One-year recurrence rate of Graves ophthalmopathy presenting as diplopia in the primary position after varied doses of intravenous methylprednisolone followed by oral prednisolone with dosing based on the magnetic resonance imaging findings.

PURPOSE: To reveal the recurrence rate of Graves ophthalmopathy (GO) presenting as diplopia in the primary position for 1 year after varied doses of intravenous methylprednisolone (IVMP) followed by oral prednisolone, with dosing based on the magnetic resonance imaging (MRI) findings. STUDY DESIGN: Retrospective study. METHODS: We analyzed the medical charts of 25 patients who were diagnosed with new-onset GO and who received treatment for diplopia in the primary position at our hospital. Treatment consisted of MRI-determined varied doses of IVMP followed by oral prednisolone. If the MRI findings showed deterioration or were unchanged after 6 g of IVMP, 3 g of IVMP was added for further treatment. Simple and multiple linear regression analyses were performed to reveal the associations between the independent variables and the dependent variable, defined as recurrence. RESULTS: The mean patient age (± standard deviation) was 61.3 ± 11.3 years. The female to male ratio was 15:10. Twenty-one of the 25 patients received a total of 6 g of IVMP, whilst the remaining 4 patients received a total of 9 g of IVMP. In 5 patients (20%), the GO recurred within 1 year of IVMP administration. Simple and multiple linear regression analyses showed that the MRI findings after 6 g of IVMP affected recurrence (P < .05). CONCLUSION: This study showed that in 20% of patients, GO recurred within 1 year of administration of varied doses of IVMP, with the dosing based on the MRI findings. Furthermore, assessment of inflammation by use of MRI after 6 g of IVMP has a potential role in predicting recurrence.

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing.

Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees. The first and second most frequently mutated genes were EYS and RP1, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively. Examinations of variant frequency in total and by phenotype showed high accountability of a frequent EYS missense variant (c.2528G>A). In addition to the two known EYS founder mutations (c.4957dupA and c.8805C>G) of arRP, we observed a frequent RP1 variant (c.5797C>T) in patients with arMD/CORD.

The Prevalence of Brain Abnormalities in Japanese Patients with Optic Nerve Hypoplasia.

The purpose of this study was to investigate the clinical characteristics of Japanese patients with optic nerve hypoplasia (ONH), with particular attention to the prevalence of brain abnormalities. We retrospectively analysed the medical charts of 16 patients who were diagnosed with ONH and who underwent magnetic resonance imaging (MRI) at Niigata University Medical and Dental Hospital. We recorded the age, sex, laterality, initial eye and visual symptoms, best-corrected visual acuity, and brain abnormalities on MRI (excluding ONH). The median age at the first visit to the Ophthalmology Clinic was 2.4 years old. Four patients were male and 12 were female. ONH was bilateral in 11 patients and unilateral in five. Best-corrected visual acuity ranged from no light perception to 20/20. Seven patients (43.8%) had brain abnormalities including agenesis of the septum pellucidum, pituitary gland hypofunction, cerebral dysplasia, and West syndrome. Five of these seven patients had general manifestations since the neonatal or infantile period. Our study revealed the prevalence of brain abnormalities associated with optic nerve hypoplasia in Japanese patients at a single institute. Because two of 11 patients had no general manifestations since the neonatal or infantile period but demonstrated brain abnormalities, MRI should be performed to investigate all patients with ONH.

Visual outcome of aquaporin-4 antibody-positive optic neuritis with maintenance therapy.

PURPOSE: To assess the effect of maintenance therapy on visual outcomes in preventing recurrences one year after first onset in patients with aquaporin-4 antibody (AQP4Ab)-positive optic neuritis. STUDY DESIGN: Retrospective study. METHODS: The medical charts of 56 patients with optic neuritis (22 with AQP4Ab-positive and 34 with AQP4Ab-negative) at Niigata University Medical and Dental Hospital were retrospectively analyzed. Clinical characteristics, including visual acuity and number of recurrences one year after first onset, were compared among patients who were AQP4Ab-positivie with and those without maintenance therapy such as oral prednisolone and azathioprine, as well as those who were AQP4Ab-negative. RESULTS: The mean ages were 49.3 and 45.2 years in the AQP4Ab-positive and the AQP4Ab-negative groups. The female to male ratio was 21:1 and 18:16 in the two groups, respectively. Multiple between-group comparison showed a statistically significant difference in visual acuity one year after first onset between the AQP4Ab-positive without maintenance therapy group and the AQP4Ab-negative group (0.05 (median, same applies below) vs. 1.0, p < 0.01). There was also a statistically significant difference in the number of recurrences in the year after first onset between the AQP4Ab-positive with and without maintenance therapy groups (1 vs. 0, p < 0.01). CONCLUSION: This study demonstrates that patients with AQP4Ab-positive optic neuritis without maintenance therapy had the poorest visual acuity and the most recurrences one year after first onset. These results indicate that reducing the number of recurrences with maintenance therapy could improve the visual outcomes in patients with AQP4Ab-positive optic neuritis.

Iridocorneal contact as a potential cause of corneal decompensation following laser peripheral iridotomy.

PURPOSE: This study aimed to investigate the relationship between corneal decompensation following laser peripheral iridotomy (LPI) and iridocorneal endothelial contact. STUDY DESIGN: Retrospective observational case series. METHODS: Specular microscopy images of LPI recipients with narrow angles were taken at the central cornea and the 8 midperipheral corneal regions at approximately 3 mm from the center. Eleven eyes of 11 patients had a minimum of ≤ 1600 cells/mm2 among 8 midperipheral corneal endothelial cell densities (ECDs). Radial scans of the angles in the 8 directions were taken with ultrasound biomicroscopy (UBM) in the supine and face-down positions. The minimum and maximum angle opening distance at 750 µm from the scleral spur of the 8 directions were defined as the narrowest and widest angles, respectively. The ECD of the narrowest angle direction was compared with the ECD of the widest angle direction. RESULTS: When UBM was performed with the subject in the supine position, the iris and cornea at the narrowest angle were in contact in only 4 of 11 eyes, while in the face-down position, the iris and the cornea at the narrowest angle were in contact in 10 of the 11 eyes. In the face-down UBM, the midperipheral ECD of the narrowest angle direction was significantly smaller than the midperipheral ECD of the widest angle direction (P = 0.006). CONCLUSION: The ECD of the narrow angle direction can decrease after LPI. This suggests that corneal endothelial cell damage following LPI may be due to mechanical damage from iridocorneal endothelial contact.

Clinical Stages of Occult Macular Dystrophy Based on Optical Coherence Tomographic Findings.

Purpose: To determine the course of occult macular dystrophy (OMD, Miyake's disease) and to propose stages of OMD based on the optical coherence tomographic (OCT) findings. Methods: Sixty-one patients from 33 families with OMD who carried one of the proven variants of the RP1L1 gene were studied at seven centers in Japan. Ophthalmological examinations including the best-corrected visual acuity (BVCA) and OCT were performed. Results: The median age at the last visit was 50 years with a range of 10 to 88 years, and the median age at the symptom onset was 30 years with a range of 3 to 60 years. There were significant negative correlations between the duration of OMD and BCVA, the central retinal thickness (CRT) and the thickness between external limiting membrane and retinal pigment epithelium (ERT). The BCVA gradually decreased for 10 years after symptom onset and was stable thereafter. Kaplan-Meier survival curves of the BCVA and retinal thickness showed that all of the patients had retained a vision of 1.0 logMAR, and over 80% of the patients had retained 50% thickness of the normal CRT and ERT for at least 60 years after symptom onset. The stages of OMD based on the visual symptoms and OCT findings are proposed. Conclusions: The photoreceptors do not become completely atrophic even at the late stage, which may account for the good retinal pigment epithelium (RPE) structure and normal-appearing fundus. The proposed stages facilitate the investigation of the pathogenicity of OMD and provide information to determine the effectiveness of therapeutic procedures.

Parafoveal Photoreceptor Abnormalities in Asymptomatic Patients With RP1L1 Mutations in Families With Occult Macular Dystrophy.

Purpose: To report the clinical characteristics of asymptomatic cases with RP1L1 gene mutations in four families with occult macular dystrophy (OMD). Methods: Four asymptomatic cases from four families were selected from a cohort of 40 subjects (16 families) with RP1L1 pathogenic variants. Clinical data of the four asymptomatic cases and three symptomatic patients in the same families were reviewed. The three asymptomatic cases did not have any visual symptoms in either eye, and one was unilaterally affected. Ophthalmologic examinations, including spectral-domain optical coherence tomography (OCT) were performed, and the morphologic characteristics of the photoreceptor layer of the asymptomatic cases were compared to those of the symptomatic patients within the same family. Results: The OCT images demonstrated photoreceptor abnormalities in the parafoveal regions in all of the four asymptomatic cases (i.e., absence of the interdigitation zone and blurring of the ellipsoid zone). However, these microstructures were preserved at the foveal center. The longitudinal reflectivity profiles clearly identified this distinct pattern in the asymptomatic cases. In contrast, no distinct abnormalities were detected by other examinations including perimetry, fundus autofluorescence images, and multifocal electroretinograms (ERGs). Conclusions: The sparing of the central foveal photoreceptor layer accounts for the well-preserved visual acuity in the asymptomatic patients. The sparing may represent either the initial phase of typical OMD or a subtype of macular lesion associated with OMD. It is necessary to examine asymptomatic subjects in families with OMD because some of them may progress to the typical phenotype of OMD.

Clinicopathological features in anterior visual pathway in neuromyelitis optica.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOsd) is an autoimmune disorder of the central nervous system characterized by aquaporin-4 (AQP4) autoantibodies. The aim of this study was to elucidate the characteristics of involvement of the anterior visual pathway (AVP) and neurodegeneration via glia-neuron interaction in NMOsd. METHODS: Thirty Japanese patients with serologically verified NMOsd were assessed with a neuro-ophthalmological study. Using 27 tissue blocks from 13 other cases of NMOsd, we performed neuropathological analysis of glial and neuroaxonal involvement in the AVP. RESULTS: The AVP involvement in NMOsd was characterized by the following, compared to multiple sclerosis: (1) longitudinally extensive optic neuritis (ON); (2) more severe visual impairment and worse prognosis for ON; (3) unique AQP4 dynamics, including loss of AQP4 immunoreactivity on astrocytes with complement activation in ON lesions, loss of AQP4 immunoreactivity on Müller cells with no deposition of complement in the retinas, and densely packed AQP4 immunoreactivity on astrocytes in gliosis of secondary anterograde/retrograde degeneration in the optic nerves and retinal nerve fiber layer (RNFL); and (4) more severe neurodegeneration, including axonal accumulation of degenerative mitochondria and transient receptor potential melastatin 4 channel with complement-dependent astrocyte pathology in ON lesions, mild loss of horizontal cells, and RNFL thinning and loss of ganglion cells with abundance of AQP4(+) astrocytes, indicating secondary retrograde degeneration after ON. INTERPRETATION: Severe and widespread neuroaxonal damage and unique dynamics of astrocytes/Müller cells with alterations of AQP4 were prominent in the AVP and may be associated with poor visual function and prognosis in NMOsd.

Early morphological recovery of the optic chiasm is associated with excellent visual outcome in patients with compressive chiasmal syndrome caused by pituitary tumors.

OBJECTIVES: The study objectives are (1) to identify factors predicting the excellent visual recovery after transsphenoidal removal of pituitary tumors and (2) to describe the association of excellent visual recovery and early restoration of symmetry of the decompressed optic chiasm. METHODS: Thirty-five patients with visual symptoms due to pituitary tumors underwent endoscopic endonasal surgery. All patients received perioperative diagnostic magnetic resonance (MR) imaging and ophthalmological assessments within 2 weeks before surgery, within 2 weeks after surgery, and 3 months or later after surgery. Preoperative best-corrected visual acuity (BCVA ≧ 20/20), degree of visual field deficit (VFD, less than half of VF), thickness of retinal nerve fiber layer (RNFL) measured by optical coherence tomography (OCT), and thickness of ganglion cell complex (GCC) measured by OCT were considered for statistical analysis as predictive factors of VF outcome. Multivariate logistic regression models were used in statistical evaluation of data. RESULTS: In the multivariate analysis, RNFL (odds ratio  =  62.137, P < 0.001) and preoperative VFD (odds ratio  =  8.244, P < 0.02) proved to be effective as factors predicting sufficient VF recovery. Postoperative restoration of symmetry of the optic chiasm was related to sufficient VF recovery (P < 0.0001, Fisher's exact test) and RNFL (P < 0.0001, Fisher's exact test). DISCUSSION: Early decompression is crucial for sufficient VF recovery, in particular, while RNFL preserves normal or borderline thickness and while VFD keeps within hemianopia. Morphological reversibility is associated with functional reversibility in the optic chiasm compressed by a pituitary tumor. In particular, early morphological recovery suggests functional recovery, which indicates neurocyte reserve in the compressed optic pathway with functional recovery.

[Long-term observation over ten years of four cases of cone dystrophy with supernormal rod electroretinogram].

BACKGROUND: 'Cone dystrophy with a supernormal rod electroretinogram (ERG)' is rare form of cone dystrophy, and no longitudinal description of the disease course has been reported in a Japanese population. Here, we describe long-term courses of 10 to 15 years in four Japanese patients with mutations in the KCNV2 gene. CASES: Four patients from three families were recruited. Two were siblings (Case 1, 24 y/o women; Case 2, 17 y/o man), and two were sporadic cases (Case 3, 17 y/o women; Case 4, 21 y/o women). All the patients presented with characteristic ERG findings. There were minimal abnormalities in fundus appearance: slight mottling of retinal pigment epithelium in the macula in all four cases, and granular change in the macula in Case 4. The visual acuity in Cases 1 and 2 did not change during the follow-up period, but the acuity in Cases 3 and 4 gradually decreased. Photoreceptor abnormalities in optical coherence tomography were found in all the cases, but were more severe in Cases 3 and 4. CONCLUSION: The long-term courses in Japanese patients were variable. The OCT was helpful in evaluating the disease progression.

Molecular characteristics of four Japanese cases with KCNV2 retinopathy: report of novel disease-causing variants.

PURPOSE: To describe the molecular characteristics of four Japanese patients with cone dystrophy with supernormal rod responses (CDSRR). METHODS: Four individuals with a clinical and electrophysiological diagnosis of CDSRR were ascertained. The pathognomonic findings of the full-field electroretinograms (ERGs) included a decrease in the rod responses, a square-shaped a-wave, an excessive increase in the b-wave in the bright flash responses, and decreased cone-derived responses. Mutational screening of the coding regions and flanking intronic sequences of the potassium channel, subfamily V, member 2 (KCNV2) gene was performed with bidirectional sequencing. The segregation of each allele was confirmed by screening other family members. Subsequent in silico analyses of the mutational consequences for protein function were performed. RESULTS: There were two siblings from one family and one case in each of the two families. One family had a consanguineous marriage. Mutational screening revealed compound heterozygosity for the two alleles, p.C177R and p.G461R, in three patients, and homozygosity for complex alleles, p.R27H and p.R206P, in one patient from the consanguineous family. There were three putative novel variants, p.R27H, p.C177R, and p.R206P. The four variants in the families with KCNV2 were highly conserved in other species. In silico analyses predicted that all of the missense variants would alter protein function. CONCLUSIONS: Biallelic disease-causing variants were identified in four Japanese patients with CDSRR suggesting that the pathognomonic electrophysiological features are helpful in making a molecular diagnosis of KCNV2. Three novel variants were identified, and we conclude that there may be a distinct spectrum of KCNV2 alleles in the Japanese population.

Clinical characteristics of occult macular dystrophy in family with mutation of RP1l1 gene.

PURPOSE: To report the clinical characteristics of occult macular dystrophy (OMD) in members of one family with a mutation of the RP1L1 gene. METHODS: Fourteen members with a p.Arg45Trp mutation in the RP1L1 gene were examined. The visual acuity, visual fields, fundus photographs, fluorescein angiograms, full-field electroretinograms, multifocal electroretinograms, and optical coherence tomographic images were examined. The clinical symptoms and signs and course of the disease were documented. RESULTS: All the members with the RP1L1 mutation except one woman had ocular symptoms and signs of OMD. The fundus was normal in all the patients during the entire follow-up period except in one patient with diabetic retinopathy. Optical coherence tomography detected the early morphologic abnormalities both in the photoreceptor inner/outer segment line and cone outer segment tip line. However, the multifocal electroretinograms were more reliable in detecting minimal macular dysfunction at an early stage of OMD. CONCLUSION: The abnormalities in the multifocal electroretinograms and optical coherence tomography observed in the OMD patients of different durations strongly support the contribution of RP1L1 mutation to the presence of this disease.

Dominant mutations in RP1L1 are responsible for occult macular dystrophy.

Occult macular dystrophy (OMD) is an inherited macular dystrophy characterized by progressive loss of macular function but normal ophthalmoscopic appearance. Typical OMD is characterized by a central cone dysfunction leading to a loss of vision despite normal ophthalmoscopic appearance, normal fluorescein angiography, and normal full-field electroretinogram (ERGs), but the amplitudes of the focal macular ERGs and multifocal ERGs are significantly reduced at the central retina. Linkage analysis of two OMD families was performed by the SNP High Throughput Linkage analysis system (SNP HiTLink), localizing the disease locus to chromosome 8p22-p23. Among the 128 genes in the linkage region, 22 genes were expressed in the retina, and four candidate genes were selected. No mutations were found in the first three candidate genes, methionine sulfoxide reductase A (MSRA), GATA binding 4 (GATA4), and pericentriolar material 1 (PCM1). However, amino acid substitution of p.Arg45Trp in retinitis pigmentosa 1-like 1 (RP1L1) was found in three OMD families and p.Trp960Arg in a remaining OMD family. These two mutations were detected in all affected individuals but in none of the 876 controls. Immunohistochemistry of RP1L1 in the retina section of cynomolgus monkey revealed expression in the rod and cone photoreceptor, supporting a role of RP1L1 in the photoreceptors that, when disrupted by mutation, leads to OMD. Identification of RP1L1 mutations as causative for OMD has potentially broader implications for understanding the differential cone photoreceptor functions in the fovea and the peripheral retina.

Superior segmental optic nerve hypoplasia in youth.

PURPOSE: The clinical characteristics of superior segmental optic nerve hypoplasia (SSOH) in youth were investigated to help establish diagnostic criteria. METHODS: Eleven eyes of seven young patients (male/female ratio, 3/4; age, 15.1 +/- 3.4 years) who had good visual acuity and inferior visual field defects (VFDs) were evaluated. Goldmann and Humphrey perimetries and optic disc morphology were analyzed, and the patients were prospectively followed for a long period. RESULTS: Visual field defects were wedge shaped and oriented to the blind spot, but discontinuous in mild cases. Nerve fiber layer defects (NFLDs) were consistent with the VFDs. The optic disc appearance was variable, with double ring signs in seven eyes, small discs in three eyes, and an incomplete topless disc in one eye. The mothers of none of the patients had gestational diabetes. Visual field defects did not progress during the prospective 8.3 +/- 1.3 years follow-up. CONCLUSIONS: Characteristic VFD patterns on Goldmann perimetry and corresponding NFLDs are important in the diagnosis of SSOH, but not optic disc morphology.

[Multifocal visually evoked responses in two children with optic neuritis].

PURPOSE: Central visual functions of two children with idiopathic optic neuritis were analyzed and followed in the course of the disease by using multifocal visually evoked potentials (mVEP) and other ophthalmological tests. SUBJECTS AND METHODS: Two girls 10 and 11 years of age with unilateral optic neuritis participated in this study. At the initial onset of the disease, visual acuity of the patients was below 20/400 and severe central visual field impairment was found in the affected eyes. There were no abnormal neurological or radiological findings suggesting multiple sclerosis in these patients. The mVEPs were recorded with a stimulus of 37 hexagons composed of black and white triangles subtending 35 degrees of visual angle. RESULTS: The amplitude of mVEPs from many stimulating locations was severely reduced in the course of the recovery of these patients. Although visual acuity and perimetric sensitivity in the affected eyes recovered to normal after steroid pulse therapy, the amplitude of mVEPs still remained 1/3 to 1/2 of that of the opposite healthy eye. The mVEPs gradually recovered to near the level of the opposite healthy eyes at the latest examination. CONCLUSIONS: Recovery from the central visual impairment due to infantile optic neuritis is more gradual than that suggested by subjective ophthalmological examinations. There is still optic nerve dysfunction after visual acuity and visual field have recovered to normal. The mVEP is one of the most sensitive tools for detecting optic nerve dysfunction in patients with optic neuritis.