Vogt-Koyanagi-Harada syndrome presenting with bilateral optic disc swelling and leptomeningeal enhancement

Abstract

Vogt-Koynagi-Harada (VKH) disease is a clinical syndrome with classical ocular and extraocular findings that is not uncommonly described in Asian, Middle-Eastern and South American populations. We describe a case of VKH in an elderly Polish-Australian distinguished by prominent bilateral disc swelling rather than uveitis and marked leptomeningeal enhancement on MRI which led to extensive investigation including brain biopsy. Both disc oedema and MRI abnormalities improved dramatically with systemic steroid therapy. VKH disease is an important differential to consider in older patients with an uveo-meningeal picture and atypical eye findings where other causes have been excluded.

Background

Vogt-Koynagi-Harada (VKH) disease received its name in 1939 following its description in various case reports by its eponymous authors.¹ Although most well described in the ophthalmology literature, VKH disease is a systemic autoimmune disease most likely arising from a T-cell mediated process against melanocytes.² While diagnostic criteria were first devised in 1978, revised criteria were established in 1999 at an international meeting to take into account the multiorgan nature of the disease, and the early and late stages of the ocular manifestations.³ The concept of definite (with either complete or incomplete) and probable disease was also introduced. Since this time the pathophysiological understanding of the disease has continued to develop. The strong genetic association with HLA-DRB1*0405 and VKH disease is already well known and has been described in various ethnic populations, but more recent studies have also noted an association with a genetic polymorphism in CTLA-4, a negative regulator of the T-cell response. Other studies have suggested a key role for IL-23 inducing production of IL-17 by CD4+ T cells. In addition to the prominent role of Th1 in VKH disease, the potential importance of Th17 in VKH disease and other autoimmune causes of uveitis have also been hypothesised. Current treatment recommendations for VKH disease advocate aggressive systemic steroid therapy, and secondary immunosuppressive agents such as cyclosporine and azathioprine in more refractory cases.^{1 3}

Case presentation

A 69-year-old Polish-born woman initially presented with symptoms of occipital headache, reduced visual acuity and floaters. She was diagnosed with bilateral cataracts and underwent sequential cataract surgery 8 months later. Her symptoms initially resolved in the month following her operations, but then recurred with symptoms of worsening occipital headache and floaters in both eyes. She was reviewed by an optometrist who suspected papilledema and referred her to an Australian tertiary hospital for further evaluation under the neurology team. On further history she also reported forgetfulness, light headedness, unsteadiness and occasional tinnitus.

On ocular examination visual acuity was 6/9 in the right eye, and 6/6 in the left eye, with Ishihara score of 13/13 in both eyes. Humphrey visual field testing detected subtle peripheral field loss in both eyes. Pupils were equal and reacting to light. Ocular movements were full. Slit limp examination demonstrated few fine keratic precipitates on the corneal endothelium and 0.5+ cells in the anterior chamber of both eyes. There were also findings of bilateral florid disc oedema with mild vitritis. Macula appeared unremarkable in both eyes. Fundus fluorescein angiography (FFA) was performed which demonstrated bilateral disc leakage and patchy retinal vasculitis (figures 1 and 2). Neurological including cranial nerve examination did not reveal any abnormalities aside from mild upper and lower limb ataxia. Cognitive screening tests demonstrated a mini mental state examination (27/30) within normal limits but a reduced Addenbrooke’s cognitive examination revised score (64/100) with significant deficits in verbal fluency and memory. Audiology studies demonstrated mild bilateral sensorineural hearing loss.

Figure 1.

Fundus fluorescein angiography of left eye showing disc leakage vasculitis.

Figure 2.

Fundus fluorescein angiography  of right eye showing patchy vasculitis.

MRI of her brain and spine showed diffuse leptomeningeal enhancement along the spinal cord, including the brain stem (pons, medulla), with abnormal ependymal enhancement along the lateral ventricles and perivascular spaces, patchy and slightly nodular leptomeningeal enhancement involving both cerebral hemispheres (figure 3). Subtle enhancement and bulkiness to the left medial temporal lobe was noted. Cerebral spinal fluid (CSF) examination demonstrated monocytic pleocytosis (35×10⁶/L cells), elevated protein (1.28) and oligoclonal banding consistent with intrathecal immunoglobulin synthesis. Other CSF findings were normal with opening pressure of 9 mm Hg, normal glucose, no evidence of a monoclonal lymphocyte population on flow cytometry, and no malignant cells on cytological examination.

Figure 3.

MRI (postcontrast fluid-attenuated inversion recovery (FLAIR)) brain imaging demonstrating leptopmeningeal enhancement of medial temporal lobes bilaterally.

Aside from lymphopaenia and mildly elevated erythrocyte sedimentation rate (35 mm), complete blood count, other inflammatory markers (C reactive protein) and biochemistry were within normal limits. Extensive blood tests for underlying infective, autoimmune, malignant and paraneoplastic aetiologies were negative. CT of chest, abdomen, pelvis and whole body positron emission tomography scan did not show evidence of lymphoproliferative malignancy. She proceeded to right frontal brain biopsy, which yielded only normal dural and cerebral cortical tissue. Vitreous biopsy was also non-diagnostic.

She continued to be closely monitored on an outpatient basis by ophthalmology, immunology and neurology specialists. Her ocular abnormalities persisted with ongoing disc swelling, although her visual acuity remained stable. MRI abnormalities persisted on serial imaging; however, her headaches settled with lumbar puncture presumably due to lowering of CSF pressure and there was also no evidence of progression of cognitive deficits on repeat testing. Six months following her initial work-up, she reported the development of pruritus, redness and new white patches on her face and torso. While she had a past medical history of vitiligo (onset in her 30s) and hypothyroidism, her vitiligo involvement had previously been limited to her neck. Skin biopsy of a white patch on her back confirmed vitiligo histologically, while further biopsy of an erythematous patch on her chin demonstrated loss of melanocytes associated with lymphocytic inflammatory cell infiltrate into areas of epidermal spongiosis. The extensive investigations thus far were suggestive of an inflammatory aetiology, with the structures being targeted all rich in melanocytes excluding the eye—the choroid is the melanocyte rich structure in the eye. A B-mode scan was organised which revealed bilateral diffuse choroidal thickening. Idocyanine green angiography (ICGA) showed multifocal choroidal hypoflourescent lesions in both eyes, diffuse choroidal vascular leakage and staining of the choroidal vessels, all in keeping with ongoing bilateral choroidal inflammation. HLA typing for DR1, DR4 and DR53 were negative.

A diagnosis of VKH disease was made on the basis of the combined ocular (choroiditis), neurological (meningoencephalitis) and integumentary (inflammatory vitiligo, inner ear involvement) findings in the absence of other autoimmune, malignant or infective aetiologies identified following extensive investigations and a nearly 1 year period of observation.

Outcome and follow-up

Following the diagnosis of VKH disease, the patient was commenced on a 3-day course of intravenous methylprednisolone (1 g daily) followed by oral prednisolone 1 mg/kg/day. Repeat MRI showed marked improvement (but not resolution) in leptomeningeal enhancement, while ophthalmic assessment demonstrated dramatic resolution in disc swelling and resolution of choroidal thickening by 3 months.

On last follow-up after 2 years of initial presentation, the patient was on low dose steroids of 5 mg daily and methotrexate 15 mg/week with no clinical evidence of active inflammation. She continued to have residual leptomeningeal enhancement on her repeat MRI despite a lack of neurological symptoms.

Discussion

Patients with VKH disease typically present with uveitis with the diagnosis being made by ophthalmologists. Our patient’s presentation was remarkable for the prominence of the neurological findings including extensive leptomeningeal abnormalities on MRI and bilateral disc swelling in the absence of serous detachment and classical FFA findings of VKH disease. This ‘uveo-meningeal’ picture led to the necessity of excluding neoplastic (lymphoma, melanoma), paraneoplastic, inflammatory/autoimmune (sarcoidosis, atypical Cogan, vasculitides) and infectious (syphilis, tuberculosis) causes. Her condition did not strictly meet the revised criteria for the diagnosis of VKH due to the history of preceding cataract surgery. However, VKH disease is the most consistent diagnosis given the combination of ocular and neurological findings followed by the development of skin involvement, with all targeted structures being rich in melanocytes (meninges, cochlea, skin and choroid). While uveitis and serous retinal detachment are the classically described ocular manifestations, VKH disease with marked disc oedema as the predominant finding, as was the case with our patient, has now been recognised as a distinct subtype. In a recent Japanese study, retrospective analysis of 96 patients who were classified as either serous retinal disease (82/96) or optic disc-swelling (14/96) type disease found the latter group to be characterised by older age of onset, female predisposition, milder visual loss, longer treatment lag and higher frequency of chronic disease (if poor pretreatment visual acuity).⁴ This subtype of VKH disease has yet to be incorporated into the diagnostic criteria.

Another limitation of the diagnostic criteria is the inadequacy of the neurological criteria, which currently comprise only pleocytosis and meningismus. Leptomeningeal enhancement on MRI has now been described since 2010,⁵ and likely reflects involvement of melanocyte-rich tissues. Ocular findings of symmetric choroidal thickening with retinal detachment, as well as scattered periventricular white matter lesions on T2-weighted/FLAIR imaging may also be seen on MRI.⁶ As neurological involvement is thought to develop early along with ocular involvement, but more than 50% of patients lack extra-ocular symptoms in the early phase of the syndrome,⁷ this may be an important investigation to facilitate earlier diagnosis. Our patient’s neurological imaging findings were so prominent it resulted in brain biopsy, as well as multiple lumbar punctures and serial MRIs for what is typically primarily an ophthalmological presentation, work-up and diagnosis. Despite this her neurological symptoms were relatively mild and non-progressive.

By having the opportunity to closely observe our patient over a 1-year period without treatment, we were able to confirm previous observations that skin findings follow neurological and ocular findings. Interestingly during this period of observational management, while MRI and ocular abnormalities were persistent, clinically she remained stable with no deterioration in visual acuity or cognition. Systemic corticosteroid therapy resulted in significant improvement in her disc oedema and MRI abnormalities, which have subsequently recurred with prednisolone tapering, although clinically she is asymptomatic.

This case illustrates the diagnostic dilemma when an elderly patient presents with an uveo-meningeal picture but atypical eye findings. VKH disease is an important differential to consider in patients with ocular and neurological findings where other causes have been excluded. As our case highlights, and consistent with recent developments in the literature, the spectrum of clinical findings in VKH disease is also wider than what is described in the current diagnostic criteria. Finally, we would like to emphasise that VKH disease can present as bilateral optic disc swelling subtype and in these cases, the choroidal involvement can be silent. Investigations such as B-mode scan, enhanced depth imaging OCT, ICGA can confirm the choroidal involvement and facilitate accurate diagnosis.

Learning points.

• Vogt-Koyanagi-Harada (VKH) disease can present with prominent neuroimaging abnormalities and should be a differential diagnosis for those presenting with a uveo-meningitic picture.

• Neurological symptoms may be mild and not in keeping with extensive imaging abnormalities.

• The optical findings of VKH disease can be myriad and require a high index of suspicion.