Intracerebral Hemorrhage

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Intracerebral Hemorrhage Carlos S. Kase, Ashkan Shoamanesh, Steven M. Greenberg, Louis R. Caplan

KEY POINTS • Intracerebral hemorrhage (ICH) accounts for 10–35% of stroke cases depending on the population studied. • Its incidence has remained stable over the past three decades despite improvements in primary prevention measures, such as blood pressure management. • ICH can result from a number of mechanisms, the predominant one being hypertension, while others include vascular malformations, brain tumors, sympathomimetic drugs, anticoagulant and fibrinolytic agents, cerebral amyloid angiopathy, vasculitis, and hemorrhagic transformation of ischemic infarction. • Hemorrhagic transformation of ischemic infarction occurs spontaneously as part of the natural history of cerebral embolism, but its presence and severity can be enhanced by agents that alter blood coagulation, especially therapeutic thrombolysis. • The acute phase of ICH is characterized by a high frequency of hematoma expansion in the early hours after onset, and this phenomenon is highly associated with neurological deterioration. The imaging counterpart of this phenomenon is the “spot sign” detected in computerized tomography angiography, a finding that results from ongoing blood extravasation at the site of the hematoma. • The clinical aspects of ICH in the various brain locations often include the combination of features of increased intracranial pressure (headache, vomiting, depressed level of consciousness), along with the neurological deficits that result from the specific site of the hematoma in the brain. • Novel neuroimaging markers such as cerebral microbleeds, superficial siderosis and remote small diffusion-weighted imaging hyperintense lesions are encountered frequently in individuals with ICH. However, many unanswered questions remain pertaining to their clinical significance and ability to guide individual patient care. • The management of ICH requires monitoring and treatment in an ICU setting, and treatment decisions regarding conservative versus surgical treatment are highly individualized and depend on the size and location of the hematoma, presence of associated hydrocephalus, intraventricular hemorrhage, and increased intracranial pressure.

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Intracerebral hemorrhage (ICH) occurs as a result of bleeding from an arterial source directly into the brain substance. Although its relative frequency in patients with stroke is subject to geographic and racial variations, values between 5% and 10% are most commonly quoted in Western populations.1–3 In a consecutive series of 938 patients with stroke entered into the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) Data Bank, primary ICH accounted for 10.7% of the cases.4 Similar figures were obtained in population or community studies from Denmark (10.4%),5 Holland (9%),6 Oxfordshire, England (10%),7 southern Alabama (8%),8 Italy (13.5%),9 France (11%),10 and Iran (12.7%).11 However, within the INTERSTROKE study, which recruited 3000 participants from 22 countries, ICH accounted for 22% of the cases. This higher proportion was largely driven by ICH in African, South American and South East Asian populations where ICH accounted for 22–34% of cases (n = 2578) in comparison to 9% in designated ‘highincome’ countries (n = 422).12 The incidence rates are relatively constant in predominantly white populations: rates range between 7 and 11 cases per 100,000 (Table 28-1).13–17 The figures were higher in a U.S. population (southern Alabama) with a mixture of white and black people because the former had an incidence rate of 12 per 100,000; in black people, the rate was 32 per 100,000.8 Similar comparisons between white and black people in Cincinnati, Ohio, yielded an overall age- and sex-adjusted incidence of ICH that was 1.4-fold higher in black people.13 The difference in ICH incidence was even higher (2.3-fold) for black persons who were younger than 75 years. In addition, a Hispanic population in New Mexico had a high incidence of ICH (34.9), whereas non-Hispanic Whites from the same population had an incidence rate (16.6) comparable to that of Whites in other geographic locations.18 Some series from Asian countries, such as that from Shibata, Japan,19 report severalfold higher incidence rates of ICH (61). A recent systematic review suggests that these racial differences may in part be attributed to regional environmental factors.20 In reviewing incidence rates among 36 studies encompassing roughly 9 million people from 21 countries, van Asch et al. observed an overall ICH incidence of 24.6/100,000, and within pooled analyses, global incidence rates (per 100, 000) were comparable between white persons (24.2), black persons (22.9), Hispanics (19.6), Indian people (21.4) and Maoris (22.2), but increased twofold in East and South East Asian people (51.8). When examining regional differences however, they observed that incidence of ICH was higher in black persons in Northern Manhattan (49.5), in comparison to those in Martinique (23.1), south London (14.9), and Barbados (17.6). The same was true when comparing Hispanic people in Manhattan (24.0) to those in Chile and Brazil (14.5), whereas the incidence of ICH among white people in Manhattan (22.6) was comparable to that of white people in other populations. Similarly, in Auckland they observed that the incidence rate of ICH in East and South East Asian



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TABLE 28-1  Incidence of Intracerebral Hemorrhage in Studies from Various Geographic Locations Location Rochester, Minnesota Framingham, Massachusetts Southern Alabama Cincinnati, Ohio Giessen, Germany Shibata, Japan L’Aquila, Italy Bernalillo Co., New Mexico Non-Hispanic Whites Hispanics

Chapter Reference 13 3 8 14 15 17 10 16

No. of Cases

Rate*

81 58 13 154 100 97 588

7 10 12 11 11 61 16

47 39

17 35

*Per 100,000 population.

immigrants (20.7) was similar to that of white (18.6) and Maori people (22.2) in the same region, but lower than values reported in Asian people living in China and Japan (57.6).20 Regional differences in incidence rates were confirmed by the European Registers of Stroke which found ICH incidence rates ranging from 7.3–25.2/100,000 when comparing populationbased stroke registers in six European countries.21 Prior reports had noted a general trend toward declining rates of ICH, starting in the 1960s with the initial observation in Göteborg, Sweden22 and subsequently confirmed in the US in a population from Rochester, Minnesota.14,23 From analysis of data encompassing a 32-year period (1945 to 1976), Furlan et al.14 showed a significant decrease in incidence between the first and second parts of this period: 13.3 per 100,000 for 1945 to 1960 and 6.7 per 100,000 for 1961 to 1976. These figures correlated with a similar decline in the frequency and severity of hypertension in the population studied. A similarly declining trend in the incidence of ICH had been reported from Hisayama, Japan,24 where it was also related to a decrease in the frequency of hypertension. However, figures from Gothenburg, Sweden, documented no changes in ICH incidence in men and women when comparing years 1987 to 1989, 1990 to 1994, and 1995 to 1999, and van Asch et al. did not detect a significant decrease in incidence of ICH between 1980 and 2008 in their comprehensive systematic review.20 The incidence of ICH increases with advancing age,3,13,20,25 which is a feature that applies to all types of stroke, both ischemic and hemorrhagic. A publication from the Dijon Stroke Registry (Dijon, France) found that, although incidence of ICH appeared stable between 1985 and 2008, the incidence had decreased 50% in individuals below 60. Conversely, it had increased roughly 80% in people aged ≥ 75 years. This increased incidence was driven largely by lobar ICH and coincided with an increase in use of antithrombotic therapy. These results suggest that the beneficial effects of primary prevention measures over previous decades, such as blood pressure control, might be offset by antithrombotic-induced ICH in older individuals who are more vulnerable to bleeding-prone vasculopathies such as cerebral amyloid angiopathy (CAA).10 This potential association is supported by a hospital-based study that documented a fivefold increase in the incidence of anticoagulant-associated ICH in greater Cincinatti/Northern Kentucky from 1988 to 1999. The incidence among persons age ≥ 80 increased 18-fold during this time.26 However, data from a similar time period (1993–2008) from Northern Ostrobothnia, Finland, showed a decrease in anticoagulantassociated ICH despite a 3.6-fold increase in warfarin use. This paradox was attributed to a high initial rate of ICH at the beginning of the study period and subsequent decline with improved patient selection for warfarin therapy and INR monitoring.27 There also appears to be an ‘age-by-race interaction’,

whereby white persons are particularly more prone to increasing ICH incidence with increasing age in comparison to black persons. The REasons for Geographic and Racial Differences in Stroke (REGARDS) study reported that ICH risk in Blacks is roughly 5.4-fold greater than Whites at age 45, but only one-third that of Whites at age 85. Whites were found to have an adjusted ICH hazard ratio of 2.03 for each subsequent decade of life, whereas rates did not differ significantly with age in Blacks.28 The underlying contributors to the observed ‘age-by-race interaction’ remain unclear. In assessing demographic trends in our aging population, Stein and colleagues project that by the year 2050, the proportion of all patients with ICH ≥ 80 years will be 2.5-fold higher than in 2009, with substantial increases in ICH cases (35.2% increase), severe disability (36.8%), and in-hospital mortality (60.2%).29 The role of hypertension as a leading risk factor is wellestablished, and its frequency has been estimated to be between 72%2,14,30 and 81%.2,14,30 The causative role of hypertension is supported by the high frequency of left ventricular hypertrophy in autopsy cases of ICH31–33 and the significantly higher admission blood pressure readings in patients with ICH than in those with other forms of stroke.34 The autopsy study by McCormick and Rosenfield35 challenged the view that hypertension represents the main causative factor in ICH. Their series included a large number of cases of ICH due to blood dyscrasias, vascular malformations, and tumors, and hypertension was regarded as the sole basis for the bleeding in only 25% of the total. This difference from most reported series of ICH may reflect a referral pattern bias in this series as well as more stringent criteria for establishing a causal relationship between hypertension and ICH. However, clinical series have also questioned the validity of the concept of ICH as a condition most commonly related to hypertension. Brott et al.16 found a history of hypertension in only 45% of 154 patients, which is a figure that rose to only 56% when electrocardiographic or chest radiographic evidence of cardiomegaly was added to criteria for the diagnosis of hypertension. Similarly, Schütz et al.17 labeled only 59% of their cases of ICH as due to hypertension. Certain subgroups of hypertensive patients, however, appear to be at particularly high risk of ICH. They include subjects who are 55 years or younger, smokers, and those who have stopped taking their antihypertensive medications.36 In the INTERSTROKE study, hypertension (selfreported history or mean blood pressure >160/90) was the strongest risk factor for ICH, accounting for 73.6% of the population-attributable risk.12 A number of other risk factors in addition to advancing age, hypertension, and race have been evaluated, including cigarette smoking, alcohol consumption, and serum cholesterol levels. Abbott et al.37 showed a higher risk of intracranial hemorrhage (both ICH and subarachnoid hemorrhage [SAH]) in cigarette-smoking Hawaiian men of Japanese ancestry. The risk

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SECTION III  Clinical Manifestations

of “hemorrhagic stroke” was 2.5 times higher in smokers, which was an effect that was independent of other risk factors. However, the diagnosis of ICH was often made on clinical grounds, without verification by imaging or autopsy findings. In a study based on computed tomography (CT) diagnosis of ICH in Finland, Juvela et al.38 found that smoking was not an independent risk factor for ICH. However, recent data from the Physicians’ Health Study and the Women’s Health Study39 documented a significant association between cigarette smoking and both SAH and ICH risk in men and women.39,40 After controlling for a number of vascular risk factors, investigators found that smoking 20 or more cigarettes per day was an independent risk factor for SAH (relative risk [RR] = 3.22; 95% confidence interval [CI], 1.26–8.18) and ICH (RR = 2.06; 95%CI, 1.08–3.96) in a cohort of predominantly white male physicians.40 Corresponding figures for women who smoked 15 or more cigarettes per day were RR of 4.02 (95%CI, 1.63– 9.89) for SAH and 2.67 (95%CI, 1.04–6.90) for ICH in the Women’s Health Study.39 The series reported by Donahue et al.41 and Juvela et al.38 also documented an increased risk of ICH in relation to alcohol ingestion, which was an effect that operated independently of other risk factors. Both studies showed a strong dose–response relationship between alcohol use and ICH. Juvela et al.38 documented a similar effect for alcohol ingestion within 24 hours and within 1 week before onset of ICH. Moreover, there are data that suggest that ICH occurs at a younger age in heavy alcohol users.42 Low serum cholesterol level, defined as serum cholesterol less than 160 mg/dL, has been shown to be associated with a higher risk of ICH in Japanese men19 as well as in Hawaiian men of Japanese origin.43 Similar results were documented in a population-based study in Rotterdam, Netherlands.44 Increased risk of ICH in relation to excessive smoking (>20 cigarettes per day), alcohol intake, and low cholesterol levels (particularly non-HDL cholesterol) were confirmed in the INTERSTROKE study.12 Increased ICH risk was also observed with increased waist-to-hip ratio, psychosocial stress, unhealthy diet (red meat, organ meat, egg, salty or fried food consumption and cooking with lard), whereas increased physical activity, and consumption of fruit and fish were protective. These modifiable risk factors combined with hypertension, smoking status and alcohol intake accounted for 90.8% of the population-attributable ICH risk.12 The risk of ICH attributable to statin therapy is controversial. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study,45 the overall benefit of active treatment with atorvastatin in secondary stroke prevention included an approximate 70% increase in risk of ICH.46 Initially, pooled analysis from a systematic review encompassing 8832 participants from four studies confirmed an approximate 70% increase in risk of ICH among statin users with prior cerebrovascular disease.47 However, a subsequent larger metaanalyses encompassing > 90,000 participants did not show a significant association between statin therapy and increased rates of ICH.48,49 The discrepancy likely reflects the populations being studied, with the more recent negative analyses being largely comprised of data from primary prevention studies or populations without known cerebrovascular disease. The suggested increased rate of ICH in persons with prior cerebrovascular disease seems to be independent of the cholesterol-lowering effects of statin therapy, and has been postulated to result from possible antifibrinolytic and/or antiplatelet properties of statins.46,47 Additional risk factors have been suggested in some studies. Cirrhosis was highly represented (15.5%) in the autopsy series of Boudouresques et al.,50 but its significance could not be assessed because comparison with a control autopsy series of the general population was not available. The occasional

association of ICH with cirrhosis has been linked to thrombocytopenia and other abnormalities in coagulation.51 Interestingly, in a nationwide multicenter case-control study, the risk of ICH increased by 30% per each number of childbirths, an association that persisted following adjustment for multiple covariates. The biological mechanism of this observation is uncertain but may be due to hormonal influences, physical and environmental factors during pregnancy, such as the increased risk of pregnancy-induced hypertension with increasing parity, and psychosocial stress and adverse lifestyle factors attributed to the rearing of multiple children.52 The role of aspirin use in the risk of ICH is controversial. The Physicians’ Health Study, which evaluated the effect of low-dose aspirin (325 mg every other day) in comparison with placebo in the primary prevention of coronary events, documented a borderline-significant increase in the relative risk of hemorrhagic stroke (ICH and SAH) in the aspirin group.53 Similarly, the Swedish Aspirin Low-Dose Trial (SALT), a secondary stroke prevention trial, documented a significantly higher frequency of hemorrhagic stroke in the group assigned to aspirin (75 mg/day) than in the group given placebo.54 These data contrast with those from other secondary stroke prevention trials, in which various doses of aspirin did not lead to a higher risk of ICH.55–60 CAA is a diagnosis being recognized with increasing frequency. The difficulty of diagnosing CAA in living subjects makes precise figures on disease incidence or prevalence hard to ascertain. CAA without ICH is clearly a common phenomenon in the elderly brain. A review of published autopsy series suggests a prevalence for CAA of approximately 10% to 30% among unselected brains and 80% to 100% among brains with accompanying Alzheimer’s disease (AD).61 When these figures are compared with the annual rate for all types of ICH, approximately 0.1% among North American and European elderly,14,17,18 it is clear that only a minority of pathologically advanced CAA results in hemorrhagic stroke. Despite the low frequency of hemorrhage, those produced by CAA account for a substantial proportion of all spontaneous ICHs in elderly patients. Estimated rates of 11% to 15% emerged from autopsies of elderly patients with ICH (age ≥ 60 years) at the Japanese Yokufukai Geriatric Hospital between 1979 and 199062 and the Hawaiian Kuakini Hospital between 1965 and 1976.63 Analysis of consecutively encountered clinical patients at the Massachusetts General Hospital (MGH) between 1994 and 2001 suggests an even greater proportion of hemorrhages, approximately 34%, attributable to CAA (Table 28-2). The apparently higher frequency of CAA in the MGH cohort might reflect either a lower incidence of hypertensive ICH in this Western population or secular improvements in blood pressure control as well as the methodologic differences between autopsy-based and clinic-based studies. Examination of the clinical characteristics that predispose to CAA-related ICH (Box 28-1) suggests that its incidence is likely to rise with the aging of the population and is unlikely to be reduced through control of modifiable risk factors. Advancing age is the strongest clinical risk factor for CAArelated ICH, as predicted by the age dependence of the underlying disease.61,64–66 There is no marked predilection for gender in either clinical (54% men, 46% women)2 or pathologic (49% men, 51% women)67 series. Dementia has generally been considered a major risk factor for CAA-related ICH because of the close molecular relationship between CAA and AD. A pathologic study of 117 consecutive brains with AD demonstrated advanced CAA to be common; moderate-to-severe CAA was found in 25.6% of specimens and CAA-related hemorrhages were found in 5.1%.68 Despite the frequent overlap of AD with CAA, approximately 60% to 80% of patients given diagnoses of CAA-related



Intracerebral Hemorrhage TABLE 28-2  Estimated Prevalence of CAA-Related ICH in a Clinical Series of Elderly Patients ICH Location (n = 355)

Percentage of Total*

Lobar

45.9 × 74%† = 34% of all primary ICHs in elderly due to CAA 41.1 3.7 8.5 0.9

Deep hemispheric Brainstem Cerebellum Intraventricular

CAA, Cerebral amyloid angiopathy; ICH, intracerebral hemorrhage. *Data from 355 consecutive patients age ≥55 presenting to Massachusetts General Hospital with spontaneous ICH. † The estimated proportion of primary lobar ICH in the elderly caused by CAA, based on detection of advanced CAA in 29 of 39 consecutive pathology specimens of lobar ICH.

BOX 28-1  Risk Factors for CAA-Related ICH RISK FACTORS FOR CAA Advanced age ApoE ε2 or ε4 Alzheimer’s disease RISK FACTORS FOR LOBAR ICH (NOT SPECIFICALLY LINKED TO CAA) Family history of ICH Frequent use of alcohol Previous ischemic stroke Low serum cholesterol CAA, Cerebral amyloid angiopathy; ICH, intracerebral hemorrhage; ApoE, apolipoprotein E.

ICH do not show clinical symptoms of dementia before their initial hemorrhagic stroke.67,69,70 It is thus unclear from a clinical standpoint whether the presence or absence of dementia is useful in making the diagnosis of CAA. The association of CAA and AD appears to be due in part to the shared genetic risk factor apolipoprotein E (ApoE) ε4, although there are substantial differences between the roles of ApoE in the two disorders. Despite the clear importance of hypertension in promoting necrosis and rupture of the deep penetrating vessels,71 there is little evidence for a similar role in CAA-related ICH. The estimated prevalence of hypertension in CAA is in the range of 32% (determined from pathologic cases67) to 49% (measured in clinical subjects2), which are figures not much greater than the expected rate of hypertension for the general elderly population. Hypertension is significantly less common in lobar ICH than in ICH of the deep hemispheres, cerebellum, or pons in most17,70,72,73 though not all36,74 studies of the elderly. Among other vascular factors, neither diabetes mellitus nor coronary atherosclerosis has demonstrated an elevated frequency in CAA. Other clinical risk factors have been suggested for lobar ICH without specific evidence linking them to CAA. Midpoint analysis of the population-based Greater Cincinnati/Northern Kentucky study identified family history of ICH, previous ischemic stroke, and frequent alcohol use in addition to ApoE genotype as predictors of lobar ICH in a multivariable model.75 Low serum cholesterol has been found to be associated with ICH in several other population-based studies.76–78 The few studies that have analyzed ICH according to location or presumed etiology have not indicated a specific relationship of cholesterol to CAA-related hemorrhages.79

469

CAA can also present clinically with non-hemorrhagic features. These include the following: 1. There are accumulating data to suggest that advanced CAA may sufficiently affect blood flow (possibly by the effects on vascular reactivity)80 to cause ischemic brain injury as well as ICH. Various types of ischemic lesions are reported in association with CAA, including punctate areas of gliosis in the cerebral cortex81 and regions of myelin loss and focal gliosis in the white matter, termed microinfarcts.82 Although microinfarcts are conventionally reported on pathology, asymptomatic small diffusion-weighted imaging hyperintense lesions are being increasingly recognized on MRIs of persons with CAA, and may be a radiographic marker for the formation of these lesions.83,84 A histopathologic study of 73 postmortem brains found a correlation between white matter lesions and the proportion of amyloidpositive vessels but not with age or severity of Alzheimer pathology.76 Similarly, magnetic resonance imaging (MRI) analysis of subjects with probable CAA demonstrated significantly greater volume of white matter T2-hyperintensity (median normalized volume, 19.8 cm3) than similar-aged subjects with AD (11.1 cm3) or mild cognitive impairment (10.0 cm3).77 Furthermore, it has been shown that Pittsburgh compound B (PiB) – a ligand that labels both vascular and parenchymal amyloid – retention on positron emission tomography (PET) is strongly correlated with degree of white matter T2-hyperintensity in individuals with CAA.85,86 Radiographic markers of white matter lesions in CAA appear to correlate with cognitive impairment,78 which suggests that ischemic brain injury may be an important contributor to neurologic disability in these patients. 2. A subset of patients with CAA is seen with clinical and radiographic features related to vascular inflammation. Although some increase in inflammatory cells may be a common feature of advanced CAA,69,87 a minority of patients demonstrate more robust reactions ranging from perivascular giant cells to frank vasculitis.79,87,88 These patients are more likely to be seen with subacute cognitive decline or seizures than with symptomatic ICH. MRI often shows T2-hyperintensity that is asymmetrical, extends to subcortical white matter and the overlying cortex, and improves dramatically with courses of immunosuppressive agents such as high-dose corticosteroids or cyclophosphamide.89 The clinical and radiographic response of many subjects to treatment suggests that CAA-related inflammation may be an important subtype to diagnose during life. 3. CAA can also manifest as transient neurologic symptoms,90–92 another syndrome for which diagnosis during life is of particular practical importance. A multicenter retrospective cohort study observed transient neurological symptoms to be a common occurrence in CAA (14.5% of 172 cases).93 The neurologic symptoms can include focal weakness, numbness, paresthesias, or language abnormalities, often occurring in a recurrent and stereotyped pattern. Spells typically last for minutes and may spread smoothly from one contiguous body part to another during a single spell. Transient neurologic symptoms in CAA appear to be related to the hemorrhagic rather than the ischemic component of the disease because gradient-echo MRI commonly demonstrates otherwise asymptomatic hemorrhage in the cortical region corresponding to the spell.90 Superficial siderosis and cerebral microbleeds have also been visualized at neuroanatomical sites that correspond with the presenting symptoms.93,94 Spells often cease with anticonvulsant treatment. The major practical issue is to differentiate these episodes by clinical or radiographic means from true transient ischemic attacks because administering anticoagulant

28

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SECTION III  Clinical Manifestations

agents in this setting may severely increase the risk of major ICH. A systematic review has shown the future risk of ICH at 2 months following an episode of transient neurological symptoms to be approximately 17%.93

GENETICS The study of the genetics of cerebrovascular disease has focused mainly on ischemic stroke, but some researchers have also addressed ICH.95 Alberts et al.96 addressed the issue of familial aggregation of cases of ICH. Their prospective study in North Carolina found that 10% of probands had a history of ICH. No significant clinical or demographic differences separated those with and without family history of ICH. Data reported by Woo et al.75 indicated that the presence of a first-degree relative is a risk for ICH of the lobar variety. These investigators also documented that the occurrence of lobar ICH is associated with the ε2 and ε4 alleles of the ApoE gene. These alleles, particularly ε4, have been identified as factors related to an increased risk of lobar ICH, presumably owing to the presence of CAA.70 In addition, the presence of the ε4 allele was found to determine an earlier age of onset of ICH in its carriers compared with the age of presentation of CAA-related ICH in those without the allele.70 A potential association between a point mutation in codon 34 of exon 2 for factor XIII Val34Leu and ICH was suggested by Catto et al.97 The suggested association was based on the known protective effect of this mutation for myocardial infarction (MI), as a result of its interfering with the formation of cross-linked fibrin. This last feature suggested the hypothesis that the mutation may result in an increased risk of ICH via the formation of weak fibrin structures. The study, which involved a large cohort of patients with stroke of both ischemic and hemorrhagic varieties, suggested that the mutation was significantly more common in subjects with ICH than in controls and in those with cerebral infarction.97 However, a similar study from Korea did not show an association between factor XIII Val34Leu polymorphism and ICH.98 These inconsistent observations may simply reflect the differences in the cohorts studied, and further data from other population samples will be required before a definitive statement can be made about the potential role of this mutation in the risk of ICH. A study in Chinese people of Han ancestry suggested an association between the 1425G/A single nucleotide polymorphism in the PRKCH gene in chromosome 14q22-q23 and increased incidence of ICH.99 Growing literature also suggests that angiotensin-converting enzyme (ACE) gene polymorphism, resulting in hypertension and possible vessel wall remodeling by way of higher ACE levels and activity, increases ICH risk.100 Similarly, genetic risk scores devised to assess burden of risk alleles related to hypertension, suggest that larger burdens of

Q (Dutch)

risk alleles for hypertension are associated with risk of ICH, particularly in deep regions, larger hematoma volume and worse outcome.101,102 Dominant mutations in the gene encoding type IV collagen α1 (COL4A1), a basement membrane protein, confer a highly penetrant genetic predisposition to familial cerebral smallvessel disease, characterized by retinal vascular tortuosity, T2-white matter hyperintensities, cerebral microbleed formation and predominantly deep ICH.103,104 Recently, novel COL4A1 mutations have also been identified in cases of sporadic (non-familial) ICH.105

Familial Cerebral Amyloid Angiopathy Several familial forms of CAA have been identified in which a protein entirely unrelated to amyloid beta (Aβ) accumulates in vessels, assumes amyloid conformation, and promotes vascular dysfunction. The clinical presentation of these familial CAAs differs from mutation to mutation, suggesting that each protein deposit provokes its own specific reaction. Substitution of glutamine for leucine at position 68 in the protease inhibitor cystatin C results in Icelandic CAA, which is characterized by very early deposition of a mutant protein fragment in vessel walls and symptomatic ICH by the third or fourth decades.106 ICH is much less prominent in familial British dementia, a disorder caused by mutation in the BRI gene.107 A single nucleotide substitution in the BRI stop codon causes cerebrovascular deposition of an abnormal carboxyl-terminus peptide fragment and a clinical syndrome of dementia and ataxia.108 A third clinical presentation is associated with mutations in the transthyretin gene. When these mutations affect the central nervous system, they favor leptomeningeal and subependymal deposition, causing varying combinations of SAH, seizures, hydrocephalus, cognitive changes, ataxia, and hearing loss.109 The other major forms of familial CAA are caused by mutations or duplications of the APP gene. Interestingly, the APP mutations associated with CAA cluster within the Aβ-coding region of APP (Fig. 28-1) rather than flanking the Aβ-coding segment like the AD-associated mutations.110 The Dutch-type hereditary CAA caused by substitution of glutamate to glutamine at Aβ position 22111,112 manifests as recurrent lobar ICH in the fifth or sixth decades and progresses to an early mortality.113 A similar clinical picture is produced by the Italian substitution of lysine at this position.114,115 Dementia and AD-like neuritic pathology are more prominent features of duplication of the APP locus116 and of two other CAAassociated APP mutations, the Flemish substitution of glycine at Aβ position 21117 and the Iowa asparagine for aspartate substitution at residue 23.118 Although differences have emerged among the various mutations in their effects on APP

N (Iowa)

K (Italian) G (Arctic) 1

G (Flemish)

42

KMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVI *

***

Figure 28-1.  Mutations of the APP (β-amyloid precursor protein) gene associated with familial cerebral amyloid angiopathy (CAA). The boxed segment of APP contains the region representing Aβ42 as well as the amino acid substitutions at positions 21 to 23 associated with familial CAA (see text for references). Asterisks indicate the positions of some of the mutations linked with early-onset Alzheimer’s disease.



Intracerebral Hemorrhage

processing and Aβ bioactivity,119,120 the precise mechanisms by which they predispose toward specific combinations of CAA and AD pathology remain unclear.

Sporadic Cerebral Amyloid Angiopathy The genes associated with familial CAA do not appear to play major roles as risk factors for sporadic CAA. Among 55 patients with sporadic CAA-related ICH examined for the cystatin C Icelandic mutation,121,122 only one positive finding has been reported. Similar searches for APP mutations at Aβ position 22 or 23 have yielded no instances in 111 reported patients with sporadic CAA.118,121 ApoE has emerged as the strongest predictor of risk for sporadic CAA-related ICH. The ApoE ε2 and ε4 alleles appear to promote CAA-related ICH at two distinct steps in the disease’s pathogenesis, as previously described.123–125 Each of these alleles was over-represented more than twofold among 182 reviewed pathologic cases of CAA-related ICH.126 The general importance of ApoE to lobar ICH was further supported by the midpoint analysis of the Greater Cincinnati/Northern Kentucky cohort, in which the presence of ApoE ε2 or ε4 was associated with an adjusted odds ratio for lobar ICH of 2.3.75 The ApoE alleles had an attributable risk for lobar ICH of 29% in this study, which is the largest proportion for any risk factor examined. ApoE ε2 and ε4 appear to associate with not only greater risk of ICH occurrence,123 but also a younger age at first hemorrhage125 and a shorter time until ICH recurrence (see later).127 The ApoE ε2 allele in particular has also been associated with intrahematomal contrast extravasation during CT angiography (CTA), termed ‘spot sign’, in lobar and CAA-related ICH, hematoma expansion, larger hematoma volumes, as well as poor functional outcomes and mortality at 90 days.128,129 ApoE polymorphism may also influence the risk of lobar ICH attributable to treatment for the secondary prevention of ischemic stroke, such as statin therapy, by way of a ‘gene-by-drug effect’.130

PATHOLOGIC FEATURES AND PATHOGENESIS Spontaneous ICH occurs predominantly in the deep portions of the cerebral hemispheres. Its most common location is the putamen; this site accounts for 35% to 50% of the cases.2,4,14,131– 133 The second site of preference varies in different series; in most, it is the subcortical white matter,2,14,32,132 and the frequency is 30%. The thalamus follows, with a uniform frequency of 10% to 15%.2,4,14,132–136 Pontine hemorrhage accounts for 5% to 12% of cases of ICH.2,4,14,132,134 The distribution figures in a series of 100 unselected cases of ICH are shown in Table 28-3. The hemorrhages of putaminal, thalamic, and pontine location occur in the vascular distribution of small, perforating intracerebral arteries: the lenticulostriate, thalamoperforating, and basilar paramedian groups, respectively. Cerebellar TABLE 28-3  Distribution by Site of 100 Cases of ICH at the University of South Alabama Medical Center Type Putaminal Lobar Thalamic Cerebellar Pontine Miscellaneous Caudate Putaminothalamic ICH, Intracerebral hemorrhage.

No. of Cases 34 24 20 7 6 5 4

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hemorrhage occurs in the area of the dentate nucleus,137,138 which is supplied by small branches of both the superior and the posterior–inferior cerebellar arteries.137 Thus, most ICHs originate from the rupture of small, deep arteries71 with diameters between 50 and 200 µm. The same arteries are recognized to be those occluded in cases of lacunar infarcts,139 a form of stroke correlated primarily with chronic hypertension and diabetes.140,141 Thus, it is apparent that these various groups of small arteries, located in well-defined anatomic areas, become the targets of chronic hypertension, and the result can be either occlusion or rupture, leading to lacunar infarcts or ICH, respectively.

Vascular Rupture The actual mechanism of vascular rupture leading to ICH has been the subject of considerable interest, and several detailed pathologic studies142–144 have addressed this point. Because hypertension is one of its main causative factors,145 arterial changes associated with it have been commonly implicated in its pathogenesis. Since Charcot and Bouchard146 described “miliary aneurysms” in brain specimens from patients with hypertensive ICH in 1868, these lesions have been the subject of extensive interest. Initially, they were thought to represent true dilatations of the arterial wall, and their preferential location deep in the hemispheres lent support to their pathogenic role. In the early twentieth century, however, with the use of a more precise histologic technique, Ellis147 was able to show that miliary aneurysms represent “false aneurysms” and are actually made of blood collected outside the vessel wall, as “masses of blood” surrounded by either “remains of the vessel wall” or fibrin. His view of the pathogenesis of ICH implied a primary intimal lesion, with or without secondary involvement of the media and adventitia, and the former often led to passage of blood into the vessel wall and formation of a dissecting aneurysm. Either form of vascular abnormality (dissecting aneurysm or simple “weakening” of the vessel wall by extension of the primary intimal lesion into the media and adventitia) would then be responsible for rupture and hemorrhage. Over the following years, miliary aneurysms in the brains of hypertensive patients were shown through the use of thick frozen sections148 and x-ray imaging of brain specimens injected with radiopaque media.149 Green148 demonstrated three such lesions, two of which were associated with a fresh hemorrhage in the pons and frontal lobe. His view was that these lesions were mainly related to atherosclerosis and that they “may be responsible for some cases of cerebral hemorrhage.” However, the definitive work that established the relationship between hypertension and miliary aneurysms was performed by Ross Russell,149 who combined postmortem angiography with routine histologic study of brain specimens. He found miliary aneurysms in 15 of 16 brains of hypertensive patients and in ten of 38 normotensive patients. The aneurysms were found mostly in the basal ganglia, internal capsule, and thalamus and less commonly in the centrum semiovale and cortical gray matter. Ross Russell149 regarded these lesions as most likely acquired, strongly related to hypertension, and possibly causally related to ICH. He rejected the notion that aneurysms may be consequences rather than causes of ICH, as they were present in brains of hypertensive patients without ICH. This study was followed by a series of observations reported by Cole and Yates142,143,150 in a systematic analysis of 100 brains from hypertensive patients and an equal number of brains from normotensive persons. Miliary aneurysms were found in 46% of hypertensive brains but only in 7% of normotensive brains; furthermore, they occurred in 85% of the hypertensive

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patients with massive ICH and in all of those with small “slit” hemorrhages, which suggested that small hemorrhages probably result from microaneurysmal “leaks.”142 These researchers did not, however, establish a relationship between microaneurysms and bleeding sites, thereby failing to prove that these leaks had a causal role in ICH. In 1971, Fisher71 reported the study of two brains containing three ICHs, one pontine and two putaminal, by serial sections of blocks of tissue containing the hemorrhage. In both putaminal hemorrhages, the primary arterial bleeding sites were identified along with multiple sites of secondary bleeding. The latter was thought to result from mechanical disruption and tearing of smaller vessels at the periphery of the enlarging hematoma. In the pontine ICH, only the secondary bleeding sites were recognized. No instances of microaneurysm formation were found in immediate relationship to the hematomas, whereas “lipohyalinosis” was a common abnormality of the walls of small arteries harboring the bleeding sites. Miliary aneurysms were identified in both hemorrhages, although not in relation to the bleeding points. Fisher71 thought the aneurysms were unlikely to be sources of major hemorrhage and more probably the end result of old small sites of arterial rupture (“the end stage of a limited extravasation”). A year later, Fisher151 reported a detail of the types of microaneurysms found in brains of hypertensive patients. He described “saccular,” “lipohyalinotic,” and “fusiform” varieties of microaneurysms and suggested that the lipohyalinotic form may be the process underlying ICH (as well as lacunar infarcts). He regarded the saccular and fusiform varieties as less likely to be important factors in the pathogenesis of ICH. On the basis of these two studies, Fisher71,151 concluded that hypertensive ICH most likely results from rupture of one or two lipohyalinotic arteries, followed by secondary arterial ruptures at the periphery of the enlarging hematoma in a cascade or avalanche fashion.

Active Bleeding Early studies conducted before the wide availability of CT scanning suggested that the period of active bleeding in ICH is rather brief (<1 hour),152 and the observation of clinical deterioration after admission was frequently attributed to the effects of brain edema,2,152 although instances of continuous bleeding were occasionally reported.153 A number of subsequent CT studies of the early phases of ICH have helped to clarify these concepts. Broderick et al.154 evaluated eight patients with ICH by CT within 2.5 hours of onset and again several hours later (within 12 hours of onset in seven patients), documenting a substantial increase in hematoma size (mean percentage increase, 107%) (Fig. 28-2). This increase in the volume of the hemorrhage was accompanied by clinical deterioration in six of the eight patients, all of whom had a 40% increase in hematoma volume. In five patients, the clinical deterioration occurred with blood pressure measurements of 195 mm Hg or higher. These investigators suggested that a prolongation of active bleeding for several hours (up to 5 or 6 hours) after onset may not be uncommon as a mechanism of early clinical deterioration in ICH. Similarly, Fehr and Anderson155 reviewed 56 cases of hypertensive ICH in the basal ganglia and thalamus and documented enlargement of the hematoma with CT in four (7%); in two of the four, the increase in hematoma size was documented within 24 hours from onset, and in the other two, it was documented on days 5 and 6. Three of the patients had neurologic deterioration. In two who experienced deterioration within 24 hours, it occurred in the setting of poorly controlled hypertension, whereas the others had adequate blood pressure control. One of two patients with adequate blood pressure control was a chronic alcoholic, leading the investigators to suggest that alcoholism may be a risk factor for delayed progression of ICH.

A

B Figure 28-2.  Enlargement of left putaminal hemorrhage (A) from 25 mL on CT scan performed 35 minutes after onset, to (B) 44 mL on scan obtained 70 minutes later (105 minutes after onset). (Reprinted with permission from Broderick JP, et al. Ultra early evaluation of intracerebral hemorrhage, J Neurosurg, 72, 2, February, p 195–9, 1990.)



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Three subsequent studies further clarified the patterns of early enlargement of ICH. Fujii et al.156 studied 419 patients with ICH, in whom they performed the first CT within 24 hours of onset and the follow-up CT within 24 hours of admission, which showed hematoma enlargement in 60 patients (14.3%). Kazui et al.157 conducted sequential CT evaluations in 204 patients with acute ICH, documenting enlargement of at least 12.5 cm3, or by 40% of the original volume, in 20% of the cases. The highest frequency of detection of hematoma enlargement was seen in patients in whom the initial CT scan was performed within 3 hours of stroke onset (36%); the detection of enlargement declined progressively as the time from ICH onset to first CT increased, and there was no documentation of enlargement in those first scanned more than 24 hours after onset. These observations suggest that the period of hematoma enlargement can extend for a number of hours from onset as a result of active bleeding, which is a phenomenon that is frequently, but not always, associated with clinical deterioration. The study reported by Brott et al.158 involved 103 patients in whom first CT scans were obtained within 3 hours of ICH onset and follow-up CT scans were obtained 1 hour and 20 hours after the initial scans. ICH enlargement (>33% volume increase) was detected in 26% of patients at the 1-hour follow-up scan, and an additional 12% showed enlargement between the 1-hour and 20-hour CT scans. The change in hematoma volume was often associated with clinical deterioration, but there were exceptions. These researchers found no predictors of ICH enlargement, evaluating age, hemorrhage location, severity of initial clinical deficit, systolic and diastolic blood pressure at onset or history of hypertension, use of antiplatelet drugs, platelet counts, prothrombin time, and partial thromboplastin time. Recent data suggest that the presence of small foci of contrast extravasation (the “spot sign”159) during CTA in patients with acute ICH may predict subsequent hematoma enlargement.159,160 The documentation of active bleeding by this technique (Fig. 28-3), especially when CTA is performed within the first few hours from symptom onset, has been correlated with a high frequency of hematoma enlargement (in up to 77% of patients with the spot sign) in comparison with patients without the sign (with only 4% showing hematoma

Baseline non-contrast CT (total hematoma volume 19.6 mL)

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expansion).159 In the PREDICT (predicting haematoma growth and outcome in intracerebral haemorrhage using contrast bolus CT) study, a multicenter prospective observational cohort study, 30% of 268 ICH cases presenting within 6 hours of symptom onset were spot sign positive. Presence of spot sign within this cohort had a positive predictive value of 61% and negative predictive value of 78% for hematoma expansion (sensitivity 51%, specificity 85%).161 Similar figures have also been reported in ICH cases where the spot sign was visualized greater than 6 hours from symptom onset.162 Spot sign independently predicts 3-month disability (defined by the modified Rankin scale) and mortality.161,163 The following criteria for the definition of the spot sign have been outlined:164 a spot-like or serpiginous focus of enhancement located within a parenchymal hematoma without connection to vessels outside the ICH, with a diameter greater than 1.5 mm, and with Hounsfield units (HU) at least double that of the background hematoma density. Further evidence for the value of the spot sign for predicting hematoma expansion includes its correlation with features such as number of spot signs (≥ 3), maximal diameter (≥ 5 mm), and maximal attenuation (HU ≥ 180), all of which were found to be independent predictors of hematoma expansion.165 Of these, the number of spot signs has been suggested as most predictive of hematoma expansion.166 Further studies are needed to identify potential risk factors of early ICH enlargement so that attempts can be made to prevent its associated neurologic morbidity and mortality. Promising additional markers for early ICH enlargement currently under investigation include spot sign visualized on CT perfusion source images,167 visualization of a striate artery feeding the point of CTA contrast extravasation (termed ‘spot and tail’ sign),168 postcontrast CT extravasation,169 irregular hematoma shape and heterogeneous density on non-contrast CT,170,171 as well as the presenting average hematoma growth rate, estimated as the baseline ICH volume divided by the time from symptom onset to baseline neuroimaging.172 These studies should be facilitated with the use of techniques of hematoma volume measurement that are easy to apply.173–175 The “abc method”174 uses the formula (a × b × c)/2, in which a is the largest diameter of the hematoma in the CT slice with

Baseline CTA (single spot-sign positive)

24 h follow-up non-contrast CT (total hematoma volume 110.8 mL)

Figure 28-3.  Computed tomographic angiogram (CTA) scan demonstrating intrahematomal contrast extravasation – “spot sign” – corresponding to ongoing bleeding at that site, and subsequent hematoma expansion on 24 hours follow-up CT scan. (Reprinted with permission from Demchuk AM et al. Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study, Lancet Neurology, 11, 4, April, pp. 307–14, 2012.)

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4.3 cm

2.9 cm

Figure 28-4.  Method of calculating hematoma volume on CT, in which a is the largest diameter, b is the largest diameter perpendicular to a, and c is the number of slices with hematoma times the slice thickness in centimeters. The formula [(a × b × c)/2] gives the hematoma volume in cubic centimeters.

the largest area of ICH; b is the largest diameter of the hemorrhage perpendicular to line a; and c is the number of slices with hematoma times the slice thickness; this formula yields hematoma volume in cubic centimeters (Fig. 28-4). The use of these volumetric measurements of ICH should improve our understanding of the clinical consequences of early changes in hematoma size and their risk factors so that we may better define clinical and CT patterns of ICH evolution. The use of volumetric measurements of ICH in the early phase, along with neuroimaging techniques used to predict ongoing bleeding, should serve as the background for new strategies of management of ICH and their eventual testing in randomized clinical trials; one such trial is the STOP-IT trial, which will evaluate hematoma growth in patients with ICH and a CTAdetected spot sign at baseline, with randomized treatment allocation to activated factor VII or placebo. It is expected that the study of patients with ICH at high risk of hematoma expansion will help identify treatments with potential for arresting this process. Lastly, whether MRI markers of cerebral small-vessel disease, such as cerebral microbleeds or white matter hyperintensities (indicating possible underlying vascular fragility vulnerable to Fisher’s aforementioned ‘avalanche theory’), are helpful in predicting hematoma growth remains to be confirmed.176–178

Secondary Brain Injury In contrast to the immediate primary injury of hematoma formation, which ensues from mechanical damage to surrounding brain tissue during expansion, secondary injury of ICH is believed to result from the potentiation of various parallel cascades (namely inflammation, coagulation, and red cell lysis) resulting in cerebral edema and neuronal death.179 Extravasated blood exposes perihematomal brain tissue to blood components including red blood cells, leukocytes, and

plasma proteins, which in turn activate surrounding microglia and astrocytes.180 Activated microglia/macrophages serve a major protective role in clearing the hematoma and tissue debris. However, experimental models suggest that they also increase blood–brain barrier permeability and promote surrounding brain tissue damage by releasing inflammatory cytokines, reactive oxygen species, and proteases, which contribute to ICH-induced secondary brain injury.180 Astrocytes play both a neuroprotective role, by promoting neurotrophic factors and cascade modulation, and a neurotoxic one, through the secretion of inflammatory cytokines and metalloproteinases in concert with migroglia, and by promoting reactive gliosis. Attempts at minimizing ICH-induced neurotoxicity through the use of anti-microglial therapies, such as minocycline,181,182 have proven to reduce ICH-induced edema and neuronal injury in murine models. However, the apparent combined neurotoxic and neuroprotective actions of microglia/ macrophages and astrocytes in response to ICH require further characterization in order to better identify therapeutic targets within their cascades that minimize neurotoxicity while preserving neuroprotective actions. Red blood cell lysis occurs within 3 days of ICH, causing the release of hemoglobin and heme, which are then phagocytized and degraded by microglia/macrophages by way of heme-oxygenases.179 Heme degradation products – carbon monoxide, biliverdin, and iron – are believed to contribute to oxidative stress, edema formation, and neuronal death. The role of iron in ICH-induced secondary injury is supported by the neuroprotective role of the iron-chelator deferoxamine in experimental ICH models.183 These observations have led to ongoing clinical trials aimed at reducing post-ICH ironmediated toxicity.184 Thrombin formation, resulting from activation of the coagulation cascade in order to limit hematoma expansion, can also initiate several deleterious pathways at high concentrations that promote cerebral edema formation, and both neuronal and astrocytic death, serving as another potential therapeutic target.185,186

Gross Pathologic Anatomy The gross pathologic anatomy of ICH includes a number of features peculiar to the various locations of the hematomas.

Putaminal Hemorrhage The common putaminal variety originates at the posterior angle of this nucleus and spreads in a concentric fashion but generally extends more in the anteroposterior than the transverse diameter.134 The result is an ovoid mass of maximal anteroposterior diameter collected in the putamen and the structures located laterally to it, the external capsule and claustrum. The insular cortex is pushed laterally, whereas the internal capsule is either displaced medially or involved directly by the hematoma (Fig. 28-5). The origin of this form of ICH in the lateral–posterior aspect of the putamen is bleeding from a lateral branch of the striate arteries.134 The lumens of these laterally placed middle cerebral artery perforating branches are between 200 µm and 400 µm wide at their entry to the brain,149 and they supply the putamen, internal capsule, and head of the caudate nucleus. From its initial putaminal–claustral location, a sufficiently large hematoma may extend to other structures in the vicinity: medially into the internal capsule and lateral ventricle, superiorly into the corona radiata, and inferolaterally into the white matter of the temporal lobe (Fig. 28-6). These variations in the pattern of extension result in clinical variants of putaminal hemorrhage. The extension of the hemorrhage from its site of origin can follow several patterns, of



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Figure 28-6.  Large left putaminal–capsular hemorrhage, with tracking into the white matter of the temporal lobe.

Figure 28-5.  Massive left putaminal hemorrhage involving the posterior half of the putamen, globus pallidus, posterior limb of the internal capsule, and claustral area. Effacement of the ipsilateral lateral ventricle and midline shift is present.

which the most common is dissection along the course of adjacent white matter fibers. The common medial extension of the hematoma leads to communication with the lateral ventricle, through a process of slow leakage of blood rather than as direct communication between active bleeding site and ventricular system.134 Direct communication of the hematoma with the ventricular system, at times with associated hydrocephalus, is more likely to result from bleeding at sites adjacent to the ventricular space, such as the thalamus128 and the head of the caudate nucleus.187 A putaminal hematoma that extends directly into the ventricle is usually large and thus is associated with high mortality.188

Caudate Hemorrhage A variant of striatal hematomas is that occurring in the head of the caudate nucleus. Although the bleeding source is thought to be the same as in putaminal hemorrhage (the lateral group of striate arteries), this form of ICH is less common.187 The recognized low frequency of this type of striatal hemorrhage in hypertensive patients leads the clinician to search for a different underlying cause, such as an arteriovenous malformation (AVM) or aneurysm. This variation in the frequency of two types of striatal bleeding (putaminal and caudate) from the same arterial source is unexplained and may reflect a higher rate of arterial rupture at the more proximal segments of these arteries. This higher rate, in turn, may correlate with a higher frequency of “lipohyalinosis” or “microatheroma” at the more proximal segments of these vessels, as shown by Fisher189 in serial studies of the underlying vascular lesions in cases of capsular infarcts. Fisher implied that the same basic vascular abnormality (lipohyalinosis or microatheroma) may be the basis for both lacunar infarcts and ICH in hypertensive patients.134 The predominantly proximal location of these

Figure 28-7.  Hemorrhage originating from the head of the left caudate nucleus, with involvement of the anterior limb of the internal capsule and direct ventricular extension with formation of a ventricular cast.

lesions could therefore explain the low frequency of caudate hemorrhage because it originates from the distal ends of these lateral striate branches. Caudate hemorrhage occurs most commonly in the head of this nucleus (Fig. 28-7), and ventricular entry is an early event; this component is sometimes many times larger than the parenchymal hematoma.188 Involvement of the anterior limb of the internal capsule is the rule.

Thalamic Hemorrhage Thalamic hemorrhages can involve most or the entire nucleus, and their extension is mostly in the transverse direction, into the third ventricle medially and the posterior limb of the internal capsule laterally (Fig. 28-8). Because the hemorrhage commonly extends transversely, it produces a pressure effect or extends directly inferiorly into the tectum and tegmentum of the midbrain. Moderate-sized and large thalamic hematomas often extend superiorly into the corona radiata and parietal white matter, following the orientation of their fibers.

Lobar (White Matter) Hematoma White matter (lobar) hematomas collect along the fiber bundles of the cerebral lobes, most commonly at the parietal and occipital levels (Fig. 28-9).132,190 Blood usually collects

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between the cortex and underlying white matter, separating them and often extending along the white matter pathways. These hematomas are close to the cortical surface, at a distance from the ventricular system and midline structures, and usually not in direct contact with deep hemispheric structures (e.g., internal capsule or basal ganglia).

Cerebellar Hemorrhage Cerebellar hemorrhages usually occur on one hemisphere, originating in the area of the dentate nucleus (Fig. 28-10).137,138 From here they extend into the hemispheric white matter as well as the cavity of the fourth ventricle. The adjacent brainstem (pontine tegmentum) is rarely involved directly by the hematoma but is often compressed by it, at times with resultant pontine necrosis. A variant of cerebellar hemorrhage, the midline hematoma originating from the cerebellar vermis is virtually always in direct commu­nication with the fourth ventricle through its roof and frequently extends into the pontine tegmentum bilaterally. The bleeding artery in this variety usually corresponds to distal branches of the superior

Figure 28-8.  Right thalamic hemorrhage, involving most of this nucleus, with extension into the corona radiata as well as inferiorly into the subthalamic area, with compression of the dorsal midbrain.

A

B

cerebellar artery. These two forms of cerebellar hemorrhage have distinct clinical and prognostic features.

Pontine Hemorrhage In pontine hemorrhages, the bleeding sites correspond to small paramedian basilar perforating branches.71 The result is a medially placed hematoma that extends symmetrically to involve the basis pontis bilaterally, with variable degrees of tegmental extension (Fig. 28-11). Tracking of the hematoma into the middle cerebellar peduncle is rarely seen. A partial unilateral variety of pontine hematoma, predominantly tegmental in location, is recognized clinically and documented by CT scans.191,192 These hypertensive hemorrhages result from rupture of distal tegmental segments of long circumferential branches of the basilar artery.192 The hematomas usually communicate with the fourth ventricle, and they extend laterally and ventrally into the tegmentum and upper part of the basis pontis on one side.

Figure 28-10.  Left cerebellar hemorrhage with mass effect on the pontine tegmentum. (Reprinted with permission from Kase CS: Cerebellar hemorrhage, Kase CS, Caplan LR, editors: Intracerebral hemorrhage, Boston, 1994, Butterworth-Heinemann, p 425.)

C

Figure 28-9.  A, Left subcortical (white matter) occipital lobe hemorrhage, without extension into the ventricular system or midline shift. B, Large left frontal subcortical hemorrhage, with extension into the lateral ventricle and marked midline shift. C, Large left frontoparietal lobar hemorrhage, with cortical involvement and communication with the subarachnoid space; marked mass effect and midline shift.



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28

R

Figure 28-11.  Massive midline basal pontine hemorrhage, with bilateral destruction of basis and tegmentum.

Recurrence of Intracerebral Hemorrhage The ICH of hypertensive patients is often a one-time event: in a group of 101 patients with ICH entered into the NINCDS Stroke Data Bank,4 history of a prior hemorrhage was documented in only one instance. Long-term follow-up studies in patients with ICH have found a low frequency of recurrent bleeding,193 which clearly differentiates ICH from aneurysms and AVMs, in which rebleeding is a prominent feature. In a study reported by Gonzalez-Duarte et al.,194 however, data showed ICH recurrence in approximately 6% of an unselected series of patients with ICH. Among hypertensive patients, the pattern of recurrence was that of repeated episodes of basal ganglionic ICH, whereas recurrence of lobar ICH was observed more often in non-hypertensive subjects, in whom the predominant putative mechanism of ICH was CAA. A similar rate of recurrence (5.4%) was documented by Bae et al.195 within a median interval of about 2 years from the first episode of ICH. The risk of ICH recurrence was significantly increased by poor hypertension control, which stresses the value of hypertension treatment in the prevention of ICH. Occasionally, multiple simultaneous ICHs can occur.196,197 In a series of 600 consecutive cases of ICH diagnosed by CT scan, Weisberg189 found 12 patients (2%) with multiple hematomas. These double lesions were probably simultaneous (because of equal CT attenuation values) in 11 instances, and they occurred in the same intracranial compartment (supratentorial or infratentorial) in all patients but one, in whom thalamic and cerebellar hematomas coexisted. The incidence of hypertension was unusually low (two of 12 patients) in this series, which suggests that cases of multiple spontaneous ICHs may frequently have other causative factors.

Cerebral Amyloid Angiopathy Among the survivors of CAA-related ICH, the major neurologic risk is hemorrhage recurrence. A pooled analysis of patients monitored after lobar ICH reported a recurrence rate of 4.4% per year.198 The value for cumulative ICH recurrence rate among the consecutive patients followed up at MGH was approximately 10% per year,127 perhaps reflecting a higher prevalence of CAA among the patients with lobar ICH in this population. Recurrent hemorrhages, like the initial hemorrhages, are typically lobar, although generally at a site distinct from that of the initial ICH (Fig. 28-12).

L

Figure 28-12.  Multiple intracerebral hemorrhages of different ages in a patient with autopsy-documented cerebral amyloid angiopathy: acute fatal left lobar, subacute right lateral parietal, and chronic (with ocher discoloration) right upper parietal locations.

The strongest risk factors for CAA-related ICH recurrence are a history of previous recurrences, ApoE genotype, antithrombotic exposure, posterior predominant white matter changes and number of hemorrhages (microbleeding plus macrobleeding) detected by gradient-echo MRI.126,127,199 The prognosis for good functional outcome after a second CAArelated ICH appears to be relatively poor.127 These observations highlight secondary hemorrhage prevention as an important treatment goal in CAA.

Histopathologic Studies The studies on the histopathology of ICH have been mostly concerned with pathogenic issues. However, the main features of the microscopic anatomy of ICH and its changes with time are well-documented. The initial arterial rupture leads to local accumulation of blood, which in part destroys the parenchyma locally, displaces nervous structures in the vicinity, and dissects at some distance from the initial focus. The bleeding sites are at times difficult to locate, and serial sections are needed to show them.55 The bleeding sites appear as round collections of platelets admixed with and surrounded by concentric lamellae of fibrin, so-called bleeding globes or fibrin globes.71 These fibrin or bleeding globes at the primary and secondary sites are histologically identical, except that the fibrin globes are larger. The bulk of the hematoma is formed by a compact mass of red blood cells, and the bleeding sites are characteristically found at its periphery. García et al.200 have described in detail the sequential histologic changes that take place in the hematoma. After hours or days, extracellular edema develops at the periphery of the hematoma, resulting in pallor and vacuolation of myelin sheaths. After 4 to 10 days, the red blood cells begin to lyse, eventually turning into an amorphous mass of methemoglobin. Cellular infiltration by polymorphonuclear leukocytes appears at the periphery of the hematoma as early as 2 days after onset, and the number of leukocytes peaks at 4 days.201 This event is followed by the arrival of microglial cells, which become foamy macrophages after the ingestion of cellular debris, including products of disintegration of myelin as well as blood-derived pigments, especially hemosiderin. The final stages of this process consist of the proliferation of astrocytes at the periphery of the hematoma, where these cells become enlarged and display prominent eosinophilic cytoplasm (gemistocytes), which at times contains hemosiderin granules.

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Figure 28-13.  A 2-month-old right putaminal–insular hemorrhage, with partial cavitation, good demarcation from the adjacent parenchyma, and lack of signs of mass effect.

Figure 28-14.  Old right thalamic hemorrhage reduced to a slit with hemosiderin-stained edges.

Once the late stage of hematoma reabsorption and repair has been reached, the astrocytes are replaced by abundant glial fibrils. This histologic process is correlated with macroscopic changes in the hematoma, which initially becomes a soft, spongy mass of brick-red, altered blood (Fig. 28-13). After many months of slowly progressing phagocytosis, the residua of the hematoma is confined to a flat, collapsed cavity lined by reddish orange discoloration resulting from the accumulation of hemosiderin-laden macrophages (Fig. 28-14).33

Cerebral Amyloid Angiopathy CAA appears on pathologic analysis as a variable combination of vascular amyloid deposition and vessel wall breakdown (Fig. 28-15). Affected vessels are the capillaries, arterioles, and small- and medium-sized arteries primarily of the cerebral cortex, overlying leptomeninges, and cerebellum; the white matter and deep gray structures are largely spared. The distribution of CAA is typically patchy and segmental, such that heavily involved vessel segments may alternate with essentially amyloid-free regions (see Fig. 28-15C).88 In its mildest detectable form, congophilic material accumulates at the border of the vessel’s media and adventitia (see Fig. 28-15A). Amyloid-lined vacuoles often seen at this stage88 may represent former sites of vascular smooth muscle cells that have died in apparent response to the surrounding amyloid. In moderately severe segments of CAA, vascular amyloid extends throughout the media to replace essentially the entire smooth muscle cell layer (see Fig. 28-15B).

The most advanced extent of CAA is marked by not only severe amyloid deposition but also pathologic changes in the amyloid-laden vessel wall. These vasculopathic changes can include microaneurysms, concentric splitting of the vessel wall (see Fig. 28-15D), chronic perivascular or transmural inflammation, fibrinoid necrosis (see Fig. 28-15E), and even perivascular giant-cell reaction (Fig. 28-15F).69,87–89 CAA-related vasculopathic changes are often associated with paravascular red cells or hemosiderin deposits, which suggests ongoing leakage of blood. It is this combination of extensive amyloid deposition and breakdown of the amyloid-laden vessel walls that appears to act as the substrate for symptomatic hemorrhagic strokes.69,88,116,123 The principal constituent of both vascular amyloid in CAA and plaque amyloid is the β-amyloid peptide (Aβ). The Aβ peptides are 39- to 43-amino-acid proteolytic fragments of the 695- to 770-residue β-amyloid precursor protein (APP). The subset of Aβ peptides with carboxyl termini extending to positions 42 or 43 (denoted Aβ42) appears to be an important trigger to amyloid aggregation in both vessels and plaques.202 In support of Aβ42 deposition as an early step in initiation of CAA is the observation that mildly affected vessels can stain positive for Aβ42 but stain negative for the more common Aβ fragments terminating at positions 39 or 40 (Aβ40).203 It is Aβ40, however, that appears to be the predominant species in more heavily involved vessel segments.204–206 Quantitative analysis of brains with mild and severe CAA suggests a progressive addition of Aβ40 to previously seeded vessel segments.206 A variety of other proteins or protein fragments can also be detected as components of vascular amyloid, although the pathogenic role in the breakdown of the vessel wall is not known. These CAA-associated proteins include apoE, cystatin C, α-synuclein, heparan sulfate proteoglycan, amyloid P component, and several complement proteins.207,208 The relationship of the pathology of CAA and ApoE genotype provides an interesting insight into the importance of both Aβ deposition and vessel breakdown to the pathogenesis of CAA-related ICH. The ApoE ε2 and ε4 alleles, each a suggested risk factor for CAA-related ICH, appear to act at these two distinct stages of CAA to promote hemorrhage. ApoE ε4 associates in a dose-dependent manner with increased deposition of Aβ in vessels as it does in plaques;124 ApoE ε2 appears instead to promote the CAA-related vasculopathic changes such as concentric vessel splitting and fibrinoid necrosis.123,125 The mechanism for this unexpected effect of ApoE ε2 on vascular breakdown is unknown. The domain of the ApoE protein containing the ε2 determinant is present in both vessel and plaque amyloid deposits208 but has not been linked to any specific pathogenic function. One experimental approach to clarifying pathogenic mechanisms for CAA has been to study the effects of Aβ on vessel components in vitro. Aβ exerts toxic effects on a variety of vascular cells in culture, including cerebrovascular smooth muscle cells, endothelial cells, and pericytes.119,209 Cell death is enhanced when the Aβ peptide used is either wild-type Aβ42 or mutant Aβ40 containing one of the amino acid substitutions associated with hereditary CAA,114,120,210 which suggests that particular chemical properties of Aβ can specifically promote toxicity. Death of the cultured cerebrovascular smooth muscle cells appears to require a series of events on the cell surface, including assembly of Aβ into amyloid fibrils (Fig. 28-16) and accumulation of the secreted aminoterminal portion of APP.211 Another in vitro property of Aβ is to stimulate tissue-type plasminogen activator (t-PA),212 which raises the intriguing possibility that CAA might promote ICH through direct effects on the coagulation– thrombolysis cascade as well as on the integrity of the vessel wall.



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A

B

C Figure 28-15.  Pathologic appearances of cerebral amyloid angiopathy (CAA). A, Vessel in longitudinal section. In mild stages of disease, amyloid appears at the outer edge of the vessel media, creating vesicle-like structures (arrows) at sites believed to be previously occupied by smooth muscle cells. B, Further amyloid deposition replaces the media and all smooth muscle cells. C, Specimen taken from a brain with the Iowa APP mutation. Amyloid deposits can cause marked thickening of vessel wall segments that alternate with skipped areas of normal caliber (arrows). Further vasculopathic changes in amyloid-laden vessels include concentric splitting of the vessel wall, creating a vessel-in-vessel appearance.

The pathogenesis of CAA has also been studied in transgenic mouse models (Fig. 28-17). Substantial CAA develops at advanced ages in lines of mice expressing high levels of mutant APP.205,206 Affected vessels in these animals can demonstrate several pathologic features reminiscent of human CAA, including disruption or loss of the vascular smooth muscle, microaneurysms, and perivascular cerebral hemorrhages.213–215 Because the expression of human APP in these animals is virtually all neuronal, the occurrence of CAA demonstrates that Aβ produced by neurons is capable of reaching vascular sites of deposition, possibly via the interstitial fluid drainage pathway.216 Once produced, Aβ may be cleared by proteolytic enzymes such as neprilysin17,62 or insulin-degrading enzyme63 or may exit the brain by receptor-mediated efflux across the blood–brain barrier.64 A further insight to come from these transgenic studies is the possibility that Aβ may have specific effects on vessel physiology. Investigations in mouse models of CAA using a variety of techniques to measure blood flow have indicated blunted vasodilatory response to pharmacologic or functional stimulation.65–67 These hints of altered vascular physiology, raised as well by earlier studies of isolated vessel segments exposed to Aβ, have found important parallels in studies of vascular reactivity to visual stimulation in humans with CAA.68

Other Causes of Non-traumatic   Intracerebral Hemorrhage There are a number of instances in which ICH occurs. These mechanisms of ICH are (1) vascular malformations and angiopathies such as Moyamoya disease (discussed elsewhere), (2) sympathomimetic drugs, (3) brain tumors, (4) hemorrhagic diathesis (discussed elsewhere), (5) anticoagulants, (6) fibrinolytic agents, (7) vasculitides (discussed elsewhere), and (8) hemorrhagic infarction. In a consecutive series of 378 surgical samples from patients with non-traumatic ICH, the majority of which were supratentorial and superficial, vascular pathologies (33.5%) prevailed in cases where a putative origin of ICH was determined, with arteriolosclerosis (15.6%) and CAA (10.1%) being the most frequent. Vascular malformations were encountered in 7.1%, hemorrhagic infarction in 1.6%, and brain tumor in 2.4%. These figures differed widely from preoperative assumptions where brain tumors, vascular malformations, and hemorrhagic infarctions were overestimated, while arteriolosclerosis and CAA were underestimated.217

Sympathomimetic Drugs ICH related to the use of amphetamines has been documented in several publications.218–221 The preparation most commonly

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D

E

F Figure 28-15, cont’d (D) and fibrinoid necrosis (E), signifying entry of plasma components into the wall. F, Some instances of advanced CAA are accompanied by visible inflammatory changes such as perivascular giant cell reaction. (A, D, and F stained by Luxol fast blue–hematoxylineosin; B and C by anti-β-amyloid immunostain with hematoxylin counterstain; and E with phosphotungstic acid–hematoxylin.)

implicated has been intravenous methamphetamine,210 but cases related to intranasal220 or oral219 use of this drug and amphetamine have also been reported. Another sympathomimetic drug, pseudoephedrine, has been associated with one reported instance of ICH.221 In these cases, ICHs have developed usually within minutes (20 to 40) to a few hours (4 to 6) after the use of the drug; frequently, the ICH represents an established pattern of drug abuse for months beforehand, but at times it has followed a first-time use.219 An association with transiently elevated blood pressure has been noticed in about 50% of cases, and most of the hematomas have been of lobar location.220,221 Their pathogenesis has been related to either transient drug-induced elevation in blood pressure219 or an arteritis-like vascular change histologically similar to periarteritis nodosa.222 The latter is considered either a direct “toxic” effect of the drug on cerebral blood vessels or a hypersensitivity reaction to the drug or its vehicle. The cerebral “arteritis” related to use of these drugs is characterized angiographically by beading (multiple areas of focal

arterial stenosis or constriction) of medium-sized and large intracranial arteries,220,221,223–225 which is an effect that has been shown to be reversible after use of steroids and discontinuation of drug abuse.225 However, it is likely that these reversible vascular changes correspond not to a true vasculitis but rather to a nonspecific phenomenon of multifocal spasm related to the effects of the sympathomimetic drug on the vessel wall. In isolated instances, intravenous use of methamphetamine precipitated an ICH from a Sylvian-region AVM,226 and oral use of dextroamphetamine was associated with SAH in the presence of a small middle cerebral artery aneurysm.227 Most other reports of amphetamine-related ICH and SAH have not documented preexisting vascular malformations or mycotic aneurysms. Other sympathomimetic agents have been related to episodes of ICH. Phenylpropanolamine (PPA) has been associated with instances of ICH and SAH. Most affected patients have been young (median age in the third decade), have been women more often than men, and generally have lacked other



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Figure 28-16.  Deposition of β-amyloid (Aβ) on cerebrovascular smooth muscle cell. This transmission electron micrograph shows a cultured human cerebrovascular smooth muscle cell treated with Dutch-type mutant Aβ40 for 6 days. Under these conditions, Aβ assembles into amyloid fibrils on the cell surface (seen at top). (Courtesy of William E. Van Nostrand.)

Figure 28-18.  Multifocal areas of arterial constriction and dilatation (“beading”) in the vertebrobasilar system after an episode of severe headache and transient hypertension (200/110 mm Hg), shortly after the ingestion of a phenylpropanolamine-containing nasal decongestant. (Reprinted with permission from Kase CS, et al. Intracerebral hemorrhage and phenylpropanolamine use, Neurology, 37, 3, March, pp. 399–404, 1987.)

Figure 28-17.  Cerebral amyloid angiopathy in a transgenic mouse (Tg2576). Vascular and parenchymal amyloid deposits are identified by systemic administration of methoxy-XO4 (blue) and vessel lumens with intravenous Texas red-labeled dextran (red). In vivo imaging is performed by multiphoton fluorescent microscopy. (Courtesy of Michal Arbel-Ornath and Brian Bacskai.)

risk factors for ICH.228 Results of a case-control study reported by Kernan et al.221 have suggested the potential association between PPA and ICH. These investigators found that women who used appetite suppressants containing PPA had a significantly higher risk of intracranial hemorrhage (odds ratio [OR], 16.58; 95%CI, 1.51–182.21; P = 0.02). The hemorrhages occur shortly after PPA ingestion (most between 1 and 8 hours).228–234 The ICHs are most commonly of lobar location, and about two-thirds of the patients that have undergone angiography have shown widespread beading of intracranial

arteries (Fig. 28-18), without documentation of other vascular lesions responsible for bleeding, such as AVM and aneurysm. Histologic examination of blood vessels from biopsy material has been nondiagnostic, except for one instance in which changes consistent with vasculitis were found.235 The pathogenesis of these PPA-related hemorrhages is obscure. Although rare patients have been previously hypertensive, transient hypertension was noted at presentation in about 50% of the reported cases.228 This finding suggests that a possible mechanism of vascular rupture is drug-induced transient hypertension associated with multifocal arterial changes due to vasospasm or, less commonly, vasculitis. However, transient hypertension alone is an unlikely explanation for these hemorrhages because the hypertension has generally been modest, even in comparison with blood pressure rises documented under physiologic conditions.236 These observations suggest that mechanisms other than transient hypertension must be present in order for intracranial hemorrhage to occur under these circumstances. Cocaine is being increasingly reported as a cause of cerebral hemorrhage in young individuals, especially in its precipitate form, known as “crack.” Instances of ICH and SAH have occurred within minutes to 1 hour from use of crack cocaine.237

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The ICHs can be lobar, but are predominantly subcortical (Fig. 28-19); occasionally there are multiple hemorrhages in both locations.238,239 The mechanism of these ICHs is unclear, although these lesions are, in many respects, similar to those related to the use of amphetamine or PPA; the angiographic beading that characterizes ICHs due to amphetamine or PPA use is relatively uncommon in cocaine-related ICHs, which, in turn, have shown a stronger association with AVMs or aneurysms as the bleeding mechanism.237 This association suggests that the hypertensive response that commonly follows cocaine use may act in some instances as a precipitant of ICH in preexisting vascular malformations. In one case, ICH after cocaine use was related to pathologically documented vasculitis of a small intraparenchymal artery.240 A recent report observed that

Figure 28-19.  Left putaminal hemorrhage secondary to use of crack cocaine.

A

patients with cocaine-associated ICH had higher rates of intraventricular hemorrhage, worse functional outcome, and a threefold increase in in-hospital mortality in comparison with patients with ICH unrelated to cocaine use.239

Intracranial Tumors Intracranial tumors are a well-recognized but uncommon cause of ICH. Underlying tumors have accounted for 1% to 2% of cases of ICH in autopsy series,32 whereas rates of 6% to 10% have been found in clinical-radiologic series.241,242 The great majority of the underlying neoplasms have been malignant, either primary or metastatic, but rarely, meningiomas243 or oligodendrogliomas241 have manifested as ICH. An example of a generally benign tumor with relatively high tendency to bleed is pituitary adenoma, which was associated with bleeding in 15% of the cases in one large series of brain tumors.244 Among the primary malignant brain tumors causing ICH, glioblastoma multiforme predominates;241 the metastatic tumors have been melanoma, choriocarcinoma, renal cell, and bronchogenic carcinoma.242,245–248 The frequency of hemorrhagic metastases was estimated at 60% for germ cell tumors, 40% for melanoma, and 9% for bronchogenic carcinoma.249 The bleeding tendency in neoplasms is thought to be directly related to the richness of their vascular components and their pathologic, neoplastic character.250 In the case of metastatic choriocarcinoma, these features are enhanced by the normal biological tendency of trophoblastic tissue to invade the walls of blood vessels.246,251 The location of the hemorrhage relates to some extent to the type of neoplasm involved: hemorrhages occurring in glioblastoma multiforme are frequently deep into the hemispheres, basal ganglia, or corpus callosum.241 Hemorrhages due to metastatic tumors occur more often in the subcortical white matter (Fig. 28-20)245 because metastatic nodules commonly deposit at the gray– white matter junction. In approximately half of the reported instances of ICH within an intracerebral tumor, the hemorrhage was the first clinical manifestation of the neoplasm. The radiologic diagnosis by CT can be established easily in instances of multiple metastatic lesions,245 but cases of ICH into a single tumor can be more difficult to diagnose. Such a diagnosis should be suspected with the finding of large areas of low-density edema surrounding the hematoma (Fig. 28-21) of an area of contrast enhancement at the periphery of the hematoma, frequently forming a ring pattern on initial presentation with ICH.241,245 Because ring enhancement is not expected on presentation of spontaneous, hypertensive ICH,251–254 its presence should strongly suggest the possibility of an underlying, previously asymptomatic primary or metastatic brain tumor. Other features suggesting ICH into a brain tumor are: (1) finding of

B

Figure 28-20.  A, Large hemorrhage into a metastatic lesion (from bronchogenic carcinoma) in the right frontal subcortical white matter. A second, nonhemorrhagic metastasis is present in the white matter of the left frontal lobe. B, Hemorrhagic metastases from melanoma, with visible necrotic tumor at the center of the larger hemorrhage, extending into both medial parietal lobes.



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A

B

C

D

E

F

Figure 28-21.  CT scan (A) and T2-weighted MR images (B to F) of acute hemorrhage into glioblastoma multiforme, showing the acute hematoma with marked edema extending well beyond the immediate vicinity of the acute hemorrhage.

papilledema at presentation with acute ICH; (2) atypical location of the ICH, in areas such as the corpus callosum, which is rarely the site of “spontaneous” ICH and is commonly involved by malignant gliomas (Fig. 28-22); and (3) a ringlike high-density area corresponding to blood around a lowdensity center, resulting from bleeding by tumor vessels at the junction of tumor and adjacent brain parenchyma.255 In addition, Iwama et al.256 have suggested that a low-density indentation of the periphery of an ICH on CT should raise the suspicion of an underlying tumor nodule. These clinical and radiologic features should prompt a search for a primary or metastatic brain tumor with MRI and cerebral angiography. If the results of these studies are inconclusive, biopsy of the hematoma cavity should be considered to establish the diagnosis of an underlying brain tumor because the therapeutic options and prognosis are radically different from those for spontaneous or hypertensive ICH.

Anticoagulant and Thrombolytic Therapy Warfarin.  Long-term oral anticoagulation with warfarin is often listed among the causes of ICH. In a consecutive series of 100 cases of ICH that Kase et al.257 observed over a 3-year period, warfarin anticoagulation was a factor in 9% of the cases. Boudouresques et al.50 reported that in their autopsy series of 500 cases of ICH, anticoagulation was implicated in 11%. After excluding cases due to trauma, ruptured aneurysm, or concomitant brain tumor, Rådberg et al.258 documented an anticoagulant-related mechanism in 14% of 200 consecutive

patients with ICH. Furthermore, anticoagulation is second only to hypertension as a causative factor in series of cerebellar259 and lobar190 locations. The risk of ICH in patients undergoing long-term oral anticoagulation has been shown to be eight to 11 times that in patients of similar age who are not receiving anticoagulants.260–263 The incidence of ICH in patients receiving warfarin after MI is approximately 1% per year.253 A number of factors are known to contribute to a higher risk of ICH in these patients, including advanced age (>70 years),264,265 hypertension,257,263,264,266–268 and concomitant use of aspirin, which has been estimated to double the rate of ICH in comparison with individuals taking oral anticoagulants alone.261,269 Other features related to ICH in patients receiving anticoagulants are as follows: Duration of anticoagulation therapy before onset of ICH. In two series, most ICHs (70%,257 54%258) occurred during the first year after the start of treatment. In another report, only one third of ICHs occurred after that period of time;260 the other two-thirds appeared between 2 and 18 years after the start of treatment. Relationship between intensity of anticoagulant effect and risk of ICH. Excessive anticoagulant effect is now well-established as a powerful risk factor for ICH.247,263–266,268,270 Hylek and Singer,264 reporting data from an anticoagulant therapy unit, showed that the risk of ICH doubled with each 0.5-point increase in the prothrombin time ratio above the recommended limit of 2.0. Data from the Stroke Prevention in

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therapy in this study, its findings were subsequently supported by two additional cohorts where CMBs strongly correlated with anticoagulation-related ICH.276,277 Additional data are required to determine the utility of CMBs on MRI within the risk–benefit analysis of implementing chronic anticoagulation therapy at an individual patient level. Location of ICH. A high frequency of cerebellar location was found in some studies,257,258,278 whereas others found no differences in location of ICH between patients who were and were not receiving anticoagulation therapy.260,261,263 Characteristics. Characteristics of these hemorrhages include a tendency to occur in the absence of signs of systemic bleeding, lack of relationship between the ICH and preceding cerebral infarction, frequent leisurely progression of the focal neurologic deficits (at times over periods as long as 48 to 72 hours), and high mortality (46% to 68%) related to hematoma size (the hematoma is generally larger than in hypertensive ICH).258,260,261 In addition, warfarin-related ICHs are associated with a high risk of hematoma expansion,279 which in turn correlates with clinical deterioration (Fig. 28-23) and increased mortality. On CT scan, the hemorrhages often show blood-fluid levels, which result from “sedimentation” of red blood cells in a hematoma that does not clot because of the anticoagulation effect (Fig. 28-24).

Figure 28-22.  CT scan of hemorrhage into glioblastoma multiforme, with bleeding into the corpus callosum and adjacent thalamus and deep parietal lobe as well as extensive surrounding low-density edema.

Reversible Ischemia Trial,271 a secondary stroke prevention trial in which patients with transient ischemic attack or minor ischemic stroke were randomly assigned to receive either aspirin (30 mg/day) or warfarin (to achieve an international normalized ratio [INR] of 3.0 to 4.5), add further evidence of the effect of excessive anticoagulation and frequency of ICH: the trial was stopped early, after the occurrence of 24 ICHs (14 fatal) in the warfarin group in comparison with only three ICHs (one fatal) in the aspirin group; there was a strong relationship between bleeding complications and rise in INR values. A relationship between increasing INR values and large ICH volume has also been reported.272,273 Presence of leukoaraiosis. Severe and confluent areas of leuko­ araiosis were associated with a higher risk of ICH in warfarin-anticoagulated subjects in the Stroke Prevention in Reversible Ischemia Trial.271 Similarly, data reported by Smith et al.268 documented CT-detected leukoaraiosis as an independent risk factor (OR, 12.9; 95%CI, 28–59.8) for ICH in subjects receiving anticoagulation therapy with warfarin after an episode of ischemic stroke. Presence of cerebral microbleeds. Cerebral microbleeds (CMBs), represent remnants of previous blood degradation in the form of hemosiderin-laden macrophages,274 and are believed to result from underlying bleeding-prone microangiopathy. The largest study to date investigating the association of CMBs and antithrombotic-related ICH (antiplatelet or warfarin), prospectively followed 908 stroke patients presenting to a regional stroke center in Hong Kong for an average period of 2.2 years, and noted a dose-dependent independent relationship between the number of CMBs on baseline MRI and subsequent ICH while on antithrombotic therapy, reaching a hazard ratio of 9.81 (95%CI, 2.76–34.83) in individuals with five or more CMBs.275 Although the majority of antithrombotic use was in the form of antiplatelet

The actual mechanism of ICH in patients undergoing anticoagulation is unknown, in part because of the lack of adequate pathologic studies with serial histologic sections aimed at identifying the type of bleeding vessel and the histopathologic abnormality at the bleeding site. Such studies should determine whether anticoagulant-related ICHs have different microscopic pathologic features from that of spontaneous ICH, in terms of the type of affected vessel as well as the eventual presence of local vascular disease (i.e., microaneurysm, fibrinoid necrosis, lipohyalinosis, or CAA) at the rupture site as a possible substrate for this complication of warfarin anticoagulation. Hart et al.261 have hypothesized that ICH in patients undergoing anticoagulation could result from enlargement of small, spontaneous hemorrhages that would otherwise occur without clinical consequence in individuals with normal coagulation function. The contributing role of local vascular disease, such as CAA, is favored by observation of a high frequency of this angiopathy in individuals with warfarinrelated ICH. Rosand et al.280 documented CAA in brain tissue samples from seven of 11 patients with warfarin-related ICH. In addition, these investigators found an over-representation of the ApoE ε2 allele, a marker of CAA, in patients with warfarin-related ICH in comparison with a control group. Heparin.  The occurrence of ICH during intravenous heparin anticoagulation represents a different situation because this complication generally occurs in the setting of preceding acute cerebral infarction (because ICH is extremely uncommon in patients receiving intravenous heparin for noncerebrovascular indications, such as deep vein thrombosis and MI281,282). Thus, a recent cerebral infarction with local ischemic blood vessels is a likely site for the occurrence of secondary ICH, especially in embolic infarcts, which tend to become hemorrhagic as part of their natural history.283 ICH in this setting occurs within 24 to 48 hours of the start of heparin treatment,284 and excessive prolongation of the activated partial thromboplastin time (aPTT) is common.285,286 Other risk factors for ICH in the setting of intravenous heparin therapy for acute cerebral infarction are infarcts of large size and uncontrolled hyper­ tension (blood pressure exceeding 180 mm Hg systolic/ 100 mm Hg diastolic).287 These findings have led to recommendations that the immediate use of intravenous heparin anticoagulation in acute nonseptic cerebral infarction be limited to those patients



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1:48 AM ICH volume: 4.25 cc NIHSS: 3

3:36 AM ICH volume: 43 cc NIHSS: 14

5:52 AM ICH volume: 73.7 cc NIHSS: >20

Figure 28-23.  Gradual enlargement of hematoma in patient receiving anticoagulation with warfarin, showing progression over time of the volume of the hematoma and the corresponding neurologic deterioration, as measured by the National Institutes of Health Stroke Scale (NIHSS) score.

supporting the value of any parenteral antithrombotic agents in this setting.288 Because intravenous heparin has not been properly tested in patients with acute ischemic stroke of nonlacunar type, a prospective, randomized clinical trial, the Rapid Anticoagulation Prevents Ischemic Damage (RAPID) trial,289 was performed in Europe. The design involved the comparison between aspirin and unfractionated heparin (administered within 12 hours of stroke symptom onset) given for 1 week, with regard to the primary endpoint of rate of favorable outcome, measured as a modified Rankin Scale (mRS) score of 2 or less at 90 days. Although the sample size for the study was 592 patients, the trial was stopped early because of low recruitment (only 67 patients had been recruited after 30 months from study onset). An analysis of the small sample of 67 patients showed no significant differences between the groups in terms of mRS, National Institutes of Health Stroke Scale (NIHSS) score < 1, mortality, ischemic stroke worsening, or stroke worsening related to hemorrhage, whereas a trend (P = 0.09) in favor of unfractionated heparin was detected for the secondary endpoint of ischemic stroke recurrence.290 Based on these limited data, the authors planned to conduct a larger multicenter trial to test the hypothesis that early administration of unfractionated intravenous heparin may have a neuroprotective effect in patients with acute ischemic stroke.

Figure 28-24.  CT of acute intracerebral hemorrhage in left frontal white matter, with blood-fluid level.

with subtotal infarcts in a given vascular territory but without uncontrolled hypertension (i.e., blood pressure <180/ 100 mm Hg) and that it be accompanied by close adherence to a prolongation of the aPTT value within the recommended therapeutic range (1.5 times the control value).286 However, the immediate use of intravenous heparin after cerebral infarction has been questioned in view of the lack of data

Anticoagulation and cerebral amyloid angiopathy.  Iatrogenic ICH occurring during anticoagulation or thrombolysis is an especially important manifestation of CAA. Anticoagulation is hypothesized to promote ICH by allowing small leakages of blood to expand into large symptomatic hemorrhages and might thus be particularly risky in the setting of advanced CAA. This possibility is supported by demonstration of advanced CAA in individuals who have ICH after thrombolysis or during warfarin therapy. CAA may also have a role in ICH occurring with antiplatelet treatment.75,199 These observations raise the important possibility that an individual’s risk for CAA could ultimately be incorporated into the decision whether to treat with thrombolytic or anticoagulant therapy. Novel oral anticoagulants.  In recent years a number of randomized controlled trials have compared novel oral

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anticoagulants to warfarin therapy for the prevention of stroke and systemic embolism in the management of nonvalvular atrial fibrillation. These agents interfere with the coagulation cascade by way of either direct thrombin (dabigatran) or factor Xa (apixaban, edoxaban, rivaroxaban) inhibition. In addition to providing at least non-inferior stroke prevention, an attractive benefit of these agents is lower rates of ICH in comparison to warfarin therapy, with significant absolute risk reductions (ARR) in hemorrhagic stroke of 0.23% for apixaban,291 0.31% and 0.21% for the 30 mg and 60 mg dose of edoxaban, respectively,292 0.26% and 0.28% for the 110 mg and 150 mg dose of dabigatran, respectively,293 and an ARR in intracranial hemorrhage of 0.20% for rivaroxaban.294 Accordingly, these agents offer a promising alternative to individuals with atrial fibrillation who are also at higher risk of ICH, but whether the benefits of these novel oral anticoagulants can be extrapolated to this particular subgroup of patients remains to be determined. Reassuringly, in the case of dabigatran the lower rates of ICH in comparison to warfarin also occurred in subgroup analysis of individuals aged 75 years and older who were at high risk of CAA, and apixaban has been observed to have a similar ICH rate as aspirin, while being superior to aspirin for stroke prevention.295,296 The specific targeting of the novel agents of a single factor within the coagulation cascade (factor Xa or IIa [thrombin]), rather than the inhibition of four vitamin-K-dependent factors (II, VII, IX and X) by warfarin, has been speculated to account for these differences.297 Fibrinolytic agents.  Fibrinolytic agents, especially t-PA, are used in the treatment of coronary, arterial, and venous thromboses in the limbs and pulmonary circulation. The ability of these agents to produce clot lysis and a relatively low level of systemic hypofibrinogenemia makes them ideal choices for the treatment of acute thrombosis. However, their most feared complication is ICH, which has been reported in 0.4% to 1.3% of patients with acute MI treated with the single-chain t-PA alteplase.298 The clinical and CT features of ICHs related to coronary thrombolysis with t-PA have been extensively reviewed.299–303 The hemorrhages tend to occur early after the start of t-PA treatment: in one study, 40% of the hemorrhages started during the infusion, and another 25% occurred within 24 hours of the onset of treatment.299 In 70% to 90% of cases, the hemorrhages are lobar, in about 30% of cases are multiple,300 the latter being associated with a mortality of 44% to 66%.299–302 The mechanism of bleeding in this setting is unknown. On occasions, patients have had excessively prolonged aPTT values at the time of onset of intracranial hemorrhage as a result of the use of intravenous heparin (aimed at preventing reocclusion of reperfused coronary arteries).300–302 Other factors suggested as significant in raising the risk of ICH after the use of t-PA in acute MI are advanced age (>65 years), history of hypertension, and the use of aspirin before t-PA therapy;302 in one study, however, none of these factors was found to be significantly different in patients with or without ICH.301 A possible role for local cerebral vascular disease has been considered because examples of pretreatment head trauma301 and concomitant CAA303–305 have been documented in association with ICH after the use of t-PA. Other coagulation defects related to this treatment, such as hypofibrinogenemia and thrombocytopenia, have not been found to correlate with this complication.

Vasculitis The cerebral vasculitides generally result in arterial occlusion and cerebral infarction and are only rarely responsible for ICH. Most of these unusual examples of ICH secondary to cerebral arteritis have been secondary to granulomatous angiitis

of the nervous system (GANS).306 This primary cerebral vasculitis occurs in the absence of systemic involvement. Histologically, it is characterized by mononuclear inflammatory exudates with giant cells in the media and adventitia of small and medium-sized arteries and veins. This vascular inflammation is occasionally associated with the formation of microaneurysms. The cerebral disease evolves with chronic headache, progressive cognitive decline, seizures, and recurrent episodes of cerebral infarction.291 Because of its primary cerebral location, systemic features such as malaise, fever, weight loss, arthralgias, myalgias, anemia, and elevated sedimentation rate are absent.307,308 The diagnosis is favored by the finding of lymphocytic cerebrospinal fluid (CSF) pleocytosis with elevated protein levels, and angiography may show a beading pattern in multiple medium-sized and small intracranial arteries. The instances of ICH reported in patients with GANS have occurred in the setting of progressive encephalopathy or myelopathy,309,310 although ICH has occasionally been the first manifestation of the condition.311 The hemorrhages have been predominantly lobar in location, and in rare instances, histologic examination of cerebral vessels has shown the association of GANS with CAA,312,313 which suggests that either vascular lesion could have been responsible for the episode of ICH.

HEMORRHAGIC INFARCTION Hemorrhagic infarction (HI) differs pathologically from ICH as it results from reperfusion of infarcted tissue. Restoration of blood flow to necrotic tissue leads to the extravasation of blood through altered capillaries and arterioles resulting in scattered petechial blood-staining, with more advanced HI resulting in confluent petechial areas of hemorrhage or even frank hematoma. This process occurs predominantly in deep and cortical gray matter, owing to the higher density of capillaries in these regions in comparison to white matter.314 The spectrum of HI severity has been categorized by the European Cooperative Acute Stroke Study (ECASS) investigators315 into HI-1 (small petechiae along the margins of the infarct), HI-2 (confluent petechiae within the infarcted area but without space-occupying effect), parenchymal hematoma 1 (PH)-1 (blood clot not exceeding 30% of the infarcted area with some mild space-occupying effect) and PH-2 (dense blood clot[s] exceeding 30% of the infarct volume with significant spaceoccupying effect or hematoma remote from the infarcted area). As the bleeding predominantly occurs in areas of already infarcted tissue, most cases of HI are asymptomatic, with only a subset being accompanied by neurological deterioration. Although the occurrence of PH-2 is often a symptomatic event associated with acute neurological deterioration,316 there are suggestions that worse 90-day outcomes can be observed in the setting of HI-2 and PH-1,317 leading to questioning of the often-held notion of clinical irrelevance of these less dramatic forms of HI.318 The most frequent causes of HI are embolic ischemic stroke and cerebral venous thrombosis, while a less common cause is global hypoperfusion from cardiogenic shock followed by reinstitution of cerebral perfusion resulting in hemorrhagic transformation of borderzone infarcts (Fig. 28-25). In the case of embolic stroke, reperfusion is believed to result from fragmentation and distal migration of arterial emboli or by way of leptomeningeal collateral blood flow, the former tending to cause HI at the initial site of occlusion and the latter in a purely distal gyral pattern.283,319,320 HI is part of the natural history of ischemic stroke, and occurs in approximately 40% of cases,321,322 however HI rates in the literature have ranged widely from 5% to 50% when examining all ischemic strokes irrespective of particular subtype.323 The majority of cases of



Figure 28-25.  Gross pathology demonstrating bilateral cortical borderzone hemorrhagic infarctions following cardiac arrest. (Image courtesy of Dr. Robert H. Ackerman, Massachusetts General Hospital, Boston, MA.)

HI occur within 3–14 days of symptom onset.322,324 In the absence of thrombolytic therapy, the strongest predictors of hemorrhagic transformation of an ischemic infarct have been large infarct volume, detection of focal hypodensity on early CT (<5 hours), worse neurological status on admission, cardio­embolic or cryptogenic stroke subtype, hyperthermia, hyperglycemia, hypertension, albuminuria, as well as high baseline matrix metalloproteinase-9 (MMP-9) and cellular fibronectin levels.323,325 In addition to their role in the treatment of acute MI, intravenous thrombolytic agents (t-PA) are the only approved therapy for patients with acute ischemic stroke. HI is a common phenomenon that follows thrombolysis of patients with acute ischemic stroke. T-PA is believed to increase the rates of HI by way of increased recanalization rates, fibrinolysis, and possibly indirect upregulation of MMP-9.326 Initial pilot studies with the use of intra-arterial agents, mainly urokinase and t-PA, yielded encouraging rates of reperfusion, in the order of 55% of patients treated, and hemorrhagic complications (i.e., HI and ICH) and neurologic deterioration occurred in about 11% of patients.327 The initial experience with intravenous thrombolytics administered within 8 hours of stroke onset, reported by del Zoppo et al.,328 yielded angiographically documented rates of reperfusion at a disappointingly low level, in the range of 26% to 38%. Despite this low level of recanalization, hemorrhagic changes with neurologic deterioration occurred in 9% of patients. In addition, the study showed that the rate of hemorrhagic complications was significantly higher in patients in whom t-PA was administered more than 6 hours after stroke onset, in comparison with patients treated within 6 hours.329 Nonangiographic studies of intravenous t-PA in acute stroke, the ECASS315 and the National Institute of Neurological Diseases and Stroke (NINDS) rt-PA Stroke Study,330 used entry windows (time after onset during which patients could be entered into the study) of 6 hours and 3 hours, respectively, and doses of alteplase of 1.1 mg/kg (to a maximum of 100 mg) and 0.9 mg/kg (to a maximum of 90 mg), respectively. Results of both studies were positive, especially those of the NINDS study, which showed an improved functional outcome at 3 months in the group treated with t-PA without a higher mortality due to hemorrhagic complications. Despite a tenfold increase in symptomatic ICH during the first 36 hours in patients treated with t-PA (6.4% versus 0.6% for the placebo

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group), a net benefit accrued for the t-PA-treated group as measured by three functional scales 3 months after treatment. The intracranial hemorrhages in the t-PA group occurred in both the lobar white matter and the deep gray nuclei (Fig. 28-26), and they carried a high mortality (45%).331 The risk factors for intracranial hemorrhage after thrombolysis with intravenous t-PA within 3 hours of acute ischemic stroke onset include the severity of the neurologic deficit (as measured by the NIHSS score), the presence of edema and mass effect in the baseline CT scan, degree of early ischemic changes on CT as measured by the ASPECTS (Alberta Stroke Program Early CT Score) score, and antiplatelet use (particularly dual therapy with aspirin and clopidogrel).331–333 When intravenous t-PA was given between 3 and 6 hours from stroke onset, the baseline DWI lesion volume, history of atrial fibrillation, 24-hour weighted average systolic blood pressure, and evidence of early post-t-PA reperfusion were independent predictors of the risk of HI.334,335 Higher risk has also been reported in individuals with infective endocarditis,336 severe renal impairment (glomerular filtration rate < 30 mL/min),337 severity of leuko­ araiosis,338 degree of hypoperfusion and very low regional cerebral blood volume on perfusion imaging,339,340 and fluidattenuated inversion recovery hyperintensity within the acute ischemic territory on MRI.341 Other potential factors associated with increased risk of postintravenous t-PA bleeding include hyperglycemia at baseline342 and elevated serum levels of biomarkers indicative of vascular fragility or abnormal permeability of the blood–brain barrier such as MMP-9,343,344 cellular fibronectin,345 endogenous activated protein C,346 vascular adhesion protein-1/semicarbazide-sensitive amine oxidase activity,347 and markers of endogenous fibrinolysis.348 The Safe Implementation of Treatment in Stroke-Monitoring Study (SITS-MOST)349 identified nine independent risk factors for symptomatic ICH (defined as PH-2 accompanied by ≥4point worsening on the NIHSS score or death) among 31,267 ischemic stroke patients treated with IV alteplase: baseline NIHSS score, serum glucose, systolic blood pressure, history of hypertension, age, body weight, stroke onset to treatment time, aspirin monotherapy, and dual antiplatelet therapy with aspirin and clopidogrel. From these data, they devised a 12-point score (SITS SICH risk score) with good discriminatory ability in the identification of stroke patients at high risk of symptomatic ICH following IV alteplase.350 Three clinical trials of intravenous streptokinase in acute ischemic stroke found an alarmingly high rate of ICH and mortality.351–353 The use of 1.5 million IU of streptokinase within 4351 or 6352,353 hours from stroke onset resulted in rates of symptomatic ICH between 6%283 and 21.2%,351 with mortality rates of 19%352 and 34%353 at 10 days and 43.4%351 at 90 days, resulting in the termination of the trials. It is possible that the higher rates of ICH after streptokinase therapy than after t-PA therapy in acute ischemic stroke patients may reflect a dose of streptokinase that is too high for this indication (as opposed to its safer profile in the treatment of patients with acute MI354). Additional possible reasons for such observations include a more pronounced and longerlasting systemic fibrinolytic effect with streptokinase than with t-PA.355 The use of intra-arterial recombinant prourokinase (proUK) was tested in the PROlyse in Acute Cerebral Thromboembolism (PROACT) I356 and II trials.357 When given directly into a middle cerebral artery clot, proUK was associated with a recanalization rate of 66% (compared with 18% for the control group) in the PROACT II study.357 This rate correlated with a significantly better functional outcome at 3 months for the treated group, without differences in mortality, even though the rate of symptomatic ICH was 10% in treated patients and only 2% in the control subjects. Virtually all proUK-related

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1

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6

7

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14

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Figure 28-26.  CT scans of hemorrhages from the National Institutes of Neurological Diseases and Stroke (NINDS) trial of tissue-type plasminogen activator (t-PA). Cases 3 through 22 are from the t-PA-treated group; cases 1 and 2 are from the control group. Reprinted with permission from The NINDS t-PA Stroke Study Group, Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke, Stroke, 28, 11, November, pp. 2109–18, 1997.)

ICHs were massive (Fig. 28-27), and all occurred in the area of the qualifying acute infarct in the middle cerebral artery distribution.358 Among a number of possible risk factors for post-proUK symptomatic ICH, only hyperglycemia at baseline was identified as being potentially associated with a higher risk.358 Concerns regarding whether individuals with CMBs are at higher risk of ICH following thrombolysis have been raised, particularly following reports of post-thrombolysis ICH occurring at sites of previous CMBs remote from areas of acute infarction.359 Although a number of nonrandomized observational studies have yet to produce a significant association between CMBs and post-thrombolysis ICH, they were all limited by small sample size, and pooled data from two recent systematic reviews suggest possibly higher rates of postthrombolysis ICH in individuals with CMBs,360,361 and particularly in those with high CMB burden.360 The pooled data were,

however, largely unadjusted, stressing the need for larger welldesigned trials. Additionally, whether CMBs in purely lobar regions, suggestive of CAA, confer additional risk for postthrombolysis ICH remains to be determined.

BRAIN IMAGING The imaging aspects of ICH are discussed in Chapters 45, 46, and 47. This section only briefly highlights developments in this area. The view that CT is superior to MRI for the diagnosis of acute ICH has been challenged by new observations. With the use of susceptibility-weighted (also known as gradient-echo) MRI sequences, Linfante et al.362 were able to document acute ICHs within periods as short as 30 minutes after symptom onset. Their observations, along with those of others,363,364 suggest that in the early phase of ICH, MRI protocols that



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28

Figure 28-27.  CT scans of hemorrhages from the PROlyse in Acute Cerebral Thromboembolism (PROACT) II trial. Cases 1 through 12 are from the recombinant pro-urokinase (r-proUK) group, and cases A and B are from the control group. (Reprinted with permission from Kase CS, et al. Symptomatic intracerebral hemorrhage after intra-arterial thrombolysis with prourokinase in acute ischemic stroke: The PROACT II trial, Neurology, 57, 9, November, p 1603–10, 2001.)

include susceptibility-weighted sequences are as reliable as CT for diagnosis.

Cerebral Microbleeds An additional value of these MRI sequences is their ability to document areas of CMBs, detected as areas of low signal of up to 10 mm in diameter (Fig. 28-28), that correspond to deposits of hemosiderin as a sequelae from past episodes of minor bleeding.274,365–369 CMBs are visualized on MRI in 5% of neurologically healthy individuals, and their prevalence increases with age and history of cerebrovascular disease, reaching 60% in individuals with ICH.370 Their presence is considered to reflect an underlying bleeding-prone microangiopathy, most commonly in the form of hypertensive vasculopathy or CAA, with CMBs located in the deep gray/white matter and brainstem favoring hypertension as their mechanism while those located in superficial lobar regions favor CAA.371–374 The importance of these lesions stems from their potential role in instances of major hemorrhage in subjects receiving anticoagulants or after treatment with thrombolysis. The potential association between CMBs and ICH after use of anticoagulants or thrombolytics, as outlined above, is still controversial.

Although the known correlation between CMBs, especially those located in lobar regions, and subsequently increased risk of spontaneous ICH375–377 raises a potential concern about the use of oral anticoagulants in patients with a heavy burden of CMBs, the currently available data suggest that a balance between this risk, on the one hand, and the expected benefits in the prevention of ischemic stroke, on the other, should drive this clinical decision in individual patients.378 The data on antiplatelet agents use derived from a population-based study in Rotterdam, The Netherlands, indicate that CMBs may be more prevalent in subjects receiving aspirin and clopidogrel monotherapy than in those not receiving these agents.379,380 Data from observational studies199,381,382 further suggest a relationship between antiplatelet treatment, CMBs, and risk of ICH, but additional prospectively collected data are required before these observations can be applied to clinical decisions in individual patients. Moreover, although once assumed to be asymptomatic, several case reports have suggested that strategically placed CMBs may result in focal neurological deficits in themselves,94,383,384 and there is a growing evidence implying that their overall burden may contribute to vascular cognitive impairment,385–390 as well as gait,391,392 and mood

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Figure 28-28.  MRI, gradient-echo sequence, showing multiple microbleeds as small black round foci corresponding to hemosiderin deposits. The microbleeds predominate in the cortical and subcortical areas in this patient suggestive of underlying cerebral amyloid angiopathy.

disturbances.393,394 CMBs were also found to be predictive of overall, cardiovascular-related, and stroke-related mortality in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study.395 In view of their consistent association with vascular risk factors, in particular hypertension,396 future studies aimed at reducing the evolving burden of CMBs by way of risk factor modification may prove beneficial in reducing the overall burden of microvascular neuronal injury and functional deficit in individuals with cerebral small-vessel disease, in addition to the risk of future ICH.

DIFFUSION-WEIGHTED IMAGING HYPERINTENSITIES Recently, with the increasing use of MRI in the assessment of ICH, diffusion-weighted imaging hyperintense lesions (DWIHL) have been recognized to occur concurrently with acute ICH at remote sites in 15% to 41% of individuals.83,397–403 In the absence of direct radiographic-pathologic concordance studies, these lesions are presumed to be ischemic in nature. DWIHLs are typically small (< 15 mm) and occur either ipsilateral or contralateral to the presenting ICH in corticalsubcortical and deep regions. They have been observed to occur more frequently in individuals with higher CMB burden,83,398,399,402 white matter changes,398,399 larger hematoma volumes,402 intraventricular extension of hematoma,402 prior history of stroke,397,402 rapid therapeutic reductions in mean arterial pressure,397,401,402 and in individuals who had undergone surgical evacuation of ICH.397 DWIHLs are likely an inherent manifestation of the underlying cerebral small-vessel disease as they have been observed to continue to occur at a lower rate outside of the acute postICH period.400,402 In view of their association with degree of blood pressure lowering, the triggering event for the higher rates observed in the acute post-ICH period has been hypothesized to be related to hypoperfusion from aggressive blood pressure management that is aggravated by impaired cerebral autoregulation.402 However, this association may be attributed to residual confounding from increased admission blood pressures observed within these individuals – possibly as a manifestation of the degree of underlying hypertensive

vasculopathy in a proportion of cases – rather than a treatment effect.403 In line with this view are results reported by the ICH ADAPT investigators, which did not show a clinically relevant reduction in cerebral blood flow or blood volume in individuals with acute ICH who had rapid reduction of systolic blood pressure to <150 mmHg in comparison to <180 mm Hg.404 An alternate plausible explanation is that the rapid release of cytokines resulting from acute ICH create a prothrombotic/ inflammatory central nervous system milieu that promotes microthrombosis in vulnerable cerebral vessels afflicted by small-vessel disease. Associations between DWIHLs and larger hematoma volume, intraventricular extension, and surgical evacuation, all of which could exacerbate the inflammatory response, support this notion. Indeed, serum C-reactive protein has been reported to markedly increase over the first 48–72 hours following ICH and is proportional to ICH volume.405 Moreover, although DWIHLs are largely considered to be ischemic, a recent report suggests that at least subsets of these lesions in the acute post-ICH period are acute/subacute CMBs captured in evolution.406 If confirmed in large prospective studies, the concurrent development of both small ischemic and hemorrhagic lesions at sites distant from the primary ICH would favor inflammatory cascades inciting both microthrombosis and increased vascular permeability at sites of diseased small vessels over hemodynamic fluctuations as the causative trigger.

HYPERACUTE INJURY MARKER (HARM) Further evidence of global alterations in blood–brain barrier permeability following ICH comes from the novel observation from one retrospective cohort analysis of 46 cases of ICH who had undergone post-gadolinium MRI within 5 days of symptom onset. It was noted that in 85% of cases, some degree of sulcal enhancement was present on post-gadolinium FLAIR sequences at sites that were noncontiguous with the hematoma, a finding termed Hyperacute Injury Marker (HARM).407 Although confirmation of these findings and further research into the clinical relevance of HARM following ICH is required in additional cohorts, HARM may ultimately prove useful in participant selection



for targeted therapeutic trials aimed at reducing the secondary injury of ICH.179

PERIHEMATOMAL EDEMA Perihematomal edema can be visualized on both CT and MRI. It is believed to occur initially from clot-retraction followed by neurotoxicity and blood–brain barrier dysfunction, predominantly as a result of cascades triggered by erythrocyte degradation products. Recent longitudinal studies have shown that, although maximal within the first 48 hours, perihematomal edema formation continues until approximately 1–2 weeks post-ICH.408–410 The perihematomal region is characterized on MRI by delayed perfusion and increased diffusivity (vasogenic edema), with admixed areas of reduced diffusion suggestive of cytotoxic edema.411 However, artifacts from magnetization gradients induced by the paramagnetic properties of erythrocyte degradation products need to be considered when interpreting MRI signal characteristics in the perihematomal border, and conclusions regarding the underlying physiologies at play must be derived cautiously. If the reduced diffusion is indeed representative of cytotoxic edema, however, data suggest that the mechanism may be inflammatory/ mechanical cellular injury rather than ischemia.404 The most consistent predictor of larger absolute perihematoma edema volume is larger hematoma volume.409,410 A predictor of late perihematomal edema growth is high admission serum hematocrit, implying that a higher dose of erythrocytes and their ensuing degradation products may have a role in prolonging edema formation.410 Erythrocyte heme iron content is believed to play a key role in triggering cellular cascades that promote such edema formation, and serves as one of many targets in current trials aimed at minimizing the secondary injury that ensues from ICH.179

GENERAL CLINICAL AND   LABORATORY FEATURES The different forms of ICH share a number of clinical features that result from the progressive accumulation of a mass of blood in the parenchyma. These features include mode of onset as well as clinical manifestations reflecting increased intracranial pressure. ICH occurs characteristically during activity,71,138 and its onset during sleep is extremely rare.412 It occurred in only one instance in the series reported by Fisher,412 and in only 3% of ICH cases included in the NINDS Data Bank.4 The type of onset, studied in 70 cases of ICH prospectively included in the Harvard Cooperative Stroke Registry, was found to be one of gradual and smooth progression in twothirds of the cases; the deficit was maximal at onset in the remainder.2 No cases showed a regressive course in the early phase, which supports the clinical dictum that a definite improvement in the early hours of a stroke syndrome rules out ICH.413 Along with a gradual onset over periods of 5 to 30 minutes, patients with ICH frequently show some decrease in alertness at the time of admission. The frequency and severity of this sign vary to some extent according to the location of the hemorrhage, but when all forms are considered, a decrease in alertness is present in at least 60% of cases;2,188 in two-thirds of them, the decrease is to a level of coma.2,101 Coma has been correlated with ventricular extension of the hemorrhage,133,365 large hematoma,135 and poor vital prognosis.133,188,414,415 The clinical features of ICH associated with increased intracranial pressure are headache and vomiting. Although these features also vary widely in frequency with the location of hemorrhage, their overall diagnostic value at the onset of ICH is limited.2 Of 54 patients alert enough to report the symptom, only 36% reported headache in the study by Mohr

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et al.2; in Aring’s416 series, the frequency of headache was 23%. The reporting of vomiting at onset follows similar frequencies: 44%2 and 22%416 in two series. These findings stress the important clinical point that absence of a headache or vomiting does not rule out ICH. On the other hand, when present, these signs suggest ICH (or SAH) as the most likely diagnosis because they are present in less than 10% of ischemic strokes.2 Seizures at the onset of ICH are uncommon. They have been reported at rates as low as 7%,2 11%,14 and 14%416,417 when all forms of ICH are considered together. In some groups, such as in patients with lobar hemorrhages, seizures have been reported with a frequency as high as 32%.132 Previous ICH, cortical involvement, younger age and worse neurological deficit are factors that have been reported as independent predictors of seizures at onset.417 In the general physical examination, a common abnormality is hypertension, found in as many as 91% of the cases in some series.2 The high frequency of elevated blood pressure on admission in all forms of ICH correlates with other physical signs indicative of hypertension, such as left ventricular hypertrophy418 and hypertensive retinopathy.412 The examination of the ocular fundi in a case of suspected ICH serves the dual purpose of detecting signs of hypertensive retinopathy and allowing careful search for subhyaloid hemorrhages. The latter represent blood collections in the preretinal space, and their presence is virtually diagnostic of SAH406 because they rarely occur in primary ICH.190,259,413 Although an occasional case of massive primary ICH does show this sign,419 its presence has a high correlation with ruptured aneurysm as the cause of the intracranial hemorrhage. The neurologic findings permit the differentiation of the different topographic varieties of ICH (see later). Communication of the hematoma with the ventricular space accounts for the presence of bloody or xanthochromic CSF in 70% to 90% of cases.2,14,133,259,412,416,420 A somewhat lower frequency of bloody CSF (63%) has been reported in hematomas of lobar location,190 probably reflecting the less frequent communication with the ventricular system132 due to the subcortical location of the hematoma. The small percentages of cases with clear CSF in all series of ICH reflect hematomas of small size that do not reach the ventricular system even though located close to it. Furthermore, on account of the small size of such hematomas, the clinical presentation may not clearly indicate ICH; signs of increased intracranial pressure may be lacking in such cases, so differentiating them from ischemic strokes is difficult. It is in this particular group of strokes that CT scan has had its most dramatic impact. In addition to simple inspection of the CSF for bloody or xanthochromic aspect, spectrophotometric CSF analysis can disclose blood products in virtually 100% of cases.421 However, this technique is not routinely used because the two widely available anatomic means of diagnosis (CT and MRI) have made CSF examination unnecessary in establishing the presence of an ICH. Moreover, the uncommon but well-recognized precipitation of uncal or tonsillar herniation by lumbar puncture in supratentorial ICH134,413,422 has contributed to the abandonment of this test for the diagnosis of ICH. The use of angiography in the evaluation of cases of ICH has similarly declined since the introduction of CT and MRI. Angiography most commonly shows the nonspecific signs of mass effect at the site of the hematoma423 and occasionally has detected extravasation of contrast medium.424,425 The study by Mizukami et al.426 correlated the angiographic pattern of displacement of the lenticulostriate arteries with functional prognosis in putaminal hemorrhage. Because of the obvious advantages of CT and MRI in disclosing most of the anatomic features of ICH, angiography is now used only in selected instances. Its main role at present is in the evaluation of

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nonhypertensive forms of ICH, multiple ICHs, and ICHs located in atypical sites, to look for AVM, aneurysm, or tumor as the possible cause of the hemorrhage. Even this role for angiography is steadily diminishing with improvements in noninvasive brain imaging.

SUPRATENTORIAL INTRACEREBRAL HEMORRHAGE Most cases of ICH occur in the supratentorial compartment, usually involving the deep structures of the cerebral hemispheres, the basal ganglia, and the thalamus.2,14,34,128,132,133 In addition, a substantial number of hemispheral ICHs occur in the subcortical white matter of the cerebral lobes, the so-called lobar hemorrhages.132,190 These various forms of ICH have distinctive features in terms of clinical presentation, CT aspects, course, and therapy.

Putaminal Hemorrhage The several clinical subtypes of putaminal hemorrhage, which is the most common form of ICH, are determined by the size and pattern of extension of the hematoma. Each of these variables in turn determines the prognosis. Overall, a mortality of 37% is expected,188 which is a value that is far lower than those quoted in the pre-CT literature,427 which did not include the undiagnosed smaller cases. The classic presentation of massive putaminal hemorrhage (Fig. 28-29) is with rapidly evolving unilateral weakness accompanied by sensory, visual, and behavioral abnormalities. Headache is common, as is vomiting, within a few hours

Figure 28-29.  Massive right putaminal hemorrhage with ventricular extension. Incidental finding of a small hemorrhage on the posterior corner of the contralateral (left) putamen.

of onset.2 Although the onset is abrupt, there is often a gradual worsening of both the focal deficit and the level of consciousness in the following minutes or hours.412,413 A “maximal from the onset” deficit is uncommon. Whether with sudden or gradual onset, medium-sized or large hematomas are invariably accompanied by a decreased level of alertness correlated with hematoma size. Once the syndrome is well developed, neurologic examination shows a dense flaccid hemiplegia with a hemisensory syndrome and homonymous hemianopia, with global aphasia if the hematoma is in the dominant hemisphere and hemi-inattention if it is in the nondominant hemisphere.412,413 A horizontal gaze palsy, with the eyes conjugately deviated toward the side of the lesion, is usually found, which can be reversed momentarily by doll’s head maneuver or ice-water caloric testing.415 The pupillary size and reactivity are normal unless uncal herniation has occurred; if it has, signs of an ipsilateral third cranial nerve palsy are present.412 These abnormalities in oculomotor function have a poor prognosis.188 Total unilateral motor deficit, coma, and clinical progression after admission all correlate with large hematoma size and poor functional and vital prognosis, as does ventricular extension of the hematoma by CT scan.188 The presence of two hypertensive putaminal hemorrhages, one recent and one old, has been described in pathologic material.32,51,71,135 The occurrence of simultaneous fresh bilateral putaminal hemorrhages (Fig. 28-30), although occasionally reported,428 is distinctly uncommon: it was observed in only two of 86 cases in Fisher’s series128 and in none of 42 hypertensive ICH cases from the series reported by McCormick

Figure 28-30.  CT scan of bilateral, symmetric putaminal hemorrhages in a hypertensive subject. (Reprinted with permission from Silliman S, et al. Simultaneous bilateral hypertensive putaminal hemorrhages, J Stroke Cerebrovasc Dis, 12, 1, January, p 44–6, 2003.)



and Schochet.51 Multiple ICHs are rare unless due to bleeding diathesis associated with thrombocytopenia,128,429 metastatic tumor,245 or CAA.430

Syndromes Due to Small Hemorrhages The availability of CT and MRI allows the diagnosis of a number of variations in the presentation of small putaminal ICHs, which in the pre-CT era would have been clinically diagnosed as small infarcts. They are as follows: Pure motor stroke.  Instances of pure motor stroke due to small putaminal–capsular hemorrhages have been rarely documented.431,432 The clinical presentation in such cases has consisted of a mild and transient pure motor syndrome affecting the face and limbs, and the small hematomas originated from the posterior angle of the putamen, with impingement of the posterior limb of the internal capsule. At times, a small capsular hemorrhage has manifested as pure motor stroke and dysarthria,433 although the clinical syndrome has been more properly that of a “pure sensory-motor” stroke, related to a component of lateral thalamic compression accompanying the capsular lesion. Pure sensory stroke.  The syndrome of pure sensory stroke, related to thalamic lacunar infarction, has rarely been due to a small putaminal ICH. Three such cases were reported among a group of 152 patients with putaminal ICH.434 All three patients had posteriorly located putaminal hemorrhages that were adjacent to the posterior limb of the internal capsule and the adjacent thalamus. The clinical syndrome was a contralateral hemisensory syndrome involving both superficial and deep sensory modalities, with more severe involvement of the leg than the arm and face. The imaging studies demonstrated involvement of the dorsolateral thalamus or the ascending thalamocortical projections located in the posterior (“retrolenticular”) portion of the posterior limb of the internal capsule. Hemichorea–hemiballism.  A unilateral dyskinetic syndrome, hemichorea–hemiballism is most commonly due to lacunar infarction in the basal ganglia, thalamus, or subthalamic nucleus but can rarely result from a small putaminal hemorrhage.435,436 In both series reporting such cases, a right, laterally placed putaminal hemorrhage manifested as contra­ lateral chorea and ballism in the absence of hemiparesis, hemisensory loss, gaze paresis, and hemineglect. The prognosis was excellent in both cases.

Clinical Syndromes in Relationship to the Location of Putaminal Hemorrhage In a study of 100 patients with putaminal hemorrhage, Weisberg et al.437 established the following clinicoanatomic correlations: 1. Medial hemorrhages extended medially from the putamen and involved the genu and posterior limb of the internal capsule. This finding correlated with a contralateral hemisensory syndrome, but there were no abnormalities of ocular motility, visual fields, or level of consciousness. Affected patients generally had full clinical recovery. 2. Lateral hemorrhages originated from the lateral putamen and extended anteriorly along the external capsule. They produced a contralateral hemiplegia and sensory deficits. More than half the patients showed delayed neurologic deterioration, and persistent deficits were more common than full recovery. 3. Putaminal hemorrhages with extension to the internal capsule and subcortical white matter extended medially through the internal capsule and superiorly into the corona radiata,

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causing a more severe syndrome of hemiplegia and hemianesthesia, often but not always with homonymous hemianopia and conjugate ocular deviation. Most patients were left with persistent neurologic sequelae. 4. Putaminal hemorrhages with subcortical and hemispheric extension were large hematomas that extended into the white matter of adjacent cerebral lobes, causing mass effect on the lateral ventricle and frequently extending into the ventricular system. They were clinically similar to those of the preceding group, except for having more prominent aphasia or parietal lobe findings and causing impaired consciousness. The mortality rate in this group was 16%, and the majority of the survivors had deficits that interfered with independent living. 5. Putaminal–thalamic hematomas, the largest group, extended from the putamen into the thalamus (through the internal capsule) and into the subcortical white matter. They all were accompanied by intraventricular hemorrhage. The clinical picture included impaired consciousness in all patients, frequently associated with hemiplegia, abnormalities of horizontal more than vertical gaze, and homonymous hemianopia. The mortality rate in this group was 79%. These clinical–CT correlations allowed Weisberg et al.437 to characterize a number of clinically useful patterns as follows: (1) intraventricular hemorrhage was seen with large hematomas, and both features were associated with high mortality rates; (2) all patients had combined motor and sensory deficits; (3) the best functional outcome was seen in patients with medial or lateral putaminal hematomas that did not involve the internal capsule or the corona radiata; and (4) delayed neurologic deterioration occurred only in patients with hematomas that extended into the cerebral hemisphere or the thalamus. Chung et al.433 analyzed the clinicoanatomic correlations in 192 patients with putaminal hemorrhage. They divided their cases into five anatomic types – middle, posteromedial, posterolateral, lateral, and massive – and related the outcomes to the presumed ruptured arterial branches leading to hematoma formation. The middle type (Fig. 28-31) was caused by rupture of medial lenticulostriate arteries, with bleeding into the medial putamen and globus pallidus; the result was a benign syndrome of mild contralateral hemiparesis and hemisensory loss, with a low frequency of impairment of consciousness and with transient conjugate ocular deviation toward the side of the hematoma. Intraventricular extension of the hemorrhage did not occur, and all patients survived. This group of lesions was equivalent to the medial putaminal hemorrhages described by Weisberg et al.437 The posteromedial type (Fig. 28-32) corresponded to small hematomas confined to the posterior limb of the internal capsule (“capsular” hemorrhages) and were associated with contralateral hemiparesis, hemisensory loss, and dysarthria. The small hematomas, which did not reach the ventricular system, were associated with excellent functional outcome and no mortality. The bleeding vessel in this type of hemorrhage is a branch of the anterior choroidal artery, which supplies a portion of the posterior limb of the internal capsule.438 The posterolateral type (Fig. 28-33) was a putaminocapsular hemorrhage caused by rupture of posterior branches of the lateral lenticulostriate arteries. These larger hematomas occasionally ruptured into the lateral ventricle and produced a more severe syndrome consisting of impaired consciousness, frequent conjugate ocular deviation toward the affected hemisphere, and constant and generally severe contralateral hemiparesis and hemisensory loss, along with aphasia or hemineglect, depending on hematoma location in the dominant or nondominant hemisphere, respectively.

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Figure 28-31.  CT scan of the medial variety of striatocapsular (putaminal) hemorrhage with minimal mass effect on the frontal horn of the lateral ventricle. (Reprinted with permission from Chung C, et al, Striatocapsular haemorrhage. Brain, 123, Pt 9, p 1850–62, 2000.)

Figure 28-32.  CT scan of posteromedial (“capsular”) form of putaminal hemorrhage. This small hemorrhage is limited to the posterior limb of the internal capsule.

Figure 28-33.  CT scan of posterolateral putaminal hemorrhage. Moderate-sized hematoma originating in the posterior putamen, with compression and medial displacement of the posterior limb of the internal capsule but without ventricular extension.

The lateral type of hematoma (Fig. 28-34) originated from rupture of the most lateral branches of the lenticulostriate arteries. It remained confined to an elliptical hematoma collected between the putamen and the insular cortex, producing contralateral hemiparesis, often without an associated hemisensory loss but frequently with either aphasia or hemi­ neglect, depending on the side of the brain involved. The outcome was generally excellent, except in cases of large hematomas, which frequently ruptured into the ventricular system and often required surgical treatment, which in turn was generally associated with a good outcome. This lateral type of putaminal ICH in the dominant hemisphere is occasionally the cause of the syndrome of conduction aphasia.439 The massive type (Fig. 28-35) involved the entire striatocapsular area and probably resulted from rupture of the same branches (posteromedial branches of the lateral lenticulostriate arteries) that cause the posterolateral type of putaminal ICH. Affected patients had a depressed level of consciousness and hemiparesis, frequently associated with ipsilateral conjugate eye deviation, and often progressed to coma with brainstem involvement and death despite treatment with surgical drainage of the hematoma. This group corresponds to the “putaminal–thalamic” group described by Weisberg et al.437 In a separate study, Weisberg et al.440 analyzed 14 cases of massive putaminal–thalamic hemorrhage. All of their patients were young black people with hypertension who were seen with headache several hours before the onset of the focal deficit, and all became hemiplegic and comatose over periods of 4 to 12 hours. The hematomas were large, with marked mass effect and intraventricular extension. All patients died within 72 hours of onset of symptoms despite treatment of hypertension and increased intracranial pressure.



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Caudate Hemorrhage

Figure 28-34.  CT scan of lateral variety of putaminal hemorrhage. The lens-shaped hematoma has collected between the insula and the putamen without ventricular extension.

Figure 28-35.  CT scan of massive type of putaminal hemorrhage, showing marked mass effect with midline shift and effacement of the lateral ventricle as well as intraventricular extension.

Caudate hemorrhage represents approximately 5% to 7% of cases of ICH (see Table 28-3).134 Most of the published series on caudate ICH have identified hypertension as the leading cause.187,441,442 However, other causes not generally associated with deep spontaneous ICH are frequently identified, including cerebral aneurysms,443 arteriovenous malformations,444,445 and the basal vascular abnormalities associated with moyamoya disease.441,446 The last mechanism is thought to lead to ICH through rupture of the anastomotic channels that develop in the area of the basal ganglia, including the head of the caudate, as a result of the progressive occlusion of trunks of the circle of Willis.447 The bleeding vessels correspond to deep penetrating branches of the anterior and middle cerebral arteries, which are vessels similar in diameter to those that supply the putamen and thalamus.448 Because of its paraventricular location, the caudate also receives blood supply from ependymal arteries that flow outward from the ventricular surface into the parenchyma. These arteries originate beneath the ependymal surface as terminal branches of the anterior choroidal artery, posterior choroidal artery, and striatal rami of the middle cerebral artery.449 A number of reported cases of spontaneous hemorrhage in the caudate nucleus have delineated a relatively consistent clinical picture.187,441–443,450,451 The onset has generally been abrupt, with headache and vomiting commonly followed by variably decreased level of consciousness, resembling the onset of SAH from aneurysmal rupture. Seizures at onset have been reported rarely444 and were not encountered in the series of 12 patients reported by Stein et al.187 Consistent physical findings have included neck stiffness and various types of behavioral abnormalities, of which the latter are most commonly abulia, impairment of memory (both short-term and long-term), and abnormalities of speech, especially verbal fluency.187,441 These deficits are thought to occur as a result of interruption of cortical–subcortical tracts between the caudate nucleus and the frontal cortex.441 The neuropsychological abnormalities of caudate hemorrhage have been described in detail by Fuh and Wang441 and by Kumral et al.442 A common pattern is that of presentation with abulia, confusion, and disorientation at onset, followed by the development of a prominent amnestic syndrome, at times accompanied by language disturbances. The latter have most often included a nonfluent aphasia,442 and occasional examples of transcortical motor aphasia have also been recorded.438 Hematomas in the nondominant hemisphere generally do not produce unilateral disturbances of attention,187,438 although one patient reported by Kumral et al.442 developed visuospatial neglect. In approximately 50% of cases, the common clinical features are accompanied by others, which most often take the form of transient gaze paresis and contralateral hemiparesis and, rarely, features of an ipsilateral Horner’s syndrome.187 The abnormalities described in gaze mechanisms have most often been horizontal gaze palsies with conjugate deviation or preference toward the side of the hemorrhage, with full correction by oculocephalic maneuvers. Less commonly, vertical gaze palsy has been described, either combined with a horizontal gaze palsy or, more commonly, as an isolated phenomenon. Occasionally, the motor deficit is accompanied by a transient hemisensory syndrome. In those cases in which hemiparesis is a feature, the weakness tends to be slight (never to the point of hemiplegia) and transient, resolving within days of the onset.187,450 The generally small size and the localized character of caudate hemorrhage are the reasons why focal neurologic deficits such as transient hemiparesis are relatively uncommon

28

496

SECTION III  Clinical Manifestations

A

B

Figure 28-36.  A, Hemorrhage originating in the head of the right caudate nucleus with extension into the anterior limb of the internal capsule and into the lateral ventricle and third ventricle. B, Extensive amount of intraventricular blood in the body of the lateral ventricles, primarily on the right side, associated with moderate hydrocephalus.

(in 30% of the 23 cases studied by Chung et al.433). The virtually consistent extension into the ventricular system accounts for the high frequency of headache and meningeal signs, which resemble those seen in SAH. Rare instances of bilateral caudate ICH452 or hemorrhage associated with intraventricular extension with acute hydrocephalus187 can have a more dramatic presentation, with coma and ophthalmoplegia; the latter is presumably due to oculomotor nuclei involvement as a result of aqueductal dilatation.453 In typical cases, a CT scan shows a hematoma located in the area of the head of the caudate nucleus (Fig. 28-36). Ventricular extension into the frontal horn of the ipsilateral ventricle is an invariable feature.187 In approximately 75% of cases, mild-to-moderate hydrocephalus of the body and temporal horns of the lateral ventricles has been present. Hemorrhages that are medium-sized or large are frequently accompanied by transient gaze palsies and hemiparesis, and those accompanied by an ipsilateral Horner’s syndrome extend more inferiorly and laterally. Occasionally, the hematomas extend from the region of the head of the caudate nucleus into the anterior portions of the thalamus (Fig. 28-37). In those instances, the clinical syndrome has featured a prominent but transient short-term memory defect.134 Before the introduction of CT, these cases of caudate ICH with consistent extension into the ventricular system may have been diagnosed as “subarachnoid hemorrhage with negative arteriography” or even as “primary intraventricular hemorrhage.”449 The latter is probably a rare condition,34 in most instances reflecting a lack of documentation of the parenchymal or meningeal (in cases of ruptured aneurysm) site of origin of the hemorrhage rather than a hemorrhage truly confined to the ventricular space. Caudate hemorrhage can be separated from putaminal and thalamic hemorrhage clinically and radiographically. Headache, nausea, vomiting, and stiff neck regularly accompany caudate hemorrhage,187 but are less common manifestations in putaminal hemorrhage.188 Disorders of language are regular features of putaminal and thalamic hemorrhage in the dominant hemisphere,136,188,454 whereas hemorrhages that remain confined to the caudate nucleus are only rarely associated with aphasia.442 Furthermore, caudate hemorrhages in the

Figure 28-37.  Hemorrhage originating from the head of the left caudate nucleus with extension into the anterior-dorsal aspect of the thalamus (arrow), lateral ventricle, and third ventricle.

nondominant hemisphere do not cause hemi-inattention and anosognosia, the behavioral abnormalities associated with thalamic455–457 and putaminal188 hemorrhages in that hemisphere. Caudate hemorrhage must be distinguished from anterior communicating artery aneurysms that bleed into the brain



parenchyma. In primary caudate hemorrhage, there is no accumulation of blood in the interhemispheric fissure, and most of the blood is located in the lateral ventricle adjacent to the involved caudate nucleus. In addition, extension of the hemorrhage into the basal frontal region, a feature invariably seen when hemorrhage into the parenchyma results from ruptured anterior communicating aneurysm, is rarely present in caudate ICH.187 The outcome in caudate hemorrhage is usually benign, and most patients recover fully, without permanent neurologic deficits.187 The accompanying hydrocephalus characteristically tends to disappear as the hemorrhage resolves, and ventriculoperitoneal shunting for persistent hydrocephalus is rarely required.187 This generally benign outcome in caudate ICH occurs despite the virtually consistent ventricular extension of the hemorrhage.

Thalamic Hemorrhage The thalamic form of ICH accounts for 10% to 15% of parenchymatous hemorrhages.2,4,128,132,133,135,136 Its clinical and pathologic characteristics are well-recognized, and the spectrum of clinical variations reflects the size and pattern of extension of the hematoma. The mass originates in the thalamus and, if it enlarges, extends laterally (into the internal capsule), medially (into the third ventricle), inferiorly (into the subthalamus and dorsal midbrain), upward, and into the parietal white matter.413,456,458 The main cause of thalamic hemorrhage is hypertension, which accounts for 74% to 83% of cases.458–460 Other reported mechanisms are the use of anticoagulant and thrombolytic agents,461 use of cocaine,458 rupture of posterior cerebral artery aneurysm,462 and cavernous malformations.463 The hemorrhages due to these mechanisms are not clinically different from those caused by hypertension, except for (1) the tendency toward recurrent bleeding in those due to cavernous angioma463 and (2) the potential for multiple ICHs after use of cocaine238 and after thrombolysis.461 The clinical picture has several distinctive features. They are listed in Table 28-4 which summarizes data from a total of 41 patients in two series.136,464 A typical mode of presentation features a rapid onset of unilateral sensorimotor deficit, frequent occurrence of vomiting (about half the cases) but a low frequency of headache (less than one third of cases). In some, the onset was signaled by coma.136 A slowly progressive initial course with headache preceding the focal deficits is distinctly uncommon,413 and only four of 13 patients in the series reported by Walshe et al.136 experienced symptoms for 1 to 2 hours before hemiparesis occurred. In a few cases, unilateral sensory symptoms (numbness) precede the onset of hemiparesis and stupor.136,465 The physical findings include hemiparesis or hemiplegia in 95% of cases,136,454,455,464 virtually all of which have an associated severe hemisensory syndrome (see Table 28-4). This syndrome usually appears as a decrease or loss of all sensory modalities over the contralateral limbs, face, and trunk.460 The severity and distribution of the motor and sensory symptoms are similar to those of putaminal hemorrhage and therefore are not useful differentiating points. Homonymous hemianopia is an uncommon finding and tends to be transient,134,412 probably reflecting the location of the lateral geniculate body below and lateral to the hematoma. This sign would be expected in large hemorrhages with extrathalamic extension, but these lesions also affect consciousness severely, generally precluding detection of the visual field defect. The clinical presentation of thalamic hemorrhage has distinctive oculomotor findings. The most characteristic combination is one of upward gaze palsy with miotic, unreactive

Intracerebral Hemorrhage

497

TABLE 28-4  Clinical Features of Thalamic Hemorrhage Walshe et al.136 (n = 18) HISTORY Age (years) (mean) Headache Vomiting PHYSICAL FINDINGS Level of consciousness Alert Drowsy Stuporous Comatose Hemiplegia-hemiparesis Hemisensory deficit Homonymous hemianopia Aphasia Mutism Anosognosia Upward gaze palsy Horizontal ocular deviation Toward side of lesion Opposite side of lesion Pupillary abnormalities Miosis Absence of light reflex Mortality

Barraquer-Bordas et al.464 (n = 23)

64 22% 77%

68 30% 48%

6% 33% 33% 28% 100% 100% –

21% 40% 18% 21% 100% 100% 18%

4/7* 1 2/3* 94%

4 1 2 35%

6 3

3 6

100% 62% 50%

70% 13% 39%

*Number of patients with deficit/number of patients tested.

pupils134,136,412,465 and elements of Parinaud’s syndrome caused when the enlarging mass presses on the upper midbrain. The upward gaze palsy determines the ocular position at rest of conjugate downward deviation, sometimes associated with convergence, as if the eyes were peering at the tip of the nose.134 In addition, nystagmus retractorius on attempted upward gaze and skew deviation are commonly present.134,412 Other, less common oculomotor abnormalities reported in thalamic hemorrhage are downward gaze palsy;134,412 anisocoria with ipsilateral miosis, sometimes associated with palpebral ptosis;412 transient opsoclonus;466 and ipsilateral136,464 or contralateral464,467 horizontal ocular deviation. The classic combination of upward gaze palsy with miotic unreactive pupils has high diagnostic value, and it is due to compressive or destructive effects of the thalamic hematoma on the underlying midbrain tectum.134,412,419,464 The precise anatomic structures involved in these oculomotor abnormalities have been delineated by experimental studies in monkeys468,469 and a number of observations in humans.470,471 The experimental observations of Pasik et al.469 established that involvement of the posterior commissure and the “nucleus interstitialis of the posterior commissure” were consistently associated with upward gaze palsy. Areas that were not essential for the development of the gaze palsy included the superior colliculi, the nucleus of Darkschewitsch and the interstitial nucleus of Cajal, and the medial thalamus. Christoff et al.,470,472 from their observations in human clinicopathologic material, concluded that most lesions producing upward gaze palsy required bilateral or midline involvement of the midbrain tectum, particularly when loss of pupillary light reflex was also present.470 Denny-Brown and Fischer,468 however, performed unilateral midbrain tegmental lesions in monkeys, which resulted in upward gaze palsy, skew deviation (with the ipsilateral eye in a higher position than the contralateral eye), and head tilt. In addition, after performing unilateral stereotactic lesions of the dorsolateral midbrain tegmentum in humans for the treatment of pain syndromes, Nashold and Seaber471

28

498

SECTION III  Clinical Manifestations

recorded symmetrical upward gaze palsy in 13 of 16 subjects. In ten subjects, downward gaze was also impaired but never without upward gaze palsy. Of their 16 patients, 15 had miotic nonreactive pupils, 11 had convergence paralysis, and ten showed skew deviation; the ipsilateral eye was in a lower position in two-thirds. In summary, virtually all the oculomotor findings observed in thalamic hemorrhage have been described after unilateral tegmental midbrain lesions in humans. This fact supports the view that the oculomotor findings in this condition are due to compression or extension of the hemorrhage into the midbrain tegmentum. However, other observations suggest that CSF hypertension and hydrocephalus associated with the hemorrhage may play an additional role in the production of the oculomotor findings because ventricular shunting has been shown to reverse these manifestations.465,473,474 In conclusion, a compressive effect on the tegmental–tectal portion of the midbrain, either directly from unilateral compression by the hematoma or indirectly through hydrocephalus, results in the classic oculomotor and pupillary abnormalities of thalamic hemorrhage.

Contralateral Conjugate Eye Deviation Some patients with thalamic hemorrhage may show horizontal eye deviation, with or without the characteristic downward deviation at rest. This horizontal eye deviation is more commonly ipsilateral (toward the side of the lesion),136 as is routinely observed in putaminal hemorrhage, but a contralateral conjugate deviation (toward the side of the hemiplegia) is occasionally observed.136,464 This eye deviation occurs in the direction opposite that is expected in a supratentorial lesion and is thus labeled the “wrong-way eye deviation.”475 Although this peculiar sign has been recorded in instances of unilateral subarachnoid–Sylvian hemorrhage with frontal and insular extension476 and in frontoparietal subcortical hematoma,477 most reported cases have occurred in association with thalamic hemorrhage. The mechanism of the sign is obscure. Postdecussation involvement of horizontal oculomotor pathways by compression by the hematoma at the midbrain level has been suggested, and support exists from autopsy data.477

Aphasia in Dominant Hemisphere Thalamic Hemorrhage Occasionally, left thalamic hemorrhages have been associated with a peculiar form of language disturbance.136,412,464 The relatively low frequency reported for this disturbance is probably because its detection is restricted to cases of small dominant hemisphere hemorrhages, as large ones are likely to be accompanied by stupor or coma.474 A detailed analysis of three cases by Mohr et al.454 stressed the main feature of this syndrome: fluctuating performance in language function from almost normal to a profusely paraphasic, fluent speech akin to a delirium. The almost “uncontrollable” character of the para­ phasias, in conjunction with intact repetition, led these investigators to postulate the removal by the thalamic lesion of a controlling influence of that structure over the intact cerebral surface speech areas. Similar clinical observations were reported by Reynolds et al.,474 who commented on the frequency of aphasic abnormalities after left stereotactic thalamotomy and suggested that language disorders occurring after acute thalamic lesions may, to some extent, be mediated by disturbances in attention and recent memory. A study by Alexander and LoVerme478 involved nine cases of aphasia in left thalamic hematomas, in which the speech profile was a fluent, relatively well-articulated speech with poor naming, relatively good repetition, and prominent paraphasias. These researchers commented on the lack of distinctive features in aphasias from putaminal and thalamic

hemorrhages. They also suggested a prominent role for memory and attention deficits in the production of the language disturbances.

Neglect in Thalamic Hemorrhage of the Nondominant Lobe Syndromes of hemineglect are classically associated with lesions of the nondominant parietal lobe. Other areas, such as the frontal lobe, can rarely give rise to a similar set of symptoms.479 Among ICHs, those in the putamen can be associated with this syndrome.188 The occurrence of the syndrome in thalamic hemorrhage is rare. Reports by Walshe et al.136 and Barraquer-Bordas et al.464 each described two patients with anosognosia from right thalamic hemorrhages. Watson and Heilman455 reported hemineglect in three patients with right thalamic hemorrhages. These patients exhibited prominent anosognosia and hemispatial agnosia, and two of them (cases 1 and 2) showed limb akinesia, manifested as lack of spontaneous movements of the left limbs despite only mild weakness. The patients in this study, particularly the two with limb akinesia, had relatively small thalamic hemorrhages that disrupted sensation only partially in case 1 and affected motor function partially, to a level of weakness only, in cases 1 and 2. In the third patient, a larger hemorrhage was associated with arm paralysis, marked leg weakness, absence of sensation, bilateral Babinski signs, and drowsiness, whereas patients 1 and 2 were alert and cooperative. These three cases illustrated a neglect syndrome similar to that observed in nondominant cortical surface disease, from documented medium-sized and small right thalamic hematomas.

Clinical Syndromes Related to the Topography of Thalamic Hemorrhage Both Kumral et al.459 and Chung et al.458 delineated the clinical syndromes related to specific areas of involvement of the thalamus by hemorrhage. These two groups divided the thalamic hematomas into anterior, posteromedial, posterolateral, dorsal, and global, and related each location to the presumed arterial rupture within the thalamus.458 The clinical features of hemorrhages in these various locations were as follows: Anterior.  Hematomas located in the most anterior portion of the thalamus, in the territory of the polar or tuberothalamic artery (Fig. 28-38), are often associated with ventricular extension and are clinically characterized by memory impairment and apathy, preservation of alertness, rare and transient sensory motor deficits, and absence of ophthalmologic findings. Posteromedial.  Posteromedial hemorrhages occur from rupture of thalamoperforating arteries. Hematomas are located in the medial aspect of the thalamus, with frequent rupture into the third ventricle and hydrocephalus, along with extension into the midbrain (Fig. 28-39). Small, localized hematomas result in memory disturbances and behavioral abnormalities, whereas larger lesions with downward extension into the midbrain are associated with early stupor or coma along with severe motor deficits and oculomotor disturbances. Posterolateral.  Posterolateral hemorrhages are due to rupture of thalamogeniculate arteries (Fig. 28-40). They are generally large and commonly extend into the internal capsule and ventricular space. Clinical features are severe sensory motor deficits as well as aphasia or hemineglect. Large hematomas also cause ipsilateral Horner’s syndrome, a depressed level of consciousness, and ophthalmologic abnormalities.459 Approximately one-third of patients with posterolateral



Intracerebral Hemorrhage

499

28

Figure 28-38.  CT scan of anterior type of thalamic hemorrhage. Small hematoma confined to the most anterior aspect of the thalamus, with ventricular extension (blood in the atrium of the ipsilateral lateral ventricle).

Figure 28-40.  T2-weighted MR image of posterolateral form of thalamic hemorrhage, in which hematoma abuts the atrium of the lateral ventricle without ventricular extension.

thalamic hemorrhage reported by Chung et al.458 showed delayed onset of a “thalamic pain syndrome.” The aphasia of dominant posterolateral thalamic hematomas has been most often described as “transcortical motor” type,459,480 although in hematomas of the pulvinar nucleus, the aphasia can be so markedly paraphasic that it becomes jargon.454 The syndromes of hemi-inattention in nondominant thalamic hemorrhage have included marked anosognosia,480 in one instance with prominent associated mania,481 and examples of motor neglect or “inertia” manifested as lack of use of limbs with normal strength.482 Dorsal.  Rupture of branches of the posterior choroidal artery causes hematomas located high in the thalamus, with frequent extension into the parietal white matter and the ventricular space (Fig. 28-41). They are characterized clinically by mild and transient sensory motor deficits, generally without oculomotor disturbances, with rare confusion and memory abnormalities in hemorrhages located most posteriorly (in the area of the pulvinar nucleus). Global.  The global type corresponds to involvement of the whole thalamus by a large hematoma that commonly enters the ventricular system (with associated hydrocephalus) and extends into the suprathalamic hemispheric white matter (Fig. 28-42). The clinical features are stupor or coma, severe sensory motor deficits, and paralysis of upward more than downward gaze, skew deviation, and small and unreactive pupils.

Unusual Sensory Syndromes Figure 28-39.  CT scan of posteromedial type of thalamic hemorrhage, with small hematoma along the medial aspect of the thalamus that does not extend into the third ventricle.

Unusual sensory syndromes are infrequently encountered in thalamic hemorrhage. The best recognized is the thalamic pain syndrome described by Dejerine and Roussy,483 which is usually regarded as a feature of thalamic infarction in the distribution

500

SECTION III  Clinical Manifestations

of the perforating branches of the posterior cerebral artery.484,485 The profoundly distressing dysesthesias and spontaneous pain characteristically arise days to weeks after onset. The occurrence of this syndrome after thalamic hemorrhage is variable: Alexander and LoVerme478 commented on the presence of a central pain syndrome in six of their nine patients with

Figure 28-41.  CT scan of dorsal thalamic hemorrhage, located in the medial portion of the upper thalamus, without ventricular extension.

thalamic hemorrhages; Chung et al.458 reported it in one-third of their patients with the posterolateral form of thalamic hemorrhage. The relative rarity of this syndrome in the setting of hemorrhage has suggested that partial thalamic lesions of a precise lateral-posterior location are necessary to produce it.485 This sensory syndrome is an uncommon feature of the usually more massive thalamic destruction due to hematoma. A second unusual sensory syndrome is a form of pure sensory stroke, classically associated with small (lacunar) thalamic infarcts.486 Small thalamic hemorrhages have occasionally presented as pure sensory stroke.487–489 Thalamic hematomas of dorsal location have caused a pure hemisensory syndrome, with loss of sensation to pinprick predominating over that of vibration and joint position sense; motor strength was preserved, but coordination in the affected arm was abnormal with the eyes closed, reflecting the “sensory” rather than cerebellar character of the ataxia.487 Paciaroni and Bogousslavsky488 reported two patients with involvement of all sensory modalities affecting the face, arm, and leg contralaterally to a small hemorrhage in the center of the thalamus that involved all the ventral nuclei and the parvocellular and dorsocaudal nuclei but sparing the pulvinar. Shintani et al.489 reported two patients with sensory loss in the arm and leg more than the face, with contralateral lesions in either the ventral-posterior-lateral (VPL) nucleus or the ventral-posteriormedial (VPM) nucleus; another patient with restricted “cheirooral” (affecting the hand and the corner of the mouth) dysesthesias with a “burning” quality in the absence of sensory loss to superficial or deep modalities had a small hematoma in the border between the VPL and VPM. The syndrome of sensory ataxic hemiparesis has also been reported in the setting of small thalamic hemorrhages.490 The clinical presentation differed from that of lacunar ataxic hemiparesis,491 in that the ataxia of the patients with hemorrhages corresponded to proprioceptive sensory loss, as opposed to the cerebellar character of the ataxia in lacunar ataxic hemiparesis. The hematomas were small (mean volume, 7.2 mL), were located in the dorsolateral thalamus, and were associated with marked impairment of proprioception but preservation of superficial sensory modalities; the associated hemiparesis was transient and predominated in the leg. The CT aspects of thalamic hemorrhage are shown in Table 28-5. Of interest are the high frequency of ventricular extension (reflecting the location of the hematoma adjacent to the third ventricle) and the resulting high rate (about 25%)363 of hydrocephalus. The mortality rate reported after thalamic hemorrhage has ranged from 25% to 52%,458–460 and it is closely correlated to the volume of the hematoma, level of consciousness at presentation, and presence of intraventricular hemorrhage and hydrocephalus.459,460,492 When comparing patients with or without intraventricular hemorrhage who were otherwise comparable in regard to clinical features with prognostic significance, Steinke et al.460 found a significantly higher mortality rate for those with

TABLE 28-5  CT Aspects of Thalamic Hemorrhage

Figure 28-42.  CT scan of large, global type of thalamic hemorrhage, with mass effect on the third ventricle and extension into the third and lateral ventricles.

Side of hematoma   Right/left Size of hematoma   <3.3 cm   >3.3 cm Ventricular extension Hydrocephalus

Walshe et al.136 (n = 18)

Barraquer-Bordas et al.464 (n = 23)

8/10

17/6

11 7 66% 27%

– – 50% 21%



Intracerebral Hemorrhage

intraventricular extension. The finding suggests that this factor is an independent predictor of mortality. In addition, the different locations of hemorrhage within the thalamus have been associated with outcome: anterior and dorsal hematomas had a benign course, whereas posterolateral, posteromedial, and global hemorrhages were associated with higher mortality rates and higher levels of disability.458 The functional motor outcome in survivors after thalamic hemorrhage is compromised by extension of the hematoma into the internal capsule, midbrain, or putamen. Cognitive impairment as a sequela correlates with initial disturbance of consciousness and ventricular extension of the hematoma.492 Performance in activities of daily living is influenced by advanced age and hematoma size492 as well as by the presence of unilateral spatial neglect, aphasia, and severity of paresis of the lower limb.493

White Matter (Lobar) Hemorrhage The main clinical features of lobar hemorrhage were delineated in the early 1980s,132,190 and still there are no reliable criteria for a choice of therapy.175,494

Anatomy Lobar hemorrhages occur in the subcortical white matter of the cerebral lobes, usually extending longitudinally in a plane parallel to the overlying cortex. As they become larger, their shape changes into the more common oval or round one. They occur in all cerebral lobes but have a predilection for the parietal, temporal, and occipital lobes (Table 28-6).132,190 This predilection for the posterior half of the brain in lobar ICH is unexplained and is probably not a reflection of differences in relative lobe size because the ratio of 3 : 1 between parietotemporooccipital and frontal hematomas132 is larger than the anatomic volumetric ratio between these two areas, which is 2 : 1 or 3 : 2. A possible explanation for this finding is the predilection of intracerebral microaneurysms for the parietooccipital area found by Cole and Yates.150 These investigators found that the junction of cortical gray matter and white matter contained about 30% of the microaneurysms, and the diagrams included in their article show a higher concentration of these lesions on the parietooccipital areas and proportionately smaller numbers of them in the frontal and temporal poles. Although the causal relationship between microaneurysms and ICH has not been established, these anatomic correlations in lobar ICH lend some support to it. Alternatively this posterior predominance can be attributed to underlying CAA as, for yet to be determined reasons, there also exists a posterior predilection for pathological and neuroimaging changes related to this microangiopathy.495

TABLE 28-6  Location of Lobar ICH Location

No.

Frontal Parietal Temporoparietal Parietooccipital Parietotemporooccipital Parietofrontal Occipital Total

4 3 8 2 1 2 2 22

18 (82%)

From Kase CS, Williams JP, Wyatt DA, et al: Lobar intracerebral hematoma: Clinical and CT analysis of 22 cases. Neurology 32:1146, 1982. ICH, Intracerebral hemorrhage.

501

Etiology The etiologic factors in lobar ICH may be somewhat different from those in other forms of ICH, particularly with regard to a less significant role of hypertension.32,35,132,190,252 Ropper and Davis190 reported chronic hypertension in only 31% of their cases of lobar ICH, and in the series reported by Kase et al.,132 only 50% of the patients had elevated blood pressure on admission; in half of this group high blood pressure had been documented before the hemorrhage. In Weisberg’s252 study, only 33% of the patients with lobar ICH had hypertension compared with 81% of the patients with deep (ganglionic–thalamic) ICHs. However, data reported by Broderick et al.74 suggest that hypertension contributes to lobar hemorrhage as much as it does to deep hemispheric, cerebellar, or pontine hemorrhages. These authors found hypertension to be the likely explanation of ICH in 67% of their patients with lobar ICHs and in 73% with deep hemispheric, 73% with cerebellar, and 78% with pontine hemorrhages. This predominance of the hypertensive mechanism in lobar ICH remained unchanged with advancing age, which argues against the notion that nonhypertensive mechanisms such as CAA may be the predominant cause of lobar ICH in elderly patients. Etiologic factors other than hypertension that are relevant in lobar ICH include (1) AVMs, which occur at rates between 7% and 14%, (2) tumors, which occur in 7% to 9%, and (3) blood dyscrasias or anticoagulation, in 5% to 20% of the hemorrhages.313 There is a large group of patients (22% in one series132) in whom the mechanism for ICH remains unknown. This fact raises the possibility that some etiologic factors may exist for white matter (lobar) ICH that are more common than in other forms of ICH. One such factor is CAA, which is being increasingly recognized as the substrate of recurrent, sometimes multiple ICHs in elderly nonhypertensive patients. In this CAA-related category of lobar hemorrhage, O’Donnell et al.127 found that the presence of ε2 or ε4 alleles of the ApoE gene was associated with a high risk of recurrent ICH (28% at 2 years compared with 10% in patients with lobar ICH who did not have the ε2/ε4 alleles). An additional factor that is highly correlated with the risk of lobar ICH recurrence is the presence and number of microhemorrhages detected at the time of presentation with the initial lobar ICH.375

Clinical Features The clinical manifestations of lobar ICH have been extensively analyzed, and a number of differences from other types of ICH have been noted.73,132,190,496 The circumstances at onset are listed in Table 28-7, which compares series of lobar ICH with those including all forms of ICH.2,73,132,190,496–498 The distinguishing features of lobar ICH are lower frequency of hypertension and coma on admission and higher frequency of headache and seizures. The higher frequency of headache at onset may reflect the larger number of patients with lobar ICH who are awake and can give a history. Ropper and Davis190 described the headaches as located in and around the ipsilateral eye in occipital hematomas, around the ear in temporal hemorrhages, anteriorly in frontal hemorrhage, and anterior temporal (temple) in parietal lobe hematomas. The low incidence of coma on admission in lobar ICH is probably related to the peripheral location of the hematoma, at a distance from midline structures.190 Seizure as a common event at the onset of lobar ICH has been well-documented.73,132,496,499–503 The mechanism of seizures in lobar hematomas may reflect the location of the hemorrhage in the gray matter–white matter interface, which creates a situation similar to the surgical isolation of cortex by

28

502

SECTION III  Clinical Manifestations

TABLE 28-7  Comparison of Clinical Features of Lobar ICH with all Forms of ICH All Forms of ICH (%)* Feature Hypertension   History   On admission Headache Vomiting Seizures Coma

HCSR2 72 91 33 51 6 24

Lausanne3

Lobar ICH (%)* Kase et al132

Ropper and Davis190

22 66 61 33 33 18

31 46 46 61 0 0.4

55† 40 ? 7 22

Weisberg496

SDB73

30 56 72 32 28 ?

55 ? 60 29 16 19

From Kase CS: Lobar hemorrhage. In Kase CS, Caplan LR, editors: Intracerebral hemorrhage. Boston, 1994, Butterworth-Heinemann, p 363. *Percentages rounded to the closest whole number (decimals from the original omitted). † Not specified whether hypertension was diagnosed by history or at entry examination. HCSR, Harvard Cooperative Stroke Registry; ICH, intracerebral hemorrhage; SDB, Stroke Data Bank; ?, information not provided.

subcortical injury that results in sustained paroxysmal activity from the isolated cortex.504 The neurologic deficits seen with lobar ICH depend on the location and size of the hematoma.190 They include (1) sudden hemiparesis, worse in the arm, with retained ability to walk, in frontal hematoma, (2) combined sensory and motor deficits, the former predominating, and visual field defects in parietal hemorrhage, (3) fluent paraphasic speech with poor comprehension and relative sparing of repetition in left temporal lobe hematomas, and (4) homonymous hemianopia, occasionally accompanied by mild sensory changes (extinction to double simultaneous stimulation), in occipital lobe hemorrhages. In the group of 24 patients described by Kase et al.,132 hemiparesis and visual field defects were the most common abnormality, found in 60% and 30% of patients who were not comatose on admission, respectively. Those patients in whom the two signs coexisted had larger and more anteriorly placed hematomas, whereas those with hemianopia and no hemiparesis had posterior hemorrhages. From these data, the clinical presentation in a lobar parietooccipital hematoma emerges as sudden onset of headache, sometimes associated with vomiting, not uncommonly associated with seizure activity, with state of consciousness in the alert or obtunded level, associated with mild contralateral hemiparesis and visual field defect. Specific deficits in speech or spatial function are seen when the hematomas are of dominant frontotemporal or nondominant parietal location, respectively, mimicking the deficits seen with infarction.505,506

Cerebral Amyloid Angiopathy and Lobar Hemorrhage The best recognized clinical manifestation of CAA is spontaneous ICH. The hemorrhages largely follow the distribution of the vascular amyloid, appearing with highest frequency in the corticosubcortical or lobar regions and less commonly in cerebellum, generally sparing the brainstem and deep hemispheric structures.62,67 Lobar ICH in CAA is more likely to dissect into the subarachnoid space than into the lateral ventricles.62,507,508 Despite extensive involvement of the leptomeningeal vessels, symptomatic subarachnoid hemorrhage due to CAA is rare.507,509 Conversely, MRI studies have shown a high prevalence of hemosiderin staining within the sulci of individuals with CAA ranging from 40% to 60%, suggestive of previous small occult subarachnoid hemorrhage.510,511 Subdural hematomas (SDH) have been recently reported to occur in 20% of primary lobar ICH and be predictive of mortality. The vast majority of SDHs are contiguous with the underlying presenting ICH. Accordingly, this occurrence has been hypothesized to result from rupture of an amyloid-laden

leptomeningeal artery adjacent to the dura with bleeding into both the underlying parenchyma and overlying subdural space.512 CAA-related lobar ICH presents much like other types of lobar ICH,498 with early onset of neurologic symptoms and a variable combination of headache, seizures, and decreased consciousness according to hemorrhage size and location. Hemorrhagic lesions in CAA can also be small and clinically silent.81 These small corticosubcortical “microbleeds” are wellvisualized by gradient-echo or T2*-weighted MRI techniques, which enhance the signal dropout associated with deposited hemosiderin.513 By detecting even old hemorrhagic lesions, gradient-echo MRI provides a clinical method for demonstrating an individual’s lifetime history of hemorrhage and thus for identifying the pattern of multiple lobar lesions characteristic of CAA (Fig. 28-43). CAA-related microbleeds, like symptomatic “macrobleeds,” occur typically in corticosubcortical locations54 or at the superficial cortical surface.71 The Boston criteria for CAA codify the typical features of CAA-related ICH into the diagnostic categories “definite,” “probable,” and “possible” disease, as listed in Table 28-8.70,514 Although diagnosis of definite CAA requires demonstration of advanced disease through postmortem examination, a clinical diagnosis of probable CAA can be reached during life through radiographic demonstration of at least two strictly lobar or corticosubcortical hemorrhagic lesions (either large symptomatic macrobleeds or smaller microbleeds) without other definite hemorrhagic process. In a small clinical-pathologic validation study, 13 of 13 subjects given a clinical diagnosis of probable CAA also had pathologic evidence of CAA,514 which suggests that the criteria may be sufficiently specific to be useful in practice. In the same study, gradient-echo MRI detected the diagnostic pattern in eight of 11 patients (73%) with pathologically documented CAA, providing an estimate for the sensitivity of the diagnosis. The Boston criteria propose a separate category of probable CAA with supporting pathology for patients with lobar ICH and an antemortem brain sample containing evidence of CAA (see Table 28-8). A validation study for this diagnosis suggested that CAA of at least moderate severity in a random tissue sample was a reasonably specific marker for severe CAA in the brain as a whole.61 For reasons that are poorly understood, CAA pathology72,73 and CAA-related hemorrhagic lesions localize preferentially to posterior (parietooccipital or temporooccipital) cortical brain regions. In a study of 321 macrobleeds and microbleeds detected by gradient-echo MRI among 59 subjects with probable CAA, 26.5% of the lesions were in occipital cortex and 30.5% were in temporal cortex, which was significantly greater than the proportions (18.3% and 22.3%, respectively)



Intracerebral Hemorrhage

503

28

B

A

Figure 28-43.  Recurrent intracerebral hemorrhage (ICH). A, The CT scan shows a left temporal ICH in an 80-year-old man with a history of previous cognitive decline. B, A gradient-echo MRI sequence obtained 2 years later demonstrates recurrent ICH in the left parietal lobe as well as multiple punctate hypointense lesions (arrowheads) consistent with chronic asymptomatic hemorrhages. The presence of two or more strictly lobar hemorrhagic lesions is consistent with a diagnosis of probable cerebral amyloid angiopathy (see Table 28-8).

TABLE 28-8  Boston Criteria for Diagnosis of CAA–Related ICH Definite CAA

Full postmortem examination of brain shows lobar ICH, severe CAA (Vonsattel et al.),88 and no other diagnostic lesion

Probable CAA with supporting pathology

Clinical data and pathologic tissue (evacuated hematoma or cortical biopsy specimen) showing some lobar CAA in pathologic specimen, and no other diagnostic lesion

Probable CAA

Clinical data and MRI or CT demonstration of two or more hemorrhagic lesions restricted to lobar regions (cerebellar hemorrhage allowed), patient age ≥55 years, and no other cause of hemorrhage*

Possible CAA

Clinical data and MRI or CT demonstration of single lobar ICH, patient age ≥55 years, and no other cause of hemorrhage*

CAA, Cerebral amyloid angiopathy; CNS, central nervous system; CT, computed tomography; ICH, intracerebral hemorrhage; INR, international normalized ratio; MRI, magnetic resonance imaging. *Other causes of ICH defined as excessive anticoagulation (INR > 3.0), antecedent head trauma or ischemic stroke, CNS tumor, vascular malformation or vasculitis, blood dyscrasia or coagulopathy. INR > 3.0 or other nonspecific laboratory abnormalities permitted for diagnosis of possible CAA.

predicted by the volumes of these cortical regions.54 The posterior predilection of CAA has been further corroborated by the distribution of the amyloid-ligand Pittsburgh Compound B detected by positron emission tomographic imaging in subjects with probable CAA but without dementia.36,74

Prognosis for Lobar Hemorrhage The prognosis in lobar hematomas is usually less grave than in other forms of ICH. The mortality rates reported have been between 11.5% and 29%,132,190,253,515 all of which are lower than the rates for the other varieties of ICH. A low frequency (6%) has been reported in an autopsy series,135 whereas in clinical series, the frequency is between 10% and 32%.132,190,253 In addition, the functional outcome for survivors is generally

better than in those with deep hemispheric ICHs; a good outcome was reported in 57% to 85% of patients.515–517

Computed Tomography Aspects After the early phase of the ICH, lobar hematomas can adopt a number of residual patterns, as analyzed by Sung and Chu.518 Frequently (27% of the time), the ICH leaves no CT- demonstrated residual, although a slit and a round cavity (34%) are the most common CT sequelae; rarely (3%), only calcification at the ICH site remains. Ropper and Davis190 provided two-dimensional measurements of 26 hematomas and commented on the tendency of these lesions to enlarge mostly in the transverse and anteroposterior planes of the CT section. In Weisberg’s252 series of 45 patients with lobar ICH, ten were found to have intraventricular extension, a factor that did not affect the mortality rates in this group. The CT features of the 22 cases reported by Kase et al.132 are shown in Table 28-9. The hematomas could be divided by volume into three main groups, which in turn correlated with the presence and severity of mass effect. Ventricular extension was a factor that correlated with location (proximity to ventricular system) rather than size of the hematoma. The outcome was in part a function of hematoma size; no patient with a hematoma larger than 60 mL survived, whereas all those with small hematomas (<20 mL) did. In the group with moderatesized hematomas, 75% survived, and the functional level was, in general, poorer than in the group with small hematomas. In a subsequent analysis of Mayo Clinic data, Flemming et al.519 reported observations on 81 patients with lobar ICH. Volume larger than 40 mL on CT was associated with poor outcome; in patients with hemorrhage smaller than 40 mL, interval from symptom onset to hospital presentation of less than 17 hours and a Glasgow Coma Scale (GCS) score of 13 or less were predictive of a poor outcome. These data stress the importance of hematoma enlargement as a factor in the deterioration of patients who are seen early after the onset of lobar ICH. These figures, in addition, give some indication of the possible role of surgical drainage as a therapeutic option in lobar ICH. The Surgical Trial in Intracerebral Hemorrhage (STICH)

504

SECTION III  Clinical Manifestations

TABLE 28-9  Computed Tomography Features and Outcome of Lobar Intracerebral Hematomas Hematoma Size

No. of Cases

Midline Shift

5 7

1 6

0 1

Massive (>40 mL)

10

10

7

Total

22

17

8

Small (<20 mL) Moderate (20–40 mL)

Ventricular Extension

Outcome/Operated 5 6 1 4 6

improved/0 improved/3 died/0 improved/2 died/1

From Kase CS, Williams JP, Wyatt DA, et al: Lobar intracerebral hematomas: Clinical and CT analysis of 22 cases. Neurology 32:1146, 1982.

compared surgical and nonsurgical treatment of patients with both deep and lobar ICH in a randomized multicenter international study and detected no difference among groups.520 However, in a prespecified subgroup analysis a favorable trend towards surgical management was noted in cases of lobar ICH located at 1 cm or less from the cortical surface. Based on this observation, the subsequent STICH II trial examined the benefit of conservative management versus surgical therapy within 48 hours of ictus in patients with lobar ICH located at 1 cm or less from the cortical surface with a volume of between 10 mL and 100 mL, and without intraventricular extension.521 Again, there were no significant differences found between early surgical and initial conservative medical management. However, 21% of participants randomly assigned to the conservative management group underwent surgery following randomization according to the clinical judgment of treating physicians. Despite this methodological limitation, post hoc analyses observed that patients deemed to have baseline characteristics that put them in a poor prognostic category (calculated by an algorithm derived from patient age, Glasgow Coma Scale, and ICH volume at randomization) were more likely to have favorable outcome with early surgery (OR, 0.49, 95%CI, 0.26 to 0.92; P = 0.02), implying a target population that may possibly benefit from early surgical treatment. Moreover, almost all patients in STICH II underwent conventional craniotomy, and currently on-going trials are assessing the benefit of promising minimally invasive procedures for hematoma evacuation in patients with ICH522 which, if successful, may provide additional reasons for considering special subsets of patients with ICH for early evacuation of the hematoma.

HEMORRHAGE AFFECTING THE   BRAINSTEM AND CEREBELLUM Cerebellar Hemorrhage In a landmark article in 1959, Fisher et al.138 described the main clinical features of cerebellar hemorrhage. Especially important diagnostic features were the inability to walk, gaze palsy without hemiplegia, and the absence of unilateral limb paresis. These investigators found that surgical decompression could be lifesaving, occasionally even in patients in deep coma before surgery. More important, patients who had been treated surgically were often able to return to active lives without the overwhelming disability often retained by survivors of basal ganglionic hemorrhages. Although these diagnostic formulations were initially subject to dispute, CT scanning and MRI have made the detection of smaller cerebellar hematomas possible,523,524 essentially confirming the initial observations of Fisher et al.138 Cerebellar hemorrhage appears at a rate variously quoted as between 5% and 15%.128,137,525–528 The average rate is about 10%, which is also approximately the percentage of brain weight accounted for by the cerebellum. Although 10% is a relatively low frequency, the importance of establishing the

Figure 28-44.  CT scan of right cerebellar hemorrhage originating in the area of the dentate nucleus, with extension into the adjacent fourth ventricle.

diagnosis resides in the good prognosis after prompt surgical treatment.128,259,529 Cerebellar hemorrhage usually occurs in one of the hemispheres, generally originating in the region of the dentate nucleus, from distal branches of the superior cerebellar artery138 or occasionally the posterior–inferior cerebellar artery.226 In the study by Fisher et al.,138 the left hemisphere was affected twice as often as the right. McKissock et al.530 also commented on a left hemisphere preponderance in cerebellar hemorrhage. Most other series do not report hemorrhage laterality. The hematoma collects around the dentate and spreads into the hemispheral white matter, commonly extending into the cavity of the fourth ventricle as well (Fig. 28-44). The adjacent brainstem (pontine tegmentum) is rarely involved directly by the hematoma but is often compressed by it, which, at times, leads to pontine necrosis. The midline variant of cerebellar hemorrhage originates from the vermis and represents only about 5% of the cases.138 It virtually always communicates directly with the fourth ventricle through its roof and frequently extends into the pontine tegmentum bilaterally (Fig. 28-45). The bleeding vessel in this variety corresponds to



Intracerebral Hemorrhage

505

TABLE 28-10  Neurologic Findings in Cerebellar Hemorrhage for Noncomatose Patients Neurologic Finding Appendicular ataxia Truncal ataxia Gait ataxia Dysarthria Gaze palsy Cranial nerve findings   Peripheral facial palsy   Nystagmus   Miosis   Decreased corneal reflex   Abducens palsy   Loss of gag reflex   Skew deviation   Trochlear palsy Hemiparesis Extensor plantar response Respiratory irregularity Nuchal rigidity Subhyaloid hemorrhage

28

No.

%

17/26 11/17 11/14 20/32 20/37

65 65 78 62 54

22/36 18/35 11/37 10/33 10/36 6/30 4/33 0/36 4/35 23/36 6/28 14/35 0/34

61 51 30 30 28 20 12 – 11 64 21 40 –

From Ott KH, Kase CS, Ojemann RJ, et al: Cerebellar hemorrhage: Diagnosis and treatment. Arch Neurol 31:160, 1974.

Figure 28-45.  Vermian cerebellar hemorrhage with pressure on the pontine tegmentum.

distal branches of the superior or the posterior–inferior cerebellar artery. These two forms of cerebellar hemorrhage have distinctive clinical and prognostic features. Distribution of etiologic factors in cerebellar hemorrhage is similar to that in other forms of ICH, and hypertension is the leading cause.138,259 AVMs are said to be common in the cerebellum:527,430 they accounted for five out of 15 cerebellar hematomas in the autopsy series reported by McCormick and Rosenfield;35 in other series,259 lower rates of AVMs (4%), similar to those for ICH at other sites, have been reported.190 Anticoagulation is an important etiologic factor in cerebellar hemorrhage and was the second most common cause reported by Ott et al.259 Among 24 ICHs in patients undergoing oral anticoagulation therapy,257 nine occurred in the cerebellum. Three of these were of the less common vermian or midline variety. Fisher et al.138 commented on a relative female preponderance in their series (13 : 8); in other series, the femaleto-male ratio was reported as 26 : 30,530 6 : 6,137 5 : 14,531 and 17 : 17.530 Symptoms usually develop while the patient is active. Occasionally a single prodromal episode of dizziness or facial numbness may precede the hemorrhage. The most common symptom is an inability to stand or walk, which in many patients has been dramatic in onset. One man leaned against a fence while painting and could not right himself; another bumped downstairs on his bottom to call for help. Crawling or propelling oneself prone on the floor to get to the bathroom to vomit has been mentioned. Rare patients maintain their ability to walk a few steps, but scarcely any patient with a sizable hemorrhage (>2 cm) walks into the emergency room or physician’s office. Vomiting is also very common, being present in 42 of 44 patients,259 12 of 12 patients,529 and 14 of 18 patients138 in various series. Vomiting usually occurs soon after the onset in cerebellar and subarachnoid hemorrhage but often develops later, after other symptoms, in putaminal hemorrhage. Dizziness is also common, occurring in 24 of 44 patients,259 eight of 21 patients,138 and four of 12 patients529 in various series. More often the feeling is one of insecurity, a “drunken feeling,” or wavering rather than true rotational vertigo.

Headache is also very common, occurring in 32 of 44 patients,259 ten of 21 patients,138 and 12 of 12 patients137 in various series. Most often the pain is occipital, but occasionally it can occur on the side of the head or frontally. At times the headache is abrupt and excruciating, closely mimicking SAH. In other patients the pain is located primarily in the neck or shoulder. Dysarthria, tinnitus, and hiccups occur but are less common. Loss of consciousness at onset is unusual,259,532 and only one-third of patients are obtunded by the time they reach the hospital.259 Most patients show gradual worsening over 1 to 3 hours, as in other forms of ICH.2 The classic physical findings are a combination of a unilateral cerebellar deficit with variable signs of ipsilateral tegmental pontine involvement. These are detailed in Table 28-10, from an analysis of 38 noncomatose patients in the series reported by Ott et al.259 Appendicular and gait ataxia occurred in 65% and 78%, respectively, of patients who were alert enough to cooperate for cerebellar function testing. Other patients lean to the side when placed upright. On the side of the hemorrhage, there usually is overshoot or inability to brake the limb quickly; this sign is more common than fingerto-nose or finger-to-object ataxia. Signs of involvement of the ipsilateral pontine tegmentum include peripheral facial palsy, ipsilateral horizontal gaze palsy, sixth cranial nerve palsy, depressed corneal reflex, and miosis. In some patients the hemorrhage presses laterally in the area of the cerebellopontine angle, producing peripheral facial palsy, deafness, and diminished corneal response. From analysis of the relative frequency of signs in noncomatose patients reported by Ott et al.,259 a characteristic triad consisting of appendicular ataxia, ipsilateral gaze palsy, and peripheral facial palsy was suggested; at least two of the three signs were present in 73% of the patients tested for all three. Ocular skew deviation is also common.525 Additional findings useful in differential diagnosis are hemiplegia and subhyaloid hemorrhages, both of which are uncommon enough in cerebellar hemorrhage that their presence essentially rules out the diagnosis.259 The frequency of unilateral limb weakness in cerebellar hemorrhage has been a matter of controversy. In the study by Fisher et al.,138 hemiplegia was observed only in the setting of a prior stroke, and similar findings were recorded by Ott et al.259 In two autopsy series,

SECTION III  Clinical Manifestations

however, hemiplegia was reported in 50% and 20% of the cases,527,529 and Richardson528 noted contralateral hemiplegia in more than 50% of cases in his clinical series. Although in some instances reports of ipsilateral hemiplegia may have corresponded to decreased mobility of grossly ataxic limbs or decreased spontaneous movement, a contralateral hemiplegia cannot be explained on those bases, so one must assume involvement of the corticospinal tract in the ipsilateral basis pontis. Other neurologic findings add little specific diagnostic data: the pupils are commonly small and reactive to light, dysarthria is present in two-thirds of cases, and the respiratory rhythm is usually unaffected.259 Unilateral involuntary eye closure has been occasionally observed,475,533 the involved eye usually being contralateral to the hematoma. This sign has been interpreted as eye closure for avoidance of diplopia, but this interpretation is probably not always correct because the sign occurs in the absence of diplopia, in both infratentorial and supratentorial strokes.475 Other less common oculomotor abnormalities, such as ocular bobbing, have occasionally been reported in cerebellar hemorrhage259,534,535 but with a lower frequency than in pontine hemorrhage and infarction. Some patients have a head tilt. Neck stiffness and unwillingness to move the head or neck either actively or passively probably signify increased pressure in the posterior fossa. Along with these focal neurologic manifestations, patients with cerebellar hemorrhage may be seen with variable levels of decreased alertness. Of the 56 cases reported by Ott et al.,259 14 (25%) were alert, 22 (40%) were drowsy, five (9%) were stuporous, and 15 (26%) were comatose. That two-thirds of the patients are responsive (alert or drowsy) on admission justifies the intensive efforts to diagnose this condition early because the surgical prognosis largely depends on the preoperative level of consciousness. The clinical course in cerebellar hemorrhage is notoriously unpredictable: some patients who are alert or drowsy on admission can deteriorate suddenly to coma and death without warning,138,259,536 whereas others with similar clinical status have an uneventful course with complete recovery of function. Of those patients who were not comatose on admission, only 20% had a smooth, uneventful recovery in the series reported by Ott et al.;259 80% deteriorated to coma, and in one-fourth of these patients, this occurred within 3 hours of onset (Fig. 28-46). A similar frequency was observed in the study by Fisher et al.,138 in which only two of 18 patients had a benign course; the other 16 deteriorated to coma at variable intervals, mostly within a few hours after onset. Most patients deteriorate early in the course, but occasional patients have shown fatal decompensation at a later stage, even a month later, after being stable in the interim.537 Because prediction of the clinical course cannot be made on the basis of clinical variables on admission, Ott et al.259 recommended that surgical evacuation of the hematoma should be undertaken whenever the diagnosis is made within 48 hours of onset.259 They justified the need for prompt diagnosis and emergency surgery by pointing to poor surgical outcome with worsening preoperative mental status: the surgical mortality was 17% for responsive and 75% for unresponsive patients.259 These figures have proved generally accurate, despite occasional reports of good surgical results in comatose patients.538 The use of CT and MRI in cerebellar hemorrhage has permitted the recognition of many different aspects of these lesions, some of which are useful early predictors of clinical course.523,524,539 Little et al.523 reported two groups of patients with cerebellar hemorrhage: one group had abrupt onset, a more severely depressed level of consciousness, and a tendency toward progressive deterioration, and the other had a

40 Patients remaining responsive

506

30

20

10

0 0

1

2

3

4

5

6

7

8

9 10 11 12 13 14

Days after onset Figure 28-46.  Coma in patients with cerebellar hemorrhage as a function of time after onset. (Reprinted with permission from Ott KH, et al., Cerebellar hemorrhage: Diagnosis and treatment, Arch Neurol, 31, 3, September, pp. 160–7, 1974.)

more benign, stable course. The first group required surgical treatment, whereas the second group did well with a medical program. CT scans of the first group showed hematomas 3 cm or more in diameter, obstructive hydrocephalus, and ventricular extension of the hemorrhage; in the second group of patients, all of whom had hematomas less than 3 cm in diameter, the other two features were absent. These observations, along with those of others,540 have identified a group of cerebellar hemorrhages with a benign course. It may be possible to make accurate predictions from the combined analysis of clinical and CT data at the time of onset. Especially important is careful monitoring of the status of the patient. The development of obtundation and extensor plantar responses is ominous and is virtually always followed by a fatal outcome unless surgery is performed. In an attempt to identify predictors of neurologic deterioration, St. Louis et al.536 analyzed a series of 72 patients with cerebellar hemorrhage. For the 33 patients (46%) with deterioration, independent predictors of such a course were a vermian location of the hemorrhage and hydrocephalus. On the basis of these data, St. Louis et al.536 suggested that patients with these features are likely to require neurosurgical treatment. The same group analyzed clinical factors predictive of poor outcome in a group of 94 patients. Poor outcome was predicted by admission systolic blood pressure higher than 200 mm Hg, hematoma diameter more than 3 cm, brainstem distortion, and acute hydrocephalus, and death was predicted by abnormal brainstem reflexes (corneal and oculocephalic), GCS score less than 8, acute hydrocephalus, and intraventricular hemorrhage.541 Kirollos et al.542 have made further refinements in the approach to the treatment of cerebellar hemorrhage. They evaluated 50 consecutive patients and used the level of mass effect in the fourth ventricle (graded as absent, compression, or complete obliteration), size of hematoma, GCS score, and hydrocephalus as the variables correlated with type of management and outcome. Their findings indicated that patients with an obliterated fourth ventricle, even if conscious on admission, had a high rate of subsequent neurologic deterioration (43%) and that surgical treatment with posterior fossa craniectomy for clot evacuation was recommended before



Intracerebral Hemorrhage

507

28

Figure 28-48.  Midbrain hemorrhage in a patient with bleeding diathesis.

Figure 28-47.  CT scan of large midline (vermian) cerebellar hemorrhage with extension into the fourth ventricle and compression of the tegmentum of the pons.

these patients experienced neurologic deterioration. Of interest, 60% of subjects in whom hematoma diameter was more than 3 cm but who had only moderate compression or normal size of the fourth ventricle did not require surgery for clot evacuation. The uncommon midline (vermian) cerebellar hematoma still represents a serious diagnostic challenge, and its outcome is generally poor. Its frequency in autopsy series has been 6% of all cerebellar hemorrhages.137 Our experience has documented syndromes featuring relatively early onset of coma, ophthalmoplegia, and respiratory abnormalities, and the severity of bilateral limb weakness has been variable. Early extension of the vermian hematoma into the midline pontine tegmentum is probably responsible for the abrupt onset of coma and bilateral oculomotor signs (Fig. 28-47). This variant of cerebellar hematoma carries a poor prognosis, similar to that of primary pontine hemorrhage. At times, a relatively small hematoma in this location results in fatal brainstem compression.

Midbrain Hemorrhage Spontaneous, nontraumatic mesencephalic hemorrhage is rare. In most instances, the hemorrhage has dissected down from the thalamus or putamen, is part of a lesion originating in the cerebellum or pons, or arises from blood dyscrasias or AVMs. Mesencephalic AVMs generally produce a stepwise pro­ gressive deterioration. Ataxia and ophthalmoplegia (especially third cranial nerve palsy and paralysis of upward gaze) are common. Aqueductal or third ventricular blockage or

distension often leads to hydrocephalus. Bleeding diathesis can lead to isolated midbrain hemorrhage, as shown in Figure 28-48, a brain tissue specimen from an elderly woman with leukemia in whom a third cranial nerve palsy and contralateral intention tremor developed shortly before death. Hypertensive primary mesencephalic hemorrhage is very rare but does occur. One might predict that the hemorrhage would be in the tegmentum in the territory supplied by branches of the superior cerebellar arteries, as in the hypertensive patients reported by several groups.543–545 The details of these cases follow. Durward et al.544 described two patients with mesencephalic hematomas. Their first patient was a 71-year-old hypertensive man (blood pressure 230/130 mm Hg) who suddenly could not stand or open his eyes. Signs included bilateral third cranial nerve paralysis, bulbar weakness, and extensor plantar responses. CT scan revealed a 1-cm hematoma in the ventral tegmentum of the midbrain with rupture into the third ventricle. He experienced obstructive hydrocephalus, which was treated with a ventriculoperitoneal shunt, and survived with bilateral third cranial nerve palsies and poor balance with a tendency to fall backward. Arteriographic findings were normal. Although there was no pathologic confirmation, this case may represent a primary hypertensive mesencephalic tegmental hematoma. The second patient was a normotensive young man who experienced Weber’s syndrome (crossed third cranial nerve palsy and hemiparesis) after a week of prodromal headache. The CT scan showed a right midbrain hematoma. After further deterioration, the hematoma was surgically decompressed, and microscopic examination of the wall of the hematoma revealed an AVM. The patient survived but was grossly ataxic. A 71-year-old patient reported by Morel-Maroger et al.545 had midbrain hemorrhage due to hypertension. After being treated for hypertension for 5 years, he suddenly lost consciousness and awakened confused and dizzy. He had a diffuse headache and vomited. Clinical findings included a right third cranial nerve palsy, left hemiparesis, and a cerebellar-type ataxia of the right limbs. Blood pressure was 290/110 mm Hg. CT scan documented a 12 × 16-mm hematoma in the right superior cerebellar peduncle. The patient recovered after antihypertensive therapy without surgical intervention.

508

SECTION III  Clinical Manifestations

Roig et al.543 described two patients with hypertensive mesencephalic hematomas detected on CT. One patient had an ipsilateral third cranial nerve paralysis with contralateral hemihypesthesia and limb ataxia. The hyperdense lesion was high in the right mesencephalic tegmentum near the midline, probably draining into the third ventricle. Vertebral angiographic findings were normal. A second patient had a right third cranial nerve palsy and left hemiparesis. The lesion was high in the right side of the midbrain. Both patients survived. A 10-year-old boy reported by Humphreys546 suddenly demonstrated right hemiparesis and confusion. Neuroophthalmologic findings were not given in detail. A CT scan showed a large hematoma in the basis pedunculi extending into the interpeduncular fossa. The lesion was drained surgically and was found to contain nuclear debris. The nature of the lesion is unknown, but it was likely a hemorrhage into an AVM or a benign tumor. LaTorre et al.547 described a 38-year-old woman who, after complaining of headache and intermittent diplopia for 2 years, vomited and demonstrated bilateral sixth cranial nerve palsies and paralysis of upward gaze. CSF was found to contain blood, and ventriculography visualized a beaded aqueduct and hydrocephalus. Surgical exploration of the midbrain discovered an AVM of the quadrigeminal plate with a blood clot embedded in the aqueduct. A single patient was reported by Scoville and Poppen.548 The 44-year-old woman experienced an ataxic right hemiparesis in stepwise fashion over 1.5 years. Vomiting, bilateral third cranial nerve paralysis, stupor, and pinpoint pupils suddenly supervened. After a blood clot was drained from her left cerebral peduncle, the patient awakened. Normal blood pressure and coagulation values and the gradual onset favored an AVM in this patient. A number of further observations have stressed the presentation of small midbrain hemorrhages with features of isolated forms of ophthalmoplegia.549–551 These have included isolated fourth549 and third550,551 nerve palsies as well as various combinations of a dorsal midbrain syndrome.552,553 Most of these cases were remarkable for the absence or paucity of signs of long-tract involvement, stressing the fact that small midbrain ICHs can present with isolated ophthalmoplegia.

Pontine Hemorrhage The early clinicopathologic observations in pontine hemorrhage correspond to those made by Fang and Foley554 and later by Dinsdale,137 who reviewed the necropsies at Boston City Hospital and found 511 ICHs among 19,093 autopsies, of which 30 were pontine (6%). Two-thirds of the patients in this autopsy series had been comatose when first seen, 13% vomited, and 78% were dead within 48 hours. One patient who survived for 23 days had a small hemorrhage in the right pontine tegmentum. All of the remainder had massive hemorrhages, usually in the midpons at the junction of the basis pontis and tegmentum that frequently spread rostrally into the midbrain; the hemorrhages almost never spread caudally to the medulla but frequently ruptured into the fourth ventricle. In 1971 Fisher,71 using serial sections from a patient with a massive fatal pontine hemorrhage, identified numerous small vessels with “fibrin globes,” which he thought were related to the vascular rupture causing the hemorrhage. “From the gaping end of each of these torn vessels there protruded a large mass of platelets partially encircled by thin concentric layers of fibrin.” He suggested that the primary hemorrhage led to pressure on surrounding vessels, which subsequently ruptured, causing a cascade or avalanche effect and producing

gradual enlargement of the hematoma. Ross Russell149 had demonstrated large asymptomatic fusiform enlargements on the penetrating vessels of the pons in patients with “atherosclerosis” and hypertensive vascular disease. Cole and Yates,142 Rosenblum,144 Fisher,71 and Caplan555 all explained bleeding in hypertensive patients as leakage from tiny penetrating vessels damaged by lipohyalinosis and containing small microaneurysms. Kornyey556 reported a patient whose pontine hemorrhage occurred during clinical observation; the slow march of signs was similar to the pattern of development seen in ganglionic and thalamic hemorrhages, providing support for Fisher’s postulation of the slowly evolving avalanche. Kornyey’s patient was a 39-year-old man referred for admission because of malignant hypertension. While his admission history was being taken, he complained of numb hands, weakness, and dizziness. His blood pressure was 245/170 mm Hg. He became restless and apprehensive and complained that he could not hear and had difficulty swallowing and breathing. A bilateral sixth cranial nerve palsy and dilated pupils developed, and his corneal reflexes disappeared. Speech became “bulbar,” he was deaf, and he could not move his left leg. Within 15 minutes, the patient was comatose; the pupils were small, and the eyes were converged. Bilateral bulbar palsy, stiff limbs with exaggerated reflexes, and extensor plantar responses were observed. Two hours after onset, the patient died. A large hemorrhage in the tegmentum of the pons, with some spreading into the right basis pontis, was found at necropsy.556 In other patients observed during the onset of pontine hemorrhage, development of the deficit usually evolved gradually over minutes (1 to 30 minutes) and was not as instantaneous as aneurysmal SAH. In the pons, the largest penetrating arteries enter medially, arise perpendicular to the basilar artery, and course from the base to the tegmentum. Other small penetrating arteries originate from the short and long circumferential vessels and enter more laterally, also coursing from base to tegmentum. Some arteries enter the tegmentum laterally and course horizontally across it.192 Because vessels in all of these sites are potentially susceptible to hypertensive damage and lipohyalinosis, they could theoretically also be sites for pontine bleeding. Silverstein557,558 reviewed the pathologic material from Philadelphia General Hospital and confirmed that these sites (Fig. 28-49) were the usual regions of pontine hemorrhage. Of 50 cases, 28 were massive central hemorrhages presumably arising from large paramedian penetrators; 11 were more lateralized,

SCA

d

c

e

a AICA

b BA

Figure 28-49.  Schematic representation of common sites of hypertensive pontine and cerebellar hemorrhages: a, massive, paramedian pontine; b, basal pontine; c, lateral tegmental pontine; d, cerebellar vermian; e, cerebellar hemispheral. AICA, anterior–inferior cerebellar artery; BA, basilar artery; SCA, superior cerebellar artery.



Figure 28-50.  Massive pontine hemorrhage with dissection into brachium pontis and fourth ventricle.

usually spreading from base to tegmentum; and 11 had a tegmental location, of which four remained unilateral and seven involved the tegmentum bilaterally. Not until the mid-1970s, when CT became available, was it possible to diagnose smaller nonfatal pontine hemorrhages accurately and to separate them positively from pontine infarction during life. MRI data, acquired through the use of gradient-echo sequences, indicate that pontine microhemorrhages tend to adopt a distribution similar to that of the large, symptomatic hemorrhages,559 favoring the dorsal aspect of the basis pontis.

Large Paramedian Pontine Hemorrhage Massive pontine hemorrhage results from rupture of parenchymal midpontine branches originating from the basilar artery. The bleeding vessel is thought to be a paramedian perforator in its distal portion,137 causing initial hematoma formation at the junction of tegmentum and basis pontis,137,558 from which the mass grows into its final round or oval shape and replaces most of both subdivisions of the pons (Fig. 28-50). The lesion usually begins in the middle of the pons and extends along the longitudinal axis of the brainstem into the lower midbrain. The hematoma may track into the middle cerebellar peduncles but usually does not extend caudally beyond the pontomedullary junction.137 In the process of rapid hematoma expansion, destruction of tegmental and ventral pontine structures results, with the classic combination of signs caused by involvement of cranial nerve nuclei, long tracts, autonomic centers, and structures responsible for maintenance of consciousness. Large pontine hematomas also regularly rupture into the fourth ventricle.137,557,558 The classic form of pontine hemorrhage, bilateral and massive, is almost exclusively of hypertensive origin. Other etiologies, such as cryptic vascular malformation, account for 10% or less of the cases in most series.137,558 Russell560 regarded pontine hemorrhage as a form of ICH most likely to occur in patients with so-called malignant hypertension or hypertension associated with chronic nephropathy. Clinical presentation is characteristically one of rapid development of coma (80% of cases) without warning signs. Dana561 recognized that some patients were conscious when first examined; in three different series, four of 19 patients (22%),554 ten of 30 patients (33.3%),137 and five of 50 patients (10%)557,558 were alert when initially seen. By 48 hours, approximately 80% were dead.137,554 In some patients (30%), a complaint of severe occipital headache preceded by minutes the catastrophic onset of coma.557,562

Intracerebral Hemorrhage

509

Vomiting was noted in four of 30 (13%)137 and four of 19 (22%)554 patients in two series, occasionally being a prominent early symptom. The frequency of seizures at onset, estimated to be as high as 22%,557 probably represents a combination of true convulsive phenomena in rare instances, along with episodes of spasmodic decerebrate posturing and even the sometimes violent shivering associated with autonomic dysfunction and rapidly evolving hyperthermia. Some patients are seen before the development of coma with focal pontine signs, such as facial or limb numbness, deafness, diplopia, bilateral leg weakness, or progressive hemiparesis. Physical examination often reveals an abnormal respiratory rhythm or apnea.137,558,563 Steegmann563 analyzed these respiratory abnormalities in detail and reported a variety of abnormal respiratory patterns, including “inspiratory gasps of apneustic respiration,” CheyneStokes rhythm, slow and labored respirations, “gasping” respiration, and apnea. Two-thirds of his 17 patients exhibited either apnea or severely abnormal patterns of hypoventilation. Hyperthermia frequently coexisted, with temperatures above 39°C in more than 80% of the patients,562 in one-fourth of whom it reached levels of 42°C to 43°C,557 usually in the preterminal stages. Neurologic findings characteristically result from involvement of cranial nerve nuclei and long tracts; they include quadriplegia with decerebrate posturing, bilateral Babinski signs, absence of corneal reflexes, pinpoint miotic pupils, and various forms of ophthalmoplegia.184,562,563 The oculomotor findings include miotic pinpoint pupils, absence of horizontal eye movements, and ocular bobbing. Miotic pinpoint pupils are usually about 1 mm in diameter. They react to light if a strong light source is used, and a tiny constriction can be detected with a magnifying lens.475,532 Pontine hemorrhage can be confused with opiate poisoning.563 The pupillary abnormality probably results from bilateral interruption of descending sympathetic pupillodilator fibers.475,532 Because pupillary dilatation preceded miosis in Kornyey’s556 patient, it is possible that early stimulation of these fibers could lead to transient pupillary dilatation. Absence of horizontal eye movements, detected with reflex testing with the doll’s head maneuver or ice-water caloric stimulation, reflects bilateral injury of the paramedian pontine reticular formation. This sign occurs in partial forms or variants such as the one-and-a-half syndrome,475 also referred to as paralytic pontine exotropia,564 which represents a combination of unilateral horizontal gaze palsy plus ipsilateral internuclear ophthalmoplegia, resulting in one immobile eye and abduction preserved only in the contralateral one. It is more commonly seen in the smaller unilateral lesions from infarcts,475,564 partial hematomas,191,565,566 AVMs,564 or tumors,564 which result in unilateral involvement of the paramedian pontine reticular formation and the dorsally located ipsilateral medial longitudinal fasciculus. In one of our patients with a hematoma limited to the basis pontis, there was no voluntary horizontal gaze, but reflex movements were preserved. This situation, which has been described by Halsey et al.,567 reflects damage to supranuclear fibers traveling with corticobulbar fibers in the pontine basis before they reach the tegmental paramedian pontine reticular formation. Described by Fisher,535 ocular bobbing denotes brisk movements of conjugate ocular depression, followed within seconds by a slower return to midposition. It occurs most commonly from a pontine lesion, either hemorrhage or infarction, although it has also been described in cerebellar hemorrhage.259,535,568 Typically, it affects both eyes simultaneously and is accompanied by bilateral paralysis of horizontal gaze.535 Atypical varieties include unilateral or markedly asymmetrical forms and those occurring when horizontal eye movements are still present.535,568 The latter form is less strictly localizing

28

510

SECTION III  Clinical Manifestations

to pontine disease, as it can be seen in cerebellar hemorrhage, SAH, and even coma of nonvascular mechanism.535 Weakness of pontine and bulbar musculature is invariable in the larger median hemorrhages but is difficult to assess because patients with bilateral tegmental damage are always comatose. Puffing of the cheeks with expiration, diminished eyelid tone, and pooling of secretions in the oropharynx are commonly observed. Deafness, dysarthria, dizziness, and facial numbness occasionally precede the development of coma. Facial weakness is often asymmetrical and may be associated with a crossed hemiplegia at the time the patient is first seen.569 Limb motor abnormalities are also always present in large tegmental–basal hemorrhages; usually it is quadriplegia with stiffness of all limbs. Hemiplegia was noted in four of 15 tegmental–basal hemorrhages by Goto et al.,569 but was present in only three of 28 cases of bilateral hemorrhages reviewed by Silverstein.557,558 The motor abnormality is usually bilateral with minor asymmetries. Asymmetries in decerebrate posturing, reflexes, or clonus are commonly detected. Tremor, shivering, restless limb movements, and dystonic postures have been common in our experience; patients may suddenly stiffen, giving the false impression of convulsive phenomena. Shivering occurs as the patient’s condition worsens and can indicate failing motor function. Decerebrate posturing was noted in 12 of 15 patients reported by Goto et al.569 Surprisingly, only two of the 28 patients in Silverstein’s557,558 series of large bilateral pontine hematomas were reported to have decerebrate rigidity, but 13 had flaccid quadriplegia, and ten had “generalized flaccidity.” Massive pontine hemorrhages are always fatal, although death does not come instantaneously. Steegmann556 noted no deaths among 17 patients in less than 2 hours. Death usually occurs between 24 and 48 hours.137,554,558,563 Survival for 2 to 10 days is not unusual and depends on the vigor of nursing and supportive care and the presence of complicating respiratory or urinary sepsis. Factors found to be early predictors of mortality include hyperthermia (temperature > 39°C), tachycardia (heart rate > 110 beats/min), CT evidence of extension into midbrain and thalamus, and acute hydrocephalus.570 Some patients with medium-sized hemorrhages survive.570,571 On rare occasions, a patient has survived the surgical removal of a pontine and fourth ventricular clot,565,572 which usually has been due to bleeding from a pontine AVM. Because the development of such lesions is so rapid, it is unlikely that surgical treatment could be provided early enough in the larger hemorrhages to be helpful. No other medical or surgical therapy seems likely to help these grave lesions.

Unilateral Basal or Basotegmental Hemorrhages Unilateral basal or basotegmental hemorrhages are less common than the large paramedian lesions already discussed. In his autopsy-based series, Silverstein558 described 11 such lesions (22%); three were limited to the base, and eight were basotegmental. The larger lesions ruptured into the fourth ventricle. Reports based on CT scans have shown more restricted syndromes,524,573 increasing the range of causes of a pure motor syndrome. Gobernado et al.574 described a hypertensive woman with the gradual development over 3 days of a pure motor hemiplegia affecting the right arm and leg, sparing the face. A CT scan defined a small hematoma limited to the base of the left pons. Another patient with a small hematoma confined to the right basis pontis had an “ataxic hemiparesis” of the left limbs.575 Small unilateral hematomas limited to the base manifest as syndromes indistinguishable from lacunar infarction in the same region (Fig. 28-51). Tuhrim et al.576 reported a patient with dysarthria, limb ataxia,

Figure 28-51.  CT scan of a small left basal paramedian pontine hemorrhage.

and extensor plantar response due to a small basal pontine hematoma; although they labeled this case dysarthria– clumsy hand syndrome, it more closely resembles ataxic hemiparesis.141 Bleeding originating from a pontine penetrating artery may start in the basis pontis but also frequently dissects dorsally into the tegmentum. When the lesion spreads to the tegmentum, an ipsilateral facial palsy and conjugate gaze or sixth cranial nerve palsy often accompanies the contralateral hemiplegia.577 Larger unilateral lesions may rupture into the fourth ventricle after spreading within the tegmentum (Fig. 28-52). In Silverstein’s series,558 these larger unilateral basotegmental lesions usually lead to hemiplegia, coma, and death.

Lateral Tegmental Brainstem Hematomas Lateral tegmental brainstem hematomas usually originate from vessels penetrating into the brainstem from long circumferential branches. They enter the tegmentum laterally and course medially. Small hematomas remain confined to the lateral tegmentum, and larger lesions spread across to the opposite side and can destroy the entire tegmentum. Neurologic examination reveals a predominantly unilateral tegmental lesion with variable degrees of basilar involvement.191,192 Oculomotor abnormalities, especially the “one-and-a-half syndrome,” horizontal gaze palsy, internuclear ophthalmoplegia, partial involvement of vertical eye movements, and ocular bobbing, have been described.191,192,571,577–579 The tegmental location of the spinothalamic tract makes sensory symptoms common. Ataxia, either unilateral or bilateral, may also accompany the oculomotor signs.191,192 Action tremor has developed as the transient hemiparesis improves; this observation can be possibly explained by involvement of the red nucleus or its connections.192 Facial numbness, ipsilateral miosis, and hemiparesis have also been noted.191,192 Two



Intracerebral Hemorrhage

511

28

Figure 28-52.  Unilateral basotegmental pontine hemorrhage with rupture into the fourth ventricle. TABLE 28-11  Tegmental Pontine Hemorrhages Extraocular Movements

Study

Motor

Sensory

Other Cranial Nerves

Cerebellar

Computed Tomography Diagnosis Caplan and Goodwin192

No vertical, R gaze, R 6th, bilat. INO

L ↑ toe

L ↓ pin

R 7th, dysarthria, ptosis

Ataxia R > L

Caplan and Goodwin192

“112 ,” vertical nystagmus

L hemip, ↑ ↑ toes

L ↓ pin

R 7th, 8th, ptosis, dysarthria

Ataxia L > R

Müller et al.

R INO

L hemip, ↑ ↑ toes

L ↓ pin

R 5th, 7th

–

Kase et al.191

“1 ,” No ↑ gaze

R hemip

R ↓ pin and joint position sense

Dysarthria, L 7th

Ataxia L

Kase et al.191

L INO and 6th, R 4th, bobbing

R hemip

R ↓ pin

Dysphagia, L 7th

Ataxia R & L

Caplan and Goodwin192

“1 ,” bobbing, OD ↓ & inward

L hemip, Babinski

L ↓ pin

Dysarthria

Ataxia R>L

Tyler and Johnson578

No horizontal or ↑ gaze, bobbing, skew

L hemip, ↑ ↑ toes

L ↓ pin

R 5th, 7th, dysarthria, dysphagia, ptosis

R tremor

Dinsdale137

R gaze palsy

L hemip

L ↓ pin

R 7th, 8th

–

Silverstein

R gaze palsy

L hemip, ↑ ↑ toes

L ↓ pin

R 7th, ptosis, dysphagia

–

Pierrott-Deseilligny et al.566

“1 ”

L hemip, ↑ ↑ toes

L hemis

R 5th, 7th, 8th

Ataxia R arm

524

1 2

Autopsy Cases

558

1 2

1 2

Hemip, hemiparesis; hemis, hemisensory syndrome; INO, internuclear ophthalmoplegia; OD, right eye; “112 ” the “one-and-one-half” syndrome; R, right; L, left.

patients191 developed Cheyne-Stokes respirations, one of the short-cycle type,415,532 the other of the classic variety. Table 28-11 reviews some reported examples of tegmental pontine hematomas.137,191,192,534,558,566,578 We examined two patients with tegmental pontine hemorrhage, and Lawrence and Lightfoote580 studied a patient with a pontine AVM; all three patients showed vertical pendular ocular oscillations with dizziness and vertical oscillopsia weeks after the hemorrhage. Delayed pain in the contralateral limbs, as in the thalamic pain syndrome, began during recovery from a unilateral tegmental hemorrhage in another patient. We have also observed “palatal myoclonus” as a sequela of lateral tegmental hematomas.

Medullary Hemorrhage Hemorrhage into the medulla oblongata (Fig. 28-53) is even less frequent than hemorrhage into the midbrain. Arseni and Stanciu581 described a 40-year-old woman with dizziness, vomiting, and headache with diplopia and right limb paresthesias. She suddenly became somnolent and ataxic, with a stiff neck, left hemiparesis, diminished pain and temperature sensation on the left side of the face, left limb ataxia, nystagmus, dysphonia, and dysphagia. Surgical exploration found a hematoma on the floor of the fourth ventricle laterally. After drainage of the clot, the patient was said to do well.

512

SECTION III  Clinical Manifestations

A

B

Figure 28-53.  Right dorsolateral medullary hemorrhage on CT scan (A) and gradient-echo MR image (B).

Kempe582 reported on a similar patient who had a lateral medullary hematoma. The 25-year-old woman noted diminished hearing on the left and then suddenly became ill with headache, vomiting, vertigo, and hiccups. She was ataxic and fell to the left. Findings included left nystagmus, diminished pain and temperature sensation on the left side of the face, and left facial weakness; the left ear was deaf and unreactive to caloric stimuli. Pneumoencephalography documented a defect in the rhomboid fossa of the fourth ventricle, which at surgical exploration was found to be a clot bulging through the floor of the fourth ventricle medial to the restiform body. Both this patient and the one described by Arseni and Stanciu581 had findings similar to those in patients with lateral medullary infarcts, and each had a stepwise course. Arteriography was not performed, and CT and MRI were not available. We suspect that the underlying process in both patients was a cavernous angioma. In another patient,415 the explanation was an AVM. At age 37, the woman experienced weakness and decreased position sense in her left arm and leg. Right vocal cord and hypoglossal paralysis developed at age 60, and 2 years later, she became gradually and then abruptly worse and was hypertensive. Necropsy revealed a hemorrhage in the medial medullary tegmentum with spreading into the dorsal medulla and right lateral medulla. Mastaglia et al.583 reported two cases of medullary hemorrhage with quite different clinical features. In one case, an 87-year-old hypertensive woman was found unconscious with a right gaze palsy, right facial weakness, and left hemiplegia. The hemorrhage was largest in the lateral pons and descended into the medullary pyramid. The cause seems to have been a pontine basal–tegmental hemorrhage with unusual caudal dissection, but its clinical picture did not differ from that already described in unilateral pontine hemorrhage. The other patient was hypertensive and had been undergoing anticoagulation with warfarin. She demonstrated an unusual clinical picture consisting of markedly decreased postural sensation and incoordination of her left arm and leg, diminished left

arm reflexes, numbness over the right eye, and subjective numbness of the right limbs. Autopsy showed a hemorrhage into the rostral spinal cord with dissection into the left medullary pyramid. The most likely etiologic factor in this patient was anticoagulation, perhaps compounded by hypertension. There is one well-documented case of medullary hemorrhage due to hypertension, but whether the hemorrhage arose in the medulla or arose in the caudal pontine tegmentum and dissected into the medulla is not certain.540 The patient, a 56-year-old, previously hypertensive man, experienced difficulty swallowing, and examination found paralysis of the left side of the face, soft palate, vocal cord, and tongue. A left Horner’s syndrome, deafness in the left ear, and paresthesias of the right limbs were also found. CT scan showed a left medullary tegmental hematoma, but the signs of deafness and facial palsy might indicate some pontine involvement. Barinagarrementeria and Cantú584 described four cases of their own and reviewed 12 others from the literature. The characteristic profile was one of sudden onset of headache, vertigo, dysphagia, dysphonia or dysarthria, and limb incoordination. Common findings on examination were palatal weakness (88%); nystagmus, cerebellar ataxia, or both (75%); limb weakness (68%); and hypoglossal nerve palsy (56%). Less common signs were facial palsy and Horner’s syndrome. The mechanism of the medullary hemorrhage could be determined in only seven of the 16 patients, corresponding to ruptured vascular malformation (three), hypertension (three), and anticoagulation treatment (one). The mortality rate for the group was 19% (three of 16), and in most of the survivors, residual neurologic deficits were either mild (56%) or absent (19%). Unusual presentations of medullary hemorrhage have included a patient with isolated hiccups from a small dorsal ICH,585 and a second patient with dorsolateral hemorrhage into an area of infarction586 who was seen initially with features of Wallenberg’s syndrome. The complete reference list can be found on the companion Expert Consult website at www.expertconsult.inkling.com.



Intracerebral Hemorrhage

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28

514

SECTION III  Clinical Manifestations

in primary intracerebral hemorrhage identifies patients at highest risk for hematoma expansion: the spot sign score. Stroke 2009;40:2994. 173. Broderick J, Brott TG, Duldner JE, et al. Volume of intracerebral hemorrhage: A powerful and easy-to-use predictor of 30-day mortality. Stroke 1993;24:987. 174. Kothari RU, Brott T, Broderick JP, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996;27:1304. 179. Ziai WC. Hematology and inflammatory signaling of intracerebral hemorrhage. Stroke 2013;44:S74. 187. Stein RW, Kase CS, Hier DB, et al. Caudate hemorrhage. Neurology 1984;34:1549. 190. Ropper AH, Davis KR. Lobar cerebral hemorrhages: Acute clinical syndromes in 26 cases. Ann Neurol 1980;8:141. 191. Kase CS, Maulsby GO, Mohr JP. Partial pontine hematomas. Neurology 1980;30:652. 192. Caplan LR, Goodwin JA. Lateral tegmental brainstem hemorrhages. Neurology 1982;32:252. 194. González-Duarte A, Cantú C, Ruiz-Sandoval JL, et al. Recurrent primary cerebral hemorrhage: Frequency, mechanisms, and prognosis. Stroke 1802;29:1998. 197. Weisberg L. Multiple spontaneous intracerebral hematomas: Clinical and computed tomographic correlations. Neurology 1981;31:897. 198. Bailey RD, Hart RG, Benavente O, et al. Recurrent brain hemorrhage is more frequent than ischemic stroke after intracranial hemorrhage. Neurology 2001;56:773. 199. Biffi A, Halpin A, Towfighi A, et al. Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy. Neurology 2010;75:693. 200. García JH, Ho KL, Caccamo DV. Intracerebral hemorrhage: Pathology of selected topics. In: Kase CS, Caplan LR, editors. Intracerebral Hemorrhage. Boston: Butterworth-Heinemann; 1994. p. 45. 205. Mann DM, Iwatsubo T, Ihara Y, et al. Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer’s disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. Am J Pathol 1996;148:1257. 206. Alonzo NC, Hyman BT, Rebeck GW, et al. Progression of cerebral amyloid angiopathy: Accumulation of amyloid-β40 in already affected vessels. J Neuropathol Exp Neurol 1998;57:353. 208. Cho HS, Hyman BT, Greenberg SM, et al. Quantitation of apoE domains in Alzheimer disease brain suggests a role for apoE in Abeta aggregation. J Neuropathol Exp Neurol 2001;60:342. 216. Weller RO, Massey A, Newman TA, et al. Cerebral amyloid angiopathy: Amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer’s disease. Am J Pathol 1998;153: 725. 218. Delaney P, Estes M. Intracranial hemorrhage with amphetamine abuse. Neurology 1980;30:1125. 228. Kase CS, Foster TE, Reed JE, et al. Intracerebral hemorrhage and phenylpropanolamine use. Neurology 1987;37:399. 229. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 1826;343: 2000. 237. Levine SR, Brust JCM, Futrell N, et al. Cerebrovascular complications of the use of the “crack” form of alkaloid cocaine. N Engl J Med 1990;323:699. 241. Little JR, Dial B, Bellanger G, et al. Brain hemorrhage from intracranial tumor. Stroke 1979;10:283. 242. Scott M. Spontaneous intracerebral hematoma caused by cerebral neoplasms: Report of eight verified cases. J Neurosurg 1975; 42:338. 257. Kase CS, Robinson RK, Stein RW, et al. Anticoagulant-related intracerebral hemorrhage. Neurology 1985;35:943. 258. Rådberg JA, Olsson JE, Rådberg CT. Prognostic parameters in spontaneous intracranial hematomas with special reference to anticoagulant treatment. Stroke 1991;22:571. 259. Ott KH, Kase CS, Ojemann RG, et al. Cerebellar hemorrhage: Diagnosis and treatment. Arch Neurol 1974;31:160. 260. Franke CL, deJonge J, van Swieten JC, et al. Intracerebral hematomas during anticoagulant treatment. Stroke 1990;21:726. 261. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Stroke 1995;26:1471.

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515

437. Weisberg LA, Stazio A, Elliott D, et al. Putaminal hemorrhage: Clinical-computed tomographic correlations. Neuroradiology 1990;32:200. 442. Kumral E, Evyapan D, Balkir K. Acute caudate vascular lesions. Stroke 1999;30:100. 443. Weisberg LA. Caudate hemorrhage. Arch Neurol 1984;41:971. 458. Chung CS, Caplan LR, Han W, et al. Thalamic haemorrhage. Brain 1973;119:1996. 459. Kumral E, Kocaer T, Ertubey NO, et al. Thalamic hemorrhage: A prospective study of 100 patients. Stroke 1995;26:964. 460. Steinke W, Sacco R, Mohr JP, et al. Thalamic stroke: Presentation and prognosis of infarcts and hemorrhages. Arch Neurol 1992;49:703. 467. Keane JR. Contralateral gaze deviation with supratentorial hemorrhage: Three pathologically verified cases. Arch Neurol 1975;32:119. 475. Fisher CM. Some neuro-ophthalmological observations. J Neurol Neurosurg Psychiatry 1967;30:383. 476. Pessin MS, Adelman LS, Prager RJ, et al. “Wrong-way eyes” in supratentorial hemorrhage. Ann Neurol 1981;9:79. 480. Karussis D, Leker RR, Abramsky O. Cognitive dysfunction following thalamic stroke: A study of 16 cases and review of the literature. J Neurol Sci 2000;172:25. 483. Dejerine J, Roussy G. Le syndrome thalamique. Rev Neurol 1906;12:521. 484. Percheron SMJ. Les artères du thalamus humain. Rev Neurol 1976;132:297. 497. Bogousslavsky J, Van Melle G, Regli F. The Lausanne Stroke Registry: Analysis of 1,000 consecutive patients with first stroke. Stroke 1988;19:1083. 501. Sung C-Y, Chu N-S. Epileptic seizures in intracerebral hemorrhage. J Neurol Neurosurg Psychiatry 1989;52:1273. 514. Knudsen KA, Rosand J, Karluk D, et al. Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston criteria. Neurology 2001;56:537. 519. Flemming KD, Wijdicks EF, Li H. Can we predict poor outcome at presentation in patients with lobar hemorrhage. Cerebrovasc Dis 2001;11:183. 520. Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in INtracerebral Haemorrhage (STICH): A randomized trial. Lancet 2005;365:387. 521. Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet 2013;382:397. 532. Fisher CM. The neurological examination of the comatose patient. Acta Neurol Scand Suppl 1969;45:44. 535. Fisher CM. Ocular bobbing. Arch Neurol 1964;11:543. 536. St. Louis EK, Wijdicks EF, Li H. Predicting neurologic deterioration in patients with cerebellar hematomas. Neurology 1998;51: 1364. 541. St. Louis EK, Wijdicks EF, Li H, et al. Predictors of poor outcome in patients with a spontaneous cerebellar hematoma. Can J Neurol Sci 2000;27:32. 542. Kirollos RW, Tyagi AK, Ross SA, et al. Management of spontaneous cerebellar hematomas: A prospective treatment protocol. Neurosurgery 2001;49:1378. 566. Pierrott-Deseilligny C, Chain F, Serdaru M, et al. The “one-anda-half” syndrome: Electro-oculographic analysis of five cases with deductions about the physiological mechanisms of lateral gaze. Brain 1981;104:665. 570. Wijdicks EF, St. Louis E. Clinical profiles predictive of outcome in pontine hemorrhage. Neurology 1997;49:1342. 584. Barinagarrementeria F, Cantú C. Primary medullary hemorrhage: Report of four cases and review of the literature. Stroke 1994; 25:1684. 586. Jung HH, Baumgartner RW, Hess K. Symptomatic secondary hemorrhagic transformation of ischemic Wallenberg’s syndrome. J Neurol 2000;247:463.

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Intracerebral Hemorrhage

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Clinical Manifestations

357. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke: The PROACT II Study: A randomized controlled trial. JAMA 2003;282:1999. 358. Kase CS, Furlan AJ, Wechsler LR, et al. Symptomatic intracerebral hemorrhage after intra-arterial thrombolysis with prourokinase in acute ischemic stroke: The PROACT II trial. Neurology 2001; 57:1603. 359. Kidwell CS, Saver JL, Villablanca JP, et al. Magnetic resonance imaging detection of microbleeds before thrombolysis: an emerging application. Stroke 2002;33:95. 360. Shoamanesh A, Kwok CS, Lim PA, et al. Postthrombolysis intracranial hemorrhage risk of cerebral microbleeds in acute stroke patients: a systematic review and meta-analysis. Int J Stroke 2013;8:348. 361. Charidimou A, Kakar P, Fox Z, et al. Cerebral microbleeds and the risk of intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2013;84:277. 362. Linfante I, Llinas RH, Caplan LR, et al. MRI features of intracerebral hemorrhage within two hours from symptom onset. Stroke 1999;30:2263. 363. Schellinger PD, Jansen O, Fiebach JB, et al. A standardized MRI stroke protocol: Comparison with CT in hyperacute intracerebral hemorrhage. Stroke 1999;30:765. 364. Patel MR, Edelman RR, Warach S. Detection of hyperacute primary intraparenchymal hemorrhage by magnetic resonance imaging. Stroke 1996;27:2321. 365. Tanaka A, Ueno Y, Nakayama Y, et al. Small chronic hemorrhages and ischemic lesions in association with spontaneous intracerebral hematomas. Stroke 1999;30:1637. 366. Roob G, Schmidt R, Kapeller P, et al. MRI evidence of past cerebral microbleeds in a healthy elderly population. Neurology 1999;52:991. 367. Atlas SW, Thulborn KR. MR detection of hyperacute parenchymal hemorrhage of the brain. AJNR Am J Neuroradiol 1998;19: 1471. 368. Fazekas F, Kleinert R, Roob G, et al. Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR Am J Neuroradiol 1999;20:637. 369. Schrag M, McAuley G, Pomakian J, et al. Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study. Acta Neuropathol 2010;119:291. 370. Cordonnier C, Al-Shahi Salman R, Wardlaw J. Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 2007;130: 1988. 371. Greenberg SM, Finklestein SP, Schaefer PW. Petechial hemorrhages accompanying lobar hemorrhage: Detection by gradientecho MRI. Neurology 1996;46:1751. 372. Park JH, Seo SW, Kim C, et al. Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment. Ann Neurol 2013;73:584. 373. Yates PA, Sirisriro R, Villemagne VL, et al. Cerebral microhemorrhage and brain beta-amyloid in aging and Alzheimer disease. Neurology 2011;77:48. 374. Maxwell SS, Jackson CA, Paternoster L, et al. Genetic associations with brain microbleeds: Systematic review and metaanalyses. Neurology 2011;77:158. 375. Greenberg SM, Eng JA, Ning MM, et al. Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke 2004;35:1415. 376. Charidimou A, Kakar P, Fox Z, et al. Cerebral microbleeds and recurrent stroke risk: systematic review and meta-analysis of prospective ischemic stroke and transient ischemic attack cohorts. Stroke 2013;44:995. 377. Bokura H, Saika R, Yamaguchi T, et al. Microbleeds are associated with subsequent hemorrhagic and ischemic stroke in healthy elderly individuals. Stroke 2011;42:1867. 378. Koenneke H-C. Cerebral microbleeds on MRI: Prevalence, associations, and potential clinical implications. Neurology 2006;66: 165.

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SECTION III  Clinical Manifestations

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Intracerebral Hemorrhage

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515.e12

SECTION III  Clinical Manifestations

580. Lawrence WH, Lightfoote WE. Continuous vertical pendular eye movements after brainstem hemorrhage. Neurology 1975;25:896. 581. Arseni C, Stanciu M. Primary hematomas of the brain stem. Acta Neurochir 1973;28:323. 582. Kempe LG. Surgical removal of an intramedullary hematoma simulating Wallenberg’s syndrome. J Neurol Neurosurg Psychiatry 1964;27:78. 583. Mastaglia FL, Edis B, Kakulas BA. Medullary hemorrhage: A report of two cases. J Neurol Neurosurg Psychiatry 1969;32:221.

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