OBJECTIVE: To be able to discuss the signs and symptoms, what organ is affected, and pathophysiology of Cerebrovascular Disease.

y To be able to list the types of cerebrovascular disease (CVD) and the major causes of each. y Discuss the pharmacologic and surgical interventions in CVD. y

INTRODUCTION: Cerebrovascular disease (CVD) includes all disorders in which an area of the brain is transiently or permanently affected by ischemia or bleeding and one or more of the cerebral blood vessels are involved in the pathological process. Cerebrovascular Disease is the 4th highest caused of human deaths with 9.66% of annual worldwide deaths. In the developed countries, 3,346,000 deaths were recorded while 1,381,000 deaths were recorded in developing countries. This disease is commonly known as stroke. It is a group of brain dysfunctions related to disease of the blood vessels supplying the brain. The most important cause of stroke is hypertension; it damages the blood vessel lining, endothelium, exposing the underlying collagen where platelets aggregate to initiate a repairing process which is not always complete and perfect.

Types of Cerebrovascular Disease: A. Ischemic Stroke - A stroke is a serious medical condition that occurs when the blood supply to the brain is disturbed or interrupted. In order to function properly, the brain like all organs needs oxygen and nutrients that are provided by the blood. However, if the blood supply is restricted or stopped, brain cells will begin to die. This can lead to brain damage and possibly death. - An ischemic stroke occurs when the blood supply to the brain is blocked as a result of a blood clot (where blood thickens and becomes solid). This is the most common cause of a stroke. The main symptoms of a stroke can be remembered with the word FAST, which stands for Face-Arms-Speech-Time. Each of the symptoms is explained below.

y y

Face the face may have fallen on one side, the person may not be able to smile, or their mouth or eye may have drooped. Arms the person who has had a suspected stroke may not be able to raise both arms and keep them there due to arm weakness or numbness. Speech they may have slurred speech. Time it's time to dial 999 immediately if you see any of these signs or symptoms.

B. Subarachnoid hemorrhage - A subarachnoid hemorrhage is a less common cause of stroke. It occurs when blood leaks from blood vessels onto the surface of the brain. - During a subarachnoid hemorrhage the bleeding occurs in the arteries that run underneath a membrane in the brain called the arachnoid, which is located just below the surface of the skull. - Like all strokes, a subarachnoid haemorrhage is a medical emergency that requires immediate treatment to prevent serious complications, brain damage and death. Three quarters of all subarachnoid haemorrhages are the result of an aneurysm rupturing (bursting). An aneurysm is a bulge in a blood vessel that's caused by a weakness in the blood vessel wall. Other causes of a subarachnoid haemorrhage include: y severe head injury
y

arteriovenous malformations an uncommon type of birth defect that affects the normal formation of blood vessels

C. Transient ischaemic attack (TIA) - A transient ischaemic attack (TIA) or 'mini-stroke' is caused by a temporary fall in the blood supply to part of the brain, which results in a lack of oxygen to the brain. - This can cause symptoms that are similar to a stroke, although they don't last as long (stroke symptoms usually persist until treatment is provided). The symptoms of a TIA tend to last for a few minutes only. However, having a TIA should be taken seriously because it's an early warning sign. There's around a one-in-five chance that people who have a TIA will experience a full stroke during the four weeks that follow the TIA.

D. Vascular dementia - Dementia causes a range of related symptoms that are associated with an ongoing decline of the brain and its abilities. These include:
y y y y y

thinking language memory understanding judgement

Vascular dementia is the second most common type of dementia after Alzheimers disease. It's caused by brain damage that results from:
y y y

a stroke a TIA a silent brain infarction a type of mild stroke that doesn't cause any noticeable symptoms but still results in brain damage

SIGNS AND SYMPTOMS: 1. Internal Carotid Artery occlusion: a. no characteristic clinical picture b. may range from a TIA to infarction of a major portion of the ipsilateral (on the same side) hemisphere c. if adequate intracranial collateral circulation is present, may see no signs or symptoms d. Neurological symptoms: 1. monoparesis to hemiparesis with or without a defect in vision 2. impairment of speech or language 3. transient monocular blindness 2. Middle Cerebral Artery occlusion: a. most occlusions in the first portion of this artery are due to emboli and typically produce a neurological deficit b. opportunity for collateral circulation is restricted to anastomotic blood flow from the anterior and posterior cerebral arteries on the surface of the brain c. Neurological symptoms: 1. 2. 3. 4. hemiplegia (paralysis of one side of the body) hemisensory deficit hemianopsia (blindness in 1/2 of the visual field) aphasia (if infarct is in the dominant hemisphere)

3. Anterior Cerebral Artery occlusion: a. Neurological symptoms: 1. weakness of the opposite leg with or without sensory involvement 2. apraxia (particularly of gait) 3. possible cognitive impairment

4. Vertebrobasilar system: a. Neurological symptoms: 1. severe vertigo, nausea, vomiting, dysphagia, ipsilateral cerebellar ataxia 2. decreased pain and temperature discrimination 3. diplopia, visual field loss, gaze palsies

Other symptoms include: y y y y y y y y y y y y y Paralysis or weakness of an arm, leg and one side of the face. Numbness or tingling with decreased sensation. Changes in vision or loss of vision. Inability to speak or slurred speech, difficulty in reading or writing. Difficulty in swallowing or drooling. Nausea or vomiting. Loss of memory. Loss of balance or coordination. Personality changes. Change in mood such as depression or apathy. Drowsiness, lethargy or loss of consciousness. Uncontrolled eye movements or eyelid drooping. Unusually severe headache

ANATOMY: Over view of the Brain: A. B. C. D. FOREBRAIN- contains cerebrum and diencephalon MIDBRAIN- mesencephalon HINDBRAIN- cerebellum BRAIN STEM- pons and medulla oblongata

FOREBRAIN 1. Cerebrum a. Frontal lobe - Voluntary movement and language center (Brocas Area)

b. Parietal lobe - Sensory Impulses and tactile sensation

c. Temporal lobe - Memory, emotions, taste, smell, auditory (Wernix Area)

d. Occipital lobe - Visual perception 2. Diencephalon a. Thalamus - Pathway of motor and sensory impulses b. Hypothalamus - Regulates hormonal function c. Limbic System - Modulates emotion MIDBRAIN Mesencephalon - Process visual and auditory information

HINDBRAIN Cerebellum Modulates movement Gross movement of the body

BRAIN STEM a. Pons - Visceral (Smooth muscles) and Somatic (Skeletal muscles) motor control b. Medulla Oblongata - Autonomic (Cardiac muscles) functioning of motor organs

Carotid Artery distribution-carotid arteries perfuse the majority of the cerebrum Common Carotid Artery-->splits into the Internal Carotid Artery and the External Carotid Artery, then the Internal Carotid Artery-->divides into the

Anterior Cerebral Artery (ACA) and the Middle Cerebral Artery (MCA); both a left and right side are present

a. ACA-supplies the medial surface of the frontal lobe, parietal lobe and occipital lobe b. MCA-the largest branch of the internal carotid artery

Vertebrobasilar Artery distribution-perfuses base of cerebrum and majority of cerebellum 2 Vertebral Arteries-->join to form the Basilar Artery-->branching from the Basilar Artery are the 2 Posterior Cerebral Arteries (PCA)

a. Basilar Artery and PCA-supply the occipital lobe, brain stem and cerebellum

DIAGNOSTIC TESTS: Different diagnostic methods to detect cerebrovascular disease include: 1. Physical Examination: During a physical examination, the doctor listens, with the help of a stethoscope, to detect abnormal sounds of blood flow (called bruit) on the neck. However, in severe cases of atherosclerosis, the bruit is less common. A physician may look for specific neurological, motor and sensory deficits such as changes in vision or visual fields, abnormal reflexes, abnormal eye movements, muscle weakness, decreased sensation and other changes. 2. Cerebral Angiography or Vertebral Angiogram or Carotid Angiogram: In this radiological diagnostic method, a catheter (a long narrow flexible tube) is inserted into the patients artery (usually from his/her leg) with the help of a needle and guided through the main vessels of the abdomen and chest until it is placed in the arteries of the neck. The whole procedure is monitored with the help of a fluoroscope. X-ray pictures are taken after injecting a contrast dye in the neck with the help of the catheter. 3. Carotid Duplex or Carotid Ultrasound: In this noninvasive test, ultrasound waves are used to detect plaque, blood clots, or other blood flow problems in the carotid arteries. The images of carotid arteries and pulse wave forms are carefully observed on a monitor. 4. Computed Tomography (CT or CAT scan): This method is used to diagnose and detect hemorrhagic strokes, since blood, bone and brain tissue can be easily distinguished due to their difference in densities. It is important to note that damage from ischemic stroke cannot be detected by this scanning method. 5. Doppler Ultrasound: In this noninvasive test, high frequency sound waves are directed with the help of a transducer on to the artery or vein in question and detected on the Doppler. 6. Electroencephalogram (EEG): In this method, small metal discs (electrodes) are placed on the patients scalp to detect electrical impulses, which are printed out as brain waves. 7. Magnetic Resonance Imaging (MRI): In this method of diagnosis, three dimensional images of body structures are produced using magnetic fields and computer technology. The clear pictures of nerve tissue, brain stem and posterior brain can help determine signs of prior strokes if any. 8. Magnetic Resonance Angiogram (MRA): The MRA shows actual blood vessels in the neck and brain and helps in detecting blockage and aneurysms.

9. Lumbar Puncture (Spinal Tap): In this invasive diagnostic test a sample of cerebrospinal fluid is taken from the space surrounding the spinal cord to test for traces of blood due to cerebral hemorrhage.

TREATMENT AND MANAGEMENT ACCORDING TO TYPE: A. Treatment of Tramsient Ischemic Attack 1. Eliminate or control risk factors. 2. Education of patient regarding risk-factor reduction and signs and symptoms of TIAs and mild stroke. 3. Surgical Interventions a. Carotid Endarterectomy (CEA)

y surgical removal of the atheromatous plaque y reserved for patients with an ulcerated lesion or clot that occludes > 70%
of blood flow in the carotid artery y may decrease risk of stroke by 60% over the two years following the procedure y vertebral endarterectomy no longer used 4. Endovascular procedures a. Balloon Angioplasty

y consists of placing a small deflated balloon in the stenosed vessel y the balloon is then inflated pressing the atheromatous plaque against the
wall y has a risk of dislodging emboli that can be carried to the brain or retina b. Stent Placement

y experimental procedure y consists of placing a stainless steel coil into the vessel which then sticks to
wall of artery

5. Antiplatelet Agents a. Aspirin 1. Mechanism of Action

y inhibition of platelet aggregation y decreases release of vasoactive substances from platelets y irreversible inactivation of platelet cyclooxygenase; effect lasts for the life
of the platelet (5-7 days) 2. Efficacy

y ASA has shown clinically significant reductions (22-24%) in stroke risk and
death in randomized trials in patients who have experienced a previous TIA or stroke (secondary prevention) y doses have ranged from 50 to 1500 mg/day y more recent trials have evaluated lower doses (30 to 325 mg/day); results indicate that lower doses may be as beneficial with less adverse effects y some studies suggest that ASA is more effective in men than in women b. Dipyridamole (PERSANTINE) 1. Mechanism of Action

y weak inhibitor of platelet aggregation y inhibits platelet phosphodiesterase

2. Efficacy

y clinical trials have not supported the use of dipyridamole in cerebral

ischemia y no additive effect found with aspirin

c. Sulfinpyrazone (ANTURANE) 1. Mechanism of Action

y reversible inhibition of cyclooxygenase

2. Efficacy

y clinical trials have not supported use

d. Ticlopidine (TICLID) 1. Mechanism of Action

y inhibits ADP-induced platelet aggregation y inhibits platelet aggregation induced by collagen, PAF, epinephrine and
thrombin y bleeding time prolonged y minimal effect on cyclooxygenase 2. Efficacy

y has been shown to reduce the incidence of stroke by approximately 22% y y y y

in patients who have experienced previous TIAs or stroke may be more effective than aspirin with less GI effects no gender difference seen with ticlopidine as with ASA dosed at 500 mg/day divided into 2 doses (250 mg PO BID) adverse effects: diarrhea, rash, increased total serum cholesterol (ratio of HDL:TChol unchanged), neutropenia occurred in 1-2% of patients; must monitor CBC every 2 weeks for the first 3 months of therapy

6. Anticoagulation a. Warfarin 1. no studies that prove the superiority of anticoagulants over antiplatelet agents 2. may reduce the risk of stroke in patients with a prior MI 3. may be useful in those patients who continue to be symptomatic despite antiplatelet therapy 4. the major exception is in patients with cerebral embolism of cardiac origin

B. Treatment of Acute Cerebral Infarction/Ischemic Stroke 1. Accurate diagnosis is key! A CT Scan must be done to rule out a hemorrhagic stroke before initiation of any treatment. a. most patients do not have impaired consciousness in the first 24 hours b. if consciousness is impaired, suspect a stroke-related seizure, hemorrhage, hypoxia or increased intracranial pressure 2. Supportive care a. Maintain adequate tissue oxygenation: May require airway support and ventilatory assistance. Check for possible aspiration pneumonia. b. BP: In most cases, BP should not be lowered. If severe HTN, lower BP cautiously as neurological status may worsen when BP is lowered. c. Volume status: Correct for hypovolemia and keep electrolytes in the normal range. d. Fever: treat and look for source of fever. e. Hypoglycemia/hyperglycemia: Keep under control. Hyperglycemia may worsen the ischemic injury. f. DVT Prophylaxis: This is a must as stroke patients have a high risk for DVT! It is important to use either sc heparin 5,000 IU q. 8 or 12 hrs. or sc enoxaparin 30 mg q. 12 hrs. plus early ambulation! 3. Pharmacologic Therapy a. Recombinant Tissure Plasminogen Activator (r-tPA) Protocol--(For Select Patients Only!!) 1. efficacy is influenced by the length of time between the onset of the stroke and the initiation of treatment 2. rapid diagnosis and immediate administration of tPA increases its efficacy and may limit the potential for hemorrhagic conversion of ischemic stroke 3. Inclusion Criteria: y y ischemic stroke within 3 hours SBP < 185; DBP < 110

4. Exclusion Criteria: y y y y y y isolated neurological deficit another stroke or serious head injury within the previous 3 months INR > 1.7 use of heparin in the prior 48 hours major surgery in the prior 14 days platelet count < 100,000/mm3

5. tPA dose: y y y 0.9 mg/kg body weight; max. dose 90 mg give 10% of the dose as a bolus over 1-2 minutes and the rest as a continuous infusion over 1 hour No antiplatelets or anticoagulants within 24 hours!!

6. Results: y y improved outcome with regard to disability and death that persists 3 months after therapy there is a higher incidence of intracerebral hemorrhage (6.4% vs. 0.6%)

b. Intra-arterial Thrombolysis o early clot lysis and recanalization in about 50% of the patients with intra-arterial streptokinase and urokinase o intra-arterial r-pro UK 6 mg given within 6 hours of the stroke resulted in a 58% recanalization rate vs. 14% with placebo o main concern is hemorrhagic transformation of the ischemic lesion o risk of bleeding may increase with concomitant heparin o should still be considered investigational until further data collected c. Heparin o useful for progressing stroke; questionable role in stable or improving stroke o dosing: 50-70 U/kg as a loading dose, followed by 10-25 U/kg/hour; goal PTT 1.5-2.0X control o may opt to not use a loading dose in these patients o major concerns are conversion of an ischemic stroke into a hemorrhagic stroke secondary to heparin, bleeding and thrombocytopenia o careful selection of patients is important

d. Low-Molecular Weight Heparin (LMWH) o o o o o Org 10172 has been studied in acute stroke patients synthetic low-molecular-weight fraction of heparin undergoing investigation in several clinical trials less risk of hemorrhage(?) and thrombocytopenia(?) cannot be recommended for treatment until the results of an ongoing multicenter study are reported

e. Ancrod (ARVIN) o derived from the venom of the Malayan pit viper snake o enzyme that breaks down fibrinogen to a soluble ancrod-fibrin complex without allowing stabilization of fibrin (fibrin is not crosslinked) o may stimulate tPA activation from vascular endothelium o causes fibrinolysis soon after administration; low risk of hemorrhagic complications o dose: 0.5 U/kg in NS over 6 hours; administered for 7 days following stroke in the clinical trials; titrate to a fibrinogen level of 0.5-1.0 g/L o cannot recommend for use until further clinical trials are completed; role in therapy not yet established 4. Investigational Therapies for Acute Ischemic Stroke a. Dextran Infusion - decreased blood viscosity by volume expansion - decreased platelet function - decreased blood interaction with endothelium

b. Prostacycli - potent vasodilator and platelet suppressant - has fibrinolytic activity

c. Calcium Channel Blockers - may increase CBF by smooth muscle relaxation.

- may preserve neuronal function by preventing the calcium influx into neurons that occurs during ischemia - nimodipine 30 mg PO every 6 hours for 28 days used in clinical trials; nicardipine also evaluated - role in therapy not fully known at this time; seems to work best if initiated within 6-8 hours of symptom onset. d. Hemodilution - utilize albumin and fluids to decrease hematocrit to 30- 35% which decreases blood viscosity - questionable role in therapy e. 21-Aminosteroids (Tirilazad Mesylate-FREEDOX) - during ischemia, free radicals are formed which initiate lipid peroxidation - 21-aminosteroids are potent inhibitors of lipid peroxidation - doses up to 6.0 mg/kg/day divided into 4 doses IV x 5 days have been shown to be beneficial in clinical trials - role in therapy not yet defined; studies still ongoing. C. Subarachnoid hemorrhage 1. Volume expansion and induction of hypertension ("Triple H Therapy"hydration, hypertension, hemodilution) a. Volume expansion: 0.9% NaCl and 5% serum albumin solutions are used. Endpoint is to maintain PAWP of 15-20 mmHg without causing pulmonary edema. b. Induction of hypertension: Dopamine and norepinephrine are used to elevate BP. The goal is to elevate SBP to 200-220 mmHg and maintain it for 7 to 14 days. 2. Calcium Channel Blockers (Nimodipine and Nicardipine) Mechanism of Action o May improve clinical outcome by limiting fixed neurological deficits. o May inhibit the rapid influx of calcium into ischemic neurons and prevent calcium-induced damage.

o May dilate penetrating blood vessels allowing blood to be shunted back to ischemic areas of the brain and re-establish some autoregulation of cerebral blood flow. Dose: Nimodipine 60 mg PO/NGT every 4 hours for 21 days. 3. Angiography with Papaverine a. Papaverine, a non-selective muscle relaxant, is injected intra-arterially directly at the site of vasospasm. It is still considered experimental. 4. Angioplasty

CONCLUTION: After further research and study I can now conclude that: y y y Signs and symptoms, anatomy of the organ affected, and pathophysiology of the disease have been discussed. Different types of Cerebrovascular Disease have been listed and differentiated. Pharmacologic, Surgical treatment and other therapies have been specifically identified according to type of Cerebrovascular Disease.

CEREBROVASCULAR DISORDER