CEREBROVASCULAR DISEASE


Consider Ramipril for prevention of death in pts with with h/o CVA--Click HERE for more

See also:

Carotid and Cerebral Artery Stenosis

Central Venous Thrombosis

I. Transient Ischemic Attack (TIA)

  1. Definition = focal neurologic dysfunction lasting < 24h (us. < 1h)
  2. Clinical features-Same as CVA (see below)
  3. In some patients with TIA (around 40% in some series), brain imaging shows evidence of acute infarction; among such patients, near-term risk of recurrent TIA or CVA is higher than risk in TIA pts without evidence of acute infarction (Ann. Neurol. 679:86, 2005--JW)
  4. Incidence of CVA after TIA
    1. 8% at 7d and 17.3 at 3mos in one prospective study (BMJ 328:326, 2004--AFP)
    2. In a population-based study in 488 pts with first TIA, incidence of CVA was 1.2% within 6h, 2.0% within 12h, and 5.1% within 24h.  42% of the CVA's that occurred within 30d after the TIA occurred within the first 24h. (Neurology 72:1941, 2009-JW)
  5. Management of TIA
    1. Decision of whether or not to hospitalize depends in part on the likelihood of near-term subsequent CVA
    2. Prediction of risk of CVA near-term after TIA-The "ABCD" score
      1. Pt gets points for each of the following:
        1. Age > 60yo (1 point)
        2. BP at presentation > 140mm Hg systolic or > 90mm Hg diastolic (1 point)
        3. Unilateral weakness (2 points)
        4. Speech disturbance without weakness (1 point)
        5. Duration of symptoms > 60min (2 points), 10-59min (1 point), < 10min (0 points)
      2. In a validation cohort of 190 pts with TIA, 7d CVA risk was 0%, 2%, 16%, and 36% in pts with < 4, 4, 5, and 6 points, respectively (Lancet 366:29, 2005--JW)
II. CVA definitions and epidemiology
  1. Cerebrovascular Accident (CVA) = cerebral infarction due to an interruption of blood supply (may or may not be associated with hemorrhage). Focal neurologic deficit must last >24h
  2. In adults, 80% are ischemic; 20% are hemorrhagic
  3. Indicators of higher likelihood of presence of intracranial hemorrhage in patients with CVA (from data from the "OXVASC" study; referred to as the "SCAN" crtieria; J. Neurol. Neurosurg. Psychiat. 81:271, 2010-JW)
    1. BP > 180/110
    2. Confusion at onset of symptoms
    3. Nausea or vomiting at onset of symptoms
    4. Prior use of anticoagulants
  4. Risk factors for CVA
    1. Previous TIA or CVA
    2. Carotid and Cerebral Artery Stenosis
    3. Advanced age
    4. Hypertension
    5. Diabetes Mellitus
    6. Tobacco use
    7. Atherosclerosis of the thoracic aorta seen on transesophageal echocardiography (JACC 33:1317, 1999--JW)
    8. Hypercoagulable states
    9. Migraine
      1. A case-control study showed an association between migraine and CVA in women (BMJ 318:13, 1999--AFP)
      2. Frequent migraines in women were associated with increased incidence of CVA but not other cardiovascular events in a 12-year prospective study in 27,000 women 45y or older (Neurology 6/24/09; e-publication-JW)
    10. Cocaine use
    11. Periodontal disease but not gingivitis is a risk factor for nonhemorrhagic CVA (RR 2.11 in one 17y prospective cohort study; Arch. Int. Med. 160:2749, 2000--JW)
    12. Possibly, low-fat diet (inverse association between total fat & saturated fat as % of total calories and risk of ischemic but not hemorrhagic CVA in a paper using men from the Framingham study--JAMA 278:2145, 1997)
    13. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
      1. Rare, autosomal dominant condition
      2. Associated with CVA at young age
    14. Patent Foramen Ovale
III. Pathophysiology of CVA
  1. Pathogenesis of ischemic stroke, in roughly decreasing order of frequency
  1. Thrombus on atherosclerotic placque
    1. Spontaneous thrombus in hypercoagulable disorders (LA, ACLAb, Prot C/S def., Ca, DIC, thrombocythemia)
    2. Thromboemboli from carotids, vertebral aa., aorta, or heart (the latter from AFib or valvular dis., e.g. from prosthetic valve or rheumatic mitral stenosis)
  2. Severe cerebral aa. vasoconstriction (associated with migraine, subarachnoid hemorrhage)
  3. Global cerebral hypoperfusion producing focal infarct ("watershed")
  4. Foreign body emboli (air, fat, septic or tumor fragments)
  5. Giant Cell Arteritis and other Vasculitides
  6. Amyloid angiopathy (associatedd w/ mult. infarcts and intracerebral hemorrhages; dx by Bx)
  7. Carotid or vertebral aa. dissection (usually atraumatic; present w/neck pain; ipsilateral Horner's for carotid; accounts for a greater % of strokes in younger patients-19% of ischemic strokes in patinets under 45yo)
  8. Paradoxical cardioembolism (through R-L intracardiac shunt)
IV. CVA in childhood
  1. 25-30% of childhood CVA occurs in neonates, and 50% in children < 1yo
  2. Recurrence after initial CVA in childhood is common (15% at 1y and 19-41% at 5y)
  3. 45% are hemorrhagic
  4. Associated with congenital heart disease (most common risk factor), infections e.g. varicella, migraine, ruptured cerebral aneurysms, hypercoagulable states, sickle cell, moyamoya disease, an doral contraceptive use
  5. Clinical presentation similar to adults though may include more nonspecific presentations, particularly in younger children (e.g. in infants w/lethargy, hypotonia, apnea, irritability, or seizures)
  6. Management-Unclear whether anticoagulants or antiplatelets are beneficial; tPA discouraged as of 2012; Aspirin often used for secondary prevention

    V. Clinical features and differential diagnosis of CVA

    1. Sudden onset; usually hemiparesis +/- dysarthria, hemisensory loss, monocular visual loss, hemianopsia, or aphasia
    2. Basal artery distribution: depressed level of consciousness, gaze palsies, hemiparesis, dysarthria, pupillary abnormalities, and ataxia
    3. Factors which indicate a lower likelihood of cerebrovascular cause for symptoms
    1. No lateralizing symptoms or signs
    2. Positional symptoms
    3. Pain
    4. Progression of deficit over minutes rather than more rapidly
    1. Differential diagnosis
      1. Intracerebral mass lesion
      2. Cerebral hypoperfusion from hypotension or arrhythmia
      3. Hyperglycemia
      4. Hypercalcemia
      5. Radiculopathies
      6. Migraine
      7. Focal seizure
      8. Hypertensive encephalopathy (suggested by headache, lethargy, seizures, gradual onset, papilledema)
    VI. Management of Acute CVA-Diagnostic Evaluation
    1. Head CT without contrast is frequently done to r/o intracerebral hemorrhage, but MRI may be more sensitive
      1. In a study in 200 pts presenting with CVA < 6h after sx onset, all of whom had MRI (with gradient-recalled echo) followed by noncontrast CT, MRI was more sensitive for hemorrhage (detected 29 acute hemorrhages while CT detected only 25; only 1 seen on CT and not seen on MRI) (JAMA 292:1823, 2004--JW)
    2. MRI, however, may be more sensitive & specific for acute inschemic CVA than CT
      1. 50 pts with suspected ischemic CVA had both non-contrast CT and diffusion-weighted MRI within 6h of sx onset;"The correct diagnosis was established by the clinical course and follow-up CT or MRI examination." DWI had sig. higher sensitivity & specificity for dx of ischemic CVA (91% & 95% vs. 61% and 65%, respectively) (Stroke 33:2206, 2002--JW)
      2. In a prospective study in 356 pts presenting to a hospital for a possible acute CVA, all of whom had either CT or MRI, MRI was more sig. sensitive than CT for eventual diagnosis of acute CVA (89% vs. 54%) or acute ischemic CVA (Lancet 369:293, 2007--AFP)
    3. Troponin levels:
      1. Higher levels of Troponin T on admission associated with sig. greater risk of in-hospital death in a series of 181 pts with acute ischemic stroke (BMJ 320:1502, 2000--JW)
    4. BP, glucose, lytes, CBC, PT/PTT, ESR
    5. EKG to look for AFib and evidence of MI
    6. Investigation for potential cardiac source of emboli (e.g. intracardiac thrombi, vegetations, tumors, etc.; also atherosclerosis in thoracic aorta)
      1. Consider if evidence of arrhythmia, valvular disease, or other heart disease
      2. Echocardiography (transesophageal has higher sensitivity than transthoracic for intracardiac thrombi)
      3. Cardiac/Thoracic aorta CT (64-slice)-Less invasive alternative to transthoracic echocardiography, though misses some lesions found on TEE (Stroke 40:2073, 2009-JW)
      4. See above re: patent foramen ovale etc.
    7. Carotid duplex if a candidate for endarterectomy, with followup angio or MRA if positive--See under Carotid Stenosis
    8. If < 45yo consider w/u for cervical or cerebral artery dissection (MRA or duplex ultrasound) and if negative, TEE to look for cardiac anomalies e.g. PFO
    9. Consider w/u for hypercoagulable states
    10. Consider w/u for occult cancer
    11. Consider contrast echocardiography to r/o intracardiac R-L shunt

    VII. Management of Acute CVA-Treatment

    1. Antiplatelet agents
    1. In a trial in 19,400 pts with suspected acute ischemic CVA with < 48h sx ("International Stroke Trial"; Lancet 349:1569, 1997-abst) randomized in 2 x 2 fashion to:
    1. Unfractionated heparin SQ (5000 or 12,500 U BID) vs. "avoid heparin" and ASA 300 QD vs. "avoid ASA"
    2. Hep vs. avoid hep: no sig. diff in deaths within 14d or death or dependency at 6mos; with the 12,500U BID dose group ass'd w/ sig. more risk than 5,000U BID group for transfused or fatal extracranial bleeds, hemorrhagic CVA's, or deaths within 14d
    3. ASA vs. avoid ASA: no sig. difference in deaths within 14d (9.0 vs. 9.4%) or death or dependency at 6mos (62.2% vs. 63.5%), though this became sig. after adjustment for "baseline prognosis."
    1. Chinese Acute Stroke Trial (CAST, Lancet 349:1641, 1997-JW)
    1. 20,000 pts with stroke (presumably confirmed ischemic?) randomized to ASA 160 QD vs. placebo started < 48h after onset of sx and continued x 4 weeks
    2. Sig. fewer deaths during 4 weeks of study in ASA group (3.3% vs. 3.9%); fewer recurrent ischemic CVA as well (1.6% vs. 2.1%)
    1. Unfractionated IV Heparin
    1. Typically used if patient displays fluctuating or progressing neurologic deficits
      1. However, instability can also be due to hemorrhagic transformation, so consider repeat CT before starting IV Heparin
      2. Also consider new infarct, extension of the infarct, or other non-neurological causes for neurologic deterioration
    2. Typically used for 5-7d course
    3. Associated with risk of intracerebral hemorrhage
    4. In an observational study of 231 pts with embolic CVA ass'd with AFib all tx'd with Heparin IV, good functional outcome sig. more likely in pts who had heparin started within 6h of onset of sx (Arch. Neurol. 56:1098, 1999--JW)
    5. See also International Stroke Trial results above
    6. In a Cochrane meta-analysis of 22 randomized studies of anticoagulation in pts with acute ischemic CVA treated with heparin (any form, including SQ) vs. placebo, there was no sig.diff.in all-cause mortality.  Incidence of recurrent ischemic CVA and pulmonary embolus were reduced (absolute risk reduction 0.9% and 0.4%, respectively but incidence of symptomatic intracranial hemorrhage and extracranial hemorrhage were increased (absolute risk increase 0.9% for each) (Ann. Emerg. Med. 44:540, 2004--AFP)
    1. Low-molecular-weight Heparin and Heparinoids-Unlikely benefit except perhaps in setting of significant carotid occlusion or stenosis
      1. 1281 pts with acute ischemic CVA presenting < 24h after onset of sx randomized to 7d of Danaparoid IV dose-adjusted to anti-factor Xa activity vs. placebo; incidence of favorable outcomes (measured w/Glasgow Outcome Scale & Modified Barthel Index) was not sig. different at 3mos. Serious intracranial bleeding was higher in the Danaparoid group; borderline statistical significance (p = .05) ("TOAST" trial, JAMA 279:1265, 1998--abst)
      2. Subsequent analysis of the subgroup of pts with carotid occlusion or stenosis > 50% on carotid duplex (n = 229) showed sig. greater incidence of favorable neurologic outcomes at 3mos (68% with danaparoid vs. 53% with placebo) (Neurol. 53:122, 1999--JW)
      3. LMWH vs. ASA: In a randomized trial in 449 pts with atrial fibrillation hospitalized for ischemic CVA randomized to Dalteparin 100IU/kg SQ BID vs. ASA 160mg PO BID x 2wks, there were no sig. differences in the 14d incidence of recurrent CVA, cerebral hemorrhage, or all-cause mortality (Lancet 355:1205, 2000--AFP)
    1. 2002 American Academy of Neurology/American Stroke Association guidelines on antithrombotics in acute ischemic CVA (Neurol. 59:13, 2002--JW).  Performed systematic review of 10 studies on antithrombotics in acute stroke and found that:
      1. ASA 160-300mg QD was ass'd with reduction in early recurrent ischemic CVA and small benefit in mortality and functional status
      2. Adjusted-dose unfractionated heparin IV-No good data
      3. Fixed-dose unfractionated heparin SQ-Small reduction in early recurrent ischemic CVA, outweighed by small increase in CNS hemorrhage; no benefit in morbidity or mortality
      4. LMWH-No difference in mortality; inconsistent data on long-term morbidity, variable increase in CNS and non-CNS hemorrhage.
      5. They recommended ASA 160-325mg QD for ischemic CVA presenting < 48h after symptom onset if no contraindications or planned thrombolysis; Recommended using hep only for DVT prophylaxis.
    1. Thrombolytics
    1. European Cooperative Acute Stroke Study (ECASS) JAMA 274:1017, 1995-JW
    1. Multicenter trial randomized 620 pts to tPA (1.1 mg/kg) vs. placebo
    2. Pts all had acute ischemic hemishperic CVA and mod-severe neurol. deficits with < 6h of sx and CT showing no bleed or evidence of major infarct [sic]
    3. Found sl. improvement in neurol. outcome with tPA but higher rate of ICH, nonsig. higher mort. at 30d in tPA group
    4. On review of CT's, 109 pts should have been excluded b/c did have evid. of major infarct; in analysis excluding these pts, tPA group showed better neurol. fn at 90d
    5. Bottom line--better 3mo outcome with t-PA given in first 6h
    1. National Institute of Neurologic Disorders and Stroke Study (NINDS) NEJM 333:1581, 1995-JW
    1. t-PA (0.9 mg/kg) vs. placebo given within 3h of onset of ischemic CVA to 312 pts; nearly half, within 90minutes
    2. Higher rates of ICH during hospitalization with t-PA (6.4% vs. 0.6% with placebo)
    3. Better functional outcomes with t-PA (52% with minimal or no disability per "Barthel" index at 3mos vs. 38% w/placebo); no sig. diff. in mortality at 3 mos
    4. At 1y f/u, still sig. more pts in t-PA group with minimal or no disability (50% vs. 38%) but still no sig. diff. in mortality rates (NEJM 340:1781, 1999--JW)
    5. Bottom line--better 3mo & 12mo outcome with t-PA given in first 3h
    1. Multicenter Acute Stroke Trial (MAST-I) Lancet 346:1509, 1996-JW
    1. IV streptokinase alone or with ASA <6h after sx onset
    2. Streptokinase associated with higher 10d mortality rate; no reduction of risk of severe disability at 6mos
    3. Bottom line--no improved 6mo outcome w/streptokinase given in first 6h
    1. NEJM 335:145, 1996-JW
    1. Multicenter trial randomized 310 pts to streptokinase vs. placebo median 4.5h after onset of acute ischemic CVA in MCA territory
    2. Mortality sig. higher at 10d with streptokinase (34% vs. 18%), mostly due to fatal ICH
    3. Mortality sig. higher at 6mos with streptokinase (47% vs. 38%)
    4. Among survivors, those who got streptokinase were less likely to be severely disabled
    5. Bottom line--worse 6mo survival w/streptokinase given at median 4.5h
    1. JAMA 276:961, 1996-JW
    1. 340 adults with moderate-severe ischemic stroke and not on anticoagulants presenting <4h after onset of sx randomized to IV streptokinase (1.5million U) vs. placebo
    2. At 3mo, nonsig. trend toward worse outcomes among pts tx'd with streptokinase, esp. if rx'd <3h after sx onset
    3. Bottom line--worse 3mo outcome with streptokinase in first 6h
    1. "ECASSII" trial--Lancet 352:1245, 1998-JW
    1. 800 pts with clinical dx of mod-severe ischemic CVA and no or only minor CT findings of infarction presenting < 6h after sx onset randomized to t-PA vs. placebo
    2. No sig. diff. in 90d mortality (10.5% with t-PA vs. 10.7% with placebo)
    3. No sig. diff. in % with favorable 90d functional outcome ("modified Rankin scale") seen in (40.3% with t-PA vs. 36.6% with placebo)
    4. Sig. more t-PA pts were "independent" at 90d (54.3% vs. 46.0% w/placebo)
    5. Symptomatic intracranial hemorrhage more common with t-PA (8.8% vs. 3.4%)
    6. No diff. in outcomes between tx in < 3h vs. 3-6h after sx onset
    7. Bottom line--marginally better 3mo outcome with t-PA in first 6h
    1. "ATLANTIS" trial--JAMA 282:2019, 1999--JW & abst.
    1. 547 pts with CVA 3-5h after stroke onset randomized to t-PA 0.9mg/kg IV vs. placebo
    2. No sig. diff. in functional outcome at 90d; 90d mortality nonsig. higher (11% vs. 6.9%) wih t-PA
    3. Bottom line--No diff in 3mo outcome with t-PA at 3-5h; possibly higher mortality
    1. ("DIAS-2" trial; 
      1. In a study in 186 pts 18-85yo with acute ischemic CVA randomized to low- or high-dose desmopletase or placebo, there was no sig. diff. amonng the groups in overall clinical improvement at 90d; all-cause mortality was sig. higher in the high-dose desmopletase group compared with the other two.  (Lancet Neurol. 8:141, 2009-JW)
    1. One meta-analysis of 12 randomized controlled trials involving 3,400 pts found total mort. 22% w/thrombolytics vs. 18% with placebo; concomitant use of ASA increased mortality; streptokinase ass'd w/more mortality than t-PA; "it is difficult to justify the routine use of thrombolysis outside randomized trial" (Lancet 350:607, 1997-JW)
    1. Ultrasound as an adjunct to IV thrombolysis for ischemic CVA
      1. In a study in 126 pts with acute ischemic CVA due to MCA occlusion, all of who underwent t-PA within 3h of sx onset, randomized to ultrasound vs. placebo; the patency rates for the u/s group were higher immediately after the procedure, but there was no sig. diff. in incidence of "dramatic clinical recovery" at 24h or favorable clinical outcomes at 3mos (NEJM 351:2170, 2004--abst)
    2. Intra-arterial Thrombolytics--may improve outcomes c/w placebo
      1. 180 pts with acute ischemic CVA of < 6h duration caused by MCA occlusion but no hemorrhage or "major early infarction signs on CT" randomized to intra-arterial prourokinase vs. placebo; all received IV heparin; at 90d, prourokinase group had RR 1.6 (40% vs. 25%; sig.) for slight-or-no neurologic disability; no diff. in mortality at 90d; 10% of prourokinase pts vs. 2% of placebo pts had intracranial hemorrhage w/neurologic deterioration within 24h of administration (p = 0.6) ("PROACT II" trial; JAMA 282:2003, 1999--abst & JW)
    3. Embolectomy
      1. In an uncontrolled study in 151 pts with ischemic CVA presenting < 8h after symptom onset, embolectomy was associated with recanalization of about 40% of the patients and in those patients an improvement of clinical symptoms was seen ("Mechanical Embolus Removal in Cerebral Ischemia" ("MERCI") Trial; Stroke 36:1432, 2005-JW)
    1. NXY-059
      1. A "free-radical-trapping agent"
      2. In a study in 1,722 pts presenting within 6h of onset of sx of acute ischemic CVA randomized to NXY-059 infusion x 72hvs. placebo, functional scores at 90d were sig. better in the active-tx group, but there was no sig. diff. in mortality (NEJM 354:588, 2006--JW)
    2. Ancrod
      1. Purified fraction of Malaysian pit viper (Caloselasma rhodostoma) venom
      2. Cleaves fibrinopeptide A from fibrinogen, inducing rapid defibrinogenation in vitro
      3. In the Stroke Treatment with Ancrod Trial ("STAT"), 500 pts with acute or progressing ischemic CVA and sx < 3h old randomized to Ancrod (target fibrinogen 1.18-2.03 umol/l) vs. placebo; 90d survival with good functional status was sig. greater in the Ancrod group (42.2% vs. 34.4%) though mortality was not sig. different; nonsig. greater # of symptomatic intracranial hemorrhage in the Ancrod group (5.2% vs. 2.0%) (JAMA 283:2395, 2000--abst)
      4. In a study in 1,222 pts with acute ischemic CVA presenting < 6h after symptom onset randomized to ancrod vs. placebo, there was no sig. diff. in functional outcomes at 3mos and incidence of death and intracerebral hemorrhage were sig. higher with ancrod ("European Stroke Treatment with Ancrod" ("ESTAT") Trial; Lancet 368:1871, 2006--JW)
    1. Magnesium sulfate IV-Probably not beneficial
      1. In a randomized study in 2,589 pts presenting < 12h after onset of CVA sx randomized to MgSO4 (4g IV over 15min then 16.15mg over 24h) vs. placebo, 90d incidence of (death or disability) was not sig. diff. between the two groups (Lancet 363:439, 2004--AFP)
    2. Ca-blockers have been suggested
      1. Nimodipine--conflicting results in trials
    3. Bedrest until stable & clearly able to walk safely
      1. DVT prophylaxis if on bedrest!
    4. Feeding issues in patients with CVA
      1. Poor nutritional intake is associated with mortality after CVA
      2. General practice is to keep pt NPO until swallow evaluation can be completed to determine aspiration risk (due to impaired airway reflexes)
      3. Tube feeding ("enteral feeding")
        1. Usually initiated within a few days after CVA if aspiration risk precludes oral feeding
        2. Options include nasogastric (NG) feeding, nasoduodenal (ND) feeding, or feeding via percutaneous gastrostomy tube (PEG)
        3. Early vs. late initiation of tube feeding
          1. In a randomized trial in 859 patients s/p CVA with impaired airway reflexes precluding oral feeding randomized to immediate initiation of tube feeds vs. delay for 7d (during which the pts received only parenteral hydration, the early-tube-feeding group had no sig. diff. in 6mo mortality and sig. higher prevalence of poor functional outcomes at 6mos (37% vs. 32%) (Lancet 365:755, 2005--JW)
        4. Feeding via NG vs. PEG
          1. In a study in 30 pts with CVA and swallowing difficulty randomized to NG feeds vs. immediate PEG, 77% of PEG pts gained weight vs. 12% of NG pts; 3 PEG pts were able to resume normal eating vs. none of NG pts (BMJ 312:13, 1996-JW)
          2. In a randomized trial in 321 patients s/p CVA with impaired airway reflexes precluding oral feeding randomized to NGT vs. PEG, 6mo incidence of (death or poor outcome) was "borderline" significantly higher in PEG group (89% vs. 81%) (Lancet 365:764, 2005--JW)
    1. Treat hyperglycemia, if present, because it may worsen ischemia
    2. Approach to Hypertension in CVA (sources include Neurology 43:461, 1993)
    1. BP often rises above baseline in all types of CVA (for unclear reasons), declining to baseline in first few days
    2. SBP < 155 and DBP < 70 were both associated with RR 2.0 for death compared to values of 155-200 and 70-105, respectively, in an observational study of 357 pts with acute ischemic stroke presenting < 24h after symptom onset (Neurol. 65:1179, 2005--JW)
    3. Physiology of cerebral perfusion in CVA (CBF = cerebral blood flow; CPP = cerebral perfusion pressure; CVR = cerebrovascular resistance; ICP = intracranial pressure; MAP = mean arterial pressure)
    1. CBF = CPP / CVR
    2. CPP = systemic arterial BP - venous backpressure (us. negligible)
    3. CPP is reduced by reductions in systemic BP (or local arterial occlusive disease) or increase in venous backpressure, which is most commonly caused by increased ICP
    4. CVR is down-regulated when CPP falls to maintain near-constant CBF; this is termed [cerebrovascular] "autoregulation" and applies for MAP 60-150mm Hg in most folks; higher in hypertensives
    5. If CPP falls below the "autoregulatory limit," autoregulation is no longer sufficient to maintain CBF and CBF falls
    1. Theoretical risk of treating HTN in ischemic CVA: In ischemic CVA, the central core of anoxic tissue is surrounded by a zone of still-viable tissue where minimally sufficient perfusion is maintained by maximally dilated collateral vessels; any reduction in CPP may increase the size of the infarct
    2. Theoretical benefits to reducing BP in ischemic CVA: less edema, less risk of hemorrhagic transformation
    3. Lower thresholds for treating hypertension is often recommended in hemorrhagic CVA than ischemic CVA (e.g. systolic of 180mmg Hg vs. 220mm Hg).
    4. Traditionally accepted indications for treating hypertension in pts with CVA:
      1. Malignant HTN (with sx of papilledema, encephalopathy, nephropathy, microangiopathic hemolytic anemia)
      2. Ongoing Myocardial Infarction
      3. Ongoing Heart Failure
    5. Studies of treatment of hypertension in acute stroke
      1. In a study of pts with acute ischemic CVA and severe hypertension (mean BP over 2 readings > 200/110 at 6-24h post-admission or > 180/105 at 24-36h after admission) randomized to candesartan 4mg/d vs. placebo x 1wk (after which all pts received candesartan); over 12mos f/u, incidence of overall mortality was nonsig. lower in candesartan group though total vascular event incidence was sig. lower in candesartan group (9.8% vs. 18.7%) (Stroke 34:1699, 2003--AFP)
      2. In setting of Intracranial Hemorrhage, with attendant risk of increased intracranial pressure, thiopental for HTN may reduce ICP, incontrast to increases from nifedipine, reserpine, and chlorpromazine (Stroke 19:314, 1988 cited in above review)
      3. In a study in 2,000 pts with acute CVA and SBP > 140mm Hg randomized to candesartan (titrated up to max 16mg/d) vs. placebo, there was no sig. diff. between the groups in 6mo incidence of (CVA, MI< or vascular death) but candesartan group had sig. worse functional status at 6mos.  No benefit to candesartan group seen in subgroups with SBP > 180mm Hg, SBP > 200mm Hg, or hemorrhagic CVA. ("SCAST" study; Lancet 377:741, 2011-JW)
    1. If deteriorating, consider dx of cerebral edema which us. occurs 2-3d after the CVA
    1. CT provides definitive dx
    2. Mannitol
    1. Keep serum osmolality around 320mosm/l so as not to dehydrate
    2. Taper rather than sudden d/c; us. not used for >2-3d
    1. Lasix is used; glycerol used in the UK
    2. Mechanical hyperventilation with pCO2 around 25
    3. Corticosteroids are of no value

    VIII. Primary prevention of ischemic CVA

    1. In a meta-analysis of 5 placebo-controlled studies w/total 52,251 subjects, mean f/u of 4.6y, and ASA doses 75-650mg/d, risk of CVA was not sig. different than placebo; subgroup analysis did not reveal any subgroups for whom ASA exerted a significant effect (Arch. Neurol. 57:326, 2000--JW)
    2. Tx with HMG CoA-Reductase inhibitors may reduce risk of CVA in pts with abnormal lipid levels--See under "Dyslipidemias"

    IX. Secondary prevention of ischemic cerebrovascular events

    1. Control risk factors (see above)
    2. ASA: the first-line antiplatelet
    1. Reduces incidence of repeat CVAs by about 20%; also reduces incidence of CVA after TIA by about 20-25%
    2. Didn't yield sig. results for women in early studies, poss. b/c few women were included.
    3. One study showed similar benefits post-TIA/CVA for ASA 30mg vs. 283mg QD (NEJM 325:1261, 1991)
    1. Second-line antiplatelets--Ticlopidine and Clopidogrel--Similar results to ASA
    1. Ticlopidine vs. Aspirin Stroke Study ("TASS") randomized 3069 pts with recent TIA to ticlopidine vs. ASA 650 BID in pts with TIA or minor ischemic CVA; slightly better outcomes with ticlopidine (NEJM 321:501, 1989)
    2. 1,809 African-American pts s/p ischemic CVA randomized to ticlopidine 500mg/d vs. ASA 650mg/d; over 2y f/u, risk of primary outcome (recurrent CVA, MI, or vascular death) was not sig. different between the two groups ("African American Anti-platelet Stroke Prevention Study," "AAASPS"; JAMA 289:2947, 2003--AFP)
    3. The CAPRIE study showed some advantage of clopidogrel over ASA in secondary prevention of ischemic events, including CVA (click link for details)
    4. Clopidogrel 75mg/d + ASA 75mg/d c/w clopidogrel alone, over 18mo f/u, was associated with no sig. diff. in incidence of of (ischemic CVA, MI, vascular death, or hospitalization for TIA, angina, or peripheral arterial disease) or all-cause mortality in a randomized trial in 7,599 pts s/p ischemic CVA or TIA in prior 3mos plus at least one of (prior CVA, prior MI, angina, DM, or symptomatic peripheral arterial disease) (Lancet 364:331, 2004--abst)
    1. Aspirin-Dipyridamole combination (25mg/200mg BID, "Aggrenox") for prevention of CVA
      1. In other dosage combinations, ASA + dipyridamole hasn't been shown to be more effective at secondary prevention of CVA than ASA alone (Med. Letter 42:11, 2000)
      2. In a randomized trial of 6602 pts with h/o TIA or CVA, with 2y f/u, risk of CVA was sig. less in pts on Aggrenox than pts on ASA 25mg BID alone or Dipyridamole 200mg BID alone; no sig. diff. in risk of death (J. Neurol. Sci. 143:1, 1996--Med. Letter)
      3. In a study of 2,763 pts with recent TIA or minor ischemic stroke randomized to Aspirin alone vs. Aspirin + Dipyridamole (200mg BID) (Aspirin doses ranged from 30-325mg/d), over mean 3.5y f/u, the incidence of (CVA, MI, vascular death, or major hemorrhage) was sig. lower in the dual-therapy group (13% vs. 16)  ("ESPRIT" Trial; Lancet 367:1665, 2006--JW)
    1. Warfarin
    1. At PT 1.2-1.5x control lowers risk of repeat CVA after CVA ass'd w/nonrheumatic Atrial Fibrillation
    2. Some have suggested Warfarin in pts with risk factors for recurrent CVA, e.g. Hypercoagulable States
    3. Usually used chronically following embolic CVA with prosthetic heart valves, intracardiac thrombus, cardiac aneurysm, severe hypokinesis, & rheumatic valvular dis.
    4. Warfarin vs. ASA for secondary prevention of ischemic CVA
      1. One study found no advantage over ASA 325mg/d (NEJM 323:1505, 1990)
      2. Coumadin with target INR 3.0-4.5 vs. ASA 30mg QD; the former was ass'd w/sig. higher risk of death and major bleeding complications in 1300 pts s/p TIA or "minor" ischemic CVA; no diff. in incidence of nonhemorrhagic ischemic events (Ann. Neurol. 42:857, 1997-JW)
      3. 2206 pts with nonembolic ischemic CVA within previous 30d randomized to warfarin (target INR 1.4-2.8) vs. ASA 325mg/d; over avg. 2y f/u, risk of combined endpoint of (recurrent ischemic CVA or death) was not sig. diff. in 2 groups; ditto for risk of major hemorrhage; risk of minor hemorrhage sig. more common with Warfarin (20.8 vs. 12.9 per 100 pt-years) (NEJM 345:1444, 2001--JW)
    1. Carotid endarterectomy--see under "Carotid Stenosis"
    1. ACE Inhibitors + Diuretics even if normotensive!
      1. 6105 pts with prior CVA or TIA, 48% of whom had hypertension, randomized to perindopril vs. placebo; perindopril could also have indapamide "at discretion of treating physicians" over mean 4y f/u, risk of recurrent CVA was sig. lower in perindopril group (10% vs. 14%; RR 0.72).  This reduction was limited to those pts on combination perindopril + indapamide tx; the perindopril-only pts did NOT have sig. fewer CVA's than placebo pts; the subgroup of pts who were not hypertension did have sig. risk reduction (RR 0.73); no sig. diff. in overall mortality rate ("PROGRESS" trial, Lancet 358:1033, 2001--abst)
    2. Tx with HMG CoA-Reductase inhibitors may reduce risk of CVA in pts with h/o TIA or CVA--See under "Dyslipidemias"
    3. Phosphodiesterase Inhibitors
      1. In a study in 135 pts < 2wks s/p ischemic CVA randomized to cilostazol 100mg BID vs. placebo (all pts also received ASA), 6mo progression of symptomatic intracranial arterial stenosis was sig. less in cilostazol recipients (6.7% vs. 28.8%) (Stroke 36:782, 2005--JW)

     (Sources include Core Content Review of Family Medicine, 2012)