Stroke Etiologic Classification- how do we do it now and what might be the future
Author: Mira Katan Kahles, MD, MS, Departement of Neurology, University Hospital Zurich
At least one stroke survivor out of six will suffer another stroke within 5 years1. To prevent stroke recurrence we treat our patients based on the presumed underlying etiology. For instance, we operate patients with symptomatic high-grade carotid stenosis, we anticoagulate patients with cardioembolic infarcts due to atrial fibrillation and we treat patients with infective endocarditis with antibiotics. But how do we identify the underlying cause?
Various stroke etiologic classification systems have been developed. The TOAST 2 classification system is the most commonly used in patients with ischemic stroke. By means of clinical judgment applied to results of the patient’s neurological exam, brain imaging (CT/MRI), standard 24-hour electrocardiography, echocardiography and ultrasound of extra and intracranial arteries, the most likely etiology is determined. Specifically, the TOAST system classifies ischemic strokes as due to large-vessel atherosclerosis, cardioembolic source, small vessel disease, other “determined” causes, and stroke of “undetermined” etiology. The last mentioned category comprises also those patients without known cause due to incomplete evaluation or due to the occurrence of multiple competing causes.
Other somewhat newer sub-classification systems, the Causative Classification of Stroke (CCS) system3 and the A-S-C-O classification 4are also available. The CSS system is advancing the accuracy of ischemic stroke subtype diagnosis by taking into account the level of diagnostic evidence in order to devise the “most likely mechanism” in the presence of multiple potential causes. The process goes beyond the results of etiologic testing and basically standardizes the clinical decision-making process, replacing an algorithm for the individual clinician’s judgment, to arrive at the cause of the stroke. The A-S-C-O classification system does not determine a final stroke etiology per se but rather takes into account the combination of all potential mechanisms graded by their impact, thus this approach is more descriptive, or phenotypic.
Despite the fact that the newer classification systems may have better discriminatory value, in clinical practice we are unable to identify the underlying cause in up to 30% of patients 5. Thus in these patients secondary prevention cannot be tailored towards the underlying etiology and the relative benefits of antiplatelet and anticoagulant therapy remain uncertain6.
To address part of this problem recently a group of scientists suggested defining a new entity within the “undetermined” category and they called it embolic stroke of undetermined source (ESUS)5 if even after extensive evaluation no underlying cause can be identified. They proposed that most of these types of stroke are of an embolic nature.
Diverse low-risk sources are the presumed origin of thromboemboli causing infarcts in embolic strokes of undetermined source, including, low-burden or undetected paroxysmal atrial fibrillation, patent foramen ovale, mild left ventricular dysfunction, aortic-arch atherosclerosis, and nonstenosing atherosclerotic plaques in cervical and intracranial arteries 6. Currently there are several trials ongoing, which aim to prove that all these patients might benefit from the novel anticoagulants (e.g. RESPECT ESUS, NAVIGATE ESUS and ATTICUS trials).
But then again how well do old and newer stroke classification schemes measure up to recent advances in precision medicine? Blood biomarkers, for example may provide additional insight into stroke etiology. Distinct gene expression profiles were able to accurately differentiate stroke patients with atrial fibrillation from patients with large artery stenosis7. Several studies have confirmed that natriuretic peptides, mainly N-terminal brain natriuretic peptide (NT-proBNP)8 and mid-regional atrial natriuretic peptide (MRproANP)9 are able to identify primarily cardioembolic stroke subtypes as well as stroke risk10. In addition higher NTproBNP levels were associated with a relative benefit of warfarin compared with aspirin for prevention of recurrent stroke11.
If confirmed in randomized controlled trials precision medicine tools such as blood biomarkers may help in detecting underlying etiology and thus guide secondary prevention12.
- Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics-2017 update: A report from the american heart association. Circulation. 2017;135:e146-e603
- Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Toast. Trial of org 10172 in acute stroke treatment. Stroke. 1993;24:35-41
- Ay H, Benner T, Arsava EM, Furie KL, Singhal AB, Jensen MB, et al. A computerized algorithm for etiologic classification of ischemic stroke: The causative classification of stroke system. Stroke; a journal of cerebral circulation. 2007;38:2979-2984
- Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG. New approach to stroke subtyping: The a-s-c-o (phenotypic) classification of stroke. Cerebrovascular diseases. 2009;27:502-508
- Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, et al. Embolic strokes of undetermined source: The case for a new clinical construct. The Lancet. Neurology. 2014;13:429-438
- Saver JL. Clinical practice. Cryptogenic stroke. N Engl J Med. 2016;374:2065-2074
- Jickling GC, Xu H, Stamova B, Ander BP, Zhan X, Tian Y, et al. Signatures of cardioembolic and large-vessel ischemic stroke. Annals of neurology. 2010;68:681-692
- Llombart V, Antolin-Fontes A, Bustamante A, Giralt D, Rost NS, Furie K, et al. B-type natriuretic peptides help in cardioembolic stroke diagnosis: Pooled data meta-analysis. Stroke. 2015;46:1187-1195
- Katan M., Fluri F., Schuetz P., Morgenthaler N.G., Zweifel Ch., Bingisser R., et al. Midregional pro-atrial natriuretic peptide and outcome in patients with acute ischemic stroke Journal of American College of Cardiology. 2010;56:1045-1053
- Mira Katan, Yeseon P. Moon, Myunghee C. Paik, Beat Mueller, Andreas Huber, Ralph L. Sacco, et al. Procalcitonin and midregional-proatrial natriuretic peptide as markers of ischemic stroke: The northern manhattan study Stroke 2016
- Longstreth WT, Jr., Kronmal RA, Thompson JL, Christenson RH, Levine SR, Gross R, et al. Amino terminal pro-b-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. Stroke. 2013;44:714-719
- Elkind MS. Stroke etiologic classification-moving from prediction to precision. JAMA Neurol. 2017;74:388-390