ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY

Etiologic classification of ischemic stroke

Created 19/04/2023, last revision 07/11/2023

  • 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

Brain imaging

  • assess the nature, size, and location of the lesion on brain CT/MRI; note any pathological findings
    • both CT and MRI are used in the acute stroke setting
  • in patients with suspected acute stroke and a negative baseline CT/MRI, adding follow-up imaging to confirm the diagnosis is reasonable (AHA/ASA 2021  2a/B-NR)
  • in patients with TIA and negative imaging, adding a follow-up MRI is reasonable (AHA/ASA 2021  2a/B-NR)
  • follow-up CT/MRI is advisable before initiating anticoagulation to assess the extent of ischemia and exclude possible hemorrhagic transformation (best visualized 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, standard baseline imaging in most centers comprises brain CT+CT angiography (alternatively, 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 (CTA from the aortic arch to the vertex is recommended)
  • 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
  • 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 characterized by a duration of arrhythmia > 30  seconds 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  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:
  • 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 for 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, a higher detection of Afib was observed 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 smartwatches or phones (e.g., AliveCor AliveCor ) → see more
    • reliability needs to be verified
    • offers easy, cheap, and long-term monitoring  [Verbrugge, 2019]
  • insertable cardiac monitor (ICM) –  např. Reveal XT, Reveal LINQReveal 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 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 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 (particularly in patients without associated heart failure)
    • NT-proBNP in patients with atrial fibrillation usually ranges from 800-1100 pg/mL and decreases after successful cardioversion [Marsiliani, 2010]
      • high values predict a lower chance of successful cardioversion
  • 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
 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
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 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 if vasculitis is suspected
    • 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
    • troponin elevation is often due to brain lesion, not MI
  • other tests
    • toxicology (drugs)
    • CSF analysis (vasculitis, DDx of neuroinfection)
    • biopsy for conditions like vasculitis (brain and meninges), CADASIL (skin), etc.
    • genetic testing  (e.g., CARASIL, CADASIL, ACTA2, Grange syndrome, hypercoagulable states)
    • consider screening for obstructive sleep apnea (OSA) (AHA/ASA 2021 2b/B-R)

Classification of ischemic stroke

  • stroke is a very heterogeneous disease in terms of etiology and course
  • multiple different classifications and subdivisions exist, many of them mix different elements (e.g., etiopathogenetic mechanism with risk factors or clinical presentation ), leading to potential confusion
  • TOAST classification seems to be 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 offers a simplified representation of complex etiopathogenesis (multiple mechanisms may coexist – e.g., arteriolopathy may have a thrombotic or atherothrombotic component, etc.)

Etiologic classification

  • TOAST classification of stroke remains the most widely utilized system for stroke categorization
    • only a summary is presented below
  • other improved classification systems include:
  • variability in reported proportions of each stroke subtype exists, multiple factors may contribute
  • the proportional representation of stroke subtypes may change with the development of diagnostic methods (e.g., long-term ECG monitoring increases the detection of paroxysmal AFib, thus decreasing the percentage of cryptogenic strokes, 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 may 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

  • accounts for 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 vascular territories support embolic etiology   Cardioembolic stroke with multiple territory embolisation Cardioembolic stroke
    • lacunar infarct, however, does not rule out cardioembolic cause
  • detection of left atrial thrombus on baseline CTA helps determine the correct etiological diagnosis

→ more about cardioembolic stroke here

TOAST 3 – Small artery disease (arteriolopathy, microangiopathy)

  • arteriolopathy (affecting arteries 0.4-0.5 mm in diameter) may lead to cerebral infarction or hemorrhages in deep structures
  • the primary etiology is lipohyalinosis
    • especially prevalent in patients with hypertension
    • lipohyalinosis is characterized by arterial wall thickening, leading to vessel stenosis or 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 +/- pseudobulbar syndrome (attributable 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 more common in younger patients [Zhou, 2018]
      • high-resolution MRI can be used for diagnosis  [Petrone, 2016]
    • embolization (originating 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

  • cause of stroke remains undetermined due to insufficient diagnostic certainty
    • ≥2 potential causes of stroke were identified (e.g., atrial fibrillation + 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) 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 of lacunes from old small hemorrhages is possible on MRI  (GRE or SWI sequences)

→ 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 (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 a hypotension episode)

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

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)

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Etiologic classification of ischemic stroke
link: https://www.stroke-manual.com/etiologic-classification-ischemic-stroke/