Cerebrovascular Disease

Overview of Cerebrovascular Diseases

Introduction

predominates in the middle and late years of life

causes approx. 200,000 deaths in the US each year as well as considerable neurologic disability; 3^rd leading killer in US

these diseases cause either ischemia-infarction (85-90%) or intracranial hemorrhage (10-15%)

morbidity and mortality from cerebrovascular diseases has been diminishing in recent years, due largely to better recognition and treatment of the underlying arterial and cardiac diseases, including hypertension

Co-morbidity of atherosclerotic disease: CAD, cerebrovascular disease, PAD

Risk Factors: Non-modifiable Þ age, family history, sex; modifiable Þ smoking, DM, hyperlipidemia, HTN, obesity

Stroke – permanent neurological deficits caused by ischemic damage from thromboemboli to the retina or brain

Frequency of complete stroke: atherothrombotic (61%); cerebral embolus (24%); intracerebral hemorrhage (7%); sub-arachnoid hemorrhage (7%)

most cerebrovascular diseases present as the abrupt onset of a focal neurologic deficit

the deficit may remain fixed, or it may rapidly improve or progressively worsen

this abrupt onset of nonconvulsive and focal neurologic deficit is referred to as stroke or cerebrovascular accident (CVA)

Classification Of Cerebrovascular Diseases:

(1) Cerebral Ischemia-Infarction: Thrombotic occlusion and embolic occlusion (artery to artery and cardiogenic)

Cerebral ischemia is caused by a reduction in blood flow that lasts for several seconds or a few minutes.
If the cessation of flow lasts for more than a few minutes, infarction of brain tissue results.

Generalized reduction in cerebral blood flow due to systemic hypotension (e.g., cardiac arrhythmia, myocardial infarction, or hemorrhagic shock) usually produces syncope, infarction in the border zones between the major cerebral artery distributions, or widespread brain necrosis, depending on the duration of hypotension

FOCAL ischemia or infarction, on the other hand, is usually caused by disease in the cerebral vessels themselves or by emboli from a proximal arterial source or the heart.

Four Causes Of Ischemic Stroke

(1) Thrombosis (53%): Atherosclerosis, vasculitis, arterial dissection, hematologic disorders

Thrombotic strokes occur without warning symptoms in 80-90%. 10-20% are heralded by one or more transient ischemic attacks (TIA’s). Thrombotic strokes often present with stuttering and fluctuating symptoms that worsen over several minutes or hours.

(2) Embolism (35%): can be cardiac source or atherothrombotic arterial source

Embolic strokes usually present with a neurologic deficit that is maximum at onset

(3) Vasoconstriction: Vasospasm and reversible cerebral vasoconstriction

(4) Venous: Dehydration, pericranial infection, postpartum and postoperative states, systemic cancer

(2) Intracranial Hemorrhage: Intracerebral, Subarachnoid, Subdural (usually traumatic), and Epidural (traumatic)

Subdural and epidural hematomas are usually the result of trauma, not cerebrovascular disease
the majority of intracerebral hemorrhages are associated with hypertension

Subarachnoid hemorrhage (SAH) is usually due to a ruptured saccular aneurysm or, less commonly, an arteriovenous malformation

Cerebral Ischemia-Infarction

General Pathophysiology Of Cerebral Ischemia And Infarction:

within 10 sec after cerebral blood flow ceases: metabolic failure of brain tissue and EEG shows slowing of electrical activity

if the circulation is immediately restored Þ abrupt and complete recovery of function

if persists for a few minutes Þ neuronal injury

with restoration of flow, recovery of function takes several min/hr and may be incomplete. In addition, during the circulatory failure, the blood elements may sludge, the capillary endothelium may swell, and the blood flow may not reestablish itself, even when primary cause of the flow failure is corrected (the "no-reflow" phenomenon)

more prolonged periods of ischemia Þ frank tissue necrosis

Cerebral edema follows and progresses over the subsequent 2 to 4 days
if the region of infarction is large, edema may produce considerable mass effect with its attendant consequences

decreased CO Þ decreased cerebral blood flow Þ ischemic (border zone areas most vulnerable – watershed areas)

causes of cerebral ischemia and infarction are atherosclerosis with thromboembolism and cardiogenic embolism

Atherosclerotic Ischemia and Infarction

Atherosclerosis is maximal at arterial bifurcations, and it commonly affects the origin of the internal carotid artery in the neck and the origin of major and minor arterial branches inside the head

atherosclerotic plaques can cause an arterial stenosis that produces a hemodynamic obstruction to flow. If this regional ß in cerebral blood flow falls below a critical level, it will cause a transient or permanent ischemic event.

artery-to-artery emboli – important cause of retinal and hemispheric ischemia and infarction. When an atherosclerotic plaque on the arterial wall ulcerates, the necrotic material may dislodge and serve as emboli or may provide a surface on which aggregation of platelets and coagulation of fibrin occurs. The resulting fibrin clot also may dislodge into the arterial circulation, or it may enlarge and produce thrombotic occlusion of the artery

Lacunar infarcts are small infarcts in the deep white matter of the hemisphere or brainstem. Due to HTN-induced lipohyalinosis or arteriosclerosis of small penetrating arteries

although the exact cause of ischemia or infarction in a given patient with atherosclerosis is not always known, the primary abnormality is clearly atherosclerosis with its complicating lesion, the fibrous plaque. The plaque may result in stenosis or ulceration, with subsequent thrombosis or embolization

Clinical Manifestations Of Ischemic Stroke

typical ischemic stroke presents with the abrupt onset of a focal neurologic deficit

A TIA is manifested by a neurologic deficit lasting < 24 h (usually 5 to 20 min). It is often referred to as a mini-, warning, or transient stroke, because it quickly resolves but often portends an impending stroke. The deficit is focal and confined to an area of the brain perfused by a specific artery.

mechanisms for TIA’s are:

(1) low flow in an artery due to tight stenosis or occlusion

(2) embolism from heart, proximal arterial/atherosclerotic plaque debris, thrombus

any obstructive vascular process in extra- or intracranial arteries can cause low-flow TIA if collateral flow to potentially ischemic brain is also impaired, and can lead to arterial thrombosis; if symptoms persist >24 hrs, infarction has occurred

TIA’s are highly predictable for stroke – risk of stroke is 33% within 5 yrs of last TIA; also age and frequency of TIA’s increase risk (>5 TIA’s in 2 wks Þ 20% have stroke in 3 months, and 30% in 6 months)

Internal Carotid Artery Disease Þ attacks of transient monocular blindness; TIA’s; frequent unaccustomed headaches; associated history of CAD or PVD; neck bruits, retinal infarcts or cholesterol plaques

ACA (anterior cerebral artery) stroke: contralateral hemiplagia

Posterior circulation (large vessel disease): cranial nerve dysfunction; cerebellar involvement; Horner syndrome; ANS nuclei and tracts; abnormal respiratory control; altered LOC; corticospinal, spinothalamic involvement

Reversible ischemic neurologic deficit (RIND) is an infrequently used term that defines an ischemic event in which the deficit usually recovers over a 24- to 72-h period, but which may take as long as 1 week to resolve

Completed stroke (cerebral infarction) of the thrombotic type is generally nonhemorrhagic. It typically evolves to its maximal deficit within a few hours. Often, patient awakens with a completed deficit. A completed stroke is sometimes heralded by one or more TIA’s in preceding days/weeks/months, most likely when tight arterial stenosis is causative.

In progressing stroke, or stroke-in-evolution, the focal ischemia worsens from min to min or hr to hr. There are usually stepwise incremental increases in neurologic deficit occurring over a several-hour period. While there may be several pathogenic mechanisms producing a progressing stroke, one such mechanism appears to be a thrombus-in-evolution, with a thrombus extending from its site of origin in a primary artery and progressively obliterating collateral branches, thereby interfering with anastomotic vessels.

the hallmark presentation is the abrupt onset of a hemiparesis in an individual in the atherosclerotic age group.

Lacunar Disease

lacunar infarction refers to infarction following atherothrombotic or lipohyalinotic occlusion of one of the penetrating branches of the circle of Willis, middle cerebral artery stem, or vertebral and basilar arteries.

deficit evolves gradually with frequent fluctuations and progression

Pathophysiology

the middle cerebral artery stem, the arteries comprising the circle of Willis, and basilar and vertebral arteries all give rise

to 100- to 300-m m diameter branches that penetrate the deep gray and white matter of the cerebrum or brainstem

each of these small branches can thrombose either by atherothrombotic disease at its origin or by the development of lipohyalinotic thickening. Thrombosis of these vessels causes small infarcts that are referred to as lacunes

HTN (also DM) is principal risk factor for such small-vessel disease. Lacunar infarcts cause ~20% of all strokes.

Penetrating and branch artery disease Þ subintimal foam cells and deposition of fibrinoid material within vessel walls, therefore NO penumbrum (no collateral flow); whorles, tangles of connective tissue

Syndromes Þ pure motor hemiparesis, dysarthria-clumsy hand, pure sensory deficit (thalamic syndrome), and sensory-motor strokes

Laboratory And Imaging Evaluation

accurate diagnosis is based largely on the history and examination, supplemented by judicious use of blood tests and imaging of the brain [CT and MR imaging (MRI)] and its blood vessels (arterial Doppler ultrasonography, MRA (magnetic resonance angiogram) and x-ray angiography, and invasive angiogram (gold standard))

electrocardiogram (ECG) may demonstrate conduction abnormalities and arrhythmias or reveal evidence of recent MI

CT scan will often demonstrate an area of infarction and will confirm or exclude the presence of an intracerebral, subdural, or epidural hemorrhage or other mass lesion. Moreover, it may demonstrate large aneurysms and AVM’s and subarachnoid or intraventricular blood.

A lumbar puncture (LP) will confirm or exclude subarachnoid hemorrhage or meningitis due to syphilis or other chronic infections. An LP should not be performed on patients with intracranial mass lesions

MRI scanning is the most sensitive method to detect embolic infarction

Ex: large MCA infarct Þ 1^st step is CT Þ 2^nd MRI of brain Þ 3^rd diffusion weighted MRI (shows abnormal perfusion)

Treatment and Prevention

of the atherosclerosis factors, hypertension is of the greatest importance. In general, all HTN should be treated.

General Measures: avoid hyperglycemias; nutrition support; normothermia; dVT prophylaxis; infection prevention; seizure control; maintain fluid and electrolyte balance

Blood Pressure management (decrease BP below 180 SBP before therapy)

Other Therapeutic Options:

(1) Antiplatelet agents:

Platelet antiaggregation agents prevent atherothrombotic events, including TIA and stroke. They inhibit the formation of intraarterial platelet aggregates that can form on diseased arteries, induce thrombus formation, and occlude the artery or embolize into the distal circulation. Aspirin and ticlopidine are used most.

Aspirin – Its antiplatelet effect is accomplished by acetylating the cyclooxygenase enzyme in platelets. This irreversibly inhibits the formation in platelets of thromboxane A₂, a platelet aggregating and vasoconstricting prostaglandin. Aspirin also inhibits the formation in endothelial cells of prostacyclin, an antiaggregating and vasodilating prostaglandin.

Ticlopidine (and clopidogrel bisulfate) – blocks the ADP receptor on platelets and thus prevents the cascade resulting in activation of the glycoprotein IIb/IIIa receptor that leads to fibrinogen binding to the platelet and consequent platelet aggregation. Ticlopidine is more effective than aspirin. Side effects: neutropenia, diarrhea, and skin rash

Dipyridamole is an antiplatelet agent that acts by inhibiting platelet phosphodiesterase, which is responsible for the breakdown of cyclic AMP. The resulting elevation in cyclic AMP inhibits aggregation of platelets

(2) Anticoagulation therapy:

Heparin (ie nadroparin) is widely used for "unstable TIA " (i.e., crescendo or recent-onset TIA)
if long-term anticoagulation is chosen, warfarin is administered.

(3) Surgical therapy: carotid endarterectomy, microsurgery, neuroendovascular, stereotactic radiosurgery

surgery for atherosclerotic occlusive disease is largely limited to carotid endarterectomy for plaques located at the origin of the internal carotid artery in the neck; clamp off arteries Þ make incision Þ clean out plaque Þ stitch up

surgery in the proximal common carotid, the subclavian, and the vertebral arteries is uncommon.

anastomosing extracranial scalp arteries to major intracranial arteries to bypass inoperable obstructions in the internal carotid artery is of no value.

Stenosis < 50% Þ antiplatelet therapy; no benefit with surgery

Stenosis 50-70% Þ usually surgical benefit; individualize to patient

Stenosis >70% Þ surgery benefits

Asymptomatic patients and stenosis > 60% Þ carotid endarterectomy provides absolute risk reduction of 5.8% over 5 yrs; relative risk reduction of 55% (decrease risk from 2% to 1% so not as overwhelming as it looks); no effect shown in women, only helpful for men

Neuroendovascular therapy Þ minimally invasive surgery Þ carotid artery stenting; no more effective than surgery

(4) Angioplasty and stenting

HHH therapy (HTN, hemodilution, hypervolemia) Þ present with vasospasms, thus Ý BP and flow to areas of brain

Treatment (Acute management)

when cerebral infarction occurs, the immediate goal is to optimize cerebral perfusion of the ischemic area

Thrombolysis – lyse the clot

t-PA: give if within 3 hrs of deficit; IV administer if within 6 hrs – anti-coagulant

do not give to patients with hemorrhage or people with signs of infarct on CT Þ may increase chance of hemorrhage

Pathology

cerebral infarcts may be pale (nonhemorrhagic) or red (hemorrhagic).

Vascular congestion of varying degree is common in all infarcts, but extravasation of blood is usually associated with embolic infarcts.
because emboli migrate and lyse, recirculation into the infarcted brain may cause petechial hemorrhages.
sometimes there is enough seepage of blood into the infarct to cause visible hemorrhagic infarction on a CT scan.
infarcts in the distribution of small, penetrating arteries leave small cavities or lacunes (lacunar infarcts), whereas major arterial occlusions produce a wide area of necrosis that leaves a large, fluid-filled cavity in the brain.

Edema invariably accompanies the tissue necrosis. In small infarcts it may be relatively insignificant. In large infarcts, however, massive edema compresses adjacent tissue and adds to the ischemic process; it also increases intracranial pressure and may cause herniation of the brain from one intracranial compartment to another.

Intracranial Hemorrhages

Intracerebral Hemorrhage

most common type of nontraumatic intracranial hemorrhage. Important cause of stroke, esp. in Asians and blacks.

hypertension and cerebral amyloid angiopathy cause the majority of these hemorrhages. Minor causes Þ tumors and vascular malformations

advanced age and heavy alcohol consumption increase the risk. Cocaine-induced hemorrhage is one of the most important causes in the young.

Symptoms Þ headaches plus something else

Causes of Intracranial Hemorrhage: Spontaneous intracerebral hemorrhage (hypertensive, amyloid angiopathy);

Ruptured arteriovenous malformation (saccular, mycotic); Ruptured aneurysm; Cocaine, amphetamines; Trauma;
Bleeding with brain tumors; Systemic bleeding disorders, including anticoagulation therapy; Hemorrhagic infarction

Pathophysiology And Pathology

intracerebral hemorrhage usually results from spontaneous rupture of a small penetrating artery deep in the brain.

the most common sites are:

(1) the basal ganglia (putamen, thalamus, and adjacent deep white matter)
(2) the deep cerebellum

(3) the pons

the small arteries in these areas seem most prone to hypertension-induced vascular injury

the leak may be small, or a large clot may form and compress adjacent tissue, causing herniation and death

rupture or seepage into the ventricular system often occurs; primary intraventricular hemorrhage is rare

if the patient survives, the clot liquefies, is absorbed, and leaves only a small residual cleft

most hypertensive intracerebral hemorrhages develop over 30 to 90 min, whereas those associated with anticoagulant therapy may evolve for as long as 24 to 48 h. Once bleeding stops, it generally does not start again. Within 48 h macrophages begin to phagocytize the hemorrhage at its outer surface. After 1 to 6 months, the hemorrhage is generally resolved.

Morbidity – 88% disability; 33% mortality Þ very deadly disease

Prevention: Hypertension is the leading cause of primary cerebral hemorrhage. Prevention is primarily aimed at reducing hypertension, excessive alcohol use, and use of illicit drugs such as cocaine and amphetamines.

Treatment (Acute Management) – ~75% with a hypertensive intracerebral hemorrhage die. Size/location of the hematoma determines prognosis.

surgical evacuation of hematoma in certain instances Þ indications for surgery are uncertain!

Mannitol (osmotic agent) ß intracranial pressure that has been raised by the volume of the hematoma and edema

Subarachnoid Hemorrhage

the commonest cause of spontaneous SAH is a ruptured saccular aneurysm; can occur any time after adulthood

other causes – bleeding from an AVM or extension into the subarachnoid space from a primary intracerebral hemorrhage

Pathophysiology And Pathology

Saccular aneurysms occur at the bifurcations of the large arteries at the base of brain and rupture into subarachnoid space in the basal cisterns
~85% of aneurysms occur on the anterior circulation (15% in posterior circulation), mostly on the circle of Willis.

Clinical Manifestations

Aneurysms can undergo small ruptures and leaks of blood into the subarachnoid space, so-called warning leaks

Sudden unexplained headache at any location should raise suspicion of SAH

At the moment of aneurysmal rupture with major SAH, the intracranial pressure suddenly rises. Abrupt, severe, and generalized vasospasm may occur transiently. These events may account for the sudden transient loss of consciousness that occurs in nearly half of patients Þ the hemorrhage is not the problem, the increased intracranial pressure is!! (if it continues to increase, on perfusion to brain)

the headache (usually generalized) is often called by the patient "the worst headache of my life."

Vomiting is common and when coupled with sudden headache should always raise the suspicion of SAH.

Diagnosing headaches – differentiating from SAH

sentinel: sudden onset; no history of headaches – most likely to be SAH

tension: bilateral pain; contraction of neck or pericranial muscles; no neurologic events

migraine: history of headache; gradual onset; visual disturbance; nausea; throbbing quality

cluster: unilateral pain; no visual/cerebral symptoms; facial erythema; rhinorrhea; brief

Laboratory And Imaging Evaluation (The hallmark of aneurysmal rupture is blood in CSF)

CT scan confirms 95% of SAH’s – if scan negative, or headache for > 4 days; lumbar puncture indicated

the extent and location of subarachnoid blood on CT scan help locate the underlying aneurysm and identify the cause of any neurologic deficit. The clot also will help predict delayed vasospasm.

A noncontrast CT scan should be done first, because on an enhanced scan normal arteries in the basal cisterns may be mistaken for clotted blood.

LP prior to scanning is indicated only if a CT scan is not available at the time of the suspected SAH.
Once the diagnosis of hemorrhage from ruptured saccular aneurysm has been established, four-vessel angiography (both carotids and vertebrals) is generally performed to localize and define the anatomic details of the aneurysm and to determine if other unruptured aneurysms exist.

Treatment: endovascular surgery (put platinium coils into the aneurysm); gamma knife surgery

Arteriovenous Malformation

Vascular malformations, or angiomas, may be tiny and cryptic or massive anomalies that cause headaches, brain damage, seizures, and hemorrhages
AVM’s are the most important vascular malformations of the nervous system and consist of a tangle of abnormal vessels forming an abnormal communication between the arterial and venous systems
Most are developmental arteriovenous fistulas in which the involved vessels enlarge with the passage of time.
AVM’s vary in size from a small blemish a few millimeters in diameter to a huge mass of tortuous channels.
Hypertrophic and dilated arterial feeders approach the main lesion, disappear below the cortex, and break up into a network of thin-walled blood vessels that connect directly with draining veins. These often form huge, dilated, pulsating channels carrying away arterial blood.
the blood vessels forming the tangle interposed between arteries and veins are usually abnormally thin.
AVM’s occur in all parts of the brain, brainstem, and spinal cord, but the largest ones are most frequently in the posterior half of the hemispheres; AVM’s are more frequent in men
the chief clinical symptoms and signs are headache, seizures, and those associated with rupture.
AVM’s less than 0.5 cm in diameter are usually low-pressure venous angiomas that bleed infrequently and minimally
If they bleed, surgical or gamma-knife resection or obliteration should be considered.
Lobar pattern of hemorrhage on CT scan

Treatment: endovascular or gamma knife surgery