This patient's symptoms began with a nonspecific "cold", low grade fever, and generalized aching headaches. Subsequently, she developed meningismus (stiff neck), progressive worsening of the headaches, decreased visual acuity (requiring new and renewed prescription eyeglasses), metamorphopsia (bumpy, curved floor), dysacusis, tinnitus, impairment in memory and concentration, and painful injected eyes. The ophthalmologic examination revealed mild anterior and marked posterior uveitis with multiloculated exudative retinal detachments bilaterally. These symptoms and signs of meningitis, encephalopathy, and uveitis indicated multiple system involvement. The differential diagnosis of uveoretinal meningoencephalitis includes inflammatory diseases, infectious processes, and eye/CNS diseases.
Inflammatory Diseases
Systemic lupus erythematosus: This patient did not have a skin rash, photosensitivity, or systemic symptoms or signs. Moreover, lupus choroidopathy occurs with significant vasculitis, renal complications (including systemic hypertension), and rarely is associated with retinal pigment epithelial disease or secondary retinal detachment.
Sarcoidosis: CNS involvement is present in 5% of cases and presents clinically as a basal meningitis with cranial nerve VII most frequently involved, followed by V and II. The optic nerve may be swollen, and patients may have uveitis and meningoencephalitis with hypothalamic involvement. The uveitis is usually anterior rather than posterior. Moreover, retinal detachment is unusual. Although periphlebitis and periarteritis may occur; neither was present in this patient. Furthermore, large sarcoid granulomas were not seen in the choroid.
Ocular lyme borreliosis can present with iridocyclitis, vitreitis, and occasionally panuveitis and retinal detachment. Our patient resided in a low-prevalence area. She had no history of tick bite, radiculopathy, neuropathy, or focal deficits such as optic neuritis, all of which are common in Lyme.
Other inflammatory diseases: These include multiple sclerosis (the history, physical examination, and CSF results did not support this diagnosis); Behcet (there was no history of genital or oral ulcers, arthritis, or acne); and inflammatory bowel disease (no GI symptoms or arthralgia).
Infectious Diseases
Syphilis can present with meningitis 6-12 months after the primary infection with focal deficits, including cranial nerve palsies (VII, VIII, VI, and II). However, uveitis, chorioretinitis, and optic neuritis are late manifestations. Our patient had no history of sexually transmitted disease or skin rash, and her CSF VDRL was non-reactive.
Tuberculosis meningitis can be acute and fulminant, with encephalopathy, seizures, focal deficits, and hydrocephalus; or chronic, with personality changes leading to lethargy and coma. The CSF white blood cells and protein are markedly elevated with glucose less than 50% of the serum level in 50-85% of the cases. Chest x-ray is abnormal in 50-90% of cases, and imaging studies demonstrate basal meningitis, with or without masses, that reflect the tuberculomas. Our patient had no history of exposure to TB, had a subacute meningitis that was not fulminant, and CSF findings that were not characteristic of TB. Moreover, the CSF AFB smear was negative. Retinal changes are limited to "multifocal" granulomas, large or small; neither were present in this patient.
Herpes Simplex encephalitis (HSE) was considered in the differential. However, the patient did not have florid behavioral changes, amnesia, focal deficits, seizures, or disorientation which are common presentations with this diagnosis. The CSF was not hemorrhagic, as frequently seen in HSE. Herpes zoster can cause a similar picture, but usually the uveitis, conjunctivitis, keratitis, and encephalitis follow ophthalmic zoster, of which the patient had no history. H.S. intraocular disease is usually a necrotizing retinitis, which were not noted in this case.
Whipple disease can rarely involve the CNS without GI symptoms. The most common presentation is dementia. Other manifestations include seizures, myoclonic jerks, cerebellar ataxia, clouding of consciousness, visual symptoms, papilledema, supranuclear ophthalmoplegia, and myelopathy. Our patient did have decreased visual acuity, but otherwise, did not clinically fit the picture for Whipple's disease. The diagnosis of Whipple disease requires a jejunal biopsy, but this was not carried out.
Fungal infections may affect immunocompetent hosts. Fungal infections, however, are subacute to chronic infections which at times are associated with encephalitis, hydrocephalus, focal deficits, and cranial nerve palsies. In cryptococcal meningitis, there are ocular deficits in 40% of the patients, including papillitis, decreased visual acuity, diplopia, and papilledema. CSF is usually abnormal with pleocytosis, elevated protein, and decreased glucose. In our patient, there was no evidence of immunodeficiency (no history of repeated infections, SDT risk, diabetes, renal disease, or prior immunosuppressive therapy). CSF cryptococcal antigen was negative, as well as the CSF smear and fungal cultures.
Other: HIV meningitis can cause a similar clinical picture with acute meningitis 3-6 weeks after the primary infection, but the eye findings are varied (cotton-wool spots being the most common). Our patient did not have risk factors nor fit the clinical picture for this diagnosis. CMV causes retinitis and encephalitis, but only in immunocompromised patients. The same argument follows for toxoplasmosis.
Eye/CNS Diseases
Sympathetic ophthalmia can present in a similar fashion, with rapid bilateral visual loss associated with anterior segment inflammation, disk edema/hyperemia, choroidal thickening, and serous retinal detachments. However, the lack of a history of ocular trauma or surgery make this diagnosis less likely.
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an acute condition occurring in both men and women from 15-50 years of age classically in the recovery phase after a viral illness and is characterized by loss of central vision associated with the appearance of multiple pale lesions in the retinal pigment epithelium. The patients may occasionally have papillitis and serous detachment of the retina or CNS involvement with headache, transient ischemic attacks, dysacusis and tinnitus. It is a self-limited disease, resolving in 2-3 weeks. Our patient's visual acuity continued to deteriorate three weeks after the onset of her symptoms. Our patient also had marked posterior uveitis, as well as evidence of mild anterior uveitis which is less common in APMPPE.
Multifocal secondary retinal and pigment epithelial detachments are also seen in (Grade IV) systemic hypertension, and pregnancy-induced hypertension.
Vogt-Koyanagi-Harada syndrome consists of bilateral, rapid, and painful loss of vision associated with posterior or panuveitis. It is associated with meningitis, dysacusis, uveitis, and much later with depigmentation of the uveal tract and skin. Multifocal and multiloculated serous pigment epithelial and retinal detachments are seen on ophthalmoscopic exam and documented on fluorescein angiography. This patient had all the classical features of this syndrome and therefore Vogt-Koyanagi-Harada syndrome was considered to be the most likely diagnosis.
Summary
This patient was diagnosed with Vogt-Koyangi-Harada syndrome based on the history, physical examination, ancillary studies, and exclusion of other possible etiologies. The fluorescein angiogram confirmed multiple serous retinal and retinal pigment epithelial detachments and the characteristic "stars at night" appearance of the myriad pin-point leaks of fluorescein from the RPE as seen in VKH.
The patient received high-dose intravenous steroids for five days. On discharge, the retinal detachments had almost completely resolved and visual acuity was 20/50 in each eye. The neurological exam remained abnormal with brisk reflexes and abnormal posterior column signs (decreased vibration and proprioception). Mentation improved, but she still had a decreased attention span. She had only mild nuchal rigidity and headache, occurring only in the A.M. She was discharged on oral steroids to be tapered according to clinical status.
Five days following discharge, her corrected visual acuity was 20/25 OD and 20/30 OS. Intraocular pressures were normal. The fundus examination showed essentially complete resolution of the secondary retinal detachments and most of the pigment epithelial changes, although there were some residual subretinal precipitates. One month later, she was asymptomatic and visual acuity was 20/15 OU.
Discussion
Vogt-Koyanagi-Harada syndrome (VKH) is a rare disease characterized by panuveitis, serous retinal detachment, and signs of meningeal irritation. Auditory disturbances and skin changes may also be present. The syndrome was first described in 940-1010 AD by Ali-ibn-Isa, an ophthalmologist, and reported independently by Vogt, Harada, and Koyanagi at the turn of the 20th century.[10] In 1932, Babel classified the disease as Vogt-Koyanagi-Harada (VKH) syndrome.[10]
VKH occurs most often in pigmented individuals, rarely in fair individuals. There is a slight preponderance of females. The age of onset is usually between the second and fifth decades, with a mean age of 30-40 years. The youngest alleged age reported is in a 4 year old boy.[2]
In the United States, the incidence of VKH is 1-4% of all uveitis cases.[10] The incidence of uveitis is 15 per 100,000. Uveitis is an inflammation of the uveal tract (the iris, the ciliary body, and the choroid). Anterior uveitis involves the iris (iritis); intermediate uveitis involves the ciliary body (cyclitis), and posterior uveitis involves the choroid (choroiditis). Panuveitis is the term used when all the uveal tracts are involved. In VKH, however, the choroidal disease manifests as a breakdown in the pump/barrier function of the RPE, leading to the exudative retinal detachments.
Clinical Presentation
VKH presents clinically with diverse manifestations, but the syndrome can be categorized into prodromal, uveitic, convalescent, and recurrent phases.[5,10]
Prodromal Phase: This phase, also called the meningeal phase, lasts for a few days, during which patients have headache, fever, and meningismus. Other complaints include confusion, and photophobia. Auditory symptoms, such as tinnitus and dysacusis (hearing impairment with distortion of frequency or intensity and discomfort for certain sounds) are seen in the majority of patients, and can occur at any stage. CSF reveals lymphocytic pleocytosis.
Uveitic Phase: The uveitic phase, which lasts for several weeks, consists of acute blurring of vision in both eyes, eye pain secondary to ciliary spasm, photodysphoria, decreased visual acuity secondary to anterior chamber or vitreous inflammation, injected eyes, and cyclitis. Ophthalmoscopic examination reveals choroidal thickening, disk hyperemia and exudative retinal detachments. These detachments and their multifocal, multi-leak origins are best resolved with fluorescein angiography.
Convalescent Phase: This phase is characterized by dermatologic changes that include patchy alopecia, patchy poliosis (i.e. graying of the hair of the eyebrows, lashes, and scalp), and symmetrical vitiligo over the head and trunk. There is also uveal depigmentation, the earliest of which is perilimbal vitiligo (Sugiura's sign), followed 1-2 months later by pigment epithelial depigmentation (sunset-glow fundus). However, the RPE/choroidal features have been considerably moderated with the early intervention with systemic steroids.
Chronic Phase: The chronic phase consists of smoldering panuveitis with acute episodes of anterior uveitis. The recurrence of posterior uveitis is distinctly uncommon. In this stage complications of VKH develop.
Diagnostic Criteria
Because of the varied clinical manifestations, the American Uveitis Society adopted in 1978 the following diagnostic criteria:[16]
No history of ocular trauma or surgery
At least three out of the following four criteria:
Bilateral chronic iridocyclitis
Posterior uveitis, including multifocal exudative retinal and RPE detachments, and disc hyperemia or edema
Neurological signs of tinnitus, neck stiffness, cranial nerve or central nervous system dysfunction, or cerebrospinal fluid pleocytosis
Cutaneous findings of alopecia, poliosis, or vitiligo (late)
In the majority of cases, the diagnosis is made clinically.[10] Fluorescein angiography, ultrasonography, lumbar puncture, and other studies substantiate the diagnosis, especially in atypical cases. The fluorescein angiography reveals hyperfluorescence at the level of the RPE with pooling of the dye into the subpigment epithelial and/or subretinal spaces, delineating the serous retinal detachments.[10,13]
Pathology and Pathogenesis
The few available pathology reports emphasize the presence of granulomatous panuveitis with many of the epithelioid and giant cells containing melanin pigment. In the chronic stage, there is disappearance of the melanocytes of the choroid and vitiliginous skin. Similar findings are believed to occur in the meninges and the inner ear at the site of melanin-containing cells.[5,10,13]
The pathogenesis is not known but is believed to be an autoimmune process directed against melanocytes. Evidence in support of this theory include:
Reports of other autoimmune diseases, such as Hashimoto thyroiditis, in patients with VKH.[8]
Antiretinal antibodies detected in the sera of VKH patients.[10]
On histopathology, there is inflammation and loss of melanocytes in the uveal tract and skin.
Lymphocytes from peripheral blood and CSF of VKH patients exhibit cytotoxic activity against B-36 melanoma cell lines.[10] One report detected IL-2 dependent T-lymphocytes that have specificity toward normal melanocytes and S-allogenic melanoma cells, suggesting an autoimmune process against melanocytes. In addition, there is an increase in activated T-lymphocytes within choroidal inflammatory foci. Class II MHC antigens are expressed on choroidal melanocytes and endothelium of choriocapillaries, suggesting a T-cell mediated delayed type of hypersensitivity against choroidal melanocytes that aberrantly express class II MHC antigens in response to an autoimmune process.[9,12,18]
Genetics
The Japanese have studied the genetics of VKH in depth. HLA-DR4 and DwS3 have strong associations with VKH in Japanese and Chinese patients. A recent study demonstrated a significant association of HLA-DPB1*0501 with VKH and linkage disequilibrium with the primarily associated allele DRB1*0405.[7,14,15]
Therapy
The goal of therapy in VKH is to suppress the initial intraocular inflammation with early and aggressive use of systemic corticosteroids, followed by a slow taper over 3-6 months. Treatment with prednisone may shorten the duration of the disease, prevent complications, and decrease the occurrence of extraocular signs. If patients are resistant to steroids, then IV IgG may be helpful. Helveston described a patient that did not respond to high dose steroids, but the addition of IV IgG resulted in improvement of neurological symptoms. Combination treatment with immunoglobulins and high dose corticosteroids may be optimal treatment for refractory neurological deficits. Proper diagnosis will assure early and effective treatment of this rare and interesting disease.[4]
References
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