Abdelbari Gdeh
Introduction
Vogt-Koyanagi-Harada disease (VKH) is a neurological condition that specifically impacts vision and hearing. Although descriptions of this ailment trace back to the 12th century, it gained its name from three physicians in the 20th century who collectively detailed its manifestations. In 1906, Alfred Vogt first outlined bilateral iridocyclitis and eyebrow depigmentation. Subsequently, Yoshizo Koyanagi, in 1926, described bilateral serous detachments in conjunction with cerebrospinal fluid (CSF) pleocytosis. Einosuke Harada shortly thereafter identified the integumentary symptoms of the disease. VKH disease manifests with signs and symptoms indicating a breakdown of immune tolerance to melanocytes in the meninges, eyes, skin, hair, and ears.
Initially, VKH disease was divided into two distinct categories:
• Vogt-Koyanagi syndrome, marked by persistent severe anterior uveitis, alopecia, poliosis, cutaneous, and perilimbal vitiligo (also referred to as Sugiura’s sign), and dysacusia.
• Harada’s disease, distinguished by bilateral exudative uveitis accompanied by cerebrospinal fluid pleocytosis.
Due to significant overlap in signs and symptoms between these two entities, Babel proposed in 1932 to designate the condition as Vogt-Koyanagi-Harada disease
Aetiology
The precise cause of VKH remains uncertain, though current theories propose that patients develop T-cell mediated immunity against melanocytes after recovering from a triggering viral environmental factor. While Cytomegalovirus and Epstein Barr virus have been implicated in the disease process, no definitive link has been established. VKH is believed to result from the breakdown of tolerance to melanocytes, resulting in non-necrotizing granulomatous inflammation in the eyes, inner ear, skin, and hair.
Recent genetic investigations have associated the presence of human leukocyte antigen (HLA) cell surface markers, including HLA-DRB4, HLA-DRB1-0405, and HLA-DRB-0401, along with non-HLA genes related to lymphocyte regulations in IL-12 and IL-17 production. Downregulation of microRNA affecting interleukin production and changes in non-coding RNA may also contribute to this condition.
Pathophysiology
In response to an environmental trigger, Th1-mediated inflammation emerges against melanocytes. The tyrosinase peptide is a recognized target of T-cells, particularly in melanocytes expressing HLA DRB1-04*05. Comparative analysis of the tyrosinase peptide and a cytomegalovirus peptide has revealed homology between the two proteins. Additionally, studies have detected EBV DNA in the cerebrospinal fluid (CSF) of VKH patients using PCR.
This inflammatory process results in the formation of non-necrotizing granulomas in affected organs. In the eyes, these granulomas manifest as sub-retinal pigment epithelial (RPE) aggregates known as Dalen-Fuchs nodules. Similar nodules may also be observed in other granulomatous conditions, particularly sympathetic ophthalmia
Clinical presentation
Vogt-Koyanagi-Harada disease typically begins with symptoms such as headaches, deep eye pain, vertigo, and nausea. Within a few weeks, these symptoms are followed by the onset of eye inflammation (uveitis) and blurred vision. This inflammation may affect both eyes simultaneously or initially impact one eye and later involve the other. As the condition progresses, there is a risk of retinal detachment and noticeable hearing loss.
The chronic stage emerges within a few weeks, characterized by alterations in the eyes and skin. Eye changes may involve the loss of colour in the choroid, the layer filled with blood vessels that nourish the retina, and the development of small yellow nodules in certain parts of the retina. Skin changes may include the appearance of smooth, white patches resulting from the loss of pigment-producing cells (vitiligo). These patches are typically distributed over the head, eyelids, and torso. The chronic stage can persist for several months to several years.
While treatment can enhance vision and hearing for many individuals, some may experience lasting issues, including deficits in vision and hearing, as well as hair loss with associated loss of colour in the hair, eyelashes, and skin. Persistent visual effects may include the development of secondary glaucoma and cataracts.
Diagnosis
The diagnostic criteria for VKH disease involve inflammation in both eyes, the absence of evidence pointing to another ocular disease causing the inflammation, and no history of trauma or ocular surgery. An international group of experts has defined three categories of the disease:
a. Complete VKH disease: This category encompasses diffuse choroiditis affecting both eyes, potentially leading to serous retinal detachments. Some patients may also experience inflammation of the iris and ciliary body. Neurologic signs, such as tinnitus, neck stiffness, and cells in the cerebrospinal fluid (pleocytosis), are present, along with dermatological signs like white patches on the arms or torso, sudden hair loss (alopecia), or loss of colour in the hair, eyelashes, or eyelids (poliosis).
b. Incomplete VKH disease: Individuals in this category exhibit a similar eye disease as those with complete VKH disease but lack both neurologic and dermatological signs. Patients must have either neurologic manifestations or dermatological signs.
c. Probable VKH disease: Patients in this category display a similar eye disease as those with complete VKH disease but without the presence of neurologic and dermatological signs.
Differential diagnosis
• Sympathetic Ophthalmia
• Uveal lymphoid infiltration
• Intraocular lymphoma
• Ocular Lyme disease
• Sarcoidosis
• Uveal effusion syndrome
• Lupus choroidopathy
• Posterior scleritis
• Cat scratch disease
• Acute posterior multifocal placoid pigment epitheliopathy (APMPPE)
• Acute Leukaemia
• Metastatic Carcinoma
• Exudative retinal detachments due to malignant hypertension
• Central serous chorioretinopathy after steroid use
Complications
Read et al reported at least one complication developed in 51% of eyes with VKH disease. The most common complications are:
• Cataracts
• Glaucoma
• Choroidal Neovascularization
• Subretinal Fibrosis
• Choroidal Atrophy
• Posterior Synechiae
• Optic Atrophy
Management
During the acute phase, it is customary to recommend intravenous high-dose corticosteroids (IV methylprednisolone 1g or IV dexamethasone 100mg administered over 1 hour, following the exclusion of systemic infection and contraindications, and under the supervision of a physician) for a duration of 3 days. Subsequently, high-dose oral steroids are prescribed and tapered gradually.
The treatment protocol entails the immediate initiation of systemic corticosteroids administered orally at a dosage of 1-1.5mg/kg per day for a minimum period of 6 months. Notably, a study by Lai TY et al indicated that patients treated for less than 6 months had a higher likelihood of recurrences (58.8%) compared to those treated for 6 months or longer (11.1%). The initial high dose is upheld for 2-4 weeks, followed by a systematic tapering of the medication. There exists divergence among authors regarding the preferred first-line therapy for VKH disease, with some advocating for immunosuppressants as the treatment of choice. This inclination is attributed to the intent of circumventing the numerous side effects associated with prolonged corticosteroid use. Notably, the utilization of immunosuppressant therapy as the primary treatment has demonstrated superior visual acuity outcomes when compared to corticosteroid therapy alone. Immunomodulatory agents proven effective in clinical trials include Azathioprine (1-2.5mg/kg/day) and Cyclosporine A (3-5mg/kg/day), with Mycophenolate mofetil and Rituximab also finding application.
It is imperative to underscore the necessity for vigilant monitoring and evaluation of immunosuppressant administration, in collaboration with an internist, to promptly identify and address any potential complications or side effects arising from the treatment.
Conclusion
In conclusion, Vogt-Koyanagi-Harada disease manifests as a severe, bilateral, granulomatous pan-uveitis characterized by serous retinal detachments, disk hyperaemia, oedema, vitritis, and associated symptoms like headaches, nausea, meningismus, alopecia, vitiligo, and hearing loss. While the extraocular manifestations can vary, early detection and intervention are crucial. Timely and aggressive treatment can lead to favourable outcomes for patients with Vogt-Koyanagi-Harada disease, helping to mitigate potential complications such as sunset glow fundus, cataracts, glaucoma, subretinal fibrosis, and choroidal neovascularization.
References
1. Ghazala A. Datoo O’Keefe MD and Narsing A. Rao MD. Vogt-Koyanagi-Harada disease. Survey of Ophthalmology Journal. 2nd December 2016. Available from:
Vogt-Koyanagi-Harada disease – ScienceDirect
2. Bykhovskaya I, Thorne JE, Kempen JH, Dunn JP, Jabs DA. Vogy-Koyanagi disease: clinical outcomes. Am J Ophthalmol. 2005;140:674-8. Available at:
Vogt-Koyanagi-Harada Disease – Symptoms, Causes, Treatment | NORD (rarediseases.org)
3. Gonzalez-Delgado M, Gonzalez C, Blazquez JI, et al., Intravenous immunoglobulin therapy in Vogt-Koyanagi-Harada syndrome. Neurologia. 2004;19:401-3. Available at:
Vogt-Koyanagi-Harada Disease – Symptoms, Causes, Treatment | NORD (rarediseases.org)
4. Vogt-Koyanagi-Harada disease (no date) EyeWiki. Available at:
Vogt-Koyanagi-Harada Disease – EyeWiki (aao.org)