Stroke – General Information and Physiology
(Transient ischemic attack): transient neuronal dysfunction secondary to focal ischemia (of brain, spinal cord, or retina) without (permanent) acute infarction1 (note: obsolete operational definitions used an arbitrary 24-hour cutoff for duration of symptoms).
Only 3% of ischemic strokes occur in patients < 40 yrs of age.20 Over 10% of ischemic strokes occur in patients ≤ 55 yrs.21 Incidence: 10 per 100,000 persons age 35–44 yrs,22 73 per 100,000 for age < 55 yrs.21
routine: electrolytes, CBC, platelet count and/or function, ESR (elevation may suggest SLE, arteritis, atrial myxoma… but a normal ESR does not rule out vasculitis), PT/PTT, VDRL (should be obtained in all young adults with stroke), fasting lipid profile
for unexplained stroke: ANA, antithrombin III, protein C, protein S, homocysteine, factor V Leiden, PPD, sickle-cell screen, toxicology screen (blood and urine, to R/O drugs such as cocaine), SPEP, lupus anticoagulant, serum amino acid, tissue plasminogen-activator and -inhibitor
cerebral angiography: not always necessary for patients with obvious systemic disease or strong evidence for cardiac embolism; may occasionally diagnose cerebral embolism if performed within 48 hrs of ictus
Atherosclerotic plaques begin to form in the carotid artery at 20 yrs of age. In the extracranial cerebral circulation, plaques typically start on the back wall of the common carotid artery (CCA). As they enlarge, they encroach on the lumen of the ICA. Calcified hard plaques may not change with time. The risk of stroke correlates with the degree of stenosis and with certain types of plaque morphology, and is also increased in hypercoagulable states and with increased blood viscosity.
“Vulnerable” plaques are atherosclerotic plaques likely to cause thrombotic complications, or those that tend to progress rapidly. Criteria for vulnerable plaques include: intimal thickening, plaque fissure, lipid/necrotic core with thin fibrous cap, calcification, thrombus, intraplaque hemorrhage, and outward remodeling. Some of these features can be identified with high-resolution MRI.34 , 35 , 36 , 37
Carotid artery lesions are considered symptomatic if there are one or more lateralizing ischemic episodes appropriate to the distribution of the lesion. A lesion is considered to be asymptomatic if the patient only has non-specific visual complaints, dizziness, or syncope not associated with TIA or stroke.38 The majority (80%) of carotid atherothrombotic strokes occur without warning symptoms.39
Usually discovered as a carotid bruit. Asymptomatic bruit: prevalence increases with age (2.3% in ages 45–54 yrs, 8.2% at ≥ 75).40 Accuracy of a bruit in predicting ICA stenosis: 50–83% (depending on cohort, criteria for stenosis…). Sensitivity is as low as 24%.41
May present as a TIA, RIND, or stroke with any of the following findings; see also ICA occlusion syndromes:
Classification of patients based on the hemodynamics and also the embolic propensity of carotid lesions has thus far been too complex to be utilized in large studies. The tests described below place a great deal of emphasis on the greatest degree of stenosis, which is probably an oversimplification. Plaque composition and morphology is probably important.
the U.S. Preventive Services Task Force (USPSTF) currently recommends against screening for carotid stenosis in the adult general population (grade D recommendation: moderate or high certainty that the service has no net benefit or that the harm outweighs the benefit)42
the AHA Primary Prevention of Stroke Guidelines does not recommend screening for asymptomatic carotid stenosis43
the American Society of Neuroimaging advised that screening should be considered only for age ≥ 65 years with 3 or more cardiovascular risk factors44
the Society of Vascular Surgery recommends ultrasonography screening for age ≥ 55 years with cardiovascular risk factors, such as HTN, diabetes, smoking, hypercholesterolemia, or known cardiovascular disease45
See also recommendations for which tests to use.
bindicates degrees of stenosis for which surgery was NOT of clear benefit for symptomatic stenosis
The “gold standard” test is a catheter arteriogram. It cannot be justified as a screening test because it is invasive, and too costly and risky ( recent data show < 1% risk of transient or permanent deficit (risk is 2–3 times higher in symptomatic patients than in asymptomatic)46 , 47 , 48 in good hands). Also, unlike duplex Doppler and MRA, it does not provide any information about the thickness of the plaque. Different definitions of the degree of stenosis are employed; Table 80.5 compares the definitions used by the NASCET study49 to those of the ECST.50 For both, N is the linear diameter of the carotid artery at the site of greatest narrowing. The studies differ in the denominator, NASCET uses D (the diameter of the normal artery distal to the carotid bulb, taken at the first point at which the arterial walls become parallel), whereas the ECST uses B (the estimated carotid bulb diameter).
For example, using the NASCET definition, the degree of stenosis is shown in Eq Equation 80.2.
B-mode image evaluates the artery in cross-sectional plane, and spectrum analysis shows blood flow. Performs poorly with a “string sign.” Cannot scan above the angle of the mandible. Lower frequencies give greater depth of penetration, but signal definition is sacrificed (used in transcranial Doppler). Sensitivity: 88%, specificity: 76%.52
May obviate the need for angiography in some cases of carotid stenosis, specifically in symptomatic patients with a focal “gap” of signal intensity loss with distal reappearance of signal.53 , 54 Sometimes overestimates the degree of stenosis.55 Sensitivity: 91%, specificity: 88% for extracranial carotid disease.56 2D TOF-MRA is adequate (contrast-MRA shows more, but is not necessary for surgical lesions57 ).
Can be performed at the time as MRI with stroke protocol in TIA/stroke patients, and also detects thrombus or dissection. As with Doppler, has difficulties distinguishing very severe stenosis from occlusion. Less operator dependent than Doppler, but is more expensive and time-consuming. MRA is more difficult to perform if the patient is critically ill, unable to lie supine, or has claustrophobia, a pacemaker or ferromagnetic implants. High-resolution MRI may also detect vulnerable plaques.
CTA involves ionizing radiation (X-rays) and IV iodinated contrast, limiting its use in patients with dye allergies and renal dysfunction. Results are comparable to MRA and Doppler. CTA can be performed within a few seconds and yields high-resolution images of all vessels from the aortic arch through the intracranial/extracranial vessels as well as the surrounding soft tissues (Fig. 80.3). In a meta-analysis, sensitivity and specificity for detection of a 70% to 99% stenosis were 85% and 93%, respectively.58 CTA is still evolving and may help detect vulnerable plaques. Another potential advantage: ability to obtain CT-perfusion studies at the same time.
Despite a great deal of research on the subject, there are no data to support a particular testing algorithm.1 Doppler, CTA, or MRA are acceptable initial screening tests. In patients with an abnormal screening test, a common strategy is to obtain a second confirmatory noninvasive test to evaluate the carotid bifurcation before intervention. The combination of carotid ultrasound and MRA has proved cost effective with good interobserver reliability.59 If 2 noninvasive tests are discordant, catheter angiography should be considered before intervention.
patients with asymptomatic A-fib should be treated with anticoagulation; see Cardiogenic brain embolism
Irreversibly inhibits cyclooxygenase, preventing synthesis of vascular prostacyclin (a vasodilator and platelet inhibitor) and platelet thromboxane A2 (a vasoconstrictor and platelet activator). Platelets, lacking cellular organelles, cannot resynthesize cyclooxygenase, whereas the vascular tissues do so rapidly.60 NB: < 1000 mg ASA per day probably does not help with high grade stenosis where there is perfusion failure or flow failure. Some (but not all) studies show less effectiveness in women,61 and no large study has shown that ASA prevents a second stroke in patients that have already had one.
℞: For angina, a bolus dose of 160–325 mg PO is followed by maintenance doses of 80–160 mg/d (lower doses appear to be as effective as higher doses).62 Optimal dose for cerebrovascular ischemia continues to be debated. 325 mg PO q d reduces risk of stroke following TIA by 25–30%. Daily doses of 81 or 325 mg when compared to higher doses were associated with a lower rate of stroke, MI, and death (6.2% vs. 8.4%) following carotid endarterectomy.63
Combination of extended release dipyridamole and ASA (Aggrenox) is more effective than ASA alone for prevention of TIA, stroke, and myocardial infarction.64 , 65 , 66 Aggrenox was not superior to clopidogrel, with increased hemorrhage with Aggrenox.67 Side effects: H/A with initial therapy.
A thienopyridine. Incidence of severe neutropenia (0.04%) is close to that of ASA (≈ 0.02%).68 Interferes with platelet membrane function by inhibiting ADP-induced platelet fibrinogen binding and release of platelet granule contents, as well as subsequent platelet-platelet interactions. Produces a time- and dose-dependent irreversible inhibition of platelet aggregation and prolongation of bleeding time. May replace ASA if intolerance or resistance. Used in combination with ASA for some endovascular procedures. Although clopidogrel plus aspirin is recommended over aspirin for acute coronary syndromes, the MATCH69 results do not suggest a similar benefit for stroke and TIA. Combination therapy significantly increased risk of hemorrhage.69
Pharmacokinetics: Dosed once daily. Requires several days to reach maximal effect (∴ a loading dose may be used, e.g. after an acute event such as an MI, or before stenting). Takes ≈ 5 days off the drug for platelet inhibition to reverse.
Individualization is recommend for antiplatelet agents for secondary stroke prevention. ASA is effective, and its low cost may help compliance. A small reduction of vascular events with Aggrenox may justify its expense from a broader healthcare perspective. Clopidogrel is appropriate for those intolerant or resistant to ASA. Clopidogrel plus ASA may be indicated in patients with recent cardiac ischemia or vascular stenting.70
Level I71 : CEA is reasonable in asymptomatic patients with > 70% ICA stenosis if risk of perioperative stroke, MI, and death is low
Level II71 : It is reasonable to choose CEA over CAS when revascularization is indicated in older patients especially when the anatomy is unfavorable for endovascular intervention
Level II71 : It is reasonable to choose CAS over CEA when revascularization is indicated in patients with anatomy unfavorable for surgery
Level II71 : prophylactic CAS may be considered in highly selected patients with asymptomatic ICA stenosis (≥ 60% by angiography, > 70% by validated Doppler ultrasound), but the effectiveness compared to medical therapy alone is not well-established
Level II71 : In patients with high risk of complications by either CEA or CAS (includes: age > 80 years, NYHA heart failure class II or IV, LVEF < 30%, class III or OV angina pectoris, left main or multivessel CAD, need for cardiac surgery within 30 days, MI within 4 weeks, and severe chronic lung disease), the effectiveness of revascularization over medical therapy alone is not well-established
Natural history studies reflect an annual stroke risk of 1–3.4% with asymptomatic carotid artery stenosis of 50–99% at 2–3 years.75 , 76 , 77 , 78 , 79 , 80 A cohort study found similar cumulative rates of ipsilateral stroke over 10 years (9.3%, or 0.9%/year) and 15 years (16.6%, or 1.1%/year).81
Attempts to identify subgroups of patients with asymptomatic carotid stenosis at elevated stroke risk suggest that the rate of unheralded stroke ipsilateral to a hemodynamically significant extracranial carotid artery stenosis is 1–2% annually, with some data suggesting that the stroke rate may be higher with progressing stenosis or with more severe stenosis. Asymptomatic carotid stenosis is an important marker of concomitant ischemic cardiac disease.75 , 76 , 77 , 80 , 81 In the REACH Study,82 patients with asymptomatic carotid stenosis (n = 3164) had statistically significantly higher age- and sex-adjusted 1-year rates of transient ischemic attack, non-fatal stroke, fatal stroke, and cardiovascular death compared to patients without asymptomatic carotid stenosis (n = 30 329).
The largest multicenter randomized trial to date83 revealed a moderate benefit for immediate CEA vs. medical management in patients age < 75 with asymptomatic stenosis ≥ 60%.
Details: 3,120 patients with ≥ 60% stenosis by duplex ultrasound were randomized to immediate CEA (50% had CEA within 1 month, 88% within 1 year) or medical therapy at the discretion of the treating physician. Mean follow-up: 3.4 years. Exclusion criteria included: poor surgical risk, prior ipsilateral CEA, and probable cardiac emboli. Surgeons were required to have a perioperative morbidity and mortality rate of < 6%.
Net five-year risk for all stroke or perioperative stroke or death: 6.4% in the CEA group, vs. 11.8% in the medical group (p< 0.0001). Fatal or disabling stroke: 3.5 vs. 6.1%. Fatal stroke alone: 2.1 vs. 4.2%. Although men and women benefited, men benefited more. CEA did not demonstrate a statistically significant benefit for patients over the age of 75. Statistical benefit was not seen in the immediate CEA group until nearly two years after surgery, despite a relatively low perioperative morbidity and mortality rate of 3.1%, (in contrast to patients with symptomatic stenosis (NASCET84 ) where benefit was seen much earlier).
CEA reduces ipsilateral neurologic events, but did not reduce the rate of ipsilateral strokes nor death (most deaths were secondary to MI). This trial did not include women and was not powered to detect differences in outcome subgroups.
No difference in outcome between CEA vs. aspirin (new stroke or death), but an unusual protocol lessened its statistical validity.88
There were no major strokes or deaths in either the medical or the endarterectomy group. Surgically treated patients were not given aspirin, and 26% had an MI compared to 9% in the aspirin-treated medical arm, reflecting the high incidence of concomitant CAD in patients with an asymptomatic carotid artery stenosis.
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35 Saam T, Cai J, Ma L, et al. Comparison of symptomatic and asymptomatic atherosclerotic carotid plaque features with in vivo MR imaging. Radiology. 2006;240:464-472. DOI: 10.1148/radiol.2402050390
36 Saam T, Hatsukami TS, Takaya N, et al. The vulnerable, or high-risk, atherosclerotic plaque: noninvasive MR imaging for characterization and assessment. Radiology. 2007;244:64-77. DOI: 10.1148/radiol.2441051769
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43 Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke. Stroke. 2006;37:1583-1633. DOI: 10.1161/01.STR.0000223048.70103.F1
44 Qureshi AI, Alexandrov AV, Tegeler CH, et al. Guidelines for screening of extracranial carotid artery disease. J Neuroimaging. 2007;17:19-47. DOI: 10.1111/j.1552-6569.2006.00085.x
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56 Debrey SM, Yu H, Lynch JK, et al. Diagnostic accuracy of magnetic resonance angiography for internal carotid artery disease: a systematic review and meta-analysis. Stroke. 2008;39:2237-2248. DOI: 10.1161/STROKEAHA.107.509877
57 Babiarz LS, Romero JM, Murphy EK, et al. Contrast-enhanced MR angiography is not more accurate than unenhanced 2D time-of-flight MR angiography for determining > or = 70% internal carotid artery stenosis. AJNR Am J Neuroradiol. 2009;30:761-768. DOI: 10.3174/ajnr.A1464
58 Koelemay MJ, Nederkoorn PJ, Reitsma JB, et al. Systematic review of computed tomographic angiography for assessment of carotid artery disease. Stroke. 2004;35:2306-2312. DOI: 10.1161/01.STR.0000141426.63959.cc
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66 Verro P, Gorelick PB, Nguyen D. Aspirin plus dipyridamole versus aspirin for prevention of vascular events after stroke or TIA: a meta-analysis. Stroke. 2008;39:1358-1363. DOI: 10.1161/STROKEAHA.107.496281
67 Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359:1238-1251. DOI: 10.1056/NEJMoa0805002
69 Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337. DOI: 10.1016/S0140-6736(04)16721-4
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83 Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet. 2004;363:1491-1502.
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