RECENT TRENDS IN THE CUMULATIVE INCIDENCE AND INTERVENTION PATTERNS OF RETINOPATHY OF PREMATURITY IN JAPAN: A Multicenter Analysis, 2011-2020.

PURPOSE: To investigate recent trends in the cumulative incidence and treatment patterns of retinopathy of prematurity (ROP) in Japan. METHODS: A retrospective multicenter cohort was conducted from 2011 to 2020 using the Diagnosis Procedure Combination inpatient database. Preterm newborns with birth weight <2,500 g were categorized by birth weight. The cumulative incidence of ROP, treatment patterns, and association between treatment and birth weight were investigated. RESULTS: A total of 82,683 preterm infants were identified, of whom 9,335 (11.3%) were diagnosed with ROP. The cumulative incidence of ROP increased by 15% in those with birth weight <500 g over the study period. Among the ROP infants, 20.2% received treatment, including laser photocoagulation (94.8%), intravitreal injection (3.8%), or both (1.8%). The proportion receiving laser photocoagulation decreased followed by an increase in intravitreal injection. This shift in intervention pattern was most conspicuous for those with birth weight 750 to 1,249 g. The risk ratio of receiving laser and intravitreal injection for those weighing <500 g was 24.7 (95% confidence interval, 10.5-58.2) and 28.4 (5.8-138.1), respectively, as compared with infants weighing >1,500 g. CONCLUSION: The cumulative incidence of ROP increased in infants with birth weight <500 g. A shift from laser photocoagulation to intravitreal injection was observed in the more recent years.

Clinically Diagnosed Occult Macular Dystrophy Habouring an m.14502T>C Mitochondrial DNA Mutation Associated with Leber's Hereditary Optic Neuropathy: Case Report and Literature Review.

A 29-year-old female with no family history presented with bilateral progressive blurred vision. Her symptoms appeared at 12-years-old and her visual acuity had since deteriorated from 0.6 to 0.2 bilaterally with decreased critical flicker frequency and bilateral central scotomas. She did not have a relative afferent pupillary defect. Fundoscopy revealed no distinct disc hyperaemia, atrophy, or peripapillary telangiectatic vessels. The retinal nerve fibre layer appeared normal on optical coherence tomography in each eye; however, loss of the interdigitation zone and the disruption of the ellipsoid zone at the fovea were observed in both eyes. Multifocal electroretinography revealed decreased amplitudes at both macula regions. Mitochondrial deoxyribonucleic acid analysis identified an m.14502T>C mutation, one of the primary mutations causing Leber's hereditary optic neuropathy (LHON). Despite the presence of a marked LHON mutation, however, she was clinically diagnosed as having an occult macular dystrophy. There have only been five previous case reports, all of which were sporadic, which detail the clinical characteristics of the m.14502T>C mutation. The m.14502T>C phenotype is somewhat consistent with that of the other major mutations, including young onset, bilateral progressive visual impairment, and a typical LHON fundus. Nevertheless, m.14502T>C alone has an extremely low penetrance and its phenotype may be minimal or subclinical, as seen in our case. Since little is known about the clinical course of the m.14502T>C mutation it may be possible that the LHON phenotype may appear in later stages of life. Moreover, m.14502T>C may function as a modifier gene, which alters the phenotype of other coexisting major LHON mutations, including penetrance and the severity of the disease, through synergistic effects.

Predicting retinal sensitivity using optical coherence tomography parameters in central serous chorioretinopathy.

PURPOSE: To predict changes in retinal sensitivity using optical coherence tomography (OCT) in eyes with central serous chorioretinopathy (CSC). METHODS: Twenty-three eyes in 23 patients with CSC were enrolled. Retinal sensitivity was measured twice using microperimetry in all the examined eyes. Spectral domain OCT measurements were simultaneously conducted. The relationship between retinal sensitivity and the thicknesses of (i) the retinal nerve fiber layer plus the ganglion cell layer (RNFL + GCL), (ii) the inner nuclear layer (INL), (iii) the outer nuclear layer (ONL), and (iv) the serous retinal detachment height (SRDH) were investigated in a point-wise manner. The associations between the change in retinal sensitivity and the OCT parameters at baseline were also investigated. RESULTS: The mean age of the participants was 49.8 ± 10.7 years. The mean SRDH was significantly lower (p < 0.001), and the mean retinal sensitivity (p < 0.001) was significantly higher at the second examination, compared with the first; however, the logMAR visual acuity (VA) did not differ significantly between the two examinations (p = 0.063). The logMAR VA was associated with retinal sensitivity at both the first and second examinations (p < 0.001). The retinal sensitivity at the second examination was significantly correlated with the retinal sensitivity, RNFL + GCL, INL, ONL, and SRDH at the first examination and with the improvement in SRDH. CONCLUSIONS: Retinal sensitivity was associated with the retinal structure in eyes with CSC; these parameters could be useful for predicting the change in visual function prior to treatment.

Immunomodulatory effects of Radix isatidis polysaccharides in vitro and in vivo.

Radix isatidis (R. isatidis) is a commonly used traditional Chinese herbal medicine, which has been used for thousands of years in China and is believed to have the pharmacological properties of heat-clearing and detoxification. Heat-clearing and detoxification are theories of traditional Chinese medicine meaning that R. isatidis could treat febrile disease by clearing heat and reducing swelling. Polysaccharides isolated from R. isatidis by water extraction and alcohol precipitation have exhibited numerous biological activities, including antiviral and immunomodulatory effects. The present study was performed to investigate the immunomodulatory effects of water-soluble R. isatidis polysaccharides (RIPs) on RAW264.7 macrophages and murine splenocytes, and attempt to preliminarily identify the mechanism of immunomodulation. In vitro, RIPs had a low cytotoxicity, as shown by CellTiter 96® AQueous One Solution Cell Proliferation Assay. RAW264.7 cells treated with different concentrations of RIP displayed different morphological changes, from a round shape and aggregation to polygonal shape and dispersion in a dose-dependent manner. In the 5 mg/ml RIP-treated group, the changes of morphology were as same as the lipopolysaccharide-treated group. RIP also significantly enhanced the release of nitric oxide as shown by Griess method, and the secretion of TNF-α and IL-6 in RAW264.7 cells was confirmed by ELISA assay. Western blotting revealed a significant increase of toll-like receptor-4 (TLR-4) in RIP-treated RAW264.7, suggesting that TLR-4 may be associated with the immunomodulatory mechanism of RIP. Animal experiments also demonstrated through ELISA assays a significant increase in IFN-γ and IL-10 levels after the splenocytes of RIP-immunized mice were stimulated by inactivated herpes simplex virus type 2. The immune function of RIP-immunized mice was improved. The present study suggested that RIP could be potentially used as a novel immunomodulator.

Changes in entropy on polarized-sensitive optical coherence tomography images after therapeutic subthreshold micropulse laser for diabetic macular edema: A pilot study.

PURPOSE: To investigate the dynamics of the healing process after therapeutic subthreshold micropulse laser (SMPL) for diabetic macular edema (DME) using polarization-sensitive optical coherence tomography (PS-OCT). METHODS: Patients with treatment-native or previously-treated DME were prospectively imaged using PS-OCT at baseline, 1, 2, 3, and 6 months. The following outcomes were evaluated: changes in the entropy value per unit area (pixel2) in the retinal pigment epithelium (RPE) on the B-scan image; changes in the entropy value in each stratified layer (retina, RPE, choroid) based on the ETDRS grid circle overlaid with en face entropy mapping, not only the whole ETDRS grid area but also a sector irradiated by the SMPL; and the relationship between edema reduction and entropy changes. RESULTS: A total of 11 eyes of 11 consecutive DME patients were enrolled. No visible signs of SMPL treatment were detected on PS-OCT images. The entropy value per unit area (pixel2) in the RPE tended to decrease at 3 and 6 months from baseline (35.8 ± 17.0 vs 26.1 ± 9.8, P = 0.14; vs 28.2 ± 18.3, P = 0.14). Based on the en face entropy mapping, the overall entropy value did not change in each layer in the whole ETDRS grid; however, decrease of entropy in the RPE was observed at 2, 3, and 6 months post-treatment within the SMPL-irradiated sectors (P < 0.01, each). There was a positive correlation between the change rate of retinal thickness and that of entropy in the RPE within the SMPL-irradiated sector at 6 months (r2 = 0.19, P = 0.039). CONCLUSION: Entropy measured using PS-OCT may be a new parameter that facilitates objective monitoring of SMPL-induced functional changes in the RPE that could not previously be assessed directly. This may contribute to a more promising therapeutic evaluation of DME. CLINICAL TRIAL: This clinical study was registered in UMIN-CTR (ID: UMIN000042420).

Association Between Retinal Artery Angle and Visual Function in Eyes With Idiopathic Epiretinal Membrane.

Purpose: This study investigated the relationship between retinal artery angle and visual function in eyes with idiopathic epiretinal membrane (ERM). Methods: Ultra-wide field fundus imaging was conducted to analyze ERM and normal contralateral eyes. In addition to the logMAR visual acuity (VA) measurement, the average of the vertical and horizontal metamorphopsia scores (Mave) was measured using m-Charts for each eye. We calculated the retinal artery angle (Yugami correlated angle [YCA]) in all the examined eyes using ImageJ software. The YCAs were then compared between the ERM and normal contralateral eyes. Additionally, the relationship between YCA and visual function was investigated in the ERM eyes. Results: Data from 40 patients with ERM were analyzed. The mean age of the participants was 67.1 ± 8.1 years. The YCA was significantly smaller in the ERM eyes, compared with the contralateral eyes (P < 0.001, respectively; Wilcoxon signed rank test). Among age, axial length, YCAs, central retinal thickness (CRT), and central choroidal thickness (CCT), the optimal model for logMAR VA included age, YCA, and CRT. On the other hand, the optimal model for Mave included YCA and CCT. Conclusions: The retinal artery angle may be useful for predicting visual function in eyes with ERM. Translational Relevance: Our established quantitative measurements in fundus photography have potential clinical use in predicting visual function in ERM.

Visual outcomes and prognostic factors of vitrectomy for lamellar macular holes and epiretinal membrane foveoschisis.

PURPOSE: To evaluate the visual outcomes of vitrectomy for lamellar macular hole (LMH) and epiretinal membrane (ERM) foveoschisis and to investigate the prognostic factor for postoperative visual acuity. METHODS: We retrospectively reviewed 15 LMH and 17 ERM foveoschisis eyes that had undergone a standard three-port pars plana vitrectomy with (12 eyes) or without (20 eyes) cataract surgery. Best-corrected visual acuity (BCVA) at postoperative three months and the final visit were compared to the preoperative measurements. We investigated the relationship between BCVA at the final visit and baseline parameters (age, preoperative BCVA, the presence of epiretinal proliferation [EP] and ellipsoid zone [EZ] disruption). The best explanatory variables for the final BCVA were investigated using the corrected Akaike information criterion (AICc) model selection. RESULTS: The mean age was 67.2 years. The mean follow-up duration was 30.7 months. Fifteen of 32 examined eyes were diagnosed as LMH and 17 eyes as ERM foveoschisis. Twelve eyes in LMH had EP and 13 eyes showed the disruption of EZ integrity. In total, BCVA significantly improved at 3 months postoperatively (p = 0.0013). A significant improvement was observed in ERM foveoschisis (p = 0.0085) but not in LMH group (p = 0.071). Comparing the BCVA between the baseline and the final visit, significant improvements were observed in total, ERM foveoschisis and LMH group (p<0.001, p<0.001 and p = 0.026, respectively). The optimal model for BCVA at the final visit included preoperative BCVA and the presence of EZ disruption (p<0.001 and p<0.001, respectively). CONCLUSION: Our results suggested that the final BCVA was dependent on preoperative BCVA and the presence of EZ disruption. Surgical indications might be warranted for LMHs with EZ disruption.

Quantification of residual ellipsoid zone and its correlation with visual functions in patients with cone-rod dystrophy.

Cone-rod dystrophy (CORD) is one of the inherited retinal diseases that result in central visual field deterioration and decreased visual acuity (VA). In CORD patients, impaired photoreceptor cells are observed as the disruption of ellipsoid zone (EZ) on optical coherence tomography (OCT) images. In the present study, we calculated the index of residual EZ (rEZ) to quantify the function of photoreceptor cells and investigated the correlation between rEZ index and visual functions. Twenty-six eyes of 13 patients with clinical suspicion of CORD were examined. Visual field was tested with the Humphrey Visual Field Analyzer (HFA 10-2 program). We simultaneously obtained OCT images and calculated the area of decreased EZ intensity (EZa). Using the binarized OCT images, the percentage of the rEZ in a 3 × 3 mm area surrounding the macula was analyzed. To clarify interrator reproducibility, intraclass correlation coefficient (ICC) was calculated. Moreover, we investigated the association between OCT parameters and VA as well as the mean deviation (MD) value measured with HFA. The mean age of the patients was 48.5 ± 16.9 years. The mean central retinal thickness was 122.7 ± 73.2 µm. The mean EZa and rEZ were 22.2 ± 23.6 µm2 and 0.35 ± 0.31, respectively. The ICC of each rEZ index was 0.91 (95% CI: 0.89 < ICC < 0.93). Multivariate analysis indicated rEZ was significantly related to logMAR VA (p = 0.05) and rEZ and EZa were associated with the MD value (p = 0.014 and p = 0.009, linear mixed model). Furthermore, rEZ was also associated with photopic a- and b-wave amplitudes (p = 0.027 and p = 0.0024, respectively, linear mixed model). Taken together, the current results suggested the usefulness of rEZ quantification for predicting visual functions in CORD patients.

Multidisciplinary Diagnostic Approach in Intraocular Lymphoma Featuring Pseudo-hypopyon: Case Series and Literature Review.

PURPOSE: Diagnosis of intraocular lymphoma (IOL) is usually achieved by histopathological analysis. However, it may lead to inconclusive results due to the scarcity of malignant cells obtained by biopsy, hence leading to delayed diagnosis. We report two cases of IOL with pseudo-hypopyon, a rare feature of IOL, as their initial ocular feature, diagnosed using a multidisciplinary diagnostic approach. Common clinical features of IOL with pseudo-hypopyon were also investigated. METHODS: Retrospective case series and literature review. RESULTS: Two cases of IOL, a 78-year-old female and a 59-year-old male, whom had been diagnosed with systemic B-cell lymphoma developed pseudo-hypopyon and visual impairment during the course of their chemotherapy. Diagnosis of IOL was achieved from anterior chamber aspiration samples with supplementary diagnostic tools including flow cytometric immunophenotyping, interleukin and IgH gene rearrangement analysis in addition to the conventional histopathological analysis. Generally, pseudo-hypopyon was more commonly seen in secondary IOL and may associate with hyphema and high intraocular pressure. CONCLUSION: Pseudo-hypopyon is a rare feature of IOL, more commonly seen in secondary IOL, which can be accompanied by hyphema and high intraocular pressure. Supplementary diagnostic tools such as flow cytometric immunophenotyping, interleukin analysis, and immunogloblin H gene rearrangement analysis are useful for supporting the diagnosis of IOL with pseudo-hypopyon.

Short wavelength automated perimetry and standard automated perimetry in central serous chorioretinopathy.

Short wavelength automated perimetry (SWAP) is known for detecting the early reduction of retinal sensitivity (RS) in glaucoma. It's application in retinal diseases have also been discussed previously. We investigated the difference in RS measured between standard white-on-white automated perimetry (WW) and blue-on-yellow SWAP in central serous chorioretinopathy (CSC). The overall RS (W-RS, S-RS) as well as the RS inside and outside of the serous retinal detachment (SRD) region were investigated in 26 eyes of 26 CSC patients using WW and SWAP. The central retinal thickness, central choroidal thickness, SRD area (SRDa), and SRD height at the fovea were measured using optic coherence tomography. RS inside the SRD region was lower than that of outside for both perimetries (both p < 0.001). The difference between RS inside and outside of the SRD region was greater in SWAP compared to WW (p < 0.001). Univariate analysis revealed significant correlations between SRDa and both W-RS and S-RS (both p < 0.001); moreover, multivariate analysis indicated that only S-RS was selected as the optimal model for SRDa. Our study demonstrated that SWAP was detected the decrease in RS more accurately than WW in CSC. These results may suggest the usefulness of SWAP for detecting change of retinal function in CSC.

Therapeutic Changes in Bilateral Choroidal Metastasis from Non-Small Cell Lung Cancer with Response to Afatinib: A Case Report.

A 49-year-old male presented with a three-day onset of blurred vision and metamorphopsia in the left eye. Fundoscopy and OCT images identified multiple subretinal masses with associating serous retinal detachment in both eyes. Bilateral choroidal metastasis was suspected, and further evaluation revealed a mass in the lower left lobe of the lung with multiple metastatic loci. Ultimately, the patient was diagnosed with Stage IVB (T2aN2M1c) adenocarcinoma of the lung. Genetic analysis revealed an exon 19 deletion mutation in the epidermal growth factor receptor (EGFR) gene. The patient was started on afatinib, a second-generation tyrosine kinase inhibitor. Drastic improvement in both tumor volume and visual acuity was observed after 1.5 months. The primary site and other metastatic loci also improved significantly during the observed period. Our report demonstrated the effectiveness of afatinib alone for the treatment of bilateral choroidal metastasis in a non-small cell lung cancer patient exhibiting EGFR mutation.

Site Specific Evaluation of Lymphatic Vessel Sclerosis in Lower Limb Lymphedema Patients.

BACKGROUND: Histological changes in the collecting lymphatics in patients with lymphedema are classified as Normal type, Ectasis type, Contraction type, and Sclerosis type (NECST) classification. In this study, we investigated the condition of the lymphatic vessels in different sites of the legs. PATIENTS AND METHODS: We prospectively investigated the lymphatic vessels of patients with lymphedema who underwent lymphaticovenous anastomosis (LVA) from August 8, 2014 to August 4, 2015 based on the NECST classification. Lymphedema was diagnosed using lymphoscintigraphy, indocyanine green (ICG) lymphography, and the International Society of Lymphology (ISL) Classification. The affected limbs were divided into four sites: proximal thigh (Site 1), distal thigh (Site 2), proximal crus (Site 3), and distal crus (Site 4). RESULTS: A total of 109 patients (205 limbs and 1028 lymphatics) were included in this study. Of the 109 patients, there were 100 women and 9 men with an average age of 61 years. The ratio of Ectasis type vessels increased toward the distal end of the limb with the highest occurrence rate being 54% at Site 4. As ISL stage, ICG stage, and lymphoscintigraphy stage advanced, so too did the ratio of Sclerosis type. In secondary lymphedema patients with lymphedema, the ratio of Ectasis type was more predominant in the distal end of the limb, whereas this tendency was not observed in primary lymphedema patients. CONCLUSIONS: Sclerotic lymphatics are more predominantly found in the proximal limb whereas nonsclerotic vessels are more often found toward the distal end. These findings help lymphatic surgeon determine incision sites.

Lymphaticovenous Anastomosis Releases the Lower Extremity Lymphedema-associated Pain.

BACKGROUND: We investigate the effectiveness of lymphaticovenous anastomosis (LVA) in releasing lymphedema-associated pain. METHODS: We performed a retrospective analysis. Subjects of this study included lower extremity lymphedema patients who presented persistent and constant degrees of pain in their lower limbs. LVA was performed under local anesthesia. The preoperative lower extremity pain and postoperative lower extremity pain were surveyed using the visual analog scale on a score from 0 to 10. The circumferences of the limbs were also recorded. RESULTS: A total of 8 patients (16 lower limbs) were included. The subjects included 1 man and 7 women, and their average age was 72 years. The average follow-up period was 17 months. The average preoperative and postoperative visual analog scale scores were 5.3 and 1.8, respectively. Moreover, 7 patients who had records of their lower extremity circumference observed an average changing rate of -4.7% in lower extremity lymphedema index after the surgery. CONCLUSION: LVA can release the pain in the affected limbs of lymphedema.

Multisite Lymphaticovenular Bypass Using Supermicrosurgery Technique for Lymphedema Management in Lower Lymphedema Cases.

BACKGROUND: The impact of lymphaticovenous anastomosis on lymphedema has yet to be defined. The authors investigated the clinical evidence regarding the effectiveness of lymphaticovenous anastomosis in lower limb lymphedema. METHODS: Eighty-four patients (162 limbs; 73 female and 11 male patients) with lower limb lymphedema who underwent multisite lymphaticovenous anastomosis in the authors' clinic between August of 2010 and May of 2014 were included in this retrospective study. Lymphedema was diagnosed using lymphoscintigraphy and indocyanine green lymphography. All lymphaticovenous anastomoses were performed under local anesthesia. The lymphatic vessels that were identified were classified using the normal, ectasis, contraction, and sclerosis type (NECST) classification. Limb circumference, subjective symptoms, and frequency of cellulitis were evaluated. RESULTS: The average patient age was 60 years (range, 24 to 94 years); mean postoperative follow-up period was 18.3 months (range, 6 to 51 months). The postoperative change rate in limb circumference indicated that 67 limbs (47.7 percent) were classified as improved, 35 (27.3 percent) were classified as stable, and 32 (25 percent) were classified as worse. Postoperative interview revealed improvement in subjective symptoms in 67 limbs (61.5 percent), no change in 38 (34.9 percent), and exacerbation in four (3.7 percent). The postoperative mean occurrence of cellulitis was decreased to 0.13 times per year compared with 0.89 preoperatively, which was statistically significant (p = 0.00084). Multiple regression analysis using the postanastomosis limb circumference and NECST classification confirmed the following results: change rate (percent) = -0.40 + (0.30 × N) + (-0.84 × E) + (0.22 × C) + (-0.61 × S). CONCLUSION: Lymphaticovenous anastomosis is effective for lower limb lymphedema, in point of limb circumference, subjective symptoms, and the frequency of cellulitis. CLINCAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Case report: a new hybrid surgical approach for treating mosaic pattern secondary lymphedema in the lower extremities.

Two of the most common surgical lymph reconstructive interventions for the treatment of secondary lymphedema today are lymphaticovenous anastomosis (LVA) and lymph node transplant. However, neither of these approaches has proven enough evidence to be considered as an effective treatment measure. In this case report, we will introduce a "hybrid method" where combinations of these two conventional methods are used in treating a 52-year-old female patient who displays a mosaic pattern of aggravating secondary lymphedema. Preoperative indocyanine green lymphography assessment was used to identify the different stages of lymphedema within the symptomatic limbs. The application of the hybrid method has resulted in a faster improvement in limb circumference and tissue tenderness compared with when only LVA is performed and has resulted in successful recovery from lymphedema in our case. The hybrid method allows surgeons to select the most appropriate surgical approach for each region displaying a different severity staging of lymphedema, establishing a new order-made remedy for chronic secondary lymphedema patients.