Full revision for pathophysiology of stroke by occlusion of extracranial arteries

2. DR. LEONARDO BALLESTAS MALDONADO
VASCULAR SURGERY RESIDENT
UNIVERSIDAD DE ANTIOQUIA
DR. IVAN ARISMENDI
VASCULAR SURGERY TEACHER
IPS UNIVERSITARIA
UNIVERSIDAD DE ANTIOQUIA

3. 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

4. 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

5. 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

6. 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:
Large artery atherosclerosis
Cardioembolism
Small vessel oclussion
Stroke of other, unusual, determined etiology
Stroke of undetermined etiology
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

7. • 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

8. 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

9. CEREBRAL ARTERY OCCLUSION
• 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

11. 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

12. CEREBRAL AUTOREGULATION
• 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

13. CEREBRAL AUTOREGULATION
SMOOTH MUSCLE IN CEREBRAL VESSELS

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

15. CEREBRAL AUTOREGULATION DURING
STROKE
CEREBRAL
PERFUSION
PRESSURE
FALLS
CEREBRAL
BLOOD
VESSELS
DILATE
INCREASE
CEREBRAL
BLOOD
FLOW
OXYGEN
EXTRACTION
FRACTION IS
INCREASED
AUTOREGULATION
IMPAIRED
LOW LEVELS OF OXYGEN
DELIVERY TO THE BRAIN

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

17. 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

18. CONSEQUENCES OF REDUCTION IN
BLOOD FLOW DURING STROKE
FOCAL ISCHEMIA
CENTRAL
CORE
PENUMBRA

19. 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

20. MECHANISM OF ISCHEMIC CELL
INJURY AND DEATH
ISCHEMIA
ELECTRICAL FAILURE

21. MECHANISM OF ISCHEMIC CELL
INJURY AND DEATH
MULTIPLE PATHWAYS

22. EXITOTOXICITY
SODIUM – INFLUX OF
WATER
Sodium causes reversal of the
normal process of glutamate
uptake by astrocyte glutamate
transporters
NA
NITRIC OXIDE
FREE RADICALS
DNA DAMAGE
MITOCHONDRIAL
FAILURE
APOPTOSIS

23. INFLAMATORY
RESPONSE

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

25. APOPTOSIS

27. 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

28. • 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

29. • 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

30. REPERFUSION SYNDROME

31. 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 FlowMetab 24:351–371

32. INTRODUCTION
• 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
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.

33. INTRODUCTION
• 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
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.

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

35. SYMPTOMS OF CEREBRAL
REPERFUSION SYNDROME
HEADACHE
HYPERTENSION
seizure
contralateral
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.

36. 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 velocity
Adhiyaman V, Alexander S. Cerebral hyperperfusion syndrome following carotid endarterectomy. QJM. Apr
2007;100(4):239-44

37. 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.

38. 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.

39. 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

40. 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.

41. ASSESMENT OF RISK FOR
REPERFUSION INJURY
Preoperative transcranial Doppler ultrasonography
• 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
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.

42. ASSESMENT OF RISK FOR
REPERFUSION INJURY
Preoperative acetazolamide SPECT scanning
• 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
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.

43. 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.

44. PREVENTION OF REPERFUSION
INJURY
• 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

45. PREVENTION OF REPERFUSION
INJURY
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

46. PREVENTION OF REPERFUSION
INJURY
Free-radical scavengers and antiadhesion therapy