• individualized stroke prevention is based on the presumed underlying etiology ( patients with symptomatic high-grade carotid stenosis can be treated with CEA, while patients with cardioembolic infarcts caused by AFib are treated with anticoagulants)
  • the use of standardized diagnostic algorithms and established classifications (such as TOAST and CISS) is recommended for accurate diagnosis and treatment

Evaluation of ischemic stroke etiology

Brain imaging

  • assess the nature, size, and location of the lesion on brain CT/MRI scans; note any other pathological findings
    • both CT and MRI are commonly used in the acute stroke setting
    • based on the affected arterial territory, a specific artery occlusion can be assumed
  • it is reasonable to perform follow-up imaging for patients with suspected acute stroke and a negative baseline CT/MRI to confirm the diagnosis (AHA/ASA 2021  2a/B-NR)
  • for 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)
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 assess probable etiology (atherosclerosis, dissection, FMD, etc.)
    • in acute stroke patients, standard baseline imaging in most centers consists of brain CT+CT angiography (alternatively, MRI+MRA)
    • in most medical centers, standard baseline imaging for acute stroke patients includes a brain CT+ CT angiography (alternatively MRI + MRA)
    • patients with mRS 0-3, who are not eligible for recanalization therapy, should have vascular imaging within 24 h of admission (in the non-acute setting, neurosonology is the most commonly used method)
    • 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, transcranial Doppler with TIBI grading scale may be used to identify and monitor intracranial occlusion (the method has become less valuable 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
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 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
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
  • 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 advised due to the low detection rate and the high cost
  • autoantibodies testing if vasculitis is suspected
    • screening is not recommended due to the low detection rate and high cost
  • cardiac enzyme testing (CK, CKMB, LD, high-sensitivity cardiac troponin)
    • to exclude concomitant myocardial infarction (MI), which may be a source of cardioembolism
    • troponin elevation is often attributed to a brain lesion rather than MI
  • other tests

Classification of ischemic stroke

  • stroke is a highly heterogeneous disease in terms of etiology and clinical manifestation
  • numerous classifications and subdivisions exist, many of them combining different elements (e.g., etiopathogenetic mechanism with risk factors or clinical presentation ), which can potentially lead to confusion
  • there are many different ways to classify and categorize strokes
  • some systems combine multiple factors, such as etiopathogenetic mechanism with risk factors or clinical presentation, which can potentially lead to confusion
  • TOAST classification is widely recognized and seems to be most practical and useful for clinical purposes
Classification based on etiology and pathophysiology

Classification based on the appearance and location of ischemia (which may indicate etiology)

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

Pathophysiologic classification

  • the diagram provides a simplified representation of complex etiopathogenesis, where 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 categorizing stroke
    • only a summary is presented below
  • other improved classification systems include:
  • the variability in the reported proportions of individual stroke subtypes is due to the age composition of the cohort and the diagnostic methods used).
    • the proportional representation of stroke subtypes may change with the development of new diagnostic methods (e.g., long-term ECG monitoring increases the detection of paroxysmal AFib, thus decreasing the percentage of cryptogenic strokes, 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 may be caused by branch artery atherosclerosis (see the 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, ranging 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)
  • 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 the most common; hypoperfusion is less frequent (⇒ typically resulting in border zone infarcts, as seen in conditions like cardiomyopathy)
  • clinical syndromes and infarct features on brain imaging are usually indistinguishable from TOAST 1
    • usually, there is no reliable “cardioembolic pattern” present; however, multiple infarcts in different vascular territories support embolic etiology   Cardioembolic stroke with multiple territory embolisation Cardioembolic stroke
    • the presence of a lacunar infarct does not rule out a cardioembolic cause
  • detection of left atrial thrombus on baseline CTA can help establish the correct etiological diagnosis

→ more about cardioembolic stroke here

  • arteriolopathy (primarily affecting arteries 0.4-0.5 mm in diameter) may lead to cerebral infarction or hemorrhages in deep brain structures
  • the primary cause of arteriolopathy is lipohyalinosis
    • particularly prevalent in patients with arterial hypertension
    • lipohyalinosis is characterized by thickening of the arterial wall, which can result in 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 scaleARWMC scale)
  • clinical presentation
    • asymptomatic cases
    • lacunar syndromes
    • encephalopathy with cognitive impairment +/- pseudobulbar syndrome (attributable to the status lacunaris)
  • + the 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 are 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)
  • vasculitides
  • non-inflammatory vasculopathies (dissection, FMD, etc.)
  • genetic microangiopathies
  • hematologic disorders
  • iatrogenic insults, etc.

→ separate chapter about TOAST classification

  • 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 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)