Subclinical Ocular Changes after Intravitreal Injections of Different Anti-VEGF Agents for Neovascular Age-Related Macular Degeneration.

Intraocular inflammations (IOIs) have been reported to occur after intravitreal injections of brolucizumab, and one of their causes has been suggested to be drug-specific features. We evaluated the anterior chamber by the aqueous flare value (AFV) and the retina by flicker electroretinography (ERG) after the initial intravitreal injection of aflibercept (IVA), brolucizumab (IVBr), or faricimab (IVF) for neovascular age-related macular degeneration (nAMD). The AFV and flicker ERGs were determined before, 2 weeks after, and 4 weeks after the injections in 14 eyes of 14 patients for each drug. After the injections, none of the patients had an IOI, but the AFV increased significantly in the IVA and IVF groups. The increase in the IVF group was +4.6 photon count/ms, which was significantly greater than in the other groups, but was not clinically significant. The implicit time was significantly prolonged in the IVBr group but unchanged in the IVA and IVF groups. These results suggest that brolucizumab, administered at high molar doses, may cause transient retinal disturbances that are not detectable by general ophthalmologic examinations but affect the implicit ERG times.

Association of eye strain with dry eye and retinal thickness.

PURPOSE: The purpose of this cohort study was to investigate the association between the prevalence of abnormal ocular examination results and the common visual symptoms of eye strain, blurred vision and photophobia. METHODS: Consecutive first-visit outpatients with best-corrected visual acuity better than 20/30 in both eyes were enrolled and those with a history of intra-ocular lens implantation and glaucoma were excluded. Dry eye-related examinations and retinal thickness measurement were conducted. The odds ratio (OR) was calculated with logistic regression analyses of ocular data in relation to the presence of visual symptoms. RESULTS: A total of 6078 patients (3920 women, mean age 49.0 ± 20.4 years) were analyzed. The prevalence of each symptom was 31.8% for eye strain, 22.5% for blurred vision and 16.0% for photophobia. A significant risk factor for eye strain was short tear break-up time (TBUT) (OR 1.88), superficial punctate keratitis (SPK) (OR 1.44), and thickness of ganglion cell complex (GCC) (OR 1.30). Risk factors for blurred vision were short TBUT (OR 1.85), SPK (OR 1.24) and GCC (OR 0.59). Risk factors for photophobia were short TBUT (OR 1.77) and SPK (OR 1.32). Schirmer test value, peripapillary nerve fiber layer thickness and full macular thickness were not associated with the tested symptoms. CONCLUSION: The current study successfully identified female gender, short TBUT, and SPK as significant risk factors for eye strain, blurred vision, and photophobia with considerable ORs.

Effects of continuous positive air pressure on intraocular pressure in patients with obstructive sleep apnea during the split-night study: An open-label randomized controlled trial.

BACKGROUND: Intraocular pressure (IOP) is known to increase at midnight, when continuous positive airway pressure (CPAP) is initiated in split-night CPAP titration (SN-CPAP titration), in patients with obstructive sleep apnea (OSA); therefore, possible excessive increase in the IOP should be investigated. However, related studies on this topic are scarce. OSA causes increases and decreases in the IOP; however, its fluctuation during sleep remains unclear. Therefore, we determined the timing of these fluctuations in the IOP during sleep at night. METHODS: This study included 25 patients with OSA. A 7-hour period of night sleep was divided into first (Sleep-1) and second halves (Sleep-2). Patients were randomly divided into the SN (natural breathing during Sleep-1, CPAP applied during Sleep-2) and C (without CPAP) groups. IOP was measured using the iCare Pro before Sleep-1 and after Sleep-1 and Sleep-2. The main hypothesis was that IOP would be significantly higher in the SN group than in the C group. The sub-hypothesis was that the effects of OSA on IOP are manifested at different times. The correlation is shown as Pearson's r for normally distributed data or Spearman's rho for non-normally distributed data. The difference between the SN and C groups in the time course of IOP during the night's sleep was analyzed using repeated-measures analysis of variance. A P value of <.05 was considered significant. RESULTS: No significant difference was found in IOP between the groups, but the SN group showed a significantly increased IOP during Sleep-2 (post hoc Bonferroni test). The apnea-hypopnea index inversely correlated with IOP changes in Sleep-1 and positively correlated with those in Sleep-2. CONCLUSION: This study does not support our main hypothesis that SN-CPAP titration promotes the effect of CPAP in increasing IOP. However, an expected range of the effect of increased CPAP on IOP has also been suggested. IOP-lowering and IOP-raising effects were predominant in the first and second halves of sleep in OSA, thereby providing a new perspective on measured IOP and supporting the subhypothesis.

Efficacy of Psychiatric Treatment to Treat a Specific Phobia of Intravitreal Injections in a Patient with Neovascular Age-Related Macular Degeneration.

Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is essential for the treatment of macular diseases such as wet age-related macular degeneration and macular edema. Although continued treatment is needed to maintain good vision, some patients cannot continue such injections for various reasons, including specific phobias. Here, we report a case of a patient with a specific phobia of intravitreal injections who could resume treatment after undergoing combined drug and cognitive-behavioral therapy (CBT). A 74-year-old Japanese man diagnosed with retinal angiomatous proliferation by fluorescein angiography and indocyanine green angiography was treated with intravitreal anti-VEGF injection. However, at 8 months after the first treatment, he became difficult to treat because of a phobia of injections. He was treated with photodynamic therapy, but his macular edema did not improve. After a psychiatric consultation, he was diagnosed with a specific phobia of intravitreal injections. Combined drug and CBT enabled him to resume receiving intravitreal injections. This case demonstrates that a specific phobia of intravitreal injections may benefit from combined drug and CBT. In this regard, some patients with high anxiety and fear of intravitreal injections should be referred to a psychiatrist at an early stage.

Cataract type and pupillary response to blue and white light stimuli.

We evaluated the pupil reaction to blue and white light stimulation in 70 eyes with cataract and in 38 eyes with a selective blue-light filtering intra-ocular lens. The diameter of the pupil before stimulation was set as baseline (BPD) and, after a stimulus duration of 1 s, the post-illumination pupillary response (PIPR) was measured using an electronic pupillometer. The BPD showed no significant difference among three grades of nuclear sclerosis (NS). In contrast, the PIPRs differed significantly among the NS grades eyes including with and without subcapsular cataract (SC) and IOL eyes for white light (p < 0.05, Kruskal-Wallis test), but not for blue light. Subcapsular opacity did not affect the BPD or PIPR in all cataract grades for either light stimulus. The tendency of larger PIPR in the pseudophakic eyes than the cataract eyes for both lights, however significant difference was found only for white light (p < 0.05 for white light, p > 0.05 for blue light). Our study demonstrates retention of the PIPR for blue light, but not for white light in cataract eyes. We also confirmed that the pupillary response in pseudohakic eyes with a selective blue light-filtering intra ocular lens was greater than that in cataractous eyes for white light.

A Purkinje image-based system for an assessment of the density and transmittance spectra of the human crystalline lens in vivo.

A method for rapid and objective assessment of ocular lens density and transmittance is needed for research and clinical practice. The aim of this study was to determine whether the Purkinje image-based technique can be used for objective and accurate quantification of spectral density and transmittance of ocular media (the mainly crystalline lens) in visible light. Twenty-six individuals (10 young, 9 middle-aged and 7 older individuals) participated in this study. Spectral lens density was evaluated by detecting the intensity of the IVth Purkinje image for different wavelengths. Subsequently, optical density index (ODI), the area under the curve in the lens density spectrum, was calculated and ODIs were compared with clinical lens opacification scales assessed subjectively using a slit lamp. Spectral lens transmittance was estimated from the lens density spectrum. Lens densities were higher in the short wavelength region of the visible spectrum across all age groups. ODI was highly correlated with the clinical opacification scale, while lens transmittance decreased with aging. Our results showed that spectral transmittance of the human crystalline lens can be easily estimated from optical density spectra evaluated objectively and rapidly using the Purkinje image-based technique. Our results provide clinicians and scientists with an accurate, rapid and objective technique for quantification of lens transmittance.

Seasonal variation of intra-ocular pressure in glaucoma with and without dry eye.

The management of intra-ocular pressure (IOP) is important for glaucoma treatment. IOP is recognized for showing seasonal fluctuation. Glaucoma patients can be at high risk of dry eye disease (DED). We thus evaluated seasonal variation of IOP with and without DED in glaucoma patients. This study enrolled 4,708 patients, with mean age of 55.2 years, who visited our clinics in Japan from Mar 2015 to Feb 2017. We compared the seasonal variation in IOP (mean ± SD) across spring (March-May), summer (June-August), fall (September-November), and winter (December-February). IOP was highest in winter and lowest in summer, at 14.2/13.7 for non-glaucoma without DED group (n = 2,853, P = 0.001), 14.5/13.6 for non-glaucoma with DED group (n = 1,500, P = 0.000), 14.0/13.0 for glaucoma without DED group (n = 240, P = 0.051), and 15.4/12.4 for glaucoma with DED group (n = 115, P = 0.015). Seasonal variation was largest across the seasons in the glaucoma with DED group. IOP was also inversely correlated with corneal staining score (P = 0.000). In conclusion, the seasonal variation was significant in most of study groups and IOP could tend to be low in summer.

Association between Retinal Nerve Fiber Layer Thickness and Eye Fatigue.

Eye fatigue is a common health problem across all age groups. Herein, we explored the correlation between eye fatigue and thickness of the retinal nerve fiber layer (NFL). Included in the NFL are intrinsically photosensitive retinal ganglion cells (ipRGCs), which are associated with trigeminal pain. This retrospective cross-sectional study included outpatients with best-corrected visual acuity above 20/30 in both eyes and without dry eye, glaucoma, or retinal disease. A total of 1981 patients were initially enrolled and 377 patients were declared as eligible for the study analysis. We tested subjects for the presence of major ocular symptoms and measured thickness of ganglion cell complex (GCC) using optical coherence tomography. A total of 377 outpatients (46.4% men, mean age of 57.1 years) were enrolled for analysis, based on the interview-reported prevalence of six eye symptom, as follows: 31.5% for eye fatigue, 19.2% for blurring, 18.6% for dryness, 15.7% for photophobia, 13.5% for irritation, and 4.6% for pain. The macular GCC was significantly thicker in subjects with eye fatigue compared to the group not reporting eye fatigue (103.8 µm versus 100.3 µm, P = 0.014). Regression analysis identified eye fatigue (P = 0.026, ß=0.122, adjusted for age and sex) and dryness (P =0.024, ß=0.130) as significantly correlated with the macular GCC thickness, while the full macular thickness showed no significant correlation. In conclusions, eye fatigue and dryness were positively associated with thickness of the macular GCC. Nonvisual symptoms might therefore play a role in the development of eye fatigue.

Electrophysiological responses from intrinsically photosensitive retinal ganglion cells are diminished in glaucoma patients / Disminución de las respuestas electrofisiológicas de las células ganglionares de la retina intrínsecamente fotosensibles en los pacientes con glaucoma

Purpose: To record electroretinograms (ERGs) from intrinsically photosensitive retinal ganglion cells (ipRGCs) of glaucoma patients. Methods: ERGs were recorded in 10 normal subjects and 15 patients with glaucoma. The ERG illumination system was built to achieve receptor-silent substitution, and comprised an optical diffuser and four-in-one light-emitting diodes. Results: The ERG recordings of ipRGC from normal subjects showed an «on» response and an «off» response. The mean (± SD) implicit time for the on and off responses in normal subjects was 103.0 ± 24.9 and 337.9 ± 45.8ms, respectively, with corresponding amplitudes of 7.7 ± 2.8 and 7.3 ± 3.4μV, respectively. In glaucoma patients, the implicit time of the on and off responses was 135.0±28.9 and 368.2 ± 17.3ms, respectively. The corresponding amplitudes of the on and off responses in these patients were 0.47±0.18 and 0.66 ± 0.32μV, respectively. Conclusions: The results demonstrate successful ERG recording of ipRGCs from advanced glaucoma patients, with marked reductions in amplitude, although not implicit time, compared with normal subjects (AU)

Objetivo: Registrar los electrorretinogramas (ERG) de las células ganglionares de la retina, intrínsecamente fotosensibles (ipRGCs) de los pacientes con glaucoma. Métodos: Se registraron los ERG de diez sujetos normales, y de quince pacientes con glaucoma. El sistema de iluminación del ERG se preparó para lograr la sustitución de los receptores silentes, incluyendo un difusor óptico y un sistema de cuatro-en-uno diodos emisores de luz. Resultados: Los registros ERG de las ipRGC en los sujetos normales reflejaron una respuesta «on» y una respuesta «off». El tiempo implícito medio (± DE) para las respuestas «on» y «off» en los sujetos normales fue de 103,0 ± 24,9 y 337,9 ± 45,8ms, respectivamente, con amplitudes correspondientes de 7,7 ± 2,8 y 7,3 ± 3,4μV, respectivamente. En los pacientes con glaucoma, el tiempo implícito de las respuestas «on» y «off» fue de 135,0 ± 28,9 y 368,2 ± 17,3ms, respectivamente. Las amplitudes correspondientes de las respuestas «on» y «off» en dichos pacientes fueron de 0,47 ± 0,18 y 0,66 ± 0,32μV, respectivamente. Conclusiones: Los resultados demuestran unos registros exitosos de ERG de los ipRGCs en pacientes con glaucoma avanzado, con unas reducciones marcadas en cuanto a amplitud, aunque no en lo referente a tiempo implícito, en comparación a los sujetos normales (AU)

Electrophysiological responses from intrinsically photosensitive retinal ganglion cells are diminished in glaucoma patients.

PURPOSE: To record electroretinograms (ERGs) from intrinsically photosensitive retinal ganglion cells (ipRGCs) of glaucoma patients. METHODS: ERGs were recorded in 10 normal subjects and 15 patients with glaucoma. The ERG illumination system was built to achieve receptor-silent substitution, and comprised an optical diffuser and four-in-one light-emitting diodes. RESULTS: The ERG recordings of ipRGC from normal subjects showed an "on" response and an "off" response. The mean (±SD) implicit time for the on and off responses in normal subjects was 103.0±24.9 and 337.9±45.8ms, respectively, with corresponding amplitudes of 7.7±2.8 and 7.3±3.4µV, respectively. In glaucoma patients, the implicit time of the on and off responses was 135.0±28.9 and 368.2±17.3ms, respectively. The corresponding amplitudes of the on and off responses in these patients were 0.47±0.18 and 0.66±0.32µV, respectively. CONCLUSIONS: The results demonstrate successful ERG recording of ipRGCs from advanced glaucoma patients, with marked reductions in amplitude, although not implicit time, compared with normal subjects.

[Case of acute zonal occult outer retinopathy (AZOOR): a 15 years' mislabeling as retrobulbar optic neuritis].

A 30-year-old woman was admitted to Mie University Hospital for recurrence of sudden visual field defect with photopsia in the right eye. She had experienced the same episodes at the age of 15, 20, 25 and 28 years old. A diagnosis of retrobulbar optic neuritis had been made at each episode, but corticosteroid therapy failed to resolve the symptoms. Neurologic examination on admission was unremarkable except for the visual field defect of the right eye. Brain MRIs with and without gadolinium enhancement were normal. On ophthalmologic examination, visual acuity was normal, but the Mariotte blind spot of the right eye was expanded. Ophthalmoscopic examination, visual evoked potential, flicker electro-oculogram and Hess test were normal. Multifocal electroretinogram (ERG) revealed reduction in the inferior temporal response of the right eye that corresponded to the expansion of the Mariotte blind spot These findings were consistent with conditions of acute zonal occult outer retinopathy (AZOOR). The visual symptoms of AZOOR thus resemble those of retrobulbar optic neuritis and findings of multifocal ERG were useful to differentiate them. AZOOR is a newly established condition, and it is necessary to pay more attention to AZOOR on the differential diagnoses of acute-onset mono ocular visual disturbances.

Negative scotopic ERG and photopic ERG ON response impairment in a patient with normal dark adaptation.

PURPOSE: To present ocular findings in a patient who showed negative scotopic electroretinogram (ERG) and reduced ON response, but normal dark adaptation. CASE: An 18-year-old Japanese male patient who complained of severe asthenopia. His corrected visual acuities were 1.2 in both eyes. His fundi were normal. He had normal contrast sensitivity and normal dark adaptation. METHODS: The patients underwent ERG (including the standard protocol and photopic long flash recordings). RESULTS: The amplitudes of the rod ERG b-wave were reduced. The scotopic standard combined ERG response showed negative configuration. The photopic response to long flash revealed the reduced b-wave (ON response), while the amplitude of the first peak of the d-wave (OFF response) was within the normal range. CONCLUSIONS: Postsynaptic abnormalities in both the rod and cone ON-pathways, which are often found in patients with night blindness, were suggested in the ERG findings, but the dark adaptation of our patient was normal. Neuromuscular evaluation of the patient and ophthalmological evaluation, including ERG, of his parents were normal. To our knowledge, the ophthalmological and electrophysiological findings of our patient cannot be attributed to any known clinical entity.

Time-dependent course of electroretinograms in the spontaneous diabetic Goto-Kakizaki rat.

PURPOSE: This study evaluates the relevance to human retinopathy of electroretinograms (ERGs) from the spontaneously diabetic Goto-Kakizaki (GK) rat. METHODS: Starting from 4 weeks of age, we obtained ERGs every 4 weeks from six GK rats and seven Wistar (control) rats, and from two GK and two Wistar rats at 14 days of age. The a-wave, b-wave, and oscillatory potentials (OPs) were recorded after stimulation with a single bright flash. We compared the amplitudes and implicit times and measured a-wave latencies to evaluate photoreceptor function. RESULTS: The amplitudes of the a-wave, b-wave, and OPs (O1 and O2) of the GK rats were reduced between 4 and 48 weeks of age. The time-dependent courses of change in a-wave, b-wave, and O2 amplitude did not differ between the two groups. The a-wave latencies in GK rats were significantly prolonged, but not the implicit times of OPs. At 14 days of age, the a-wave amplitudes were significantly smaller in GK than in Wistar rats. CONCLUSION: Functional abnormalities of photoreceptors might be induced by inheritable degeneration at an early age in the GK rat. Although hyperglycemia would cause retinal hypoxia, it would not be severe enough to disturb the generation of OPs.

Changes in electroretinogram oscillatory potentials during dark adaptation.

PURPOSE: To investigate changes in the oscillatory potentials (OPs) of electroretinograms (ERGs) during dark adaptation (DA). METHODS: ERGs were recorded from ten normal subjects. Following 15 min of light adaptation, ERGs were recorded every 30 s for 20 min to follow the changes in the OPs during the course of DA. A 20-ms, 560-nm rectangular pulse of light was presented at 3.3 Hz to elicit the ERGs. RESULTS: The latencies of OP1 and OP2 did not change significantly, but the amplitudes decreased slightly during DA. OP3 was not observed at 30 s, but appeared after 1 min of DA between OP2 and OP4. Similar results were obtained with stimulus durations of 10 to 100 ms in 10-ms steps. The amplitude of OP3 increased to 10 min of DA and then plateaued. CONCLUSION: The characteristics of OP3, which increases during DA, indicate that it is probably related to rod activity.

Absolute sensitivity of the electroretinogram and of the optic nerve action potential in the perfused feline eye.

PURPOSE: To assess and characterize the electroretinogram (ERG) and the optic nerve response (ONR) at threshold stimulus intensity in the isolated perfused cat eye. METHODS: Eyes were enucleated from deeply anesthetized adult cats and arterially perfused with oxygenated serum-enriched tissue culture medium. Light stimuli of 20- to 400- msec duration from a xenon arc source, attenuated down to threshold intensities by neutral density filters, were delivered via a modified fundus camera in full dark adaptation. Vitreal ERGs and ONRs were amplified, digitized, averaged and analyzed using LabVIEW for Windows software. RESULTS: The threshold intensities in log scot q/deg(2) per second for the negative scotopic threshold response (STR), for the ERG b-wave, and for the ONR were at 2.87+/-0.35, 3.53+/-0.35 and 1.78+/-0.48, respectively. CONCLUSION: The in vitro perfused mammalian eye preparation exhibits remarkably low thresholds for the ERG and particularly for the ONR near the intensity required for the human psychophysical threshold.

Effects of the beta1-selective adrenergic antagonist betaxolol on electroretinography in the perfused cat eye.

The effects of the beta1-selective adrenergic antagonist betaxolol on electroretinography (ERG) were studied in the isolated and arterially perfused cat eye. Betaxolol increased the perfusion flow rate, significantly at the administrations of more than 50 microM concentrations and induced a dose-related, reversible increase in the amplitudes of both the a-wave and b-wave of ERG. These results suggest that the calcium-channel blocking mechanism of betaxolol has a beneficial influence on ocular blood flow and retinal electrical activity in response to light. As it is known that ERG is a good indicator of the functional integrity of the retina, this indicates that betaxolol could be an ideal drug for treating glaucoma in which ischemia is involved to some extent.