What is the pathophysiology of an ischemic stroke?

Pathophysiology of Ischemic Stroke

Ischemic stroke occurs when blood flow to the brain is interrupted due to vessel occlusion, leading to a cascade of cellular events that result in neuronal death, with the core infarct surrounded by potentially salvageable penumbra tissue.

Primary Mechanisms of Vessel Occlusion

• Thrombotic occlusion: Formation of a blood clot within cerebral vessels, typically due to:

  • Large-artery atherosclerosis (extracranial or intracranial)
  • Small vessel disease (arteriolosclerosis)

• Embolic occlusion: Blood clot or debris that forms elsewhere and travels to cerebral vessels

  • Cardioembolism (from atrial fibrillation, valvular disease, etc.)
  • Artery-to-artery embolism (from carotid/vertebral plaques)
  • Paradoxical embolism (through patent foramen ovale)

• Other mechanisms:

  • Arterial dissection
  • Hypercoagulable states
  • Sickle cell disease 1

Cellular Cascade Following Occlusion

1. Initial ischemia: Interruption of cerebral blood flow leads to energy failure

   • Reduced oxygen and glucose delivery
   • Depletion of ATP stores
   • Failure of Na+/K+ ATPase pumps

2. Excitotoxicity:

   • Excessive glutamate release
   • Calcium influx into neurons
   • Activation of destructive enzymes (proteases, lipases)

3. Mitochondrial dysfunction:

   • Increased reactive oxygen species (ROS) production
   • Disruption of the electron transport chain
   • Release of pro-apoptotic factors 1

4. Inflammatory response:

   • Activation of microglia
   • Infiltration of leukocytes
   • Release of inflammatory cytokines
   • Blood-brain barrier disruption

5. Cell death pathways:

   • Necrosis (in ischemic core)
   • Apoptosis (in penumbra)

Ischemic Core vs. Penumbra

• Ischemic core:

  • Region with severe blood flow reduction (<10-15% of normal)
  • Rapid cell death (minutes to hours)
  • Generally irreversible damage

• Ischemic penumbra:

  • Surrounding region with moderate blood flow reduction (15-40% of normal)
  • Functionally impaired but viable tissue
  • Potentially salvageable with timely reperfusion
  • Indicated by diffusion-perfusion mismatch on MRI 1

Vascular Responses and Collateral Circulation

• Autoregulation failure: Loss of cerebral blood flow autoregulation in ischemic regions

• Collateral circulation:

  • Critical determinant of infarct size and clinical outcome
  • Can be graded from 0 (no collaterals) to 4 (complete and rapid collateral flow) 1
  • More robust collaterals associated with smaller infarct volumes and better outcomes

Reperfusion and Associated Complications

• Beneficial effects:

  • Restoration of oxygen and nutrients
  • Salvage of penumbral tissue

• Reperfusion injury:

  • Oxidative stress from sudden oxygen influx
  • Increased inflammatory response
  • Microvascular obstruction (no-reflow phenomenon)

• Hemorrhagic transformation:

  • Occurs in approximately 10-40% of ischemic strokes
  • More common after thrombolytic therapy
  • Results from blood-brain barrier breakdown 2

Mitochondrial Dynamics in Ischemic Stroke

Recent research highlights the crucial role of mitochondrial dynamics in stroke pathophysiology:

• Mitochondrial fission and fusion:
  • Fission (division of mitochondria) increases after ischemia
  • Dynamin-related protein 1 (Drp1) mediates fission
  • Phosphorylation of Drp1 at serine 616 increases after global cerebral ischemia
  • Inhibition of Drp1 has been shown to reduce infarct volume in experimental models 1

Clinical Manifestations Related to Pathophysiology

• Symptom onset and progression:

  • Sudden onset reflects abrupt vascular occlusion
  • Progression may indicate ongoing penumbral loss or evolving thrombosis

• Stroke severity:

  • Correlates with extent of tissue damage and location
  • Measured clinically using standardized scales like NIHSS

• Perfusion status:

  • Can be assessed using TICI (Thrombolysis in Cerebral Infarction) perfusion categories
  • Ranges from Grade 0 (no perfusion) to Grade 3 (complete perfusion) 1

Implications for Treatment

Understanding the pathophysiology guides treatment approaches:

• Time-critical interventions:

  • "Time is brain" – approximately 1.9 million neurons lost per minute of untreated stroke
  • Thrombolysis and thrombectomy aim to restore blood flow to salvage penumbra

• Neuroprotective strategies:

  • Target various steps in the ischemic cascade
  • Aim to extend the therapeutic window for reperfusion

• Secondary prevention:

  • Addresses underlying mechanisms (antiplatelet therapy, anticoagulation, etc.)
  • Targets modifiable risk factors 3

Understanding the complex pathophysiology of ischemic stroke is essential for developing effective treatment strategies that can minimize brain damage and improve patient outcomes.