Cerebrovascular Disease

1. Cerebrovascular Disease October 22, 2010 Roberta Seidman, M.D.

2. Contents of this lecture General features of energy metabolism of the brain General concepts of ischemic injury Global hypoperfusion Overview / review of the blood supply of the brain Relevance of vascular anatomy to pathophysiology Focal infarction Intracranial Hemorrhage

3. Your focus Understand the general features of energy metabolism of the brain, the concept of selective vulnerability and the concept of excitotoxicity Understand what is a stroke (Understand the clinical presentation of stroke- Dr. Guido) Know the general types of strokes and their major underlying pathophysiological processes Understand the important relationship between vascular anatomy and the cause of stroke Understand the evolution of reactive changes in the brain following a stroke

4. Delivery of oxygen and glucose to the brain Under normal circumstances, brain uses only glucose for fuel Oxygen is needed for its metabolism Perfusing the Brain Ventilation and circulation are required Cerebral perfusion pressure = mean arterial pressure �intracranial pressure

5. Cerebral autoregulation Within certain limits, regardless of mean arterial pressure, cerebral blood flow is maintained at a constant level

6. Just for numbers people Requirements of brain (per 100 gm) Every minute, 50 ml blood delivered 25mmol glucose extracted 150 mmol of O2 for oxidation

7. Blood flow requirements of brain

8. More blood flow in gray matter than white matter- the picture shows the blood vessels in cerebral cortex and subcortical white matter Vessels branch until RBC�s pass single file in capillaries Average Cerebral Blood Flow = 50ml/100gm/minute Grey matter flow 80ml/100 gm/minute White matter flow 20-25 ml/100gm/minute (about 750 ml per whole brain) No need to memorize the numbers

9. Cerebral blood flow- local autoregulation CBF is coupled to metabolism = Brain areas that are active have more blood flow = Local autoregulation; factors that mediate this are not known. Possible candidates: ?pH ?Adenosine ?Nitric oxide

10. Delivery of glucose to the brain- 1) from blood vessels to neurons 2) from blood vessels to astroctyes

11. Brain energy metabolism Glycolysis- in glia Glucose to pyruvate or lactate Some through Pentose Phosphate shunt- forms NADPH- for regenerating glutathione- increased in oxidative stress To neurons Then to TCA cycle as acetyl CoA- complete metabolism requires oxygen

12. Glucose- the primary fuel of the brain Infant brain can use lactate- ability disappears with brain maturation and inability of lactate to enter brain Starvation- brain utilizes ketone bodies, which circulate at elevated levels Hypoglycemia- brain utilizes ketone bodies can also use endogenous substrates formed from breakdown of brain tissue

13. Effects of hypoglycemia Energy failure Reduced glycolysis Catabolism of protein and lipid Slower turning of Krebs cycle Decreased formation of acetyl CoA results in tissue buildup of oxaloacetate (OAA normally combines with acetyl CoA to form citrate) Oxaloacetate + glutamate Aspartate + a- Ketoglutarate This results in excess aspartate, which causes excitotoxicity through NMDA receptor activation Blocked by NMDA receptor antagonists

14. Ischemia Global Affects entire brain Usually due to a process occurring outside the brain Focal Affects only a limited geographic region of brain

15. Effects of Ischemia Glucose and Oxygen not delivered Energy failure = Na-K pump failure ATP is hydrolyzed = drop in pH Metabolic waste is not removed Nitric oxide, produced by neurons, glial and inflammatory cells responding to ischemic injury, contributes to neuronal damage by acting as a free radical Excitotoxicity occurs The result is NECROSIS Less severe ischemia: selective neuronal necrosis More severe ischemia: infarction

16. Effects of ischemia- Modulating factors Duration of ischemia Under usual conditions, neurons can survive 4 minutes when perfusion ceases Consciousness is lost in 10 seconds Degree of ischemia Brain temperature- Hypothermia is protective (decreases metabolic demands, decreases free radicals) Blood glucose Hypoglycemia is protective Hyperglycemia results in excess lactate and acidosis Experiments in which glycolysis is blocked show decreased damage from ischemia

17. Effects of Ischemia Selective Neuronal Necrosis Due to EXCITOTOXICITY Neurons are more vulnerable to ischemia than other tissue elements Glutamate, released in ischemia, causes overwhelming influx of calcium into dendrites, resulting in neuronal death = excitotoxicity

20. Selective vulnerability in Global IschemiaAn insult is given to the entire brain, but only restricted regions show damage Vulnerable areas CA1 region of the hippocampal formation Purkinje cells of the cerebellum Globus Pallidus Layers 3 and 5 of the cerebral cortex Due to specific properties of the neurons in those zones Some proposed explanations CA 1 region of hippocampus has abundant NMDA receptors Other areas have loss of GABAergic neurons Cerebellar Purkinje cells have AMPA receptors, which allow for calcium influx

21. Some neurons that are particularly vulnerable to hypoxic-ischemic insults

22. Take home messages Global ischemia can cause neuronal necrosis or infarction Certain populations of neurons are most vulnerable There are modulating factors that determine the effect of ischemia Severity Duration Body temperature Glucose level

23. Cerebrovascular disease Stroke- �rapidly developing clinical signs of focal (at times global) disturbance of cerebral function, lasting more than 24 hours or leading to death with no apparent cause other than that of vascular origin� (WHO) Is stroke common?

24. Clinical presentation Sudden Note: other disorders can present suddenly Neurological signs and symptoms reflect the region of the brain affected Later, secondary changes can occur, which will alter the clinical signs Herniation due to swelling Herniation is when brain shifts from one intracranial compartment to another because of mass effect Vasospasm due to the presence of blood Other complications

25. Types of vascular events Global Drop in systemic perfusion pressure causes necrosis in one of a variety of expected patterns Focal Infarction- Lack of blood flow through a vessel results in death of tissue supplied by that vessel Neurons die after 4 minutes without arterial supply Hemorrhage- A vessel ruptures or leaks- bleeding is the first event Outside the brain Inside the brain

26. Functional Neuroanatomy- Localization of the lesion is important because it tells you which vessel is affected

27. The anatomy of the affected vessel provides information about the cause of the infarct

28. Anatomy of blood vessels is related to the most likely cause of a stroke Superficial vessels- emboli Deep penetrating vessels (D)- affected by hypertension Watershed zones (W) = border zones between territories supplied by two arteries- vulnerable to hypotension

29. The cause of the infarct determines the treatment.

30. Arterial supply of the brain Anterior circulation- from Internal Carotids Posterior circulation- from Vertebrals Circle of Willis- connects them

32. Medial surface- anterior cerebral artery

33. Middle Cerebral Artery

37. Medial surface- posterior cerebral artery

38. Blood supply of the brainstem Midbrain- Posterior cerebral arteries Pons- Basilar artery Medulla Vertebral arteries

39. Arterial supply of the brain

40. Variability of the Circle of Willis:Anomaly occurs in 50% of circles

41. Variability in Circle of Willis leads to Variable clinical effect of occlusion of the right internal carotid artery-

42. Veins of the Brain They do not run with the arteries They drain into the dural venous sinuses

43. Veins of the brain The dural sinuses

44. Focal infarction

45. Causes of Focal Infarction Atherosclerotic plaque Thrombosis Plaque itself occludes vessel Hemorrhage into plaque Embolism From atherosclerotic plaque From thrombus From heart Other- bone marrow embolus, air embolus Arteriosclerosis, usually due to hypertension Watershed infarction - focal infarction that results from global drop in perfusion pressure

46. Less common causes of focal infarction Thrombosis due to clotting disorder Vasospasm due to irritation of a vessel Amyloid deposition in blood vessels Compression of vessel when there is herniation Others

47. Atherosclerosis

48. Atherosclerotic plaqueCarotid atherosclerosis, stenosis and thrombosis

49. Atherosclerotic plaque Carotid atherosclerosis and thrombosis

50. Atherosclerotic plaque Acute Infarction ICA territory- the left cerebral hemisphere is swollen- notice the left-right shift of brain parenchyma and compression of left lateral ventricle

51. Atherosclerotic plaque Basilar artery thrombosis

53. Where we have been and where we are going General principles of hypoxic and ischemic injury TYPES OF VASCULAR EVENTS Global- drop in systemic perfusion pressure Focal Infarction- Lack of blood flow through a vessel results in death of tissue supplied by that vessel Atherosclerotic plaque Thrombosis Plaque itself occludes vessel Hemorrhage into plaque Embolism From atherosclerotic plaque From thrombus From heart Other- bone marrow embolus, air embolus Arteriosclerosis, usually due to hypertension Watershed infarction - focal infarction that results from global drop in perfusion pressure Hemorrhage- A vessel ruptures or leaks- bleeding is the first event

54. Embolism

55. Causes of Focal Infarction Atherosclerotic plaque Thrombosis Plaque itself occludes vessel Hemorrhage into plaque Embolism From atherosclerotic plaque From thrombus From heart Other- bone marrow embolus, air embolus Arteriosclerosis, usually due to hypertension Watershed infarction - focal infarction that results from global drop in perfusion pressure

56. EmbolismAtheroembolus- The wall of the artery is intact; the lumen contains material with cholesterol clefts from a piece of atherosclerotic plaque that broke off and entered the circulation.

57. Embolism Embolism of thrombus- the artery wall is intact; the lumen is occluded by platelet-fibrin thrombus

58. EmbolismThe Heart is a common source of embolic material

59. Embolism from cardiac valve:Non-bacterial thrombotic endocarditis

60. Embolism Infective endocarditis

61. Embolism from mural thrombus following myocardial infarction

62. Left atrial thrombus in left atrial appendage (LAA) as source of an embolus-seen in an echocardiogram

63. Acute Infarction MCA territory

64. Hemorrhagic Infarction First, there is occlusion of a vessel Then there is reperfusion into infarcted (dead) tissue The vessels are leaky, so this results in hemorrhage This hemorrhagic infarct could be due to the following: Embolus to a branch of the MCA causing infarction Lysis of thromboembolus Reperfusion with hemorrhage into infarcted (dead) tissue Or reperfusion from anastomotic collateral blood vessels

65. Arteriosclerosis- most often a result of hypertension

66. Hypertension Causes arteriopathy of deep penetrating arteries, like the lenticulo-striate arteries Small arteries and arterioles are typically affected by hypertension Infarction in Basal ganglia / thalamus Pons Cerebellum

67. Arteriosclerosis in hypertension � wall is thickened (but weak)

68. Multiple infarcts (seen as cavities) in the basal ganglia, due to hypertension

69. Infarct in left pontine base, due to hypertension

70. ????-

71. Evolution of gross changes after vascular occlusion Immediately- Over first three days- Around 1 week- Eventually-

72. Acute infarct- several hours to one day old

73. Acute infarct- about 1 - 2 days old- greater degree of swelling than previous case

74. Subacute infarct- the intact brain is separating from the infarcted area- starts at about 1 week; this example is estimated at about 2 weeks old

75. Old infarct- eventually it becomes a cavity

76. Evolution of histological changes Immediately- nothing Approximately 6-12 hours- red neurons Then cell shrinkage, edema 18 � 24 hours- neutrophils migrate in 24 hours � weeks (months)- macrophages Astrocytes form the scar

77. �Red neurons�- cytoplasm is red

78. Neutrophils in infarct- 18 � 24 hours

82. Old infarct- a cavity; a small number of macrophages remain probably forever

83. Intracranial Hemorrhage Outside the brain (Traumatic epidural / subdural hemorrhage) Subarachnoid hemorrhage (Trauma) Berry (saccular) aneurysm Arteriovenous malformation, other vascular malformations Within the brain Hypertensive hemorrhage Amyloid angiopathy Arteriovenous malformation, other vascular malformations Bleeding disorder (Trauma)

84. Effect of Hemorrhage on Brain Action of blood as a mass Direct tissue disruption with destruction Tissue destruction by compression Increased intracranial pressure Action of blood as an irritant Vasospasm

86. Saccular aneurysm- arising from anterior communicating artery

87. Subarachnoid hemorrhage- post-mortem angiogram shows an aneurysm of the anterior communicating artery

88. Hemorrhage within the Brain Hypertension Vascular malformation Amyloid angiopathy Coagulopathy Tumor

89. Hypertensive hemorrhage Basal ganglia Pons Cerebellum (Follows the distribution of Charcot � Bouchard microaneurysms)

90. Hypertensive hemorrhage

91. Acute Hypertensive hemorrhage � Basal ganglia

92. Subacute BG hemorrhage

93. Old hemorrhage � Basal ganglia

94. Hypertensive hemorrhage - pons

95. If there is survival, the flow of CSF is blocked Hydrocephalus develops Increased intracranial pressure results

96. Cerebellar hemorrhage- a surgical emergency

97. Sclerotic arteries have weakened walls

98. Microaneurysms in hypertension- outpouchings of wall of arteriole(Charcot-Bouchard microaneurysms)

99. Amyloid Angiopathy-Lobar Hemorrhage

100. Amyloid angiopathy Immunohistochemistry for A-beta (amyloid)- the brown staining indicates that amyloid is present H&E

101. Vascular malformations- Cavernous angioma

103. Arteriovenous malformation

104. Hemorrhage in coagulopathy- randomly distributed hemorrhages

105. Herniation of the cerebrum can cause secondary hemorrhage in the brainstem

106. Hemorrhage due to herniation (Duret hemorrhage)

107. Summary - Stroke Neurological event on a vascular basis Clinical presentation- sudden onset Infarction Atherosclerosis Thrombosis Embolism Hemorrhage Outside the brain Subarachnoid hemorrhage Inside the brain Hypertensive Hemorrhage Treatment is determined by the cause Remember the veins- They are vessels, too