A detailed lecture on stroke epidemiology, pathophysiology, clinical presentation, latest treatment strategies.

1. STROKE ARLYN M. VALENCIA , M.D. Associate Professor, UNSOM Diplomate, American Board Of Psychiatry & Neurology

3. LEARNING OBJECTIVES To be able to define stroke, discuss its pathophysiology and risk factors To emphasize early evaluation and management of stroke patients To discuss the latest stroke treatment strategies CASE STUDIES: To be able to analyze clinical situations, localize the stroke lesion, determine probable etiology

4. ”THE BRAIN IS A VERY UNIQUE, HIGH-MAINTENANCE END- ORGAN. IT IS VERY DEPENDENT ON MOMENT-TO-MOMENT SUPPLY OF GLUCOSE AND OXYGEN TO SUSTAIN ITS HIGH-POWERED ACTIVITIES. IT IS VERY SENSITIVE TO THE SYSTEMIC STATE. ANY SEVERE MEDICAL INSULT, THEREBY, HAS TREMENDOUS IMPACT ON THE BRAIN METABOLISM. ANY MEDICAL EMERGENCY IS A NEUROLOGIC EMERGENCY!” A. Valencia, M.D.

5. The biology of stroke is such that each moment of ischemia and tissue injury increases the degree of irreversible tissue damage.

6. CEREBROVASCULAR ACCIDENT OR “BRAIN ATTACK” Third leading cause of death 750, 000 cases/year Leading cause of significant disability Cost: $40 billion/year

7. Major Causes of Death in the United Sates, 1995

8. Annual Economic Costs of Stroke (All Types) In The US

9. Death Rates for Stroke per 100,000 Population

10. Types of Stroke Ischemic, 80% - thrombosis, 50% (small & large-vessel) - embolism, 30% [now believed significantly higher] Hemorrhagic, 20% - intracerebral (HTN as risk) - subarachnoid (aneurysm)

11. Stroke vs. TIA Transient ischemic attack (TIA): A clinical syndrome characterized by an acute loss of focal brain or monocular function with symptoms lasting less than 24 hrs and which is thought to be due to inadequate cerebral or ocular blood supply, without ischemic changes in Diffusion Weighted Imaging (DWI) Stroke: Clinical syndrome characterized by an acute loss of focal brain or monocular function with symptoms lasting greater than 24 hrs and which is thought to be due to inadequate cerebral or ocular blood supply.

12. Risk Factors for Stroke That Cannot Be Changed Increased age Being male Race (e.g., African-Americans) Diabetes mellitus Prior stroke/transient ischemic attacks Family history of stroke Asymptomatic carotid bruit

13. Up to approximately 30% of people who suffer transient attacks (TIAs) will develop a stroke within 5 years.

14. Relative Incidence of Atherothrombotic Stroke and MI by Age and Gender

16. Death Rates for Stroke per 100,000 PopulationGroups Defined by Race, Age, and Gender: 1993

17. Risk Factor For Stroke: Treatable Major Hypertension Heart disease, esp. atrial fibrillation Cigarette smoking Transient ischemic attacks Dyslipidemia Physical inactivity Obesity Less Well Documented Excessive alcohol intake / drug abuse Acute infection*

18. Alcohol Consumption as a Risk Factor for Stroke Heavy alcohol consumption may increase risk of stroke by a number of mechanisms. The reported effects of alcohol consumption on risk of ischemic stroke have been inconsistent. A differential effect of alcohol consumption on stroke risk in men compared to women has been observed.

19. Alcohol Consumption as a Risk Factor for Stroke Light and moderate alcohol use tend to raise levels of high-density-lipoprotein (HDL) -- the "good" lipoprotein. Heavy drinking or binge drinking, is related to an increased incidence of stroke as a cause of death Light or moderate alcohol consumption, is related to a reduced risk of coronary heart disease. There is positive, dose-related effect of alcohol consumption on risk of intracranial hemorrhage, both arachnoid and intracerebral .

20. Less Well Documented Geography/climate Socieconomic factors

21. The Stroke Belt

22. Potential Genetic Risk Factors for Stroke Apolipoprotein E4 Elevated homocysteine levels Factor V mutation

24. Focal plaques: eccentric thickening at bifurcations; addition of massive extracellular lipids that displaced normal cells and matrix

26. Role of Monocytes and T-Lymphocytes in the Transformation to Foam Cells

27. Oxidation of LDL-Cholesterol

28. Oxidized LDL-cholesterol Contributes To Atherogenesis In Three Other Ways: It has cytotoxic properties that may promote endothelial injury; It acts as a chemoattractant for circulating monocytes, leading to their increased accumulation with plaques; and Inhibits egress of macrophages from plaques.

29. Smooth Muscle Cell Migration and Proliferation

30. Smooth Muscle Cell Migration and Proliferation Along with macrophages, smooth-muscle cells proliferate in the intima during atherogenesis. Smooth muscle cell layer makes up a substantial bulk of the atherosclerotic lesion, which may rise several millimeters above the surface of the surrounding intima

31. Role of Platelets Platelet adhesion may be promoted by type II injury and by toxic products Platelets release growth factors that stimulate SM migration and proliferation and formation of “fibrointimal lesions” and the outside capsule of “fatty lesions

32. Plaque Fissuring and Formation of Platelet Thrombus The vulnerability of such a structure to fissuring appears to be related to circumferential stress on the plaque cap in systole, as well as infiltration of the cap tissue with foam cells (with reduction of total collagen content and a concomitant fall in tensile strength)

33. Potential Outcomes of Plaque Fissuring Acute episodes of transient ischemia and ischemic stroke (as well as myocardial infarction, unstable angina, as sudden death) may be precipitated by thrombosis on atherosclerotic plaques.

34. Thrombus Formation I -- Platelet Activation On contact with collagen, platelets become activated, with platelet adhesion, secretion of platelet contents, and platelet aggregation at the site of injury. The activated platelet surface is an essential catalytic surface for several coagulation reactions that generate thrombin, a key factor in the coagulation sequence

35. Thrombus Formation II -- Platelet Activation and Blood Flow

36. Thrombus Formation III -- Activation of Coagulation Cascade

38. Evolution of Cerebral Atherothrombosis

39. Atherothromboticocclusion of larger arteries Embolism: Artery-to artrey, cardiogenic Primary small vessel disease (lipohyalinosis)

40. Thromboembolism

41. Cardiogenic Emboli Cardiogenic emboli lodge in the middle cerebral artery or its branches in 80% of cases, in the posterior cerebral artery or its branches 10% of the time, and in the vertebral artery or its branches in the remaining 10% of cases.

42. Major Blood Vessels Of The Brain

43. Major Blood Vessels Of The Brain

44. Control Centers of the Brain

46. Cellular Injury During IschemiaNeuronal Function: Importance of Oxygen and Glucose The transient change in voltage induced by the action potential is determined by the concentration of ions on either side of the cell membrane. Maintaining these ionic gradients is an energy-consuming process that requires a constant supply of glucose and oxygen to the neuron.

47. Cellular Changes As Ischemia Progresses The duration, severity, and location of focal cerebral ischemia determine the extent of brain function and thus the severity of stroke

48. Cellular Injury During IschemiaInadequate Energy Supply Lack of glucose and oxygen deplete the cellular energy stores required to maintain electrical potentials and ion gradients. The membrane that surrounds each affected neuron becomes "leaky," and the cell loses potassium and adenosine triphosphate (ATP), the tissue's medium for energy exchange

49. THE ISCHEMIC PENUMBRA

51. Stroke Warning Signs Sudden weakness, paralysis, or numbness of the face, arm and the leg on one or both sides of the body Loss of speech, or difficulty speaking or understanding speech Dimness or loss of vision, particularly in only one eye Unexplained dizziness (especially when associated with other neurologic symptoms), unsteadiness, or sudden falls Sudden severe headache and/or loss of consciousness

52. Left & Right HemisphericStroke: Common Patterns Middle Cerebral Artery (MCA): supplies the lateral surface of hemisphere except for: 1. frontal lobe 2. strip along superomedial border of frontal lobe 3. lowest temporal convolutions Most frequently affected in embolic & thrombotic stroke

53. Left and Right Hemisphere Stroke: Common Patterns Left (Dominant) Hemisphere Stroke: Common Pattern Right (Non-dominant) Hemisphere Stroke: Common Pattern Aphasia Right hemiparesis Right-sided sensory loss Right visual field defect Poor right conjugate gaze Dysarthria Difficulty reading, writing, or calculating Neglect of left visual field Extinction of left-sided stimuli Left hemiparesis Left-sided sensory loss Left visual field defect Poor left conjugate gaze Dysarthria Spatial disorientation

54. Posterior Circulation (Vertebrobasilar Territory) Stroke Ataxia, gait abnormalities Diplopia, oscillopsia, nystagmus, dysconjugate eye movements Nausea & vomiting (center is in area post-rema) Crossed hemiparesis, hemisensory deficits Headache more common

56. Differential Diagnosis of Stroke Craniocerebral / cervical trauma Meningitis/encephalitis Intracranial mass Tumor Subdural hematoma Seizure with persistent neurological signs Migraine with persistent neurological signs Metabolic Hyperglycemia Hypoglycemia Post-cardiac arrest ischemia Drug/narcotic overdose

57. AHA Stroke Council Recommended Assessment of a Person with Suspected Stroke EMS should be instructed in the rapid recognition, evaluation, treatment and transport Baseline assessment within minutes, CT scan ASAP; use National Institutes of Health Stroke Scale (NIHSS)

58. AHA Stroke Council Recommended Assessment of a Person with Suspected Stroke EMS should be instructed in the rapid recognition, evaluation, treatment and transport Baseline assessment within minutes, CT scan ASAP; use National Institutes of Health Stroke Scale (NIHSS) Immediate evaluation of the following: 1. Airway 2. Vital signs 3. General medical assessment (including evidence of injury, cardiovascular abnormalities) 4. Neurological assessment (frequent)

59. EVALUATION AND WORK-UP History and PE Computed Tomography (CT) scan of the head 12-lead EKG, chest X-ray Complete blood count, PT, PTT Chemistries (sodium, phosphate, glucose abnormalities may mimic stroke) Urine and serum toxicology (drugs and alcohol)

60. Under special circumstances, the following tests may be required: Cervical spine x-ray Arterial blood gas Lumbar puncture Electroencephalogram (EEG)

61. Other Neuroimaging Techniques & Ancillary Tests Magnetic Resonance Imaging (MRI) Diffusion Weighted Imaging (DWI), Magnetic Resonance Angiography (MRA) Ultrasound (Carotid Duplex, Transcranial Doppler, 2-D echo) Conventional Angiography Single Photon Emission Computed Tomography (SPECT) Positron Emission Tomography

63. Computed Tomography

65. Carotid Duplex

66. Transcranial Doppler

67. Cerebral Angiography

68. Functional abnormality demonstrated with PET exceeds that seen with structural imaging techniques such as X-ray, CT, or MRI and is more representative depiction of the underlying functional state of the brain.

69. SPECT and Xenon Contrast CT

70. EMERGENT SUPPORTIVE CARE OF ACUTE STROKE PATIENT Maintenance of adequate tissue oxygenation: protecting the airway, O2 inhalation Maintaining optimal blood pressure (autoregulation faulty or lost in stroke patients)

71. STROKE MANAGEMENT

72. EMERGENT SUPPORTIVE CARE OF ACUTE STROKE PATIENT Management of blood glucose abnormalities (hyperglycemia associated with poorer prognosis) Management of fever and infections (ischemia worsened by hyperthermia, improved by hypothermia

73. ACUTE SROKE CARE 2007: Therapies with FDA Approval or Positive Trials For Ischemic Stroke IV TPA (< 3hours) IA fibrinolysis (< 6 hours) IA MERCI retriever < 8 hours Endovascular temperature control

76. Acute Stroke Treatment Intravenous recombinant tissue plasminogen activator (TPA): within 3 hours of stroke symptom onset Intraarterial TPA: within 6 hours; MCA territory stroke by angiography

77. The Merci Retrieval System

78. Hypothermia For Acute Stroke:Intravascular Cooling

79. Physiologic Effects Of Various Levels Of Hypothermia

80. Known Factors That Cause Stroke Progression Hypotension Hyperglycemia Hyperthermia Infection Cerebral hypoperfusion

81. Brain Edema

82. TREATMENT OF BRAIN SWELLING Cerebral perfusion pressure =MAP-ICP Fluid Restriction (1200 ml /day/m2) Controlled hyperventilation: 25 mm Hg Mannitol, 0.25 mg/kg IV over 20 minutes; repeat PRN, serum osmolality maintained in the range of 300-320mOsm/l Barbiturate coma, with ICP monitoring (subarachnoid bolt, IV catheter or Camino catheter): maintain CPP greater than 50 mmHg; pentobarbital serum level of 2-4 mg/dl Surgery (wait 2 weeks)

83. Management of Cerebral Edema, Increased Intracranial Pressure and Hydrocephalus Brain edema peaks at 3-5 days Treatment includes: 1. hyperventilation (lower PCO2) 2. osmotic diuretics 3. drainage of CSF (ventriculostomy) 4. surgery (lobectomy)

84. Neuroprotective Agents Several trials going on So far, trial on one free-radical scavenger showed positive results Phase II trials have proven beneficial; Phase III (human efficacy trials) non-benefial to negative Common measures may “neuroprotect”

85. Stroke Prevention Anticoagulants (Heparin, Warfarin) Antiplatelets (aspirin, clopidogreldipyridamole/ASA combination, ticlopidine) Statin ARB (-sartan), or ACE inhibitor + HCTZ Carotid endarterectomy if indicated Carotid or intracranial stent. Risk factor control!!!

86. Concept of Stroke Teams &Stroke Units “Time is brain” Stroke awareness Common mistakes may lead to fatal consequences “Boutique stroke neurology”: Patients will receive best care; length of stay shortened

87. THANK YOU!