Continued bleeding following acute intracerebral hemorrhage

In this Ph.D. thesis, ‘Continued bleeding following acute intracerebral hemorrhage’, we have discussed the background literature, risk factors, and underlying biology of hematoma expansion, as well as the clinical applicability of the CT angiography (CTA) 'spot sign' as an imaging marker of this continued bleeding following intracerebral hemorrhage. In the first part of this thesis we describe several studies examining the occurrence, frequency and outcome of hematoma expansion (continued bleeding) following acute intracerebral hemorrhage. We show that continued bleeding is common and occurs in 40% of all patients and negatively impacts functional outcome. Furthermore, it is shown that expansion is preventable if diagnosed in a timely fashion. In the second part of the thesis we have further examined the underlying biology of continued bleeding following intracerebral hemorrhage. Two genetic studies show that the Apolipoprotein E ε2 allele is associated with both hematoma expansion and an imaging marker of this continued bleeding, termed the ‘CT angiography spot sign’. These findings confirm the ‘avalanche model’ of cascading small vessel injury as underlying mechanism for this expansion. This part of the thesis also includes two studies further examining the spot sign imaging marker and its role in order types of brain hemorrhages. In het third and final part we describe studies aimed at personalized treatment of patients with intracerebral hemorrhage. The main results include the development of a prediction model to accurately assess which patients are at the highest risk of hematoma expansion based on a few important factors: size of the hematoma, time of onset, coagulation status and neuroimaging findings. With this easily obtainable information we can risk stratify patients for medical and surgical treatments, which is currently tested in an ongoing clinical trial also described in this section of the thesis. By selecting a high-risk population using clinical prediction models, patients selected for treatment are theoretically much more likely to benefit. Moreover, patients at low risk of hematoma expansion would in turn not be needlessly exposed to the potential harms of medications or invasive procedures. With this approach, we have the tantalizing opportunity to create an individualized and patient-based scheme to treat our intracerebral hemorrhage patients. This is of pivotal importance, since there is a pressing need for treatment options, as currently no proven medical or surgical therapies are available. In conclusion, the studies included in this thesis show that in primary intracerebral hemorrhage; 1.) Hematoma expansion is common and preventable; 2.) Genetic, clinical, and neuroimaging predictors (termed the CTA spot sign) have been identified that help comprehend the underlying biology of expansion; 3.) Selection of patients at highest risk of expansion is feasible. These findings contribute to a better understanding and prediction of hematoma expansion, and could result in individualized treatment and trial design for patients with spontaneous intracerebral hemorrhage.