Etiopathogenesis of stroke

STROKE

1. ETIOPATHOGENESIS OF SROKE Dr Srija Inuri PG Registrar

2. Definition Stroke refers to any damage to the brain or the spinal cord caused by an abnormality of the blood supply. (Caplan-texbook of stroke) Stroke is defined as an  "acute neurological dysfunction of vascular origin with sudden(within seconds) or atleast rapid(with in hours) occurrence of symptoms and signs corresponding to involvement of focal areas in the brain" (Goldstein, Barnet et al, 1989)

3. Epidemiology Stroke (including ischaemic stroke and haemorrhagic stroke) affects 13.7 million people globally per year and is the second leading cause of death, with 5.5 million deaths per year An estimated 1 in 4 adults will experience a stroke in their lifetime  The estimate includes an almost equal risk of stroke among women and men in Global Burden of Disease Study 2016.

4. PATHOLOGY OF STROKE two major categories (1) ischemia, which is a lack of blood flow depriving brain tissue of needed fuel and oxygen;  thrombosis, embolism, and decreased systemic perfusion (2) hemorrhage, which is the release of blood into the brain and into extravascular spaces within the cranium.

5. Ischemic stroke Thrombotic stroke (large vessel and small vessel types) Embolic stroke (with/without known cardiac and/or arterial factor) Systemic hypoperfusion (Watershed or Border Zone stroke)

6. Hemorrhagic stroke   Intracerebral   Subarachnoid   Subdural   Epidural

7. Thrombosis-Large vessel disease Atherosclerosis affects chiefly large arteries Less common causes include primary hematologic problem fibromuscular dysplasia arteritis, dissection of the vessel.

8. Small Vessel Disease Thrombotic occlusion of the small penetrating arteries 20% to 30% of all ischemic strokes.  Strongly associated with hypertension Characterized pathologically by  lipohyalinosis ,  microatheroma ,  fibrinoid necrosis, 

9. Embolism In embolism, material formed elsewhere within the vascular system lodges in an artery and blocks blood flow. Two main sources Cardiac Artery-artery Paradoxical emboli

10. Decreased Systemic Perfusion Diminished flow to brain tissue cardiac pump failure (most often due to myocardial infarction or arrhythmia)  systemic hypotension (due to blood loss or hypovolemia). Responsible for watershed infarcts.

11. Subarachnoid Hemorrhage originates from  aneurysms arteriovenous malformations,  bleeding diatheses or  Trauma Ischemia is because of increasing intracranial pressure Vasoconstriction-blood within the subarachnoid space often contains substances that promote vasoconstriction of the basal arteries that are bathed in cerebrospinal fl uid.

12. Intracerebral Hemorrhage/Parenchymal Hge bleeding directly into the brain substance. Hypertension Bleeding diatheses, especially from Iatrogenic prescription of anticoagulants or Trauma,  vascular malformations,and vasculopathies(such as cerebral amyloid angiopathy), Intracerebral hemorrhages are at first soft and dissect along white matter fiber tracts.When bleeding dissects into the ventricles or onto the surface of the brain, blood is introduced into the cerebrospinal fluid may hamper CSF absorption leading to communicating hydrocephalus.

13. Subdural and Epidural Hemorrhages almost always caused by head trauma. Subdural hemorrhages arise from injured veins. Bleeding is most often slow and accumulates during days, weeks, and even a few months. Epidural hemorrhages are caused by tearing of meningeal arteries, most often the middle meningeal artery. Blood accumulates rapidly over minutes to hours Both  cause symptoms and signs by compressing brain tissue and increasing intracranial pressure

14. Normal Metabolism and Blood Flow Brain uses about one quarter of the body’s energy supply. Brain cells depend mainly on oxygen and glucose (sole substrate for energy metabolism) to survive. Glucose is oxidized to carbondioxide (CO2) and water (H2O)-ATP To keep the major extracellular cations Ca (calcium ions) and Na (sodium ions) outside the cells and the intracellular cation K (potassium ions) within the cells. uses approximately 500 mL of oxygen and 75 to 100 mg of glucose each minute, a total of 125 g of glucose each day

15. Cerebral Blood Flow Brain constituttes for 2% of adult body weight,uses 20% of cardiac output in resting state. Normal cerebral blood flow (CBF) is approximately 50-to 60 ml/100g/ Min. In response to ischemia, the cerebral autoregulatory mechanisms compensate for a reduction in CBF.

16. Autoregulation The capacity of the cerebral circulation to maintain relatively constant levels of CBF despite changing blood pressure .  (80–150mmHg) The range of autoregulation is shifted to the right, i.e. to higher values, in patients with hypertension and to the left during hypercarbia.

17. Autoregulatory mechanisms The myogenic theory of autoregulation: changes in vessel diameter caused by the direct effect of blood pressure variations on the myogenic tone of vessel walls. 1. By local vasodilatation 2. Opening the collaterals 3. Increasing the extraction of oxygen and glucose from the blood

18. Development of permanent neurologic sequelae is a time dependent process ; for any given blood flow level, low CBF values are tolerated only for a short period

19. Schematic drawing of the different cerebral blood flow thresholds in man. Between CBF values of 22 mL/100 mg/min to 8 mL/100 mg/min, brain tissue maintains its structural integrity and, most importantly, can be salvaged with reperfusion.

20. Ischemic stroke

21.   Ischemic core/penumbra Ischemic core - irreversibly damaged tissue The ischemic penumbra represents tissue that is functionally impaired but structurally intact and, as such, potentially salvageable. Salvaging this tissue by restoring its flow to nonischemic levels is the aim of acute stroke therapy.

22. Area of oligemia - represents mildly hypoperfused tissue from the normal range down to around 22 mL /100 mg/min. Usually not at risk of infarction In hypotension, fever, or acidosis, oligemic tissue can be incorporated into penumbra and subsequently undergo infarction.

23. IMPAIRED PERFUSION >3 MINUTES – DECREASE IN ATP MITOCHONDRIA – LOSS OF INCOMING OXYGEN ANAEROBIC GLYCOLYSIS RELEASE OF OXYGEN FREE RADICALS ACCUMULATION OF LACTIC ACID INFLAMMATION DAMAGE TO BLOOD BRAIN BARRIER EDEMA

24. Thrombus formation three types of thrombi Red thrombi are composed mostly of red blood cells and fi brin, and they form in areas of slowed blood flow. White thrombi, in contrast, are composed of platelets and fibrin exclusively in areas in which the arterial wall or endothelial surface is abnormal Disseminated fi brin deposition in smallvessels

25. Effects at cellular level

26. Excitotoxicity Excitotoxicity is the pathological process by which neurons are damaged by the overstimulation of receptors by the excitatory neurotransmitter glutamate, such as the NMDA receptor and AMPA receptor.       Doble A. The Role of Excitotoxicity in Neurodegenerative Disease: Implications for Therapy. Pharmacol Ther. 1999; 81(3): 163-221.

27. Excitotoxicity Excitotoxicity is the pathological process by which neurons are damaged and killed by the overreactions of receptors for the excitatory neurotransmitter glutamate, such as the NMDA receptor and AMPA receptor. Doble A. The Role of Excitotoxicity in Neurodegenerative Disease: Implications for Therapy. Pharmacol Ther. 1999; 81(3): 163-221.

28. Classic pathway

29. In the ischemic zone, the glutamate binds to postsynaptic receptors which triggers increased calcium influx through glutamate receptor-coupled ion channels.

30. Glutamate overstimulates -N-methyl-D-aspartate (NMDA) -alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) and -kainite-type glutamate receptors Results in sodium influx and potassium efflux through the glutamate receptor activated membrane channels.

31. NMDA channels are highly permeable to calcium and contribute to the influx of calcium into the cell. The influx of calcium from the extracellular fluid is thought to be the primary factor in calcium contributory mechanisms of cell death after ischemic stroke

32. Lo E, Dalkara T, Moskowitz M. Mechanisms, challenges and opportunities in stroke. Nature Reviews. 2003; 4: 399-415

33. Increased calcium levels in the cytosol Increased activation of calcium-dependent synthases and proteases Degradation of cytoskeletal and enzymatic proteins Increased levels of nitric oxide and peroxynitrite within the cell through activation of degrading enzymes such as phospholipase , proteases and endonucleases .

34. The potassium efflux through the NMDA channels and other ion imbalances can increase caspase activity, triggering apoptosis. The primary caspases responsible for apoptosis due to ischemic stroke are caspases 9 and 3. Caspase 9 activates caspase 3. Caspase 3 degrade substrate proteins within the cell and produce internucleosomal endonuclease activity and DNA fragmentation.

35. Oxidative stress A potential pathway for cellular damage in ischemic stroke may be the occurence of oxidative stress, which is the increased occurrence of reactive oxygen species (ROS) above physiological levels. Free radicals can cause membrane damage through peroxidation of unsaturated fatty acids in the phospholipids making up the cell membrane

36. Image retrieved from http://journals.prous.com/journals/dot/20033901/html/dt390019/images/Kulkarni_f4.gif

37. Apoptosis Apoptosis is a form of programmed cell death, which involves : Shrinkage of the cell cytoplasm Cleavage of DNA within the nucleus Condensation of chromatin in the nucleus Formation of apoptotic bodies, Cell death

38. Mechanisms

39. Mitochondria mediated  Translocation of pro-apoptotic Bcl-2 members like Bax into the mitochondria, a cascade of events are triggered . This leads to mitochondria releasing substances such as cytochrome c, procaspase-9, and Apaf-1 from its intermembrane space . Lotocki G and Keane R. Inhibitors of Apoptosis Proteins in Injury and Disease. Life. 2002; 54: 231-240

40. Endoplasmic reticulum The ER initiates unfolded protein response (UPR) . During this UPR, three ER transmembrane effector proteins are activated (PERK, IRE1, and ATF-6). IRE1 has been shown to be involved in the activation of caspase-12 . Nakka VP, Gusain A, Mehta SH, Raghubir R. Molecular mechanisms of apoptosis in cerebral ischemia: multiple neuroprotective opportunities. Mol Neurobiol. 2008; 37:7-38

41. Extrinsic mechanisms Death receptors are tumor necrosis factor receptors (TNFR) and include TNFR-1, Fas , and p75 . A transcription factor, Forkhead1, stimulates the expression of genes including Fas ligand ( FasL ). FasL initiates apoptosis by binding to the Fas receptor and recruiting the Fas -associated death domain protein (FADD)

42. Factors Affecting Tissue Survival (1) the adequacy of collateral circulation, (2) the state of the systemic circulation, (3) serologic factors, (4) changes within the obstructing vascular lesion, and (5) resistance within the microcirculatory bed

43. Conclusions The local and systemic effects that occur after a stroke, such as the immune response and excitotoxicity , have lasting effects on the amount of function and independence a person can regain after a stroke. It is paramount to understand the cell biology mechanics that occur prior to and following a stroke in order to mount the most effective response and diminish the subsequent injury to the brain and body following the initial insult.

44.                                         THANK YOU

45. References Text book of stroke-Caplan Ischemic stroke: Pathopysiology and principles of localisation , Neurology board review manual: Mathew Brandon Mass, Joseph E Safdieh . Pathophysiology , treatment, and animal and cellular models of human  ischemicstroke Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV.Mol Neurodegener . 2011 Jan 25;6(1):11. doi : 10.1186/1750-1326-6-11.