Dr. Bogousslavsky of the Genolier Swiss Medical Network has no relevant financial relationships to disclose.)
Dr. Levine of the SUNY Health Science Center at Brooklyn has received honorariums from Genentech for service on a scientific advisory committee and a research grant from Genentech as a principal investigator.)
This article includes discussion of hemorrhagic transformation of ischemic stroke, hemorrhagic brain infarction, hemorrhagic cerebral infarction, hemorrhagic conversion, hemorrhagic infarct, hemorrhagic infarction, hemorrhagic transformation, hemorrhagic transformation of ischemic stroke, hemorrhagic transformation of stroke, red infarction, hemorrhagic infarct, and parenchymatous hematoma. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Hemorrhagic transformation after ischemic stroke is an often underdiagnosed phenomenon. With increasing and widespread use of tPA and with improved imaging capabilities afforded by newer sequences on MRI, it's now possible to predict which patients might be at increased risk of clinically significant hemorrhagic transformation. In this article, the authors have added information about the risk of hemorrhagic transformation with tPA, the use of minocycline to decrease risk of hemorrhagic transformation, and the predictive value of hemorrhagic transformation in long-term prognosis.
• Hemorrhagic transformation is a complication of ischemic stroke; it occurs in about 10% of patients.
• The spectrum of hemorrhagic transformation ranges from minor petechial bleeding (hemorrhagic infarct) to major mass-producing hemorrhage (parenchymal hematoma).
• Only parenchymal hematoma, seen in about 3% of patients, is associated with adverse outcome.
Historical note and terminology
Historically, hemorrhagic infarction, initially designated as "red softening," has long been recognized by neuropathologists to occur as a natural consequence of ischemic brain injury. Several early theories were advanced to explain the pathogenesis of secondary bleeding into a bland (pale, anemic) infarction. Cohnheim proposed that hemorrhagic infarction resulted from the embolic occlusion of end arteries followed by venous reflux into damaged vascular beds (Cohnheim 1872). “Infarction” to Cohnheim still had the original sense of “stuffing.” In this case, the stuffing was “hemopoietic,” hemorrhagic, that is. He observed 2 successive events: (1) the retrograde filling and the distension with blood of the venous and capillary void distal to the plug and (2) the subsequent diapedesis of red corpuscles through the vessel wall, damaged secondarily by the loss of their normal blood supply (Paciaroni Bogousslavsky 2009). The following year, Liddel recognized that hemorrhagic changes may occur early, often within 2 days, following embolic infarction (Liddel 1873). The role of venous reflux was later discounted by Hiller, who cited the potential importance of collateral circulation in the genesis of secondary bleeding (Hiller 1935).
Fisher and Adams' landmark paper established the special predilection for embolic infarcts to undergo a dynamic process of hemorrhagic transformation (Fisher and Adams 1951). The concept of "migratory embolism" rested on their observations that the hemorrhagic portion of an infarction often lay proximal to identified emboli, whereas pale zones of infarction were distal to persisting occlusions. They proposed that the molding and fragmentation of emboli due to hemodynamic forces results in distal clot migration, thereby exposing an ischemically damaged vascular bed to reperfusion and subsequent bleeding.
Hain and colleagues cited 2 prerequisites for the production of a hemorrhagic infarction: "one, a sufficient volume of blood must flow through the vessels distal to the site of occlusion to produce a hemorrhagic area, and two, there must be sufficient alteration in the permeability of the vessel wall to permit the escape of blood into the tissue" (Hain et al 1952).
The current classification of hemorrhagic transformation encompasses a broad spectrum of secondary bleeding ranging from small areas of petechial hemorrhage to massive space-occupying hematomas. The distinction between hemorrhagic infarction and parenchymatous hematoma is important, as the clinical outcome and perhaps the pathogenesis of these 2 types of hemorrhagic transformation may differ (Fiorelli 1999). Hemorrhagic infarction on CT scan appears as patchy petechial or more confluent areas of bleeding (increased attenuation), often with indistinct margins and confined within the vascular territory of the infarction. This pattern of hemorrhagic transformation is thought to represent the diapedesis of blood cells through ischemic capillaries without frank rupture of a vessel. Involvement of cortical tissues often appears gyriform in pattern.hemosiderin produces T2 shortening with signal loss, whereas methemoglobin results in a high-signal appearance on T1-weighted images. MRI is more sensitive in detecting small areas of hemorrhage than is CT (Hesselink et al 1986; Kidwell et al 2004).
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