The Curious Case of VKH: A Review of the Diagnosis, Treatment and Management of Vogt-Koyanagi-Harada Syndrome

Born and raised in Canada, Dr. Andrea De Souza received her Biomedical Science degree at the University of Waterloo in Ontario. She went on to receive her Doctor of Optometry degree from the New England College of Optometry in Boston and completed her residency training in Primary Care and Contact Lens at the UC Berkeley School of Optometry. Today, Dr. De Souza works as a clinical instructor at the UC Berkeley School of Optometry teaching third and fourth year students in the field of ocular disease, contact lenses and primary care. She also provides pre-operative and post- operative care at the University’s Refractive Surgery Center and serves on the board of the Alameda and Contra Costa Counties Optometric Society. On her spare time, Dr. De Souza enjoys wood-work, crafts, hiking and international travel.

Introduction:

            Vogt­Koyanagi­Harada (VKH) syndrome is an autoimmune inflammatory disorder involving the ocular, auditory, integumentary and central nervous system. VKH typically presents in women between the ages of 20 to 50 years old and is most common in people of pigmented race, including Indians, Hispanics, Asians, Native Americans and Middle Easterners.¹ It is one of the most common causes of uveitis in China and Latin American and accounts for up to eight percent of all uveitic cases in Japan. Conversely, VKH only accounts for one to four percent of uveitis referrals in the United States.^1,2 

Although the exact etiology is unknown, research indicates that VKH is a T-cell mediated autoimmune response directed against the tyrosine antigens of melanocytes found in various organs.¹ Viral prodromal symptoms are common among patients with VKH, which has led to some to suggest that viruses, such as the Epstein­Barr virus, trigger the disorder. No known study, however, has been able to isolate a specific virus from the eyes or cerebrospinal fluid of patients with VKH.¹

VKH has also been linked to HLA­DR4 and HLA­Dw53, particular the HLA­DRB1*0405 haplotype which is a common allele in Japanese.³ In a study by Yamaki, et. al., T-cell lymphocytes of patients with VKH have been shown to proliferate and stimulate an inflammatory response when in the presence of tyrosinase family proteins, a melanocyte-associated antigen presented to T-cells via major histocompatibility complexes such as HLA-DRB1*0405. The study has also demonstrated that an autoimmune disease clinically and histologically resembling VKH can be induced in pigmented rats that have been injected with these tyrosine family proteins.³

Case:

            An 18-year-old Japanese male presented to our clinic with a chief complaint of acute and rapidly progressing blur in the right eye, which began two nights prior. He reported recent stress and lack of sleep as he had been preparing for auditions for acceptance into music colleges. Aside from eczema, he was in good health. His medication was limited to a topical steroid cream to treat facial eczema, which he began using two days prior to the onset of his symptoms.  He denied ocular pain, photophobia, discharge and spectacle or contact lens wear.

            Upon examination his entering uncorrected visual acuity was 20/400 in the right eye and 20/20-3 in the left eye. Pupils and extra-ocular motility were normal. Anterior segment evaluation revealed mild bulbar hyperemia and a clear anterior chamber in both eyes. Intraocular pressures were measured at 18mmHg and 19mmHg in the right and left eyes respectively, using goldmann applanation tonometry.

            Posterior segment evaluation revealed a large multi-lobed serous retinal detachment (RD) over the macula of the right and multiple smaller serous RD temporal to the macula in the left eye (Figure 1.) The posterior segment of both eyes was otherwise unremarkable.

Figure 1: multi-lobed serous RDs in the right and left eye.

            Given the clinical findings, sex of the patient, recent stress and use of topical steroids, the patient was diagnosed with central serous retinopathy (CSR). The patient was advised to reduce his stress and consult with his dermatologist regarding discontinuation of the topical steroid as all forms of steroid use may contribute to the development of CSR, including skin creams, nasal sprays and joint injections.¹¹  Given that the clinical presentation of CSR was atypical, he was advised to return to clinic two days later. As the patient intended to leave that evening to audition for colleges around the country and would not return until the following week, he was advised to consult with a local retinal specialist should his symptoms significantly worsen or new symptoms develop.

            Eight days later the patient presented again to our clinic complaining of severe blur in his left eye in addition to his right. He reported visiting the ER the night prior due to a severe headache and bilateral tinnitus. At the ER he was treated for dehydration and sent home. He admitted to refusing to seek care with a retinal specialist while traveling, despite worsening symptoms, for the sake of his auditions. At this visit, uncorrected visual acuities were 20/310 in the right eye and 20/400 in the left eye. Pupils and extra-ocular motility were normal and intraocular pressures measured at 16mmHG in both eyes. Anterior segment evaluation revealed grade 1 bulbar hyperemia and gr 1+ anterior uveitis in both eyes. Posterior segment evaluation revealed 360 bilateral serous retinal detachments, choroidal inflammation and multiple pigment epithelial detachments (PEDs) (Figures 2 and 3). No vitreous cells were present.

Figure 2: Mild disc edema, serous RDs and choroidal inflammation visible 360 in the right eye

Figure 3: Mild disc edema, serous RDs and choroidal inflammation visible 360 in the left eye

Figfigure 4a and 4b: Macular OCT eight days after the initial visit; severe macular serous RD and PEDs visible in the right and left eye respectively.

            Given the anterior uveitis, severe headache, tinnitus and rapid decline in vision, he was diagnosed with the acute uveitic stage of Vogt-Harada-Koyanagi syndrome and urgently referred to a retinal specialist that afternoon. Figure 4 depicts the severity of bilateral macular serious RDs eight days after initial presentation. Although CSR does manifest with PEDs and serous RDs, it is predominantly a unilateral condition and typically presents with only one area of subretinal fluid. It most commonly presents in males although it primarily affects those in their third or fourth decade.¹¹ CSR does not progress this rapidly, does not manifest with intraocular inflammation or 360° RDs and frequently self-resolves within weeks or months.¹¹  

The patient was immediately hospitalized and treated with IV Solu-Medrol for three days. Subretinal fluid and tinnitus had drastically decreased and visual acuities improved to 20/40 in the right eye and 20/60 in the left eye, four days after initiating treatment. He was subsequently treated with 60mg prednisolone a day, tapering by 10mg a day every 2 weeks. By week five the subretinal fluid had completely resolved and his vision stabilized at 20/20-2 in both eyes. Macular OCTs during the five week follow-up revealed only mild RPE disruption in both eyes (Figure 5).

Figfigure 5a and 5b: Macular OCT five weeks after initiating treatment; slight RPE disruption is visible in the right and left eye respectively

Stages of Disease:

            There are four stages to the disease course of VKH. In the first stage, the prodromal stage, the patient may experience symptoms of a viral illness, including fever and malaise, in addition to neurological and auditory symptoms such as severe headaches, nausea, tinnitus, meningeal irritation and dysacusia.⁴ This stage typically occurs a few days prior to the onset of ocular symptoms and may persist for days to weeks.¹

            Ocular symptoms typically begin in the second stage, the acute uveitic stage. This stage may present with bilateral vision loss secondary to papillitis, vitritis and most commonly choroiditis, which may be focal or diffuse. ⁴The inflamed and thickened choroid results in focal areas of subretinal fluid, which can rapidly develop into bullous serous retinal detachments.⁴ Anterior uveitis may also be present. This stage will typically last several weeks. ¹

             The third stage, the convalescent (or chronic) stage, may last months or years. It is characterized by gradual resolution of the uveitis and exudative retinal detachments, and depigmentation of the skin (vitiligo), hair (poliosis), RPE and choroid.^1,4 Perlimbal vitiligo (Sugiura’s sign) is typically the earliest manifestation of the convalescent stage and is found in up to 85% of Japanese. ¹ Depigmentation of the choroid gives the fundus a sunset-glow appearance and round, yellow-white subretinal lesions known as Dalen-Fuchs nodules often appear in the mid-periphery.^1,4

            Most vision threatening complications develop in the fourth stage, the chronic recurrent stage. If left untreated, this stage presents with recurring episodes of acute granulomatous anterior uveitis, including stromal iris atrophy, posterior synechiae and Busacca nodules. ^1,4 Chronic inflammation commonly results in the formation of posterior subcapsular cataracts, angle closure or open angle glaucoma, choroidal neovascular membranes and subretinal fibrosis.^1,4 These recurring bouts of inflammation are frequently resistant to topical and systemic steroid therapy and instead require treatment with immunomodulatory agents.¹

Criteria for Diagnosis:

In 2001, the First International Workshop on Vogt-Koyanagi Harada Disease revised the diagnostic criteria for VKH. The criteria are as follows:

(1) no history of penetrating trauma or surgery

(2) no clinical or laboratory evidence suggestive of other ocular disease

(3) bilateral ocular involvement

(4) neurological/auditory findings at any point during the course of the disease

(5) integumentary findings not preceding the onset of ocular central nervous system disease.⁵

Criteria 1 to 3 must be met for the diagnosis of probable VKH, all five criteria must be met for the diagnosis of complete VKH, and criteria 1 to 3 and either 4 or 5 must be met for the diagnosis of incomplete VKH.⁵ According to these criteria, our patient falls under the classification of incomplete VKH as he did not develop integumentary findings. Although this patient has a history of eczema, this is not a typical integumentary manifestation of VKH.

Diagnosis:

            The diagnosis of early VKH can be challenging, particularly when serous RDs are absent. Optical coherence tomography (OCT), fluorescein angiography (FA) and indocyanine green angiography (ICG) can all be useful in its diagnosis. OCT can clearly display areas of subretinal fluid, typically divided into multiple segments, and may show areas of RPE folding. RPE folds are created in the presence of choroidal thickening; an early characteristics of VKH which may be found in up to 2/3 of cases.¹⁰ Early FA may display multiple pinpoint areas of hyperfluorescence at the level of RPE with late multilobular pooling, whereas ICG would display hazy choroidal vessels, a reduced number of large choroidal vessels and dark areas of hypofluorescence.¹⁰

Treatment:

Vogt-Koyanagi-Harada syndrome necessitates aggressive systemic therapy to shorten disease duration and to reduce the risk of extraocular complications or progression to a chronic stage. The first line of treatment is typically oral or intravenous corticosteroids. Oral corticosteroids are typically dosed at 1-2mg/kg/day and intravenous methylpresdnisone is dosed at 1mg/day for three days followed by a slow oral taper.⁶ According to Read et al, there is no statistically significant difference in final visual acuity or risk of cataract formation between VKH patients treated with oral corticosteroids versus IV and oral corticosteroids.⁶ Any concomitant anterior uveitis should also be treated with 1% prednisolone acetate, in addition to the systemic steroid therapy.

Rate of recovery is dependent on early diagnosis and treatment; urgent referral to retina is warranted. In a study by Fujioka et al, if systemic corticosteroids were initiated within two weeks of onset of the disease, intraocular inflammation typically resolved within three to six months. If the treatment was delayed however resolution could take up to 45 months.⁷ Systemic corticosteroids should be slowly tapered over a period of three to six months to reduce the risk of recurrence. Rubsamen and Gass found disease recurrence in 43% and 52% of patients with VKH within 3 months and 6 months respectively. In most cases, this occurred when steroids were tapered too rapidly.⁸ Recurring and chronic VKH often necessitate immunosuppressive agents, such as cyclosporine or azathioprine, as they tend to be resistant to systemic corticosteroids, even at higher doses.⁸

Prognosis:

            Approximately 60% of patients with VKH result in a visual acuity of 20/30 or better after 6 months of treatment with systemic corticosteroids or immunosuppressants. Two thirds of patients will result in a visual acuity of 20/40 or better.⁴ Complications of VKH which lead to reduction in acuity include cataracts (particularly posterior subcapsular cataracts), glaucoma and choroidal neovascular membranes. These complications occur in 25%, 33% and less than 10% of cases, respectively, and are more likely to develop with chronic recurrent anterior segment inflammation.^1,4 A study by Ohno et al. also indicated that younger age and poorer visual acuity at presentations are associated with poorer final visual acuity.⁹                                                                                                     

Conclusion:

            In summary, atypical or multilobular areas of subretinal fluid should raise a high level of suspicion for VKH, particularly when accompanied by neurological symptoms, general malaise or mild anterior chamber reaction or vitritis. Prompt diagnosis and treatment is crucial to ensure a more rapid recovery and better visual prognosis. In cases of atypical or early acute VKH without serous RDs, the presence of retinal folds may provide an important clue to its diagnosis.

References:

1. Damico, F. et. al. “Vogt­Koyanagi­Harada Disease”. Seminars in Ophthalmology (2005); 20:183–190

2. Fang, W. and Yang, P. “Vogt­Koyanagi­Harada Syndrome”. Current Eye Research (2008); 33:517–523

3. Yamaki, K. et. al. “Tyrosinase Family Proteins Are Antigens Specific to Vogt-Koyanagi-Harada Disease”. The Journal of Immunology (2000); 165: 7323–7329

4. Moorthy, R. et al. “Major Review: Vogt­Koyanagi­Harada Disease”. Survey of Ophthalmology (1995); 39(4): 265­292

5. Read, R. et. al. “Revised Diagnostic Criteria for Vogt-Koyanagi-Harada Disease: Report of an International Committee on Nomenclature”. American Journal of Ophthalmology (2001); 131(5): 647-652

6. Read, R. et al. “Vogt­Koyanagi­Harada Disease”. Current Opinion in Ophthalmology (2000); 11: 437–442

7. Fujioka T. et al. “A statistic Study of Vogt-Koyanagi-Harada Syndrome”. Nippon Ganka Gakkai Zasshi (1980); 84:1979-1982

8. Rubsamen, P. and Gass, D. “Vogt­Koyanagi­Harada Syndrome: Clinical Course, Therapy, and Long­term Visual Outcome”. Archives of Ophthalmology (1991); 109: 682­687.

9. Ohno, S. et al. “Clinical Studies of Vogt-Koyanagi-Harada’s Disease”.  Japanese Journal of Ophthalmology (1988); 32: 334-343

10. Attia, S. et. al. “Clinical and multimodal imaging characteristics of acute Vogt-Koyanagi Harada disease unassociated with clinically evident exudative retinal detachment”. Int. Ophthalmology (2015)

11.  Nicholson, B. et. al. “Central Serous Chorioretinopathy: Update on Pathophysiology and Treatment”. Survey of Ophthalmology (2013) 58:2 103-126

ese Journal of Ophthalmology (1988); 32: 334-343