Adnan I. Qureshi, MD, Professor of Neurology and Radiology
15 Prognosis and Outcomes Following Intracerebral Hemorrhage
Stanley Tuhrim, MD , Directora, Professorb
a Division of Cerebrovascular Diseases, bDepartment of Neurology, Mount Sinai School of Medicine , New York , New York, USA
INTRODUCTION
Intracerebral hemorrhage (ICH) is the most lethal form of stroke, with mortality estimates ranging from 23% to 58% in various modern series ( 1–3 ). The study of the characteristics, behaviors, and outcomes of ICH has progressed through 3 phases. Early reports concerning outcome were largely descriptive and focused on specifi c lesion locations. These reports often identifi ed spe-cifi c clinical fi ndings of prognostic signifi cance. Subsequently, the advent of more sophisticated statistical analysis allowed for the development of multivariate models that provided powerful predictive instruments for large classes of ICH patients. These models have proven useful for estimating the effects of certain characteristics in heterogeneous patient groups (e.g., supraten-torial hemorrhages), but they often lack specifi c clinical detail. Most recently, the prognostic signifi cance of individual factors has been confi rmed by clinical trial and observational data from larger data sets. This chapter describes the prognostic information gleaned from these 3 phases.
PROGNOSIS BY SPECIFIC LESION SITE Putaminal Hemorrhage
ICH occurs primarily in the deep portions of the cerebral hemispheres, most commonly in the putamen (∼ 40%), with a broad spectrum of clinical presentations and a wide range of outcomes.
In an early CT-based study of 24 cases of putaminal hemorrhage, pupillary abnormalities, disturbances in extraocular movement, and bilateral Babinski signs were associated with larger hematomas and a poor chance of survival, whereas preserved higher cortical function and partial sparing of motor function were associated with good outcome. Four patients with absent extra-ocular movements had massive hemorrhages and fatal outcomes. Age, gender, and admission blood pressure were unrelated to outcome ( 4 ). Predictive CT scan fi ndings included large hemor-rhage size and presence of intraventricular blood. Kanaya, on the basis of extensive experience with medically and surgically treated patients, developed a detailed classifi cation schema based on the involvement of adjacent structures. He indicated that lesions that involve only the anterior limb of the internal capsule (Grades I and II) fare much better than those involving the posterior limb (Grades III and IV) or thalamus (Grade V) ( 5 ).
Caudate Hemorrhage
Although the caudate is supplied by deep penetrating branches of larger, superfi cial arteries, similar to branch vessels supplying putamen and thalamus, hemorrhage originating in the caudate accounts for only 5% to 7% of all ICH. Patients with caudate hemorrhage can be divided into two groups on the basis of initial presentation. One group mimics subarachnoid hemorrhage [due to the invariable presence of intraventricular hemorrhage (IVH), with meningismus, vomiting, headache, and changes in level of consciousness and behavior]. These patients usually recover completely. In addition to the manifestations described above, a second group has hemiparesis and conjugate gaze paresis, indicating compression of the internal capsule. These patients fre-quently take longer to recover, but mortality remains low ( 6 ). The consistently good outcome in these patients, despite IVH, stands in sharp contrast to putaminal hemorrhage, in which such extension is strongly associated with a fatal outcome.
Thalamic Hemorrhage
Thalamic hemorrhage represents 10% to 15% of ICH. Overall survival in thalamic hemorrhage appears comparable to putaminal hemorrhage. In early descriptive studies, hematoma size emerged as the most important predictor of mortality. In the earliest report of the CT scan era, 18 hypertensive thalamic hemorrhages were noted; all of those with a maximum diameter > 3.3 cm were fatal, whereas the overall mortality rate was 50% ( 7 ). Other reports of a small series sug-gested 2.5, 3.0, and 3.3 cm as the crucial lesion diameter ( 8–10 ). In the largest series to date, Weis-berg noted that no patients with maximum-diameter hematoma of < 2.5 cm died, whereas those with hematomas > 3 cm had ventricular extension, became comatose, and died. Although a precise hematoma size that results in mortality has not been defi ned, it is apparent that hematoma size correlates with prognosis and that patients with thalamic lesions > 3 cm in diameter rarely survive. Ventricular extension occurs in most thalamic hemorrhages and is associated with a variable prognosis, but hydrocephalus, presumably secondary to IVH, is associated with a high mortality rate ( 10 ).
Level of consciousness is consistently related to survival. For example, Piepgras and Rieger reported that 6 of 7 patients admitted in coma died, but 5 of 6 with an initially clear sensorium survived ( 11 ). Posterior thalamic lesions rarely result in signifi cant permanent defi cit. Complete recovery is typical with a described syndrome of posterior thalamic hemorrhage that consists of ipsilateral ptosis and miosis, contralateral sensory neglect and hemiparesis, defective pursuit toward the lesion, and hypometric saccades away from the lesion ( 12 ). Similarly, the aphasia associated with left thalamic hemorrhage usually resolves completely ( 10 ).
Lobar Hemorrhage
Lobar hemorrhage may carry a lower mortality risk than ICH in other locations. Reported mortality rates range from 9% to 32%. A history of hypertension is present in only approximately one-third of lobar hemorrhage patients ( 13–16 ). Patients without a history of hypertension have a substan-tially better prognosis. In a series of 50 patients, all normotensive patients survived, most with little or no residual disability. Among those with hypertension, 50% worsened in the hospital, 28%
died, and 77% of survivors had signifi cant neurologic disability ( 16 ). Hypertension was strongly associated with hematoma size. Consciousness level, hemorrhage size, intraventricular extension, and degree of midline shift have been identifi ed as important prognostic variables ( 13–16 ).
Pontine Hemorrhage
Pontine hemorrhage accounts for only 5% of ICH ( 17 ). Previously, this lesion was universally believed to be almost fatal. Bilateral paramedian pontine hemorrhage with ventricular extension is usually fatal, and those who survive are neurologically devastated. However, modern imaging has demonstrated small hemorrhages limited to the pontine tegmentum or encompassing a small portion of the basis pontis, and patients with these abnormalities typically have signs and symptoms that mimic lacunar syndromes ( 18 ). These more lateral lesions are frequently associated with vascular malformations ( 19 ).
The prognosis in these small hemorrhages is excellent, with full recovery reported ( 20–22 ).
Cerebellar Hemorrhage
Cerebellar hemorrhages, accounting for ~ 10% of ICH, usually occur in the cerebellar hemispheres.
Patients who remain conscious fare far better than those who become stuporous or comatose, regardless of whether they undergo evacuation of the hematoma. When patients are operated upon while still arousable, the reported mortality rate is < 30%, but evacuation of a cerebellar hematoma after the onset of coma is associated with at least a 72% mortality rate ( 23,24 ). Other clinical fi ndings at presentation do not reliably predict outcome. Hemorrhage diameter > 3 cm, obstructive hydrocephalus, and IVH are associated with a decreased level of consciousness and a high mortality rate ( 24 ). Overall, the survival rate for cerebellar hemorrhage is higher than for other ICH locations. For example, in the National Institute of Neurological Disorder and Stroke Data Bank series, more than 80% of cerebellar hemorrhage patients survived at least 30 days.
Frequently, those patients who survive make an excellent recovery ( 24,25 ).
GENERAL PROGNOSTIC FEATURES
The information in the preceding section regarding specifi c hemorrhage locations is based on observations of small groups of patients. Another approach assesses outcome in larger, more
heterogeneous groups (e.g., patients with supratentorial hemorrhage). The potential advantage of the second approach is the ability to apply powerful statistical techniques; however, the ability to collect information such as is collectible with small subgroups might be lost.
Several early studies ( 26–33 ) performed only univariate analysis of factors associated with outcome. Age, lesion location, electrocardiographic abnormalities, and hypertensive his-tory were inconsistently associated with prognoses, but shift of midline structures on CT scan was associated with fatal outcome in the two studies that evaluated this fi nding. Ropper noted an association between level of consciousness and degree of horizontal displacement of the pineal body in acute hemispheral mass lesions, mainly ICHs ( 34 ). Level of consciousness is the clinical sign most consistently associated with ICH prognosis. The consistent importance of hemorrhage size, level of consciousness or Glasgow Coma Scale (GCS), and IVH extension mirror the prominent role that these factors play in descriptions of specifi c hemorrhage types.
Studies that employed multivariate analysis ( 35 – 43 ) produced fairly consistent results, despite minor variations in patient selection, variables assessed, and statistical methods. The variables identifi ed as independent predictors of outcome in these studies are listed in Table 1 . Hemorrhage size, intraventricular extension of blood, and GCS or level of consciousness emerge as consistent, independent predictors of survival. Midline shift, oxygen saturation, and electrocardiographic abnormalities have been identifi ed in some models, but too infrequently to be included in the table. Serum glucose and age are frequently examined, but with contra-dictory results.
LONG-TERM PROGNOSIS
Long-term outcome has been studied less frequently than early mortality for several reasons:
( i ) there are relatively fewer survivors overall (though short-term prognosis has improved partly because of the ability to identify relatively mildly affected individuals, with modern imaging techniques); ( ii ) obtaining information at appropriate intervals postdischarge is more diffi cult than determining early mortality; and ( iii ) it is more diffi cult to measure recovery or functional capacity than the clear endpoint of mortality. Many early long-term stroke outcome studies did not separate ICH from infarction; the results of several of the larger studies that did are summarized below. One study reported on 63 of 100 consecutive patients with spontaneous ICH, who survived the fi rst month. Of these, 34 remained paretic (11 plegic), although only 5 of those were not ambulatory. Thirty-fi ve returned to work, and only 6 remained institution-alized. Functional status was largely independent of hemorrhage location but was related to original hematoma size and GCS ( 29 ).
Of the 69 survivors from among 104 nonoperated ICH patients followed for 1 year in another study, 51 made a good to excellent recovery ( 28 ). The 18 patients with persistent, severe neurologic defi cits who had signifi cantly larger hemorrhages were older (mean age 65 vs. 58), and were twice as likely to have had IVH.
Another group followed 42 survivors from a series of 70 ICH patients for an average of 29 months. Another 7 died during the follow-up period; none died of vascular disease, and 5 patients suffered seizures. Only 5 of the 35 surviving patients returned to work, 19 walked with-out assistance, and 13 ambulated with assistance. The authors noted that functional status of most patients did not change during the follow-up period. The GCS was used to assess functional status following ICH in a cohort of 166 ICH patients, of whom 95 survived 6 months, and 78% of them functioned independently at 6 months. Limb weakness, language disorders, hemorrhage size, and ventricular hemorrhage were related to outcome. Initial survival was unrelated to age, but age was an important determinant of functional recovery ( 36 ).
Tuhrim et al. used factors predictive of 30-day survival (GCS, hemorrhage size, pulse pressure, and ventricular extension) to devise a model for predicting long-term outcome. The model correctly classifi ed 95% of patients as having a good (defi ned as alive, Barthel’s index
> 60) or poor (defi ned as dead or Barthel’s index < 60) outcome at 1 year. This study made no attempt to determine if age or premorbid level of function related to long-term outcome ( 35 ).
Another group did include premorbid Rankin scale in a multivariate analysis of predictors of 6-month outcome and found that it, along with age and GCS, was helpful as a predictor ( 42 ).
Given the caveat that the data are more limited, the same factors that determine early mortality appear to be predictive of poor long-term functional outcome. Age may play a greater
Table 1 Predictors of Intracerebral Hemorrhage Outcome Intracerebral Intraventricular Glasgow Coma hemorrhage hemorrhage IVH Scale (GCS) Blood Fourth Refs . Age (ICH) size (IVH) +/− vol Loc Location Hydro pressurea Glu vent Dixon et al. (37) − + + N + + N − N N Portenoy et al. (38) N + + N + − N − N N Senant et al. (39) + + + N + − N − − N Daverat et al. (36) + + + N + − N N N N Tuhrim et al. (35) N + + N + N N + − N Broderick et al. (44) − + N + N − N − N N Lisk et al. (45) + + + + + − − − N N Shapiro et al. (46) − + + N + N N N N N Mase et al. (47) − + + N + − N − N N Qureshi et al. (3) − + + N + − N − N N Fogelholm et al. (48) − − − N − N − + + N Diringer et al. (49) − − − − − − + − N N Fujii et al. (50) + +b − − − + N N − N Razzaq and Hussain (51) − + + N + − + + N N Tuhrim et al. (52) N + − − + N + + N N Phan et al. (53) − + + N + − + − − N Hemphill et al. (41) + + + N + + N − − N Hallevy et al. (54) + + + N + − N − N N Cheung and Zou (43) − − + + + − − + − N Fangc et al. (55) + + + N + + N − + N aSystolic, diastolic, mean arterial blood pressure, or pulse pressure. b ICH growth. cGCS, ICH, IVH, location, and age as composite ICH score.
role in determining functional outcome than in predicting initial survival. Several authors suggest that for a given initial stroke severity, long-term functional recovery is better for ICH survivors than for those who suffer infarctions, but this has not been rigorously studied. How-ever, in recent controlled comparison, outcomes were actually slightly poorer in patients with primary ICH than in ischemic stroke patients matched for prestroke disability, early neurologic impairment, and age ( 2 ).
SPECIFIC PROGNOSTIC FEATURES Hydrocephalus
Hydrocephalus is present in as many as half of ICH patients at some time during the course of their illness; however, it has received relatively little attention as a prognostic factor.
In a descriptive study of 100 patients with thalamic hemorrhage, hydrocephalus was noted as an important predictor of mortality, but a multivariate analysis was not performed ( 56 ). Similarly, another descriptive study noted 67% mortality in patients with contralateral ventricular dilatation, compared with 30% overall mortality among 200 consecutive ICH patients ( 57 ). In a separate study of the signifi cance of ventricular blood in supratentorial hemorrhage, hydrocephalus correlated with mortality, but external ventricular drainage did not appear to alter outcome ( 58 ). A more defi nitive, multivariate study analyzed 81 ICH patients treated in a neurointensive care setting, creating a detailed method of assessing the degree of hydrocephalus ( 49 ). Forty patients with at least some degree of hydrocephalus fared much worse (50% mortality) than those without (2% mortality). Only male gender, GCS, pineal shift, and hydrocephalus were independent predictors of mortality in this patient population. ICH location did not affect outcome or modify the effect of hydrocephalus on outcome. This latter fi nding is at odds with the fi ndings of a later study that used the same method to quantify hydrocephalus in 100 consecutive ICH patients and then divided them into those with medial (thalamic and caudate) or lateral (putaminal) hemorrhages ( 53 ).
Hydrocephalus, thus calculated, was present in 86% of those who died and was an inde-pendent predictor of mortality in the whole group. However, when the medial and lateral groups were considered separately, hydrocephalus was an independent predictor of out-come only in the lateral group. The authors noted that hydrocephalus in the medical group might be caused by a small dorsomedial thalamic hemorrhage with intraventricular exten-sion, while in the lateral group, hydrocephalus was associated with larger intraparenchymal hemorrhage volume. This implies that hydrocephalus might be confounded with hemorrhage size in that population. In summary, hydrocephalus appears to be a poor prognostic sign in ICH. In the two studies that performed multivariate analyses, hydrocephalus, rather than hem-orrhage size, appeared in the fi nal model, although hemhem-orrhage size, as in many other studies, was associated with outcome when considered alone.
Anticoagulant-Related Hemorrhage
Chronic anticoagulation, often for the purpose of preventing ischemic stroke, is a risk factor for ICH. It also appears to be associated with an increased likelihood of a poor outcome in patients who suffer an ICH. Two early reports focused on prognosis in anti-coagulant-related hemorrhage. One reported that 20 of 40 patients did not survive, but 18 of 20 survivors recovered completely. Five patients suffered concomitant subdural hematomas, but no patients had multiple ICHs ( 59 ). The second report found that 28 of a series of 200 patients with ICH had been taking warfarin at the time of the hemorrhage ( 57 ). The mor-tality of the entire group was 30%, but 57% of those with anticoagulant-related hemorrhages died. The anticoagulant-related hemorrhages were also larger on average ( 57 ). A 2004 study attempted to quantify the independent effect, on ICH prognosis, of anticoagulation with warfa-rin by assessing 435 consecutive ICH patients over age 55, of whom 102 were taking warfawarfa-rin at the time of hemorrhage ( 60 ). The use of warfarin more than doubled the 3-month mortality rate.
Higher admission international normalized ratio (INRs) were associated with greater mortality.
Hemorrhage size was not measured in this study. Several studies, including the second that is cited above ( 57 ), have suggested that patients with anticoagulant-related hemorrhages have larger hemorrhages; thus, warfarin use might simply be acting as a proxy for hemorrhage
size. However, in a Taiwanese study that excluded anticoagulated patients, prothrombin times were signifi cantly higher among nonsurvivors after adjusting for initial hemorrhage size ( 55 ), suggesting that noniatrogenic coagulopathies might play a more important role in ICH than is currently appreciated. Anticoagulant-related ICH may also have a greater likelihood of expansion (see below). Regardless of the etiology, anticoagulant-related hemorrhages tend to be larger, with a poorer prognosis. Hemorrhage size, IVH, and level of consciousness or GCS con-tinue to predict outcome accurately in these patients, as they do for most patients with ICH.
Hematoma Expansion
Recently recognized to occur in ~ one-third of all ICH patients who were scanned repeatedly within 24 hr of onset, hematoma expansion is associated with poor outcome and might account in part for the poorer prognosis in anticoagulant-related hemorrhage. In another recent study of 70 supratentorial ICH patients who were rescanned within 7 days of onset, warfarin use was associated with an increase in hematoma volume of at least 33% from baseline size of the hemorrhage ( 61 ). Hematoma expansion was detected later in the hospital course, and expan-sion was associated with a greater risk of mortality than is typical for spontaneous, idiopathic hemorrhages.
Warfarin use is a major determinant of hematoma expansion, but other factors have also been identifi ed. In a multivariate analysis of 327 ICH patients admitted within 24 hr of onset, Fujii et al. ( 50 ) identifi ed time from onset, amount of alcohol consumed, irregular shape of hematoma, decreased level of consciousness, and lower fi brinogen level as risk factors for hematoma expansion. Hematoma expansion was associated with increased mortality. Patients taking anticoagulants or antiplalelet agents were excluded from analysis. The phenomenon of hematoma expansion after initial presentation is better understood due to the advent of rapid evaluation of stroke patients who are studied with intravenous thrombolysis for acute ischemic stroke. The earlier a patient gets to the hospital and undergoes an initial CT scan, the more likely hematoma expansion is to be found ( 62 ).
In a study at hospitals participating in acute thrombolysis trials, of 142 patients who presented but were excluded because their CT scans diagnosed ICH within 3 hr of symptom onset, at least 38% had hematoma expansion of at least 33% of the baseline size within 24 hr.
This might represent an underestimate, as one-third of the patients did not undergo a follow-up CT scan at 20 hr postbaseline because they were moribund, had undergone surgery, or had died. No signifi cant predictors of hemorrhage growth were identifi ed in this study ( 63 ).
A recent dose-fi nding trial that evaluated activated factor VII in preventing hematoma expan-sion noted that 32% of the placebo group had substantial expanexpan-sion within 24 hr (and also noted signifi cantly less growth in the group treated with activated factor VII) ( 64 ).
Various measures of blood pressure have been associated with poorer prognosis in ICH. In a recent meta-analysis, high systolic blood pressure has been associated with hematoma expansion, as well as worse outcome. One study estimated that patients with high systolic blood pressure had twice the rate of hematoma expansion ( 65 ).
In summary, frequently, hematoma expansion occurs within 24 hr of presentation and is associated with a worse outcome. Patients with anticoagulant-related hemorrhage or other evidence of a coagulopathy and those with elevated blood pressure are more likely to suffer hematoma growth and, therefore, have a poorer prognosis. Prevention of hematoma growth may be feasible and could improve outcome.
Blood Pressure
Elevated blood pressure occurs in ~ 90% of ICH patients early after onset but frequently declines spontaneously ( 66 ). A 1997 study demonstrated that the prognostic signifi cance of ini-tial blood pressure readings related to the site of hemorrhage. The mean iniini-tial blood pressures in 383 patients with fatal outcomes were compared to those in 1318 patients who survived, and higher blood pressures were found in the fatal putaminal and thalamic hemorrhages but not in the fatal subcortical, cerebellar, or pontine hemorrhages, relative to those who survived ( 67 ).
Another study not only confi rmed that elevated initial mean arterial blood pressure (MABP
> 145 mmHg) was associated with a worse outcome but also that lowering blood pressure (to MABP < 125 mmHg) 2 to 6 hr following admission was associated with a better outcome ( 68 ).
An effect of blood pressure on hematoma enlargement is one possible explanation for the association of poorer outcome with lowering initially high blood pressure. This was perhaps