Electrophysiological Assessment in Birdshot Chorioretinopathy: Flicker Electroretinograms Recorded With a Handheld Device.

Purpose: The flicker electroretinogram (ERG) is a sensitive indicator of retinal dysfunction in birdshot chorioretinopathy (BCR). We explored recordings from a handheld device in BCR, comparing these with conventional recordings in the same patients and with handheld ERGs from healthy individuals. Methods: Non-mydriatic flicker ERGs, using the handheld RETeval system (LKC Technologies), were recorded with skin electrodes at two centers. At one center (group 1), the stimuli (85 Td·s, 850 Td background) delivered retinal illuminance equivalent to international standards; at the other center (group 2), a different protocol was used (32 Td·s, no background). Patients also underwent international standard flicker ERG recordings with conventional electrodes following mydriasis. Portable ERGs from patients were also compared with those from healthy individuals. Results: Thirty-two patients with BCR (mean age ± SD, 56.4 ± 11.3 years) underwent recordings. Portable and standard ERG parameters correlated strongly (r > 0.75, P < 0.01) in both groups. Limits of agreement for peak times were tighter in group 1 (n = 21; -4.3 to +2.0 ms [right eyes], -3.9 to 1.5 ms [left eyes]) than in group 2 (n = 11; -3.4 to +6.9 ms [right eyes], -4.8 to +9.0 ms [left eyes]). Compared with healthy controls (n = 66 and n = 90 for groups 1 and 2, respectively), patients with BCR showed smaller mean amplitudes and longer peak times. Conclusions: Portable ERGs correlated strongly with conventional recordings, suggesting potential in rapid assessment of cone system function in office settings. Translational Relevance: Flicker ERGs, known to be useful in BCR, can be obtained rapidly with a portable device with skin electrodes and natural pupils.

Incidence of ophthalmic involvement in Behçet's disease in the United Kingdom: a British Ophthalmic Surveillance Unit (BOSU) study.

BACKGROUND: Behçet's disease (BD) is a relapsing-remitting vasculitis, which can manifest in different organ systems including the eyes. There is currently limited published data describing the incidence of ophthalmic disease within the United Kingdom. The primary aim of this study was to survey the incidence and manifestations of ophthalmic BD prospectively, with a secondary aim of reviewing treatment modalities initiated in first-line therapy. METHODS: Using the British Ophthalmic Surveillance Unit reporting system between October 2016 and November 2018, we prospectively surveyed the number of cases of BD presenting to UK ophthalmologists. A total of 89 cases of ophthalmic manifestations of BD were reported and complete information was collected on 58 patients. RESULTS: 93 eyes of 58 patients were affected. The median age of reported cases was 31 years (range 13-55 years) who were born in 15 different countries. Most cases (n = 35, 60%) had bilateral involvement. Vitritis was the most common ocular manifestation (68%; n = 63) followed by anterior uveitis (46%; n = 43). The greatest causes of visual morbidity were cystoid macular oedema, vitritis and retinal ischaemia. Most patients were prescribed either topical or oral corticosteroids (59%; n = 34), with some given intravitreal or intravenous corticosteroids. Five patients (8.6%) were initiated on disease-modifying anti-rheumatic drugs and one given an anti-TNF monoclonal antibody. CONCLUSIONS: This is the first prospective study to analyse the incidence of ophthalmic involvement in BD over a 2-year period, finding an annual incidence of 0.04 per 100,000 individuals in the UK.

KIR3DL1/S1 Allotypes Contribute Differentially to the Development of Behçet Disease.

Behçet disease is a chronic, relapsing-remitting autoinflammatory syndrome with a strong HLA-B*51 association. In this paper, we describe a human cohort of 267 individuals with Behçet disease and 445 matched controls from a tertiary referral center in the U.K. HLA-B*51 was confirmed as a genetic risk factor in this group (p = 0.0006, Bonferroni-Dunn correction for multiple testing [Pc] = 0.0192, odds ratio [OR] 1.92, 95% confidence interval [CI] 1.33-2.76). KIR3DL1/S1 allele-level analysis indicated that low-expressing KIR3DL1/S1 alleles in combination with KIR3DS1 increased the risk of developing Behçet disease (KIR3DL1LOW/KIR3DS1: p = 0.0004, Pc = 0.0040, OR 2.47, 95% CI 1.43-4.25), whereas high-expressing KIR3DL1/S1 alleles in combination with a null-expressing KIR3DL1 reduced the risk of disease (KIR3DL1HIGH/KIR3DL1NULL: p = 0.0035, Pc = 0.0350, OR 0.53, 95% CI 0.33-0.87). Behçet disease can manifest as a purely mucocutaneous disease or can involve other organ systems such as the eyes. In the U.K. cohort studied in this study, KIR3DL1LOW/KIR3DS1 increased the risk of ophthalmic disease (p = 1.2 × 10-5, OR 3.92, 95% CI 2.06-7.47), whereas KIR3DL1HIGH/KIR3DL1NULL reduced the risk of having purely mucocutaneous disease (p = 0.0048, OR 0.45, 95% CI 0.25-0.81). To our knowledge, this is the first analysis of KIR3DL1/S1 allelic variation in Behçet disease and may provide insight into the pathogenic role of HLA-B*51 and its interaction with KIR3DL1/S1.

Isolated endogenous Fusarium endophthalmitis in an immunocompetent adult after a thorn prick to the hand.

PURPOSE: To report the case of an immunocompetent adult presenting with endogenous Fusarium endophthalmitis. OBSERVATIONS: A woman in her thirties presented with symptoms and signs of a unilateral anterior uveitis. After initial improvement with topical corticosteroids, she continued to develop a panuveitis with an associated drop in vision to counting fingers. A vitreous biopsy confirmed Fusarium solani by 18S rRNA fungal gene detection and PCR sequencing. Despite treatment with pars plana vitrectomy, intravitreal amphotericin B and systemic voriconazole her visual outcome was poor. Detailed review of her antecedent history revealed the route of acquisition to be a thorn prick to the hand two weeks prior to presentation. CONCLUSIONS AND IMPORTANCE: This patient's endophthalmitis most likely resulted from cutaneous inoculation of Fusarium solani with subsequent hematogenous spread. Endogenous Fusarium endophthalmitis is well recognized in the immunocompromised but is very rarely seen in the immunocompetent. This case highlights the importance of thorough history-taking and consideration of fungal endophthalmitis in the differential diagnosis of a treatment-refractory uveitis.

Aspergillus fumigatus Endophthalmitis with Necrotizing Scleritis following Pars Plana Vitrectomy.

We present a case of Aspergillus fumigatus endophthalmitis complicated by necrotizing scleritis in a 68-year-old man with diet-controlled diabetes, after retinal detachment repair. He was initially treated with systemic steroids for surgically induced necrotizing scleritis following routine pars plana vitrectomy. An additional diagnosis of endophthalmitis was made when the patient developed a hypopyon. Repeat vitreous culture isolated Aspergillus fumigatus. Symptoms improved following antifungal treatment leaving the patient with scleromalacia and an advanced postoperative cataract. Fungal scleritis and endophthalmitis are rare complications of intraocular surgery with sight-threatening consequences, and, as this case demonstrates, may even occur concomitantly. The overlapping features of both conditions can make differentiating one from the other difficult. A fungal aetiology should be considered in cases of postoperative scleritis and endophthalmitis that are protracted and refractory to standard therapy. Even in cases of early diagnosis and treatment, visual outcomes in Aspergillus endophthalmitis and scleritis are variable and often disappointing, not infrequently necessitating enucleation of a painful blind eye.

Behçet's Disease: Do Natural Killer Cells Play a Significant Role?

Behçet's disease (BD) is a complex inflammatory disease, of unknown etiology. While disease pathogenesis remains unclear, a strong relationship between BD and HLA-B*51 has been established over the last 30 years. A number of theories exist regarding the cause of BD; however, few are able to account for the increased rates of HLA-B*51 positive individuals, particularly around the Mediterranean basin and Middle-East where the prevalence is highest. This review outlines current immunogenetic data on BD and the immunoregulatory role natural killer cells may play. It also describes the interaction of the killer immunoglobulin-like receptor - KIR3DL1 with its ligand Bw4, which is found on HLA-B51. Finally, CD94/NKG2D, MICA, and ERAP are outlined with regard to their potential roles in BD.

Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behçet disease.

INTRODUCTION: The etiology of Behçet's disease (BD) is unknown, but widely considered an excessive T-cell mediated inflammatory response in a genetically susceptible host. Recent genome-wide association studies (GWAS) have shown limited number of novel loci-associations. The rarity and unequal distribution of the disease prevalence amongst different ethnic backgrounds have hampered the use of GWAS in cohorts of mixed ethnicity and sufficient sample size. However, novel statistical approaches have now enabled GWAS in admixed cohorts. METHODS: We ran a GWAS on 336 BD cases and 5,843 controls. The cases consisted of Western Europeans, Middle Eastern and Turkish individuals. Participants from the Generation R study, a multiethnic birth cohort in Rotterdam, The Netherlands were used as controls. All samples were genotyped and data was combined. Linear regression models were corrected for population stratification using Genomic Principal Components and Linear Mixed Modelling. Meta-analysis was performed on selected results previously published. RESULTS: We identified SNPs associated at genome-wide significant level mapping to the 6p21.33 (HLA) region. In addition to this known signal two potential novel associations on chromosomes 6 and 18 were identified, yet with low minor allele frequencies. Extended meta-analysis reveal a GWS association with the IL12A variant rs17810546 on chromosome 3. DISCUSSION: We demonstrate that new statistical techniques enable GWAS analyses in a limited sized cohort of mixed ethnicity. After implementation, we confirmed the central role of the HLA region in the disease and identified new regions of interest. Moreover, we validated the association of a variant in the IL2A gene by meta-analysis with previous work. These findings enhance our knowledge of genetic associations and BD, and provide further justification for pursuing collective initiatives in genetic studies given the low prevalence of this and other rare diseases.

Therapy for ocular toxoplasmosis--the future.

BACKGROUND: Treatment of ocular toxoplasmosis is aimed at stabilizing visual function and reducing recurrence rates. METHODS: Small controlled studies indicate that available treatments do not affect visual outcome and recurrence rates, and no antibiotic in current use will kill bradyzoites. RESULTS: Antiparasitic treatment is justified in center-involving lesions and in large aggressive lesions namely in South American patients. Antibiotic treatment is needed for disease in the immunosuppressed, and this needs to be systemic. There exists strong agreement that a monotherapy, using steroids, is contraindicated. Prophylactic antibiotics may reduce recurrence rates in endemic areas and immunosuppressed patients. CONCLUSION: An ideal therapeutic strategy includes the strain of parasite, localization of the lesion, and severity of the inflammatory response as a basis for therapeutic decision making. New treatments targeting aspects of the parasite s physiology are very promising. On a global scale, public health measures to prevent transmission from animals and to access potable water are required.

TIRAP Ser180Leu polymorphism is associated with Behcet's disease.

OBJECTIVES: The initiating cause of Behçet's disease (BD) is unknown, but an aberrant response to infection has been suggested. In this study, single nucleotide polymorphisms in Toll-like receptors (TLRs) and associated molecules that have a sentinel function at mucosal surfaces were analysed in patients with BD. METHODS: TLR expression was determined by immunohistochemistry in buccal mucosal tissue from patients with BD, in tissue from patients with lichen planus (LP) or pyogenic granuloma (PG) as disease controls, or from healthy individuals. Using SSP-PCR we analysed SNP in CD14, TLR2, TLR4 and TIRAP (TIR domain-containing adaptor protein) in patients with BD from different geographical regions. RESULTS: TLR expression was increased in buccal lesions from patients with BD compared with healthy controls; however, a similar increase was seen in lesion tissue from patients with LP or PG, suggesting that this was a generalized inflammatory response as opposed to a BD-specific response. SNP analysis showed no association between CD14, TLR2 or TLR4 polymorphisms. However, TIRAP 180Leu was significantly associated with BD in UK, but not Middle Eastern, patients. CONCLUSION: TLR expression showed no difference in tissue from patients with BD compared with either disease or healthy controls. Likewise, SNPs in TLR genes were no different from healthy controls. The association with the increased function variant of TIRAP suggests that encounter with a pathogen at mucosal sites will lead to increased cytokine production and tissue damage with persistence of mucosal lesions.

Use of the double-pass technique to quantify ocular scatter in patients with uveitis: a pilot study.

PURPOSE: to assess whether the double-pass technique can be employed to quantify the amount of light scattering in patients with uveitis. METHODS: 56 eyes of 44 patients with intraocular inflammation were consecutively recruited from the uveitis clinic over 9 months. The degree of intraocular inflammation was recorded according to the Standardization of Uveitis Nomenclature criteria and the eyes were grouped as having anterior, intermediate, posterior or panuveitis. Objective scatter index (OSI) was assessed using a double-pass technique with the Optical Quality Analysis System II. RESULTS: twenty-four eyes had anterior uveitis, 9 eyes had intermediate uveitis, 10 eyes had posterior uveitis and 13 eyes had panuveitis. The OSI was significantly different between all 4 groups (p = 0.0005). The mean OSI was highest in eyes with anterior uveitis (2.6 ± 3.1) and lowest in posterior uveitis (1.9 ± 1.3). Anterior chamber cells significantly correlated with OSI (R(2) = 0.8726, p = 0.007), unlike posterior chamber cells (R(2) = 0.0189, p = 0.588) and flare (R(2) = 0.0048, p = 0.471). CONCLUSION: patients with anterior uveitis have more ocular scatter, and anterior chamber cells scatter more light. This pilot study opens new avenues for research in use of the double-pass technique to assess light scattering in uveitis.

Optical coherence tomography may be used to predict visual acuity in patients with macular edema.

PURPOSE: To determine whether the volume of retinal tissue passing between the inner and outer retina in macular edema could be used as an indicator of visual acuity. METHODS: Diabetic and uveitic patients with cystoid macular edema (81 subjects, 129 eyes) were recruited. Best corrected logMAR visual acuity and spectral optical coherence tomography (OCT/SLO; OTI, Toronto, ONT, Canada) were performed in all patients. Coronal OCT scans obtained from a cross section of the retina between the plexiform layers were analyzed with a grid of five concentric radii (500, 1000, 1500, 2000, and 2500 µm centered on the fovea). The images were analyzed to determine the amount of retinal tissue present within each ring. A linear regression model was developed to determine the relationship between tissue integrity and logMAR visual acuity. RESULTS: A linear relationship between tissue integrity and VA was demonstrated. The volume of retinal tissue between the plexiform layers in rings 1 and 2 (up to 1000 µm from the foveal center) predicted 80% of visual acuity. By contrast, central macular thickness within the central 1000 µm predicted only 14% of visual acuity. CONCLUSIONS: This study showed that the cross-sectional area of retinal tissue between the plexiform layers in cystoid macular edema, as imaged by OCT, is the best indicator of visual function at baseline. Further prospective treatment trials are needed to investigate this parameter as a predictor of visual outcome after intervention.

Case report: ampiginous chorioretinopathy associated with eales disease in a patient with presumed tuberculosis.

PURPOSE: The purpose of this study was to present a case of ampiginous chorioretinopathy followed by Eales disease in association with mycobacterium tuberculosis infection. METHODS: Case report. RESULTS: The patient presented with signs of ampiginous chorioretinopathy, which subsequently developed into Eales disease with a background of mycobacterium tuberculosis infection. CONCLUSION: This case describes the unusual manifestations of tuberculosis in the retina.

Intravitreal bevacizumab to facilitate vitrectomy in idiopathic ischaemic retinal vasculitis.

To describe the use of intravitreal bevacizumab in idiopathic retinal vasculitis prior to vitrectomy and delamination. A young healthy male presented with idiopathic retinal vasculitis. His condition was refractory to panretinal photocoagulation and systemic steroids. The progression of his condition necessitated vitrectomy and delamination. Intravitreal bevacizumab was used to facilitate the surgical procedure, with effective results. Intravitreal bevacizumab can be an adjunct to vitrectomy in idiopathic retinal vasculitis. However, caution must be taken due to its ability to promote fibrosis and to produce further tractional and/or rhegmatogenous retinal detachment. Further controlled studies are required to understand its benefits in managing complicated idiopathic retinal vasculitis.

Acute retinal necrosis: the effects of intravitreal foscarnet and virus type on outcome.

PURPOSE: To study the effects of intravitreal foscarnet and the clinical differences between varicella zoster virus (VZV) and herpes simplex virus (HSV) induced acute retinal necrosis (ARN). DESIGN: Retrospective comparative case series. PARTICIPANTS: Eighty-one eyes of 74 patients. METHODS: A retrospective case note analysis was performed in 2 tertiary referral centers. MAIN OUTCOME MEASURES: Presenting and final visual acuity, and progression to retinal detachment. RESULTS: Thirty-three eyes had HSV-ARN and 48 had VZV-ARN. The average age for HSV-ARN was 34 years and 51 for VZV-ARN (P<0.001). Visual acuity on presentation was similar (P = 0.48), but a larger proportion had better vision (> or =20/60) in the HSV-ARN group (52%) than the VZV-ARN group (35%). A greater proportion of eyes with poor vision (< or =20/200) was found at the 12-month follow-up in the VZV-ARN group (60%) compared with the HSV-ARN group (35%). A greater degree of visual loss in the VZV-ARN group (0.4 logarithm of the minimum angle of resolution [logMAR]) compared with the HSV-ARN group (0.04 logMAR) was detected (P = 0.016). Retinal detachment was 2.5-fold more common in VZV-ARN (62%) compared with HSV-ARN (24%). When comparing eyes treated with (n = 56) and without (n = 25) intravitreal foscarnet, there was a 40% lower rate in retinal detachment (53.6% vs 75.0%) for VZV-ARN (P = 0.23). The numbers with HSV-ARN were too small for analysis. CONCLUSIONS: The results support the difference of outcome in HSV-ARN and VZV-ARN. Therefore, viral identification serves as a key to predicting outcome in these patients. Intravitreal foscarnet seems to be a useful adjunct for the treatment of ARN in that it reduced rate of retinal detachment.

Low prevalence of NOD2 SNPs in Behçet's disease suggests protective association in Caucasians.

OBJECTIVE: It has been shown previously that three nucleotide-binding oligomerization domain containing 2 (NOD2) variants (Arg702Trp, Gly908Arg and Lue1007fs) are associated with Crohn's disease (CD), a disorder clinically resembling Behçet's disease (BD). We studied the frequency of these variants in BD patients. METHODS: DNA samples of 200 BD patients [59 Caucasians, 139 Middle Easterns (MEs) of Arab descent and 2 Asians] and 520 healthy controls (444 Caucasians and 76 MEs) were genotyped using a Taqman assay. RESULTS: Both the Arg702Trp and Leu1007fs (frameshift) variants were significantly less frequently present among BD patients compared with healthy controls (0.5 vs 5.8%; P < 1.10(-5) and 0.0 vs 1.8%; P < 0.007, respectively). In the Caucasian subpopulation, Arg702Trp was significantly less frequent in the BD group as compared with the controls (P = 0.04); whereas in the ME subpopulation, a trend was observed (P < 0.06). CONCLUSIONS: Of the three CD-associated single nucleotide polymorphisms, one of the variant NOD2 alleles, was found to be present significantly less in Caucasian BD patients.

Genotype analysis of polymorphisms in autoimmune susceptibility genes, CTLA-4 and PTPN22, in an acute anterior uveitis cohort.

PURPOSE: Acute anterior uveitis (AAU) is the most common form of uveitis and is thought to be autoimmune in nature. Recent studies have described genes that act as master controllers of autoimmunity. Protein tyrosine phosphatase type 22 (PTPN22) and Cytotoxic T lymphocyte antigen-4 (CTLA-4) are two of these genes, and single nucleotide polymorphisms (SNPs) in the genes encoding these molecules have been associated with several autoimmune diseases. In this study we have analyzed SNPs in PTPN22 and CTLA-4 in patients with AAU. METHODS: The functional protein tyrosine phosphatase type 22 (PTPN22) SNP (R620W rs2476601, 1858C/T), and two CTLA-4 SNPs (rs5742909, -318C/T and rs231775, 49A/G) were analyzed in 140 patients with AAU and 92 healthy controls by sequence-specific primer -polymerase chain reaction (SSP-PCR). Data was analyzed by chi(2) analysis and Fisher's exact test. RESULTS: There was no significant association between PTPN22 620W, CTLA-4 -318C/T, or CTLA-4 49A/G and AAU. Similarly, there was no association with the three SNPs when patients were classified by race or gender. Finally, there was no association with the presence of ankylosing spondylitis in the patient cohort. CONCLUSIONS: The data do not support an association between SNPs in PTPN22 and CTLA-4, genes regarded as genetic master switches of autoimmunity. This raises the issue of the etiology of AAU and the possibility that it should be regarded as an autoinflammatory rather than an autoimmune condition.