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

After the occlusion of the vessel:

Neurovascular unit

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 re- vascularization) 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 the clinical signs of different types of stroke)

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

The Heart

Small vessels

Blood

Big vessels

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 nonvalvular 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

Genetic defect on Notch 3 gene (cromozome 19) Clinical phenotype - variable combinations of:
Migraine with aura Seizures Ischemic stroke Dementia

Arteriopathy with Subcortical Infarction and Leukoencephalopathy

Fig. 1

Fig. 2

Fig. 1 MRI aspect of CADASIL. Typical white matter lesions are seen as a hypersignal in FLAIR sequencewhite arrows Fig. 2 : evolutive pattern of CADASIL (it is not mandatory to have all the clinical manifestations but the majority of patients finally will be demented)

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, CK- MB, 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 carotid artery

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)

MCA

ACA

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 Correct the glycaemia, electrolytes
Do not give Glucose iv (5 or 10%), unless you have to correct hypoglycaemia because it will worsen acidosis

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
Proven efficacy in 2 large trials (NASCET, ECST) Possible complications:
Hypoglossus paresis Complications related to anesthesia Acute thrombosis after endarterectomy restenosis
Patients with endarterectomy should receive one antiplatelet drug, Clopidogrel or Aspirin

Angioplasty with stenting

Increased efficay after improvement of technique and th use of protective filters Possible complications:
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 reinsertion 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