Cryptogenic Stroke

Learning objectives

Defining cryptogenic stroke Appropriate investigations Managing the patient with cryptogenic stroke

Introduction

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

Investigations

• 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

Thrombophilias

• 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]

Finding	Clinical signs	Confirmatory tests
Carotid/Vertebral dissection	Minor head/neck trauma, headache, facial pain, Horner's syndrome, XII palsy	Cervical MRI with fat suppression, angiography
Atherosclerotic large vessel	Multiple vascular risk factors, TIA, Carotid bruit	Carotid/vertebral doppler, MRA
Small Vessel disease	HTN, DM, LACI syndrome, Capsular warning syndrome	MRI DWI
Patent Foramen Ovale	Stroke during valsalva, Stroke with DVT/Immobilisation	TOE or TCD with microbubbles
Other cardioembolic disease	History, large vessel cortical stroke, haemorrhagic transformation, multiple infarcts in different vascular territories	ECG, Holter, TTE, TOE, Holter
Pulmonary Fistulae	R to L shunt, no PFO, Osler-weber-rendu syndrome	Chest CT
SLE	Anaemia, arthralgia, Low platelets, high ESR, renal disease	Anti dsDNA, ANA, sm
Antiphospholipid syndrome	Miscarriages, Venous thrombosis, prolonged APTT	Lupus anticoagulant, anticardiolipin, beta-2, glycoprotein antibodies
Sneddon's syndrome	Livedo reticularis, Ischaemic and Haem strokes	Skin biopsy, digital artery biopsy
Takayasu's disease	Absent radial, brachial pulses. Blood pressure difference	CT/MRA thorax, aortic PET
Primary CNS Vasculitis	Multiple strokes, encephalopathy, fever	LP, DSA or MRA, meningeal brain biopsy
Moyamoya syndrome	Multiple strokes ischaemic and haemorrhagic, cognitive decline	Angiography (MRA/CTA/DSA)
Retinopathy and retinocochlearcerebral arteriopathy	Visual loss, progressive deafness	ENT/Ophthalmological review
Sickle Cell Disease	African origin	HB electrophoresis, genetic testing, TCD
Inherited thrombophilia	Venous mainly but and possibly arterial strokes	AT3, FVL, Protein C/S testing, genetic testing
CADASIL	Migraine with aura, small vessel strokes, dementia, psychosis	Skin biopsy, genetic testing
HANAC syndrome (COL4a1)	Small vessel disease, cerebral aneurysms, porencephaly, retinal artery tortuosity, kidney disease, muscle cramps	Genetic testing
Fabry's disease	Skin, ocular, renal disease, vertebrobasilar dolicooectasia	Genetic testing, a-galactosidase activity
MELAS	Migraine, seizures, deafness , short stature	EMG, muscle biopsy, Genetic testing
Hyperhomocystinaemia		Homocysteine levels
Reversible Cerebral Vasoconstriction Syndrome	Repeated thunderclap headaches and stroke in middle aged females	Reversible vasoconstriction on angiography
Infections causing stroke		Serum levels for syphilis, borrelia, zoster, Hepatitis B, Hepatitis C (also cryoglobulins), HIV
Infective endocarditis	Embolic stroke, Haemorrhage	Blood cultures, CRP, TOE
TB meningitis	Headache, coma, meningism	LP, CXR, Cultures, HIV, TCD test
HIV vasculopathy	Small vessel vasculopathy	HIV test, CD4, Viral load, LP
Cysticercosis	Affects 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

Management

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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