Intraarterial Bevacizumab Administration Through the Middle Meningeal Artery for Chronic Subdural Hematoma

Abstract

Chronic subdural hematoma has a rising incidence and a high burden of disability and mortality worldwide. The disease process once thought to be from an insidious venous hemorrhage is now believed to be related to chronic inflammation and angiogenesis mediated by vascular endothelial growth factor and other angiogenic factors. Middle meningeal artery embolization is being increasingly used as sole therapy or as a surgical adjunct in the management of chronic subdural hematoma. However, this treatment has risk of migration of embolic material in the presence of unrecognized anastomoses with the retina or other neural tissue. Bevacizumab is a vascular endothelial growth factor‐A receptor antagonist used in the treatment of a number of diseases. We herein report the first case of intraarterial bevacizumab injection in the middle meningeal artery for the treatment of chronic subdural hematoma.

Nonstandard Abbreviations and Acronyms

cSDH

chronic subdural hematoma

MMA

middle meningeal artery

Clinical Perspective

• We describe the injection of bevacizumab intraarterially into the middle meningeal artery for the treatment of chronic subdural hematoma when traditionally obstructive embolic agents or coils have been used.

• This provides a safer, cheaper, and more easily administered agent that provides targeted and localized antiangiogenic treatment to subdural membranes where devascularization can tip the balance toward resorption of blood and resolution of the hematoma.

Chronic subdural hematoma (cSDH) is largely a disease of the elderly and is increasing in prevalence. ¹ It carries significant morbidity and has been recognized as a sentinel health event leading to subsequent decline and mortality. ² Management strategies are individualized, and recurrence rates with both conservative and surgical treatments remain high. ² Embolization of the middle meningeal artery (MMA) with particles or liquid embolysates have gained traction as preliminary data suggest decreased recurrence and an acceptable safety profile. Bleeding happens with an initial traumatic event, followed by a cascade of inflammation, impaired coagulation, fibrinolysis, and angiogenesis, which is the basis of the pathophysiology of cSDH. Neovascularization leads to repeated hemorrhage from fragile new vessels into the subdural space and reaccumulation of blood products. The subdural membranes and subdural fluid have high concentrations of inflammatory cytokines and vascular endothelial growth factor (VEGF), ³ which is thought to be involved in cSDH pathogenesis. Bevacizumab is a monoclonal antibody that inhibits microvascular growth and angiogenesis mediated by VEGF. ⁴ We present a case of cSDH treated with intraarterial bevacizumab administration to the MMA.

Patient Presentation

A 72‐year‐old man with a history of hypertension presented to our center with a first‐time seizure in the setting of a month of headache. He was found to have a 10‐mm right sided mixed‐density cSDH with septations and a 3‐mm midline shift (Figure 1). On hospital arrival, he had no focal neurological deficits. The risks and benefits of management strategies including burr hole craniostomy, MMA embolization, and observation were discussed with this patient. The patient was not keen to pursue craniostomy. With respect to MMA embolization, the risk of vision loss or other potential neurological deficits were not acceptable to this patient. As such, we discussed MMA treatment with the selective VEGF inhibitor bevacizumab, and the patient elected to proceed. He was treated with intraarterial injection of 200 mg (2 mg/kg) of bevacizumab into the right MMA via the transfemoral approach (Figure 2). He tolerated the procedure well and was discharged home the next day without immediate postoperative complication. Repeat imaging showed near resolution of the cSDH as early as 1 month (Figure 3) with near total resolution at 6 months (Figure 4). The patient remains asymptomatic and on antiepileptic medications. He has not had a seizure since the index event, and antiepileptic medications are planned to be weaned off at 18 months. A computed tomography scan at 1 year did not show any recurrence (Figure 5). The authors declare that all supporting data are available within the article.

Figure 1.

Baseline noncontrast computed tomography of the head showing a right‐sided, mixed‐density, chronic subdural hematoma.

Figure 2.

Nonstandard view of a superselective middle meningeal artery (MMA) injection with microcatheter placed in the main trunk of the intracranial MMA.

Figure 3.

Noncontrast computed tomography of the head at 1 month after intra‐arterial bevacizumab injection.

Figure 4.

Noncontrast computed tomography of the head at 6 months after intra‐arterial bevacizumab injection.

Figure 5.

Noncontrast computed tomography of the head at 1 year after intra‐arterial bevacizumab injection.

Discussion

We describe the first case of intraarterial bevacizumab administration for cSDH. There was near total resolution of the hematoma at 6 months imaging. The administration of an intraarterial bevacizumab provides targeted and localized therapy and eliminates the risk of neurologic deficits associated with migration of particulate material and liquid embolysates more traditionally used in MMA embolization. The conventional management remains a subject of debate and there is significant variation in clinical practice. Asymptomatic patients with small cSDH (<10 mm) and minimal radiographic mass effect are generally managed conservatively. Surgical drainage via craniostomy is the standard of care for symptomatic patients with large hematomas with mass effect, but is associated with a significant recurrence rate in as high as 39% of patients. ⁵ , ⁶ Recurrence, or lack of resolution, can occur with conservative treatment strategies and may be exacerbated by the increasingly widespread use of antiplatelet and anticoagulant therapies, and may become more common as the population ages. ¹ , ⁷ , ⁸ In addition, most patients with cSDHs tend to have significant comorbidities, making them poor surgical candidates; as such, less invasive endovascular options become attractive. MMA embolization has been increasingly adopted as sole or adjunct therapy to surgery with good efficacy and safety. However, there remains risk associated with embolic agent injection to the MMA particularly in the presence of unrecognized anastomoses with the globe, the facial nerve, or the brain. The administration of a nonocclusive biologically active agent may have utility in these situations.

cSDH is classically triggered by a traumatic event causing injury to the dural border cells and the bridging veins leading to extravasation of cerebrospinal fluid and blood into the subdural space. ⁹ The liquefaction of clotted blood into serous fluid that accumulates between the dura and the arachnoid meningeal layers can prevent reabsorption, leading to a cascade of chronic inflammation and angiogenesis mediated by cytokines and angiogenic factors such as VEGF. ¹⁰ Neovascularization leads to continuous leakage of blood products into the membranes with reaccumulation and recurrence of the cSDH. Extremely high levels of VEGF have been reported in the hematoma fluid, ¹¹ the highest concentration being associated with hyperdense or mixed‐density type hematomas as seen on noncontrast head computed tomography. Additionally, higher concentrations in the outer membrane have been associated with increased risk of recurrence after surgical treatment. ¹² Bevacizumab is a monoclonal antibody that inhibits angiogenesis used in the treatment of various diseases including glioblastoma multiforme. It targets VEGF‐A, an isoform of VEGF that stimulates endothelial proliferation. ¹³

The MMA supplies the majority of the dura of the cranial convexity. The goal of MMA embolization is to devascularize the subdural membranes and disrupt the cycle of continued blood leakage and reaccumulation. ¹⁴ Complications can arise when embolic agents penetrate unrecognized anastomoses supplying eloquent structures and have been reported at 2% in 2 recent meta‐analyses, though the actual complication rate may be higher because of publication bias. ¹⁵ , ¹⁶ At the skull base, the petrosal branch of the MMA can supply directly the facial nerve and can have dangerous anastomoses with the accessory meningeal artery, the ascending pharyngeal artery, and the inferolateral and the meningohypophyseal trunk of the internal carotid artery, which can lead to neurologic injury with aberrant or unintended embolization. The anterior branch of the MMA can anastomose with the ethmoidal arteries leading to the retina. The posterior branch can anastomose with the occipital artery, the posterior meningeal artery, and the vertebral artery into the posterior fossa. ¹⁷ Dangerous anastomoses are common and have been reported as high as 5%. ¹⁸ The injection of a nonembolic agent eliminates the risk associated with unwanted migration of embolic agent into the retina or neural tissue leading to permanent neurological deficit, which can cause additional disability.

In 2016, Suzuki et al. reported a case of complete clearance of cSDH after intravenous bevacizumab treatment for recurrent glioblastoma multiforme. This case report was considered as proof of concept and the basis of our treatment strategy in this patient, particularly in the presence of membranes and mixed density fluid. Intravitreal bevacizumab has been used to prevent choroidal neovascularization, and we postulated that the small doses that would reach the retina and choroid would not have deleterious effects, especially as it would be washed out nearly immediately.

Intravenous bevacizumab (10 mg/kg) every 2 weeks is currently used to treat recurrent glioblastoma multiforme following standard therapy with chemoradiation. ¹⁹ However, it can cause significant systemic side effects including bowel perforation and pulmonary embolism. Additionally, there are associated risks with wound healing, such as dehiscence, ecchymosis, surgical site bleeding, and wound infection. This might be problematic with need for emergent surgical rescue in patients who underwent intraarterial injection to the MMA. For this reason, we used direct MMA administration rather than intravenous bevacizumab administration. The dose used was lower than what has been used in systemic or intracarotid administration. Safety and tolerability of intraarterial bevacizumab has been reported with doses as high as 10–15 mg/kg when injected for recurrent glioblastoma multiforme. ²⁰ We conservatively used one‐fifth of the dose to reduce the risk of wound healing if surgery was required. When contrast is administered in the MMA, it has a propensity to accumulate in the subdural membranes and space. By the same token, bevacizumab is also likely to segregate predominantly in the subdural space with less of a systemic effect so lower total doses would likely suffice. It is also unclear if a second dosing would be beneficial for a larger subdural collection.

While the procedural cost associated with MMA embolization is higher than that associated with craniostomy, recent reports have shown that total hospitalization cost is lower or equivalent with MMA embolization as compared with surgery. ²¹ , ²² Procedural cost associated with MMA embolization can vary depending on the embolic material used, superselection of MMA branches, and need for multiple catheters. The cost of the most typically used embolic materials at this moment varies between $2000 for a 1.5‐mL vial of Onyx, $4000 for 1 g of n‐BCA, and around $2000 for 1 coil. One vial of 100 mg of bevacizumab costs around $835; for the majority of patients undergoing bilateral MMA injections at a dose of 2 mg/kg per side, the maximum cost associated would be approximately $2500. If a single dose is enough, then this could be superior to current techniques—likely less costly and with decreased risk of vison loss or other cranial neuropathies. Moreover, there is less need for distal catheterization, which may be safer and lead to shorter procedure times. cSDHs tend to resolve on the basis of natural history, and it may be clinically sufficient to tilt the balance toward resorption.

Conclusions

We present the first reported case of intraarterial injection of bevacizumab to the MMA for the treatment of cSDH. The patient was asymptomatic, with near total resolution of the cSDH on repeat imaging at 6 months. This serves as an exploratory study, and further study is warranted to evaluate dosing, safety, and efficacy.

Sources of Funding

None.

Disclosure

None.