• 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

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)
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
  • 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:
  • 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 with an event loop (detection in up to 20% of cases)
    • 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 whenever palpitations occur (arrhythmia detection is lower with this method)
  • interesting possibilities are offered by smartwatches or phones (e.g., AliveCor 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 LINQReveal link
    • 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
  • 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)
    • 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
  • 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
  • N-terminal pro-brain natriuretic peptide (NT-proBNP) > 265 pg/ml  [Fonseca, 2014]
  • thyreopathy
  • cardiac failure
  • decompensated hypertension and diabetes
  • pulmonary diseases

Cardiac imaging

  • 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
Cardiac CT/MRI
  • an alternative for patients who are unable/unwilling to undergo transesophageal echocardiography (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 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.)
  • 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)
  • 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

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

→ separate chapter about TOAST classification

  • 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 commonly 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 between lacunes and old small hemorrhages is possible using MRI  (particularly GRE or SWI sequences)
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 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   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 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)

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