Did Edgar Degas have Stargardt disease?

Renowned French painter Edgar Degas suffered of progressive light sensitivity and blurred central vision in both eyes, which affected his life and art in many ways. A first cousin from his mother's side, Estelle Musson of New Orleans also lost vision in a similar fashion at a comparable age. We postulated that Edgar and Estelle shared the same retinal pathology that possibly developed in a hereditary fashion, and we were interested whether any of their living family descendants might carry ABCA4 mutations to test the possibility that Edgar Degas may have had Stargardt disease.Edgar was never married and had no children, but Estelle had five children, four of whom from her marriage to Edgar's younger brother, and there are several descendants still living in New Orleans area. Genetic testing on five of Estelle's great grandchildren (Edgar's great grandnieces) were performed searching for ABCA4 mutations.We could not document any disease-causing variations in the ABCA4 gene in any of the descendants and therefore concluded that Edgar Degas most likely did not have Stargardt disease. Estelle and Edgar may have shared a different hereditary disease or have had two different retinal dystrophies or had another eye disease, including the unlikely possibility of inflammatory disease.

Membrane potential as the sum of ionic and metabolic components.

The resting potential of a molluscan neuron can be separated experimentally into two components: one which depends on ionic gradients and permeabilities in accordance with the Goldman equation, and a second which depends on the electrogenicity of active sodium transport.

ISCEV Standard for full-field clinical electroretinography (2008 update).

This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV), presents an updated and revised ISCEV Standard for clinical electroretinography (ERG). The parameters for flash stimulation and background adaptation have been tightened, and responses renamed to indicate the flash strength (in cd x s x m(-2)). The ISCEV Standard specifies five responses: (1) Dark-adapted 0.01 ERG (rod response); (2) Dark-adapted 3.0 ERG (combined rod-cone response); (3) Dark-adapted 3.0 oscillatory potentials; (4) Light-adapted 3.0 ERG (cone response); (5) Light-adapted 3.0 flicker (30 Hz flicker). An additional Dark-adapted 10.0 ERG or Dark-adapted 30.0 ERG response is recommended.

The membrane of giant molluscan neurons: electrophysiologic properties and the origin of the resting potential.

The molluscan neuron, because of its large size and accessibility, has been an important model for studying the electrophysiology of nerve cells. This review catalogs data about specific molluscan neurons, but the greater importance of this material is in the broad picture of how a neuronal membrane maintains internal potential and is responsive to changes in the environment. Electrical properties of the membrane. The mechanisms which contribute to the resting potential in molluscan neurons can be separated into ionic and metabolic components. When the electrogenic sodium pump is eliminated experimentally, the ionic component of the potential follows the constant field equation quite closely. Many of the "constants" and "parameters" which characterize the membrane of molluscan neurons are actually variables which depend upon temperature, ionic environment, and membrane potential. The evaluation of the electrical parameters is complicated by extensive infoldings of the somatic membrane, and by large axons which drain current from the soma. Most molluscan neurons have a very high specific membrane resistance and a correspondingly low potassium permeability. Membrane capacitance is close to the 1 microF/cm2 value which characterizes biological membranes. The current-voltage relation of molluscan neurons may be complicated by inward-going rectification, but if that is inhibited the I-V curve follows the prediction of either the constant field equation or a simple electrical model. Factors which modify membrane behavior. The resting potential of molluscan neurons is very sensitive to changes in temperature and Ko, through a combination of effects upon the electrogenic sodium pump, inward-going rectification, and the membrane "parameters". Inward-going rectification depends upon a rectifying K conductance, and can be eliminated by cold or the removal of Ko. Strong or prolonged currents have time-dependent effects upon the membrane, and excessive polarization leads to a "high conductance state". The underlying (non-rectifying) K permeability of the membrane is relatively insensitive to temperature and ionic changes, whereas the Na permeability increases with warming. Membrane resistance varies with both temperature and ions (because the I-V curve is sensitive to these conditions) but membrane capacitance is relatively insensitive to external factors. Electrogenic sodium transport. Sodium transport is electrogenic in molluscan neurons. It can be stimulated by warm temperatures and an excess of substrate (e.g. high Nai); it can be inhibited by cold, by an absence of substrate (e.g. low Ko), or by pharmacologic agents such as cyanide or ouabain.(ABSTRACT TRUNCATED AT 400 WORDS)

Vision, eye disease, and art: 2015 Keeler Lecture.

The purpose of this study was to examine normal vision and eye disease in relation to art. Ophthalmology cannot explain art, but vision is a tool for artists and its normal and abnormal characteristics may influence what an artist can do. The retina codes for contrast, and the impact of this is evident throughout art history from Asian brush painting, to Renaissance chiaroscuro, to Op Art. Art exists, and can portray day or night, only because of the way retina adjusts to light. Color processing is complex, but artists have exploited it to create shimmer (Seurat, Op Art), or to disconnect color from form (fauvists, expressionists, Andy Warhol). It is hazardous to diagnose eye disease from an artist's work, because artists have license to create as they wish. El Greco was not astigmatic; Monet was not myopic; Turner did not have cataracts. But when eye disease is documented, the effects can be analyzed. Color-blind artists limit their palette to ambers and blues, and avoid greens. Dense brown cataracts destroy color distinctions, and Monet's late canvases (before surgery) showed strange and intense uses of color. Degas had failing vision for 40 years, and his pastels grew coarser and coarser. He may have continued working because his blurred vision smoothed over the rough work. This paper can barely touch upon the complexity of either vision or art. However, it demonstrates some ways in which understanding vision and eye disease give insight into art, and thereby an appreciation of both art and ophthalmology.

Retinal detachment from hyperosmotic intravitreal injection.

Hyperosmotic solutions were injected into the rabbit vitreous to study their effects upon the retina. Injection of 0.05 ml of a 1000 mOsm solution caused rapid whitening of the posterior retina followed by the development of a large detachment and permanent retinal degeneration. The weakest solutions which produced ophthalmoscopically visible changes in the retina (after an injection of 0.05 ml) were near 500 mOsm. Sodium chloride, sodium aspartate, EDTA, mannitol, sucrose, and penicillin were effective at similar osmolarities. An osmotic load in the vitreous caused immediate loss of the c-wave of the electroretinogram (ERG), and a slower decline of the a- and b-waves. The reported intravitreal toxicity of some drugs may relate to osmotic rather than pharmacologic effects. Osmolarity should be accounted for in planning the amount and location of any vitreous injection.

Effects of retinal adhesion of temperature, cyclic AMP, cytochalasin, and enzymes.

We have studied factors that contribute to retinal adhesion, by measuring directly the force required to peel rabbit retina from the retinal pigment epithelium (RPE). Exposing the tissue to either testicular hyaluronidase or neuraminidase, or acidifying the medium to pH 6.0, reduced the peeling force within 2 min. Cooling the tissue to 25 degrees C or 4 degrees C increased the peeling force to such a degree that retinal separation occurred by rupture of the RPE cells rather than widening of the subretinal space. Inhibition of the cytoplasmic contractile system with cytochalasin had no significant effect on peeling force, but dibutyryl cAMP (which decreases fluid absorption by the RPE) weakened adhesion. These results suggest that retinal adhesion involves a number of interrelated physical and metabolic factors.

Metabolic influences on the absorption of serous subretinal fluid.

Experimental detachments were made in Dutch rabbit eyes by injecting autologous serum or Hanks' solution into the subretinal space through a glass micropipette. The serum was resorbed at a rate of 0.064 +/- 0.023 microliter/mm2/hr, which is approximately half as fast as Hanks' solution. Both cyclic GMP and dibutyryl cyclic GMP accelerated serum resorption by 23%, whereas cyclic AMP and dibutyryl cyclic AMP (both used with IBMX) decreased the absorption rate by 46%. The absorption rate for Hanks' solution did not differ significantly between light and dark. Intravenous administration of acetazolamide (50 mg/Kg) and mannitol (2.5 g/kg) failed to alter the serum resorption rate significantly. Thus, cyclic nucleotides (and presumably metabolic transport) are important to absorption of serous fluid, but acetazolamide and hyperosmotic agents have less effect than on nonproteinaceous subretinal fluid.

Irregular retinal and RPE damage after pressure-induced ischemia in the rabbit.

PURPOSE: Pressure-induced ocular ischemia is a frequent model for the investigation of the mechanisms and therapy of retinal ischemic damage. It is important to know whether the tissue damage in such experiments is uniform or irregular. METHODS: We reviewed histologic features of Dutch rabbit eyes after 60-80 min of pressure-induced ischemia. The eyes were enucleated 4 hr, 1 day, or 1 wk after circulation was restored, at which times the electroretinogram b-wave was moderately reduced. RESULTS: Light microscopy showed an irregular distribution of damage involving all retinal layers and retinal pigment epithelium. Some regions of damage (or preservation) were several millimeters wide; others were as small as a few cell widths. Correlation with electroretinogram reduction in individual eyes was difficult. CONCLUSIONS: These results show that pressure-induced ischemic damage in the rabbit, sufficient to reduce the electroretinogram, has a patchy and irregular effect on retina and retinal pigment epithelium. Erroneous judgments may be made about ischemic damage, or therapeutic intervention, if only small or selected regions of retina are examined histologically.

Retinal adhesive force in living rabbit, cat, and monkey eyes. Normative data and enhancement by mannitol and acetazolamide.

Small retinal detachments (blebs) were made in living eyes by injecting balanced salt solution into the subretinal space with a micropipette. A second micropipette, inserted into the same bleb, measured subretinal pressure using a resistance servonulling system. The adhesive force was calculated from the pressure difference across the retina according to Laplace's law. The retinal adhesive force in rabbit, cat, and monkey eyes averaged 1.0, 1.8, and 1.4 x 10(2) dyne/cm, respectively. In rabbit eyes, 2 hr after intravenous administration of 15 mg/kg acetazolamide, the retinal adhesive force was increased to 133%. In monkeys, this dose of acetazolamide increased retinal adhesion to 144% of control values. Mannitol (2 g/kg) increased retinal adhesion in the monkey to 153% of control values 90 min after intravenous injection (compared with an increase of 145% in previous experiments in the rabbit). Because both mannitol and acetazolamide enhance retinal adhesiveness in living primate eyes, it seems likely that they will have a similar effect in humans that they may be clinically useful.

Effects on retinal adhesive force in vivo of metabolically active agents in the subretinal space.

The in vivo effects on the retinal adhesive force of injecting metabolically active agents into the subretinal space of rabbits were studied. Small retinal detachments (blebs) were made in living Dutch rabbit eyes by injecting experimental solutions into the subretinal space with a micropipette. A second micropipette, inserted into the same bleb, measured fluid pressure using a resistance servonulling system. The adhesive force was calculated according to Laplace's law. Blebs containing dibutyryl cyclic adenosine monophosphate, furosemide, and amiloride showed retinal adhesiveness to be decreased to 69%, 86%, and 81% of control values, respectively. Dibutyryl cyclic guanosine monophosphate and acetazolamide had no significant effect. Ouabain increased retinal adhesiveness to 119% of normal. The nonspecific metabolic toxin, dinitrophenol, reduced adhesiveness to an unmeasurable level. For some agents, the rate at which subretinal fluid was absorbed also was measured. Furosemide and amiloride in the subretinal space caused slight slowing of subretinal fluid absorption; acetazolamide had no effect. These data support the concept that metabolic factors contribute to retinal adhesion in vivo.

Quantitative estimation of metabolic transport of subretinal fluid.

A new technique to measure the ongoing rate of subretinal fluid resorption inside the living eye is described. Experimental non-rhegmatogenous detachments (blebs) were made in the posterior pole of rabbit eyes by injecting fluid directly into the subretinal space, and the height of these blebs was measured with a YAG laser focusing system utilizing dual He-Ne beams. The resorption rate for Hanks' balanced salt solution was relatively constant during the initial 2.5 hr, and averaged 0.12 +/- 0.04 microliter/mm2/hr. The resorption rate for blebs made with non-ionic solution (isotonic sucrose) was only 0.03 microliter/mm2/hr. The resorption rate for blebs made with Hanks' solution plus 1 mM DNP was 0.04 microliter/mm2/hr. These data support the concept that subretinal fluid is resorbed primarily across the retinal pigment epithelium, and suggests that 70% of this absorption is dependent upon active ionic transport. The remaining 30% is probably driven by the higher oncotic pressure of the choroid.

Mechanisms of subretinal fluid resorption in the cat eye.

Small, non-rhegmatogenous retinal detachments (blebs) were made in cat eyes by injecting fluid into the subretinal space, and the time course of fluid resorption was monitored. Blebs made with Hanks' solution over the pigmented RPE resorbed 22% faster than those over the tapetum. Blebs made with a non-ionic solution (isotonic sucrose) took 43% longer to resorb than those made with Hanks' solution, and blebs containing 3 X 10(-3) M sodium cyanide took 32% longer than controls. These results suggest that active ionic transport is involved in the absorption of subretinal fluid in the cat, as it is in the rabbit. Oncotic pressure in the choroid may also contribute to resorption, because blebs made with autologous serum took roughly 3 times longer to resorb than those made with non-proteinaceous Hanks' solution. The retinal vascular system does not appear to contribute, since the resorption time was similar for Hanks' blebs made under normal retina and those made under ischemic retina (produced by occluding retinal branch arteries with argon laser photocoagulation or endodiathermy).

The enhancement of retinal adhesiveness by ouabain appears to involve cellular edema.

Our previous work showed that ouabain increases retinal adhesion to the retinal pigment epithelium, but the mechanism of this effect has been unclear. In this study, we have found that the ouabain-induced increase in retinal adhesiveness was blocked reversibly by removing sodium from the medium or by exposure to hyperosmotic solution. Hyposmotic solution slowed down the postmortem failure of adhesion. Tissue edema could not be documented histologically, but retinal tissue water content increased by 2.9% after exposure to ouabain. These data suggest that the ouabain effect involves cellular edema, which may enhance adhesion by tightening the interdigitation between photoreceptor outer segments and retinal pigment epithelial microvilli.

Recovery of retinal pigment epithelial function after ischemia in the rabbit.

Survival of the rabbit retinal pigment epithelium (RPE) after ischemia was studied. The ischemia was induced by elevating intraocular pressure; retinal and RPE function were monitored by electrophysiologic recordings. The b-wave recovered to control amplitude in 1-4 hr after 30-60 min of ischemia, but it never recovered more than about 50% amplitude after 90 min of ischemia. The c-wave recovered after 30 min of ischemia but was replaced by a negative response after 60-90 min of ischemia. The RPE hyperosmolarity response was normal after 60 min of ischemia, but it was severely depressed after 90 min of ischemia. The RPE response to acetazolamide (cornea positive in the rabbit) was lost after both 60 and 90 min of ischemia. These results suggest that different components of RPE function have different tolerances to ischemia and is consistent with evidence that the RPE electrophysiologic responses differ in mechanism and response to disease.

The rate and route of fluid resorption from the subretinal space of the rabbit.

Small nonrhegmatogenous detachments were formed in living rabbit eyes by injecting a few microliters of fluid into the subretinal space. The change in volume of these detachments was followed by sequential photogrammetric measurements. Detachments of 1 to 3 mm diameter filled with a balanced salt and glucose solution (Ames' solution) resorbed at a constant rate over approximately 80 min of observation and appeared to be totally resorbed within 2 to 6 hr. The rate at which fluid resorbed per unit area of pigment epithelium was consistent with the rate of resorption in other transporting epithelia as well as with clinical observations in humans. Detachments filled with isotonic sucrose resorbed much more slowly than those filled with saline solutions, suggesting that fluid resorption requires the passage of ions through cell membranes. Hypoxia markedly and reversibly reduced the rate of resorption, suggesting that active transport is involved in the removal of the saline solutions from the subretinal space Anatomical and physiological evidence indicate that the site of active transport is the pigment epithelium. Active resorption of subretinal fluid is probably a factor in the maintenance of normal retinal adhesion.

Similarities between the c-wave and slow PIII in the rabbit eye.

The c-wave of the electroretinogram was recorded from the eyes of Dutch rabbits and compared with the slow PIII response isolated by intravenous infection of sodium iodate and intravitreal injection of sodium aspartate. Although opposite in polarity, the waveforms of the two responses were remarkably similar over a wide range of stimulus intensities and durations. Plots of time-to-peak vs. log stimulus energy show that both responses follow the Bunsen-Roscoe law. Curves plotting the locus of all points for which the Bunsen-Roscoe law held were approximately parallel for the two responses, and the critical durations for each stimulus intensity were equivalent. The slow PIII peaked earlier than the c-wave, consistent with published observations that the time-to-peak of light-induced K+ changes is shorter near the photoreceptor inner segments than near the pigment epithelium. These data support the hypothesis that there is a common generator for the c-wave and slow PIII.

The resorption of subretinal fluid after diffuse damage to the retinal pigment epithelium.

We studied the role of the retinal pigment epithelium (RPE) in the resorption of different subretinal fluids from under small experimental retinal detachments (blebs) in the rabbit. Damaging the RPE with sodium iodate caused the resorption time, for blebs made with an ionic solution (Hanks'), to decrease from 2-6 hours to only about 30 minutes. Blebs made with sucrose also absorbed much more quickly after iodate. However, blebs made with autologous serum resorbed no faster after iodate. We conclude that iodate destroys the membrane barrier properties of the RPE, allowing subretinal fluid to cross freely according to oncotic pressure. We postulate that in the normal eye, where osmotic fluid movement is low because of the high resistance barrier, the RPE must transport fluid actively to keep the subretinal space dehydrated.

Effects of subretinal and systemic osmolality on the rate of subretinal fluid resorption.

Small norhegmatogenous retinal detachments (blebs) were made in Dutch rabbit eyes by injecting solution into the subretinal space. There was no difference in resorption time between blebs made with isotonic, hypertonic or hypotonic sodium chloride. However, blebs made with sucrose solution took longer to resorb than those made with Hanks' solution, regardless of whether the sucrose was hypotonic or hypertonic. Intravenous injection of hyperosmotic solution (mannitol) accelerated the resorption of Hanks'-filled blebs but the injection of hypoosmotic solution (water) had no clear effect. The authors conclude that osmotic differences between the subretinal space, and the vitreous and/or choroid, are rapidly equilibrated by the surrounding tissues; but the rate of bleb resorption will be affected by the size and membrane permeability of the molecules within the subretinal space. The effects of increased serum osmolality may involve not only osmotic pressure but an opening of the tight junctions of the RPE.

Effects of intraocular pressure and other factors on subretinal fluid resorption.

We observed the effects of intraocular pressure (IOP), vitreous pressure and gravity on the resorption of small retinal detachments (blebs) made with Hanks' solution or autologous serum. Raising the IOP decreased the absorption time moderately and lowering the IOP increased it. These effects were greater when the RPE had been damaged by sodium iodate or laser burns, but we conclude that IOP makes only a small, limited contribution to normal subretinal fluid absorption. Neither liquefaction of the vitreous nor retinal weight had a significant influence on fluid absorption.