ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY

Etiologic classification of ischemic stroke

Created 19/04/2023, last revision 04/05/2023

  • 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

Evaluation of ischemic stroke etiology

Classification of stroke

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)

→ Computed Tomography in stroke diagnosis

→ Magnetic Resonance Imaging (MRI)

→ MR-DWI in acute stroke diagnosis

Acute ischemia (12-24 hours)
Cardioembolic stroke with multiple territory embolisation
PWI-DWI mismatch
Acute ischema on DWI

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)
  • 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)
Carotid stenoses on CTA with different plaque densities
Laminar and turbulent flow on CDI/CFM
MCA occlusion

Arrhythmias detection

ECG monitoring
  • 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 characterized by a duration of arrhythmia >30s in most studies
    • it is not clear what 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 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:
  • ECG monitoring at the ICU/stroke unit (at least for 24h) – AFib detection ∼3-6%  [Seet, 2011]  
  • ECG Holter monitoring

  • ZIO PATCH detector is a waterproof device allowing 14 days of monitoring   ZIO Patch detektor (mSTOPS,  EPACS trials) 
  • 30-day external monitoring – event loop (up to 20%)
    • Vitaphone, ECG Pocket   Vitaphone
      • continuous rhythm detection and recording in case of arrhythmia detection
      • in the EMBRACE trial, there was a higher detection of Afib compared to repeated Holter monitoring (3% vs. 16% within 30 days) [Sanna,2014]
    • episodic recorder    Episodic recorder
      • inserted by the patient at the precordium in regular intervals or when palpitations occur (arrhythmia detection is lower)
  • interesting possibilities are also offered by smart watch or phone (e.g., AliveCor AliveCor ) → see more
    • reliability to be verified
    • offers easy, cheap, and long-term monitoring  [Verbrugge, 2019]
  • insertable cardiac monitor (ICM) –  např. Reveal XT, Reveal LINQ  Reveal link
    • the 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
    • monitoring for months to years
    • increasing 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 84 days! (HR 8.78), 92.3% of patients had AFib lasting > 6 minutes
Pulse monitoring
  • pulse monitoring on the wrist seems to be useful, cheap, and easy
  • a larger trial is planned
Biomarkers
  • 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
  • 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 (in patients without associated heart failure)
    • NT-proBNP in patients with atrial fibrillation tends to be as high as 800-1100 pg/mL and decreases after successful cardioversion [Marsiliani, 2010]
      • high values predict a lower chance of successful cardioversion
  • troponin and GDF-15 are predictors of bleeding and are part of the ABC score
Markers associated with a higher incidence of AFib
Electrophysiological
 Biochemical
  • N-terminal pro-brain natriuretic peptide (NT-proBNP) > 265 pg/ml  [Fonseca, 2014]
 Morphological
 Comorbidities
  • thyreopathy
  • cardiac failure
  • decompensated hypertension and diabetes
  • pulmonary diseases

Cardiac imaging

TTE
  • the effectiveness of routine screening is uncertain (AHA/ASA 2019 IIb/B-NR)
  • check:
    • atrial size
    • 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
TEE
  • thrombus or spontaneous echo contrast/smoke (most commonly in the left atrial appendage) [Castro, 2010]    Thrombus in the left atrial appendage on TEE     
  • PFO   Patent Foramen Ovale on TEE with positive bubble test
  • atrial septal aneurysm Atrial septum aneurysm on TEE
  • detection of aortic plaques/thrombi   → aortic arch atherosclerosis
  • vegetations in pulmonary veins and valves
  • intracardiac tumor  Myxoma
Cardiac CT/MRI
  • alternative for patients who are unable/unwilling to undergo TEE   Postcontrast MRI with detection of right-to-left shunt after contrast agent administration (left image). Amplatzer occluder on cardiac MRI (right image)  Myxoma on cardiac imaging
  • can be combined with myocardial perfusion imaging
  • MRI can detect thrombus even if echocardiography is negative 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
Classification based  on the shape and location of ischemia (appearance may indicate etiology)

  • territorial (hemispheral)
  • lacunar
  • border zone infarcts (BZI)
Classification based on the duration (together with brain imaging)

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.)

TOAST 1 – Large artery atherosclerosis (macroangiopathy)

  • significant stenosis (> 50%) or occlusion of a relevant extra- or intracranial artery due to atherosclerosis   Large artery atherosclerosis (TOAST 1)
  • brain imaging (CT/MRI)
    • cortical lesion   Territorial cortical infarctions
    • 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)
  • 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)

TOAST 2 – Cardioembolic stroke

  • 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   Cardioembolic stroke with multiple territory embolisation Cardioembolic stroke
    • lacunar infarct, however, does not rule out cardioembolic cause
  • detection of a thrombus in the left atrium on baseline CTA helps determine the correct diagnosis

→ more about cardioembolic stroke here

TOAST 3 – Small artery disease (arteriolopathy, microangiopathy)

  • 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) Lacunar infarction in the left thalamus  or subcortical ischemic leukoencephalopathy  Leukoencephalopathy on FLAIR  (→ 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  Non-arteriolopathic pontine infarction caused by probable Branch Artery Disease (BAD) or embolization
    • 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)

TOAST 4 – Stroke of other determined etiology

  • vasculitis
  • non-inflammatory vasculopathies
  • genetic microangiopathies
  • hematologic disorders
  • iatrogenic insults, etc.

→ separate chapter about TOAST classification

TOAST 5 – Stroke of undetermined etiology

  • 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

Territorial (hemispheral) infarct
  • 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 often of atherothrombotic or cardioembolic etiology
Lacunar stroke
  • small infarcts (< 1.5 cm by definition) caused by 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 of lacunes from old small hemorrhages is possible by MR GRE

→ see separate chapter Lacunar stroke

Extensive leukoencephalopathy in Binswanger´s disease (FLAIR)
Lacunar infarct in the left thalamus (DWI)
CADASIL with typical external capsule involvement
Border Zone Infarct (BZI)
  • BZI or watershed infarcts develop at the boundaries of cerebral arteries
    • areas with permanently functional anastomoses (convexial 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 a hypotension episode)

Significant stenosis/occlusion of the ICA   Recent external BZI due to ICA dissection   External BZI in a patient with spontaneous ACI dissection (blue arrow on the right side indicates a false thrombosed lumen)

  • hypoperfusion and/or multiple (micro)embolizations  Recent BZI on DWI/ADC caused by the left ICA stenosis (50-70% according to NASCET)

Cardiac failure

  • cardiomyopathy
  • myocarditis
  • hypokinesis after myocardial infarction

Acute systemic hypotension (e.g., during surgery in ECC, CPR, etc.)

  • often a combination of several factors is involved (artery stenosis + hypotension + microangiopathy)

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   External Border Zone Infarct caused by the carotid artery stenosis
Border zone infarcts (BZI) - internal green, external blue

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Etiologic classification of ischemic stroke
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