Hi, my name is Ben Davidson, and I'm a fourth year neurosurgery resident at the University of Toronto. My supervisor for this work was Dr. Michael Cusimano. The title of this talk is Chronic Subdural Hematomas, the Crucial Role of Eosinophils in the Life Cycle, Radiographic Architecture, and Risk of Recurrence. This work was generously supported by the Codman Fellowship in Neurotrauma and Critical Care. Chronic subdural hematomas are among the most common neurosurgical pathologies. The incidence is approximately 10 in 100,000 person years. They are most commonly a disease of the elderly, although they can occur in all age groups. The mean age in most series is around 76 years. Chronic subdural hematomas occur more commonly in males. It should be noted that the incidence of chronic subdural hematomas is expected to increase in the coming years, with the population over 65 expected to double by 2050. The pathogenesis of chronic subdural hematomas is complex and not yet fully understood. Inflammation, angiogenesis, and hyperfibrolysis are all key concepts. In this diagram, inflammatory pathways are coloured in green, primarily centred around white blood cells including neutrophils, lymphocytes, macrophages, and eosinophils. In red are the angiogenic pathways, centred around the molecule VEGF, and in blue, fibrinolytic mechanisms, which break down fibrin clots and maintain the fluidity of a hematoma. Numerous studies have demonstrated that these factors are increased in chronic subdural hematomas, and in some cases, predictive of recurrence or long-term outcome. The progressive enlargement of a subdural hematoma is driven by its outer membrane, shown in the image on the left here. This membrane is the site of new angiogenesis, with immature, leaky blood vessels forming, which generally lack robust basement membranes and tight junctions, resulting in microhemorrhages and exudation. Although there is immense variability between chronic subdural hematomas, a radiographic study has suggested that there is a life cycle of a chronic subdural hematoma that can be visualized through CT imaging. Nakaguchi et al., in 2001, were among the first to describe the life cycle of a chronic subdural hematoma, as shown on a CT scan. Theirs and other longitudinal studies have suggested that most chronic subdural hematomas essentially begin as a hypodense, homogeneous-appearing lesion, as shown on the left. Over time, through the processes described previously, primarily inflammation, they mature into a trabecular hematoma, shown here on the right, with numerous internal septations or membranes. Along the way, they often go through this transformation, with a laminar appearance followed by a separated appearance. The laminar and separated CT subtypes are associated with an elevated risk of recurrence, and the trabecular with the lowest risk of recurrence. Following surgical evacuation of chronic subdural hematomas, the rate of recurrence require re-operation is reported to be approximately 3-20%. Given the implications of this, many patients requiring repeat surgery, usually within 60 days, there is substantial room for improvement in how we manage chronic subdural hematomas. Now changing gears slightly, a few years ago, our pathologist commented that he'd been noticing that some of our subdural hematoma specimens contained eosinophils, while others did not, which is what led us to look into the literature, and in fact we found that it's been reported multiple times that eosinophils are present in approximately 40-60% of chronic subdural hematomas. The remarkable thing about this is that there is generally either a dense eosinophilic infiltrate or not. So what is the significance of this? Eosinophils account for approximately 1% of all white blood cells. They are not normally found within the brain. They act like sentinels, with numerous receptors responding to their local environment and initiating a cascade of events. Although perhaps best known for their pathological role in asthma and other allergic reactions, eosinophils play vital roles in antiviral, antihelminth, antibacterial, and in some cases antineoplastic functions. The objectives of this study were to determine the association between eosinophilic infiltrate and CT appearance, and to compare the risk of symptomatic recurrence in chronic subdural hematomas with and without eosinophils. Because eosinophils are easily visible with the standard hematoxylin and eosin stain used by pathologists, they can be readily evaluated, which could lead to clinical application with improving the understanding of the stage of a chronic subdural hematoma and its risk of recurrence. Standard pathology slides with H&E staining were examined from 51 primary chronic subdural hematoma specimens and 11 recurrent specimens. The assessment was performed by two physicians blinded to the clinical and radiographic status of the patient. Displayed here are the representative slides from a specimen graded as sparse on the left and a specimen graded as dense on the right. You can see the yellow arrows highlighting some of the many eosinophils present on this slide. Eosinophils appear as a bright red or bright pink with the H&E staining. You can see multiple granules within their cytoplasm and a bilobed or multilobed nucleus. For each case, the immediate preoperative CT scan was graded according to the Nakaguchi et al. grading scheme as previously described as homogeneous, laminar, separated, or trabecular. For each patient, the postoperative records and imaging were reviewed to determine the rate of recurrence requiring reoperation. Again, just reviewing the four stages of CT subtype. This table demonstrates the basic demographic information pertaining to the specimen. As you can see, the average age in both groups was in the 70s, fairly representative of chronic subdural hematoma as described in the literature. The rate of chronic subdural hematoma in female patients in our sample was slightly higher than reported elsewhere, with males only outnumbering them by about 1.75. But generally, this is a fairly representative sample. You can see the far right column that the rate of recurrence requiring reoperation was around 11.8% in primary specimens. In the recurrent specimens, it was 18%, simply meaning that two of the 11 recurrent specimens went on to require a third operation. The central finding of this study was that the rate of recurrence requiring reoperation was 0% in specimens with dense eosinophilic infiltrate. So we then asked ourselves, does this dense eosinophilic infiltrate have any connection to the CT subtypes described earlier? Well, in fact it did. Eosinophilic infiltrate was highest in the laminar and separated chronic subdural hematoma subtypes. You may recall earlier, I described chronic subdural hematomas tend to evolve from a homogeneous to laminar to separated to trabecular appearance. It appears that eosinophils infiltrate into the outer membrane of chronic subdural hematomas during these middle two stages and then filter back out leading to the trabecular stage. It may be that the presence of an eosinophilic infiltrate signals a healing stage where the hematoma is transitioning to the trabecular appearance. With the appearance of trabecular membranes confers a lower risk of re-bleeding, whereas laminar and separated hematomas without eosinophilic infiltrate may not yet be at this stage of healing. As for next steps, we are in the midst of collecting additional specimens, aiming to reach 100 soon, which should allow for suitable statistical analysis. In addition, we will be performing immunohistochemical staining on these specimens, staining for other inflammatory and angiogenic markers. Finally, we are also considering alternative outcome measures other than just recurrence requiring re-operation. Some studies have used outcome measures such as 60-day cure or percentage residual hematoma. So in conclusion, a dense eosinophilic infiltrate was found to be present in only a subset of chronic subdural hematoma specimens. Those specimens lacking a dense eosinophilic infiltrate were more associated with recurrence requiring re-operation. Eosinophilic infiltrate was found most commonly in the laminar and separated CT subtypes. Eosinophilic infiltrate, when taken in combination with CT appearance and clinical history, may signal important information about a chronic subdural hematoma's life cycle and stage of healing. Thank you.

eosinophils

chronic subdural hematomas

neurosurgery

inflammation

angiogenesis