Title:
[A challenge to primary open-angle glaucoma including normal-pressure. Clinical problems and their scientific solution].

Abstract:
Primary open-angle glaucoma (POAG), including normal-tension glaucoma (NTG), is reported by the Tajimi Study to afflict 3.9% of the total population, and this represents about 80% of all total glaucoma cases which, in total, afflict 5.0% of the population. We tried to analyze the clinical problems relating to POAG by looking at the pathogenesis, intraocular pressure (IOP), therapy, neuroprotection and surgery of the disease. To elucidate the pathogenesis of glaucoma progression, we measured retinal nerve fiber layer defect (RNFLD) angles', and divided the NTG cases into 2 groups, enlarged RNFLD and stable RNFLD. Disc hemorrhages were found to be significantly more frequent in the enlarged group than in the stable group. RNFLD was enlarged in the direction of disc hemorrhage in over 80% of the eyes. In the majority of the eyes of the enlarged group, the enlargement of RNFLD was toward the fovea. The enlargement of RNFLD in NTG was closely associated with disc hemorrhage and the deterioration of the visual field. We developed a simultaneous structure and function evaluation technique combining spectral-domain (SD) optical coherence tomography (OCT) and fundus-oriented perimeters for the detection of visual field abnormalities in the RNFLD area. We superimposed the ganglion cell complex map obtained by SD-OCT on the fundus-oriented perimeter image. We observed very early or preperimetric normal pressure glaucoma as well as disc hemorrhage adjacent to the borders of the RNFLD. The borderline of the RNFLD seemed to be the thinnest RNFL and had the lowest retinal sensitivity (Active site for RNFLD progression). To clarify the role of the circadian clock genes in the generation of a 24-hour IOP rhythm, we used the microneedle method to measure the IOP at eight time points daily, both in wild type mice and Cry-deficient (Cry 1-/-Cry 2-/-) mice. In the wild-type mice living in light-dark conditions, the pressure measured in the light phase was significantly lower than in the dark phase. This biphasic daily rhythm was maintained under dark-dark conditions. In contrast, the Cry-deficient mice did not show significant circadian changes in their IOP, regardless of the environmental light conditions. These findings demonstrate that clock genes are essential for the generation of the circadian rhythm of IOP. We evaluated the relationship between the genetic polymorphisms of the adrenergic receptor (ADR) and the diurnal IOP in untreated NTG patients. For Del 301-303 in α2B-ADR, De1322-325 in α2C-ADR, and S 49G (A/G) in βl-ADR, the major homozygotes and minor carriers had parallel diurnal IOP curves, but significantly different diurnal IOP levels. Polymorphisms of the ADR gene may predict the diurnal IOP level of patients with NTG. Looking toward the future, tailor-made medicine in glaucoma therapy, we evaluated the relationship between the polymorphisms of the prostaglandin F2α, receptor (FP receptor) gene and the effectiveness of topical latanoprost treatment in 100 normal volunteers. One SNP(rs3753380) was located in the promoter region of the FP receptor gene and was significantly correlated with % IOP reduction. Two SNPs, rs3753380 and rs3766355 (an SNP in intron 1), were associated with the degree of response to latanoprost. The genotype of these SNPs may be an important determinant of variability in response to latanoprost. To investigate the predictability of IOP response of the fellow eye in a one-eye trials, we compared the correlation of the fellow-eye's IOP response in one-eye trials performed separately for each eye with that of bilateral treatment in 41 normal subjects. Correlation of mean diurnal IOP reduction between 2 one-eye trials was poor (r2 = 0.102), even after subtracting the nontreated eye IOP fluctuations from the treated eye IOPs (r2 = 0.097), but that between fellow eyes in bilateral treatment was excellent (r2 = 0.849). Therefore, we examined the effects of multiple IOP measurements on the correlation of response to glaucoma medication between fellow eyes. Latanoprost was applied to the first eye and then to both eyes of POAG or ocular hypertension patients. IOP measurements were performed twice on different days at baseline, during treatment of the first eye only and for both eyes. No significant correlations of ΔIOP 1 (IOP at baseline-IOP after treatment) between fellow eyes were found. ΔIOP 2 (ΔIOP 1-IOP fluctuation of the contralateral eye) was significantly correlated between the fellow eyes using two post-treatment IOP measurements. Using multiple IOP measurements may improve the prediction of a fellow eye's response to glaucoma medication in one-eye trials. We used a scanning laser ophthalmoscope (SLO) for in vivo imaging and counting of rat retinal ganglion cells (RGCs). RGC survival decreased gradually after crushing the optic nerve. RGC counts by SLO were comparable to those in retinal flat mounts. We developed OCT system for rat eyes. The mean retinal nerve fiber layer (RNFL) thicknesses in the circumpapillary OCT scans were unchanged 1 week after crushing the optic nerve, but then decreased significantly and progressively after the second week. RNFL thicknesses in OCT images correlated significantly with thicknesses determined histologically. SLO and OCT will be useful for evaluating the effects of neuroprotective drugs. We developed a new glaucoma filtration surgery system using a thin honeycomb-patterned biodegradable film in rabbits. The film had a honeycomb-patterned surface that faced the subconjunctival Tenon tissue, while the other side was smooth. Postoperative IOPs of the film-treated eyes were significantly lower than those of the control eyes, but were not significantly different from those of the MMC-treated eyes. The thin honeycomb-patterned film that was attached to the inner bleb wall worked as an adhesion barrier in glaucoma filtration surgery in rabbits.