Intracerebral Hemorrhage

Maria I. Aguilar, M.D.,1 and Bart M. Demaerschalk, M.D., M.Sc., F.R.C.P.(C.)2

ABSTRACT

KEYWORDS: Intracerebral hemorrhage, anticoagulants, antithrombotic therapy, thrombolysis, microbleeds

ontraumatic or spontaneous intracerebral hemorrhage (SICH) accounts for 10 to 15% of all strokes. Sixty-thousand new intracerebral hemorrhage (ICH) cases per year occur in the United States and as many as 400,000 per year in China. In contrast with ischemic stroke, which affects mostly elderly people, spontaneous ICH is predominately a disease of young adults, resulting in high cost and enormous loss of productivity. The mortality of ICH is higher than for ischemic stroke, and the cost to the health care system is also higher.13 Traumatic ICH and epidural, subdural, and subarachnoid hemorrhage will not be included in this review.

CASE 1 A 72-year-old Caucasian female with history of hypertension presented within 2 hours of acute onset of leftsided weakness. On arrival, her National Institute of Health Stroke Scale (NIHSS) score was 8 (moderate neurologic decit). Intravenous thrombolysis was given 2 hours 15 minutes from symptom onset, and her systolic blood pressure (SBP) at the time of the infusion was in
Department of Neurology, Division of Cerebrovascular Diseases; Department of Neurology, Divisions of Cerebrovascular Diseases and Critical Care Neurology, Mayo Clinic Arizona, Phoenix, Arizona. Address for correspondence and reprint requests: Maria I. Aguilar, M.D., Department of Neurology, Division of Cerebrovascular Disease, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ 85054.
2 1

the mid-170s. Three hours after the administration of tissue plasminogen activator (tPA), her level of alertness decreased, and she required endotracheal intubation because of inability to protect her airway. Her pupils became pinpoint and bilateral decorticate posturing was observed. The computed tomography (CT) scan of the brain at that time revealed a hypodense area in the right frontal hemisphere, not seen on the CT on arrival, as well as intraparenchymal blood in the pons and midbrain extending into the ventricular system (Fig. 1). Hemorrhagic complications are the main concern with thrombolytic (tPA) therapy for stroke management. Symptomatic intracranial hemorrhage is obviously the most feared outcome. In the National Institute of Neurological Disorders and StroketPA trial,4 6.4% of participants treated with tPA developed symptomatic intracranial hemorrhages, more than half with a fatal outcome. Severe neurologic decit,4 systolic hypertension,4,5 brain edema or mass effect on the pretreatment scan,5 and high serum glucose levels6 have been identied as risk factors for the development of ICH after the administration of thrombolysis. Why do these patients bleed? Early blood-brain
Questions for the Consultant; Guest Editors, Joseph I. Sirven, M.D., Dean M. Wingerchuk, M.D., M.Sc., F.R.C.P.(C.). Semin Neurol 2007;27:376384. Copyright # 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-2007-985338. ISSN 0271-8235.

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Intracerebral hemorrhage has recently transitioned from being a neurosurgical entity into a condition where nonsurgeons have more participation in the medical decision making. Despite recent advances in the management of intracerebral hemorrhage (i.e., STICH trial and recombinant factor VII trial), guidelines published in 1999 remain the only available therapeutic consensus. The goal of this review is to address frequently encountered case scenarios when managing patients with spontaneous or nontraumatic intracerebral hemorrhage, both acutely and long-term.

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barrier (BBB) disruption seems a reasonable explanation, although this has not been proved. Reperfusion, which is the goal of thrombolytic therapy, is an independent predictor of BBB disruption.7 The return of blood ow to postischemic brain has deleterious consequences, as similarly described in reperfused myocardium, as a consequence of accelerated necrosis of irreversibly injured myocytes.14 Thrombolysis-related ICH (TICH) is usually located at the site of the index ischemic stroke, but not always. Why do these patients bleed away from the index ischemic stroke? In the cardiology tPA trials,8 the estimated rate of ICH was 0.07 to 1.5% of patients who received thrombolytics for acute myocardial infarction, with an associated mortality of 50%. The only feature signicantly affecting the absolute risk of stroke, both ischemic and ICH in these trials, was advanced age.9 Compared with SICHs, TICHs are larger, more often multifocal, and more frequently contain a blood-uid level.10 Perihematomal edema is more often seen in SICH.11,12 Asymptomatic TICH had until recently been considered benign, but it increases the likelihood of poor outcome.13 No efcacious therapy is available to manage this condition, although cryoprecipitate and platelet transfusions are used routinely, and the outcome is almost uniformly fatal. The role of hematoma evacuation in this patient population is unknown but advocated by some.15 Rigorous screening of patients prior to tPA administration is so far the only efcacious and available method to prevent this complication.4

SURGERY FOR ICH The value and role of surgical evacuation of ICH has been a source of debate for several decades. For practical purposes, surgery may be performed as a lifesaving

measure in patients with large hematomas or in young patients with cortical hemorrhages and secondary neurologic deterioration. Patients with profound coma and neurologic decits (Glasgow Coma Score [GCS] of 4 or less) are considered to be poor surgical candidates with little hope for meaningful recovery. Deep ganglionic hemorrhages are rarely evacuated, and small-volume ICH (< 10 cm3) are treated medically. Urgent surgical removal of infratentorial hematomas of 3 cm or larger diameter is generally advised to prevent life-threatening brain-stem compression. The proper management of medium-sized hematomas is still debatable.16 The largest and most inuential evidence on the topic of surgery for ICH is the International Surgical Trial in Intracerebral Hemorrhage (STICH),17 a prospective, randomized, controlled trial that compared early surgery with initial conservative treatment for patients with ICH. The denition of early surgery was hematoma evacuation within 24 hours of randomization plus appropriate medical treatment. The initial conservative treatment arm used medical treatment, although later evacuation was allowed if necessary. Patients were eligible for inclusion if they had CT scan evidence of a spontaneous supratentorial ICH that had occurred within the previous 72 hours and if the neurosurgeon was uncertain about the relative benet of surgical and medical treatments. The primary outcome was death or disability using the extended Glasgow Outcome Scale 6 months after the ICH. A total of 1033 patients were randomized from 83 centers in 27 countries. The median age was 62 years. The time from ICH to randomization varied from 2 to 72 hours. The site of hematoma was lobar in 40% of patients and median hematoma volume was 38 mL. The median depth from cortical surface was 1 cm. Twenty-six percent of patients assigned to the medical arm required surgery because of neurologic deterioration. Of the patients randomized to early surgery,

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Figure 1 Thrombolysis-related ICH. On the left, noncontrast CT scan of the brain showing intraparenchymal hemorrhage at the brain stem, involving the ventricular system. On the right, right frontal cortico-subcortical hypodense area. Blood is present in the third ventricle.

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26% had a favorable outcome compared with 24% randomized to initial conservative therapy (odds ratio 0.89 [95% CI, 0.66 to 1.19]. Therefore, patients with spontaneous supratentorial ICH in neurosurgical units showed no overall benet from early surgery when compared with initial conservative therapy. The only variable that showed a signicant interaction with functional outcome was the depth of hematoma from cortical surface. In a subgroup analysis, favorable outcome was more likely in patients randomized to early surgery if the hematoma was supercial (< 1 cm of cortical surface). STICH II will only enroll patients with supercial hematomas, will require surgery within 12 hours of randomization, and will allow the introduction of recombinant factor VII for rapid reversal of anticoagulation to allow early surgical intervention in patients with anticoagulation-related ICH.18

low yield in identifying an underlying lesion and is generally not required. On the other hand, certain radiological structural abnormalities should prompt cerebral angiography, including the presence of subarachnoid or intraventricular blood, abnormal calcication, a prominent draining vein, or blood that extends to the perisylvian or interhemispheric ssure. Current recommendations are to consider angiography for young patients with no clear source of hemorrhage who may be surgical candidates.16

BLOOD PRESSURE MANAGEMENT IN ICH The short-term management of hypertension after ICH remains controversial. Hypertension after ICH is common and is probably attributable to head pain, high levels of circulating catecholamines, withdrawal of antihypertensive medications, and brainstemmediated release of catecholamines. Hypertension after ICH has been reported as a poor prognostic indicator.16 The theoretical rationale for lowering blood pressure is to decrease the risk of ongoing bleeding from ruptured small arteries, hematoma expansion, and worsening cerebral edema. Conversely, overaggressive treatment of hypertension may decrease cerebral perfusion pressure and subsequently worsen brain injury. There is postulated to be a zone of decreased blood ow surrounding an area of hematoma that is close to ischemic levels. The American Heart Association guidelines recommend that blood pressure be maintained below a mean arterial pressure of 130 mm Hg in persons with a history of hypertension.19 Several agents are effective for lowering blood pressure in ICH. b-Blockers, nicardipine, labetalol, and angiotensin-converting enzyme inhibitors are preferred and advantageous because they have little effect on intracranial pressure (ICP). Sodium nitroprusside and nitrates should generally be avoided in patients with raised ICP because they have the potential to cause venodilation and sudden increases in ICP. Hydralazine can decrease cerebral blood ow, but its effects are negligible. Sublingual nifedipine may decrease blood pressure precipitously and is therefore not used in an acute brain-injured patient.

INDICATIONS FOR CONVENTIONAL ANGIOGRAPHY In an older patient with a history of hypertension and an ICH in a deep subcortical area, routine angiography is

MANAGEMENT OF WARFARIN-RELATED ICH The frequency of warfarin-related ICH (WICH) has increased in parallel with the wider use of oral anticoagulants for secondary stroke prevention, therefore affecting mostly older people with atrial brillation.21,22 WICH is often a lethal condition, with a mortality rate of more than 50% that has remained unchanged over time. Adequate treatment is yet to be dened, and the available evidence lacks scientic rigor.23 Current guidelines are based on the limited available evidence.24,25 Guidelines regarding the management of ICH are to be published in 2007. The risk of WICH is higher during the rst year of anticoagulation therapy, presumably due to uctuations in both the warfarin dose and the international normalized ratio (INR).26 Most WICHs occur during therapeutic INR ranges (INR 2 to 3), but when coagulopathy is present (INR > 1.4), urgently reversing the coagulation defect is the primary goal, and several

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RECOMBINANT FACTOR VIIa Recombinant factor VIIa (rfVIIa) is a procoagulant agent that is approved for the management of bleeding complications in patients with hemophilia. The rst randomized trial in SICH was published in 200520 and included 399 patients allocated to 40, 80, or 160 mg/kg of rfVIIa within 4 hours of symptom onset. The primary outcome for this phase II dose-nding study was hematoma growth at 24 hours, and the reduction in volume was statistically signicant only for the highest dosage (p 0.01). There was no effect on hematoma enlargement among those treated more than 3 hours after symptom onset. Mortality and the combined outcome of death or severe disability were signicantly reduced in patients treated with rfVIIa (Fig. 2). Arterial thrombosis occurred in 5% of the treated subjects compared with none in the placebo arm. The phase III trial has been completed (Recombinant Factor VIIa in Acute Intracerebral Hemorrhage FAST trial at www.stroketrials.gov), and results are to be released during 2007. Until then, it seems premature to use rfVIIa for SICH outside of clinical trials.

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Figure 2 Recombinant factor VIIa. (Reproduced from the Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage trial [Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777 785], with permission of Dr. Stephan A. Mayer. Copyright # 2005 Massachusetts Medical Society. All rights reserved.) Survival at 90 days according to study group by dose of rfVIIa.

different agents have been used to achieve that endpoint (Table 1). Vitamin K is widely used but the time to reach its desired effect can be as long as 24 hours. Fresh-frozen plasma (FFP) carries the risk of volume overload, which limits its use in elderly patients. Prothrombin complex concentrate (PCC) and rfVIIa have both been linked to thrombosis and are expensive.23 Until guidelines become available, the treatment of this condition will continue to vary widely among physicians and institutions. A phase II trial is currently ongoing in Italy (rFVIIa in ICH in Patients Treated with Anticoagulants or Anti-Platelets

at www.stroketrials.gov) with results expected in late 2007. While awaiting evidence to guide management, treatment strategies should be directed at immediate reversal of the coagulation defect. Time is of the essence,27 and the quote time is brain applies also to this stroke subtype.

RE-ANTICOAGULATION AFTER WICH No studies accurately estimate the risk of ICH recurrence in survivors of WICH who subsequently undergo anticoagulation. The risk of recurrence appears small

Table 1 Reversing Anticoagulation in Warfarin-Associated Intracerebral Hemorrhage

Intervention Discontinuing warfarin Vitamin K* Time to Anticoagulation Reversal 514 days 624 hours to correct the INR Factors IX and X not repleted for even longer Risk of anaphylaxis with IV injection Warfarin resistance in higher doses up to 1 week Fresh-frozen plasma Prothrombin complex concentrate Factor VIIa concentrate 36 hours for infusion Typically 1232 hours for reversal 15 minutes after 10-minute to 1-hour infusion 15 minutes after bolus infusion Limited availability, cost, variable cofactor content based on manufacturer, potentially prothrombotic Short-half life, cost, potentially prothrombotic Uncertain safety
*10 mg intravenously by slow infusion over 10 minutes. INR, international normalized ratio. Data from Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc 2007;82:8292.

Comments

Large volume needed (24 L) to normalize INR

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CASE 2 A 38-year-old male with a hypercoagulable disorder presented with left-sided hemiplegia and neglect. Initial evaluation revealed a clot at the distal right internal carotid artery and occlusion of the M1 segment of the right middle cerebral artery. Repeat CT scan of the head 1 week after onset of symptoms revealed the presence of

Figure 3 Hemorrhagic infarct. Noncontrast CT scan of the brain showing a hypodense area in the right frontal region (index ischemic infarct) with hemorrhage along the infracted brain. There is 2 mm of right-to-left midline shift.

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based on limited evidence (3%/year in subjects with prosthetic cardiac valves2832). These patients, however, are likely healthier and younger than those receiving anticoagulation for secondary prevention of cardioembolic stroke related to atrial brillation. Some factors can potentially help predict risk of recurrence: older age, burden of white matter disease, presence of microbleeds,33 amyloid angiopathy, history of a cortical or lobar ICH versus a deep or basal-ganglia ICH.34 For primary prevention (e.g., patients with atrial brillation but without stroke), the risk of ICH recurrence after resuming anticoagulation therapy may outweigh the benet.34,35 In secondary prevention (those who have suffered an ischemic stroke of presumed cardioembolic origin) and among those with prosthetic cardiac valves, the risk-benet equation seems to favor reinitiation of anticoagulation.2832 It appears safe to restart warfarin therapy 7 to 14 days after the index ICH for patients who are clinically stable.23

blood in the area of the index infarct (Fig. 3). No clinical deterioration was noted.

HEMORRHAGIC INFARCTION A hemorrhagic infarction (HI) can be dened as an ischemic infarct in which an area of bleeding exists within infarcted cerebral tissue.36 From a clinical and pathophysiologic perspective, arterial and venous infarcts are distinct entities, but both may give rise to HI. Classically, arterial HI, or red infarcts, are differentiated from pale or bland ischemic infarcts. The only signicant difference, pathologically, is the intensity and extent of hemorrhage. Even pale infarcts reveal petechial hemorrhage on microscopy in 65% of cases.36 Red infarcts appear frankly hemorrhagic, with multifocal petechiae, conuent hemorrhagic areas, with predominance in the gray matter. The topographical predilection is due to the presence of richer capillary beds in gray matter compared with white matter. The frequency of HI varies depending on patient selection and whether imaging or pathologic criteria are used to dene the presence of HI. Pathology studies estimate the frequency of HI to be 28% (18 to 42%) of all ischemic strokes, whereas CT imagingbased studies estimate 5.5% (2 to 43%). In both cases, the frequency of HI among cardioembolic infarcts (57% of pathologic and 42% of CT-dened studies) is much higher than noncardioembolic infarcts (5% and 12%, respectively).36 Petechial HI patterns depend on the width and density of hemorrhagic extension. The area of infarction appears heterogeneous with alternating hypodense and isodense zones. Radiologically, this pattern is typically easy to differentiate from a parenchymal hematoma. Frequently, the main problem is differentiating an intrainfarct hematoma (IIH) from a primary parenchymal hematoma. Several CT features favor IIH: the presence of voluminous hypodensity surrounding the hemorrhage, which differs from the usual ne collar surrounding a primary hematoma; the topography of the hypodensity that ts into a precise arterial territory; and the heterogeneous aspect of the hemorrhage. The clinical syndrome of HI may differ little from other ischemic stroke, although it should strengthen consideration of a cardioembolic mechanism. Hemorrhagic transformation to HI is most often clinically asymptomatic, but a diagnosis of IIH carries a poor prognosis. Pathophysiologic mechanisms postulated to lead to HI include direct reperfusion, reperfusion by cortical anastomoses, systemic hypertension, hyperglycemia, age, and the effect of treatment with antithrombotic agents.36,37 The risk of hemorrhage is increased 12-fold in a large infarct with mass effect and midline shift compared with smaller infarcts not associated with mass effect. The onset of hemorrhagic transformation is

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Table 2 Stroke Rates in the SPARCL Trial Based on Study Group

Atorvastatin (n 2365) Change in LDL-cholesterol (mg/dL) Strokes All fatal strokes All ischemic strokes* Intracerebral hemorrhage 133 to 73 (45%) 265 (2.3%/y) 24 225 55 Placebo (n 2366) 134 to 129 (4%) 311 (2.7%/y) 41 286 33 Relative Risk (p Value) 16% (p 0.05) 43% (p 0.03) 21% (p 0.01) 66% (p 0.02)

*Includes 19 unclassified strokes. SPARCL, Stroke Prevention by Aggressive Reduction in Cholesterol Levels. Data from Amarenco P, Bogousslavsky J, Callahan A III, et al. High-dose atorvastatin after stroke or transient ischemic attack [see comment]. N Engl J Med 2006;355:549559.

LIPIDS AND ICH Statins have proven benet in preventing cerebrovascular disease.38 If SICH is due to macrovascular or microvascular pathology, one would expect to be able to extrapolate those results into secondary prevention of SICH. Findings from the recent Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial39 seem to argue against such a concept. Those with known coronary artery disease were excluded from this phase III study. A total of 4731 participants from 205 sites on 5 continents, with stroke or transient ischemic attack (TIA) 1 to 6 months prior to entry, were assigned in a double-blind fashion to atorvastatin 80 mg/d versus placebo. Lacunar infarcts predominated as the qualifying event, and 2% of the participants had ICH as their qualifying event. All strokes were reduced by 16% (Table 2), which is similar to the reported effect of statins on stroke from

MICROBLEEDS New available magnetic resonance imaging (MRI) sequences have made possible the detection of microhemorrhages (< 10 mm) or asymptomatic petechial hemorrhages.43,44 On gradient echo studies, ferritin and hemosiderin appear profoundly hypointense because of strong magnetic susceptibility effects (Fig. 4).45 Microbleeds should be differentiated from other lesions with similar MR appearance such as calcications, cavernous angiomas, and other occult vascular malformations. These small, asymptomatic hemorrhages are associated with advanced age, hypertension, and stroke46; they have been postulated to be a marker of small-vessel disease.33 The frequency and number of microbleeds varies with the following stroke subtypes, in descending order: ICH, lacunar stroke,

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poorly dened, but it most often occurs early: 10% in the rst 24 hours, 39% in the rst week, and 54% by the second week. In contrast with arterial HI, mechanisms producing venous HI include circulatory stasis due to venous occlusion, extensive diapedesis, and hemorrhage above the site of occlusion. On CT, venous infarcts appear as hyperdensities in cortex, subcortical areas, and inltrating the white matter at the cortical base with a characteristic triangular morphology. They do not correspond with an arterial territory. The venous HIs of superior sagittal sinus thrombosis are typically bihemispheric and situated at or near the convexity. Extension to the subdural space occurs frequently. The frequency of venous HI among venous thrombosis is estimated to be 20 to 50%.36 In summary, HIs are relatively common and usually found during the early evolution of an ischemic stroke. They are particularly associated with a cardioembolic mechanism of stroke. The clinical consequences are more strongly associated with the size of the infarct than the size of the hemorrhage, except for IIH where a poor prognosis is correlated with volume of hematoma and mass effect.

pooled analysis from nonstroke trials,38 but it is less than anticipated for this aggressive reduction in cholesterol levels. There was a signicant increase in ICH among those assigned to atorvastatin, as supported before by the Heart Protection Study of patients with cerebrovascular disease, comparing simvastatin 40 mg/d with placebo (low-density lipoprotein [LDL] reduced from 136 mg/dL to 97 mg/dL).40 A meta-analysis of nonstroke trials by Amarenco and colleagues,38 which included more than 49,000 patients, failed to document increased rates of hemorrhagic stroke among those in the statin arm. Hence, increased ICH in association with statin therapy and LDL-cholesterol reduction seems limited to patients with cerebrovascular disease rather than those with coronary heart disease; this effect may not be restricted to high-dose atorvastatin but applicable to the class of statin drugs or to aggressive reduction of cholesterol levels as a result of such therapy. Do these data indicate that ICH survivors should not receive statin drugs or cholesterol-lowering therapies? Although the question remains to be answered, a conservative approach might be to avoid high-dose statin therapy and reduction of LDL beyond usual levels (LDL 100 mg/dL)41,42 in this particular patient population until additional evidence becomes available.

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cardioembolic stroke, atherothrombotic stroke.47 Peripheral vascular disease and coronary arterial disease have also been associated with the presence of cerebral microbleeds.48 Does the presence of microbleeds detected by MRI predict occurrence of ICH?49,50 Do these lesions predict hemorrhagic complications of antiplatelet therapy,51 anticoagulation therapy,23 and thrombolytic therapy?52 The question remains open. Only two studies suggest that patients with microbleeds can safely be treated with thrombolysis.5,53 Microbleeds seem likely to be part of the spectrum of small-vessel disease with unknown implications for anticoagulant and thrombolytic therapies. More prospective data are required to conrm these assumptions.

typical pattern consisting of multiple asymptomatic lobar petechial hemorrhages may be detected using gradient echo MRI; when present, these ndings allow for a presumptive diagnosis of CAA.56 CAA will become more prevalent as aging of the general population continues. Surgery has traditionally not been offered to patients with CAAH because of advanced age and the perception that vessel fragility will result in poor hemostasis and rebleeding after evacuation. Studies in this population indicate that carefully selected CAAH patients (those with supercial hematomas) may benet from surgical evacuation.8

CEREBRAL AMYLOID ANGIOPATHY Cerebral amyloid angiography (CAA) is characterized by deposition of congophilic amyloid b protein in cortical and leptomeningeal vessels. It is associated with neurodegenerative diseases, in particular Alzheimers disease. ICH associated with CAA is typically in an older individual after the age of 55 years (predominately > 80 years), lobar, often multiple, with a tendency to be located in the posterior half of the brain, and prone to recurrence.54 There are published criteria for CAA hemorrhage (CAAH) that dene three levels of diagnostic certainty: possible, probable, and denite. Possible CAAH is a single lobar ICH, age > 60 years, and absence of other causes of ICH. Probable CAAH is one lobar ICH with pathologically proven CAAH or two lobar, cortical, or cortico-subcortical ICH, age > 60 years, and absence of other causes of ICH. Denite CAAH is lobar ICH with postmortem pathologic conrmatory evidence.55 A

PREVENTION OF VENOUS THROMBOEMBOLIC DISEASE IN PATIENTS WITH ACUTE ICH What is the risk of venous thromboembolic disease (VTE) after acute ICH? Observational studies have reported deep vein thrombosis frequencies ranging from 0.4 to 13%.20,5760 There is limited information available concerning VTE prevention in patients with ICH. Current practice is based on extrapolated evidence from ischemic stroke studies. Unfractionated heparin, at doses ranging from 5000 U three times per day to 12,500 U twice daily, reduces the incidence of deep venous thrombosis in patients with acute ischemic stroke.61,62 The commonly used dose of 5000 U twice daily, however, has not shown the same benet.61 Low-molecular-weight heparin seems to be at least as efcacious as unfractionated heparin. The use of these agents has been associated with increased rates of hemorrhagic transformation of infarcted brain tissue in the eld of ischemic stroke. Whether or not this risk can be extrapolated to patients with acute ICH is not known. One randomized study63 and two guidelines/

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Figure 4 Microbleeds. Gradient echo MRI of the brain: small, rounded, hypointense areas (microbleeds) in the left basal ganglia region and right cortico-subcortical frontal region.

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consensus statements19,64 favor the use of mechanical compression devices for preventing deep vein thrombosis in patients with acute ICH. Controlled trial data are required before the routine use of heparin and congeners can be recommended in this setting.
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