ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY
Etiologic classification of ischemic stroke
David Goldemund M.D.
Updated on 09/11/2023, published on 04/04/2021
Updated on 09/11/2023, published on 04/04/2021
- individualized stroke prevention is based on the presumed underlying etiology (CEA in patients with symptomatic high-grade carotid stenosis, anticoagulation in patients with cardioembolic infarcts due to AFib)
- the use of standardized diagnostic algorithms and established classifications (TOAST, CISS) is recommended
- it used METAMIZOLE
Evaluation of ischemic stroke etiology
Brain imaging
- assess the nature, size, and location of the lesion on the brain CT/MRI; note any pathologic findings
- both CT and MRI are used in the acute stroke setting
- in patients with suspected acute stroke and a negative baseline CT/MRI, it is reasonable to add a follow-up imaging to confirm the diagnosis (AHA/ASA 2021 2a/B-NR)
- in patients with TIA and negative imaging, it is reasonable to add a follow-up MRI (AHA/ASA 2021 2a/B-NR)
- follow-up CT/MRI is also advisable before the initiation of anticoagulation ⇒ to assess the extent of ischemia and exclude possible hemorrhagic transformation (best seen on GRE/SWI) (AHA/ASA 2021 2b/B-NR)
Vascular imaging
- vascular imaging is used to detect stenosis or occlusion and to assess probable etiology (atherosclerosis, dissection, FMD, etc.)
- in acute stroke patients, brain CT+CT angiography became standard baseline imaging in most centers (the others use MRI+MRA)
- patients with mRS 0-3 who are not candidates for recanalization therapy should have vascular imaging within 24 h of admission (in the non-acute setting, neurosonology is most commonly used)
- both extra- and intracranial arteries should be evaluated (perform CTA from the aortic arch to the vertex)
- in acute stroke patients, brain CT+CT angiography became standard baseline imaging in most centers (the others use MRI+MRA)
- methods:
- CT angiography (see an in-depth tutorial on vascular assessment of stroke patients)
- MR angiography
- neurosonology
- in the acute stroke setting, TIBI may be used to detect and monitor intracranial occlusion (the method became less useful with the availability of CTA and the advent of mechanical recanalization)
- DSA (most commonly used for endovascular procedures)
Arrhythmias detection
- the detection of atrial fibrillation (AFib) or its paroxysmal form is essential
- ECG Holter monitoring should be performed for at least the first 24 hours (AHA/ASA 2021 I/B-R
- paroxysmal AFib is typically characterized by a duration of > 30 seconds in most studies
- it remains unclear what specific duration actually increases the risk of cardioembolism; very short paroxysms of AFib probably do not increase the risk of stroke [Swiryn, 2016]
- according to some cardiologists and neurologists, the threshold is > 5-6 minutes; others suggest a duration ranging from tens of minutes to hours [Diener, 2014]
- baseline standard 12-lead ECG
- assess baseline rhythm, ischemic changes, left ventricular hypertrophy, block, preexcitation, and conduction intervals (PR, QRS, QT)
- possible predictors of paroxysmal AFib:
- atrial premature beats (APBs) or premature atrial contractions (PACs) [Himmelreich, 2018]
- prolonged QTc interval > 438 ms [Hoshino, 2014]
- P-wave pathology (P-maximum and P-wave dispersion) [Howlett, 2015]
- ECG monitoring at the ICU/stroke unit (at least for 24h) – AFib detection ∼3-6% [Seet, 2011]
- ECG Holter monitoring
- 24 hours (AFib detection ~ 2-3%)
- 24-72 hours (~2-5%)
- 7-days Holter (5.7-18%)
[Higgins, 2013] [Seet, 2011][Jabaudon, 2004]
- ZIO PATCH detector is a waterproof device allowing for 14 days of monitoring
(mSTOPS, EPACS trials)
- 30-day external monitoring with an event loop (detection in up to 20% of cases)
- Vitaphone, ECG Pocket
- continuous rhythm detection and recording in case of arrhythmia detection
- in the EMBRACE trial, a higher detection of Afib was observed compared to repeated Holter monitoring (3% vs. 16% within 30 days) [Sanna,2014]
- episodic recorder
- inserted by the patient at the precordium in regular intervals or whenever palpitations occur (arrhythmia detection is lower with this method)
- Vitaphone, ECG Pocket
- interesting possibilities are offered by smartwatches or phones (e.g., AliveCor
) → see more
- reliability needs to be verified
- wearables offer easy, cheap, and long-term monitoring [Verbrugge, 2019]
- insertable cardiac monitor (ICM) – such as Reveal XT, Reveal LINQ
- ICM is a small medical device, about the size of a pen cap, that is inserted under the skin, usually in the left upper chest area
- the monitoring duration ranges from months to years
- increased AFib detection at 6 months, 1, and 3 years was reported in the CRYSTAL AF trial
- 8.9% vs. 1.4%/6 months (HR 6.43)
- 12.4% vs 2% /12 months (HR7.32)
- 30% vs. 3% / 3 years
- median AFib detection was 84 days! (HR 8.78); 92.3% of patients had AFib lasting > 6 minutes
- pulse monitoring on the wrist seems to be useful, cheap, and easy
- a larger trial is planned to further investigate its effectiveness
- N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin (hs-cTn), growth differentiation factor 15 (GDF-15), high-sensitivity C-reactive protein (hs-CRP), cystatin C are important biomarkers.
- NT-proBNP appears to be the most significant so far [Svennberg, 2016]
- cut-off values indicating an increased risk of AFib vary in different papers (particularly in patients without associated heart failure)
- > 265 pg/mL [Fonseca, 2014]
- > 90 pg/mL in women, > 60 pg/mL in men, OR 2.65 [Asselbergs, 2010]
- NT-proBNP in patients with atrial fibrillation usually ranges from 800-1100 pg/mL and decreases after successful cardioversion [Marsiliani, 2010]
- higher values predict a lower chance of successful cardioversion
- cut-off values indicating an increased risk of AFib vary in different papers (particularly in patients without associated heart failure)
- both troponin and GDF-15 serve as predictors of bleeding and are integral components of the ABC score
| Markers associated with a higher incidence of AFib |
| Electrophysiological |
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| Biochemical |
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| Morphological |
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| Comorbidities |
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Cardiac imaging
- the effectiveness of routine screening is uncertain (AHA/ASA 2019 IIb/B-NR)
- check:
- atrial size
- atrial enlargement (LAVI – Left Atrial Volume Index) is associated with an increased risk of AFib [Jordan, 2019] [Howlett, 2015]
- left ventricular size and function + wall thickness
- low EF (∼ 20-30%), dilation, focal akinesia
- atrial dilation and wall enlargement increase the risk of AFib
- valvular defects
- atrial size
- thrombus or spontaneous echo contrast/smoke (most commonly in the left atrial appendage) [Castro, 2010]
- Patent Foramen Ovale (PFO)
- atrial septal aneurysm
- aortic plaques/thrombi → aortic arch atherosclerosis
- vegetations in pulmonary veins and valves
- intracardiac tumor
- an alternative for patients who are unable/unwilling to undergo transesophageal echocardiography (TEE)
- can be combined with myocardial perfusion imaging
- MRI can detect thrombus, even in cases where echocardiography is negative (due to MRI’s superior soft tissue characterization and three-dimensional imaging capabilities) Weinsaft, 2011]
Laboratory tests
- assess vascular risk factors (AHA/ASA 2021 1/N-BR)
- consider testing for hypercoagulable states in selected cases
- screening is not beneficial due to the low detection rate and high cost
- autoantibodies testing in suspected vasculitis
- screening is not recommended due to the low detection rate and high cost
- cardiac enzymes (CK, CKMB, LD, high-sensitivity cardiac troponin)
- to exclude concomitant MI, which may be a source of cardioembolism
- often, troponin elevation is due to brain lesion, not MI
- other tests
- toxicology (drugs)
- CSF analysis (vasculitis, DDx of neuroinfection)
- biopsy – vasculitis (brain and meninges), CADASIL (skin), etc.
- genetic testing (e.g., CADASIL, ACTA2, Grange syndrome, hypercoagulable states)
- consider screening for OSA (obstructive sleep apnea) (AHA/ASA 2021 2b/B-R)
Classification of ischemic stroke
- stroke is a very heterogeneous disease in terms of etiology and course
- there are different classifications and subdivisions – many of them mix different items (e.g., etiopathogenetic mechanism with risk factors or clinical presentation ), which can make the situation confusing
- TOAST classification seems to be the most useful for clinical practice
Classification based on the etiology and pathophysiology
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Classification based on the shape and location of ischemia (appearance may indicate etiology)
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Classification based on the duration (together with brain imaging)
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Pathophysiologic classification
- the diagram greatly simplifies the complex etiopathogenesis (often several mechanisms are combined – e.g., arteriolopathy may have a thrombotic or atherothrombotic component, etc.)
Etiologic classification
- the most widely used classification is the TOAST classification of stroke
- only a brief summary is presented below
- other improved classification systems have been introduced:
- the proportions of each stroke subtype are reported differently, a combination of several factors is possible
- proportions can be expected to change with new diagnostic methods (e.g., long-term ECG monitoring increases the detection of paroxysmal AFib at the expense of cryptogenic stroke, etc.)
- significant stenosis (> 50%) or occlusion of a relevant extra- or intracranial artery due to atherosclerosis
- evidence of plaque hemorrhage, thrombus, plaque cap rupture, or angiogenesis indicates high-risk plaque, regardless of the stenosis degree
- → assessement of atherosclerotic plaques
- search for aortic arch atherosclerosis; which is categorized as large artery atherosclerosis in TOAST and CISS classifications
- brain imaging (CT/MRI)
- cortical lesion
- subcortical lesion > 1.5 cm (originally published)
- it is known, however, that even smaller lesions can be caused by branch artery atherosclerosis (see CISS classification)
- cortical lesion
- common mechanisms of stroke in the TOAST 1 category
- thromboembolism, atheroma embolization, or both (artery-to-artery embolization)
- the composition of the embolus may vary from a fragile fresh fibrin thrombus that easily fragments to a compact, tightly organized thrombus with solid plaque masses
- thrombosis or intraplaque bleeding leading to arterial occlusion
- occlusion of perforators caused by large plaques
- hypoperfusion due to severe stenosis (⇒ border zone infarcts)
- thromboembolism, atheroma embolization, or both (artery-to-artery embolization)
- reported to be the cause of 20-45% of all ischemic strokes (the proportion increases with advanced cardiac imaging and prolonged ECG monitoring)
- thromboembolism from the left atrium or ventricle is most common; hypoperfusion is less frequent (⇒ typically border zone infarcts in e.g., cardiomyopathy)
- clinical syndromes and infarct features on brain imaging are usually indistinguishable from the TOAST 1
- often there is no reliable “cardioembolic pattern” present; multiple infarcts in different territories support embolic etiology
- lacunar infarct, however, does not rule out cardioembolic cause
- often there is no reliable “cardioembolic pattern” present; multiple infarcts in different territories support embolic etiology
- detection of a thrombus in the left atrium on baseline CTA helps determine the correct diagnosis
- arteriolopathy (arteries 0.4-0.5mm wide) can lead to cerebral infarction or hemorrhages in deep structures
- it is caused by lipohyalinosis
- especially in patients with hypertension
- the main feature of lipohyalinosis is the thickening of the wall with vessel stenosis or even occlusion
- brainstem or subcortical lacunar infarcts on CT/MRI (diameter < 1.5 cm)
or subcortical ischemic leukoencephalopathy 
(→ FAZEKAS scale, ARWMC scale) - clinical presentation
- asymptomatic
- lacunar syndrome
- encephalopathy with cognitive impairment with/without pseudobulbar syndrome (due to status lacunaris)
- + presence of traditional vascular risk factors (hypertension, dyslipidemia, diabetes, etc.)
- distinguish non-arteriolopathic occlusion of perforating arteries
- atherosclerosis of the parent artery near the perforator origin – Branch Artery Disease (BAD) / Branch Occlusive Disease (BOD)
- infarcts tend to be larger compared to classic arteriolopathy and in younger patients [Zhou, 2018]
- high-resolution MRI can be used for diagnosis [Petrone, 2016]
- embolization (from proximal arterial segments or cardioembolism)
- atherosclerosis of the parent artery near the perforator origin – Branch Artery Disease (BAD) / Branch Occlusive Disease (BOD)
- vasculitis
- non-inflammatory vasculopathies
- genetic microangiopathies
- hematologic disorders
- iatrogenic insults, etc.
- the cause of the stroke could not be determined with sufficient certainty
- ≥2 potential causes of stroke identified (e.g., atrial fibrillation in a patient with carotid stenosis > 50%, significant carotid stenosis + microangiopathy, etc.)
- cryptogenic stroke (CS) – no etiology identified despite extensive evaluation [Bang, 2014]
- incomplete diagnostic evaluation
Classification based on characteristics of ischemic lesion
- affects both cortex and subcortical white matter
- usually due to thrombotic or embolic occlusion of an intracranial artery (or in combination with an extracranial lesion)
- most commonly of atherothrombotic or cardioembolic etiology
- small infarcts (< 1.5 cm by definition) are caused by the occlusion of a deep perforating artery
- etiology:
- arteriolopathy (TOAST 3)
- microembolization
- atheromatous plaque at the ostium of the perforating artery
- typically occur in subcortical structures (basal ganglia, internal capsule, thalamus, and brainstem)
- in addition to isolated lacunar infarcts, advanced arteriolopathy leads to leukoaraiosis ⇒ confluent white matter lesions periventricularly (typically in Binswanger´s disease, CADASIL, etc.)
- differentiation between lacunes and old small hemorrhages is possible using MRI (particularly GRE or SWI sequences)
- BZI or watershed infarcts develop at the boundaries of cerebral arteries
- areas with permanently functional anastomoses (convexal pial arteries)
- areas where non-anastomosing terminal branches of different territories are adjacent (interface between deep perforating and pial arteries, for example, in the semiovale center)
- perfusion pressure in these areas gets most easily below the ischemic threshold (e.g., in significant ICA stenosis or during episodes of hypotension)
Internal BZI
- the junction between the lenticulostriatal arteries and the anterior choroidal artery and penetrating cortical branches of the MCA
External (cortical) BZI
- the junction between the superficial arterial system of MCA/ACA and MCA/PCA
Significant stenosis/occlusion of the ICA 
- hypoperfusion and/or multiple (micro)embolizations
Cardiac failure
- cardiomyopathy
- myocarditis
- hypokinesis following myocardial infarction
Acute systemic hypotension (e.g., during surgery in ECC, during CPR, etc.)
- often, a combination of several factors is involved (artery stenosis + hypotension + microangiopathy)
