increased photoreceptor outer segment volume ...

INCREASED PHOTORECEPTOR OUTER SEGMENT VOLUME FOLLOWING SYSTEMIC TREATMENT OF BIRDSHOT CHORIORETINOPATHY Gavin Docherty, MD, Rosanna Martens, MD, Farzin Forooghian, MD, MSc, FRCSC

Purpose: Retinal degeneration in birdshot chorioretinopathy can be quantified using spectral domain optical coherence tomography by measuring the photoreceptor outer segment (PROS) volume. The purpose of this study was to determine if the PROS volume in BSCR responds to systemic immunomodulatory therapy (IMT). Methods: Retrospective chart review with analysis of PROS volume derived from spectral domain optical coherence tomography. Results: We identified a total of three patients who met our inclusion criteria. At baseline, all patients had abnormal PROS and/or ellipsoid layer findings on spectral domain optical coherence tomography. After systemic immunomodulatory therapy, these abnormalities improved, and PROS volume increased, in all patients (P , 0.05). Conclusion: PROS volume can increase after systemic treatment of birdshot chorioretinopathy. This SD-OCT parameter may serve as a useful marker of retinal degeneration in BSCR, and may be a useful outcome measure in monitoring treatment response in birdshot chorioretinopathy. RETINAL CASES & BRIEF REPORTS 0:1–5, 2017

From the Department of Ophthalmology, University of British Columbia, Vancouver, British Columbia, Canada.

In a recent article, we described a quantitative method of determining photoreceptor outer segment (PROS) volume in patients with BSCR.3 Our goal was to develop a method based on SD-OCT that could quantitatively assess the retinal degeneration in BSCR. We showed that PROS volume in BSCR is lower than in healthy controls.3 Furthermore, PROS volume in BSCR patients with electroretinography abnormalities was lower than in BSCR patients with normal electroretinography.3 The purpose of our current study was to determine if PROS volume, as measured by SD-OCT, could respond favorably to systemic IMT.

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etinal degeneration, as well as its’ potential to respond favorably to immunomodulatory therapy (IMT), has previously been described in birdshot chorioretinopathy (BSCR).1 The retinal degeneration in BSCR has mainly been described using electroretinography,1 but spectral domain optical coherence tomography (SD-OCT) has emerged as a powerful tool for visualization of photoreceptor degeneration in BSCR. Investigators have described attenuation of the ellipsoid layer in BSCR.2 Furthermore, these degenerative photoreceptor changes seen on SD-OCT have been qualitatively shown to normalize after systemic IMT.2

Methods We identified patients with an established diagnosis of BSCR who were seen at the University of British Columbia Uveitis Clinic between May 2011 and November 2016. This study involved the same cohort of BSCR patients who were examined in our previous study.3 From this cohort, we excluded any patients

None of the authors has any financial/conflicting interests to disclose. Reprint requests: Farzin Forooghian, MD, MSc, FRCSC, Department of Ophthalmology, St. Paul’s Hospital, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada; e-mail: farzin. [email protected]

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Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.

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with a history of local steroid treatment, cystoid macular edema, choroidal neovascular membrane, or epiretinal membrane. Ethics approval was obtained from the Research Ethics Board at the University of British Columbia and the research study adhered to the tenets set forth in the Declaration of Helsinki. Spectral domain optical coherence tomography scans captured using Spectralis SD-OCT (Heidelberg Engineering, Heidelberg, Germany) were analyzed to determine PROS volume for all patient visits. Manual segmentation of the PROS layer and calculation of PROS volume were performed by a medical retina specialist (FF) using previously described methods.3 Briefly, the segmentation line that normally delineates the internal limiting membrane was manually moved to the ellipsoid layer line. Following this, the SD-OCT software automatically calculated the PROS volume as part of its’ normal macular volume determination. To determine whether or not the rate of PROS volume increase is significantly higher than zero, we used a one-sample t-test. For statistical analysis, alpha was set at P , 0.05, and data were analyzed using GraphPad Prism software (version 6; GraphPad Software Inc, San Diego, CA). Results From our initial cohort of 11 BSCR patients, we identified 3 who met our inclusion criteria. All patients were HLA-A29 positive, had leakage on fluorescein angiography, and had depressed electroretinography. All SD-OCT B-scans demonstrated adequate visualization of the ellipsoid layer to allow for proper visualization and segmentation. At baseline, all patients had abnormal PROS and/or ellipsoid layer findings on SD-OCT (Figures 1–3, A). At the final visit, there was some resolution of the abnormal SDOCT findings in all patients (Figures 1–3, B). All patients had a statistically significant increase in PROS volume after treatment (P , 0.05). There was a temporal relationship with PROS volume increase and initiation of treatment. The increase in PROS volume appeared to occur soon after prednisone initiation, whereas the increase in PROS volume after mycophenolate mofetil and adalimumab was delayed. Furthermore, we observed a temporal relationship with PROS volume decrease and discontinuation of prednisone in one patient. A brief description of each of the three cases is given below: Case 1 A 48-year-old Caucasian woman presented with BSCR OU. The patient complained of decreased

Fig. 1. Photoreceptor outer segment volume increase after treatment (Case 1). A. Graphical representation of PROS volume plotted against time. Data points indicate the mean PROS for both eyes, and error bars indicate standard deviation. Black data points indicate patient was taking prednisone, and red data points indicate patient was not taking prednisone. Black arrows correspond to prednisone pulse, single blue arrow corresponds to initiation of MMF 1,000 mg BID, and double blue arrow corresponds to increase in MMF dosage to 1,500 mg BID. B. Spectral domain optical coherence tomography scan at baseline shows loss of the PROS hyporeflective space, and (C) Spectral domain optical coherence tomography at final visit shows restoration of the PROS hyporeflective space in the right eye. The response in the left eye was identical, and has not been shown for brevity.

vision OU. Best-corrected visual acuity was 20/25 OU, intraocular pressure was 15 mmHg OU, and slitlamp examination was within normal limits OU. Dilated fundus examination revealed trace vitreous haze OU. Her baseline SD-OCT scan showed loss of the PROS hyporeflective space (which corresponds to the photoreceptor outer segments) OU (Figure 1A). The patient was pulsed with prednisone 1 mg/kg. On her next visit, her best-corrected visual acuity was still 20/25 OU, but she noted subjective improvement in her vision. The vitreous haze OU had resolved, and the PROS volume OU had increased (Figure 1C). The prednisone was tapered over the next few weeks. On her fourth visit, the prednisone had been stopped, and


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she noted subjective worsening of vision OU. The PROS volume OU had decreased to baseline values (Figure 1C). She was pulsed with prednisone 1 mg/kg again, along with initiation of mycophenolate mofetil 1,000 mg BID, which was increased to 1,500 mg BID on her next visit. On her sixth visit, when the prednisone had been discontinued again, the PROS volume OU had once again returned to baseline values (Figure 1C). However, on future visits, her PROS volume increased steadily, rising above baseline values at her final visit (Figure 1C). Her final SDCOT showed restoration of the hyporeflective PROS space OU (Figure 1B). The rate of PROS volume increase from baseline to final visit was 0.27 mm3/year (P = 0.0289). Case 2 A 51-year-old Caucasian woman with BSCR complained of progressive nyctalopia and peripheral vision loss despite treatment with adalimumab 40 mg SC every 2 weeks. Her electroretinography also showed progressive worsening of responses OU. Best-corrected visual acuity was 20/25 OU, intraocular pressure was 16 mmHg OU, and slit-lamp examination was within normal limits OU. Dilated fundus examination revealed trace vitreous haze OU. Her baseline SD-OCT scan showed attenuation of the ellipsoid layer and a decrease in the PROS hyporeflective space OU (Figure 2A). The patient was pulsed with prednisone 1 mg/kg. On her next visit, her best-corrected visual acuity was still 20/25 OU, but she noted subjective improvement in her vision. The vitreous haze OU had resolved, and the PROS volume OU had increased (Figure 2C). Prednisone taper was initiated, and on her fourth visit the adalimumab dosage was increased to 40 mg SC every week. Her PROS volume continued to increase throughout all her visits (Figure 2C), and repeat electroretinography testing showed improvement in her responses. Her final SD-OCT showed some restoration of the ellipsoid laser, along with an increase in the PROS hyporeflective space OU (Figure 2B). The rate of PROS volume increase from baseline to final visit was 0.36 mm3/year (P , 0.0001). Case 3 A 49-year-old Caucasian man with BSCR complained of worsening vision OU. Best-corrected visual acuity was 20/20 OU, intraocular pressure was 18 mmHg OU, and slit-lamp examination was within normal limits OU. Dilated fundus examination revealed trace vitreous haze OU. Spectral domain optical coherence tomography at baseline showed a decrease in the PROS hyporeflective space OU (Figure 3A).

Fig. 2. Photoreceptor outer segment volume increase after treatment (Case 2). A. Graphical representation of PROS volume plotted against time. Data points indicate the mean PROS for both eyes, and error bars indicate standard deviation. Black data points indicate patient was taking prednisone, and red data points indicate patient was not taking prednisone. Black arrows correspond to prednisone pulse, and single blue arrow corresponds to changing of adalimumab dosage to 40 mg every week. B. Spectral domain optical coherence tomography scan at baseline showed attenuation of the ellipsoid layer and a decrease in the PROS hyporeflective space, and (C) Spectral domain optical coherence tomography at final visit showed some restoration of the ellipsoid laser, along with an increase in the PROS hyporeflective space in the right eye. The response in the left eye was identical, and has not been shown for brevity.

The patient was treated with mycophenolate mofetil 1,000 mg BID, and PROS volume OU was noted to have increased on his subsequent visit (Figure 3C). On his third visit, he was pulsed with prednisone 1 mg/kg, followed by taper. On his final visit, the PROS volume OU had increased again (Figure 3C). His final SDOCT showed an increase in the PROS hyporeflective space OU (Figure 3B). The rate of PROS volume increase from baseline to final visit was 0.24 mm3/year (P = 0.0374). Discussion We observed an increase in PROS volume after systemic IMT in patients with BSCR. Based on


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Fig. 3. Photoreceptor outer segment volume increase after treatment (Case 3). A. Graphical representation of PROS volume plotted against time. Data points indicate the mean PROS for both eyes, and error bars indicate standard deviation. Black data points indicate patient was taking prednisone, and red data points indicate patient was not taking prednisone. Black arrows correspond to prednisone pulse, and single blue arrow corresponds to initiation of MMF 1,000 mg BID. B. Spectral domain optical coherence tomography scan at baseline showed a decrease in the PROS hyporeflective space, and (C) Spectral domain optical coherence tomography at final his visit showed an increase in the PROS hyporeflective space in the right eye. The response in the left eye was identical, and has not been shown for brevity.

qualitative observation of the SD-OCT scans, this corresponded to lengthening of the PROSs (increase in PROS hyporeflective space), which was observed in all patients. Animal models of uveitis have shown that under inflammatory conditions, PROSs can decrease in length.4,5 It is thus conceivable that in BSCR PROSs are shortened secondary to inflammatory changes in the retina. Systemic IMT would remove inflammatory cells and mediators, thereby allowing the PROS length and volume to increase. Photoreceptor damage and recovery, as evidenced by attenuation and subsequent restoration of the ellipsoid layer on SD-OCT, has previously been qualitatively described in BSCR.2 To our knowledge, this is the first report showing quantification of this recovery in BSCR.

Our study suggests that PROS volume, derived from SD-OCT scans, may represent a novel method of following treatment response in patients with BSCR. Currently, serial electroretinography testing is the main method for monitoring retinal degeneration in BSCR. This testing can give variable results, is not always readily available, is a lengthy procedure, and can be difficult for patients to perform.6 Quantitative assessment of PROS volume using SD-OCT may serve as an alternative or adjunctive modality for monitoring treatment response in BSCR. Further validation is required in this regard. The manual method of segmentation used in our study was laborious and not practical for use as part of standard clinical practice. Prototype automated algorithms for quantitative PROS assessments have previously been described.7 Further development of these algorithms is required for SD-OCT to become a useful clinical tool for the monitoring of retinal degeneration in BSCR. The limitations of this study include its’ retrospective nature, as well as the small sample size. Patients with cystoid macular edema and epiretinal membrane had to be excluded, because both of these conditions could affect PROS volume.8 The need to exclude patients with cystoid macular edema and epiretinal membrane may impose some limitations on the use of this parameter as a generalized marker of retinal degeneration in BSCR. Furthermore, the image analysis we performed requires clear visualization of the ellipsoid zone, which may not be possible in eyes with media opacity or severe macular atrophy. Thus, PROS volume may be useful only in a subset of patients (i.e., those without cystoid macular edema/epiretinal membrane, media opacity, or advanced disease). Furthermore, the error and normal inter-visit variation in PROS volume measurements is not known. SD-OCTderived parameters such as choroidal thickness have been shown to have normal and diurnal variations.9 Choroid thickness measurements are also dependent on age, gender, and axial length.10 The fact that the increase in PROS volume we observed was statistically significant, and had a temporal relationship with IMT initiation/discontinuation, would suggest that our observations were secondary to treatment effect. Furthermore, we observed that increase in PROS volume appeared to occur soon after prednisone initiation, whereas the increase in PROS volume after mycophenolate mofetil and adalimumab was more delayed. This is in keeping with the expected clinical onset of action of these medications. Nevertheless, further investigations into the normal variation of PROS volume measurements, as well as the potential effects of age, gender, and axial length, are warranted.


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Key words: birdshot chorioretinopathy, optical coherence tomography, photoreceptor outer segment, treatment. References 1. Sobrin L, Lam BL, Liu M, et al. Electroretinographic monitoring in birdshot chorioretinopathy. Am J Ophthalmol 2005;140:52–64. 2. Forooghian F, Gulati N, Jabs DA. Restoration of retinal architecture following systemic immunosuppression in birdshot chorioretinopathy. Ocul Immunol Inflamm 2010;18:470–471. 3. Symes R, Young M, Forooghian F. Quantitative assessment of retinal degeneration in birdshot chorioretinopathy using optical coherence tomography. Ophthalmic Surg Lasers Imaging Retina 2015;46:1009–1012. 4. Hayakawa K, Ishikawa M, Yamaki K. Ultrastructural changes in rat eyes with experimental Vogt-Koyanagi-Harada disease. Jpn J Ophthalmol 2004;48:222–227.

5 5. Yamaki K, Kondo I, Nakamura H, et al. Ocular and extraocular inflammation induced by immunization of tyrosinase related protein 1 and 2 in Lewis rats. Exp Eye Res 2000;71:361–369. 6. Birnbaum AD, Fawzi AA, Rademaker A, Goldstein DA. Correlation between clinical signs and optical coherence tomography with enhanced depth imaging findings in patients with birdshot chorioretinopathy. JAMA Ophthalmol 2014;132:929–935. 7. Forooghian F, Stetson PF, Gross NE, Meyerle CB. Quantitative assessment of photoreceptor recovery in atypical multiple evanescent white dot syndrome. Ophthalmic Surg Lasers Imaging 2010;41:S77–S80. 8. Shiono A, Kogo J, Klose G, et al. Photoreceptor outer segment length: a prognostic factor for idiopathic epiretinal membrane surgery. Ophthalmology 2013;120:788–794. 9. Brown JS, Flitcroft DI, Ying GS, et al. In vivo human choroidal thickness measurements: evidence for diurnal fluctuations. Invest Ophthalmol Vis Sci 2009;50:5–12. 10. Ooto S, Hangai M, Yoshimura N. Effects of sex and age on the normal retinal and choroidal structures on optical coherence tomography. Curr Eye Res 2015;40:213–225.
