Carlos Eduardo Hirata

HLA-DRB1∗0405 is the Predominant Allele in Brazilian Patients With Vogt-Koyanagi-Harada Disease

Vogt-Koyanagi-Harada (VKH) disease is a rare disorder affecting pigmented structures especially the eye and is the main cause of autoimmune non-infectious uveitis in the Brazilian population. The autoimmune target is believed to be the melanocyte. A strong association of VKH disease with HLA-DR4 in the Japanese population is well known. The same association, albeit with lower relative risks has been found in other populations. A secondary association to HLA-DR1 involving a sequence linked with susceptibility to Rheumatoid Arthritis has also been described. VKH disease is more common in non-Caucasian populations. Brazilian patients of varying ethnic origins have been typed for HLA class II antigens. Several of the features found in other population samples are present. Over half of the patients typed HLA-DR4 (20/37) and typing with sequence-specific oligonucleotides disclosed predominance of the DRB1*0405 allele with a relative risk of 11.76 over the general population. In addition, HLA-DR1 and DQ4 were also present, in patients both positive and negative for HLA-DR4. These results suggest that, as in other autoimmune diseases, multiple overlapping susceptibility factors encoded by the MHC complex contribute to the overall susceptibility for the disease, the major factor however, being the presence of the DRB1*0405 allele.

Enhanced depth imaging optical coherence tomography in long-standing Vogt–Koyanagi–Harada disease

Aim To evaluate the choroidal thickness (CT) in patients with long-standing Vogt–Koyanagi–Harada (VKH) disease using enhanced depth imaging optical coherence tomography (EDI-OCT). Methods A prospective case–control study developed at a tertiary centre at São Paulo, Brazil. EDI-OCT images were obtained in 16 patients (30 eyes) with VKH disease who had had the disease for more than 6 months since disease onset, and in 17 normal individuals controlled by age (32 eyes). Comprehensive ophthalmic examination and EDI-OCT evaluation were performed. CT was measured at the fovea and at 1000 µm intervals from the foveal centre in both temporal and nasal directions. CT was correlated with disease duration, clinical disease activity and fundus-based disease severity. Results Mean subfoveal CT was 333 µm (±85.8) in controls and 250.7 µm (±93.3) in VKH patients (p=0.002). The choroid was significantly thinner in patients when compared to controls in all but one nasal point. In patients, the CT measurements at the foveal centre presented a negative correlation with disease duration (p<0.001). No significant difference in CT measurements was observed between eyes with and without clinical inflammation (p=0.42). There was a trend towards more severe fundus changes being associated with a thinner choroid (p=0.28). Conclusions Patients with VKH and long-standing disease had thinner choroids when compared to controls. Progressive choroidal thinning related to disease duration was observed at the macula of these patients. Whether this finding is part of the natural history of the disease or the result of a clinically undetected choroidal inflammation remains to be determined.

Revised Diagnostic Criteria for Vogt-Koyanagi-Harada Disease: Considerations on the Different Disease Categories

PURPOSE To evalulate the applicability of the Revised Diagnostic Criteria for Vogt-Koyanagi-Harada (VKH) disease to Brazilian patients and to verify the association between different disease categories, clinical parameters, and the presence of HLA-DRB1*0405. DESIGN A retrospective observational case series. METHODS Medical charts of 67 patients (10 to 64 years in age; 12 men and 55 women), from the Uveitis Service, Hospital das Clínicas, University of São Paulo School of Medicine (HCFMUSP), São Paulo, Brazil were reviewed. Patients, previously diagnosed with VKH disease using criteria proposed by the American Uveitis Society, underwent retrospective classification based on the Revised Diagnostic Criteria. The degree of concordance was assessed. At presentation, 46 patients (69%) were in the early phase. In this group, the mean time from disease onset to treatment was 15 days (range, one to 30 days). Forty-eight patients (72%) were typed for HLA-DRB1*0405 by polymerase chain reaction-sequence specific primer and polymerase chain reaction-sequence-specific oligonucleotides primer. Disease categories, phase at initial presentation, and ocular complications were analyzed. RESULTS There was a 100% of concordance between the two criteria. Disease was classified as complete in 10 patients (15%), incomplete in 37 patients (55%), and probable in 20 patients (30%). In each group, respectively, 90%, 76%, and 45% were in the early phase at presentation (P = .017). There was no association between disease categories, the presence of HLA-DRB1*0405, and clinical parameters. CONCLUSION The Revised Diagnostic Criteria proved useful for diagnosis of VKH disease in Brazilian patients. The present retrospective study did not find any association between disease category and severity parameters. To better understand the relevance of disease categories, a minimum follow-up period to categorize patients should be included in future prospective studies.

Chlorambucil and cyclosporine A in Brazilian patients with Behçet's disease uveitis: a retrospective study

PURPOSE To assess the efficacy and side effects of immunosuppressive therapy in patients with Behçets disease uveitis. METHODS A nonrandomized retrospective case-series study analyzed data from 22 patients with Behçets disease uveitis, from a single Uveitis Service, São Paulo, Brazil (period 1978-2007), under systemic chlorambucil and/or cyclosporine A, for at least 6 months with a minimum one-year follow-up. Drug efficacy was measured by reduction in relapse rate and reduction of prednisone dose. RESULTS Patients (10M/12F) mean age was 29 (range 10-43) years-old at the onset of uveitis. The median duration of followup was 11 (range 1-29) years-old. Chlorambucil (2-6 mg/day) was used in 13 patients and cyclosporine A (3-5 mg/kg/day) in 9 patients at initiation. Drugs were switched because of no effectiveness or side-effects. Chlorambucil was effective in 78.5% (11/14) and induced disease remission in 43% (6/14) of patients, whereas cyclosporine A was effective in 57% (8/14) of patients. Chlorambucil and cyclosporine A were discontinued due to side effects in 21% (leucopenia) and in 57% of patients (nephrotoxicity, 36% and gastrointestinal complications, 21%), respectively. No case of late malignancy was observed. 36% (16/44) of eyes had final visual acuity < or =0.1, among which 69% (11/16) had already this visual acuity at the first visit. CONCLUSION This study reiterates previous data that chlorambucil can induce long-term remission of Behçets disease uveitis, whereas cyclosporine is effective but side effects limit its use. Chlorambucil therapy may still be a reasonable option in patients with intractable, sight-threatening Behçets disease uveitis.

Fundus-Based and Electroretinographic Strategies for Stratification of Late-Stage Vogt-Koyanagi-Harada Disease Patients

PURPOSE To propose an analytic framework for ocular fundus alterations in late-stage Vogt-Koyanagi-Harada (VKH) disease, to describe the characteristics of overall retinal function as measured with full-field electroretinography (ERG), and to correlate the intensity of the fundus changes with full-field ERG alterations and to stratify patients accordingly. DESIGN Cross-sectional case series. METHODS Forty-seven eyes of 26 patients with late-stage VKH disease (> 6 months past disease onset) followed-up at the University of São Paulo School of Medicine underwent fundus photography within 2 months of a full-field ERG examination, both according to predefined protocols. Fundus pictures were evaluated by two observers regarding diffuse fundus depigmentation, nummular lesions, pigment clumps, and subretinal fibrosis, and an overall analysis classified the fundus changes as mild, moderate, or severe. Full-field ERG results were analyzed according to fundus-based stratification and also were stratified into 3 groups solely on the basis of decreasing amplitudes (ERG based or cluster stratification). The concordance between fundus-based and full-field ERG-based stratification strategies was estimated. RESULTS Overall fundus grading showed substantial interobserver concordance (kappa = 0.78). Comparison of full-field ERG parameters of the three fundus-based stratified groups showed diffusely diminished amplitudes with preservation of implicit times (P < .05). Fundus-based and full-field ERG-based stratification strategies also showed substantial concordance (kappa = 0.68). CONCLUSIONS The analytic framework for fundus findings proposed in this study seems reproducible and useful, because the severity categories do correlate with retinal function as measured by full-field ERG. This system may allow more precise exchange of information between practitioners as well as researchers with regard to identifying patients with greater retinal compromise rapidly as well as in comparison of outcomes of different treatment regimens.

Vogt-Koyanagi-Harada disease: review of a rare autoimmune disease targeting antigens of melanocytes

Vogt-Koyanagi-Harada disease (VKHD) is a rare granulomatous inflammatory disease that affects pigmented structures, such as eye, inner ear, meninges, skin and hair. This disease is mainly a Th1 lymphocyte mediated aggression to melanocytes after a viral trigger in the presence of HLA-DRB1*0405 allele. The absence of ocular trauma or previous intraocular surgery sets VKHD appart from sympathetic ophthalmia, its main differential diagnosis. The disease has an acute onset of bilateral blurred vision with hyperemia preceded by flu-like symptoms. The acute uveitic stage is characterized by a diffuse choroiditis with serous retinal detachment and optic disc hyperemia and edema. Fluorescein angiography in this phase demonstrates multiple early hyperfluorescent points. After the acute uveitic stage, ocular and integumentary system pigmentary changes may appear. Ocular findings may be accompanied by lymphocytic meningitis, hearing impairment and/or tinnitus in a variable proportion of patients. Prompt diagnosis followed by early, aggressive and long-term treatment with high-dose corticosteroids is most often ensued by good visual outcomes. However, some patients may experience chronic uveal inflammation with functional eye deterioration. The current review discusses the general features of VKHD, including epidemiology, classification into categories, differential diagnosis and current therapeutic approaches.

Indocyanine green angiography findings in patients with long-standing Vogt-Koyanagi- Harada disease: a cross-sectional study

BackgroundTo investigate indocyanine green angiography (ICGA) findings in patients with long-standing Vogt-Koyanagi-Harada (VKH) disease and their correlation with disease activity on clinical examination as well as with systemic corticosteroid therapy.MethodsTwenty-eight patients (51 eyes) with long-standing (≥6 months from disease onset) VKH disease whose treatment was tapered based only in clinical features were prospectively included at a single center in Brazil. All patients underwent standardized clinical evaluation, which included fundus photography, fluorescein angiography and ICGA. Clinical disease activity was determined based in the Standardization in Uveitis Nomenclature Working Group. Fisher exact test and logistic regression models were used for statistical analysis.ResultsDisease-related choroidal inflammation on ICGA was observed in 72.5% (31 of 51 eyes). Angiographic findings suggestive of (choroidal and/or retinal) disease activity were not observed on FA. Clinically active disease based on clinical evaluation was observed in 41.2% (21 of 51 eyes). In these 21 eyes, disease-related choroidal inflammation on ICGA was observed in 76.2% (16 of 21 eyes); in the remaining eyes (without clinical active disease) disease-related choroidal inflammation on ICGA was observed in 70.0% (21 of 30 eyes). In respect to systemic corticosteroid therapy, 10 patients (18 of 51 eyes) were under treatment with prednisone. In these 10 (18 of 51 eyes) patients, disease-related choroidal inflammation on ICGA was observed in 83.3% (15 of 18 eyes); in the remaining patients (33 of 51 eyes) disease-related choroidal inflammation on ICGA was observed in 66.7% (22 of 33 eyes).ConclusionICGA findings suggestive of disease-related choroidal inflammation were observed in a considerable proportion of patients with long-standing VKH disease, independent of the inflammatory status of the disease on clinical examination or current use of systemic corticosteroid. Therefore, the current study reinforces the crucial role of ICGA to assist the management and treatment of patients with long-standing VKH disease.

Severe bilateral necrotising retinitis caused by Toxoplasma gondii in a patient with systemic lupus erythematosus and diabetes mellitus

Ocular toxoplasmosis may be remarkably atypical in situations of evident immunosuppression such as acquired immunodeficiency syndrome, malignancy, and use of chronic immunosuppressive drug therapy.1 Aggressive forms in immunocompetent hosts are very rare.2,3 We present a case of severe, bilateral necrotising retinitis by Toxoplasma gondii initially misdiagnosed as an acute retinal necrosis (ARN) syndrome, in a patient with systemic lupus erythematosus (SLE) and diabetes mellitus type 2, who was taking medium dose prednisone. A 47 year old woman reported a 3 month history of rapid visual loss in the right eye followed by a decrease in her left eye vision 2 months later. Twenty days before the onset of ocular symptoms the patient had a seizure. Her medical history showed a SLE,4 with an active lupus central nervous system disease controlled with prednisone (0.5 mg/kg/day), and type 2 diabetes mellitus. At her first visit to our service, visual acuity was hand movements in both eyes. Slit lamp examination showed 3+ aqueous cells and flare, and 2+ anterior vitreous cells in both eyes. The fundus showed a 2+ vitreous haze and almost 360° creamy white necrotising retinitis extending from the ora serrata to the posterior pole, including the macula in both eyes (Fig 1A and B). Thumbprint patches at the border between necrotic and scanty normal retina could be observed, and also diffuse vascular attenuation. Figure 1 (A) Fundus appearance of …

Frosted branch angiitis and cerebral venous sinus thrombosis as an initial onset of neuro-Behçet’s disease: a case report and review of the literature

BackgroundFrosted branch angiitis is a rare, severe condition. It can be either a primary or a secondary condition and is characterized by rapid deterioration of vision and fulminant retinal vasculitis that manifests as diffuse sheathing of retinal vessels, macular edema, papillitis, vitritis and anterior uveitis. We aimed to describe a case of frosted branch angiitis and cerebral venous sinus thrombosis as an initial neuro-Behçet’s disease onset. Diagnosis of Behçet’s disease was based on the current 2014 International Criteria for Behçet’s Disease and the International consensus recommendation criteria for neuro-Behçet’s disease. In addition, a literature review using search parameters of “frosted branch angiitis”, “Behçet” and “neuro-Behçet” in the PubMed database is presented.Case presentationA 28-year-old Brazilian pardo woman presented to our hospital with abrupt bilateral vision loss associated with recurrent aphthous oral ulcers 6 months before visual symptom onset. A fundus examination showed bilateral widespread retinal vasculitis with venous and arterial white sheathing, optic disc swelling, macular edema, and retinal hemorrhages, leading to the diagnosis of frosted branch angiitis. An extensive systemic workup for retinal vasculitis was uneventful, except for brain magnetic resonance imaging demonstrating cerebral venous sinus thrombosis and lymphocytic aseptic meningitis. A diagnosis of neuro-Behçet’s disease was made, and treatment was started with methylprednisolone therapy 1 g/day for 5 consecutive days, followed by oral mycophenolate mofetil and infliximab 5 mg/kg infusion. The patient’s response was rapid, with improvement of visual acuity to hand movement and counting fingers by day 7 and final visual acuity of counting fingers and 20/130.ConclusionsFrosted branch angiitis may be associated with infectious, noninfectious, or idiopathic causes. An extensive workup should be done to exclude systemic vasculitis such as Behçet’s disease. Treatment with systemic steroids must be promptly initiated in association with specific treatment aimed at inflammation control and blindness risk reduction.

Fundus autofluorescence as a marker of disease severity in Vogt-Koyanagi-Harada disease.

icant past medical history presented to KK Women’s and Children’s Hospital, Singapore, on 21 October 2015 complaining of fever and a ‘black dot’ in her left upper eyelid for 3 days. She just returned from Malaysia with close contact with dogs during the trip. On examination, there was left upper eyelid erythema, oedema and the presence of a dog tick at the eyelid margin (Fig. 1A). Anterior segment examination was unremarkable. A procedure was performed under informed consent with topical tetracaine anaesthesia. Thermal energy was applied using a portable monopolar cautery device to the tick’s body (Fig. 1B), facilitating en bloc removal by inducing detachment of the tick. Microscopic examination of the organism revealed that it belonged to the genus Ixodes (Fig. 1C). There were no complications, and the patient recovered uneventfully. Ocular manifestations of ticks include conjunctivitis, keratitis, uveitis as well as embedment of the organism in the meibomian gland orifice presenting as a mass, oedema and erythema at the eyelid margin. Early removal of tick from its host is crucial as the risk of disease transmission increases significantly after 24 hr of attachment. Therefore, an efficient method of tick removal is crucial to avoid vector transmission of infectious diseases and localized inflammation and infection. There had been several methods of tick removal described in the literature. However, none of these methods is superior in terms of safety and efficacy profile (Fig. 1D). Many chemicals have been studied for tick removal. Compounds such as deodorized kerosene resulted in voluntary detachment in approximately 25% of the ticks that were treated (Knight et al. 1962). However, the use of chemical compounds can pose potential danger of toxicity to the ocular tissues. Chemical eradication of the organism may also precipitate regurgitation by the tick and transmission of infectious agents to its host (Flicek 2007). The use of forceps for direct mechanical tick removal could result in retained mouthparts in ocular tissues as well as fragmentation of its body which would then require further excision, complicating the removal process (Flicek 2007). Blepharoplasty incision allowing for an en bloc excision of the organism has been described (Love et al. 2001). However, this procedure is more invasive with a risk of ocular tissue loss and disruption of the ocular architecture. Tick removal using portable monopolar diathermy is a novel technique to the best of our knowledge. It is simple to perform, requiring only a few sequential thermal burns to the tick body to induce its detachment. This avoids trauma to the surrounding ocular tissues and need for excision. However, this technique might be more suitable for less tenacious ticks with shallow bites. Monopolar cautery for tick removal may be a superior and relative safe novel technique for en bloc removal of tick with minimal trauma to the surrounding ocular tissues.