Hemorrhagic transformation of ischemic stroke

Haemorrhagic transformation is a complication of cerebral ischaemic infarction and can significantly worsens prognosis. 

It should be noted that the term haemorrhagic transformation is a little variably used and collectively refers to two different processes, which have different incidence, appearance and prognostic implications. These are: 

1. petechial haemorrhage
2. intracerebral haematoma 

As such when using the term one should try and be explicit as to which of these one is referring to. 

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Epidemiology

The patient group affected is a subset of those affected by cerebral infarction, and thus is dominated by the elderly with multiple cardiovascular risk factors. 

The rates of haemorrhagic transformation of ischaemic strokes has been variably reported, but generally over half of all cerebral infarcts at some stage develop some haemorrhagic component, although the majority (89%) are petechial haemorrhages, and a minority (11%) haematomas ^5-6. Importantly cardioembolic strokes, especially large ones, are more likely to undergo haemorrhagic transformation than atherothrombotic strokes ¹. 

Although haemorrhagic 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 over all rate of spontaneous haemorrhagic transformation (with haematoma) has been reported to be as high as ~5% ⁵. 

The incidence of symptomatic haemorrhagic transformation is however much lower, between 0.6 and 3% in untreated patients and up to 6% in patients treated with IV tP ^2,4,6. 

Predictors of haemorrhagic transformation when thrombolysis is used 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

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

In un-treated patients, haemorrhagic 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, haemorrhage occurs in the vast majority within 24 hours of the start of treatment ³. 

Pathology

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

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

Radiographic features

The radiographic features differ for petechial haemorrhage and secondary haematoma. 

Petechial haemorrhages usually appear, as the name suggests, as tiny punctate regions of haemorrhage, often not able to be individually resolved, but rather resulting in increased attenuation of the region on CT of 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 haematomas the radiographic features on both CT and MRI are merely a summation of the features of a ischaemic infarct, with superimposed cerebral haemorrhage. The amount of haemorrhage relative 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 haemorrhagic. This may not be the case if the haemorrhage is large and the underlying infarct small. 

CT

Petechial haemorrhage 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 haematomas 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. Haemorrhage 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 ischaemic 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 haemorrhage 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 petichial haemorrhage, neither prognosis or treatment are usually affected. The same cannot be said for secondary haematomas, which when large can have a dramatic negative impact on survival and morbidity. In fact in many thrombolysis trials, it is these secondary haematomas which almost offset the gains made by successful reperfusions.