Published papers

Purpose: To report a novel "piggyback" penetrating keratoplasty technique performed in a patient with severe keratoconus. Methods: A 43-year-old man underwent cataract surgery and a new "piggyback" penetrating keratoplasty (PKP) technique in his right eye, as he suffered from severe keratoconus and mature cataract due to severe atopic dermatitis. Under general anesthesia, phacoemulsification and aspiration (PEA), intraocular lens (IOL) implantation, and "piggyback" PKP while avoiding open-sky surgery was performed to prevent serious complications including IOL and vitreous prolapse. This PKP technique had been completed as a totally closed surgery. Results: One year after "piggyback" PKP and cataract surgery, the grafted cornea remained clear and IOL was also well positioned. Best-corrected visual acuity improved from hand motions to 30/100. Conclusions: A novel "piggyback" PKP technique was successfully performed in a patient with severe keratoconus. The new "piggyback" corneal transplantation technique may become an indispensable tool for transplant surgeons who want to improve surgical safety and predictability.

Purpose To evaluate the relationship between subjective symptoms and clinical signs in dry eye disease (DED) in office workers using visual display terminals (VDTs). Design Cross-sectional study. Methods This study involved 672 Japanese young and middle-aged office workers who use VDTs. The subjects completed questionnaires designed to detect subjective symptoms and risk factors for DED. Dry eye tests, including tear film break-up time (TBUT), corneal-conjunctival staining with fluorescein and lissamine green, and the Schirmer test, were performed. Based on the Japanese diagnostic criteria for DED, the subjects were classified into 3 groups: definite DED, probable DED, and non-DED. Between each group, subjective symptoms and clinical signs were compared. Results Of the 672 subjects, 561 (374 male, 187 female) completed the questionnaire (response rate: 83.5%). Definite DED was diagnosed in 65 subjects (11.6%), probable DED in 303 subjects (54.0%), and non-DED in 193 subjects (34.4%). The mean subjective symptom score was significantly less in subjects with probable DED (2.05 ± 0.42) and non-DED (1.63 ± 0.38) than in those with definite DED (2.19 ± 0.40) (P <.05 and P <.01, respectively). In the subjects with probable DED, a subgroup with positive subjective symptoms and abnormal TBUT (≤5 seconds) was categorized as short TBUT-type DED, and it was found that they had a higher subjective symptom score (2.09 ± 0.40), equivalent to that of those with definite DED (P =.269). Conclusions Despite no or minor epithelial damage, the severity of subjective symptoms was greater in short TBUT-type DED, most likely attributable to tear film instability. Thus, it might prove important to evaluate TBUT to successfully treat those patients.

Purpose: To analyze the association between macular pigment optical density (MPOD), which reflects lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) in the macula, and background characteristics. Methods: Fifty-five healthy adult volunteers were analyzed. Macular pigment optical density was measured using a heterochromatic flicker photometry technique, and serum concentrations of carotenoids and lipoproteins were by high-performance liquid chromatography and enzyme-linked immunosorbent assay, respectively. Dietary intake of nutrient was determined by a validated self-administered questionnaire on ingestion frequency. Results: Macular pigment optical density was positively correlated with serum concentrations of L and Z and dietary L intake and inversely correlated with serum oxidized low-density lipoprotein (LDL). Although MPOD decreased with age (95% confidence interval, -0.011 to -0.002; correlation coefficient, -0.269; P 0.007), serum L/Z and dietary L intake did not. In contrast, serum oxidized LDL was positively correlated with age (95% confidence interval, 0.69-2.34; correlation coefficient, 0.333; P 0.0004). After adjusting for age, sex, and oxidized LDL, serum L was positively correlated with MPOD (95% confidence interval, 0.88-1.69; P 0.000001). After adjusting for age, sex, and serum L, serum oxidized LDL was inversely correlated with MPOD (95% confidence interval, -0.002 to -0.0004; P 0.006). Conclusion: Macular pigment optical density was inversely correlated with serum oxidized LDL. Further study to know the impact of oxidized LDL on MPOD may be warranted.

Importance: Dry eye disease has become an important health problem. A lack of concordance between self-reported symptoms and the outcome of dry eye examinations has raised questions about dry eye disease. Objective: To explore the association between subjective happiness and objective and subjective symptoms of dry eye disease. Design: The study adopted a cross-sectional design. Setting: All the employees of a company in Osaka, Japan. Participants: 672 Japanese office workers using Visual Display Terminals (age range: 26-64 years). Methods: The dry eye measurement tools included the Schirmer test, conjunctivocorneal staining, the tear film break-up time, as well as the administration of a dry eye symptoms questionnaire. Happiness was measured by the Subjective Happiness Scale. Main Outcome Measures: Dry eye examination parameters, dry eye symptoms questionnaires, and the Subjective Happiness Scale score. Results: Of the 672 workers, 561 (83.5%) completed the questionnaires and examinations. The mean Subjective Happiness Scale score was 4.91 (SD = 1.01). This score was inversely correlated with the dry eye symptom score (r = -0.188, p < 0.001), but was not associated with objective findings which include conjunctivocorneal staining, low Schirmer test score, or low tear film break-up time. The level of subjective happiness was the lowest in the group without objective results, but reported subjective symptoms of dry eyes (p < 0.05). Conclusions and Relevance: There is evidence of the relationship between subjective happiness and self-reported symptoms of dry eyes. Findings of this study revealed a new perspective on dry eye disease, including the potential for innovative treatments of a specific population with dry eye disease.

Background: This study compared post-operative quality of life and sleep according to the type of cataract opacity and color of the implanted intra-ocular lens (IOL). Methods: This is a cohort study and participants were 206 patients (average age 74.1 years) undergoing cataract surgery with the implantation of a clear ultra-violet (UV)-blocking IOL (C) or a yellow blue-light-blocking IOL (Y). Participants were evaluated using the National Eye Institute Visual Function Questionnaire (VFQ-25) and Pittsburgh Sleep Quality Index (PSQI) before surgery and 2 and 7 months after surgery. Changes in sub-scale scores of VFQ-25 and PSQI were compared. Results: Sub-scale analyses for improvement after surgery revealed significant differences in ocular pain scores on the VFQ-25 (Y>C; the higher the score, the better the outcome). Furthermore, there were significant differences between the two IOLs in terms of the sleep latency score (C>Y) and sleep disturbances score (C>Y). A posterior sub-capsular cataract was significantly correlated with improvements in ocular pain and sleep latency scores. These effects were successfully represented by the change in scores rather than absolute post-operative scores because individual standard of response may often change after intervention, recognized as a response shift phenomenon in patient-reported outcome study. Regarding seasonal differences, patients who had surgery in summer exhibited relatively better sleep quality than those who had surgery in winter. Conclusions: Analysis of sub-scales of health indices demonstrated characteristic prognoses for each IOL and cataract type. Cataract surgery may potentially contribute to systemic health in older adults.

Purpose. To confirm that subjects with primary open-angle glaucoma (POAG) who avoid driving in high-risk situations are less likely to be involved in motor vehicle collisions (MVCs) than those who do not. Methods. This study evaluated 252 consecutive Japanese aged between 40 and 85 years with POAG. All participants were requested to answer a questionnaire on their driving habits, including self-restriction in driving at night, in rain, in fog, on freeways, and lane changing, and history of MVCs. Those who reported restricting their driving in one or more ways constituted the self-restriction group, and those who reported no self-restriction made up the no-restriction group. The prevalence of MVCs and the crash rate (number of MVCs/10,000 km driven) were compared between the two groups. The association between prevalence of MVCs and the number of driving self-restrictions was also evaluated. Results. The association between driving self-restriction and MVCs was observed among the male subjects, not among the female subjects. Among the male subjects, the prevalence of MVCs was significantly higher in the no-restriction group than in the self-restriction group (no-restriction group, 33/107 = 30.8%; self-restriction group, 9/66 = 13.6%, p = 0.01). The crash rate was also significantly higher in the no-restriction group (no-restriction group, 1.4 T 0.8; self-restriction group, 0.4 T 0.3, average T SE, p = 0.01). No restriction was significantly associated with MVCs (multivariable-adjusted odds ratios, 2.43 [95% confidence interval, 1.03 to 5.73]). The number of driving self-restrictions was also associated with MVCs (multivariable- adjusted odds ratios, 0.41 [95% confidence interval, 0.18 to 0.99], per one increment of self-restriction). Conclusions. Driving self-restriction may be associated with a reduced prevalence of MVCs in men with POAG.

Oxidative stress in the retinal pigment epithelium (RPE) is a well-accepted pathogenic change in vision-threatening diseases such as age-related macular degeneration. One source of oxidative stress is excessive light exposure, which causes excessive activation of the visual cycle. Because short wavelength light (blue light) has more energy, it is reported to be more harmful to photoreceptor cells than the other wavelengths of light. However, the biological effect of blue light in the RPE of living animals and the protective effect of a yellow intraocular lens (IOL) material that blocks blue light is still obscure. Therefore, we compared the pathogenic effect in the RPE-choroid complexes of mice exposed to light in a box made of a clear or a yellow IOL material. We measured the level of reactive oxygen species (ROS) using 2', 7'-dichlorodihydrofluorescein diacetate, the mRNA levels of inflammatory cytokines and a macrophage marker by real-time polymerase chain reaction, and the protein level of monocyte chemotactic protein-1 (MCP-1) by ELISA. The ROS level after light exposure was suppressed in the RPE-choroids of light-exposed mice in the yellow IOL material box. In parallel, all the inflammatory cytokines that we measured and a macrophage marker were also suppressed in the RPE-choroids of light-exposed mice in the yellow IOL material box. Therefore, a yellow IOL material suppressed, and thus blue light exacerbated, the increase in the ROS level and inflammatory cytokine expression as well as macrophage recruitment in the RPE-choroid invivo after light exposure.

Ocular surface mucosa is the first-line ocular tissue to be exposed to environmental stress. We evaluated tear functions and keratoconjunctival epithelial alterations after sidestream cigarette smoke (SCS) exposure and tried to clarify the role of the transcription factor nuclear factor erythroid 2-related factor 2 (Nfe2l2, also known as Nrf2), on the ocular surface. In wild-type and Nrf2-/- mice, tear volume did not change after SCS exposure. Tear film breakup time (tear stability) in Nrf2-/- mice was significantly shorter than that in wild-type mice after SCS exposure. Vital staining scores, including fluorescein and Rose Bengal staining, showed significantly higher values in Nrf2-/- mice than in wild-type mice after SCS exposure. Excessive oxidative stress accumulation was detected in Nrf2-/- mice after SCS exposure using immunohistochemical analysis. Immunohistochemical analysis also revealed decreased mucin 1 (Muc1) and Muc5ac staining in Nrf2-/- mice after SCS exposure. mRNA expression levels of Muc1, Muc4, and Muc5ac and of SAM-pointed domain epithelial-specific transcription factor in Nrf2-/- mice were lower than those in wild-type mice after SCS exposure. Mean tear IL-6 concentrations increased significantly in Nrf2-/- mice after SCS exposure. In conclusion, SCS exposure induced decreased tear stability, ocular surface damage, and altered conjunctival phenotype in Nrf2-/- mice. Nrf2 could play an important role in protection of the ocular surface against SCS exposure.

We describe a 91-year-old woman who suffered from fungal keratitis after corneal transplantation. The causative organism was identified as Wickerhamomyces anomalus (formerly Pichia anomala or Hansenula anomala) on the basis of morphological characteristics and the sequence of the internal transcribed spacer region of the ribosomal RNA gene. The patient was successfully treated with topical micafungin (MCFG) only. We present the first report of a case of W.anomalus fungal keratitis that responded to topical treatment with the antifungal MCFG.

Purpose To describe the clinical and molecular characteristics of patients with childhood-onset Stargardt disease (STGD). Design Retrospective case series. Participants Forty-two patients who were diagnosed with STGD in childhood at a single institution between January 2001 and January 2012. Methods A detailed history and a comprehensive ophthalmic examination were undertaken, including color fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and pattern and full-field electroretinograms. The entire coding region and splice sites of ABCA4 were screened using a next-generation, sequencing-based strategy. The molecular genetic findings of childhood-onset STGD patients were compared with those of adult-onset patients. Main Outcome Measures Clinical, imaging, electrophysiologic, and molecular genetic findings. Results The median ages of onset and the median age at baseline examination were 8.5 (range, 3-16) and 12.0 years (range, 7-16), respectively. The median baseline logarithm of the minimum angle of resolution visual acuity was 0.74. At baseline, 26 of 39 patients (67%) with available photographs had macular atrophy with macular/peripheral flecks; 11 (28%) had macular atrophy without flecks; 1 (2.5%) had numerous flecks without macular atrophy; and 1 (2.5%) had a normal fundus appearance. Flecks were not identified at baseline in 12 patients (31%). SD-OCT detected foveal outer retinal disruption in all 21 patients with available images. Electrophysiologic assessment demonstrated retinal dysfunction confined to the macula in 9 patients (36%), macular and generalized cone dysfunction in 1 subject (4%), and macular and generalized cone and rod dysfunction in 15 individuals (60%). At least 1 disease-causing ABCA4 variant was identified in 38 patients (90%), including 13 novel variants; ≥2 variants were identified in 34 patients (81%). Patients with childhood-onset STGD more frequently harbored 2 deleterious variants (18% vs 5%) compared with patients with adult-onset STGD. Conclusions Childhood-onset STGD is associated with severe visual loss, early morphologic changes, and often generalized retinal dysfunction, despite often having less severe fundus abnormalities on examination. One third of children do not have flecks at presentation. The relatively high proportion of deleterious ABCA4 variants supports the hypothesis that earlier onset disease is often owing to more severe variants in ABCA4 than those found in adult-onset disease.

Purpose: Unstable tear film characterized by shorting of tear break-up time (BUT) is associated with discomfort and dryness in contact lens wearers. The glycocalyx is thought to be crucial in maintaining the wettability and lubrication of the ocular surface. We evaluated the ocular surface glycocalyx in soft contact lens (SCL) wearers using a fluorescein-labeled wheat germ agglutinin (F-WGA) as a marker to demonstrate the ocular surface glycoconjugates in vivo. Methods: Twenty experienced SCL wearers and 20 healthy volunteers with no history of CL wearing (controls) were enrolled in the study. After applying a 5% F-WGA solution to the eyes of study individuals, fluorescent intensities in their respective central corneas were measured by fluorophotometry. The relationship between F-WGA intensity in the corneal surface and clinical parameters associated with contact lens wear were analyzed. Results: F-WGA fluorescence intensity in the SCL group was 418.5 ± 103.3, which was significantly lower than that of the controls (825.0 ± 179.8; p < 0.0001, Mann–Whitney test). F-WGA fluorescence intensity was not correlated with Schirmer’s test values or age, whereas a statistically significant correlation between F-WGA fluorescence intensity and tear film BUT was observed (r = 0.77, p < 0.0001). The decrease in F-WGA fluorescence intensity could be reversed by discontinuation of SCL use. Conclusion: Reduction and/or compositional alteration of ocular surface glycocalyx may be one of the causative factors of SCL-induced eye dryness.

Purpose To determine the relationship between abdominal breathing and tear meniscus volume in healthy women, we investigated the change in tear meniscus volume in two groups: normal breathing and abdominal breathing. Methods We used a crossover experimental model and examined 20 healthy women aged 20-54 years (mean ± SD, 32.7 ± 11.1 years). The participants were randomly assigned to one of two groups. During the first visit, the normal breathing group was subjected to normal breathing for 3 min, whereas the abdominal breathing group was subjected to abdominal breathing (4-second inhalation and 6-second exhalation) for 3 min. During the second visit, the protocols were swapped between the two groups. We estimated the R wave to R wave (R-R) interval, tear meniscus volume, salivary amylase activity, pulse, and blood pressure before and immediately after, 15 min after, and 30 min after completion of the breathing activity. Results After abdominal breathing, compared to that before breathing, the tear meniscus volume increased significantly 15 min after breathing (P<.01). Furthermore, systolic blood pressure showed a significant decrease immediately after abdominal breathing (P<0.05). No significant difference was found in the test parameters in the normal breathing group. Conclusion Abdominal breathing for 3 minutes increases the tear meniscus volume in healthy women. Consequently, abdominal breathing may be considered in the treatment of dry eye disease.

Purpose. This study evaluated the effects of using a newly developed eye cleansing formulation (Eye Shampoo) to cleanse the eyelids for 4 weeks in a parallel-group comparative study in women with chronic eye discomfort caused by heavy use of eye makeup and poor eye hygiene habits. Methods. Twenty women participants who met the inclusion criteria were randomly allocated to 2 groups comprising 10 participants each. The participants were asked to use either artificial tears alone or artificial tears in conjunction with Eye Shampoo for 4 weeks. The participants answered the questionnaire again and were reexamined, and changes in symptoms within each group and variations of symptoms between the two groups were statistically analyzed. Results. In the group using only artificial tears, improvements in subjective symptoms but not in ophthalmologic examination results were found. In the group using Eye Shampoo together with artificial tears, significant improvements were observed in the subjective symptoms, meibomian orifice obstruction, meibum secretion, tear breakup time, and superficial punctate keratopathy. Conclusion. In patients with chronic eye discomfort thought to be caused by heavy eye makeup, maintaining eyelid hygiene using Eye Shampoo caused a marked improvement in meibomian gland blockage and dry eye symptoms.

Purpose. This study examined the association between the severity of visual field defects and the prevalence of motor vehicle collisions (MVCs) in subjects with primary open-angle glaucoma (POAG). Methods. This is a cross-sectional study. Japanese patients who have had driver's licence between 40 and 85 years of age were screened for eligibility. Participants answered a questionnaire about MVCs experienced during the previous 5 years. Subjects with POAG were classified as having mild, moderate, or severe visual field defect. We evaluated associations between the severity of POAG and the prevalence of MVCs by logistic regression models. Results. The prevalence of MVCs was significantly associated with the severity of POAG categorized by worse eye MD (control: 30/187 = 16.0%; mild POAG: 17/92 = 18.5%; moderate POAG: 14/60 = 23.3%; severe POAG: 14/47 = 29.8%; P = 0.025, Cochran-Armitage trend test). Compared to the control group, the adjusted OR for MVC prevalence in subjects with mild, moderate, or severe POAG in the worse eye was 1.07 (95% CI: 0.55 to 2.10), 1.44 (95% CI: 0.68 to 3.08), and 2.28 (95% CI: 1.07 to 4.88). Conclusions. There is a significant association between the severity of glaucoma in the worse eye MD and the prevalence of MVCs.

Screening of dry eye disease in visual display terminal workers during occupational health examinations: The Moriguchi study: Motoko KAWASHIMA, et al. Department of Ophthalmology, Keio University School of Medicine-Purpose: The aim of this study was to estimate the prevalence of dry eye disease (DED) in Japanese visual display terminal (VDT) workers and identify simple methods for screening DED during occupational health examinations. Methods: This study involved 369 (331 men and 38 women; mean age, 44.4 [8.8] years) workers engaged in PC development with approximately 6 hours of VDT use daily. The participants completed questionnaires on dry eye and physical symptoms affecting QoL, and their ability to keep their eyes open for 10 seconds was tested for DED screening. They also underwent assessment of conjunctival and corneal vital staining with lissamine green and fluorescein, measurement of tear film breakup time, and Schirmer's test for DED diagnosis. Sensitivity, specificity, and positive predictive value of the screening methods were assessed. Results: The DED group included 218 (definite, 14; probable, 204) participants. They had markedly high frequencies of 11 dry eye symptoms, especially ocular fatigue (OR, 17.1; 95% CI, 9.9 to 29.7) and dry sensation (OR, 8.2; 95% CI, 3.6 to 18.4), and were more often unable to keep their eyes open for 10 s. With either ocular fatigue or dry sensation as the cutoff criterion, the sensitivity, specificity, and positive predictive value were 89.9, 66.9, and 79.7%, respectively. Conclusions: Approximately 60% of the VDT workers were diagnosed with DED on the basis of diverse eye symptoms affecting their ability to work. The dry eye symptom questionnaire and 10-s eye-opening workerstest are simple, noninvasive, and inexpensive methods for screening DED during occupational health examinations.

The aim of the present study was to measure gait velocity in cataract and simulated patients. The study was performed on 239 cataract patients, 115 age-matched subjects, and 11 simulated patients. We measured gait velocity and analyzed gait using a three-dimensional motion analysis system. Mean gait velocity before and 2 and 7 months after cataract surgery was 0.91 ± 0.19, 1.04 ± 0.21, and 1.06 ± 0.21 m/s, respectively, for males and 0.84 ± 0.22, 0.91 ± 0.24, and 0.92 ± 0.25 m/s, respectively, for females. The increase after surgery was significant in both groups at 7 months (P < 0.05). Gait velocity was significantly slower in cataract patients compared with controls before surgery, but no longer different after surgery. In simulated patients, mean velocity was 87.0 ± 11.4% of normal vision with a 3° visual field and 92.4 ± 12.3% of normal when counting fingers. Initial velocity was 89.1 ± 14.6% of normal vision with a 3° visual field and 92.7 ± 11.6% of normal when counting fingers. There was a significant difference between normal and impaired visual function (P < 0.05). The results demonstrate the close relationship between visual function and gait in cataract patients and simulated patients.

Objective. Immunoglobulin G4 (IgG4)-related Mikulicz's disease (MD) is a fibrosis-associated inflammatory disease, often accompanied by lacrimal gland swelling. Although much attention has been paid to the inflammatory aspects of this disease, the mechanisms of the fibrotic processes are still unclear. We focused on the fibrotic changes occurring in the lacrimal glands of IgG4-related MD patients, by examining molecules involved in the epithelial-mesenchymal transition (EMT). Methods. Lacrimal gland tissue specimens were obtained from 3 IgG4-related MD patients and 3 control patients with Sjögren's syndrome (SS). The glands were examined by immunohistochemistry and transmission electron microscopy. Results. Storiform fibrosis, a characteristic of IgG4-related MD, was observed in the lacrimal glands of IgG4-related MD, but rarely in those of SS. Reduced E-cadherin expression, increased phalloidin-stained filamentous actin, and increased α-smooth muscle actin, snail, and heat-shock protein 47 levels were observed in the lacrimal glands of IgG4-related MD compared with those of SS. Transmission electron microscopy revealed an abnormal periodicity of collagen bundles, and basal membrane thickening in the IgG4-related MD compared with that in the SS tissues. Conclusion. EMT-like changes were frequently observed in the lacrimal gland epithelia from patients with IgG4-related MD. Thus, EMT may be involved in the pathology of IgG4-related MD fibrosis.

Wide-angle viewing systems (WAVSs) were originally established for pars plana vitrectomy. However, their application to scleral buckling surgery was recently reported. In this study, we compared the outcomes of scleral buckling using a noncontact WAVS with that of scleral buckling using conventional indirect ophthalmoscopy for rhegmatogenous retinal detachment. The clinical records of 39 eyes (39 patients) with rhegmatogenous retinal detachment primarily treated between November 2012 and June 2014 at the Vitreo-Retina Surgical Division Clinic at the Department of Ophthalmology, Keio University Hospital were retrospectively reviewed. Scleral bucking was performed using WAVS with surgical placement of an endoilluminator in 16 eyes and indirect ophthalmoscopy in 23 eyes. The patients in these groups were consecutive over different intervals. The preoperative demographics, success rate of retinal reattachment, intraoperative findings, and postoperative complications were evaluated. There were no significant differences in pre- or postoperative conditions between groups, and similar surgical outcomes were achieved with the WAVS and conventional procedures. However, compared with the conventional procedure, the WAVS procedure resulted in fewer intraoperative corneal epithelial disorders (p = 0.049) and decreased the surgical duration of segmental buckling (p = 0.02); therefore, it may be suggested as an effective alternative procedure.

Kaatsu training is an exercise method involving the application of pressure to the target muscle, and is being increasingly used in rehabilitation programs for heart disease patients in some hospitals. This method restricts blood flow to the muscles during exercise, and the resultant hypoxia effectively causes muscle hypertrophy and strengthening. However, no medical guidelines or risk factors for its use have been established. We report a case involving a 45-year-old man who suffered from 2 episodes of central retinal vein occlusion (CRVO), both occurring on the day following a Kaatsu training session. As a characteristic of the CRVO and its subsequent complications, the affected eye lost vision despite treatment. The patient had a history of hypertension and diabetes, and thus was at an increased risk of CRVO. Kaatsu training, which changes the heart rate and serum growth hormone levels, may have triggered the onset of CRVO. This case highlights that underlying medical conditions such as hypertension, diabetes, and the consequent inflammation, could be risk factors for vascular side effects resulting from Kaatsu training. Further studies are required before the medical and recreational use of Kaatsu training become widespread.