Coexisting choroidal neovascularization and active retinochoroiditis—an uncommon presentation of ocular toxoplasmosis

Background

Necrotizing retinochoroiditis caused by an obligate intracellular parasite, Toxoplasma gondii, is a common inflammatory lesion of the fundus accounting for up to 70 % of cases
with retinochoroiditis 1], 2]. By virtue of high affinity for neural tissue and retinal ganglion cells 3], the T. gondii localizes in retina and causes recurring ocular inflammation. Focal necrotizing retinitis
adjacent to old retinochoroidal scar is the characteristic lesion in ocular toxoplasmosis.
The diagnosis of ocular toxoplasmosis can be made on the basis of clinical findings
alone 3]. In the year 1969, Freidman and Knox 4] described the following three clinical presentations of active toxoplasmic retinochoroiditis
(which occurs due to inflammatory response to activation of congenital toxoplasmosis
5]):

1) Large destructive active retinitis with associated vitritis (most common);

2) Punctate inner areas of retinitis with minimal associated edema and vitreous reaction;

3) Deep retinal punctate lesions with subretinal exudate (most unusual) associated
with a minimal amount of vitreous reaction and with turbid subretinal fluid or blood.

When these lesions heal, they lead to scars with an atrophic, “punched out” appearance
and variable pigmentary changes. The various reported late complications include secondary
glaucoma, retinochoroidal vascular anastomosis, capillary non-perfusion, branch retinal
artery and vein occlusion, choroidal neovascularization, cystoid macular edema, and
optic atrophy 6]. Choroidal neovascularization (CNV) developing at the margins of the healed Toxoplasma scar lesion is an important cause of vision loss in young patients with maculopathy
2]. The prevalence of choroidal neovascular membrane (CNVM) in toxoplasmosis cases is
reported to be 2–19 % 7], 8] during the late stage of the disease 9], 10]. CNV has been well reported to occur during the stage of healed toxoplasmosis 2], 9]. However, CNVM coexisting with active retinochoroiditis is uncommon. We report the
clinical presentation and management of three such patients.

Case 1

A 15-year-old male patient presented with sudden onset blurring of vision in his right
eye for 2 days and in the left eye for 2 years. His visual acuity at presentation
in the right eye was 20/50, N18, and in the left eye 9/200, N36. Anterior segment
findings were unremarkable. The right eye showed 1+ vitreous cells and a yellow-white
active retinitis lesion (approximately 1 disc diameter, infero-temporal to fovea)
adjacent to an old pigmented scar, a portion of which is embedded in the active lesion
(Fig. 1). Coexisting subretinal hemorrhage was present at and inferior to the fovea along
with macular thickening and subretinal fluid at the posterior pole. The left eye fundus
showed disc pallor and a large (approximately 1.5 disc diameter in size), punched
out, hyperpigmented scar at the macula. Fundus fluorescein angiography (FFA) and optical
coherence tomography (OCT) (Fig. 1) confirmed the presence of a coexisting active lesion with classic choroidal neovascular
membrane in the right eye. A diagnosis of recurrent Toxoplasma retinochoroiditis with active CNVM in the right eye and a healed Toxoplasma scar in the left eye was made. He was treated with an intravitreal injection of
anti-vascular endothelial growth factor (anti-VEGF) (bevacizumab) along with oral
anti-parasitic medication (320 mg trimethoprim and 1600 mg sulfamethoxazole—i.e.,
cotrimoxazole twice a day) along with anti-inflammatory medication (oral prednisone
60 mg/day). The visual acuity started improving within 1 week (right eye visual acuity—20/25
at 1 week with reduced subretinal fluid at macula). Cotrimoxazole was continued, and
a dose of oral prednisolone was tapered over 1 month to 10 mg/day. Oral steroids were
gradually tapered off while cotrimoxazole was discontinued after 2 weeks. At 20 weeks,
the visual acuity was 20/20 with healing and scarring of the chorioretinal lesion
(Fig. 1).

Fig. 1. At presentation—a Color fundus photo of the right eye of case 1 shows a yellow-white active retinitis
lesion (approximately 1 disc diameter, infero-temporal to fovea) adjacent to an old
pigmented scar, a part of which is embedded in the active lesion. Coexisting subretinal
hemorrhage was present at and inferior to the fovea along with macular thickening
and subretinal fluid at the posterior pole. b Optical coherence tomography scan (horizontal) over the lesion shows an elevated foveal contour with increased retinal thickness,
hyper-reflectivity, and pockets of subretinal fluid. At 20 weeks of follow up—c Color fundus picture shows healed, pigmented, and scarred lesion infero-temporal
to fovea and d OCT scan over the lesion shows reduced retinal thickness, distorted architecture
of retinal layers temporal to the fovea, reduced amount of subretinal fluid, and relative
restoration of the foveal contour

Case 2

A 51-year-old female patient presented with diminution of vision in the right eye
for 7 months. Visual acuity at presentation was 6/200 in the right eye and 20/20 in
the left eye. Anterior segment examination was unremarkable. Fundus examination in
the right eye showed minimal vitritis with a well-defined pigmented Toxoplasma scar and a yellowish-white necrotizing retinitis lesion adjacent to the scar with
subretinal hemorrhage. FFA and OCT confirmed the presence of coexisting CNVM and active
retinitis. She was treated with monthly injections of intravitreal anti-VEGF (bevacizumab)
for 3 months along with an oral anti-Toxoplasma drug (cotrimoxazole) and a tapering dosage of oral corticosteroids for 6 weeks. After
4 months, her visual acuity improved to 20/200 in the right eye with healed chorioretinal
scar with regression of CNVM.

Case 3

A 32-year-old female presented with gradual diminution of vision in the left eye for
4 months. Visual acuity in the left eye was 3/200. Anterior segment examination of
both eyes and fundus in the right eye was unremarkable. Fundus of the left eye had
minimal vitritis with a yellowish-white retinitis lesion (at the posterior pole) and
subretinal hemorrhage adjacent to a long-standing hyperpigmented scar (temporal to
the fovea). FFA and OCT confirmed the presence of coexisting CNVM and active retinitis
in the left eye. The left eye was treated with intravitreal injection of anti-VEGF
(bevacizumab), oral anti-Toxoplasma drug (cotrimoxazole), and systemic corticosteroids. Intravitreal injection of bevacizumab
was repeated at 1 month. The visual acuity improved to 20/100 and subretinal fluid
regressed with healing and scarring of the retinitis lesion which remains stable at
2 months of follow-up.

Discussion

In 1977, Willerson et al. 11] reported the first case of subretinal neovascularization in association with active
Toxoplasma retinochoroiditis. The pathogenesis of CNVM during the active stage of Toxoplasma retinochoroiditis is thought to occur by a break in Bruch’s membrane and choriocapillaris
12] due to intense retinal inflammation. Because of this lesion, impeded retinal venous
outflow may lead to active vasoproliferation and retinochoroidal vascular anastomosis
13]. Friable vascular channels may ultimately lead to formation of CNVM. Fundus fluorescein
angiography (FFA) and optical coherence tomography (OCT) help in confirming the presence
of coexisting neovascular membrane and active retinochoroiditis. Monnet et al. 14] described the OCT features of active toxoplasmosis as the presence of highly reflective
intraretinal area corresponding with the area of retinitis, a thickened posterior
hyaloid, and a shadow effect of the underlying choroidal tissue. CNVM during the healed
stage generally occurs at the edge of the Toxoplasma scar 8]; while in the active stage, CNVM may be seen anywhere in the active retinitis lesion.

Options to treat CNVM secondary to resolved Toxoplasma retinitis include observation, corticosteroids, laser photocoagulation 15], photodynamic therapy (PDT) 16], submacular surgery 17], and intravitreal anti-VEGF agents 15], 18]. Management of CNVM in cases of healed toxoplasmosis with anti-VEGFs has been associated
with reactivation of the retinochoroiditis lesion, so few authors do recommend concomitant
use of oral anti-Toxoplasma treatment as prophylaxis 19]. However, if the CNVM coexists with the active stage of Toxoplasma retinochoroiditis, the combination therapy (anti-VEGF and anti-Toxoplasma treatment) becomes very important as the combined approach addresses both the active
Toxoplasma lesion and the CNVM, thus achieving better anatomic and visual outcomes 20]. The anti-VEGFs are also effective in the management of subfoveal or juxtafoveal
neovascular membrane as they also reduce the collateral tissue damage to neurosensory
retina and choroid as is seen with PDT or laser photocoagulation or submacular surgery
20].

In conclusion, all three patients presented with coexisting CNVM with activation of
retinochoroiditis. The diagnosis was based on clinical evaluation, FFA, and OCT. All
three patients were promptly started on anti-Toxoplasma medical treatment along with intravitreal anti-VEGF injection guided by the clinical
evaluation and the imaging findings. The lesions healed with regression of the neovascular
membrane in all three patients with improvement in visual outcome and remained stable
during a follow-up period ranging from 2 to 4 months.