May. 04, 2021
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
In the lobar variety of intracerebral hemorrhage, hematoma is located in one of the cerebral lobes (frontal, parietal, temporal, or occipital). Lobar hemorrhage is the major clinical manifestation of cerebral amyloid angiopathy. Hypertension continues to be an important factor in the pathogenesis of lobar intracerebral hemorrhage. Patients treated with oral anticoagulants have an increased risk of intracerebral lobar hemorrhage. Carriers of apolipoprotein E2 and E4 also have an increased risk of intracerebral hemorrhage in lobar regions, presumably because of the effects of these gene variants on the risk of cerebral amyloid angiopathy. Cerebral amyloid angiopathy is a risk factor for thrombolysis and anticoagulant-related intracerebral hemorrhage as well. Cerebral microbleeds detected by gradient-echo MRI suggest the presence of advanced microangiopathy with potential for intracerebral hemorrhage. In patients with lobar hemorrhage, microbleeds are associated with a 2- or 3-fold increase in hematoma and a large hematoma size. Finger-like projections within hemorrhage, convexity subarachnoid hemorrhage, and subdural hemorrhage are frequently observed neuroimaging abnormalities in cerebral amyloid angiopathy-related lobar hemorrhage. Cortical superficial siderosis, a distinct neuroimaging pattern, is shown to be associated with the occurrence of the first-ever symptomatic lobar hemorrhage, early lobar hemorrhage recurrence, and a greater hematoma expansion. COVID-19 infection is associated with an increased risk of intracerebral hemorrhage. COVID-19-associated intracerebral hemorrhages are often in lobar locations. Findings of the STICH II trial suggest that early surgery may have a small survival benefit for patients with superficial lobar intracerebral hemorrhage. Oral anticoagulants following lobar hemorrhage can be resumed as they decrease thromboembolic complications and long-term mortality without increasing bleeding risks. In this article, the author has reviewed in detail the different aspects of lobar intracerebral hemorrhage.
• Lobar hemorrhages occur either within the subcortical white matter or at the junction of the hemispheric gray-white matter.
• Cerebral amyloid angiopathy, anticoagulation, coagulopathies, fibrinolytic therapy, microbleeds, and vascular malformations are common causes.
• Hypertension is a less common risk factor in lobar hemorrhage.
• Recombinant activated factor VII can limit ongoing bleeding and improve outcomes when administered within 3 hours.
• Surgical evacuation of hematoma is not beneficial.
• Hematoma size and Glasgow coma scale score are important determinants of prognosis.
The first complete description of an intracerebral hemorrhage was published in 1658 by Wepfer in his treatise on apoplexy (69). In that article he noted intracerebral hemorrhage and subarachnoid hemorrhage in different patients. In 1938 Scholz, for the first time, described pathological changes of cerebral amyloid angiopathy. In 1960 Neumann reported a case of cerebral amyloid angiopathy in a 45-year-old woman who had multiple lobar intracerebral hemorrhages. Later publications of Jellinger and Zenkevich, in 1977 and 1978, respectively, firmly established congophilic or cerebral amyloid angiopathy as a cause of lobar intracerebral hemorrhage (96). In 1980, Ropper and Davis suggested that hypertension is not an etiologic factor in most lobar hemorrhages (91).
By definition, lobar intracerebral hemorrhages occur either within the subcortical white matter or at the junction of the hemispheric gray-white matter.
In some cases, a lobar intracerebral hemorrhage may differ from a basal ganglionic intracerebral hemorrhage with respect to the clinical presentation, etiology, and pathological findings. The clinical symptoms and signs vary depending on the size and location of the bleed. There are important differences in the risk-factor profile and presentation of lobar intracerebral hemorrhage, compared to intracerebral hemorrhages in other locations.
Headache or vomiting occurs at presentation in 50% to 68% of cases of lobar intracerebral hemorrhage. These symptoms occur in less than half of all intracerebral hemorrhages (63). Seizures are well known to occur at the onset of intracerebral hemorrhage. Seizures are more common in lobar hemorrhages in comparison to subcortical hemorrhages. Seizures are often focal or generalized, are usually brief, and are associated with loss of consciousness. Seizures frequently occur during the initial 72 hours after insult in the majority of patients. Posthemorrhagic seizures were associated with neurologic worsening on the National Institute of Health Stroke Scale and with an increase in midline shift (106). In a series, seizures were reported to occur in one third of patients with intracerebral hemorrhage (25). In over half of these patients, the seizures were purely electrographic. Authors identified proximity of hemorrhage to the cortical surface as a strong predictor of electrographic seizures (23% of lobar vs. 11% of deep hemorrhages). Coma is an uncommon presenting symptom for lobar intracerebral hemorrhage, whereas up to 50% of patients with deep intracerebral hemorrhage present in coma (63; 51). This difference may be due to the more peripheral location of lobar intracerebral hemorrhages, with less impingement on midline structures.
Lobar intracerebral hemorrhages occur most commonly in the temporoparietal-occipital region.
As such, clinical findings may not always include a marked hemiparesis (63), although mild weakness is often present. Other findings include neglect syndromes, agnosias, apraxias, visual field abnormalities, and behavioral changes. Sensory findings, if present, may be difficult to elicit due to lack of patient cooperation and a superimposed neglect syndrome. Bleeds involving the dominant temporal lobe may produce a fluent aphasia with paraphasic errors. More anteriorly located intracerebral hemorrhages (in the dominant hemisphere) produce motor findings and a nonfluent aphasia (51). Smaller intracerebral hemorrhages typically produce less dramatic findings. Due to their location at the junction of the gray-white matter, lobar intracerebral hemorrhages often extend in an anterior-posterior axis.
Several serial imaging studies have consistently demonstrated that enlargement of hematoma size due to active bleeding is a major cause of clinical deterioration within the first 3 hours after the onset of hemorrhage (17). A study observed that the volumes of lobar hemorrhage increased more than 2- or 3-fold in the patients with microbleeds (Lee at al 2006). Moreover, the presence of microbleeds was an independent risk factor for a large-sized hemorrhage. White matter changes are frequent in lobar hemorrhage. These white matter abnormalities may be associated with cortical microbleeds, the radiological hallmark of cerebral amyloid angiopathy.
Cerebral amyloid angiopathy causes hemorrhages located primarily in the cortical or subcortical (or lobar) regions of the cerebral hemispheres. Predisposing factors for lobar hemorrhage in patients with cerebral amyloid angiopathy include apolipoprotein e4 and e2 alleles, thrombolytic, anticoagulation and antiplatelet use, hypertension, minor head trauma, and anti-amyloid therapies (110).
Cortical superficial siderosis is a distinct imaging pattern that results from the deposition of hemosiderin along cortical sulci, particularly over the convexities of the cerebral hemispheres. Cortical superficial siderosis has many possible etiologies, but cerebral amyloid angiopathy is considered its important cause. In 1 study that included 236 patients with probable cerebral amyloid angiopathy without lobar hemorrhage at baseline, cortical superficial siderosis prevalence was 34% (22). During a median follow-up of 3.26 years, 27 of 236 patients (11.4%) had a first-ever symptomatic lobar hemorrhage. Cortical superficial siderosis also predicts of early lobar hemorrhage recurrence (defined as a new lobar hemorrhage within 6 months of the index event) in patients with cerebral amyloid angiopathy (89). The presence of cortical superficial siderosis is an independent determinant of larger lobar hematoma volume (14).
This predilection for a lobar location is likely the consequence of the fact that cerebral amyloid angiopathy most commonly and severely involves the superficial vessels of the cortex as opposed to the deep penetrating vessels supplying to the subcortical structures. In patients with cerebral amyloid angiopathy-related lobar intracerebral hemorrhage the parietal lobes are the most frequently affected site (43). Approximately 80% to 100% of patients with Alzheimer disease have vascular pathology related to cerebral amyloid angiopathy, and 5% to 7% of patients have cerebral amyloid angiopathy-related lobar microhemorrhages at autopsy. In one study, lobar microhemorrhages were detected by gradient-echo MRI in 15% of patients with early-stage dementia and were suggested to contribute to dementia severity (05).
Anticoagulation is also associated with a substantial risk of lobar intracerebral hemorrhage, with an estimated 9% to 14% of all intracerebral hemorrhages attributable to antithrombotic therapy.
Patients treated with oral anticoagulants have an increased risk of intracerebral hemorrhage, which is more often fatal than a spontaneous intracerebral hemorrhage. In oral anticoagulant-related intracerebral hemorrhage, a progressive neurologic deterioration during the first 24 to 48 hours after admission is frequent. Anticoagulants not only increase the risk but also increase the severity of intracerebral hemorrhage by causing hematoma expansion. Hematoma growth within 24 hours has been reported to occur in 27% of patients on oral anticoagulants (44). Lower level of consciousness at presentation and larger initial intracerebral hemorrhage volume predict poor prognosis in patients with warfarin-associated intracerebral hemorrhage (119). Warfarin use was associated with larger initial intracerebral hemorrhage volume, but this effect was only observed for international normalized ratio values greater than 3.0 (32). Larger intracerebral hemorrhage volume among warfarin users accounts for part of the excess mortality in this group. Leukoaraiosis is an independent risk factor for warfarin-related intracerebral hemorrhage in survivors of ischemic stroke, including those in the commonly employed range of anticoagulation. The presence of cerebral microbleeds may be an independent risk factor for warfarin-related intracerebral hemorrhage (103). Antiplatelet agents with anticoagulation and the combined use of aspirin plus clopidogrel further increase the risk of intracerebral hemorrhage. However, modest blood pressure lowering significantly reduces the risk of intracerebral hemorrhage during antiplatelet therapy (41). One study suggests that incidence of warfarin-related intracerebral hemorrhage is independently associated with number of underlying microbleeds (56). Cervera and colleagues determined risk factors for oral anticoagulant-associated intracerebral hemorrhage to include the effects of aging, the level of anticoagulation, genetic factors, and a high prevalence of concurrent cerebrovascular conditions, such as cerebral amyloid angiopathy, leukoaraiosis, or previous strokes (21). A systemic review suggests that oral anticoagulants can safely be resumed after intracerebral hemorrhage. Oral anticoagulants decrease thromboembolic complications and reduce long-term mortality without increasing bleeding risks (88).
Intracerebral hemorrhage is the most serious complication of fibrinolytic therapy for acute myocardial infarction, pulmonary embolism, and ischemic stroke. There is increasing evidence that cerebral amyloid angiopathy, which itself can cause hemorrhage, may be a risk factor for thrombolysis-related intracerebral hemorrhage. Cerebral amyloid angiopathy and thrombolysis-related intracerebral hemorrhage share some clinical features, such as predisposition to lobar or superficial regions of the brain, multiple hemorrhages, increasing frequency with age, and an association with dementia (68). An investigation revealed that in approximately half of patients with thrombolysis-related intracerebral hemorrhage there is a preexisting vascular lesion of brain, such as cerebral microbleeds, cerebral infarcts, and areas of white matter hyperintensity (28).
A study found that 77% of all hemorrhages related to tissue plasminogen activator administration for acute myocardial infarction had a lobar location. Such hemorrhages were likely to be large (median volume 72 mL) and have a blood-fluid level (82%), but with little edema (median 9 mL) (36). In 60% of such cases with pathologic examination, underlying cerebral amyloid angiopathy was found (95). These hemorrhages are often large, can expand, and may be multiple. The mortality in such cases can be up to 66%. Risk factors for such bleeds include advanced age, concomitant hypertension, use of anticoagulants, and preexisting dementia. Thrombolytics used to treat an acute ischemic stroke can cause intracerebral hemorrhages, some in a lobar location. Among patients treated with thrombolysis for acute stroke, severe leukoaraiosis of the deep white matter is an independent risk factor for symptomatic intracerebral hemorrhage (74). There is increasing evidence that cerebral amyloid angiopathy, which itself can cause hemorrhage, may be a risk factor for thrombolysis-related intracerebral hemorrhage. However, the presence of cerebral microbleeds on gradient echo imaging does not appear to substantially increase the risk of either symptomatic or asymptomatic brain hemorrhage following IV tPA administered between 3 and 6 hours after stroke onset (50).
Cerebral amyloid angiopathy is the principal feature of hereditary cerebral hemorrhage with amyloidosis Dutch type, a familial condition associated to a point mutation G to C at codon 693 of the amyloid beta precursor protein gene. The Dutch variant has a later onset (age 40 to 60 years) than the Icelandic form of hereditary intracerebral hemorrhage (age 20 to 30 years). Multiple and recurrent hemorrhages leading to premature death are common with both forms of hereditary cerebral hemorrhage with amyloidosis. A superimposed dementia with the Dutch variant may be due to multiple bleeds or, in rare cases, can develop without intracerebral hemorrhages. In many cases of the Dutch form, senile plaques are seen in the cerebral cortex (62). The Dutch form is due to 1 or more mutations in the amyloid precursor protein gene (62; 57; 42). In patients with the Icelandic form of hereditary intracerebral hemorrhage with amyloidosis, a pathogenic mutation in exon 2 of the cystatin C gene has been found (58).
Several reports have indicated that COVID-19 infection is associated with an increased risk of intracerebral hemorrhage. COVID-19-associated intracerebral hemorrhages are often seen in patients with severe COVID-19. Severe COVID-19, in addition to acute respiratory insufficiency, is also characterized by marked coagulopathies, endothelial dysfunction, and cerebral microangiopathy. Intracerebral hemorrhages in COVID-19 have a close resemblance to that of anticoagulant-associated intracerebral hemorrhage. On neuroimaging, COVID-19-associated brain hematomas are often in lobar locations. In addition, they may be multiple, irregular in shape, and may have intraventricular extensions. Fluid-blood levels within the COVID-19-associated brain hematomas have also been described (09). A meta-analysis noted that intracerebral hemorrhages associated with COVID-19 more frequently affect younger patients. These patients are frequently male and are less likely to be hypertensive. The use of anticoagulant drugs enhances the risk of COVID-19-associated intracerebral hemorrhage. COVID-19-associated intracerebral hemorrhage carries a high mortality and worse functional outcomes at discharge (53; 10; 54; 72).
Less than half of patients with intracerebral hemorrhage survive 1 year and less than one third survives 5 years. An analysis of 122 studies suggested that 1-year survival in these patients was 46% and 5-year survival was 29%. Consistent predictors of death were increasing age, decreasing Glasgow Coma Scale score, increasing intracerebral hemorrhage volume, presence of intraventricular hemorrhage, and deep/infratentorial location. Risks of recurrent intracerebral hemorrhage and ischemic stroke after intracerebral hemorrhage were similar (82).
Complications of an intracerebral hemorrhage are divided into direct and indirect effects. Direct effects are those caused by the intracerebral hemorrhage; they are the result of the mass of the hematoma, as well as the cerebral edema that often forms around the bleed (67). Perihemorrhagic edema develops early after intracerebral hemorrhage and doubles within the first 7 to 11 days after the initial bleeding event. This additional mass effect may contribute to secondary clinical deterioration and mortality, especially in larger intracerebral hemorrhage (98).
Obstructive hydrocephalus can occur if a large lobar intracerebral hemorrhage compresses or obstructs the foramen of Munro or cerebral aqueduct. Another complication, which was not fully appreciated until a few years ago, is expansion of the clot that evolves over several hours after the initial bleed. Lobar intracerebral hemorrhages may produce seizures due to their close proximity to the cortex.
Spot sign has been shown to have a prognostic significance. Mortality at 3 months was 43.4% (23 of 53) in CT angiography spot sign-positive patients versus 19.6% (31 of 158) in CT-angiography spot sign-negative patients (26).
The risk of recurrent stroke after lobar intracerebral hemorrhage remains high in comparison to that in patients with deep intracerebral hemorrhage (114). Poor outcome in patients with lobar hemorrhage is associated with a hemorrhage size of more than 40 cm3, Glasgow coma score less than or equal to 13, but also dependent on time interval between ictus and presentation. Stupor and septum pellucidum shift greater than 6 mm on CT scan at presentation predict a hopeless outcome in conservatively treated patients. Ninety-one percent of patients were treated medically; thus, these outcomes are largely a reflection of the natural history of spontaneous lobar hemorrhage (34). Chronic obstructive pulmonary disease appeared as the most important predictor of death during hospitalization after lobar cerebral hemorrhage, a finding not reported earlier. Other predictive variables included altered consciousness, previous cerebral infarct, and chronic liver disease (04). Nontraumatic subdural hematoma has been found to be frequently associated with primary lobar intracerebral hemorrhage. Patel and coworkers demonstrated subdural hematoma in 40 of 200 patients (20%) with primary lobar intracerebral hemorrhage (Patel el 2009). Subdural hematoma in lobar intracerebral hemorrhage is associated with higher 30-day mortality. Rupture of an amyloid-laden leptomeningeal vessel, with extravasation into the brain parenchyma and subdural space, has been suggested as the pathogenic mechanism.
A study examined the effect of apolipoprotein E genotype on recovery of function in patients with intracerebral hemorrhage (not just lobar hemorrhages). This study found increased mortality and a worse functional outcome in patients with the apolipoprotein E4 genotype, compared to those without the E4 allele. For patients with a 2/3 or 3/3 genotype, the mortality rate was 20%, compared to 69% for patients with an E3/E4 genotype (02). The biological basis for these differences remains unclear, but it does not appear to be related to age, sex, or racial factors (03). Another study observed that vasculopathic changes associated with the apolipoprotein E2 allele might also have a role in determining the severity and clinical course of lobar intracerebral hemorrhage. In this study, apolipoprotein E4 was not associated with lobar intracerebral hemorrhage volume, functional outcome, or mortality (12).
Authors in a study determined whether number hemorrhages detected at the time of a symptomatic lobar intracerebral hemorrhage predicted the major clinical complications of cerebral amyloid angiopathy like recurrent intracerebral hemorrhage or decline in cognition and functional status. Ninety-four consecutive survivors of primary lobar intracerebral hemorrhage with gradient-echo MRI at presentation were followed. Study endpoints were recurrent symptomatic intracerebral hemorrhage or clinical decline, defined as onset of cognitive impairment, loss of independent functioning, or death. It was observed that the total number of hemorrhages at baseline predicted risk of future symptomatic intracerebral hemorrhage (3-year cumulative risks 14%, 17%, 38%, and 51% for subjects with 1, 2, 3 to 5, or 6 baseline hemorrhages). Higher numbers of hemorrhages at baseline also predicted increased risk for subsequent cognitive impairment, loss of independence, or death among subjects not previously demented or dependent. For subjects followed after a second MRI, new microhemorrhages appeared in 17 of 34 and predicted increased risk of subsequent symptomatic intracerebral hemorrhage (37).
There is increased dementia risk after spontaneous intracerebral hemorrhage, particularly with lobar hemorrhage. In 1 investigation, the incidence of new-onset dementia was more than 2 times higher in patients with lobar intracerebral hemorrhage than for patients with nonlobar intracerebral hemorrhage (73).
A 77-year-old white female presented with acute onset of confusion and left-sided weakness. She had a history of progressive memory loss over the past 3 to 4 years, but no history of hypertension or vascular disease. Her only medications were an occasional ibuprofen for arthritis and conjugated estrogen. On examination, her vital signs were normal. No carotid or cardiac abnormalities were noted. Neurologic exam showed her to be alert, but not fully oriented. Speech was fluent. Short-term memory was one third after 3 minutes. She did not know who the president was, nor could she do complex calculations. Moderate finger-hand apraxia was noted. She had profound left-sided neglect with some denial of her deficits. There was a left visual field homonomous hemianopsia. Slight dysarthria was noted, along with a mild left hemiparesis. Gait and cerebellar functions were normal. Reflexes were increased on the left, and a left Babinski sign was present. Several frontal-release reflexes were present. A head CT showed a moderately sized right parietal hemorrhage at the gray-white junction. Some cortical atrophy was noted.
The patient made a recovery with supportive care. She was instructed to stop taking ibuprofen and use acetaminophen for routine pain control. Three months after her presentation, her examination was nearly normal, except for minimal left-sided weakness. She still exhibited cognitive dysfunction with poor orientation and memory. Detailed neuropsychological testing showed evidence of diffuse cognitive deficits consistent with a degenerative dementia such as Alzheimer disease.
Several disorders produce lobar intracerebral hemorrhage. One prospective surgical study of 29 patients with lobar intracerebral hemorrhage found microaneurysms to be the most common cause (11 of 29 patients, 38%), followed by vascular malformations (9 of 29 patients, 31%), amyloid angiopathy (6 of 29 patients, 21%), and tumors (2 of 29 patients, 7%) (113). Other studies found that between 67% and 75% of lobar intracerebral hemorrhages were due to cerebral amyloid angiopathy (111; 46).
In general, hypertension is a less common risk factor in lobar intracerebral hemorrhage than for hemorrhages in other locations. In a population-based study, risk factors for primary intracerebral hemorrhage and its subtypes were explored in a case-control design (Zia at al 2006). As compared to the control group, high systolic blood pressure was significantly associated both with nonlobar and lobar primary intracerebral hemorrhage. Meta-analyses of studies comparing the frequency of hypertension as a risk factor for deep versus lobar supratentorial intracerebral hemorrhage, excluding hemorrhages with identified secondary causes, suggested that hypertension is about twice as common in deep than in lobar hemorrhage (48). However, some studies found similar rates of hypertension when comparing lobar intracerebral hemorrhage to all types of intracerebral hemorrhage (16). It has been demonstrated that hypertension plays a role in the pathogenesis of lobar intracerebral hemorrhage in patients with cerebral amyloid angiopathy (20). Arterial hypertension was noted to be the most frequent risk factor for anticoagulant-associated intracerebral hemorrhage as well. Patients with lobar intracerebral hemorrhage were more likely than patients with lacunar or nonlacunar cerebral infarction to have retinopathy lesions (microaneurysms, retinal hemorrhages, cotton-wool spots, and hard exudates), suggesting breakdown of the blood-retina barrier in patients with lobar intracerebral hemorrhage. These findings support a distinct vasculopathy in lobar intracerebral hemorrhage compared with other acute stroke subtypes resulting from cerebral small vessel disease or ischemic infarction (07).
Up to 20% of lobar intracerebral hemorrhages may be due to coagulopathies of some type, including the use of warfarin (51). In many cases of lobar hemorrhages associated with warfarin use, cerebral amyloid angiopathy is found on pathologic examination (92). Other acquired coagulopathies, particularly due to the expanding use of thrombolytic agents, are increasingly recognized causes of lobar hemorrhage. The use of tPA for acute myocardial infarction or stroke is an increasingly common etiology for such hemorrhages (Levy et al 1994; 95).
Aneurysms, arteriovenous malformations, cavernous angiomas, dural arteriovenous fistulas, and venous malformations all can result in lobar intracerebral hemorrhage. The predictors of hemorrhage in arteriovenous malformation include increasing age, deep brain location, and exclusive deep venous drainage. The risk of spontaneous hemorrhage may be low in patients with arteriovenous malformations without these risk factors (97). In one study patients with arteriovenous malformation-associated intracerebral hemorrhage were younger, had lower pre-stroke and admission blood pressure and higher admission Glasgow Coma Scale (104). Case fatality throughout 2-year follow-up was lower following arteriovenous malformation-associated intracerebral hemorrhage than spontaneous intracerebral hemorrhage.
Lobar hemorrhages due to cocaine, amphetamine, or phenylpropanolamine use may be secondary to sudden elevation in blood pressure, multifocal cerebral vessel spasm, or drug-induced vasculitis.
Lobar intracerebral hemorrhage is not an uncommon presentation in cases of previously unsuspected brain tumor. Hemorrhage is more likely with certain types of tumors, including glioblastoma, hemangioblastoma, oligodendroglioma, and metastatic tumors. Metastatic tumors with a high propensity to hemorrhage are choriocarcinoma, malignant melanoma, renal cell, prostate, and lung cancer.
Cerebral amyloid from angiopathy is a major cause of lobar intracerebral hemorrhage and cognitive impairment in the elderly. Cerebral amyloid angiopathy is associated with a high prevalence of magnetic resonance imaging markers of small vessel disease, including cerebral microbleeds and white matter hyperintensities (109). According a meta-analysis, there was no association between cerebral amyloid angiopathy and intracerebral hemorrhage in any location, deep intracerebral hemorrhage, or cerebellar intracerebral hemorrhage. Cerebral amyloid angiopathy was significantly associated with lobar intracerebral hemorrhage, both overall and in the 3 studies where average ages for cases and controls were comparable (94). The factors associated with lobar intracerebral hemorrhage were age (greater than 70 years), underweight, unfavorable outcome, and daily alcohol consumption. Hypertension and intraventricular bleeding were significantly less common in patients with lobar intracerebral hemorrhage than those with nonlobar intracerebral hemorrhage (64). Patients presenting even with isolated lobar microbleeds on MRI have a genetic, neuroimaging, and hemorrhagic risk profile suggestive of severe cerebral amyloid angiopathy and have a substantial risk of intracerebral hemorrhage (105). The exact mechanisms leading to intracerebral hemorrhage in these conditions are unclear. Cerebral amyloid angiopathy is because of the deposition of amyloid alpha protein within the adventitia and media of leptomeningeal and parenchymal arteries. In the arteries affected by cerebral amyloid angiopathy, local muscle and elastic elements are replaced by amyloid fibrils, thereby weakening the wall of the vessel. Brittleness of arterioles with poor contractile capability is possibly responsible for the occurrence of hemorrhage and early growth of hematomas after rupture. It has been suggested that because arteriolar bleeding is slower than arterial bleeding, there is the possibility to intervene to stop ongoing hematoma expansion. For example, recombinant factor VIIa or other therapies may be useful (06).
Conflicting reports in the literature exist regarding the association of apolipoprotein E alleles and lobar intracerebral hemorrhage. Apolipoprotein E genotype is associated with cholesterol metabolism, ischemic heart disease, and cerebral amyloid angiopathy, and so may affect risk of both ischemic and hemorrhagic stroke. It has been estimated that a third of all cases of lobar intracerebral hemorrhages are attributable to possession of an apolipoprotein E4 or E2 allele (116). The apolipoprotein E genotype was also found to be significantly associated with the risk of hemorrhage recurrence. Carriers of the epsilon2 or epsilon4 allele had a 2-year rate of recurrence of 28%, as compared with only 10% for patients with the common apolipoprotein E epsilon3/epsilon3 genotype. Early recurrence occurred in 8 patients, 4 of whom had the uncommon epsilon2/epsilon4 genotype (77). In cerebral amyloid angiopathy hemorrhage, APOE epsilon 4 enhances deposition of amyloid-beta protein in the walls of cerebral blood vessels. APOE epsilon 2 may interact with putative risk factors for hemorrhage, including antiplatelet or anticoagulant medication, minor head trauma, and hypertension (75). In a study, independent significant risk factors for lobar intracerebral hemorrhage included apolipoprotein E4, untreated hypertension, anticoagulant use, a first-degree relative with intracerebral hemorrhage, and equal or more than high school education (compared with an education level below high school). Treated hypercholesterolemia (compared with "no history of hypercholesterolemia”) was associated with a decreased risk of lobar intracerebral hemorrhage. Haplotype association analysis demonstrated a significant association of the apolipoprotein E gene with lobar intracerebral hemorrhage among whites and blacks (117). An observation noted that among carriers of the epsilon2 or epsilon4 allele of the apolipoprotein E polymorphism, Asians have greater risk of intracerebral hemorrhage of all types (both lobar and deep) than Europeans (102). In Poland, authors found a positive association between the studied glutathione peroxidase 1 polymorphism and lobar intracerebral hemorrhage in a Polish population (81). Glutathione peroxidase 1 is a key enzyme of the antioxidant system.
Among patients with lobar intracerebral hemorrhage, the presence of the apolipoprotein E epsilon 2 allele predicts larger hematoma volumes. Epsilon 2 predisposes individuals with lobar intracerebral hemorrhage to hematoma expansion. This effect is even more pronounced in patients with amyloid angiopathy-related intracerebral hemorrhage (18).
Cerebral microbleeds detected by gradient-echo MRI are considered an evidence of advanced microangiopathy with potential for intracerebral hemorrhage. These dot-like low-intensity spots (dot-like hemosiderin spots) on T2-weighted MRI images have been histologically diagnosed as old cerebral microbleeds. Cerebral microbleeds might indicate a higher risk of future intracerebral hemorrhage and may be a marker of cerebral small-vessel disease and cerebral amyloid angiopathy. Intracerebral hemorrhage without microbleeds was more common in younger patients with precipitating events, whereas intracerebral hemorrhage with microbleeds was more common in elderly patients with prominent ischemic change and frequent use of antithrombotics or anticoagulants (49). Asian patients with intracerebral hemorrhage are more likely to have cerebral microbleeds than non-Asian patients. In cerebral amyloid angiopathy, microhemorrhages predict the risk of recurrent lobar intracerebral hemorrhage (108). In one study, the authors performed a radiologic evaluation on the cerebral microbleeds and volume of intracerebral hemorrhage in the patients with supratentorial intracerebral hemorrhage (Lee at al 2006). In the patients with lobar or putaminal hemorrhage, the hemorrhage volumes increased more than 2- or 3-fold in the patients with microbleeds. Moreover, the presence of microbleeds was an independent risk factor for large-sized hemorrhage. One study revealed that microbleeds were more frequent in antiplatelet users with intracerebral hemorrhage than in matched antiplatelet users without intracerebral hemorrhage and patients with non-antiplatelet-related intracerebral hemorrhage (40). The study also noted that the frequency of lobar microbleeds was 11 in 16 (69%) in antiplatelet-related intracerebral hemorrhage versus 11 in 33 (33%) in non-antiplatelet-related intracerebral hemorrhage. Hematoma volume is larger in lobar hemorrhages in comparison to deep intracerebral hemorrhage. In a multivariable linear regression analysis, independent predictors of hematoma volume were intensity of anticoagulation and antiplatelet treatment (30). Surgically resected hematomas from 20 patients with spontaneous intracerebral hemorrhage were examined with light microscopy. Evidence of cerebral amyloid angiopathy was observed in 8 of the 20 specimens, each of which came from lobar locations. Evidence of cerebral amyloid angiopathy was not found in any of the basal ganglia specimens (29).
In a prospective hospital-based stroke registry, over a 12-year period, 2500 acute stroke patients were included (04). In this series 97 cases of lobar hematoma were observed. Lobar hematomas accounted for 3.9% of all acute stroke patients and 35.9% of intracerebral hemorrhages. In a population-based study from Sweden, risk factors for primary intracerebral hemorrhage and primary intracerebral hemorrhage subtypes were investigated in 22,444 men and 10,902 women (118). In this study147 subjects with CT or autopsy-verified first-ever primary intracerebral hemorrhage during the follow-up period were compared with 1029 stroke-free controls. High systolic blood pressure, diabetes, high triglycerides, short stature, and psychiatric morbidity remained significantly associated with primary intracerebral hemorrhage. High systolic blood pressure was significantly associated both with nonlobar and lobar primary intracerebral hemorrhage. Diabetes and psychiatric morbidity were associated with nonlobar primary intracerebral hemorrhage. Smoking doubled the risk for lobar primary intracerebral hemorrhage, but was unrelated to nonlobar primary intracerebral hemorrhage. Incidence rates of primary intracerebral hemorrhage are known to be higher in American blacks than whites. In one study authors sought to define incidence rates for different intracerebral hemorrhage locations in a biracial population (33). Annual incidence rates per 100,000 persons 20 years of age or older were 48.9 for blacks and 26.6 for whites. Annual incidence rate per 100,000 blacks in lobar location was 15.2. Annual incidence rate for lobar hemorrhage per 100,000 whites was 9.4. The greatest excess risk of intracerebral hemorrhage in blacks compared with whites was found among young to middle-aged (35 to 54 years) persons and hypertension was the predominant risk factor. Cerebral amyloid angiopathy is estimated to account for more than 20% of all intracerebral hemorrhage in patients older than 70 years.
In another population-based, prospective cohort study of intracerebral hemorrhage adult population of 695,335), Samarasekera and co-workers studied the incidence, characteristics, and outcome of lobar and nonlobar intracerebral hemorrhage (93). In this cohort, there were 128 subjects with first-ever primary intracerebral hemorrhage. The overall incidence of lobar intracerebral hemorrhage was similar to nonlobar intracerebral hemorrhage (9.8 vs. 8.6 per 100,000 adults per year). At baseline, adults with lobar intracerebral hemorrhage were more likely to have preceding dementia, lower Glasgow Coma Scale scores, larger intracerebral hemorrhages, subarachnoid extension, and subdural extension than those with nonlobar intracerebral hemorrhage. One-year case fatality was lower after lobar intracerebral hemorrhage than after nonlobar intracerebral hemorrhage. Recurrences were noted only in patients with lobar hemorrhage.
The incidence of anticoagulant-associated intracerebral hemorrhage quintupled in our population during the 1990s. The majority of this change can be explained by increasing warfarin use. Anticoagulant-associated intracerebral hemorrhage now occurs at a frequency comparable to subarachnoid hemorrhage (31). UK stroke mortality data, however, suggest that the incidence of hemorrhagic stroke has fallen in the past 20 years. Data from the Oxford Community Stroke Project and the Oxford Vascular Study suggested that in the population aged less than 75 years the incidence of intracerebral hemorrhage decreased substantially (60). However, above age 75 years the proportion of intracerebral hemorrhage cases that were nonhypertensive with lobar bleeds and presumed to have had mainly amyloid-related hemorrhages increased.
Improved and more aggressive treatment of hypertension is generally accepted as the main reason for the declines in the incidence and mortality of intracerebral hemorrhage during the past 20 to 30 years (60). More careful use of anticoagulants and thrombolytic therapy may also help lessen the risk of lobar intracerebral hemorrhages. The predominant predictors of clinically significant intracerebral hemorrhage in recombinant tissue plasminogen activator-treated patients include age, clinical stroke severity as assessed by the NIH stroke scale score on admission, high blood pressure, hyperglycemia, early CT changes, large baseline diffusion lesion volume, and leukoaraiosis on MRI. In order to minimize the risk of recombinant tissue plasminogen activator-related symptomatic intracerebral hemorrhage, careful attention must be given to the pre-therapeutic blood sugar level, and a strict protocol for the control of elevated blood pressure is needed during the first 24 hours (27). Patients with lobar hemorrhage and cerebral amyloid angiopathy remain at higher risk for anticoagulant-related intracerebral hemorrhage recurrence than thromboembolic events, and therefore would be best managed without anticoagulants. This recommendation is not applicable for patients with deep hemispheric hemorrhage and for patients with a high risk of ischemic stroke (like in atrial fibrillation) (78).
Patients younger than 45 years of age, patients without hypertension, and patients with lobar hemorrhage and signs of clinical deterioration should be thoroughly investigated to disclose a potential arteriovenous malformation or an aneurysm. There are no specific clinical features of cerebral amyloid angiopathy-related primary intracerebral hemorrhage, although lobar, recurrent or multiple simultaneous hemorrhages in older patients should raise suspicion of its diagnosis. White matter damage in lobar intracerebral hemorrhage is common and is associated with cognitive impairment. Lobar intracerebral hemorrhage has several causes. The differential diagnoses should include disorders not mentioned in the section on etiology: hemorrhagic transformation of an ischemic stroke, abscess or other infectious lesions, trauma, and venous thrombosis. Drugs such as sympathomimetic drugs (including cocaine and amphetamines) can cause or be associated with an intracerebral hemorrhage.
In addition to the clinical presentation and examination, a brain imaging study is crucial for making an accurate diagnosis of intracerebral hemorrhage. Typically, a noncontrast-enhanced CT shows a high-density lesion consistent with an intracerebral hemorrhage. MRI may also show a large intracerebral hemorrhage, although there is some concern that the MRI may miss very small and very acute intracerebral hemorrhages.
However, a study using susceptibility-weighted MRI found it to be sensitive for detecting hemorrhages within 5 hours of onset (79). A contrast-enhanced CT or MRI is useful for detecting vascular changes suggestive of an arteriovenous malformation or a tumor. An arteriogram is sometimes performed for similar reasons. One study reported that gradient-echo MRI can detect petechial hemorrhages in the cortex and subcortex of more than 50% of patients with lobar hemorrhages (38). Follow-up MRI showed recurrent hemorrhages in 38% of patients (39).
The ABC/2 formula is a reliable estimation technique of intracerebral hematoma volume. However, oral anticoagulant therapy-related intracerebral hemorrhage compared with primary intracerebral hemorrhage is based on a different pathophysiological mechanism, and various shapes of hematomas are more likely to occur. In patients with oral anticoagulant therapy-related primary intracerebral hemorrhage, more than 50% of bleeds are irregularly shaped. In these cases, hematoma volume is significantly overestimated by the ABC/2 formula. Modification of the denominator to 3 (ABC/3) measured intracerebral hemorrhage volume more accurately in these patients, potentially facilitating treatment decisions (45).
MRI must be performed in order to exclude any vascular malformation or neoplasms, and, in young patients, a cerebral angiography must be done in order to exclude small arteriovenous or dural malformations (61). It has been demonstrated that there is a progressive increase in white matter lesions in subjects with cerebral amyloid angiopathy (23). In this particular study, new hemorrhages, including asymptomatic microbleeds, were seen in 46% of subjects. The association of white matter lesions with lobar hemorrhages suggests that white matter damage may reflect a progressive microangiopathy due to cerebral amyloid angiopathy.
Patients below the age of 45, patients without hypertension, and patients with lobar hemorrhage should be subjected to carotid angiography to disclose a potential underlying cause of intracerebral hemorrhage like arteriovenous malformation or an aneurysm. However, the utility of angiography is limited in elderly patients with hypertension and in patients with a deep hematoma. Magnetic resonance angiography can also be used to identify secondary causes of intracerebral hemorrhage although its sensitivity is not well established (83). Multidetector row CT angiography has been demonstrated as a highly accurate imaging technique in the diagnosis of underlying vascular abnormalities in patients with spontaneous lobar intracerebral hemorrhage in comparison to conventional digital subtraction angiography (112).
The "spot sign" on CT angiography is usually present in several patients with acute primary intracerebral hemorrhage and has been reported to predict hematoma expansion. The “spot sign” is defined as spot-like or serpiginous foci of enhancement within the margin of a parenchymal hematoma without connection to outside vessels. In multivariate analysis, patients on warfarin were more likely to have a spot sign, regardless of intracerebral hemorrhage location. Apolipoprotein E epsilon 2, but not epsilon 4, was associated with the presence of a spot sign in lobar intracerebral hemorrhage (19).
Convexity subarachnoid hemorrhage and subdural hemorrhage are frequently observed neuroimaging abnormalities in cerebral amyloid angiopathy-related lobar hemorrhage. Convexity subarachnoid hemorrhage and subdural hemorrhage help in establishing the diagnosis of cerebral amyloid angiopathy-related lobar hemorrhage. Subarachnoid hemorrhage and subdural hemorrhage can be adjacent or remote from lobar hemorrhage. In addition to subarachnoid hemorrhage extension, finger-like projections in lobar hemorrhage on early magnetic resonance imaging are associated with probable cerebral amyloid angiopathy (87; 107; 85).
Florbetapir (18F) is a positron emission tomography imaging agent that binds to vascular amyloid plaques. An investigation compared cortical florbetapir retention during the acute phase between patients with cerebral amyloid angiopathy-related lobar intracerebral hemorrhage and patients with hypertension-related deep intracerebral hemorrhage. Cortical florbetapir uptake was increased in patients with cerebral amyloid angiopathy-related intracerebral hemorrhage relative to those with deep intracerebral hemorrhage. Florbetapir (18F) is a potential outcome marker and diagnostic tool as well (86).
Histological examination of brain tissue obtained during surgery or at autopsy is necessary for the definitive diagnosis of cerebral amyloid angiopathy. Rarely, a brain biopsy is done to evaluate for the presence of vasculitis or tumor. Coagulation studies are usually performed to exclude a coagulopathy.
When warfarin-related intracerebral hemorrhage occurs, immediate discontinuation of warfarin with rapid warfarin reversal remains the first-line intervention, often with neurosurgical intervention. The optimal agent for rapid warfarin anticoagulation reversal remains to be defined owing to the lack of prospective randomized trials (35). Anticoagulation should be urgently reversed either with prothrombin complex concentrates, recombinant factor VIIa, recombinant factor VIIa along with fresh-frozen plasma and prothrombin complex concentrates or fresh frozen plasma only (01). Warfarin-related intracerebral hemorrhage requires adequate transfusion of fresh-frozen plasma (10 to 20 mL/kg). For thrombolysis-related intracerebral hemorrhages, 6 units of cryoprecipitate (rich in fibrinogen) are generally recommended to increase the fibrinogen level to at least 150 mg/dL. Platelet concentrate may also be needed if massive transfusion is necessary. Prothrombin complex concentrate is an alternative, but issues of availability make its use impractical. The use of recombinant factor VIIa is a newer option (99). Early intervention focuses on rapid correction of coagulopathy in order to prevent continued bleeding. Warfarin therapy may be resumed within 3 to 10 days of intracerebral hemorrhage in stable patients in whom subsequent anticoagulation is mandatory (01).
Hematoma expansion is an accurate predictor of poor outcome of intracerebral hemorrhage. Hematoma volumes are substantially increasing in spontaneous lobar intracerebral hemorrhage patients who are older than 70 years. Pathological HbA1c levels are significantly associated and predisposing for deep intracerebral hemorrhage. These findings further support the ongoing debate of different disease entities for supratentorial intracerebral hemorrhage (for example, association of cerebral amyloid angiopathy and lobar intracerebral hemorrhage versus diabetes-induced atherosclerosis in deep intracerebral hemorrhage) (52). As hematoma growth in acute intracerebral hemorrhage is a dynamic process, treatment with early hemostatic therapy could lead to prevention of early hematoma growth. The hemostatic properties of recombinant activated factor VII (rFVIIa) are established in patients with inherited or acquired hemophilia with inhibitors and in patients with congenital factor VII deficiencies. Its predominant action limited to areas of injury, apparently without systemic activation of the coagulation cascade. Recombinant activated factor VII (rFVIIa) may be a valuable therapy during the hyperacute stage of intracerebral hemorrhage. A random evaluation demonstrated that treatment with rFVIIa within 4 hours after the onset of intracerebral hemorrhage limits the growth of the hematoma, reduces mortality, and improves functional outcomes at 90 days (65). Serious thromboembolic adverse events, mainly myocardial or cerebral infarction, occurred in 7% of rFVIIa-treated patients, as compared with 2% of those given placebo. Another study by the same group of authors suggested that therapy with rFVIIa reduced hematoma growth but did not improve survival or functional outcome. In this multicentric, randomized, double-blind, placebo-controlled trial, 841 patients with intracerebral hemorrhage were randomly assigned to receive placebo (268 patients), 20 µg of rFVIIa per kilogram of body weight (276 patients), or 80 µg of rFVIIa per kilogram (297 patients) within 4 hours after the onset of intracerebral hemorrhage. Treatment with 80 µg of rFVIIa per kilogram resulted in a significant reduction in growth in volume of the hemorrhage. The mean estimated increase in volume of the intracerebral hemorrhage at 24 hours was 26% in the placebo group, as compared with 11% in the group receiving 80 µg (66). All these patients were followed for 3 months after stroke onset, and health-related quality of life was assessed using the EuroQoL. Six hundred fifty-seven patients survived until 3 months after stroke onset, and 621 completed the EuroQoL. The vast majority of survivors have very poor health-related quality of life. Independent predictors of poor health-related quality of life were advanced age, higher baseline National Institutes of Health Stroke Scale score, higher systolic blood pressure, higher baseline intracerebral hemorrhage volume, deep (vs. lobar) hematoma location, and increase in neurologic deficit in first 72 hours after intracerebral hemorrhage onset (24).
Several safety concerns related with the usage of recombinant activated factor VII (rFVIIa) have been raised. An increased frequency of thromboembolic complications has been observed (76). In a study, 55% of patients treated with rFVIIa developed radiographic hydrocephalus. Occurrence of posthemorrhagic hydrocephalus was an unexpected complication (100). In another report authors observed an increased incidence of post-intracerebral hemorrhage troponin-T elevation and myocardial infarction with the use of recombinant activated factor VII (rFVIIa) (101). Following treatment with recombinant activated factor, a patient developed multiple acute cerebral infarcts in different vascular distributions (59). All these reports suggest that a cautious approach to treatment with recombinant activated factor VII is warranted until more data are available.
Treatment of increased intracranial pressure caused by the intracerebral hemorrhage is similar to that used in other conditions (90). Supportive measures include elevation of the head of the bed, a straight neck position, reducing agitation, and keeping patients slightly dehydrated. More aggressive steps include hyperventilation, administration of osmotic diuretics such as mannitol, and placement of an intraventricular catheter to measure intracranial pressure and remove cerebrospinal fluid, reducing intracranial pressure (90). In all cases of increased intracranial pressure, careful attention is given to the cerebral perfusion pressure. Interventions that reduce cerebral perfusion pressure below 50 to 60 mm Hg may have deleterious effects on neuronal function.
Lowering systolic blood pressure below 160 mm Hg in the first hours after intracerebral hemorrhage may prevent further bleeding. Labetalol, nitroprusside, hydralazine, and enalapril are preferred antihypertensives. Inadequate blood pressure control during follow-up are associated with higher risk of lobar hemorrhage recurrence (11).
The issue of surgical management has been reviewed in guideline publications. The Surgical Treatment for Intracerebral Hemorrhage (STICH) trial demonstrated no overall benefit from early surgery when compared with initial conservative treatment. Cases of very large hematomas tend to do poorly with either surgical or medical therapy. Cases of moderate-sized hematomas that enlarge and cause clinical worsening may be most amenable to surgical removal, particularly if the bleed is superficial. Superficial lobar intracerebral hemorrhages may be treated by open surgical evacuation (clot reaches to within 1 cm of the cortical surface). Deeper intracerebral hemorrhages may be treated with minimally invasive surgical techniques and decompressive craniectomy (15; 71). Emergency surgery in deteriorating patients with large anticoagulation-associated intracerebral hemorrhage has been found beneficial despite the presence of clinical and radiological signs of herniation before the evacuation (84). Several studies have evaluated stereotactic removal of hematomas, either with or without the use of local thrombolytics to enhance clot removal. Stereotactic infusion of urokinase into the clot cavity reduces the clot burden and risk of death, but rebleeding is common and functional outcome is not improved (15). Endoscopic hematoma evacuation provided the quick, adequate decompression of intracerebral hemorrhage. The outcomes were better than the CT-guided hematoma removal. The STICH II trial suggested that early surgery might have a small survival benefit for patients with superficial lobar intracerebral hemorrhage. In this study, 307 of 601 patients were randomly assigned to early surgery, and 294 were assigned to receive initial conservative treatment. All patients were followed up with at 6 months. Finally, 297 and 286 were included in the analysis, respectively. It was observed that 174 (59%) patients in the early surgery group had an unfavorable outcome versus 178 (62%) patients in the initial conservative treatment group (absolute difference 3 to 7%) (70).
There has been concern that operating on lobar intracerebral hemorrhages due to amyloid angiopathy might lead to further bleeding and a poor outcome. One study of 37 such patients found that 54% had a good outcome following surgery (47). Parietal hematoma location, advanced age (75 years of age or older), and intraventricular blood were associated with a worse prognosis. Only 5% of cases required repeat surgery for bleeding. Therefore, the suspicion that a lobar intracerebral hemorrhage may be due to amyloid angiopathy is not, by itself, a contraindication for surgical intervention.
Recurrence of lobar intracerebral hemorrhage is associated with previous microbleeds or macrobleeds and posterior CT white matter hypodensity, which may be markers of severity for underlying cerebral amyloid angiopathy. Use of an antiplatelet agent following lobar intracerebral hemorrhage may also increase recurrence risk (13).
Statins should be avoided in patients with a history of intracerebral hemorrhage, particularly in those cases with a lobar location (115).
In reported data from Nationwide Inpatient Sample (collected for the years 1993 through 2002), the authors identified 423 patients with pregnancy-related intracerebral hemorrhage, which corresponded to 6.1 pregnancy-related intracerebral hemorrhages per 100,000 deliveries and 7.1 pregnancy-related intracerebral hemorrhages per 100,000 at-risk person-years (compared to 5.0 per 100,000 person-years for nonpregnant women in the age range considered). The increased risk of intracerebral hemorrhage associated with pregnancy was largely attributable to intracerebral hemorrhage occurring in the postpartum period. Risk factors for pregnancy-related intracerebral hemorrhage included advanced maternal age, African American race, preexisting hypertension, gestational hypertension, pre-eclampsia or eclampsia, preexisting hypertension with superimposed pre-eclampsia or eclampsia, coagulopathy, and tobacco abuse (08).
There is no evidence 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.
Ravindra Kumar Garg MD
Dr. Garg of King George's Medical University in Lucknow, India, has no relevant financial relationships to disclose.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
Mar. 10, 2021
Stroke & Vascular Disorders
Mar. 04, 2021
Stroke & Vascular Disorders
Mar. 04, 2021