CASE REPORT

A previously healthy 30 year old Portuguese woman was admitted complaining of progressive visual loss in both eyes, over 2 weeks, associated with headaches and pain on eye movements and meningismus. Symptoms appeared 24 hours after the beginning of a flu-like syndrome. The patient had no past history of ocular trauma or surgery. On examination, the visual acuity was 20/100 in both eyes. Slit-lamp examination revealed 2+ cells in both anterior chambers with non-granulomatous keratic precipitates. Intraocular pressure was 10 mm Hg in both eyes. There were 1+ cells in the anterior vitreous of both eyes. Fundus examination revealed a bilateral papilloedema and the fluorescein angiography showed focal areas of leakage at the level of the retinal pigment epithelium and staining of the optic disc (Fig 1A, B).

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Figure 1

Late phase of the fluorescein angiogram, right eye (A) and left eye (B). Focal areas of leakage at the level of the retinal pigment epithelium (arrows) and staining of the optic disc.

The initial clinical examination revealed an erythrocyte sedimentation rate of 10 mm in the first hour (normal range 1–12), a white blood count of 4.2 g/l (normal range 4–11 g/l) with a normal differential count. Chest x ray was normal. A lumbar puncture showed a lymphocytic pleocytosis (proteins 0.37 g/l, white cells 77×10⁶/l, lymphocytes 96%), without oligoclonal bands on electrophoresis. A magnetic resonance cerebral scan was normal. Suspecting a herpetic infection, aciclovir (900 mg/8 hours), topical steroids, and prednisone (1 mg/kg) were administered on the day of admission.

Further investigations revealed that serology (cytomegalovirus (CMV), Epstein–Barr virus, herpes simplex I/II, varicella zoster virus, rubella virus, toxoplasmosis, Borrelia burgdorferi,Treponema pallidum, and HIV) was positive for anti-CMV IgM (ratio: 0.7, normal 0.6) and IgG (521 units of IgG antibody anti-CMV per ml (UA/ml), normal 15) and early CMV antigen was detected in the urine. An anterior chamber tap was performed (the day of admission, before starting antiviral and anti-inflammatory therapy); results were positive for a local production of anti-CMV immunoglobulins; the Goldmann–Witmer coefficient was 4.47 for CMV, 0.56 for herpes simplex virus, and not calculable for varicella zoster virus and for Epstein–Barr virus. Viral serologies in the cerebrospinal fluid were negative. Tests for sarcoidosis and for connective tissue disorders were negative. Immunoglobulin electrophoresis, quantitative immunoglobulin levels, PPD skin test, CD4-CD8 lymphocytes count, C3-C4, and CH50 examination were within the normal range.

Based on the clinical findings, by the positive CMV serology, the presence of early CMV antigen in the urine and by the result of the anterior chamber tap an acute CMV infection was diagnosed; aciclovir was discontinued after 4 days, and we administered the more specific drug foscarnet (180 mg/kg) for 21 days. Topical steroids and oral prednisone (1 mg/kg) were also continued for 1 month at tapering doses. After 3 weeks of treatment, visual acuity returned to 20/20 in both eyes. Papilloedema disappeared in both eyes. Two months later, viral titres revealed a decrease in CMV IgM (ratio: 0.5) and an increase of the CMV IgG to 707 U/ml. Early CMV Ag was no longer detectable in the urine.

After 3 months, the patient developed poliosis of her eyelashes, eyebrows, and scalp hair. A vitiligo appeared. Fundus examination revealed a diffuse depigmentation affecting both posterior segments, and areas of chorioretinal atrophy (Dalen–Fuchs nodules) in the periphery of both fundi (Fig 2A, B). Tests seeking to establish a hearing loss were unremarkable. HLA typing was positive for the HLA-DRB1*0701/08. On the basis of the clinical evolution, the presence of integumentary manifestations and the results of the cerebrospinal tap a VKH syndrome was diagnosed.

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Figure 2

Colour picture of right eye (A) and left eye (B). Diffuse depigmentation affecting both posterior segments, and areas of chorioretinal atrophy (Dalen–Fuchs nodules) in the periphery of both fundi.

COMMENT

VKH syndrome is a bilateral panuveitis associated with vitiligo, poliosis, auditory signs and neurological manifestations (cerebrospinal fluid lymphocytic pleocytosis, meningoencephalitis, hemiparesis). Typically, the presence of these features is variable and might depend on the race of the patient. Clinically, this syndrome is characterised by a prodromal stage (headache, fever) and followed by a panuveitis with retinal oedema and/or multiple retinal serous detachments. After several weeks of evolution, a depigmentation of the integuments and choroid appear. Moreover, most of the patients relapse and develop a chronic recurrent phase of the disease. VKH syndrome has a predilection for darkly pigmented races (Asian, Hispanics, American and Asian indians) and is uncommon in whites.1 Our patient was Portuguese and had these clinical features. Most patients are in their second to fourth decade of life at onset of the disease; nevertheless, VKH syndrome has also been reported in children and young adults.1

To date no certain aetiological factors has been reported, but taking into account that this illness affects various organs (skin, eye, central nervous system) a common aetiological factor seems to be involved in the pathogenesis. Among the hypotheses that have been formulated, the role of genetic constitution is important. Ohno first discovered, among the Japanese population, a link between VKH syndrome and HLA-DR4/Dw53.2 Other authors have reported the presence of antiretinal antibodies directed against photoreceptors and Müller cells in the sera of patients with a VKH syndrome.3 Moreover, other studies have demonstrated the presence of a close relation between melanocytes and the presence of lymphocytes directed against these cells. These findings tend to suggest the presence of an autoimmune response and/or hypersensitivity against melanocytes, leading to the development of an inflammation affecting the uvea, the skin, and the meninges resulting from a break of tolerance to self antigens. However, the initiating factor responsible of the autoimmune process is still unknown.

Autoimmune disorders are characterised by the breaking of immunological tolerance to self antigens after the activation of lymphocytes. The exact mechanism by which there is a loss of tolerance to self antigens is mostly unknown. Viruses have been implicated, as triggers, of this mechanism together with other mechanisms such as the presence of a genetic predisposition or through the activation of the cytokine network.

The induction and the development of the autoimmune process may be explained by the exposition of ocular tissue antigens to the immune system after a break of the blood-retinal barrier. It is conceivable that a tissue damage, by infectious agents, may render foreign some non-immunogenic ocular antigens.

Another mechanism by which micro-organisms can induce ocular autoimmunity is by the presence of homology between some sequences of their proteins and the sequence of uveitogenic determinants of ocular antigens. Recently, it has been shown that there is an amino acid sequence homology between certain bacterial antigens and some autoantigens and between sequences in retinal S-antigen and protein from yeast histone H3 and Escherichia coli, as well as with certain viral peptides.4-6 This similarity between self and foreign antigens called “molecular mimicry”, may induce a cross reaction with one or more self antigens sharing determinants with the foreign agents; this suggests that infectious agents can act as a trigger of organ specific autoimmunity in predisposed individuals.7 Among presumed triggers that could initiate the immune process, viruses may play a role in the pathogenesis of VKH syndrome. Indeed, various authors have reported the presence of Epstein–Barr virus genome in the cerebrospinal fluid or in the vitreous of patients with VKH syndrome,8 9 although it is difficult to establish the exact role of ubiquitous viruses in specific diseases.10 Our patient had an anti-CMV antibody synthesis in the anterior chamber and an acute CMV infection.

This case illustrates the possible implication of CMV in the aetiology of VKH syndrome; nevertheless, other known or unknown viruses may be involved in the pathogenesis of this syndrome in predisposed individuals.