Sir,

We thank Sharma et al1 for reporting a case of significant bilateral reduction in macular thickness following unilateral ranibizumab therapy for diabetic macular edema (DME). This case corroborates our feeling (based on our research and experience in the clinic) that all available anti-VEGF compounds likely have an effect on the fellow eye to some extent. Most probably, the characteristics of that contralateral effect depend, among other parameters, on the precise molecular structure of the injected drug.

Ranibizumab and bevacizumab differ in their molecular weight, structure, and pharmacokinetics.2 Ranibizumab is a 48-kDa antigen-binding fragment, which lacks a fragment crystallizable (Fc) region and is rapidly cleared from the systemic circulation.3 Our retrospective study suggests clinically meaningful contralateral effect in more than a quarter of patients treated with bevacizumab, a 150-kDa monoclonal antibody containing an Fc region.4 Contralateral effect might be more frequently observed with bevacizumab than ranibizumab due to the Fc region-dependent active transport of bevacizumab to the systemic circulation. In accordance with that, results from the IVAN study, conducted in AMD patients, underlines the difference in pharmacokinetics between bevacizumab and ranibizumab: the decrease in serum-free VEGF from baseline at 12 months is significantly greater with bevacizumab compared with ranibizumab.5 Yet, some of our patients treated with ranibizumab for DME also demonstrated a fellow eye effect (unpublished observations). As highlighted by the case presented by Sharma et al,1 systemic passage of ranibizumab may well result in effect on the fellow eye. Interestingly, such a contralateral influence of ranibizumab has been described in conditions in which inflammation has a pivotal role (uveitis, retinal vein occlusion, and diabetes-related macular edema).

Another point that certainly merits to be closely observed is the potential contralateral effect of intravitreally injected aflibercept, a 110-kDa fusion protein that, like bevacizumab and unlike ranibizumab, contains an Fc region.

Contralateral effects are important as unilateral injections may suffice to treat bilateral edema in certain patients. This phenomenon also underscores potential systemic effects of intravitreal injection of anti-VEGF compounds. Taken together, the case presented by Sharma et al, combined with our findings on bevacizumab, and other reports on the subject suggest that the incidence, extent, and consequences of such fellow eye effect should be carefully evaluated in a prospective trial.