British Journal of Neurosurgery ISSN: 0268-8697 (Print) 1360-046X (Online) Journal homepage: https://www.tandfonline.com/loi/ibjn20 Late recovery of stereotactic radiosurgery induced perilesional edema of an arteriovenous malformation after bevacizumab treatment Ece Uysal, Ozan Başkurt, İdris Avcı, Halil Olgun Peker & Suat Erol Çelik To cite this article: Ece Uysal, Ozan Başkurt, İdris Avcı, Halil Olgun Peker & Suat Erol Çelik (2020): Late recovery of stereotactic radiosurgery induced perilesional edema of an arteriovenous malformation after bevacizumab treatment, British Journal of Neurosurgery, DOI: 10.1080/02688697.2020.1742294 To link to this article: https://doi.org/10.1080/02688697.2020.1742294 Published online: 27 Mar 2020. Submit your article to this journal Article views: 20 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ibjn20 BRITISH JOURNAL OF NEUROSURGERY https://doi.org/10.1080/02688697.2020.1742294 ORIGINAL ARTICLE Late recovery of stereotactic radiosurgery induced perilesional edema of an arteriovenous malformation after bevacizumab treatment Ece Uysal, Ozan Başkurt , _Idris Avcı, Halil Olgun Peker and Suat Erol Çelik Department of Neurological Surgery, Okmeydani Research and Educational Hospital, University of Health Sciences, Istanbul, Turkey ABSTRACT ARTICLE HISTORY Purpose: Today, stereotactic surgery (SRS) is among the treatment options for many intracranial lesions including vascular pathologies. One of the most common late complications of SRS is perilesional edema which can be treated with steroids. In addition to steroids, some new medical therapies are being investigated and one of the promising one is Bevacizumab; a monoclonal antibody against vascular endothelial growth factor (VEGF). In the cases of steroid resistant perilesional edemas, however bevacizumab has a late term effect resolution of symptoms and radiological improvement can be seen as late as more than 1,5 years after its initiation. Materials and Methods: We present a 41-year old male patient who was admitted to our clinic with epileptic seizures, headaches and hemiparesis 14 months after SRS treatment for a left fronto-parietal Spetzler-Martin Grade III arteriovenous malformation (AVM). On his first-year follow-up perilesional edema was observed for which the patient received steroid treatment, but the patient did not show any benefit from it. In the cases of steroid resistant perilesional edemas, bevacizumab can be used for reducing symptoms and even radiological perilesional edema as well. Results: In our case, we have seen the effect of bevacizumab for symptomatic perilesional edema in a AVM patient after SRS treatment after radiological / neurological recovery. Our patient’s headaches decreased rapidly after 2 days after treatment and was able to mobilize himself after 2 months but total resolution of symptoms and radiological findings observed after 1,5 years. Conclusions: The duration and optimum dose of bevacizumab therapy needed to further investigation. Our study showed that bevacizumab was a long-term and effective treatment option for the cases with peritumoral edema resistant to glucocorticoid treatment, where the patient had conditions such as severe headache and neurological deficits. Received 3 December 2019 Accepted 10 March 2020 Introduction Today, stereotactic radiosurgery (SRS) is among the treatment options for many intracranial lesions including vascular pathologies such as arteriovenous malformations (AVM). Good candidates for SRS of AVMs include deep settled small Grade III – IV lesions with limited risk of bleeding which are not suitable for microsurgical resection.1 Although considered to be relatively less invasive, SRS also has complications like hemorrhage till to the full closure of the lesion, damaging to neighboring structures, radio-necrosis and late-onset perilesional edema.2 Vascular endothelial growth factor (VEGF) has generally been known as a causative factor for perilesional edema and has been documented in THE LITERATURE.3 Symptoms such as headache, neurological deficits and seizures may occur due to peritumoral changes.4,5 Steroids are first choice as a medical treatment for perilesional edema and is a powerful and effective one. Dexamethasone is a potent steroid receptor agonist to decrease the expression of VEGF and has reliably been used for the treatment of vasogenic edema induced by tumors.6,7 In addition to glucocorticoids, some new medical therapies are being investigated and one of the more promising ones is Bevacizumab; a monoclonal antibody against VEGF which is currently used in the treatment of recurrent glioblastoma.8 Although there is not KEYWORDS Stereotactic radiosurgery; Bevacizumab; arteriovenous malformation; perilesional edema definite dose or timing of the treatment yet, Bevacizumab is currently under investigation for treatment of radiotherapy-induced tissue necrosis and peritumoral edema. In the cases of steroid resistant perilesional edemas, Bevacizumab can be used for reducing symptoms and even radiological perilesional edema as well. In our study, we investigated the effect of bevacizumab for symptomatic perilesional edema in a AVM patient after SRS treatment with late radiological/neurological recovery. Case report A 41-year-old male patient was admitted to our department with headache and epileptic seizures. On his neurological examination he had right 4/5 hemiparesis. In the light of advanced survey imaging he had a left fronto-parietal Spetzler–Martin grade III AVM. Considering the location and size of the lesion he received SRS with Cyberknife to observe closure of the vascular structures as a result (Figure 1). 14 months after the SRS the patient presented to our department after having epileptic attack again. Right 3/5 hemiparesis was observed in his neurological examination. On his cranial computed tomography (CT) scan, severe perilesional edema on CONTACT Ozan Başkurt ozanbskrt@gmail.com Department of Neurosurgery, University of Health Sciences Okmeydanı Training And Research Hospital, Kaptanpaşa Mh, Dar€ulaceze Cd. No. 27, 34384 Istanbul, Turkey ß 2020 The Neurosurgical Foundation 2 E. UYSAL ET AL. Figure 1. Digital subtraction angiography (DSA) (A) and cranial MRI (B, C) of the AVM in the left parietal lobe before the radiosurgery. Figure 2. Cranial CT (A,B,C) and DSA (D,E) 12 months after radiosurgery; with significant reduction of the AVM size. the left frontal and parietal lobes was observed (Figure 2(A–C)). A brain digital subtract angiography (DSA) was performed which showed that the AVM disappeared after SRS (Figure 2(D,E)). The patient was initially placed on high-dose dexamethasone with increased antiepileptic medication. The frequency of his seizures decreased but hemiparesis, as well as the muscle jerks on the right sight, remained the same within the following months. He was suffering terribly from severe headaches during this period. After 4 months, the patient presented to our emergency department again severe headaches and 2/5 hemiparesis despite being on dexamethasone. Bevacizumab which is a VEGF antibody which has been used for peritumoral edema of glioblastoma before8 and the first time used for the treatment of severe, refractory perilesional edema due to an arteriovenous malformation treated with stereotactic radiosurgery by Williams et al.2 Given the inadequate response BRITISH JOURNAL OF NEUROSURGERY 3 Figure 3. Cranial CT 20 months after Cyberknife radiosurgery and 3 months of bevacizumab treatment. to corticosteroids and severe refractory symptoms, the option to treat perilesional edema with Bevacizumab was appropriate. A treatment protocol was initiated in which Bevacizumab was administered at a low dose infusion rate of 2.5 mg/kg over 90 minutes, which was tolerated without any significant side effects. The patient was monitored closely by periodic clinical examinations. His headaches decreased rapidly after 2 days of the treatment but neurological and radiological findings still persisting. The patient was called to our clinic for further evaluation and treatment in two weeks after the first treatment. Since no side effects were observed following the initial dose, the treatment was continued at an infusion rate of 7.5 mg/kg. After the 7.5 mg/kg dose of the treatment, a rapid improvement in the patient’s symptoms was seen in the 2nd week. The subsequent CT scan was admitted after one month of Bevacizumab therapy and it showed that the area of perilesional edema persisted. On the other hand, patient’s hemiparesis improved to 4/5. He was able to walk with little assistance. No side effects were observed up until now and full blood tests were within normal limits. A systematic physical examination, blood pressure measurements, blood and urine analysis were performed each time the patient received the treatments. We gave him 7.5 mg/kg bevacizumab infusion every 2 weeks as the maintenance treatment for 2 months. His symptoms continued to regress, and on the second month he was able to walk without assistance. Despite clinical improvement, control imaging did not show a decrease in the area of adequate edema. Since radiological healing was also targeted, follow-up was performed every 3 months as a control. At his 1.5 year of follow-up the patient has not been experiencing any headaches or seizures anymore. He was able to go to work on his own. On radiological evaluation the perilesional edema was significantly resolved (Figure 3). Reduction in radiologically targeted perilesional edema area was achieved in late period. In the light of this case, Bevacizumab is promising for the treatment of intracranial perilesional edema. Also we need to be emphasized that treatment needs to be continued because the edema is resolved completely in the late period. Discussion Stereotactic radiosurgery (SRS) has been widely used as a treatment option for selected patients with intracranial lesions9 and seems usually to be a safe treatment, but 5% to 40% of patients experience treatment-related complications like seizures, increased headache, temporary or persistent muscle weakness or neurologic deficits and perilesional edema.10,11 As a complication of SRS treatment, new or worsening peritumoral edema has been reported in 14% 25% of patients.4,9,12,13 Venous obstruction, pial supply, location, tumor volume, tumor grade with histological subtype, VEGF receptor expression and patient age were accused for peritumoral edema (PTE) in meningiomas.14–17 The risk of developing peritumoral edema is mostly associated with high dose radiation.18 Conti et al.19 reported 229 cases with meningioma that were treated with radiotherapy in which complications were as follows: 17 patients had epileptic seizures, 13 patients had focal deficits, 12 patients complained about headaches and symptomatic PTE was seen in 19 patients. Four variables were found to be associated with edema development, including tumor volume bigger than 4.5 ml, non-basal tumor location, tight brain/tumor interface and atypical histology. According to their results, a parasagittal location was associated with an increased risk of PTE. In a report of 111 supratentorial meningioma cases, Patil et al.16 found that patients with parasagittal meningiomas were at greater risk of peritumoral symptomatic edema after SRS. In our case, the AVM had a large volume and had been draining to the superior sagittal sinus and it was located parasagittally. It has also been reported that lesions with drainage into the wide sinuses have an increased risk of perilesional edema after stereotactic radiosurgery.9 Perilesional edema is usually a late-onset complication of radiosurgery. In a study by Kondziolka et al.20 the onset of edema typically occurred 6–8 months after SRS (range 1–23 months). Kan et al.13 found that the mean time to development of the edema was 5.5 months after SRS and the mean duration was 16 months. Parallel to this information; the symptoms in our patient have begun approximately 14 months of stereotactic radiosurgery. There are various medications and treatment methods used for PTE such as corticosteroids, vitamin E, pentoxifylline, anticoagulation treatments, interstitial laser thermal therapy and hyperbaric oxygen.21,22 In a study by Sheehan et al.18 both the radiological and the clinical regression was observed in only 7 of the 16 patients that received glucocorticoids for PTE manifested by headache. In our case, low or high dose treatment with dexamethasone did not show its desired benefits. Severe hemiparesis and epileptic seizures persisted. In vivo and in vitro data indicate that VEGF is a primary mediator of peritumoral edema.3,15,23 Ischemic changes in the edematous brain parenchyma may lead to the expression of 4 E. UYSAL ET AL. VEGF and also VEGF receptors have been shown to exhibit a significantly positive relationship to edema volume.14,24 Although some studies do not support this conclusion5,25 VEGF has been accepted as a factor in the formation of PTE associated with meningiomas.26,27 VEGF inhibitors such as Bevacizumab have been shown to reduce the peritumoral edema as well as the edema following radiosurgery and radiation therapy.28,29 Bevacizumab was first used for the side effects of fractionated radiotherapy in a study by Gonzalez et al.30 8 patients were treated at the dose of 5–7.5 mg/kg every 2–3 weeks. As a result, improvements in MRI imaging and clinical examination were correlated by the reduction of previously given steroid doses. In this study, post-treatment brain imaging performed an average of 8.1 weeks after the start of bevacizumab therapy. Levin et al.28 treated 14 patients with progressive neurologic symptoms via intravenous Bevacizumab at a dose of 7.5 mg/kg every 3 weeks for 12 weeks due to the central nervous system radiation necrosis secondary to irridation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Based on this data, more clinical and radiological improvements were observed at 7.5 mg/kg doses compared to 5 mg/kg. Williams et al.2 used Bevacizumab first time to control symptomatic perilesional edema refractory to corticosteroid therapy after SRS for an intracranial AVM in 2012. Their patient presented to the emergency department with headache and hemiparesis 9 months after Gamma knife surgery. On not benefit from other treatment options for perilesional edema, they used Bevacizumab as the first dose of 2.5 mg/kg and the second dose of 7.5 mg/kg 1 week after. They demonstrated clinical improvement after the administration of bevacizumab therefore they did not continue the maintenance treatment. Deibert et al.31 evaluated the clinical benefits and radiological response of bevacizumab for refractroy adverse radiation effects in 29 patients with brain tumors or vascular malformations. They compared initial diagnosis, SRS dose, bevacizumab treatment protocols, magnetic resonance imaging of edema volumes before and after bevacizumab administration. Patients who involved in this study, received an average dose of 7.4 mg/kg over a mean of 5.7 weeks at a median of 16 months following SRS. %90 with clinically symptomatic due to adverse radiation effects had neurological improvement after bevacizumab therapy. 26 patients had a decrease in edema volumes however 2 patients showed progression. Symptoms recurred in 11 of the 20 patients after discontinuing therapy. They emphasize the duration and optimum dose of bevacizumab therapy needed to further investigation. Similarly, our study showed that bevacizumab was a longterm and effective treatment option for the cases with peritumoral edema resistant to glucocorticoid treatment, where the patient had conditions such as severe headache and neurological deficits. Our patient received 7,5 mg/kg bevacizumab infusion every 2 weeks as the maintenance treatment for 2 months. It should be import once again that treatment needs to be continued for late recovery. As some complications may develop, Bevacizumab treatment should be administered by an experienced clinic. We did not encounter any complications in our case. In a study of 2712 Japanese patients with colorectal cancer, 2696 patients were investigated in terms of safety analysis. Hypertension (13.1%), hemorrhage (10.5%) and proteinuria (4.5%) were the most common adverse drug reactions. 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