Lacrimal sac massage for congenital nasolacrimal duct obstruction: a multicentre randomised controlled trial.

AIM: Congenital nasolacrimal duct obstruction (CNLDO) is the most common cause of epiphora and mucous discharge in the newborn. We conducted a multicentre randomised controlled trial to determine whether Crigler massage promotes the resolution of CNLDO in infants under 1 year of age. METHODS: A total of 102 infants aged 3-11 months with unilateral CNLDO were enrolled in the study. Patients were randomly assigned to the massage and non-massage groups (n=51/group). As an allocation adjustment factor, the patients were divided into age groups of 3-5, 6-8 and 9-11 months. In the massage group, the guardian performed 10 strokes two times per day for each day until resolution or 1 month. The primary endpoint was a comparison of the 1-month resolution rate in the massage and non-massage groups. RESULTS: This study included 49 male and 53 female patients with a mean age of 6.4±2.4 months. Overall, in this study, the resolution rate was not significantly different between the massage and non-massage groups (31.4% and 33.3%, respectively). However, the resolution rate was higher in the massage group in the 3-5 months age group among the protocol-compliant patients after excluding those with insufficient massage frequency (the massage group, 68.8% and the non-massage group, 28.6%, p=0.022). CONCLUSIONS: There was no increase in the resolution rate after 1 month of lacrimal sac massage in patients 3-11 months old with unilateral CNLDO. However, in protocol-compliant younger age groups, Crigler massage may be effective. TRIAL REGISTRATION NUMBER: UMIN Clinical Trial Registry (UMIN000032840; www.umin.ac.jp/).

Diversity in Lacrimal Pathway Morphology Among Patients with Congenital Nasolacrimal Duct Obstruction.

Purpose: This prospective observational study aimed to explore the diversity in lacrimal pathway morphology among patients with congenital nasolacrimal duct obstruction (CNLDO) by examining dacryocystography (DCG) images. Patients and Methods: The study included 64 patients who underwent DCG before undergoing general anesthesia probing for unilateral CNLDO. Several parameters were measured from the lateral view of the DCG images: (1) the lacrimal sac (LS) and the nasolacrimal duct (NLD) angle, (2) the angle formed by the superior orbital rim (SOR), LS, and the NLD, (3) LS length, and (4) bony NLD length. Additionally, frontal views of the DCG images were utilized to measure (5) LS-NLD angle and (6) LS angle concerning the midline. Results: The average age of the patients was 34.3 months. The mean ± standard deviation of the measurements of the above parameters was (1) -1.2° ± 16.5° (range: -44.6° ± 46.6°), (2) -5.0° ± 10.3° (range: -24.0° ± 19.0°), (3) 10.2 ± 2.4 mm (range: 6.5-16.0 mm), (4) 8.0 ± 2.5 mm (range: 3.1-14.8 mm), (5) 15.6° ± 11.2° (range: -16.8° ± 41.0°), and (6) 15.1 ± 5.2° (range: 3.3°-29.8°). All parameters, except for parameter (3), conformed to a normal distribution. Conclusion: This study provides valuable anthropometric data derived from DCG images, highlighting the substantial variability in lacrimal pathway morphology among patients with CNLDO. Furthermore, anatomical constraints made probing with a straight metal bougie anatomically infeasible in 25.0% of the patients included in this study.

Understanding the morphology of the lacrimal pathway is crucial for the successful probing treatments in patients with congenital nasolacrimal duct obstruction (CNLDO). This study represents an initial effort to quantify anthropometric parameters of the lacrimal drainage system through dacryocystography images, specifically aiming to highlight the limitations of blind probing procedure. The results underscore significant variations in the morphology of the lacrimal drainage system among patients, which could impact diagnostic approaches and treatment strategies. Additionally, the findings suggest that patients with CNLDO who do not respond to blind probing may have underlying anatomical complexities. Therefore, rather than relying on repeated blind probing, employing dacryoendoscopy-guided probing under direct visualization could offer a more effective therapeutic alternative for complicated cases of CNLDO.

Otoscopy-assisted intranasal cyst marsupialization for congenital dacryocystocele.

We describe 3 infants with congenital dacryocystocele resistant to conservative treatment who were treated with a novel, simple intranasal cyst marsupialization (ICM) technique. Otoscopy-guided ICM was performed by an otolaryngologist in the manner of otoscopic myringotomy for cases with nasal cyst distension. All 3 infants were treated successfully by a single surgical procedure under topical anesthesia in an office setting.

Accuracy of the Lacrimal Syringing Test in Relation to Dacryocystography and Dacryoendoscopy.

Purpose: This study aimed to evaluate the accuracy of the lacrimal syringing test (syringing) in relation to dacryocystography (DCG) and dacryoendoscopy (DE) in lacrimal pathway (LP) obstruction. Methods: We retrospectively reviewed 101 patients (188 LPs) who underwent syringing, cone-beam computed tomography (CBCT)-DCG, and DE to diagnose the degree and site of LP obstruction. The degree of obstruction was classified into patent, partial obstruction, and complete obstruction. The degree of LP obstruction was determined by combining the findings of DE and CBCT-DCG and was designated as DCG+DE. When differentiating complete or partial obstruction on DE was uncertain, complete or partial obstruction was assigned if the DCG showed evidence of contrast media obstruction or passage, respectively. The consistency between syringing and DCG+DE was evaluated by calculating the weighted kappa coefficient. Results: The sensitivity and specificity of syringing were 94% and 89%, respectively. The weighted Cohen's kappa value of agreement between syringing and DCG+DE was κ = 0.73 (SE = 0.04, 95% confidence interval [CI]: 0.66-0.80, p < 0.01). When divided into presaccal and postsaccal obstruction categories, the kappa values were κ = 0.40 (SE = 0.11, 95% CI: 0.19-0.62, p < 0.01) and 0.55 (SE = 0.09, 95% CI: 0.37-0.73, p < 0.01), respectively. Furthermore, when limited to common canaliculus obstruction (stenoses), which accounted for 78% (46 LPs) of the total presaccal obstructions, the kappa value was κ = 0.29 (SE = 0.12, 95% CI: 0.05-0.54, p = 0.021), which demonstrated the lowest consistency between syringing and DCG+DE. Conclusion: Syringing was "substantially" in agreement with DCG+DE in detecting the degree of LP obstruction. Moreover, syringing was a sufficiently sensitive and specific test when performed by an experienced clinician. However, distinguishing between complete and partial obstructions by syringing was sometimes difficult, particularly in the common canaliculus obstruction (stenosis).

HLA-DRB1*04:05 is involved in the development of Vogt-Koyanagi-Harada disease-like immune-related adverse events in patients receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) activate anti-tumor activity by inhibiting immune checkpoint molecules that suppress inflammatory T-cell activity. However, ICIs can initiate excessive immune responses, thereby causing immune-related adverse events (irAEs). ICI-associated uveitis (ICIU) is an irAE that affects the eyes. Although Vogt-Koyanagi-Harada disease (VKH)-like uveitis is a common form of ICIU, it is unclear which factors determine the ICIU form. We retrospectively reviewed the medical records of nine ICIU cases treated with ICIs for malignancies. We also performed HLA typing in seven cases to investigate the association between HLA and disease type. Fisher's exact test was used for the statistical analysis. Five of the ICIU cases were VKH-like ICIUs, and four were non-VKH-like ICIUs. No association was found between mean age, sex, primary disease, ICI, time to onset, and disease type. Four patients with VKH-like uveitis underwent HLA genotyping and were all positive for HLA-DRB1*04:05. All 3 patients with non-VKH-like uveitis were negative for HLA-DRB1*04:05. Statistical analysis showed that HLA-DRB1*04:05 was significantly associated with developing VKH-like ICIU (P = 0.029). In ICIU, HLA-DRB1*04:05 was associated with the pathogenesis of VKH-like uveitis, suggesting that ICI-associated VKH-like uveitis has a similar pathogenesis to VKH.

Analysis of Lacrimal Duct Morphology from Cone-Beam Computed Tomography Dacryocystography in a Japanese Population.

Purpose: The dacryoendoscope is a practical instrument for the examination and the treatment of lacrimal duct obstruction. Nevertheless, as it is a rigid fiberscope, manipulation of the endoscope is somewhat affected by the patient's lacrimal duct alignment and the skeletal structure of the face. The morphology and inclination of the lacrimal duct vary among individuals and ethnic groups. We aimed to evaluate the alignment of the lacrimal duct from the perspective of endoscopic maneuverability in a Japanese population. Methods: This retrospective study analyzed the cone-beam computed tomography dacryocystography (CBCT-DCG) images of 102 patients diagnosed with unilateral primary acquired nasolacrimal duct obstruction (PANDO) at Ehime University Hospital from December 2015 to May 2021. The following parameters of the lacrimal duct on the contralateral side of unilateral PANDO were investigated: (1) angle formed by the superior orbital rim-internal common punctum-nasolacrimal duct opening, (2) angle formed by the lacrimal sac and the nasolacrimal duct, (3) length of the lacrimal sac, and (4) length of the nasolacrimal duct. Results: Measurements of the above parameters were (1) 10.2° ± 7.8° (range, -11° to +27°), (2) -6.3° ± 14.1° (range, -43° to +40°), (3) 8.9 ± 2.3 mm (range, 4.3-17.1), and (4) 13.2 ± 2.7 mm (range, 5.7-20.7), respectively. The Shapiro-Wilk test demonstrated that the values of all parameters, except (3), followed a normal distribution (p = 0.55, 0.30, 0.0002, and 0.39, respectively). No significant difference was found between the female and male groups (p > 0.05). Conclusion: This study reported anthropometric analysis data of the morphology of the lacrimal ducts using CBCT-DCG in a Japanese population. In our cohort, the line from the superior orbital rim through the internal common punctum to the nasolacrimal duct opening inclined anteriorly in 92% of the patients.

Does the Interaction of KIR and HLA Affect the Development of Non-Infectious Uveitis?

Immune tolerance is established in the eye to prevent permanent blindness associated with destructive damage to the cornea and retina caused by immune cell infiltration; hence, the immune responses and subsequent inflammations are strongly suppressed. While non-infectious uveitis develops from a disruption of immune tolerance in the eye, its onset is a result of accumulating etiologic factors, including genetic predisposition, environmental factors, and aging. Many non-infectious uveitis cases are genetically predisposed to human leukocyte antigen (HLA) as the most substantial disease susceptibility region. HLA class I molecules are critical for natural killer (NK) cells to distinguish between self and non-self. The killer cell Ig-like receptor (KIR) family is one of the essential components of these receptors. Evidence has accumulated that NK cells are involved in innate and acquired immunity by interacting with other immunocompetent cells to develop several autoimmune diseases. This review summarizes the possible role of KIR in the development of non-infectious uveitis.

Comparison of the efficacies of 1.0 and 1.5 mm silicone tubes for the treatment of nasolacrimal duct obstruction.

This retrospective observational study analyzed the postoperative outcomes of bicanalicular intubation using different diameters of tube stents for treating postsaccal nasolacrimal duct obstruction. A total of 130 patients diagnosed with postsaccal obstruction who underwent endoscopic-assisted silicone tube intubation were included in the study. Patients intubated with a 1.5-mm large-diameter tube were designated as the LD group, and those with a 1.0-mm normal-diameter tube were designated as the ND group. The patency rates of the two groups at 1 year after tube removal were compared using the Kaplan-Meier curve and restricted mean survival time (RMST) method with τ = 365 days. Results demonstrated that the recurrence rate after tube removal was significantly lower in the LD group as compared with the ND group (p = 0.001). The patency rates at 1 year after removal in the LD and ND group were 85.7% (95% confidence interval [CI]: 75.4, 91.9) and 73.9% (95% CI: 61.7, 82.8), respectively. When comparing the patency rates by the RMST method at τ = 365 days, the RMST difference, RMST ratio, and RMTL ratio were higher in the LD group at p = 0.045, 0.052, and 0.046, respectively.

Vaccination inhibits the human adenoviral transduction in a mouse keratoconjunctivitis model.

Adenovirus infections are a major cause of epidemic keratoconjunctivitis (EKC), which can lead to corneal subepithelial infiltrates and multifocal corneal opacity. In the current study, we investigated the use of an E1/E3-deleted adenovirus serotype 5 (Ad5) vector as a vaccine administered intramuscularly (IM) or intranasally (IN) against subsequent challenges with a luciferase-expressing Ad5 (Ad5-Luci) vector via eyedrop. We evaluated the adaptive immune response to Ad5 vector vaccination and confirmed a robust polyfunctional CD8 T cell response in splenic cells. Neutralizing Ad5 antibodies were also measured in the sera of vaccinated mice as well as Ad5 antibody in the eye wash solutions. Upon challenge with Ad5-Luci vector 8 weeks post the primary immunization, transduction was significantly reduced by > 70% in the vaccinated mice, which was slightly better in IM- vs. that in IN-vaccinated animals. Resistance to subsequent challenge was observed 10 months post primary IM vaccination, with sustained reduction up to 60% in the Ad5-Luci vector transduction. Passive immunization of naive mice with antisera from IM to vaccinated mice subsequently challenged with the Ad5-Luci vector resulted in approximately 40% loss in transduction efficiency. Furthermore, the mice that received IM immunization with or without CD8 T cell depletion showed > 40% and 70% reductions, respectively, in Ad8 genomic copies after Ad8 topical challenge. We conclude that Ad-vector vaccination successfully induced an adaptive immune response that prevented subsequent Ad transduction in the cornea and conjunctiva-associated tissues in a mouse model of adenovirus keratoconjunctivitis, and that both cellular and humoral immunity play an important role in preventing Ad transduction.

Prophylactic and therapeutic vaccine against Pseudomonas aeruginosa keratitis using bacterial membrane vesicles.

PURPOSE: Pseudomonas aeruginosa (P. aeruginosa) infection is one of the major causes of keratitis. However, effective prophylactic and therapeutic vaccines against P. aeruginosa keratitis have yet to be developed. In this study, we explored the use of P. aeruginosa membrane vesicles (MVs) as a prophylactic vaccine as well as the use of immune sera derived from P. aeruginosa MV-immunized animals as a treatment for P. aeruginosa corneal infections in C57BL/6 mice. METHODS: C57BL/6 mice were intramuscularly immunized with P. aeruginosa MVs; the mouse corneas were then scarified and topically infected with several P. aeruginosa strains, followed by determination of corneal clinical score and corneal bacterial load. Next, immune sera derived from P. aeruginosa MV-immunized ICR mice were administered intraperitoneally to naïve C57BL/6 mice, followed by topical P. aeruginosa challenge. Finally, the immune sera were also used as a topical treatment in the mice with established P. aeruginosa corneal infections. RESULTS: P. aeruginosa-specific IgG and IgA antibodies induced by intramuscular immunization were detected not only in the sera but also in the eye-wash solution. Both active and passive immunization significantly inhibited P. aeruginosa corneal infection. Finally, topical treatment with immune sera in the mice with established P. aeruginosa corneal infections notably decreased the corneal clinical score and corneal bacterial load. CONCLUSIONS: P. aeruginosa keratitis can be attenuated by vaccination of P. aeruginosa MVs and topical application of P. aeruginosa MV-specific immune sera.

Association of toll-like receptor 2 gene polymorphisms with normal tension glaucoma.

PURPOSE: Toll-like receptor 2 (TLR2) is a transmembrane receptor that mediates immune responses to exogenous and endogenous ligands, and interacts with heat-shock proteins, which are reportedly involved in normal tension glaucoma (NTG). We investigated whether TLR2 polymorphisms are associated with NTG. METHODS: 200 Japanese patients with NTG and 128 healthy Japanese controls were recruited. We genotyped five single-nucleotide polymorphisms (SNPs) in the TLR2 gene and assessed the allele and haplotype diversities between cases and controls for all SNPs. RESULTS: No significant differences in the frequency of TLR2 alleles and haplotypes in the NTG cases were detected, compared with the controls. CONCLUSIONS: Our study showed no evidence for an association between TLR2 polymorphisms and NTG. TLR2 polymorphisms may not play an important role in NTG pathogenesis in the Japanese population.

The association analysis between HLA-A*26 and Behçet's disease.

The strongest genetic risk factor of Behçet's disease (BD) is HLA-B*51. Our group previously reported that HLA-A*26 is independently associated with the risk of the onset of BD apart from HLA-B*51. Here, we re-evaluated the association between HLA-A*26 and BD in the Japanese population. We also performed a comprehensive literature search and meta-analyzed the extracted published data concerning the relationship between HLA-A*26 and BD to estimate the odds ratio (OR) of HLA-A*26 to BD. In this study, we genotyped 611 Japanese BD patients and 2,955 unrelated ethnically matched healthy controls. Genotyping results showed that the phenotype frequency of HLA-A*26 was higher in BD patients than in controls (OR = 2.12, 95% CI: 1.75-2.56). Furthermore, within the HLA-B*51-negative populations, the phenotype frequency of HLA-A*26 was significantly higher in BD patients than in controls (OR = 3.10, 95% CI: 2.43-3.95). Results obtained from meta-analysis combined with our data showed that the modified OR of HLA-A*26 became 1.80 (95% CI:1.58-2.06), whereas within the HLA-B*51-negative population, the modified OR became 4.02 (95% CI: 2.29-7.05). A subgroup analysis arranged by the geographical regions showed HLA-A*26 is in fact associated with the onset of BD in Northeast Asia (OR = 2.11, 95% CI: 1.75-2.56), but not in the Middle East or in Europe.

Treatment Paradigms for Retinal and Macular Diseases Using 3-D Retina Cultures Derived From Human Reporter Pluripotent Stem Cell Lines.

We discuss the use of pluripotent stem cell lines carrying fluorescent reporters driven by retinal promoters to derive three-dimensional (3-D) retina in culture and how this system can be exploited for elucidating human retinal biology, creating disease models in a dish, and designing targeted drug screens for retinal and macular degeneration. Furthermore, we realize that stem cell investigations are labor-intensive and require extensive resources. To expedite scientific discovery by sharing of resources and to avoid duplication of efforts, we propose the formation of a Retinal Stem Cell Consortium. In the field of vision, such collaborative approaches have been enormously successful in elucidating genetic susceptibility associated with age-related macular degeneration.

Genetic characterization and susceptibility for sarcoidosis in Japanese patients: risk factors of BTNL2 gene polymorphisms and HLA class II alleles.

PURPOSE: Sarcoidosis is a heterogeneous and multisystem granulomatous disorder. The etiology still is uncertain, but the disease currently is thought to be triggered by various genetic as well as environmental factors. Recently, an association between sarcoidosis and the butyrophilin-like 2 (BTNL2) gene located in close proximity to the HLA-DRB1 gene was reported. The purpose of our study was to verify the relationship between BTNL2 and HLA risk alleles for the susceptibility to sarcoidosis, and to assess whether the BTNL2 association is independent of the HLA risk alleles. METHODS: In our study, 11 single nucleotide polymorphisms (rs28362677, rs2076533, rs2076530, rs2076529, rs2294881, rs3763304, rs2076523, rs28362682, rs3806156, rs9268499, rs3763317), including the functional rs2076530 (G > A) of the BTNL2 gene, and HLA-DRB1 and -DQB1 alleles, were genotyped in 237 Japanese patients diagnosed with sarcoidosis and 287 healthy Japanese control subjects. RESULTS: In the patient group, the HLA-DRB1*08:03 (P = 6.15 × 10(-5), odds ratio [OR] = 2.43) and BTNL2 rs2076530_A (P = 6.90 × 10(-6), OR = 1.84) were associated with disease susceptibility. Upon stratification analysis in search for a synergistic effect given the extensive linkage disequilibrium between BTNL2 rs2076530_A and HLA-DRB1*08:03, our results suggested that the risk-bearing allele of these two loci interact negatively. No significant differences were observed in allele frequencies for alleles in patients with ocular and other systemic sarcoidosis. CONCLUSIONS: Our studies implicated that the HLA-DRB1 allele is a major contributing genetic factor in the development of sarcoidosis in Japan. However, further studies are needed to verify how HLA or BTNL2 alleles confer the disease phenotype, severity of sarcoidosis.