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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 1  |  Issue : 2  |  Page : 313-316

Rapidly progressing granulomatous retinochoroiditis with vasculitis: An extensive imaging and laboratory characterization of an unusual variant of sympathetic ophthalmia


1 Advanced Eye Center, Department of Ophthalmology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
2 Department of Ophthalmology, University Vita Salute, Hospital San Raffaele, Milano, Italy
3 Department of Immunopathology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
4 Department of Cytology and Gynecological Pathology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
5 Department of Internal Medicine, Division of Rheumatology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
6 Department of Ophthalmology, West Coast Retina Medical Group, San Francisco, CA, USA

Date of Submission27-Jun-2020
Date of Acceptance19-Nov-2020
Date of Web Publication01-Apr-2021

Correspondence Address:
Dr. Vishali Gupta
Professor of Ophthalmology, Advanced Eye Center, Post Graduate Institute of Medical Education and Research (PGIMER), Sector 12, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijo.IJO_2047_20

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  Abstract 


A 36-year-old male suffered a traumatic open globe injury to his right eye resulting in phthisis. One year later, he developed a sudden progressive decrease in vision in the fellow (left) eye. Examination revealed arteriolar attenuation, multifocal deep subretinal infiltration, retinal edema, and necrosis. The patient underwent diagnostic vitrectomy in the left eye, and diagnostic enucleation of the phthisical right eye after suboptimal response to intravenous corticosteroid, antiviral, and antibiotic therapy. Detailed immuno-histopathological evaluation revealed extensive retinal disorganization with photoreceptor loss, perivascular infiltration, Dalen-Fuchs nodules, and granulomatous inflammation with central necrosis and melanin pigment, suggestive of a rare variant of sympathetic ophthalmia.

Keywords: Atypical retinal pathology, choroiditis, Dalen Fuchs nodules, fluorescein angiography, granulomatous uveitis, indocyanine green angiography, non-necrotizing retinitis, optical coherence tomography, sympathetic ophthalmia


How to cite this article:
Agarwal A, Sharma S, Kumar A, Marchese A, Sehgal S, Singh M, Gupta N, Sharma A, Gupta A, Agarwal A, Gupta V. Rapidly progressing granulomatous retinochoroiditis with vasculitis: An extensive imaging and laboratory characterization of an unusual variant of sympathetic ophthalmia. Indian J Ophthalmol Case Rep 2021;1:313-6

How to cite this URL:
Agarwal A, Sharma S, Kumar A, Marchese A, Sehgal S, Singh M, Gupta N, Sharma A, Gupta A, Agarwal A, Gupta V. Rapidly progressing granulomatous retinochoroiditis with vasculitis: An extensive imaging and laboratory characterization of an unusual variant of sympathetic ophthalmia. Indian J Ophthalmol Case Rep [serial online] 2021 [cited 2021 Aug 3];1:313-6. Available from: https://www.ijoreports.in/text.asp?2021/1/2/313/312353



Intraocular inflammation in sympathetic ophthalmia (SO) can lead to severe visual loss if not treated promptly with appropriate immunosuppressive therapy. Although rare, SO results in diffuse damage to the uveal tissue. Typically, SO presents as a bilateral granulomatous panuveitis characterized by choroidal granulomas and multiple pockets of exudative retinal detachment following trauma or surgery in the fellow eye.[1],[2],[3]

A rare blinding variant of SO that presents with multifocal chorioretinitis and progressive subretinal fibrosis was described in the literature more than 2 decades ago.[4],[5] In this report, we describe an atypical case of SO along with extensive novel imaging, immunological and histopathological analysis.


  Case Report Top


A 36-year-old Asian Indian male presented with loss of vision in the right eye (OD) following trauma with a pellet from an air gun. He had an open globe injury with a corneoscleral laceration involving the nasal limbus. The injury was repaired and the patient was treated with oral corticosteroid (1 mg/kg oral prednisolone) postoperatively. Examination of the left eye (OS) was unremarkable, with a best-corrected visual acuity (BCVA) of 20/20. A week after the trauma, BCVA was no light perception in OD. No intervention was done in OD at this time. Monthly examinations with tapering doses of oral corticosteroids were performed.

A year later, the patient presented with a sudden loss of vision in OS. BCVA was hand motions close to face (HMCF) OS. Slit-lamp examination showed absence of corneal edema, 3+ cells and flare, granulomatous keratic precipitates (KPs), and dense vitritis. OD also had diffuse conjunctival injection, granulomatous KPs, and 3+ cells and flare. Through a hazy media, multiple round-to-oval yellowish subretinal lesions, and mild optic disc edema were noted in OS [Figure 1]. A provisional diagnosis of SO was considered. Fluorescein angiography (FA) revealed early optic disc hyperfluorescence, and early hypofluorescent mid-peripheral lesions which became hyperfluorescent in the late phase. Swept-source optical coherence tomography (SS-OCT) revealed diffuse loss of the photoreceptor layer with retinal disorganization and relatively preserved retinal pigment epithelial (RPE) layer [Figure 1]. Ultrasound B-scan did not reveal any choroidal thickening. While the FA was not very typical of SO, initial treatment with intravenous methylprednisolone (IVMP) 1 gm/day was initiated. Preliminary laboratory tests revealed a negative tuberculin skin test (5 mm × 5 mm), negative tests for HIV, syphilis, toxoplasmosis, and QuantiFERON TB Gold®. Contrast-enhanced computerized chest tomography was within normal limits. The total leucocyte count was 6,500/μL (65% neutrophils, 18% lymphocytes, 7% eosinophils, and 10% monocytes). No blast cells were seen on the peripheral blood smear.
Figure 1: Fundus photographs at baseline reveal dense vitritis resulting in a hazy view of the retina of the left eye (a and b). The optic disc margins are blurred and multiple deep subretinal gray-white lesions are seen involving the retinal mid-periphery. Swept-source optical coherence tomography (c) passing through the center of the macula in left eye shows few hyper-reflective dots in the vitreous cavity suggestive of vitreous cells. There is a diffuse architectural damage to the photoreceptor layer with numerous hyper-reflective dots in the outer retina and patchy changes to the retinal pigment epithelial layer. There are multiple hyper-reflective dots in the choroid and choriocapillaris as well. Fluorescein angiography (d and e) (in the late arteriovenous phase) reveal dye leakage from the optic nerve head and staining of the venous endothelium. There are deep subretinal patches of ill-defined hyper-fluorescence in the retinal mid-periphery as seen in the superior retina (e)

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Over the next 3 days, with IVMP, the patient had an improvement in the media haze with reduction in vitritis, but no improvement in BCVA. Fundus examination revealed arteriolar narrowing and sheathing, and distinct multifocal retinal and subretinal patches of whitening in the mid-periphery [Figure 2]. SS-OCT revealed further disorganization with areas of retinal thickening with edema and adjacent areas of dense opacification, and widespread RPE loss [Figure 2]. Indocyanine green angiography (ICGA) revealed a much more widespread involvement of the choroid with multiple hypofluorescent lesions all over the fundus [Figure 2]. Meanwhile, the patient tested negative for hepatitis B and C, anti-neutrophil cytoplasmic antibody (ANCA) (both PR3 and MPO), anti-nuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA) (for systemic vasculitis), and human leucocyte antigen (HLA)-B 51 (for Behcet's disease). The patient was shifted to oral corticosteroids (prednisolone 1 mg/kg/day), and oral doxycycline 100 mg twice a day, and oral valganciclovir 900 mg twice a day were added to empirically treat any atypical bacterial or viral infection. Other possibilities considered were intraocular lymphoma or a masquerade. Contrast-enhanced magnetic resonance imaging (MRI) brain and orbit did not reveal any lesions. Whole-body positron emission tomography (PET)-scan did not reveal abnormal uptake anywhere in the body.
Figure 2: Fundus photograph of the left eye 3 days after initial therapy with intravenous methylprednisolone shows a clearer media. Apart from optic disc edema, there is diffuse retinal arteriolar attenuation and dense periarteriolar infiltration obscuring the blood column (a). In the retinal mid-periphery and periphery, there are numerous subretinal round-to-oval whitish lesions. The perivascular retina appears pale, whitish and edematous (magnified images). Fundus autofluorescence of the left eye (b) shows mottled pattern of hyper and hypo-autofluorescence. Indocyanine green angiography (ICGA) (c) revealed numerous round-to-oval hypofluorescent lesions all over the fundus which remained hypofluorescent in the late phase suggestive of diffuse infiltration of the choroid with granulomatous inflammation. Follow-up swept-source optical coherence tomography (SS-OCT) (d and e) revealed complete disorganization of all the retinal layers with diffuse loss of the photoreceptor layer, widespread loss of the RPE and replacement with amorphous and partly fibrotic material

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After 3 weeks of therapy, BCVA dropped to light perception in OS. A diagnostic pars plana vitrectomy (PPV) was performed in OS. Cytokine analysis of the vitreous fluid revealed a marked increase of interleukin (IL) ratio of IL10/IL6 < 0.001, thus negating a diagnosis of lymphoma. Myeloid differentiation protein 88 (MyD88) mutation (L265P) (to detect vitreoretinal lymphoma) was negative. Vascular endothelial growth factor (VEGF) levels were markedly increased in the vitreous (950 pg/ml). Giemsa staining of the vitreous aspirate showed predominantly mature lymphocytes (90%) but no blast cells. Polymerase chain reaction (PCR) for pan-bacterial, pan-viral (including cytomegalovirus, herpes simplex virus 1 and 2, and varicella zoster virus), toxoplasmosis, and tuberculosis were negative. To characterize the nature of the inflammation, RNA was also isolated from peripheral blood; reverse transcribed to cDNA and then tested for expression of pro-inflammatory genes which were upregulated [Figure 3]. The pro-inflammatory genes included tumor necrosis factor (TNF)-α, caspase 1, and interleukin (IL)-1β.
Figure 3: Figure 3 shows the expression of tumor necrosis factor (TNF)-α (a), caspase 1 (b), interleukin (IL)-1β (c), and NOD-like receptor protein 3 (NLRP3) (d). There was a significant upregulation of caspase 1, IL1β and TNF-α suggesting intense inflammation

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Four weeks after the initial presentation, BCVA improved to HMCF. Oral corticosteroids were continued at 1 mg/kg (oral prednisolone) and oral valganciclovir was continued with no improvement over the next 2 weeks. Finally, a diagnostic enucleation of the phthisical OD was performed. One ml of sterile phosphate-buffered saline was injected into the globe and fluid was aspirated for flow cytometry. A marked increase of CD3 cells was observed indicating it to be a predominantly T-cell inflammation (consistent with SO) [Figure 4].[6] The eyeball was fixed in 10% buffered formalin and 5 μ thick sections were stained with hematoxylin and eosin, periodic acid-Schiff (PAS), Masson's trichrome, and anti-CD68 antibodies. Microscopically, there was complete disorganization of the chorioretinal architecture. The histopathological description is provided in [Figure 5].
Figure 4: Flow cytometry image of the ocular fluid of the inciting eye showed a predominant population of CD3 cells (44.2%) while B cells accounted for 6% of the gated lymphocytes

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Figure 5: (a) A representative section of the enucleated eye showing multiple granulomas, entrapped melanin (yellow asterisk), destruction of muscle fibers with an epithelioid giant cell (200X magnification and Hematoxylin and Eosin (H&E) staining) (yellow arrow). (b) Relatively intact but irregular, multilayered retinal pigment epithelial (RPE) cells (yellow asterisk) with a typical Dalen-Fuchs nodule below the RPE cells (white arrowheads). Ciliary muscle fibers were also involved while the pigment containing ciliary processes were spared. No neural retinal structures were identifiable (200X H&E). The whole globe is shown in the inset. (c) An area of the section showing dense lymphoid aggregates, a few histiocytes with clear perivascular lymphocytic cuffing in some areas (black arrowheads) while other areas (not included in the picture showed plump endothelial cell proliferation of arterioles almost occluding the lumen (200X H&E). (d) A low power view of another field showing destructive panuveitis defying architectural details; multiple granulomas are seen (yellow asterisks); some with central melanin pigment, hyalinization (black arrow), with foamy histiocytes, more active lesion destroying the muscle fibers (white arrow) while other areas showed fibrosis (100X H&E)

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The patient was initiated on immunosuppressive therapy with oral azathioprine (2 mg/kg) and tapering doses of oral corticosteroids. Oral anti-viral and antibiotic therapy were stopped. Two months after the initial presentation, the patient had a BCVA of light perception in OS and significant retinal disorganization on SS-OCT, diminished retinal perfusion on FA and retinal opacification on examination [Figure 6].
Figure 6: Fundus imaging obtained at the follow-up visit 2 months from the first presentation shows significant retinal pallor, occluded vessels with extensive sheathing, and widespread perivascular retinal whitening (a). Fluorescein angiography (b) shows significant non-perfusion and vascular occlusion. In addition, there are multiple round hyperfluorescent transmission defects corresponding to the multifocal infiltration of the choroid with inflammatory granulomas. Swept-source optical coherence tomography (c – passing through the foveal center) reveals extensive inner retinal necrosis, disorganization and thinning, with significant photoreceptor and outer retinal loss, and patches of relatively preserved retinal pigment epithelium (d – scan passing inferior to the fovea)

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  Discussion Top


In 1996, Gass et al.[4] presented a series of three elderly patients who developed severe chorioretinal inflammation leading to progressive blindness and extensive structural disorganization. The findings of the histopathological examination from the enucleated fellow eye in their cases revealed an atypical picture for SO – complete photoreceptor loss, extensive granulomatous reaction, and dense perivascular infiltration (with occlusive vasculitis). Apart from the report by Gass et al., there have been few other case reports that have described atypical SO with progressive subretinal fibrosis with uveitis in the literature.[7],[8]

Wang et al.[5] in 2002 observed a similar clinical phenotype in an elderly Caucasian male who had a history of multiple surgeries in the fellow eye. Histopathology of the enucleated specimen revealed T cell-mediated granulomatous inflammation with fibrosis and necrosis. The authors postulated that their case shared clinical and histopathological features with the case by Gass et al.,[4] and suggested that entity possibly represents a form of an atypical SO – “sympathetic retinitis”.

The clinical examination, retinal imaging, and histopathology of our case shows that there was significant retinal inflammation (retinitis), retinal vascular inflammation and occlusion (vasculitis), and choroidal inflammation with Dalen Fuchs nodules (choroiditis). Our case differed from “typical” SO which is characterized by a diffuse granulomatous, non-necrotizing inflammatory response with thickened choroid, no/minimal retinal vasculitis, and sparing of the retina and choriocapillaris.[1],[2],[3],[9] Despite aggressive therapy, including systemic high-dose corticosteroids, this condition does not show an optimal healing response and the visual outcome remains extremely poor (either no light perception or bare light perception, unlike typical SO in which visual acuity is better than 20/400 at 10 years follow-up).[9],[10],[11]


  Conclusion Top


In conclusion, our case highlights the importance of recognizing this entity early using multimodal imaging. It is important to recognize and diagnose this entity because of the blinding nature of the condition.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rao NA. Mechanisms of inflammatory response in sympathetic ophthalmia and VKH syndrome. Eye (Lond) 1997;11(Pt 2):213-6.  Back to cited text no. 1
    
2.
Marak GE. Recent advances in sympathetic ophthalmia. Surv Ophthalmol 1979;24:141-56.  Back to cited text no. 2
    
3.
Cunningham ET, Kilmartin D, Agarwal M, Zierhut M. Sympathetic ophthalmia. Ocul Immunol Inflamm 2017;25:149-51.  Back to cited text no. 3
    
4.
Gass JD, Margo CE, Levy MH. Progressive subretinal fibrosis and blindness in patients with multifocal granulomatous chorioretinitis. Am J Ophthalmol 1996;122:76-85.  Back to cited text no. 4
    
5.
Wang RC, Zamir E, Dugel PU, Sipperley JO, Thirkill CE, Shabatian B, et al. Progressive subretinal fibrosis and blindness associated with multifocal granulomatous chorioretinitis: A variant of sympathetic ophthalmia. Ophthalmology 2002;109:1527-31.  Back to cited text no. 5
    
6.
Shah DN, Piacentini MA, Burnier MN, McLean IW, Nussenblatt RB, Chan CC. Inflammatory cellular kinetics in sympathetic ophthalmia a study of 29 traumatized (exciting) eyes. Ocul Immunol Inflamm 1993;1:255-62.  Back to cited text no. 6
    
7.
Palestine AG, Nussenblatt RB, Parver LM, Knox DL. Progressive subretinal fibrosis and uveitis. Br J Ophthalmol 1984;68:667-73.  Back to cited text no. 7
    
8.
Cantrill HL, Folk JC. Multifocal choroiditis associated with progressive subretinal fibrosis. Am J Ophthalmol 1986;101:170-80.  Back to cited text no. 8
    
9.
Chang GC, Young LH. Sympathetic ophthalmia. Semin Ophthalmol 2011;26:316-20.  Back to cited text no. 9
    
10.
Galor A, Davis JL, Flynn HW Jr, Feuer WJ, Dubovy SR, Setlur V, et al. Sympathetic ophthalmia: Incidence of ocular complications and vision loss in the sympathizing eye. Am J Ophthalmol 2009;148:704-10.e2.  Back to cited text no. 10
    
11.
Tan XL, Seen S, Dutta Majumder P, Ganesh SK, Agarwal M, Soni A, et al. Analysis of 130 cases of sympathetic ophthalmia - A retrospective multicenter case series. Ocul Immunol Inflamm 2019;27:1259-66.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]



 

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