a DVT as this will require anticoagulation and if positive will complement an echocardiogram (transthoracic or trans-oesophageal) which shows a PFO as to aetiology. There is a long list of possibilities. Risks should be reduced e.g. smoking cessation and any vascular risk factors. Many of these patients are young and dyslipidaemia is unlikely to be the aetiology and the role of statins is unknown and possibly unnecessary. A long term anti-platelet e.g. aspirin 75 mg or Clopidogrel 75 mg is usually appropriate. These patients are best discussed within an MDT type process and a second opinion is often wise to have a fresh look at causality and to underwrite the plans suggested.

In young patients there should be a fairly exhaustive search for a cause when a stroke occurs. However in about 30% of young strokes no cause is found. It is important to be sure initially that the episode in a young person is indeed a stroke and MRI DWI is very useful. Demyelinating illnesses such as MS, PML and ADEM can all cause subcortical hypodensities which could be misinterpreted as vascular. The screening test for young strokes will be discussed in the Investigation section. Great care must be taken, finding a PFO does not mean the stroke was a paradoxical embolism and thrombophilia screens and antibody tests should all be interpreted with caution and may show some change over time.In a young patient my usual policy is to continue an anti-platelet life long. This would include through pregnancy. Patients are usually assessed in pregnancy for VTE risks and those with higher risks given LMWH. How long do we continue this path is a frequent questions and it is really until we find better evidence or more effective preventative strategies. Despite all tests many strokes have an indeterminate cause - otherwise known as the term cryptogenic which personally I don't like. There are several reasons to find out the cause of a stroke to answer the following questions.Finding a cause may not be in itself a bad thing and may suggest a more favourable prognostic outcome. Certainly better than finding something untreatable and risky.

  • Will it happen again - what are my risks of a further stroke
  • What can I do to reduce risks - are there any preventative measures
  • Is there a risk to children e.g. Hereditary causes
  • Is this a new disease, is there a pattern suggesting a new aetiology

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