MTT Heterogeneity in Perfusion CT Imaging as a Predictor of Outcome after Aneurysmal SAH

BACKGROUND AND PURPOSE:Impairment of tissue oxygenation caused by inhomogeneous microscopic blood flow distribution, the so-called capillary transit time heterogeneity, is thought to contribute to delayed cerebral ischemia after aneurysmal SAH but has so far not been systematically evaluated in patients. We hypothesized that heterogeneity of the MTT, derived from CTP parameters, would give insight into the clinical course of patients with aneurysmal SAH and may identify patients at risk of poor outcome.MATERIALS AND METHODS:We retrospectively analyzed the heterogeneity of the MTT using the coefficient of variation in CTP scans from 132 patients. A multivariable logistic regression model was used to model the dichotomized mRS outcome. Linear regression was used to eliminate variables with high linear dependence. T tests were used to compare the means of 2 groups. Furthermore, the time of the maximum coefficient of variation for MTT after bleeding was evaluated for correlation with the mRS after 6 months.RESULTS:On average, each patient underwent 5.3 CTP scans during his or her stay. Patients with high coefficient of variation for MTT presented more often with higher modified Fisher (P = .011) and World Federation of Neurosurgical Societies grades (P = .014). A high coefficient of variation for MTT at days 3–21 after aneurysmal SAH correlated significantly with a worse mRS score after 6 months (P = .016). We found no correlation between the time of the maximum coefficient of variation for MTT after bleeding and the patients'' outcomes after 6 months (P = .203).CONCLUSIONS:Heterogeneity of MTT in CTP after aneurysmal SAH correlates with the patients'' outcomes. Because the findings are in line with the pathophysiologic concept of the capillary transit time heterogeneity, future studies should seek to verify the coefficient of variation for MTT as a potential imaging biomarker for outcome.

From the 9 in 100,000 individuals with an aneurysmal SAH (aSAH) per year, up to 40% die within 1 month despite improved intensive care and current treatment strategies.^1-4 Subsequent physical impairment, cognitive impairment, and secondary long-term psychosocial deterioration mean that most survivors cannot return to their former work life.^5,6The etiology of the detrimental long-term changes after SAH remains poorly understood. In terms of temporal progression, 2 distinct harmful phases of pathophysiologic changes can be distinguished. The term “early brain injury” describes initial pathophysiologic changes within the first 3 days, whereas “delayed cerebral ischemia” (DCI) represents a complex of reactions that occur later during the course of the disease.⁷During DCI, various pathophysiologic reactions and mechanisms result in cerebral ischemia and neuronal energy depletion. DCI likely involves microvascular dysfunction; disturbances in cerebral microcirculation; angiographic vasospasms; thrombosis of cerebral, primarily cortical, vessels; cortical spreading depolarization and ischemia; as well as inflammatory reactions.^7-10 Finally, DCI may lead to cerebral infarction and, therefore, irreversible loss of function.In general, the important factors for brain tissue survival are adequate oxygenation and glucose supply, among others. Historically, it was assumed that oxygenation mainly relies on the CBF, and previously macroscopic, angiographically visible vasospasms were assumed to be the main driver of DCI. However, it turned out that for this simplified assumption, the blood flow in capillaries must be identical throughout the whole capillary bed, which is not the case. In addition to the CBF, the microvascular blood distribution across capillaries, also known as the capillary transit time heterogeneity (CTH), was found to be the a crucial factor for the oxygenation of brain tissue.^11,12 Recently, Østergaard et al¹¹ presumed that the CTH also contributes to DCI-related ischemia. According to the group''s model, an increased CBF can lead to better tissue oxygenation as long as the CTH has not crossed a critical threshold. If the threshold is exceeded, any further increase in CBF will lead to a reduced oxygen extraction efficacy in brain tissue, due to capillary shunting in hyperemic areas, resulting in hypoxic brain tissue.¹² Østergaard et al defined this state as malignant CTH.^11,12 In such a case, adequate oxygenation of the brain tissue may be achieved only by reducing the CBF and thereby slowing the flow of erythrocytes through the shunting capillaries. This mechanism could be an explanation for the occurrence of vasospasm in patients with aSAH.¹¹CTH has been mainly evaluated in simulations, rodent models, and humans predominately with ischemic stroke or neurodegenerative diseases, such as Alzheimer disease. In the patient population, evaluation has so far mainly relied on MR imaging. Moreover, Østergaard et al¹¹ recently established the relative transit time heterogeneity (RTH) as the ratio of CTH to MTT.¹³ In doing so, the inherent dependency of CTH on the MTT was removed, making the RTH an improved indicator of the capillary transit heterogeneity.¹³ Furthermore, Østergaard et al have based the calculation of CTH and RTH on elaborated Bayesian approaches, and CTH evaluation is not readily available in clinical software for perfusion evaluation. Hence, to date, there is no routinely available radiologic readout for the CTH or RTH in the clinical setting of aSAH.So far, the concept of capillary transit time heterogeneity has not been systemically evaluated in patients with aSAH. We hypothesized that the higher heterogeneity of MTT derived from CTP parameters will allow us to gain insight into the clinical course of patients with aSAH and to predict a worse outcome. In the present study, we, therefore, retrospectively analyzed the heterogeneity of MTT in CTP scans obtained within 3 weeks after SAH and assessed a potential association with the initial neurologic status on admission and clinical outcome after 6 months.