Neuropharmacology & Neurotherapeutics
Gene therapy of cerebrovascular disease
Aug. 24, 2021
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Basal ganglia hemorrhage is one of the most severe types of stroke. This update highlights important clinical trial results on the treatment of intracerebral hemorrhage, including blood pressure management and surgery.
• Intracerebral hemorrhage is a neurologic emergency that requires immediate diagnosis and treatment.
• The most common cause of basal ganglia is hypertension.
• The risk of hematoma expansion and neurologic deterioration is highest within the first few hours after presentation.
• Outcome depends on volume, location, age, level of consciousness, intraventricular extension, and warfarin use.
• Coagulopathy, if present, should be corrected.
• Rapid blood pressure control is safe but does not improve the clinical outcome significantly.
• Surgical treatment has a limited role in the treatment of intracerebral hemorrhage.
• 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 (58). He described both intracerebral hemorrhage and subarachnoid hemorrhage. 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 it is vague.
• Most patients with basal ganglia hemorrhage have high blood pressure.
• The neurologic deficits depend on the location, size, and expansion of the hematoma.
• The small hemorrhages may resemble lacunar infarctions, whereas the large ones may present as coma.
The clinical symptoms and signs depend 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 hemorrhages expand within the first few hours after presentation, with an additional 12% having expansion in the next 20 hours (25). A large hematoma may present as obtundation or even coma, whereas a small hemorrhage may be clinically confused with lacunar infarction (97).
The typical clinical features include focal neurologic signs, headache, nausea, vomiting, and decreased level of consciousness (76; 91). Elevated blood pressure is found in over 90% of patients acutely, even in absence of history of hypertension (130).
The most common location for a basal ganglia hemorrhage is the putamen (130; 91). Putaminal hemorrhage in the dominant hemisphere may cause aphasia, contralateral hemiparesis, hemisensory loss, visual field defects, and gaze deviation towards the bleed. In the nondominant hemisphere, putaminal hemorrhage may cause additional neglect or apraxia. Uncal herniation may cause palsy of the ipsilateral third nerve. Other symptoms include auditory agnosia (183), cortical deafness (11), amnesia and acalculia (171), persistent lightheadedness (103), memory impairment (33; 175), or supernumerary phantom limb (96).
Caudate bleeding is less common, accounting for 5% to 7% of all intracerebral hemorrhages (175). Rupture into the ventricular system may cause nuchal rigidity, headache, nausea, vomiting, and decreased consciousness. Contralateral hemiparesis may also occur (175; 91).
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 (15).
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 transfalcine and uncal herniation as well as 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 (17). The acute in-hospital mortality is between 30% and 50%. The prognosis relates to the size and location of the bleed, expansion, intraventricular extension, presenting status, and age of the patient (116; 160). The volume cutoff for poor outcome also depends on location (107). Globus pallidus and putamen lesions are associated with worse disability and mortality (48). Fever is an independent predictor of poor prognosis (169).
The mortality rate is 50% at 30 days and 62% at 1 year according to the Oxfordshire Community Stroke Project (16). Mortality is higher in elderly, African Americans, on warfarin, and in coma (42; 151; 162; 159; 54).
Warfarin is associated with a larger initial hemorrhage, greater expansion, and higher mortality (62% versus 17%, P< 0.001) (40).
The “ICH Score" predicts mortality at 1 month (72). 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 (34) and has been shown to be predictive of 12-month functional outcome (73).
A premature do-not-resuscitate order is an independent risk factor for poor prognosis, as it leads to a self-fulfilling prophecy (18; 75). 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 (118).
Retrospective studies have suggested an increased risk of dependency and death with higher initial mean arterial blood pressure (41; 191). 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 (142).
Diffusion tensor imaging may better prognosticate recovery by using the mean fractional anisotropy as a measure of neuronal destruction (128).
Clinical seizures are rare after basal ganglia hemorrhage (143). However, subclinical electrographic seizures have been reported in 20% to 30% of patients with intracerebral hemorrhage, including those with basal ganglia hemorrhage (185). These 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 include pneumonia, urinary tract infection, sepsis, deep venous thrombosis, and pulmonary embolism. These complications may prolong hospitalization and worsen outcome. 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 (172).
The risk of hemorrhage recurrence after frameless stereotactic blood aspiration was increased by previous use of antiplatelet medication and the presence of intraventricular hemorrhage in a study (173) and by a history of diabetes mellitus and midline shift on admission imaging in another (153).
Chronic intracerebral hematoma is rare and may be due to uncontrolled hypertension, trauma, or coagulopathy (196). There are 2 histological types of hematomas: encapsulated caused by a vascular anomaly and liquefied caused by hypertension (147). 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 (170).
A 56-year-old man was brought to the emergency room after collapsing at home. 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 15 years. He was not compliant with the antihypertensive medications. He smoked a pack of cigarettes per day for 30 years and drank 5 beers per day.
On examination 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 were deviated to the left, with a normal response to doll's eyes maneuver. Corneal reflexes were intact. The right side of his face was weak, as was the gag reflex. 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 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 and coagulation profile, were normal.
The patient was admitted to a neurologic intensive care unit. His head was elevated to 30 degrees, and his neurologic status was closely monitored. He was ventilated to normocarbia. The elevated blood pressure was treated with intravenous nicardipine. 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% (130; 57; 26; 168). One large study using older criteria for hypertension (systolic blood pressure more than 160 mmHg or diastolic blood pressure more than 90 mmHg) found that 73% of patients with deep intracerebral hemorrhage were hypertensive (23).
Hypertension is a greater risk factor for cerebral hemorrhage in Asians than in whites (199).
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 (141). Perivascular spaces in both basal ganglia and center semiovale are associated with transient ischemic attack or ischemic stroke, but not with intracerebral hemorrhage (106). 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 (46). 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 (60).
Diabetes and renal and liver failure are independent risk factors for cerebral hemorrhage (135; 83; 37). Other risk factors include male gender, cigarette smoking, and drinking more than 2 alcoholic units daily (56; 10; 102; 154; 84).
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 (85). In contrast, a large study in South Korean autoworkers found no such association (177). 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 (29). 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 (63). 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 (82; 50). The incidence of anticoagulant-associated intracerebral hemorrhage has increased significantly with increasing use of warfarin (53). Aspirin use also increases the relative risk of intracerebral hemorrhage by 40%, although the absolute increased risk is small (approximately 0.15% per year) (69). 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 (197). Overall, it has been estimated that about 10% of all intracerebral hemorrhages are related to the use of antithrombotic agents (69). Recent thrombolytic therapy also increases the risk of intracerebral hemorrhage (43).
The appetite suppressants and cold and cough medications containing the sympathomimetic agent phenylpropanolamine, currently banned from market, have also been responsible for intracerebral stroke (94).
Other sympathomimetic drugs, including cocaine and amphetamine or amphetamine derivatives, may cause intracerebral hemorrhage (112). In an autopsy series of 17 young patients with fatal intracranial hemorrhages, all 5 patients with basal ganglionic hemorrhages were cocaine positive (136). Cannabis was associated with basal ganglia hemorrhage in only 3 cases (13).
Certain genetic mutations are associated with intracerebral hemorrhage. COL4A1 mutations that impair COL4A1 secretion are associated with sporadic intracerebral hemorrhage (190). 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 (19).
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 (161). Another study found aneurysms in 46% of hypertensives and in 85% of patients with large intracerebral hemorrhages (35). 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 (52). 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 (180).
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 (188; 155). 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 (155).
Forms of hereditary intracerebral hemorrhage are seen among Dutch and Icelandic populations (88; 67). Bleeds in these patients are due to mutations in the amyloid precursor protein gene or the cystatin gene, respectively (114; 113). A search for these mutations in patients with sporadic intracerebral hemorrhage was negative (65).
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 (125; 80) and matrix metalloproteinases (03; 193) that contribute to neuronal death. Edema develops over hours to days due to clot retraction (187) followed by breakdown of the blood-brain barrier (195; 27) and leukocyte trafficking into the brain (117; 166). The triggers and mechanisms of injury have not yet been fully elucidated but likely include thrombin (110; 192), activation of Toll-like receptor 4 (166), and substances released from red blood cells, including iron and hemoglobin degradation products (81; 78). Iron-mediated damage has generated great interest, as the iron chelator deferoxamine has been shown to be protective against secondary injury in animal models (79; 138). These pathways offer opportunities for development of new treatments for intracerebral hemorrhage and are an area of active research.
• The incidence of intracerebral hemorrhage has decreased over several decades.
• Men, lower socioeconomic status, increasing age, and certain racial groups have a higher incidence of hemorrhage.
• There is a projected increase in the incidence of intracerebral hemorrhage due to demographic changes.
The incidence of spontaneous intracerebral hemorrhage is 37,000 to 52,000 cases per year in the United States (21). Although the incidence decreased from 1950 to 1979, likely because of better control of hypertension (57), it is expected to double by the year 2050 due to aging and changing racial demographics (182). Men have a relative risk of 1.8 of deep intracerebral hemorrhage compared to women (104). The incidence of intracerebral hemorrhage is associated with increasing age (10) and lower socioeconomic status (86).
Several racial groups have a higher incidence of intracerebral hemorrhage. In northern Manhattan, the relative risk for deep intracerebral hemorrhage was 4.8 in blacks compared to whites and 3.7 in Hispanics compared to whites (104). 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 (55). The highest disparity between intracerebral hemorrhage rates of blacks and whites occurred at younger ages (100). Worldwide, the Japanese have a high rate of intracerebral hemorrhage, with an incidence of 55 per 100,000 (178).
• Improved hypertension treatment has decreased the incidence and mortality of intracerebral hemorrhage.
• Lifestyle modifications may also significantly decrease the risk of hemorrhage.
Improved treatment of hypertension has decreased the incidence and mortality of intracerebral hemorrhage (57). In patients with prior stroke, the combination of a thiazide diuretic and an angiotensin-converting-enzyme inhibitor reduced the risk of intracerebral hemorrhage by 50% (31).
Reduction of diastolic blood pressure has 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 (09).
Moderate and high levels of exercise appear to reduce the risk of cerebral hemorrhage (109). Reduction of other risk factors, including excessive alcohol intake and cigarette smoking, is also reasonable.
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 includes hemorrhagic transformation of an ischemic stroke, bleeding from a tumor, vascular malformation, aneurysm (mycotic, saccular), abscess or other infectious lesions, trauma, vasculitis or vasculopathy (including amyloid angiopathy and moyamoya disease), hypertensive encephalopathy, cerebral venous sinus thrombosis with hemorrhagic venous infarction, and acute hemorrhagic leukoencephalopathy (20; 92; 91; 181). Among these, unsuspected arteriovenous malformation was the most common lesion found after angiography (68).
Some tumors are likely to bleed: metastatic melanoma, bronchogenic carcinoma, choriocarcinoma, and renal cell carcinoma. Of the primary brain tumors, glioblastoma multiforme, followed by oligodendroglioma, are the most likely to bleed (129). In a series of 2514 evacuated hematomas, 110 were found to be due to a tumor (4.4%) (115).
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.
• Noncontrast head CT is the test of choice for the diagnosis of intracerebral hemorrhage due to its sensitivity and availability.
• CT angiography may predict the risk of hematoma expansion.
• MRI brain with and without contrast improves the detection of an underlying lesion.
• Catheter angiography is the test of choice for diagnosing vascular lesions.
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.
MRI is as good as CT in detecting acute hemorrhage and more sensitive in detecting chronic hemorrhages (95). 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 (30).
Microhemorrhages seen on gradient echo have been associated with an increased risk of symptomatic cerebral hemorrhages (49). The location of the micro-bleeds may also be associated with the location of a symptomatic hemorrhage (111).
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 (32).
Contrast-enhanced CT or MRI and CT and MRI angiography help identify 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 (129).
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% (186). 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% (62). 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 (68). 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 (200). 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 intracerebral hemorrhage therapy are as follows:
• Prevention of hematoma expansion
• Prevention of recurrent hemorrhage
• Reduction of intracranial pressure to optimize cerebral perfusion
• Preserve or improve neurologic function
The treatment should follow the American Heart Association/American Stroke Association guidelines that are updated periodically (74).
Disposition. Admission to a neurologic intensive care unit reduces mortality compared to a general intensive care unit (45; 157). Transferring patients to a center that has a neurologic intensive care unit lowers the risk of death (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.
Hemostasis. Oftentimes, patients with basal ganglia hemorrhage have an acquired coagulopathy. This should be emergently reversed, keeping in mind the main side effect: thrombosis.
For warfarin and other vitamin K antagonists associated with intracerebral hemorrhage, vitamin K 10 mg intravenously and prothrombin complex concentrates are preferred to fresh frozen plasma (176). Although prothrombin complex concentrates correct the international normalized ratio faster, the study was not powered enough to detect differences in clinical outcome. Protamine sulfate reverses unfractionated heparin completely but only partially reverses low molecular weight heparin (44). Aripazine has shown promising results against low molecular weight heparin and fondaparinux.
The number of patients taking direct oral anticoagulants for nonvalvular atrial fibrillation is increasing. Idarucizumab is the antidote for dabigatran (145), andexanet alpha for apixaban and rivaroxaban (36), and ciraparantag for edoxaban (08).
In patients experiencing hemorrhagic transformation of an ischemic stroke following thrombolysis, fibrinogen level should be measured and cryoprecipitate 10 units administered empirically. Further doses may need to be given to maintain a fibrinogen level above 150 mg/dL. Platelets may be transfused in the event of thrombocytopenia (194).
The hemostatic agent rFVIIa may enhance thrombin generation on the surface of activated platelets. Although promising in a phase IIB trial (124), rFVIIa failed to improve clinical outcome (24; 123; 61). Tranexamic acid did not improve functional status after 90 days (174). For patients who received antiplatelet agents, platelet transfusion increased the odds of death, and dependence and is not recommended (14).
Blood pressure control. Elevated blood pressure is common in acute intracerebral hemorrhage and worsens prognosis (41; 148). In some but not all studies, hypertension was associated with hematoma expansion (93; 137; 87). In another study, while 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 (156).
The concern that aggressive blood pressure treatment causes perihematomal ischemia has not been confirmed. Local metabolism is reduced (150; 198; 98), and cerebrovascular reactivity is preserved (146). Moreover, perfusion studies have shown no evidence for a perihemorrhagic ischemic penumbra (167).
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 better in the intensive therapy arm (06). Nevertheless, larger reductions of systolic blood pressure (greater than 20 mmHg) within the first hour lowered the risk of poor outcome (189). A meta-analysis of 4 studies including 3315 patients found that intensive blood pressure reduction is safe (184).
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 (12). 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 (149). 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 (108).
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 to be safe. Chronic hypertension tends to shift the cerebral circulation autoregulation curve to the right (144). 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 (28).
In a small study, atenolol decreased mortality, systemic inflammatory response syndrome, and pneumonia compared to amlodipine (90). 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 (38; 71). 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.
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 (179). All patients should undergo formal dysphagia screening to prevent aspiration pneumonia (77). 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 (121). Percutaneous endoscopic gastrostomy was needed in 25% of intracerebral hemorrhage cases (99).
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%) (59). Elevated troponin was associated with increased in-hospital mortality in 1 study (165) but not at 30 days if not associated with ECG changes in another study (120).
Neurogenic pulmonary edema developed in 35% of patients with intracerebral hemorrhage and is associated with 37% mortality at 1 year (89). 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 (47). Low tidal volume ventilation with attention to avoid increased intracranial pressure or hypoxia is a reasonable strategy in these patients (119).
Renal failure occurred in 8% of patients with intracerebral hemorrhage and is not increased by CT angiography (139). Renal dysfunction is also associated with deep cerebral microbleeds in patients with intracerebral hemorrhage (105). Acute renal failure is associated with higher rates of in-hospital mortality and moderate to severe disability at discharge (164).
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.
Venous thromboembolism can be prevented by heparin (5000 IU subcutaneous injections every 12 hours) or low molecular weight heparin after 1 to 4 days of onset and intermittent pneumatic stockings (74). 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 (143) and may be associated with worse outcome (127).
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 is an independent prognostic factor for poor outcome after intracerebral hemorrhage (169). It is reasonable to evaluate and treat fever with acetaminophen, ice packs, and cooling blankets, if needed.
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 days compared with placebo (122).
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% (22). Intraventricular extension of hemorrhage is associated with worse outcome (126).
The large, multicenter International Surgical Trial for Intracerebral Hemorrhage (STICH) did not find benefit from surgery in patients with hemorrhage (126). 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 (140).
Optimal timing of surgery for supratentorial hemorrhage is unknown. A meta-analysis of 8 surgical trials (2816 cases) has shown that surgery improves outcome if randomization is within 8 hours of ictus (66). However, patients with basal ganglia hemorrhage did not benefit from early surgery. Ultra-early surgery, within 4 hours of onset, was associated with worse outcome (133).
Minimally invasive surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE trial) reduced the clot size and edema (132; 134). 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 (152).
Endoscopic surgery has shown promise in small studies. Real-time ultrasound guided endoscopic surgery may minimize brain injury during basal ganglia hematoma evacuation (163). A meta-analysis of 7 studies that used minimally invasive surgery did not demonstrate superiority to medical management (02). Another study showed decreased mortality of minimally invasive endoscopic hematoma evacuation compared with medical management (64). One potential alternative to tPA administration for clot lysis, still in the experimental stage, is transcranial MR-guided focused ultrasound (131). 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 (51). The success of the endoscopic hematoma evacuation is operator dependent. Renal failure on hemodialysis and liver cirrhosis were associated with poor removal rate (70). 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 intracranial pressure and impair consciousness. Reduction of increased intracranial pressure follows the same steps used in other conditions (158). 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 may be used to measure and adjust the intracranial pressure by removing cerebrospinal fluid (158). The cerebral perfusion pressure, defined as the mean arterial blood pressure minus intracranial pressure, should be maintained above 50 to 60 mmHg. Hyperventilation to pCO2 30 to 35 mmHg 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) (39). Hypertonic saline is another effective treatment for elevated intracranial pressure. Clinical outcomes have not been prospectively compared between the 2 treatments.
Diffusion tensor imaging may help predict outcome in basal ganglia hemorrhage (128).
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 (101).
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
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Neuropharmacology & Neurotherapeutics
Aug. 24, 2021
Stroke & Vascular Disorders
Cerebellar infarction and hemorrhage are life-threatening conditions with significant risk for neurologic decline due to brainstem compression and hydrocephalus. They frequently present with headache, nausea and vomiting, dizziness, and a striking difficulty standing or walking. Embolism from an arterial or cardiac source and intracranial atherosclerosis are the main culprits. Hypertension is the most common cause of cerebellar hemorrhage.
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Stroke & Vascular Disorders
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Stroke & Vascular Disorders
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Stroke & Vascular Disorders
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Stroke & Vascular Disorders
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Stroke & Vascular Disorders
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