Cryptogenic Stroke

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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. Postpartum Pregnant smoker with a 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


  • 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 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, 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.


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 an artery to artery embolism. It is wise to check a 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 a young patient with an ischaemic stroke and non cause found my usual policy is to continue an anti-platelet lifelong. 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 question 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.

Long term

  • 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