Clinical manifestations

Presentation and course

In hypertensive intracerebral hemorrhage, focal neurologic deficits depend on the location, size, and effects (mass effect and edema) of the hemorrhage. The classic signs of intracerebral hemorrhage are summarized in Table 1 (20).

As the hematoma grows, symptoms and neurologic deficits reach a maximum intensity over a period of 10 to 30 minutes in most cases, or as long as 3 hours (20). A large hematoma produces a characteristic syndrome consisting of progressive focal neurologic signs accompanied by vomiting, headache, and decreased alertness. Conversely, small hematomas can mimic ischemic lacunar syndromes. Early improvement and a fluctuating course are not consistent with hemorrhage. Most intracerebral hemorrhages occur during activity hours.

Alertness is impaired in approximately 60% of cases due to involvement of the reticular activating system. Coma is common in patients with hemorrhages into the thalamus or pons. When stupor and coma develop in patients with putaminal or lobar hemorrhage, the prognosis is poor.

Headache, present in at least 60% of patients (113), results from pressure on the pain-sensitive meninges or surface arteries. Vomiting, caused by pressure on the floor of the fourth ventricle, occurs in half of the patients (20).

Table 1. Signs of Intracerebral Hemorrhage at Various Sites

Prognosis and complications

Cerebral edema. Approximately 60% of patients with stroke present with elevated blood pressure (137). High blood pressure within the first 24 hours after onset is associated with an increased risk of perihematomal edema (177), severe morbidity, and mortality (30).

Edema formation starts within 3 hours (168); it increases gradually and peaks at 10 to 20 days (72). There is a positive association between perihematomal edema and hyperthermia, likely mediated by the inflammatory response (71).

Early neurologic deterioration. Early neurologic deterioration was caused by hematoma expansion in approximately half of the patients. This is radiologically defined by an increase in size of 12.5 cm³ or greater than 1.4 times. Expansion occurs in up to 36% of patients within 24 hours but is very rare afterwards (80). Hematoma expansion was more frequent in patients with ionized calcium lower than 1.12 mmol/L (196).

Seizures. Seizures occur in approximately 25% of patients with primary intracerebral hemorrhage, especially in lobar hemorrhage (54%), when blood extends into the cerebral cortex. In one half of these, the seizure begins within 24 hours of the onset of the hemorrhage. Seizures are relatively rare with basal ganglia hemorrhage (19%) and do not occur in patients with thalamic, pontine, or cerebellar hematomas (38).

Seizures, initially focal, occur more often with cortical lesions, nonhypertensive intracerebral hemorrhage, younger age, and severe neurologic deficits (123).

Continuous EEG detected seizures in up to 31% of patients with intracerebral hemorrhage despite anticonvulsant therapy (179; 27).

Temperature dysregulation. Hyperthermia, present in 39% of patients, is associated with increased mortality. Only 29% of cases are infectious. The hemorrhage volume, intraventricular extension, external ventricular drainage or surgical evacuation, and positive blood cultures are associated with hyperthermia (48). Fever caused by pontine hemorrhage is difficult to treat (157).

Hypothermia occurs more often in intracerebral hemorrhage than in traumatic brain injury, acute ischemic stroke, or subarachnoid hemorrhage. Mortality is increased compared with fever (143).

Coma. Coma at presentation correlates with 64% mortality (164). Mortality within the first week is 32 times higher in patients with a Glasgow Coma Scale score lower than 8 and 14.5 times higher in those with signs of brainstem compression (191). Among these are absent corneal and occulocephalic responses and lack of localization of the painful stimulus (167).

Death. The overall mortality of primary intracerebral hemorrhage is approximately 25% to 50% (159; 20). Fatal outcome correlates with the size of the hematoma and Glasgow Coma Scale score (91). Other risk factors include age and systolic blood pressure on admission, fever, hyperglycemia, elevated neutrophil count, serum fibrinogen levels of greater than 523 mg/dL, and hypodensities on CT head (93; 70; 171; 08).

Mortality within 30 days of onset is associated with intracerebral hemorrhage volume greater than 32 ml supratentorially or 21 ml infratentorially (154). Mortality increases dramatically with thalamic and cerebellar hemorrhages larger than 3 cm in diameter and pontine hemorrhages larger than 1 cm in diameter. For cerebellar hematomas, mortality was 17% in responsive patients and 75% in unresponsive patients (132). The prognosis of lesions smaller than 1.5 cm is generally excellent, except in elderly patients or when there may be a significant amount of intraventricular bleeding (82).

Radiological predictors of death are acute hydrocephalus and intraventricular hemorrhage (167). Intraventricular hemorrhage is associated with 66% death and disability as compared to 49% in intracerebral hemorrhage alone (75). Horizontal displacement (midline shift) of the pineal body of 3 to 4 mm from the midline is associated with drowsiness, 6 to 8.5 mm with stupor, and 8 to 13 mm with coma (148).

The intracerebral hemorrhage score is used to determine mortality at 30 days. The elements of this score are Glasgow Coma Scale score, the hemorrhage volume, presence of intraventricular blood, infratentorial origin of blood, and age (59). The functional outcome of intracerebral hemorrhage may be predicted with the FUNC score (149).

Recurrence of intracerebral hemorrhage. The recurrence rate of intracerebral hemorrhage is approximately 2.4% per year, with a 3.8-fold increase for lobar hemorrhage (65). Most recurrent hemorrhages occur at a different site (26). Up to 20% of recurrent intracerebral hemorrhages had a different cause, suggesting the need to investigate thoroughly every instance of recurrence (194; 188).

The risk factors for intracerebral hemorrhage recurrence include poor functional status, prior history of ischemia, lobar location, older age, ongoing anticoagulation, multiple microbleeds on MRI, surgical treatment, and renal insufficiency. SSRIs or NSAIDs were not associated with increased risk of recurrence, and antihypertensive medication reduces this risk (83; 60; 161).

Recurrent hemorrhage was also associated with variant genotype combinations of ACE and αADDUCIN (110) and presence of apolipoprotein E ε2 and ε4 alleles (109). The HAS-BLED score was developed to assess the risk of recurrent intracerebral hemorrhage (23).

Biological basis

Etiology and pathogenesis

Elevated blood pressure was found in 60% of patients with intracerebral hemorrhage presenting to hospital (137). Systolic blood pressure above 200 mmHg and the proportion of blood pressure measurements above 180 mmHg were associated with hematoma expansion (80; 144). However, this relationship was not confirmed in another study (76).

Chronic hypertension is the major cause of nontraumatic or spontaneous intracerebral hemorrhage. Thirty-nine single nucleotide polymorphisms (SNP) were found to be related to blood pressure. Although no single SNP was associated with intracerebral hemorrhage or pre- intracerebral hemorrhage hypertension, the blood pressure-based unweighted genetic risk score was associated with the risk of intracerebral hemorrhage and intracerebral hemorrhage in the deep regions, but not with lobar intracerebral hemorrhage (36).

The diagnosis of hypertensive intracerebral hemorrhage is based on (1) history of hypertension; (2) bleeding into a site typical for penetrating artery territories, such as putamen, thalamus, pons, and cerebellum; and (3) no other cause of hemorrhage. Elevated blood pressure on admission may reflect altered hemodynamics due to the increased intracranial pressure or acute release of catecholamines.

Chronic hypertension may be distinguished from this stress response by findings of cardiomegaly on chest x-ray, left ventricular hypertrophy by electrocardiogram or echocardiogram, renal dysfunction, or hypertensive retinopathy on funduscopic examination.

In a large population study, the relative risk of hypertension for intracerebral hemorrhage was 3.9 (14). For the presence of hypertension by history, left ventricular hypertrophy, and cardiomegaly, the relative risk was 5.4. For black persons with a history of hypertension, the relative risk was 8.2; for hypertension, left ventricular hypertrophy, and cardiomegaly, the relative risk was 13.3.

Pathology. The association between miliary aneurysms of intracerebral arteries and parenchymal hemorrhage described by Charcot (24) was later supported by other investigators (152; 28).

Most hypertensive intracerebral hemorrhages originate from the rupture of arterioles with diameters between 50 and 200 µm. Both aneurysmal and nonaneurysmal hemorrhages, due to rupture of lipohyalinotic or arteriosclerotic arteries, occur in the deep regions of the brain (42).

Postmortem angiography revealed that hypertension is associated with miliary aneurysms in the small vessels (100 to 300 µm in diameter) of the basal ganglia, internal capsule, thalamus, and, less commonly, centrum semiovale and cortical gray matter (152; 28). This explains the location of most hypertensive hemorrhages: deep structures: putamen (40% to 50% of cases), subcortical white matter–lobar (20%), thalamus (15%), cerebellum (8%), pons (8%), and caudate nucleus (8%) (20).

Another study found ruptured miliary aneurysms in a minority of histological specimens. The predominant finding was degeneration of the arterial media near bifurcations, the most likely site for rupture (170). The Charcot-Bouchard aneurysm is not a significant cause of intracerebral hemorrhage but a marker of cerebrovascular disease severity (100).

Hemorrhage occurs not only in the arteries damaged by chronic hypertension but also in the normal small arteries during spikes of blood pressure as during emotional stress, cold weather, severe dental pain, sympathomimetic drug abuse, and trigeminal stimulation (19; 90).

Cerebral amyloid angiopathy results from deposition, primarily of the beta-amyloid peptide in the walls of arterioles and capillaries in the leptomeninges, cerebral cortex, and cerebellar hemispheres (lobar territories). Cerebral amyloid angiopathy occurs in elderly patients with apolipoprotein E genotypes containing the ε2 or ε4 alleles.

A pathogenetic classification of intracerebral hemorrhage was proposed—SMASH-U: structural vascular lesions (S), medication (M), amyloid angiopathy (A), systemic disease (S), hypertension (H), or undetermined (U). Structural lesions, like cavernomas and arteriovenous malformations, caused 5% of the hemorrhages. Approximately 14% of cases were caused by anticoagulation and 5% by systemic disease. Amyloid angiopathy and hypertensive angiopathy were the most common causes at 20% and 35% respectively. Etiology remained undetermined in 21% of cases (107).

Hematoma expansion is associated with poor outcome. Repeat CT after baseline CT performed within 3 hours of intracerebral hemorrhage onset revealed hematoma expansion in 26% of patients after 1 hour and another 12% after 20 hours of the initial scan (13). Expansion of hematoma was detected in patients who had CT performed early after intracerebral hemorrhage onset, irregular shape of hematoma, and increasing plasma level of matrix metalloproteinase-9 (193).

Accumulation of blood compresses and injures the local brain parenchyma and dissects for some distance. If the hematoma is large, midline shift and compression of brainstem vital centers may lead to coma and death. Within 1 hour from onset, accumulation of serum proteins resulting from blood clot retraction leads to formation of the perihematoma edema (184).

After 2 to 4 days, inflammatory cells arrive at the margins of the hemorrhage. Hemosiderin-laden macrophages and extracellular deposits of hematoidin are present after 3 weeks. The level of CD163, a scavenger receptor for hemoglobin, was significantly lower in patients with larger perihematoma edema and may be a useful prognostic biomarker (150).

Astrocytic proliferation occurs in the neighboring parenchyma. Apoptosis plays a major role in cell death after intracerebral hemorrhage and is associated with activation of nuclear factor-kB (NF-kB), ICAM-1 IL-1B (187). In the chronic stage, the hematoma shrinks to a cavity lined by hemosiderin-laden macrophages.

Extension of the hemorrhage into the subarachnoid space has been associated with fever and worse outcome (54).

In 2% to 3% of hemorrhagic strokes, there are multiple foci of bleeding. The presumed mechanism is bleeding from the penetrating arteries caused by sustained hypertension during acute cerebral hemorrhage. The differential diagnosis includes hematologic disorders, vasculitis, anticoagulant therapy, illicit drug use, cerebral amyloid angiopathy, or hemorrhage due to multiple infarctions with hemorrhagic transformation (105).

Epidemiology

Intracerebral hemorrhage accounts for approximately 10% of strokes (104; 113). The annual incidence is estimated to be between 10 and 22.9 per 100,000 (53; 12) with a male predominance (60%) (87).

Hypertension is the leading cause of intracerebral hemorrhage. The significantly higher incidence in the black population as compared to the white population (32 vs. 12 per 100,000) may reflect the higher prevalence of hypertension (53). Additionally, if hypertension is not treated, the risk of intracerebral hemorrhage in all anatomic locations is greater in blacks and Hispanics relative to whites (185). Over the past several decades, the proportion of patients with intracerebral hemorrhage who were hypertensive declined from 84% to 50% (45). This may reflect both improvement in hypertension treatment and diagnostic imaging of alternative causes of intracerebral hemorrhage.

In young adults (16 to 49 years of age), the incidence is lower, 4.9 out of 100,000. The most common risk factors are hypertension (29.8%) and smoking (22.3%). Structural lesions are more common in young compared to elderly patients (25% vs. 4.9%). In patients younger than 40 years of age, intracerebral hemorrhage tends to be less severe and has a better prognosis (151). In 22.5% of cases, no etiology was found after MRI and angiography were performed (86).

Although no seasonal variation has been identified, the risk of intracerebral hemorrhage increases significantly between 8:00 am and 4:00 pm (129). In a small study, drop in atmospheric pressure 2 days before ictus was associated with deep but not lobar intracerebral hemorrhage, suggesting a link to hypertensive etiology (68).

Prevention

It was estimated that by eliminating hypertension from the population, the incidence of intracerebral hemorrhage would decrease by 49% (14).

Uncontrolled blood pressure at 3 months following the initial hemorrhagic stroke was associated with higher recurrent stroke risk and mortality. Those presenting with poorly controlled blood pressure and Black, Hispanic, and Asian survivors of intracerebral hemorrhage were at the highest risk for uncontrolled hypertension at 3-month follow-up (07). A decrease of diastolic blood pressure by 10 mmHg may reduce the risk of stroke by up to 56% (99). The treatment of isolated systolic hypertension is equally important (163).

After the acute intracerebral hemorrhage period, a reasonable goal is a target normal blood pressure of less than 130/80 mmHg (60).

Alcohol intake reduction in patients who drink more than two units per day would reduce the deleterious effects of alcohol as well as improve hypertension control (145).

Differential diagnosis

Confusing conditions

As the clinical features of ischemic and hemorrhagic stroke often overlap, CT is used to quickly and reliably differentiate between types of stroke. Determining the cause of intracerebral hemorrhage is based on demographic and risk factors and the location and appearance of the lesion on CT and MRI.

Amyloid angiopathy. Amyloid angiopathy occurs in the elderly and results in microinfarcts, subarachnoid hemorrhage, intracerebral hemorrhage, and dementia. Multiple hemorrhages occur over time at several sites within the cerebral hemispheres, especially in the posterior portion of the hemisphere in the parietal and occipital lobes. Bleeding in the basal ganglia, thalamus, pons, and cerebellum is rare. Beta-amyloid may be detected by temporal artery biopsy (174).

Drug-related intracerebral hemorrhage. Sympathomimetic drugs and stimulants associated with intracerebral hemorrhage include amphetamines, cocaine, phencyclidine, phenylpropanolamine, ephedrine, and methylphenidate (128; 18). Headache, drowsiness, confusion, and psychotic appearance suggest the etiology. The location of the drug-induced intracerebral hemorrhage closely mimics hypertensive intracerebral hemorrhage except that more of the drug-related hematomas are lobar. The diagnosis is confirmed by a history of recent drugs and a positive drug screen.

Anticoagulant and antiplatelet-related intracerebral hemorrhage. Intracerebral hemorrhage due to anticoagulation occurs at a rate of nearly 1% per year; 70% are intracerebral hematomas, of which 60% are fatal. Risk factors include older age, hypertension, prior ischemic stroke, and intensity of anticoagulation. Heparin, especially if given as a bolus (58), warfarin use if INR is greater than 3.0 (43), and aspirin are associated with intracerebral hemorrhage (16). In a population-based study, prior use of either warfarin or aspirin are independent risk factors for death after intracerebral hemorrhage (156).

Thrombolytic therapy–related intracerebral hemorrhage. Thrombolysis-related hemorrhage occurs in 0.36% of patients with acute myocardial infarction and in 6.4% of patients with ischemic stroke (126). The location can be deep, lobar, or in the region of an infarction. In a pooled analysis, 7 of 10 patients who died of thrombolysis-related hemorrhage and underwent autopsy had cerebral amyloid angiopathy (106).

Hematological disorders. A few examples are hemophilia, thrombocytopenia, and leukemia.

Vascular malformation and aneurysm. Any young patient with lobar or subependymal intracerebral hemorrhage who is not hypertensive should be evaluated for a vascular malformation with a contrast-enhanced CT or MRI. Delayed scans may detect lesions missed in the acute stage due to compression by the adjacent hematoma.

Brain tumor. Glioblastoma multiforme is the most frequent cause of intracerebral hemorrhage from a primary tumor (97). Although choriocarcinoma and malignant melanoma have a high frequency of intracerebral hemorrhage (50% and 29%, respectively), the most common cause of intracerebral hemorrhage is bronchogenic carcinoma (155). Tumor diagnosis is suggested by a contrast-enhanced lesion surrounded by vasogenic edema on CT or MRI.

Hemorrhagic infarction. Hemorrhagic transformation usually occurs after an embolic cerebral infarction. Typically, the neurologic deficits are maximal at onset. Mild transformation may be asymptomatic. Hemorrhagic transformation appears on CT scan as spotted and mottled high attenuation inside the infarction.

Unusual causes of intracerebral hemorrhage. The following conditions all have in common an acute rise in blood pressure or blood flow: exposure to cold weather, dental pain or manipulation, manipulation of the trigeminal nerve, carotid endarterectomy, and correction of congenital heart defects and cardiac transplantation in the young (20). The location of the hematomas in these conditions is identical to that of intracerebral hemorrhage in chronically hypertensive patients.

Associated or underlying disorders

Left ventricular hypertrophy. Left ventricular hypertrophy is associated with chronic hypertension and intracerebral hemorrhage (133).

Hypothyroidism. Hypothyroidism leads to endothelial disorders and atherosclerosis and was found more often in patients with intracranial hemorrhage (69).

Diagnostic workup

Any patient with intracerebral hemorrhage should have coagulation parameters (prothrombin time and international normalized ratio) tested in addition to a hemogram, blood chemistry panel, and troponin.

Noncontrast CT. Head CT may detect and localize the hematoma, distinguish it from ischemic stroke, and evaluate for hematoma expansion and its complications: edema, hydrocephalus, and brain herniation (198). The resolution of CT is a few millimeters. Intracerebral hemorrhage appears as an area of high density, with an absorption value in the range of 40 to 90 Hounsfield units (162). This high-density lesion is due mainly to the hemoglobin protein (globin) contained in the extravasated blood (124).

Vasogenic edema is plasma derived and surrounds the acute hematoma (17). After 7 to 10 days, the high-attenuation values of the hematoma begin to decrease, always from the periphery towards the center. The entire hematoma becomes isodense in 2 to 3 weeks if small or in 2 months if large (124). The reduction in size and attenuation values in intracerebral hemorrhage have been estimated at rates of 0.65 mm and 1.4 Hounsfield units per day, respectively (34). The final stage in the CT evolution is the complete absorption of the necrotic and hemorrhagic tissue, leaving a residual cavity after 2 to 4 months. At times, this cavity can be indistinguishable from that of an old cerebral infarct.

Heterogenous intensities within the hematoma and irregular margins (hypodensities, fluid level, swirl, black hole, island, or satellite sign) are markers for increased risk of hematoma expansion and poor prognosis (120; 119). Repeat CT scan is useful within 24 hours of onset or in patients with a low Glasgow Coma Score (GCS) or neurologic deterioration (01; 98).

Contrast-enhanced CT. Contrast-enhanced CT may facilitate the diagnosis of an arteriovenous malformation or a neoplasm. "Ring enhancement" occurs between 1 to 6 weeks from the onset of intracerebral hemorrhage and may last up to 2 to 6 months. It is due to hypervascularity at the periphery of the evolving hematoma (198) or disruption of the blood-brain barrier (34).

CT angiogram. In patients younger than 70 years with lobar spontaneous intracerebral hemorrhage, younger than 45 years with deep or posterior fossa intracerebral hemorrhage, or between 45 to 70 years without hypertension, CT angiogram in combination with venography may detect secondary causes of intracerebral hemorrhage.

Contrast extravasation on early CT angiography (“spot sign”) may predict hematoma expansion (50; 181). The Spot Sign Score (SSSc) that includes the number of spot signs, their maximum axial dimension, and attenuation was validated prospectively for prediction of significant expansion of hematoma, severe disability, and mortality (146). The “blush sign,” another predictor for hematoma expansion, seems to be a better predictor than the spot sign (176).

MRI and MR angiogram. MRI not only distinguishes hemorrhage from infarction but also provides insight into the evolution of hemorrhage by detecting the chemical changes of hemoglobin. Five stages of an evolving hematoma have been described: (1) hyperacute (first 24 hours), (2) acute (1 to 3 days), (3) early subacute (longer than 3 days), (4) late subacute (longer than 7 days), and (5) chronic (longer than 2 weeks). Four zones have also been described: (1) inner core, (2) outer core, (3) rim, and (4) reactive brain (09). However, no MRI-autopsy correlation has been reported. The different stages of hemorrhage, the changes of hemoglobin, and the intensity on MRI are as follows (Table 2) (09).

Table 2. Stages of Hemorrhage

Using diffusion-, T2-, and T2* -weighted images, MRI has been shown to detect intracerebral hemorrhage within 6 hours of onset. The hemorrhage is typically target-like appearance (39). The hyperacute hemorrhage is composed of three distinct areas: (1) center: isotense to hyperintense signal on T2* - and T2-weighted images; (2) peripheral: hypointense (deoxyhemoglobin) mostly on T2* -weighted images; (3) rim: hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging, representing vasogenic edema encasing the hematoma (96).

Gradient-echo T2-weighted MRI detects chronic microbleeds in more than half of the patients (54%) with primary intracerebral hemorrhage. Microbleeds are seen as round, hypointense foci smaller than 5 mm due to the perivascular hemosiderin. They result either from hypertensive vasculopathy or from cerebral amyloid angiopathy (180). The microbleeds located in basal ganglia, thalamus, and the infratentorial region are more likely to be associated with primary intracerebral hemorrhage (147).

Enlarged perivascular spaces (EPVS) seen on brain MRI are a promising marker of small vessel disease and are common in patients with intracerebral hemorrhage. Based on their anatomical distribution, the mechanism of formation may be inferred. Severe centrum semiovale EPVS may indicate cerebral amyloid angiopathy, whereas basal ganglia EPVS suggests hypertensive arteriopathy (25).

Catheter intra-arterial digital subtraction angiography. Cerebral arteriography is used in selected cases for further confirmation or plan of treatment of arteriovenous malformation, aneurysm, tumor, and vasculitis if detected by CT angiogram. Patients younger than 70 years with lobar intracerebral hemorrhage, younger than 45 years with deep/posterior fossa intracerebral hemorrhage, and 45 to 70 years without hypertension and a negative CT or MR angiogram may benefit from digital subtraction angiography (197). In patients without a clear cause and negative angiogram, a repeat angiogram after the resolution of the hematoma may uncover small vascular malformations (67). Extension of intracerebral hemorrhage into the ventricular system is not usually associated with vascular malformations and the yield of catheter angiography is low (78).

Additionally, digital subtraction angiography is recommended in patients with isolated intraventricular hemorrhage or abnormal CTA or MRA suggestive of a macrovascular cause.

Although CT angiography is as accurate as digital subtraction angiography for the diagnosis of vascular lesions, it cannot characterize the angioarchitecture (190). A simple, practical score to detect secondary intracerebral hemorrhage (SICH) based on noncontrast CT characteristics, age, and presence of hypertension or coagulopathy may guide further cerebrovascular imaging (31). CT angiography must be carefully reviewed, even in elderly patients, if the hemorrhage location is atypical for hypertensive arteriopathy. For example, an aneurysm of the lateral posterior choroidal artery was found on the CT angiogram of a 60-year-old man (44).

Management

The most important measures to control hypertensive intracerebral hemorrhage include the following:

The American Heart Association/American Stroke Association has provided a comprehensive review for the management of spontaneous intracerebral hemorrhage in adults (60).

Maintenance of ventilation. Airway patency and maintenance oxygen saturation above 95% are the first concerns. Endotracheal intubation is needed in case of impaired consciousness, hypoxia (PO2 < 60 mmHg, PCO2 > 50 mmHg), or aspiration of secretions (131). Prolonged coma or pulmonary complications beyond 2 weeks may require elective tracheostomy.

Blood pressure control. Aggressive blood pressure control does not seem to adversely affect the tissue surrounding the hematoma. Here, the metabolism is reduced (81) and the cerebrovascular reactivity is preserved (135). A study using diffusion- and perfusion-weighted MRI showed no evidence for a perihemorrhagic ischemic penumbra (160).

At the same time, intensive blood pressure control does not improve clinical outcome or mortality (73; 04; 74; 138). A meta-analysis of four studies including 3315 patients found that although intensive blood pressure reduction was safe, it did not reduce the unfavorable outcome (173). If blood pressure control is contemplated, lowering it within 2 hours of onset and avoiding large variability in systolic blood pressure may improve the functional outcome (122).

The lack of improved outcome despite increasingly aggressive management of blood pressure was illustrated by the case report of global cerebral ischemia in a patient in whom the blood pressure was promptly reduced to normal level (47). Moreover, the ATACH-2 trial showed that patients whose systolic blood pressure was lowered below 140 mmHg within 2 hours and maintained for at least 2 hours had higher rates of neurologic deterioration and cardiac-related adverse events (139). Another study of 286 patients found decreased systolic blood pressure below 120 mmHg to be associated with ischemic lesions, whereas no patients with minimal systolic blood pressure above 130 mmHg had such lesions (15).

Although the optimum blood pressure target and urgency of achieving it are unknown, the current guidelines recommend treatment based on the level of mean arterial pressure and intracranial pressure, with a goal of cerebral perfusion pressure greater than 60 mmHg.

If systolic blood pressure is 150 to 220 mmHg, rapid lowering of systolic blood pressure to 140 mmHg (range 130 to 150 mmHg) with minimal fluctuations is safe and may improve the functional outcome. However, in the same patients, decreasing systolic blood pressure to less than 130 mmHg is potentially harmful (51).

In a small study, atenolol was found to decrease mortality, SISRS, and pneumonia, compared to amlodipine (79). Insufficient data exist regarding treatment of severe, sustained systolic blood pressure higher than 220 mmHg.

Increased intracranial pressure monitoring and control. Intracranial pressure above 20 mmHg for more than 5 minutes is considered elevated. This may result from the mass effect of hematoma and secondary hydrocephalus. The compartmentalized structure of the brain favors an increase in intracranial pressure only around the hematoma (22).

Intracranial pressure monitoring. Intracranial pressure is monitored by a pressure sensor inserted into the brain parenchyma. In addition to measuring intracranial pressure, insertion of an external ventricular device allows drainage of the cerebrospinal fluid according to a preset intracranial pressure. In general, ventricular drainage is considered in patients with intracerebral hemorrhage/intraventricular hemorrhage when hydrocephalus is responsible for decreased consciousness.

It is reasonable to monitor intracranial pressure in patients with a Glasgow Coma Scale (GCS) score lower than 8 due to the hematoma, clinical evidence for transtentorial herniation, significant intraventricular hemorrhage, or hydrocephalus. The cerebral perfusion pressure goal is 50 to 70 mmHg, depending on the status of cerebral autoregulation (60).

Noninvasive monitoring of intracranial pressure based on transcranial Doppler or optic nerve sheath diameter are promising developments (101; 21). However, in the only multicenter-controlled trial in traumatic brain injury patients, conducted in Ecuador and Bolivia, invasive monitoring of increased intracranial pressure failed to improve outcome compared to using clinical status and CT imaging (49). A systematic review and meta-analysis of 14 studies including 24,792 patients found no reduction in mortality by invasive monitoring. However, a newer study showed a benefit of invasive monitoring (195).

General measures. General measures for intracranial pressure reduction include elevation of the head of the bed to 30°, mild sedation, and avoidance of endotracheal tube ties that might impair the cerebral venous return (189). Stool softeners may also help.

Hypertonic solutions. Hyperosmolar therapy can transiently reduce intracranial pressure. However, neither mannitol nor hypertonic saline of 3% reduce mortality (06; 183). A meta-analysis did not find a significant difference between these agents (142). The rebound phenomenon of increasing edema volume after hypertonic solutions infusion limits the efficacy of this measure (140). Hyperosmolar therapy is only a temporizing measure (51).

Controlled hyperventilation. Hypocarbia (pCO2 25 to 33 mmHg) during controlled hyperventilation induces cerebral vasoconstriction (92). Cerebral blood flow decreases almost immediately, though it may take up to 30 minutes for maximum effect to occur. Refractory intracranial hypertension may benefit from induced barbiturate coma.

Ventriculostomy. Ventriculostomy for CSF drainage can reduce the intracranial pressure and improve the outcome in patients with hydrocephalus if it contributes to decreased level of consciousness. However, this invasive procedure may be complicated by hemorrhage and infections (33).

If intracranial pressure is refractory to all medical management, decompressive craniectomy has been used; however, even if performed early (less than 48 hours), it does not improve mortality compared to medical treatment (127).

Cerebral microdialysis for determination of the lactate/pyruvate ratio as a marker of brain tissue hypoxia (85) and invasive brain oxygen monitoring (61) are still in the experimental stages. A small prospective randomized study showed that brain oxygen monitoring seems to be superior to intracranial pressure monitoring alone (95).

Intraventricular hemorrhage management. Intraventricular hemorrhage occurs in 45% of patients with spontaneous intracerebral hemorrhage (55). A retrospective review demonstrated that external ventricular drain reduced mortality and improved short-term outcomes in these patients (63). The CLEAR-IVH trial showed that in patients with small intracerebral hemorrhage and large intraventricular hemorrhage, administration of low-dose tPA in the ventricular system in order to accelerate blood clot removal is safe; however, the impact on functional recovery is unknown (115). The CLEAR III trial showed that although ventricular irrigation with alteplase was safe, it did not improve functional outcomes at the mRS=3 cutoff compared to saline (57).

Seizures. Depressed levels of consciousness out of proportion to the size or location of the hemorrhage should prompt continuous EEG monitoring. Clinical or electrographic seizures should be treated, but the use of anticonvulsants prophylactically in patients without documented seizures is not recommended (108).

Recombinant activated factor rFVIIa. rFVIIa failed to show significant difference in clinical outcome, despite its ability to prevent hematoma enlargement (11; 37).

Prevention and treatment of medical complications. Fluid and electrolyte balance should be monitored, particularly if hyperosmolar agents and diuretics are used. Inappropriate antidiuretic hormone secretion can occur in patients with intracerebral hemorrhage.

Dysphagia. Dysphagia is diagnosed in 68% of patients with intracerebral hemorrhage (169). All patients should undergo formal dysphagia screening to prevent aspiration pneumonia (66). In general, patients should receive nothing by mouth for the first 24 to 48 hours, and normocaloric parenteral nutrition or enteral nutrition should be instituted within 48 hours.

Percutaneous endoscopic gastrostomy was needed in 25% of intracerebral hemorrhage cases (84).

Myocardial infarction. Approximately 0.3% of patients with intracerebral hemorrhage develop acute myocardial infarction during the first 3 days of treatment and increased mortality from 2% to 14.5% (46). In one study, elevated troponin was associated with increased in-hospital mortality but not at 30 days if not associated with ECG changes in another study (103; 158). Continuous cardiac monitoring for 24 to 72 hours and serial cardiac enzymes should be obtained to detect cardiac arrhythmia or ischemia (51).

Neurogenic pulmonary edema. Pulmonary edema develops in 35% of patients with intracerebral hemorrhage and is responsible for 37% mortality at 1 year (77). Acute respiratory distress syndrome occurs in 27% of patients with intracerebral hemorrhage; it is associated with a high tidal volume and with inpatient mortality (35). Low tidal volume ventilation with attention to avoid increased intracranial pressure or hypoxia is reasonable (102).

Renal dysfunction. Renal failure occurred in 8% of patients with intracerebral hemorrhage and is not increased by CT angiography (130). Renal dysfunction is also associated with cerebral microbleeds in patients with intracerebral hemorrhage (89). Acute renal failure is associated with higher rates of in-hospital mortality and moderate to severe disability at discharge (153)

Pulmonary embolism. Pulmonary embolism may occur in bedridden individuals with hemiplegia. Deep vein thrombosis can be prevented by heparin (5000 IU subcutaneous injections every 12 hours) or low molecular weight heparin in patients with lack of mobility after 24 to 48 hours of intracerebral hemorrhage onset. Intermittent pneumatic compression devices decrease the risk of pulmonary embolism and should be instituted on the day of diagnosis (60). If anticoagulation is contraindicated, insertion of a retrievable filter may serve as a bridge until coagulation is initiated. In patients with proximal deep vein thrombosis or pulmonary embolism, anticoagulation may be started after 1 to 2 weeks of hemorrhage onset (51).

Fever. Fever occurs frequently and is associated with increased mortality. Infections or inflammatory causes should be investigated and treated. A Cochrane analysis failed to prove any benefit of targeted temperature management (32).

Hyperglycemia. Monitoring glycemia helps avoid both hypoglycemia (< 40 to 60 mg/dL) and hyperglycemia (> 180 to 200 md/dL) (NICE-SUGAR Investigators 2009).

Do not resuscitate order. A do-not-resuscitate order instituted early is an independent predictor for poor outcome as it implies a lower intensity of care (62). Avoidance of do-not-resuscitate orders within the first 5 days, along with management according to the guidelines, reduces mortality more than expected based on the intracerebral hemorrhage score (118).

Statin use. Statin use after intracerebral hemorrhage could be associated with early neurologic improvement and may reduce mortality at 6 months (171). Moreover, discontinuation of statins may be related to an increased mortality (172).

Surgical treatment. Preoperative state of alertness and hematoma volume are the main determinants of outcome. A GCS less than 8 and a hematoma volume greater than 60 ml had a mortality rate of 91% (10). Intraventricular extension of hemorrhage is associated with worse outcome (165).

Hematoma evacuation for supratentorial intracerebral hemorrhage. A large clinical trial, International Surgical Trial for Intracerebral Hemorrhage (STICH), failed to show benefit of early surgery, within 24 hours of randomization, versus initial conservative treatment. Patients with lobar clots larger than 30 mL and within 1 cm of the surface appeared to benefit from surgery (165). The STICH II trial that enrolled conscious patients with superficial lesions between 10 and 100 mL did not show a benefit of early surgery (166).

A meta-analysis of 10 trials with 2059 patients concluded that surgery for supratentorial hematomas was associated with reduction in death and disability, but the result is not very robust (136). In patients who are in a coma with large hematoma, large midline shift, or elevated intracranial pressure resistant to medical management, craniectomy with or without hematoma evacuation may be considered as a lifesaving procedure (51).

Optimal timing of surgery for supratentorial hemorrhage is unknown. A randomized feasibility study of surgery within 24 hours of onset did not show improved morbidity at 3 months (199). Surgery performed within 12 hours of randomization was not more effective than conservative management. However, the patients with poor prognosis were more likely to benefit from early surgery (166). A meta-analysis of eight surgical trials (2816 cases) shows that surgery improves outcome if the patients were randomized within 8 hours of ictus; the Glasgow Coma Scale was 9 to 12, and the hematoma volume was 20 to 50 ml (52). Subgroup analysis of the patients with supratentorial hematoma showed a small benefit from surgery earlier than 21 hours (166). Ultra-early (within 4 hours from onset) surgery was associated with increased risk of rebleeding and mortality (117).

Less is known about surgical intervention in patients with a Glasgow Coma Scale score less than 8. In a small retrospective series of spontaneous intracerebral hemorrhage, all comatose patients who lost upper brainstem reflexes and had extensor posturing died despite emergency craniotomy (141). For patients with GCS less than 8, surgical intervention was associated with increased risk or poor outcome and is probably harmful (165). Decompressive hemicraniectomy without clot evacuation in dominant-sided hemorrhage with intracranial pressure crisis was also attempted in five patients with a GCS between 5 to 9. At 6 months, one patient died, two were dependent (mRS 4 and 5), and two were independent (mRS 2 and 3) (64).

Hematoma evacuation for infratentorial intracerebral hemorrhage. In patients with a cerebellar hematoma volume greater than 15 mL, neurologic worsening, hydrocephalus, or brainstem compression, urgent surgical decompression may by lifesaving (51). However, hematoma evacuation does not improve functional outcome (88).

Initial loss of consciousness strongly predicts poor survival (41). Obliterated cisterns predict a poor outcome irrespective of treatment, and ventricular drainage alone is not indicated (175).

Minimally invasive surgery. Minimally invasive surgery with endoscopic or stereotactic aspiration aims at reducing the morbidity associated with conventional craniectomy. In a randomized trial, minimally invasive surgery of the basal ganglia hemorrhage did not reduce mortality but improved the functional outcome at 3 months in the surviving patients (186). A systematic review and meta-analysis of five randomized controlled trials and nine prospective controlled studies involving 2466 patients showed that patients with supratentorial intracerebral hemorrhage benefit more from minimally invasive surgery than from craniectomy (192).

Addition of thrombolysis with alteplase to the minimally invasive surgery for intracerebral hemorrhage evacuation (MISTIE) trial reduced the clot size and perihematomal edema compared to patients who received placebo, but it did not improve clinical outcome (116; 121; 111). However, at 365 days, mortality was lower in the minimally invasive surgery group compared to the medical management group without an increase in the proportion of patients with severe disability (112).

For patients with a supratentorial intracerebral hemorrhage volume of greater than 20 to 30 mL and a GCS of 5 to 12, minimally invasive surgery reduced mortality compared to medical management alone and functional disability compared to conventional craniotomy (51).

A meta-analysis comparing endoscopic surgery, minimally invasive surgery and urokinase, minimally invasive surgery and alteplase, craniotomy, and standard medical management found that endoscopic surgery was the most effective in improving survival and minimizing disability (94).

An alternative to tPA thrombolysis, still in the experimental stage, is transcranial MR-guided focused ultrasound (114).

Frameless, image-driven robotic stereotactic assistance (ROSA) of catheter insertion is a new development (03). A pilot study of CT-guided endoscopic surgery (Intraoperative Computed Tomography–guided Endoscopic Surgery for Brain Hemorrhage, ICES) showed similar results to the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation, MSTIE, but was not powered to detect benefit (178). A meta-analysis of 28 studies comparing mild hypothermia and minimally invasive surgery to minimally invasive surgery alone showed improved neurologic outcome and decreased mortality (56).

Patient transfer to another facility. Not all hospitals have neurosurgical services. Considering the uncertainty regarding efficacy of the surgical intervention, the decision to transfer a patient with intracerebral hemorrhage to a neurosurgical center is often made. In a study of 1175 cases, the transferred patients had a lower risk of death relative to those remaining at the referral center, despite whether they had surgery (02). Where remote consultation is considered, decision making should rely not only on head CT imaging but also on the video assessment of the patient (182).

Outcomes

Early decision to not resuscitate accounted for much of the observed difference in outcome. Data from a nationwide inpatient sample show that in the United States, the in-hospital mortality of patients who underwent surgical treatment was 27.2%, and the complication rate was 41%. Male gender, preoperative comorbidities, complications, and low surgery volume were associated with increased in-hospital mortality (134).

Special considerations

Pregnancy

In the United States it has been found that 6.1 pregnancy-related intracerebral hemorrhage per 100,000 deliveries and 7.1 pregnancy-related intracerebral hemorrhage occur per 100,000 at-risk person-years (compared to 5.0 per 100,000 person-years for nonpregnant women) in the age range of 15 to 44 years. The risk of intracerebral hemorrhage associated with pregnancy is greatest in the postpartum period, advanced maternal age (greater than or equal to 35 years), African American race, hypertension, coagulopathy, and tobacco abuse. The rate of eclampsia or preeclampsia is 30.5% in the patients with pregnancy-related intracerebral hemorrhage (05).