Dec 8 th , 2014
Lama Al-Khoury, MD
Clinical Assistant Professor
Neurology
UCI Medical Center

 Incidence of stroke in USA is 795,000/ year in the United States of America
 Incidence of Non-fatal strokes is 15 million/year in the world
 Stroke: 4 rd killer in USA (used to be third)
2 nd killer in world
 Secondary disability is present in one third of stroke survivors

Stroke is Acute brain injury caused by:
 Ischemic stroke: Reduced blood supply to a region of the brain resulting in brain ischemic and neuronal death (87%)
 Hemorrhagic stroke: Primary brain hemorrhage resulting in compression of normal brain tissue (13%)

Anterior and Posterior Cerebral Arterial
Circulation
 Internal carotid arteries and their branches: supply the anterior circulation
 Vertebral arteries and the basilar artery
(and their branches): supply the posterior cerebral circulation

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Mechanism of Ischemic Stroke and
Transient Ischemic Attacks
Atherosclerotic cerebrovascular disease (20%):
1.
Extracranial carotid or vertebral artery disease
2.
Intracranial cerbrovascular disease
Penetrating small arterial disease (25%)
Cardiogenic source (33%):
1.
Atrial fibrillation & other arrythmias
2.
Myocardial infarction
3.
Valvular disease
4.
Ventricular thrombi
5.
Aortic plaque
Unusual causes (<5%): dissection, migraine, illicit drugs, vasculitis, venous strokes, hypercoagulability,…
Cryptogenic source (no mechanism identified)

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Definition: duration of transient neurologic symptoms lasting less than 1 hour
Transient reduction of blood flow to a region in brain in the absence of evidence of infarction on brain imaging
Mechanisms for TIA similar as for ischemic stroke
Reconstitution of flow to the hypoperfused region hence the resolution of symptoms
Significance of TIAs is increased risk of stroke after a TIA specifically early on after a TIA
Prompt evaluation of mechanism and appropriate treatment

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ABCD2 score
 Age ≥ 60 years: score 1
 HTN (≥140/90): score 1
 Diabetes mellitus: score 1
 TIA duration: 10-59 min (score 1); ≥60min (score2)
 Clinical: Hemiparesis with or without speech deficit (score
2); speech impairment without hemiparesis (score 1)
Higher ABCD2 scores are associated with greater risk of stroke during the 2, 7, 30, and 90 days
Definite admission for ABCD2 score of ≥4
Caution to work the TIA patients urgently to address underlying source and treat appropriately

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Hemiparesis or quadriparesis ( latter in basilar occlusion)
Facial weakness
Aphasia
Dysarthria
Limb/truncal/gait ataxia +/- nausea & vomiting
Vertigo, tinnitus, hearing deficit (posterior circ.)
Impairment of vision in homonymous visual field defect
Adopted from
AHA
Monocular impairment of vision (amaurosis fugax)
Diplopia
Impairment or loss of consciousness or confusion
Hemineglect (visual or sensory)
Headache (non-specific symptom)
New onset seizure (3-4%) or acute new movement abnormality

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Space occupying lesion
(tumor, infection/ abscess, Epidural,
Subdural Hematomas)
Subarachnoid hemorrhage
 Seizures
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Hypoglycemia
Migraine
Syncope
Labyrinthine disorders

 Designed for acute stroke trials.
 Quick (5-10 min) & reproducible.
 Requires speech/language cards & safety pin.
 Quantifies clinical stroke deficit: o < 4 = mild stroke o > 15 = poor prognosis if no treatment o > 22 =
 risk for ICH

“ Traditional” order of items ”
1a.
LOC
1b.
LOC questions
1c.
LOC commands
2.
Best gaze
3.
Visual fields
4.
Facial palsy
5a.
Right arm motor
5b.
Left arm motor
6a.
Right leg motor
6b.
Left leg motor
7.
Limb ataxia
8.
Sensory
9.
Best language
10.
Dysarthria
11.
Extinction/ inattention

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Urgent transport to the nearest stroke receiving hospital via 911 syste
Notification of the destination ED
Alert ED of the need for urgent CT

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Cardiac monitoring, pulse-ox, ECG
Stat CT brain c-xray
CBC, Platelet, PT, PTT
Accucheck & blood glucose, serum electrolytes
Cardiac markers, ABG’s
Blood alcohol level, Toxicology screen,
Pregnancy test

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IV line: IVF bolus/hydration
2 nd IV line in anticipation of IV t-PA
Non contrast CT: rule out hemorrhage
Usually later but may need stat: Carotid U/S,
Echocardiogram, MRI and MR-a, CT-a brain and cerebral vessels

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NINDS Stroke Study group: randomized placebo controlled clinical trial (N Engl J Med 1995)
Intravenous recombinant tissue Plasminogen
Activator (IV t-PA) given within 3 hour of symptoms onset in acute ischemic strokes
N=624 patients (IV t-PA or placebo):dose
0.9mg/kg, 10% IV bolus, then the remainder is IV drip over 1 hour

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Patients in the t-PA arm were at least 30% more likely to have minimal or no disability at 3 months
Symptomatic Intracranial Hemorrhage was 6.4% in the t-PA group versus 0.6% in the placebo arm
Mortality at 3 months was not statistically different between t-PA and placebo
The benefit of IV t-PA was sustained at one year follow up
The earlier the treatment the better the outcome

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IV t-PA was FDA approved for acute ischemic stroke Rx based on the NINDS study group
Inclusion and Exclusion criteria

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ECASS 3: N Eng J Med sept 2008
This study showed persistent benefit of IV t-PA up to 4.5 hours from onset in acute ischemic stroke
Excluded patients>80 years of age
Excluded patients with severe deficit NIHSS>25
Excluded patients who have combination of previous stroke and diabetes
Excluded patients who were on anticoagulation regardless of the INR

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Standard FDA approved therapy for acute stroke Rx
Window of treatment has been prolonged after ECASSIII to 4.5 hours
 Not all patients are eligible for the 3 to 4.5 hour window

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Ischemic Stroke clinically
Persistent neurologic deficit beyond an isolated sensory deficit / ataxia
CT brain: No Blood
Initiation of Rx within 3 hours

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Onset to treatment >3 hr
(NINDS)
Rapid improvement
Blood on CT
Oral anticoagulant &
PT>15 sec, INR>1.7
Heparin (last 48 hr) & increased PTT
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Platelet<100,000
SBP>185 or DBP>110
Aggressive treatment of b.p.
Stroke or head trauma (3 months)
Major surgery (2 wks)

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Prior ICH
GI tract/ Urinary bleed (14 d)
Seizure at onset
Signs & Sx’s of SAH
Non-compressible site of arterial puncture (7d)

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Age≥80 years
Any use of anticoagulant regardless of the
PT/PTT
NIHSS≥25
Coexistent history of stroke and diabetes mellitus

Management Post Thrombolysis
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Admit to ICU
BP monitoring (Q 15 m x2 h, Q 30 m x6 h, Q 1 h x16 h)
Treat SBP≥185 and DBP≥110
No anticoagulants, no anti-platelet for 1 st 24 hr post t-PA

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Worsening of neurologic state---CT brain
ICH---Neurosurgery consult
Possible surgical intervention
Preferably: no foley or NG for 2 hr > t-PA
(t1/2-t-PA = 8-12 min)

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Intraarterial thrombolysis or mechanical thrombectomy
Successful recanalization has been shown
Clinical benefit?
PROACT II: intra-arterial pro-Urokinase was positive
3 interventional studies published in 2013 were negative for benefit from endovascular Rx
Implementation of stent retrieval devices (superior in recanalization)
MR CLEAN (Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands) : positive trial
SWIFT PRIME halted enrollment pending review of data

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At the time being and in the United States the only
FDA approved acute treatment for stroke is IV t-PA
Mechanical thrombectomy: (currently)
 Add on-Rx to the standard FDA approved stroke
Rx IV t-PA in cerebral infarction with proximal large arterial occlusion within 8 hours from onset
 Or as alternative Rx in patients who do not qualify for IV t-PA
For basilar artery occlusion the window is prolonged to up to 24 hours for concern of locked in syndrome

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Age
Elevated blood sugar
Initial NIHSS score which is a measure of the patient’s initial deficit
Cerebral infarction changes on CT brain

 Primary prevention
 Secondary prevention

 Primary prevention starts at the level of the physician playing the role of the primary care and occasionally at the level of the cardiologist and the stroke neurologist
 Key is identification of underlying risk factors and modification and treatment of modifiable risk factors

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Establishing good medical history and family history
Identifying the patient’s vascular risks including medical illnesses, habits such as smoking and substance use and genetic predisposition through review of significant family history for cardiovascular risk factors and stroke
Exam elements which are key: pulse (rate and establishing how regular), blood pressure, carotid auscultation ( bruits ), cardiac auscultation
( murmurs and abnormal rhythm ), symmetry and detection of pulses, diabetic peripheral changes

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 Age: the risk of stroke doubles with every decade after the age of 55 years
 Sex: lifetime risk in Male>Female but risk in
F>M after age of 80 years
 Race and ethnicity:
 Stroke incidence and subtypes: higher in African
Americans and Hispanics >Caucasians
 Stroke related mortality is higher in African
American population
 Asian population has an increased risk of hemorrhagic stroke subtype compared to
Caucasians

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Genetic Factors
Family history: inherited susceptibility, inherited predisposition to risk factors, similar culture and lifestyle
Hyperhomocysteinemia: C677T allele (one or more) of the methylenetetrahydrofolate reductase gene (MTHF)
Inherited coagulopathies:
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FV Leiden mutations, prothrombin gene mutation
PC, PS deficiencies
 Anticardiolipin antibodies/LA are genetic in 10% cases
 Others
CADASIL: Cerebral autosomal dominant arterof iopathy with subcortical infarcts and leukoencephalopathy: NOTCH 3 gene mutation on chromosome 19
Others: Marfan and NF I and II, Fibromuscular dysplasia (FMD), Ehlers-
Danlos syndrome IV, polycystic kidney disease
Novel genes identified which may have specific associations with large artery stroke

 Hypertension
 Smoking
 Diabetes Mellitus
 Carotid disease
 Cardiac disease: Atrial Fibrillation , Myocardial infarction secondary to coronary artery disease
 Dyslipidemia or hyperlipidemia (high cholesterol, high LDL, low HDL)
 Migraine with aura in women
 Obstructive sleep apnea

 Obesity
 Lack of exercise
 Poor diet
 Alcohol abuse
 Hyperhomocysteinemia
 Illicit drug abuse
 Hypercoagulopathy
 Sickle cell disease
 Estrogen/HR hormonal therapy
 Inflammation
 Infection

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Prevalence in USA is 29%- Improved control of HTN over the years 50%
A patient who is normotensive at 55 years of age has a 90% life time risk of developing hypertension
More than 2/3 of patients ≥ 65 yrs of age have hypertension
Major risk factor for ischemic and hemorrhagic strokes
Throughout usual range of blood pressure (BP) including the normal BP ranges, the higher the blood pressure the greater the risk of stroke
HTN is undertreated
It ‘s prevalence is increasing partly due to increased prevalence of patients who are overweight and obese
One of the most important modifiable risk factors for stroke
Hypertension increases stroke risk due to the following:
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It worsens atherosclerosis
It predisposes to small vessel disease
 It accelerates heart disease

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Multiple clinical trials have established that treatment of BP with antihypertensive medications reduces risk of stroke
Several meta-analyses evaluated and compared specific antihypertensive agents
One meta-analysis: Thiazide diuretics, ACEI and Ca channel blockers each reduced risk of stroke compared to placebo
Another meta-analysis: showed diuretics superior to ACEI
Subgroup analysis in one trial: benefit if diuretic is more prominent among African Americans
A meta-analysis of 13 trials in patients with hypertension:
ACEI and ARBs reduced significantly stroke risk
Recent evidence that calcium channel blockers are better in reducing variability in blood pressure that betablockers

Hypertension Evaluation and Treatment
Current Guidelines
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Regular blood pressure screening
Behavioral life style modifications should be recommended to hypertensive patients:
 management of obesity/ weight loss,
 diet: low salt, encourage vegetables. Reduce red meat
(AHA, DASH, Mediterranean diets)
 Encouragement of exercise
Treatment with antihypertensive agents to achieve BP< 140/90 mm Hg
Intraindividual variability of blood pressure may cause additional risk

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Current AHA guidelines in chronic hypertension < 140/90 mm Hg
Most trials did not test a goal of less intensive therapy being less than140/90
 One meta-analysis compared clinical trials with more intensive BP reduction with those of less intensive reduction and found a 23% reduced risk of stroke in more intensive therapy

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Cigarette smoking doubles the risk of ischemic stroke
It also increases subarachnoid hemorrhage by 2-4 folds
Inconsistent data for parenchymal intracerebral hemorrhage
Inconsistent data with second hand smoking
Contributes to increased risk of stroke by:
 Increased thrombus generation in atherosclerotic arteries
 Increased atherosclerosis

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Close to 11% of US population are estimated to have diabetes mellitus
Studies have shown that diabetes mellitus increases the risk of stroke 1.8 - 6 fold
 This increase in stroke risk is related to increased risk of atherosclerosis & increased pro-atherogenic risk factors in diabetic patients

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Patients with DMII and persistent microalbuminuria
Intervention with intensive therapy with behavioral risk factor modification and statin,
ACEI, ARB, or antiplatelet as appropriate versus conventional Rx
 Intensive therapy was associated with significant reduction in each of death, cardiovascular events and stroke endpoints

Diabetes Mellitus: Glycemic control?
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North Manhattan Study: subjects who had diabetes and fasting blood glucose (FBG)> 126 mg/dl had 2.7 fold increase in stroke risk versus no increase in risk if FBG<126 mg/dl
3 clinical trials: ACCORD , ADVANCE , and a trial which enrolled US veterans
Failure to demonstrate reduction in stroke in the group of intensive glycemic control
ACCORD: halted earlier due to increased all-cause mortality in the intensive-glycemic control group

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Use standard guidelines for glycemic control
Avoid lowering of HbA1c<6.5 in patients with cardiovascular disease or the presence of vascular risk factors

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Evidence from studies and meta-analyses to suggest that more aggressive bp control in DM lowers further risk of stroke
There is an increased risk of adverse events with more aggressive antihypertensive Rx

 Clinical evidence of the benefit of statins in stroke risk reduction in diabetic patients
 No supportive evidence for fibrates in stroke prevention in diabetic patients

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No statistically significant benefit from aspirin in prevention of stroke in diabetes mellitus has been found
Use in patients with established carotid disease or coronary artery disease

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Modest association of elevated total cholesterol or LDL with increased risk of ischemic stroke
Association between low HDL and increased risk of ischemic stroke
 Relationship between low total cholesterol as well as LDL-C and a higher risk of hemorrhagic stroke

No consistent association between triglycerides and risk of stroke

Statins (HMG-CoA Reductase Inhibitors)
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Statins: 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitors
Statins lower LDL cholesterol by 30-50%
Treatment with statins reduces the risk of stroke in patients with or at high risk for atherosclerosis
Meta-analysis of 26 trials: statins reduced risk of all strokes by 21%
Risk of all strokes was reduced by 15.6% for each 10% reduction of LDL-C
Statins reduce progression and promote regression of atherosclerotic plaque
Beneficial effect on carotid intima media thickness (IMT) mostly with higher intense Rx with statins

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National Cholesterol Education Program (NCEP)
NCEP recommends LDL lowering as primary target
Lifestyle modification
Decrease saturated fat, trans fat and cholesterol intake weight reduction
Exercise
PMH of CHD and CHD risk equivalents (DM and symptomatic carotid artery disease): aim at LDL at least ≤ 100 and preferably ≤70

ACC/AHA Guidelines for the Treatment of
Blood Cholesterol in Primary Prevention
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Recommendations based on the 10 year risk for cardiovascular disease
Shifts away from specific cholesterol goals
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Estimated risk dictates intensity of statin Rx: high risk mandates high intensity statin Rx
Atorvastatin 10 mg is moderate intensity statin Rx and 40 t0 80 mg is high intensity
 10 year Risk calculator

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Statin therapy with intense lipid lowering effect is recommended to reduce stroke risk in the population of ischemic stroke and TIA patients (SPARCL)
 Target LDL-C<70 mg/dl or 50% lowering of baseline LDL
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May use other agents if patient can not take statins (Niacin, Gemfibrozil)
No established benefit in stroke reduction

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Indicated with proven benefit in severe symptomatic extracranial carotid artery disease
Symptomatic = clinical or radiologic evidence of stroke in the distribution of that carotid artery
 Stenting is an alternative in patients who are not eligible for CEA

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Increased risk of stroke with carotid artery stenosis
Asymptomatic Carotid Artery Study (ACAS)
Asymptomatic Carotid Surgery Trial (ACST)
Number needed to treat to prevent 1 stroke patient was 40
The low benefit may not justify the risks of carotid revascularization: individualize patients and assess risk factors
The annual rate of stroke associated with asymptomatic carotid stenosis has significantly declined with intensive medical management ≤1%
(Statins and antiplatelet Rx)

May consider carotid revascularization in severe asymptomatic carotid artery stenosis but with perioperative and surgical risk <3 %

 Cardiac arrhythmias with increased risk of cardiac clots and cardioembolism: atrial fibrillation
 Coronary artery disease, myocardial infarction/ ischemic cardiomyopathy
 Valvular heart disease (septic embolism or thromboembolism)
 Aortic arch atheroma
 Paradoxical embolism: presence of right to left shunt such as a PFO in the presence of a venous thrombus

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Both persistent and paroxysmal atrial fibrillation are potent predictors of first as well as recurrent stroke
Atrial fib >2 million Americans
Increases with age
Atrial fibrillation patients with prior strokes and TIAs have the highest risk of recurrent stroke
Other risk factors: age, HTN, CHF, diabetes mellitus

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Age ≥ 75 years (1)
HTN (1)
DM (1)
CHF (1)
Ischemic stroke or TIA (2)
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 Total score: ------ (maximum is 6)

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Anticoagulation: CHADS2 >1
Antiplatelet Rx for CHADS=0
CHADS2=1 either anticoagulation or antiplatelet
ASA plus clopidogrel maybe used in patients who have contraindication to anticoagulation
If there is Stroke/TIA with atrial fibrillation then anticoagulation is the recommendation
Patient has to be cleared for the absence of fall risk

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Warfarin (valvular and non-valvular A.Fib.)
Apixaban((approved for non-valvular A.Fib.)
Rivaroxaban(approved for non-valvular A.Fib.)
Dabigatran (approved for non-valvular A.Fib.)

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No role for CEA in carotid occlusion
No benefit from EC/IC bypass in carotid occlusion
 SAMPRIS: In intracranial cerebral artery stenosis, best medical management is superior to angioplasty and stenting

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An independent risk factor for stroke in women
It is still unknown if migraine preventive therapy will reduce the risk of stroke
A woman who has migraines with aura, who smokes tobacco and who is on oral contraceptive pills has a 7-9 fold increase in the risk of stroke
Cessation of smoking and consideration of avoiding OCPs in patients with migraines with aura

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Increases risk of stroke and cardiovascular disease
Screening for symptoms of OSA and appropriate referrral to sleep center for evaluation and treatment when appropriate

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Some increased risk of ischemic stroke
May avoid or stop using if additional risk factors for stroke
 Stop/avoid use if patient is a smoker and esp. if it is a woman who has migraines with aura

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Alcohol beyond 2 drinks/day for men and beyond
1 drink /day for women increases the risk of stroke
Illicit drug use increases the risk of intracerebral hemorrhage (ICH) and ischemic strokes esp. with
Cocaine and Amphetamines/ derivatives
Substance use increases the risk of development of poorly controlled BP and its complications
Cessation should be recommended however with the help of detox and rehab programs

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No benefit in primary prevention
Consider in diabetic patient with high risk factors and carotid artery disease
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May have some benefit in women ≥ 65 years old (AHA / AHS guidelines)
Recent FDA warning about use of aspirin in primary prevention due to increased hemorrhagic risks which are not offset by any significant benefit

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Goal should be primary prevention in stroke
Role of the primary care and sometimes the neurologist and cardiologist in assessing risk factors for stroke
 Intervention with education about life style modification and treatment of risk factors for stroke

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Family history: identify people who have higher risk and counseling those patients
Genetic counseling for rare genetic disorders
Non-invasive imaging/ screening for patients with specific disorders: screen for cerebral artery aneurysms in patients with ≥ 2 first degree members with SAH/cerebral aneurysms, EDS IV, polycystic kidney disease

 Physical activity is recommended:
 Moderate to vigorous intensity aerobic
 Suggested ≥ 40 min/ time, 3-4 days /wk 2013
AHA/ACC guidelines
Weight reduction for BMI≥ 25 
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Dietary restriction of salt and increased potassium in diet (HTN conrtol)
DASH, AHA, Mediterranean diets

 Cessation of smoking esp. in women who have migraines with aura and who are on
OCPs
 Cessation of illicit drugs
 Cessation of alcohol or limitation to ≤1 drink/day for women and ≤2 drinks/day for men

 Control of BP<140/90 mm Hg
 Control of blood sugar but avoid intensive glycemic control
 Use of statins in diabetic patients maybe protective and particularly if high risk factors
 Maximize medical management with statins and antiplatelets in carotid artery disease
 Anticoagulation is reserved for atrial fibrillation and cardiac thrombi or potent hypercoagulable states (latter in secondary prevention)

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Use of ACE Inhibitors and or an angiotensin II receptor blocker (ARB) in diabetes mellitus
No documented benefit for aspirin in primary prevention of stroke (may consider patients with high risk factors) with the exception of some possible benefit for women>65 years old

Lama Al-Khoury, MD
Clinical Assistant Professor
UCI Medical Center
Stroke Center
T:(714)456-7637
Fax: (714)456-2333