Vogt-Koyanagi-Harada disease.

Vogt-Koyanagi-Harada disease is a rare, multisystem, autoimmune disorder with numerous clinical manifestations, mediated through a T-helper 1 response against melanocytes in the eye, inner ear, central nervous system, hair and skin. We describe a 20-year-old British-Honduran man with recent worsening headache and photophobia, vomiting and visual blurring. On examination, his pupils reacted sluggishly and visual acuities were bilaterally reduced. Optical coherence tomography showed gross retinal swelling and neurosensory detachments. MR scan of the brain was normal, but cerebrospinal fluid showed a reactive picture with 258 ×109 lymphocytes./L (normal ≤5×109/L). Following treatment with immunosuppression (prednisolone, tacrolimus, mycophenolate mofetil, adalimumab), he made a full recovery. Clinicians should consider Vogt-Koyanagi-Harada disease in patients presenting with headache with acute profound visual loss. A prompt diagnosis and immunosuppressive therapy can lead to complete resolution.

Absence of recognition of common melanocytic antigens by T cells isolated from the cerebrospinal fluid of a Vogt-Koyanagi-Harada patient.

PURPOSE: Vogt-Koyanagi-Harada (VKH) syndrome is an autoimmune disease characterized by inaugural uveomeningitidis and hearing loss and at late stages a depigmentation in eyes and skin. Melanocytes are the cells common to the four affected tissues, namely eye, brain, inner ear, and skin. Melanocytes are therefore considered as the source of self-antigens. The melanocytic proteins tyrosinase-related protein-1 (TRP1), TRP2, tyrosinase, and gp100 have been proposed as the proteins targeted by autoreactive T cells from VKH patients bearing human leukocyte antigen (HLA)-DRB1*04:05, the HLA allele classically associated with VKH disease. The objective of this work was to determine the antigens recognized by a large number of potentially autoreactive CD4 T lymphocytes obtained from the cerebrospinal fluid of one VKH patient who did not express HLA-DRB1*04:05. METHODS: T cells were isolated from the cerebrospinal fluid of a newly diagnosed HLA-DRB1*14:01,*15:03;-DPB1*01:01,*04:02 patient in the acute phase of the VKH disease and cloned by limiting dilution. Each of the 107 T cell clones, of which 90% were CD4(+), was tested for its ability to secrete cytokines upon contact with autologous antigen-presenting cells loaded with either of the melanocytic proteins TRP1, TRP2, tyrosinase, gp100, Melan-A and KU-MEL-1. The sensitivity of our recombinant bacteria-based approach was validated with a CD4 T cell clone with known antigen specificity. The ability of each of the 107 clones to secrete cytokines upon nonspecific stimulation was verified. RESULTS: None of the 107 T cell clones was able to secrete tumor necrosis factor-α, interferon-γ, interleukin (IL)-5, or IL-17 upon contact with autologous B cells loaded with any of the six common melanocytic proteins. Nine clones secreted high-level IL-17 upon stimulation with beads coated with antibodies. CONCLUSIONS: The self-antigens that triggered the VKH disease in this patient probably derive from proteins other than the six melanocytic proteins mentioned above. Further study of antigens that are recognized by potential autoreactive T cells from VKH patients is likely to benefit from testing a broader set of melanocytic proteins.

Teaching neuroimages: cerebral white matter involvement in a patient with Vogt-Koyanagi-Harada syndrome.

A 27-year-old man presented with decreased vision bilaterally. Ophthalmologic examination revealed panuveitis with bilateral serous retinal detachments (figure 1) characteristic of Vogt-Koyanagi-Harada (VKH) syndrome. Analysis of CSF revealed mild pleocytosis. No oligoclonal bands were detected. On MRI, there was bilateral abnormal thickening of the choroid with retinal detachment (figure 2, A and B), with hyperintense lesion on fluid-attenuated inversion recovery (FLAIR) image in the periventricular deep white matter (figure 2C). VKH syndrome is one of the causes of uveo-meningeal syndromes. Differential diagnosis of VKH syndrome includes Wegener granulomatosis, sarcoidosis, and Behçet disease.(1) The main disorders showing association with hyperintense plaques on deep white matter FLAIR images are inflammatory, metabolic, vascular, degenerative, autoimmune, and demyelinating diseases. MRI is a helpful tool in diagnosing VKH syndrome; in addition to the typical bilateral ocular findings, scattered periventricular white matter lesions on FLAIR are also described.(2.)

Melanin-laden macrophages in the CSF to diagnose Vogt-Koyanagi-Harada simulating ocular syphilis.

PURPOSE: To describe a case of Vogt-Koyanagi-Harada (VKH) disease initially presenting as ocular syphilis. METHODS: A 51-year-old woman presented with counting fingers vision in both eyes. She underwent a complete ophthalmic examination, serological testing, fluorescein angiography, and CSF analysis. RESULTS: Serological testing revealed positive titers for syphilis. Fluorescein angiography demonstrated findings suggesting VKH. CSF cytology showed macrophages containing melanin granules consistent with VKH. Subsequent treatment with corticosteroids and cyclosporine resulted in significant improvement of vision. CONCLUSION: The presence of melanin-laden macrophages within the CSF allows for the differentiation of VKH from ocular syphilis.

Influence of early cerebrospinal fluid-guided diagnosis and early high-dose corticosteroid therapy on ocular outcomes of Vogt-Koyanagi-Harada disease.

PURPOSE: To evaluate the importance of early cerebrospinal fluid (CSF)-guided diagnosis and early high-dose corticosteroid therapy on the complications and visual prognosis of Vogt-Koyanagi-Harada (VKH) disease. PATIENTS AND METHODS: Charts from patients with VKH disease who had been seen at Tokyo Medical and Dental University Hospital and Miyata Eye Hospital between 1994 and 2002 were retrospectively reviewed. The patients were classified into two groups. The first group (group A) consisted of patients who had received a full work-up including CSF examination and corticosteroid pulse therapy at the acute ophthalmic stage of disease. The second group (group B) consisted of patients who were referred to us by local ophthalmologists long after the disease onset, had not had a CSF examination and had been treated with low-dose systemic corticosteroids or topical corticosteroid therapy. The ocular complications, systemic complications and visual prognosis were compared between the two groups. RESULTS: Twenty-two patients were included in group A and ten patients in group B. The initial diagnosis at the acute ophthalmic stage had been VKH disease in all patients of group A, while, in group B, the diagnosis was idiopathic uveitis in six patients (60%) initially. Frequency of recurrent uveitis and integumentary symptoms were significantly lower in group A. Intensity of sunset glow fundus was significantly more severe in group B. All eyes in group A obtained a final visual acuity of 0.8 or better, whereas 11 eyes (55%) in group B were below this level. CONCLUSIONS: The results indicate that early diagnosis, helped by CSF examination and early high-dose corticosteroid therapy, decreased the complication rate and improved the visual prognosis.

Utility of lumbar puncture in diagnosis of Vogt-Koyanagi-Harada disease.

PURPOSE: To determine the significance of lumbar puncture in diagnosis of Vogt-Koyanagi-Harada disease (VKH). METHOD: A retrospective analysis was conducted on 116 consecutive patients diagnosed with VKH. Two additional patients who presented with acute VKH were included in the analysis. Demographic characteristics, including gender, age, and ethnicity, were extracted from the medical record. The stage of disease at presentation was documented. Pertinent laboratory results and diagnostic procedures such as lumbar puncture, fluorescein angiography, and echography that contributed to the diagnosis of VKH were collected. RESULTS: Lumbar puncture results for 10 patients were available. Eight of these patients presented with pleocytosis consistent with a diagnosis of VKH. Clinical features and fluorescein angiography confirmed the diagnosis in these patients. Both of the patients who did not exhibit cerebrospinal fluid (CSF) pleocytosis presented with headache, vision loss, and bilateral uveitis. Fluorescein angiography disclosed multiple foci of leakage at the retinal pigment epithelium level with accumulation of dye under the retina and disc leakage, confirming diagnosis of VKH. CONCLUSION: The utility of lumbar puncture as a diagnostic criterion for VKH should be re-evaluated given that clinical features and fluorescein angiography alone often support the diagnosis. The inherent risks and complications associated with the procedure must prompt the clinician to reserve this evaluation for atypical presentations.

Vogt-Koyanagi-Harada's disease presenting polymorphonuclear pleocytosis in the cerebrospinal fluid at the early active stage.

We report a 16-year-old woman with Vogt-Koyanagi-Harada's (VKH) disease, presenting polymorphonuclear pleocytosis in the cerebrospinal fluid (CSF) and neurological manifestation similar to meningoencephalitis. VKH disease, which has severe neurological manifestations including numerous CSF polymorphonuclear pleocytosis, should be considered as a differential diagnosis from infectious meningoencephalitis.

Chemokine profile in the cerebrospinal fluid and serum of Vogt-Koyanagi-Harada disease.

We analyzed the concentrations of four chemokines in the cerebrospinal fluid (CSF) and sera in Vogt-Koyanagi-Harada disease (VKH), an autoimmune uveomeningitis syndrome against melanocyte-associated proteins, with ELISA. CSF-CXCL10/IP-10 and CSF-CCL17/TARC were significantly elevated in VKH than in controls. In the majority of VKH cases and controls, CSF-CXCL10 was higher than serum-CXCL10, and CSF-CCL17 was lower than serum-CCL17. CCL11/Eotaxin was not different between groups. CSF-CCL2/MCP-1 was significantly lower in VKH than in control. The changes in VKH were essentially similar to those in multiple sclerosis, a known Th1-dominant condition.

Bcl-2 expression by CD4 T lymphocytes in Vogt-Koyanagi-Harada disease.

PURPOSE: To determine whether Bcl-2 is expressed on CD4(+ ) lymphocytes in the aqueous humor (AH) and cerebrospinal fluid (CSF) of patients with Vogt-Koyanagi-Harada (VKH) disease, and to determine whether Fas will induce apoptosis of lymphocytes in the CSF. METHODS: The percentages of CD4, CD8, CD45RO, Fas, and Bcl-2 positive T lymphocytes in the AH and CSF of eight patients with active VKH and five healthy controls were determined by flow cytometry. Soluble Fas ligand (sFasL) in the CSF was measured by ELISA. Freshly isolated cells from the CSF were cultured with anti-Fas antibody (Ab) and apoptosis was assessed by the TUNEL method. RESULTS: Fas(+) CD4(+) lymphocytes were the predominant lymphocytes in the AH and CSF of VKH patients. Bcl-2 was strongly expressed in these cells. Soluble FasL was also detected in the CSF. The number of apoptotic cells detected by anti-Fas Ab was not significantly increased in the CSF of VKH patients. CONCLUSIONS: In spite of the high expression of Fas antigen on CD4(+) cells and the presence of sFasL in the CSF, apoptosis was not observed. Bcl-2 expression may contribute to the regulation of apoptosis of inflammatory cells in the CSF of VKH patients.

Vogt-Koyanagi-Harada disease presenting initially as aseptic meningoencephalitis.

Vogt-Koyanagi-Harada (VKH) disease in a Gypsy woman was diagnosed 4 months after her initial complaints. The delay is explained by the facts that: (1) the characteristic ophthalmological symptoms, which usually herald the disease and ensure early diagnosis, developed only late during the course; and (2) only retrospective analysis of the cerebrospinal fluid (CSF) cell preparation proved the presence of melanin-laden macrophages (MLMs), specific for the syndrome. We emphasize that VKH syndrome may initially present as aseptic meningitis, without specific ophthalmological symptoms. In suspected cases a very detailed CSF cell analysis is needed, because the presence of MLMs could confirm the diagnosis. However, VKH syndrome has a much higher incidence in Asia; cases in other races, including white people in Europe, also occur.

Melanin-laden macrophages in cerebrospinal fluid in Vogt-Koyanagi-Harada syndrome.

OBJECTIVE: To identify basophilic granules in the cytoplasm of macrophages in cerebrospinal fluid (CSF) smears from patients with Vogt-Koyanagi-Harada (VKH) syndrome as melanin pigment. DESIGN: Morphological and immunocytochemical studies were performed on CSF smears obtained from 7 patients with VKH syndrome. Specimens were stained with May-Grünwald and evaluated by a silver impregnation method (Fontana-Masson staining). For immunocyto-chemical study, the smear was reacted with mouse anti-human melanoma cell (HMB-45) monoclonal antibody. RESULTS: Basophilic granules were detected in the cytoplasm of macrophages in CSF cell smears obtained from 6 of 7 patients with VKH syndrome in the early stages (within 25 days). Using the silver impregnation method, these basophilic granules were strongly stained black. Moreover, they were identified as melanin by positive immunocytochemical staining. The total number of cells containing cytoplasmic granules ranged from 3 to 8 per 10,000 total cells in CSF. In contrast, no cells containing cytoplasmic granules were found in control CSF cell smears from patients with viral, bacterial, or noninflammatory diseases. CONCLUSION: The identification of melanin-laden macrophages in the CSF of patients with VKH syndrome suggests that these cells are responsible for pleocytosis in the immunopathologic process of VKH syndrome.

Characterization of T-cell subsets, soluble interleukin-2 receptors and interleukin-6 in Vogt-Koyanagi-Harada disease.

The lymphocyte subunits and subsets of 12 patients with Vogt-Koyanagi-Harada disease (VKH disease) were characterized using two-color flow cytometry techniques, both in cerebrospinal fluid (CSF) and in peripheral blood (PB). Soluble interleukin-2 receptor (sIL-2R) levels and interleukin-6 (IL-6) levels were also measured. The percentage of T cells was significantly higher in CSF than in PB (P less than 0.01), but the percentage of B cells was decreased in CSF (P less than 0.05). As for T-cell subsets, the percentage of helper T cells was especially high in CSF (P less than 0.01). Also, the ratio of helper T cells/suppressor T cells was significantly larger in CSF than in PB. These data suggest that helper T cells play an important role in the early stages of VKH disease. sIL-2R and IL-6 levels were not elevated in CSF of patients with VKH disease. The level of sIL-2R in serum also was not elevated.

Immunologic analysis of cerebrospinal fluid lymphocytes in Vogt-Koyanagi-Harada disease.

In this study, we focused upon the immunologic aspects of Vogt-Koyanagi-Harada disease (VKH) by comparing the cytotoxic activity of peripheral blood leukocytes (PBL) to that of cerebrospinal fluid leukocytes (CSFL) against the human melanoma cell line (P-36) and the human cervical carcinoma cell line (HeLa-S3). The PBL from patients with VKH showed significant cytotoxic activity against P-36 (P less than 0.01), but did not show cytotoxic activity against HeLa-S3. The CSFL showed significantly weaker cytotoxic activity against P-36 compared to that of PBL (P less than 0.02). We also analyzed the cell membrane surface markers applying monoclonal antibodies on PBL and CSFL. The percentage of OKT8+ (CD8: T cytotoxic/suppressor lymphocytes) cells was significantly lower in CSFL than in PBL (P less than 0.05). There was a tendency toward a higher percentage of HLA-DR+ cells (B lymphocytes, monocytes, macrophages, and activated T lymphocytes) and a higher ratio of OKT4+/8+ cells (CD4/CD8: T helper/inducer lymphocytes/T cytotoxic/suppressor lymphocytes) in CSFL from patients with VKH than in their PBL (P less than 0.1).