VIENNA (FRONTLINE MEDICAL NEWS) – The concept of cryptogenic stroke is outdated and should be replaced by the relatively new clinical construct of embolic stroke of undetermined source or ESUS, Dr. Hans Christoph Diener said at the annual European Stroke Conference.

The underlying premise is that these strokes of so-called unknown cause are actually due to thromboembolic events from more minor-risk or covert cardiac sources and thus could potentially be prevented by anticoagulation with the newer non-vitamin K oral anticoagulants (NOACs). In fact, Dr. Diener noted that the concept of ESUS came about because researchers wanted to do secondary prevention trials in cryptogenic stoke but the U.S. Food and Drug Administration would not allow it as there was no was to truly diagnose it.

The paradigm of cryptogenic stroke was developed at a time when sophisticated imaging was not available, Dr. Diener of the University of Duisburg-Essen, Germany, observed, noting that it was a diagnosis of exclusion. The term could also encompass cases where incomplete diagnostic evaluation had been performed.

ESUS on the other hand was “positively defined” and required a clear set of criteria (see box) to be met as set out recently by the Cryptogenic Stroke/ESUS International Working Group ( Lancet Neurol. 2014;13:429–438 ). These criteria relied on a minimum diagnostic work-up including brain computed tomography (CT) or magnetic resonance imagine (MRI), 12-lead ECG, precordial echocardiography, cardiac monitoring for 24 hours or longer, and imaging of both the extra- and intracranial arteries supplying the area of brain ischemia.

The criteria are:

* Stroke detected by CT or MRI that is not lacunar

* Absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in the arteries supplying the area of ischemia

* No major-risk cardioembolic source of embolism

* No other specific cause of stroke identified (e.g. arteritis, dissection, migraine/vasospasm, drug misuse)

According to the established TOAST (Trial of Org 10172) Criteria ( Stroke. 1993;23:35–41 ) there are five main categories of ischemic stroke: large vessel disease, cardio-embolic disease, small vessel disease unknown (cryptogenic), or other causes or those with conflicting etiology. “These criteria were developed to include people with a particular pathophysiology into randomized trials,” Dr. Diener noted and using this classification a quarter of all ischemic strokes are generally classified as cryptogenic. Another quarter can be due to large artery atherosclerotic stenosis, another quarter to small artery disease (lacunar stroke), a fifth due to major-risk cardio-embolic disease, and the remainder to unusual events, such as dissection or arteritis.

“These different entities have different consequences for treatment,” Dr. Diener noted. “In someone who had a significant large artery atherosclerotic stenosis most probably it would be surgery or stenting,” he said while “in someone who has an identified cardiogenic source of embolism it is clearly anticoagulation.” Patients with small vessel disease would probably be treated via risk factor management.

“And then we have this entity called cryptogenic stroke,” he said. Because this category of stroke was so heterogeneous and defined by what it is not rather than what it is, treatment options were not clearly defined and performing secondary prevention trials just not possible, until now.

ESUS could include a range of pathophysiologies, he acknowledged, although the majority were likely to be unrecognized paroxysmal atrial fibrillation (AF). Others could be atrial high rate episodes, heart failure, silent myocardial infarction, patent foramen ovale, atherosclerotic plaques in the aortic arch, or nonstenotic atherosclerotic plaques in the cervical or intracranial arteries.

There are two possible strategies for stroke prevention in patients with ESUS, Dr. Diener suggested. The first was to use more sophisticated tools to detect clinically silent AF. Methods of detecting clinically silent AF via cardiac monitoring has evolved greatly from the original Holter monitoring equipment to the ambulatory devices and implantable recorders available today. Trials such as EMBRACE ( N Engl J Med. 2014;370:2467-77 ) and CRYSTAL-AF ( N Engl J Med. 2014; 370:2478-2486 ) had shown the respective benefits of prolonged ambulatory and implantable device monitoring, he said. The next generation of technology could include ECG- and perhaps even biomarker monitoring via the iPhone and Apple Watch, Dr. Diener said.

The second strategy for secondary stroke prevention in ESUS was to treat irrespective of the possible etiology or to develop new and more effective anticoagulatnt therapies. Dr. Diener is co-chair of the RE-SPECT ESUS-trial , which is currently recruiting patients using the new ESUS definition and will randomize a target of 6,000 patients to treatment with dabigatran, aspirin, or matching placebos. There is also another trial, NAVIGATE ESUS comparing the NOAC rivaroxaban to aspirin with a similar design and 7,000-patient target accrual, he said. Both trials are event driven and are expected to run for 2-3 years. Results should be available in 2018.

“The old concept of cryptogenic stroke is not very useful if you want to do randomized trials in a defined population and this is why we created the definition of ESUS,” Dr. Diener said.

“In the future, we have two ways to address this problem. One way is much more sophisticated diagnostic testing to detect silent AF and the other way is to treat and to improve the medical treatment of these patients. Hopefully, three years from now, we have evidence that we have something to offer that is superior to aspirin and has a superior side effect profile.”

Introducing the concept of ESUS has not been not without its critics, however, and in a comment published in the Lancet Neurology, Dr. Martin Dennis of the Western General Hospital in Edinburgh, Scotland, pointed out that the name selected might mislead clinicians.

“An unknown proportion of patients with ESUS will not have an embolic stroke, but a stroke due to in-situ thrombosis,” he argued. “Although one can see the advantages of the name for gaining support from funders and clinicians for a trial, and for marketing new oral anticoagulants if they prove effective, the name will mislead clinicians.”

Dr. Dennis suggested that a better name might be to refer to these strokes as “non-lacunar ischaemic stroke without a defined cause”.

Dr. Diener and his institution have received financial support from a number of German and European funding bodies, and wide range of pharmaceutical companies.