Ischemic stroke pathophysiology: Difference between revisions

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{{Stroke}}
{{Stroke}}
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{{CMG}}{{AE}} {{MHP}},{{AA}}
==Overview==
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.


==Pathophysiology==
==Pathophysiology==
Ischemic stroke occurs due to a loss of blood supply to part of the brain, initiating the [[ischemic cascade]].  Brain tissue ceases to function if deprived of oxygen for more than 60 to 90 seconds and after a few hours will suffer irreversible injury possibly leading to death of the tissue, i.e., [[infarction]]. Atherosclerosis may disrupt the blood supply by narrowing the lumen of blood vessels leading to a reduction of blood flow, by causing the formation of blood clots within the vessel, or by releasing showers of small [[emboli]] through the disintegration of atherosclerotic plaques. Embolic infarction occurs when emboli formed elsewhere in the circulatory system, typically in the heart as a consequence of atria fibriliation, or in the carotid arteries. These break off, enter the cerebral circulation, then lodge in and occlude brain blood vessels.
===Physiology===
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 arterie]]s. 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 [[neuron]]s 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.


Due to [[Anastomosis|collateral circulation]],  within the region of brain tissue affected by ischemia there is a spectrum of severity.  Thus, part of the tissue may immediately die while other parts may only be injured and could potentially recover.  The ischemia area where tissue might recover is referred to as the ''ischemic penumbra''.
===Pathogenesis===
[[Stroke|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:<ref name="pmid23469845">{{cite journal| author=Rodrigo R, Fernández-Gajardo R, Gutiérrez R, Matamala JM, Carrasco R, Miranda-Merchak A et al.| title=Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. | journal=CNS Neurol Disord Drug Targets | year= 2013 | volume= 12 | issue= 5 | pages= 698-714 | pmid=23469845 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23469845  }} </ref><ref name="pmid21266064">{{cite journal| author=Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV| title=Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. | journal=Mol Neurodegener | year= 2011 | volume= 6 | issue= 1 | pages= 11 | pmid=21266064 | doi=10.1186/1750-1326-6-11 | pmc=3037909 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21266064  }} </ref><ref name="pmid1346887">{{cite journal| author=Pulsinelli W| title=Pathophysiology of acute ischaemic stroke. | journal=Lancet | year= 1992 | volume= 339 | issue= 8792 | pages= 533-6 | pmid=1346887 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1346887  }} </ref><ref name="pmid18037922">{{cite journal| author=Moustafa RR, Baron JC| title=Pathophysiology of ischaemic stroke: insights from imaging, and implications for therapy and drug discovery. | journal=Br J Pharmacol | year= 2008 | volume= 153 Suppl 1 | issue=  | pages= S44-54 | pmid=18037922 | doi=10.1038/sj.bjp.0707530 | pmc=2268043 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18037922  }} </ref><ref name="pmid10441299">{{cite journal| author=Dirnagl U, Iadecola C, Moskowitz MA| title=Pathobiology of ischaemic stroke: an integrated view. | journal=Trends Neurosci | year= 1999 | volume= 22 | issue= 9 | pages= 391-7 | pmid=10441299 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10441299  }} </ref><ref name="pmid22712739">{{cite journal| author=Xing C, Arai K, Lo EH, Hommel M| title=Pathophysiologic cascades in ischemic stroke. | journal=Int J Stroke | year= 2012 | volume= 7 | issue= 5 | pages= 378-85 | pmid=22712739 | doi=10.1111/j.1747-4949.2012.00839.x | pmc=3985770 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22712739  }} </ref><ref name="pmid20074922">{{cite journal| author=Deb P, Sharma S, Hassan KM| title=Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. | journal=Pathophysiology | year= 2010 | volume= 17 | issue= 3 | pages= 197-218 | pmid=20074922 | doi=10.1016/j.pathophys.2009.12.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20074922  }} </ref><ref name="pmid10812160">{{cite journal| author=del Zoppo GJ, Hallenbeck JM| title=Advances in the vascular pathophysiology of ischemic stroke. | journal=Thromb Res | year= 2000 | volume= 98 | issue= 3 | pages= 73-81 | pmid=10812160 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10812160  }} </ref><ref name="pmid9547024">{{cite journal| author=Futrell N| title=Pathophysiology of acute ischemic stroke: new concepts in cerebral embolism. | journal=Cerebrovasc Dis | year= 1998 | volume= 8 Suppl 1 | issue=  | pages= 2-5 | pmid=9547024 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9547024  }} </ref><ref name="pmid19075733">{{cite journal| author=Taoufik E, Probert L| title=Ischemic neuronal damage. | journal=Curr Pharm Des | year= 2008 | volume= 14 | issue= 33 | pages= 3565-73 | pmid=19075733 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19075733 }} </ref><ref name="pmid25970836">{{cite journal| author=Mangubat E, Sani S| title=Acute global ischemic stroke after cranioplasty: case report and review of the literature. | journal=Neurologist | year= 2015 | volume= 19 | issue= 5 | pages= 135-9 | pmid=25970836 | doi=10.1097/NRL.0000000000000024 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25970836  }} </ref><ref name="pmid8594224">{{cite journal| author=Siesjö BK, Katsura K, Zhao Q, Folbergrová J, Pahlmark K, Siesjö P et al.| title=Mechanisms of secondary brain damage in global and focal ischemia: a speculative synthesis. | journal=J Neurotrauma | year= 1995 | volume= 12 | issue= 5 | pages= 943-56 | pmid=8594224 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8594224  }} </ref><ref name="pmid: 19690757">{{cite journal| author=Mărgăritescu O, Mogoantă L, Pirici I, Pirici D, Cernea D, Mărgăritescu C| title=Histopathological changes in acute ischemic stroke. | journal=Rom J Morphol Embryol | year= 2009 | volume= 50 | issue= 3 | pages= 327-39 | pmid=: 19690757 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19690757  }} </ref><ref name="pmid27166383">{{cite journal| author=Brinjikji W, Duffy S, Burrows A, Hacke W, Liebeskind D, Majoie CB et al.| title=Correlation of imaging and histopathology of thrombi in acute ischemic stroke with etiology and outcome: a systematic review. | journal=J Neurointerv Surg | year= 2016 | volume= | issue=  | pages=  | pmid=27166383 | doi=10.1136/neurintsurg-2016-012391 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27166383  }} </ref><ref name="pmid24372222">{{cite journal| author=Sierra C| title=Essential hypertension, cerebral white matter pathology and ischemic stroke. | journal=Curr Med Chem | year= 2014 | volume= 21 | issue= 19 | pages= 2156-64 | pmid=24372222 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24372222  }} </ref><ref name="pmid15155970">{{cite journal| author=Price CJ, Menon DK, Peters AM, Ballinger JR, Barber RW, Balan KK et al.| title=Cerebral neutrophil recruitment, histology, and outcome in acute ischemic stroke: an imaging-based study. | journal=Stroke | year= 2004 | volume= 35 | issue= 7 | pages= 1659-64 | pmid=15155970 | doi=10.1161/01.STR.0000130592.71028.92 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15155970  }} </ref><ref name="pmid22712739" /><ref name="pmid10812160" />
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
! style="background: #4479BA; padding: 5px 5px;" rowspan=2 | {{fontcolor|#FFFFFF|Type of ischemia}}
! style="background: #4479BA; padding: 5px 5px;" colspan=4 | {{fontcolor|#FFFFFF|Pathogenesis}}
|-
! style="background: #4479BA; padding: 5px 5px;" | {{fontcolor|#FFFFFF|Underlying cause}}
! style="background: #4479BA; padding: 5px 5px;" | {{fontcolor|#FFFFFF|Part of the brain involved}}
! style="background: #4479BA; padding: 5px 5px;" | {{fontcolor|#FFFFFF|Time of initiation of cell death}}
! style="background: #4479BA; padding: 5px 5px;" | {{fontcolor|#FFFFFF|Type of cell death}}
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Focal<ref name="pmid8594224">{{cite journal| author=Siesjö BK, Katsura K, Zhao Q, Folbergrová J, Pahlmark K, Siesjö P et al.| title=Mechanisms of secondary brain damage in global and focal ischemia: a speculative synthesis. | journal=J Neurotrauma | year= 1995 | volume= 12 | issue= 5 | pages= 943-56 | pmid=8594224 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8594224 }} </ref>'''
! style="padding: 5px 5px; background: #F5F5F5;" |
Thrombosis<br>
Embolism
! style="padding: 5px 5px; background: #F5F5F5;" |
Focal area supplied by the occluded vessel
! style="padding: 5px 5px; background: #F5F5F5;" |
Acute onset (3-4 hrs)<br>
Cell death (12 hrs)
! style="padding: 5px 5px; background: #F5F5F5;" |
Necrosis-central area<br>
Apoptosis- Peripheral area
|-
| style="padding: 5px 5px; background: #F5F5F5;" | '''Global<ref name="pmid8594224">{{cite journal| author=Siesjö BK, Katsura K, Zhao Q, Folbergrová J, Pahlmark K, Siesjö P et al.| title=Mechanisms of secondary brain damage in global and focal ischemia: a speculative synthesis. | journal=J Neurotrauma | year= 1995 | volume= 12 | issue= 5 | pages= 943-56 | pmid=8594224 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8594224  }} </ref>'''
! style="padding: 5px 5px; background: #F5F5F5;" |
Systemic hypoperfusion
! style="padding: 5px 5px; background: #F5F5F5;" |
Water shed area <br>
Hippocampal pyramidal cells, cerebellar purkinjee cells, cortical laminar cells
! style="padding: 5px 5px; background: #F5F5F5;" |
Delayed onset (12 hrs)<br>
Cell death (days to weeks)
! style="padding: 5px 5px; background: #F5F5F5;" |
Apoptosis
|}
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.<ref name="pmid32584600">{{cite journal |vauthors=Chang JC |title=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 |journal=Clin Appl Thromb Hemost |volume=26 |issue= |pages=1076029620913634 |date=2020 |pmid=32584600 |pmc=7427029 |doi=10.1177/1076029620913634 |url=}}</ref><ref name="pmid8327124">{{cite journal |vauthors=Caplan LR |title=Brain embolism, revisited |journal=Neurology |volume=43 |issue=7 |pages=1281–7 |date=July 1993 |pmid=8327124 |doi=10.1212/wnl.43.7.1281 |url=}}</ref>


As oxygen or glucose becomes depleted in ischemic brain tissue, the production of [[high energy phosphate]] compounds such as adenosine triphosphate (ATP) fails leading to failure of energy dependent processes (such as ion pumping) necessary for tissue cell survival.  This sets off a series of interrelated events that result in cellular injury and death. A major cause of neuronal injury is release of the excitatory neurotransmitter glutamate. The concentration of glutamate outside the cells of the nervous system is normally kept low by so-called uptake carriers, which are powered by the concentration gradients of ions (mainly Na<sup>+</sup>) across the cell membrane. However, stroke cuts off the supply of oxygen and glucose which powers the ion pumps maintaining these gradients. As a result the transmembrane ion gradients run down, and glutamate transporters reverse their direction, releasing glutamate into the extracellular space.  Glutamate acts on receptors in nerve cells (especially NMDA receptors), producing an influx of calcium which activates enzymes that digest the cells' proteins, lipids and nuclear material. Calcium influx can also lead to the failure of [[mitochondria]], which can lead further toward energy depletion and may trigger cell death due to [[apoptosis]]. 
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


Ischaemia also induces production of [[Radical (chemistry)|oxygen free radicals]] and other [[reactive oxygen species]].  These react with and damage a number of cellular and extracellular elements.  Damage to the blood vessel lining or [[endothelium]] is particularly important. In fact,  many antioxidant neuroprotectants such as [[uric acid]] and [[NXY-059]] work at the level of the endothelium and not in the brain ''per se''. Free radicals also directly initiate elements of the [[apoptosis]] cascade by means of [[redox signaling]].
===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<ref name="pmid22712739">{{cite journal| author=Xing C, Arai K, Lo EH, Hommel M| title=Pathophysiologic cascades in ischemic stroke. | journal=Int J Stroke | year= 2012 | volume= 7 | issue= 5 | pages= 378-85 | pmid=22712739 | doi=10.1111/j.1747-4949.2012.00839.x | pmc=3985770 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22712739  }} </ref><ref name="pmid10812160">{{cite journal| author=del Zoppo GJ, Hallenbeck JM| title=Advances in the vascular pathophysiology of ischemic stroke. | journal=Thromb Res | year= 2000 | volume= 98 | issue= 3 | pages= 73-81 | pmid=10812160 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10812160  }} </ref>
*Cerebral auto regulation maintains the perfusion pressure in the brain between the pressure range of 60-150 mm Hg via [[vasoconstriction]] and [[vasodilatation]].<ref name="pmid10812160">{{cite journal| author=del Zoppo GJ, Hallenbeck JM| title=Advances in the vascular pathophysiology of ischemic stroke. | journal=Thromb Res | year= 2000 | volume= 98 | issue= 3 | pages= 73-81 | pmid=10812160 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10812160 }} </ref>
*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.


These processes are the same for any type of ischemic tissue and are referred to collectively as the ''ischemic cascade''. However, brain tissue is especially vulnerable to ischemia since it has little respiratory reserve and is completely dependent on [[aerobic metabolism]], unlike most other organs.
===Molecular pathophysiology in ischemic stroke===
The sequence of molecular changes that may result due to ischemia include:<ref name="pmid21266064">{{cite journal| author=Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV| title=Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. | journal=Mol Neurodegener | year= 2011 | volume= 6 | issue= 1 | pages= 11 | pmid=21266064 | doi=10.1186/1750-1326-6-11 | pmc=3037909 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21266064  }} </ref><ref name="pmid22712739">{{cite journal| author=Xing C, Arai K, Lo EH, Hommel M| title=Pathophysiologic cascades in ischemic stroke. | journal=Int J Stroke | year= 2012 | volume= 7 | issue= 5 | pages= 378-85 | pmid=22712739 | doi=10.1111/j.1747-4949.2012.00839.x | pmc=3985770 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22712739  }} </ref>
*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<ref name="pmid23469845">{{cite journal| author=Rodrigo R, Fernández-Gajardo R, Gutiérrez R, Matamala JM, Carrasco R, Miranda-Merchak A et al.| title=Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. | journal=CNS Neurol Disord Drug Targets | year= 2013 | volume= 12 | issue= 5 | pages= 698-714 | pmid=23469845 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23469845  }} </ref>
*Excitatory neurotransmitter -[[glutamate]] is increased in neuronal synapses leading to NMDA receptor activation<ref name="pmid10441299">{{cite journal| author=Dirnagl U, Iadecola C, Moskowitz MA| title=Pathobiology of ischaemic stroke: an integrated view. | journal=Trends Neurosci | year= 1999 | volume= 22 | issue= 9 | pages= 391-7 | pmid=10441299 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10441299  }} </ref><ref name="pmid22712739">{{cite journal| author=Xing C, Arai K, Lo EH, Hommel M| title=Pathophysiologic cascades in ischemic stroke. | journal=Int J Stroke | year= 2012 | volume= 7 | issue= 5 | pages= 378-85 | pmid=22712739 | doi=10.1111/j.1747-4949.2012.00839.x | pmc=3985770 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22712739  }} </ref>
*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.
*Release of [[proteases]] ([[matrix metalloproteinases]], MMP) due to cell membrane damage-ATP depletion + free radicals<ref name="pmid23469845">{{cite journal| author=Rodrigo R, Fernández-Gajardo R, Gutiérrez R, Matamala JM, Carrasco R, Miranda-Merchak A et al.| title=Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. | journal=CNS Neurol Disord Drug Targets | year= 2013 | volume= 12 | issue= 5 | pages= 698-714 | pmid=23469845 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23469845  }} </ref><ref name="pmid21266064">{{cite journal| author=Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV| title=Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. | journal=Mol Neurodegener | year= 2011 | volume= 6 | issue= 1 | pages= 11 | pmid=21266064 | doi=10.1186/1750-1326-6-11 | pmc=3037909 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21266064  }} </ref>
*MMP causes degradation of [[collagen]] and laminins in the [[basement membrane]] of the cells and blood vessels
*Disruption of [[Blood-brain barrier|blood brain barrier]] may lead to [[hemorrhage]]
*[[Cerebral edema]] due to increased Na+, Ca2+ and water influx into the cells.


Brain tissue survival can be improved to some extent if one or more of these processes is inhibited.  Drugs that scavenge [[Reactive oxygen species]], inhibit [[apoptosis]], or inhibit excitotoxic neurotransmitters, for example, have been shown experimentally to reduce tissue injury due to ischemia. Agents that work in this way are referred to as being ''neuroprotective''.  Until recently, human [[clinical trial]]s with neuroprotective agents have failed, with the probable exception of deep barbiturate coma.  However,  more recently  [[NXY-059]],  the disulfonyl derivative of the radical-scavenging spintrap phenylbutylnitrone, is [http://content.nejm.org/cgi/content/short/354/6/588 reported] be neuroprotective in stroke.  This agent appears to work at the level of the blood vessel lining or [[endothelium]]. Unfortunately, after producing favorable results in one large-scale clinical trial,  a second trial failed to show favorable results.
==Genetics==
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.<ref name="pmid30975520">{{cite journal |vauthors=Dichgans M, Pulit SL, Rosand J |title=Stroke genetics: discovery, biology, and clinical applications |journal=Lancet Neurol |volume=18 |issue=6 |pages=587–599 |date=June 2019 |pmid=30975520 |doi=10.1016/S1474-4422(19)30043-2 |url=}}</ref>


In addition to injurious effects on brain cells, ischemia and infarction can result in loss of structural integrity of brain tissue and blood vessels, partly through the release of matrix metalloproteases, which are zinc- and calcium-dependent enzymes that break down collagen, [[Hyaluronan|hyaluronic acid]], and other elements of [[connective tissue]].  Other proteases also contribute to this process.  The loss of vascular structural integrity results in a breakdown of the protective [[blood brain barrier]] that contributes to [[cerebral edema]], which can cause secondary progression of the brain injury.
The following gene loci may also increase the risk for stroke:
*PITX2 and ZFHX3- [[atrial fibrillation]] and cardio embolic stroke
*HDAC9- large vessel disease
*ABO- ischemic [[stroke]]


As is the case with any type of [[Traumatic brain injury|brain injury]], the [[immune system]] is activated by cerebral infarction and may under some circumstances exacerbate the injury caused by the infarction.  Inhibition of the [[Inflammation|inflammatory response]] has been shown experimentally to reduce tissue injury due to cerebral infarction, but this has not proved out in clinical studies.
==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'''<ref name="pmid18037922">{{cite journal| author=Moustafa RR, Baron JC| title=Pathophysiology of ischaemic stroke: insights from imaging, and implications for therapy and drug discovery. | journal=Br J Pharmacol | year= 2008 | volume= 153 Suppl 1 | issue= | pages= S44-54 | pmid=18037922 | doi=10.1038/sj.bjp.0707530 | pmc=2268043 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18037922  }} </ref>


Hemorrhagic strokes result in tissue injury by causing compression of tissue from an expanding [[hematoma]] or hematomas.  This can distort and injure tissue. In addition, the pressure may lead to a loss of blood supply to affected tissue with resulting infarction, and the blood released by brain hemorrhage appears to have direct toxic effects on brain tissue and vasculature.
==Microscopic pathology==
*Within 1-6 min of ischemia, red neurons and vacoulation results <ref name="pmid: 19690757">{{cite journal| author=Mărgăritescu O, Mogoantă L, Pirici I, Pirici D, Cernea D, Mărgăritescu C| title=Histopathological changes in acute ischemic stroke. | journal=Rom J Morphol Embryol | year= 2009 | volume= 50 | issue= 3 | pages= 327-39 | pmid=: 19690757 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19690757 }} </ref>
*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: <ref name="pmid: 19690757">{{cite journal| author=Mărgăritescu O, Mogoantă L, Pirici I, Pirici D, Cernea D, Mărgăritescu C| title=Histopathological changes in acute ischemic stroke. | journal=Rom J Morphol Embryol | year= 2009 | volume= 50 | issue= 3 | pages= 327-39 | pmid=: 19690757 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19690757  }} </ref><ref name="caplan">{{cite journal | author=  Caplan LR | title=  Intracerebral hemorrhage | journal=  Lancet | year=1992 | pages=656-8 | volume=339 | issue=8794 | id=PMID 1347346}}</ref>
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Duration}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Gross pathology}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Microscopic pathology<ref name="pmid: 19690757">{{cite journal| author=Mărgăritescu O, Mogoantă L, Pirici I, Pirici D, Cernea D, Mărgăritescu C| title=Histopathological changes in acute ischemic stroke. | journal=Rom J Morphol Embryol | year= 2009 | volume= 50 | issue= 3 | pages= 327-39 | pmid=: 19690757 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19690757  }} </ref>}}
 
|-
| style="padding: 5px 5px; background: #DCDCDC;" |Immediate
<24 hrs
| style="padding: 5px 5px; background: #F5F5F5;" |No change
| style="padding: 5px 5px; background: #F5F5F5;" |Cellular edema
|-
| style="padding: 5px 5px; background: #DCDCDC;" |Acute
<1 week
| style="padding: 5px 5px; background: #F5F5F5;" |Edema
 
Loss of grey and white matter junction
| style="padding: 5px 5px; background: #F5F5F5;" |Red neurons
 
Necrosis
 
Neutrophilia<ref name="pmid15155970">{{cite journal| author=Price CJ, Menon DK, Peters AM, Ballinger JR, Barber RW, Balan KK et al.| title=Cerebral neutrophil recruitment, histology, and outcome in acute ischemic stroke: an imaging-based study. | journal=Stroke | year= 2004 | volume= 35 | issue= 7 | pages= 1659-64 | pmid=15155970 | doi=10.1161/01.STR.0000130592.71028.92 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15155970  }} </ref>
|-
| style="padding: 5px 5px; background: #DCDCDC;" |Subacute
1-4 weeks
| style="padding: 5px 5px; background: #F5F5F5;" |Soft friable tissue
 
Cyst formation
 
| style="padding: 5px 5px; background: #F5F5F5;" |Macrophages
 
Liquifactive necrosis
|-
| style="padding: 5px 5px; background: #DCDCDC;" |Chronic
>4 weeks
| style="padding: 5px 5px; background: #F5F5F5;" |Fibrosis
 
Fluid filled cysts with dark grey margin
 
| style="padding: 5px 5px; background: #F5F5F5;" |Gliosis
 
Necrotic tissue cleared by macrophages
|-
|}


==References==
==References==
{{reflist|2}}
{{reflist|2}}


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Latest revision as of 04:59, 30 August 2023

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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]

Overview

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.

Pathophysiology

Physiology

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.

Pathogenesis

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[12]

Thrombosis
Embolism

Focal area supplied by the occluded vessel

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

Necrosis-central area
Apoptosis- Peripheral area

Global[12]

Systemic hypoperfusion

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

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

Apoptosis

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:

Pathologies affecting large intracranial vessels include:

Embolic strokes are divided into four categories:

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.

Genetics

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]
Immediate

<24 hrs

No change Cellular edema
Acute

<1 week

Edema

Loss of grey and white matter junction

Red neurons

Necrosis

Neutrophilia[16]

Subacute

1-4 weeks

Soft friable tissue

Cyst formation

Macrophages

Liquifactive necrosis

Chronic

>4 weeks

Fibrosis

Fluid filled cysts with dark grey margin

Gliosis

Necrotic tissue cleared by macrophages

References

  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.


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