Pathophysioloy of stroke

MECHANISMS OF CEREBRAL DAMAGE FOLLOWING ISCHEMIC EVENT AND

REPERFUSION SYNDROMELiterature Revision

DR. LEONARDO BALLESTAS MALDONADOVASCULAR SURGERY RESIDENTUNIVERSIDAD DE ANTIOQUIA

DR. IVAN ARISMENDIVASCULAR SURGERY TEACHER

IPS UNIVERSITARIAUNIVERSIDAD DE ANTIOQUIA

INTRODUCTION

• The term ischemic stroke is used to describe a variety of condictions in which blood flow to part or all of the brain is reduced, resulting in tissue damage

• Although in some cases this may be a chronic condition, most strokes occurs acutely

• The stroke is currently the second leading cause of death in western world

Scott Kinlay .Changes in Stroke Epidemiology, Prevention, and Treatment. Circulation. 2011;124:e494-e496

OBJETIVE

The goal of this review is to provide an overview of the underlying factors, such as hemodinamic changes and mollecular and

celular pathways, wich are involved in stroke-realted brain injury AND correlate these events with reperfusion syndrome and its treatment

EVIDENCE

• A SEARCH OF EVIDENCE IN THE DATABASE: MEDLINE, EMBASE, COHCRANE, TRIPDATABASE, SCIELO

• KEY WORDS: ISCHEMIC STROKE, BRAIN DAMAGE, PATHOPHYSIOLOGY, CEREBRAL ARTERY OCLUSSION, MECHANISMS, REPERFUSION SYNDROME, HIPERPERFUSION

STROKE SUBTYPES

• Acute ischemic stroke subtypes are often classified in clinical studies using a system developed by investigators of the TOAST trial, based upon the underlying cause

• Strokes are classified into the following categories:

Adams HP Jr., Bendixen BH, et al. Classification of suptype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in acute Stroke treatment. Stroke 1993; 24:35

Large artery atherosclerosisCardioembolismSmall vessel oclussionStroke of other, unusual, determined etiologyStroke of undetermined etiology

• Ischemic strokes are due to a reduction or complete blockage of blood flow

• This reduction can be due to decreased systemic perfusion, severe stenosis or occlusion of a blood vessel

• Ischemic strokes represent about 80 percent of all strokes

Caplan LR. Basic pathology, anatomy, and pathophysiology of stroke. In: Caplan's Stroke: A Clinical Approach, 4th ed, Saunders Elsevier, Philadelphia 2009. p.22

CEREBRAL ARTERY OCCLUSION

• Thrombosis refers to obstruction of a blood vessel due to a localized occlusive process within a blood vessel

• The obstruction may occur acutely or gradually

• Atherosclerosis may cause narrowing of the diseased vessel

• This may lead to restriction of blood flow gradually

• Platelets may adhere to the atherosclerotic plaque forming a clot leading to acute occlusion of the vessel

• Atherosclerosis usually affects larger extracranial and intracranial vessels

CEREBRAL ARTERY OCCLUSION

CEREBRAL AUTOREGULATION

• Under normal conditions, the rate of cerebral blood flow is primarily determined by the amount of resistance within cerebral blood vessels, which is directly related to their diameter

• Cerebral blood flow is also determined by variation in the cerebral perfusion pressure

Markus HS. Cerebral perfusión and stroke. J Neurol Neurosurg Psychiatry 2004; 75:353

• Is the phenomenon by which cerebral blood flow is maintained at a relatively constant level despite moderate variations in perfusion pressure

• The mechanism by which autoregulation occurs is not well understood, and may involve multiple pathways


R Aaslid, K F Lindegaard, W Sorteberg and H Nornes. Cerebral autoregulation dynamics in humans. Stroke. 1989;20:45-52

SMOOTH MUSCLE IN CEREBRAL VESSELS



Maintenance of cerebral blood flow by autoregulation typically occurs within a mean arterial pressure range of 60 to 150 mmHg

CEREBRAL AUTOREGULATION DURING STROKE

CEREBRAL PERFUSION PRESSURE

FALLS

CEREBRAL BLOOD

VESSELS DILATE

INCREASE CEREBRAL

BLOOD FLOW

OXYGEN EXTRACTION FRACTION IS INCREASED

AUTOREGULATIONIMPAIRED

LOW LEVELS OF OXYGEN DELIVERY TO THE BRAIN

CEREBRAL AUTOREGULATION DURING STROKE

Aries MJ, Elting JM, et al. Cerebral autoregulation in stroke: a review of transcranial Doppler studies. Stroke 2010; 41:2697

CONSEQUENCES OF REDUCTION IN BLOOD FLOW DURING STROKE

• The human brain is exquisitely sensitive and susceptible to even short durations of ischemia

• The brain is responsible for a large part of the body's metabolism and receives about 20 percent of the cardiac output although it is only 2 percent of total body weight

• The brain contains little or no energy stores of its own, and therefore relies on the blood for their delivery

Markus HS. Cerebral perfusión and stroke. J Neurol Neurosurg Psychiatry 2004; 75:353

CONSEQUENCES OF REDUCTION IN BLOOD FLOW DURING STROKE

FOCAL ISCHEMIA

CENTRAL CORE

PENUMBRA

MECHANISM OF ISCHEMIC CELL INJURY AND DEATH

• DEPLETION ATP

• CHANGES IN IONIC CONCENTRATIONS OF NA, K AND CA

• INCREASED LACTATE ACIDOSIS

• ACCUMULATION OF OXYGEN FREE RADICALS

• INTRACELLULAR ACCUMULATION OF WATER

• ACTIVATION OF PROTEOLYTIC PROCESSES


ISCHEMIA

ELECTRICAL FAILURE


MULTIPLE PATHWAYS

EXITOTOXICITY

SODIUM – INFLUX OFWATER

Sodium causes reversal of the normal process of glutamate uptake by astrocyte glutamate transporters

NA

NITRIC OXIDEFREE RADICALS

DNA DAMAGE

MITOCHONDRIALFAILURE APOPTOSIS

INFLAMATORYRESPONSE

Cell death following cerebral ischemia or stroke can occur by either necrosis or by apoptosis:

APOPTOSIS

LOSS OF BRAIN STRUCTURAL INTEGRITY

• Cerebral edema complicating stroke can cause secondary damage by several mechanisms, including :

INTRACRANEAL PRESSURE

DECREASE CEREBRAL BLOOD FLOW

MASS EFFECT

• Cytotoxic edema is caused by the failure of ATP-dependent transport of sodium and calcium ions across the cell membrane

• The result is accumulation of water and swelling of the cellular elements of the brain, including neurons, glia, and endothelial cells

• Vasogenic edema is caused by increased permeability or breakdown of the brain vascular endothelial cells that constitute the BBB

• This allows proteins and other macromolecules to enter the extracellular space, resulting in increased extracellular fluid volume

REPERFUSION SYNDROME

INTRODUCTION

• Cerebral hyperperfusion, or reperfusion syndrome, is a rare, but serious, complication following revascularization

• Restoration of blood flow following ischemic stroke can be achieved by means of thrombolysis or mechanical recanalization (endarterectomy)

• In the treatment of acute stroke, restoration of the blood supply can reduce more extensive brain tissue injured by salvaging a reversibly damage penumbra of tissue

Schaller B, Graf R (2004) Cerebral ischemia and reperfusion: the pathophysiologic concept as a basis for clinical therapy. J Cereb Blood Flow Metab 24:351–371

• Hyperperfusion is defined as a major increase in ipsilateral cerebral blood flow (CBF) that is well above the metabolic demands of the brain tissue

• The terms hyperperfusion and reperfusion are often used interchangeably

• When patients are identified and treated early, the prognosis is better and the incidence of intracraneal hemorrage is decreased

INTRODUCTION

Karapanayiotides T, Meuli R, Devuyst G, Piechowski-Jozwiak B, Dewarrat A, Ruchat P, et al. Postcarotid endarterectomy hyperperfusion or reperfusion syndrome. Stroke. Jan 2005;36(1):21-6.

• Outcomes are dependent on timely recognition and prevention of precipitating factors

• Most important is the treatment of hypertension before it can inflict damage in the form of edema or hemorrahge

• The prognosis following hemorrhagic transformation is poor

INTRODUCTION

Yoshimoto T, Shirasaka T, Yoshizumi T, Fujimoto S, Kaneko S, Kashiwaba T. Evaluation of carotid distal pressure for prevention of hyperperfusion after carotid endarterectomy. Surg Neurol. Jun 2005;63(6):554-7; discussion 557-8.

• Mortality in such cases is 36-63%, and 80% of survivors have significant morbidity

• Damage to the blood-brain barrier (BBB), an important factor in reperfusion injury

INTRODUCTION

Wagner WH, Cossman DV, Farber A, Levin PM, Cohen JL. Hyperperfusion syndrome after carotid endarterectomy. Ann Vasc Surg. Jul 2005;19(4):479-86

SYMPTOMS OF CEREBRAL REPERFUSION SYNDROME

HYPERTENSION

HEADACHE

seizurecontralateral neurological

deficits

• The time frame in which symptoms arise can be from immediately after restoration of blood flow to up to 1 month after restoration

• Patients are usually symptomatic within the first week

Coutts SB, Hill MD, Hu WY. Hyperperfusion syndrome: toward a stricter definition. Neurosurgery. Nov 2003;53(5):1053-58; discussion 1058-60.

CAUSES OF CEREBRAL REPERFUSION INJURY

• Postoperative hypertension• High-grade stenosis with poor collateral flow• Decreased cerebral vasoreactivity• Increased peak pressure, such as in contralateral

carotid occlusion• Recent contralateral CEA (< 3 months)• Intraoperative distal carotid pressure of less than

40 mm Hg• Intraoperative ischemia peak flow velocityAdhiyaman V, Alexander S. Cerebral hyperperfusion syndrome following carotid endarterectomy. QJM. Apr 2007;100(4):239-44

HYPERTENSION• Elevated blood pressure is the most common

factor found in syntomatic patients

• During acute ischemic stroke, systemic blood pressure often rises as a physiologic compensation of cerebral ischemia

• The key to reperfusion injury in this scenario is ischemic disruption of the blood-brain barrier (BBB)

McCabe DJ, Brown MM, Clifton A. Fatal cerebral reperfusion hemorrhage after carotid stenting. Stroke. Nov 1999;30(11):2483-6.

DYSAUTOREGULATION

• Cerebral autoregulation protects the brain against changes in systemic blood pressure

• In patients with high-grade stenosis, CBF is maintained at the expense of maximal arteriolar vasodilatation

• Chronic cerebral hypoperfusion (eg, critical stenosis) leads to the production of carbon dioxide and nitric oxide

• Correction of a critical stenosis causes rapid and large changes in the CBF, which can lead to edema or hemorrhage

Hosoda K, Kawaguchi T, Shibata Y, Kamei M, Kidoguchi K, Koyama J, et al. Cerebral vasoreactivity and internal carotid artery flow help to identify patients at risk for hyperperfusion after carotid endarterectomy. Stroke. Jul 2001;32(7):1567-73.

ISCHEMIA - REPERFUSION

• Is characterized by oxidant production, complement activation, and increased microvascular permeability

• At the site of ischemia itself, activated leukocytes release free radicals and toxins, causing further destruction

• The combination results in an impaired BBB, which can lead to cerebral edema and/or hemorrhage

REPERFUSION INJURY AFTER REVASCULARIZATION

• Symptomatic hemorrhagic transformation rates within 24-36 hours of stroke are increased in the setting of revascularization therapy, regardless of modality

• In the absence of revascularization therapy, hemorrhagic transformation is a common and natural consequence of infarction

• Hemorrhagic transformation is now known to be a multifactorial process

• Patient selection based on physiologic parameters is likely important to reduce late hemorrhage attributable to revascularization

Khatri P, Wechsler LR, Broderick JP. Intracranial hemorrhage associated with revascularization therapies. Stroke. Feb 2007;38(2):431-40.

ASSESMENT OF RISK FOR REPERFUSION INJURY

• Low preoperative distal carotid artery pressure (< 40 mm Hg) and an increased peak blood flow velocity have been found to be predictive of postoperative hyperperfusion

• TCD can be used to select patients for aggressive postprocedure observation and management

Preoperative transcranial Doppler ultrasonography

Ogasawara K, Inoue T, Kobayashi M, Endo H, Fukuda T, Ogawa A. Pretreatment with the free radical scavenger edaravone prevents cerebral hyperperfusion after carotid endarterectomy. Neurosurgery. Nov 2004;55(5):1060-7.

• Cerebrovascular reactivity (CVR) to carbon dioxide can be used to test cerebral hemodynamic reserve

• Normally, administration of acetazolamide (a carbonic anhydrase inhibitor that causes a local increase in carbon dioxide) induces a rapid increase in CBF

• This iatrogenic CBF surge is measured using single-photon emission computed tomography (SPECT) scanning

ASSESMENT OF RISK FOR REPERFUSION INJURY

Preoperative acetazolamide SPECT scanning

Cikrit DF, Burt RW, Dalsing MC, Lalka SG, Sawchuk AP, Waymire B, et al. Acetazolamide enhanced single photon emission computed tomography (SPECT) evaluation of cerebral perfusion before and after carotid endarterectomy. J Vasc Surg. May 1992;15(5):747-53; discussion 753-4.

PREVENTION OF REPERFUSION INJURY

• The most important factor in preventing reperfusion syndrome is early identification and control of hypertension

• The use of TCD ultrasonography preoperatively and postoperatively can aid in identifying patients with increased CBF and, consequently, increased risk of hyperperfusion

• Blood pressure should then be controlled aggressively if CBF elevates

Naylor AR, Evans J, Thompson MM, London NJ, Abbott RJ, Cherryman G, et al. Seizures after carotid endarterectomy: hyperperfusion, dysautoregulation or hypertensive encephalopathy?. Eur J Vasc Endovasc Surg. Jul 2003;26(1):39-44.

• Pressures can be reduced gently with antihypertensives that do not increase CBF or cause excessive vasodilatation

• According to the American Stroke Association stroke and intracerebral hemorrhage guidelines, the blood pressure goal for an acute intracerebral hemorrhage is a mean arterial pressure (MAP) of less than 110 mm Hg


Free-radical scavengers and antiadhesion therapy


• Free radicals produced during ischemia are a purported culprit in reperfusion injury

• Free-radical scavengers and antiadhesion therapy have shown promise in decreasing the incidence of endothelial injury

• Animal studies using various methods of modulating the cytokine response have shown beneficial effects from modulation of IL-1 and TNF

Free-radical scavengers and antiadhesion therapy


THANKS

Health & Medicine

Pathophysioloy of stroke