MRI of the Brain/MRA of the Neck and Brain

• 
  

  To localize the lesion.

  
  
• 
  

  To try to understand the mechanism by integrating all MRI and MRA data:

  
  
  
  
  1. 
     

     ▪ small-vessel lacunar infarction

     
     
  2. 
     

     ▪ large-artery atherosclerosis

     
     
  3. 
     

     ▪ embolism

     
     
  4. 
     

     ▪ hemodynamic

     
     
  5. 
     

     ▪ venous

  
  
  
  
• 
  

  The location and pattern of infarct(s) are helpful to determine etiology (watershed may refer to stenosis, whereas multiple vascular territories may suggest cardioembolic, etc.).

  
  
• 
  

  To visualize what’s acute using DWI and what’s old using T2/FLAIR. Old strokes may help to determine etiology.

  
  
• 
  

  To understand the tissue physiology (perfusion imaging).

  
  
• 
  

  To examine the entire cervical and cerebral vasculature for stenosis (atherosclerosis, dissection, etc.), aneurysm, arteriovenous malformation (AVM).

Repeat Head CT

Consider if patient is not able to have MRI.

• 
  

  To localize the lesion.

  
  
• 
  

  To look for hemorrhagic transformation of the infarct.

  
  
• 
  

  To evaluate the deteriorating patient:

  
  
  
  
  • 
    

    blood

    
    
  • 
    

    cerebral edema

    
    
  • 
    

    enlargement of infarct

  
  

CT Angiogram (CTA) of the Neck and Brain

May be performed with the head CT in the acute evaluation, as an alternative to MRA.

• 
  

  To look for extracranial or intracranial arterial stenosis, dissection, aneurysm.

Transthoracic Echocardiogram (TTE)

Order with “bubble study.”

• 
  

  To assess for embolic source (anterior wall or apical akinesis, clot, valvular disease, large PFO).

  
  
• 
  

  Low ejection fraction (20–30% is generally agreed upon as a cutoff) significantly increases thromboembolic risk due to stasis, and also should trigger further specific cardiac evaluation and treatment. Left atrial enlargement may signify valvular disease, occult atrial fibrillation, or atrial cardiopathy.

Transesophageal Echocardiogram (TEE)

Order with “bubble study.”

• 
  

  To assess for embolic source not seen well on TTE (aortic atheroma, PFO, atrial septal aneurysm, spontaneous echo contrast, left atrial appendage clot).

  
  
• 
  

  If a PFO is found, consider screening for hypercoagulable states, a bilateral lower-extremity ultrasound, and MR venogram of the pelvis to look for venous thrombosis. See discussion on Patent Foramen Ovale at the end of this chapter.

Carotid Ultrasound (CUS)

• 
  

  To assess for internal carotid artery stenosis or occlusion and direction of vertebral artery flow.

  
  
• 
  

  You might not need it if you have a good-quality normal MRA or CTA of the extracranial circulation. CUS can be used to confirm a stenosis seen on MRA or CTA. If these non-invasive tests are concordant, it may not be necessary to do an invasive DSA to determine candidacy for endovascular or surgical treatment of a carotid stenosis.

  
  
• 
  

  Also gives you a non-invasive benchmark for following carotid lesions longitudinally.

  
  
• 
  

  CUS may also show high-risk ulcerated plaques, and can be used with transcranial Doppler (below) for emboli detection.

Transcranial Doppler (TCD)

Order with or without “bubble study.”

• 
  

  To monitor clot presence and lysis in the acute setting.

  
  
• 
  

  To confirm intracranial stenosis/occlusion of major arteries seen on MRA or CTA.

  
  
• 
  

  To be used for emboli detection/monitoring.

  
  
• 
  

  To screen for PFO by injecting microbubbles. TCD with “bubble study” is the most sensitive and least expensive/invasive way to screen for right-to-left shunting (whether intracardiac or intrapulmonary). See Appendix 2.

  
  
• 
  

  To test hemodynamic reserve (breath-holding index [BHI], vasomotor reactivity).

  
  
• 
  

  To evaluate collateral flow patterns.

Digital Subtraction Angiography (DSA)

• 
  

  Gold standard for determining degree of stenosis.

  
  
• 
  

  Most sensitive way to definitively delineate and follow aneurysms or AVMs, dissection, vasculitis, or other arteriopathies.

Fasting Lipids

• 
  

  Establish baseline for total cholesterol, triglycerides, LDL (target LDL < 70 mg/dL), HDL.

Hemoglobin A1c (HGBA1c)

• 
  

  Screen for diabetes and its recent control.

1. Blood Pressure Control

Hypertension is the single most important modifiable stroke risk factor. The risk of cardiovascular disease, beginning at BP 115/75 mmHg, doubles with each increment of 20/10 mmHg.¹ Multiple large randomized controlled trials (RCTs) have shown the efficacy of antihypertensive treatment in primary and secondary prevention of stroke. Many drugs have been shown to reduce stroke in primary prevention (beta-blocker in SHEP, diuretic in SHEP and ALLHAT, calcium channel blocker in ALLHAT, ACE inhibitor in HOPE and PROGRESS, ARB in LIFE).^2–6 A combination of perindopril (Aceon), a tissue-specific ACE inhibitor, and indapamide (Lozol), a diuretic, has been shown to reduce stroke in secondary prevention even among non-hypertensive patients (PROGRESS).⁴ Whether this effect is due to the tissue-specific ACE inhibition rather than an ACE-inhibitor class effect, or whether an ACE inhibitor needs to be used in combination with a diuretic, remains unclear. Recent meta-analysis seems to support the superiority of diuretics.⁷ The most important point is blood-pressure reduction, not the specific drug.

Guidelines for treatment of high blood pressure in adults were revised in 2017.⁸ Treatment should begin with lifestyle modification including exercise, diet and salt restriction, and reduced alcohol. Pharmacologic treatment in patients with vascular disease including stroke should occur for SBP ≥ 140 or DBP ≥ 90. In general, bring down BP slowly with oral antihypertensives after acute ischemic stroke. A reduction of MAP by no more than 15% in the first 24 hours is reasonable, especially if there is large-vessel occlusive disease. Guidelines recommend starting with a thiazide diuretic as a first-line pharmacologic therapy, recognizing that more than one drug is commonly needed. In the hospital setting, especially after a stroke, a patient’s fluid intake may be poor. A diuretic while on IV fluids does not make sense. Start a diuretic in stroke inpatients only if the patient is drinking fluids consistently. The usual first choice is an ACE inhibitor or calcium channel blocker. ACE inhibitors are less effective as monotherapy in African-Americans. If tachycardia is an issue, a beta-blocker can be useful, though not typically first line as a blood-pressure reducing agent.

In patients with severe hypertension, we usually start with IV nicardipine or labetalol to control the SBP to < 180 in patients after tPA, SBP ~140 in patients with acute ICH, and SBP 120–140 after successful endovascular revascularization. We transition to oral agents as soon as possible. We avoid the use of medications that require multiple daily dosing, because adherence to therapy is less likely if such agents are used.

According to recent guidelines, influenced by the SPRINT trial, the target BP for patients with atherosclerotic cardiovascular disease is ≤ 130/80 mmHg.⁹ It is important to note that patients with stroke were excluded from this trial. However, based on prior studies in stroke patients, we agree that it is reasonable to target BP < 130/80 mmHg in patients with small-vessel ischemic stroke or intracerebral hemorrhage. In patients with extensive atherosclerotic disease and elderly patients, BP < 140/90 mmHg may be more practical. We expect that the stroke-specific secondary prevention guidelines will update blood-pressure recommendations for secondary stroke prevention.

2. Lipid Control

The most recent American College of Cardiology (ACC) and American Heart Association (AHA) guidelines for the management of cholesterol revised their recommendations in patients with atherosclerotic cardiovascular disease (ASCVD), including those with ischemic stroke or transient ischemic attack (TIA).¹⁰ These guidelines recommend initiation of high-dose statins (atorvastatin 40 or 80 mg or rosuvastatin 20 or 40 mg) for ASCVD regardless of the patient’s age (in the past, this recommendation was only for patients < 75 years old).

The target of LDL < 70 mg/dL was influenced by the SPARCL trial. The SPARCL trial compared placebo with 80 mg of atorvastatin in patients with recent TIA/stroke with no known coronary artery disease or diabetes mellitus with LDL 100–190 mg/dL (2.6–4.9 mmol/L). LDL was lowered to < 70 mg/dL in the treatment group. Treatment with atorvastatin 80 mg was associated with a 2.2% 5-year absolute risk reduction (ARR) in fatal or non-fatal stroke and a 3.5% 5-year ARR in major cardiovascular events. There was a small increase in the incidence of hemorrhagic strokes.¹¹

In order to assess patient adherence to therapy with statins and the effectiveness of statins at decreasing LDL cholesterol, we obtain a baseline lipid panel in the acute setting and a repeat lipid panel 8–12 weeks after statin initiation.

We recommend starting with a statin based on the ACC/AHA guidelines. If target LDL is not achieved, ezetimibe can be added, and if the target is still not reached, a PCSK-9 inhibitor.

Statins may benefit patients more than just by the amount they lower cholesterol. This mechanism is not entirely defined. The MRC/BHF Heart Protection Study treated patients with coronary artery disease or other occlusive arterial disease, or diabetes mellitus, with simvastatin or placebo irrespective of initial cholesterol concentrations and found significant reductions in MI, stroke, and revascularization procedures.¹²

3. Hyperglycemia and Insulin Resistance

Guidelines state that hyperglycemia during the first 24 hours after acute ischemic stroke is associated with worse outcomes, and that it is reasonable to treat hyperglycemia to achieve blood glucose levels in the range of 140–180 mg/dL.¹³ However, this is a class C recommendation. A large randomized study recently showed that more aggressive glucose lowering (to 80–130 mg/dL) did not result in better 3-month outcome than more relaxed treatment (to 140–180 mg/dL).¹⁴

Diabetic patients should have appropriate education, diet counseling, and pharmacotherapy started before discharge.

Insulin resistance may be a target for secondary stroke prevention. Insulin resistance can be defined by the homeostasis model assessment of insulin resistance (HOMA-IR) index (fasting glucose in mmol/L × fasting insulin in microunits/mL ÷ 22.5). Insulin resistance is present if the index is ≥ 3.0 when measured more than 14 days post stroke. In one recent study non-diabetic TIA or stroke patients with insulin resistance had a lower subsequent incidence of diabetes or recurrent stroke/MI if treated with pioglitazone.¹⁵ However, this was accompanied by a higher risk of edema and bone fracture, so such treatment should be individualized.

4. Lifestyle Modification

Lifestyle modification is an important part of the control of blood pressure, lipids, and glucose.

• 
  

  Stop smoking. This is one of the most important things patients can do to prevent not only ischemic stroke but also heart disease, lung cancer, head and neck cancer, etc.

  
  
• 
  

  Based on results of the PREDIMED trial,¹⁶ the Mediterranean-style diet is recommended for secondary stroke prevention. Refer patients to a dietician who can educate them about this diet and the diabetic diet or a low-sodium diet if indicated.

  
  
• 
  

  More exercise. Counsel the patient to adopt a less sedentary lifestyle and participate in even moderate exercise. Forty minutes, five times per week, is optimal.

  
  
• 
  

  Estrogen in the form of hormonal contraceptives or hormone replacement therapy should be avoided in most cases.^17–19

  
  
• 
  

  Drugs of abuse and alcohol should be avoided and discouraged, especially vasoactive drugs such as cocaine and amphetamines. There are conflicting data on alcohol use. Data suggest that more than one drink per day (women) and more than two drinks per day (men) should be avoided. Moderate red wine consumption has been associated with lower vascular disease risk.

Antiplatelets

Current acute ischemic stroke guidelines recommend aspirin started within 24–48 hours of stroke onset.¹³ This is a generic “one size fits all” recommendation for all ischemic stroke patients. The guidelines do not specify a dose. Long-term aspirin therapy results in a ~20% relative risk reduction (RRR) of secondary stroke/other vascular events.²⁰

There are alternatives to aspirin that include:

• 
  

  Clopidogrel (Plavix) – May be slightly better than aspirin in preventing vascular events, particularly in patients with peripheral vascular disease, and better tolerated. However, the drug must be converted in the stomach to its active metabolite by cytochrome P450 2C19 (CYP2C19), and patients with an allele of the CYP2C19 gene that results in loss of function may be resistant. CYP2C19 activity can be assessed by a blood test, but using this test to guide therapy, while logical, has not yet been proven to improve outcomes.

  
  
• 
  

  Aspirin/dipyridamole ER (Aggrenox, Asasantin) – Two trials showed this combination to be 30% better than aspirin alone.^{21, 22} In another, aspirin/dipyridamole was comparable to clopidogrel but caused a slightly higher risk of bleeding.²³ Headache is a frequent side effect.

  
  
• 
  

  Prasugrel (similar to clopidogrel but without dependence on CYP2C19 activity) or ticagrelor may be useful (but more expensive) alternatives, but to date they have not been sufficiently studied in stroke patients to be certain of long-term safety and superiority over aspirin or clopidogrel. Ticagrelor is an antiplatelet agent that reversibly interacts with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. In the SOCRATES trial, patients with high-risk TIA or ischemic stroke with low NIHSS (< 6) were randomized to aspirin (300 mg load followed by 100 mg) versus ticagrelor (180 mg load, 90 mg BID for 90 days).²⁴ In prespecified subgroup analyses, there was benefit of ticagrelor in patients with stroke of atherosclerotic etiology and in aspirin-naïve patients.^{24, 25}

  
  
• 
  

  Cilostazol  is used mainly for intermittent claudication in patients with peripheral artery disease. Controlled trials in Asian patients have found that cilostazol is effective for preventing cerebral infarction compared to placebo, but no better than aspirin.²⁶ Bleeding was slightly less with cilostazol but headache, diarrhea, dizziness, and tachycardia were more frequent. As yet there are no high-quality data regarding the use of cilostazol for secondary stroke prevention in non-Asian ethnic groups.

  
  
• 
  

  Triflusal is an antiplatelet agent that is structurally related to aspirin. It is available in some European and Latin American countries, but is considered investigational in the United States. A meta-analysis of four trials showed that the effectiveness of triflusal was similar to aspirin at preventing vascular events after stroke, and it had a lower rate of hemorrhagic complications.²⁷

Anticoagulants

Acute anticoagulation with heparin or an alternative has been addressed in Chapter 3. Here we consider choices for long-term secondary stroke prevention that you should consider after the work-up has been complete. The conditions are listed below more or less in order of the frequency you will encounter them. Anticoagulants most often used include warfarin (Coumadin) or one of the newer direct oral anticoagulants (DOACs), namely the direct thrombin inhibitor dabigatran, or one of the factor Xa inhibitors rivaroxaban, apixaban, or edoxaban. The decision to go with warfarin or a DOAC should be individualized, but the trend is to use DOACs, for several reasons:

• 
  

  Multiple trials show that DOACs are as effective as and probably safer than warfarin.³⁴ There have been no “head-to-head” studies comparing the various DOACs. Rivaroxaban is the only one that can be dosed once daily; reading “between the lines” in the various studies, data suggest that apixaban may provide the best safety profile, and that dabigatran may provide the best efficacy profile.

  
  
• 
  

  All DOACs provide effective anticoagulation within hours, thereby shortening hospital stay and obviating the need for “bridging.”

  
  
• 
  

  DOACs are easy to dose, with only slight adjustment for age or renal insufficiency.

  
  
• 
  

  Cost is less of an issue than when DOACs were first marketed, and they are probably no more costly over the long term when considering their better safety/efficacy profile and absence of INR monitoring.

  
  
• 
  

  There are now reversal agents available for both direct thrombin inhibitors and Xa inhibitors.

  
  
• 
  

  The main disadvantage of DOACs is that there is no way to determine the level of anticoagulation by an accurate and quick point-of-care test. Therefore, for patients with severe clotting tendency where you want to be absolutely sure the patient remains anticoagulated, warfarin may be a better choice as long as the patient is willing and able to have frequent INR monitoring.

For most of the following, the use of warfarin or a DOAC can be considered based on either randomized trials (level A) or consensus recommendations (level C). However, except for those with class I evidence (i.e., where there is general agreement with anticoagulant use), either antiplatelet drugs or an anticoagulant can be used.

• 
  

  Atrial fibrillation, except for “lone AF” (see below) (class I evidence).

  
  
• 
  

  Critical extracranial carotid stenosis, string sign or total occlusion, especially if intraluminal thrombus is seen.

  
  
• 
  

  Basilar thrombosis/stenosis.

  
  
• 
  

  Arterial dissection.

  
  
• 
  

  Other “embologenic” cardiac conditions:

  
  
  
  
  1. 
     

     ▪ rheumatic valvular disease or mechanical valve (class I evidence)

     
     
  2. 
     

     ▪ low left ventricular ejection fraction (< 30%)

     
     
  3. 
     

     ▪ akinesis or severe hypokinesis of left-ventricle segments (especially anterior wall or apex)

     
     
  4. 
     

     ▪ stroke soon after myocardial infarction, especially if mural thrombus is identified on TTE

     
     
  5. 
     

     ▪ aortic atheroma > 4 mm

  
  
  
  
• 
  

  Coagulopathy, especially if history of venous thrombosis or pulmonary embolism.

  
  
• 
  

  Cerebral venous sinus thrombosis.

Detection

The chance of detecting AF is greatest in proximity to the stroke, so careful scrutiny of any prehospital or ED ECGs is useful. Up to one-third of patients with stroke due to AF are in normal sinus rhythm on admission and may require prolonged cardiac monitoring to establish the diagnosis. If embolic stroke is suspected, continuous telemetry during the acute hospitalization is indicated. Occult AF can be detected with long-term monitoring using either a surface or implanted cardiac loop recorder. The optimal duration of extended monitoring is debatable. Multiple studies have shown that occult AF will be found in roughly 10% additional patients with monitoring up to 6 months post stroke, with most of those events occurring during the first month.³⁵ Recent studies have shown that extended monitoring will yield AF in 12–16% of patients with cryptogenic strokes within the first 12 months.^{36, 37} The importance of finding a brief episode of AF 6 months after a stroke is uncertain.

In patients in whom an embolic source is suspected based on imaging or other clinical features, we usually recommend monitoring for at least 1 month, using at minimum surface recording. Among patients with higher suspicion for AF, including patients with left atrial enlargement and patients with recurrent embolic stroke of undetermined source, an implantable device is reasonable. In the future, “wearable” devices will be more widely employed, such as the recently marketing Apple watch.

An important area of ongoing research is whether there are other structural or functional atrial abnormalities, but without AF, that might be associated with embolic stroke.