The definition of cryptogenic stroke (CS) is unclear.
CS is generally defined as stroke
which remains unexplained as to cause after adequate evaluation.
However that concept is vague due to uncertainty about what
constitutes an adequate evaluation. Moreover, some consider
uncertain presentations with more than one plausible substrate
identified as CS. The latter category is not considered CS for
purposes of discussion in the paper. In an attempt at clarity the
authors subdivide CS into 1) unknown cause after “standard
evaluation” (CSSE) and
2) unknown cause after “advanced evaluation” (CSAE).
Standard evaluation is defined as: echo (TTE and/or TEE depending on
clinical circumstances), in hospital telemetry or 24 hour Holter,
stroke imaging (it doesn't specify whether this is CT and/or MRI),
and noninvasive vascular imaging of the head and neck (CTA or MRA).
Advanced evaluation consists of: invasive angio, transcranial
doppler, vasculitis tests, outpatient monitoring up to 4 weeks and
thrombophilia tests (arterial thrombophilia tests in unselected
patients but venous thrombophilia tests only in those with suspected
intracardiac shunt). A third category called “specialized
evaluation” exists. It consists of: genetic tests, LP, brain
biopsy, advanced cardiac testing and 1 to 3 year monitoring via an
implanted monitor.
Causes of CS
A long list of rare causes is contained in the on line supplement to
the paper. Here are the more important ones:
Occult atherosclerosis (nonstenosing but unstable plaques,
intracranial and extracranial)
Thoracic origin stenosis
Nonatherosclerotic arteriopathies (eg dissection, vasculitis)
Hypercoagulable states (arterial in unselected cases, venous if
paradoxical embolism is considered)
Low burden atrial fibrillation
Dilated cardiomyopathy
Paradoxical embolism
Likely causes by age
Realizing considerable overlap they can be categorized as follows:
18-30: Dissection is most
common. Also consider thrombophilia and structural (congenital)
heart disease.
31-60: Premature atherosclerosis, structural heart disease
Over 60: occult atrial fibrillation
Published stroke classification schemes may guide evaluation.
Recommendations
for evaluation of CS
Recommended tests for the various
levels of evaluation were listed in the first section above. Certain
points warrant elaboration:
No particular order of testing
was
given within categories.
Small deep white matter infarcts, which might otherwise be
categorized as CS, may not need advanced testing in patients over 50
or who have standard vascular risk factors.
Recommended vasculitis serologic tests consist of ESR, CRP, ANA, RF
and ANCA.
Transcranial doppler monitoring for up to 60 minutes may detect
covert microemboli, either of cardiac or arterial origin.
Invasive, as compared to noninvasive, angiography better evaluates
medium and small arteries and may be useful in detecting vasculitis
(which may be associated with negative serologic tests) and other
unusual arterial diseases.
Special considerations in atrial fibrillation
The author recommends that when AF is detected during hospitalization
anticoagulation with a NOAC be started by the time of discharge.
This is a more aggressive approach than found in the guidelines and
would raise some bleeding concerns in my mind. The guidelines, in
contrast to the review article, state no preference between warfarin
and NOACs other than to say that rivaroxaban has a IIa recommendation
while warfarin, dabigatran and apixaban have a class I
recommendation. Moreover, the guideline recommended start time is
“within 14 days” in many strokes but delayed beyond that time in
large infarcts or those with increased bleeding risk. Given the
short hospital stay for most strokes these days the review author
seems to favor anticoagulation significantly earlier than what the
guidelines call for. Moreover, given the rapid onset of action of
NOACs this approach would have the patient fully anticoagulated just
a few days after stroke onset.
For CSSE the paper recommends discharge with ambulatory monitoring
for 30 days, and on a NOAC if there are multiple AF risk factors but
on antiplatelets if not.
For patients with negative 30 day monitoring and no AF risk factors
the author would dismiss AF from further consideration and treat with
antiplatelet therapy. If AF risk factors are present the author
would recommend an implanted monitor with consideration for
continuing the NOAC for a year followed by reassessment.
If
low burden AF is found on 30 day monitoring the recommendation is to
continue the NOAC but if no AF risk factors are present to consider
stopping it after a year.
Further reading: here is a CS resource on the American Stroke
Association website.