What is a cryptogenic stroke?

Cryptogenic Stroke: A Diagnosis of Exclusion

Cryptogenic stroke is defined as an ischemic stroke for which no probable cause is identified despite a thorough diagnostic evaluation, accounting for approximately 25-40% of all ischemic strokes. 1, 2 This classification represents a diagnosis of exclusion that should only be made after systematically ruling out all identifiable causes of stroke.

Diagnostic Criteria for Cryptogenic Stroke

To classify a stroke as cryptogenic, the following criteria must be met after a complete evaluation:

• Absence of large artery atherosclerosis
• Absence of major cardioembolic sources
• Absence of small vessel disease
• Absence of other identifiable causes 1

Patient Characteristics

• More common in younger patients than older patients 3
• Less likely to have classic risk factors for atheroembolic stroke (hypertension, hyperlipidemia, diabetes) 2
• Higher likelihood of having a patent foramen ovale (PFO) compared to the general population 2

Comprehensive Diagnostic Workup

Neuroimaging

• Brain imaging: MRI with diffusion-weighted sequences to determine infarct pattern (lacunar vs. non-lacunar) 1
• Vascular imaging: MR-Angiography or CT-Angiography of intra- and extracranial vessels 1
• Advanced imaging: 4-vessel cerebral angiography when non-invasive imaging is unremarkable 1

Cardiac Evaluation

• 12-lead ECG: To identify cardiac arrhythmias 1
• ECG monitoring: Extended monitoring (>24 hours) for patients with suspected embolic stroke 2
• Echocardiography:
  • Transthoracic echocardiography (TTE) to evaluate structural heart disease
  • Transesophageal echocardiography (TEE) for better detection of PFO, atrial septal aneurysm, and other cardiac sources 1

Laboratory Tests

• Complete blood count
• Electrolytes and renal/liver function tests
• Blood glucose and lipid profile
• Coagulation tests for hypercoagulable states 1

Potential Underlying Mechanisms

Cardiac Sources (Most Common)

• Paradoxical embolism via patent foramen ovale (PFO)
• Paroxysmal atrial fibrillation
• Valvular heart disease
• Atrial septal aneurysm 3

Vascular Causes

• Complex aortic plaques
• Fabry's disease
• Vasculitis
• Vascular anomalies 3, 4

Other Mechanisms

• Hypercoagulable disorders
• Occult malignancy
• Vasospasm 5

Embolic Stroke of Undetermined Source (ESUS)

ESUS is an important subgroup of cryptogenic stroke, characterized by:

• Non-lacunar infarct pattern
• Presumed embolic origin
• No identifiable source after standard evaluation
• Represents approximately 1 in 6 ischemic strokes 1

Management Considerations

• Antiplatelet therapy: Remains the recommended treatment for most patients with cryptogenic stroke 1
• PFO management: In young patients (≤60 years) with PFO, careful evaluation is necessary to determine if they may benefit from closure 1
• Extended cardiac monitoring: Significantly increases detection of atrial fibrillation in cryptogenic stroke patients, with detection rates up to 23.7% with sequential multiphase monitoring 1

Clinical Pitfalls to Avoid

• Premature diagnosis: Classifying a stroke as cryptogenic before completing a thorough workup
• Inadequate cardiac monitoring: Missing paroxysmal atrial fibrillation due to insufficient monitoring duration
• Overlooking rare causes: Failing to consider conditions like Fabry's disease, occult vasculitis, or hypercoagulable states in appropriate clinical contexts
• Underestimating recurrence risk: Recent studies have challenged the view that cryptogenic stroke is benign, showing higher rates of recurrence and adverse outcomes at long-term follow-up 6

Cryptogenic stroke remains a significant diagnostic challenge that requires a systematic and thorough evaluation to ensure appropriate secondary prevention strategies are implemented to reduce recurrence risk and improve patient outcomes.