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.

RP2-associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review, identifying a genotype-phenotype association.

The retinitis pigmentosa 2 (RP2) gene is one of the causative genes for X-linked inherited retinal disorder. We characterized the clinical/genetic features of four patients with RP2-associated retinal disorder (RP2-RD) from four Japanese families in a nationwide cohort. A systematic review of RP2-RD in the Japanese population was also performed. All four patients were clinically diagnosed with retinitis pigmentosa (RP). The mean age at examination was 36.5 (10-47) years, and the mean visual acuity in the right/left eye was 1.40 (0.52-2.0)/1.10 (0.52-1.7) in the logarithm of the minimum angle of resolution unit, respectively. Three patients showed extensive retinal atrophy with macular involvement, and one had central retinal atrophy. Four RP2 variants were identified, including two novel missense (p.Ser6Phe, p.Leu189Pro) and two previously reported truncating variants (p.Arg120Ter, p.Glu269CysfsTer3). The phenotypes of two patients with truncating variants were more severe than the phenotypes of two patients with missense variants. A systematic review revealed additional 11 variants, including three missense and eight deleterious (null) variants, and a statistically significant association between phenotype severity and genotype severity was revealed. The clinical and genetic spectrum of RP2-RD was illustrated in the Japanese population, identifying the characteristic features of a severe form of RP with early macular involvement.

Clinical and genetic characteristics of 10 Japanese patients with PROM1-associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population.

Variants in the PROM1 gene are associated with cone (-rod) dystrophy, macular dystrophy, and other phenotypes. We describe the clinical and genetic characteristics of 10 patients from eight Japanese families with PROM1-associated retinal disorder (PROM1-RD) in a nationwide cohort. A literature review of PROM1-RD in the Japanese population was also performed. The median age at onset/examination of 10 patients was 31.0 (range, 10-45)/44.5 (22-73) years. All 10 patients showed atrophic macular changes. Seven patients (70.0%) had spared fovea to various degrees, approximately half of whom had maintained visual acuity. Generalized cone (-rod) dysfunction was demonstrated in all nine subjects with available electrophysiological data. Three PROM1 variants were identified in this study: one recurrent disease-causing variant (p.Arg373Cys), one novel putative disease-causing variant (p.Cys112Arg), and one novel variant of uncertain significance (VUS; p.Gly53Asp). Characteristic features of macular atrophy with generalized cone-dominated retinal dysfunction were shared among all 10 subjects with PROM1-RD, and the presence of foveal sparing was crucial in maintaining visual acuity. Together with the three previously reported variants [p.R373C, c.1551+1G>A (pathogenic), p.Asn580His (likely benign)] in the literature of Japanese patients, one prevalent missense variant (p.Arg373Cys, 6/9 families, 66.7%) detected in multiple studies was determined in the Japanese population, which was also frequently detected in the European population.

Development and spontaneous closure of a secondary macular hole associated with submacular hemorrhage due to polypoidal choroidal vasculopathy: a case report.

BACKGROUND: Macular hole (MH) is a retinal break in the fovea involving partial or complete dehiscence of the neural retinal layers affecting the visual quality by decreasing visual acuity (VA) and visual deformation. We describe a case of secondary MH associated with submacular hemorrhage (SMH) due to polypoidal choroidal vasculopathy (PCV), which showed spontaneous closure. CASE PRESENTATION: A 67-year-old man developed decreased VA in his right eye due to an SMH. The VA was 20/50, and monthly intravitreal injection of aflibercept was administered three times. The SMH gradually decreased, and 10 months later the external limiting membrane was found to be perforated, resulting in MH. The old clot disappeared, and the MH remained for 10 months. Twenty-three months later, serous retinal detachment (SRD) involving the macula appeared and the MH had disappeared. SRD gradually disappeared, and macular configuration recovered. VA gradually improved and became 20/20 38 months later. CONCLUSION: Dynamic change of the ultrastructure in an unusual case of secondary-developed and spontaneously closed MH was clearly observed. Although the mechanism was unknown, the small diameter size and exudative PCV are thought to have contributed to the closure.

Retinal function determined by flicker ERGs before and soon after intravitreal injection of anti-VEGF agents.

BACKGROUND: To evaluate the retinal function before and soon after an intravitreal injection of an anti-vascular endothelial growth factor (anti-VEGF) agents. METHODS: Seventy-nine eyes of 79 patients that were treated by an intravitreal injection of an anti-VEGF agent for age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO) with macular edema (ME) were studied. The RETeval® system was used to record 28 Hz flicker electroretinograms (ERGs) from the injected and non-injected eyes before (Phase 1, P1), within 2 h after the injection (P2), and 2 to 24 h after the injection (P3). Patients were grouped by disease or by the injected agent and compared. The significance of the changes in the implicit times and amplitudes was determined by t tests. RESULTS: The amplitudes were not significantly different at the three phases. The implicit time of the injected eye was 31.2 ± 3.2 msec at P1, and it was not significantly different at P2 (31.7 ± 3.1 msec) but it was significantly longer at P3 (32.2 ± 3.3 msec, P < 0.01, ANOVA for both). The implicit time in the non-injected fellow eye was 30.5 ± 3.3 msec at P1, and it was significantly longer at P2 (31.1 ± 3.2 msec) and phase 3 (31.3 ± 3.4 msec, P < 0.01, ANOVA for both). CONCLUSIONS: The results indicate that an intravitreal anti-VEGF injection will increase the implicit times not only in the injected eye but also in the non-injected eye soon after the intravitreal injection.

Visual prognosis better in eyes with less severe reduction of visual acuity one year after onset of Leber hereditary optic neuropathy caused by the 11,778 mutation.

BACKGROUND: Patients with Leber hereditary optic neuropathy (LHON) have a progressive decrease of their visual acuity which can deteriorate to <0.1. Some patients can have a partial recovery of their vision in one or both eyes. One prognostic factor associated with a recovery of vision is an early-age onset. The purpose of this study was to determine other clinical factors that are predictive of a good visual recovery. METHODS: Sixty-one Japanese LHON patients, with the 11,778 mutation and a mean age of 23.1 ± 12.1 years at the onset, were studied. All patients were initially examined at an acute stage of LHON and were followed for 3 to 10 years. At 1 year after the onset, the lowest visual acuity was <0.1 in all eyes. We studied the following parameters of patients with/without a final visual acuity of ≥ 0.2: sex; heavy consumption of cigarettes and alcohol; taking idebenone; mean age at onset; mean lowest visual acuity; and distribution of the lowest and the final visual acuity. RESULTS: Fifteen (24.6%) of the 61 patients or 25 (20.5%) of the 122 eyes had a recovery of their visual acuity to ≥ 0.2. The mean age at onset of these 15 patients with visual recovery to ≥ 0.2 was 17.5 ± 7.7 years, and that of the 46 patients without visual recovery to ≥ 0.2 was 25.0 ± 12.8 years (P = 0.02, Mann-Whitney U test). The mean lowest visual acuity of the 25 eyes with visual recovery ≥ 0.2 was 0.04, and that of the 97 eyes without visual recovery to ≥ 0.2 was 0.015 (P < 0.001, Mann-Whitney U test). Fifty percent (15/30) of the eyes whose lowest visual acuity was ≥ 0.04 during 1 year after the onset had a visual recovery to ≥ 0.2, while 11% (10/92) of the eyes whose the lowest visual acuity was ≤ 0.03 had a visual recovery to ≥ 0.2 (P < 0.001, χ 2 test). There were no significant differences in the other clinical factors. CONCLUSION: A final visual acuity of ≥ 0.2 was associated with a less severe reduction of the visual acuity at 1 year after the onset. Our findings can be used to predict the visual prognosis in LHON patients.

Detailed analysis of family with autosomal recessive bestrophinopathy associated with new BEST1 mutation.

PURPOSE: To describe the clinical and genetic findings in a patient with autosomal recessive bestrophinopathy (ARB) and his healthy parents. METHODS: The patient and his healthy non-consanguineous parents underwent detailed ophthalmic evaluations including electro-oculography (EOG), spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Mutation analysis of the BEST1 gene was performed by Sanger sequencing. RESULTS: The FAF images showed multiple spots of increased autofluorescence, and the sites of these spots corresponded to the yellowish deposits detected by ophthalmoscopy. SD-OCT showed cystoid macular changes and a shallow serous macular detachment. The Arden ratio of the EOG was markedly reduced to 1.1 in both eyes. Genetic analysis of the proband detected two sequence variants of the BEST1 gene in the heterozygous state: a novel variant c.717delG, p.V239VfsX2 and an already described c.763C>T, p.R255W variant associated with Best vitelliform macular dystrophy and ARB. The proband's father carried the c.717delG, p.V239VfsX2 variant in the heterozygous state, and the mother carried the c.763C>T, p.R255W variant in the heterozygous state. The parents who were heterozygous for the BEST1 variants had normal visual acuity, EOG, SD-OCT, and FAF images. CONCLUSIONS: In a truncating BEST1 mutation, the phenotype associated with ARB is most likely due to a marked decrease in the expression of BEST1 promoted by the nonsense-mediated decay surveillance mechanism, and it may depend on the position of the premature termination of the codon created.

One-year outcomes with half-dose verteporfin photodynamic therapy for chronic central serous chorioretinopathy.

PURPOSE: To assess the 1-year outcome of half-dose verteporfin photodynamic therapy (PDT) for patients with chronic central serous chorioretinopathy (CSC). DESIGN: Retrospective, interventional case series with no controls. PARTICIPANTS: A total of 204 eyes of 204 patients with chronic CSC were studied. METHODS: Fluorescein angiography (FA) and indocyanine green angiography (ICGA) were performed before PDT. The best-corrected visual acuities (BCVAs) were measured and optical coherence tomography was performed before and 1, 3, 6, 9, and 12 months after PDT. MAIN OUTCOME MEASURES: The main outcome measures were the resolution of the serous retinal detachment (SRD), changes in BCVA, and ocular and systemic complications at 12 months. RESULTS: A total of 182 of 204 eyes (89.2%) had complete resolution of the SRD at 12 months after the PDT. Eleven eyes (5.4%) had a persistent SRD throughout the follow-up period, and 12 eyes (5.9%) had a recurrence of the SRD after an earlier resolution. One of the 12 eyes had a spontaneous resolution of the SRD 6 months after PDT. The mean±standard deviation BCVA in logarithm of the minimum angle of resolution (logMAR) units significantly improved from 0.11±0.25 before to 0.07±0.23 at 1 month, 0.02±0.23 at 3 months, 0.01±0.23 at 6 months, 0.00±0.24 at 9 months, and -0.01±0.22 at 12 months (P<0.0001). The eyes with an SRD at 12 months were more likely to have an intermediate hyperfluorescence on ICGA (chi-square test, P<0.001) and poorer BCVA before the half-dose PDT (Student t test, P=0.04) than those without SRD at 12 months. None of the patients developed any systemic complications or experienced any severe visual reduction after the half-dose PDT. However, polypoidal lesion appeared in 1 eye 8 months after the PDT. CONCLUSIONS: Half-dose PDT is an effective and safe method to treat eyes with chronic CSC with an SRD. The CSC resolved and the BCVA improved significantly after PDT. Half-dose PDT was less effective for cases without intense hyperpermeability on ICGA and those with lower BCVA before the PDT.

Photoreceptor inner and outer segment layer thickness in multiple evanescent white dot syndrome.

PURPOSE: To evaluate the photoreceptor inner and outer segment layer thickness in eyes with MEWDS. DESIGN: Prospective, non-comparative, observational case series. The follow-up duration was 4 months. METHODS: Four women were diagnosed with unilateral MEWDS. The ages of the patients were 25, 24, 35, and 40 years. The retinal microstructure was assessed by spectral-domain optical coherence tomography (SD-OCT). The thickness of the photoreceptor inner (IS) and outer (OS) segments and sum of them (IS + OS) at the fovea were analyzed. RESULTS: The visual acuity was reduced in three of four eyes at the acute phase. SD-OCT showed that the border of IS and OS (IS/OS) line and the cone outer segment tips (COST) line in the macula area were not detected in all four eyes. The IS + OS thickness was 50.3 ± 5.6 µm and that of the healthy fellow eyes was 73.5 ± 7.0 µm (n = 4 eyes). The thickness of the IS was 27.8 ± 2.6 µm and that of the OS was 45.8 ± 7.3 µm. In all eyes, there was a spontaneous improvement of the visual acuity. SD-OCT showed a recovery of only the IS/OS line in the macular area, but the COST line was not visible in three cases. The mean IS + OS thickness increased to 56.0 ± 7.9 µm (n = 4), IS = 26.0 ± 2.0 µm (n = 3), and OS = 30.1 ± 8.7 µm (n = 3) in the early recovery phase, and to 64.8 ± 9.3 µm (n = 4), IS = 28.5 ± 1.7 µm (n = 4), and OS = 36.3 ± 7.9 µm (n = 4) in the late recovery phase. The mean inner and outer segment thickness remained unchanged in the fellow eyes. CONCLUSION: Eyes with MEWDS have changes in the photoreceptor microstructures. The change in the IS + OS thickness during the natural recovery course might be due to an increase in the OS length.

Quantification of metamorphopsia in chronic central serous chorioretinopathy after half-dose verteporfin photodynamic therapy.

PURPOSE: To determine the degree of metamorphopsia before and 1 year after half-dose verteporfin photodynamic therapy in eyes with chronic central serous chorioretinopathy. METHODS: This was a retrospective, noncomparative, interventional case series. Forty-five eyes of 45 consecutive patients with chronic central serous chorioretinopathy were evaluated. The degree of metamorphopsia was measured with M-CHARTS before and at 1, 3, 6, 9, and 12 months after half-dose verteporfin photodynamic therapy. The best-corrected visual acuity was also measured. RESULTS: Forty of the 45 eyes had a complete resolution of the serous retinal detachment at 1 month, 1 eye at 3 months, and 3 eyes at 6 months. The serous retinal detachment in one eye persisted throughout the follow-up period. The mean horizontal metamorphopsia score improved significantly from 0.61 ± 0.52° at baseline to 0.49 ± 0.56° at 12 months (P = 0.04). The vertical metamorphopsia score improved significantly from 0.52 ± 0.53° at baseline to 0.33 ± 0.46° at 12 months (P = 0.005). CONCLUSION: Half-dose verteporfin photodynamic therapy for chronic central serous chorioretinopathy results in significant improvements of metamorphopsia at 1 year, especially in eyes with good best-corrected visual acuity at the baseline. Half-dose verteporfin photodynamic therapy can be a therapeutic option for patients with good visual acuity who complain of metamorphopsia.

Comparisons of pattern visually evoked potentials elicited by different response time liquid crystal display screens.

PURPOSE: To evaluate the usefulness of a liquid crystal display (LCD) with higher driving frequency and shorter response time (2 ms) as a visual stimulator to elicit pattern reversal visually evoked potentials (p-VEPs). METHOD: p-VEPs were recorded from 12 eyes of 12 healthy volunteers (28.3 ± 9 years). The p-VEPs elicited by a conventional cathode ray tube (CRT) screen were compared to those elicited by a high-speed LCD screen (2-ms LCD, GD245HQbid, Acer, Taipei, Taiwan). The luminance changes of each monitor were measured with a photodiode. RESULTS: During the reversal phase the luminance of the 2-ms LCD screen with 97% contrast was transiently reduced, which can elicit an electroretinogram (ERG) and therefore a flash VEP. The 2-ms LCD with 81% contrast checkerboard had a minimal luminance reduction during the reversal phase, and therefore no ERGs were elicited. No significant differences in the amplitude of P100 and the implicit times of N75 and P100 were observed in the p-VEPs elicited by a CRT or the 2-ms LCD screens as stimulators. CONCLUSION: The luminance change can elicit flash VEPs, and this artifact can be minimized by using a 2-ms LCD screen with reduced contrast of the checkerboard stimulus.

What monitor can replace the cathode-ray tube for visual stimulation to elicit multifocal electroretinograms?

To compare a conventional cathode-ray tube (CRT) screen to organic light-emitting diode (OLED) and liquid crystal display (LCD) screens as visual stimulators to elicit multifocal electroretinograms (mfERGs), mfERGs were recorded from seven eyes of seven healthy volunteers (21 ± 2 years). The mfERGs elicited by a conventional CRT screen (S710, Compaq Computer Co.) were compared to those elicited by a studio-grade master OLED monitor (PVM-1741, Sony, Japan) and a conventional LCD (S1721, Flexscan, Eizo Nanao Corp., Japan). The luminance changes of each monitor were measured with a photodiode. CRT, OLED, and LCD screens with a frame frequency of 60 Hz were studied. A hexagonal stimulus array with 61 stimulus elements was created on each monitor. The serial white stimuli of the OLED screen at 60 Hz did not fuse, and that of the LCD screens fused. The amplitudes of P1 and P2 of the first-order kernels of the mfERGs were not significantly different from those elicited by the CRT and OLED screens, and the P1 amplitude of the first-order kernel elicited by the LCD stimuli was significantly smaller than that elicited by the CRT in all the groups of the averaged hexagonal elements. The implicit times were approximately 10 ms longer in almost all components elicited by the LCD screen compared to those elicited by the CRT screen. The mfERGs elicited by monitors other than the CRT should be carefully interpreted, especially those elicited by LCD screens. The OLED had good performance, and we conclude that it can replace the CRT as a stimulator for mfERGs; however, a collection of normative data is recommended.

Binocular interaction of visually evoked cortical potentials elicited by dichoptic binocular stimulation.

To analyze the interaction of cortical potentials elicited by dichoptic stimulation of the dominant and fellow eyes at different frequencies, a pair of programmed power supply units were used to drive a light emitting diode (LED) mounted in the right and left eyes of light-proof goggles to elicit the visually evoked cortical responses (VECPs). The right eye was stimulated at 11.5 Hz and the left eye at 11.0 Hz. Then the stimulation was repeated with the frequency of stimulation switched to the other eyes. The stimulus duration was 5 ms. The sampling rate was 1.0 Hz, and the duration of collection was 200 ms. The VECP of each eye was extracted separately. Individual VECPs could be recorded separately after simultaneous dichoptic stimulation of each eye. The amplitudes of the VECPs were not significantly different after stimulating the dominant eye and the fellow eye separately. The implicit times of negative peak (N-2) and the second positive peak (P-2) were shorter after stimulation of the dominant eye than after stimulation of the fellow eye, but the difference was not significant. However, the implicit time of N-2 elicited by stimulating the dominant eye was significantly shorter when the stimulation rate was 11.5 Hz. The VECPs elicited by stimulating the two eyes can be recorded separately by simultaneous dichoptic stimulation. Dichoptic simultaneous stimulation required a shorter time and may be a more sensitive method of analyzing binocular interactions compared to the classic VECPs using monocular stimulation.

Safety and Effectiveness of Intravitreal Brolucizumab Injection in Combination With Sub-Tenon's Capsule Triamcinolone Acetonide Injection for Polypoidal Choroidal Vasculopathy During the Loading Phase.

BACKGROUND: This study evaluated the safety and effectiveness of combining intravitreal brolucizumab injection with sub-tenon's capsule triamcinolone acetonide injection (STTA) during the loading phase for polypoidal choroidal vasculopathy (PCV). METHODS: In this retrospective observational study, untreated patients with PCV receiving intravitreal brolucizumab injections with STTA during loading at Saitama Medical University Hospital's Eye Center from May 2021 to June 2022 were analyzed. Complete regression rates of polypoidal lesions were assessed using indocyanine green angiography 12 weeks post-treatment initiation. RESULTS: Nineteen patients (19 eyes) participated. Best-corrected visual acuity significantly improved at eight weeks compared to baseline. No significant intraocular pressure increases occurred throughout the loading phase, while central foveal and choroidal thickness significantly reduced at 4, 8, and 12 weeks. Subretinal fluid was present in all patients before treatment, rapidly resolving post-intravitreal brolucizumab injections and STTA, with residual rates of 36.8% (seven eyes) and 5.3% (one eye) at four and 12 weeks, respectively. Intraocular inflammation did not occur during the loading phase, and the complete regression rate of polypoidal lesions was 89.5% (17 eyes). CONCLUSIONS: Combining intravitreal brolucizumab injection with STTA during the loading phase may be one treatment option for PCV management.

Electroretinographic Evaluations Using Skin Electrode of Eyes with Bleb-Related Endophthalmitis Following Vitrectomy with 0.025% Povidone Iodine Irrigation.

Purpose: To determine whether 0.025% povidone-iodine (0.025% PI) in the irrigation solution during vitrectomy for endophthalmitis is safe. Methods: Two cases of bleb-associated endophthalmitis were treated with vitrectomy using 0.025% PI in the irrigation solution. The RETevel electroretinographic (ERG) system with skin electrodes was used to assess the physiology of the retina pre- and postoperatively. Case: Case 1 was a 46-year-old man who had atopic keratoconjunctivitis and underwent trabeculectomy with the creation of a bleb after there was a rise in the intraocular pressure. One month postoperatively, a mild filtering bleb-associated endophthalmitis developed, and the eye was treated with intravitreal and subconjunctival injections of vancomycin (VCM) and ceftazidime (CAZ). After three days, the fundus was not visible and B-mode echography showed an area of high brightness in the retina. Vitrectomy with irrigation with VCM and CAZ, and 0.025% PI was performed successfully. Pre- and postoperative ERGs showed an improvement in both the a- and b-wave amplitudes and the b/a ratio was stable at 2.0. Case 2 was a 63-year-old man who had undergone trabeculectomy for glaucoma. Five years later, the eye developed blebitis which was treated with topical and subconjunctival injections of VCM and CAZ. Three days later, vitreous opacities appeared and a high brightness area was seen in the B-mode echographic images. Vitrectomy with VCM and CAZ, and 0.025% PI irrigation was successfully performed. Comparisons of the pre- and postoperative ERGs found that the a- and b- wave amplitudes of the ERGs increased and the b/a ratio was stable at approximately 1.5. Conclusion: Vitrectomy with 0.025% PI irrigation is safe and ERG recordings with skin electrodes can be used to evaluate the pre- and postoperative retinal physiology safely.

We report our findings in two cases of bleb-related endophthalmitis that underwent pars plana vitrectomy (PPV) with irrigation with 0.025% povidone-iodine (PI)-Balanced Salt Solution (BSS) PLUS (Alcon Laboratories, Fort Worth, TX). The retinal function was evaluated by full-field electroretinograms (ERGs) recorded with skin electrodes before and after the vitrectomy. At present, there is no consensus on whether patients with bleb-related endophthalmitis should be treated with PPV or treated solely by intravitreal antibiotics. It was recently reported that vitrectomy using an irrigation solution containing 0.025% PI followed by postoperative antibiotics was effective and safe for the treatment of endogenous endophthalmitis and postoperative endophthalmitis. However, iodine is known to be retinotoxic depending on its concentration. Electroretinography is a useful method to evaluate the safety of medications because it represents the physiology of the entire retina. However, conventional recording procedures with contact lens electrodes cannot be used in eyes with bleb associated endophthalmitis. Therefore, we performed ERG using skin electrodes which were introduced relatively recently. As a result, electroretinographic response showed that retinal function was not altered after surgery in these two cases.

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.

Liquid crystal display screens as stimulators for visually evoked potentials: flash effect due to delay in luminance changes.

PURPOSE: The cathode-ray tube (CRT) screen has recently been replaced by liquid crystal display (LCD) screens as visual stimulators for pattern-reversal visually evoked potentials (p-VEPs). The aim of the study was to evaluate the usefulness of LCD screen to elicit p-VEPs. METHODS: The waveforms of the p-VEPs elicited by a LCD panel were compared with those elicited by a conventional CRT screen. The changes in the luminance of each screen were measured with a photodiode, and the mean luminance change was measured with a luminance meter. VEPs and electroretinograms (ERGs) were also recorded when the monitor was covered by a diffuser. RESULTS: The p-VEPs elicited by the LCD consisted of the N75 and P100 components of the conventional VEPs and had good reproducibility. The average latency of these components was significantly delayed by 9.8 ms for N75 and 10.2 ms for P100, and the N75-P100 amplitude was significantly larger than the conventional p-VEP elicited by the CRT screen. During the reversal phase, especially from black-to-white, the luminance of the LCD screen was transiently reduced, and it elicited a flash VEP and ERG. A reduction in the contrast of the checks minimized the transient change in the luminance, and the VEP waveform was more similar to that elicited by the CRT screen. CONCLUSIONS: The results suggest that when an LCD monitor is used as an alternative visual stimulator to elicit p-VEPs, the delay in the luminance change and the flash effect needs to be taken into account.

Improvement of visual acuity after transcorneal electrical stimulation in case of Best vitelliform macular dystrophy.

PURPOSE: To report an improvement of the visual acuity after transcorneal electrical stimulation (TES) in a case of Best vitelliform macular dystrophy (BVMD). PATIENT AND METHODS: A 26-year-old woman diagnosed with BVMD presented with reduced vision. Her best corrected visual acuity (BCVA) was reduced to 20/200 in the right eye, and TES was performed once a month for two sessions. The current of the biphasic pulses (anodic first; duration, 10 msec; frequency, 20 Hz) was delivered using a DTL-electrode, and the duration of the TES was 30 min. RESULTS: The BCVA in the right eye slowly improved after the TES, and 6 months later the BCVA was 20/25. The results of Humphrey visual field tests (VF) and multifocal ERGs (mfERGs) were only slightly changed. Two years later, the BCVA decreased, and it was improved again after another session of TES with the same parameters of the electrical pulses. CONCLUSION: The improvement of the visual acuity in our case of BVMD indicates that TES should be tried in other cases of retinal dystrophy. Further clinical and laboratory studies on TES are needed.

[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.

Modified Basket Suture for a Floppy or Irregular Iris in Endothelial Keratoplasty.

ABSTRACT: Performing endothelial keratoplasty in an eye with a damaged or irregular iris can result in uneven air filling, air escape behind the pupil, anterior iris curvature, a shallow anterior chamber, an uneven anterior chamber depth, difficulty inserting and opening the graft, and iris trauma. We herein present a modified basket suture technique to prevent these iris complications. Before insertion of the corneal donor graft, a double-armed 9-0 polypropylene suture on a curved needle is inserted from 4 equidistant points at the corneal limbus to create a box configuration directly anterior to the iris. These sutures prevent the iris from moving toward the cornea and the anterior chamber from becoming shallow when air replacement is performed. The suture also reduces intraoperative or postoperative iris-related problems because the air filling is more uniform and less prone to migration.