To clarify the pathophysiology of repeat spontaneous cSDHs, we investigated tissue samples of the dura mater and cSDH membranes from a patient with repeat spontaneous cSDHs and a normal control. A thick DBC layer and OM of the cSDHs that were not histologically distinguishable were observed in the patient with cSDHs. Extensive laminin-positive neovascularization in the DBC layer and OM in the patient resulted in a 5.9-fold higher vasculature volume density than in the normal DBC layer. Fragile pathological sinusoidal capillaries that were not detected in the normal dura mater were observed in the DBC layer and OM. The vasculature was widely distributed in DBC layer, and the OM was connected to the MMAs in the periosteal layer through the penetrating arteries. In addition, the formation of lymphatic vessels in the periosteal and meningeal layers in the patient with cSDHs was increased compared to that in the normal control. Based on these findings, it can be postulated that an incomplete but abundantly neovascularized OM of cSDHs forms from the DBC layer of the dura mater, and repeat spontaneous bleeding occurs from the fragile pathological capillaries in the OM of cSDHs that connect to MMAs via penetrating arteries.
According to previous reports 1,14,15,17, the histological characteristics of cSDHs are as follows: 1) blood collects between the DBC layer of the dura mater and arachnoid mater; 2) outer and inner membranes (neomembranes) of cSDHs form with fibroblasts and collagen fibers; and 3) extensive neovascularization with sinusoidal capillaries occurs in the DBC dural layer and OM of cSDHs. The blood components that accumulate between the dura and arachnoid mater stimulate the recruitment of inflammatory cells to repair the damaged DBC layer by forming granulation tissues. Type 1 (PICP) and type 3 (PIIINP) procollagens, which are abundant in SDHs, also induce the proliferation of fibrous connective tissues in the DBC layer 1. This process is similar to that during wound healing and is known as neomembrane formation 1,17. It has been reported that the inner membrane is generally not associated with neovascularization, and blood vessels in the inner membrane disappear as cSDHs mature 18. Meanwhile, neovascularization develops in the OM of cSDHs, and the neovascularized OM has been suspected to evoke the growth of cSDHs 18. Additionally, in this study, we observed a histologically indistinguishable DBC layer of the dura mater and OM of cSDHs. Accordingly, we considered that the neovascularized OM forms from the DBC layer in the dura mater facing cSDHs.
Neovascularization in the OM of cSDHs is thought to be a result of the hematoma. As blood accumulates in the subdural space, inflammatory cells, including neutrophils, lymphocytes, macrophages and erythrocytes, migrate and release cytokines and angiogenetic factors around the hematoma and adjacent dural layer 16,17. Usually, the presence of proinflammatory cytokines such as IL-2, IL-5, IL-6, IL-7 and IL-8 increases to a greater extent than that of anti-inflammatory cytokines such as IL-10 and IL-13 16. The concentration of VEGF, a characteristic angiogenic factor, is much higher in SDHs than in peripheral blood. The level of angiopoietin-2, which normally promotes cell death and disrupts vessels, increases more in the OM than in the brain parenchyma, promoting neovascularization in the OM as it cooperates with VEGF 23. In addition, the concentration of VEGF-2, which is known to play a critical role in the regeneration of meningeal vessels after head injury, increases substantially 24. Based on this background evidence, a phase II randomized proof-of-concept clinical trial with atorvastatin for immunoregulation and dexamethasone for vascular repair was conducted in patients with cSDHs 25. The results showed that atorvastatin combined with low-dose dexamethasone reduced hematoma and improved neurological function. This finding suggests that inflammation and neovascularization may be closely related to repeat spontaneous bleeding, and the modulation of associated factors is a potential therapeutic target for the resolution of cSDHs.
In general, there are three types of capillaries, continuous, fenestrated and sinusoidal capillaries that can be distinguished by endothelial cell structures. Continuous capillaries have tight junctions between endothelial cells, and fenestrated capillaries have pores with diaphragms between endothelial cells. Continuous and fenestrated capillaries are known to exist in the normal dura mater; however, only continuous capillaries were identified in this study. Sinusoidal capillaries are mainly found in the liver, spleen, bone marrow, and brain circumventricular organs but not in the dura mater 22. Thus, the observation of sinusoidal capillaries in the DBC dural layer and OM indicates pathological changes in cSDHs 15. In this study, pathological sinusoidal capillaries were observed in the DBC layer of the dura mater and OM of cSDHs but not in the normal control. Sinusoidal capillaries (or macrocapillaries) have been considered fragile and leaky compared with other types of capillaries because of certain characteristics, such as thin or absent basement membranes, a lack of smooth muscle cells and pericytes, and gaps 14,17. Therefore, these capillaries have been considered the main cause of repeat bleeding 1,14,15. The osmotic-oncotic pressure hypothesis involving the transport of CSF into the encapsuled hematoma has been suggested as another cause of repeat spontaneous cSDHs 26. However, this theory has now been discarded because studies failed to demonstrate differences in osmotic-oncotic pressure among hematomas, plasma and cerebrospinal fluid 4. The clotting cascade dysfunction hypothesis posits that the subdural blood clot liquefies and causes persistent bleeding 27, and the local hyperfibrinolysis hypothesis involves excessive fibrinolytic activity due to a pre-existing latent coagulation disorder. However, these hypotheses cannot explain most cases of repeat spontaneous cSDHs 28.
For the past two decades, since the first case report of cSDHs refractory to several surgical procedures in 2000, embolization of MMAs with glue and particles has shown potential as an alternative to conventional surgery 18,21,29. A recent meta-analysis showed that the recurrence rate after MMA embolization was 2.4% for recurrent cSDHs and 4.1% for primary cSDHs compared to the usual postoperative recurrence rate of 10–20%, confirming the excellent inhibitory effect of MMA embolization on cSDHs 29,30. The newly formed capillaries located in the DBC layer of the dura mater and OM of cSDHs were found to be connected to MMAs in the periosteal dural layer via penetrating arteries in this study. Based on such histological findings, it is speculated that MMA embolization can block the blood supply to sinusoidal capillaries (Fig. 6). In brief, a microcatheter is inserted into MMAs ipsilateral to cSDHs via the external carotid artery, and then, glue or particles are injected into the MMAs to interrupt the blood supply to the targeted dura mater 19.
In the pathological dura mater facing the cSDHs, greater increases in lymphangiogenesis and blood vessels were observed compared to the normal control (Fig. 5). The morphological changes such as sprouting and loop formation of the lymphatics observed in this study are generally seen during angiogenesis and lymphatic vessel regeneration after traumatic brain injury 31,32. The meningeal lymphatic system is known to be involved in passing immune cells and draining waste from the brain to the deep cervical lymph nodes 33. In addition, an animal study showed that hematomas drained out of the subdural space through the meningeal lymphatic vessels and lymphatic dysfunction caused by meningeal lymphatic ligation led to the attenuation of SDH resorption 34. Therefore, it may be a general concept that blood components are resolved throughout the meningeal veins and lymphatics once SDHs accumulate. Meanwhile, if spontaneous bleeding from the neovascularized OM of cSDHs occurs repeatedly, the accumulation of cSDHs could surpass the resorption capacity of the meningeal veins and lymphatics, ultimately resulting in clinical symptoms and signs. In such a repetitive situation, symptomatic cSDHs can be treated by craniotomy followed by removal of the neovascularized dura mater and OM or MMA embolization rather than by simple burr hole trephination.
In summary, neovascularization with pathological sinusoidal capillaries were observed in the DBC dural layer and OM of cSDHs. The pathological capillaries were connected to MMAs via penetrating arteries. Based on these findings in this study, the neovascularized OM of cSDHs may form from the DBC layer of the dura mater, and repeat spontaneous cSDHs may originate from the neovascularized OM. Interruption of the blood supply to the neovascularized OM of cSDHs could lead to resolution via the meningeal veins and lymphatics. Thus, MMA embolization appears to be very promising as a less invasive treatment for patients with repeat spontaneous cSDHs.