Acute ischemic stroke pathophysiologic principles

Cerebral blood flow

CBF = CPP / CVR

CPP = MAP - ICP

Ischemia is defined as CBF <20 ml/100gr/min. Prolongued ischemia will produce neuronal death.

Cerebral autoregulation

The vascular tone of the cerebral vessels decreases by increasing PaCO2. Within the PaCO2 range of 20-80 mmHg, CBF increases linearly with increasing PaCO2. Within the CPP range of 50-150 mmHg the the CVR of normal brain varies so that CBF is almost constant.

Cerebral Metabolic Rate of Oxygen Consumption (CMRO2)

The rate of oxygen consumption of the resting brain is approx. 3.0 - 3.8 ml/100 gr/min. Increased cortical activity can produce increases of ~ 30% in local CBF and ~ 5% in CMRO2.

Mechanisms of ischemia

Thrombosis

Localized occlusive process in one or more blood vessels. Vascular pathology types include:

• Atheromatosis
• Fibromuscular dysplasia
• Arteritis
• Dissection of the vascular wall
• Hemorrhage into atheromatous plaque

Embolism

Occlusion by material formed elsewhere in the vascular system. Types of occluding materials include:

• Fibrin-rich (“red”) thrombi
• Platelet-rich (“white”) thrombi
• Cholesterol-rich material derived from ruptured atheromatous plaque
• Septic thrombi
• Tumor cell conglomerates
• Fat emboli
• Air emboli

Of all the above types, only the first can be dissolved by thrombolytic treatment

Decreased systemic perfusion

Globally diminished arterial supply to the brain caused by myocardial infarction, arrythmia or systemic hypotension (hypovolemia, blood loss, iatrogenic)

When MAP falls, the vascular beds at the border (or “watershed”) zones between major cerebral arterial networks experience the most precipitous decrease in perfusion. Thus, the parenchyma in such areas is most susceptible to ischemic injury, “watershed” infarction. The watershed areas in the brain are:

1. Cortical wedge-shaped zones:
   • ACA-MCA: Frontal lobe, from anterior horn to cortex
   • MCA-PCA: Parieto-occipital region from posterior horn to cortex
2. Deep linear/band-like zones parallel to the lateral ventricles in the centrum semiovale and corona radiata. They extend between deep ACA-MCA, MCA-PCA and perforating medullary, lenticulostriate, anterior choroidal and recurrent artery of Heubner territories.

Stroke types

Atherosclerotic

• 40-45% of all strokes
• Large territorial infarcts are most commonly caused by artery-to-artery embolism from emboli arising from vulnerable atherosclerotic plaques.

Small vessel disease

• 15-30% of all strokes
• Lacunar infarcts are defined as lesions measuring <15 mm in diameter
• Many infarcts may be clinically silent
• May be embolic, thrombotic or atheromatous
• Most common site are the penetrating deep arteries of the basal ganglia and thalami

Cardioembolic disease

• 15-25% of all strokes
• Atrial fibrillation, myocardial infarction and valvular heart disease are the most common causes

Cryptogenic

• 25-40% of all strokes
• Defined as brain infarction not clearly attributable to a definite cardioembolim, large artery atherosclerosis or small artery disease despite extensive investigation
• PFO, ASD, left atrial thrombus, mitral valve strands and aortic arch atheroma may be identifiable causes discoverable by transesophageal echocardiography
• Occult paroxysmal AF or flutter may be discoverable by Holter monitoring or more prolonged outpatient telemetry
• CSF examination, hypercoagulability testing and other laboratory tests may be waranted depending on the clinical context

Other

• ~5% of all strokes
• Strokes with miscellaneous but known etiology

Determinants of stroke severity

Collateral circulation

Perfusion through collateral networks can rescue brain tissue distal to major artery occlusion/stenosis. The presence and density of collaterals is a major determinant of clinical outcome.

See this section for a description of the most important anastomotic networks.

Systemic circulation

Factors that reduce CBF:

• Low blood pressure
• Heart failure
• Hypovolemia
• Increased blood viscosity
  • Elevation of blood pressure increases CBF, except at malignant ranges.
  • Decrease of hematocrit by phlebotomy to 40% can increase CBF up to 50%.
  • Maintaining blood volume and pressure levels optimises flow through collateral networks.

Biochemical factors

Detrimental factors include:

• Hypoxia
• Hypoglycemia
• Hyperglycemia

Potential detrimental factors include:

• Hypercalcemia
• High blood alcohol level

Prior state of the microcirculatory bed

Degenerative changes in the small vessels such as from hypertension or diabetes have a significant detrimental effect in outcome.

Increased ICP

Increased intracranial pressure from cytotoxic oedema after large infarcts reduces CBF and increases venous sinus pressure thus reducing venous drainage and facilitating vasogenic oedema and further increases in ICP.

State of the obstructing lesion

Reactive vasoconstriction caused by the sudden obstruction can further compromise tissue-at-risk. Embolus propagation more distally in the vascular tree and clot fragmentation may block potential collaterals. Thrombus extension is facilitated in hypercoagulable states.