Secondary Intraparenchymal Hemorrhages

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Chapter 11 Secondary Intraparenchymal Hemorrhages

Alejandro A. Rabinstein, Steven J. Resnick

Multiple causes other than hypertension may provoke intraparenchymal hematomas. Recognizing them may be difficult, especially in the acute phase. However, some of these causes must be promptly identified to avoid devastating complications. Hemorrhages induced by excessive anticoagulation and those produced by bleeding vascular anomalies are examples of highly dangerous situations that demand immediate therapeutic intervention.

The patient’s history may offer clues to unveil the source of bleeding. Patients with amyloid angiopathy often manifest signs of cognitive deterioration preceding their first clinical hemorrhage. Patients and relatives must be probed to investigate whether there is any history of substance abuse or consumption of sympathomimetic drugs (decongestants, appetite suppressants). Previous episodes of bleeding in other sites may indicate an underlying hemorrhagic diathesis, and previous thromboembolic events should raise suspicion of cerebral venous thrombosis. History of cancer favors the possibility of brain metastasis, whereas recurrent cerebral hemorrhage may be a sign of amyloid angiopathy, untreated vascular anomalies, or coagulopathy. Any recent history of recent head trauma may be significant and should be noted. Fevers or preexistent debilitating systemic illness may be manifestations of infectious endocarditis.

Certain physical signs can also provide helpful information. Examination should specifically focus on searching for external signs of head trauma (raccoon’s eyes, Battle’s sign in the mastoid area), fever, cardiac murmur and other features of endocarditis (subungual splinter hemorrhages, petechiae, splenomegaly, Roth spots, Janeway lesions, Osler’s nodes), lymphadenopathy, peripheral tracks of venous puncture (suggesting intravenous drug use), and exaggerated skin bruises (possibly disclosing bleeding diathesis). Blood studies must include a complete cell count, platelet count, prothrombin time, activated partial thromboplastin time, liver enzymes, and urine drug screen.

Brain imaging is particularly valuable in the distinction of secondary causes of intraparenchymal hematoma (Table 11-1). Radiological hints are frequently subtle but quite reliable. Imaging often provides the first, and sometimes only evidence that a secondary cause is responsible for the hemorrhage. Throughout this chapter we attempt to summarize useful discriminating signs as we present examples of the most common secondary causes of intraparenchymal bleeding.

TABLE 11-1 Secondary causes of intraparenchymal hemorrhage

Cerebral amyloid angiopathy

Hemorrhagic transformation of ischemic infarction

Anticoagulation

Thrombolysis

Intrinsic coagulation disorders

Sympathomimetic drugs (cocaine, amphetamines, decongestants, anorectics)

Infective endocarditis

Vasculitis

Moyamoya disease

Neurosurgical and neuroendovascular procedures

Cerebral venous thrombosis

Vascular anomalies

Saccular aneurysms

Arteriovenous malformations

Cavernous malformations

Dural arteriovenous fistulas

Tumors (primary or metastatic)

Head trauma

CEREBRAL AMYLOID ANGIOPATHY

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid β and other amyloidogenic peptides in the walls of medium and small cortical and leptomeningeal vessels leading to vascular fragility and probably dysfunction.^1,² Amyloid deposition and hemorrhage are favored by the presence of APOE 2 and 4 alleles,³ and vascular amyloid deposits are often (but not always) seen in combination with changes of Alzheimer’s disease.⁴ The restricted location of the deposits explains why hemorrhages are always lobar and involve the cortex of the brain (or, much less commonly, the cerebellum). It may account for more than one third of cases of lobar intracerebral hemorrhage (ICH) in the elderly population (age > 65 years).^5,⁶ The prevalence of CAA in brain-bank studies exceeds 50% in patients over age 70,⁷ and it is severe in more than 10% of patients over age 80.⁸ Thus the incidence of CAA-related hemorrhages is likely to continue to increase substantially with the aging of the population.

The definitive diagnosis of CAA requires pathological demonstration. However, in practice this is rarely feasible or justified. Criteria have been designed to make the diagnosis of possible or probable CAA based solely on clinical and radiological data.⁹ Possible CAA requires CT or MRI evidence of a single lobar ICH in a patient 55 years or older with no other cause for the hemorrhage. When there is clinicoradiological evidence of two or more lobar cerebral or cerebellar hemorrhages in a patient 55 years or older with no other causes for the lesions the diagnosis is probable CAA.

These criteria focus on the identification of cases of lobar ICH that can only be attributed to CAA. However, CAA may also play a role in the genesis of lobar hematomas in patients with coexistent causes. In fact, it has been shown that CAA increases the risk of intracranial bleeding in patients receiving anticoagulants ¹⁰ and thrombolytic agents.¹¹

The diagnosis of CAA is relying increasingly on the use of MRI, particularly gradient-recall echo sequences. This is well illustrated in the following case vignette and elaborated in the subsequent teaching points.

Case Vignette

A 73-year-old man without previous known illnesses was brought to the emergency department by his son for evaluation of acute speech changes. On physical examination, the patient was fully awake and had fluent dysphasia without associated motor or sensory deficits. Head CT scan disclosed a left parietal hemorrhage of moderate volume (Figure 11-1). When specifically questioned, the patient’s son acknowledged that he had noticed subtle changes in the behavior of his father over the previous year. His memory had been declining for a longer time. Brain magnetic resonance imaging (MRI) revealed multiple cortical microhemorrhages, supporting the clinical suspicion of cerebral amyloid angiopathy. The patient developed episodes of agitation during the hospitalization and only achieved minimal recovery from his dysphasia.

Figure 11-1 Computed tomography scan of the head shows a left parietal hemorrhage ascribed to amyloid angiopathy (upper row). Note characteristic lobar location and heterogeneity, likely caused by bleeding in stages. On brain magnetic resonance imaging, the hematoma has mixed hyperintense and isointense signals on the T1-weighted sequence (middle row, left) and it is predominantly hypointense on the T2-weighted sequence (middle row, right), reflecting the acute to early subacute nature of the hemorrhage. Gradient-recall echo sequence demonstrates multiple other areas of cortical microhemorrhage (lower row), a distinctive feature of amyloid angiopathy.

♦ Lobar hemorrhages related to CAA may have variable sizes. Symptomatic hematomas are often voluminous, but most lesions are small and asymptomatic.

♦ Symptomatic hematomas often have heterogeneous appearance, suggesting that bleeding may occur in more than one temporal phase. The clinical correlate of this observation is the presentation with deficits that often have progressed over hours, unlike those accompanying hypertensive hemorrhages or ischemic strokes.

♦ CAA-related hemorrhages have a predilection for the temporal and occipital lobes.¹² The reasons for this spatial clustering in the posterior aspects of the brain remain speculative.

♦ Lobar ICH from CAA has an elevated rate of recurrence (as high as 14% per year in patients at highest risk based on their apolipoprotein E genotype)³ (Figure 11-2).

♦ Gradient-recall echo has excellent sensitivity for the detection of lobar microhemorrhages. Identification of these small asymptomatic lesions is highly supportive of the diagnosis of CAA in an elderly patient with lobar hemorrhage (Figure 11-3).

♦ The total burden of microhemorrhages on MRI predicts the risk of recurrent symptomatic lobar transpose.¹³

♦ On MRI scan, patients with CAA and lobar hemorrhage(s) often exhibit signs of concomitant extensive white matter damage. This combination of lesions suggests more widespread vascular dysfunction and is associated with cognitive impairment ¹⁴ (Figure 11-3).

Figure 11-2 A 74-year-old man with progressive decline and recent hemorrhage causing left leg weakness (2–3 weeks earlier) was transferred for evaluation of recurrent lobar hematoma producing confusion, right hemiparesis, and partial neglect. Brain magnetic resonance imaging is shown in the upper row. It discloses a relatively small right frontal parasagittal hemorrhage hyperintense on T1-weighted sequence (left) and with hyperintense core surrounded by hypointense rim on gradient-recall echo (GRE) (right), consistent with a late subacute hematoma. In addition, it also reveals a larger right parietal hemorrhage which is isointense on T1-weighted sequence and predominantly hypointense (with some areas of increased signal intensity) on GRE, reflecting the acuteness of this lesion. The patient recovered fairly but was readmitted 3 months later with a massive left hemispheric hemorrhage seen on the computed tomography scan displayed in the lower row. Notice again the heterogeneous characteristic of the lesion in this very early phase.

Figure 11-3 Brain magnetic resonance imaging shows extensive leukoaraiosis on fluid-attenuated inversion recovery sequence (upper left) associated with multiple cortical microhemorrhages in the cerebellar (upper right) and cerebral hemispheres (lower row) best seen on gradient-recall echo/T2* sequence.

HEMORRHAGIC TRANSFORMATION

Hemorrhagic transformation is common during the evolution of large ischemic strokes, particularly those caused by embolism. In the majority of cases, the hemorrhagic component is seen on computed tomography (CT) or MRI scan but does not produce clinical deterioration. However, some patients develop a true hematoma within the infraction, and the resulting mass effect may be rapidly fatal. These cases of “malignant” hemorrhagic transformation are most often associated with the use of anticoagulation or thrombolysis. Brain imaging may provide helpful clues to avoid this devastating complication. Hemorrhagic complications after thrombolysis represent a particularly important form of hemorrhage after ischemic infarction and are discussed separately in the next section.

Case Vignette

An 86-year-old woman with history of hypertension and right parietal meningioma was found unresponsive on her bed during a cruise. She was intubated and emergently transferred to our hospital for evaluation. On arrival, she was drowsy, globally aphasic, and had flaccid right hemiplegia. Her pulse was irregularly irregular, and electrocardiogram confirmed the diagnosis of atrial fibrillation. Initial CT scan is shown in Figure 11-4, A and B.

Figure 11-4 (A) Large left middle cerebral artery infarction seen on the computed tomography scan of the head with contrast (upper row). Notice blockage of flow in the middistal M1 segment (arrow) and early contrast extravasation in the core of the infarction., Signs of hemorrhagic conversion of the ischemic infarction are seen on computed tomography scan (C). T1-weighted magnetic resonance imaging with gadolinium demonstrates linear areas of contrast enhancement within the infarction (D). Fluid-attenuated inversion recovery sequence shows heterogeneous signal change in the area of ischemia complicated with hemorrhagic transformation (E). Gradient-recalled echo sequence clearly discloses the hemorrhagic changes of the infarction (F).

Case Vignette

CT scan of the head and brain MRI obtained 48 hours after symptom onset showed evidence of hemorrhagic transformation (Figure 11-4, C–F). The patient had been taking aspirin before the stroke, and 325 mg of aspirin had been administered since admission. Anticoagulation had not been initiated because of the perceived high risk of hemorrhagic conversion of the ischemic infarction. On the third day after stroke onset, the patient’s neurological status deteriorated because of progression of mass effect. She responded favorably to treatment with mannitol. Her subsequent clinical course was complicated with the development of acute renal failure, congestive heart failure, bilateral pneumonia, and sepsis. She required tracheostomy and was eventually transferred to a nursing home in fair condition. Six months later, she had improved communication abilities but remained functionally dependent.

♦ MRI is more sensitive than CT scan for the diagnosis and quantification of hemorrhagic transformation of ischemic infarction.

♦ Hemorrhagic transformation is most often asymptomatic. It tends to affect focal areas of the infarction, frequently close to the cortex (where blood probably arrives from leptomeningeal collaterals) (Figures 11-5, 11-6, and 11-7).

♦ Hemorrhagic transformation is often associated with early contrast parenchymal enhancement, also a marker of disrupted blood-brain barrier.¹⁵

♦ MRI is particularly superior to CT scan for the detection of hemorrhage after intra-arterial thrombolysis, when extravasated contrast may be confused with blood.¹⁶

♦ Hemorrhage may be facilitated by delayed recanalization of the occluded vessel due to clot autolysis (or therapeutic thrombolysis) (Figure 11-8).

♦ Radiological evidence of asymptomatic hemorrhagic transformation should be carefully considered when deciding the timing of initiation of anticoagulation in patients with large embolic strokes.

♦ Even pronounced hemorrhagic conversion of a small infarction may be safe, whereas lesser degrees of hemorrhage into large infarctions may precipitate herniation.

♦ In our experience, the risk of symptomatic severe hemorrhagic transformation is greater in patients with proximal middle cerebral artery (MCA) occlusions in whom the infarction involves the territory perfused by the lenticulostriate branches (Figure 11-9).

♦ Hemorrhage into the deep ganglia often results in rapid and often fatal herniation (Figure 11-9).

Figure 11-5 Multiples examples of hemorrhagic conversion of ischemic infarctions on head computed tomography scans.

Figure 11-6 Brain imaging displaying a cortical area of hemorrhagic conversion of a large anterior cerebral artery infarction. A, Computed tomography scan of the head with hemorrhagic region signaled by arrow. B, Diffusion weighted imaging with acute infarction exhibiting restricted diffusion (bright signal) and hemorrhage distinguished by increased diffusion (dark signal). C, T1-weighted sequence displays the hemorrhage with isointense signal, indicating acute bleeding. D, fluid-attenuated inversion recovery sequence with increased signal in the area of ischemic infarction and decreased signal in the zone of hemorrhagic conversion.

Figure 11-7 A 62-year-old man who suffered a large left middle cerebral artery embolic infarction from cardiac embolism caused by atrial fibrillation. Diffusion-weighted imaging and apparent diffusion coefficient map are shown in the upper row, T1-weighted sequence before and after gadolinium administration in the middle row, fluid-attenuated inversion recovery in the left frame of the lower row and gradient-recalled echo (GRE) in the right frame of the lower row. Note contrast extravasation in the contrast-enhanced T1-weighted image and small areas of hemorrhagic conversion on GRE.

Figure 11-8 A 58-year-old man with acute left middle cerebral artery occlusion due to atrial fibrillation was evaluated in the emergency department of the referring hospital 5 hours after symptom onset. Head computed tomography (CT) scan at that time (left) showed an extensive hyperdense middle cerebral artery sign (arrow). By the time he arrived to our hospital, he was beyond the window for intra-arterial therapy. On the second day of admission, he was found unresponsive in the stroke unit. Emergency CT scan (right) showed resolution of the hyperdensity in the middle cerebral artery (clot autolysis) and revealed extensive hemorrhage in the area of the deep nuclei with intraventricular extension and marked regional mass effect.

Figure 11-9 Two examples of “malignant” hemorrhagic transformation involving the deep portions of middle cerebral artery infarctions and causing severe tissue displacement. The complication was fatal in both cases. Computed tomography (CT) scans of first case shown in upper row. Second case is illustrated by CT scan (left) and fluid-attenuated inversion recovery sequence of magnetic resonance imaging (right) in the lower row.

HEMORRHAGIC COMPLICATIONS OF THROMBOLYSIS

Intracranial hemorrhage is the most feared complication of thrombolysis. Symptomatic hemorrhagic transformation occurs in 6% to 7% of patients who receive treatment with recombinant tissue plasminogen activator (rt-PA) within 3 hours of symptom onset.^17,¹⁸ The rate of hemorrhage is about 10% after intra-arterial lysis.¹⁹ Hemorrhagic risks with combined intravenous–intra-arterial lysis²⁰ and mechanical embolectomy²¹ also fall within this range. It tends to occur early after infusion of rt-PA and carries high mortality. However, it does not negate the value of thrombolysis in appropriate candidates for this acute intervention.

Clinical factors include older age, pretreatment hypertension, pretreatment hyperglycemia, history of diabetes mellitus, use of antiplatelets other than aspirin before stroke onset, greater stroke severity (i.e., higher score on the National Institutes of Health stroke scale) at baseline, and higher blood pressure over the first 24 hours after lysis.²²^–²⁶ Radiological predictors on initial CT scan include hypodense lesion greater than one third of MCA territory and hyperdense MCA sign.^22,²³ MRI with diffusion-weighted imaging/perfusion-weighted imaging (DWI/PWI) may be particularly useful because very low initial apparent diffusion coefficient (ADC) values, persistent perfusion deficits on PWI, and very large areas of restricted diffusion on DWI strongly correlate with heightened risk of hemorrhagic transformation.^22,²⁷^–³¹ Although DWI and PWI are not usually available when thrombolysis is administered within the 3-hour window, the predictive information provided by these sequences may become important if thrombolysis is considered at later times in patients with persistent radiological penumbra. Leukoaraiosis has also been associated with increased risk of ICH after thrombolysis.³² However, the presence of cerebral microhemorrhages seen on T2* sequence does not appear to influence substantially the risk of symptomatic ICH.³³ Although the factors influencing the risk of hemorrhage after intra-arterial thrombolysis or multimodality therapy have been less studied, available evidence indicates that they do not differ significantly from those that determine the risk after intravenous lysis.^34,³⁵

It has been appropriately postulated that the deleterious consequences of symptomatic ICH after thrombolysis may have been overestimated by failing to consider the predicted outcome at the time of initial assessment in patients who subsequently had symptomatic ICH.³⁶ Because outcome in many of these patients is anticipated to be poor (because of older age, more severe deficits, and larger strokes), when the predicted functional outcome is compared with the actual outcome after ICH, the number necessary to harm for intravenous thrombolysis turns out to be much smaller than commonly thought. In other words, symptomatic ICH after thrombolysis may further worsen outcome in patients with poor chances of recovery without thrombolysis, but it rarely causes devastating damage in patients with better anticipated outcome at the time of treatment.

Case Vignette

A 68-year-old man with previous history of a left hemispheric stroke presented to the emergency department with sudden onset of left-sided weakness within 2 hours of symptom onset. Examination revealed right gaze preference, left homonymous hemianopia, left hemiparesis, and partial left hemibody neglect. Initial CT scan is shown in Figure 11-10 (upper row). He had no contraindications for intravenous thrombolysis and consequently received rt-PA with the bolus given 2 hours and 45 minutes after instauration of deficits. Three hours later, the patient was noticed to be somnolent, and his weakness had worsened to the point of hemiplegia. Emergent repeat CT scan displayed intraparenchymal and subarachnoid hemorrhage (Figure 11-10, middle row). He was treated with fresh frozen plasma and cryoprecipitate. Although his deficits remained severe, he subsequently improved. Brain MRI on day 5 showed the hemorrhagic transformation of his right MCA infarction with mild regional mass effect (Figure 11-10, lower row).