Beatrix Feigl

Age-related maculopathy : Linking aetiology and pathophysiological changes to the ischaemia hypothesis

Age-related maculopathy (ARM) has remained a challenging topic with respect to its aetiology, pathomechanisms, early detection and treatment since the late 19th century when it was first described as its own entity. ARM was previously considered an inflammatory disease, a degenerative disease, a tumor and as the result of choroidal hemodynamic disturbances and ischaemia. The latter processes have been repeatedly suggested to have a key role in its development and progression. In vivo experiments under hypoxic conditions could be models for the ischaemic deficits in ARM. Recent research has also linked ARM with gene polymorphisms. It is however unclear what triggers a persons gene susceptibility. In this manuscript, a linking hypothesis between aetiological factors including ischaemia and genetics and the development of early clinicopathological changes in ARM is proposed. New clinical psychophysical and electrophysiological tests are introduced that can detect ARM at an early stage. Models of early ARM based upon hemodynamic, photoreceptor and post-receptoral deficits are described and the mechanisms by which ischaemia may be involved as a final common pathway are considered. In neovascular age-related macular degeneration (neovascular AMD), ischaemia is thought to promote release of vascular endothelial growth factor (VEGF) which induces chorioretinal neovascularisation. VEGF is critical in the maintenance of the healthy choriocapillaris. In the final section of the manuscript the documentation of the effect of new anti-VEGF treatments on retinal function in neovascular AMD is critically viewed.

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.

Intrinsically Photosensitive (Melanopsin) Retinal Ganglion Cell Function in Glaucoma

PURPOSE To determine whether glaucoma alters intrinsically photosensitive retinal ganglion cell (ipRGC) function. METHODS Forty-one patients (25 with glaucoma and 16 healthy age-matched control participants) were tested. Intrinsically photosensitive retinal ganglion cell function was directly measured by the sustained, postillumination pupil response (PIPR). Forty-one eyes of 41 participants were tested with 7°, 10-second, short-wavelength (488 nm; bluish) and long-wavelength (610 nm; reddish) stimuli (14.2 log photons · cm(-2) · s(-1)) presented to the right eye in Maxwellian view, and the consensual pupil response of the left eye was measured by infrared pupillometry. The difference between PIPR amplitude (percentage baseline pupil diameter), net PIPR (percentage change) and kinetics (time in mm · s(-1) to the PIPR plateau) for the blue and red stimuli in patients with early and advanced (moderate/severe) glaucoma was compared to that in age-matched control participants. RESULTS The blue PIPR was significantly smaller between normal participants and patients with advanced glaucoma, as well as between those with early and those with advanced glaucoma (P < 0.05). The kinetics of the red and blue PIPRs were not significantly different between any groups. Normal age-matched participants and patients with early-stage glaucoma were not significantly different on any parameter, and neither was the normal and glaucoma group (advanced and early combined). CONCLUSIONS Persons with moderate and severe glaucoma have a dysfunctional ipRGC-mediated PIPR. Intrinsically photosensitive retinal ganglion cell function measured directly with the PIPR may become a clinical indicator of progressive changes in glaucoma.

Intrinsically photosensitive melanopsin retinal ganglion cell contributions to the pupillary light reflex and circadian rhythm

Recently discovered intrinsically photosensitive melanopsin retinal ganglion cells contribute to the maintenance of pupil diameter, recovery and post‐illumination components of the pupillary light reflex and provide the primary environmental light input to the suprachiasmatic nucleus for photoentrainment of the circadian rhythm. This review summarises recent progress in understanding intrinsically photosensitive ganglion cell histology and physiological properties in the context of their contribution to the pupillary and circadian functions and introduces a clinical framework for using the pupillary light reflex to evaluate inner retinal (intrinsically photosensitive melanopsin ganglion cell) and outer retinal (rod and cone photoreceptor) function in the detection of retinal eye disease.

The post‐illumination pupil response of melanopsin‐expressing intrinsically photosensitive retinal ganglion cells in diabetes

Purpose:  This study investigates the clinical utility of the melanopsin‐expressing intrinsically photosensitive retinal ganglion cell (ipRGC) controlled post‐illumination pupil response (PIPR) as a novel technique for documenting inner retinal function in patients with Type II diabetes without diabetic retinopathy.

Melanopsin-expressing intrinsically photosensitive retinal ganglion cells in retinal disease.

&NA; 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. Intrinsically photosensitive retinal ganglion cells can be divided into five 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 behavioral 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 and 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 PLR can be extended to AMD assessment as a tool for the measurement of inner and outer retinal dysfunction.

Cone-mediated multifocal electroretinogram in early age-related maculopathy and its relationships with subjective macular function tests

Purpose. To investigate the multifocal electroretinogram (mfERG) and subjective function in early age-related maculopathy (ARM). Methods. Seventeen subjects with early ARM with visual acuity (VA) of 6/12 or better and 20 age-matched control subjects were examined. We assessed mfERGs, high and low contrast distance VA, near VA, low luminance VA, contrast sensitivity, saturated and desaturated Panel D-15 and visual fields (mean sensitivity). The mfERG responses were analysed by comparing central-overall (method 1) and superior-inferior (method 2) ratios. Results. The mfERG did not discriminate between the groups whereas colour vision (tritan deficiency), contrast sensitivity, and high contrast and low contrast VA showed significantly reduced responses for the early ARM group compared with the control group (p ≤⃒ 0.01). The mfERG first-order kernel responses correlated significantly with the desaturated D-15 in both methods (r = −0.5, p ≤⃒ 0.05). Fundus grading was not correlated with the mfERG measures. Conclusions. Although the mfERG correlated significantly with the desaturated D-15 in early ARM, suggesting it operates at a sensitive level, it failed to discriminate between the control and ARM groups. In our sample, the subjective function measures were more sensitive than the mfERG measures.

Cone- and rod-mediated multifocal electroretinogram in early age-related maculopathy

PurposeTo investigate the cone- and rod-mediated multifocal electroretinograms (mfERG) in early age-related maculopathy (early ARM).Methods and subjectsWe investigated the cone- and rod-mediated mfERG in 17 eyes of 17 subjects with early ARM and 16 eyes of 16 age-matched control subjects with normal fundi. All subjects had a visual acuity of 6/12 or better. We divided the ARM subjects into two groups based on drusen size and retinal pigment epithelium abnormalities—a less advanced (ARM1) and a more advanced (ARM2) group. The mfERG data were compared to templates derived from the control group. We analysed the mfERG results for the central and peripheral fields (CP method) and the superior and inferior fields (SI method).ResultsWhile the mean cone results showed no statistically significant difference between the groups, the rods showed significantly delayed responses in the ARM1 group for the CP and the SI methods, but not in the ARM2 group, although there was a trend of longer latencies compared to the control group.ConclusionOur results show a functional impairment of the rods in early ARM subjects. As there is histopathological evidence showing earlier rod than cone impairment in early ARM, following the rod function with the mfERG might be helpful in diagnosis or for monitoring the progression of early ARM.

Persons with Age-Related Maculopathy Risk Genotypes and Clinically Normal Eyes Have Reduced Mesopic Vision

PURPOSE To determine whether participants with normal visual acuity, no ophthalmoscopically signs of age-related maculopathy (ARM) in both eyes, and who are carriers of the CFH, LOC387715, and HRTA1 high-risk genotypes (gene-positive) have impaired rod- and cone-mediated mesopic visual function compared with persons who do not carry the risk genotypes (gene-negative). METHODS Fifty-three Caucasian study participants (mean 55.8 ± 6.1) were genotyped for CFH, LOC387715/ARMS2, and HRTA1 polymorphisms. Single-nucleotide polymorphisms were genotyped in the CFH (rs380390), LOC387715/ARMS2 (rs10490924), and HTRA1 (rs11200638) genes using optimized gene-expression assays. The critical fusion frequency (CFF) mediated by cones alone (long-, middle-, and short-wavelength sensitive cones, LMS) and by the combined activities of cones and rods (LMSR) were determined. The stimuli were generated using a four-primary photostimulator that provides independent control of the photoreceptor excitation under mesopic light levels. Visual function was further assessed using standard clinical tests, flicker perimetry, and microperimetry. RESULTS The mesopic CFF mediated by rods and cones (LMSR) was significantly reduced in gene-positive compared to gene-negative participants after correction for age (P = 0.03). Cone-mediated CFF (LMS) was not significantly different between gene-positive and -negative participants. There were no significant associations between flicker perimetry and microperimetry and genotype. CONCLUSIONS This is the first study to relate ARM risk genotypes with mesopic visual function in clinically normal persons. These preliminary results could become of clinical importance because mesopic vision may be used as a biomarker to document subclinical retinal changes in persons with risk genotypes and to determine whether those persons progress into manifest disease.

Monitoring retinal function in early age-related maculopathy: visual performance after 1 year

PurposeTo monitor visual performance in early age-related maculopathy (ARM).MethodsWe measured monocular visual function—high-contrast visual acuity (HC-VA), central visual fields (mean sensitivity, MS), colour vision (desaturated Panel D-15), Pelli–Robson (P–R), and cone- and rod-mediated multifocal electroretinograms (mfERG) in 13 ARM subjects and 13 age-matched control subjects with normal fundi at baseline and after 1 year. All had visual acuity of 6/12 or better. The mfERG data were compared to templates derived from the control group at baseline. We analysed the mfERG results by averaging the central and peripheral fields and the superior and inferior fields (CP and SI methods) and by calculating the local responses.ResultsThe mean rod-mediated responses were significantly delayed in the ARM group for the CP (P=0.04) and the SI methods (P=0.03) at baseline compared to the control group. This did not change significantly after 1 year, whereas the mean cone-mediated responses were within the normal range at both times. Although the local analysis revealed lower amplitudes for the cone- and rod-mediated responses at baseline this was not found after 1 year and only the local rod-mediated latencies were delayed at both times (P<0.01). HC-VA, desaturated Panel D-15 and P–R were significantly worse in the ARM group (P⩽0.01) at baseline but did not show further significant deterioration. Progressive fundus changes were found in only two subjects (18%).ConclusionAlthough there was significant impairment of retinal function in early ARM at baseline no further deterioration was evident after 1 year.