Paradoxical Exudative Retinopathy and Macular Star Formation After Treatment Initiation in Coats Disease

Abstract

Purpose: This work describes a unique clinical feature in Coats disease. Methods: A retrospective series of 2 cases is reported. Results: Two pediatric patients receiving treatment for Coats disease were included. In both cases, vision worsened secondary to paradoxically increased exudation and macular star formation following standard treatment with intravitreal bevacizumab, sub-Tenon triamcinolone acetonide, and laser photocoagulation. After serial treatments under general anesthesia, the exudates in both cases consolidated. Conclusions: A paradoxical exudative retinopathy can occur in some patients when initiating standard treatment of Coats disease. Longitudinal follow-up with continued intravitreal antivascular endothelial growth factor agents, laser photocoagulation, and corticosteroids might help control persistent exudation in these cases.

Introduction

Coats disease is a rare retinal vascular disease primarily affecting adolescent males and occurring in 0.09 per 100 000 of the population; early diagnosis can help preserve vision. ¹ Disease pathophysiology involves the breakdown of the endothelial layer of the blood–retinal barrier (BRB), which leads to plasma leakage into the vessel wall followed by vessel wall thickening. ² Peripheral telangiectasias develop in response to high vascular endothelial growth factor (VEGF) levels, in a mechanism similar to that in diabetic retinopathy. ² Retinal aneurysms result from proliferation of abnormal pericytes and endothelial cells. ²

The differential diagnosis for Coats can vary based on the stage of disease but includes familial exudative vitreoretinopathy, retinoblastoma, retinitis pigmentosa, retinopathy of prematurity, and branch retinal vein occlusion. ³ Typical clinical features in Coats disease include retinal telangiectasias, intraretinal and subretinal exudates, aneurysms, and hemorrhages.

Treatment options include laser photocoagulation, cryotherapy, intravitreal antivascular endothelial growth factor (anti-VEGF) agents, and triamcinolone acetonide.^{2,4 -6} Similar treatment modalities are used to target telangiectatic vessels that contribute to exudation in other conditions that have comparable disease processes, such as familial exudative vitreoretinopathy, incontinentia pigmenti, diabetic retinopathy, and other exudative retinopathies. ⁷ If untreated, Coats disease can result in vision-threatening complications, including neovascular glaucoma or an irreparable retinal detachment, requiring enucleation. ¹

We report 2 cases in which patients with Coats disease developed worsening vision secondary to a paradoxical exudative retinopathy and macular star formation following standard treatment of Coats disease. To our knowledge, this is the first report of a macular star developing after the initiation of treatment in Coats disease.

Methods

A retrospective chart review of 2 clinical cases was conducted, in compliance with the tenants of the Declaration of Helsinki.

Results

Case Report

Case 1

A 4-year-old boy with a medical history of spina bifida presented with a 2-day history of vision loss in the right eye. The visual acuity (VA) was 20/40 in the right eye (OD) and 20/30 in the left eye (OS). The intraocular pressure (IOP) was 17 mm Hg in the right eye and 12 mm Hg in the left eye. Examination under anesthesia (EUA) revealed peripheral retinal exudation with dilated and telangiectatic vessels in the right eye. The left eye examination was normal. Fluorescein angiography (FA) (RetCam, Clarity Medical Systems) revealed telangiectasias with avascularity peripherally and late leakage in the right eye. No macular edema was present on optical coherence tomography (OCT) (Heidelberg Spectralis, Heidelberg Engineering) (Figures 1A and 3A). The patient was treated with intravitreal bevacizumab 1.25 mg/0.05 mL (Avastin, Genentech) and peripheral diode laser photocoagulation to telangiectatic vessels and areas of nonperfusion.

Figure 1.

Fundus photograph (A and B: RetCam3; C: Optos), top panel. Optical coherence tomography (A to C: Heidelberg Spectralis), bottom panel. A 4-year-old patient with Coats disease (A) at presentation with no baseline macular edema, and (B) at 3 months with increased exudation in a macular star configuration after first round of laser photocoagulation and intravitreal bevacizumab. (C) There was resolution of macular edema at the 14-month follow-up.

Figure 3.

Fundus and fluorescein angiography (FA) montages (RetCam3) of a 4-year-old patient with Coats disease (Case 1) (A) at the beginning of the treatment sequence and (B) 14 months later at the end of the sequence. Fundus and FA montages of an 18-month-old Coats disease patient (Case 2) (C) at the beginning of the initial treatment sequence and (D) 11 months after the initial treatment sequence.

Three months later, the VA in the right eye declined to 4/200 with a +4.00 diopter trial frame. The VA in the left eye remained 20/20. The IOP remained normal bilaterally. EUA revealed the development of a macular star in the right eye. An intraoperative OCT scan (Heidelberg Spectralis) showed new intraretinal exudates at the level of the outer plexiform layer and intraretinal fluid (Figure 1B). FA (RetCam, Clarity Medical Systems) showed persistent peripheral nonperfusion and vascular leakage. The patient was treated with intravitreal bevacizumab, sub-Tenon triamcinolone acetonide, and laser photocoagulation followed by repeated treatments performed under EUA every 6 weeks for a total of 8 EUAs. Final vision was 20/300 and the macular edema had fully resolved after 14 months, with macular fibrosis limiting visual recovery (Figures 1C and 3B).

Case 2

An 18-month-old boy with congenital heart disease was referred to the clinic for management of Coats disease in the left eye (Figures 2A and 3C). The patient underwent 5 EUAs over a period of 6 months with intravitreal bevacizumab (1.25 mg/0.05 mL) and peripheral diode laser photocoagulation in the left eye. Two months after the initial treatment, the patient developed massive macular exudation (Figure 2B). After 2 treatments over the course of 3 months, increased extensive yellow exudates in a macular star configuration were seen (Figure 2C) and an additional treatment of intravitreal bevacizumab and peripheral diode laser was performed. The following month, there was resolution of the macular star with improved subretinal fluid (Figure 2D). The exudates consolidated 6 months after initial treatment, leaving fibrotic nodules in the macula (Figure 2E) and remained stable at the 11-month follow-up (Figure 3D).

Figure 2.

Fundus photograph (A to E: RetCam3), left panel. Optical coherence tomography (A to E: Heidelberg Spectralis), right panel. An 18-month-old boy with Coats disease showing paradoxically increased exudates in a macular star formation and progressive submacular fibrosis (A) at presentation and (B) 2 months, (C) 3 months, (D) 4 months, and (E) 6 months after initial treatment. Laser photocoagulation and intravitreal bevacizumab was administered at each time point other than at 2 months, during which only intravitreal bevacizumab was administered.

Discussion

Standard treatment targeting culprit telangiectatic vessels using laser photocoagulation and intravitreal bevacizumab were used in the 2 cases of Coats disease presented herein. In general anti-VEGF agents reduce disease burden caused by increased VEGF levels and are expected to result in improved exudative retinopathy associated with Coats disease. ⁴ Ong et al ⁸ reported that VA outcomes in the era of anti-VEGF therapy were better than in the previous period, presumably due to its beneficial effect on exudation. Nonetheless, Coats disease is inherently a progressive condition requiring long-term monitoring and treatment. Chiu et al ⁹ described worsening exudation at a median follow-up of 3 months (range, 1.6-15.1 months) in 53% of 30 patients receiving primary treatment for Coats disease. Most patients requiring retreatment had a favorable anatomic outcome by the end of the study period (median 3.8 years).

Of interest was the formation of a macular star in response to management in our series. To our knowledge, this has not been previously described in the literature as it pertains to the treatment of Coats disease. Exudation in this pattern develops because of lipid deposition within the outer plexiform layer and is seen in conditions such as neuroretinitis, hypertensive retinopathy, and papilledema. ¹⁰ Macular star formation is a multifactorial process in which vascular damage to the peripapillary retina results in a compromised BRB. ¹¹ An exudative retinopathy has been described following conventional laser photocoagulation in patients with retinopathy of prematurity due to potential damage to the BRB from the laser. ¹² Similarly, necrosis and inflammation caused by cryotherapy is known to lead to increased subretinal exudation, retinal holes, and retinal detachment. ⁴

It is plausible that the paradoxical worsening of macular exudation in our series can be ascribed to the inflammation caused by extended, high-energy laser therapy in the setting of an already compromised BRB related to Coats disease. ² In support of this theory, Kumar and Kumar ¹³ proposed that inflammation related to laser treatment in a case of adult-onset Coats disease contributed to epiretinal membrane formation. An alternative hypothesis for the paradoxical exudative retinopathy in our cases is a vasodilatory response to lipid exudates and inflammatory mediators released from the regressed or ablated vascular abnormalities. Kan et al ¹⁴ theorized that the exudative retinopathy associated with Coats-like retinitis pigmentosa is attributed to toxic products of the photoreceptors and retinal pigment epithelium. Finally, it is possible that the efficacy of the selected anti-VEGF agent was not sufficiently robust in neutralizing circulating intraocular VEGF levels. Patel et al ⁶ reported a similar case in which intravitreal brolucizumab led to effective resolution of macular exudation in a case of Coats disease that was refractory to bevacizumab injections.

Conclusions

Our findings support that intravitreal bevacizumab, laser ablation, and adjunctive sub-Tenon triamcinolone acetonide administered at regular intervals might be sufficient for treating the paradoxical macular exudation in Coats disease described here. The final VA appeared to correlate with the degree of submacular fibrosis once the exudative reaction had resolved. Hard exudates have been shown to reduce pattern retinal sensitivity and might have played a role in the diminished visual outcomes. ¹⁵

Finally, we show that a critical component of Coats disease management is using multimodal imaging during serial EUAs.^16,17 It is possible that smaller treatments with laser photocoagulation across multiple sessions will be necessary to mitigate the formation of a macular star in select cases. Further large-scale comparative studies are needed to determine the risk factors for paradoxical macular star formation when initiating treatment for Coats disease. These factors might include the degree of peripheral nonperfusion at baseline, location of telangiectasias, supine positioning, and predisposing genetic variants.