Ischemic stroke pathophysiology

(Redirected from Stroke pathophysiology)
Jump to navigation Jump to search

Stroke Main page

Patient Information




Hemorrhagic stroke
Ischemic stroke

Differentiating Stroke from other Diseases

Epidemiology and Demographics


NIH stroke scale
Glasgow coma scale

Epidemiology and Demographics

Risk Factors


Natural History, Complications and Prognosis


Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings



Echocardiography and Ultrasound

CT scan


Other Imaging Findings

Other Diagnostic Studies


Medical Therapy



Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Ischemic stroke pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides


American Roentgen Ray Society Images of Ischemic stroke pathophysiology

All Images
Echo & Ultrasound
CT Images

Ongoing Trials at Clinical

US National Guidelines Clearinghouse

NICE Guidance

FDA on Ischemic stroke pathophysiology

CDC on Ischemic stroke pathophysiology

Ischemic stroke pathophysiology in the news

Blogs on Ischemic stroke pathophysiology

Directions to Hospitals Treating Psoriasis

Risk calculators and risk factors for Ischemic stroke pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maryam Hadipour, M.D.[2],Aysha Anwar, M.B.B.S[3]


The pathophysiology of ischemic stroke may depend on the underlying cause of ischemia. Ischemic infarct may be categorized into two types depending on the area of the brain involved as focal ischemic stroke or global ischemic stroke. Hemodynamic changes in ischemic stroke results from cerebral auto regulation dysfunction as brain tissue is highly sensitive to mild changes in oxygen levels. Several minutes of hypoxia leads to irreversible injury. Cerebral auto regulation maintains the perfusion pressure in the brain between the pressure range of 60-150 mm Hg via vasoconstriction and vasodilatation. Prolonged ischemia decreases oxygen delivery to the cells causing anaerobic glycolysis and increased production of free oxygen and nitrate radicals which in turn causes cell membrane, DNA damage and cell death.



The brain receives blood from two sources: the internal carotid arteries, which arise at the point in the neck where the common carotid arteries bifurcate, and the vertebral arteries. The internal carotid arteries branch to form two major cerebral arteries, the anterior and middle cerebral arteries. The right and left vertebral arteries come together at the level of the pons on the ventral surface of the brainstem to form the midline basilar artery. The basilar artery joins the blood supply from the internal carotids in an arterial ring at the base of the brain (in the vicinity of the hypothalamus and cerebral peduncles) called the circle of Willis. The posterior cerebral arteries arise at this confluence, as do two small bridging arteries, the anterior and posterior communicating arteries. Conjoining the two major sources of cerebral vascular supply via the circle of Willis presumably improves the chances of any region of the brain continuing to receive blood if one of the major arteries becomes occluded. The physiological demands served by the blood supply of the brain are particularly significant because neurons are more sensitive to oxygen deprivation than other kinds of cells with lower rates of metabolism. In addition, the brain is at risk from circulating toxins, and is specifically protected in this respect by the blood-brain barrier. As a result of the high metabolic rate of neurons, brain tissue deprived of oxygen and glucose as a result of compromised blood supply is likely to sustain transient or permanent damage. Brief loss of blood supply (referred to as ischemia) can cause cellular changes, which, if not quickly reversed, can lead to cell death. Sustained loss of blood supply leads much more directly to death and degeneration of the deprived cells.


The pathogenesis of ischemic stroke may depend on the underlying cause of ischemia. Ischemic infarct may be categorized into two types depending on the area of the brain involved:[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][6][8]

Type of ischemia Pathogenesis
Underlying cause Part of the brain involved Time of initiation of cell death Type of cell death


Focal area supplied by the occluded vessel

Acute onset (3-4 hrs)
Cell death (12 hrs)

Necrosis-central area
Apoptosis- Peripheral area


Systemic hypoperfusion

Water shed area
Hippocampal pyramidal cells, cerebellar purkinjee cells, cortical laminar cells

Delayed onset (12 hrs)
Cell death (days to weeks)


Traditionally, stroke has been classified into 2 broad categories of stroke syndrome: hemorrhagic (bleeding) stroke and thrombotic (ischemic) stroke. These 2 phenotypes are considered to be diametrically opposite conditions because hemorrhage is characterized by bleeding into the brain tissue resulting in hematoma and brain tissue shift while ischemia is due to thrombosis characterized by “blood clots” within intracranial vasculature leading to hypoxia to a certain part of the brain due to reduced blood supply. Both may result in different clinical brain syndromes even in the same locality.[17][18]

Pathologies affecting large extracranial vessels include:

  • Atherosclerosis
  • Giant cell arteritis
  • Dissection
  • Takayasu arteritis
  • Fibromuscular dysplasia

Pathologies affecting large intracranial vessels include:

  • Atherosclerosis
  • Dissection
  • Arteritis/vasculitis
  • Noninflammatory vasculopathy
  • Vasoconstriction

Embolic strokes are divided into four categories:

  • Those with a known source that is cardiac
  • Those with a possible cardiac or aortic source based upon transthoracic and/or transesophageal echocardiographic findings
  • Those with an arterial source (artery to artery embolism)
  • Those with a truly unknown source in which tests for embolic sources are negative

Hemodynamic changes in ischemic stroke

  • Hemodynamic changes in ischemic stroke results from cerebral auto regulation dysfunction as brain tissue is highly sensitive to mild changes in oxygen levels
  • Several minutes of hypoxia leads to irreversible injury[6][8]
  • Cerebral auto regulation maintains the perfusion pressure in the brain between the pressure range of 60-150 mm Hg via vasoconstriction and vasodilatation.[8]
  • Pressure changes below 60 mm Hg and more than 150 mm Hg disrupts the normal auto regulation.
  • Below 60 mm Hg, initially there is extensive vasodilatation of the affected vessels to increase blood flow to the affected area. This is mediated by increase in endothelial nitric oxide production.
  • Extensive increase in nitric oxide production due to sustained hypoxia results in massive vasodialation and formation of large amounts of nitric oxide free radicals causing damage to cellular structures.
  • Drop in blood flow rates below 30ml/100gm results in inhibition of protein synthesis and increase in anaerobic glycolysis
  • Blood flow rates below 20ml/100gm results in extensive membrane damage causing cell death.

Molecular pathophysiology in ischemic stroke

The sequence of molecular changes that may result due to ischemia include:[2][6]

  • Prolonged ischemia- decrease in oxygen delivery to the cells
  • Anaerobic glycolysis with decline in ATP production
  • Increased lactic acid production
  • Increased free oxygen and nitrate radicals-cell membrane and DNA damage[1]
  • Excitatory neurotransmitter -glutamate is increased in neuronal synapses leading to NMDA receptor activation[5][6]
  • NMDA receptor activation causes opening of ion channels in the cell membrane causing K+ efflux and Na+, Ca2+ and water influx
  • Increased Ca2+ influx activates apoptotic cell death pathways
  • ATP required for final steps of apoptosis, hence massive decline in ATP results in necrosis of cells

Cellular changes in Ischemic stroke

The sequence of cellular changes during ischemic stroke results in loss of structural integrity of brain causing disruption of blood brain barrier and cerebral edema.


Advances in sequencing technology have facilitated the discovery of single-gene disorders associated with stroke beyond classic syndromes, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and sickle-cell disease. In addition, heterozygous mutations within the 3ʹ untranslated region of COL4A1 (the gene encoding collagen 4A1) is identified as a cause of pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL). Heterozygous mutations (in particular, glycine substitutions) in the triple helical domains of COL4A1 or COL4A2 cause a different syndrome characterized by hemorrhagic stroke along with additional neurological and non-neurological manifestations.[19]

The following gene loci may also increase the risk for stroke:

Gross pathology

  • Central necrotic tissue is called umbra
  • Peripheral tissue which surrounds area of necrosis and can be salvaged with increased blood flow is called pneumbra[4]

Microscopic pathology

  • Within 1-6 min of ischemia, red neurons and vacoulation results [13]
  • If ischemia lasts > 6 min, karryorhexis and cell death occurs

Gross and microscopic changes that may occur due to ischemia with the passage of time is tabulated below: [13][20]

Duration Gross pathology Microscopic pathology[13]

<24 hrs

No change Cellular edema

<1 week


Loss of grey and white matter junction

Red neurons




1-4 weeks

Soft friable tissue

Cyst formation


Liquifactive necrosis


>4 weeks


Fluid filled cysts with dark grey margin


Necrotic tissue cleared by macrophages


  1. 1.0 1.1 1.2 Rodrigo R, Fernández-Gajardo R, Gutiérrez R, Matamala JM, Carrasco R, Miranda-Merchak A; et al. (2013). "Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities". CNS Neurol Disord Drug Targets. 12 (5): 698–714. PMID 23469845.
  2. 2.0 2.1 2.2 Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV (2011). "Pathophysiology, treatment, and animal and cellular models of human ischemic stroke". Mol Neurodegener. 6 (1): 11. doi:10.1186/1750-1326-6-11. PMC 3037909. PMID 21266064.
  3. Pulsinelli W (1992). "Pathophysiology of acute ischaemic stroke". Lancet. 339 (8792): 533–6. PMID 1346887.
  4. 4.0 4.1 Moustafa RR, Baron JC (2008). "Pathophysiology of ischaemic stroke: insights from imaging, and implications for therapy and drug discovery". Br J Pharmacol. 153 Suppl 1: S44–54. doi:10.1038/sj.bjp.0707530. PMC 2268043. PMID 18037922.
  5. 5.0 5.1 Dirnagl U, Iadecola C, Moskowitz MA (1999). "Pathobiology of ischaemic stroke: an integrated view". Trends Neurosci. 22 (9): 391–7. PMID 10441299.
  6. 6.0 6.1 6.2 6.3 6.4 Xing C, Arai K, Lo EH, Hommel M (2012). "Pathophysiologic cascades in ischemic stroke". Int J Stroke. 7 (5): 378–85. doi:10.1111/j.1747-4949.2012.00839.x. PMC 3985770. PMID 22712739.
  7. Deb P, Sharma S, Hassan KM (2010). "Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis". Pathophysiology. 17 (3): 197–218. doi:10.1016/j.pathophys.2009.12.001. PMID 20074922.
  8. 8.0 8.1 8.2 8.3 del Zoppo GJ, Hallenbeck JM (2000). "Advances in the vascular pathophysiology of ischemic stroke". Thromb Res. 98 (3): 73–81. PMID 10812160.
  9. Futrell N (1998). "Pathophysiology of acute ischemic stroke: new concepts in cerebral embolism". Cerebrovasc Dis. 8 Suppl 1: 2–5. PMID 9547024.
  10. Taoufik E, Probert L (2008). "Ischemic neuronal damage". Curr Pharm Des. 14 (33): 3565–73. PMID 19075733.
  11. Mangubat E, Sani S (2015). "Acute global ischemic stroke after cranioplasty: case report and review of the literature". Neurologist. 19 (5): 135–9. doi:10.1097/NRL.0000000000000024. PMID 25970836.
  12. 12.0 12.1 12.2 Siesjö BK, Katsura K, Zhao Q, Folbergrová J, Pahlmark K, Siesjö P; et al. (1995). "Mechanisms of secondary brain damage in global and focal ischemia: a speculative synthesis". J Neurotrauma. 12 (5): 943–56. PMID 8594224.
  13. 13.0 13.1 13.2 13.3 Mărgăritescu O, Mogoantă L, Pirici I, Pirici D, Cernea D, Mărgăritescu C (2009). "Histopathological changes in acute ischemic stroke". Rom J Morphol Embryol. 50 (3): 327–39. PMID 19690757 : 19690757 Check |pmid= value (help).
  14. Brinjikji W, Duffy S, Burrows A, Hacke W, Liebeskind D, Majoie CB; et al. (2016). "Correlation of imaging and histopathology of thrombi in acute ischemic stroke with etiology and outcome: a systematic review". J Neurointerv Surg. doi:10.1136/neurintsurg-2016-012391. PMID 27166383.
  15. Sierra C (2014). "Essential hypertension, cerebral white matter pathology and ischemic stroke". Curr Med Chem. 21 (19): 2156–64. PMID 24372222.
  16. 16.0 16.1 Price CJ, Menon DK, Peters AM, Ballinger JR, Barber RW, Balan KK; et al. (2004). "Cerebral neutrophil recruitment, histology, and outcome in acute ischemic stroke: an imaging-based study". Stroke. 35 (7): 1659–64. doi:10.1161/01.STR.0000130592.71028.92. PMID 15155970.
  17. Chang JC (2020). "Stroke Classification: Critical Role of Unusually Large von Willebrand Factor Multimers and Tissue Factor on Clinical Phenotypes Based on Novel "Two-Path Unifying Theory" of Hemostasis". Clin Appl Thromb Hemost. 26: 1076029620913634. doi:10.1177/1076029620913634. PMC 7427029 Check |pmc= value (help). PMID 32584600 Check |pmid= value (help).
  18. Caplan LR (July 1993). "Brain embolism, revisited". Neurology. 43 (7): 1281–7. doi:10.1212/wnl.43.7.1281. PMID 8327124.
  19. Dichgans M, Pulit SL, Rosand J (June 2019). "Stroke genetics: discovery, biology, and clinical applications". Lancet Neurol. 18 (6): 587–599. doi:10.1016/S1474-4422(19)30043-2. PMID 30975520.
  20. Caplan LR (1992). "Intracerebral hemorrhage". Lancet. 339 (8794): 656–8. PMID 1347346.

Template:WS Template:WH