EssaySubmitted for partial fulfillment of Master DegreeIn Neurology & PsychiatryPresented ByAhmed Abd El-Aty ShehataM.B.Bch

I would like to express myDeepest gratitude andappreciation to:

Prof. Dr. Mohamed YasserMohamed Metwaly

Professor of NeurologyFaculty of Medicine - Ain Shams

University

Introduction

Stroke is currently the second leading cause of deathin the Western world, ranking after heart diseases andbefore caner and is the most common reason forpermanent disability.

Patients presenting in the early hours of stroke onsetconstitute a category of stroke patient known as the"hyperacute stroke patient."

Pathophysiology Of Stroke

Advances in understanding the patho-physiology andevolution of ischemic brain injury are the basis for thedevelopment of therapy for acute ischemic stroke.

Ischemic Penumbra

The penumbra concept of focal ischemia is ofconsiderable interest for the understanding of strokepathophysiology because it is the basis not only for theprogressive evolution of ischemic injury, but also forthe therapeutic reversal of the acute neurologicalsymptomatology arising from stroke.

Ischemic Penumbra

Ischemic penumbra is usually peripheral in location,where blood flow is sufficiently reduced to causehypoxia, severe enough to arrest physiologicalfunction, but not so complete as to cause irreversiblefailure of energy metabolism and cellular necrosis.

Ischemic Penumbra Diffusion-weighted MRI abnormalities identify

ischemic tissue where failure of high-energymetabolism has occurred, and perfusion weightedMRI provides information about relative CBF andmean transit time. It was suggested that ischemicregions with abnormal PWI and normal DWIrepresent an approximation of the ischemicpenumbra.

Ischemic Penumbra Perfusion CT can also be used to identify and give an

approximation of the ischemic penumbra in acuteischemic stroke patients. The area of mismatch withreduced CBF but without CBV collapse provides anapproximation of the ischemic penumbra.

Ischemic Cascade

It has been well documented that abrupt deprivationof oxygen and glucose to neuronal tissues elicits aseries of pathological cascades, leading to spread ofneuronal death.

Ischemic Cascade Of the numerous pathways identified, excessive

activation of glutamate receptors, accumulation ofintracellular calcium cations, abnormal recruitment ofinflammatory cells, excessive production of freeradicals, and initiation of pathological apoptosis arebelieved to play critical roles in ischemic damage,especially in the penumbral zone.

Ischemic Cerebral Edema

Cytotoxic edema is pathological cell swelling due todisruptions in cell volume regulation . It is the initial,and to some extent the predominant, type of edemafollowing cerebral ischemia.

Ischemic Cerebral Edema Ionic edema is the earliest phase of endothelial

dysfunction triggered by ischemia and precedesvasogenic edema. Increased permeability ofendothelial cells is usually due to the increased activityand/or expression of ion transport proteins triggeredby ischemia or associated toxic metabolites.

Ischemic Cerebral Edema After ionic edema, the second phase of endothelial

dysfunction triggered by ischemia is vasogenic edema,which is characterized by the breakdown of tightjunctions within the blood-brain barrier and anaccumulation of fluid into the brain’s interstitialspace.

Intravenous rt-PA

Tissue-type plasminogen activator has severaladvantages as a thrombolytic agent: It has a functionalhalf-life of about 5 minutes, compared to about 16minutes for urokinase and 23 minutes forstreptokinase ; thus, if bleeding occurs or invasiveprocedures are needed, the thrombolytic action of thedrug disappears shortly after the infusion isdiscontinued.

Intravenous rt-PA It is clot-specific because of its high affinity for

plasminogen in the presence of fibrin. This allowsefficient activation of the fibrin clot without activationoccurring in the plasma. It causes only a modestreduction in fibrinogen concentration compared withthe reduction caused by streptokinase. It isnonantigenic and usually causes no adverse reactionsother than bleeding.

Intravenous rt-PA In 1995, the National Institute of Neurological

Disorders and Stroke (NINDS) study group reportedthat patients with acute ischemic stroke who receivedalteplase within three hours after the onset ofsymptoms were at least 30% more likely to haveminimal or no disability at three months than thosewho received placebo.

Intravenous rt-PA There was the first European Cooperative Acute

Stroke Study (ECASS I), in which a higher dose of rt-PA was used (1.1 mg/kg) and patients were randomizedup to six hours after the onset of symptoms.

Intravenous rt-PA In the ECASS II trial, the dose of rt-PA was identical to

that used in the NINDS trial, but there was a six-hourtreatment window.

The Alteplase Thrombolysis for Acute Non-interventional Therapy in Ischemic Stroke(ATLANTIS) study randomized patients from three tofive hours after stroke and also showed negativeresults.

3 TO 4 ½ HOURS:ECASS III: NEJM 2008

ECASS III is the second randomized trial to showsignificant treatment efficacy with intravenousalteplase when administered 3 to 4.5 hours after theonset of stroke symptoms.

Intravenous rt-PARe-canalization may exacerbate tissue

injury by;- promoting reperfusion injury.- excessive cerebral edema.- hemorrhagic transformation.

Hemorrhagic complication

The most feared complication in acute ischemic stroke Risk factors; Age, hypertension, diabetes mellitus or,

extent of early ischemic signs shown on brain CT scanor the volume of cerebral ischemic lesions on diffusionweighted MRI, and the presence of leukoaraiosis.

Predictors of good outcome afterthrombolysis:

Milder baseline stroke severity:The initial severity of a stroke is a strong predictor of the

functional and neurologic outcome and of the risk ofdeath.

Predictors of good outcome afterthrombolysis: Early treatment:

Early treatment remains essential. The effect size ofthrombolysis is time-dependent. Some studies showedthat treatment with alteplase is nearly twice asefficacious when administered within the first 1.5hours after the onset of a stroke as it is whenadministered within 1.5 to 3 hours afterward

Predictors of good outcome afterthrombolysis: Younger age :

Recent data from several studies on use of rt-PA haveshown that the risk of sICH in the elderly iscomparable to that of younger patients. In certainStudy , the rate of sICH increased with age from 4.9%in patients younger than 55 years to 10.3% in patientsaged 75 years and older.

Predictors of good outcome afterthrombolysis Normal pretreatment blood pressure:

A systolic blood pressure of 141–150 mm Hg wasassociated with the most favourable outcomes. Somestudies showed that systolic blood pressure has alinear association with symptomatic haemorrhage anda U-shaped association with mortality anddependence at 3 months.

Predictors of good outcome afterthrombolysis Normal pretreatment blood glucose level; Baseline

hyperglycemia is found more commonly in patientswith preexisting diabetes but is also present in asignificant proportion of nondiabetic patients.Multiple studies showed that in IV-tPA–treated strokepatients, admission hyperglycemia was independentlyassociated with increased risk of death, SICH, andpoor functional status at 90 days.

Predictors of good outcome afterthrombolysis Normal CT scan ; The ECASS I and ECASS II trials

have shown that the presence of early ischemic changein more than one-third of the MCA territory beforethrombolysis is accompanied by an increase in thehemorrhagic transformation risk and poor clinicaloutcome.

Intravenous rt-PA Alteplase is still under used; it is estimated that fewer

than 2% of patients receive this treatment in mostcountries, primarily because of delayed admission to astroke center, insufficient public warning andknowledge of stroke symptoms, the limited number ofcenters able to perform thrombolysis and an excessivefear of hemorrhagic complications.

Intra-arterial Thrombolysis

Intra-arterial therapy has been shown to improveclinical outcome when administered 3 to 6 hours fromsymptom onset using intra-arterial thrombolytics, andis approved up to 8 hours using mechanical clotretrieval suction thrombectomy.

Intra-arterial Thrombolysis IAT has several theoretic advantages over IV

thrombolysis. the occluded intracranial vessel isdirectly accessible and the fibrinolytic agent can beinfused directly into the thrombus. This permits asmaller dose of fibrinolytic agent to reach a higherlocal concentration than that reached by systemicinfusion.

Intra-arterial Thrombolysis With the smaller dose, complications from systemic

fibrinolytic effects, including intracranial hemorrhage,can theoretically be reduced. For these reasons, thetreatment window for endovascular techniques can beextended beyond the typical IV window.

Limitations of IA Thrombolysis

The time to treatment for IA thrombolysis is longercompared to that of IV thrombolysis because there arelogistical factors involved, such as the need toassemble the angiography team and confirm occlusionangiographically before administration ofthrombolytics.

Invasiveness of angiography. The monetary cost of IA thrombolysis and associated

hospitalization.

Intra-arterial ChemicalThrombolysis

Anterior circulation; The optimal window for IAthrombolysis is 6-hour from symptom onset.However, if the occlusion does not involve thehorizontal MCA segment and the lenticulostriatearteries, the treatment window can be extended to 12hours following symptoms.

Intra-arterial ChemicalThrombolysis posterior circulation; The time window for

thrombolysis in the posterior circulation has beenthought to be longer than that of anterior circulationbecause of lower risk of hemorrhagic transformationas a result of smaller infarct volumes, worse outcomeswith conventional therapy, and additionalpathophysiological differences including collateralflow patterns that may lead to a slower evolution ofirreversible ischemia within this lesion.

Intra-arterial MechanicalThrombolysis

Interventional neuroradiologists have made advancesin the use of technologies, such as , intra-arterialthrombolysis, stenting, and mechanical retrievaldevices, which have provided teams with a number ofinterventions to optimize outcomes in stroke.

Intra-arterial MechanicalThrombolysis Mechanical strategies have several advantages over

pharmacologic thrombolysis and may be used asprimary or adjunctive strategies.

1-They lessen and may even preclude the use ofchemical thrombolytics, in this manner very likelyreducing the risk of ICH.

Intra-arterial MechanicalThrombolysis 2- By avoiding the use of chemical thrombolytics, it is

possible to extend the treatment window beyond thelimit of 6–8 hours.

3- Fragmenting a clot mechanically Increases thesurface area accessible to fibrinolytic agents andallows inflow of fresh plasminogen,which, in turn,may increase the speed of thrombolysis.

Intra-arterial MechanicalThrombolysis 4- Clot-retrieval devices may provide faster

recanalization and may be more efficient at copingwith material resistant to enzymatic degradation.

Intra-arterial MechanicalThrombolysis

Disadvantage; The possibility of occlusion or damageof perforating arteries, vessel dissection, or endothelialinjury, which could lead to intracranial hemorrhage orendothelial flap stenosis and occlusion. Otherproblems include clot fragmentation because ofmicrocatheter or device manipulation within the clotwith distal embolic infarction and reduction in distalperfusion.

Neuroprotection In Stroke

The concept of neuroprotective therapy for acuteischemic stroke to salvage tissue at risk and improvefunctional outcome is based on scientific principlesand extensive preclinical animal studiesdemonstrating efficacy. However, mostneuroprotective drugs in clinical trials have failed toconfirm benefit.

Management Of Hypertension An acute hypertensive response occurs within 24 h in

up to 80% of patients with acute stroke. Blood pressure tends to decline spontaneously without

pharmacological intervention in the first few days toweeks after stroke onset.

Management Of Hypertension

Systolic blood pressure has a linear association withsymptomatic haemorrhage and a U-shapedassociation with mortality and dependence at 3months: a systolic blood pressure of 141–150 mm Hgwas associated with the most favourable outcomes.

Management Of Hypertension

In patients with acute stroke, blood pressure should bereduced gradually with special attention for possiblecontraindications. The decrease in blood pressureshould not exceed 10–20% of the initial level to avoidthe risk of poor perfusion of affected brain area.

Management Of Hypertension

Indications to actively lower blood pressure arecoexisting critical conditions, such as hypertensiveencephalopathy, aortic dissection, heart failure, acutemyocardial infarction, acute renal failure, orpreeclampsia and eclampsia.

Management Of Ischemic CerebralEdema Cerebral edema is frequently encountered in clinical

practice in critically ill patients with acute stroke andis a major cause of increased morbidity and death.

The consequences of cerebral edema can be lethal andinclude cerebral ischemia from compromised regionalor global cerebral blood flow and intracranialcompartmental shifts due to intracranial pressuregradients that result in compression of vital brainstructures.

Management Of Ischemic CerebralEdema

The overall goal of medical management of cerebraledema is to maintain regional and global CBF to meetthe metabolic requirements of the brain and preventsecondary neuronal injury from cerebral ischemia.

Management Of Ischemic CerebralEdema Medical management of cerebral edema involves using

a systematic and algorithmic approach, from generalmeasures (optimal head and neck positioning forfacilitating intracranial venous outflow, avoidance ofdehydration and systemic hypotension, andmaintenance of normothermia) to specific therapeuticinterventions (controlledhyperventilation,administration of corticosteroids anddiuretics, osmotherapy, and pharmacological cerebralmetabolic suppression).