Ischemic stroke

Objectives
Pathophysiology of
ischemic stroke
Imagistic aspects
Etiology
Clinical aspects
Diagnosis
Treatment

Ischemic stroke = absence of the

blood flow
Consequences of the vascular occlusion depend on the dimensions of the
vessel and on the presence and patency of the brain vessels anastomosis
Cervical occlusion of ICA circulation can be compensated by ACoA or
PoCoA. External carotid artery can be another source of supply, through
ophtalmic artery or other anastomosis
VA Occlusion compensatory flow can be provided by deep cervical
arteries, , thyreocervical arteries or from the contralateral VA
MCA/ACA occlusion (outside the circle of Willis) meningeal anastomosis
In case of the occlusion of a big artery, the cerebral infarction can vary
between

0 100% of the area vascularized by the occluded vessel

Neurovascular

After the occlusion of the

unit vessel:

lack of oxygen and glucose

failure of energy production
distruction of cell
components, of membranes
cell death

Depending on the duration

of the vessel obstruction
and on the level of the
blood flow, theese changes
can be permanent or
reversible

Cerebral blood flow (CBF)

CBF = Cerebral blood volume (CBV)/Mean transit time (MTT)
CBF level influences the dimension of stroke (cerebral infarction)
Initial event : increase in MTT due to the occlusion or stenosis of a vessel
MTT is influenced by the place of the occlusion/stenosis and by the
presence of collaterals
In response to the increase of MTT the mechanisms of cerebral
autoregulation determine the vasodilation of the vessels distally from the
site of occlusion and the increase of oxygen extraction rate from the blood
Vasodilation leads initially to an increase of CBF in order to maintain a
constant level of blood flow supply despite the obstruction of the vessel
When the capacity of vasodilation is exhausted, the MTT will continue to
increase, the cerebral blood volume will decrease and finally the CBF will
decrease upt to levels which are incompatible with survival
Neuronal death (necrosis) will occur

Hemodynamics
Normal CBF = 55 mL/100gr cerebral tissue /min
CBF < 10-12ml/100gr/min leads to infarction irrespective of
the duration of the occlusion
Critical hypoperfusion = 23-12 mL/ 100gr/ min neuronal
function is abolished and the brain tissue is affected
EEG shows slow waves
Below this level the EEG becomes flat (iso-electric)

CBF of 6-8 ml/100gr/min :

ATP depletion, K extracelular, Ca intracelular, celular

acidosis histologic signs of necrosis
Activation of phospholypases distruction of neuronal
membrane
Accumulation of Prostaglandines, Leucotriens, Free radicals
altered intracelular enzymes and proteins
neuronal balonization cytotoxic edema

Ischemic stroke = absence of the

blood flow
Some of these processes are reversible (by revascularization)
In the center of the ischemic area the lesions are
irreversible (necrotic core)
The margins of this area are hyperemic, being vascularized
by collaterals in this area the neurons are at risk, but
can be salvaged if the blood flow is re-established

From pathophysiology
to imagistic aspects

Magnetic resonance imaging

DWI/PWI mismatch
Diffusion Weighted Imaging
(DWI) reflects biochemical
compromise (core of infarction)
Changes are visible within the
first hour after vessel obstruction
(in 3 h 100% of patients will
show hanges on DWI sequences)
Perfusion Weighted Imaging
(PWI) reflects hemodynamic
compromise
The differences between the two
areas represents the salvageable
tissue (penumbra)

MRI aspects

In the first hours, on T2 seq stroke

is not visible, but it can be seen on
DWI (red arrow)

Early signs
Noncontrast CT of the head is
the first-line imaging modality
for the assessment of strokes
to differentiate ischemic from
hemorrhagic strokes and to
rule out other intracranial
pathologies. It is very sensitive
at detecting intracerebral and
subarachnoid hemorrhages, as
well as subdural hematomas.
Hemorrhage appears as a
readily identifiable hyperdense
area within the brain.

The CT reveals early signs of a

middle cerebral artery stroke,
with loss of definition of the
gyri and grey white boundary
(arrow)

Early signs
In ischemic strokes, an early head
CT may be grossly normal because
edema and infarction have not yet
developed adequately to be
identified. However, other subtle
findings may include:
loss of the gray-white matter
differentiation (red arrow)
obscuration of the lentiform
nucleus (white asterisk)
sulcal asymmetry (yellow arrow)
an insular ribbon sign
Hyperdense MCA

This CT scan was taken 24 h after a stroke

Hyperdense MCA

M1 segment

M1 segment

M2 segment the dot

sign

Figure 4. A. Axial unenhanced CT image, obtained in a 73-year-old woman 21/2 hours after the onset
of left hemiparesis, shows hypoattenuation and obscuration of the posterior part of the right
lentiform nucleus (white arrow) and a loss of gray matterwhite matter .
B. Normal aspect (I = insula, C= caudate nc, L= lentiform nc, IC = internal capsule),
M1 M3 arterial territory of MCA

Srinivasan A et al. Radiographics 2006;26:S75-S95

2006 by Radiological Society of North America

Sub- acute
stroke
As the ischemic cascade
progresses, more signs are visible on
head CT. Effacement of the third
ventricle (blue arrow), a midline shift
(yellow line), hypodense areas in a
vascular watershed pattern, and sulcal
effacement (red arrow) will develop over
time. Midline shift may be subtle and is
best determined by drawing a line from
the anterior to posterior attachments of
the falx cerebri and looking for any
deviation. The head CT shown was taken
on day 3 after an acute ischemic stroke.

Hemorrhagic
transformation

Presence of the blood (white arrow) in an area of brain

ischemia, due to late recanalization of some of the
occluded vessels and passage of the blood into the brain
parenchima through the altered blood brain barrier

Old stroke

Old lesions are intensely hypodense, similar to

CSF density (red arrows)

Risk factors for stroke

Non- modifiable :

Age
Gender
Family history of stroke
Personal history of stroke

Modifiable

Arterial hypertension
Hypercholesterolemia
Diabetes
Smoking
Obesity
Physical inactivity

Clinical aspects
Practically every neurological sign and symptom due to a
dysfunction of the Central Nervous System can be caused
by a transient or permanent occlusion of a vessel
If the signs and symptoms are transient and the imagistic
studies (MRI) do not show a lesion of the brain, we call this
a transient ischemic attack (TIA) . The definition of the TIA
admits a duration of the symptoms 24 h, but typical TIAs
last 1 h.
If the occlusion is permanent, a cerebral infarction will
occur and we call this an ischemic stroke

The media campaign for increasing public awareness towards stroke included the most
frequent signs of stroke, and stressed out the importance of acting fast, because time
is brain
Facial paresis, decrease in force of the arm or leg, dysarthria or aphasia are present in
almost 2/3 of strokes
Other signs, like cerebellar signs, hemianopia, brainstem signs can occur if the affected
vessel is in the vertebro-basilar territory (see also the lecture about brain arteries for

TIA transient ischemic attack

TIA is an emergency !
The patient must be evaluated rapidly and treated because
acting in this way we can prevent a permanent stroke
Causes and mechanisms for stroke and TIAs are similar
(will be detailed in the next slides)
The clinical judgement of the case and the investigations
are similar for stroke and TIA
Treatment for the acute period and for secondary
prevention are similar for stroke and TIA
The ABCD2 score is a risk assessment tool design to predict
short term stroke risk (at 2 days) but also stroke risk at 90
days from the TIA

Even if the patient is not

hospitalized, he/she must be rapidly
evaluated and treated

Stroke etiology
Small
vessels

The
Heart

Bloo
d

Big

The Heart
Left atrium

Thrombi due to atrial fibrillation

Atrial mixoma

Valves (Mitral valve, Aortic

valve)
Prosthesis

Mechanical (metallic)
Biological

Endocarditis

Infectious
Non- infectious
Marantic (para neoplastic)
SLE (Liebman- Sachs)

The Heart
Ventricles
Myocardial infarction
(hypokinesia, aneurysms and
thrombi)

Paradoxical embolism
Persistent Foramen Ovale
(PFO)
Interatrial septal defect
Interatrial septal aneurysm

Atrial fibrillation
The most common cause of
cardioembolic stroke
Any form of atrial fibrillation
can cause a stroke
(paroxysmal or permanent)
AF is more frequent in men,
but strokes due to AF are
more frequent in women
(reasons are not clear )
Prevalence of AF increases
with age

The majority of cases are

non-valvular AF, but AF
can be associated with
valvular disease (mitral
stenosis)
A person with AF and
stroke must receive
anticoagulant therapy
(unless there are clear
contraindications for long
term oral anticoagulants)

PFO
In order to affirm a stroke due
to paradoxal embolism:
Presence of PFO
Right to left shunt
Presence of deep vein
thrombosis

Treatment :

Antiplatelet
drugs/Anticoagulant drugs (not
enough data)
If under treatment, a recurrent
stroke occurs we can consider
PFO closure (Amplazer device is
the most popular)
Epithelized device)

Big vessels:
I. Atheromatosis
II. Dissection

I . Atheromatosis
Plaques
Stenosis
Occlusion

Preferential sites: low shear stress regions : ICA bulb,

CCA bifurcation
Do not forget the aortic crosa !!! (sometimes, even if the
ICA is clean, we can identify ateromatous plaques with
thrombosis on the aortic crosa by Trans Esophageal
Ecocardiography)

Big vessels : Atheromatosis

Plaques

Accumulation of lipids (foam cells) in tunica media

Hyperplasia of smooth muscle cells
Hypertrophy of smooth muscle cells
Colagen fibers
Neo- vascularization (sometimes these vessel bleed and intraplaque
hemorrhage maques the plaque unstable)
Calcifications

There is endothelial dysfunction and the endothelium above the

plaque is prone to rupture (exposes the lipid core, and causes
thrombosis)

Thrombosis in situ, with complete acute occlusion of the vessel

Arterial embolism : thrombus will be fragmented and will occlude smaller
vessels

Atheromatous plaques

Atheromatous plaques can be

visualized by Doppler Ultrasound
examination

Atheromatosis: stenosis, occlusion

Stenosis
High velocities inside stenosis
(Can determine the rupture of
the plaque and arterial
embolism)
Combined with a decreased
systemic blood pressure can
lead to hemodynamic
infarction (low flow infarction,
watershed infarction =
infarcts that occur between
superficial territories of main
vessels or between superficial
/deep territory of one main
vessel (ACA, MCA, PCA)

Doppler Ultrasound : extracranial

(ECD) can visualize stenosis or
occlusion (yellow arow)

Doppler ultrasound transcranial

(TCD)
Gives us information about the
circle of Willis

Transtemporal approach; through a good

window one can easily visualize MCA,
ACA, PCA

Watershed infarction

II. Dissection
Young patients

Minor trauma
Idiopatic
Extension from aortic dissection (rare)

Clinical aspects :

Stroke or TIA
Lateral cervical pain
Claude Bernard Horner Syndrome
Pulsatile Tinnitus
headache
Hypoglossus paralysis

Location : most frequent in the

carotid channel (the bone channel
through which the ICA enters into the
skull)
The mechanism : cleavage between
intima and media; blood enters
between intima and media, can cause
stenosis or occlusion; about 30% of
dissections recanalize

Ecographic aspect of aspect of

ICA

Small vessels
Small arteries : diameter between
100 400 mcrons
Arterioles: Vessels with a diameter
< 100 microns
The strokes will have small
dimensions and are called lacunar
infarcts (yellow arrow); are situate in
the subcortical white matter, basal
ganglia, brainstem (especially pons)
Main causes:
Arterial hypertension
Diabetes mellitus
Vasculitis
Inflammatory
Isolated CNS vasculitis
Secondary (infectious, in cancer, toxic
origin, autoimmune disorders)

Non- inflammatory
Susac syndrome
Sneddon Syndrome
Post-partum angiopathy

Genetic disorders : CADASIL

CADASIL :Cerebral Autosomal Dominant

Arteriopathy with Subcortical Infarction and

Fig. 1
Genetic
defect
on
Notch
3
Leukoencephalopathy
gene (cromozome 19)
Clinical phenotype variable combinations of:

Migraine with aura

Seizures
Ischemic stroke
Dementia

Fig. 1 MRI aspect of CADASIL. Typical

white matter lesions are seen as a
hypersignal in FLAIR sequence- white
arrows
Fig. 2 : evolutive pattern of CADASIL (it is
not mandatory to have all the clinical

Fig. 2

Blood
Red cells
Policytemia vera
Sickle cells disease

White cells
Leukemias (acute or chronic)
Lymphoma (there is a rare form of intravascular
lymphoma)

Platelets
Thrombocytosis
Thrombocytopenia (i.e in thrombotic thrombocytopenic
purpura)

Plasma
Waldenstrm Macroglobulinema

Thrombophilias
Hyperhomocysteinemia
Antiphospholipid antibodies

How we diagnose stroke ?

Anamnesis:

Medical history (risk factors, associated diseases, age, family history

of stroke)
Sudden onset (it is important to establish exactly the moment of
onset, and the time interval from the onset to the emergency room)
Rapid progression of the clinical signs
Altered consiousness or coma with focal neurological signs (in
massive strokes or vertebro- basilar strokes)

Clinical exam

From clinical point of vue, a sudden or a subacute onset can also be

determined by:

Cerebral hemorrhage
Subdural hematoma
Necrosis or hemorrhage inside a brain tumor (primary tumor or a metastasis)
Acute enkephalytis

How we diagnose stroke ?

Clinical exam
Stroke mimics (ask about headache, seizures or psychiatric antecedents it
can also be a migraine, a post seizure paresis (Todd paresis) or malingering)

Cerebral CT scan (mandatory !)

Can differentiate immediately between ischemic and
hemorrhagic lesions
Can differentiate ischemic stroke from other lesions (tumors,
trauma)

In daily practice CT is usually enough for the diagnostic.

If there is a problem of differential diagnostic, CT with
contrast or an MRI will be neccesary

Our patient has a stroke.

Why did this happen?
If we know the cause, we will be more efficient in preventing a
second ischemic stroke
You keep in mind the list of possible etiologies (keep in mind the
frame; there are many other causes ot inccluded on the slides)
Start looking for the most frequent causes
Continue by searching the less frequent
Despite our extensive search arround 20% of strokes will remain
classified as undetermined etiology
Searching the cause can take several days, sometimes weeks.
The patient will be treated from the beginning, according to
general principles of treatment for the ischemic stroke and the
treatment will be adjusted later if it is neccessary the according
to the results of the investigations

First line investigations

(after we have
performed CT scan (or MRI), and we know it is an ischemic
stroke)
Measure arterial blood pressure (ABP), heart rate,
respiratory rate, pulse oxymetry, body temperature
ECG
Blood analysis (FBC, ESR, cogulation tests, glycemia, AST,
ALT, BNU, creatinine, LDL- cholesterol, HDL-chol, CK, CKMB, LDH)
Doppler ultrasound (ECD + TCD)
Transthoracic ecocardiography (TTE), and in selected
cases, transesophageal ecoardiography (TEE)

Second line investigations

ECG continuous monitoring on 24 hours (purpose : to discover
episodes of paroxysmal AF, or other rhythm disorders)
BP monitoring on 24 hours (purpose : to adjust the treatment)
CTA, MRA (combined with Doppler can quantify stenoses)
Angiography (can offer a precise measurement of stenosis, can
certify an occlusion, may identify specific changes in small vessel
vasculitis)
Blood analysis for thrombophilias, vasculitis, certain infectious
diseases (like shyphilis), dosage of alfa galactosidase (for Fabry
disease)
Skin biopsy : osmiophilic garnulations (in CADASIL)
And other...

CTA (computed tomography

angiography)
Can visualize intracranial/
extracranial vessels :
Stenosis
Occlusion
Aneurysms
Arterio- venous
malformation
Fig. 2 : Normal aspect of
supraaortic vessels (CCA, ICA,
ECA, subclavian A, VA, basilar
artery

Fig. 2
Fig. 1 : stenosis of the internal

MRA (Magnetic resonance

angiography)

Can visualize intracranial/

extracranial vessels :
Stenosis
Occlusion
Aneurysms
Arterio- venous
malformation
Fig. 1 : Circle of Willis
MCA
ACA
ICA
PCA
Basilar artery
Vertebral
artery

DSA. Digital subtraction

angiography
The gold standard for vessels` investigation
A four vessel angiography should be performed (injection
of contrast substance through both ICA and both VA
Image can be rotated so that the localization of an abnormal
finding (stenosis, aneurysm) can be very precise
Can differentiate between stenosis/occlusion
Can visualize arterio-venous malformations (AVM) and
identify feeding arteries and drainage veins
Can visualize specific changes in vasculitis (narrowing of
small vessels)

DSA (digital subtraction

angiography)

MC
A

AC
A

Small infarctions in the basal ganglia and cortex (blue arrows) and focal narrowings
of the small vessels (yellow arrows) in a case of postpartum angiopathy

Management of stroke patients

I.

Primary prevention

II. Acute stroke treatment

III. Secondary prevention
IV. Neurorehabilitation

Primary prevention
Treat the risk factors

Arterial hypertension (the best results seem to be with ACE inhibitors +

indapamide)
Diabetes mellitus: keep glycemia into normal ranges
Dyslipidemia : use statins
Cholesterol dependent effects : they decrease LDL chol and triglycerides (use
guidelines for the target level of LDL chol)
Non- cholesterol dependent effects: statins improve endothelial dysfunction,
stabilize the plaque, may determine the decrease of plaque dimensions)

Change lifestyle : less food, less alcohol, more sports, no

smoking !
Use existing scores to calculate risk (i.e SCORE risk)
Do not use routinely Aspirin for primary prevention of stroke. It
was not proven to be efficient. Use Aspirin when the patient has
a high risk of stroke, like high grade carotid stenosis
Use anticoagulants if the patient has a proven source of cardiac
emboli or if he/she has AF with a CHADS score 2

For AF use CHADS2 or CHADS- Vasc

score

CHADS- vasc
Attention !
When a person already
had a stroke we are
speaking about secondary
prevention !

II. Management of acute stroke

Admit the patient in the stroke unit
(monitoring, specialized personnel)
Stabilize the vital functions

Intubate if necessary
Give oxygen if needed
IV lines for hydration and medication

Do not give Glucose iv (5 or 10%), unless

you have to correct hypoglycaemia
because it will worsen acidosis

Correct the glycaemia, electrolytes

Treat cerebral edema with Mannitol

20% 125 ml, iv perfusion, slow rhythm,
maximum dose 6 perfusions/day
Lower body temperature in case of
fever *

* hypothermia (around 32 C can be an

important method for neuronal protection,
but it is not a routine for the moment

In the first 48 hours after stroke

treat blood pressure only if it
exceeds
220/120 mm Hg
If the patient is a candidate for
thrombolysis, the cut-off value is
185/110 mm Hg
Stroke is a stressful condition for the
patient and blood pressure increase
is a compensatory reaction.
Lowering blood pressure will
aggravate the patients prognostic
Do not lower fast the blood pressure
Preferred drugs:
Labetalol
Enalapril iv (when Labetalol is not
available)

Management of the acute stroke

Thrombolysis
Criteria for thrombolysis:

Interval from stroke onset to thrombolysis 4.5 h

TA < 185/110 mm Hg
Glycaemia > 50 mg/dL
Platelets > 100.000/mmc
There are a lot of exclusion criteria, listed in a protocol, so that
the physician can check everything, i.e:

- wake up stroke because there is no certainty about the moment of

stroke onset
- Surgical intervention in the last three weeks
- Hemorrhagic stroke in medical history
- Age < 18 years
- And others

Thrombolysis
Check inclusion/exclusion criteria
Cerebral CT scan
Give 0.9 mg/kg body weight of rTpa (recombinant tromboplasminogen
activated), but no more than 90 mg in one hour, with an initial bolus of 10%
The patient is monitored in the next 24 hours, especially for blood pressure
The sooner we give rTpa the greater are the chances to recanalize the
vessel (Time is brain); always try to gain time !
Complications :
Bleeding (especially brain hemorrhage)
Allergy to rTpa
Re- thrombosis after an initial recanalization (we can not repeat thrombolysis)

Intravenous thrombolysis can be combined with intraarterial thrombolysis

(bridging)
In selected cases (especially in basilar occlusion) intrarterial thrombolysis
(through catheterism) may be the irst choice

In a recent trial which compared

thrombolysis/mechanical devices
thrombolysis was proved to be more efficient

Management of acute stroke

If the patient is not a candidate for thrombolysis treat all the
complications (stabilize vital functions, treat infections, feed the
patient with iv solutions or nasogastric tube, prevent pressure
sores, prevent deep venous thrombosis); Of course we will treat
all these also in thrombolyzed patients
Aspirin is the only drug proven to be efficient in acute stroke :
325 mg/day
Anticoagulants are indicated in cardioembolic stroke, but if the
stroke is massive, has a spontaneous risk of hemorrhagic
transformation and it is better to delay anticoagulation 48- 72
hours; Aspirin will be given in this time interval
After thrombolysis antiplatelet or anticoagulants can be given
only after 24 hours.

III. Secondary prevention

Treat risk factors and associated diseases

For arterial hypertension the preferred combination is ACEI + Indapamide

Change lifestyle
Give oral anticoagulants in cardioembolic stroke (especially in
AF)

Acenocoumarol (Warfarin, Sintrom) : variable dosage, needs INR control

monthly (at least); in case of supradose or due to increase of the effect
because of associated drugs hemorrhage can occur.
The antidot: fresh frozen plasma
Direct thrombin inhibitors (Dabigatran, 150 mg bid or 110 mg bid); do not
need INR control, but Cr Clearance must be checked in case of dysfunction
of the kidney, the dosage must be decreased
Inhibitors of Factor X activated (Rivaroxaban, Apixaban) recently
approved by FDA

Secondary prevention
For all other strokes give antiplatelets
Clopidogrel 75 mg/day
Aspirin + Extended release Dipiridamol (Agrenox)
Aspirin 75 mg/day

If the patient is treated with Aspirin and has a recurrent

stroke , Aspirin will be replaced by Clopidogrel
The association of Clopidogrel + Aspirin increases the
risk of hemorrhages and should be reserved to selected
cases

Secondary prevention
Revascularization procedures
If a stroke occurs in the distribution territory of the
internal carotid artery and ICA has a stenosis of 70%, this
stenosis is considered symptomatic.
If no stroke occured and the discovery of the stenosis is
incidental, the stenosis is considered asymptomatic
Asymptomatic stenosis must not be re- vascularized
routinely
Symptomatic stenosis > 70% must be re-vascularized

The best results are obtained if the procedure is performed in the

first 14 days after stroke

All patients with

carotid stenosis
should receive:
Antiplatelets
Statins

Revascularization
Endarterectomy

Angioplasty with stenting

Proven efficacy in 2 large

trials (NASCET, ECST)
Possible complications:

Increased efficay after

improvement of technique
and th use of protective
filters
Possible complications:

Hypoglossus paresis
Complications related to
anesthesia
Acute thrombosis after
endarterectomy
restenosis

Patients with endarterectomy

should receive one antiplatelet
drug, Clopidogrel or Aspirin

Arterial hypotension
Acute stent thrombosis
Restenosis

Patients with carotid stenting should

receive for at least 30 days after the
procedure a combination of Clopidogrel 75
mg/day + Aspirin 75 mg/day

Carotid Stenting

ICA stenosis (white arrow), revascularization after introduction of the stent (red arrow),
and the aspect of the stent inside the vessel (yellow arrow)

IV Neurorehabilitation
It is very important for the recovery of normal functions, for social
and familial re-insertion of the patient
Should be started very early, in the post acute period
The neurorehabilitation team should include:

Neurologist, physiotherapist, logopedist, occupationl therapist, social worker

Every aspect should be assessed: motor function, spasticity,

equilibrum, deglutition, speech, cognitive disorders
Cognitive disorders are an important aspect in stroke patients. It is
not correct to diagnose dementia immediatey after stroke, but the
patients should be monitored and re- evaluated because incidence
of dementia is 9 fold increased in the first year after stroke
Depression also has an increased incidence and should be diagnosed
and treated because if untreated it influences negatively the
rehabilitation process