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Year : 2019  |  Volume : 67  |  Issue : 7  |  Page : 1219-1221

Commentary: Appraisal of histopathological correlations in Vogt-Koyanagi-Harada uveitis

Uveitis Services, Aravind Eye Hospital, Puducherry, India

Date of Web Publication25-Jun-2019

Correspondence Address:
Dr. Sivaraman Bala Murugan
Uveitis Services, Aravind Eye Hospital, Puducherry - 605 007
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_409_19

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How to cite this article:
Murugan SB. Commentary: Appraisal of histopathological correlations in Vogt-Koyanagi-Harada uveitis. Indian J Ophthalmol 2019;67:1219-21

How to cite this URL:
Murugan SB. Commentary: Appraisal of histopathological correlations in Vogt-Koyanagi-Harada uveitis. Indian J Ophthalmol [serial online] 2019 [cited 2021 Mar 2];67:1219-21. Available from: https://www.ijo.in/text.asp?2019/67/7/1219/261043

Vogt-Koyanagi-Harada (VKH) panuveitis or uveo-meningo-encephalititis is a multisystem disorder involving the trosinase peptide[1] as a target antigen from the lineages of melanocytes. Being a disease with spectrum, it is subdivided into four distinct stages of the disease as: (1) prodromal stage with neurologic symptoms only (headache, tinnitus, meningismus), (2) uveitis stage with exudative retinal detachment, vitritis, disk hyperemia, (3) chronic stage with retinal pigmentary changes, sunset glow fundus, Dalen--Fuchs (DF) nodules, Sugiura sign, and (4) chronic recurrent stage with predominately anterior uveitis and degenerative fundal changes.

In the earlier era, choriocapillaries were considered to be spared in sympathetic ophthalmia (SO) but involved in VKH.[2] But this concept is challenged and the current understanding is that the histopathology (HP) of VKH and SO is virtually identical, except the history of trauma.

Fundamentally, all the uveal granulomatous conditions are divided into three morphological subtypes as: (1) zonal granulomatous (seen in tuberculosis, fungal, few rheumatoid arthritis, and phacoanaphylactic endophthalmitis), (2) sarcoidal granulomatous, (3) diffuse granulomatous. Classically, VKH and SO belong to the third subgroup of diffuse granulomatous type without necrosis and spares the choriocapillaries. The uniqueness of VKH is that its HP changes with the stages of the VKH disease mentioned above. In the chronic stage, HP is a nongranulomatous uveitis (infiltration by lymphocytes, plasma cells, absence of epithelioid histiocytes). But in the acute and chronic recurrent phase, it is a granulomatous uveitis with involvement of choriocapillaries.[3]

In the acute uveitic phase, the subretinal fluid of the serous retinal detachment contains an eosinophilic proteinaceous material. Basically, being a stromal choroidoidopathy, there is diffuse infiltration of lymphocytes, epithelioid histiocytes, and multinucleated giant cells. But the RPE and choriocapillaries are spared in this stage due to a special protein called RPE protein.[4] In the absence of necrosis, the cytoplasm of these cells contain uveal pigment granules that stain positive for S-100, muramidase, and lectin by immunohistochemistry. This proves the origin of these infiltrating cells from histiocytes/macrophages but was a serious controversy in the earlier literature.

Rather than the concordance of clinical findings with the HP, the discordance is observed at the retinal pigment epithelial (RPE) level. This is because in flourescein angiogram (FA), there are focal leaks at RPE level in the acute stage. But HP shows intact RPE with lymphocytes under it. What is observed clinically as DF nodule at this acute stage is a focal collection of sub-RPE monocytes. In addition, these nodules also contain lymphocytes, pigment-laden macrophages, epithelioid cells, and altered/proliferated RPE cells mimicking epithelioid histiocytes. IHC had confirmed the presence of T-helper more than suppressor cells/cytotoxic cells.

In the convalescent stage, uveal melanocytes express class П major histocompatibility complex antigens. But in the acute stage, these melanocytes are seen hand in hand with T-lymphocytes, postulating their role as an antigen presenting cells. Detailed studies have elegantly captured the target antigen as tyrosinase peptides.

In VKH, a panuveitis by definition, the inflammation spans the iris (epithelium, stroma), ciliary body (pars plicata and plana) and the choroid. But in HPE, the severity of infiltration is more severe in the juxtapapillary choroid than the iris and cliliary body. This translates into early identification of evolving VKH by differential choroidal thickening by B-scan at the peripapillary area for the beginners.

The chronic convalescent stage of VKH shows a remarkable transition in HP. In this stage, there is a nongranulomatous infiltration (as opposed to granulomatous in the earlier stage) with focal aggregation of lymphocytes and sparse macrophages. The depigmented fundal glow due to choroid reveals spindle cells devoid of melanin. However, the intact RPE reveals its melanin contents. This contrasting picturesque appearance is clinically seen as sunset glow appearance. The atrophic lesions seen in this stage, erroneously called as DF nodules reveals focal RPE loss with chorioretinal adhesions. This beautifully correlates with the window defects seen in FA at this stage.

The chronic recurrent stage of VKH is back to square 1 with diffuse granulomatous infiltration. However, the uveal thickening is less prominent with obviously no serous retinal detachment. The hallmark of this stage is the chorioretinal adhesions with RPE atrophy/proliferation. Electron microscopy of the RPE proliferations reveals a sessile or papillary/tubular pattern with apical microvilli and basal lamina. Such RPE proliferations occur with associated neovascular channels and mound-like appearance simulating a neoplasm.

Sometimes, the proliferated RPE without pigments reorganize as subretinal fibrosis due to the pathologic phenomenon called metaplasia. The RPE changes, photoreceptor degenerations, and gliosis are also visible in neural retina at this stage (that was elegantly spared in the acute stage). Such degenerations are severe enough to transcend the choriocapillaries as well in this unique stage (to recap: Choriocapillaries sparing is seen in acute stage).

The classic HP finding of DF nodule is sparsely seen in enucleated globes. Such DF-like nodule is also seen in sarcoidosis and other granulomatous disease. Typically, it has a hemispherical mound with the roof of proliferated RPE cell. Sub RPE histiocytes, epithelioid mononuclear cells lie on the Bruch's membrane. The composition of DF nodule varies with the VKH stages. In the acute stage, the contents are made up of lymphocytes and monocytes that transition to sparse inflammatory cells in the chronic convalescent stage. But in the chronic recurrent stage, the DF contents are made up of calcification and basophilic homogenous staining pattern (which completes the color spectrum of H-E as well). Fundamental and pivotal in the understanding of all these clinicopathological findings is that VKH and SO are virtually identical except history of trauma.

What is intriguing is that the DF nodules are morphologically characterized into three subtypes[5],[6] and correlate with the FA findings seen clinically based on its contents and leaking patterns. Of late, optical coherence tomogram[7] is quite handy in elegantly capturing them noninvasively.

Last but not the least, the reader should understand a closer differential diagnosis that is misinterpreted both clinically and pathologically is “'phacoanaphylactic uveitis.” Clinically, this differential has one eye entirely quiet when the other eye starts to get inflamed,[8] whereas VKH/SO are more often bilateral.[9] In particular, there is marked plasma cell reaction, absent epithelioid cells showing pigment phagocytosis, with a spotty distribution of the infiltrates to delineate phacoanaphylactic uveitis from VKH/SO.[8] We all got it why Sir William Osler did say, “As is our pathology, so is our practice!”

  References Top

Yamaki K, Gocho K, Hayakawa K, Kondo I, Sakuragi S. Tyrosinase family proteins are antigens specific to Vogt-Koyanagi-Harada disease. J Immunol 2000;165:7323-9.  Back to cited text no. 1
Perry HD, Font RL. Clinical and histopathologic observations in severe Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1977;83:242-54.  Back to cited text no. 2
Rao NA. Pathology of Vogt–Koyanagi–Harada disease. Int Ophthalmol 2007;27:81-5.  Back to cited text no. 3
Rao NA, Wu GS. Free radical mediated photoreceptor damage in uveitis. Prog Retin Eye Res 2000;19:41-68.  Back to cited text no. 4
Reynard M, Riffenburgh RS, Minckler DS. Morphological variation of Dalén-Fuchs nodules in sympathetic ophthalmia. Br J Ophthalmol 1985;69:197-201.  Back to cited text no. 5
Allinson RW, Le TD, Kramer TR, Snyder RW. Fluorescein angiographic appearance of Dalen-Fuchs nodules in sympathetic ophthalmia. Ann Ophthalmol 1993;25:152-6.  Back to cited text no. 6
Varghese M, Raghavendra R. Dalen Fuch's nodules and serous retinal detachment on optical coherence tomography in sympathetic ophthalmitis. Indian J Ophthalmol 2013;61:245-46.  Back to cited text no. 7
[PUBMED]  [Full text]  
Easom HA, Zimmerman LE. Sympathetic ophthalmia and bilateral phacoanaphylaxis: A clinicopathologic correlation of the sympathogenic and sympathizing eyes. Arch Ophthalmol 1964;72:9-15.  Back to cited text no. 8
Clinicopathological and immunohistochemistry correlation in a case of Vogt- Koyanagi -Harada disease IJO_1800_18  Back to cited text no. 9


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