Gyrate atrophy of the choroid and retina is a rare genetic condition of autosomal recessive inheritance. It is characterized by widespread chorioretinal degeneration due to deficiency of the enzyme ornithine ketoacid aminotransferase that results in a 10 to 20 times increase in the level of the amino acid ornithine in plasma.1 Ocular manifestations in the form of myopia, chorioretinal degeneration, cataract formation, and intraretinal cystic spaces predominate in the condition, with few recorded systemic associations including abnormal electroencephalograms, epilepsy, and abnormal muscle morphology.1–4
Clinically, affected patients initially complain of night blindness and loss of peripheral vision due to the development of chorioretinal atrophy that starts in the peripheral retina and spreads centrally to involve the macula, possibly due to hyperornithinemia.2 Patients may also develop foveoschisis, cystoid macular edema, or intraretinal cystic spaces that involve the macula, leading to diminution of visual acuity. However, the pathogenesis of these macular conditions is currently unknown.5–7
Bevacizumab is a full-length humanized monoclonal anti-vascular endothelial growth factor (VEGF) antibody that has been used in the off-label treatment of intraretinal cystic spaces associated with various retinal conditions, including diabetic macular edema,8 Coats disease,9 and retinal dystrophies.6 Although there is a current concern that repeated intravitreal injections of anti-VEGF agents could potentially result in worsening of retinal ischemia and decreased neuroprotection,8,10,11 there was no worsening of the clinical condition or the visual field of a patient with retinitis pigmentosa and associated choroidal neovascularization who was treated over an 8-year period with repeated intravitreal injections of various anti-VEGF agents,12 which may indicate the possible safety of long-term use of these agents in retinal dystrophies.
We previously reported the improvement of intraretinal cystic spaces in a patient with gyrate atrophy following repeated intravitreal bevacizumab injections.13 In this pilot study, we report the results of three monthly intravitreal bevacizumab injections for intraretinal cystic spaces associated with gyrate atrophy of the choroid and retina in 5 eyes of 3 patients, two of whom were brothers. We also report the macular microperimetric and optical coherence tomography angiography (OCTA) findings before and after the injections in one of these patients.
Patients and Methods
This was a retrospective study performed at Cairo University Hospital to evaluate the use of intravitreal bevacizumab injections for the treatment of intraretinal cystic spaces associated with gyrate atrophy of the choroid and retina. The study was approved by the research ethics committee of Cairo University and followed the tenets of the Declaration of Helsinki. Written informed consents were obtained from the patients' parents before inclusion in the study.
Chart review of all patients with gyrate atrophy of the choroid and retina who underwent intravitreal bevacizumab injections for intraretinal cystic spaces between December 2016 and December 2018 at our institute was performed. All relevant information available was obtained for all included patients, including history, examination findings, optical coherence tomography (OCT), OCTA, fluorescein angiography, and microperimetry findings before and after the intravitreal injections. Exclusion criteria included concomitant retinal conditions such as diabetic retinopathy, history of uveitis, history of ocular surgery, presence of an epiretinal membrane or vitreomacular traction on OCT, and previous or concomitant treatment for intraretinal cystic spaces other than bevacizumab injections, such as carbonic anhydrase inhibitors and nonsteroidal anti-inflammatory drugs.
Statistical analysis was done using IBM SPSS version 20.0 statistical software (IBM Corporation). Descriptive statistics were calculated, and the data were summarized as mean ± standard deviation for the numerical data. Comparison of measurements before and after the injections was performed using the paired t test. Results were considered statistically significant if the P value was less than .05 (2-tailed).
Five eyes of 3 patients with intraretinal cystic spaces associated with gyrate atrophy treated with intravitreal bevacizumab injections were included in the study. Table 1 summarizes the demographic information and the data before and after injection of the 3 patients. The mean age of the patients was 11 ± 4.6 years. All patients had elevated plasma ornithine levels and a clinical picture consistent with gyrate atrophy. The two male patients were brothers. Intraretinal cystic spaces were diagnosed using OCT (Optovue, Inc). All patients received three consecutive monthly intravitreal bevacizumab injections. The mean corrected distance visual acuity (CDVA) was 0.27 ± 0.10 before the injections and improved to 0.36 ± 0.12 at 1 month after the third injection, which was statistically significant (P = .015). The mean central macular thickness (CMT) as measured by OCT was 569 ± 127 µm before the injections and improved to 422 ± 123 µm at 1 month after the third injection, which was close to being statistically significant (P = .067). The older brother (case 1) showed marked improvement in CMT in response to the injections compared to his younger brother (case 2), as detailed below.
Demographic, Baseline, and Post-treatment Data of Patients
A 12-year-old boy was brought in by his parents because he complained of gradually progressive diminution of vision in his left eye for several years. He also complained of difficulty seeing at nighttime. He had a history of a traumatic macular hole and retinal detachment in the right eye 1 year ago that was treated by pars plana vitrectomy and silicone oil injection but complicated by proliferative vitreoretinopathy and recurrent detachment. His medical history included epilepsy since childhood. He was receiving anti-epileptic medications that controlled his condition.
Examination of the child revealed a CDVA of 20/200 in the left eye with no light perception in the right eye (findings in the right eye are irrelevant to this report and will not be discussed further). Anterior segment examination of the left eye was unremarkable. Posterior segment examination of the left eye revealed macular cysts with extensive peripheral scalloped chorioretinal atrophic patches characteristic of gyrate atrophy. Laboratory investigations showed an elevated plasma ornithine level of 753 µmol/L, confirming the diagnosis. OCT of the macula revealed intraretinal cystic spaces with a CMT of 671 µm (Figure 1A). Macular microperimetry (Optos) showed decreased sensitivity of the central, superior, and temporal macular areas with a mean sensitivity of 12.8 dB (Figure 1C). OCTA (Optovue, Inc) of the central 6 × 6 mm macular area was performed and revealed temporal macular ischemia with few areas of capillary drop-out superiorly and inferiorly and a foveal avascular zone (FAZ) area of 0.364 mm2 (Figure 1E). Treatment with monthly intravitreal bevacizumab injections (1.25 mg/0.05 mL) was started, and 1 month after the third injection CDVA improved to 20/100, OCT showed marked improvement of the intraretinal cystic spaces with a CMT of 336 µm (−335 µm compared to baseline) (Figure 1B), microperimetry revealed improved macular sensitivity with a mean sensitivity of 13.8 dB (Figure 1D), and OCTA showed improved vascular density measurements and a decrease of FAZ area to 0.326 mm2 (Figure 1F). During this period of intravitreal bevacizumab treatment, the patient also underwent restriction of arginine in his diet and received vitamin B6 supplementation, which resulted in an approximately 50% reduction in his plasma ornithine level after 3 months.
Multimodal imaging findings of the left eye of case 1 at baseline and after treatment. (A) Optical coherence tomography (OCT) at baseline showed prominent intraretinal cystic spaces with a central macular thickness (CMT) of 671 µm. (B) One month after three intravitreal bevacizumab injections, there was marked improved in intraretinal cycstic spaces and CMT improved to 336 µm. (C) Macular microperimetry at baseline showed decreased sensitivity in the central, superior, and temporal macular areas with a mean sensitivity of 12.8 dB. (D) One month after three intravitreal bevacizumab injections, there was improvement in the macular sensitivity with a mean of 13.8 dB. (E) OCT angiography at baseline showed areas of capillary drop-out, especially in the temporal macula. (F) One month after three injections, there was improvement in macular vascular density measurements.
A 6-year-old boy was brought in by his parents for an ophthalmic examination because his brother (case 1) had been diagnosed as having gyrate atrophy. Unlike his brother, he had no ocular or medical history.
Examination of the child revealed a CDVA of 20/60 in both eyes. Anterior segment examination was normal. Posterior segment examination revealed macular cysts and peripheral chorioretinal atrophic patches similar to his brother and characteristic of gyrate atrophy. Laboratory investigations revealed hyperornithinemia with a level of 824 µmol/L, confirming the diagnosis. OCT of the macula revealed intraretinal cystic spaces in both eyes with a CMT of 538 µm in the right eye and 628 µm in the left eye (Figure 2A). Microperimetry could not be performed reliably due to the patient's age and OCTA showed excessive motion and blink artifacts with a low signal strength (Figure 2B). The patient received three monthly intravitreal bevacizumab injections (1.25 mg/0.05 mL) in both eyes. At 1 month following the last injection, CDVA improved to 20/50 in the right eye and 20/40 in the left eye, OCT showed mild improvement of the CMT of the right eye to 522 µm (−16 µm compared to baseline) and the left eye to 555 µm (−73 µm compared to baseline) (Figure 2C), and OCTA of the left eye revealed areas of macular ischemia, especially temporally (Figure 2D). The patient also underwent the same dietary modifications as his brother during the injection period, which also resulted in an approximately 50% reduction in his plasma ornithine level after 3 months.
Optical coherence tomography (OCT) and OCT angiography (OCTA) imaging of the left eye of case 2 at baseline and after treatment. (A) OCT at baseline showed prominent intraretinal cystic spaces with a central macular thickness (CMT) of 628 µm. (B) OCTA at baseline showed multiple motion and blink artifacts with a low signal strength (3/10). There were also temporal areas of capillary drop-out. (C) One month following three injections there was mild improvement of intraretinal cystic spaces with a CMT of 555 µm. (D) OCTA after treatment showed less imaging artifacts with improved signal strength (6/10) and persistent areas of capillary drop-out temporally.
Details on case 3, the first case with intraretinal cystic spaces associated with gyrate atrophy to be treated with intravitreal bevacizumab, have been previously published elsewhere.13
Several modalities have been employed to reduce the progression of chorioretinal degeneration and to preserve the vision of patients with gyrate atrophy, including the restriction of arginine in the diet and the administration of vitamin B6. However, the effect of these treatment modalities on the intraretinal cystic spaces associated with gyrate atrophy has been variable, which suggests that the pathophysiology of intraretinal cystic spaces associated with gyrate atrophy may be due to other causes in addition to the hyperornithinemia.14,15
In the current study, we found evidence of both structural and functional improvement of the macula of 5 eyes of 3 patients with intraretinal cystic spaces associated with gyrate atrophy evaluated by clinical examination, OCT, OCTA, and microperimetry following 3 monthly intravitreal bevacizumab injections. Although our sample size was small, gyrate atrophy of the choroid and retina is a rare autosomal recessive condition and our study currently represents the largest study reported to date that evaluated anti-VEGF injections for the treatment of intraretinal cystic spaces associated with gyrate atrophy. The statistical improvement of vision compared to the non-statistical improvement of CMT in the current study suggests that improvement in CMT is possibly not the only factor accounting for vision improvement in our patients following the injections and that there could possibly be another disease-modifying effect from the injections. This could be better addressed in future studies with a larger number of patients and a control group.
Regarding patients with gyrate atrophy who have intraretinal cystic spaces and respond well to bevacizumab injections, we currently recommend close follow-up of these patients after short periods of treatment and possible pro re nata regimen for future treatment as needed. However, we do not recommend prolonged periods of injections until the safety of such long-term therapy is first assessed in patients with gyrate atrophy. Regarding patients with poor response to injections, other treatment alternatives could be tried, including carbonic anhydrase inhibitors or nonsteroidal anti-inflammatory drugs. The long-term treatment of these patients will depend on which drug they best respond to with the fewest side effects and most compliance. This could be addressed in future comparative studies.
Other available and previously reported treatment alternatives for intraretinal cystic spaces associated with gyrate atrophy include intravitreal or sub-Tenon injection of triamcinolone acetonide,5,16 but these carry the risk of elevation of the intraocular pressure and progression of cataract.17 We also reported the results of using monthly intravitreal bevacizumab injections for the treatment of intraretinal cystic spaces associated with gyrate atrophy in 2 eyes of a single patient whose results are also included in this study.13 Although the patient's visual acuity in both eyes only improved partially, our findings suggested a possible therapeutic effect of using bevacizumab in such cases, which we further statistically analyzed in this larger case series. In that case, we performed OCTA imaging of the macula before the injections, which showed evidence of capillary dropouts in the temporal macula similar to those found in the current study; however, we did not perform OCTA imaging after the injections and so could not evaluate the effect of bevacizumab injections on the macular perfusion.13 In the current study, OCTA imaging before and after the injections in a single eye showed improvement of macular ischemia following the injections, but larger and longer term studies are needed to evaluate this effect. In case 2, we could not obtain reliable OCTA images before the injections, possibly due to the impaired visual acuity and relatively long scanning time associated with OCTA scanning that could lead to imaging artifacts, especially in uncooperative patients and in children, and thus could pose a challenge in imaging pediatric retinal conditions.18 Images obtained after injections, however, were better in the same patient, which suggests that better images could be obtained with improved visual acuity and with training of patients. Bevacizumab has also been previously reported to be safe and effective in treatment of choroidal neovascularization associated with gyrate atrophy in a single patient.19
The mechanism by which bevacizumab results in improvement of intraretinal cystic spaces associated with gyrate atrophy is not fully understood,13 but the presence of ischemic areas on OCTA and macular leakage on fluorescein angiography in some cases with gyrate atrophy suggests that some patients with intraretinal cystic spaces associated with gyrate atrophy may have elevated VEGF levels that could be lowered by anti-VEGF injections.5,13,20,21 This could be best confirmed by measuring intravitreal VEGF levels in patients with gyrate atrophy, as has been previously done in other retinal pathologies.9,22 The intraretinal cystic spaces associated with gyrate atrophy may also represent cytotoxic edema, which is thought to occur due to accumulation of intracellular fluid inside glial cells (Müller cells) that is often associated with ischemia that affects the transport capabilities of cells due to energy depletion without blood–retina barrier abnormalities.23 This could possibly explain the presence of intraretinal cystic spaces in patients with gyrate atrophy with ischemia but without evidence of leakage on fluorescein angiography, which is improved by VEGF inhibition.13
Microperimetry is a real-time, fundus-tracking controlled visual field examination that allows the projection of small stimuli in an exact retinal area both at baseline and automatically during follow-up examinations, which allows evaluation of changes in the sensitivity of discrete retinal areas.24 Fundus-tracking allows overcoming the random eye movements and retinal fixation changes and allows obtaining precise retina-related sensitivity data. Classically, microperimetry has been used in the diagnosis and follow-up of age-related macular degeneration, but has also been found useful in many other macular conditions.24,25 In our study, macular microperimetry findings in a single eye of a single patient showed improved macular sensitivity following the injections, confirming functional improvement in this case; however, this should be confirmed in larger studies.
Previous studies have shown that gyrate atrophy may manifest with different severity in siblings. There were differences in electroretinogram responses and rate of cataract formation between siblings in one study indicating phenotype differences between family members affected by the same mutation.26 This could explain the clinical differences and the different response to bevacizumab injections observed in the two brothers in our study. Another factor that could explain this difference is the relatively wide age difference between them (6 years), which suggests that patients with a younger age may be more resistant to injections, but this finding requires further validation in a larger study.
Our study is limited by its retrospective nature, small number of included patients, short duration of treatment, and a possible confounding effect from the dietary modifications on the treatment response. However, the two brothers had an only approximately 50% reduction in their plasma ornithine level following dietary modifications, whereas the female patient previously described did not undergo dietary modifications.13 This indicates a probable therapeutic effect from the bevacizumab injections on the intraretinal cystic spaces. Another limitation of our study is that we did not perform genetic analysis for the patients and so were not able to determine the effect of specific genotypes of gyrate atrophy on the response to intravitreal bevacizumab injections for the associated intraretinal cystic spaces. This could be performed in future studies.
We report structural and functional improvement of the macula of 5 eyes of 3 patients with gyrate atrophy of the choroid and retina following intravitreal bevacizumab injections. Larger studies, preferably in the form of multicenter randomized controlled studies, are needed to confirm findings from this study.
- Potter MJ, Berson EL. Diagnosis and treatment of gyrate atrophy. Int Ophthalmol Clin. 1993;33(2):229–236. doi:10.1097/00004397-199303320-00021 [CrossRef]
- Berson EL. Nutrition and retinal degenerations. Int Ophthalmol Clin. 2000;40(4):93–111. doi:10.1097/00004397-200010000-00008 [CrossRef]
- Valtonen M, Näntö-Salonen K, Jääskeläinen S, et al. Central nervous system involvement in gyrate atrophy of the choroid and retina with hyperornithinaemia. J Inherit Metab Dis. 1999;22(8):855–866. doi:10.1023/A:1005602405349 [CrossRef]
- Sipilä I, Simell O, Rapola J, Sainio K, Tuuteri L. Gyrate atrophy of the choroid and retina with hyperornithinemia: tubular aggregates and type 2 fiber atrophy in muscle. Neurology. 1979;29(7):996–1005. doi:10.1212/WNL.29.7.996 [CrossRef]
- Vasconcelos-Santos DV, Magalhães EP, Nehemy MB. Macular edema associated with gyrate atrophy managed with intravitreal triamcinolone: a case report. Arq Bras Oftalmol. 2007;70(5):858–861. doi:10.1590/S0004-27492007000500024 [CrossRef]
- Salvatore S, Fishman GA, Genead MA. Treatment of cystic macular lesions in hereditary retinal dystrophies. Surv Ophthalmol. 2013;58(6):560–584. doi:10.1016/j.survophthal.2012.11.006 [CrossRef]
- Zhioua Braham I, Ammous I, Maalej R, et al. Multimodal imaging of foveoschisis and macular pseudohole associated with gyrate atrophy: a family report. BMC Ophthalmol. 2018;18(1):89. doi:10.1186/s12886-018-0755-9 [CrossRef]
- Elnahry AG, Abdel-Kader AA, Raafat KA, Elrakhawy K. Evaluation of the effect of repeated intravitreal bevacizumab injections on the macular microvasculature of a diabetic patient using optical coherence tomography angiography. Case Rep Ophthalmol Med. 2019;2019:3936168. doi:10.1155/2019/3936168 [CrossRef]
- Elnahry AG, Sallam EM, Guirguis KJ, Talbet JH, Abdel-Kader AA. Vitrectomy for a secondary epiretinal membrane following treatment of adult-onset Coats' disease. Am J Ophthalmol Case Rep. 2019;15:100508. doi:10.1016/j.ajoc.2019.100508 [CrossRef]
- Manousaridis K, Talks J. Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease?Br J Ophthalmol. 2012;96(2):179–184. doi:10.1136/bjophthalmol-2011-301087 [CrossRef]
- Elnahry AG, Abdel-Kader AA, Raafat KA, Elrakhawy K. Evaluation of changes in macular perfusion detected by optical coherence tomography angiography following 3 intravitreal monthly bevacizumab injections for diabetic macular edema in the IMPACT Study. J Ophthalmol. 2020;2020:5814165. doi:10.1155/2020/5814165 [CrossRef]
- Miyata M, Oishi A, Oishi M, Hasegawa T, Ikeda HO, Tsujikawa A. Long-term efficacy and safety of anti-VEGF therapy in retinitis pigmentosa: a case report. BMC Ophthalmol. 2018;18(1):248. doi:10.1186/s12886-018-0914-z [CrossRef]
- Elnahry AG, Hassan FK, Abdel-Kader AA. Bevacizumab for the treatment of intraretinal cystic spaces in a patient with gyrate atrophy of the choroid and retina. Ophthalmic Genet. 2018;39(6):759–762. doi:10.1080/13816810.2018.1536220 [CrossRef]
- Doguizi S, Sekeroglu MA, Anayol MA, Yilmazbas P. Arginine restricted therapy resistant bilateral macular edema associated with gyrate atrophy. Case Rep Ophthalmol Med. 2015;2015:137270. doi:10.1155/2015/137270 [CrossRef]
- Casalino G, Pierro L, Manitto MP, Michaelides M, Bandello F. Resolution of cystoid macular edema following arginine-restricted diet and vitamin B6 supplementation in a case of gyrate atrophy. J AAPOS. 2018;22(4):321–323. doi:10.1016/j.jaapos.2017.12.016 [CrossRef]
- Alparslan S, Fatih MT, Muhammed S, Adnan Y. Cystoid macular edema secondary to gyrate atrophy in a child treated with subtenon injection of triamcinolone acetonide. Rom J Ophthalmol. 2018;62(3):246–249. doi:10.22336/rjo.2018.37 [CrossRef]
- Elnahry AG. Letter to the editor regarding: “cystoid macular edema secondary to gyrate atrophy in a child treated with subtenon injection of triamcinolone acetonide”. Rom J Ophthalmol. 2018;62(4):317–318. doi:10.22336/rjo.2018.50 [CrossRef]
- Spaide RF, Fujimoto JG, Waheed NK. Image artifacts in optical coherence tomography angiography. Retina. 2015;35(11):2163–2180. doi:10.1097/IAE.0000000000000765 [CrossRef]
- Inanc M, Tekin K, Teke MY. Bilateral choroidal neovascularization associated with gyrate atrophy managed with intravitreal bevacizumab. Int Ophthalmol. 2018;38(3):1351–1355. doi:10.1007/s10792-017-0579-2 [CrossRef]
- Oliveira TL, Andrade RE, Muccioli C, Sallum J, Belfort R Jr, . Cystoid macular edema in gyrate atrophy of the choroid and retina: a fluorescein angiography and optical coherence tomography evaluation. Am J Ophthalmol. 2005;140(1):147–149. doi:10.1016/j.ajo.2004.12.083 [CrossRef]
- Raval V, Kapoor A, Nayak S, Rao S, Das T. Optical coherence tomography angiography and macular vessel density analysis of cystoid macular edema in gyrate atrophy. Ophthalmic Surg Lasers Imaging Retina. 2019;50(7):423–427. doi:10.3928/23258160-20190703-03 [CrossRef]
- He YG, Wang H, Zhao B, Lee J, Bahl D, McCluskey J. Elevated vascular endothelial growth factor level in Coats' disease and possible therapeutic role of bevacizumab. Graefes Arch Clin Exp Ophthalmol. 2010;248(10):1519–1521. doi:10.1007/s00417-010-1366-1 [CrossRef]
- Spaide RF. Retinal vascular cystoid macular edema: review and new theory. Retina. 2016;36(10):1823–1842. doi:10.1097/IAE.0000000000001158 [CrossRef]
- Markowitz SN, Reyes SV. Microperimetry and clinical practice: an evidence-based review. Can J Ophthalmol. 2013;48(5):350–357. doi:10.1016/j.jcjo.2012.03.004 [CrossRef]
- Cideciyan AV, Swider M, Aleman TS, et al. Macular function in macular degenerations: repeatability of microperimetry as a potential outcome measure for ABCA4-associated retinopathy trials. Invest Ophthalmol Vis Sci. 2012;53(2):841–852. doi:10.1167/iovs.11-8415 [CrossRef]
- Kaiser-Kupfer MI, Caruso RC, Valle D. Gyrate atrophy of the choroid and retina. Long-term reduction of ornithine slows retinal degeneration. Arch Ophthalmol. 1991;109(11):1539–1548. doi:10.1001/archopht.1991.01080110075039 [CrossRef]
Demographic, Baseline, and Post-treatment Data of Patients
|Parameter||Case 1||Case 2||Case 3|
|Plasma ornithine (µmol/L)||753||824||851|
|Baseline CDVA (Snellen)||20/200||20/600, 20/60||20/60, 20/80|
|Final CDVA (Snellen)a||20/100||20/50, 20/40||20/50, 20/70|
|Baseline CMT (µm)||671||538/628||344/665|
|Final CMT (µm)a||336||522/555||263/433|
|Change CMT (µm)||−335||−16/−73||−81/−232|