Jeff June: The Stroke That Wasn’t New – Why ‘Cryptogenic’ Often Means Undetected

Jeff June, Innovation Advisor at Early Stage Digital Health, MedTech, Venture Capital, and Accelerator Programs, posted on LinkedIn:

‘The Stroke That Wasn’t New

Recurrent stroke is rarely mysterious. What’s mysterious is how often it happens — and how often the cause is never clearly identified.

A 2026 review published in the Journal of the American Heart Association underscores a growing reality in stroke care: symptomatic carotid plaques with less than 50% stenosis — often considered ‘non-actionable’ in routine workups — can still cause ischemic stroke. These non-stenotic, high-risk plaques are increasingly linked to strokes labeled cryptogenic.

In other words, the mechanism is often present. It’s just below our detection threshold.

Cryptogenic stroke is not rare. It is routine.

In the United States:

1. 20–35% of all ischemic strokes are classified as cryptogenic after standard evaluation
2. That translates to ~160,000–240,000 patients every year discharged without a clear mechanism
3. Nearly 1 in 3 ischemic stroke patients leaves the hospital with an unanswered ‘why’

Cryptogenic stroke is not an edge case.

It is one of the largest stroke populations we manage.

‘Cryptogenic’ often means ‘not yet detected’

Large-artery atherosclerosis is a prime example.

Multiple studies now show that:

1. Non-stenotic carotid plaques (<50%) can be embolic
2. Plaque composition and inflammation matter more than lumen narrowing alone
3. Many embolic strokes occur before stenosis reaches surgical or interventional thresholds

Yet in U.S. imaging-based workflows, carotid disease often becomes ‘real’ only after:

1. ≥50–70% narrowing
2. Recurrent symptoms
3. Or a second stroke

By then, biology has already been active for years.

Undetected carotid disease is common in the U.S.

Population data suggest that:

1. 30–40% of adults over age 60 have measurable carotid atherosclerosis
2. A significant fraction have moderate disease without symptoms
3. Among patients with vascular risk factors, carotid plaque is common even when imaging is not pursued aggressively

Despite this, carotid imaging is not routine after many cryptogenic strokes, particularly when initial CTA or ultrasound appears ‘non-actionable.’

The result is a large population of patients with real vascular disease — and no mechanistic label.

Cryptogenic stroke is not benign

Patients labeled cryptogenic do not ‘reset’ their risk.

Evidence shows that:

• Recurrent stroke risk in cryptogenic patients approaches that of known subtypes over time
• Many recurrences later reveal a mechanism, including carotid disease or cardioembolism
• The second stroke is often when the diagnosis finally becomes obvious

What appears to be a new event is often the completion of an earlier diagnostic delay.

This is not a failure of care. It’s a failure of timing.

U.S. stroke systems excel at:

1. Acute imaging
2. Rapid intervention
3. Post-event classification

They struggle with:

1. Detecting active biology before anatomy declares itself
2. Identifying which cryptogenic patients are on a predictable path to recurrence
3. Escalating surveillance based on biologic risk rather than imaging thresholds alone

Cryptogenic stroke is where these limitations converge.

Atherosclerosis is a complex problem, beyond an arbitrary standard

Atherosclerosis is:

1. Inflammatory
2. Metabolically driven
3. Biologically active long before it becomes anatomically severe

Two patients with the same ‘mild’ carotid stenosis do not share the same embolic risk.

Yet our classifications treat them as interchangeable.

That gap is where cryptogenic stroke lives.

Why this matters for prevention

If one in three ischemic strokes lacks a clear cause at discharge, prevention cannot rely solely on:

1. Waiting for stenosis to worsen
2. Waiting for recurrence
3. Waiting for anatomy to explain biology

In my work as a stroke researcher, investor, and company founder at Ischemia Care , I would suggest thinking of cryptogenic stroke as:

1. A high-risk category, not a neutral one
2. A prompt for deeper biologic investigation
3. A population where earlier mechanistic insight can change trajectories

Because preventing a second stroke is not only about faster response once a stroke occurs. It’s about earlier recognition.

Recurrent stroke is rarely a surprise to biology

By the time carotid disease causes a second stroke, the signals have been present for years.

The tragedy is not just that recurrence happens. It’s that we often quantify the risk only after the damage is done. Cryptogenic stroke is not just a diagnosis. It is a warning.’

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