May. 04, 2021
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Basal ganglia intracerebral hemorrhage remains among the most severe of stroke types. This update highlights some important clinical trial results on intracerebral hemorrhage, including blood pressure management and surgical interventions. The author discusses these advances and updates on the epidemiology and pathophysiology of intracerebral hemorrhage.
• Intracerebral hemorrhage is a neurologic emergency that requires immediate neuroimaging to differentiate it from acute ischemic stroke.
• Intracerebral hemorrhage in the basal ganglia is usually caused by hypertension.
• Patients presenting within the first few hours have a high risk of hemorrhage expansion and neurologic deterioration.
• Prognosis is based on multiple factors, including volume and location of hemorrhage, age, level of consciousness, presence of intraventricular hemorrhage, and warfarin use.
• Coagulopathy, if present, should be corrected.
• Rapid blood pressure control is safe but does not improve the clinical outcome significantly.
• Clinical trials have failed to prove benefit of the surgical treatment.
• New endoscopic minimally invasive surgical techniques are being tested with encouraging results.
Intracerebral hemorrhage was described for the first time in 1658 by Wepfer in his treatise on apoplexy (54). He noted both intracerebral hemorrhage and subarachnoid hemorrhage in different patients. Through the years, intracerebral hemorrhage has also been termed "cerebral hemorrhage," "intracranial hemorrhage," “hemorrhagic stroke,” and "cerebral bleed." The advent of head CT has greatly improved the detection, localization, and characterization of brain hemorrhages. Intracranial hemorrhage refers to any bleeding within the cranial vault, including subdural and epidural hematomas and subarachnoid hemorrhage. Intracerebral hemorrhage refers specifically to bleeding within the brain parenchyma. The term “hemorrhagic stroke” is best avoided as its meaning varies widely – some use this term to indicate an ischemic stroke that has had hemorrhagic conversion and others to denote a primary intracerebral hemorrhage or even subarachnoid hemorrhage.
The clinical symptoms and signs vary depending on the size, location, and rate of expansion of the bleed. Symptoms can evolve over several minutes to hours due to hematoma expansion. Almost a third of patients have significant expansion of their hemorrhage in the first few hours after presentation, with an additional 12% having expansion in the next 20 hours (23).
The typical clinical features include focal neurologic signs, headache, nausea, vomiting, and alteration in the level of consciousness (72; 87). Not all these features occur in all patients. Elevated blood pressure is found in over 90% of patients acutely, even in absence of history of hypertension (126).
The most common location for a basal ganglia hemorrhage is the putamen (126; 87). Putaminal hemorrhage in the dominant hemisphere, if large, can produce aphasia, contralateral hemiparesis, hemisensory loss, contralateral visual field defects, and gaze deviation toward the side of the bleed. In the nondominant hemisphere, putaminal hemorrhage may cause neglect syndrome or apraxia, in addition to the motor and visual findings noted above. Significant mass effect or extension into the frontal horns of the ventricular system can produce obtundation or even coma at presentation. In uncal herniation, compression of the ipsilateral third nerve can cause either partial or complete palsy. Smaller bleeds produce subsets of these symptoms. Headache is common. Large bleeds or intraventricular extension may cause nausea, vomiting, and nuchal rigidity. Bilateral putaminal hemorrhages may cause cortical deafness (10) or a combination of amnesia and acalculia (166). Left putaminal lesion caused auditory agnosia for both verbal and nonverbal sounds (176). A patient with left basal ganglia hemorrhage had persistent moderate lightheadedness. The core vestibular projection, highlighted by diffusion tensor imaging, was discontinued at the basal ganglia level (99).
Caudate bleeding is less common, accounting for 5% to 7% of all intracerebral hemorrhages (169). Rupture into the ventricular system may cause headache, nausea, vomiting, and altered consciousness. Nuchal rigidity from the subarachnoid blood is common. Contralateral hemiparesis may also occur (169; 87). Transient horizontal gaze paresis has been reported. Involvement of the nucleus basalis may produce memory impairment (31; 169). Supranumerary phantom limb was also described in patients with basal ganglia hemorrhage (92).
Occasionally extremely small (less than 1.5 cm diameter) hemorrhages occur in the basal ganglia and internal capsule. Such hemorrhages cause symptoms resembling a lacunar infarction, emphasizing the need for brain imaging in all patients with sudden neurologic deficits (93). Outcome is generally very good.
A systematic review of all prospective studies that followed patients longitudinally after an intracerebral hemorrhage found a recurrence rate of 2.1% per patient-year in those patients who initially had a deep hemorrhage, compared to 4.4% per patient-year after a first lobar hemorrhage (13).
Complications of intracerebral hemorrhage can be divided into direct and indirect. Direct effects are caused by the local mass effect of hematoma and the surrounding edema. These include brain herniation (transfalcine, uncal) and midbrain compression. Hydrocephalus results from obstruction of the foramen of Monro or cerebral aqueduct or from a massive intraventricular hemorrhage.
Intracerebral hemorrhage is associated with higher mortality and more severe disability compared to ischemic stroke (15). The acute in-hospital mortality is between 30% to 50%. The prognosis relates to the size and location of the bleed, expansion of the original clot, presenting status, presence of intraventricular hemorrhage, and age of the patient (112; 155). Globus pallidus and putamen are associated with increased odds of worse disability whereas caudate nucleus is associated with lower mortality (44). The volume cut-off for poor outcome also depends on location, which is important for clinical trial design (103).
Fever within the first few days of intracerebral hemorrhage is an independent predictor of a poor prognosis (164).
The 30-day mortality is 40% to 50% (14; 20). Mortality is higher in elderly, African Americans, on warfarin, and in coma (39; 146; 157; 154; 50).
In a prospective cohort, patients on warfarin had larger initial hemorrhages, greater hemorrhage expansion within the first 72 hours, and 3 times higher mortality (62% versus 17%, P< 0.001) compared to those not on warfarin (37).
The “ICH Score" is a prognostic tool combining age, size of hemorrhage, Glasgow coma score, location (infratentorial or not), and presence of intraventricular hemorrhage into a composite factor that predicts mortality (68). The ICH Score is the sum of individual points assigned as follows:
Glasgow coma score of 3 to 4
Thirty-day mortality rates for patients with intracerebral hemorrhage scores of 0, 1, 2, 3, 4, and 5 or greater were 0%, 13%, 26%, 72%, 97%, and 100%, respectively. The score has been externally validated (32) and has been shown to be predictive of 12-month functional outcome (69).
Premature do-not-resuscitate orders are an independent risk factor for poor prognosis, as they lead to a self-fulfilling prophecy (16; 71). A modified intracerebral hemorrhage (MICH) score is more predictive of poor functional outcome and death at 72 hours from onset than at baseline, supporting the approach to delay discussions about withdrawal of care for a few days (114).
Several retrospective studies have correlated outcome with initial mean arterial blood pressure. Higher blood pressure is associated with increased risk of death and dependency (38; 184). However, definitive conclusions cannot be drawn about an independent role for blood pressure in prognosis. Elevated blood sugar levels are also associated with a worse outcome, even in non-diabetic patients (138).
Diffusion tensor imaging, a novel MRI technique, may better prognosticate recovery by measuring the mean fractional anisotropy, a measure of neuronal destruction. Higher fractional anisotropy on pons correlated with better motor recovery (124).
Clinical seizures are uncommon after basal ganglia hemorrhage. In a large observational study, only 4 out of 382 patients with deep hemorrhages had seizures (139). However, subclinical electrographic seizures have been reported in 20% to 30% of patients with intracerebral hemorrhage, including those with basal ganglia hemorrhage (178). Such seizures were associated with neurologic deterioration and progressive midline shift. However, there was no significant difference in outcome between patients with and without subclinical electrographic seizures.
Indirect complications from intracerebral hemorrhage are related to patient immobilization, indwelling vascular catheters, urinary catheters, and intubation. These include pneumonia, urinary tract infection, sepsis, deep venous thrombosis, and pulmonary embolism. In a study of hospital records from 1979 to 2003, 1,606,000 patients had hemorrhagic stroke. Pulmonary embolism occurred in 11,000 (0.68%) and deep venous thrombosis occurred in 22,000 (1.37%). These rates did not change over 25 years of observation (167). Ventilator-acquired pneumonia and infections from indwelling urinary, venous, and arterial catheters are common and can prolong hospitalization and worsen outcome after intracerebral hemorrhage.
Postoperative rehemorrhage risk was increased by previous use of antiplatelet medication and presence of intraventricular hemorrhage in a study (168) and by history of diabetes mellitus and midline shift on admission imaging in another (148).
Chronic intracerebral hematoma is rare and may be due to uncontrolled hypertension, trauma, or coagulopathy (188). There are 2 histological types of hematomas: encapsulated caused by a vascular anomaly and liquefied caused by hypertension (142). In a small retrospective study of 112 patients with intracerebral hemorrhage, 4 patients (4.9%) developed chronically expanding intracerebral hematoma and only the layer sign was significantly related/associated with it (165).
Diffusion tensor imaging may help predict outcome in basal ganglia hemorrhage (124).
A 56-year-old man was brought to the emergency room after collapsing at home. That morning, he complained of a severe left-sided headache. Several minutes later, he developed slurred speech and weakness of the right arm and leg. He went to bed hoping that the symptoms would resolve. His wife attempted to awaken him in 1 hour and found him difficult to arouse. When he was moved from the bed he appeared to be confused and had trouble walking. When placed in a chair, he collapsed to the floor and was then taken to the emergency room.
His past medical history was significant for hypertension for roughly 15 years. He took antihypertensive medications irregularly and had not been taking his medications for the past 3 weeks. He also smoked roughly 1 pack of cigarettes per day for 30 years and drank 5 beers per day.
On physical exam he was stuporous, with a blood pressure of 200/105, pulse 66, respirations 20, without fever. He was intubated to protect his airway. His neck was somewhat stiff. Neurologic examination showed no response to verbal stimulation. His pupils were 4 mm and reactive. Eyes showed left gaze deviation with a normal response to doll's eyes maneuver. Corneal reflexes were intact. There was right facial weakness and the gag reflex was weak. Motor exam showed flicker movement on the right to deep pain but purposeful withdrawal on the left. Deep tendon reflexes were increased on the right.
A head CT scan showed a 40 ml intracerebral hemorrhage centered in the left putamen, with blood extending into both lateral ventricles. Mild left-to-right midline shift was also seen. Laboratory studies, including platelet count, prothrombin time, and partial prothromboplastin time, were normal.
The patient was admitted to a neurologic intensive care unit. His head was elevated to 30 degrees, and he received close neurologic monitoring. His elevated blood pressure was aggressively treated with an intravenous nicardipine infusion. He was ventilated to normocarbia. A ventriculostomy was placed to drain blood and cerebrospinal fluid. His intracranial pressure was initially 21 mm Hg but decreased quickly and then remained normal. Three days later, the ventriculostomy was removed and he was extubated on hospital day 7. Two weeks after admission, he was discharged to an acute rehabilitation facility.
Although intracerebral hemorrhage can be due to an underlying anatomic lesion such as a vascular malformation, cerebral venous sinus thrombosis, or bleeding into a tumor, our discussion will be limited to spontaneous hemorrhage, which by definition is not associated with these factors and is not caused by trauma.
Hypertension is the most important risk factor for spontaneous, deep intracerebral hemorrhage.
Differences in methodology explain the variability in reports of hypertension as the cause of intracerebral hemorrhage, ranging from 56% to 89% (126; 53; 24; 163). One large study with rigid criteria for defining preexisting hypertension found that 73% of patients with deep intracerebral hemorrhage had a history of hypertension (21).
Hypertension is a greater risk factor for cerebral hemorrhage in Asians than in whites (191). The areas most affected by intracerebral hemorrhage are also common sites for small vessel ischemic stroke (ie, basal ganglia, thalamus, pons), supporting the concept that damaged small vessels either rupture causing intracerebral hemorrhage or become occluded causing a lacunar stroke.
The distribution of small vessel disease predicts the cause of the basal ganglia hemorrhage; lobar lacunes are associated with cerebral amyloid angiopathy whereas deep lacunes with hypertensive hemorrhage (137). Perivascular spaces in both basal ganglia and center semiovale are associated with transient ischemic attack or ischemic stroke, but not with intracerebral hemorrhage (102). In a study of 1678 participants, MRI burden of dilated perivascular spaces in basal ganglia was associated with a higher risk of any stroke and intracerebral hemorrhage even after correction for vascular risk factors (42). The number of perforators seen on 7T brain MRI was lower in patients with deep intracerebral hemorrhage (P = 0.02) than in controls. The pulsatility index in the basal ganglia was higher in deep intracerebral hemorrhage patients (1.02±0.11, P = 0.11) than in controls (56).
Diabetes and renal and liver failure are independent risk factors for cerebral hemorrhage (131; 79; 34). Other risk factors include male gender, cigarette smoking, and drinking more than 2 alcoholic units daily (52; 09; 98; 149; 80).
The role of low cholesterol in intracerebral hemorrhage is less clear. A large population-based study in Japanese men found that the risk of death from intracranial hemorrhage was 3 times higher in hypertensive men with serum cholesterol levels under 160 mg/dL compared to those with higher cholesterol levels (81). In contrast, a large study in South Korean autoworkers found no such association (170). The concern that statins increase the risk of intracerebral hemorrhage has not been confirmed. The Pravastatin Pooling Project reported no effect of pravastatin 40 mg on the risk of intracerebral hemorrhage in 2 large trials (27). Subsequently, however, a post-hoc analysis of the SPARCL trial reported a small increase in the incidence of intracerebral hemorrhage among the patients randomized to atorvastatin 80 mg who had prior hemorrhage, older age, stage 2 hypertension, and male gender (59). The reason for this association was not related to reduction in LDL levels (05).
Warfarin increases the risk of intracerebral hemorrhage, especially in patients older than 85 years and with supratherapeutic levels (78; 46). The incidence of anticoagulant-associated intracerebral hemorrhage has increased significantly with increasing use of warfarin (49). Aspirin use also increases the relative risk of intracerebral hemorrhage by 40%, although the absolute increased risk is small (approximately 0.15% per year) (65). Clopidogrel appears to be associated with a similar risk. The combination of aspirin and clopidogrel may increase the risk of intracerebral hemorrhage in an additive fashion (189). Overall, it has been estimated that about 10% of all intracerebral hemorrhages are related to the use of antithrombotic agents (65). Recent thrombolytic therapy also increases the risk of intracerebral hemorrhage (40).
The appetite suppressants and cold and cough medications containing the sympathomimetic agent phenylpropanolamine, currently banned from market, have also been responsible for intracerebral stroke (90).
Other sympathomimetic drugs, including cocaine and amphetamine or amphetamine derivatives, may cause intracerebral hemorrhage (108). In an autopsy series of 17 young patients with fatal intracranial hemorrhages, all 5 patients with basal ganglionic hemorrhages were cocaine positive (132). Cannabis was associated with basal ganglia hemorrhage in only 3 cases (12).
Certain genetic mutations are associated with intracerebral hemorrhage. COL4A1 mutations that impair COL4A1 secretion are associated with sporadic intracerebral hemorrhage (183). The apolipoprotein epsilon 2 and epsilon 4 alleles increase the risk of lobar intracerebral hemorrhage whereas the epsilon 4 allele also increases the risk of deep intracerebral hemorrhage (17).
The cause of spontaneous intracerebral hemorrhage is the rupture of a small blood vessel within the brain parenchyma. Most commonly, hypertension leads to arteriolar damage, leaving the vessel at increased risk of rupture. It was thought that longstanding hypertension leads to the formation of microaneurysms in the vessel wall, which subsequently rupture. One study found such aneurysms in the brains of 15 of 16 hypertensive patients (156). Another study found aneurysms in 46% of hypertensives and in 85% of patients with large intracerebral hemorrhages (33). However, it was later suggested by Fisher that lipohyalinosis of small vessels leads to vessel rupture and subsequent intracerebral hemorrhage, without the formation of aneurysms (48). Electron microscopy reveals severe arterial arteriosclerotic changes, including degeneration of the media and fragmentation and atrophy of the smooth muscle, without aneurysms, usually at the middle and distal portions of perforating arteries (173).
Cerebral amyloid angiopathy (due to deposition of beta-amyloid in vessel walls) is presumed to be the cause of many cases of lobar hemorrhages, especially in the elderly (181; 150). In a pathologic study of 129 brains of patients with hypertension, the authors also found a weak association between amyloid angiopathy and deep intracerebral hemorrhage (150).
Forms of hereditary intracerebral hemorrhage are seen among Dutch and Icelandic populations (84; 63). Bleeds in these patients are due to mutations in the amyloid precursor protein gene or the cystatin gene, respectively (110; 109). A search for these mutations in patients with sporadic intracerebral hemorrhage was negative (61).
After the initial bleeding, a cascade of events leads to secondary neuronal injury. Infiltration of leukocytes and activation of resident microglia result in the release of cytokines, including TNF-alpha (121; 76) and matrix metalloproteinases (03; 186) that contribute to neuronal death. Edema develops over hours to days due to clot retraction (180) followed by breakdown of the blood-brain barrier (187; 25) and leukocyte trafficking into the brain (113; 161). The triggers and mechanisms of injury have not yet been fully elucidated but likely include thrombin (106; 185), activation of Toll-like receptor 4 (161), and substances released from red blood cells, including iron and hemoglobin degradation products (77; 74). Iron-mediated damage has generated great interest, as the iron chelator deferoxamine has been shown to be protective against secondary injury in animal models (75; 134). These pathways offer opportunities for development of new treatments for intracerebral hemorrhage and are an area of active research.
The incidence of spontaneous intracerebral hemorrhage is 37,000 to 52,000 cases per year in the United States (19). Although the incidence decreased from 1950 to 1979, likely as a result of improved treatment of hypertension (53), it is expected to double by the year 2050, probably due to the aging of the population and changing racial demographics (175). Men have a higher risk of deep intracerebral hemorrhage than woman, with a relative risk of 1.8 (100). The incidence of intracerebral hemorrhage increases with age, roughly doubling the relative risk with every 10-year increase in age (09). Lower socioeconomic status is also associated with increased risk of hemorrhage (82).
Several racial groups have a higher incidence of intracerebral hemorrhage. In northern Manhattan, the relative risk for deep intracerebral hemorrhage in blacks compared to whites was 4.8 and 3.7 in Hispanics compared to whites (100). In the Cincinnati area, the annual incidence rates of intracerebral hemorrhage per 100,000 adults were 48.9 in blacks and 26.6 in whites. For deep intracerebral hemorrhage only, the annual incidence rate per 100,000 was 25.7 in blacks compared to 13.0 in whites (51). The highest disparity between intracerebral hemorrhage rates of blacks and whites occurred at younger ages (96). Worldwide, the Japanese have a high rate of intracerebral hemorrhage, with an incidence of 55 per 100,000 (171).
Improved treatment of hypertension has led to significant decline in incidence and mortality of intracerebral hemorrhage during the middle of the twentieth century (53). In patients with prior stroke, the combination of a thiazide diuretic and an angiotensin-converting-enzyme (ACE) inhibitor reduced blood pressure by a mean 9/4 mm Hg, which corresponded to a relative risk reduction of 50% for intracerebral hemorrhage (29).
In patients with a history of hypertensive intracerebral hemorrhage, reduction of diastolic blood pressure significantly reduced the recurrence of intracerebral hemorrhage from 10.0% per patient-year in patients with diastolic BP greater than 90 mm Hg to less than 1.5% in those with lower diastolic BP (p less than 0.001). No patients with diastolic BP less than 70 mm Hg experienced rebleeding (08).
Moderate and high levels of exercise appear to reduce the risk of cerebral hemorrhage (105). Reduction of other risk factors, including excessive alcohol intake and cigarette smoking, should also reduce the risk of intracerebral hemorrhage.
The differential diagnosis for an abrupt change in neurologic status includes both ischemic stroke and intracerebral hemorrhage, migraine, seizure, encephalitis, and tumor. Noncontrast head CT scan can quickly identify hemorrhage and rule out most of these diagnoses.
The differential diagnosis of intracerebral hemorrhage includes hemorrhagic transformation of an ischemic stroke, bleeding from a tumorvascular malformation, aneurysm (mycotic, saccular), abscess or other infectious lesions, traumatic contusion, vasculitis or vasculopathy (including amyloid angiopathy and Moyamoya disease), hypertensive encephalopathy, cerebral venous sinus thrombosis with hemorrhagic venous infarction, and acute hemorrhagic leukoencephalopathy (18; 88; 87; 174). Among these various disorders, unsuspected arteriovenous malformations were the most common lesion found after investigation with angiography (64).
Some tumors have a propensity for undergoing hemorrhagic transformation. Metastatic melanoma, bronchogenic carcinoma, choriocarcinoma, and renal cell carcinoma carry a high risk of hemorrhage. Of the primary brain tumors, glioblastoma multiforme, followed by oligodendroglioma, are the most likely to bleed (125). In a series of 2514 evacuated hematomas, 110 were found to be due to a tumor (4.4%) (111). Glioblastomas were the most common tumor (33%), followed by metastases (21%), anaplastic gliomas (13%), low-grade gliomas (12%), meningiomas (12%), adenomas (5%), hemangioblastomas (2%), and melanomas (2%).
Cerebral venous sinus thrombosis is an important cause of intracerebral hemorrhage to identify, as the treatment is distinct form that of other causes of intracerebral hemorrhage. Intracerebral hemorrhage due to cerebral vein thrombosis occurs due to impaired venous drainage and venous bleeding. Clues to the presence of cerebral vein thrombosis include subacute onset of neurologic symptoms, especially headache and visual symptoms, young age, and presence of a known hypercoagulable state.
In addition to the clinical presentation and examination, brain imaging study is crucial for making an accurate diagnosis of intracerebral hemorrhage. A noncontrast head CT will show a high-density lesion consistent with a hematoma and is the test of choice at most centers because of availability, cost, and speed of acquisition.
MRI may also be used to identify acute hemorrhage, although MRI characteristics of intracerebral hemorrhage are more complex.
Compared to CT within the first 6 hours of a neurologic event, MRI has good sensitivity for hemorrhage. Gradient recalled echo sequences on brain MRI are superior to CT in detecting acute hemorrhagic transformation within an infarct and chronic hemorrhages. There were 3 patients that had acute hemorrhage detected by CT and were misclassified as chronic hemorrhage on MRI; all were small hemorrhages (91). The utility of early MRI/MRA depends on age of the patient. In a retrospective analysis of 400 patients with intracerebral hemorrhage, structural abnormalities were detected in 12.5% of patients. The diagnostic yield of MRI/MRA was 0% in patients older than 65 years with basal ganglia or thalamic hemorrhages (28).
Microhemorrhages seen on gradient echo have been associated with an increased risk of symptomatic cerebral hemorrhages (45). The location of the micro-bleeds may also be associated with the location of a symptomatic hemorrhage (107).
MRI-visible perivascular spaces seen predominantly in basal ganglia are associated more often with hypertensive angiopathy whereas those predominantly seen in centrum semiovale and associated with cortical surface siderosis are seen with lobar hemorrhages (30).
Contrast-enhanced CT or MRI and CT and MRI angiography help in identifying an underlying lesion like arteriovenous malformation, dural arterio-venous fistula, cerebral vein thrombosis, acute hemorrhagic leukoencephalitis, hemorrhagic transformation of infarction, or tumors. Advanced imaging studies, eg, 99mTc-MIBI SPECT, may also be helpful in determining the presence of underlying tumor (125).
CT angiography may also predict hemorrhage expansion in the acute phase. The “spot sign,” a hyperdense spot within the intracerebral hemorrhage, is caused by extravasation of contrast. In a prospective cohort of 39 patients imaged within 3 hours of hemorrhage onset, the positive predictive value of the spot sign for significant hemorrhage expansion was 77% and the negative predictive value was 96% (179). In a retrospective cohort imaged at a later range of time points, the spot sign had a much lower positive predictive value (24%) but maintained a significant negative predictive value of 98% (58). The clinical utility of using the CT angiography spot sign to predict expansion remains to be validated in a prospective trial. The “spot sign” was also demonstrated by extravasation of gadolinium during a cerebral MRI performed in 1 patient with rapidly expanding hematoma (04).
Catheter angiography is the gold standard for identifying underlying vascular lesions. The most common abnormalities seen with angiography are arteriovenous malformation and aneurysm (64). In a prospective study of 206 patients who underwent both CT scan and angiography, those with putaminal, thalamic, or posterior fossa intracerebral hemorrhage cases were divided into 4 groups according to age (45 years old or younger and over 45 years old) and whether they had preexisting hypertension. The angiographic yield was 48% in the younger normotensive group with putaminal, thalamic, or posterior fossa intracerebral hemorrhage, and 63% in those with lobar intracerebral hemorrhage. In older hypertensive patients, the yield was 0% with deep intracerebral hemorrhage and 10% with lobar intracerebral hemorrhage (192). Thus, older patients with a history of hypertension and basal ganglia hemorrhages do not usually need angiography.
In cases of a suspected tumor, a systemic workup to rule out metastasis from another source (lung, melanoma, renal cell, or other) is indicated. Complete blood count and coagulation studies to rule out bleeding diathesis should be performed as well as urine and blood toxicology.
The goals of therapy are to prevent hematoma expansion and recurrent hemorrhage, reduce intracranial pressure while optimizing cerebral perfusion, prevent tissue shifts, and preserve or improve neurologic function. The treatment should follow the American Heart Association/American Stroke Association guidelines that are updated periodically (70).
Disposition. Mortality is lower following admission to a neurologic intensive care unit as compared to general intensive care units (41; 152). Not all hospitals have neurosurgical services. A study including 1175 cases of intracerebral hemorrhage showed that the transferred patients had lower risk of death relative to those remaining at the referral center, whether they had surgery or not (01). Early decision to not resuscitate accounted for much of the observed difference. Data from a nationwide inpatient sample shows 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.
Correction of coagulopathy. Any coagulopathy must be emergently reversed. This includes the administration of protamine for heparin-induced bleeding; vitamin K and either fresh frozen plasma or prothrombin complex concentrates for warfarin-associated intracerebral hemorrhages; idarucizumab for dabigatran; andexanet alpha for apixaban; and rivaroxaban, cryoprecipitate, and platelets for hemorrhage due to thrombolytics. Platelet transfusions should be used in patients with thrombocytopenia.
Blood pressure management. Elevated blood pressure is common in acute intracerebral hemorrhage (143). The patients with higher blood pressure have worse prognosis (38). In several studies, hypertension was associated with hematoma expansion (89; 133), but this relation was not confirmed, suggesting that in some patients, the hematoma growth may be the cause of high blood pressure (83). In another study, although none of the blood pressure variables were related to hematoma growth, the systolic blood pressure load defined as the proportion of readings greater than 180 mmHg was associated with hematoma growth (151).
Aggressive lowering of blood pressure does not jeopardize the perihematomal cerebral perfusion. Although hypoperfusion was noted in this region, no ischemia was detected, as the local metabolism was reduced to an even greater degree (145; 190; 94) and the cerebrovascular reactivity is preserved (141). Another study using diffusion- and perfusion-weighted MRI showed no evidence for a perihemorrhagic ischemic penumbra (162).
Intensive decrease of systolic blood pressure within 6 hours from onset to values lower than 140 mmHg decreased hematoma growth without an improved clinical outcome at 90 days (07). The follow-up study failed to demonstrate decrease of death and severe disability; however, the functional outcome was improved in patients who underwent intensive therapy (06). Nevertheless, larger reductions of systolic blood pressure (greater than 20 mmHg) within the first hour lowered the risk of poor outcome (182). A metaanalysis of 4 studies including 3315 patients found that intensive blood pressure reduction is safe (177).
The ATACH open-label pilot trial attempted to define the optimal blood pressure target for intensive management within 6 hours from onset. Although safe, the neurologic deterioration, adverse events, and 3-month mortality were lower than expected at all blood pressure tiers: 170 to 200 mmHg, 140 to 170 mmHg, and 110 to 140 mmHg (11). The ATACH-II trial was stopped prematurely because achieving the target systolic blood pressure of 110 to 139 mmHg failed to decrease mortality and disability compared to a less restrictive target of 140 to 179 mmHg (144). However, in the same study, intensive blood pressure reduction led to decreased perihematomal edema, which is associated with poor outcome if present in basal ganglia (104).
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. Acute lowering of systolic blood pressure to 140 mmHg for those patients presenting with a systolic blood pressure of 150 to 220 mmHg appears safe. Chronic hypertension tends to shift the cerebral circulation autoregulation curve to the right (140). Rapidly lowering blood pressure to levels below which autoregulation is effective may cause ischemia in patients with chronic hypertension even at normal blood pressure levels, thus, negating the benefits of rapid blood pressure control. Those patients in whom systolic blood pressure was lowered below 130 mmHg had, on brain MRI, ischemic lesions in addition to intracerebral hemorrhage (26).
In a small study, atenolol was found to decrease mortality, SISRS, and pneumonia, compared to amlodipine (86). Insufficient data exist regarding treatment of severe, sustained systolic blood pressure higher than 220 mmHg or of hematomas that are large and severe enough to require decompressive surgery.
Nitrate-based drugs (nitroprusside, nitroglycerin) and nifedipine can increase the intracranial pressure and are best avoided (35; 67). Antihypertensives less likely to increase intracranial pressure include beta-blockers (labetalol, esmolol), angiotensin-converting-enzyme inhibitors (enalapril, captopril), and nicardipine. Fast-acting, titratable, intravenously administered agents are preferred.
Recombinant activated factor rFVIIa. The hemostatic agent rFVIIa may enhance thrombin generation on the surface of activated platelets and potentially reduce the hematoma growth. Although promising in a phase IIB trial (120), the rFVIIa failed to improve the clinical outcome (22; 119). The future of rFVIIa therapy in intracerebral hemorrhage is uncertain. A trial selecting patients with the spot sign for treatment with rFVIIa failed to show improved outcome compared with placebo (57).
Medical complications. Fluid and electrolyte balance should be monitored, particularly for those treated with hyperosmolar agents and diuretics. Inappropriate antidiuretic hormone secretion can occur in patients with intracerebral hemorrhage. In general, patients should receive nothing by mouth for the first 24 to 48 hours, and normocaloric parenteral nutrition or enteral nutrition (via Dobbhoff tube) should be instituted within 48 hours.
Dysphagia was diagnosed in 68% of patients with intracerebral hemorrhage (172). All patients should undergo formal dysphagia screening to prevent aspiration pneumonia (73). Bedside examination, including surveying for coughing while swallowing 3 ounces of water, has a good sensitivity and specificity for risk of aspiration in patients with neurologic injury (117). Percutaneous endoscopic gastrostomy was needed in 25% of intracerebral hemorrhage cases (95).
Approximately 0.3% of patients with intracerebral hemorrhage develop acute myocardial infarction during the first 3 days of treatment, and this association increased mortality at discharge (14.5% vs. 2%) (55). Elevated troponin was associated with increased in-hospital mortality in 1 study (160) but not at 30 days if not associated with ECG changes in another study (116).
Neurogenic pulmonary edema developed in 35% of patients with intracerebral hemorrhage and is associated with 37% mortality at 1 year (85). Acute respiratory distress syndrome occurs in 27% of patients with intracerebral hemorrhage; it is common in patients ventilated with a high tidal volume and is associated with in-patient mortality (43). Low tidal volume ventilation with attention to avoid increased intracranial pressure or hypoxia is a reasonable strategy in these patients (115).
Renal failure occurred in 8% of patients with intracerebral hemorrhage and is not increased by CT angiography (135). Renal dysfunction is also associated with deep cerebral microbleeds in patients with intracerebral hemorrhage (101). Acute renal failure is associated with higher rates of in-hospital mortality and moderate to severe disability at discharge (159).
Glucose level should be monitored, and both hypoglycemia and hyperglycemia should be avoided. It is reasonable to treat fever, but therapeutic cooling is still investigational at this time.
Deep vein thrombosis and pulmonary embolism can be prevented by heparin (5000 IU subcutaneous injections every 12 hours) or low molecular weight heparin in the immobilized patients after 1 to 4 days from onset. Pneumatic devices also decrease the risk of pulmonary embolism (70). If deep venous thrombosis occurs, a vena cava filter should be considered, as anticoagulation is contraindicated.
Clinical seizures after deep intracerebral hemorrhage are rare. Prophylactic anticonvulsants do not decrease the incidence of seizures (139) and may be associated with worse outcome (123).
Aspiration pneumonia can be prevented by formal speech and swallow evaluations before oral intake in all stroke patients. Foley catheters use should be minimized to prevent urinary tract infections. Fever should be immediately evaluated and aggressively treated with acetaminophen, ice packs, and cooling blankets if necessary. Duration of fever is an independent prognostic factor for poor outcome after intracerebral hemorrhage (164).
In a small study of 30 patients with intracerebral hemorrhage, early administration of fluoxetine was safe and improved the Fugl-Meyer motor scale at 90 compared with placebo (118).
Surgical treatment. Preoperative state of alertness and hematoma volume are the main determinants of outcome. A Glasgow Coma Scale score of less than 8 and a hematoma volume greater than 60 ml had a mortality rate of 91% (20). Intraventricular extension of hemorrhage is associated with worse outcome (122).
The large, multicenter International Surgical Trial for Intracerebral Hemorrhage (STICH) enrolled 1033 patients from 83 centers in 27 countries and compared surgery to conservative treatment. Surgery was performed at a median of 30 hours after onset. There was no benefit from surgery in patients with hemorrhage. Limitations of this study include a high crossover rate (25%) from medical to surgical treatment, potential bias toward inclusion of patients least likely to benefit from surgery, and heterogeneity of surgical practices for intracerebral hemorrhage evacuation (122).
Another randomized study of subcortical or putaminal intracerebral hemorrhage larger than 30 mL within 8 hours from ictus showed improved functional outcome compared to medical treatment but no benefit in overall survival (136).
Optimal timing of surgery for supratentorial hemorrhage is unknown. A metaanalysis of 8 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. Patients with basal ganglia hemorrhage did not benefit from early surgery (62). Ultra-early (within 4 hours from onset) surgery was associated with increased risk of rebleeding and mortality (129).
Minimally invasive surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE trial) reduced the clot size and edema (128; 130). Clinical efficacy will be evaluated in the ongoing phase III trial. A systematic review of minimally invasive surgery with or without thrombolysis found 11 studies, of which only 2 were of high quality. Minimally invasive surgery for primary supratentorial hemorrhage was associated with a significant reduction in the relative risk of death when compared to craniotomy or medical management (147).
Endoscopic surgery has shown promise in small studies. Real-time ultrasound guided endoscopic surgery may minimize brain injury during basal ganglia hematoma evacuation (158). A metaanalysis of 7 studies that used minimally invasive surgery did not demonstrate superiority to medical management (02). However, a more recent study showed decreased mortality of minimally invasive endoscopic hematoma evacuation compared with medical management (60). One potential alternative to tPA administration for clot lysis, still in the experimental stage, is transcranial MR-guided focused ultrasound (Monteith et el 2013). The INVEST trial is an ongoing randomized, controlled trial that aims to investigate the safety and efficacy of image-guided minimally invasive endoscopic surgery with Apollo device in comparison with best medical management for supratentorial intracerebral hemorrhage (47). The success of the endoscopic hematoma evacuation depends on the experience of the operator. Renal failure on hemodialysis and liver cirrhosis were associated with poor removal rate (66). The impact on the clinical outcome of these interventions is not yet known, and more studies are needed before they can be recommended.
Large hemorrhages may increase the intracranial pressure leading to decreased consciousness. Reduction of increased intracranial pressure follows the same steps used in other conditions (153). An intracranial pressure monitor in patients with a Glasgow coma score of less than 9 may guide optimization of intracranial pressure and cerebral perfusion pressure when the neurologic examination is unreliable due to decreased level of consciousness. Supportive measures include maintaining a straight neck position and reducing agitation and pain. Ventriculostomy can be used to measure and adjust the intracranial pressure by removing cerebrospinal fluid (153). In all cases, careful attention must be given to the cerebral perfusion pressure, which is the mean arterial blood pressure minus intracranial pressure. Interventions that reduce cerebral perfusion pressure below 50 to 60 mm Hg may have deleterious effects on neuronal function. Hyperventilation to pCO2 30 to 35 mm Hg and osmotic diuretics such as mannitol are useful temporizing measures but do not provide long-term reduction in intracranial pressure. The effectiveness of mannitol was evaluated in a trial of 141 patients with temporal lobe intracerebral hemorrhage and evidence of herniation (coma, enlarged pupil) who were going emergently to the operating room for hematoma evacuation. They were randomized to low-dose (0.7 g/kg) or high-dose (1.4 g/kg) mannitol. High-dose mannitol was associated with significantly better 6-month clinical outcomes (p < 0.005) (36). Hypertonic saline is another effective treatment for elevated intracranial pressure. Clinical outcomes have not been prospectively compared between the 2 treatments.
The Baltimore-Washington Cooperative Young Stroke Study found the risk of intracerebral hemorrhage during pregnancy was 2.5 times greater than for nonpregnant women of similar age and race. This relative risk was increased dramatically at 28.3 in the 6 weeks postpartum (97).
No evidence exists to suggest that general anesthesia causes or precipitates intracerebral hemorrhage. Anesthetic agents that cause a significant increase in intracranial pressure or a dramatic fall in blood pressure may be deleterious when given to patients with large intracerebral hemorrhages.
Adrian Marchidann MD
Dr. Marchidann of Kings County Hospital owns stock in Lilly, Merck, Pfizer, Abbot, Aeterna Zentaris, and Illumina.See Profile
Steven R Levine MD
Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
May. 04, 2021
Stroke & Vascular Disorders
Apr. 15, 2021
Stroke & Vascular Disorders
Mar. 18, 2021
Stroke & Vascular Disorders
Mar. 18, 2021
Stroke & Vascular Disorders
Mar. 18, 2021
Stroke & Vascular Disorders
Mar. 18, 2021
Mar. 10, 2021
Stroke & Vascular Disorders
Mar. 04, 2021