Michelle Christina Johansen, MD
Reuter B, Grudzenski S, Chatzikonstantinou E, Meairs S, Ebert S, Heiler P, et al. Thrombolysis in Experimental Cerebral Amyloid Angiopathy and the Risk of Secondary Intracerebral Hemorrhage. Stroke. 2014
With an aging population facing the stroke neurologist and the increasing evidence that patients 80 years or older have a statistical benefit from IV tPA therapy, the understanding of the pathophysiology of cerebral amyloid and the impact it has on treatment of acute ischemic stroke grows more critical. Symptomatic intracranial hemorrhage (ICH) is a severe side effect that must be discussed with all patients prior to administration of tPA, but are patients with cerebral amyloid angiopathy at increased risk?
It is recognized that the deposition of amyloid in the cerebrovascular system increases the incidence of spontaneous lobar hemorrhage and advancing MRI techniques have made us increasingly aware of the presence of cortical microbleeds in these patients. Given the predisposition of the vessels towards dysfunction, Reuter and colleagues set out to investigate the risk of secondary intracerebral hemorrhage in an animal model after treatment with an adjusted dose of rtPA. In this study, APP23-transgenic mice and wildtype littermates underwent induced ischemic stroke via MCA occlusion, were treated with rtPA and functionally were assessed 24hrs after occlusion. The brains of both cohorts underwent histological processing to evaluate infarct size and degree of acute intracerebral bleeding.
In their study, the transgenic mice (9/13) displayed a higher risk (p=0.05) of developing ICH after stroke and thrombolytic therapy compared to the wildtype (3/11). A higher severity of bleeding (Grade 2 or 3) corresponded to an increased infarct burden in the amyloid cohort. The authors appropriately raise a point of caution that the models were not evaluated in the absence of rtPA thereby potentially leading to an overestimation of the hemorrhagic burden caused by tPA.
Notably neurologic deficit and mortality were not statistically different between the amyloid and wildtype animals. The authors observed no intracranial hemorrhage after rtPA-treatment outside of the infarct area and offer this as an explanation for the lack of increased functional deficit in the amyloid cohort.
Although the n is small and the data is derived from an animal model, the study raises several points of discussion. Would the results be influenced by a greater delay prior to administration of rtPA? What if the study had been conducted using a model looking at posterior circulation stroke? Would the outcome scores have differed more than 24hrs after occlusion?
While the incidence of hemorrhage in patients with amyloid may be increased, it would appear from this data that there is no increased risk of mortality after administration of rtPA thereby freeing the clinician to use the last known normal and standard contraindications to guide care of the elderly. Certainly only further investigation can help us move towards a better understanding of using thrombolytics in patients with cerebral amyloid deposition but this study provides a launching point.