Stroke

Introduction
Stroke is the 2nd most common cause of death
worldwide
Is the 5th leading cause of death in the US.
Stroke is an acute medical emergency

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Stroke is classified into two major types:
◦ Brain ischemia due to thrombosis, embolism,
or systemic hypoperfusion.
◦ Brain hemorrhage due to intracerebral
hemorrhage (ICH) or subarachnoid
hemorrhage (SAH).
A stroke is the acute neurologic injury
that occurs as a result of one of these
pathologic processes.

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EPIDEMIOLOGY
Approximately 795,000 strokes occur in the US
each year.
◦ 610,000 new strokes
◦ 185,000 recurrent strokes
Incidence increases especially after age 55 years.
It is the leading cause of long-term disability in
adults,
◦ 90% of survivors having residual deficits
◦ 70% of survivors have moderate-to-severe disability
and
◦ 15% to 30% of survivors are permanently disabled

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There are currently over 7 million stroke
survivors in the US.
Total costs of $33.9 billion reported in the
United States in 2013.

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ETIOLOGY AND CLASSIFICATION
Strokes can either be
◦ ischemic (87% of all strokes) or
◦ hemorrhagic (13% of all strokes)

Ischemic stroke, which may be thrombotic

or embolic

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A thrombotic occlusion occurs when
◦ a thrombus forms inside an artery in the brain.
An embolic stroke typically occurs when a
piece of thrombus,
◦ originating either inside or outside of the
cerebral vessels,
◦ breaks loose and is carried to the site of occlusion
in the cerebral vessels.
An extracerebral source of emboli is often
the heart, leading to cardioembolic stroke.
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Hemorrhagic stroke is a result of
bleeding into the brain and other spaces
within the CNS
Hemorrhagic stroke includes
◦ subarachnoid hemorrhage (SAH),
◦ intracerebral hemorrhage (ICH), and
◦ subdural hematomas

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A. SAH results most often due to
◦ trauma or rupture of a cerebral aneurysm or
arteriovenous malformation (AVM).
 Bleeding into a subarachnoid space
B. ICH is bleeding directly into the brain
parenchyma,
◦ Often as a result of chronic uncontrolled hypertension.
C. Subdural hematomas result from bleeding
under the dura covering the brain and
◦ most often occur as a result of head trauma

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 Transient ischemic attack (TIA)
 It is a transient episode of neurological
dysfunction caused by
◦ focal brain, spinal cord, or retinal ischemia without
acute infarction.
It have a rapid onset and short duration,
typically lasting
◦ less than 1 hour and often < 30 minutes
No deficit remains after the attack
TIAs are a risk factor for acute ischemic stroke

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Kleindorfer et al. Stroke. 2021
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TOAST classification of ischemic stroke [5]

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 Risk Factors
An important component of stroke
prevention, diagnosis, and treatment.
Modifiable and nonmodifiable risk factors .

Hypertension is one of the major risk factors

for both ischemic and hemorrhagic stroke.

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PATHOPHYSIOLOGY
Ischemic Stroke
 Thrombus formation usually starts with lipid deposits in the vessel
wall that cause turbulent blood flow.

 This leads to vessel injury and exposure of vessel collagen to

blood.

 This vessel injury initiates the platelet aggregation process due to

the exposed subendothelium.

 Platelets release ADP, which causes platelet aggregation and consolidation

of the platelet plug.
 Thromboxane A2 is released, contributing to platelet aggregation and
vasoconstriction.
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The vessel injury also activates the
◦ coagulation cascade, which leads to thrombin
production.
 Thrombin converts fibrinogen to fibrin,

 clot formation as fibrin molecules, platelets,

and blood cells aggregate.

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Can diminish or block blood flow to the
affected area of the brain.
Cerebral blood flow in the normal
adult brain is 30 to 70 mL/100 g of
brain tissue/minute.

If reduced to <12 mL/100 g/minute,

the affected neurons become
sufficiently anoxic to die within minutes
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After the initial event,
◦ secondary events occur at the cellular level that
contribute to cell death
 Excitatory amino acids such as glutamate
accumulate within the cells,
 causing intracellular calcium accumulation

 Inflammation occurs and oxygen free radicals are

formed resulting in the common pathway of cell
death.

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There is often a core of ischemia containing
unsalvageable brain cells
Surrounding this core is an area termed the
◦ ischemic penumbra
 In this area, cells are still salvageable
 however, this is time-sensitive.
Without restoration of adequate perfusion, cell
death continues, ultimately leading to
neurological deficits.
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Elisabetta Bandera. Stroke. Cerebral Blood Flow Threshold of Ischemic Penumbra
and Infarct Core in Acute Ischemic Stroke, Volume: 37, Issue: 5, Pages: 1334-
1339, DOI: (10.1161/01.STR.0000217418.29609.22)

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Hemorrhagic Stroke
The presence of blood in the brain tissue
and/or surrounding spaces resulting in
compression.
Brain tissue swelling and injury is a result
of
◦ inflammation caused by thrombin and other blood
products.
This can lead to increased intracranial
pressure (ICP) and herniation.
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Delayed cerebral ischemia, or vasospasm,
◦ is a potential consequence of aneurysmal
SAH that results in vasoconstriction of
cerebral vessels and clinical symptoms of
ischemia.
◦ It occurs in about 30% of patients
surviving the initial hemorrhage,
◦ Mostly between days 4 and 10 after
aSAH.

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 Primary prevention of Ischemic
Stroke
Reduction in risk factors (e.g., control of
hypertension, smoking cessation, control of
diabetes, cholesterol reduction).
Use of ASA for general CV prophylaxis in
men and women with
◦ a 10-year CV risk of >10% and in women who
are at high risk for stroke.
Cilostazol may be considered for prevention
of a first stroke in patients with PAD.

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Statin use, in addition to lifestyle
modifications, in patients
◦ estimated to have a high 10-year risk of
cardiovascular events
Lowering BP in hypertensive patients
reduces the RR of both ischemic and
hemorrhagic stroke.
Patients should be assisted and
encouraged in smoking cessation.
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AF is an important and well-documented
risk for stroke.
◦ Up to 70% of cases are inappropriately
treated.
Asymptomatic carotid stenosis, cardiac
disease, sickle cell disease, obesity,
excessive alcohol use, and physical
inactivity are other risks that should be
assessed and managed appropriately

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Treatment
Desired Outcomes
Ischemic stroke
Short-term treatment goals
◦ reducing secondary brain damage by reestablishing
and maintaining adequate perfusion to marginally
ischemic areas of the brain (i.e., neuroprotection).
Long-term treatment goals
◦ prevention of a recurrent stroke through reduction
and modification of risk factors and by use of
appropriate treatments.

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Hemorrhagic stroke
Short-term treatment goals
◦ to maintain adequate oxygenation, breathing, and
circulation.
◦ Management of increased ICP and BP
Long-term management
◦ prevention of complications and of a recurrent bleed
and delayed cerebral ischemia (DCI).
Prevention of long-term disability and death
related to stroke is important regardless of stroke
type.
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 General Approach
Differentiate
an ischemic stroke from a
hemorrhagic stroke, and
For those with an ischemic stroke
◦ determine the appropriateness of reperfusion
therapy.
In hemorrhagic stroke,
◦ a surgical evaluation to assess the need for
 surgical clipping of an aneurysm or
 other procedure to control the bleeding and prevent
rebleeding and other complications.
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 Early Management of Acute Ischemic
Stroke
The important determinates in treatment
are:
◦ Identification of the time of symptom onset and
presentation.
◦ Documenting risk factors, previous functional status,
and
◦ NIHSS to assess stroke severity and current
disability due to stroke.
 The NIHSS quantifies neurological deficits in stroke
patients.
 It is used as a measure of daily functioning
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`

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Supportive Measures
Supportive interventions and treatments
to prevent acute complications of acute
ischemic stroke should be initiated.
Include
◦ cerebral edema, increased ICP, seizures, and
hemorrhagic conversion (i.e., conversion of
ischemic stroke into hemorrhagic stroke).

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Screen for AF and other cardiac diseases.
Oxygen saturation should be maintained at 94%
(0.94) or greater.
Volume status and electrolytes should be corrected.
When blood glucose < 60 mg/dL (3.3 mmol/L) is
present, bolus with 25 mL of 50% dextrose
immediately.
◦ both hyperglycemia and hypoglycemia may worsen brain
ischemia
Treat hyperglycemia to achieve blood glucose levels
in a range of 140–180 mg/dL

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Ifthe patient is febrile, treat with acetaminophen
because
◦ fever is associated with brain ischemia and increased
morbidity and mortality.
Alternatively, cooling devices can be used
Low-dose UFH or LMWH should be initiated
for VTE prophylaxis in patients who are not
candidates for IV fibrinolytic therapy.
In patients receiving fibrinolytic therapy,
◦ It should be delayed until 24 hours after fibrinolytic
administration to avoid bleeding complications.

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In the setting of acute ischemic stroke,
◦ up to 80% have an elevated BP in the first 24 to 48 hours.
Hypertension should generally not be treated in the
acute period (12–24 hours) because
◦ it may cause decreased BF in ischemic areas, potentially
increasing the infarction size.
The cautious use of antihypertensive medications in
patients with
◦ severely elevated BP (SBP > 220 mm Hg or DBP > 120
mm Hg) who are otherwise candidates for fibrinolytic
therapy or endovascular therapy.
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In those not eligible for fibrinolytic or
endovascular therapy,
if BP reduction is necessary,
◦ aim for a 15% reduction in SBP and DBP in the
first 24 hours after stroke onset.

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Fibrinolytic Therapy
Alteplase (rt-PA) as first-line acute
treatment for ischemic stroke
Approved for treatment within 3 hours of
symptom onset.
A dose of 0.9 mg/kg (maximum 90 mg) is
recommended;
◦ the first 10% is given as an IV bolus, and
◦ the remainder is infused over 1 hour.

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Current guidelines recommend that
alteplase may be given 3 to 4.5 hours
after symptom onset in patients
◦ regardless of age,
◦ in those on warfarin with an INR ≤ 1.7,
◦ in mild disabling stroke, and in those with
diabetes and stroke
Alteplaseis currently contraindicated in
minor, nondisabling stroke

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Current clinical guidelines support 3 - 4.5 hrs.

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Tenecteplase 0.25 mg/kg (maximum 25 mg) IV
bolus
◦ also be useful in place of alteplase in patients without
contraindications to thrombolytics.

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Antiplatelet Agents
ASA initial dose of 160 to 325 mg is
recommended in most patients within 24
to 48 hours after symptom onset.
◦ ASA dose decreased to 75 to 100 mg daily to
reduce bleeding complications.
Should be delayed for 24 hours in
patients receiving alteplase or
tenecteplase.

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In patients with minor stroke or TIA,
◦ aspirin plus clopidogrel started within 24
hours of symptom onset and
◦ continued for 21 days reduced the risk of
subsequent stroke.
The risk of moderate-to-severe bleeding
is mitigated by discontinuing dual
antiplatelet therapy at 21 days.

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 Non-pharmacologic Therapy
Carotid Endarterectomy (CEA)
Removal of a thrombus from the carotid artery
Acceptable surgical risk for patients with TIA
or mild to moderate stable stroke undergoing
CEA within 48 hours
However, patients with unstable neurological
status and more severe strokes demonstrated
worse outcomes.

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Endovascular Treatment
New generation stent retrievers in patients meeting
specific criteria within 6 hours of symptom onset.
The majority of the patients received IV alteplase
initially followed by endovascular therapy.
It may be a useful treatment in patients not eligible
for IV alteplase.

Improved outcome at 90 days in patients who

received endovascular therapy compared to placebo.
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 Secondary Prevention Following an
Ischemic Stroke
Once the acute ischemic stroke has been
managed, typically within the first 24 to 48
hours after symptom onset,
◦ the focus shifts to prevent another stroke and
manage risk factors.

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Nonpharmacologic Therapy
Carotid Endarterectomy (CEA)
It is recommended to prevent ipsilateral stroke in
patients with
◦ symptomatic carotid artery stenosis of ≥ 70% when the
surgical risk is less than 6%.
It is not beneficial for
◦ symptomatic carotid stenosis < 50% and should not be
considered in these patients.
It is recommended within 14 days of the initial stroke
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Carotid Artery Stenting (CAS)
Less invasive procedure
CAS is an alternative to CEA in high-risk
surgical candidates with greater than
50% symptomatic carotid stenosis with a
surgical risk less than 6%

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Pharmacologic Therapy
ASA dose of 50 to 325 mg daily
Lower ASA doses are currently recommended
Clopidogrel
◦ slightly more effective than ASA and
◦ similar in efficacy to the combination of extended-
release (ER) dipyridamole plus ASA
Usual dose is 75 mg orally taken once daily.
◦ case reports thrombotic thrombocytopenic purpura
(TTP)
 Most occurred within the first 2 weeks of therapy
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An H2-blocker may be preferred in patients who
require both acid suppression and clopidogrel.
◦ Use of an alternate agent such as ticagrelor
Clopidogrel is considered first-line therapy in patients
who also have PAD or are allergic to ASA

Low-dose ASA plus clopidogrel combination therapy

◦ did not show a significant benefit in reducing recurrent
stroke compared with either clopidogrel or aspirin alone.
An increased risk of major bleeding was observed.
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Extended-Release Dipyridamole Plus Aspirin
Has been found to be more effective in
preventing stroke than either agent alone

Thecombination of ER dipyridamole plus

ASA to clopidogrel found
◦ no difference in outcomes, however,
◦ adverse events occurred more frequently in the
combination of ER dipyridamole plus ASA group.

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Ralph L. Sacco et al. N Engl J Med 2008
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 Meta-analysis findings

Figure 3. (A) A forest plot of comparison: any stroke; (B) A forest plot of comparison:
ischemic stroke.
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 In patients with minor strokes or TIA,
◦ dual antiplatelet therapy with aspirin and clopidogrel should be
initiated immediately and continued for 21 days.
 After a major stroke, dual antiplatelet therapy with aspirin
and clopidogrel should be initiated and continued for 90 days.
 However, guidelines differ slightly on their
recommendations
 When a patient is on therapeutic doses of ASA, yet
experiences a recurrent TIA or stroke,
◦ switching to either
 clopidogrel or
 combination of ER dipyridamole and ASA is a reasonable option.

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Oral Anticoagulants
Long-term anticoagulation with warfarin or
other newer agents is recommended
◦ in the primary and secondary prevention of
cardioembolic stroke.
The newer oral anticoagulants
◦ have only been studied for stroke prevention in
nonvalvular AF.

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Prevention of second ischemic event, if
patient has
◦ Atrial fibrillation (warfarin or DOACs),
◦ Rheumatic mitral valve disease (warfarin),
◦ Mechanical prosthetic heart valves (warfarin),
◦ Bioprosthetic heart valves (warfarin), or
◦ Left ventricular mural thrombus formation
(warfarin)

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Grangeret al. N Engl J Med 2011

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 Cumulative Hazard Rates for the Primary Outcome of
Stroke or Systemic Embolism, According to Treatment
Group.

Connolly SJ et al. N Engl J Med 2009;361:1139-1151.

Blood Pressure Management
Patients previously treated with
antihypertensives should be reinitiated on
therapy several days after acute ischemic stroke.
Diuretics, either alone or in combination with
an ACE-I,
◦ have been shown to be beneficial in reducing stroke
recurrence.
Goal less than 130/80 mm Hg

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Reduction in all modifiable risk factors
Management of diabetes and lipids based on treatment
guidelines,
Cessation of smoking,
Increased physical activity, and
Reducing alcohol use in heavy drinkers are additional
recommendations for management of patients with previous
stroke or TIA.

Statintherapy is recommended in patients with

previous stroke or TIA, regardless of history of CHD.
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Stephen M. Davis et al. N Engl J Med 2012.

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Treatment of Acute Hemorrhagic Stroke

Supportive Measures
There is no proven treatment for ICH.
◦ Management is based on neurointensive care
treatment and prevention of complications.
Manage the needs of the critically ill
patient including management of
◦ increased ICP, seizures, infections, and
prevention of rebleeding and
◦ delayed cerebral ischemia in patients with SAH.

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In those with severely depressed consciousness,
◦ rapid endotracheal intubation and MV.
BP is often elevated after hemorrhagic stroke;
◦ appropriate management is important to prevent rebleeding and
expansion of the hematoma.
In patients presenting with SBP >220 mm Hg,
BP lowering using continuous IV infusion is
recommended.
◦ Labetalol 10 to 80 mg IV boluses every 10 minutes up to a
maximum of 300 mg or Labetalol (0.5–2 mg/min) IV infusions or
◦ Nicardipine (5–15 mg/hour) IV infusions

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DVT prophylaxis with
◦ intermittent compression stockings should be
implemented.
In those patients with SAH,
◦ once the aneurysm has been treated, heparin may
be instituted.
In ICH patients with lack of mobility after 1
to 4 days,
◦ heparin or LMWH may be started.

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Nonpharmacologic Therapy
Evaluated for surgical treatment of SAH
and ICH.
In SAH, either
◦ clipping of the aneurysm or
◦ coil embolization is recommended within 72
hours after the initial event to prevent
rebleeding
Surgical removal of the hematoma in
patients with ICH is controversial.

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Pharmacologic Therapy
Delayed cerebral ischemia
◦ occurs 4 to 14 days after the initial aneurysm rupture
and is a common cause of neurological deficits and death.
Oral nimodipine is recommended in SAH to
prevent delayed cerebral ischemia.
Should begin no later than 96 hours following
SAH.
Nimodipine 60 mg orally every 4 hours for 21 days
following aneurysmal SAH
◦ reduces the risk of a poor outcome and delayed cerebral
ischemia.

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OUTCOME EVALUATION
Measure stroke outcomes based on
◦ neurological status and
◦ functioning of the patient after the acute event.

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Any Question?

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