Yoriko Nakanishi

Altered expression of aquaporins 1 and 4 coincides with neurodegenerative events in retinas of spontaneously diabetic Torii rats

Evidence is mounting that not only microangiopathy, but also neurodegenerative events occur in the retinas of humans and rodents with early diabetes. Diverse pathologies are known to alter the amount and/or location of glial expression of the water-selective channels aquaporins (AQPs) 1 and 4. However, the temporal relationships among glial activation, the altered expression of the AQP proteins and neuronal death in the retinas of diabetic animals remains to be investigated. Male spontaneously diabetic Torii (SDT) rats reportedly develop diabetes by 40 weeks of age at the latest and manifest proliferative diabetic retinopathy at 50 weeks or later. This study compared temporal changes in neuroretinal apoptosis, glial fibrillary acidic protein (GFAP) expression and the expression of AQPs 1 and 4 between SDT rat retinas and age-matched Sprague-Dawley (SD) rat retinas. Cell death was detected by terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate nick end-labeling on retinal flatmounts and activated caspase 3 immunofluorescence of retinal cryosections. The expression of GFAP and AQPs 1 and 4 was assessed by immunohistochemistry of cryosections and retinal flatmounts. Diabetes started to develop around 15 weeks in SDT rats. Apoptotic cells in the ganglion cell layer and the inner nuclear layer were significantly more numerous in 40-week-old SDT rat retinas than in either age-matched SD rat retinas or 10-week-old SDT rats. GFAP immunoreactivity was confined to the nerve fiber layer both in SD and SDT rats at 10 weeks, whereas it spanned the whole retina in SDT rats, but not in SD rats, at 40 weeks. AQP1 was expressed in the outer retina, whereas AQP4 was expressed in the perivascular and end feet of Müller cells and astrocytes in the inner retina in the control SD rats and the SDT rats at 10 weeks. The perivascular AQPs shifted from AQP4 to AQP1 in 40-week-old SDT rats that exhibited marked hyperglycemia. Thus, the development of diabetes increases neuroretinal apoptosis, and this coincides with an altered expression pattern of GFAP and water-selective channels AQPs 1 and 4 in SDT rats.

Intraocular Pressure Elevation after Injection of Triamcinolone Acetonide : A Multicenter Retrospective Case-Control Study

PURPOSE To determine the risk factors for intraocular pressure (IOP) elevation after the injection of triamcinolone acetonide (TA). DESIGN Retrospective interventional case-control study. METHODS SETTING Multicenter. PATIENT POPULATION Four hundred and twenty-seven patients. OBSERVATION PROCEDURES Intraocular pressure levels after TA treatment by the sub-Tenon capsule injection (STI; 12 mg, 20 mg, or 40 mg), intravitreal injection (IVI; 4 mg or 8 mg), or the combination of STI (20 mg) and IVI (4 mg), and IOP levels after two TA treatments. MAIN OUTCOME MEASURE Risk factors for IOP levels of 24 mm Hg or higher. RESULTS Younger age (hazards ratio [HR], 0.96/year; P < .0001), IVI (HR, 1.89/year; P < .0001), and higher baseline IOP (HR, 1.15/mm Hg; P = .003) were identified as risk factors. Dose dependency was shown in STI-treated eyes (HR, 1.07/mg; P = .0006), as well as after IVI (HR, 1.64/mg; P = .013). The combination of STI and IVI was a significant risk factor (HR, 2.27; P = .003) compared with STI alone. In eyes receiving two TA treatments, IVI (HR, 2.60; P = .010), higher IOP elevation after the first injection (HR, 1.18/mm Hg; P = .011), and increased dosage of STI (HR, 1.07/mm Hg; P = .033) were risk factors. CONCLUSIONS Younger age, higher baseline IOP, IVI, and increased TA dosage were associated with TA-induced IOP elevation. IOP elevation after repeated TA injection was frequently associated with eyes treated with IVI, high IOP elevation after the first injection, and high doses of STI.

Akt is activated via insulin/IGF-1 receptor in rat retina with episcleral vein cauterization

The Akt serine/threonine kinase mediates pro-survival signalings in retina and was reported to be activated in a response to some retinal and optic nerve injuries. Human and experimental glaucoma induce apoptosis of retinal ganglion cells (RGCs). The purpose of this study is to test whether episcleral vein cauterization (EVC) to chronically elevate intraocular pressures (IOPs) in rats increase apoptosis of RGCs and affect activation of Akt and its upstream insulin-like growth factor (IGF)-1 receptor/Insulin receptor. Three episcleral veins in left eyes of Sprague-Dawley rats were cauterized to elevate IOPs. Up to 6 months, IOPs were monitored and the retina was dissected at several time points. The numbers of terminal dUTP nick end labeling (TUNEL)-positive cells and those of RGCs labeled with fluorogold were counted in flat-mounted retina. Immunohistochemistry and immunoblotting were performed to identify cells expressing phosphorylated Akt and to quantify the phospho- to total ratios of Akt and IGF-1 receptor/insulin receptor. EVC significantly elevated IOPs up to 2 months, increased TUNEL-positive cells in an IOP-dependent fashion, and reduced 34.5% of RGCs at 6 months (P<0.001) compared with contralateral retinas. Phosphorylated Akt was specifically expressed in RGCs until 1 month after cauterization. Akt (P=0.036) and IGF-1 receptor/Insulin receptor (P=0.003) were transiently phosphorylated at 3 days. Intrinsic activation of the IGF-1 receptor/Insulin receptor to Akt pathway may occur in RGCs in retina with EVC.

Retinal Nerve Fiber Layer Thickness in Optic Tract Syndrome

BackgroundOptic tract syndrome (OTS) is characterized by incongruous homonymous hemianopia and a perpendicular pattern of bilateral optic atrophy due to the optic tract lesion. However, loss of retinal nerve fiber layer thickness (RNFLT) associated with OTS has not been quantitatively assessed.CaseA 20-year-old woman with blunt head trauma showed normal visual acuity, color vision, ocular motility, and intraocular pressure. Because of a relative afferent pupillary defect in her left eye and left-sided homonymous hemianopia, we suspected right-sided optic tract damage, although magnetic resonance imaging detected no intracranial lesion.ObservationsUsing optical coherence tomography (OCT), the RNFLT of this case was measured at 31 months after the trauma and compared with age-matched normal controls (n = 41). Nasal, temporal, superior, and inferior quadrant RNFLT was reduced by 22%, 21%, 5%, and 46% in the right eye and 76%, 64%, 25%, and 27% in the left eye, respectively. The reduction was > 3 × the standard deviation of the normal mean values in the nasal and temporal quadrants of the left eye and in the inferior quadrant of the right eye.ConclusionsOCT can determine the RNFLT reduction corresponding to the characteristic patterns of optic atrophy of OTS. Jpn J Ophthalmol 2005;49:294–296

Evaluation of optic nerve head configuration in various types of optic neuropathy with Heidelberg Retina Tomograph

PurposeTo test whether Heidelberg Retina Tomograph (HRT) is applicable to assess the optic nerve head (ONH) configuration of the atrophic phase of non-glaucomatous optic neuropathy when a default set of the reference plane is used.MethodsTen eyes with non-arteritic anterior ischaemic optic neuropathy (NAION), 17 eyes with Lebers hereditary optic neuropathy (LHON), 40 eyes with compressive optic neuropathy (CON) owing to chiasmal tumour, and 241 eyes of control individuals were examined with HRT using the default reference plane. The global values of HRT parameters were evaluated among the groups of patients and controls. The sectoral measurements of the eyes with LHON and CON were compared with controls. To eliminate the influence of disc size and age on HRT measurements, eyes with disc area- and age-matched normal controls were used for comparison with eyes with NAION and LHON.ResultsCup parameters in eyes with NAION were similar to those in controls. The retinal nerve fibre layer (RNFL) thickness was significantly thinner in eyes with NAION than that of controls. The eyes with LHON had significantly larger cup parameters, smaller rim volume, and thinner mean RNFL thickness than controls. Eyes with CON had significantly larger rim area and smaller cup parameters but similar RNFL thickness compared with controls.ConclusionsWhen the default reference plane is used, HRT can measure the ONH configuration in eyes with NAION and LHON as expected. However, caution must be made to interpret the parameters obtained from the eyes with CON.

Quantification of retinal nerve fiber layer thickness reduction associated with a relative afferent pupillary defect in asymmetric glaucoma

Aim: The relative afferent pupillary defect (RAPD) is an important clinical sign of asymmetrical retinal ganglion cell and axonal damage. Although glaucoma essentially affects bilateral eyes, a subset of patients manifests asymmetrical glaucomatous optic neuropathy (GON), which exhibits an RPAD in the more advanced eyes. However, the degree to which axonal loss occurs before an RAPD is clinically detectable has not been substantiated. The purpose of this study is to assess the relationship between the depth of a clinically detectable RAPD and the reduction ratio of retinal nerve fiber layer (RNFL) thickness in the more advanced eyes relative to that in the contralateral less advanced eyes of patients with asymmetrical GON. Methods: Enrolled were 29 consecutive glaucoma patients with the clinically detectable RAPD. An RAPD was quantified by placing log-scaled neutral density filters over the less advanced eyes while performing the swinging flashlight test. Average RNFL thickness was determined using the Fast RNFL thickness programme of optical coherence tomography 3000. Correlation coefficient and Linear regression analyses were used in assessing the relationship between the RAPD and the ratio of RNFL thickness in the more advanced eyes relative to that in the less advanced. Results: RAPD ranged from 0.6 to 2.4 log units. The log-scaled RAPD had a statistically significantly inversed correlation with the average RNFL thickness ratio (rs = −0.729, p<0.0001). Linear regression analysis found an equation that the average RNFL thickness ratio in the more affected eyes relative to that in the less advanced (%)  = (0.827−0.169×RAPD (log units))×100 (R2 = 0.557, p<0.0001). Conclusions: When an RAPD is clinically detected, the RNFL thickness in the more advanced eyes was in average reduced to about 73% of that in the less advanced.

Different transitions of multifocal electroretinogram recordings between patients with age-related macular degeneration and polypoidal choroidal vasculopathy after photodynamic therapy.

Aim: To compare and evaluate the transitions in retinal function after photodynamic therapy (PDT) between age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) using multifocal electroretinograms (mfERGs). Methods: 10 eyes with choroidal neovascularisation (CNV) secondary to AMD and 11 eyes with CNV secondary to PCV were included in the study. mfERGs were recorded before PDT, and 1 week and 3 months after PDT. mfERG recordings were acquired by a Veris system (V.3.1.3) using a 103 hexagon stimulus. The first-order kernel was used to calculate amplitudes and latencies. Mean amplitudes and latencies from two central rings rated 0–4° of visual angle were analysed and compared with each disease. Results: In AMD, the mean first negative peak (N1) amplitudes tended to decrease, and the mean first positive peak (N1P1) amplitudes reduced to significant levels (p = 0.047) 1 week after PDT. 3 months after PDT, there were no significant differences in the mean N1 and N1P1 amplitudes compared with pre-PDT values. In PCV, there were no significant changes in the mean N1 and N1P1 amplitudes 1 week after treatment. However, 3 months after PDT, mean amplitudes showed significant increases in N1 (p = 0.008) and N1P1 (p = 0.006) amplitudes compared with pre-PDT values. Conclusions: mfERG recording transitions are different between patients with AMD and those with PCV. In patients with AMD, these results may show transient impairments in retinal function 1 week after PDT, but in those with PCV, the efficacy of PDT is superior to the impairment after PDT.

Disagreement between Heidelberg Retina Tomograph and optical coherence tomography in assessing optic nerve head configuration of eyes with band atrophy and normal eyes

Background/aims: To evaluate to what extent the optic nerve head (ONH) parameters as measured with Heidelberg Retina Tomograph (HRT) differed from those measured with optical coherence tomography (OCT) in eyes with compressive optic neuropathy (CON) that had band atrophy (BA) of the optic disc. Methods: A total of 30 eyes from 19 patients with BA due to chiasmal tumour and 162 eyes from 162 normal subjects were examined with HRT and Stratus OCT using the fast optic nerve scan protocol. Parameters measured by the two devices, including the disc area, cup/disc (C/D) area ratio, cup area, cup volume, rim area and rim volume, were compared between the eyes of BA patients and controls. Bland–Altman plots were used to evaluate agreement for each parameter between OCT and HRT in both groups of eyes. Intermethod discrepancy of the measurements for each parameter was compared between the two groups of eyes. Results: Eyes with BA had smaller cup and larger rim parameters than control eyes when measured with HRT, whereas they had significantly larger cup and significantly smaller rim parameters than control eyes when measured with OCT. HRT measurements tended to be consistently lower in the C/D area ratio and cup area and higher in the rim area and rim volume than OCT measurements for both control eyes and eyes with BA. The intermethod discrepancy for all the parameters except the disc area was significantly larger in eyes with BA than in control eyes. Conclusion: The increased optic disc excavation was detected with OCT but not with HRT in CON eyes with BA of the optic disc. Thus, the distinct algorithms used by these two modalities affected the measurements of ONH parameters, particularly when assessing optic discs with temporal rim thinning.

Nipradilol protects rat retinal ganglion cells from apoptosis induced by serum deprivation in vitro and by diabetes in vivo.

Purpose: To investigate if nipradilol has an anti-apoptotic effect in serum-deprived RGC-5 cells and in the streptozotocin-induced diabetic rat retina. Methods: Apoptosis was quantified by activated caspase-3 immunohistochemistry or terminal dUTP nick end-labeling assay. Results: Nipradilol dose-dependently suppressed apoptosis in a protein kinase A- and G-dependent manner and counteracted glutamate-induced calcium entry in the RGC-5 cells and reduced apoptotic cells in the retinal ganglion cell layer of 4- and 12-week diabetic retinas compared to controls when instilled for 5 days. Removal of the nitric oxide moiety from nipradilol blocked these effects. Conclusions: Nipradilol protects RGCs from apoptosis induced by serum-deprivation in vitro and by diabetes in vivo. The NO-related signaling pathway mediates the anti-apoptotic ability of nipradilol.

Macular thickness reduction in eyes with unilateral optic atrophy detected with optical coherence tomography

AimsTo assess the changes in macular and peripapillary retinal nerve fibre layer (RNFL) thickness in eyes with unilateral optic atrophy and to evaluate the relationship between retinal thickness and visual function.MethodsEnrolled were 22 patients with unilateral optic atrophy. Macular thickness at the divided nine areas and peripapillary RNFL thickness in quadrantic sections were measured by optical coherence tomography. Thickness values in the affected eyes were compared with those in the contralateral unaffected eyes. The correlation of foveal thickness with best-corrected visual acuity (BCVA) was evaluated. The correlation between retinal thickness and the remaining visual field area circumscribed with I-4-e isopter in superior and inferior hemifield was assessed.ResultsMacular thinning was observed in all areas (P<0.001 in each area) other than the fovea (P=0.068). Peripapillary RNFL thickness decreased in all quadrantic sections (P<0.001 in each section). The affected to unaffected eye ratio of retinal thickness was more than 0.6 in each area. BCVA did not correlate with foveal thickness (correlation coefficient=0.094, P=0.668). Although not statistically significant (P=0.281, superior hemifield; P=0.053, inferior hemifield), there was a tendency that eyes with severe visual field loss show more marked retinal thinning.ConclusionsMacular thinning with the preserved foveal thickness is a hallmark of eyes with optic atrophy. Together with no correlation between foveal thickness and BCVA, this finding would help in differential diagnosis of macular and optic nerve diseases.