Early panretinal abnormalities on fundus autofluorescence and spectral domain optical coherence tomography after intravitreal ocriplasmin

Abstract

Intravitreal ocriplasmin, a recombinant truncated form of plasmin with proteolytic activity against laminin and fibronectin (Hermel et al. 2010), has recently been approved as treatment strategy for vitreomacular traction (VMT). However, concerns have been raised regarding its ocular safety (Kim 2014). Clinical trials reported adverse events that included transient visual loss, dyschromatopsia and photopsias, usually associated with decreased amplitudes on electroretinography (ERG) (Stalmans et al. 2012). Spectral domain optical coherence tomography (SD-OCT) abnormalities have been detected within the macula, and ERG studies have demonstrated diffuse retinal dysfunction related to presumed ocriplasmin toxicity (Fahim et al. 2014; Tibbetts et al. 2014). Herein, we demonstrate that early structural abnormalities to the photoreceptors as detected by fundus autofluorescence (FAF) and SD-OCT may affect not only the macula but also the peripheral retina as well. A 69-year-old woman presented with visual acuity of 20/32 and metamorphopsia in her right eye. Fundus examination and SD-OCT revealed VMT with small detachment of the foveal cones; FAF was normal (Fig. 1A,E). The day after uneventful intravitreal ocriplasmin (0.125 mg/0.1 ml), her vision decreased to 20/50 and she complained of dyschromatopsia. SD-OCT demonstrated the appearance of subfoveal fluid and multifocal shallow subretinal detachments (Fig. 1J–L), as well as focal areas of attenuation/thinning of the ellipsoid zone line and disappearance of the interdigitation zone line of the photoreceptors. Photoreceptor abnormalities corresponded to patchy areas of abnormally increased FAF signal within the macula (Fig. 1B,F) as well as to radial lines of abnormally increased FAF signal towards the retinal periphery (Fig. 1I). At day 7, her vision improved to 20/40 and dyschromatopsia was resolved. SD-OCT demonstrated the released VMT, decreased subfoveal fluid and shaggy photoreceptors in the fovea (Fig. 1C,G). Persisting attenuation/thinning of the ellipsoid zone line and further disappearance of the interdigitation zone line were noted. After 4 months, FAF and SD-OCT abnormalities disappeared completely (Fig. 1D,H). Clinical trials that compared intravitreal ocriplasmin to placebo in treatment of VMT indicated that visual symptoms were greater in patients receiving ocriplasmin (Stalmans et al. 2012). In addition, decreased amplitudes in all ERG variables were noted, indicating the presence of panretinal dysfunction that persisted for several months (Fahim et al. 2014; Tibbetts et al. 2014). Our imaging study supports these functional findings; indeed, structural damage to the photoreceptors was not confined within the macula, but was actually widespread throughout the periphery. These abnormalities may be due to a protease effect on laminin, which is present not only in the vitreous but also throughout the retina, including the interphotoreceptor matrix (IPM) (Fahim et al. 2014). Interestingly, in our case, there was greater and broader damage to the interdigitation zone line compared to the ellipsoid zone line. Normal reflectivity of the interdigitation zone line arises from well-oriented and aligned interdigitations of apical processes of the retinal pigment epithelium (RPE) with outer segments of the photoreceptors. We hypothesize that lysis of the IPM caused by ocriplasmin may create a loss of the normal alignment between photoreceptors and RPE microvilli, therefore causing reduced reflectivity of the interdigitation zone line. In addition, given the pivotal role of a healthy IPM for maintaining adhesion between retina and RPE, lysis of the IPM may reduce strength of the adhesion and thus cause multifocal detachments of the retina in areas where vitreoretinal traction was not significant. In summary, although ocriplasmin is effective in releasing VMT, presumed toxic effects of the drug may lead to visual disturbances as well as to early but transient panretinal structural abnormalities, especially involving the interdigitation zone. We suggest evaluating carefully the retinal periphery after ocriplasmin injection to detect any possible toxicity for the photoreceptors. Given the limited follow-up of patients who experienced presumed ocriplasmin toxicity, further research is needed to investigate risk factors, duration of recovery and ways to prevent or minimize toxic effects of the drug.