The intraocular pressure response to dehydration: a pilot study

This study was designed to determine the Intraocular Pressure (IOP) response to differing levels of dehydration. Seven males participated in a 90 minute treadmill walk (5 km/h and 1 % grade) in both a cool (22 °C) and hot (43 °C) climate. At Baseline and at 30 minute intervals measurements of IOP, by tonometery, and indicators of hydration status (nude weight and plasma osmolality (Posm)) were taken. Body temperature and heart rate were also measured at these time points. Statistically significant interactions (time point (4) by trial (2)) were observed for IOP (F = 10.747, p = 0.009) and body weight loss (F = 50.083, p < 0.001) to decrease, and Posm (F = 34.867, p < 0.001) to increase, by a significantly greater amount during the hot trial compared to the cool. A univariate general linear model showed a significant relationship between IOP and body weight loss (F = 37.63, p < 0.001) and Posm (F = 38.53, p < 0.001). A significant interaction was observed for body temperature (F = 20.908, p < 0.001) and heart rate (F = 25.487, p < 0.001) between the trials and time points, but there was negligible association between these variables and IOP (Pearson correlation coefficient < ±0.5). The present study provides evidence to suggest that IOP is influenced by hydration status

Melanopsin-expressing intrinsically photosensitive retinal ganglion cells in retinal disease

Melanopsin containing intrinsically photosensitive Retinal Ganglion Cells (ipRGCs) are a class of photoreceptors with established roles in non-image forming processes. Their contributions to image forming vision may include the estimation of brightness. Animal models have been central for understanding the physiological mechanisms of ipRGC function and there is evidence of conservation of function across species. ipRGCs can be divided into 5 ganglion cell subtypes that show morphological and functional diversity. Research in humans has established that ipRGCs signal environmental irradiance to entrain the central body clock to the solar day for regulating circadian processes and sleep. In addition, ipRGCs mediate the pupil light reflex (PLR), making the PLR a readily accessible behavioural marker of ipRGC activity. Less is known about ipRGC function in retinal and optic nerve disease, with emerging research providing insight into their function in diabetes, retinitis pigmentosa, glaucoma and hereditary optic neuropathy. We briefly review the anatomical distributions, projections and basic physiological mechanisms of ipRGCs, their proposed and known functions in animals and humans with and without eye disease. We introduce a paradigm for differentiating inner and outer retinal inputs to the pupillary control pathway in retinal disease and apply this paradigm to patients with age-related macular degeneration (AMD). In these cases of patients with AMD, we provide the initial evidence that ipRGC function is altered, and that the dysfunction is more pronounced in advanced disease. Our perspective is that with refined pupillometry paradigms, the pupil light reflex can be extended to AMD assessment as a tool for the measurement of inner and outer retinal dysfunction

Functional outcomes after multiple treatments with ranibizumab in neovascular age-related macular degeneration beyond visual acuity

Purpose: To evaluate neuroretinal function and anatomical outcomes in patients with neovascular age-related macular degeneration (AMD) after three treatments with ranibizumab.\ud \ud Design: Observational case reports.\ud \ud Methods: We investigated visual function in three patients, one female (80 years) and two male (77 and 74 years) with neovascular AMD. Twenty healthy participants served as control group. We measured visual acuity (Bailey-Lovie charts), contrast sensitivity (Pelli-Robson) and neuroretinal function using the multifocal electroretinogram (mfERG). Central macular thickness was evaluated using optical coherence tomography (OCT). Main outcome measures were central and peripheral mfERG peak to trough (N1P1) response density amplitudes and peak (P1) implicit times. All tests were performed before the first treatment (baseline) and after each of the three treatments with intravitreal 0.3 mg ranibizumab.\ud \ud Results: Visual acuity and contrast sensitivity remained stable or improved. Central macular thickness decreased after three treatments in all three patients. We found no significant change in central and peripheral neuroretinal function in the AMD patients between pre- and posttreatments 2 and 3. Although the mfERG amplitudes in the AMD patients were not significantly reduced compared with the age-similar group at baseline, there was a statistically significant reduction in central and peripheral mfERG amplitudes after three treatments.\ud \ud Conclusion: Anatomical outcomes and central visual function improved or remained stable in the three AMD patients in concordance with past reports. Further investigations of possible adverse effects of ranibizumab on the central and peripheral neuroretina in large prospective clinical trials are suggested

Melanopsin-Driven Pupil Response and Light Exposure in Non-seasonal Major Depressive Disorder

Background: Melanopsin-expressing intrinsically photosensitive Retinal Ganglion Cells (ipRGCs) signal non-imaging forming effects of environmental light for circadian phoentrainment, the pupil light reflex, and mood regulation. In seasonal affective disorder, ipRGC dysfunction is thought to cause abberant transmission of the external illumination for photoentrainment. It is not known if patients with non-seasonal depression have abnormal melanospin mediated signaling and/or irregular environmental light exposure.Methods: Twenty-one adults who live in a sub-tropical region, including eight patients with non-seasonal depression and thirteen age-matched healthy controls were recruited. The Mini International Neuropsychiatry Interview diagnosed the presence of a major depressive disorder. Light exposure was determined using actigraphy over a 2 week period. The melanopsin mediated post-illumination pupil response (PIPR) and outer retinal inputs to ipRGCs (transient pupil response and maximum pupil constriction amplitude) were measured in response to 1 s, short and long wavelength light with high and low melanopsin excitation.Results: The mean daylight exposure as a function of clock hours and total light exposure duration (mins) to illumination levels commonly recommended for depression therapy were not significantly different between groups. Out of 84 pupil measurements (42 each in the depression and control groups), the melanopsin-mediated PIPR amplitude, transient pupil response, and pupil constriction amplitude were not significantly different between groups.Conclusions: This report provides initial evidence of normal melanopsin function and environmental light exposures in patients with pre-dominately mid and moderate non-seasonal depression in a subtropical location in the southern hemisphere

Standards in Pupillography

The number of research groups studying the pupil is increasing, as is the number of publications. Consequently, new standards in pupillography are needed to formalize the methodology including recording conditions, stimulus characteristics, as well as suitable parameters of evaluation. Since the description of intrinsically photosensitive retinal ganglion cells (ipRGCs) there has been an increased interest and broader application of pupillography in ophthalmology as well as other fields including psychology and chronobiology. Color pupillography plays an important role not only in research but also in clinical observational and therapy studies like gene therapy of hereditary retinal degenerations and psychopathology. Stimuli can vary in size, brightness, duration, and wavelength. Stimulus paradigms determine whether rhodopsin-driven rod responses, opsin-driven cone responses, or melanopsin-driven ipRGC responses are primarily elicited. Background illumination, adaptation state, and instruction for the participants will furthermore influence the results. This standard recommends a minimum set of variables to be used for pupillography and specified in the publication methodologies. Initiated at the 32nd International Pupil Colloquium 2017 in Morges, Switzerland, the aim of this manuscript is to outline standards in pupillography based on current knowledge and experience of pupil experts in order to achieve greater comparability of pupillographic studies. Such standards will particularly facilitate the proper application of pupillography by researchers new to the field. First we describe general standards, followed by specific suggestions concerning the demands of different targets of pupil research: the afferent and efferent reflex arc, pharmacology, psychology, sleepiness-related research and animal studies

Melanopsin-Mediated Post-Illumination Pupil Response in Early Age-Related Macular Degeneration

PURPOSE. To determine whether melanopsin-expressing intrinsically photosensitive retinal ganglion cell (ipRGC) inputs to the pupil light reflex (PLR) are affected in early age-related macular degeneration (AMD). METHODS. The PLR was measured in 40 participants (20 early AMD and 20 age-matched controls) using a custom-built Maxwellian view pupillometer. Sinusoidal stimuli (0.5 Hz, 11.9 seconds duration, 35.68 diameter) were presented to the study eye and the consensual pupil response was measured to lights with high melanopsin excitation (464 nm [blue]) and with low melanopsin excitation (638 nm [red]) that biased activation to the outer retina. Two melanopsin PLR metrics were quantified: the phase amplitude percentage (PAP) during the sinusoidal stimulus presentation and the post-illumination pupil response (PIPR). The PLR during stimulus presentation was analyzed using latency to constriction, the transient pupil response and maximum pupil constriction metrics. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) curves. RESULTS. The blue PIPR was significantly less sustained in the early AMD group (P &lt; 0.001). The red PIPR was not significantly different between groups (P &gt; 0.05). The PAP and blue stimulus constriction amplitude were significantly lower in the early AMD group (P &lt; 0.05). There was no significant difference between groups in the latency or transient amplitude for both stimuli (P &gt; 0.05). ROC analysis showed excellent diagnostic accuracy for the blue PIPR metrics (area under the curve &gt; 0.9). CONCLUSIONS. This is the initial report that the melanopsin-controlled PIPR is dysfunctional in early AMD. The noninvasive, objective measurement of the ipRGC controlled PIPR has excellent diagnostic accuracy for early AMD

The Effects of Short-Term Light Adaptation on the Human Post-Illumination Pupil Response

PURPOSE. We determine the effect of short-term light adaptation on the pupil light reflex and the melanopsin mediated post-illumination pupil response (PIPR). Inner and outer retinal photoreceptor contributions to the dark-adapted pupil response were estimated. METHODS. In Experiment A, light adaptation was studied using short wavelength lights ranging from subthreshold to suprathreshold irradiances for melanopsin signaling that were presented before (5-60 seconds) and after (30 seconds) a melanopsin-exciting stimulus pulse. We quantified the pupil constriction and the poststimulus response amplitudes during dark (PIPR) and light (poststimulus pupil response, PSPR) adaptation. In Experiment B, colored prestimulus adapting lights were univariant for melanopsin or rod excitation. RESULTS. Increasing the prestimulus duration and irradiance of adapting lights increased the pupil constriction amplitude when normalized to the dark-adapted baseline but reduced its amplitude when normalized to the light-adapted baseline. Light adaptation at irradiances suprathreshold for melanopsin activation increased the PIPR amplitude, with larger changes at longer adaptation durations, whereas the PSPR amplitude became more attenuated with increasing irradiances, independent of duration. Rod versus melanospin univariant adaptation did not alter the constriction amplitude but increased the PIPR amplitude in the rod condition. Correlations between millimeter pupil constriction and PIPR amplitudes were eliminated when normalized to the baseline diameter. CONCLUSIONS. The findings have implications for standardizing light adaptation paradigms and the choice of pupil metrics in both laboratory and clinical settings. Light and dark adaptation have opposite effects on the pupil metrics, which should be normalized to baseline to minimize significant correlations between constriction and PIPR amplitudes

Intraocular pressure is a poor predictor of hydration status following intermittent exercise in the heat

Current hydration assessments involve biological fluids that are either compromised in dehydrated individuals or require laboratory equipment, making timely results unfeasible. The eye has been proposed as a potential site to provide a field-based hydration measure. The present study evaluated the efficacy and sensitivity of intraocular pressure (IOP) to assess hydration status. Twelve healthy males undertook two 150 min walking trials in 40°C 20% relative humidity. One trial matched fluid intake to body mass loss (control, CON) and the other had fluid restricted (dehydrated, DEH). IOP (rebound tonometry) and hydration status (nude body mass and serum osmolality) were determined every 30 min. Body mass and serum osmolality were significantly (p<0.05) different between trials at all-time points following baseline. Body mass losses reached 2.5±0.2% and serum osmolality 299±5 mOsmol.kg-1 in DEH. A significant trial by time interaction was observed for IOP (p = 0.042), indicating that over the duration of the trials IOP declined to a greater extent in the DEH compared with the CON trial. Compared with baseline measurements IOP was reduced during DEH (150 min: -2.7±1.9 mm Hg; p<0.05) but remained stable in CON (150 min: -0.3±2.4 mm Hg). However, using an IOP value of 13.2 mm Hg to predict a 2% body mass loss resulted in only 57% of the data being correctly classified (sensitivity 55% and specificity 57%). The use of ΔIOP (-2.4 mm Hg) marginally improved the predictive ability with 77% of the data correctly classified (sensitivity: 55%; specificity: 81%). The present study provides evidence that the large inter-individual variability in baseline IOP and in the IOP response to progressive dehydration, prevents the use of IOP as an acute single assessment marker of hydration status

Intraocular pressure is a poor predictor of hydration status following intermittent exercise in the heat

Current hydration assessments involve biological fluids that are either compromised in dehydrated individuals or require laboratory equipment, making timely results unfeasible. The eye has been proposed as a potential site to provide a field-based hydration measure. The present study evaluated the efficacy and sensitivity of intraocular pressure (IOP) to assess hydration status. Twelve healthy males undertook two 150 min walking trials in 40°C 20% relative humidity. One trial matched fluid intake to body mass loss (control, CON) and the other had fluid restricted (dehydrated, DEH). IOP (rebound tonometry) and hydration status (nude body mass and serum osmolality) were determined every 30 min. Body mass and serum osmolality were significantly (p<0.05) different between trials at all-time points following baseline. Body mass losses reached 2.5±0.2% and serum osmolality 299±5 mOsmol.kg-1 in DEH. A significant trial by time interaction was observed for IOP (p = 0.042), indicating that over the duration of the trials IOP declined to a greater extent in the DEH compared with the CON trial. Compared with baseline measurements IOP was reduced during DEH (150 min: -2.7±1.9 mm Hg; p<0.05) but remained stable in CON (150 min: -0.3±2.4 mm Hg). However, using an IOP value of 13.2 mm Hg to predict a 2% body mass loss resulted in only 57% of the data being correctly classified (sensitivity 55% and specificity 57%). The use of ΔIOP (-2.4 mm Hg) marginally improved the predictive ability with 77% of the data correctly classified (sensitivity: 55%; specificity: 81%). The present study provides evidence that the large inter-individual variability in baseline IOP and in the IOP response to progressive dehydration, prevents the use of IOP as an acute single assessment marker of hydration status

The Circadian Response of Intrinsically Photosensitive Retinal Ganglion Cells

Intrinsically photosensitive retinal ganglion cells (ipRGC) signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central) or intrinsic (retinal) network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18–30 years) with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC) and outer retina (cone photoreceptors) was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux). Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO) was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin) retinal ganglion cells mediate this circadian variation