Central serous chorioretinopathy in uveitis patients after corticosteroid therapy: a report of 6 cases

Purpose. To report central serous chorioretinopathy (CSCR) in uveitis patients.Material and methods. A retrospective chart review of uveitis patients seen in a time frame of 20 years at the Centre for Ophthalmic Specialised Care, Lausanne, Switzerland. The ophthalmic and systemic features are presented.Results. Out of 1793 uveitis patients followed at the Centre for Ophthalmic Specialised Care, 6 patients (0.3%) developed CSСR following corticosteroid therapy due to uveitis. The mean age of patients was 40 ± 13.4 years, disease incidence was not associated with gender. In all 6 patients’ clinical disease was unilateral but subclinical signs were present in all fellow eyes. The mean duration of corticosteroid therapy before CSCR had occurred was 4.95 ± 4.0 months. The mean best-corrected visual acuity at the moment of CSCR was 0.6 ± 0.26 and 0.8 ± 0.17 after discontinuation of corticosteroids. Neurosensory retinal detachment and pigment epithelium detachment were observed in 3 eyes, respectively. During fluorescein angiography (FA), focal dye leakage and areas of alteration of RPE were observed in 6 out of 10 eyes. Diffuse hyperfluorescence of choroidal vessels observed by ICGA was detected in all eyes.Conclusion. Central serous chorioretinopathy should be suspected when functional and morphological deterioration occurs in uveitis patients receiving corticosteroid therapy with no signs of inflammation reactivation. This complication is extremely rare but serious condition which needs a prompt tapering and discontinuing of corticosteroids.

Central serous chorioretinopathy (CRSC) was initially described in 1866 by Albrecht von Graefe who called the disease "recurrent central retinitis" [1]. Takashi Masuda examined 192 cases and gave the name of "central serous chorioretinitis" to the disease in 1917 [2]. CSCR is one of the causes of vision loss in middle-aged predominantly male patients. The disease is characterized by the detachment of neurosensory retina (NSRD) with or without pigment epithelial detachment (PED).
Fluorescein angiography (FA) usually reveals leakage sites, demonstrating "ink-plot" or "smokestack" pattern of hyperfluorescent diffusion in acute CSCR. Multiple leakage sites, retinal pigment epithelium (RPE) atrophy, and diffuse epitheliopathy are observed in chronic cases. Indocyanine green angiography (ICGA) findings comprise increased choroidal permeability which is manifested by areas of hyperfluorescence from the mid-phase of the angiogram on and diffuse late choroidal hyperfluorescence [3]. Optical coherence tomography (OCT) signs include subretinal fluid (neurosensory retinal detachment (NSRD), PED, and disturbances of RPE in chronic cases [4].
The aetiology of CSCR remains uncertain despite the numerous studies which have been published since 1866. The recent systematic review and meta-analysis have revealed several CRCS risk factors including systemic hypertension, steroid usage, sleep disturbance, autoimmune disease, psychopharmacologic medication use, and type-A behavior [5].
One theory considers a dysfunction of the RPE ion pump as a major reason of CSCR development leading to a reverse of fluid movement from the choroid to the retina [6].
However, more recently, CSCR has been included in the newly named group of pachychoroidal diseases [7]. The pathogenesis is thought to be triggered by cortisol and aldosterone which affect the autoregulation of the choroidal vasculature. S. Kuroda, et al. reported a diffusely thickened choroid in CSCR patients [8], while Y. Chung, et al. reported an increased Haller layer both in the affected eye and the unaffected fellow eye of CSCR patients [9]. Similar changes were noted by R. Agrawal et al., who showed that the choroidal vascularity index was higher in eyes with acute CSCR in comparison to healthy eyes and resolved CSCR eyes [10]. These findings strongly suggest that both choroidal vascular dilatation and hyperpermeability play a crucial role in the development of CSCR [11]. Hyperpermeable choroidal vessels are presumed to increase hydrostatic pressure in the choroid leading to the barrier dysfunction of the RPE and fluid accumulation between the RPE and the retina [3,11].
High endogenous serum cortisol levels [12] or corticosteroid administration in any form, systemic or topical on skin or on oral, nasal and conjunctival mucosae, are two important promoters of CSCR, as shown in numerous studies [13][14][15][16][17][18][19]. A relation was found between high cortisol levels in Cushing's syndrome and thickening of the choroid and between intravitreal dexamethasone and pachychoroid and CSCR development [20,21], indicating that the role played by corticosteroids in the development of CSCR was through choroidal thickening.
Diagnosis of corticosteroid induced CSCR is relatively straightforward but gets a little trickier when it occurs in uveitis cases receiving systemic corticosteroid therapy.
The AIM of this study was to report a series of uveitis patients that developed CSCR.

MATERIAL AND METHODS
Medical charts of patients treated for uveitis and presenting CSCR were retrieved for retrospective analysis. Patients had had a complete work-up applied to patients with uveitis, comprising, in addition to routine features such as Snellen visual acuity, slit-lamp examination, applanation tonometry, and fundoscopy, laser flare photometry (LFP), computerized visual field (VF) testing, OCT, and dual FA and ICGA. The study was performed in accordance with the ethical standards laid down in the Declaration of Helsinki (1964) and in accordance with the IRB of our institution authorizing retrospective, anonymous and non-interventional studies.

RESULTS
Out of 1793 uveitis patients followed at the Centre for Ophthalmic Specialised Care during a period of twenty years, 6 patients (0.3%) developed CSСR under treatment. All of them had corticosteroids in their therapeutic regimen. The mean age (range) of patients (3 men/3 women) was 40 ± 13.4 (17-57) years. The mean duration of corticosteroid therapy before CSCR had occurred was 4.95 ± 4.0 months. The mean best-corrected visual acuity (BCVA) at the moment of CSCR diagnosis was 0.6 ± 0.26, whereas it was 0.8 ± 0.17 at last follow-up (p = 0.05, Student's t test). Patients demographics and clinical data are presented in Table 1.
Mean LFP values were 44.7 ± 91.4 ph/ms showing medium inflammation (normal value of 4-6 ph/ms). OCT which was available in 4 patients (8 eyes) revealed NSRD in 3 eyes and small PEDs in 3 eyes as well. Concomitant NSRD and PED were observed in 1 eye. In 6 out of 10 eyes, focal dye leakage and areas of alteration of RPE were observed on FA. ICGA revealed diffuse hyperfluorescence of choroidal vessels in 10 out of 10 eyes (Table 2).
Three cases are briefly reported here.
Case 1 (patient 1 on Table 1). A 43-year-old Caucasian man with the diagnosis of birdshot retinochoroiditis (BRC) was given oral prednisone (1 mg/kg) and cyclosporine A (5 mg/kg) 2 years after the diagnosis because of worsening of the inflammatory eye condition. The diagnosis was based on the presence of papillitis, diffuse retinal vasculitis, pseudo-delay in retinal FA arteriovenous circulation time, massive fluorescein impregnation of the retina, and cystoid macular oedema. On ICGA multifocal dark dots present in the intermediate and late ICGA phases as well as fuzziness of choroidal vessels seen during the intermediate and late phases of ICGA were typical of BRC. The HLA-A29 antigen was present. For 2 years, the patient's condition had remained relatively пигментного эпителия. Во всех глазах отмечена диффузная гиперфлюоресценция хориоидальных сосудов, выявленная с помощью ангиографии с индоцианином зеленым. Заключение. При функциональном и морфологическом ухудшении у пациентов с увеитом, получающих кортикостероидную терапию, без признаков реактивации воспаления следует подозревать ЦСХР. Это крайне редкое, но серьезное осложнение, требующее незамедлительного снижения дозы и отмены кортикостероидов. Ключевые слова: увеит; лечение; серозная хориоретинопатия; кортикостероиды Конфликт интересов: отсутствует. Прозрачность финансовой деятельности: никто из авторов не имеет финансовой заинтересованности в представленных материалах или методах. Для цитирования: Скворцова Н.А., Папасаввас И., Херборт К.П. Центральная серозная хориоретинопатия у пациентов с увеитом после кортикостероидной терапии: шесть клинических случаев. Российский офтальмологический журнал. 2021; 14 (3): 65-72. https://doi.org/10.21516/2072-0076-2021-14-3-65-72 stable without treatment, BCVA remaining at 1.0 for both eyes, and laser flare photometry not detecting a subclinical anterior chamber inflammation. Both eyes had a slight vitritis and their fundus showed scattered, punched-out creamy lesions. At the moment of  corticosteroid and immunosuppressive therapy administration, the BCVA of the left eye was 0.8 with an anterior chamber inflammation having increased (laser flare photometry for OS = 15.1 ph/ms but normal values for OD (5.1 ph/ms), and visual field deterioration was noted in both eyes. After 10 weeks of systemic treatment, BCVA in both eyes was again 1.0 and LFP decreased to 5.4 ph/ms in the left eye. However, a few months later the patient presented a decrease of vision to 0.4 in the left eye with inflammatory parameters under control on both sides. FA revealed a hyperfluorescent leaking point and ICGA showed a focal brightly hyperfluorescent spot that corresponded to the leakage area on FAG (Fig. 1). All these findings were compatible with CSRC. Therefore, prednisone was progressively tapered with improvement of visual acuity to 0.7 in the left eye. It is interesting to note that hyperpermeable (hyperfluorescent) choroidal vessels were already present on ICGA before corticosteroid administration. As explained hereunder uveitis entities with predominant choroidal inflammation are more prone to secondary CSCR. Case 2 (patient 3 on table 1). A 47-yearold Caucasian man presented with photophobia and vision loss in the right eye. BCVA was 0.2 for the right eye, while BCVA was 0.8 for the left. LFP revealed anterior chamber inflammation (LPF OD: 49.4 ph/ms, OS: 21.2 ph/ms). Vitritis, snowballs, retinal scars, and cystoid macular oedema were observed in the right eye. Mantoux -test showed a hyper-reaction with a skin papule size of 12 11 mm. The diagnosis of presumed tuberculous (TB)related uveitis was posed. After administration of triple anti-TB therapy and oral prednisone (30 mg), BCVA improved to 1.0 in both eyes in 10 days. Five weeks later, the patient presented with a decreased BCVA to 0.6 (OD), while anterior chamber inflammation had substantially decreased (LFP RE: 18.1 ph/ms, LE: 9.3 ph/ms) under 20 mg of prednisone. The condition was interpreted as a recurrence of the inflammatory process and dosage of prednisone was raised up to 50 mg. 5 days later, the patient's condition did not change but laser flare photometry decreased slightly (16.0 ph/ms on the right eye). NSRD and PED were noted. Central serous chorioretinopathy was diagnosed and steroid treatment was discontinued. 6 months later, on the last followup, no signs of active inflammation were seen, BCVA was 1.0 on the right eye, and LFP remained stable at 21.7 ph/ms. LFP was very helpful to precisely follow intraocular inflammation and to avoid incriminating an increase in inflammation for a decrease in function caused by CSCR (Fig. 2, 3).
Case 3 (patient 5 on table 1). Inflammatory disorder had started with right-side episcleritis, myositis, scleritis, which was well controlled with local treatment in a 41-year-old Caucasian female. 4 years later scleritis had developed on the left side, and systemic corticosteroid treatment was administered. The following year, under the dose of 10 mg prednisone and methotrexate, uveitis developed on the left side. Immunosuppressive treatment was intensified (32 mg of prednisone with slow tapering plus 200 mg of azathioprine). 6 months later, the patient presented with vision deterioration in the right eye (under 24 mg of prednisone). BCVA was 0.2 for the right eye and 0.5 for the left eye, respectively. PED in the left eye (Fig. 4) was detected by FA and OCT suggestive of CSCR. Corticosteroid therapy was stopped (following tapering during 3 months), anti-TNF-alpha therapy (Infliximab) was administered. 9 months later, the treatment regimen was azathioprine 200 mg/day, Infliximab every 6 weeks. At the last follow-up after cataract surgery, BCVA was 0.6 for the right eye and 0.5 for the left eye. LFP was 6.5 ph/ms for OD and 6.7 ph/ms for OS, respectively. OCT did not reveal NSRD nor PED in the right eye and FA did not reveal signs of papillitis nor vasculitis.

DISCUSSION
Glucocorticosteroid therapy remains the first-line treatment for the majority of ocular inflammatory diseases including uveitis. Use of systemic and local corticosteroids can be involved in CSCR development. However, reports on CSCR in posterior uveitis patients receiving corticosteroid therapy are limited [22][23][24]25]. In our collective of 1793 cases of uveitis patients seen in our centre, 6 uveitis cases (0.3 %) treated with systemic corticosteroids developed CSCR. While CSCR development in autoimmune diseases has been reported often [15,26], occurrence of CSCR in corticosteroid treated uveitis patients tends to be rare. In three of our six cases, inflammation involved the choroid. Predilection of CSCR for choroiditis entities has been reported previously [25].
CSCR that develops in patients with uveitis represents a particular situation. Its diagnosis can be challenging as it may be confused with worsening of the pre-existing uveitis [24]. This is what occurred in case 2 of our series, leading to intensifying the corticosteroid treatment with exacerbation of CSCR as a consequence. Combining FA, ICGA, and OCT contributes substan-tially to the diagnosis of CSCR during corticosteroid treatment of inflammatory eye diseases.
Laser flare photometry is another crucial investigation as it measures exactly intraocular inflammation and can so precisely exclude an inflammatory reactivation [30].
There may be similarities between acute initial-onset Vogt -Koyanagi -Harada disease and bilateral CSCR. However, the ICGA and OCT patterns differ sufficiently to differentiate the diseases [31,32].
The management of corticosteroid induced CSCR in posterior uveitis consists in diligent tapering of corticosteroid therapy and discontinuation associated with replacement by other immunosuppressive or immunomodulatory therapies [33]. If this is not sufficient, mineralocorticoid antagonists may be used as for idiopathic CSRC [34]. Indeed, glucocorticosteroid and mineralocorticoid receptors were shown to be co-expressed in the choroid and retina [35]. In our series we did not have to resort to mineralocorticoid antagonists, probably because the trigger of CSCR occurred through the glucocorticoid receptors or through a weaker stimulation of mineralocorticoid receptors by glucocorticoids so that discontinuation of glucocorticosteroids was sufficient [36].

CONCLUSION
Though the rate of CSCR among uveitis patients treated with corticosteroid therapy is rare, misinterpretation of CSCR as worsening of the uveitis is the pitfall to avoid. Indeed, this could lead to the vicious circle of increasing corticosteroids with its harmful consequences. Careful assessment of fundus appearance, laser-flare photometry, FA, ICGA, and OCT enable the clinician not to miss signs of CSCR. This disease should be borne in mind when vision deterioration occurs in uveitis patients under corticosteroid therapy with no signs of reactivating inflammation. It should lead the clinician to tapering and discontinuation of corticosteroids with replacement by other immunosuppressive agents, if necessary. (a) ФАГ показала картину гиперфлуоресцентной диффузии в виде «дымовой трубы» на правом глазу, (b) ФАГ выявила точку просачивания красителя в левом глазу, (c) на ОКТ видна отслойка нейросенсорной сетчатки с нарушением РПЭ (небольшие отслойки) в правом глазу, (d) на ОКТ видна небольшая отслойка пигментного эпителия в левом глазу