Regression of treatment-resistant gyrate atrophy-associated intraretinal cystic spaces using long-term diet restriction: A case report

Introduction

Gyrate atrophy of the choroid and retina (GA) is a rare autosomal recessive disorder which is characterized by the development of progressive chorioretinal atrophy. Pathophysiology of the disorder is rooted in a congenital deficit in ornithine aminotransferase, which in turn yields an elevation of ornithine concentrations in plasma, urine, cerebrospinal fluid, and aqueous humor. ¹

Patients frequently initially present with night blindness and deficits in peripheral vision in the second decade of life; by the fifth decade of life, this can progress to loss of central vision. ² Thorough imaging studies have demonstrated that intraretinal cystic spaces (ICS) is a common finding in patients with GA and contributes significantly to vision loss and disturbance. ³ Treatment modalities for GA-associated ICS documented in the medical literature include dietary modifications such as arginine-restricted diets, ⁴ vitamin B6 supplementation, ⁵ or a combination of both, ⁶ and intravitreal bevacizumab injections (IVB), ⁷ carbonic anhydrase inhibitors (CAIs), ⁸ and non-steroidal anti-inflammatory drugs (NSAIDs). ⁸ Herein, we report a patient with GA-associated ICS who poorly responded to CAIs, NSAIDs, and repeated IVB but favorably responded to prolonged dietary modifications.

Case description

An otherwise healthy six-year-old Middle Eastern male with no medical history was screened for gyrate atrophy after his brother was found to be positive for the condition (characteristic clinical picture including patches of chorioretinal atrophy and hyperornithinemia). Examination of the child revealed a best corrected visual acuity (BCVA) of 20/60 in the right eye (OD) and in the left eye (OS). The anterior segment examination was unremarkable. Fundus examination disclosed macular cysts and peripheral chorioretinal atrophic patches characteristic of GA (Figure 1A and C). Laboratory investigations showed hyperornithinemia with an ornithine level of 824 μmol/L, confirming the diagnosis. Optical coherence tomography (OCT) of the macula re­vealed intraretinal cystic spaces (ICS) in both eyes (OU) with a central macular thickness (CMT) of 538 μm OD and 628 μm OS (Figure 2A and B)

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Figure 1.

At presentation, there was evidence of macular cysts (a) and patchy areas of peripheral chorioretinal atrophy (c). Fundus examination following the loss to follow up during the COVID-19 pandemic showed stable chorioretinal atrophy compared to previous visits (b and d).

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Figure 2.

Optical coherence tomography findings on initial presentation demonstrating intraretinal cystic spaces in the macula of the right (a) and left (b) eyes. Following 6 monthly intravitreal bevacizumab injections and 3 months of topical nepafenac and dorzolamide, there was mild reduction in CMT in both eyes (c and d). One year following dietary restriction and vitamin B6 supplementation without additional medications, there was marked reduction in the intraretinal cystic spaces in both eyes, especially for the central macular cyst in the right eye (e) and the outer retinal cysts in the left (f).

The patient was subsequently initiated on an arginine-restricted diet with vitamin B6 supplementation. Over the course of the next 3 months, the patient received monthly intravitreal injections of bevacizumab in both eyes. At the three-month follow-up, his BCVA improved modestly to 20/50 OU. CMT was 522 µm OD and 621 µm OS with persistent ICS. Over the following three months, the patient continued to receive monthly bevacizumab injections to bring his total injections to six monthly injections. Furthermore, treatment was initiated with topical nepafenac and dorzolamide and continued over the same period. The patient also remained on an arginine-restricted diet with vitamin B6 supplementation throughout this period, which resulted in approximately 50% reduction in his plasma ornithine level (to 435 μmol/L). One month following the 6^th bevacizumab injection, his visual acuity was 20/50 OD and 20/40 OS. OCT revealed minimal changes; CMT OD was 518 µm and CMT OS was 555 µm with persistent ICS (Figure 2C and D).

Over the course of the ensuing year, the patient was lost to follow-up due to the coronavirus disease 2019 pandemic. When he returned, his mother reported that he had continued only on diet restriction and vitamin B6 supplementation with no other medications or interventions. His plasma ornithine level at that point was 278 μmol/L and BCVA was 20/50 OU. Fundus examination showed stable chorioretinal atrophy compared to his previous visits (Figure 1B and D). OCT imaging revealed CMT of 357 µm OD and 468 µm OS with significant improvement of ICS OU (Figure 2E and F). Follow-up 3 months later showed continued stabilization of the condition using the same dietary modifications with no other treatments.

Discussion

Several interventions have been reported for the treatment of GA-associated ICS including the use of arginine-restricted diets, vitamin B6 supplementation, IVB, CAIs, and NSAIDs.^4–8 Importantly, all these modalities were used in our patient, but only prolonged dietary modifications gave consistent results. Previously, Kaiser-Kupfer et al. studied a group of 27 patients with gyrate atrophy; of these, 17 (mean age = 13.9 years) followed an arginine-restricted diet and 10 (mean age 14.1) were unable to do so. ⁴ The target plasma ornithine level was below 400−500 μmol/L. Using electroretinogram, combined and flicker responses, and Goldmann kinetic perimetry as outcome measures, that study found that an arginine-restricted diet significantly slowed loss of function in patients. The effect on ICS, however, was not reported. Casalino et al. reported on an eight-year-old boy with GA and failure to thrive who was found to have BCVA of 20/40 OU and the presence of ICS OU. Following three months of an arginine-restricted diet and vitamin B6 supplementation and no other intervention, the patient was found to have resolution of ICS; this anatomical improvement remained at a three-year follow-up. ⁶ Other studies, however, did not show such improvement of ICS with diet. ¹ While there is no definitive evidence that vitamin B6 impacts visual and anatomic outcomes in GA, some studies have suggested that it may decrease levels of ornithine. ⁶

The authors have previously reported on the use of bevacizumab injections for the treatment of ICS in GA. A retrospective review ⁷ of five eyes of three patients (mean age = 11.0 years) with gyrate atrophy and ICS who received three monthly bevacizumab injections found significant improvements in CMT and resolution of ICS in two patients; the patient from that study who did not demonstrate these changes was the same patient described in this report. Importantly, his older brother was treated with monthly bevacizumab injections, arginine-restricted diet, and vitamin B6 supplementation and demonstrated profound improvement within three months.

Previously, CAIs have demonstrated efficacy in management of cystoid macular edema associated with retinitis pigmentosa and uveitis.^9,10 However, evidence for oral CAIs such as acetazolamide tends to be stronger than that of topical CAIs such as dorzolamide. Limited reports exist on the use of topical CAIs for the treatment of ICS associated with gyrate atrophy. Cavdarli et al. reported a case of a 26-year-old man with gyrate atrophy who was treated with only topical brinzolamide and nepafenac with no dietary modification or vitamin supplementation and subsequently demonstrated profound CMT improvements and regression of ICS. It appears that CAIs did not provide significant visual or anatomic benefit to our patient.

Importantly, our six-year-old patient seemingly failed all treatment modalities except for the combination of dietary restriction and vitamin B6 supplementation that led to lowering of his plasma ornithine level. He demonstrated minor fluctuations in visual acuity with mild overall visual or anatomic improvement while on medical and procedural management which may have also been influenced by dietary modifications. However, while on a prolonged regimen of an arginine-restricted diet and vitamin B6 supplementation, he demonstrated significant anatomical improvement with stable vision. Given the link between ornithine levels and the progression of gyrate atrophy, it is unlikely that the patient's clinical and anatomic improvement simply reflects the potential for gyrate atrophy to be a self-resolving condition; indeed, there are no documented cases of this.

To our knowledge, there are no reports in the literature which have documented the use of all of these treatments for ICS in gyrate atrophy. It is unclear why the patient, unlike his older sibling, failed medical and procedural management but demonstrated anatomical improvement with arginine restriction and vitamin B6 supplementation. We propose that patients with gyrate atrophy-associated ICS can have a delayed response to dietary modifications even following failure of other treatment modalities, reaffirming the need to maintain prolonged dietary restriction. Significant gains in visual acuity, however, may not always follow these anatomical improvements. Further research should investigate the temporal course of ornithine levels during these modifications and how they correlate with visual and anatomical improvement.