Cryptogenic Stroke

Definition
Cryptogenic Stroke or stroke of undetermined origin :
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

The

cause of CS remains undetermined because the

event is transitory or reversible, investigations did not
look for all possible causes, or because some causes
truly remain unknown

Cryptogenic

stroke accounts for 23% to 40% of patients,

more frequent in younger patients

Importance ??
1. Prognosishigh risks of recurrence have been
reported after cryptogenic stroke
2. Increased morbidity - most frequently occurs in
patients < 55 y of age (young stroke)
3. Advanced diagnostic techniques aimed at the
various etiologies of cryptogenic stroke facilitate the
implementation of therapies targeting the underlying
cause of the index stroke to prevent recurrences

Etiology
Cardiac

source of embolism

Vascular

sources of embolism

coagulopathy

Cardiac

Common Causes

Rare Causes

Atrial septal aneurysm (ASA)

Atrial septal defect

PFO

Heart valve disease

Regional myocardial dyskinesia

Dilated left atrium

Endomyocardial fibrosis

Left atrial appendage

thrombi

Left atrial bands

Atrial fibrillation

Takotsubo syndrome
Ventricular thrombus

Dilative cardiomyopathy
Atrial myxoma

Restrictive cardiomyopathy*

Spontaneous echocontrast within

the right atrium

Vascular

Atherosclerosis

Large arteries (aortic plaques*)

small arteries

Fabrys disease

Aortic dissection*

Mural thrombi over dissected aortic segments*

Coagulopathy

Arterial hypercoagulability

Venous hypercoagulability
Antithrombin-III deficiency

Protein-S/Protein C deficiency

Antiphospholipid antibody syndrome

Elevated lipoprotein (a)

Tissue factor mutation

Hyperhomocysteinemia

Factor II deficiency
Prothrombin mutations

Activated protein C (APC)-resistance

Fibrinolytic system abnormalities

Hereditary hyperhomocysteinemia
Acquired causes - Acquired
hyperhomocysteinemia, Neoplasm

Common Cardia
Causes

PATENT FORAMEN OVALE

ATRIAL SEPTAL
ANEURYSM

ATRIAL FIBRILLATION

HEART VALVE DISEASE

Patent Foramen Ovale

The cardiac abnormality most frequently associated with CS is the PFO, particularly in
subjects < 55y

A PFO can be detected in 40-50% of the patients with CS(range 22-88%)

Patients > 65y of age have a 3 times higher risk to develop a stroke if a PFO is present

Paradoxical embolism usually originates from crural or pelvic veins, but at times the
stagnant flow in the tunnel like structure can lead to insitu thrombosis as well

PFO

PFO can be detected with the same accuracy by TransEsophageal

EchoCardiography as by Trans Cranial Doppler.

In case of diagnosing CS and PFO the upstream particularly crural and pelvic veins
need to be investigated for thrombosis by Doppler ultrasound, MR-venography, or
phlebography immediately after the event.

Clinical clues to the diagnosis of paradoxical embolism include the coexistence of

deep venous thrombosis, pulmonary embolism, migraine, recent prolonged travel,
sleep apnea, waking up with a transitory ischemic attack (TIA) or stroke

Atrial septal aneurysm (ASA)

ASA is defined as > 10mm excursion of the intra-atrial septum during contractions
and affects ~2% of the general population

An ASA can be detected in up to 50% of the cases with a PFO.

However ASA is independently associated with ischemic cerebral events possibly

interacting with thrombophilia

In studies, stroke recurrence is particularly increased if both PFO and ASA are
present

Intermittent or paroxysmal AF (pAF)

AF may be classified as permanent, intermittent or paroxysmal (pAF).

It is speculated that in a number of patients, CS is due to intermittent or pAF

The longer and the more intensively it is searched for pAF, the more likely it is detected.

If pAF cannot be detected by standard ECG, 24h-Holter, 48h- Holter, 7d-Holter, or

telemetry, it may be detected

Valvular heart disease

Valvular diseases include :

Rheumatic valves, thickened valves, mitral prolapse syndrome, aortic

valve strands, aortic valve stenosis, mitral valve strands, mitral valve
stenosis, mitral valve ring calcification, valve thickening, aortic valve
sclerosis, Libman-Sacks endocarditis and marantic endocarditis

These less common valve abnormalities are often missed on routine

trans thoracic echocardiography and need to be screened by TTE

ATHEROSCLEROSIS LARGE ARTERIES

(AORTIC PLAQUES)

FABRYS DISEASE

Vascular Causes

Atherosclerosis - Aortic plaques

Complex aortic plaques or complex atheroma (i.e. plaques with attached thrombus) in
the aortic arch or upstream to the left subclavian artery or the right brachiocephalic
trunk are another implicated cause of CS

It is estimated that up to one fifth of the CSs are due to embolism from these aortic
plaques

Aortic plaques can be visualized by TEE, CT- or MR-angiography, or multidirectional

3D-MRI

Another rare cause of CS, dissection in these large arteries associated with a mural
thrombus, can also be picked up using these techniques

Fabrys Disease

Fabrys disease is an X-linked recessive lysosomal storage disease resulting from

deficient alphagalactosidase

This leads to accumulation of glyco-sphingolipids in the vascular endothelium with

consecutive micro and macroangiopathy and enlargement of the arteries

The disease is the etiologic cause in 1-4% of patients of CS and is more frequent in
the vertebro-basilary artery system than in the anterior circulation

Coagulopathy

ARTERIAL
HYPERCOAGULABILITY

VENOUS
HYPERCOAGULABILITY

Arterial hypercoagulability

The most frequent condition associated with arterial hypercoagulability is the

antiphospholipid antibody syndrome.

The antiphospholipid antibodysyndrome is an acquired form of arterial and venous

hypercoagulability associated with thrombocytopenia, livedo reticularis, and increased
frequency of pregnancy-related complications, such as miscarriage, stillbirth, abortions.
or preeclampsia.

The syndrome is diagnosed on the presence of antiphospholipid and anti-cardiolipin

antibodies

Other causes include acquired hyperhomocysteinemia, the tissue factor polymorphism

+ 5466A> G, and high lipoprotein A

Venous hypercoagulability

Whether venous hypercoagulability is associated with CS is so far

unknown.

Studies have found increased prevalence of conditions like leyden

mutation in CS but conditions like prothrombin and factor XIII
polymorphisms have not been associated with increased prevalence in
CS (without a concomitant PFO)

Diagnostic Work Up

Long-term ECG-recording

CT- or MR-angiography of the aorta

and its thoracic branches

Trans Cranial Doppler

Venous ultrasound, MR-venography

Routine blood investigations - Blood

cell count (polycythemia vera,
thrombocytosis), D-dimer, urine
protein

Alpha galactosidase genetic testing

Coagulation test

1. Arterial hypercoagulability (lupus anticoagulant,

anticardiolipin
antibodies, lipoprotein A, tissue factor
mutations, hyperhomocysteinemia Homocysteine/MMA
levels)
2. Venous hypercoagulability - protein-C/S, AT-III levels,
prothrombin
gene mutations, fibrinolytic system
abnormalities

Transesophageal echocardiography
(TEE)

TEE is indicated in CS patients if TTE is nondiagnostic.

TEE detects relevant abnormalities in about half of the young patients with
CS

Relevant findings in patients with CS include: PFO (22-29%) with

spontaneous or provocable (Valsalva manoeuvre) right-to-left shunt after
application of contrast medium or a bubble test, previously undetected
valve disease (16%) (4), ASAs (1%), aortic plaques, regional myocardial
dyskinesia or dilated left atrium

Approximately 1/3rd of patients of CS have their treatment modalities

changed on the basis of TEE findings

Long-term ECG recording

Long-term ECG recording is strongly recommended in CS patients with :

Palpitations

the morphological stroke-pattern on MRI suggests an embolic cause

There is enlargement of the left atrium

Long-term ECG recording can be carried out by 24h-, 48h-, 7d- Holter, mobile
cardiac outpatient telemetry, event recorders (allow up to 30d ECG-monitoring),
or loop-recorders (recording up to 2y)

The longer we record, the higher the chances of picking up paroxysmal AF

MR- or CT-angiography and FDGPET

Done in whom complex aortic plaques or aortic dissection are suspected

Available techniques include multi-detector CT, high-resolution MRI, 3D-MRI,

multidirectional 3D-MRI, or FDGPET

Noninvasive FDG-PET has a complementary value for the evaluation of atherosclerotic

plaque composition and activity since lipid-rich plaques are more inflamed than
calcified or collagen-rich plaques

Special Blood work

If venous thrombosis with paradoxical embolism or sinus venous

thrombosis are suspected, determination of the D-dimer may be
helpful.

If Fabrys disease is suspected, the urine should be investigated for

increased protein and for serum levels of alphagalactosidase. If the
alpha-galactosidase is reduced, genetic testing can be opted for

If an anti-phospholipid antibody syndrome is suspected the

thrombocyte count, the lupus anticoagulant, and the anti-cardiolipin
antibodies should be determined

Challenges in Diagnosis

At times there is only mild degree of stenosis in vessels

corresponding to the area of symptomatic vascular brain injury

However, even an artery with a mild degree of stenosis can harbor

unstable plaque, which can rupture or erupt, resulting in stroke via
arteroembolism

This is similar to thrombotic coronary artery occlusion which

usually follows rupture of an unstable plaque, and the at-risk or
vulnerable coronary artery plaque is usually not associated with
high-grade stenosis

An arterosclerotic plaque in the intracranial artery can also

protrude into a perforators orifice and occlude the lumen, causing
a subcortical infarction

Challenges in Diagnosis

Sometimes the cause of stroke may be transitory

or spontaneously reversible, and so diagnostic
workup results may be unrevealing if testing was
undertaken during the time of reversion to
normalcy Eg : paradoxical vs persistent AF

Advanced Diagnostic Techniques in

Cryptogenic Stroke

Advanced Vascular Imaging and Sonography for Arterial

Pathology

Monitoring and Imaging Techniques for Paroxysmal AF

Diagnostic Techniques for Paradoxical and Aortogenic

Embolism

Workup for Cancer-Related Coagulopathy

Advanced Imaging and Sonography for

Arterial Pathology

Plaque vulnerability can be identified by MRI. MRI for carotid plaque

imaging can identify nonstenotic ruptured unstable plaque in patients
with cryptogenic stroke

Carotid Duplex and transcranial Doppler (TCD) monitoring for

microembolism can detect high-risk patients with asymptomatic carotid
stenosis

3-D ultrasound and contrast-enhanced ultrasound has also been

introduced as a tool for evaluating the vulnerable plaque at risk for
rupture in patients with carotid atherosclerotic disease

Monitoring and Imaging Techniques for Paroxysmal AF

Guidelines recommend that cardiac monitoring should be performed for at

least the first 24 hours.

However, AF-detection rate of 24-hour Holter monitoring seems not to be

sufficient, being reportedly inferior even to serial ECG for 3 days

When compared with 24-hour Holter monitoring, higher yield of AF detection

with in- hospital and outpatient telemonitoring, and more recently
implantable loop recorder, has been reported

Besides monitoring methods, transesophageal echocardiographic (TEE) and

Coronary CT Angiography can visualize left atrial appendage (LAA) thrombus
in patients for whom chronic anticoagulation may be warranted

Diagnostic Techniques for Paradoxical

and Aortogenic Embolism

Transthoracic echocardiogram is still the first choice of technique in patients

with stroke. However, only 0.7% patients are shown to have abnormal findings
in patients with stroke without known cardiac disease

TEE is thus considered the gold standard in the evaluation of cryptogenic stroke

Agitated saline TCD monitoring and transthoracic study can be used to detect
paradoxical embolism. Agitated saline TCD monitoring is based on intracranial
detection of intravenously injected microemboli

CCTA, can also be used to detect high-risk cardiac sources of embolism in

patients with stroke. This technique can confirm the presence of a PFO with
high accuracy, and is similar to TEE in detecting Aortic arch atheroma with
better definition of atheroma morphology

Workup for Cancer-Related

Coagulopathy

Although coagulation tests such as antiphospholipid antibodies are often

carried in younger stroke patients, they are often of little value in the
evaluation of patients with stroke.

In clinical practice, a much more important cause of coagulapathy is cancer.

In a recent analysis of patients with cryptogenic stroke, patients with active

cancer were present (71 of 348 patients; 20%) and had distinctive D-dimer
levels and infarct patterns (multiple lesions in multiple vascular territories)

Therefore, patients who present with characteristic symptoms and infarct

patterns, and no other apparent explanation for their index stroke, D-dimer
level and screening for hidden malignancy (serological or radiological tests)
should be considered

Approach to Cryptogenic Stroke

Lesion Pattern Analysis

Topography of lesion could be analyzed in the following order:

1. DWI infarct pattern: embolic versus deep and large versus small
scattered.
2. DWI infarct distribution: 1 vascular territory involved.
3. Past stroke on history or fluid-attenuated inversion recovery image: the
same side versus different territory

DWI Pattern

Single cortico/subcortical lesions and multiple bilateral lesions in the

anterior and posterior circulation on DWI have been associated with
cardiac embolic sources

Whereas multiple unilateral lesions in the anterior circulation have been

linked with arterogenic embolism, such as atherosclerosis or dissection

Past Stroke on History and FLAIR

Imaging

The Stroke subtype and infarct pattern of past stroke greatly influence
on the index stroke.

Specifically, patients with cortical infarcts by atheroembolism often

have recurrent stroke with cortical infarcts within the same arterial
system,

whereas patients with deep infarcts because of branch occlusive

disease developed recurrent branch occlusion.

Selection of
Advanced
Diagnostic
Techniques

Advanced Vascular Imaging

For patients with infarcts within 1 arterial system, advanced vascular

imaging, such as high-resolution wall imaging, may help in
documentation of unstable plaque, arterial dissection, or vasculitis.

This is particularly helpful in patients with

(1) past stroke within the same vascular territory,
(2) multiple small scattered infarcts within 1 arterial system, and
(3) deep infarct that is suspected to have branch occlusive disease

Advanced Monitoring for AF

Detection

A longer monitoring may be particularly important in patients with large stroke or

strokes involving multiple vascular territories.

The clot from the left atrium or LAA IS usually large and occludes distal internal
carotid artery, proximal middle cerebral artery, or distal basilar artery,

Thus, AF is associated with more severe ischemic stroke and longer (>60
minutes) TIAs than arteroembolic stroke from carotid or intracranial disease.

Several clinical (women, diabetes mellitus), genetic, and electrophysiological

(premature atrial complex, left atrial dilation, and reduced left ventricular ejection
fraction) features have also been reported as predictors of paroxysmal AF

In addition, blood biomarkers, such as high probrain natriuretic peptide levels,

may be predictors for incident AF in patients with cryptogenic stroke.

Aortogenic Embolic Source

Evaluation

Atheromatous emboli contain mostly cholesterol crystals and are associated

with borderzone infarct, whereas large emboli containing fibrin are associated
with large territory infarcts.

Thus, DWI patterns of aortic arch atheroma embolization are characterized by

multiple small scattered lesions in multiple vascular territories that are mainly
located in cortical and borderzone regions.

Therefore, additional workup to document aortogenic sources are

recommended in elderly patients with vascular risk factor and infarct patterns
associated with complex AAA i.e.
(1) multiple brain infarcts involving multiple vascular territories
(2) small-sized infarcts
(3) location of cortical and borderzone region.

Paradoxical Embolic Source

Evaluation

Because PFO could be an incidental finding, it is important to elucidate

the specific infarct patterns related to paradoxical embolism.

DWI lesion pattern may differ depending on the presence and the degree
of right-to-left shunt.

Specifically, patients with PFO showed a higher incidence of multiple

lesions in the posterior circulation, and the majority (80%) of patients with
a large amount of right-to-left shunt have small infarcts.

Therefore, additional workup to identify paradoxical embolism may have

to be considered in young (<55 years old) patients without conventional
risk factors, history of migraine, and infarct pattern of small, multiple
infarcts involving posterior circulation

Tests for Coagulopathy and Cancer

Screening

Measurement of D-dimer and screening tests for concealed cancer may

be needed in patients with cryptogenic stroke, who had
(1) vascular risk factors that cannot sufficiently explain the stroke,
(2) atypical presentation of symptoms,
(3) multiple infarcts involving multiple vascular territories.

Patients with cancer- related stroke often present with progressive

neurological deficits for hours to days (or even weeks) rather than sudden
catastrophic events with initial maximum deficits at onset.

In many patients, multifocal thromboembolism culminates in widespread

infarcts of various sizes, producing confusion, lethargy, or dementia.

Treatment

Medical management

There is a high degree of uncertainty regarding the optimal

management of patent foramen ovale (PFO), atrial septal aneurysm
(ASA), and atheromatous aortic disease.

The management of specific coagulation disorders and the role of

hematologic testing are also unclear at the moment.

Therefore, for the majority of patients with cryptogenic stroke,

antiplatelet therapy isrecommended.

Selected patients might benefit from anticoagulant therapy.

Oral anticoagulation

OAC for secondary prevention of stroke is indicated

if there is pAF,

if the morphological stroke pattern suggests an embolic cause,

or in case of intracardiac thrombus formation.

If OAC is given in these indications it reduces the risk of recurrent stroke

by 2-8% per year

PFO

Whether OAC is indicated for primary or secondary prevention of stroke in patients

with a PFO is still debated.

Among 576 patients treated with acetyl-salicylic acid (ASS) or OAC the recurrence risk
of cardioembolic events was similar in both groups

In another study, however, the 2y rate of stroke recurrence or death was lower in
patients receiving OAC than in patients receiving antiplatetelet medication

According to recent guidelines OAC is reasonable for high-risk patients only if they
have other indications for OAC. In the majority of the cases antiplatelet treatment is
reasonable to prevent a recurrent event

The best medical treatment of patients with CS or PFO plus ASA is OAC

Patent foramen ovale closure

Arguments against PFO closure are that recurrence rates of CS between

patients with and without PFO treated with warfarin or ASS did not differ
(PICSS study)

According to recent guidelines PFO closure is indicated only in patients

with recurrent CS caused by presumed paradoxical embolism through a
PFO who have failed therapeutic dosages of OAC

Closure may be also considered if

MRI suggests multiple or recurrent CSs

when there is elevated right atrial pressure

When OAC are contra-indicated