Optic Disc Neovascularization in Vogt-Koyanagi-Harada Disease- A Case Series and Literature Review


 BackgroundVogt–Koyanagi–Harada (VKH) disease is an autoimmune disorder which affects numerous organs of the body. We report two cases of Optic Nerve Head neovascularisation (NVD) in diagnosed cases of Vogt Koyanagi Harada(VKH) disease.FindingsCase 1: A 40 years female presented with acute loss of vision in both eyes for 10 days. She had multiple serous detachments in both eyes and diagnosed as acute VKH disease. After treatment, she was observed to have NVD later on OCT Angiography(OCTA). Case 2: A 52 years old man presented with history of sudden blackouts in front of left eye since 4 months. He was a case of chronic VKH and NVD was seen clinically and on OCTA. ConclusionThe exact etiopathogenesis of neovascularization in Harada’s disease is unclear. The low grade inflammations acts as a stimulus and can induce disc neovascularization even in the absence of vascular occlusion. ONH vessels appear to be more susceptible to developing NVD than retinal vessels in presence of chronic inflammation.


Introduction
Vogt-koyanagi-Harada's(VKH) disease is an autoimmune in ammatory disorder characterised by presence of bilateral granulomatous uveitis along with systemic associations involving the CNS, auditory or integumentary systems. Exudative retinal detachments with uveitis occurs in acute stages of VKH and the chronic phases is characterised by chronic uveitis, small pupil and depigmented fundus or sunset glow fundus(SGF). It is associated with common complications like subretinal neovascularization, cataract, glaucoma in late stages, but associated neovascularisation of disc (NVD) is extremely rare.
Case Report Case 1 A 40 years old Indian woman presented with bilateral acute loss of vision since 10 days. She had history of acute redness and pain in both eyes in the past and was treated as acute anterior uveitis. She had narrow angles in both eyes and bilateral yag peripheral iridectomy was done in the past. She had history of infrequent headaches and reduced hearing in both ears. She neither gave any history of similar ocular complaints in the past nor any treatment for eye problem. She had unremarkable systemic illness and no past history of ocular trauma and ocular surgery. Her visual acuity in the right eye was counting nger, N<6/60 and in the left eye was 1/60, N<6/60. Intra ocular pressure (IOP) was 14 mm Hg in both the eyes.
Anterior segment examination showed few old pigments on corneal endothelium and AC cells 1+ and vitreous cells 1+ in both the eyes. Fundus examination showed hyperemic discs with multiple pockets of serous neurosensory detachments in the both the eyes (Fig.1a). Preliminary diagnosis of Vogt-Koyanagi-Harada disease(VKH) was made.
On fundus uorescein angiography (FFA), there were hypo uorescent dots in early frames followed by multiple areas of pin point leakages and subretinal uid accumulation in late phases in both the eyes.
The disc showed leakage in both the eyes. There was no evidence of capillary nonperfusion in the peripheral retina ( Fig.1 b,c,d,e). On optical coherence tomography(OCT)(Cirrus HD-OCT), there was evidence of serous neurosensory detachment with intervening septae and corrugated retinal pigment epithelium in both the eyes (Fig 2 a,b). The sub foveal choroidal thickness was 367μm in right eye and 387μm in left eye.
The patient received 3 doses of intravenous methyl prednisolone (IVMP) 1 gram for 3 consecutive day followed by tapering dose of oral steroids@ 1mg/kg b.w. After 3 days of IVMP, the patient was assessed and as the disc edema subsided, the right eye showed presence of neovascularization of disc (NVD). She was then subjected to an optical coherence tomography angiography (OCTA)(Zeiss Angioplex) which showed an abnormal large vessel rising above the plane of retina, best observed in vitreous plane of OCTA (Fig. 3d). The patient showed marked visual gain and the serous detachments completely resolved in 2 weeks. She was also put on oral azathioprine 50mg twice a day after receiving 2 weeks of oral steroids after baseline liver function tests examination and oral steroids were slowly tapered and stopped after 18 weeks. On her last follow-up, she was receiving azathioprine 50 mg once a day and her visual acuity was 6/9, N8 in right eye and 6/12, N8 in the left eye. The NVD had completely regressed, and documented on OCTA.

Case 2
A 52 year old Indian man presented with history of blackout in front of left eye on changing posture since 4 months and seeing oaters in the left eye since 10 days. He was a known case of diabetes and hypertension since 4 months and 7 years respectively and was on treatment for the same. He was a diagnosed case of non-alcoholic cirrhosis on treatment with a gastroenterologist. His best corrected visual acuity in both the eyes was 6/6, N6. IOP was 15 mmHg in both the eyes. Anterior segment examination in both the eyes were within the normal limits. Gonioscopy was performed which showed open angles with no evidence of neovascularization. Fundoscopic evaluation in the right eye was normal and left eye showed gross disc neovascularisation with surrounding serous retinal detachments, hypopigmentation around and inferior to optic nerve head with streak of preretinal haemorrhage and some vitreous haemorrhage (Fig. 4b). There was no evidence of any intraretinal haemorrhages, microaneurysms or diabetic and/or hypertensive retinopathy changes. The retinal vessels were of normal calibre and no venous beadings could be seen.
On FFA, the right eye was normal in all phases but the left eye showed areas of early choroidal hypo uorescence in prearterial and arterial phases. There was a mesh of arborizing vessels seen over and around the optic disc which showed hyper uorescence due to dye leakage from the fragile new vessels. Multiple pin point leaks could be seen scattered around the disc which showed increased leakage and some subretinal pooling in late frames of angiogram (Fig. 4 c,d,e,f). Areas of blocked uorescence corresponding to preretinal heme were seen inferior to ONH. The retinal vessels did not show any signs of leakage or staining and there were no areas of capillary non-perfusions. No e/o leaking microaneurysms.
OCT through the optic disc showed presence of subretinal hypore ective space with increase retinal nerve bre layer suggestive of disc edema and surrounding neurosensory detachment in the left eye (Fig. 5a). OCTA of left eye through the disc showed presence of interwoven thin vascular complex above and around the disc in an arborizing pattern in the vitreous frame (Fig. 6c). OCT and OCTA images of the right eye were normal. The sub foveal choroidal thickness was 373μm in left eye.
He was advised baseline uveitis investigations. His Haemoglobin was 13.9 g/dl, total leucocyte count was 5200 cells/cumm, differential leucocyte count showed neutrophils (60) He was diagnosed as left eye chronic VKH disease with ONH neovascularization. He was advised intravenous methyl prednisolone (IVMP) 1 gm x 3 days for 3 consecutive days after physician clearance followed by slow tapering dose of oral steroids @ 1mg/kg/bw under strict blood sugar monitoring. He received 1 dose of Bevacizumab (1.25mg/0.05ml) and dexamethasone (400 microgram/0.1 ml). We planned to put him on oral Azathioprine for his low grade in ammation but he did not get physician clearance in view of deranged liver enzymes and pre-existing non alcoholic cirrhosis pattern on ultrasonography, so oral steroids were slowly tapered and continued for 24 months. His NVD in left eye regressed completely with treatment was documented on OCTA (Fig. 6d).

Discussion
Vogt-Koyanagi-Harada (VKH) disease is an autoimmune disorder with spectrum of clinical manifestations and affects numerous organs of the body with melanocytes, including the eye, meninges, skin, and inner ear. [1] The clinical course of VKH disease follows four phases: prodromal, acute, convalescent, and recurrent/chronic. [2] In acute phase of VKH, there is marked optic disc swelling, hyperemia of disc, few vitreous cells along with serous subretinal uid pockets against normal pigmented fundus. The vessels are normal in size and calibre. Documentation of NVD on OCTA in acute phase of VKH has not been done in literature. The exact etiopathogenesis regarding the formation of NVD in acute phase is unclear. However, the presence of acute anterior uveitis in the past and narrow anterior angles requiring yag PI may suggest the possibility of presence of long standing in ammation and in ammatory in lterates in the ciliary body and choroid which later manifested as acute VKH with acute loss of vision. This also explains the infrequent headaches in the past.
In the convalescent or recurrent/chronic stage, depigmentation of the choroid results from choroidal melanocyte damage [3,4] and the fundus shows bright orange discoloration. This clinical finding is known as a ''sunset glow fundus'' (SGF). [1][2][3] SGF is highly specific to VKH disease and is identified as an important finding in the Revised Diagnostic Criteria of VKH disease. [5] In our second case, there was presence of depigmented fundus around the disc and inferiorly suggestive of the chronicity of the disease and the presence of NVD can be hypothesised due to untreated/undiagnosed low grade underlying in ammation. There were no AC or vitreous in ammation in the eye. The retinal vessels did not show any occlusive vasculitis or periphlebitis. His ACE levels were normal and the Mantoux was highly positive. He had very small hilar lymph nodes, not attributing to diagnosis of sarcoidosis.
NVD in VKH disease is a rare entity. Kanter PJ and Goldberg reported NVD in a case of presumed VKH with bilateral uveitis and exudative RD without signs of integumentary changes in 1974, similar to our rst case. [6] It was further supported by TO KW et al in 1990 when he showed angiographically established NVD in a proven case of VKH in past and on treatment. [7] We report two cases of NVD in two different stages of VKH with corresponding OCTA scans in vitreous frames passing through the vessels over the disc. The proposed hypothesis is that the chemical stimulus inducing disc neovascularization in these cases must have arisen directly from the in ammatory process rather than from areas of vessel occlusion. [1] Retinal hypoxia is a key feature for optic disc new vessels and hypoxia-inducible factor-1 (HIF-1) seems to be the key transcription factor in the pathogenesis of retinal neovascularisation. Thus, retinal neovascularisation occurs in diseases in which the underlying disease process damages retinal vessels causing areas of vessel closure and retinal ischemia leading to increased levels of HIF-1. [8] When uveitis is associated with neovascular proliferation, the proliferation is usually associated with occlusive vasculitis. We examined our patients speci cally for any signs of vessel occlusion using ophthalmoscopy and also angiographically, and did not nd any signs of occlusive vasculitis. In ammation -induced optic disc neovascularization (NVD) has been associated with several diseases such as sarcoidosis, toxoplasmosis, birdshot chorioretinopathy, serpiginous choroiditis, and idiopathic uveitis. (7) In these cases, neovascularization develops from a mature vascular bed which has been compromised by an impediment to ow. [8] SGF appearance in VKH has been reported to be associated with the severity of chronic ocular inflammation. [9] There have been cases in literature in which changes in an SGF develop a few years after onset of VKH disease, without clinically significant intraocular inflammatory findings. [10,11] This delayed development is considered to result from the persistence of subclinical choroidal inflammation. SGF represents the natural course of VKH resulting from insufficient treatment and an accurate diagnosis of SGF is important for the clinical management of this disorder. [12] The development of NVD in our patient and its complete regression with systemic steroid treatment suggests that in ammation played a major role in the pathogenesis of the NVD. OCTA proven evidence of NVD in our case series with negative sarcoid and tuberculosis workup strongly supports our diagnosis of rare complication of neovascularisation in VKH.
In conclusion, NVD may form in the case of VKH due to ongoing underlying in ammation of the choroid and needs to be evaluated. OCTA help in detection of these vessels on ONH and avoids the need for repeat FFA which may not give a clear view of disc due to profuse pre-existing disc leakage in these patients.