Anti-Neutrophil Cytoplasmic Antibody-Associated Ocular Manifestations in Japan: A Review of 18 Patients.

ABSTARCTPurpose: To investigate ocular manifestations in patients positive for serum anti-neutrophil cytoplasmic antibodies (ANCAs) in Japan.Methods: The clinical records of patients who had ocular manifestations and who were serum ANCA positive between 2011-2017 at Tokyo Medical and Dental University Hospital were retrospectively reviewed.Results: Eighteen patients were identified to be positive for serum ANCA and had ocular manifestations, including optic nerve involvement (50%), scleritis (27.8%), iritis (27.8%), retinal vasculitis (16.7%), oculomotor disorder (16.7%), and peripheral ulcerative keratitis (11.1%). Six patients had ANCA-associated vasculitis (AAV), including 5 patients with granulomatosis with polyangiitis and 1 patient with microscopic polyangiitis. Most patients with optic nerve involvement were myeloperoxidase-ANCA positive. Contrastingly, most patients with anterior segment involvement were proteinase-3-ANCA positive.Conclusion: Ocular manifestations were observed in some patients positive for serum ANCAs. Serum ANCA evaluation is useful for identifying the etiology of ocular inflammation and for diagnosing AAV, a life-threatening disease.

[Clinical Survey of Uveitis in Tokyo Medical and Dental University--Comparison between the Periods of 1998-2001 and 2007-2011].

PURPOSE: To investigate a clinical survey of uveitis in Tokyo Medical and Dental University Hospital. SUBJECTS AND METHODS: The clinical records of patients with uveitis who were treated from October 1998 to December 2001 and from January 2007 to December 2011 were reviewed. The clinical results of both periods were compared. RESULTS: A total number of 455 patients (707 eyes) and 1091 patients (1716 eyes) were analyzed in this survey. The mean age of the first period was 45.4, and of the second 50.3 years old. The incidences of sarcoidosis (11.0%, 13.7%) and Vogt-Koyanagi-Harada disease (5.7%, 5.9%) were virtually unchanged in the two series. However, the incidence of Behçet's disease was higher in the first period (10.6%) than in the second (5.8%). The frequency of herpetic iritis (1.8%, 4.7%) and intraocular lymphoma (0.4%, 2.6%)showed apparent increase. Unclassified uveitis decreased from 55.6% to 47.5%. CONCLUSIONS: The etiologies of uveitis have changed with the progress of diagnostic techniques and the establishment of new disease concepts.

Comparison of the ocular characteristics of anterior uveitis caused by herpes simplex virus, varicella-zoster virus, and cytomegalovirus.

PURPOSE: To compare the clinical characteristics of anterior uveitis (AU) caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), or cytomegalovirus (CMV). METHODS: The medical records were reviewed of 46 patients whose diagnoses were based on their clinical characteristics [e.g., unilateral involvement, presence of keratic precipitates (KPs), and elevation of intraocular pressure (IOP)] and on PCR detection of herpes virus DNA in the aqueous humor. The demographics, chief complaints, and clinical characteristics of the three types of herpetic AU were compared. RESULTS: Of the 46 patients with AU, eight had HSV-AU, 20 had VZV-AU, and 18 had CMV-AU. HSV-AU and VZV-AU shared common features, i.e., a relatively acute disease process and the presence of large KPs. Among the three groups of patients, the characteristic features of those with VZV-AU were severe intraocular inflammation, as shown by severe aqueous flare, highest viral load in the aqueous humor, and presence of segmental iris atrophy. In comparison, patients with CMV-AU had the mildest intraocular inflammation, lowest corneal endothelial cell density, and highest IOP. CONCLUSIONS: Although the AU caused by each of the three types of herpes viruses has a number of common features, each disease also has distinct features that should facilitate an accurate diagnosis.

Audiovestibular findings in patients with Vogt-Koyanagi-Harada disease.

CONCLUSION: The long-term follow-up study revealed a good audiovestibular prognosis in our patients with Vogt-Koyanagi-Harada disease (VKH) after adequate treatment. OBJECTIVES: To evaluate the audiovestibular findings and long-term prognosis of patients with VKH. METHODS: A total of 82 ears in 41 patients (9 males and 32 females, aged 18-78 years) with VKH were examined in the audiovestibular study. Of the 41 patients, 16 patients with follow-up periods of more than 12 months (13-158 months) were included in the long-term follow-up study. Audiovestibular examinations included pure-tone audiometry; positional, positioning, and spontaneous nystagmus tests; and a caloric test. RESULTS: Among the 41 patients, 28 (68%) complained of auditory symptoms at the initial visit and 28 (68%) showed sensorineural hearing loss (SNHL). Of the 24 patients who underwent nystagmus tests, only 3 (13%) presented with vestibular symptoms whereas 11 (46%) had nystagmus. Among 32 ears in 16 patients enrolled in the long-term follow-up study, 19 ears showed SNHL at the initial visit. The SNHL returned to normal in 14 ears (74%) and remained minimal in severity in the other 5 ears (26%) at the last visit. None of the patients showed persistent or repetitive vestibular symptoms.

Choroidal thickness in convalescent vogt-koyanagi-harada disease.

PURPOSE: To evaluate the subfoveal choroidal thickness (SCT) at the convalescent stage of Vogt-Koyanagi-Harada disease and to investigate the correlations among SCT, the presence of the sunset glow fundus, and size of the peripapillary atrophy (PPA). METHODS: The medical records of consecutive patients with Vogt-Koyanagi-Harada disease without active intraocular inflammation were reviewed, and one eye was randomly chosen for analyses. The disease duration was more than 3 years. Enhanced depth imaging optical coherence tomography was performed to measure SCT. The area of PPA was measured using the PDT/MPS software. Sunset glow fundi were classified into two groups according to the degree of depigmentation. RESULTS: Nineteen eyes with Vogt-Koyanagi-Harada disease were studied. The mean SCT of 12 eyes with severe sunset glow fundus was 144 ± 72 µm which was thinner than that of the 7 eyes with no or mild depigmentation (P = 0.0057). The SCT was inversely correlated with the disease duration (P = 0.048) and the PPA area (P = 0.0002). The PPA area was positively correlated with the disease duration (P = 0.007). CONCLUSION: The thinner choroid and larger PPA areas were correlated with the degree of depigmentation or disease duration and might be caused by latent choroidal inflammation in the convalescent stage of Vogt-Koyanagi-Harada disease.

Clinical course of patients with Behçet's uveitis following discontinuation of infliximab therapy.

PURPOSE: To investigate the clinical course of Behçet's uveitis patients following discontinuation of infliximab therapy. METHODS: This retrospective chart review study examined Behçet's disease patients who received infliximab treatment between 2000 and 2012. Medical records of patients whose infliximab treatment was discontinued were reviewed, with special focus on the frequency of uveitis attacks in the period before initiation, during treatment and after cessation of the infliximab therapy. Mean visual acuities were evaluated for each treatment period. RESULTS: Out of the 43 patients treated with infliximab at our uveitis clinic, ten were discontinued due to adverse events or inefficiency. Data for seven patients followed for more than 12 months before initiation and after cessation of infliximab were analyzed. Frequency of acute uveitis attacks was 7.43 per 12 months before initiation of infliximab, 2.86 during treatment and 0.57 after cessation. A statistically higher frequency of uveitis attacks was observed before initiation of infliximab compared to during (p < 0.05) and after cessation of treatment (p < 0.05). There was no statistical significance observed between the period during treatment and after cessation (p = 0.29). The mean logMAR was 0.79 at baseline, 0.68 during treatment, and 0.88 at 12 months after cessation. These differences were not statistically significant. CONCLUSIONS: A satisfactory clinical course with well-controlled ocular inflammation was found after discontinuation of infliximab therapy in Behçet's uveitis patients. These results suggest that a safe, pre-planned discontinuation of infliximab therapy can be performed in patients with Behçet's uveitis.

Regression of optic disc neovascularization in patients with Behçet's uveoretinitis after infliximab therapy.

PURPOSE: Optic disc neovascularization (NVD) in patients with Behçet's uveoretinitis is a relatively uncommon but severe complication that lacks standardized treatments. We report 2 cases of Behçet's uveoretinitis that achieved partial regression of NVD after infliximab therapy. METHODS: Intravenous infliximab infusions were administrated to 2 immunosuppressive therapy-resistant Behçet's uveoretinitis patients with severe NVD accompanied by vitreous hemorrhage (both eyes in case 1 and the left eye in case 2 ). Best-corrected visual acuity, funduscopic findings, and fluorescein angiography were evaluated before and after the treatments. RESULTS: After being switched to infliximab therapy, NVD in both cases stopped developing and regressed partially, as confirmed by fluorescein angiography and resolution of vitreous hemorrhage, which led to an improvement of the best-corrected visual acuity. CONCLUSIONS: Results suggest that infliximab administration might be an effective treatment in NVD patients with Behçet's uveoretinitis.

Indocyanine green angiography findings in initial acute pretreatment Vogt-Koyanagi-Harada disease in Japanese patients.

PURPOSE: Indocyanine green angiography (IA) is a highly sensitive method to evaluate choroidal inflammatory lesions. We present standardized IA findings of initial acute Vogt-Koyanagi-Harada (VKH) disease in Japanese patients before therapeutical intervention. METHODS: Medical records of patients with VKH disease at Tokyo Medical and Dental University Hospital and Miyata Eye Hospital were retrospectively analyzed. We analyzed six IA signs: choroidal perfusion inhomogeneity, early hyperfluorescent stromal vessels, hypofluorescent dark dots (HDDs), fuzzy or lost pattern of large stromal vessels, disc hyperfluorescence, and diffuse late choroidal hyperfluorescence. RESULTS: Ten patients from the two hospitals were studied. The most constant findings present in all eyes were early hyperfluorescent stromal vessels, HDDs, and either fuzzy or lost pattern of large stromal vessels. Disc hyperfluorescence was present in 18 eyes. Choroidal perfusion inhomogeneity was seen in six patients, and diffuse late choroidal hyperfluorescence was seen to a certain degree in all eyes. CONCLUSIONS: Four of the analyzed signs, including early hyperfluorescent stromal vessels, HDDs, fuzzy or lost pattern of large stromal vessels, and disc hyperfluorescence were consistent findings in Japanese VKH patients. Because the primary lesion is situated in the choroid, IA is the method of choice to monitor disease activity in VKH disease.

A significant association of viral loads with corneal endothelial cell damage in cytomegalovirus anterior uveitis.

AIM: The aim of the study was to investigate the correlation between the clinical manifestation and the cytomegalovirus (CMV) viral load in the aqueous humour of patients with CMV anterior uveitis. METHODS: Seven patients with CMV-associated iridocyclitis and four patients with CMV-associated corneal endotheliitis were enrolled. Presence of CMV, but not other human herpes viruses, was confirmed by multiplex polymerase chain reaction (PCR). Viral load was measured using real-time PCR. Clinical manifestations were examined using a slit-lamp microscope and ophthalmoscope, applanation tonometer and specular microscope. RESULTS: All 11 patients had unilateral recurrent anterior uveitis with high intraocular pressure and mutton fat keratic precipitates with pigmentation. Stromal oedema of the cornea was found in CMV-associated endotheliitis, but not in CMV-associated iridocyclitis patients. A significant corneal endothelium cell loss was recorded in all 11 patients with CMV-associated endotheliitis and iridocyclitis patients. High viral loads of CMV were detected in the aqueous humour of all 11 patients. A significant association was found between the corneal endothelial cell loss intensity and CMV viral load in the aqueous humour. CONCLUSION: There is a significant correlation between the CMV viral load and corneal endothelial cell loss in both CMV-associated iridocyclitis and corneal endotheliitis.

Changes in drug susceptibility and the quinolone-resistance determining region of Staphylococcus epidermidis after administration of fluoroquinolones.

PURPOSE: To evaluate the correlation between changes in the susceptibility of bacteria and mutations in the quinolone-resistance determining region (QRDR) after 3 weeks of continuous fluoroquinolone instillation. SETTING: Miyata Eye Hospital, Miyazaki, Japan. METHODS: In this prospective randomized study, gatifloxacin 0.3% eyedrops or levofloxacin 0.5% eyedrops were administered for 1 week before cataract surgery and for 2 weeks after surgery. Samples were collected from the conjunctival sac before instillation of the antibiotic agent and 14 days after surgery. Susceptibility to the fluoroquinolones and gene mutations in the QRDR of the isolated Staphylococcus epidermidis were analyzed. RESULTS: The detection rate of S. epidermidis was 27% in the gatifloxacin group (n=79 eyes) and 21% in the levofloxacin group (n=73 eyes) before instillation of the antibiotic and 6% and 19%, respectively, 14 days postoperatively. The susceptibility rates of S. epidermidis strains to levofloxacin were statistically significantly lower after instillation than before antibiotic instillation, and the number of gene mutations in the QRDR was statistically significantly higher after instillation. There was no difference in the gatifloxacin group between before and after antibiotic instillation. In the 9 eyes in which S. epidermidis was detected in samples taken before and after antibiotic instillation, most strains were genetically different from each other between the 2 time points. CONCLUSIONS: Three-week continuous instillation of levofloxacin affected the indigenous bacterial flora in the conjunctival sac, suggesting possible induction of microbial substitution to fluoroquinolone-resistant S. epidermidis. However, there was no change with gatifloxacin.

A clinical survey of uveitis in HTLV-1 endemic region.

PURPOSE: To investigate a clinical survey of uveitis in southern Kyushu of Japan, where human T-lymphotropic virus type 1 (HTLV-1) and toxoplasmosis is highly endemic. METHODS: The clinical records of patients with uveitis between 1975 and 2007 at Miyata Eye Hospital were reviewed. RESULTS: A total number of 1338 patients (2012 eyes), consisting of 526 men and 812 women with mean age of 50.5 years old, were analyzed. The most common clinical entity was HTLV-1 uveitis (17.1%), followed by Vogt-Koyanagi-Harada disease (9.9%), sarcoidosis (7.2%), toxoplasmosis (7.1%), Behçet's disease (4.3%) and others. Unclassified uveitis comprised 41.1% in the series. Anterior uveitis was seen in 30.8%, intermediate uveitis in 17.3%, posterior uveitis in 9.3%, and pan-uveitis in 42.6%. CONCLUSIONS: HTLV-1 uveitis and toxoplasmosis were the major clinical entities in southern Kyushu of Japan. This relates to the high seroprevalence of the infectious agents in this region of Japan.

Effect of bromfenac ophthalmic solution on ocular inflammation following cataract surgery.

PURPOSE: This study compared the post-cataract surgery anti-inflammatory effects of topical treatment with 0.1% bromfenac, 0.1% betamethasone or both on postoperative anterior chamber inflammation and corneal swelling. METHODS: Seventy-two patients with no eye disease other than cataract were enrolled in a prospective, randomized study to undergo phacoemulsification combined with intraocular lens implantation. After cataract surgery, patients were randomized to treatment with bromfenac, betamethasone or both agents. Twenty-five eyes were assigned to bromfenac, 23 to betamethasone and 24 to the combined treatment group. Inflammatory reactions in the anterior chamber were measured with laser flare photometry preoperatively and at 1 and 3 days, 1 and 2 weeks, and 1 and 2 months postoperatively. Intraocular pressure (IOP) and corneal thickness were measured at the same time-points. Best corrected visual acuity (BCVA) was measured preoperatively and at 2 days, 1 and 2 weeks, and 1 and 2 months postoperatively. Specular microscope endothelial photography of the central region of the cornea was performed preoperatively and at 3 months after surgery. RESULTS: There were no significant differences among the bromfenac, betamethasone and combined treatment groups in BCVA, IOP, aqueous flare or corneal thickness. Cystoid macular oedema was present in one eye treated with betamethasone. CONCLUSIONS: There were no significant differences in anti-inflammatory effects among the three treatments. These findings suggest that bromfenac is as effective as betamethasone in minimizing inflammatory reactions after cataract surgery.

A comparison of fluoroquinolone penetration into human conjunctival tissue.

INTRODUCTION: Ocular penetration of newer fluoroquinolones (FQs) has not been fully investigated in humans, especially in regard to conjunctival tissue penetration. The aim of our study was to evaluate the conjunctival permeability of 3 FQs, which do not contain benzalkonium chloride, using excised pterygium tissue. METHODS: Patients undergoing pterygium surgery received a single application of one of the following: 0.5% moxifloxacin (MFLX), 0.3% gatifloxacin (GFLX), or 0.5% levofloxacin (LVFX). Samples of conjunctival tissue were collected 10, 30, or 45 min following administration of the study drug. Each sample was analyzed by high-performance liquid chromatography, and drug concentrations were measured over time. RESULTS: Conjunctival concentration of all 3 FQs was highest 10 minutes after instillation, then gradually decreased. At all time points, MFLX showed the highest conjunctival concentrations among the 3 drugs. Mean MFLX concentrations were 116.7 +/- 28.9, 19.0 +/- 6.3, and 15.9 +/- 4.7 microg/g at 10, 30, and 45 min, respectively, and were statistically greater than GFLX or LVFX concentrations at 10 and 45 min. CONCLUSIONS: All tested FQs achieved peak concentrations within 10 min following administration. Initial peak concentrations of MFLX were greater than either GFLX or LVFX, and concentrations of MFLX remained highest among the 3 FQs throughout the 45-min time window.

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.

Detection of the bcl-2 t(14;18) translocation and proto-oncogene expression in primary intraocular lymphoma.

PURPOSE: Primary intraocular lymphoma (PIOL) is a diffuse large B cell lymphoma that initially infiltrates the retina, vitreous, or optic nerve head, with or without central nervous system involvement. This study examined the expression of the bcl-2 t(14;18) translocation, the bcl-10 gene, and high expression of bcl-6 mRNA in PIOL cells. METHODS: Microdissection and PCR analysis were used to examine vitreous specimens in patients with PIOL for the presence of bcl-2 t(14;18) translocations, the bcl-10 gene, and expression of bcl-6 mRNA. A medical record review was also conducted to determine whether the bcl-2 t(14;18) translocation correlated with prognosis. RESULTS: Forty of 72 (55%) PIOL patients expressed the bcl-2 t(14;18) translocation at the major breakpoint region. Fifteen of 68 (22%) patients expressed the translocation at the minor cluster region. The bcl-10 gene was detected in 6 of 26 (23%) patients, whereas 4 of 4 (100%) PIOL patients expressed higher levels of bcl-6 mRNA compared with inflammatory lymphocytes. An analysis of clinical outcome in 23 PIOL patients revealed no significant association between bcl-2 t(14;18) translocations and survival or relapse. However, patients with the translocation were significantly younger. CONCLUSIONS: PIOL has unique molecular patterns of bcl-2, bcl-10, and bcl-6 when compared with other systemic lymphomas. This study lays the foundation for future studies aimed at exploring the genotypic classification of PIOL based on the quantitative molecular framework of gene expression profiling, with the goal of providing useful adjuncts to the pathologic diagnosis of this complex disease.

Microdissection and gene rearrangement analysis of paraffin-embedded specimens of orbital malignant lymphoma.

PURPOSE: To determine whether a definite diagnosis of malignant lymphoma can be made from paraffin-embedded archived orbital specimens by gene rearrangement analysis using microdissection and polymerase chain reaction (PCR). METHODS: Specimens from four patients with histopathologically diagnosed orbital malignant lymphoma were examined. The malignant cells were microdissected off the paraffin-embedded specimens. DNA was extracted from the cells, and the immunoglobulin heavy chain ( IgH) gene was amplified by PCR. Gene rearrangements were detected by using primers for the third framework (FR3A), the second framework (FR2A), and the complementary determining region 3 (CDR3). Translocation of the B-cell lymphoma/leukemia-2 ( bcl-2) gene was also examined. RESULTS: Malignant cells were present on the slides of the paraffin-embedded specimens of three of four cases. The specimens from these three cases showed IgH rearrangements for FR3A, FR2A, and CDR3. A bcl-2-associated translocation was also detected in one case. CONCLUSIONS: Gene rearrangement analysis is applicable to paraffin-embedded archived orbital specimens to confirm a diagnosis of malignant lymphoma. The advantage of this method is that only a small specimen is needed because the detection sensitivity is high.