Editor, Recent reports have shown favourable short-term results with intravitreal bevacizumab (Avastin®; Genetech, San Francisco, California, USA) in the treatment of proliferative diabetic retinopathy (PDR). However, aggravation of PDR related to this relatively recent method of treatment has not been known. We encountered a case with development of multiple retinal haemorrhages after intravitreal bevacizumab as an adjunctive treatment to pars plana vitrectomy in PDR. A diabetic 65-year-old woman presented with aggravating vitreous haemorrhage after panretinal photocoagulation (PRP) with corrected vision of 20/400 and was scheduled for surgery. Right eye fundus showed vitreous haemorrhage and faintly visible multiple dot-shaped retinal haemorrhages (Fig. 1A). Combined pars plana vitrectomy, phacoemulsification with intraocular lens implantation, endolaser PRP and intravitreal injection of 1.25 mg bevacizumab at the end of surgery were performed. On postoperative day 7, her right eye showed newly developed multiple, extensive retinal haemorrhages at entire fundus (Fig. 1B) with corrected vision of 20/400 and intraocular pressure of 10 mmHg. Her systemic factors, including glycemic control, blood pressure and serum lipid levels, had been stable. On her visit 9 months after surgery, retinal haemorrhages were much resolved, but corrected vision still remained at 20/200 (Fig. 2). (A) Preoperative fundus photograph of the patient's right eye. Note diffuse vitreous haemorrhage and faintly visible dot-shaped retinal haemorrhages at entire fundus. (B) Fundus photograph taken on postoperative day 7. Development of multiple, extensive retinal haemorrhages not shown on the preoperative fundus photograph (A) are now noted. Fundus photograph taken 9 months after surgery. Retinal haemorrhages shown in Fig. 1B are resolved, However, the patient's best corrected vision remained at 20/200. We are unaware of previous reports in PubMed regarding the development of multiple retinal haemorrhages after intravitreal bevacizumab. We used 1.25 mg of bevacizumab, but considering that our case was a vitrectomized eye, actual effective dose may have been less because of rapid clearance from the vitreous cavity. No postsurgical complications of combined cataract surgery and vitrectomy (such as hypotony) were present, which could otherwise explain the development of retinal haemorrhages. Risk of haemorrhage with the use of bevacizumab has been known, especially in systemic treatment in oncology. Systemic bevacizumab for cancer therapy has promoted bleeding from mucocutaneous membranes in 20–40% of patients (BC Cancer Agency 2006). The development of metrorrhagia in a healthy nulliparous 35-year-old woman after 2 weeks of intravitreal bevacizumab for the treatment of disc neovascularization with branched retinal vein occlusion has been reported recently (Rodrigues et al. 2007). Bevacizumab is a monoclonal antibody against all isoforms of vascular endothelial growth factor (VEGF). VEGF is a regulator of endothelial cell function in proliferation, migration, differentiation and even survival (Ferrara 1999). Recent experiments in animals have suggested a central role for the 165 isoform of VEGF, specifically in the pathogenesis of diabetic macular oedema (DMO) (Qaum et al. 2001). Pegaptanib sodium injection (Macugen®; Eyetech Pharmaceuticals Inc., New York, USA), which was known to selectively block the activity of VEGF165 isoform, resulted in visual acuity gain, decrease in retinal thickness and less need for focal/grid laser intervention in DMO (Macugen Diabetic Retinopathy Study Group 2005). Blocking of physiological isoforms of VEGF, as well as pathological isoforms, with bevacizumab might have contributed to further ischaemic change in the retina and produced multiple retinal haemorrhages in our case. Intravitreal bevacizumab may need to be considered as an adjunctive treatment with more discretion, especially in patients with diabetic retinopathy.
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Lee et al. (2008) studied this question.