Hemorrhagic transformation of ischemic stroke

Hemorrhagic transformation is a complication of cerebral ischemic stroke and can significantly worsen prognosis.

Terminology

The term hemorrhagic transformation is somewhat variably used and collectively refers to two different processes, which have different incidence, appearance and prognostic implications. These are:

1. hemorrhagic infarction (petechial hemorrhages)

2. parenchymal hematoma

As such when using the term "hemorrhagic transformation" one should try and be explicit as to which of these two is occurring. 

Epidemiology

The rates of hemorrhagic transformation of ischemic strokes have been variably reported, but generally over half of all cerebral infarcts at some stage develop some hemorrhagic component. The majority of hemorrhagic transformation after stroke (89%) is petechial hemorrhages; a minority (11%) hematomas ^5,6.

The patient group affected is a subset of those affected by cerebral infarction. Therefore, patients affected by hemorrhagic transformation are those more likely to be affected by ischemic strokes, such as the elderly and those with cerebrovascular risk factors. Beyond this, certain factors increase the risk of hemorrhagic transformation of stroke, including ¹¹:

• older age

• larger stroke size

• cardioembolic stroke etiology ¹

• anticoagulant use

• fever

• hyperglycemia

• low serum cholesterol

• elevated systolic blood pressure in the acute setting

• thrombolytic therapy or other recanalization

Although hemorrhagic transformation can occur spontaneously, it is more frequently encountered in patients who receive anticoagulant therapy and even more frequent in those undergoing thrombolytic therapy ^1,2,4. The overall rate of spontaneous hemorrhagic transformation (with hematoma) has been reported to be as high as ~5% ⁵. The incidence of symptomatic hemorrhagic transformation is, however, much lower, between 0.6 and 3% in untreated patients and up to 6% of patients treated with IV tPA ^2,4,6.

After IV tPA, predictors of hemorrhagic transformation include ⁶:

• severe strokes (NIHSS >14)

• proximal middle cerebral artery occlusion

• hypodensity (CT) affecting >1/3 of the middle cerebral artery territory

• delayed recanalization (>6 hours after stroke onset)

• absence of collateral flow

Clinical presentation

While various criteria have been used for defining whether a hemorrhage is symptomatic, only parenchymal hematomas have been consistently associated with neurological deterioration and worsened long-term outcomes ¹⁰.  Many instances of hemorrhagic transformation, including most petechial hemorrhage, is not symptomatic. 

Significant hemorrhagic transformation of a cerebral infarct usually manifests in a rapid and often profound deterioration in clinical state.

In untreated patients, hemorrhagic transformation rarely occurs in the first 6 hours. It is usually seen in the first few days, the majority within 4 days of infarction. In patients who have been treated acutely with thrombolysis or thrombectomy, hemorrhage occurs in the vast majority within 24 hours of the start of treatment ³.

Pathology

Petechial hemorrhagic transformation has traditionally been referred to by pathologists as "red softening" in contrast to the more common bland or anemic infarct.

It is believed that hemorrhagic transformation occurs as a result of preserved collateral perfusion (from adjacent vessels/territories) or from reperfusion of infarcted tissues which have weakened vessels (i.e. from extravasation or diapedesis) ¹. The former explains why hemorrhagic transformation is seen in patients with permanently occluded vessels. The latter accounts for the increased incidence in patients receiving therapies designed to increase reperfusion rates.

Classification

A commonly used classification system was developed for the European Cooperative Acute Stroke Study (ECASS II), which divides hemorrhagic transformation into four subtypes ⁹:

1. hemorrhagic infarction type 1 (HI1)

   • petechial hemorrhages at the infarct margins

2. hemorrhagic infarction type 2 (HI2)

   • petechial hemorrhages throughout the infarct

   • no mass-effect attributable to the hemorrhages

3. parenchymal hematoma type 1 (PH1)

   • ≤30% of the infarcted area

   • minor mass effect attributable to the hematoma

4. parenchymal hematoma type 2 (PH2)

   • >30% of infarct zone

   • substantial mass effect attributable to the hematoma

This same classification has been incorporated into the widely used Heidelberg bleeding classification ¹².

Radiographic features

The radiographic features differ for petechial hemorrhage and secondary hematoma.

Petechial hemorrhages, as the name suggests, usually appear as tiny punctate regions of hemorrhage, often not able to be individually resolved, but rather resulting in increased attenuation of the region on CT or signal loss on MRI. Although this petechial change can result in cortex appearing near-normal it should not be confused with the phenomenon of fogging seen on CT which occurs 2 to 3 weeks after infarction.

In the case of secondary hematomas, the radiographic features on both CT and MRI are merely a summation of the features of an ischemic stroke, with superimposed cerebral hemorrhage. The amount of hemorrhage relative to the size of the infarct can vary widely, but usually, it is possible to identify significant areas of the brain which are infarcted but not hemorrhagic. This may not be the case if the hemorrhage is large and the underlying infarct small.

CT

Petechial hemorrhage typically is more pronounced in grey matter and results in increased attenuation. This sometimes mimics normal grey matter density and contributes to the phenomenon of fogging.

By the time secondary hematomas form, the underlying infarct should be easily seen and will appear as a region of low attenuation, involving both the white matter and the overlying cortex. Hemorrhage is often patchy, scattered throughout the infarcted tissue, and usually represents only a small component of the abnormal tissue ¹.

MRI

Appearances of MRI are as expected for an ischemic stroke, demonstrating restricted diffusion on DWI/ADC sequences. Sequences susceptible to signal drop out due to blood products (especially SWI) are useful as they are more sensitive than CT to early hemorrhage and may help direct therapy (e.g. withhold thrombolytic therapy) although they are difficult to obtain in the hyperacute setting.

Treatment and prognosis

In the case of petechial hemorrhage, neither prognosis or treatment are usually affected. The same cannot be said for secondary hematomas, which when large can have a dramatic negative impact on survival and morbidity. In fact, in many thrombolysis trials, it is these secondary hematomas which almost offset the gains made by successful reperfusion.

Differential diagnosis

• contrast staining post-contrast administration (e.g. for endovascular clot retrieval) ^7,8

  • follow-up CT performed 19-24 hours following intervention is the most specific way to differentiate, with persistent hyperdensity consistent with hemorrhage as contrast staining will reduce in density over time ⁷

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