A multicenter study of ocular inflammation after COVID-19 vaccination.

PURPOSE: To report the characteristics of a case series of ocular inflammatory events following COVID-19 vaccination in Japan. STUDY DESIGN: Retrospective multicenter study METHODS: In this retrospective multicenter survey, a questionnaire was sent to 16 Japanese hospitals that had uveitis specialty clinics. Information on patients who developed ocular inflammatory events within 14 days of COVID-19 vaccination between February 2021 and December 2021 was collected. RESULTS: Thirty-seven patients were diagnosed with ocular inflammatory events following COVID-19 vaccination. The mean age was 53.4 ± 16.4 years (range, 26-86 years), and the mean time to onset after vaccination was 6.3 ± 4.2 days (range, 1-14 days). Vogt-Koyanagi-Harada disease (VKH) was the most common event (n = 17 patients, 46%), followed by anterior uveitis (n = 6), infectious uveitis (n = 3), acute zonal occult outer retinopathy (AZOOR) (n = 2), sarcoidosis-associated uveitis (n = 1), acute posterior multifocal placoid pigment epitheliopathy (APMPPE) (n = 1), optic neuritis (n = 1), multiple evanescent white dot syndrome (MEWDS) (n = 1), Posner-Schlossman syndrome (n = 1), and unclassified uveitis (n = 4). Twenty-eight cases occurred after BNT162b2 vaccination (Pfizer-BioNTech) and 8 after mRNA-1273 vaccination (Moderna), whilst 1 patient had no information about vaccine type. CONCLUSIONS: COVID-19 vaccination can be related to various types of ocular inflammatory events. When we encounter patients with ocular inflammatory disease, we should consider that it may be an adverse effect of COVID-19 vaccination.

Utility of Liquid-Based Cytology and Cell Block Procedure Obtained by Vitrectomy to Diagnose Ocular Sarcoidosis-The Significance of Epithelioid Granuloma and Epithelioid Cells.

Purpose: The eyes are one of the most frequently involved organs in sarcoidosis in Asia, including Japan. Sarcoid uveitis is the major complaint of ocular sarcoidosis. The detection of epithelioid granuloma (EG) requires histological biopsy of the uvea for the precise diagnosis of sarcoid uveitis, because it is challenging to diagnose sarcoid uveitis without a history of systemic sarcoidosis. To diagnose sarcoid uveitis, we have established novel methods. Patients and Methods: In this study, we included 30 eyes of 21 patients with granulomatous uveitis diagnosed via slit-lamp examinations, gonioscopy, fundus photography, and fluorescein angiography. Vitrectomy was performed to remove the vitreous opacity with vision loss. To examine vitreous cell components, we used liquid-based cytology (LBC). To detect EG in an intraocular irrigating solution, we collected vitreous cell components, and then the cell pellets were embedded in the cell block procedure. Results: Here, we demonstrated the usefulness of the histological detection of EG and epithelioid cells (ECs) in LBC from vitreous body specimens and in the cell block procedure from vitreous cell components in an intraocular irrigating solution. Our results showed that the detection rates of EG were 6.3% (1/16) in LBC and 9.1% (1/11) in the cell block procedure in the sarcoid uveitis-suspected group and 7.7% (1/13) in LBC and 28.6% (2/7) in the cell block procedure in the sarcoidosis group. We would discuss the specificity of the EG/EC detection of ocular sarcoidosis. Conclusion: Our methods are helpful in the precise diagnosis of ocular sarcoidosis and the control of the development of systemic sarcoidosis.

Multicenter, retrospective, observational study for the Treatment Pattern of systemic corticoSTERoids for relapse of non-infectious uveitis accompanying Vogt-Koyanagi-Harada disease or sarcoidosis.

PURPOSE: Non-infectious uveitis associated with Vogt-Koyanagi-Harada (VKH) disease or sarcoidosis is commonly treated with systemic corticosteroids (SCS). We assessed the use of SCS for non-infectious uveitis relapses in Japanese clinical practice. STUDY DESIGN: Multicenter, retrospective chart review (UMIN Clinical Trial Registry; UMIN000032390). METHODS: One hundred fifty-seven patients (15- ≤ 75 years; 103 VKH disease, 54 sarcoidosis) given SCS to treat a relapse of non-infectious intermediate, posterior, or panuveitis accompanying VKH disease or sarcoidosis were studied (August 2011-December 2018). SCS dose and duration, concomitant medications, subsequent relapses, and steroid-related adverse drug reactions (ADRs) were analyzed for 12 months after target relapse treatment. Relationships between background factors and total SCS dose were analyzed (logistic regression). RESULTS: Mean (± SD) total SCS dose over 12 months after target relapse treatment was 3874 ± 2775 mg, and was higher in patients with immunosuppressants than in those without (4575 mg vs 3496 mg). Immunosuppressant use was the only factor significantly associated with higher total SCS dose (p = 0.0196). Mean duration of SCS treatment for relapse was 318.7 ± 89.3 days. Only 29.3% of patients were steroid-free after 12 months; the percentage was higher in patients without immunosuppressants (36.3% vs 16.4%). Subsequent relapse was experienced by 39.5% of patients, and 13.4% had a steroid-related ADR (mostly glaucoma or diabetes). CONCLUSION: In Japanese clinical practice, many patients with recurrent uveitis accompanying VKH disease or sarcoidosis received SCS for relapse for ≥ 300 days, suggesting that reducing corticosteroids is challenging in patients with difficulty suppressing inflammation.

Comparison of combination therapy of prednisolone and cyclosporine with corticosteroid pulse therapy in Vogt-Koyanagi-Harada disease.

PURPOSE: To compare the efficacy and safety of a combination therapy of prednisolone and cyclosporine and corticosteroid pulse therapy in Vogt-Koyanagi-Harada (VKH) disease. STUDY DESIGN: A prospective, multicenter, randomized, non-inferiority trial. METHODS: Patients of new-onset acute VKH disease at 11 centers in Japan between 2014 and 2018 were randomized to a combination (oral prednisolone 60 mg daily with gradual taper-off to 35 mg/day and cyclosporine 3 mg/kg/day) and corticosteroid (methylprednisolone 1000 mg for 3 days followed by oral prednisolone) groups, and were followed for 1 year. RESULTS: Thirty-four were assigned to the combination and thirty-six patients to the corticosteroid group. Recurrence/worsening risk was 0.15 (95% confidence-interval [CI] 0.03-0.27) in the combination group and 0.25 (95% CI 0.11-0.39) in the corticosteroid group, with a risk difference of - 0.10 (90% CI - 0.27 to 0.06), demonstrating non-inferiority of the combination group with a non-inferiority margin of 0.20 (P = 0.0013). Serious adverse events occurred in three patients (two with hyponatremia and one with severe headaches) in the combination group and none in the corticosteroid group. Sunset glow fundus grades and cataract rates at 1 year were 0.57 (95% CI 0.42-71) and 4.3% in the combination group and 0.91 (95% CI 0.78-1.04) and 34.0% in the corticosteroid group, respectively. CONCLUSIONS: Combination therapy was noninferior to corticosteroid therapy with respect to recurrence/worsening risk. Notably, the recurrence/worsening risk, sunset glow fundus grade, and cataract rate were lower in the combination group than in the corticosteroid group.

Coronin-1 is phosphorylated at Thr-412 by protein kinase Cα in human phagocytic cells.

Coronin-1, a hematopoietic cell-specific actin-binding protein, is thought to be involved in the phagocytic process through its interaction with actin filaments. The dissociation of coronin-1 from phagosomes after its transient accumulation on the phagosome surface is associated with lysosomal fusion. We previously reported that 1) coronin-1 is phosphorylated by protein kinase C (PKC), 2) coronin-1 has two phosphorylation sites, Ser-2 and Thr-412, and 3) Thr-412 of coronin-1 is phosphorylated during phagocytosis. In this study, we examined which PKC isoform is responsible for the phosphorylation of coronin-1 at Thr-412 by using isotype-specific PKC inhibitors and small interfering RNAs (siRNAs). Thr-412 phosphorylation of coronin-1 was suppressed by Gö6976, an inhibitor of PKCα and PKCßI. This phosphorylation was attenuated by siRNA for PKCα, but not by siRNA for PKCß. Furthermore, Thr-412 of coronin-1 was phosphorylated by recombinant PKCα in vitro, but not by recombinant PKCß. We next examined the effects of Gö6976 on the intracellular distribution of coronin-1 in HL60 cells during phagocytosis. The confocal fluorescence microscopic observation showed that coronin-1 was not dissociated from phagosomes in Gö6976-treated cells. These results indicate that phosphorylation of coronin-1 at Thr-412 by PKCα regulates intracellular distribution during phagocytosis.

Surgical Outcomes of Rhegmatogenous Retinal Detachment with Different Peripheral Vitreous-Shaving Procedures.

PURPOSE: To compare the surgical outcomes of vitreous surgery for rhegmatogenous retinal detachment (RRD) after two different peripheral vitreous-shaving techniques are performed. METHODS: We reviewed 269 eyes with RRD that were treated with a 25-gauge vitrectomy by a single surgeon between June 2015 and May 2020. The exclusion criteria for the proposed air tamponade selection were as follows: more than two weeks since RRD onset, giant retinal tears, a history of complications following cataract surgery, high myopia, and proliferative vitreoretinopathy classified as grade C or higher. We examined the differences in the therapeutic effect between shaving under slit lamp microscope illumination (group A) and shaving under a wide-angle viewing system (group B). RESULTS: A total of 269 eyes were included in this study, with 146 eyes in group A and 123 eyes in group B. The primary anatomical success rates did not differ between group A (97.3%; 142/146 eyes) and group B (97.6%; 120/123 eyes; P = 0.102). However, the surgical time was significantly longer in group A (60.2 ± 17.1 min) than that in group B (46.9 ± 12.6 min) (P < 0.001). The multiple linear regression analysis revealed that surgical time was significantly correlated with using the wide-angle noncontact viewing system for vitreous shaving (adjusted R 2 = 0.248; beta [standard partial regression coefficient] = -0.447, P < 0.001), the number of retinal breaks (beta = 0.182, P = 0.001), and the quadrant of retinal detachment (beta = 0.205, P < 0.001). CONCLUSION: The surgical outcomes were similar regardless of the shaving procedure performed, and the surgical time was shortened by using the wide-angle noncontact viewing system for vitreous shaving.

Intraoperative Observation of a Macular Holes Using Optical Coherence Tomography.

PURPOSE: This study aimed to observe intraoperative changes in macular hole (MH) form using intraoperative optical coherence tomography (iOCT). METHODS: A total of 10 eyes from 10 patients with MH who underwent vitrectomy using iOCT from May 2015 to October 2015 at the Yamagata University Hospital were retrospectively evaluated. Accordingly, 25-gauge pars plana vitrectomy using iOCT with internal limiting membrane (ILM) peeling and sulfur hexafluoride gas tamponade was performed on each patient. During surgery, MHs were observed using iOCT over four points, namely, before posterior vitreous detachment (PVD) formation, after PVD formation, after ILM peeling, and after fluid-gas exchange. Thereafter, basal MH diameter and minimum aperture MH diameter were postoperatively analyzed. RESULTS: Before PVD formation, after PVD formation, after ILM peeling, and after fluid-gas exchange, the mean basal MH diameters were 690.7 ± 268.4, 683.3 ± 274.2, 683.7 ± 269.5, and 668.3 ± 261.4 µm, while the mean minimum aperture MH diameters were 278.3 ± 165.2, 283.0 ± 170.2, 257.0 ± 127.8, and 188.0 ± 105.0 µm, respectively. The mean minimum aperture MH diameter decreased significantly after fluid-gas exchange (one-way repeated measures ANOVA, p < 0.05). None of the patients exhibited intraoperative closure of the MHs. However, MH closure was confirmed in all patients after the surgery. CONCLUSION: None of the patients demonstrated intraoperative MHs closure. Accordingly, the minimum aperture MH diameter was the first change formation to close after fluid-gas exchange.

Peripheral Cystoid Degeneration Finding Using Intraoperative Optical Coherence Tomography in Rhegmatogenous Retinal Detachment.

PURPOSE: The interaction between the peripheral vitreous and retina is closely associated with the pathogenesis of rhegmatogenous retinal detachment (RRD). This study was conducted to examine the peripheral vitreous and retina in patients with RRD using intraoperative optical coherence tomography (iOCT). METHODS: This retrospective study included 50 eyes of 50 patients (mean age 59.42 ± 10.80 years) that underwent vitrectomy using iOCT for treating RRD at the Yamagata University Hospital between September 2015 and September 2016. Each patient underwent 25-gauge pars plana vitrectomy that was performed by a single surgeon. During vitreous shaving with ocular indentation, the iOCT findings of the peripheral vitreous and retina were recorded and analyzed postoperatively. RESULTS: In all patients, iOCT was able to detect the peripheral retina and vitreous around the vitreous base. Peripheral cystoid degeneration was detected on the peripheral retina of 27 eyes (54%). Furthermore, cystoid degeneration was detected around the retinal tear (5 patients), at the detached retinal area (8 patients), and at the attached retinal area (14 patients). CONCLUSION: iOCT enabled the evaluation of peripheral cystoid degeneration in patients with RRD. Cystoid degeneration might be associated with the pathogenesis of RRD.

Distinguishing Features of Anterior Uveitis Caused by Herpes Simplex Virus, Varicella-Zoster Virus, and Cytomegalovirus.

PURPOSE: To determine distinguishing features of the clinical characteristics of anterior uveitis (AU) caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus (CMV). DESIGN: Retrospective, multicenter case series. METHODS: Consecutive patients with herpetic AU examined at 11 tertiary centers in Japan between January 2012 and December 2017 and who were followed for ≥3 months were evaluated. Diagnosis was made by polymerase chain reaction (PCR) for HSV, VZV, or CMV in the aqueous humor, or classical signs of herpes zoster ophthalmicus. RESULTS: This study enrolled 259 herpetic AU patients, including PCR-proven HSV-AU (30 patients), VZV-AU (50), and CMV-AU (147), and herpes zoster ophthalmicus (32). All HSV-AU and VZV-AU patients were unilateral, while 3% of CMV-AU patients were bilateral. Most HSV-AU and VZV-AU patients were sudden onset with an acute clinical course, while CMV-AU had a more insidious onset and chronic course. There were no significant differences for all surveyed symptoms, signs, and complications between HSV-AU and VZV-AU. However, significant differences were detected for many items between CMV-AU and the other two herpetic AU types. Ocular hyperemia and pain, blurring of vision, ciliary injection, medium-to-large keratic precipitates (KPs), cells and flare in the anterior chamber, and posterior synechia significantly more often occurred in HSV-AU and VZV-AU vs CMV-AU. In contrast, small KPs, coin-shaped KPs, diffuse iris atrophy, elevated intraocular pressure, and glaucoma surgery were significantly more frequent in CMV-AU vs HSV-AU and VZV-AU. CONCLUSION: This multicenter, retrospective study identified distinguishing features of HSV-AU, VZV-AU, and CMV-AU.

Quantification of the peripheral vitreous after vitreous shaving using intraoperative optical coherence tomography.

OBJECTIVE: To evaluate the technique of peripheral vitreous shaving during vitrectomy, we measured the residual peripheral vitreous using intraoperative optical coherence tomography (iOCT). METHODS AND ANALYSIS: This retrospective study included 44 eyes that underwent 25-gauge pars plana vitrectomy with iOCT by a single surgeon. In all cases, the surgery was performed via ocular indentation. Cases in group A were treated with vitreous shaving under slit lamp microscope illumination, whereas cases in group B were treated with vitreous shaving under a wide-angle viewing system. Residual peripheral posterior vitreous-cortex detachment (PVD) was quantified by iOCT. RESULTS: iOCT image analysis enabled the visualisation of the angle formed between the retina and peripheral PVD around the vitreous base in all cases. After the completion of vitreous shaving, the mean length of the peripheral PVD was shorter in group A (961.7±214.7 µm) compared with group B (1925.3.7 ± 626.1 µm; p<0.01). CONCLUSION: iOCT enabled the quantification of the residual peripheral vitreous after vitreous shaving. The quantification of the residual peripheral vitreous after different shaving procedures will be important for advocating appropriate vitreous shaving in future.

Effectiveness of Baricitinib in Refractory Seronegative Rheumatoid Arthritis and Uveitis: A Case Report.

Baricitinib is a Janus kinase (JAK) inhibitor used to treat refractory rheumatoid arthritis and blocks the subtypes JAK1 and JAK2. A 35-year-old man with seronegative rheumatoid arthritis complicated by bilateral severe non-granulomatous panuveitis was resistant to steroid treatment, multiple conventional disease-modifying antirheumatic drugs (methotrexate and salazosulfapyridine), and TNF-α inhibitors (adalimumab and infliximab). Therefore, the TNF-α inhibitors were switched to baricitinib to decrease the activity of systemic arthritis. Along with the amelioration of inflammatory activity in seronegative rheumatoid arthritis, the inflammatory activity of uveitis was decreased. Vitreous opacity, serous retinal detachment, and anterior chamber cells showed improvement. Baricitinib was effective not only in refractory systemic arthritis but also in uveitis, which may provide a new treatment option for patients with refractory uveitis.

Magnetoencephalography localizing spike sources of atypical benign partial epilepsy.

RATIONALE: Atypical benign partial epilepsy (ABPE) is characterized by centro-temporal electroencephalography (EEG) spikes, continuous spike and waves during sleep (CSWS), and multiple seizure types including epileptic negative myoclonus (ENM), but not tonic seizures. This study evaluated the localization of magnetoencephalography (MEG) spike sources (MEGSSs) to investigate the clinical features and mechanism underlying ABPE. METHODS: We retrospectively analyzed seizure profiles, scalp video EEG (VEEG) and MEG in ABPE patients. RESULTS: Eighteen ABPE patients were identified (nine girls and nine boys). Seizure onset ranged from 1.3 to 8.8years (median, 2.9years). Initial seizures consisted of focal motor seizures (15 patients) and absences/atypical absences (3). Seventeen patients had multiple seizure types including drop attacks (16), focal motor seizures (16), ENM (14), absences/atypical absences (11) and focal myoclonic seizures (10). VEEG showed centro-temporal spikes and CSWS in all patients. Magnetic resonance imaging (MRI) was reported as normal in all patients. MEGSSs were localized over the following regions: both Rolandic and sylvian (8), peri-sylvian (5), peri-Rolandic (4), parieto-occipital (1), bilateral (10) and unilateral (8). All patients were on more than two antiepileptic medications. ENM and absences/atypical absences were controlled in 14 patients treated with adjunctive ethosuximide. CONCLUSION: MEG localized the source of centro-temporal spikes and CSWS in the Rolandic-sylvian regions. Centro-temporal spikes, Rolandic-sylvian spike sources and focal motor seizures are evidence that ABPE presents with Rolandic-sylvian onset seizures. ABPE is therefore a unique, age-related and localization-related epilepsy with a Rolandic-sylvian epileptic focus plus possible thalamo-cortical epileptic networks in the developing brain of children.

Constitutive turnover of phosphorylation at Thr-412 of human p57/coronin-1 regulates the interaction with actin.

The actin-binding protein p57/coronin-1, a member of the coronin protein family, is selectively expressed in hematopoietic cells and plays crucial roles in the immune response through reorganization of the actin cytoskeleton. We previously reported that p57/coronin-1 is phosphorylated by protein kinase C, and the phosphorylation down-regulates the association of this protein with actin. In this study we analyzed the phosphorylation sites of p57/coronin-1 derived from HL60 human leukemic cells by MALDI-TOF-MS, two-dimensional gel electrophoresis, and Phos-tag® acrylamide gel electrophoresis in combination with site-directed mutagenesis and identified Ser-2 and Thr-412 as major phosphorylation sites. A major part of p57/coronin-1 was found as an unphosphorylated form in HL60 cells, but phosphorylation at Thr-412 of p57/coronin-1 was detected after the cells were treated with calyculin A, a Ser/Thr phosphatase inhibitor, suggesting that p57/coronin-1 undergoes constitutive turnover of phosphorylation/dephosphorylation at Thr-412. A diphosphorylated form of p57/coronin-1 was detected after the cells were treated with phorbol 12-myristate 13-acetate plus calyculin A. We then assessed the effects of phosphorylation at Thr-412 on the association of p57/coronin-1 with actin. A co-immunoprecipitation experiment with anti-p57/coronin-1 antibodies and HL60 cell lysates revealed that ß-actin was co-precipitated with the unphosphorylated form but not with the phosphorylated form at Thr-412 of p57/coronin-1. Furthermore, the phosphorylation mimic (T412D) of p57/coronin-1 expressed in HEK293T cells exhibited lower affinity for actin than the wild-type or the unphosphorylation mimic (T412A) did. These results indicate that the constitutive turnover of phosphorylation at Thr-412 of p57/coronin-1 regulates its interaction with actin.

Immunopathologic processes in sympathetic ophthalmia as signified by microRNA profiling.

PURPOSE: Recent discovery of microRNAs and their negative gene regulation have provided new understanding in the pathogenesis of inflammatory diseases. This study demonstrated microRNA expression profiling and their likely role in sympathetic ophthalmia, using formalin-fixed, paraffin embedded samples. METHODS: Two groups of four enucleated globes (total eight globes) from patients with clinical and histopathological diagnosis of SO (experimental samples) and one group of four age-matched, noninflamed enucleated globes (control samples) were used. Human genome-wide microRNA PCR array was performed and results were subjected to bioinformatics calculation and P values stringency tests. The targets were searched using the recently published and periodically updated miRWalk software. Quantitative real-time PCR and immunohistochemical staining were performed to confirm the validated targets in the mRNA and in the protein levels, respectively. RESULTS: No microRNA was significantly upregulated in SO, but 27 microRNAs were significantly downregulated. Among these, four microRNAs (hsa-miR-1, hsa-let-7e, hsa-miR-9, and hsa-miR-182) were known to be associated with the inflammatory signaling pathway. Only hsa-miR-9 has the validated targets, tumor necrosis factor-α, and nuclear factor kappa B1, which have been previously shown to be associated with mitochondrial oxidative stress-mediated photoreceptor apoptosis in eyes with SO. CONCLUSIONS: Identification of altered levels of microRNAs by microRNA expression profiling may yield new insights into the pathogenesis of SO by disclosing specific microRNA signatures. In the future these may be targeted by synthetic microRNA mimic-based therapeutic strategies.

Mitochondrial oxidative stress initiates visual loss in sympathetic ophthalmia.

The visual loss that occurs with sympathetic ophthalmia (SO) in the absence of recognizable retinal damage and inflammatory cell infiltration is an enigma. Experimental autoimmune uveoretinitis (EAU) is an animal model used to study human endogenous uveitis. Both innate and adaptive immune responses have been well studied in the photoreceptor damage mechanism of EAU. In our studies, in the early phase of EAU, proinflammatory molecules such as tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS) and the subsequent mitochondrial DNA damage, mitochondrial protein alteration, and mitochondrial dysfunction by oxidative stress were observed before retinal inflammatory cell infiltration. Our recent study shows the importance of Toll-like receptors (TLRs) in the production of proinflammatory molecules and the induction of mitochondrial oxidative stress. Thus, the innate immune responses occur first with the activation of TLRs; this activation upregulates proinflammatory molecules, leading to mitochondrial oxidative stress before retinal inflammatory cell infiltration and the subsequent adaptive immune responses. Like EAU, SO also results in photoreceptor mitochondrial oxidative damage without retinal inflammatory cell infiltration. Such damage was associated with TNF-α, TNF-α receptors, and iNOS expression in the photoreceptors, suggesting that this molecular mechanism without retinal inflammatory cell infiltration may initiate photoreceptor damage in SO.