Spontaneous Intracerebral Hemorrhage: a Review

Neurosurg Focus 15 (4):Article 1, 2003, Click here to return to Table of Contents

Spontaneous intracerebral hemorrhage: a review

MATTHEW E. FEWEL, M.D., B. GREGORY THOMPSON, JR., M.D., AND JULIAN T. HOFF, M.D. Department of Neurosurgery, University of Michigan Health System, Ann Arbor, Michigan

Spontaneous intracerebral hemorrhage (SICH) is a blood clot that arises in the brain parenchyma in the absence of trauma or surgery. This entity accounts for 10 to 15% of all strokes and is associated with a higher mortality rate than either ischemic stroke or subarachnoid hemorrhage. Common causes include hypertension, amyloid angiopathy, coagulopathy, vascular anomalies, tumors, and various drugs. Hypertension, however, remains the single greatest modifiable risk factor for SICH. Computerized tomography scanning is the initial diagnostic modality of choice in SICH, and angiography should be considered in all cases except those involving older patients with preexisting hypertension in thalamic, putaminal, or cerebellar hemorrhage. Medical management includes venous thrombosis prophylaxis, gastric cytoprotection, and aggressive rehabilitation. Anticonvulsant agents should be prescribed in supratentorial SICH, whereas the management of hypertension is controversial. To date, nine prospective randomized controlled studies have been conducted to compare surgical and medical management of SICH. Although definitive evidence favoring surgical intervention is lacking, there is good theoretical rationale for early surgical intervention. Surgery should be considered in patients with moderate to large lobar or basal ganglia hemorrhages and those suffering progressive neurological deterioration. Elderly patients in whom the Glasgow Coma Scale score is less than 5, those with brainstem hemorrhages, and those with small hemorrhages do not typical- ly benefit from surgery. Patients with cerebellar hemorrhages larger than 3 cm, those with brainstem compression and hydrocephalus, or those exhibiting neurological deterioration should undergo surgical evacuation of the clot. It is hoped that the forthcoming results of the International Surgical Trial in IntraCerebral Hemorrhage will help formulate evidence-based recommendations regarding the role of surgery in SICH.

KEY WORDS •intracerebral hemorrhage • epidemiology • pathophysiology • surgery • medical management

An SICH is defined in this review as a blood clot that EPIDEMIOLOGY OF SICH arises in the brain parenchyma in the absence of trauma or Incidence of SICH surgery. An SICH can be classified as either primary or secondary depending on the underlying cause of the hem- Stroke is the third leading cause of death in the US. orrhage. Primary ICH accounts for approximately 70 to Each year in the US, an estimated 37,000 to 52,400 peo- 80% of cases and is due to spontaneous rupture of small ple suffer an ICH.13,119 This rate is expected to double by vessels damaged by hypertension or amyloid angiopathy. 2050 as a result of an aging population and changing Secondary ICH is associated with a number of congenital racial demographics. Spontaneous ICH accounts for 10 to and acquired conditions such as vascular anomalies, coag- 15% of all strokes and is associated with a higher mortal- ulopathies, tumors, and various drug therapies. Table 1 ity rate than either ischemic stroke or SAH, with only 38% provides a summary of the important causes of SICH. Its of affected persons surviving 1 year.31 In a study of all most frequent sites are the basal ganglia, thalamus, sub- cases of SICH and SAH in the greater Cincinnati area dur- cortical white matter of the cerebral lobes, cerebellum, ing the year 1988, the investigators found that ICH is and brainstem. more than twice as common as SAH.15 They determined the incidence of SICH to be 15 per 100,000 individuals in the population compared with six per 100,000 for SAH. Abbreviations used in this paper: AVM = arteriovenous malfor- Variation in the incidence of SICH is seen among dif- mation; BBB = blood–brain barrier; CAA = cerebral amyloid an- ferent sexes, age groups, and races. In African Americans giopathy; CBF = cerebral blood flow; CI = confidence interval; (50 cases per 100,000) and Japanese (55 per 100,000) the CPP = cerebral perfusion pressure; CT = computerized tomogra- 16,118 phy; GCS = Glasgow Coma Scale; ICP = intracranial pressure; incidence of SICH is twofold that in caucasians. Men are more likely to suffer an SICH than women and the ICH = intracerebral hemorrhage; MABP = mean arterial blood 16 pressure; MR = magnetic resonance; SAH = subarachnoid hemor- likelihood increases with age. rhage; SBP = systolic blood pressure; SICH = spontaneous ICH; A circadian and circannual pattern of SICH onset in the SPECT = single-photon emission CT; tPA = tissue plasminogen morning and winter has been reported.40 A similar circa- activator. dian rhythm has been reported for many cardiovascular

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CAUSES OF SICH Table 1 provides an outline of the major causes of SICH. Cerebrovascular damage to small arteries and arte- rioles due to chronic hypertension is recognized as the most significant cause of primary SICH (Fig. 1).37 Racial differences in hypertension and socioeconomic factors may explain the high incidence of SICH in certain ethnic groups. Cerebral amyloid angiopathy is the other major cause of Fig. 1. Axial CT scan obtained in a 57-year-old man with a his- primary SICH and an important cause of lobar SICH in 126 tory of hypertension who presented with left hemiplegia and obtun- elderly populations. In CAA, -amyloid protein is de- dation. A typical location for hypertensive SICH is demonstrated posited in the media and adventitia of cortical and lep- in the right basal ganglia. tomeningeal blood vessels. Histological examination of brain tissue obtained during surgery or at autopsy is necessary for the definitive diagnosis of CAA. Although some investigators have emphasized the problem of intraoperative hemostasis in these patients, neurosurgery can be performed safely in those with CAA-related SICH.57 TABLE 1 Hereditary ICH with amyloidosis, Dutch type, is a rare, Summary of primary and secondary causes of SICH* autosomal-dominant type of CAA that results in recurrent, sometimes multiple, lobar hemorrhages. primary Vascular anomalies are the second most common cause hypertension of SICH overall (Fig. 2). Aneurysms, AVMs, cavernomas, amyloid angiopathy dural arteriovenous fistulas, and venous malformations secondary aneurysm all can result in secondary SICH. The hemorrhage due to saccular a ruptured aneurysm almost always has a subarachnoid fusiform component and often extends into the ventricles. There mycotic should be a high index of suspicion in young patients with vascular malformation frontal or temporal lobe clots. Arteriovenous malforma- AVM tions are associated with an estimated mean annual hem- cavernous malformation venous angioma orrhage risk of 4%. dural arteriovenous fistula Cerebral venous malformations are assumed to be con- neoplasm genital lesions resulting from aberrant venous maturation. primary These entities have also been termed venous angiomas or metastatic developmental venous anomalies. Although rarely associ- coagulopathy ated with SICH, venous malformations are the most fre- acquired quently occurring vascular lesion demonstrated in autopsy anticoagulation (Coumadin, heparin) 42 thrombolytics (tPA, urokinase) and radiological series. Their clinical significance re- blood dyscrasias (DIC, leukemia, thrombocytopenia) mains controversial, with some authors reporting a neg- hepatic failure ligible hemorrhage risk42 and others suggesting a higher platelet dysfunction (renal failure, medications) risk.76 In a series of 63 patients with known venous mal- congenital formations followed longitudinally by Naff, et al.,91 the hemophilia platelet disorders risk of hemorrhage was 0.15% per lesion-year. We believe drugs or alcohol a conservative approach to their management should be sympathomimetics (ephedrine, phenylpropanolamine, adopted, because the risks of radiosurgery or resection pseudoephedrine) probably outweigh the risk of hemorrhage. cocaine, amphetamine, Ecstasy Spontaneous ICH is not an uncommon presentation in hemorrhagic ischemic stroke cases of previously unsuspected brain tumor. Hemorrhage dural venous sinus thrombosis vasculitis/vasculopathy resulting from brain tumors can occur in up to 10% of all moyamoya disease primary or metastatic tumors. Hemorrhage is more likely arterial dissection with certain types of tumors, including glioblastoma, he- pregnancy mangioblastoma, oligodendroglioma, and metastatic tu- eclampsia, venous sinus thrombosis mors. Metastatic tumors with a high propensity to hemor- other/unknown rhage are malignant melanoma, renal cell, prostate, and * DIC = disseminated intravascular coagulation. lung cancer. An indentation of the hematoma’s surface

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these hemorrhages. Long-term prospective evidence that revascularization surgery significantly prevents rebleeding in patients with hemorrhagic moyamoya disease is lacking.134 Abuse of sympathomimetic drugs such as cocaine, amphetamine, or Ecstasy has been reported in association with SICH. The mechanism is believed to be secondary to induced arterial hypertension. Drug abuse may represent the most common cause of stroke in young adults. These drugs may also predispose unsuspected vascular anomalies to hemorrhage. In a study of 11 patients (mean age 31 years) with a history of abuse of one of these agents leading to SICH, 10 were found to harbor intracranial aneurysms or AVMs.83 Therefore, the traditional teaching that these were hypertension-related hemorrhages that did not require investigation for underlying vascular abnor- Fig. 2. Imaging studies obtained in a 26-year-old woman who mality is no longer valid. Cerebral angiography or MR presented with severe headache, vomiting, rapid progression to angiography should be a standard part of the workup of unconsciousness, and a blown left pupil. Left: Axial CT scan re- SICH in young adults, even in the presence of positive vealing a large left temporoparietooccipital SICH with midline shift. At craniotomy for emergency clot evacuation, an AVM was toxicology screen findings. observed, but no attempt at resection was made. Right: Left ver- The most commonly implicated sympathomimetic 8 tebral artery angiogram obtained after clot evacuation confirmed a medication related to SICH is phenylpropanolamine. left posterior temporal AVM with a 2-cm nidus. Feeding arteries Ephedrine, pseudoephedrine, and phencyclidine have also from the posterior cerebral artery and drainage into the transverse been described in association with SICH.109 Ginkgo bilo- sinus are shown. The patient was allowed to recover from the ini- ba is an over-the-counter herbal extract used by many peo- tial hemorrhage and then underwent resection of the AVM 1 month ple in the US and Europe as a “memory aid;” several case later. reports have described an association between its use and ICH.78 A possible antiplatelet effect and Coumadin poten- tiation mechanism has been postulated. revealed on pre–contrast CT scanning should prompt sus- Pregnancy and the puerperium can be associated with picion of a tumoral hemorrhage.56 Contrast-enhanced CT SICH due to dural venous sinus thrombosis and eclamp- scanning or contrast-enhanced MR imaging usually iden- sia. SICH occurs in one to five per 10,000 pregnancies.82 tifies the tumor, although small areas of contrast enhance- There are numerous other rare causes of SICH including ment can be obscured by hemorrhage. In young patients cerebral artery dissection,41 infections, and a host of un- without hypertension follow-up imaging is warranted if usual bleeding diatheses. initial studies are unequivocal regarding cause (Fig. 3). Patients with liver failure or coagulopathy from any Risk Factors cause are at higher risk for SICH.94 The liver is responsi- With a mortality rate of 40 to 50% in SICH, identifica- ble for synthesis of most clotting factors and fibrinogen, as tion of modifiable risk factors might help lower its inci- well as playing a major role in metabolism of platelets. dence. The role of hypertension as a risk factor for SICH Excluding neonatal intraventricular hemorrhage, struc- is well established. Hypertension continues to be the sin- tural vascular lesions are the most common cause of SICH gle greatest modifiable risk factor for SICH.15,122 The in- in children. Hematological disorders and coagulopathies, cidence of SICH has, in fact, declined coincident with as well as brain tumors, are also important causes. In a improvements in hypertension control. Authors of the Sy- series of 68 children presenting with SICH to a single in- stolic Hypertension in the Elderly Program reported that stitution, vascular anomaly or underlying brain tumor was treatment of isolated systolic hypertension in the elderly identified in 38 (56%), whereas hematological or coagula- decreased the risk of SICH by 50%.113 The relative risk for tion disorders were present in 22 (32%).4 Because sys- SICH in hypertensive individuals, however, remains 3.9 temic hypertension is rare in this population, hypertensive to 13.3 times that for normotensive individuals.20 SICH is also rare. An underlying structural lesion should Juvela and colleagues62 have reported that recent mod- be sought in all pediatric patients presenting with SICH. erate and heavy alcohol intake, hypertension, and antico- We recommend that MR imaging and angiography be agulant treatment appear to be independent risk factors for undertaken in all pediatric patients suffering unexplained SICH. Cigarette smoking seems to increase the risk for SICH as well as follow-up imaging if no cause is found. SAH, but is less strongly associated with SICH.122 Dia- Moyamoya disease is a rare disorder characterized by betes mellitus is more commonly associated with SICH progressive occlusive changes in the anterior circulation than with SAH.59 of the circle of Willis and the abnormal development Anticoagulant treatment is a well-established risk factor of collateral moyamoya vessels in the basal ganglia. Al- for SICH, especially in elderly patients (Fig. 4).38 Conven- though cerebral ischemia is usually the initial symptom in tional anticoagulation therapy increases the risk of ICH children with the disease, SICH is the most common ini- seven- to 10-fold.47 The use of thrombolytic agents can be tial presentation in adults.117 Rupture of microaneurysms complicated by ICH. In a metaanalysis of trials assessing and failure of the abnormally dilated moyamoya vessels treatment for ischemic stroke with tPA, the authors report- from hemodynamic stress are considered the cause of ed a 6.5% risk of SICH.44

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Fig. 3. Neuroimaging studies acquired in a 4-year-old girl who presented with acute headache, vomiting, and seizures. Upper Left: Axial CT scan revealing a large right frontal SICH with subdural extension. Both MR imaging and angiography were negative for underlying tumor or vascular anomaly. The patient underwent craniotomy for clot evacuation, but no definitive diagnosis was established. Upper Center: Follow-up CT scan obtained 5 months after initial presentation is unremarkable except for demonstration of a small residual right frontal hypodensity. Upper Right: The patient returned 1 month later with progressive left hemiparesis and headache. An axial CT scan demonstrated a recurrent mixed-

attenuation right frontal hemorrhagic lesion. Lower Left: Further evaluation with coronal T1-weighted MR imaging demonstrated a mixed–signal intensity right frontal hemorrhagic mass. Lower Center: Coronal enhanced T1-weighted MR image revealing enhancement of the mass, suspicious for a hemorrhagic tumor. Lower Right: The patient underwent craniotomy for resection of the lesion. Examination of an intraoperative tissue specimen suggested a supratentori-

al primitive neuroectodermal tumor. A postoperative coronal enhanced T1-weighted MR image demonstrated no obvious residual tumor.

In a recent metaanalysis of aspirin trials involving ic drug abuse, careful monitoring of anticoagulation levels 55,462 participants, aspirin was associated with a slight in patients taking warfarin, and diligent selection of pa- absolute risk increase in hemorrhagic stroke. This was tients for thrombolytic treatment for myocardial infarction outweighed, however, by the overall risk reduction in my- and acute ischemic stroke.13 ocardial infarction and ischemic stroke.48 Use of nonaspirin nonsteroidal antiinflammatory drugs does not seem 58 CLINICAL FEATURES to be associated with an overall increased risk of SICH. Initial Presentation Sympathomimetic drugs such as phenylpropanolamine and ephedrine, which are structurally similar to ampheta- The classic presentation of SICH is sudden onset of mines, have been implicated in cases of SICH.21 focal neurological deficit progressing over hours with The apolipoprotein E genotype appears to have an im- accompanying headache, nausea, vomiting, altered con- portant role in the pathogenesis of CAA, and this geno- sciousness, and elevated blood pressure. Supratentori- type is associated with an increased risk of recurrent lobar al hemorrhage is commonly accompanied by vomiting ICHs.95 and altered consciousness but is rarely seen in ischemic Recent attention has been focused on the association of stroke.22 Elevation in blood pressure occurs in as many as hypocholesterolemia and an increased incidence of SICH. 90% of patients with SICH. Seizures occur in approxi- The mechanism underlying this relationship is not clear, mately 10% of patients.10 but some investigators have proposed that the interaction The type of focal neurological deficit, of course, de- of high diastolic pressure and low cholesterol levels weak- pends on hematoma location. Patients with supratentorial ens the endothelium of intracerebral arteries.54 Alterna- hemorrhage often present with contralateral sensory or tively, there is some evidence that high plasma cholesterol motor deficits, aphasia, neglect, gaze deviation, and hemi- levels may be associated with reduced risk of SICH.122 anopia. Infratentorial hemorrhages manifest with signs of Hepatitis C virus infection may also be a risk factor for brainstem dysfunction, cranial nerve abnormalities, atax- SICH as a result of subclinical clotting disorder or vessel ia, nystagmus, and dysmetria. wall friability resulting from hypocholesterolemia.66 Blood may rupture into the ventricles and cause hydro- Prevention of SICH should emphasize treatment of hy- cephalus. Rarely, blood finds its way into the subarach- pertension, control of alcohol intake and sympathomimet- noid space. A large hemorrhage can raise ICP to the level

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Unauthenticated | Downloaded 09/30/21 05:45 PM UTC Spontaneous intracerebral hemorrhage of the blood pressure until bleeding is tamponaded. De- expansion occurred even after 6 hours of onset. Hema- pending on clot location, this can result in brain hernia- toma enlargement after 24 hours was rare. Early repeated tion, compression of the brainstem, and death. Cerebellar CT scanning appears to increase the rate of detection of clots greater than 3 cm in diameter have a poor prognosis hematoma enlargement.68 It is our practice to perform re- if left untreated. peated CT scanning within 24 hours of admission in patients in whom SICH is revealed on the initial CT scan. Risk of Hematoma Enlargement In the only prospective study of this phenomenon, Brott, et al.,19 evaluated 103 patients with SICH and found In nearly one quarter of initially alert patients present- no significant predictor of hemorrhage growth. Overall ing with SICH, secondary deterioration in level of con- hemorrhage growth occurred in 38% of patients in whom sciousness occurs within the first 24 hours after onset. CT scanning was conducted within 3 hours of symptom Hematoma expansion and edema formation are believed 81 onset. to be the major factors involved (Fig. 4). In several large Mayer79 has proposed using ultra-early hemostatic ther- recent prospective and retrospective studies, investigators apy with recombinant activated factor VII as a potential have evaluated the rate of hematoma enlargement after method of minimizing this early hematoma growth. The initial presentation and report rates ranging from 14 to author postulated that ultra-early hemostatic therapy for 38% within the first 24 hours of admission.19,39,68 39 SICH could be used as the counterpart to thrombolytic In their review of 627 patients with SICH, Fujii, et al., intervention in cases involving acute ischemic stroke to reported that CT scanning within 24 hours of admission prevent early neurological deterioration due to hematoma demonstrated enlargement of the hematoma in 14% of growth and late deterioration related to secondary effects patients. Five factors were found to be associated with of edema, ischemia, and inflammation. We have recently enlargement: admission shortly after onset of symptoms, reported our experience using recombinant activated fac- heavy alcohol consumption, irregularly shaped hemato- tor VII for rapid correction of coagulopathy in a small ma, reduced level of consciousness, and low level of fib- series of coagulopathic patients (including two with intra- rinogen. parenchymal hemorrhages) requiring urgent neurosurgical Kazui, et al.,67 used multiple logistic regression analysis intervention (Fig. 5).96 of data obtained in 186 patients with SICH to identify factors related to the risk of hematoma enlargement. They Outcome After SICH identified four factors predisposing to hematoma enlargement: history of brain infarction, liver disease, fasting glu- Despite advances in neurocritical care and neurosur- cose level greater than 141 mg/dl with SBP greater than gery, the prognosis for patients with SICH remains sober- 200 mm Hg, and HgbA1c greater than 5.1% with SBP ing. Of the estimated 37,000 Americans who suffered an SICH in 1997, 35 to 52% were dead by 1 month postictus greater than 200 mm Hg. Enlargement of the hematoma 15 was demonstrated in 22%. A long time interval between and only 20% were living independently by 6 months. onset of symptoms to the first CT scanning study as well The volume of ICH, initial GCS score, and intraventricu- as small hematoma volume ( 25 cm3) strongly reduced lar extension of the hemorrhage are powerful predictors of 30-day mortality and morbidity rates in patients with the risk of hematoma enlargement. 18,123 In another report by Kazui, et al.,68 the authors showed SICH. The 30-day mortality rate in one series of 188 patients that, although CT scanning–documented expansion of ICH was 44%, with most deaths occurring in the first 2 days was common in the hyperacute stage, 17% of hematoma after onset.15 Univariate logistic regression analysis in this series demonstrated that ICH volume, intraventricular hemorrhage volume, and initial GCS score were significant predictors of 30-day mortality, whereas age, sex, race, SBP, and location of hemorrhage were not. In patients in whom the hematoma volume was 60 cm3 or greater and the GCS score was 8 or less, the predicted 30- day mortality rate was 91% compared with only 19% in those in whom the volume was less than 30 cm3 and the GCS score was 9 or more. In another study of 156 consecutive patients with SICH, potential risk factors for death and impaired outcome were studied prospectively.60 Risk of poor outcome was predicted by GCS score, volume of hematoma, age, amount of alcohol consumed within 1 week before hemorrhage, and presence of cerebellar hematoma. Of these factors, Fig. 4. Axial CT scans obtained in a 72-year-old woman who only alcohol consumption before SICH is potentially developed right hemiparesis after being hospitalized and undergo- modifiable. ing heparin-based anticoagulation therapy for acute myocardial infarction. Left: The scan demonstrates a small left posterior frontal SICH. The heparin therapy was stopped and reversed with DIAGNOSTIC FACTORS protamine. Right: A scan was obtained several hours later when Computerizd Tomography Scanning the patient deteriorated neurologically. Significant hematoma enlargement is demonstrated. The patient subsequently died. Computerized tomography scanning is the initial diag-

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Fig. 5. Axial CT scans acquired in a 78-year-old man receiving Coumadin for atrial fibrillation who presented with a right temporoparietal SICH. Initial coagulation parameters were a prothrombin time of 28, international normalized ratio of 2.8, and an activated partial thromboplastin time of 36; after a 90-g/kg dose of recombinant activated factor VII, the values immediately corrected to, respectively, 9.6, 0.9, and 32. The patient then underwent an uncomplicated craniotomy for clot evacuation. Left: Noncontrast scan obtained at presentation. Center: Scan obtained on postoperative Day 1. Right: Follow-up scan obtained 6 weeks postoperatively. nostic procedure of choice in acute stroke. Several clinical products over time.25,33 Table 2 provides a summary of the stroke scoring systems have been developed in an effort to sequential MR imaging signal intensity changes of ICH. help clinicians distinguish between hemorrhagic and Although SICH can be classified into distinct stages, there ischemic stroke on the basis of clinical presentation alone. is considerable overlap and variation in duration of these These stroke scoring systems, however, are inadequate for stages. accurately differentiating between the two stroke types.128 Although MR imaging has been previously believed to Hematomas, even just a few millimeters in diameter, are be poorly sensitive for detecting hyperacute hemorrhage, rapidly and accurately identified on CT scans. Not only the authors of more recent reports have shown that multi- does CT scanning demonstrate the size and location of sequence MR imaging is as reliable as CT scanning in the the SICH, but it can also suggest potential causes such assessment of hyperacute SICH.98,112 In older studies a 24- as tumor, vascular malformation, or aneurysm. Related hour time period was suggested before detectable amounts complications such as hydrocephalus, edema, herniation, of paramagnetic deoxyhemoglobin would be present. The and intraventricular extension are easily identified. The results of several small studies support the hypothesis change in the CT scanning appearance of intracerebral that deoxyhemoglobin is present within the early hours hematomas over time has been well studied.28 after SICH and may be detected best by using suscepti- As mentioned previously, hemorrhage volume is one of bility-weighted sequences.75,98,112 Multimodal MR imag- the strongest predictors of outcome from SICH.18 Using a ing techniques such as diffusion- and perfusion-weighted model of 30-day mortality based on GCS score and hem- sequences may add to its diagnostic reliability in hypera- orrhage volume, outcome has been correctly predicted cute SICH. with 97% sensitivity and specificity. Many modern CT scanners are able to calculate hematoma volume directly Cerebral Angiography by using special software. If direct volume measurements Despite advances in imaging technology, conventional are not possible, a rapid, simplified method of determin- cerebral angiography remains the gold standard for diag- ing hematoma volume has been described and validated.71 nosis of vascular abnormality. A negative CT angiogram, The formula used—(A B C)/2—is an approximation MR image, and MR angiogram cannot completely ex- for the volume of an ellipsoid where A is the greatest hem- clude a vascular lesion and angiography is often needed orrhage diameter on axial CT scans, B is the largest diam- for definitive diagnosis. Although the risk of angiography eter 90° to A, and C is the number of CT slices with hem- is low, the diagnostic yield must be weighed against the orrhage multiplied by the slice thickness. procedural risk at each institution. The site of hemorrhage, Magnetic Resonance Imaging patient age, preexisting hypertension, and clinical status must all be considered collectively before choosing an- Magnetic resonance imaging and MR angiography are giography. Elderly patients in whom the risk of surgery is becoming increasingly useful in the diagnosis of SICH unacceptable or neurological disability is severe should and may eventually replace CT scanning as the initial di- not undergo angiography if identification of an underlying agnostic test of choice in stroke. Magnetic resonance im- vascular abnormality would have no effect on patient aging is helpful for identifying brain tumors and is more management. Surgery in a young patient with SICH and sensitive in detecting cavernous malformations than CT evidence of herniation should not be delayed by angiogra- scanning or angiography. The MR imaging appearance of phy (Figs. 2 and 6). SICH is complex and depends on hemoglobin breakdown Potentially treatable structural abnormalities cannot be

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TABLE 2 Evolution of ICH MR imaging–evidenced signal intensities*

MRI Signal Intensity†

ICH Stage Hemoglobin State T1-Weighted T2-Weighted hyperacute oxyhemoglobin = to ↓↑ (0–6 hrs) (intracellular) acute deoxyhemoglobin = to ↓↓ (6 hrs–3 days) (intracellular) early subacute methemoglobin ↑↑ ↓↓ (3 days–1 wk) (intracellular) late subacute methemoglobin ↑↑ ↑↑ (1 wk–1 mos) (extracellular) chronic hemosiderin & ↓↓↓ (1 mo) ferritin * “= to ↓"= "equal to decreased;” ↓ = decreased; ↓↓ = significantly Fig. 6. Imaging studies obtained in a 19-year-old man with sud- decreased; ↑ = increased; ↑↑ = significantly increased. den-onset headache and rapidly progressive loss of consciousness. † Compared with gray matter. Left: Axial CT scan demonstrating a large left cerebellar hematoma with near-complete effacement of the fourth ventricle and an enlarged right temporal horn. The patient underwent emergency excluded on the basis of hematoma location, patient age, ventriculostomy and craniectomy for clot evacuation. A presumed AVM was identified at surgery. Right: Anteroposterior left ver- or a history of preexisting hypertension. In fact, a signifi- tebral artery angiogram confirming an AVM in the far-lateral cant number of elderly hypertensive patients are found to aspect of the cerebellum. Following clot evacuation, the patient harbor potentially surgically treatable lesions. In a pro- suffered multiple lower cranial nerve deficits and bilateral sixth spective study of 100 consecutive cases of nontraumatic nerve palsies, which improved markedly over time. Cognitive sta- SICH, the authors identified aneurysms or AVMs in 49% tus normalized and he underwent resection of the AVM 6 weeks of cases.43 When a temporal lobe hematoma extended into after initial presentation. the sylvian fissure or when it was associated with SAH, structural abnormalities were identified in more than 90% of cases. Although the diagnostic yield was lower in hy- blood count, liver panel, coagulation profile, electrolytes, pertensive patients, angiography still identified an AVM and toxicology screen. Underlying renal or liver failure, or aneurysm in 25% of hypertensive patients. acquired or iatrogenic coagulopathy, infection, or drug use In another prospective study of angiography in 206 should be investigated. patients with SICH, the angiographic yield was 45% (66 of 148) in normotensive patients compared with 9% (five Histopathological Examination of 58) in hypertensive patients.137 A positive finding on angiography was identified in 53 (50%) of 105 patients In a significant percentage of surgically treated cases, younger than 45 years of age, compared with 18 (18%) of the cause of the SICH is unknown prior to surgical inter- 101 patients older than 45 years. In grouping putaminal, vention. Often these hemorrhages are attributed to hyper- thalamic, and posterior fossa hemorrhages together, the tension. Histological examination of surgical specimens angiographic yield was 12 (48%) of 25 in younger nor- obtained in a series of 84 cases of SICH in which the motensive patients compared with zero (0%) of 29 in hy- cause was unknown revealed a 25% rate of diagnosis pertensive patients. Based on their results, Zhu, et al.,137 involving specimens in which surrounding tissue was recommended that the use of angiography should be con- included.50 Biopsy sampling of adjacent hematoma wall or sidered in all patients with SICH except those older than preservation of tissue fragments identified at the time of 45 years of age with preexisting hypertension in thalamic, surgery can, therefore, be of important diagnostic value. putaminal, or posterior fossa hemorrhage. Imaging features that suggest an underlying structural PATHOPHYSIOLOGICAL MECHANISMS abnormality include SAH, extracerebral hemorrhage, temporal lobe or perisylvian location, and intraventricular Intracerebral hemorrhage commonly occurs in the basal extension (Fig. 7). Halpin, et al.,45 reported that CT scan- ganglia, thalamus, cerebral lobes, brainstem, and cerebel- ning features in patients with SICH that warrant angiogra- lum. Primary tissue damage and distortion occur at the phy include the presence of SAH, abnormal intracranial time of hematoma formation when the blood spreads be- calcification, prominent vascular structures, and perisyl- tween planes of white matter cleavage. Hemorrhage most vian hemorrhage location. In their study, angiography was commonly results from rupture of the small penetrating positive in 32 (84%) of 38 patients in whom there was one arteries damaged by the degenerative effects of chronic or more of these CT findings. Follow-up angiography and hypertension. In 1868, Charcot and Bouchard26 described MR imaging/angiography should be considered in these the rupture of “microaneurysms” as the cause of SICH. high-risk patients if initial studies are negative. Recent investigators have questioned the existence of such microaneurysms, suggesting that many of these structures are injection-related artifacts, complex vascular Laboratory Evaluation coils, subadventitial hemorrhages, or extravascular clots Laboratory evaluations should include a complete resulting from endothelial damage by the hematoma.24,37

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The authors of several studies have suggested that perilesional hypoperfusion can occur without ischemia as a result of reduced metabolic demand or diaschisis.111,136 In a study of 23 patients with SICH studied using SPECT scanning, perilesional blood flow was found to be lowest during the first 24 hours postictus, but it normalized as edema formed over the next 2 to 3 days.80 In a small study in which positron emission tomography was used, no zone of tissue hypoxia or “ischemic penumbra” was identified.51 Siddique and colleagues,114 however, analyzed ser- ial SPECT scans obtained in patients with SICH and identified perilesional hypoperfusion. They were also able to demonstrate that some of the ischemic perilesional brain recovered its perfusion in the long term. There may be a window of opportunity early after SICH during which removal of the hematoma allows recovery of CBF and prevention of secondary ischemic insult. Fig. 7. Imaging studies obtained in a 39-year-old woman who Blood and plasma products mediate many secondary presented with sudden-onset severe headache, somnolence, and 131 left hemiparesis. Left: Axial CT scan revealing a large right tem- processes initiated after SICH. After SICH occurs, in- poral SICH. Basal cistern SAH was not prominent, but the clot flammatory mediators from the blood can induce an extended inferiorly to the temporal floor and sylvian fissure. These inflammatory reaction in and around the hematoma. Neu- features, combined with the presence of intraventricular hem- trophils, macrophages, leukocytes, and activated micro- orrhage, should raise the suspicion of aneurysmal hemorrhage. glia can be found. The release of cytotoxic enzymes, free Right: Three-dimensional CT angiogram confirming the presence oxygen radicals, nitric oxide, and products of the phos- of a right middle cerebral artery bifurcation aneurysm. pholipid cascade is thought to contribute to secondary neural injury and cell death.133 Both necrotic and apoptot- ic neuronal death appear to play a role.49,104 The vasculopathy of chronic hypertension affects the Although the mechanisms of edema formation follow- perforating arteries 100 to 400 m in diameter, resulting ing ICH are not fully clarified, several mechanisms may in lipohyalinosis or focal necrosis. This helps explain the be responsible. These include hydrostatic pressure during distribution of hypertensive hemorrhages in territories hematoma formation and clot retraction; coagulation cas- supplied by the lenticulostriate arteries (basal ganglia), the cade activation and thrombin production; erythrocyte lysis thalamoperforating arteries (thalamus), the perforating ar- and hemoglobin toxicity; complement activation; mass teries of the basilar artery (pons), and the superior and an- effect; secondary perihematoma ischemia; reperfusion terior inferior cerebellar arteries (cerebellum). Lobar hem- brain injury; and BBB disruption.52,73,80,129,131 Evidence in- orrhages in the elderly are often considered to be a result dicates that thrombin formation plays an important role in of amyloid angiopathy, which preferentially involves the inducing brain injury after ICH.131 Cell toxicity and cortical and leptomeningeal blood vessels. thrombin-related BBB disruption are triggering mecha- Unlike primary tissue injury from the hematoma for- nisms for edema formation.74 In a rat SICH model, throm- mation, secondary brain injury and edema represent po- bin inhibition was shown to reduce brain edema and neu- tential therapeutic targets. The roles of edema, ischemia, rological deficits.130 mass effect, direct cellular toxicity, inflammation, and The expression of matrix metalloproteinase–9, a prote- apoptosis are being evaluated in experimental studies of olytic enzyme involved in reorganization of the extracel- SICH. There is controversy whether secondary ischemia lular matrix, has been shown to be increased following contributes to brain injury after SICH.51,80,111,114,136 Cush- SICH.1 In patients with deep-seated hemorrhages, this in- ing29 believed that brain injury due to SICH was the result creased expression of matrix metalloproteinase–9 appears of local pressure compressing the microcirculation and to be associated with perihematoma edema and neurolog- causing ischemia around a hematoma. Astrup, et al.,5 pro- ical worsening. posed the term “ischemic penumbra” to describe brain Both vasogenic and cytotoxic edema result from dis- with CBF values above a lower limit of membrane dys- ruption of the BBB, sodium pump failure, and neuronal function and cell death, but below an upper limit corre- death. In experimental animal models of SICH, brain ede- sponding to electrophysiological dysfunction. ma increases during the first 24 hours, peaks at 4 to 5 days, There are a number of animal models that have been and then begins to resolve.133 A delayed phase of edema used to study SICH and its effects on ICP, CBF, and is- formation and injury in the 2nd or 3rd weeks after SICH chemia.92 Findings included increased ICP associated with in humans may be due to hemoglobin and its degradation hematoma formation, decreased CBF adjacent to the he- products.129 Hemoglobin-induced brain edema is partially matoma, and histological ischemic changes in perihema- blocked by the iron chelator deferoxamine in animal mod- tomal brain tissue. Yang, et al.,133 have suggested that the els, supporting the hypothesis that iron has a role in hem- primary cause of edema formation in experimental mod- orrhagic brain injury.53 els of SICH may be local tissue ischemia. Breakdown of the hematoma consists of invasion by In more recent clinical studies, evidence does not clear- macrophages, progression of surrounding edema, devel- ly support the concept of perilesional ischemia in SICH.124 opment of microvessels at the clot margin, and, eventual-

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Unauthenticated | Downloaded 09/30/21 05:45 PM UTC Spontaneous intracerebral hemorrhage ly, gliosis.69 The end result is a hemosiderin-stained scar SICH was reduced by prophylactic antiepileptic drug or a cavity containing old blood surrounded by fibrous tis- therapy. sue. An unusual form of chronic intracerebral hematoma Investigators recently reported the results of a large, has been defined by Roda and colleagues.106 Their term prospective multicenter study designed to determine the “encapsulated intracerebral hematoma” refers to a chroni- incidence, outcome, and risk factors for seizures after both cally encapsulated intraparenchymal hematoma found in ischemic and hemorrhagic stroke. In 1897 patients ana- normotensive patients, usually caused by vascular malfor- lyzed, seizures occurred in 28 (10.6%) of 265 patients mations. These lesions exhibit progressive mass effect, with hemorrhagic stroke compared with 140 (8.6%) of edema, and ring enhancement. The self-perpetuating na- 1632 with ischemic stroke.10 The Kaplan–Meier survival ture of these lesions has been compared with chronic sub- analysis indicated the 1-year actuarial risk of seizures to dural hematomas. be 20% in survivors of hemorrhagic stroke. Fifty-seven percent of seizures after hemorrhagic stroke occurred in the first 24 hours. Based on multivariate analysis, the only TREATMENT OF SICH risk factor for seizures after hemorrhagic stroke was cor- Macewan reported the first successful surgery for SICH tical location. Epilepsy occurred in 47 (2.5%) of 1897 patients. Epilepsy occurred in seven (100%) of seven pa- in 1883. In general, there has been a pessimistic attitude among many medical professionals, including neurosur- tients with late-onset ( 2 weeks after SICH) seizures geons, regarding treatment of SICH. As reported by after hemorrhagic stroke. Broderick and colleagues,14 this is reflected in the fact that The effect of surgical treatment for SICH on the occur- more than 315 randomized clinical therapeutic trials for rence and development of seizures has not been well stud- acute ischemic stroke and 78 trials for SAH were com- ied. Given the results of the aforementioned report,10 we pleted or ongoing as of 1995, whereas only the results of recommend undertaking anticonvulsant therapy in all pa- four small randomized surgical trials6,9,61,84 and four small tients who present with supratentorial SICH. No consen- medical trials of SICH had been published.55,99,121,135 The sus exists on when anticonvulsant therapy can be discon- American Heart Association formed a task force that pub- tinued following SICH, but most medications can be lished practice guidelines in 1999 for the management of withdrawn after the 1st month in patients in whom no fur- SICH and emphasized the desperate need for future ran- ther seizure activity occurs. Those with late-onset seizures domized controlled trials.13 may require long-term anticonvulsant prophylaxis.23 Blood Pressure Management. Hypertension is common Medical Treatment in patients who suffer SICH and in the early clinical course. There is disagreement as to the mechanism of this Critical Care. Because the risk of clinical deterioration acute hypertensive state; however, major factors appear to after SICH is greatest during the 1st day, patients in whom be catecholamine release and the Cushing response. this entity has been diagnosed should be monitored in an Proponents of lowering blood pressure argue that doing intensive care unit for a minimum of 24 hours. The goal so reduces secondary injury due to rebleeding and edema of fluid status is to maintain euvolemia with the use of iso- formation.39 Opponents, who favor leaving hypertension tonic crystalloid intravenous solutions. Enteral nutrition, untreated, argue that preserving CPP is paramount to via a feeding tube if necessary, should begin as soon as areas in the ischemic penumbra. Although induced hyper- possible. Pneumatic sequential compression devices and tension can increase edema in experimental models, hy- elastic stockings decrease the risk of venous thrombosis pertension following SICH is not clearly related to the and pulmonary embolism. Gastric cytoprotection should development of edema. Broderick, et al.,11 found no rela- also be considered. Physical therapy, occupational thera- tionship between blood pressure and edema growth or py, speech therapy, and rehabilitation services should be neurological worsening in a study of 115 patients. Be- consulted as soon as medically feasible. cause of these complex issues, the management of hyper- Seizure Prophylaxis. The authors of retrospective stud- tension in SICH remains controversial.3 ies have suggested that seizures are more frequent in hem- The changes that occur in CBF in the setting of SICH orrhagic stroke than ischemic stroke and that the risk of are complex. An excellent review of the existing laborato- epilepsy is greater in patients with late onset of the initial ry and clinical reports on this subject was recently provid- seizure after stroke.23,116 Most seizures occur within the ed by Qureshi and colleagues.103 Cerebral autoregulation first 24 hours after SICH.10 refers to the ability to maintain constant CBF over a wide Cervoni, et al.,23 reviewed data obtained in 298 patients range of CPPs varying from approximately 60 to 150 mm with SICH and found an 18% rate of seizures. Hematoma Hg.115 Autoregulation can become deranged after a num- location was important because 35% of patients with lobar ber of cerebral insults including ischemia, SAH, traumat- hemorrhages suffered seizures compared with only 8% of ic brain injury, and SICH. When CPP decreases below the those with deep-seated hematomas. Epilepsy developed in lower limit of autoregulation, oxygen extraction increases 43% of patients affected by seizures occurring more than in a compensatory fashion. After oxygen extraction is 2 weeks after the onset of SICH, whereas it developed in maximized, ischemia occurs. In most patients with chron- only 17% of those with seizures appearing within 2 weeks ic hypertension, the autoregulatory curve is at higher pres- of onset. Passero, et al.,97 retrospectively reviewed data sures, which may increase the risk of cerebral ischemia if acquired in 761 patients with supratentorial SICH and re- blood pressure is normalized.103 ported a 30-day actuarial risk of post–SICH seizures of There are no prospective randomized placebo-con- 8.1%. They found that the risk of early seizures in lobar trolled studies in which investigators have compared the

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Unauthenticated | Downloaded 09/30/21 05:45 PM UTC M. E. Fewel, B. G. Thompson, Jr., and J. T. Hoff effects of lowering blood pressure on immediate clinical should be conducted to determine the effect of lowering status. Qureshi and colleagues102 reported, in a retrospec- blood pressure in acute SICH. tive analysis of 105 patients admitted with SICH, that a Management of Intracranial Hypertension. Elevated rapid decline in MABP within 24 hours after presentation ICP from SICH can result in herniation syn-dromes and was independently associated with an increased mortality death. Intuitively, monitoring and treatment of elevated rate. These authors postulated two mechanisms for the ICP should reduce secondary injury. Improved outcomes, deleterious effect of a rapid decline in MABP. First, a however, have not been clearly linked with monitoring rapid decline in blood pressure may lead to a reduction in and treatment of elevated ICP in SICH. Nevertheless, CPP and exacerbation of ischemic injury. Second, in re- most authors recommend treatment when ICP exceeds 20 gions with intact autoregulation, a compensatory vasodi- mm Hg with a goal CPP greater than 60 to 70 mm Hg. In lation in response to the blood pressure reduction may general, ICP monitoring devices should be considered in result in exacerbation of intracranial hypertension. all patients who present with a GCS score less 9 or in In a study in which they used SPECT scanning, Ku- those patients in whom deteriorating clinical condition is wata, et al.,72 found that a 20% reduction in SBP resulted believed to be due to elevated ICP. in decreased mean CBF in the acute period following hy- Elevated ICP can have deleterious effects on CPP and, pertensive ICH. Kaneko, et al.,65 suggested a goal of SBP therefore, global CBF. Reduction in CPP and perihema- reduction of less than 20% in the acute period on the basis toma ischemia may occur locally even in the absence of of CBF studies. In two other studies investigators have globally increased ICP. In experimental studies investi- demonstrated that a controlled pharmacologically mediat- gators have shown that a reduction in CPP leads to com- ed reduction in blood pressure does not have deleterious pensatory vasodilation, which increases intracranial blood effects on CBF.100,105 volume, in turn, increasing ICP and further decreasing In several studies improved outcomes have been report- CPP. The physiological correction of this cycle is the sys- ed with the use of antihypertension agents. Meyer and temic hypertension response that increases CPP, leading to Bauer86 published a prospective nonrandomized unblind- arteriolar vasoconstriction, decreased intracranial blood ed trial involving use of the antihypertension agent reser- volume, and lowered ICP. Rosner and Becker108 used the pine in acute SICH. They concluded that antihypertension term “ischemic response” to describe this phenomenon drugs improved the mortality rate; however, there were that Cushing proposed in 1902.29 The impact of ICP treat- important limitations to the study. Dandapini, et al.,30 also ment and hematoma evacuation on CBF has not been well demonstrated improved mortality and morbidity rates studied, but some evidence exists that surgical evacuation with blood pressure reduction, although this study was ret- and elevated ICP treatment can improve CBF.103,127 rospective and did not consider confounding variables Common strategies for managing elevated ICP include such as hematoma volume and initial GCS score. In a ret- elevation of the head of the bed, hyperventilation thera- rospective review of 188 patients with ICH, Broderick and py, osmotic therapy, sedation, and cerebrospinal fluid Brott14 found no difference in outcome in patients who drainage. Mannitol is often given when surgery is not con- received antihypertension agents compared with those sidered appropriate. Mechanical ventilation parameters who did not. should be adjusted to a PCO2 goal of 30 to 35 mm Hg. The intracranial hemodynamic effects of most antihy- Intraventricular blood is associated with a high mortality pertension agents are poorly understood. Data acquired in rate.123 Ventriculostomy, rather than fiberoptic ICP de- clinical studies of patients with SICH are limited, but most vices, should be used in patients with hydrocephalus or vasodilators have the potential to raise ICP by increasing intraventricular hemorrhage (Fig. 8). Although ventricu- intracerebral blood volume. Short-acting, mixed - and - lostomy reduces ICP, frequent clots in the catheter and blockers such as labetalol should be used as first-line infections often diminish the beneficial effect on hydro- agents. Nitroprusside, the most commonly used agent for cephalus and neurological status.2 We prefer to use pro- severe hypertension, is a vasodilator with the potential to phylactic antibiotic medications in patients with ICP mon- raise CBF and ICP, although this effect has not been dem- itoring devices. Sedation with benzodiazepines, narcotic onstrated in a clinical study. Arterial vasodilators, such as analgesics, or propofol can help control elevated ICP. hydralazine or angiotensin-converting enzyme inhibitors, Barbiturate coma or hemicraniectomy may be necessary if as well as calcium channel blockers may have less of a all other measures fail. 103 tendency to raise ICP and maintain CBF. Venodilators, Unhelpful Therapies. Based on the results of two ran- diazoxide, and ganglionic blockers should not be used in domized trials that failed to demonstrate the efficacy of patients with SICH and elevated ICP. corticosteroid therapy in ICH, its use is not indicated.99,121 In summary, there is no convincing evidence that low- The authors of two other small randomized medical trials ering blood pressure in the acute period after SICH alters evaluating hemodilution and therapy with intravenous the course or prognosis. Modest reductions in SBP may be glycerol also did not find any significant benefit.55,135 well tolerated, especially in patients with systemic hypertension complications or those at greater risk for hemorrhage expansion (such as, in coagulopathic patients). To Surgical Treatment balance the two theoretical risks of hemorrhage extension Despite a nihilistic attitude among clinicians regarding compared with worsening ischemia, the American Heart SICH, most neurosurgeons believe evacuation of certain Association recommended maintaining MABP below 130 intracerebral hematomas can reduce the mortality rate and mm Hg in patients with preexisting hypertension and CPP improve outcomes. The fact that approximately 7000 op- above 70 mm Hg.13 A large randomized controlled trial erations are performed annually in the US for SICH sup-

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GCS scores between 6 and 12 or in patients with deteriorating status.35 The optimal surgical technique for hematoma evacuation is not agreed upon, although craniotomy remains the most common.35 Traditional stereotaxy or frameless navigational systems, as well as intraoperative ultrasonographic guidance, allow more precise clot local- ization and minimization of injury to normal brain. Com- pared with craniotomy, minimally invasive techniques such as stereotactic or endoscopic clot evacuation may offer the potential for a reduced incidence of surgery-related complications and improved efficacy, but this has yet to be proven. There is a neurosurgical bias toward more aggressive surgery for nondominant hemispheric hemorrhages, although the authors of outcome studies have indicated that despite language disability associated with dominant hemispheric lesions, functional outcome is not necessari- Fig. 8. Axial CT scan acquired in an 82-year-old man with a ly worse. Standard craniotomy for extirpation of primary history of hypertension who presented with headache, vomiting, brainstem or thalamic hemorrhages has been all but aban- and progressive deterioration in consciousness. A small left cere- doned because of poor outcomes.17,46 Apparently success- bellar SICH extending into the fourth ventricle is demonstrated. ful cases of stereotactic aspiration of pontine hematomas Obstructive hydrocephalus was successfully treated by ventricu- have been reported, but the effect on prognosis remains lostomy. The patient did not require evacuation of the hematoma and made a good recovery. unproven. Although evidence favoring surgical intervention is lacking, there is good theoretical rationale for early surgery. Early hematoma evacuation may decrease the toxic ports this belief.12 The efficacy of surgery for SICH, how- effects of blood and plasma products, diminish surround- ever, remains unproven in the year 2003. ing edema and ischemia, and prevent hematoma expan- Most of the published reports regarding surgical re- sion. Liquefaction of the clot by instillation of tPA and moval of these hemorrhages, many of which are in the subsequent aspiration at 3 hours has been shown to reduce Japanese literature, are nonrandomized case series for mass effect and perihematomal edema markedly at 24 which definitive recommendations or guidelines cannot hours in a pig model.127 Clot evacuation might be com- be made. There is considerable international variation in bined with pharmacological therapy targeting the inflam- the indications and rate of surgery for SICH. In part be- matory response shown to develop around the hematoma cause of its high incidence in Japan, there has been an and leading to delayed cellular death in experimental ani- increase in the number of clinical and experimental stud- mal models.49 Early evacuation might also be combined ies being reported over the past two decades. with hemostatic therapy such as recombinant activated The Cochrane Database of Systematic Reviews pub- factor VII to help prevent the risk of rebleeding (Fig. 5).79,89 lished a metaanalysis of surgery for primary supratentorial ICH in 2001.101 The authors analyzed the randomized Randomized Trials of Surgical and Medical Manage- and quasirandomized trials of medical management com- ment. To date, there are nine prospective randomized con- bined with intracranial surgery compared with medical trolled studies in which surgical and medical management management alone. Only four surgical trials comprising of SICH has been compared.6,9,27,61,84,89,90,120,138 Overall, 260 patients met their criteria for inclusion.6,9,61,84 No trial these studies fail to demonstrate a superiority of either had blinded outcome assessment and each trial used dif- medical or surgical management. The results are also lim- ferent scales for assessing functional status. The authors ited by considerable methodological differences among of the review concluded that the available evidence to date the trials. A brief review of these trials follows. was insufficient to make a recommendation concerning McKissock, et al.,84 reported the first randomized study the safety and efficacy of surgical treatment.101 of surgery for SICH in 1961. They randomized 180 pa- In a review of supratentorial SICH by Hankey and tients in a series of 303 potential cases. Ninety-one pa- Hon46 published in 1997, the authors found a nonsignifi- tients were “randomly allocated” to best medical treat- cant increase in the likelihood of death and dependency at ment and 89 to surgery and best medical treatment, but the 6 months in surgically treated patients. In a metaanalysis method of randomization was not described. Because this conducted by Fernandes, et al.,34 the authors suggested a study was conducted well before the advent of CT scan- benefit to surgery, with a reduction in the chances of death ning, diagnosis was established using angiography or ven- and dependency after surgery by a factor of 0.63. This triculography. Although the proportion of surgically treat- analysis excluded a pre–CT scanning era trial and a Chi- ed patients who were dead or totally disabled 6 months nese trial because of methodological issues. after discharge was higher than the medically treated Patients with relatively normal consciousness (GCS group (80 and 66%, respectively), the results may not be Scores 13–15) rarely require surgery, whereas deeply co- relevant to current practice. Almost no patients underwent matose patients (GCS Scores 3–5) rarely benefit from surgery before 24 hours. In addition, neurosurgical, anes- surgery. Surgery is therefore usually considered to have thesia, and critical care techniques have improved sub- the most potential benefit for the group of patients with stantially since that time.

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Juvela and colleagues61 reported a prospective study of interim analysis of 11 patients in the 4-hour surgery arm 52 patients with supratentorial SICH randomized to sur- showed a 6-month mortality rate of 36% compared with gery or best medical therapy for SICH. The median time only 18% in the 12-hour surgical group. Because of the from onset to craniotomy for evacuation was 14.5 hours. small number of patients in these pilot studies, the differ- There were no statistically significant differences in mor- ences in mortality rates were not statistically significant. tality or morbidity rates between the two treatment Rebleeding was more common in patients undergoing sur- groups, and these authors concluded that supratentorial gery within 4 hours (40%) than 12 hours (12%). Instead of SICH should be treated conservatively. Although the mor- preventing early hematoma expansion by coagulating the tality rate of semicomatose or stuporous patients (GCS bleeding vessel, ultra-early surgery proved more difficult Scores 7–10) was statistically significantly lower in the to achieve hemostasis. Morganstern and colleagues rec- surgical group, all surviving patients in this subgroup were ommended using craniotomy within the first few hours severely disabled. after SICH with extreme caution because of the risk of Auer, et al.,6 randomly assigned 100 patients with su- rebleeding. This study did demonstrate the feasibility of pratentorial SICH to undergo stereotactic endoscopic ultra-early triage and surgery for patients with SICH much evacuation of the blood clot within 48 hours after admis- like protocols of thrombolytic therapy for acute ischemic sion or to undergo medical therapy alone. At 6 months, the stroke. In addition, patients with the smallest postopera- outcome was better in the surgically treated group with no tive hemorrhage volumes experienced the best outcomes, or minimal deficits in 40% in this group compared with arguing that removal of hemorrhage may ultimately be 25% in the medically treated group. The surgically treated beneficial. group had statistically nonsignificant lower odds of death Teernstra and colleagues120 recently reported results or dependency (odds ratio 0.45; 95% CI 0.19–1.04). from a multicenter randomized controlled trial of stereo- Batjer, et al.,9 randomized 17 hypertensive patients with tactic drainage involving plasminogen activator compared putaminal SICH of at least 3 cm to surgery or medical with medical therapy. They randomized 36 patients to therapy. The results showed a trend toward a lower rate of surgery and 35 to medical therapy, and found no statisti- death or level of dependence in the surgically treated pa- cally significant difference in mortality and morbidity tients (odds ratio 0.86; 95% CI 0.09–8.1), but the 95% CI rates at 6 months. A stereotactically placed catheter was included one. used to install urokinase to liquefy and drain the hema- Chen, et al.,27 randomized 127 patients with hyperten- toma in 6-hour intervals over 48 hours and resulted in a sive supratentorial and cerebellar hemorrhages to surgery modest 18 ml reduction in hematoma volume over 7 days. or medical management. These authors included cerebel- The International Surgical Trial in IntraCerebral Hem- lar hemorrhages, and although there was no statistically orrhage, the largest multicenter randomized controlled significant difference in mortality rates between the two trial of surgery for SICH, closed recruitment on February groups, there was a trend toward an increased risk of death 25, 2003.85 Investigators randomized 1033 patients within or dependency in those treated with surgery. 72 hours of supratentorial SICH to a surgery or medical Zuccarello, et al.,138 reported a small randomized feasi- therapy group. Although this important trial should help bility study in which they evaluated the use of surgical better define the role of surgery in SICH, it is likely to evacuation, craniotomy, or stereotactic aspiration com- generate additional questions about patient selection, tim- pared with medical treatment alone. Twenty patients were ing, and surgical technique. randomized; the median time from symptom onset to Nonrandomized Surgical Studies. Although nonran- surgery was 8.5 hours. The likelihood of a good outcome domized series of surgically treated patients with SICH (defined as 3-month GOS score 3) was 56% in the sur- are limited by methodological flaws and lack definitive gical group and 36% in the medical treatment group, al- conclusions, they do offer valuable information. In a non- though this result did not reach statistical significance. randomized report, Kaneko and colleagues64 reported The authors concluded that early clot removal in supra- good results after performing craniotomy for the evacua- tentorial SICH was feasible and warranted further investi- tion of 100 putaminal hemorrhages within 7 hours of gation in randomized clinical trials. onset and 60 hemorrhages within 3 hours of onset. They Morganstern, et al.,90 prospectively randomized 34 reported only a 7% mortality rate and complete recovery patients within 12 hours of onset. They reported a mod- or minor disability in 50%. est benefit in 6-month mortality rates in patients treated In a large nonrandomized study, Kanaya and Kuroda63 with craniotomy (19%) compared with medical therapy evaluated 7010 patients with putaminal hemorrhage. The (24%).90 Outcome was measured by an investigator un- mortality rate in alert and confused patients was signifi- blinded to treatment allocation. In addition, only one pa- cantly lower in medically treated groups; however, in tient underwent surgery within 4 hours and surgically patients who were stuporous or worse, the rate was signif- treated patients harbored a significantly larger-volume icantly lower in the surgically treated group. They recom- hemorrhage, had lower GCS scores, and more frequently mended surgical treatment if the hematoma volume was presented with deep-seated ICH. larger than 30 ml and the level of consciousness was som- In a later publication Morganstern, et al.,89 also report- nolent to semicomatose. ed preliminary results of a prospective single-center pilot In 1978 Backlund and von Holst7 proposed a new sur- study of surgery performed within 4 hours of SICH; their gical technique for subtotal hematoma removal using CT goal was to test the feasibility and safety of ultra-early clot scanning–guided aspiration with a special cannula. The evacuation compared with results of their previous 12- authors of several case series have reported encouraging hour trial. This study was stopped for safety reasons after results when using stereotactic aspiration with fibrinoly-

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Unauthenticated | Downloaded 09/30/21 05:45 PM UTC Spontaneous intracerebral hemorrhage sis.77,87,88,93,110 Doi, et al.,32 from Japan were the first to use CONCLUSIONS stereotactic aspiration with a hematoma lysis method. Despite the grim prognosis for patients suffering SICH, Successful use of both urokinase and recombinant tPA has there are reasons for optimism. There have been improve- been reported. The risk of recurrent hemorrhage in cases ments in medical treatment of hypertension and neurocrit- involving the use of thrombolytic agents has not been 93 ical care. Secondary brain injury, edema formation, and established but has been estimated to occur in up to 15%. hematoma enlargement represent potential therapeutic tar- Infectious complications of catheter placement and fibri- gets. The roles of edema, ischemia, mass effect, direct cel- nolysis vary between 0 and 5%.87,110 107 lular toxicity, inflammation, and apoptosis are being eval- Rohde and colleagues reported the first use of frame- uated in experimental studies of SICH. Neurosurgical less stereotaxy in a series of 27 patients with SICH who advances in minimally invasive techniques, endoscopy, underwent catheter placement and fibrinolysis. Frameless and frameless stereotactic systems should improve results stereotaxy has the potential advantage of allowing optimal of surgery. It is hoped that the forthcoming results of the trajectory and entry point selection, which is sometimes International Surgical Trial in IntraCerebral Hemorrhage technically limited in frame-based systems. Thrombolytic will help formulate evidence-based recommendations re- agents have also been successfully used for hemorrhage in 36 garding the role of surgery in SICH, although this trial is the ventricular system. unlikely to end the controversy. Future randomized trials Cerebellar SICH. Unlike the controversy regarding will still be needed to assess the effects of patient age, surgery for supratentorial SICH, there seems to be a gen- level of consciousness, comorbidities, hematoma volume, eral consensus regarding the role of surgery in patients hematoma location, timing of surgery, and different surgi- with infratentorial hematomas. This agreement exists de- cal procedures. spite that fact that there are no randomized controlled trials evaluating surgical methods in posterior fossa SICH. Of the eight retrospective case studies involving surgery References 46 for infratentorial SICH reviewed by Hankey and Hon, 1. Abilleira S, Montaner J, Molina CA, et al: Matrix metallopro- two were studies reporting a beneficial effect of surgery in teinase–9 concentration after spontaneous intracerebral hemor- certain patients, one was a study suggesting that surgery rhage. J Neurosurg 99:65–70, 2003 had an overall beneficial effect; and five were series re- 2. Adams RE, Diringer MN: Response to external ventricular porting either inconclusive results or no beneficial effect drainage in spontaneous intracerebral hemorrhage with hydro- of surgery. Authors of several series have reported good cephalus. Neurology 50:519–523, 1998 outcomes associated with surgical evacuation for patients 3. Adams RE, Powers WJ: Management of hypertension in acute with cerebellar hemorrhages greater than 3 cm, or with intracerebral hemorrhage. Crit Care Clin 13:131–161, 1997 13,125 4. Al-Jarallah A, Al-Rifai MT, Riela AR, et al: Nontraumatic brain brainstem compression and hydrocephalus. 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Surg Neu- rol 9:99–101, 1978 ventricle was not completely obliterated, but that con- 8. Barinagarrementeria F, Mendez A, Vega F: [Cerebral hemor- scious patients with fourth ventricular obliteration should rhage associated with the use of phenylpropanolamine.] Neu- undergo emergency clot evacuation. Most neurosurgeons, rologia 5:292–295, 1990 (Spn) however, recommend surgery for patients with cerebellar 9. Batjer HH, Reisch JS, Allen BC, et al: Failure of surgery to im- hemorrhages greater than 3 cm, with compression of the prove outcome in hypertensive putaminal hemorrhage. A pro- brainstem, or with obstructive hydrocephalus. spective randomized trial. Arch Neurol 47:1103–1106, 1990 Summary of Surgical Treatment Recommendations. 10. Bladin CF, Alexandrov AV, Bellavance A, et al: Seizures after stroke: a prospective multicenter study. Arch Neurol 57: Patients with small hemorrhages or minimal neurological 1617–1622, 2000 deficit generally do well by undergoing medical treatment 11. 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