Intralesional Injection of Bevacizumab for the Treatmentof an Apical Orbital Cavernous Venous Malformation

Surgical excision of orbital cavernous venous malformations located in the orbital apex is challenging due to difficulty obtaining surgical exposure and higher risk of morbidity. Intralesional bevacizumab injection has been utilized for the treatment of choroidal and intracranial cavernous venous malformations. A 52-year-old woman with an orbital apical mass consistent with a cavernous venous malformation causing decreased visual acuity, diminished color vision, and visual field loss was treated with intralesional bevacizumab injected under direct surgical visualization. Subsequently, she demonstrated improved visual acuity, color vision, and slow but dramatic visual field improvement over one year. Injection of bevacizumab may be a viable alternative treatment for orbital cavernous venous malformations.

Original Contribution Intralesional Injection of Bevacizumab for the Treatment of an Apical Orbital Cavernous Venous Malformation Adam R. Sweeney, MD, Michael Chappell, MD, Derek A. Khorsand, MD, Arash Jian-Amadi, MD, Courtney E. Francis, MD Abstract: Surgical excision of orbital cavernous venous malformations located in the orbital apex is challenging due to difficulty obtaining surgical exposure and higher risk of morbidity. Intralesional bevacizumab injection has been utilized for the treatment of choroidal and intracranial cavernous venous malformations. A 52-year-old woman with an orbital apical mass consistent with a cavernous venous malformation causing decreased visual acuity, diminished color vision, and visual field loss was treated with intralesional bevacizumab injected under direct surgical visualization. Subsequently, she demonstrated improved visual acuity, color vision, and slow but dramatic visual field improvement over one year. Injection of bevacizumab may be a viable alternative treatment for orbital cavernous venous malformations. Journal of Neuro-Ophthalmology 2016;36:389-392 doi: 10.1097/WNO.0000000000000425 © 2016 by North American Neuro-Ophthalmology Society C avernous venous malformations, also known as cavernous hemangiomas, are benign vascular tumors affecting the orbit. If vision threatening, cavernous venous malformations are typically managed with surgical excision. Excision of tumors located in the orbital apex is particularly challenging and associated with increased risk of vision loss. We report our experience from a single case where intralesional bevacizumab was injected under direct visualization during surgery without excision. We offer results of the patient over 4 years and a discussion of this novel treatment strategy for cavernous venous malformations at the orbital apex. Department of Ophthalmology (ARS, MC, AJA, CEF) and Department of Radiology (DAK), University of Washington, Seattle, Washington. Supported in part by an unrestricted departmental grant to the Department of Ophthalmology, University of Washington from Research to Prevent Blindness, Inc, New York, NY. The authors have no conflicts of interest to report. Address correspondence to Courtney E. Francis, MD, Department of Ophthalmology, University of Washington, 325 Ninth Avenue, Seattle, WA 98104-2499; E-mail: [e-mail] Sweeney et al: J Neuro-Ophthalmol 2016; 36: 389-392 CASE REPORT A 52-year-old woman was referred for slowly progressive vision loss in her right eye. Visual acuity was 20/25, right eye, and 20/20, left eye. She reported subjective dyschromatopsia in her right eye yet was able to correctly identify all of the pseudoisochromatic Ishihara color plates in both eyes, more slowly on the right. There was a right relative afferent pupillary defect (RAPD) and 2 mm of right proptosis. Examination of the anterior and posterior segments of each eye was unremarkable. Automated perimetry of the left eye was normal; whereas on the right, there was temporal field loss and a mean deviation (MD) of 26.32 dB (Fig. 1A). Orbital MRI showed a 0.79 cm3 ellipsoid mass centered on the right orbital apex (Fig. 2A- C). Volumetric quantification was performed approximating the lesion to an ellipsoid using standard radiographic techniques and the equation: a b c 4 Volume ¼ ð3:14Þ 3 2 2 2 where a, b, and c are diameters of the ellipsoid. The mass lesion was noted to displace the optic nerve superomedially at the orbital apex. The patient was followed for 5 months with serial examinations. Visual acuity in the right eye declined to 20/40 and right visual field worsened (Fig. 1B). After extensive discussion regarding the risks and benefits of various treatment options, the patient elected to proceed with an off-label intralesional injection of bevacizumab. A medial conjunctival peritomy was performed and the right medial rectus muscle was disinserted from the globe. Malleable retractors were used to displace the retro-orbital fat and the tumor was visualized at the orbital apex. 20 mg of bevacizumab diluted in 0.8 mL of normal saline (25 mg/mL) was injected into the tumor with a 30-gauge needle. Dosage was chosen to approximate 10-20· greater than that used for 389 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Visual field pattern deviation plots obtained at presentation (A), preoperatively (B) and postoperatively at 10 weeks (C), 6 months (D), 1 year (E), and 2.5 years (F). MD, mean deviation; PSD, pattern standard deviation. intraocular hemangiomas (1.25-2.5 mg) (1,2) and 20· less than that of systemic doses (5 mg/kg) (3). Postoperatively, the patient complained of binocular diplopia and was noted to have limited vertical ductions and a small-angle right hypertropia, which resolved over 2 months. She reported gradual improvement in her visual acuity and subjective dyschromatopsia. At 10 weeks postoperatively, visual acuity was 20/20 in the right eye, with full color vision, a persistent right RAPD and an improved visual field (Fig. 1C). Six months following surgery, there was further improvement in her visual field defect (Fig. 1D). By 1 and 2.5 years follow-up, right visual FIG. 2. Magnetic resonance imaging of right orbital cavernous venous malformation. Appearance of the lesion before treatment on axial T1 (A), axial fluid-attenuated inversion recovery (FLAIR) (B), and postcontrast coronal T1 with fat suppression (C) scans. Imaging results at 2.5 years following bevacizumab injection, on axial T1 (D), axial FLAIR (E), and postcontrast coronal T1 with fat suppression (F) sequences. The findings are most consistent with a cavernous vascular malformation. 390 Sweeney et al: J Neuro-Ophthalmol 2016; 36: 389-392 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution acuity remained 20/20, without a RAPD, no evidence of optic atrophy, and complete resolution of her prior visual field defect (Fig. 1E, F). On repeat MRI, there was decreased size of the mass from 0.79 cm3 preoperatively (Fig. 2A-C) to 0.35 cm3 at 2.5 years postoperatively (Fig. 2D-F). DISCUSSION Cavernous venous malformations affecting the orbit are slow-growing, benign lesions usually causing proptosis, decreased vision, strabismus, ptosis, or pain. They are easily detected with neuroimaging and surgical excision is the preferred treatment when symptomatic. Excision of cavernous venous malformations located in the orbital apex is challenging due to limited visualization and access via both transorbital and extraorbital approaches. In addition, there may be tenacious adhesions of the tumor capsule at the annulus of Zinn-a fibrous ring packed with neurovascular structures of the apex (4). Thus, surgical excision of tumors in this location carries the risk of diplopia, ptosis, and vision loss, including blindness. Incomplete excision of a deep orbital cavernous venous malformation has been reported with a good outcome (5); however, growth potential following incomplete resection is not predictable (4). Alternative modalities for treatment include stereotactic fractionated radiotherapy (6) and apical orbital decompression (7). Hemangiomas located throughout the body have been demonstrated to strongly express VEGF receptors (8). Intravenous anti-VEGF therapy has been used in isolated cases for hemangiomas in difficult to reach locations such as the brain (9) and the liver (10) with favorable results. Intralesional anti-VEGF injection also has been documented for a venous malformation involving the eyelid (11) as well as intravitreal injections for retinal and choroidal hemangiomas (1,2,12). Recently, Atchison et al (13) reported on VEGF receptor expressivity in vascular lesions of the orbit. This group documented that 97% of sampled venous malformations diffusely stained for vascular endothelial growth factor receptor type 2 (VEGFR2) as well as focal (14%) and diffuse (4%) staining for vascular endothelial growth factor receptor type 1 (VEGFR1). Similarly, Rootman et al (14) found that in samples of orbital venous malformations with endothelial hypercellularity, 60% demonstrated VEGFR2 staining and ubiquitous VEGFR1 staining. Our patient has remained stable for over 4 years of follow-up. We acknowledge that the salutary effect of our treatment may have been influenced by physical manipulation of the vascular malformation during surgery in addition to hemodynamic decompression or scarring from the injection itself. As the histologic response of this malformation to the anti-VEGF injection is unknown, we Sweeney et al: J Neuro-Ophthalmol 2016; 36: 389-392 plan to follow the patient annually as regrowth is possible if a return of the VEGF signaling response occurs. One caveat of this treatment is that a pathologic diagnosis cannot be confirmed and it is possible that a nonvascular tumor may be mistaken for a vascular tumor and treated with an anti-VEGF therapy. To minimize this possibility, an orbitotomy is recommended, rather than image-guided needle injection in the interventional radiology suite, so that a visual confirmation of the vascular nature of the tumor can be made intraoperatively. We are not aware of previous reports of the use of antiVEGF agents to treat orbital tumors. Further reports and prospective studies are needed to better understand the safety, efficacy, role of image guidance, and acceptable dose of bevacizumab for treating apical cavernous venous malformation of the orbit. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: Courtney Francis, AJ Amadi. b. Acquisition of data: Courtney Francis, Adam Sweeney, Michael Chappell, Derek Khorsand. c. Analysis and interpretation of data: Courtney Francis, Adam Sweeney, Michael Chappell, Derek Khorsand, AJ Amadi. Category 2: a. Drafting the manuscript: Adam Sweeney, b. Revising it for intellectual content: Courtney Francis, AJ Amadi, Adam Sweeney. Category 3: a. Final approval of the completed manuscript: Courtney Francis. REFERENCES 1. Mandal S, Naithani P, Venkatesh P, Garg S. Intravitreal bevacizumab (avastin) for circumscribed choroidal hemangioma. Indian J Ophthalmol. 2011;59:248-251. 2. 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