Pathophysiology and ischemia thresholds
Normally, cerebral blood flow (CBF) is maintained at 50–55 mL/100 g/min. When cerebral perfusion pressure drops, autoregulation is triggered: blood vessels dilate, collaterals are recruited, and cerebral blood volume (CBV) and mean transit time (MTT) increase. When vessels are maximally dilated, a further pressure drop leads to decreased blood flow and cellular dysfunction.
The severity of injury depends on ischemia thresholds:
- 15–20 mL/100 g/min: neurons lose normal electrical function, but changes are reversible.
- 10–20 mL/100 g/min (moderate ischemia): tissue can survive if blood flow is restored within several hours.
- < 10 mL/100 g/min: irreversible infarction develops within minutes.
At the cellular level, hypoxemia leads to the failure of ATP-dependent systems (including the Na+/K+-pump). Sodium and water rush into the cells, causing them to swell — cytotoxic edema develops. Over time, capillary endothelial ischemia disrupts the blood-brain barrier, allowing proteins and fluid to escape into the extracellular space, forming vasogenic edema.
Penumbra (ischemic penumbra) model
In thromboembolic occlusion, the decrease in blood flow occurs unevenly, forming three zones:
- Infarct core (Infarct core): the center of the lesion with critically low blood flow, cellular depolarization, and irreversible changes.
- Penumbra (Penumbra): the peripheral zone with moderately reduced blood flow. Electrical function is lost, but cellular integrity is preserved. This tissue is viable, and recanalization strategies are aimed precisely at saving it. However, due to poor autoregulation, treatment delay leads to penumbral death.
- Zone of benign oligemia: surrounds the penumbra. Blood flow is mildly impaired, and the tissue will survive without intervention.
TOAST classification and etiology
The TOAST system divides ischemic strokes into etiological subtypes:
- Large-vessel thromboembolism (40%): thrombosis over an atherosclerotic plaque or distal embolism. Common sites: carotid bifurcation, intracranial internal carotid artery (ICA), proximal middle cerebral artery (MCA).
- Cardioembolic (15–30%): cardiac source of thrombus (atrial fibrillation, myocardial infarction, valvular heart disease).
- Microvascular / lacunar (15–30%): small infracts (<1.5 cm) within the territories of deep perforating arteries (lenticulostriate, thalamic branches). Frequently associated with arterial hypertension and diabetes mellitus. Rare causes: Susac syndrome, CADASIL.
A distinct category is watershed infarction (watershed ischaemia). These occur at the borders of major vascular territories (e.g., between the ACA and MCA) due to a combination of local stenosis and global hypoperfusion (e.g., in heart failure).
Neuroimaging: CT and ASPECTS scale
Non-contrast CT (NECT) is critical in the hyperacute period. Its main goals are to rule out hemorrhage, rule out non-vascular causes of symptoms, and estimate infarct volume.
Early CT signs of hyperacute infarction:
- Hyperdense artery sign: the earliest sign, caused by a fresh thrombus within the lumen (often in the MCA or ICA).
- Dot sign (dot sign): thrombus in an MCA branch within the Sylvian fissure.
- Loss of grey-white matter differentiation: due to cytotoxic edema, grey matter merges with white matter (e.g., sulcal effacement, loss of definition of the lentiform nucleus and insular cortex).
The ASPECTS scale is used to assess lesion volume within the MCA territory. It helps predict outcomes and the risk of hemorrhage following thrombolysis. To better visualize early density changes, CT scans are viewed in a special “stroke window” (window width = 35, level = 35).
Management and recanalization tactics
The mainstay of therapy is intravenous administration of recombinant tissue plasminogen activator (IV r-tPA). It is effective when criteria are met: initiation within 4.5 hours, infarct volume less than 1/3 of the MCA territory, age under 80.
In large vessel occlusion (LVO), mechanical thrombectomy has become the treatment of choice. Selection criteria:
- Moderate to severe stroke (NIHSS > 5).
- CT angiography-confirmed occlusion of the intracranial ICA or proximal MCA.
- Pre-stroke disability score on the mRS scale < 3.
- Arterial puncture within 6 hours of symptom onset (the window may be extended up to 24 hours upon penumbral imaging evaluation).
Briefly: answers to topical questions
What etiological subtypes of ischemic stroke are distinguished according to the TOAST classification?
The TOAST classification distinguishes four main etiological subtypes of ischemic stroke. These include:
- Large vessel thromboembolism (large vessel thromboembolic) — occurs due to thrombus formation at the site of an atherosclerotic plaque or distal embolization.
- Cardioembolic (cardioembolic) — associated with an intracardiac thrombus, arrhythmias, or valvular pathology.
- Microvascular / small vessel disease (small vessel) — characterized by small lacunar infarcts.
- 'Other' aetiologies ('other' aetiologies).
Precise categorization into subtypes is sometimes difficult, and the stroke etiology frequently remains undetermined.
Specifically, which anatomical brain structures are evaluated when calculating the ASPECTS score?
The ASPECTS score evaluates 10 regions within the middle cerebral artery territory, comprising 4 deep structures and 6 cortical structures. Evaluation is performed on two axial slices of non-contrast CT:
- Caudate nucleus (C)
- Lentiform nucleus (L)
- Internal capsule (IC)
- Insula (I)
- MCA territory at the ganglionic level (M1, M2, M3)
- MCA territory rostral to the ganglia (M4, M5, M6)
The initial score is 10, with 1 point subtracted for each involved region.
Which MRI sequences are used to diagnose acute stroke and assess the ischemic penumbra?
To diagnose acute stroke and evaluate the ischemic penumbra, a multimodal MRI protocol is used, including:
- Diffusion-weighted imaging (DWI) — detects early ischemic injury.
- Apparent diffusion coefficient (ADC) — interpreted alongside DWI; the combination of hyperintensity on DWI and hypointensity on ADC almost always corresponds to irreversible ischemia.
- Perfusion-weighted MRI (PWI) — used to assess the ischemic penumbra and stratify revascularization risk.
- Susceptibility-weighted imaging (SWI, SWAN, FSBB, SWIp, BSI) — to detect acute hemorrhage; SWI can also reveal an intraluminal thrombus.
- FLAIR — for assessing the DWI-FLAIR mismatch.
T1-weighted imaging and contrast-enhanced MR angiography (CEMRA) are also used.
The "time is brain" rule: the faster blood flow is restored, the higher the chance of saving the penumbra from progressing to an irreversible core infarction.
Class and exam questions
How Does a Transient Ischemic Attack (TIA) Differ from a Stroke?
In TIA, neurological deficits (including amaurosis fugax) resolve completely within 24 hours. However, neuroimaging reveals small completed infarctions in 44% of patients, and the risk of a full stroke within the first month reaches 12%.
Why Is Thrombolysis Not Administered to All Ischemic Stroke Patients?
Thrombolysis has strict limitations. It is contraindicated if more than 4.5 hours have passed, if CT shows signs of hemorrhage, or if the infarction already involves more than 1/3 of the middle cerebral artery (MCA) territory.
What Does Global Hypoxic Injury Look Like on CT?
In severe hypoxia (e.g., after cardiac arrest), CT shows bilateral symmetrical hypodensity of the basal ganglia and cortex. With profound injury, a reversal of the normal gray-to-white matter density ratio is observed.
Why Is MRI Necessary in Acute Stroke?
MRI is extremely sensitive to acute ischemia. On diffusion-weighted imaging (DWI), an acute infarction appears as a bright hyperintense signal, while the SWI sequence allows visualization of the thrombus itself due to the "blooming" effect of deoxyhemoglobin.
What else to study on this topic
- Basilar Tip Syndrome
- Topography of Infarctions: How Localization Points to the Embolic Source
- Detailed Analysis of the ASPECTS Score in CT Evaluation
- MRI Diagnosis: DWI, ADC, and SWI Sequences in Acute Stroke Assessment
- Selection Criteria for Mechanical Thrombectomy in Large Vessel Occlusion (LVO)
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