Hypertensive intracerebral hemorrhage …

Adrian Marchidann MD

Stroke & Vascular Disorders

Updated 06.05.2024
Released 07.16.1996
Expires For CME 06.05.2027

Hypertensive intracerebral hemorrhage

Author: Adrian Marchidann MD

See Contributor Disclosures

Editor: Steven R Levine MD

Hypertensive intracerebral hemorrhage

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Introduction

Overview

The author provides an update on the progress in imaging modalities utilized in patients with intracerebral hemorrhage. New prognosis scores are introduced, and the impact of an early do-not-resuscitate order is discussed. In addition, the latest clinical trials on blood pressure and intracranial pressure management are reviewed.

Key points

	• An increase in hematoma size that is associated with poor outcomes may be predicted by head CT.
	• Smooth and sustained control of blood pressure may improve functional outcomes.
	• Coagulopathy associated with intracerebral hemorrhage increases the mortality rate and should be urgently corrected.
	• Continuous hyperosmolar therapy, platelet transfusion without a clear indication, or antiepileptic medications in the absence of seizures are not beneficial.
	• Minimally invasive surgery for supratentorial hemorrhage may reduce mortality but not functional outcomes.
	• Surgical cerebellar hematoma evacuation is indicated if the volume is greater than 15 ml, in neurologic deterioration, brainstem compression, and hydrocephalus.
	• Patient mobilization should be considered after 24 hours from onset, but not before, as it is associated with increased 14-day mortality.
	• Graduated knee-to-thigh compression stockings are not beneficial for deep vein thrombosis prevention.
	• Caregiver education improves coping with the challenges posed by intracerebral hemorrhage.
	• The transfer of the patients to a center with specialized neurosurgical services may improve their outcome, whether they undergo surgery or not. Telemedicine may facilitate patient selection.
	• Although patients presenting in coma rarely survive after surgical treatment, there is not enough information to recommend selection criteria for surgery.

Historical note and terminology

Intracerebral hemorrhage is bleeding into the brain parenchyma resulting from the rupture of a cerebral artery. It accounts for approximately 10% of strokes (106; 115). Hypertension is the leading risk factor for intracerebral hemorrhage, although its role has decreased over the past decades (115; 46).

Intracerebral hemorrhage was first demonstrated at autopsy by Wepfer in 1658, long before blood pressure could be measured (41). The term spontaneous or primary intracerebral hemorrhage implies the absence of a structural vulnerability. However, the most common causes of primary intracerebral hemorrhage are hypertension and amyloid angiopathy.

The introduction of CT in 1973 has markedly improved the diagnosis of intracerebral hemorrhage. CT reliably diagnoses bleeding and differentiates it from ischemic stroke. Brain MRI provides additional information about its evolution and etiology. CT angiography improves the diagnosis of secondary intracerebral hemorrhage and is as effective as digital subtraction angiography at detecting most vascular malformations.

Surgical treatment of hypertensive intracerebral hemorrhage was first reported by Cushing (29). Despite advances in surgical techniques, such as CT-guided stereotactic aspiration and clot dissolution, with few exceptions, surgical treatment is still in the experimental phase.

Clinical manifestations

Presentation and course

	• Focal neurologic symptoms evolve over minutes to hours.
	• Large hematomas are associated with symptoms of increased intracranial pressure: headache, vomiting, and decreased alertness.
	• Small hematomas may mimic lacunar strokes.

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, the neurologic deficits reach a maximum severity, usually within 10 to 30 minutes, but it may take up to 3 hours to fully develop (20). A large hematoma characteristically causes progressive focal neurologic deficits 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 the involvement of the reticular activating system. Coma commonly occurs 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 results from pressure on the pain-sensitive meninges or surface arteries and occurs in at least 60% of patients (115). Vomiting, caused by pressure on the floor of the fourth ventricle, is experienced by half of the patients (20).

Table 1. Signs of Intracerebral Hemorrhage at Various Sites

Motor and sensory signs
	Putaminal	• Contralateral hemiparesis, hemisensory loss, hemianopsia
	Thalamic	• Contralateral sensory loss, less weakness
	Pontine	• Quadriparesis decerebrate
	Cerebellar	• Ataxia
Oculomotor signs
	Putaminal	• Conjugate deviation to the same site
	Thalamic	• Conjugate deviation to the same site or opposite site, eyes down or down and in, hyperconvergence, skew, vertical gaze palsy
	Pontine	• Bilateral horizontal gaze paresis, preserved vertical reflex movements, ocular bobbing
	Cerebellar	• Ipsilateral sixth or conjugate gaze paresis; nystagmus
Pupils
	Putaminal	• Normal
	Thalamic	• Small and poorly reactive, ipsilateral smaller
	Pontine	• Small, reactive pupils
	Cerebellar	• Small reactive pupils, at times ipsilateral smaller pupils
Alertness
	Putaminal	• Normal if small lesion
	Thalamic	• Reduced
	Pontine	• Coma
	Cerebellar	• Stupor (larger lesion)
Behavioral signs
	Putaminal	• Aphasia (lt), Lt. neglect (rt)
	Thalamic	• Confusion, poor memory, aphasia (left thalamus), left-side neglect (right thalamus)

Ocular bobbing

A 68-year-old woman presented with deep coma (E1, V1, and M2) of 2 days duration. On examination the patient had pinpoint sluggishly reacting pupils, absence of extraocular movements on oculocephalic maneuvers, ocular bobbing, ...

Prognosis and complications

Cerebral edema. Approximately 60% of patients with stroke present with elevated blood pressure (140). High blood pressure within the first 24 hours after onset is associated with an increased risk of perihematomal edema (182), severe morbidity, and mortality (30).

Edema formation starts within 3 hours (172); it increases gradually and peaks at 10 to 20 days (74). There is a positive association between perihematomal edema and hyperthermia, likely mediated by the inflammatory response (73).

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 rarely afterward (82). Hematoma expansion was more frequent in patients with ionized calcium lower than 1.12 mmol/L (201).

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

Seizures, initially focal, occur more often with cortical lesions, not hypertensive, in younger patients, and with severe neurologic deficits (126).

Continuous EEG detected seizures in up to 31% of patients with intracerebral hemorrhage despite anticonvulsant therapy (184; 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 (49). Fever caused by pontine hemorrhage is difficult to treat (161).

Hypothermia occurs more often in intracerebral hemorrhage than in traumatic brain injury, acute ischemic stroke, or subarachnoid hemorrhage. Hypothermia increases mortality more than fever (146).

Coma. Coma at presentation correlates with 64% mortality (168). 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 (196). Among these are absent corneal and occulocephalic responses and lack of localization of the painful stimulus (171).

Death. The overall mortality of primary intracerebral hemorrhage ranges between 25% and 50% (163; 20). Fatal outcome correlates with the size of the hematoma and Glasgow Coma Scale score (93). 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 (95; 72; 175; 08).

Mortality within 30 days of onset increases when the hematoma volume exceeds 32 ml or 21 ml in the supratentorial and infratentorial compartments, respectively (158). An even more dramatic increase in mortality occurs if the hematoma diameter is larger than 3 cm in the thalamus and cerebellum and larger than 1 cm in the pons. Mortality in cerebellar hematomas is significantly worse in unresponsive compared to responsive patients (135). The lesions smaller than 1.5 cm have an excellent outcome, except in elderly patients or associated intraventricular bleeding (84).

Radiological predictors of death are acute hydrocephalus and intraventricular hemorrhage (171). Intraventricular hemorrhage is associated with 66% death and disability as compared to 49% in intracerebral hemorrhage alone (77). 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 (152).

Mortality within 30 days of an event can be predicted by the ICH score. The elements of this score are the Glasgow Coma Scale score, the hematoma volume, the presence of intraventricular blood, the infratentorial origin of blood, and age (60). The functional outcome of intracerebral hemorrhage can be predicted by the FUNC score (153).

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 (67). Most recurrent hemorrhages occur at a different site (26). Up to 20% of recurrent intracerebral hemorrhages has a different cause, suggesting the need to investigate thoroughly every instance of recurrence (199; 193).

The risk factors for intracerebral hemorrhage recurrence include poor functional status, history of ischemia, lobar location, old age, ongoing anticoagulation, multiple microbleeds on MRI, surgical treatment, and renal insufficiency. SSRIs or NSAIDs were not associated with an increased risk of recurrence, and antihypertensive medication reduces this risk (85; 61; 165).

Recurrent hemorrhage was also associated with variant genotype combinations of ACE and αADDUCIN (112) and the presence of apolipoprotein E ε2 and ε4 alleles (111). The HAS-BLED score was developed to assess the risk of recurrent intracerebral hemorrhage (23).

Biological basis

	• Uncontrolled hypertension is the most common cause of spontaneous intracerebral hemorrhage.
	• Chronic hypertension may be distinguished from stress hypertension by physical examination and ancillary tests.

Etiology and pathogenesis

Elevated blood pressure occurs in 60% of patients with intracerebral hemorrhage presenting to the hospital (140). Systolic blood pressure above 200 mmHg and the proportion of blood pressure measurements above 180 mmHg were associated with hematoma expansion (82; 148). However, another study did not confirm this relationship (78).

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-hemorrhage hypertension, the blood pressure-based unweighted genetic risk score was associated with the risk of intracerebral hemorrhage and deep but not lobar intracerebral hemorrhage (36).

The diagnosis of hypertensive intracerebral hemorrhage is based on (1) a history of hypertension; (2) a location typical for penetrating arteries, such as putamen, thalamus, pons, and cerebellum; and (3) no other cause of intracerebral hemorrhage.

Chronic hypertension may be distinguished from the stress response by the presence 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 combination 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.

Extreme work overload, defined as overtime above 100 hours/month, increases the risk of hypertensive intracerebral hemorrhage compared to overtime below 60 hours/month (121).

Pathology. The association between miliary aneurysms of intracerebral arteries and parenchymal hemorrhage described by Charcot (24) was later supported by other investigators (156; 28).

Most hypertensive intracerebral hemorrhages are caused by 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 (43).

Postmortem angiography revealed an association between hypertension and 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 (156; 28). This explains the location of most hypertensive hemorrhages in the 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 (174). The Charcot-Bouchard aneurysm is not a significant cause of intracerebral hemorrhage but a marker of cerebrovascular disease severity (102).

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; 92).

Cerebral amyloid angiopathy is caused by the deposition of the beta-amyloid peptide in the walls of arterioles and capillaries of 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 (109).

Hematoma expansion predicts poor outcome. After the baseline CT, hematoma expansion is seen on repeat CT in 26% of patients after 1 hour and in another 12% after 20 hours of the initial scan (13). The predictors of hematoma expansion were early repeat CT, irregular shape of hematoma, and increasing plasma level of matrix metalloproteinase-9 (198).

The pressure exerted by the blood accumulation injures the local brain parenchyma and dissects it for some distance. If large, the hematoma causes midline shift, and compression of the brainstem’s 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 (189).

Hypertensive intracerebral hematoma (autopsy specimen)

Axial section showing a large hematoma, originating in the left thalamus. The hemorrhage has dissected into the lateral ventricles. (Contributed by Dr. Sherman Stein.)

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 (154).

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 (192). 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 (55).

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 (107).

Epidemiology

	• Intracerebral hemorrhage accounts for 10% of strokes.
	• Hypertension is the leading cause of intracerebral hemorrhage.
	• Over the past few decades, the proportion of patients with intracerebral hemorrhage due to hypertension has decreased.

Intracerebral hemorrhage accounts for approximately 10% of strokes (106; 115). The annual incidence is estimated to be between 10 and 22.9 per 100,000 with a male predominance (60%) (54; 89; 12).

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 (54). Additionally, untreated hypertension raises the risk of intracerebral hemorrhage in all anatomic locations, more so in Blacks and Hispanics compared to Caucasians (190). Over the past several decades, the proportion of intracerebral hemorrhage caused by hypertension declined from 84% to 50% (46). This may reflect both improvements 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 (155). In 22.5% of cases, no etiology was found after MRI and angiography were performed (88).

Although no seasonal variation has been identified, the risk of intracerebral hemorrhage increases significantly between 8:00 am and 4:00 pm (132). In a small study, a drop in atmospheric pressure 2 days before ictus was associated with deep but not lobar intracerebral hemorrhage, suggesting a link to hypertensive etiology (70).

Differential diagnosis

Confusing conditions

As the clinical features of ischemic and hemorrhagic stroke often overlap, CT is used to quickly and reliably differentiate between these types of strokes. 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 parietal and occipital lobes. Bleeding in the basal ganglia, thalamus, pons, and cerebellum is rare. Beta-amyloid may be detected by temporal artery biopsy (179).

Drug-related intracerebral hemorrhage. Sympathomimetic drugs and stimulants associated with intracerebral hemorrhage include amphetamine, methamphetamine, cocaine, phencyclidine, phenylpropanolamine, ephedrine, and methylphenidate (131; 18; 64). Headache, drowsiness, confusion, and psychosis 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 drug use and a positive drug screen.

Anticoagulant and antiplatelet-related intracerebral hemorrhage. Intracerebral hemorrhage caused by anticoagulation occurs at a rate of 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, warfarin if INR is greater than 3.0, and aspirin use are associated with intracerebral hemorrhage (59; 16; 44). In a population-based study, prior use of either warfarin or aspirin are independent predictors of death after intracerebral hemorrhage (160).

Thrombolytic therapy–related intracerebral hemorrhage. Thrombolysis-related hemorrhage occurs in 0.36% of patients with acute myocardial infarction and 6.4% of patients with ischemic stroke (129). The location can be deep, lobar, or in the infarcted area. In a pooled analysis, 7 of 10 patients who died of thrombolysis-related hemorrhage and underwent autopsy had cerebral amyloid angiopathy (108).

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 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 (99). Although choriocarcinoma and malignant melanoma have a high frequency of intracerebral hemorrhage (50% and 29%, respectively), the most common metastatic cause of intracerebral hemorrhage is bronchogenic carcinoma (159). 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 bleeding 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 (136).

Hypothyroidism. Hypothyroidism leads to endothelial disorders and atherosclerosis and is found more often in patients with intracranial hemorrhage (71).

Diagnostic workup

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

Non-contrast CT. Head CT may detect and localize the hematoma, distinguish it from ischemic stroke, and evaluate for hematoma expansion and its complications: cerebral edema, hydrocephalus, and brain herniation (203). The resolution of CT is a few millimeters. Intracerebral hemorrhage appears as an area of high density, with an absorption value between 40 and 90 Hounsfield units (166). This high-density lesion is due to hemoglobin protein (globin) within the extravasated blood (127).

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 (127). The reduction in size and attenuation values of intracerebral hematoma occurs 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 an old cerebral infarct.

Hypertensive intracerebral hematoma (CT)

This unenhanced image shows a large, deep, right-sided hematoma with mass effect and dissection into the lateral ventricles. (Contributed by Dr. Sherman Stein.)

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 (123; 122). A repeat CT scan is useful within 24 hours of onset or in patients with a low Glasgow Coma Score (GCS) or neurologic deterioration (01; 100).

Contrast-enhanced CT. Contrast-enhanced CT facilitates 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 hematoma or disruption of the blood-brain barrier (34; 203).

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 diagnose the cause of intracerebral hemorrhage.

Contrast extravasation on early CT angiography (“spot sign”) may predict hematoma expansion (51; 186). The Spot Sign Score (SSSc), which includes the number of spot signs, their maximum axial dimension, and attenuation, predicts significant expansion of hematoma, severe disability, and mortality (150). The “blush sign” seems to be a better predictor than the spot sign for hematoma expansion (181).

MRI and MR angiogram. In addition to distinguishing hemorrhage from infarction, MRI provides insight into the evolution of hemorrhage by detecting the chemical changes in 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, the MRI findings do not correlate with those of autopsy. The different stages of hemorrhage, the changes of hemoglobin, and the intensity on MRI are described in Table 2 (09).

Table 2. Stages of Hemorrhage

Stage	Hemoglobin	T1-Weighted	T2-Weighted
Hyperacute	Oxyhemoglobin	Dark	Bright
Acute	Deoxyhemoglobin	Dark	Very dark
Subacute
• Early • Late	Methemoglobin Methemoglobin	Bright Bright	Dark Bright
Chronic
• Center • Rim	Hemachrome Hemosiderin	Bright Dark	Bright Very dark

Using diffusion-, T2-, and T2* -weighted images, MRI has been shown to detect intracerebral hemorrhage within 6 hours of onset. Typically, the hemorrhage appears target-like (39). The hyperacute hemorrhage is composed of three distinct areas: (1) center: isointense 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 surrounding the hematoma (98).

In patients with spontaneous intracerebral hemorrhage with negative CT angiogram/venogram, brain MRI and MRA may reveal non-macrovascular causes of bleeding. Among these are cerebral amyloid angiopathy, vasculopathy, cavernoma, and malignancy.

Gradient-echo T2-weighted MRI detects chronic microbleeds in more than half of the patients (54%) with primary intracerebral hemorrhage. Microbleeds appear as round, hypointense foci smaller than 5 mm due to the perivascular hemosiderin. They result either from hypertensive vasculopathy or from cerebral amyloid angiopathy (185). The microbleeds located in the basal ganglia, thalamus, and infratentorial region are more likely to be associated with primary intracerebral hemorrhage (151).

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 (202). In patients without a clear cause and a negative angiogram, a repeat angiogram 3 to 6 months later may uncover small vascular malformations initially obscured by the hemorrhage (69).

Extension of the hemorrhage into the ventricular system is not usually associated with vascular malformations and the yield of catheter angiography is low (80).

However, 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 diagnosing vascular lesions, it cannot characterize the angioarchitecture (195). 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 (45).

Management

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

• Airway and breathing maintenance
• Blood pressure control
• Intracranial pressure control
• Drainage of intraventricular blood
• Seizure control
• Management of neurologic and medical complications

The American Heart Association/American Stroke Association has published a comprehensive guideline for the treatment of spontaneous intracerebral hemorrhage in adults (52).

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 (134). Prolonged coma or pulmonary complications beyond 2 weeks may require elective tracheostomy.

Blood pressure control. Aggressive blood pressure control does not cause ischemia within the tissue surrounding the hematoma. Here, the cerebrovascular reactivity is preserved, and the metabolism is reduced (138; 83). Diffusion- and perfusion-weighted MRI showed no evidence of an ischemic penumbra around the hematoma (164).

At the same time, the clinical trials of intensive blood pressure control failed to demonstrate improved clinical outcomes or mortality (04; 75; 76; 141). Moreover, 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 (178). However, controlling hypertension within 2 hours of onset, reaching the target within 1 hour, and avoiding large variability in systolic blood pressure may improve the functional outcome (125).

The lack of improved outcomes despite the aggressive lowering of blood pressure may be explained by a case report of global cerebral ischemia following the rapid decrease in blood pressure to a normal level (48). Moreover, in the ATACH-2 trial, patients whose systolic blood pressure was decreased below 140 mmHg within 2 hours and was maintained for at least 2 hours had higher rates of neurologic and cardiac adverse events (142). Another study of 286 patients found an association between systolic blood pressure below 120 mmHg and ischemic lesions. No ischemic lesions were seen if the lowest systolic blood pressure was above 130 mmHg (15).

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

If the systolic blood pressure is 150 to 220 mmHg, rapid lowering to 140 mmHg (range 130 to 150 mmHg) with minimal fluctuations is safe and may improve the functional outcome. However, decreasing the systolic blood pressure to less than 130 mmHg in the same patients is potentially harmful (52). Moreover, analysis of the MSTIE III trial data found that a large hematoma volume on admission, a drop in systolic blood pressure by more than 80 mmHg within 24 hours, and moderate to severe white matter disease were associated with diffusion weighted imaging lesions on follow-up MRI (147).

In a small study, decreased mortality, SISRS, and pneumonia, compared to amlodipine (81). Insufficient data exist about treating severe, sustained systolic blood pressure higher than 220 mmHg.

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).

The intracranial pressure is monitored by a sensor inserted into the brain parenchyma. An external ventricular device allows measuring the intracranial pressure and drainage of the cerebrospinal fluid to maintain a set pressure. The drainage is considered when hydrocephalus caused by the bleeding leads to decreased consciousness. Because the external ventricular device is likely to fail and need replacement, a new IRRAflow self-irrigating catheter, which combines automatic irrigation, monitoring, and drainage of the CSF, has been tested successfully. This catheter decreased the duration of drainage, rate of external ventricular device exchange, and length of stay in the ICU (40).

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 (61).

Noninvasive measuring of the intracranial pressures is done by transcranial Doppler or optic nerve sheath diameter (103; 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 (50). 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 some benefits of invasive monitoring (200).

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 (194). 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; 188). A meta-analysis did not find a significant difference between these agents (145). The rebound phenomenon of increasing edema volume after hypertonic solutions infusion limits the efficacy of this measure (143). Hyperosmolar therapy is only a temporizing measure (52).

Controlled hyperventilation. Hypocarbia (pCO2 25 to 33 mmHg) resulting from controlled hyperventilation induces cerebral vasoconstriction (94). 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 intracranial pressure and may improve the outcomes in patients with hydrocephalus if this contributes to decreased consciousness. However, this 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 (130).

Cerebral microdialysis is used for measuring the lactate/pyruvate ratio as a marker of brain tissue hypoxia (87) and invasive brain oxygen monitoring (62) 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 (97).

Intraventricular hemorrhage management. Intraventricular hemorrhage occurs in 45% of patients with spontaneous intracerebral hemorrhage (56). A retrospective review demonstrated that external ventricular drain reduced mortality and improved short-term outcomes in these patients (65). 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 to facilitate blood clot removal is safe; however, the impact on functional recovery is unknown (117). 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 (58).

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 (110).

Hemostatic treatments. Recombinant activated factor VII (rFVIIa) failed to show a significant difference in clinical outcome, despite its ability to prevent hematoma enlargement (11; 37). Similarly, the effectiveness of tranexamic acid has not been established (177).

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 (173). All patients should undergo formal dysphagia screening to prevent aspiration pneumonia (68). Patients should receive nothing by mouth for the first 24 to 48 hours, and normocaloric parenteral or enteral nutrition should be instituted within 48 hours.

Percutaneous endoscopic gastrostomy was needed in 25% of intracerebral hemorrhage cases (86).

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% (47). 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 (105; 162). Continuous cardiac monitoring for 24 to 72 hours and serial cardiac enzymes should be obtained to detect cardiac arrhythmia or ischemia (52).

Neurogenic pulmonary edema. Pulmonary edema develops in 35% of patients with intracerebral hemorrhage and is responsible for 37% mortality in 1 year (79). 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 (104).

Renal dysfunction. Renal failure occurred in 8% of patients with intracerebral hemorrhage and is not increased by CT angiography (133). Renal dysfunction is also associated with cerebral microbleeds in patients with intracerebral hemorrhage (91). Acute renal failure is associated with higher rates of in-hospital mortality and moderate to severe disability at discharge (157)

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 (61). If anticoagulation is contraindicated, using a retrievable filter may serve as a bridge until coagulation is safely initiated. In patients with proximal deep vein thrombosis or pulmonary embolism, anticoagulation may be started after 1 to 2 weeks of hemorrhage onset (52).

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 mg/dL) (NICE-SUGAR Investigators 2009).

Do not resuscitate. A do-not-resuscitate order instituted early is an independent predictor for poor outcomes as it may lead to a lower intensity of care (63). 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 (120).

Statin use. Statin use after intracerebral hemorrhage may be associated with early neurologic improvement and reduces mortality at 6 months (175). Moreover, stopping statins may increase mortality (176).

Surgical treatment. The preoperative state of alertness and hematoma volume are the main determinants of outcome. A Glasgow Coma Scale score less than 8 and a volume greater than 60 ml were associated with a mortality rate of 91% (10). Intraventricular extension of hemorrhage is associated with worse outcomes (169).

Craniotomy for supratentorial hemorrhage. A large clinical trial, the International Surgical Trial for Intracerebral Hemorrhage (STICH), demonstrated that surgical evacuation within 24 hours of randomization is not superior to conservative management. Patients with lobar clots larger than 30 mL and within 1 cm of the surface appeared to benefit from surgery (169). However, the STICH II trial that enrolled conscious patients with superficial lesions between 10 and 100 mL did not show a benefit of early surgery (170).

A meta-analysis of 10 trials including 2059 patients suggests that surgery for supratentorial hematomas is associated with a reduction in death and disability, but the result is not very robust (139). In comatose patients with a large hematoma, large midline shift, or elevated intracranial pressure refractory to medical management, craniectomy with or without hematoma evacuation may be considered. However, its lifesaving effectiveness is unknown (52).

The optimal timing of surgery for supratentorial hemorrhage is unknown. In a randomized feasibility study, surgery within 24 hours of onset did not improve morbidity at 3 months (204). Surgery performed within 12 hours of randomization was as effective as conservative management. However, subgroup analysis showed a small benefit from surgery earlier than 21 hours, especially in those with poor prognosis (170). A meta-analysis of eight surgical trials (2816 cases) shows that surgery improves outcomes if randomization occurred within 8 hours of ictus; the Glasgow Coma Scale was 9 to 12, and the hematoma volume was 20 to 50 ml (53). However, ultra-early (within 4 hours from onset) surgery was associated with an increased risk of rebleeding and mortality (119).

Less is known about surgical intervention in patients with a Glasgow Coma Scale score lower than 8. In a small retrospective series, all comatose patients who lost upper brainstem reflexes and had extensor posturing died despite emergency craniotomy (144). For patients with a Glasgow Coma Scale score less than 8, surgical intervention was associated with an increased risk of poor outcomes and is probably harmful (169). Decompressive hemicraniectomy without clot evacuation in dominant-sided hemorrhage with intracranial pressure crisis was also attempted in five patients with a Glasgow Coma Scale score between 5 and 9. At 6 months, one patient died, two were dependent (mRS 4 and 5), and two were independent (mRS 2 and 3) (66).

Craniotomy for infratentorial hemorrhage. In patients with a cerebellar hematoma volume greater than 15 mL, neurologic worsening, hydrocephalus, or brainstem compression, urgent surgical decompression may be lifesaving. However, the impact of craniotomy on the functional status is unclear (90; 52).

Initial loss of consciousness strongly predicts poor survival (42). Obliterated cisterns predict a poor outcome irrespective of treatment, and ventricular drainage alone is not indicated (180).

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 (191). 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 (197).

The 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 (118; 124; 113). 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 (114).

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 (52).

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 (96).

An alternative to tPA thrombolysis, still in the experimental stage, is transcranial MR-guided focused ultrasound (116).

Frameless, image-driven robotic stereotactic assistance (ROSA) of catheter insertion is a new development (03). A pilot study of CT-guided endoscopic surgery (Intraoperative CT–guided Endoscopic Surgery for Brain Hemorrhage, ICES) showed similar results to the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation, MSTIE, but lacked the power to detect a benefit (183). A meta-analysis of 28 studies shows that adding mild hypothermia to minimally invasive surgery improved neurologic outcomes and decreased mortality compared to surgery alone (57).

Transfer to another facility. Not all hospitals have neurosurgical services. Considering the uncertainty regarding the 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, even if they did undergo 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 (187).

Outcomes

Deciding too early not to resuscitate is an independent risk for poor outcomes. 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 (137).

Media

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Adrian Marchidann MD

Dr. Marchidann of Kings County Hospital has no relevant financial relationships to disclose.
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Editor

Steven R Levine MD

Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.
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Former Authors

Te-Long Hwang MD

Patient Profile

Age range of presentation: 45 to 65+ years
Sex preponderance: male>female, >1:1
Heredity: none
Population groups selectively affected: African Americans
Occupation groups selectively affected: none selectively affected

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Hypertensive intracerebral hemorrhage

Associated Disorders

Chronic hypertension
Intracerebral hemorrhage

Differential Diagnosis

amyloid angiopathy
drug-related intracerebral hemorrhage
anticoagulant-related intracerebral hemorrhage
intracerebral hemorrhage due to thrombolytic therapy
hematological disorders
- vascular malformations
- aneurysm
- brain tumor
- hemorrhagic infarction
- exposure to very cold weather
- dental pain from manipulation of the trigeminal nerve
- carotid endarterectomy
- correction of congenital heart defects
- cardiac transplantation

	• Uncontrolled blood pressure after a hemorrhagic stroke is associated with recurrent stroke and mortality.
	• Treatment of hypertension is the most important preventive measure for intracerebral hemorrhage.
	• Treatment of isolated systolic pressure is also important.
	• Target blood pressure control is 130/80 mmHg.

Hypertensive intracerebral hemorrhage

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Signs of Intracerebral Hemorrhage at Various Sites

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Table 2. Stages of Hemorrhage

Management

Outcomes

Special considerations

Pregnancy

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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