Spontaneous Parenchymal Hemorrhage

Main Text

Preamble

Intracranial hemorrhage is not a single entity but results from a range of vascular pathologies that differ in implications for prognosis and treatment. In the absence of trauma, abrupt onset of focal neurologic symptoms is presumed to be vascular in origin until proven otherwise. Rapid neuroimaging to distinguish ischemic stroke from intracranial hemorrhage is crucial to patient management.

Primary (Spontaneous) Intracranial Hemorrhage

Epidemiology

Cerebral ischemia/infarction is responsible for almost 80% of all “strokes.” Spontaneous (nontraumatic) primary intracranial hemorrhage (pICH) causes 10-15% of first-time strokes and is a devastating subtype with unusually high mortality and morbidity. Death or dependent state is the outcome in > 70% of all patients.

Clinical Considerations

The American Heart Association (AHA) is emphasizing the use of a baseline severity score as part of evaluating and managing patients with pICH. A widely used system is the intracerebral hemorrhage (ICH) score that combines Glasgow Coma Scale (GCS), patient age (≥ 80 years), ICH volume ≥ 30 mL, presence or absence of intraventricular hemorrhage, and whether the hemorrhage is infratentorial or supratentorial.

Early deterioration with spontaneous ICH (sICH) is common. More than 20% of patients experience a decrease in a GCS score of two or more points between initial assessment by paramedics and presentation in the ED.

Active bleeding with hematoma expansion (HE) occurs in 25-40% of patients and is common in the first 1-2 hours. Patients with large hematomas, history of anticoagulation, or hypertension (HTN) are at particular risk for HE, which may occur several hours after symptom onset. HE is predictive of clinical deterioration and carries significantly increased morbidity and mortality. Therefore, swift diagnosis is needed to direct treatment.

The prognosis is grave, even with prompt intervention. 20-30% of all patients die within 48 hours after the initial hemorrhage. The one-year mortality rate approaches 60%. Only 20% of patients who survive regain functional independence and recover without significant residual neurologic deficits.

Imaging Recommendations

The 2022 AHA/American Stroke Association (ASA) guidelines recommend emergent CT as the initial screening procedure to distinguish ICH from acute ischemic stroke (AIS), as the prognosis and management are strikingly different. The vast majority of strokes in high-income countries (~ 90%) are of ischemic origin (see Chapter 8).

If a parenchymal hematoma is identified on NECT, determining its size and etiology becomes critically important in patient triage. AI programs, such as RAPID ICH (SchemaView), can identify and quantitate hematomas on NECT studies. CTA is easily obtained at the time of initial imaging and is now included in many institutions as an integral part of acute stroke protocols. If contrast or extravasation within the clot (spot sign) is present, these patients are at risk of HE.

The management of unexplained brain bleeds also varies with patient age. If the patient is older than 45 years and has preexisting systemic HTN, a putaminal, thalamic, or posterior fossa ICH is almost always hypertensive in origin. Vascular imaging may or may not be requested.

In contrast, lobar or deep brain bleeds in younger patients or normotensive adults—regardless of age—almost always require further investigation. Contrast-enhanced CT/MR with angiography &/or venography may be helpful in detecting underlying abnormalities, such as arteriovenous malformation, neoplasm, and cerebral sinovenous thrombosis.

In older patients with pICH, MR with T2* (GRE, SWI) is also helpful in detecting the presence of “surrogate markers” of small vessel disease, such as brain microbleeds, white matter hyperintensities, and lacunar infarcts.

Evolution of Intracranial Hemorrhage

Overview

We begin with a discussion of the pathophysiology of ICH. This provides the basis for considering how pICH looks on imaging studies and why its appearance changes over time. We then consider some major causes of sICH, such as HTN and amyloid angiopathy.

Solitary lesions comprise the vast majority of pICHs. The presence of more than one simultaneous macroscopic brain bleed is actually quite uncommon, accounting for just 2-3% of all pICHs. Multifocal brain microbleeds are much more common. We therefore conclude this chapter with a discussion of multifocal brain microbleeds, their etiology, pathology, imaging appearance, and differential diagnosis.

Pathophysiology of Intracranial Hemorrhage

Clot Formation

Clot formation is a complex physiologic event that involves both cellular (mainly platelet) and soluble protein components. Platelets are activated by vascular injury and aggregate at the injured site. Soluble proteins are activated by both intrinsic and extrinsic arms that merge into a common coagulation pathway, resulting in a fibrin clot.

Hemoglobin Degradation

Hemoglobin (Hgb) is composed of four protein (globin) subunits. Each subunit contains a heme molecule with an iron atom surrounded by a porphyrin ring.

Hgb within RBCs that are extravasating into a pICH rapidly desaturates. Fully oxygenated Hgb (oxy-Hgb) contains nonparamagnetic ferrous iron. In a hematoma, oxy-Hgb is initially converted to deoxyhemoglobin (deoxy-Hgb).

With time, deoxy-Hgb is metabolized to methemoglobin (met-Hgb), which contains ferric iron. As RBCs lyse, met-Hgb is released and eventually degraded and resorbed. Macrophages convert the ferric iron into hemosiderin and ferritin.

Ferritin is the major source of nonheme iron deposition in the human brain. Although iron is essential for normal brain function, iron overload may have devastating effects. Lipid peroxidation and free radical formation promote oxidative brain injury after ICH that may continue for weeks or months.

Stages of Intraparenchymal Hemorrhage

Five general stages in temporal evolution of hematomas are recognized: Hyperacute, acute, early subacute, late subacute, and chronic. Each has its own features that depend on three key factors: (1) Clot structure, (2) RBC integrity, and (3) Hgb oxygenation status. In turn, imaging findings depend on hematoma stage (5-1).

Hematomas consist of two distinct regions: A central core and a peripheral rim or boundary. In general, Hgb degradation begins in the clot periphery and progresses centrally toward the core.

Hyperacute Hemorrhage

Hyperacute hemorrhage is minutes (or even seconds) to under 24 hours old. Most imaged hyperacute hemorrhages are generally between 4-6, but < 24, hours old. Initially, a loose fibrin clot that contains plasma, platelets, and intact RBCs is formed. At this stage, diamagnetic intracellular oxyhemoglobin predominates in the hematoma.

In early clots, intact erythrocytes interdigitate with surrounding brain at the hematoma-tissue interface. Edema forms around the hematoma within hours after onset and is associated with mass effect, elevated intracranial pressure, and secondary brain injury.

Acute Hemorrhage

Acute ICH is defined as between 1-3 days old. Profound hypoxia within the center of the clot induces the transformation of oxy-Hgb to deoxy-Hgb. Iron in deoxy-Hgb is paramagnetic because it has four unpaired electrons.

Deoxy-Hgb is paramagnetic, but, as long as it remains within intact RBCs, it is shielded from direct dipole-dipole interactions with water protons in the extracellular plasma. At this stage, magnetic susceptibility is induced primarily because of differences between the microenvironments inside and outside of the RBCs.

Early Subacute Hemorrhage

Early subacute hemorrhage is defined as a clot that is from three days to one week old. Hgb remains contained within intact RBCs. Hgb at the hypoxic center of the clot persists as deoxy-Hgb. The periphery of the clot ages more rapidly and therefore contains intracellular met-Hgb. Intracellular met-Hgb is highly paramagnetic, but the intact RBC membrane prevents direct dipole-dipole interactions.

A cellular perihematomal inflammatory response develops. Microglial activation occurs as immune cells infiltrate the parenchyma surrounding the clot.

Late Subacute Hemorrhage

Late subacute hemorrhage lasts from one to several weeks. As RBCs lyse, met-Hgb becomes extracellular. Met-Hgb is now exposed directly to plasma water, reducing T1 relaxation time and prolonging the T2 relaxation time.

Chronic Hemorrhage

Parenchymal hemorrhagic residua persist for months to years. Heme proteins are phagocytized and stored as ferritin in macrophages. If the capacity to store ferritin is exceeded, excess iron is stored as hemosiderin. Intracellular ferritin and hemosiderin induce strong magnetic susceptibility.

Chronic hemorrhage in the subarachnoid space typically coats the pial surface of the brain, a condition termed “superficial siderosis” (see Chapter 6). Superficial siderosis is sometimes seen adjacent to intraparenchymal hematomas, especially those associated with amyloid angiopathy (see Chapter 10).

Imaging of Intracranial Parenchymal Hemorrhage

The role of imaging in sICH is first to identify the presence and location of a clot (the easy part), to “age” the clot (harder), and then to detect other findings that may be clues to its etiology (the more difficult, demanding part).

The appearance of pICH on CT depends on just one factor: Electron density. In turn, the electron density of a clot depends almost entirely on its protein concentration, primarily the globin moiety of Hgb. Iron and other metals contribute < 0.5% to total clot attenuation and so have no visible effect on hematoma density.

In contrast, the imaging appearance of ICH on MR is more complex and depends on a number of factors. Both intrinsic and extrinsic factors contribute to imaging appearance.

Intrinsic biologic factors that influence hematoma signal intensity are primarily related to macroscopic clot structure, RBC integrity, and Hgb oxygenation status. RBC concentration, tissue pH, arterial vs. venous source of the bleed, intracellular protein concentration, and the presence and integrity of the blood-brain barrier also contribute to the imaging appearance of an ICH.

Extrinsic factors include pulse sequence, sequence parameters, receiver bandwidth, and field strength of the magnet. Of these, pulse sequence and field strength are the most important determinants. T1- and T2-weighted images are the most helpful in estimating lesion age. T2* (GRE, SWI) is the most sensitive sequence in detecting parenchymal hemorrhages (especially microhemorrhages).

Field strength also affects imaging appearance of ICH. The MR findings delineated below and in the table (Table 5-1) are calculated for 1.5T scanners. At 3.0T, all parts of acute and early subacute clots have significantly increased hypointensity on FLAIR and T2WI.

Hyperacute Hemorrhage

CT

If ICH is imaged within a few minutes of the ictus, the clot is loose, poorly organized, and largely unretracted (5-3). Water content is still high, so a hyperacute hematoma may appear isodense or occasionally even hypodense relative to adjacent brain. If active hemorrhage is present, the presence of both clotted and unclotted blood results in a mixed-density hematoma with hypodense and mildly hyperdense components. Rapid bleeding and coagulopathy may result in fluid-fluid levels.

MR

Oxy-Hgb has no unpaired electrons and is diamagnetic. Therefore, signal intensity of a hyperacute clot depends mostly on its water content. Hyperacute clots are isointense to slightly hypointense to gray matter on T1WI. A hyperacute clot is generally hyperintense on T2 scans, although they can appear quite heterogeneous.

Because the macroscopic structure of a hyperacute clot is so inhomogeneous, spin dephasing results in heterogeneous hypointensity (“blooming”) on T2* sequences.

Acute Hemorrhage

CT

The hematocrit of a retracted clot approaches 90%. Therefore, an acute hematoma is usually hyperdense on NECT, typically measuring 60-80 HU. Exceptions to this general rule are found if hemorrhage occurs in extremely anemic patients with very low hematocrits or in patients with coagulopathies.

MR

Acute hematomas are low/intermediate signal intensity on T1WI (5-6A). Significant vasogenic edema develops around the clot and is T1 hypointense and T2/FLAIR hyperintense (5-6B). As the clot retracts, water content diminishes. Intracellular deoxy-Hgb predominates. Deoxy-Hgb is paramagnetic with four unpaired electrons, and the hematoma becomes more profoundly hypointense on T2WI. Acute hematomas “bloom” on T2* (GRE, SWI) (5-6C). Diffusion restriction is present on diffusion-weighted imaging (DWI) and ADC, although the presence of T2 and susceptibility effects can combine to produce a complex appearance in and around acute hematomas (5-6D).

Early Subacute Hemorrhage

CT

Hematoma density gradually decreases with time, beginning with the periphery of the clot. Clot attenuation diminishes by an average of 1.5 HU per day (5-9). At around 7-10 days, the outside of a pICH becomes isodense with the adjacent brain (5-10B). The hyperdense center gradually shrinks, becoming less and less dense until the entire clot becomes hypodense. A subacute hematoma shows ring enhancement on CECT (5-4).

MR

Intracellular met-Hgb predominates around the clot periphery, whereas deoxy-Hgb persists within the hematoma core. A rim of T1 shortening (hyperintensity) surrounding an isointense to slightly hypointense core is the typical appearance on T1WI (5-10C). Paramagnetic met-Hgb is not very mobile and causes pronounced T2 shortening, so early subacute clots are hypointense on T2WI. Profound hypointensity on T2* persists.

Clot appearance on DWI varies. For many forms of hemorrhage, the T2/T2* effect comprises the dominant contribution to signal intensity and therefore appears markedly hypointense (T2 “blackout effect”). In acute and subacute hemorrhage, true restricted diffusion occurs with the intrinsically long T2 of these hematomas (5-8D). The diffusion signal of hemorrhage at each stage of evolution is summarized in the table (Table 5-1).

Late Subacute Hemorrhage

CT

With progressive aging, a pICH gradually becomes hypodense relative to adjacent brain on NECT scans. Ring enhancement may persist for weeks or up to two or three months.

MR

Once cell lysis occurs, mobile free dilute extracellular met-Hgb predominates in determining signal intensity. Clots develop hyperintensity around their rim on both T1WI and T2WI (5-8C). Eventually, the clot appears very hyperintense on both sequences. A rim of T2* “blooming” generally persists. With the exception of minor susceptibility artifacts, late subacute clots appear similar on both 1.5T and 3.0T.

Chronic Hemorrhage

CT

A few very small healed hemorrhages may become invisible on NECT scan. Between 35-40% of chronic hematomas appear as a round or ovoid hypodense focus. Another 25% of patients develop slit-like hypodensities. Between 10-15% of healed hematomas calcify.

MR

Intracellular ferritin and hemosiderin are hypointense on both T1WI and T2WI. A hyperintense cavity surrounded by a “blooming” rim on T2* may persist for months or even years (5-14). Eventually, only a slit-like scar remains as evidence of a prior parenchymal hemorrhage (5-12).

Etiology of Nontraumatic Parenchymal Hemorrhages

There are many causes of nontraumatic (“spontaneous”) or unexplained ICH. The role of imaging in such cases is to localize the hematoma, estimate its age from its imaging features, and attempt to identify possible underlying causes.

The effect of age on the pathoetiology of sICH is profound. Knowing the patient’s age is extremely important in establishing an appropriately narrowed differential diagnosis.

It can be difficult to discern enhancement within an already hyperdense acute hematoma on CECT scans. Dual-energy CT (DECT) can display the presence of contrast enhancement, potentially helping distinguish between tumor bleeding and nonneoplastic (“pure”) hemorrhage. DECT can also help differentiate ICH from extravasated contrast material staining.

MR imaging with standard sequences as well as fat-saturated contrast-enhanced scans can be very helpful. A T2* sequence (GRE &/or SWI) should always be included, as the identification of other prior “silent” microhemorrhages affects both diagnosis and treatment decisions.

Newborns and Infants With sICH

ICH in the term newborn is most frequently associated with prolonged or precipitous delivery, traumatic instrumented delivery (e.g., forceps assistance or vacuum extraction), and primiparity. The most common cause of ICH in infants < 34 gestational weeks is germinal matrix hemorrhage (5-15) (5-16).

The germinal matrix is a highly vascular, developmentally dynamic structure in the brain subventricular zone. The germinal matrix contains multiple cell types, including premigratory/migratory neurons, glia, and neural stem cells. Rupture of the relatively fragile germinal matrix capillaries may occur in response to altered cerebral blood flow, increased venous pressure (e.g., with delivery), coagulopathy, or hypoxic-ischemic injury. Germinal matrix hemorrhage is discussed in greater detail in Chapter 8.

Isolated choroid plexus and isolated intraventricular hemorrhage (IVH) do not involve the germinal matrix. White matter injury of prematurity generally does not show evidence of hemorrhage (“blooming”) on T2* imaging.

The most common nontraumatic cause of spontaneous IVH in neonates beyond 34 gestational weeks is dural venous sinus thrombosis (DVST) (5-18). In contrast to older children and adults in whom the transverse sinus is most commonly affected, the straight sinus (85%) and superior sagittal sinus (65%) are the most frequent locations in infants. Multisinus involvement is seen in 80% of cases. Thalamic and punctate white matter lesions are common in infants with DVST.

Children With sICH

The most common cause of sICH in children ages 1-18 years is an underlying vascular malformation. Vascular malformations are responsible for nearly 1/2 of spontaneous parenchymal hemorrhages in this age group (5-20).

At least 25% of all arteriovenous malformations hemorrhage by the age of 15 years. Cavernous malformations, especially familial cavernous malformations (“cavernomas”), are a less common but important cause of sICH in children.

Other less common but important causes of pediatric sICH include hematologic disorders and malignancies, vasculopathy, and venous occlusion/infarction.

Primary neoplasms are a relatively rare cause of sICH in children (5-22). Infratentorial tumors are more common than supratentorial neoplasms.

Posterior fossa neoplasms that frequently hemorrhage include ependymoma and rosette-forming glioneuronal tumor. Patchy or petechial hemorrhage is more common than large intratumoral bleeds.

Supratentorial tumors with a propensity to bleed include ependymoma and the spectrum of primitive neuroectodermal tumors. Malignant astrocytomas with hemorrhage occur but are rare. In contrast to middle-aged and older adults, hemorrhagic metastases from extracranial primary cancers are very rare in children.

Young Adults With sICH

An underlying vascular malformation is the most common cause of sICH in young adults as well (5-25). Drug abuse is the second most common cause of unexplained hemorrhage (5-23). Cocaine and methamphetamine may induce extreme systemic HTN, resulting in a putaminal-external capsule bleed that looks identical to those seen in older hypertensive adults.

Vasculitis and reversible cerebral vasoconstriction syndrome (RCVS) occasionally cause pICH in young adults (5-29).

Venous occlusion/infarction with or without dural sinus occlusion is also relatively common in this age group, especially in young women taking oral contraceptives. Severe eclampsia/preeclampsia with posterior reversible encephalopathy syndrome (PRES) may cause multifocal posterior cortical and subcortical hemorrhages (5-30). Hemorrhagic neoplasms (both primary and metastatic) are rare.

Middle-Aged and Older Adults With sICH

The two most common causes of sICH in middle-aged and older adult patients are HTN and amyloid angiopathy, both of which are discussed in detail. Approximately 10% of spontaneous parenchymal hemorrhages are caused by bleeding into a brain neoplasm, generally either a high-grade primary tumor, such as glioblastoma multiforme, or hemorrhagic metastasis from an extracranial primary, such as renal cell carcinoma (5-32).

A less common but important cause of sICH in this age group is venous infarct. Venous infarcts are caused by cortical vein thrombosis with or without dural sinus occlusion. Iatrogenic coagulopathy is also common in older adult patients, as many take maintenance doses of warfarin for atrial fibrillation (5-31).

Occasionally, a ruptured saccular aneurysm presents with a focal lobar hemorrhage rather than a subarachnoid hemorrhage. The most common source is an anterior communicating artery aneurysm that projects superolaterally and ruptures into the frontal lobe.

Underlying vascular malformation is a relatively rare cause of sICH in older patients. With a 2-4% per year cumulative rupture risk, a first-time arteriovenous malformation bleed at this age can occur but is unusual (as is hemorrhage from a cavernous malformation) (5-26). However, dural arteriovenous fistulas (dAVFs)do occur in middle-aged and older adult patients. Although dAVFs rarely hemorrhage unless they have cortical venous (not just dural sinus) drainage, spontaneous thrombosis of the outlet veins may result in sudden ICH.

Rare but important causes of sICH in this age group include vasculitis (more common in younger patients) and acute hemorrhagic leukoencephalopathy.

sICH IN OLDER ADULTS

Older Adults

• Common

HTN

Amyloid angiopathy

 Neoplasm (primary or metastatic)

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