Enrique Adan Sato

The evaluation of the treatment response in obstructive meibomian gland disease by in vivo laser confocal microscopy

PurposeTo evaluate the status of periglandular inflammation, ocular surface and tear function alterations in patients with obstructive meibomian gland disease (OMGD) by in vivo confocal microscopy before and after anti-inflammatory treatment, and to compare the results with patients receiving only topical non-preserved artificial tears and sodium hyaluronate eye drops without anti-inflammatory agents.MethodsThirty-two eyes of 16 OMGD patients receiving anti-inflammatory treatment (treatment group) and 22 eyes of 11 OMGD patients receiving only topical non-preserved artificial tears and sodium hyaluronate eye drops (control group) were recruited in this prospective study. All subjects underwent slit-lamp examinations, tear film break-up time (BUT) measurements, fluorescein and Rose-Bengal stainings, Schirmer test І without anesthesia, transillumination of the lids (meibography), and in vivo laser confocal microscopy of the lids (HRTII-RCM).ResultsThe mean BUT, fluorescein staining scores, and inflammatory cell densities observed by in vivo confocal microscopy improved significantly in the group receiving anti-inflammatory treatment (p < 0.05), whereas no significant alterations of these parameters were observed in the group not receiving anti-inflammatory agents (p > 0.05).ConclusionsIn vivo confocal microscopy was able to effectively demonstrate the treatment responses in patients with OMGD. Inflammatory cell density calculation seems to be a promising new parameter of in vivo confocal microscopy in the evaluation of treatment responses.

Evaluation of lipid oxidative stress status in Sjögren syndrome patients

PURPOSE We evaluated the levels of lipid oxidative stress markers and inflammatory cells from tears and conjunctiva of patients with Sjögren syndrome (SS) and normal subjects. METHODS We examined 31 eyes of 16 patients (16 females) with SS and 15 eyes of 10 healthy controls (2 males and 8 females) in this prospective study. All subjects underwent a Schirmer test, measurement of tear film break-up time, vital stainings, confocal microscopy of the conjunctiva, tear collection for hexanoyl-lysine (HEL), ELISA, and conjunctival brush cytology. Brush cytology samples underwent immunohistochemistry (IHC) staining with HEL and 4-hydroxy-2-nonenal (4HNE). Hematoxylin-eosin and IHC staining with HEL and 4HNE also were performed on conjunctival samples of SS patients and controls. RESULTS The tear stability and vital staining scores were significantly worse in eyes of SS patients compared to the controls. Conjunctival inflammatory cell density was significantly higher in SS subjects compared to controls. The numbers of conjunctival cells stained positively for HEL and 4HNE were significantly higher in SS patients compared to controls. Tear HEL concentrations correlated significantly with staining scores and inflammatory cell density in confocal microscopy. Conjunctival specimens also revealed higher numbers of cells stained positively for inflammatory markers, as well as HEL and 4HNE in the IHC stainings. CONCLUSIONS Increase of the oxidative stress status in the conjunctiva of SS patients appears to have a role in the pathogenesis of dry eye disease. A close relationship may exist between reactive oxygen species (ROS) production, lipid peroxidation related membrane damage, and inflammatory processes in dry eye.

Conjunctival in vivo confocal scanning laser microscopy in patients with sjögren syndrome

PURPOSE To demonstrate the conjunctival alterations in patients with Sjögrens (SSDE) and non-Sjögrens syndrome dry eye (NSSDE) using a new generation confocal microscope (HRTII/ RCM; Heidelberg Engineering, Heidelberg, Germany), in a prospective controlled study. METHODS Twenty-eight right eyes of 28 patients with SSDE (28 women; mean age, 58.2 +/- 14.3 years), 7 right eyes of patients with NSSDE (7 women; mean age, 66.1 +/- 14.4 years), and 14 right eyes of 14 age- and sex-matched control subjects were studied. All subjects underwent the Schirmer test, tear film breakup time (BUT), vital staining, and confocal microscopy of the temporal bulbar conjunctiva. The density of conjunctival epithelial cells, epithelial microcysts, and conjunctival and corneal inflammatory infiltrates were also assessed. RESULTS The tear quantity, stability, and vital staining scores were significantly worse in patients with SSDE or NSSDE than in control subjects (P < 0.001 and P < 0.05, respectively). Eyes of the patients with SSDE or NSSDE had a significantly higher density of conjunctival and corneal inflammatory infiltrates than did the control eyes (P < 0.001). Conjunctival inflammatory cell densities showed a negative correlation with tear stability and tear quantity and a positive correlation with the vital staining scores. Conjunctival epithelial cell densities were significantly lower in SSDE and NSSDE compared with control subjects (P < 0.05). The density of epithelial cysts was significantly higher in SS than in healthy control eyes (P < 0.001). CONCLUSIONS Confocal scanning laser microscopy was an efficient and a noninvasive tool for the quantitative assessment of the conjunctival inflammation and epithelial cell densities as well as evaluation of conjunctival morphologic alterations, such as microcysts in patients with SSDE and NSSDE dry eye disease.

Decreased blood flow at neuroretinal rim of optic nerve head corresponds with visual field deficit in eyes with normal tension glaucoma

PurposeTo determine the relationship between the blood flow parameters of the optic disc rim and the glaucomatous visual field changes.DesignObservational cross-sectional study.MethodsTissue blood flow in the neuroretinal rim within the optic disc was determined with the Heidelberg retina flowmeter(HRF) in 54 eyes of 54 patients with normal tension glaucoma (NTG). Patients were selected whose visual field defects were confined to either the superior or inferior hemifield. Blood flow measurements were made in a 10°×2.5° area of the superior and inferior neuroretinal rim within the optic disc. The mean blood flow (MBF) was calculated by the automatic full-field perfusion image analyzer program, and the ratio of the MBF in the superior to the inferior rim areas (the S/I ratio) was calculated from the same HRF image in order to minimize the variation of measurement condition.ResultsInferior rim blood flow is less than superior rim blood flow in patients with superior hemifield defect, and superior rim blood flow is reduced compared to inferior in patients with inferior hemifield defect. The mean S/I ratios of the MBF in the patients with superior hemifield defect (1.46, n=37) was significantly higher than that in the patients with inferior hemifield defect (0.79, n=17; P<0.0001, Mann-Whitney U-test).ConclusionsThe blood flow in the neuroretinal rim was found to correspond to the regional visual field defect in eyes with NTG. Reductions in flow were associated with reductions in function.

Reduced choroidal blood flow can induce visual field defect in open angle glaucoma patients without intraocular pressure elevation following encircling scleral buckling.

Purpose: To determine the cause of the progressive glaucomatous visual field defects in three patients after an encircling scleral buckle for a rhegmatogenous retinal detachment (RRD). Methods: Scanning laser Doppler flowmetry and visual field tests were performed on three cases with unilateral progressive visual field defect after an encircling scleral buckling for a RRD. Similar measurements were made after the buckle was removed. Results: After implanting the scleral buckle, the intraocular pressure was normal and chamber angle was open. The blood flow in the neuroretinal rim of the optic disk was lower than that in the healthy fellow eye. After removing the buckle, the blood flow improved to normal levels and a further worsening of the visual field was not detected. Conclusions: These results suggest that an encircling scleral buckle may impair choroidal circulation and lead to visual field defects similar to eyes with normal tension glaucoma.

Macular nerve fibers temporal to fovea may have a greater potential to recover function in patients with Leber's hereditary optic neuropathy

PURPOSE It is known that even after visual loss, younger patients with Lebers hereditary optic neuropathy (LHON) can recover vision. The purpose of this study was to determine the mean age at onset for LHON patients with and without visual recovery who carried the 11778 mutation, and to determine the pattern of central vision recovery. METHODS Thirty-five LHON patients with the 11778 mutation of mitochondrial DNA who had visited the Keio University Hospital between 1980 and 1999 and were followed for 2 to 20 years, were the subjects of this retrospective study. The patients who had recovered vision were tested by Goldmann perimetry, Humphrey perimetry, and landmark-driven fundus microperimetry with a scanning laser ophthalmoscope (SLO). The fixation status was assessed by SLO microperimetry. RESULTS Nine of the 35 patients (14 of 70 eyes) demonstrated a recovery of visual acuity to better than 0.3 in at least one eye. The mean age of disease onset was 15.9 +/- 4.6 years in patients with visual recovery and 25.5 +/- 8.9 years in patients without visual recovery. This difference in the mean age at onset was significant (P =.0001; Welch t-test). These 9 patients (14 eyes) showed fenestrated central scotomas in testing by Humphrey 10-2 threshold and SLO microperimetry. The nasal side of the central visual fields had a higher sensitivity than the temporal side in 7 of the 9 patients in Humphrey 10-2 threshold testing. Areas insensitive to 0 dB were detected on the nasal side of the central retina in these patients by SLO microperimetry, and fixation stability was related to the degree of clinical visual acuity. CONCLUSION The LHON patients with the 11778 mutation and a younger age of onset were more likely to show visual recovery. The findings made by perimetry suggest that the nerve fiber bundles in the nasal field (retina temporal to the fovea) may have a greater potential to recover function in LHON patients.

In vivo evaluation of ocular demodicosis using laser scanning confocal microscopy.

PURPOSE To investigate the applicability of in vivo laser scanning confocal microscopy in the diagnosis and follow-up of ocular demodicosis infestation in a prospective controlled study. METHODS Fifteen right eyes of 15 patients with blepharitis associated with cylindrical dandruff (10 males, 5 females; mean age: 62.9 ± 9 years) and eight right eyes of eight age- and sex-matched control subjects underwent HRTII/RCM, evaluation of ocular symptom scores, tear function tests including vital stainings, Schirmer test, and tear clearance test, and evaluation of mite numbers in the eyelids. RESULTS In vivo confocal microscopy effectively disclosed the mites in the terminal bulbs of the eyelashes, which were not observed after treatment. Eyelids with demodicosis infestation showed marked inflammatory infiltrates around the meibomian glands and conjunctiva, which cleared with tea tree oil treatment. CONCLUSIONS Laser scanning confocal microscopy seems to be an efficient noninvasive tool in the diagnosis and follow-up of ocular demodicosis infestation.

Passive cigarette smoke exposure and soft contact lens wear.

Purpose. To prospectively investigate the effects of passive cigarette smoke exposure on the ocular surface and tear film in soft contact lens (SCL) wearers. Methods. Twelve right eyes of 12 SCL wearers without any ocular or systemic diseases and 10 right eyes of 10 subjects who never wore CLs were examined before and 2 h after 5 min of passive cigarette smoke exposure in a controlled smoke chamber. Tear evaporation rate measurement, tear film break-up time (TBUT) examination, ocular surface fluorescein, rose bengal stainings, and Schirmer I test were performed at each visit. Results. The mean tear evaporation rates, TBUTs, and vital staining scores were significantly worse in CL wearers compared with healthy control subjects. TBUTs showed significant worsening after passive smoke exposure in both groups. The mean tear evaporation rate and vital staining scores showed a significant increase with brief passive smoke exposure in subjects not wearing CLs but not in CL wearers. Conclusion. Even brief passive exposure to cigarette smoke is associated with adverse effects on the ocular surface as evidenced by an increase in tear instability and damage to the ocular surface epithelia in SCL wearers and non-CL wearers.

In vivo evaluation of superior limbic keratoconjunctivitis using laser scanning confocal microscopy and conjunctival impression cytology

PURPOSE To investigate the cytologic findings of superior bulbar conjunctiva in superior limbic keratoconjunctivitis (SLK) using laser scanning confocal microscopy and impression cytology in a prospective controlled study. METHODS Twenty-one eyes of 11 SLK patients (9 women, 2 men; mean age, 49.3 +/- 17.9 years) and 18 eyes of 9 control subjects (6 women, 3 men; mean age, 46.4 +/- 8.7 years) underwent tear function tests including vital stainings, Schirmer test, tear clearance test, digital confocal laser scanning microscopy, and conjunctival impression cytology. After confocal microscopy and impression cytology images were obtained, the mean individual epithelial cell area (MIECA), nucleocytoplasmic (N/C) ratio, and inflammatory cell density were analyzed. The correlation between confocal microscopy and impression cytology parameters was investigated. RESULTS The MIECA of SLK patients and control subjects in confocal microscopy was 786.54 +/- 463.88 microm(2) and 311.50 +/- 78.30 microm(2), respectively. The mean N/C ratio was 0.356 +/- 0.090 and 0.490 +/- 0.038, respectively. The MIECA and N/C ratio in impression cytology showed significant correlation with the corresponding confocal microscopy parameters (MIECA, P = 0.0028; N/C, P = 0.0051). The inflammatory cell density in confocal microscopy significantly correlated with superior bulbar conjunctival Rose-Bengal scores (P = 0.0264). CONCLUSIONS Laser scanning confocal microscopy seems to be an efficient noninvasive tool in the evaluation of phenotypic alterations of the conjunctival epithelium in SLK and may serve as an alternative for impression cytology. N/C ratio and inflammatory cell density appear to be two new promising parameters of in vivo confocal microscopy in the assessment of ocular surface disease in SLK.

S-1 Induces Meibomian Gland Dysfunction

Dear Editor: S-1 (Taiho Pharmaceutical Co. Ltd., Tokyo, Japan) is an anti-cancer drug containing tegafur, gimeracil, and oteracil potassium that has been approved for use in Japan, Korea, China, and Singapore in large bowel, stomach, breast, and lung cancers as a single oral agent. The drug is still waiting FDA approval in the United States. Reported systemic S-1 toxicity includes myelosuppression, gastrointestinal and renal toxicity, dermatitis, hypotension, and depression. Initial studies from the USA reported mild conjunctivitis and canalicular stenosis. We report in this single-center, prospective clinical study severe obstructive meibomian gland dysfunction (MGD) as an unreported complication of S-1 in patients who experienced ocular symptoms after commencement of S-1. Twenty eyes from 10 patients (5 women, 5 men; mean age: 67.7 11.9 years) receiving solitary oral treatment with S-1, as well as 19 eyes of 10 age and sex-matched healthy control subjects (5 women, 5 men; mean age: 62.3 18.5 years) were studied. One patient had pharyngeal cancer, 2 patients had lung cancers, 3 patients had breast cancers, 2 patients had stomach, and 2 other patients had colon cancers. All patients complained of foreign body sensation, visual discomfort, or epiphora within 4 months after commencement of S-1. The mean total drug dose was 41.0 32.7 (range, 9.0 102.9) grams and the mean duration of treatment was 21.8 17.0 (range, 6 55) months. None of the patients had prior or coexisting treatment with other chemotherapeutics or had radiotherapy. The patients did not have any history of ocular surgery, ocular/systemic diseases, or a history of topical/systemic drug use or contact lens wear that would alter the ocular surface. Informed consents were obtained from all subjects. Examination procedures were ethic board reviewed. The criteria for the diagnosis of MGD were described as follows: (1) occluded meibomian gland (MG) orifices; (2) cloudy/inspissated glandular secretion following digital pressure on the tarsus of the eyelids; (3) presence of keratinization or displacement of the mucocutaneous junction; (4) absence of inflammatory skin disorders such as atopic dermatitis, seborrhea sicca, and rosacea; (5) absence of trachoma, ocular cicatritial pemphigoid, chemical, thermal, or radiation injury; and (6) absence of excessive meibomian lipid secretion (seborrheic MGD). The patients underwent tear lipid layer interferometry, tear evaporation rate measurements from the ocular surface (TEROS), tear collection for tegafur (FT207) concentration assessment by gas chromatography, tear film break-up time (BUT) measurements, vital stainings of the ocular surface, Schirmer test I without anesthesia, in vivo laser confocal microscopy, transillumination of the eyelids with a transilluminator or infrared meibography, and the MG expressibility test. The degree of MG dropout and MG expressibility were scored as described previously. The FT-207 concentrations measured during drug ingestion ranged between 908 and 3631 ng/ml (mean, 2013.2 1014.8 ng/ml). FT-207 was undetectable in tears when the patients were on a rest period from S-1. Slit-lamp microscopy disclosed complete occlusion of MG orifices with numerous pigmentary deposits and unexpressible glands in all patients (Figure 1; available at http://aaojournal.org). Meibography revealed marked loss of glandular structures in patients compared to controls (Figure 2; available at http://aaojournal.org). Three patients had canalicular stenosis/obstruction and 4 eyes had epithelial crack lines. The mean TEROS, corneal fluorescein staining scores, BUT, the mean acinar unit density and the mean acinar unit diameter in in vivo confocal microscopy were significantly worse in S-1 users compared with the controls (Table 1; available at http://aaojournal.org). Such in vivo confocal microscopy findings together with observations of periglandular inflammation, fibrosis, and glandular atrophy provided further evidence on S-1 induced changes in the MGs (Fig 3; available at http://aaojournal. org). Corneal and MG disease did not respond well to conventional MGD treatment for at least 2 months with lid hygiene/warming/nonpreserved artificial tears and sodium hyaluronate eye drops (Table 2; available at http://aaojournal. org). S-1 treatment was observed to induce irreversible MG damage evidenced by lack of improvement in confocal microscopy and infrared meibography even after cessation of S-1 therapy in the 6 patients in remission from their primary disease. The mechanism by which S-1 induces these changes remains unknown but direct toxicity from the drug in tears is a possibility. In summary, oncology and ophthalmology health care personnel should be aware that S-1 may induce MGD, corneal epithelial damage, and evaporative dry eye disease which require careful follow up of cancer patients receiving this treatment.