Multimodal imaging of refractory Candida chorioretinitis progressing to endogenous endophthalmitis

Introduction

Endogenous fungal endophthalmitis is a serious vision-threatening condition. In the
United States, yeasts are the most common causative organism, accounting for 75 %
of cases 1]. Among yeasts, Candida albicans is the most common pathogen 1]. In 14 % of patients with Candidemia, ocular complications occur 2]. The majority of these patients develop chorioretinitis with 1.6 % of patients advancing
to endophthalmitis 2]. In patients with yeast endophthalmitis, visual acuity outcomes can be poor with
only 56 % of eyes achieving vision of 20/200 or better 1].

This case report describes the clinical course of a patient with C. albicans chorioretinitis that progressed to recalcitrant endophthalmitis. Using multimodal
imaging, we chronicle the features of chorioretinitis through multiple medical and
surgical therapies.

Case Report

A 48-year-old male presented with blurred central vision in his right eye. Past ocular
history included bilateral pseudophakia. Medical history was significant for a 4-year
history of rheumatoid arthritis on oral prednisone 15 mg daily and a recent history
of nephrolithiasis. One month prior to presentation, his nephrolithiasis was treated
with extracorporeal shock wave lithotripsy and ureteral stent placement. One week
after lithotripsy, urine cultures grew C. albicans and the patient started oral fluconazole 300 mg daily. For 3 weeks, the patient complained
of blurred central vision in the right eye without redness or floaters.

On examination, visual acuity was 20/100 OD and 20/20 OS. Pupils, intraocular pressures,
and visual fields were normal. The anterior segment showed bilateral pseudophakia
with no inflammation. Posterior segment exam demonstrated clear media without vitritis
and a white, elevated foveal infiltrate (half disk diameter) with indiscrete borders
(Fig. 1a). Fluorescein angiography (FA) displayed an early hyperfluorescent lesion with late
staining (Fig. 1b, c). In the context of his Candiduria, a diagnosis of Candida chorioretinitis was made and his fluconazole was increased to 600 mg/day. The following
day, the ureteral stent was removed without catheterization and blood cultures grew
C. albicans. Although an infectious disease consult was requested on the day of presentation,
the patient was seen 1 week later, and the fluconazole dose was increased to 800 mg
daily.

Fig. 1. Initial appearance of the chorioretinitis. Color fundus photograph (a) showing the white, elevated, and fluffy chorioretinal lesion. Early (b) and late (c) phases of the FA demonstrating early hyperfluorescence and late staining. Color fundus
photography 2 weeks later displaying significant vitritis that obscures retinal detail
(d)

The patient was lost to follow-up and presented 2 weeks later with new floaters OD.
On examination, visual acuity remained 20/100 OD, the anterior segment was unchanged,
and the posterior segment displayed vitritis with a fluffy chorioretinal lesion (Fig. 1d). Candida endophthalmitis was diagnosed, the patient received a same-day intravitreal injection
of amphotericin B (5 ?g/0.1 mL) and was placed on intravenous amphotericin B (0.1 mg/mL).
The patient developed acute kidney injury (AKI) 1 week after initiation of treatment,
requiring discontinuation of amphotericin B and resumption of fluconazole. At this
time, blood cultures were negative for C. albicans.

One week after intravitreal amphotericin B, there was improvement in the fluffy appearance
of the macular lesion. Spectral domain optical coherence tomography (SD-OCT) demonstrated
an elevated, hyperreflective foveal lesion at the vitreoretinal inferface that appeared
to be emanating from the retinal pigment epithelium (RPE), with obscuration of the
retinal layers (Fig. 2a). The patient received three intravitreal voriconazole injections (100 ?g/0.1 mL)
and was placed on systemic voriconazole (200 mg twice daily) therapy. After 2 months,
the lesion flattened and developed well-demarcated borders but vitritis persisted.
SD-OCT displayed an improving but still elevated hyperreflective lesion now localized
at the nerve fiber layer with persistent focal discontinuity of the RPE (Fig. 2b). At its borders, the inner retinal architecture showed improved definition, but
the outer retinal layers displayed atrophy with increased transmission defect. Due
to the persistent vitreous infiltrates, the patient underwent pars plana vitrectomy
(PPV). The postsurgical SD-OCT showed continued regression of the elevated, hyperreflective
lesion (Fig. 2c). The borders demonstrated preserved inner retinal layers with atrophy of the outer
retina and choroidal hyperreflectivity from transmission defect. The patient continued
systemic voriconazole for an additional month without further intravitreal therapy.

Fig. 2. Regression of the chorioretinal lesion. SD-OCT imaging performed 1 week after intravitreal
amphotericin B treatment (a), 2 months after three intravitreal voriconazole injections (b), and after PPV (c). The inner retinal hyperreflective lesion regresses with time. At its borders, the
RPE is elevated and discontinuous with loss of outer plexiform, outer nuclear, external
limiting membrane, IS/OS, and RPE. Inner retinal tissues are preserved and subretinal
scar is present

Final multimodal imaging displayed a foveal scar (Fig. 3a). On fundus autofluorescence (FAF), the scar is hypofluorescent consistent with RPE
loss (Fig. 3b). On SD-OCT, the outer retina is atrophic, the RPE layer is absent, a subretinal
scar underlies the inner retinal layers, and a postinflammatory epiretinal membrane
(ERM) co-exists (Fig. 3c). The photoreceptor loss and RPE atrophy primarily caused a final visual acuity of
20/100 OD.

Fig. 3. Final appearance of the chorioretinal lesion. Color fundus photography (a), FAF (b), and SD-OCT (c) were performed 2 months after PPV. A subfoveal scar is present (a) with destruction of outer plexiform, outer nuclear, external limiting membrane, IS/OS,
and RPE (c). The inner retinal layers, however, are preserved (c). The FAF shows loss of autofluorsescence corresponding to RPE destruction (b)

Discussion

We present a complicated case of C. albicans chorioretinitis that progressed to endogenous endophthalmitis, requiring multiple
local and systemic antifungal medications and PPV. Risk factors for endogenous yeast
endophthalmitis include hospitalization, surgery, cancer, diabetes, intravenous drug
use, and indwelling catheters 1]. Risk factors for this particular case include recent lithotripsy of renal calculi
and immunosuppression from prednisone therapy 3]. It is common for lithotripsy to cause asymptomatic Candiduria; in this immunocompromised
patient, the Candiduria likely caused Candidemia, leading to chorioretinitis. In a
prospective, multicenter study of 11 patients with chorioretinitis, none progressed
to endophthalmitis 4]. Although limited by a small number of patients, this study suggests that our patient
had been initially underdosed with fluconazole 300 mg daily. Once Candida endophthalmitis developed, our patient received both intravitreal and systemic amphotericin
B. However, therapy was changed to oral and intravitreal voriconazole after AKI from
amphotericin B. Voriconazole is effective against fluconazole-resistant C. albicans strains and has excellent ocular penetration 5]. It has been shown that Candida species preferentially infect the vitreous and form loculated microabscesses, which
may ultimately require vitrectomy for clearance 6]. In the case of our patient, despite stabilization of the infection with aggressive
systemic and intravitreal antifungal management, PPV was required to decrease the
fungal load.

To our knowledge, this is the first report using FA, SD-OCT, and FAF to follow a case
of Candida chorioretinitis progressing to endophthalmitis. Our patient initially presented with
a white, elevated chorioretinal lesion (Fig. 1a). FA displayed a foveal lesion with early hyperfluorescence and late staining (Fig. 1b, c), consistent with prior reports of Candida chorioretinitis 7]. The lack of late leakage rules out choroidal neovascularization (CNV). However,
the presence of vascular leakage near the lesion does not exclude Candida chorioretinitis as the cause of the macular lesion, as this angiogram pattern has
been documented 8].

SD-OCT and FAF imaging help the clinician determine the route of infectious seeding,
the etiology and treatment options, and the prognosis for visual recovery. SD-OCT
findings early in the course of treatment demonstrated an elevated, hyperreflective
lesion at the retina-vitreous interface with poorly defined borders and obscured underlying
retinal detail (Fig. 2a). At the edge of the lesion, elevation of the RPE suggests that the lesion originated
in the choroid. We suspect that this lesion is a focus of inflammatory and infectious
material that locally infiltrated the macula. As the lesion was treated, the inner
retinal hyperreflective lesion regressed but the borders demonstrated a persistently
elevated, discontinuous RPE (Fig. 2b, c). These characteristics suggest that the Candida infection progressed via choroidal infiltration through Bruch’s membrane and RPE,
into the retina and the vitreous. We hypothesize that this seeding is secondary to
spread through the short posterior ciliary artery rather than through the central
retinal artery 9],10] because of the initial presentation as an indolent chorioretinitis instead of an
explosive endophthalmitis. Cho et al. previously evaluated Candida chorioretinitis with SD-OCT, demonstrating RPE elevation and outer retinal destruction
in early, active lesions and inner retinal hyperreflective elevation with blockage
in late, inactive lesions 11]. Our lesion showed SD-OCT characteristics of both early, active and late, inactive
chorioretinitis stages as it evolved during the clinical course. We hypothesize that
clinically and through multimodal imaging, our lesion demonstrated active features,
especially given its pronounced hyperfluorescence on FA and its regression with treatment.

Vision loss in our patient occurred primarily due to photoreceptor loss and scarring.
SD-OCT showed loss of outer plexiform, outer nuclear, external limiting membrane,
and inner segment/outer segment (IS/OS) layers, and an area of thickened and hyperreflective
subretinal scar tissue (Fig. 3c). FAF displayed lack of fluorescence centrally, indicating RPE destruction and confirming
the presence of scar tissue (Fig. 3b). Not including the ring of hypofluorescent peripapillary atrophy, the scar is one
disk diameter, which is twice the initial infiltrate. Thus, our imaging demonstrates
centrifugal scar expansion and photoreceptor loss as the primary causes for vision
loss. In other reports, vision loss occurred in the presence of macular edema 12],13], a clinical finding absent in this case.

Our patient remains at risk for further vision loss from potential CNV. FAF and SD-OCT
imaging (Fig. 3) showed inflammatory and infectious destruction of Bruch’s membrane and RPE destruction,
creating a locus for potential development of CNV. We suspect that once the integrity
of the RPE layer has been violated, there is endophytic spread of the infection into
the retina and vitreous, which increases the risk of further visual loss and the chance
of requiring surgery. We emphasize that both SD-OCT and FAF highlight findings that
were only previously demonstrable on histopathology. More importantly, they serve
as non-invasive and readily available tools for monitoring progression and for informing
the clinician regarding the effectiveness of various treatment modalities and prognosis
for visual recovery.