National Academies Press: OpenBook
« Previous: Introduction
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 23
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 24
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 25
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 26
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 27
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 28
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 29
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 30
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 31
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 32
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 33
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 34
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 35
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 36
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 37
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 38
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 39
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 40
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 41
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 42
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 43
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 44
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 45
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 46
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 47
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 48
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 49
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 50
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 51
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 52
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 53
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 54
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 55
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 56
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 57
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 58
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 59
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 60
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 61
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 62
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 63
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 64
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 65
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 66
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 67
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 68
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 69
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 70
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 71
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 72
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 73
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 74
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 75
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 76
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 77
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 78
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 79
Suggested Citation:"Photoreceptor Properties." National Research Council. 1987. Night Vision: Current Research and Future Directions, Symposium Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/1037.
×
Page 80

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

PHOTORECEPTOR PROPERTIES

INTRODUCTION Eliot L. Berson Night blindness disorders represent a significant cause of visual loss to people all over the world. The incidence of these conditions, sometimes grouped under the heading of retinitis pigmentosa, has been estimated to be 1 in 3,500 births in the United States. Affected pa- tients can be asymptomatic and have normal visual acuity and yet have considerable compromise in visual function due to abnormalities in dark adaptation and loss of midperipheral visual field. These patients can perform visual tasks under bright daylight conditions but fall to per- form the same task under starlight or moonlight conditions and, in some cases, under dim daylight conditions as well. This variability in per- formance, depending on the conditions of illumination, poses hazards to those affected as well as to those with whom they work. Some can have 20/20 vision but are legally blind due to the profound loss of their peripheral visual field with consequent "tunnel vision." Most of these disorders occur as a consequence of malfunction and loss of rod and cone photoreceptors. Considerable progress has been made in our understanding of normal photoreceptor function, and this has provided us with a framework for understanding the pathophysiology of different types of retinal dis- eases associated with night blindness. Sensitive tests of retinal function have made it possible to diagnose these conditions in their earliest stages, sometimes many years before the patient is symptomatic or changes can be seen on routine ocular examination. Two rare heredi- tary diseases associated with night blindness and retinitis pigmentosa are treatable if detected in the early stages. Electrooptical techno1- ogy has resulted in development of the night vision pocketscope that can be used to alleviate the symptom of night blindness. The papers in this section provide examples of the wide range of approaches that are being used to understand normal and abnormal pho- -toreceptor function. These include psychophysics, electrophysiology, biochemistry, electron microscopy, and molecular genetics. Current knowledge of the mechanism of visual excitation is reviewed, as is our understanding of how conditions of illumination affect visual function. The disorders themselves are considered in the context of early diagno- sis and some aspects of pathogenesis and management. It is hoped that these papers will encourage the continued examination of methods for assessing these patients and further research on causes and possible treatments. 25

PHOTOTRANSDUCTION AND DARE NOT SE IN l ROD PHOTORECEPTORS David R. Copenhagen and Tom Reuter A study of night vision necessarily confines itself to an examina- tion of seeing mediated by rods and the rod visual pathways. In the rod system, high spatial and temporal resolution and color vision are sacrificed for an extremely high sensitivity to very dim lights. Under optimal conditions, fewer than 100 photons striking the eye are suffi- cient for rod-mediated vision. In equivalent terms, the dimmest detec- table visual stimulus corresponds to the light from a candle placed some 17 miles away. Certainly, there are mechanisms to enhance visual sensitivity as the signals travel along the rod pathways to cortical centers in the brain. However, the rod photoreceptors themselves are responsible for much of the high sensitivity of rod-mediated vision. The conversion of each photon absorption by a rod into an electrical signal is a high-gain biochemical process. This paper discusses cur- rent hypotheses related to how the rod photoreceptors transduce light into electrical energy and how they achieve their high sensitivity. One must keep in mind, however, that high gain alone does not guarantee optimum detection of a dim light. Seeing dim objects also involves an optimization of the signals with respect to the noise. This paper also addresses the origin of biological noise sources in the retina that limit night vision. TRANSDUCTION OF LIGHT IN THE RODS Structure of a Typical Rod The rods of vertebrates are cylindrical in shape and are perhaps the most structurally specialized class of neurons in the nervous system. See Figure 1 for a schematic drawing of a typical rod photo- receptor. In-depth reviews of rod transduction have recently been published (Korenbrot, 1985; Schwartz, 1985; Stryer, 1986~. The outer segments of the rods are embedded in the retinal pigment epithelium at the most distal margin of the retina. These outer segments function as the sole lock s for transduction. The inner segments of the rods are connected via a ciliary bridge to the outer segments. The inner segment of the rod contains m itochondr ia, Golgi apparatus, rough endoplasmic reticulum and, in many poikilotherms including reptiles and amphibians, 26

27 Retinal Pigment Epithelium - Outer Segment Inner Segment Rh G . PDE t~ ~ . - Light ~ ~ GMP chat / \ . ,. . ) cGMP ~ ~ I 4 Dark Current NatI,/ ¢~ C>,/ Synaptic / O 1° Tern~inal ~ Oo fig _ Horizontal Cells K+ Bipolar Cells FIGURE 1 Schematic diagram of rod and mechanisms under ying the light responses. Abbreviations: Rh, rhodopsin; PLE, phosphodiesterase; GAP, guanosine monophosphate; cGhiP, cycl ic GAP .

28 a store of glycogen. The inner segment is the site of cellular metabo- lism and protein synthesis. The synaptic terminal, at the proximal end of the inner segment, is the site specialized for communication with the second-order cells. Here, synaptic transmitter molecules are pack- aged within vesicles and secreted into the thin cleft separating the rods from the horizontal and bipolar cells, the neurons immediately postsynaptic to the rods. The outer segment consists of a plasma membrane which forms an envelope around a stack of pancake-like disks. These disks float inside the outer segment and are structurally and electrically iso- lated from the plasma membrane. They do appear to be tethered by slender strands that reach from the edges of the disks to the inside wall of the plasma membrane (Roof et al., 19821. The membrane of each disk, which is probably more correctly visualized as a flattened bal- loon, contains the photopigment rhodopsin. The absorption of incident photons by rhodopsin is the initial step in transduction. A total of 10 -10 of these protein molecules (240,000 molecular weight) are em- bedded in the membranes of the ~103 stacked disks. The wavelength at which rhodopsin exhibits its peak absorption ranges from 500 to 525 nm, depending on the species--this peak wavelength confers on the rod system an optimal sensitivity to lights in the green section of the visible spectrum. New disks are generated continuously at the base of the outer seg- ment, while the older disks are shed continuously from the tip of the outer segment where they are broken down by macrophagic and lysosomal degradation In the pigmented epithelium. Disk shedding f rom rods ap- pears to be circadian, with a peak of activity at the onset of morning light. A typical disk has a lifetime of about 10 days. Electron microscopic studies of disk membranes reveal 60-~-diameter bumps on the intradisk surface at densities of 30,000/pm2. These bumps correspond to the rhodopsin molecules. Examination of the extradisk side of the disk membrane shows large particles projecting above the surface and randomly distributed with a density of 2,000/m. These particles are believed to be the G protein, which is activated by bleached rhodopsin and is involved in the regulation of phosphocies- terase (PDE) (see below). Electrical Properties of the Rod in Darkness and in Light The generation of the electrical signal in the rods results from closure of specific ion channels located within the plasma membrane envelope of the rod's outer segment. Before covering the specific hypothesis linking the absorption of rhodopsin to the closure of these channels, it would be good to review the quiescent properties of the dark-adapted rod. In darkness, the rod is principally permeable to Na+ and K+ ions and moderately permeable to C1 and Cam. The trans- membrane potential in the dark is typically about -40 mV. The K and C1- permeability is conf ined primarily to the inner segment, while the flat permeabili ty is loca ~ ized to channels in the plasma membrane of the outer segment. Calcium ions can flow through channels in the inner and

29 outer segments. Due to the spatial separation of these selectively permeable ionic channels, a net positive current flows extracellularly along the outside of the rod from the inner segment to the outer seg- ment, enters the rod through the Na+-selective (and probably C1 - and Ca+~-selective) channels of the outer segment, and returns to the inner segment through the ciliary bridge. This ionic current is termed the dark current. The ionic gradients across the rod membrane that serve as batteries for the ion flow are maintained by an ouabain-sensitive, ATP-dependent Na+/K+ exchange pump in the inner segment membrane. This pump clears Na+ from the intracellular cytosol and pumps Kay into the interior of the rod from the extracellular space. The magnitude of the dark current is species dependent and ranges between 10 x ~o~12 and 70 x 10 12 A. Monkey rods have dark currents of 12 pA (Baylor et al., 1984), while tiger salamander rods exhibit dark currents of 55 pA; The Na+ influx into the outer segment during darkness is about 10 Na ions/rod/s in toad and frog rods. On the assumption that each of these Na+ channels has a conductance of about 60 x 10-15 Q. that the membrane potential is -40 mV, and that the reversal potential for Nat ions is 0 my, this would indicate that the 20-pA dark current is conducted through about 5 x 103 open ionic channels in the plasma membrane of the outer segment. The absorption of an individual photon by a single rhocopsin mole- cule causes an isomerization of the rhodopsin molecule from a cis to a bans configuration. This single isomerization in a rod's outer seg- ment initiates ~ cascade of events that results in the closure of 2-4 percent of the channels conducting the dark current (Baylor et al., 1979b). In toad rods, the single photon signal represents the cessa- tion of 1 pA of the dark current or about 4 percent of the total. This single-photon response corresponds to the cessation of 106 to 107 Na+ ions/e resulting from the simultaneous closing of about 200 ionic c hannel s . B iochemical L ink between Photon Absorption and Channel Closings Given the ultrastructural picture of the rod and the need to explain the amplif ication f rom the single-photon absorption to the closure of 200 channels, two requirements for transduction are evident: ( 1) there must be one or more processes which amplify the effects of a single pho- toninitiated rhodopsin isomerization. The transformation of a single molecule cannot easily explain how 200 spatially separate channels can be modulated; and (2) there must be an internal, diffusible transmitter linking the photon absorption by rhodopsin on the disk membrane with the closing of channels in the electrically isolated plasma membrane. Intense research into the mechanisms mediating the generation of the electrical signal has been going on for the last 20 or more years. Originally, Ca++ was hypothesized as the internal transmitter (Yoshikami and Hagins, 1973~. Stores of Ca++ believed to be seques- tered within disks, were thought to be released on ~somerization of the rhodopsin. Many hundreds or thousands of Ca++ ions were thought to diffuse into the plasma membrane and subsequently block the ionic

30 channels carrying the dark current. Recent experiments with C a++ buf- fers injected into outer segments (Matthews et al., 1985) and a lack of correspondence between Ca++ fluxes and the time course of the electri- cal response seriously undermine the validity of the Ca++ hypothesis (Gold, 1985~. Recent evidence indicates that the monophosphonucleotide cyclic guanosine monophosphate (cGMP) may be the internal transmitter. On this idea, cGMP levels are believed to be relatively high inside the outer segment in the dark. The presence or binding of cGMP to the cytosolic surface of the ionic channels of the plasma membrane is believed to hold these channels open to current flow. On photoiso- merization, the bleached rhodopsin is thought to activate a G protein Lasso called transducing, which in turn activates PDE molecules. The activation of PDE hydrolyzes cGMP to GMP, thereby reducing the intra- cellular concentrations of cGMP. This decrease causes the ionic chan- nels to close and thus suppress some of the dark current. Several recent results support this hypothesis. These include the demonstra- tion that cGMP can act on conductances in the plasma membrane (Fesenko, 1985; Nakatani and Yau, 1985), that cam injected into the outer seg- ment increases the dark current, and that the injection of PDE evokes a change in the rod's dark current (and membrane potential) which mimics light. Thus, cGMP is a satisfactory candidate for an internal trans- mitter. The amplification afforded by this process can be seen in an exam- ination of the number of intermediate molecules activated by each step. Under optimum conditions rhodopsin can activate 104 G prote~ns/s. One G protein can, in turn, under optimum conditions, activate 500 PDE mole- cules/s. The details of the reactions w' thin the cells themselves are still unclear, but it is known that in rods, one photoactivated rhodop- sin molecule can destroy 105 cGM~ molecules/s. Once the channels are closed by the reduction of cGMP, the cessa- tion of dark current causes the transmembrane potential to become more negative thyperpolarize). This hyperpolarization modulates the release of synaptic transmitter molecules from the synaptic terminal. This change in transmitter release signals the photon absorption to the second-order neurons in the rod pathways. These changes are relayed by similar modulatory schemes from neuron to neuron up to the higher vis- ual centers. SIGNAL DETECTION AND DARK NOISE IN THE UTICA As discussed above, a reasonable hypothesis exists for the trans- duction mechanism. Further studies are required for validation. Ir- respective of which mechanisms may be proven to underlie transduction, however, there are many additional aspects of visual processing that one must consider to understand the limits of night vision. The high- gain mechanisms of the rod are not sufficient by themselves to ensure that a photon or a group of photons get "seen." To illustrate this point, one car, visualize the problem of trying to listen to one con- ~-ersation across a crowded rood f illed with many other conversations.

31 Being able to increase the gain on a microphone (unless it is a airec- tional one) will amplify the conversation of interest and all the other conversations which for these purposes could be considered noise. So detection of a selected conversation or a dim light is a signal-to-noise task, whereby a signal of potential interest must be extracted from on- going noise. In the following sections, noise sources that limit detec- tion of dim lights by the retina are discussed. At the levels of light used for night vision, there appear to be two main noise sources that limit detection: (1) random fluctuations in the stimulus itself, and (2) biological noise in the retina. Photon Noise Light, being composed of independent photons, is random in nature and therefore inherently noisy. If one considers a brief flash of light, the randomness of the photon fluxes is evident. For a series of identical flashes, there will be a mean number of photons per flash (m). In any one flash there may be fewer or more photons than the mean. The statistical variation of the photon actually delivered per flash follows a Poisson distribution in which the probability of obtaining photons is related to the mean by: P(x = n, = beam mn'/n, Where P (x = n) is the probability that each flash will contain exactl y n photons, g iven that the mean number is m. I t can be shown that the variance of the number of flashes is equal to the mean for such a dis- tribution and the standard deviation (~) is equal to the square root of the mean. For dim lights delivering an average of 1,000 photons per flash to the rods of the eye, the standard deviation of the photon count is 31. 6. For a much dimmer light delivering 10 photons, the standard deviation is 3.16 photons. This points out an important limitation in vision. Namely, the variance/mean ratio increases for dimmer lights. For very dim lights there is a large percentage of uncertainty as to how many photons are delivered per flash. For brighter lights, e.s., where 104 photons are incident on the cornea, the ratio of the standard deviation or variance to the mean is much less. Hence, the photon noise is less prevalent. Hecht et al. (1942), in their classical experiments measuring the absolute dark-adapted sensitivity of human vision, found close agreement between the randomness of seeing, as would be predicted by photon noise, and the estimated number of photons reaching the roast Their results implicitly assumed that vision at absolute threshold was limited strict- ly by photon noise. Barlow ( 1956) disputed the photon noise assumption and postulated that a second sou rce of noise imposed severe limitations on the relia- bility with which very dim 'ights could be detected. Barlow's (1956) assertion rested on results of some of his own experiments and a recal- culation of the number of photons that actually struck the retina in

32 experiments similar to those of Hecht et al. (1942~. Barlow called this second noise source dark light and likened it to spontaneous photon-like events in the dark. That is, on a random basis the retina would wrongly register the arrival of a photon. The task of detecting an actual dim light was complicated by these spontaneous dark events. In an attempt to substantiate or rule out the Barlow (1956) hypothe- sis that these dark events limited detection in the retina, an endeavor was made to record threshold responses from ganglion cells in the retina of a rod-dominated animal and test whether the detection of dim lights was indeed influenced or limited by dark events. Recording was done extracellularly from ganglion cells in the retina of Bufo marines. The retinas of these animals can be maintained for several hours in an open eyecup preparation under an atmosphere of pure, moistened O2. This pre- paration offers several advantages. Since the anterior portion of the eye can be dissected away, light calibration is made easier. Further- more, intracellular recordings can be made of the light responses in the rods and other cells distal to the ganglion cells. Figure 2 shows typical data from ~ ganglion cell in Bufo marinus retina. Very dim flashes were presented multiple times at intensities below, at, or above those which elicited an action potential, the a) c o Q ~ 0.8 c: = o ._ ct - - ._ ce Q 1 .0 0.6- 0.4- 0.2 __-~' ~ .... X_ · / . /X . f.' :~. X - ~I I ~ -oo 0.5 1.0 1.5 Log Intensity FIGURE 2 Frequency of response functions for a ganglion cell. Abscissa plots the log (mean) flash intensity where 1. a = lo flash-indu~ed ~so- merizations within the recpetive field. The ordinate shows the fraction of flashes elicting an action potential in the ganglion cell with 2 s following the flash. Ten flashes (at interstimulus intervals of 30 s) were resented at each intensity. The dotted and solid continuous curves plot, as a function of mean intensity, the probability that the number of events, X, exceed a criterion value, c. The steeper dotted curve, the abscissa values denote flash-induced isomerizations. The flatter curves assume that the number of events is comprised of photon-elicited events plus dark events. The solid curve is plotted assuming that the rate of dark events was 0.06/rod and s. The shallowest dotted curve shows the curve assuming there were 0.24 dark events/rod and s.

33 threshold response, in the ganglion cell. The ordinate plots the per- centage of flashes causing a response at each respective intensity. The steeper dotted line plots the predicted frequency of response func- tion on the assumption that the threshold responses were responding only to the photons in the light stimulus. This curve is a cumulative Poisson distribution (Barlow, 1964~. The actual data points fell along a shallower curve. Following the example of Barlow (1964), it was assumed that there is a continuous rate of ongoing photon-like events indistinguishable from the photon events. By altering the presumed rate of these events, the best curve was fitted to the data. For Figure 2, the best fit was obtained for a dark rate equivalent to 0.05 dark events/rod and s. These data and the results from other cells indicate that threshold detection is not limited strictly by photon noise and that a second source of noise exists which can be attributed to spontaneous dark events in the rods. If there were dark events in the rods, one might expect to find evidence in horizontal cells for fluctuations caused by these dark events. Figure 3 shows intracellular recordings from a horizontal cell in Bufo marines retina. The membrane potential is seen to fluctuate in darkness, and the magnitude of the fluctuations is increased by the background light which produces 0.58 photoisomerizations/rod and s. Figure 3B is a power spectral density curve calculated by a fast Fourier transform (FFT) method. This shows the power inherent in the fluctuations as a function of frequency. Both the background and dark curves display a prominent low-frequency component (<1 Hz). A differ- ence spectrum (background-dark) is shown in Figure 3C. This difference spectrum shows the power added by the background light. Also shown ~ pluses) is the power spectral density of very dim flash responses in the same celle The overlap of the difference spectrum and the flash spectrum strongly suggest that the background fluctuations are com- prised of many single-photon events which sum linearly together. Having established the likelihood that the background fluctuations originated with photon events, the key question then becomes whether the fluctuations in the dark originate with the photon-like dark events. Since the low-frequency components of both power spectral density curves overlap with a vertical scaling (Figure 3B), it is reasonable to assume that the dark fluctuations are caused by photon-like events occurring at a frequency substantially less than the 0.58 photoisomerizations/rod and s evoked by the background light. A comparison of the total vari- ance (area under the curve) of the low-f requency components indicates that the dark fluctuations would result from a spontaneous dark rate of 0.02 photoisomerization-like events rod and s. This rate of dark events compares favorably with the rate deduced from the frequency of response curves obtained from the ganglion cells. Within the last several years, the technology of recording currents flowing into and out of individual neurons has evolved. Baylor and colleagues, by using suction-type microelectrodes, recorded the dark currents of individual rods (Baylor et al., 1979a, 1979b, 1984~. They found a stereotyped response to light flashes that elicited single pho- toisomerizations. When the rods were kept in absolute darkness for per- iods of several minutes, spontaneous photon-like responses were observed

1.or 0.5 Ok' mV 101 10-2 - I >A 3 cr: LL o 10-4 10-5 A DARKN ESS 0.5 OL 1 1 1 1 2 3 B. SECONDS _ ~ _ BACKGROUND 10 clc AIL ~ ~`> 103 DARK + ~ ~0 ~0 10-4 10-5 FREQUENCY ( Hz) BACKGROUN D 0.58 Rh. sec., I tar , ~, 4 5 6 7 8 9 10 C. Dow - +D: - + - + _ ~ _ ~ 'it Il11111117111111il~ 0.1 1 10 FREQUENCY (Hz) FIGURE 3 Horizontal cell membrane fluctuations during darkness and under backg round illumination. (A) Ten-second segments of membrane 0~1 I -2 ~= O CL 10-3

J 35 potential are shown during darkness (top trace) and background illumi- nation ~ bottom trace) . These digitized records were low-pass-filtered (<15 Hz, 24 dB per octave) and dig itized at sampling intervals of 10 ms. The resting membrane potential and flash sensitivity was -41 mV/Rh* bleached rhodopsin, respectively, in darkness and -46 mV and 5.9 mV/Rh* during backg round illumination. The backs round illumination was 500 nm of light, producing 0.58 Rh* s-1 and covering a circular area 1.5 mm in diameter centered on an impaled horizontal cell. (B) Power spectral density of membrane potentials. A 1, 024-point f ast Fourier transform algorithm was used to calculate the power spectral density of 20 10-s segments during darkness and 17 10-s segments during background illu- mination. The average spectra are shown. The variance or the low- frequency component (calculated as the area under the power spectral density c2rve for frequencies<l.2 Hz) ~2 background = 0.038 mV2 and a dark = 0.0095 mV2. (C) Comparison of background-induced fluctuations to light responses. Squares plot the difference of the two spectra shown in panel B. Pluses show the spectral density of 20-s segments which contained responses to dim flashes (0.24 Rh*/flash) . This is an average spectrum of four segments, dig itized at 19.5-ms intervals and low-pass-f iltered at 10 Hz and 24 dB/octave. The ordinate for this light flash spectrum is shown on the right. The solid line is the spectral density of a model response f Otter to the average light response dur ing the backg round. The best model f it ob- tained used the Poisson model (Baylor et al . , 1974) with five stages, having bite constants of 195 ms/stage. at a frequency of 0.02-0.03/s at 20°C. These spontaneous dark events closely matched the postulated source of the fluctuations observed in the horizontal cells and the noise source postulated to influence the frequency of response curves in the ganglion cells. It is concluded, therefore, that the dark events play a major role in limiting detection of dim lights. If the dark events are evident in the human rods, then these may, by extrapolation from experiments in animals, play a major role in limiting human night vision. Optimum performance on night vision tasks requires optimization of the signal-to-noise ratio. The biochemical and electrochemical processes that generate the electrical signals in the rods must be finch: :}.vn~ ~,~ at the: r best. Any def icits in the metabolism of the cell which reduce dark currents or interfere with the steps leading to the hydrolysis of cGMP would reduce night vision. Regulation of these pathways by chemicals such as calcium ions (not discussed) is an important area receiving new attention. Lowered calcium levels tend to sensitize the photon signal. Barium ions, known to block some calcium effects, can increase the sensitivity of the rod responses to f lashes of 1 ig ht . The ~ imitations of the photon fluctuations and biological noise are real, physical parameters that must be recognized as fundamental barriers to "super" night vision. Seeing, as judged by the ganglion eel' responses reported In this paper, is very dependent on fluctua- ~:ons n both tne photon and photon-l i ke afar k events.

36 REFERENCE S Barlow, H.B. 1956 Retinal noise and absolute threshold. Journal of the Optical Society of America 46 :634-639. 1964 The physical limits of visual discrimination. Pp. 163-202 in A.C. Giese, ea., Photophysiology, Vol. 2. New York: Academic Press. Baylor, D.A., A.L. Hodgkin, and T.D. Lamb 1974 The elects ical response of turtle cones to flashes and steps of light. Journal of Physiology 242: 685-727. Baylor, D.A., T.D . Lamb, and K .-W. Yau 1979a The membrane current of single rod outer segments. Journal of Physiology 288 :589-611. 1979b Responses of retinal rods to single photons. Journal of Physiology 288: 613-634. Baylor, D.A ., B.J . Nunn, and J .L . Schnapf 1984 The photocur rent, noise and spectral sensitivity of rods of the monkey. Macaca fascicularis. Journal of Physiology 357: 575-60 7. Fesenko, E.E., S.S. Kolesnikov, and A.L. Lyubarsky 1985 Induction by cyclic GMP of cationic conductance in plasma membrane of retinal rod outer segment. Nature 313: 310-313. Gold, G.H. 1985 Plasma membrane Ca fluxes in intact rods are inconsistent with the 'Ca hypothesis. ' Biophysiology Journal 47:356a. Hecht, SO, S. Shlaer, and M.H. Pirenne 1942 Energy, quanta and vision. Journal of General Physiology 25 :81 9-840 . Korenbrot, J .I . 1985 S ignal mechanisms of phototransduction in retinal rods. CRC Critical Reviews in Biochemistry 17~3) :223-256. Matthews, H.R., V. Torre, and T.D. Lamb 1985 Effects on the photoresponse of calcium buffers and cyclic GMP incorporated into the cytoplasm of retinal rods. Nature 313: 582-58 5. Nakatani, K., and K.-W. Yau 1985 cGMP opens the light-sensitive conductance in retinal rods. B iophysiology Journal 47: 356a. Roof, D.J., J.I . Korenbrot, and J.E. Heuser 1982 Surfaces of rod photoreceptor disk membranes: Light-activated enzymes. Journal of Cell Biology 95: 501. Schwa rt z, E .A . 1985 Phototransduction in vertebrate rods. Annual Review of Neur~ science 8:339-367. Stryer, L. 1986 Cyclic GMP cascade of vision. Annual Review of Neuroscience 9: 87-119. Yoshikami, S., and W.A. Hagins 1973 Control of the dark current in vertebrate rods and cones. In H. Langer, ea., Biochemistry and Physiology of Visual P igments. Ber 1 in: Spr inger -Ve rlag .

NIGHT BLINDING DI SORDERS: DETECTION AND DIAGNOSI S . Gerald A. Fishman The assessment of individuals who complain of poor night vision can involve a rather complicated equation that must attune itself to multi- ple factors including papillary miosis with age, deficiency in contrast sensitivity resulting from cataract development, and problems with in- creasing myopia and the effect of glare, also resulting from developing cataracts. This discussion pertains to individuals who have night blindness f rom inherited photoreceptor disease and their assessment by standard clinical tests. The Goldmann-Weekers dark adaptometer is an instrument that offers an accurate means of assessing night blindness. In its traditional application, the examiner evaluates the dark-adapted threshold of a patient using an 11-degree test target positioned approximately 11 to 15 degrees from the fovea. In most instances a white test target is used. This testing procedure is more effective if chromatic rather than white-light stimuli are employed. Optimally, chromatic stimuli in the blue and red or orange-red portions of the spectrum are alter- nated. By using these chromatic stimuli, elevated thresholds can be evaluated as to whether the test target is being seen by the rod or cone system. When rods are functioning, the patient identifies the blue target considerably sooner than the orange-red one. When cones mediate the response the orange-red target is perceived at a lower intensity than the blue target. In addition to the use of chromatic stimuli, more complete infor- mation can be obtained if the test is performed with a 2-degree rather than an 11-degree test target. Patients may manifest normal absolute thresholds with One large 11-degree test target but may show an abnor- mality in threshold with the 2-degree target. A third way to optimize information is by testing rod thresholds at several points in the visual field. At the University of Illinois, absolute thresholds are measured at 15, 30, and 45 degrees superior and inferior to the fovea. Because some patients with inherited night blinding disorders show a patchy distribution of their pigmentary changes, an examiner may obtain spurious results if only one locus in the retina Is selectively sampled. The standard Goldmann-~eekers adap- tometer is frequently set 11 ~ o 15 degrees superior to the fovea. A modif fed ver sior. of the Gold~.ann-Weekers adaptometer is now available to evaluate patients in the vertical, horizontal, and oblique meridians at variable distances from the fovea. 37

38 Chromatic stimuli that isolate the rod from the cone system can also be implemented in visual field testing with a Goldmann perimeter. By modifying the instrument and monitoring the patient's fixation, the test can be administered under scotopic conditions. Color caps, with which the examiner can determine peripheral isopters that are equal for blue and red test targets, are available with the Goldmann perimeter. If rods mediate the response under dark-adapted conditions, the field area for the blue and red targets is equal. If cones mediate the res- ponse, the isopter for the red target is appreciably larger than that for the blue. The measurement of thresholds under scotopic conditions can be facilitated by interposing fiberoptic bundles in the viewing eyepiece of the Goldmann perimeter so that the patient can maintain fixation. Small red photodiodes, or dim red bulbs, can be positioned near the patient's eyes to monitor their fixation periodically. With the dim red lights and f iberoptic bundles, the examiner can visualize the patient's pupils and maintain fixation quite adequately. The electroretinogram (ERG) is also utilized to assess patients who complain of night blindness. It is desirable to dark adapt the patient for a minimum of 30 min before measuring ERG wave forms. A low-intensity stimulus (preferably blue) can be used as either a single flash or flickering stimulus at 10 Hz to measure rod function. NIGHT BLINDING DI SORDERS Congenital Stationary flight Blindness with Normal Fundus There are three genetic types of congenital stationary night blind- ness (CSNB): ~ 1) X-linked recessive, (2) autosomal recessive, and (3) autosomal dominant. All are characterized by the early consent of moderate to severe nyctalopia, normal fundus (with the exception of changes associated with myopia), and abnormal rod function, as demon- strated by ERG and dark adaptation studies. Patients with the X-linked and, to some extent, autosomal recessive forms have var. table degrees of myopia, generally between -4 .00 and -14 .50 diopters. Visual acuity ranges between 20/40 and 20/200. The disorder tends to be stationary with regard to central acuity, peripheral fields, and night vision. A group of patients with CSNE will snow a characteristic ERG pat- tern referred to as a Schubert/Bornschein type, which demonstrates a selective reduction in the scotopic and, to a lesser extent, photopic lo-wave compared with the a-wave. This produces a negative type of ERG. Since patients with CSNB do not manifest definitive fundus changes, frequently they are not appropriately diagnosed, unless the practition- er considers this disease and obtains an ERG that shows the character- istic selective lo-wave reduction. By implementing chromatic stimuli with dark adaptation testing, it is possible to ascertain that some patients with this disorder use rods to mediate thresholds. Early studies on this disorder have suggested that the majority of patients show a monophasic dark adaptation curve, implying that cones mediate thresholds. If white light stimuli are utilized for testing, the examiner may draw an erroneous conclusion

39 that cones rather than rods mediate thresholds. The testing of visual fields under scotopic conditions using balanced isopters for red and blue can demonstrate whether the peripheral field is being mediated by rods or cones. Retinitis Pigmentosa Retinitis pigmentosa refers to a complex group of retinal disorders in which patients characteristically present initially with nyctalo- pia, generally within the first or second decade of life. This sub- jective complaint is frequently accompanied by characteristic fundus changes, which include black, bone spicule-like retinal pigmentation (most apparent within the midperipheral retina), attenuated retinal vessels, and a waxy type of optic disk atrophy. This triad of find- ings, although typical, is not obligatory or pathognomonic for the diagnosis. Some patients may present in an atypical fashion and not complain of night blindness. If dark adaptation testing is done at several loci, it is possible to find isolated retinal regions where thresholds are elevated by less than 1 log unit. As such, the patient will not complain of night blindness. However, at other retinal loci, rod thresholds may be elevated by more than than 2 log units. There- fore, unless rod thresholds are homogeneously elevated by at least 1 log unit throughout the retina, patients may not complain of night blindness. These same patients also may not manifest evidence of peripheral bone spicule pigment, attenuated vessels, or disk atrophy; thus, the diagnosis of retinitis pigmentosa can be missed based on fundus examination and dark adaptation testing. However, if multiple loci are tested at 15, 30, and 45 degrees superior and inferior to the fovea, elevated thresholds often will become apparent. Furthermore, an ERG will disclose abnormal rod as well as cone amplitudes in these patients. Therefore, even if the patient does not have a history of nyctalopia, lacks characteristic fundus changes, and shows normal find- ings on dark adaptation testing at an isolated locus, ERG recordings must be obtained to rule out the possibility of atypical retinitis pigmentosa. Other patients with atypical retinitis pigmentosa may have normal fund), full visual fields, and no history for nyctalopia. Helpful observations can be made on dark adaptation testing when several loci, superior and inferior to the retina, are evaluated. Even in early stages of the disease, patients with retinitis pigmentosa may manifest a stepladder type of evaluation of rod thresholds when measurements are taken from 15 to 45 degrees in the inferior retina. Although the abso- lute threshold may be within normal limits, the progressive elevation seen from 15 to 30 to 45 degrees is helpful in suspecting retinitis pig- mentosa. In normal patients the thresholds at these loci are approxi- mately equal. This ladderlike progression is generally not observed in the superior ret ina . other patients with retin, tis pigmentosa may appear clinically to have a sector ial disease, in that pi gmentary changes are asymmetr ic e Often these changes involve the infer for retina more than the super for

40 retina. Visual field loss corresponds to the fundus changes, in that the superior field is considerably more affected than the inferior field. If the disease follows a more benign course, patients will display a normal cone lo-wave implicit time and a substantial (although not normal) rod function. Although they manifest a progressive dis- ease, these patients have an excellent prognosis for the retention of central visual acuity and functional peripheral fields, even into the seventh and eight decades of life. In contrast, other patients appear clinically to have a sectorial disease by fundus appearance but show marked rod ERG impairment and a prolonged cone lo-wave implicit time. These latter patients tend to have a disorder that is considered to be more progressive than those who manifest a larger rod lo-wave amplitude and normal cone implicit time. The ascertainment of the type of pro- gression is helpful in counseling patients as to their visual progno- sis. In the literature, patients with normal cone implicit times are referred to as having sector retinitis pigmentosa, while those patients with a clinically apparent sectorial disease, with marked ERG rod imp pairment and a prolonged lo-wave implicit time have a type of often dominantly inherited disease that initially has a predilection for the inferior retina. However, it is this latter group of patients that eventually tends to develop more diffuse disease with concentric and extensive field loss. Pigmentary Retinal Degenerations Not Associated with Diffuse Photoreceptor Disease In some instances, patients who are carriers of hereditary retina disorders, such as ocular albinisms or choroideremia, and others with inflammatory disorders, such as rubella, are evaluated for night blinding disorders. Normal dark adaptation thresholds as well as normal ERG recordings in the majority of instances help determine that these patients, with variable degrees of fundus pigmentary changes, have a benign or at least a nonprogressive retinal disorder. CONCLUSION This review highlights just a few disorders to emphasize the impor- tance of applying dark adaptometry and electrophysiology in a produc- tive manner. Unless multiple loci with small test targets are imple- mented for dark adaptometry, either false or incomplete results will be obtained. The ERG is helpful in making specific diagnoses, as in the case of patients with stationary night blindness with normal fund), ascertaining the presence of atypical presentations of retinitis pig- mentosa, distinguishing variable degrees of photoreceptor impairment among phenotypically similar progressive night blinding disorders, and in monitoring their progression.

RETINITIS PIGME:NTOSA AND ALLIED DISEASES: SOME ASPECTS OF DIAGNOSIS, PA~=ENESIS, AD PAGEANT _ Eliot L. Berson Retinitis pigmentosa and allied diseases (Table 1) affect an esti- mated 5G, 000 to 100,000 people in the United States and countless others around the world. Diseases grouped under this heading manifest them selves as abnormalities of rod or cone function or both, with either generalized or regional involvement of the retina or pigment epithelium or both. This report will focus on some aspects of diagnosis, patho- genesis, and management, with particular emphasis on the common forms of retinitis pigmentosa that are not associated with known systemic disease. .? DIAGNOSI S The early symptoms reported by patients with retinitis pigmentosa characteristically are abnormal adaptation, photophobia, night blind- ness, and loss of midperipheral field, or some combination of these. These symptoms usually appear by age 20 but can occur as late as age 40 to 50. In the common forms, patients usually lose their peripheral islands of field vision first and then their central vision. As the fields become constricted, they report a tendency toward blue blindness or tritanopia. Some may compensate for the field loss by moving their head or eyes and for their night blindness by avoiding scotopic condi- tions of illumination, thereby minimizing their symptoms, so that lack of symptoms does not exclude the possibility that an individual is affected. In the early stages patients can have minimal, if any, changes on ophthalmoscopic examination. In more advanced stages, the character- istic fundus abnormalities include narrowed retinal vessels, depig- mentation of the retinal pigment epithelium, intraretinal bone spicule pigment distributed around the midperipheral fundus, and waxy pallor of the optic disks. The bone spicule pigment is usually seen equidistant Supported in part by Grant ROI-EY00169 from the National Eye Institute and in part by the National Retinitis Pigmentosa Foundation, Baltimore, Maryland. 41

42 TABLE 1 Retinitis Pigmentosa and Allied Diseases Dominant retinitis pigmentosa with complete penetrance Dominant retinitis pigmentosa with reduced penetrance 1. 2. 3. Autosomal recessive retinitis pigmentosa 4. Sex-linked (X-chromosome linked) retinitis pigmentosa 5. Progressive cone-rod degeneration 6. Sector retinitis pigmentosa 7. Atypical forms of retinitis pigmentosa (a) Paravenous (b) Pericentral (c) Unilateral (d) Unclassified 8. Retinitis pigmentosa sine pigmento 9. Syndromes or diseases of which retinitis pigmentosa is a part (a) Usher's Syndrome (b) Laurence-Moon-Bardet-Biedl Syndromets) (c) Bassen-Kornzweig Syndrome (d) Refsum's Disease (e) Kearns-Sayre Syndrome (f) Hereditary cerebroretinal degenerations (9) Vitreo-retinal degeneration of Goldmann-Favre Congenital amaurosis of Leber Choroideremia Generalized choroidal sclerosis Gyrate atrophy of the choroid and retina Prog ressive albipunctate dystrophy . · .. . . ~ 10. 11. 12. 13. 14. 15. Cone degenerations 16. Hereditary macular degenerations including Stargardt's disease, fundus flavimaculatus, central areolar choroidal dystrophy, Best's disease, etc. 17. Stationary forms of night blindness including dominant (Nougaret) nyctalopia, autosomal recessive and sex-linked nyctalopia, Oguchi's disease and fundus albipunctatus 18. Congenital rod monochromacy, blue cone monochromacy, etc. NOTE: The conditions listed in this table, grouped under the heading retinitis pigmentosa and allied diseases, involve abnormalities of rod or cone function, or both. Source: Berson (1985~.

43 from the fovea in all quadrants in the midperipheral zone, where the rod photoreceptors are normally present in the highest density. Some patients can have advanced disease with little, if any, pigment. This can escape detection on ophthalmoscopic examination if the examiner does not observe any retinal vessel attenuation. Other typical findings in- clude cells in the vitreous, posterior detachment of the vitreous and posterior subcapsular cataracts. Drusen of the optic disk and cystoid macular changes are seen in some cases. Psychophysical and electroretinographic testing can aid in the diagnosis of retinitis pigmentosa in patients with suspected disease. Dark adaptation testing watt the Goldmann-Weekers dark adaptOmeter after exposure to a preadapting light shows elevated thresholds in all areas of the retina tested in practically all cases, although some may have final dark-adapted thresholds minimally elevated above normal (Figure 1~. Elevations of the early cone limb of the curve (Mandelbaum, 1941; Berson et al., 1968; Berson, 1976a) could account for the symptom of night blindness often reported by patients with retinitis pigmentosa under dim photopic conditions that exist at night near streetlights or in a partially darkened theater or restaurant. For routine screening final dark-adapted thresholds can be determined in a few minutes in the dark after monocularly patching a patient in the waiting room for 30 min. While the patient is dark adapting and dilating with a patch over one eye, color vision testing can be performed on the fellow eye; a tendency toward tritanopia on the Farnsworth D-15 panel raises the - RP (2) ·-SNB -- NORMAL -L 1 1 1 0 5 10 15 20 25 TIME (MIN) 1 1 .1 30 35 43 FIGURE 1 Representative dark adaptation curves for a normal subject; a patient with congenital stationary night blindness, SNB; two patients with moderately advanced retinitis pigmentosa, RP(1) and RP(21. Source: Berson, 1976a.

44 possibility of retinal degeneration. Following dark adaptation testing, retinal function can then be assessed by full-field (Ganzfeld) electro- retinographic testing; for routine testing measurements of responses to single flashes of blue and white light (dark adapted) and then flicker- ing light at 30 Hertz (Hz) can be used to determine in a few minutes if an individual is normal or affected. The original reports of the use of the electroretinogram (ERG) in primary retinitis pigmentosa indicated that affected patients had non- detectable (less than 10 pV) or very small responses (Karpe, 1945; Bjork and Karpe, 1951), but these patients had advanced disease with marked attenuation or retinal vessels and extensive pigmentary changes in the retina. More recent studies have shown that patients with early stages of retinitis pigmentosa can have subnormal ERGs (Goodman and Gunkel, 1958; Gouras and Car r, 1964) that are still large enough to separate into rod and cone components (Berson et al., 1969; Berson and Howard, 1971; Berson, 1976b). Some of these patients are asymptomatic with minimal, if any, changes visible with the ophthalmoscope, but reduced amplitudes and delays in the temporal aspects of their responses prom vice criteria for establishing the diagnosis of widespread progressive forms of retinitis pigmentosa that affect all or nearly all of the retina even in the early stages (Berson, 1976b, 1977, 19811. Representative full-field ERGs (Figure 2) from children, age 9 to 14, with early retinitis pigmentosa and minimal, if any, fundus changes show responses that are not only reduced in amplitude but also delayed in lo-wave implicit time (i.e., time interval between stimulus onset and the major cornea-positive peak of the rod or cone response). Rod or cone lo-wave implicit times or both are delayed in all genetic types. In most patients, cone lo-wave implicit times, displayed by arrows, are so delayed that a phase shift occurs between the stimulus artifacts (vertical lines) and response peaks. A stimulus flash elicits the next but one response in contrast to the normal. In the responses to single flashes of white light {middle column), the a-wave generated by the photoreceptors is reduced in amplitude in all genetic types, pointing to the involvement of the photoreceptors in the early stages of these diseases. Isolated cases with a negative family history of retinitis pigmentosa have shown ERG wave forms comparable to those seen in auto- somal recessive disease. These subnormal responses with delayed impli- cit times and elevated final dark-adapted thresholds across the retina, seen in these widespread progressive forms of retinitis pigmentosa, contrast with the subnormal responses with normal lo-wave implicit times and normal final dark-adapted threshold in some areas and elevations in all other areas seen in self-limited sector retinitis pigmentosa. These delays in cone lo-wave implicit time in progressive forms of retinitis pigmentosa with night blindness also contrast with the normal cone lo-wave implicit time seen in stationary forms of night blindness (Berson, 1976b). The ERG abnormalities in the widespread progressive forms are usually symmetr ical in both eyes, so that ERG testing of one eye will suffice to detect affected patients. Percentages of siblings, age 6-20, with normal and abnormal full- field ERGs in families with autosomal dominant and autosomal recessive retinitis pigmentosa correspond closely with percentages that would

45 be predicted from Mendelian laws describing these patterns of inheri- tance (Berson, 1976b). This finding supports the idea that the fu~l- field ERG can be used in families with retinitis pigmentosa to identify not only those patients, age 6 or over, who are abnormal but also those patients who are normal and would not be expected to develop primary retinitis pigmentosa at an older age (Berson, 1981~. At this time no patient, age 6 or over, has been observed with normal cone and rod amplitudes and normal cone and rod lo-wave implicit times who later developed widespread retinitis pigmentosa. Young adults with a positive family history of retinitis pigmentosa in a parent, grandparent, uncle, aunt, or sibling are at higher risk than the general population for having this condition, and therefore, dark adaptation and ERG testing should be done to confirm or negate the diagnosis in these patients. In addition, astigmatism pL1.0 diopter) (Berson et al., 1980) in the less astigmatic eye and myopia 0~2.0 diop- ters) (Sieving and Fishman, 1978) have also been noted more frequently in affected patients compared with either normal relatives (Berson et Blue White White (30 cps) - Normal ==~ Dominant RP ~` (complete) : Dominant RP (recluced) Sex-linked RP Auto Rec. RP \ : ~ - dot _ ~ if' so - - c FIGURE 2 ERG responses for a normal subject and four patients with retinitis pigmentosa (RP) (ages 13, 14, 14, and 9~. Calibration symbol (lower right corner) signifies 50 ms horizontally and 100 TV vertically. Rod lo-wave implicit times in column 1 and cone lo-wave implicit times in column 3 are designated with arrows. Source: Berson, 1976b.

46 al., 1980) or the general population (Sieving and Fishman, 1978~. Patients with these refractive errors should be questioned closely with regard to whether or not they have symptoms of night blindness, and their peripheral funds should be carefully examined. Dark adaptation and ERG testing should be considered if symptoms or signs raise the possibility that these patients are affected. Some patients with early macular degeneration may have difficulty seeing at night, but on further questioning they report that this symptom occurs when driving a car at night and trying to adjust after looking at oncoming headlights. These patients can have preserved central vision with minimal macular granularity on ophthalmoscopic examination. The presence of subnormal foveal ERGs, elicited with a stimulator ophthalmoscope (Sandberg et al., 1979), can help to estab- lish the diagnosis in these patients. Patients with macular degenera- tion have central loss of cone and rod function and have a normal final dark-adapted rod threshold when fixating eccentrically and a normal full-field cone and rod ERG, in contrast to the findings in retinitis pigmentosa. Macular degeneration must be distinguished from progres- sive cone-rod degeneration, an unusual form of retinitis pigmentosa in which patients can present with light sensitivity and decreased acuity and in which cone loss predominates over rod loss across the entire retina as monitored in abnormal full-field ERGs (Berson et al., 1968~. Based on a survey in Maine, the incidence of retinitis pigmentosa is about 1 in 3,500 births (Bunker et al., 19841. It was found that 19 percent of kindreds in Maine had an autosomal dominant pattern of inheritance, 19 percent were autosomal recessive, and 8 percent were X-chromosome linked, 46 percent were isolated cases with a negative family history of retinitis pigmentosa, and 8 percent could not be genetically typed. Isolated or sporadic cases have also been reported as a large percentage of affected patients in other surveys (Fishman, 1978; Jay, 1982; Boughman et al., 1985~. Genetic typing has some implications with regard to long-term visual prognosis, as those with dominant disease usually retain central vision beyond age 60, while those with autosomal recessive disease and X-linked disease usually retain central vision to ages 45 to 60 and 30 to 40, respectively (Berson, 1981~. A prospective study of 94 patients, ages 6-49, representing the dominant, recessive, X-linked, and isolated forms in approximately equal numbers, demonstrated that full-field ERGs could be used to detect significant loss of retinal function in the majority of patients over a 3-year interval. On average, patients lost 16 percent of their remaining ERG function per year to single flashes of white light and 18.5 percent to a 30-Hz white flickering light. A relationship was observed between the increase in bone spicule pigmentation and loss of full-field ERG amplitudes. On average patients lost 4.6 percent of their remaining visual field areas per year with a V-4e white light in the Goldmann perimeter. Central visual function, as monitored by foveal cone ERG amplitudes, changed only 5.2 percent per year on average over the same period, indicating that loss of retinal function was primarily extrafoveal In those patients (Berson et al., 1985; Sandberg et al., 1985).

47 PATHOGENESIS The causes for the gradual loss of photoreceptor function in most types of retinitis pigmentosa are not known. The close functional rela- tionship of the photoreceptors and the pigment epithelium has made it difficult to determine whether the primary defect exists in one or the other cell type. Possible pathogenetic mechanisms include a defect in the capacity of photoreceptors to synthesize outer segments, an abnor- mality in the capacity of the pigment epithelium to ingest outer segment tips, a deficiency in phosphodiesterase activity in photoreceptor cells with elevation of cyclic guanosine monophosphate (cGMP) and consequent cell death, a deficiency in the interphotoreceptor matrix, or some yet to be defined metabolic defect in these cells. Ultrastructural studies of autopsy eyes (Kolb and Gouras, 1974; Szamier et al., 1979; Berson, 1982; Santos-Anderson et al., 1982; Bunt-Milam et al., 1983) from patients as young as age 24 have showed that remaining cone and rod photoreceptors have profoundly shortened outer segments that could reflect an imbalance (Ripps, 1981) in the processes of rod outer segment renewal or degradation. Phagosomes have been seen in autopsy eyes suggesting that, at least for those eyes studied, the defect is not a ma jor impairment of phagocytosis of outer segment tips, as has been described in the Royal College of Su rg eons (RCS) rat with hereditary retinal dystrophy (LaVail, 1981~. A diurnal rhythm i n the rod ERG of light-entrained normal subjects (Birch et al., 1984 ~ appears to be a functional correlate of daily shedders and phago- cytosis of rod outer segment tips based on paired ERG and anatomical measurements in light-entrained rats (Sandberg et al., 1986~; the rod ERG diurnal rhythm has been found to be abnormal in patients with don inant retin, tis pigmentosa (Sandberg et al., 1984) . Research is in progress in animal models of hereditary retinal disease to learn more about pathogenetic mechanisms that could be involved in human hereditary photoreceptor degenerations. (See LaVail et al., 1985, and Schmidt, 1985, for reviews. ~ Recently it has been reported that the polymorphic locus within XP11 (the short arm of the X-chromosome), detected by the recombinant DNA probe L1.28, is linked to the locus responsible for X-linkea retinitis pigmentosa (Bhattycharya et al., 1984; Mukai et al., 1985~. Work is performed on DNA prepared from peripheral blood specimens of patients with well-clef ined pedigrees of X-chromosome-linked disease. When the log of odds (LOD) scores of all families so far reported were combined, the score was 9. 89, with a recombination fraction of 5 per- cent. This implies that the odds for linkage of the retinitis pigmen- tosa gene locus and the locus detected by L1.28 are greater than one billion to one and that the best estimate of recombination distance is 5 centimorgans or approximately 5 million base pairs. However, the 90 percent confidence limits for the available combined data was 1.5 to 14 centimorgans, suggesting that there could be as much as a 14 percent error rate in gene carrier detection and prenatal diagnosis of X-1 inked disease using only the polymorphism defined by the DNA probe Ll.28 (Mukai et al., 1985~. The relevant portion of th~ X-chromosome is now under intensive investigation with a variety of probes (Figure 3~.

48 Prenatal diagnosis should be improved by having additional markers close to and f tanking the gene locus, and this would decrease the error rate. This research may ultimately lead to the isolation of the X-linked reti- nitis pigmentosa gene and help to def ine the biochemical defect in this disease. Gene linkage analyses have also been conducted for another X-linked progressive chorioretinal degeneration, choroideremia, and the defect has been localized to a reg ion on the long arm of the X-chrom~ some (Lewis et al., 1985) . MANAGEMENT No treatments are known for practically any of the types of retini- tis pigmentosa and allied diseases. Exceptions are the retinitis pig- mentosa associated with the Basser~-Kornzweig syndrome and that seen as part of Refeum' s Disease. In the Bassen-Ko~nzweig syndrome patients have a malabsorption syndrome, generalized retinal degeneration, diffuse neuromuscular disease similar to Friedreich's ataxia, and acanthocyt~ s is. They have low serum cholesterol and an absence of low-density plasma lipoproteins, or so-called beta-lipoproteins, and therefore, the term abetalipoproteinemia has been assigned to this disorder. In this syndrome the patient can assimilate fat into the intestinal inucosa, but p DID** R P** 1 99-6*, D2* 1 B24* lC7*IoTC*~754* ]L 1.2 8* ]58- 1* CEN *DENOTES A PROBE WHICH DETECTS A ~RFLP. ** CURRENT BEST ESTIMATE FIGURE 3 Location of selected DNA probes on the short arm of the human X-chromosome (Xp). RP designates the current best estimate of the locus for X-chromosome-linked retinitis pigmentosa. Other probes that iden- tify restr lotion f ragment length polymorphisms (RFLPs) are designated with asterisks. DMD designates the location of X-linked Duchenne's muscular dystrophy which appears to be in the same region as the locus for retinitis pigmentosa. CEN designates the centromere Of the Chris mosome. Source: Berson, 1985.

49 a defect exists in its removal from this site because of a lack of chy- lomicrons. Apparently, the liver and then the retina become depleted of vitamin A in this condition. Large doses of vitamin A have resulted in a return of dark adaptation thresholds and ERG responses to normal in the early stages (Gouras et al., 1977; Carr, 1976~. More advanced cases have not responded to therapy, but in one such case in which the retina was examined after the death of the patient, widespread loss of photoreceptor cells was observed (von Sallmann et al., 1969~. Vitamin E levels in serum have been reported to be low in these patients, and vitamin E therapy has also been advocated to prevent the progression of this retinal degeneration (Muller et al., 1977; Bishara et al., 19821. Another rare form of retinitis pigmentosa that is potentially treatable is that seen in association with Refsum's disease, an inborn error of metabolism in which the patient accumulates exogenous phytanic acid (Refsum, 1981~. Findings include a peripheral neuropathy, ataxia, an increase in cerebrospinal fluid protein with a normal cell count, and retinitis pigmentosa. Anosmia, neurogenic impairment of hearing, cardiac abnormalities, and skin changes resembling ichthyosis can be present. The fundus can be granular around the periphery with a subnormal ERG in an early stage (Berson, 1982) or show more typical retinitis pigmentosa with a nondetectable ERG in more advanced stages. A defect exists in the first step of phytanic acid oxidation in the introduction of a hydroxyl group on the alpha carbon of phytanic acid. The pathogenesis appears to involve accumulation of phytanic acid in a variety of tissues including the pigment epithelium (Toussaint and Danis, 19687. Treatment consists of restricting not only milk products and animal fats (i.e., foods that contain phytanic acid) but also green leafy vegetables containing phytol (Eldjarn et al., 19661. Success of treatment also depends on the patient receiving a sufficient number of calories; if not, body weight becomes reduced if phytanic acid is released from tissue stores resulting in an increase in phytanic acid levels in serum and exacerbation of symptoms. Refaum (1981) has re- ported that two patients whose serum phytan~c acid levels were lowered to normal have showed improvement in motor nerve conduction velocity, some relief of ataxia, and return of the cerebrospinal fluid protein to normal. Moreover, the retinitis pigmentosa and hearing impairment did not progress. One patient has been followed for over 10 years and the other for many years. The long-term effects of this diet on retinal function continue to be studied. A third rare hereditary retinal degeneration that may be potentially treatable is gyrate atrophy of the choroid and retina. It is associated with characteristic chorioretinal atrophy distributed circumferentially around the peripheral fundus and sometimes near the optic disk. Abnor- malities in electroencephalograms, muscle and hair morphology, and mito- chondrial structure in the liver have also been described. Patients usually become virtually blind between ages 40 to 55 due to extensive chorioretinal atrophy (Takki and Milton, 1981~. These patients have a 10- to 20-fold elevation of ornithine concentrations in plasma due to a deficiency of ornithine ketoacid aminotransferase (OAT) (Valle et al., 1977, Berson et al., 1978; Weleber, 1978~. Plasma lysine, glutamate and

50 glutamine, as well as serum and urine creatine, have also been noted to be reduced. Therapeutic trials have included vitamin B6 (the cofactor for OAT) (Berson et al., 1978; Weleber et al., 1981), a low-protein, low-arginine diet (Raiser-Kupfer et al., 1980), or both in an effort to lower ornithine levels In plasma. Although the hyperornithinemia asso- ciated with this condition can be lowered toward normal, it remains to be established that lowering of ornithine will alter the course of this condition over the long term {Berson et al., 1982~. Improvement in muscle morphology has been reported following creative supplementation, although no evidence exists that creative will alter the course of the chorioret~nal degeneration (Sip~la et al., 1981~. Although no treatments are known for most types of retinitis pigmentosa and allied diseases, the symptom of night blindness can be alleviated with a night vision pocketscope (Berson et al., 19~4; Berson, 1976a). This device, incorporating electro-optical technology, provides sufficient light amplification to allow impaired cones to function under dim photopic and scotopic conditions (Figure 4~. The best candidates for this device are those with better than 20/200 vision and a central visual field diameter of greater than 20 degrees in at least one eye. Some patients have found this visual aid to be helpful with respect to mobility under conditions of dim illumination. SUMMARY Progress has been made in our understanding of retinitis pigmentosa and allied diseases with respect to establishing early diagnoses, defining possible pathogenetic mechanisms, and managing some rare forms. Collaborative research involving electrophysiological, psychophysical, ultrastructural, histochemical, and tissue culture techniques, as well as the new approaches of molecular genetics should provide further opportunities to define the cellular abnormalities associated with these conditions. Since these diseases occur in as many as 1 in 3,500 births, and since the visual loss may, at first, be subtle with level of performance depending on conditions of illumination and amount of remaining visual f ield and visual acuity, every effort should be made to detect affected patients as early as possible for the safety of all. Early detection will not only facilitate vocational guidance and aid in genetic counseling but also will serve to identify affected patients who can become candidates for therapeutic trials as they may arise in the future. TECHIE ICAL NOTE ERG responses are elicited with a Ganzfeld dome in a Faraday enclo- sure. For routine testing, responses are differentially amplif fed at a gain of 1, 000 (3 decibels (dB) down at 2 Hz and 300 Hz) and dc coupled with 220 microfarads in series with an oscilloscope. If responses are to be photog raphed in superposition, a rapid-decay phosphor in the os- c illoscope is recommended. Waveforms obtained with this system are

51 equ ivalent to those obtained w ith a baste ry-powered amplif ication sys- tem previously described (Rabin and Berson, 1974~. Signal averaging is used for responses with ampl itudes of less than 10 ,u V . Responses are differentially amplif fed at a gain of 10, 000 (3 decibels down at 2 Hz and 300 Hz), attenuated at 60 Hz by a notch f liter (Q = 30), amplif fed A Low Level Light Input Power Supply i,_ ~ Eyepiece Lens . , ~Lot ~ Intensified , / ~ Image Output Objective Single-Stage Battery Lens Image Intensifier B Photocat hode ( Fiberoptic Inverter ah ~ Flberoptics /, I _ >~~~~/ (Input) J ~ Phosphor Screen 'Microchannel Plate ~ _ a. _C~ ma. r __ -a _& Intensified Image (Output) FIGURE 4 (A) Generation II night vision pocketscope adapted for patients with night blindness (left). Patient holds to her eye (right). (B) Diagram of a Generation II night vision pocketscope. Instrument is 11.8 cm in length and 0.35 kg in weight and contains a single-stage image intensifier tube. The model is produced by International Telephone and Telegraph Corporation (ITT) and contains rechargeable batteries that are periodically recharged in a portable carrying case that is plugged into an ordinary wall receptacle. (C) Single-stage image intensifier tube, 3 cm in length, contained in the night vision pocketscope. Source: Berson, 1976a.

52 at a gain of 1 to 20 by a bandpass filter (Q = 16) for responses to 30-Hz flicker, and summed by a computer with a bipolar artifact reject buffer (Berson et al., 1985~. Testing is done with a Burian-Allen bi- polar electrode contact lens placed on the topically anesthetized cor- nea after maximal dilation of the pupils with 10 percent phenylephrine hydrochloride and 1 percent cyclopentolate hydrochloride; a ground electrode is placed on the forearm. All three leads are connected via a junction box to the amplifier and all are fuse protected. REFERENCES Berson, E.L. 1976a Night blindness: Some aspects of management. Pp. 301-306 in E.E. Faye, ea., Clinical Low Vision. Boston: Little, Brown and Co. 1976b Retinitis pigmentosa and allied retinal diseases: Electro- physiologic findings. Transactions of the American Academy of Ophthalmology and Otolaryngology 81:659-666. 1977 Hereditary retinal diseases; classification with the full- field electroretinogram. Pp. 149-171 in T. Lawwill, ea., ERG, VER and Psychophysics 14th ISCERG Symposium, Louisville, Kentucky 1976. Documenta Ophthalmologica Proceedings Series 13: Dr. W. Junk, Hague. 1981 Retinitis pigmentosa and allied diseases: Applications of electroretinographic testing. International Ophthalmology 4:7-22. 1982 Nutrition and retinal degenerations: Vitamin A, taurine, ornithine, and phytanic acid. Retina 2~4~:236-255. Berson, E.L., P. Gouras, and R.D. Gunkel 1968 Progressive cone-rod degeneration. Archives of Ophthalmology 80:68-76. Berson, E.L., P. Gouras, and M. Hoff 1969 Temporal aspects of the electroretinogram. Archives of Ophthalmology 81:207-214. Berson, E.L., A.H. Hanson, B.E. Rosner, and V.E. Shih 1982 A two-year trial of low protein, low arginine diets or vitamin B6 for patients with gyrate atrophy. Pp. 209-218 in E. Cotlier, I. Maumenee, and E. Berman, eds., Birth Defects: Original Article Series, XVIII.6. New York: Alan R. Liss. Berson, E.L., and J. Howard 1971 Temporal aspects of the electroretinogram in sector retinitis pigmentosa. Archives of Ophthalmology 86:653-665. Berson, E.L., L. Mehaffey, and A.R. Rabin 1974 A night vision pocketscope for patients with retinitis pigmentosa. Archives of Ophthalmology 91:495-500. Berson, E.L., B. Roaner, and E.A. Siminoff 1980 Risk factors for genetic typing and detection in retinitis pigmentosa. American Journal of Ophthalmology 89:763.

53 Berson, E.L., M.A. Sandberg, B. Rosner, D.G. Birch, and A.H. Hanson 1985 Natural course of retinitis pigmentosa over a three-year interval. American Journal of Ophthalmology 99 (3) :240-251. Berson, E.L., S.Y. Schmidt, and V.E. Shin 1978 Ocular and biochemical abnormalities in gyrate atrophy of choroid and retina. Ophthalmology 85 :1018-1027. Bhattacharya, S.S., A.F. Wright, J.F. Clayton, W.H. Price, C.I. Phillips, C .~.E . McKeown, M. Jay, A.C . Bird, P.L . Pearson, E.M. Southern, and H .J . Evans 1984 Close genetic linkage between X-linked retinitis pigmentosa and a rest reaction fragment length polymorphism identif fed by recombinant DNA probe L1. 28. Nature 309:253. Birch, D.G., E.L. Berson, and M.A. Sandberg 1984 Diurnal rhythm in the human rod ERG. Investigative Opthalmology and Visual Science 25: 236-238. B~shara, S., S. Merin, M. Cooper, E. Azizi, G. Delpre, and R. Deckelbaum 1982 Combined vitamin A and E therapy prevents retinal electro- physiological deterioration in abetalipoproteinemia. British Journal of Ophthalmology 66: 767. B jc~rk, A., and G. Karpe 1951 The electroretinogram in retinitis pigmentosa. Acta Ophthalmologica 29:361. Boughman, J.A., S.L. Halloran, and M.}q. Cohen 1985 Genetic aspects of retinitis pigmentosa. Pp. 3-24 in ~q.~. LaVail, J.G. Hollyfield, and R.E. Anderson, eds., Retinal Degeneration: Experimental and Clinical Studies. New York: Alan R. Liss. Bunker, C.H., E.L. Berson, W.C. Bromley, R.P. Hayes, and T.H. Roderick 1984 Prevalence of retinitis pigmentosa in Maine. American Journal of Ophthalmology 97:357-365. Bunt-Milam, A.H., R.E. Kalina, and R.A. Pagon 1983 Clinical-ultrastructural study of a retinal dystrophy. Investigative Ophthalmology and Visual Science 24:458-469. Carr, R.E. 1976 Abetalipoproteinemia and the eye. Pp. 385-399 in D. Bergsma, A.J. Bron, and E. Cotlier, eds., The Eye and Inborn Errors of Metabolism. Birth Defects: Original Article Series, XII.3. New York: Alan R. Liss. Eldjarn, Le ~ Oo Stokke, and K. Try 1966 a-Oxidation of branched chain fatty acids and its failure in patients with Refsum's disease showing phytanic acid accumula- tion. Scandinavian Journal of Clinical Laboratory Investigations 18:694-695. Fishman, G.A. 1978 Retinitis pigmentosa. Genetic percentages. Archives of Ophthalmology 96: 822. Goodman, G., and R.D. Gunkel 1958 Familial electroretinographic and adaptometric studies in retin it~s pigmentosa. American Journal of Ophthalmology 46:142-l 78.

54 Gouras, P., and R.E. Carr 1964 Electrophysiological studies in early retinitis pigmentosa. Archives of Ophthalmology 72:104-119. Gouras, P., R.E. Carr, and R.D. Gunkel 1971 Retinitis pigmentosa in abetalipoproteinemia: Effects of vitamin A. Investigative Ophthalmology and Visual Science 10:784-793. Jay, M. 1982 On the heredity of retinitis pigmentosa. British Journal of Ophthalmology 66:405. Kaiser-Kupfer, M.I., F.M. deMonasterio, D. Valle, et al. 1980 Gyrate atrophy of the choroid and retina: Improved visual function following reduction of plasma ornithine by diet. Science 210:1128-1131. Karpe, G. 1945 Basis of clinical electroretinography. Acta Ophthalmology 24tsuppl.~:84. Kolb, H., and P. Gouras 1974 Electron microscopic observations of human retinitis pigmen- tosa, dominantly inherited. Investigative Ophthalmology and Visual Science 13:487-498. LaVail, M.M. 1981 Analysis of neurological mutants with inherited retinal degeneration. Fr iedenwald Lecture. Investigative Ophthalmology and Visual Science 21: 638-657. LaVail, M.M., J .G . Hollyf ield, and R.E . Anderson, eds. 1985 Retina1 Degeneration: Exper imental and Clinical Studies. New York: Alan R. Liss. Lewis, R.A., R.L. Nussbaum, and R. Ferrell 1985 Mapping X-linked ophthalmic diseases. Ophthalmology 92:800-806. Mandelbaum, J. 1941 Dark adaptation: Some physiological and clinical considera- tions. Archives of Ophthalmology 26 :203. Mukai, S., T.P. Dry ja, G.A.P. B runs, J.F. Aldridge, and E.L. Berson 1985 Linkage between the X-linked retinitis pigmentosa locus and the L1.28 locus. American Journal of Ophthalmology 100(2):225-229. Muller ,~ D ~P .R ., J .K . Lloyd , and A .C . B ird 1977 Long-term man~gement of abetalipoproteinemia: Possible role of vitamin E. Archives of Diseases in Childhood 52:209. Rabin, A.R., and E.L. Berson 1974 A full-field system for clinical electroretinography. Archives of Ophthalmology 92:59-63. Refsun`, S. 1981 Heredopathia atactica polyneur itiformis phytanic-acid storage disease, Refsum's disease: A biochemically well-defined disease with a specific dietary treatment. Archives of Neurology 38:605-606.

55 Ripps, H. 1981 Rods, rhodopsin, and the visual response. Pp. 152-169 in L.~. Proenza, J.M. Enoch, and A. Jampolsky, eds., Clinical Applications of Visual Psychophysics. Cambridge, England: University Press. Sandberg, M.A., C.A. Baruzzi, A.H. Hanson, III, and E.L. Berson 1984 Abnormal rod ERG diurnal rhythm in a family with dominant retinitis pigmentosa. Investigative Ophthalmology and Visual Science 25(Suppl):196. Sandberg, M.A., E.L. Berson, and B. Rosner 1985 Pigmentary retinal change and loss of electroretinographic function in retinitis pigmentosa over a three year interval. Pp. 109-114 in M.M. LaVail, J.G. Hollyfield, and R.E. Anderson, eds., Retinal Degeneration: Experimental and Clinical Studies. New York: Alan R. Liss. . . Sandberg, M.A., A.H. Hanson, and E.L. Berson 1983 Foveal and parafoveal cone electroretinograms in juvenile macular degeneration. Opthalmic Paediatrics and Genetics 3:83-87. Sandberg, M.A., S.G. Jacobson, and E.L. Berson 1979 Foveal cone electroretinograms in retinitis pigmentosa and juvenile macular degeneration. American Journal of Ophthalmology 88:702. Sandberg, M.A., B.S. Pawlyk, and E.L. Berson 1986 ERG sensitivity and phagosome frequency in the normal pigmented rat. Experimental Eye Research. Santos-Anderson, R.M., M.O.M. Tso, and G.A. Fishman 1982 A histopathologic study of retinitis pigmentosa. Ophthalmic Paediatrics and Genetics 1:151-168. Schmidt, S.Y. 1985 Retinal degenerations. Pp. 461-507 in A. Lajtha, ea., Handbook of Neurochemistry, Vo1. 10. New York: Plenum Publishing Corp. Sieving, P.A., and G.A. Fishman 1978 Ref ractive errors of retinitis pigmentosa patients. British Journal of Ophthalmology 62 :163-167. Sipila, I., J. Rapola, O. Simell, and A. Vannas 19 81 Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. New England Journal of Medicine 304:867. Szamier, R.B., E.L. Berson, R. Klein, and S. Meyers 1979 Sex-linked retinitis pigmentosa: Ultrastructure of photoreceptors and pigment epithelium. Investioative Ophthalmology and Visual Science 18 :145-160. Takki, K.K., and R.C. Milton 1981 The natural history of gyrate atrophy of the choroid and retina. Ophthalmology 88: 292-301. Toussaint D., and P. Danis 1968 An ocular pathologic study of Refsum' s syndrome. American Journal of Ophthalmology 72:342-347.

56 Valle, D.L., M. Kaiser-Kupfer, and L.A. Del Valle 1977 Gyrate atrophy of the choroid and retina: Deficiency of ornithine aminotransferase transformed lymphocytes. Proceedings of the National Academy of Sciences, USA 74:5159-5161. Van Sallmann, L., A.H. Gelderman, and L. Laster 1969 Ocular histopathologic changes in a case of A-beta-lipoproteinemia (Bassen-Korozweig syndrome). Ophthalmologica 26:451-460. Weleber, R.G., N.G. Kennaway, and N.R.M. Buist 1978 Vitamin Be in management of gyrate atrophy of choroid and retina. Lancet 2~8101~:1213. 1981 Gyrate atrophy of the choroid and retina. International Ophthalmology 4:23-32. Documenta

CHANGES OF I LLUMI NATI ON Walter Makous I have been asked to discuss the effects that changes of illumina- tion have on vision. Below I will promote an approach to night vision based on comparison with ideal observers of various sorts. Then I will briefly discuss changes of sensitivity, gain, and noise accompanying changes of illumination and mention some practical implications. Everyone's way of putting facts together has its idiosyncrasies, and I cannot deny that there may be some here. I cannot accept res- ponsibility for anything wholly novel here, except the particular col- lation of evidence on the roles of the different mechanisms of light adaptation shown in Figures 7 and 8, and possibly the analysis of Sakitt's (1972) data. There are no ideas in the next section that are not either explicit or implicit in the literature on quantum noise in vision and signal detection (cf. de Vries, 1943; Rose, 1948; Peterson et al., l9S4; Barlow, 1956, 1962, 1977; Pirenne and Marriott, 1959; Nachmias, 1972; Geisler, 1984; Geisler and Davila, 1985), although some of the data related to the ideas may be new. MODELS OF I DEAL PERFORMANCE Although changes of illumination are, by definition, changes in the flow of radiant energy, the emphasis here will be on the associated changes in the flow of information. To think about the consequences of such changes for vision, it may be useful to distinguish what is possi- ble from what is not possible and to compare human vision with the best visual performance possible, i.e., ideal performance. Different per- formance is considered ideal under different conditions. The way that human vision differs from these ideals has both theoretical and prac- tical significance. For illustrative purposes, let us compare vision with some simple ideal systems. Quantum Counter As light is absorbed in discrete quanta, an ideal system for detecting or extracting the information from light begins with a quantum counter attached to an information processor that may be 57

58 considered to have unlimited time and intelligence. As the environ- ment changes over time, and as nearly every organism with an eye can move with respect to the environment, information may be lost by a system that sums quanta over long periods of time. So, to decrease such losses, a limit must be set on the time over which quanta are summed, and under low illumination the amount of information available within this time may limit what can be seen. As the number of quanta counted within intervals of fixed duration (under constant illumina- tion) is variable, following a Poisson distr ibution, such variability limits the information that even an ideal system can extract from light. For example, if a mean of 2 quanta are counted per interval (trial), then on 13.5 percent of the trials no quanta will be counted at all. How, then, does the human compare with this ideal? As far as is known, the closest the human comes to an ideal light detector is in detecting brief, small stimuli in the near periphery of the completely dark-adapted retina, as first reported in the classic paper by Hecht et al. (1942~. Their observers reported detection of a flash on 60 percent of the trials when the mean flash intensity presented 54 to 148 quanta to the cornea. This is not ideal, for an ideal quantum counter of light entering the cornea would detect a flash on 60 per- cent of the trials when the mean flash intensity were only 0.9 quanta per trial. This conclusion is worth mentioning because it is the only conclusion one can make from this experiment without estimating unknown quantities. Quantum Counter with Light Loss Losses of light in the eye account for at least some of the differ- ence between the human and this particular ideal. This prompts one to consider an ideal that suffers loss of light comparable to that lost in the ocular media. When Hecht et al. (1942) took such losses into account, they concluded that their observers could detect (on 60 per- cent of the trials) a stimulus in which 5 to 14 quanta were absorbed. As this is greater than 0.9, it also is not ideal. Although their esti- mates of these losses are no longer considered correct, no reasonable estimate alters this conclusion. Poisson Noise One way that human performance differs from such ideals is that humans sometimes report a stimulus when none is delivered; that is, they make false-positive responses. As Barlow (1956) pointed out, these responses can be attributed to noise. It is now known that primate rods are subject to random spontan- eous events in the dark that are indistinguishable from those caused by photons. Baylor et al. (1984) report the occurrence of such events at a mean rate of once every 160 s. Let such events be called noise, and the events caused by absorbed quanta be called signals. As the

59 frequency distribution of such noise events counted within intervals of fixed duration follows a Poisson curve, such noise can be called Poisson noise. It would be interesting to compare human light detection with an ideal quantum counter subject to Poisson noise. Then one might deter- mine, for example, how much noise must be introduced into an ideal detector to degrade its performance until its performance is equivalent to that of the human. That amount of noise, then, can be referred to as the equivalent noise (cf. Barlow, 1956; Ahumada and Watson, 1985~. Sakitt Experiment The equivalent noise under conditions optimal for human perfor- mance is not known. To estimate it requires accurate measurement of the false-positive responses in an experiment like that of Hecht et al. (1942~. Although Hallett (1969) measured false-positive responses in an experiment nearly identical to that of Hecht et al., his estimate of equivalent noise was complicated by the nonrandomness for his blank trials. Sakitt (1972) made precise observations of the false positives under conditions similar to those of Hecht et al., but her analysis of the results did not yield an estimate of equivalent noise. Neverthe- less, her data do allow determination of it. Sakitt used stimuli of three stimulus intensities that, on average, delivered to the observers' corneas O (blank trials), 55, or 66 quanta. About 4 percent of the light was lost to reflection at interfaces, the density of the lens at the wavelengths she used was about 0.15, there were 100,000 rods/mm2 where the stimuli fell (7 degrees temporal), and the effective capture area for a rod was about 1.2 p2 (Baylor et al., 1984~. Therefore, stimuli that deliver 55 and 66 quanta to the cornea (on average) cause (on average) 5.3 and 6.4 physiological activations, respectively. Sakitt allowed her observers to grade their responses on each trial according to a seven-step rating scale, where O meant that they aid not see anything, and 6 meant that they saw a very bright light. If one assumes that all responses other than O were detections, all observers failed to detect stimuli on more than 17 percent of the trials when stimuli were presented, but one expects from Poisson statistics that fewer than 0.S percent of the stimuli would have produced no activa- tions. So, performance fell short of this ideal lacking internal noise. Reanalysis of Sakitt's Experiment Figure 1 shows the distribution of noise necessary to account for the performance of one of Sakitt's observers (BS). The left-most histogram is the distribution representing the number of noise events per trial when the mean is 7 events. The two histograms on the right represent the number of events per trial when a mean of 5.3 (middle distributions or 6.4 (right distribution) effective quanta are added to the noise events. Thus, the left distribution represents noise alone, and the other two represent the summed effects of signals and noise.

60 The dashed vertical lines represent the criteria the observer would have had to use to produce the responses observed. For example, if the number of events on a given trial (including both noise events and any events elicited by the stimulus) were 10 or less, it is sup- posed that the observer gave a O rating; and if the number of events were more than 10, it is supposed the observer gave a rating greater than 0. The areas of the three curves separated by the lines repre- senting the observer's various criteria correspond to the observed response frequencies of observer BS; as the number of events per trial are discrete, the criteria separating response categories coincide with boundaries between integers, e.g., between 10 and 11 events. This representation of Sakitt's results for observer BS corres- ponds, within probable error, to 20 of the 21 data reported for that observer (seven categories of response for the two stimulus intensi- ties and the blank trials). When the mean number of noise events is below 7 or above 10, fewer data can be reconciled with the model; 7 fits best. .~6 .12 it .0 8 o lo: o --i 2 o ~1 1 1 1 1 , 1 , 1 ' 1 11 11 1 1 1 2 1 1 1 1 e ~ · I I _ · · I ~ I I J I r I 1 1 1 1 . . . ~ _ J I : 1 1 1 1 · ~l J l 1 , ~ ~ 1 · t J e- · ~ 1: I ~ l 1 l l 1 l l 1 1 1 1 1 ! ! ,1 1 10 · · 1 ~_ 1-. j 1 L ~t ...' ... , ~ 1 1 1 ~ 1 1 1 1~ 3 EVENTS/TRIAL 4 1 l ll 1 5 1 1 1 1 !6 a- I-~) 1 ·.- ~ · · ~ ·~ 20 FIGURE 1 Probability densities for noise plus 0, 5,3, and 6.4 quanta. Source: Computed to fit the data of Sakitt (1972~.

61 The data from a second observer are wholly consistent with equiva- lent noise levels of 7 to 11 events per trial, with 9 fitting best. A third observer used few categories consistently and yielded data that failed to fit this model satisfactorily; the best estimate of equiva- lent noise for this observer was about twice that for the other two. The deviant datum from observer BS was the number of false posi- tives (probability of reporting the lowest category when there was no stimulusJ. The observed proportion of false positives was 0.71, but the theoretical probability shown in Figure 1 is 0.83. The difference between the two is 7.6 standard deviations and, hence, not attributable to chance. Nevertheless, this representation is the best possible for this observer given the constraints of the model, and a similar model with a mean of 9 noise events per trial satisfactorily describes all the data from another observer. An equivalent noise of 7 to 11 quanta best describes the performance of these two observers, but the deviant observation from BS and the deviant observer indicate deviations f rem a true representation. Noise Coincident with the Stimulus For the present, disregard the anomalous data and consider the implications of the conclusion that the performance of Sakitt's obser- vers is like an ideal quantum detector that is subject to a mean of 7-11 spontaneous, quantumlike events on each trial. Any such events occurring within the image of. the stimulus during its presentation would, by definition, be indistinguishable from those caused by the stimulus itself. The stimulus in Sakitt's experiment covered 0.183 degrees2, about 22,000 rods. If these 22,000 rods generated 7-11 spontaneous events in 16 ms, each would have to generate such events at the rate of once every 32-50 s. This interval is much shorter (that is, they occur at a faster rated than the interval of once every 160 s reported by Baylor et al. (1984) for monkey rods (the lower 0.95 f iducial limit of their estimate is once every 111 sJ. According to the physiological evidence, only 2 or 3 such events should have occurred per trial, not 7 to 11. In vitro data from monkey rods may not apply to Sakitt's observers, but it is worth considering the implications if they do; i.e., whence could the eat ra not se i n the human observer art se? Nearby Noise I f noise events in rods near the image of the stimulus, or noise events occurring just before or just after the stimulus, cannot be dis- tinguished from events caused by the stimulus itself, then such events might contribute to the additional noise. The data necessary to know how much noise to attribute to such events do not exist. Note, however, that this is a question of discriminating events separated in time or space, not summing events over time and space. Zuidema et al. (1984 J have shown that observers can discriminate a time separation of only

62 4 ms under conditions similar to those in Sakitt's experiment, and Zacks (1970) has shown a similar capability under conditions in which quanta can be summed over hundreds of milliseconds to bring a stimulus to threshold. Sakitt (1971) showed that observers can discriminate stimuli separated by 3.4 min at absolute threshold, even though the quanta can be summed to well over 30 min to bring a stimulus to thresh- old. So, although some of the extra noise can be attributed to seepage over the spatiotemporal boundaries of the stimulus, it probably does not account for all of it. Evidence like that shown in Figure 1 does not prove that an average of 7-11 quantumlike events per trial actually occurred in Sakitt's observers. The deviations of the data from the theoretical f it are evidence against this idea, suggesting, for example, that some Gaussian or other non-Poisson process contributes to the noise or that something that looks like noise, such as uncertainty (Pelli, 1985), contributes to it. Nevertheless, this is an economical and reasonably good des- cription of two of the observers' performance, and equivalent noise does serve as an index of merit for the performance. Non-Poisson Noise The probable contr ibution of non-Poi sson noise to performance at absolute threshold brings to mind Barlow's estimate (1977) that about half the noise in such experiments arises centrally, that is, in the brain. There are now several new lines of evidence that noise acts proximal to the receptors. Figure 2 shows a pair of dark adaptation curves (from Makous et al., 1976~. The higher dark adaptation curve was obtained in the conventional way, with the nontest eye patched and in the dark (as in Sakitt's experiment, 19721. The lower curve was obtained following light adaptation of both eyes. This shows that the light adaptation of one eye increases sensitivity (lowers threshold) to light presented to the other eye. The dip in the upper dark adaptation curve was produced by pressure blinding the nontest eye. Note that pressure blinding of the contest eye has the same effect as light adapting it. We interpret this as evidence that a dark-adapted eye is a source of noise that interferes with detection of signals elicited from the other eye. Evidently, both pressure blinding and light adaptation reduce that noise. The pair of dark adaptation curves in Figure 2 appears to approach different asymptotes. Figure 3, from a recent paper by Auerbach and Peac hey (1984), suggests that they are. This figure shows thresholds for both eyes of a single observer before and after light adaptation of one eye. Note that light adaptation of one eye lowers the absolute threshold in the other eye. I also have evidence (unpublished data) of this. This is evidence, then, that not all the noise that limits abso- lute thresholds comas from the immediate neighborhood of the test flash. Another line of evidence for this is shown in Figure 4, from Pulos and Makous (1982~. The upper curve shows a typical threshold

c) J o 2 a) s J o J 63 0.5 ,0~ cat -0.5 -1.0~ 1 C \~4 By_ ~ ~ \ Elinoculor\ ~ : . . .~ .7 .E .t INN jocular ~_ 2 4 6 8 10 12 14 16 18 20 Time in dark (minutes) FIGURE 2 Dark adaptation following monocular or binocular light adaptation. The nontest eye was pressure bl inded dur ing minute 13 . Source: Makous et al. (19761. 1 _ l o 0 Is J o to UO Hi...... 35 4 ) O · O ~ O S `- ................................................ ...... . _ ...... 5 15O `~. ~. ' _ MINUTES IN DARK 00. OSO I ~1 1 1 1 20 2g S5 FIGURE 3 Absolute threshold af ter contralateral light adaptation. Source: Auerbach and Peachey (l 984) .

3.o: 2.01 o EP No onnulu~ 0 onnulu. ~ == ~ ~ · · ~ ~ -~.0 -2.0 -~.0 Background Inien~itv (lo' ~co' to) FIGURE 4 Threshold versus background intensity. The white symbols represent thresholds from blocks of trials during which a 2.5-degree, 20-ms test flash was presented 200 ms after cessation of an annuls of 2.5 to 9 degrees and 300 to 500 ms. The black symbols represent thresholds from blocks of trials with no annulus present at all. The pair of points furthest to the left in each figure is the absolute threshold. Source: Pulos and Makous (1982~. versus intensity curve. The lower curve shows the threshold under the same conditions, except that the test flash followed removal of an annulus surrounding the location of the test flash. The point here is that removal of the annulus lowers the absolute threshold to a value lower than that when it is tested conventionally, that is, with no annulus at all. With no plausible pathway for these effects to reach the receptors on which the test flash falls, one is forced to conclude that the sensitizing effect of removing the annulus works by reducing desensitizing effects that act proximal to the receptors themselves. These demonstrations show that absolute thresholds can be reduced by a factor of 2 or so, but none were done under the optimal conditions of Hecht et al. (1942), nor even those of Sakitt (1972~. So, it is not known whether the absolute threshold can be forced lower than that reported by Hecht et al. (1942) , nor whether the equivalent noise in

65 Sakitt's experiment could be reduced, but these observations do raise those possibilities. Sequential Mechanisms Models In this section performance of observers at absolute threshold was compared with ideals of varying complexity: (1) a counter of quanta entering the black box (observer), and (2) a counter of physiologically active quanta; then (3} Poisson noise was added and restricted first (4) to spatiotemporal coincidence and then (5) to spatiotemporal proxi- mity; finally, (~} non-Poisson noise was added which acted (at least in part) proximal to the receptors. This comparison of human performance against ideals of increasing complexity is similar to what Geisler (Geisler, 1984; Geisler and Davila, 1985) has called sequential mechan- isms models. In two recent papers (Geisler and Davila, 1985; Geisler - and Hamilton, 1986) Geisler and coworkers applied this approach to a comparison of human observers with more complex observers on more com- plex visual tasks than those broached above. Ideal observers subject only to physical constraints use quanta 5 to 20 times more efficiently than typical humans on the tasks tested so far; namely, increment threshold, resolution, and separation discrimination. CHANG ING I LLUMINATI ON .... Changes of Sensitivity Increasing the illumination increases the size of the signals more than it increases the variability of the signals. The consequent increase in the flow of information allows the well-known increases in the temporal and spatial sensitivities illustrated in Figures 5 and 6. The increase of information also allows analysis along a new dimension, namely, color. As the concern here is with vision at night, and color tends to be of minor importance at night, little more will be said of it here. As the temporal and spatial variables are the topics of other papers in this volume, these curves are presented here only to show that they are not parallel. Hence, changing the illumination does not affect the visibility of all spatial and temporal patterns equally. Changing the illumination changes the state of the observer's adapta- tion. But state of adaptation is a dispositional property: it can be known only by testing it, and these curves tell us that the observed effect of any change of adaptation must differ, depending on the test used. Fortunately, the changes that occur in the dark, that is, during dark adaptation, are in most respects identical to those associated with dif ferent levels of steady illumination. So, the state of the eye at any time in the dark can be well characterized by a single quantity, the equ ivalent backg round (Cr afford, 1947; Rushton, 1963; Barlow and Sparrock, 1964), a concept of practical as well as theoretical · . . significance.

200 `,, 100 >I - > 50 - ._ c oo 20 c o ._ ~ 10 o ~ 5 21 1 ~~N \ x 103 Io2 \~ \ ~ 10-1 - It, \ ~o ~oO · 10 ~ cd/m , 1 .~\ ~ is\\ 1 0.5 1 2 5 lo 20 50 100 spatial frequency w in ppd FIGURE 5 Contrast sensitivity curves at varying illumination. S(w) = modulation sensitivity; w = spatial frequency; ppu = periods per degree. Source: van Meeteren and Vos (1978~. O01 0~2 0~5 0~1 n.2 0.5 OOOS _ I ~ I I ~ . Kelly :~ ~\~: . ~8so ~ ~ ~ t \\t - ~ 065 . ~ ~ \ \ ~` _ - 0.06 ~ . . , . ~ 3~00! 001 002 005 0.1 0.2 0.5 , ~ ~ 1 A,] 11 1 2 5 10 20 50 2 5 MU 2U 50 Frequency [Hz] :~ 0 10000 trolands · 1000 · 100 · 375 . 10 37S 1 0375 ~ Frequency tH2] FIGURE 6 Temporal modulation sensitivity curves. Source: Kelly (1972).

67 Changes of Gain Consideration of the effects of varying illumination requires reference to the ecological demands on the visual system that might have affected the evolution of vision. Most of what interests organisms that see are objects, and objects are defined by surfaces that are defined visually by the variations of light the different surfaces send toward the eye. As shadows, clouds, and time of day change illumination, the intensity of the retinal image may change by many orders of magnitude, but the properties of the sur- faces remain constant. Information about the objects, then, lies in differences of reflectance, not differences of luminance. To register the reflectances that define objects, the visual system must change its scale, or gain, to compensate for changes of illumination, much like placing a filter before the eye to reduce excitation of the receptors to a fixed range. Such a compensatory device would produce the changes of sensitivity expressed by Weber's law. A wealth of evidence points to the existence of such a gain-changing mechanism, and recently its effects within human cones have been demonstrated (MacLeod et al., 1985; Makous et al., 1985~. Not long ago it was popular to speak of the site of visual adapta- tion, as though there were only one. Although it is still possible to hear and read arguments about whether adaptation occurs in the recep- tors or elsewhere, there are clearly many such sites, each predominating in a different range of intensities. The best evidence that there is a process regulating sensitivity proximal to the receptors is Rushton's finding (1965) that a background light that decreases sensitivity by a factor of 3 or more produces ab- sorptions in less than 2 percent of the receptors, leaving 98 percent untouched by the adapting light. It is noteworthy that one must in- crease the retinal illuminance of a large field to 1,000 tomes thresh- old (Demon and Pirenne, 1954) before the quantum adsorptions approach 1 quantum per rod per second. This is nearly the entire scotopic range. Figures 7 and 8 represent the combined effects of the various factors that attenuate the response to increasing levels of steady illumination. They are derived from many sources, including Adelson (1982), Wyszecki and Stiles (1982), Valeton and van Norren (1983), and Makous et al. (1985~. The ordinate corresponds to the neural repre- sentation of light intensity (represented on the abscissa) at various levels of the visual system proximal to the eye. It is intended to apply to the steady state, after the processes of light adaptation have approached equilibrium. The top curve of Figure 7 represents light falling on the cornea, and the next curve represents light falling on the retina. The differ- ence between the two is due to papillary constriction. The next curve represents quantal adsorptions, so the difference between it and the curve above is due to the effect that bleaching has on the proportion of incident light absorbed by the pigments. The next curve is receptor excitation; the difference between it and the curve above is due to receptor adaptation. The last curve represents the signal passing up the optic nerve; the difference between it and the curve above is due to postreceptor adaptation.

68 CONES o 4 /' ~2' /~- // RecePtor Output //~ Optic Nerve -4 ~ 2 Pupil Bleaching ReceDtor Adaptation Post Receptor Adaptation 0 2 4 6 Log I (td) FIGURE 7 Response magnitudes (R) under different illuminations at several levels of the cone system. td, Troland. RODS Q: An o ) ~Receptor Output Optic Nerve J / I ~I -4 -2 0 Log I (td) Pupil Pteceptor Saturation Receptor Adaptation I Post Receptor Adaptation FIGURE 8 Response magnitudes (R) under different illumination at several levels of the rod system. td, Troland.

69 Figure 7 shows that the combined effects of the various stages of adaptation produces a nearly constant signal, in the steady state, as illumination increases. However, the mechanism or stage that bears the major burden for compensating for the effects of changes of illu- mination varies over the range of intensities, with postreceptor adaptation taking effect at the lowest intensities and pigment taking effect bleaching at the highest. Pupillary constriction plays a minor role over much of the higher range of intensities. Qualitatively the picture for the rods, shown in Figure 8, is simi- lar, except that receptor saturation occurs before pigment bleaching becomes significant. The curve showing the effects of rod adaptation does not distinguish how much of it is due to response compression and how much is due to a change of gain within the receptor, a controversy that can be ignored for the purposes of this evaluation. Changes of Noise The curves in Figure 8 do not relate directly to sensitivity or thresholds. For one thing, they describe conditions in the steady state, whereas sensitivity almost always represents the response to transient stimuli. Also, thresholds are affected not only by the size of the change of internal state produced by a given change of stimula- tion but also by noise. These curves do not treat the changes of noise associated with changes of illumination. The signif icance of such.changes has been demonstrated by Krauskopf and Reeves (1980~. If noise limits sensitivity during steady illumina- tion, then its sudden removal by reduction of illumination should allow a sudden increase of sensitivity that is proportional to the square root of the decrease of illumination. Such increases are shown in Figure 9. The data reported in the literature on noise above threshold is not well integrated, and current ideas are likely to change soon; therefore, this will not be discussed further. Scotopic Versus Photopic Some of the discussion presented above applies to the cone system rather than to the rod system. This is offered because the cone sys- tem does participate in vision at night and because, in the absence of direct information on the rod system, the cone system might provide a qualitative model for understanding what may also occur in the rod system. However, it should be acknowledged that differences between rod and cone behavior may be more than quantitative. For example, the rod system can be saturated (Aguilar and Stiles, 1954; Adelson, 1977) by steady viewing of blue sky, whereas cones continue to adapt (change gain) until the illumination damages the eye.

- 5 70 , w mu - w u, - lo . TESt - `~, as BAt!GROUBO : 491 .R DURATION ~ 200 RSEt DItAY: 400 RSEt ~ Be A/ - 1 ~1 i f . ~1 1 1 1 I I -A S -` -I -2 -1 0 IOC BAt`GROUBD INlENSlT' IRE: 1.0 ERC/SEC'DECREE SQUARED) ~ Off it. FIGURE 9 Threshold just before and just after extinction of a back- ground field. The difference between the two is attributed to noise under steady illumination. Source: Krauskopf and Reeves (1984~. SOME PRACTICAL CONSIDERATIONS Limits of Sensitivity Whatever the reason, the human visual system falls short of sev- eral ideals. This leaves room for enhancement of visual performance through various aids. Telescopes and microscopes are classic examples. Knowing how the eye compares with various instruments intended to do similar tasks may help to determine the best combination of eye and instrument, and knowing the specific ways in which human performance deviates from an ideal may help to design aids that will bring the entire system closer to the ideal. It was argued above that even when the eye is at its best, it adds noise to that which inevitably accost panics the signal, and that in a variety of tasks human observers do about 10 times worse than an ideal quantum detector. This suggests that the signal-to-noise ratio can be increased by amplifying the stim- ulus, noise and all, for it would reduce the relative contribution of the noi se that is intr insic to the visual system. This is no secret to those who have worked with image intensif iers. According to the

71 measurements of van Meeteren (1978), improvements of quantum eff ciency by image intensifiers are typically 100 to 1. Binocular Vision Same military applications require monocular viewing, as in sighting through optical devices and heads-up displays. Evidence presented above suggests that vision is likely to be best if light adaptation of the nonviewing eye is maintained. Transient Visual Adaptation The brief period of reduced sensitivity lasting about a second following large changes of illumination, referred to as transient visual adaptation and sometimes as neural adaptation, is of con- siderable practical importance. Therefore, it has been treated extensively in the illumination engineering literature (cf. Kaufman and Christensen, 1972) and so needs no further treatment here. Screening Procedures Human Factors and Testing Some of the issues relating to screening for night vision are not specific to vision and can be handled by specialists in testing or human factors or by reference to data in the literature on human factors, such as the text by Bailey (1982) or the reference works of Van Cott and Kinkade (1972) or Woodson (1981~. Duplicity A long-standing dogma of visual science is that the rod and cone systems form not one but two largely independent visual systems, each specialized to function under different conditions, but sharing the same retina and visual pathway. As the specialized functions of the cone system demand a high density of receptors, the small part of the retina const ituting the fovea is 9 iven over entirely to the cone sys- tem, and a ref ined eye movement mechanism has evolved the capability to bring this part of the retina to coincide with interesting parts of the retinal image. However, the proportion of the retina numer ically dominated by cones is exaggerated by our subjective experience and actually occupies less than 0.02 percent of the retina. As the two systems are specialized to operate under different levels of illumina- tion, one system tends to lie dormant while the other system is doing the work of vision, and so perhaps to save resources, both use the same pathway to the brain and the same neural machinery to process the information that their separate receptor systems gather. As the same

72 optic nerve fibers carry the information for both systems, except in the fovea, the signals from the two systems are bound to interact under some circumstances, yet under most conditions the systems operate with astonishing independence. Several practical implications follow. Insofar as the systems have different functions, and to the extent that they compete for space and access to the brain, testing one will tell little about the other, and performance that depends more on one system could even vary inversely with that which depends more on the other system. Other fac- tors, such as optical quality of the eye, affect one system more than the other, and so would tend to make performance that depends more on one system somewhat independent of performance that depends more on the other systems Conversely, insofar as the same central mechanisms are used by both systems, measures that depend primarily on central processing are likely to correlate well with one another. My own impression is that cone sensitivity, as reflected by the level of the cone plateau of dark adaptation curves, is more variable than rod sensitivity, as reflected by the dark-adapted absolute threshold. Equivalent Backgrounds One of the significant findings about light and dark adaptation is that the state of the visual system under an enormous range of condi- tions can be characterized by a single parameter referred to as the equivalent background (Crawford, 19471. Hence, to measure an indi- vidual's adaptive state, there is seldom a need to test with more than one kind of test probe. Crawford successfully generalized his finding from the simple geometric shapes of the laboratory to natural objects, such as a zeppelin over Hamburg, a small boat in a harbor, and a dis- tant house on the horizon. SUMMARY Through a consideration of human performance at the absolute threshold for detecting light, I have tried to illustrate the value of comparing human performance with ideal systems and to stress the limits on vision attributable to noise. I have pointed to the many different sites at which adaptation to changing illumination occurs and estimated the magnitude of each under different illumination. Finally, I have discussed ways of reducing the limits that intrinsic noise places on visual performance and the implications that the mechanisms of visual adaptation might have for night vision screening procedures.

73 REFERENCES Adelson, E.H. 1977 Transient rod saturation with moderate stepped backgrounds. Investigative Ophthalmology and Visual Science 16(Suppl.~:28. 1982 Saturation and adaptation in the rod system. Vision Research 22:1299-1312. Aguilar, M., and W.S. Stiles 1954 Saturation of the rod mechanism of the retina at high levels of stimulation. Optica Acta 1:59-65. Ahumada, Jr., A.J.A., and A.B. Watson 1985 Equivalent-noise model for contrast detection and discrimination. Journal of the Optical Society of America A 2:1133-1139. Auerbach, E., and N.S. Peachey 1984 Interocular transfer and dark adaptation to long-wave test lights. Vision Research 24:1043-1048. Bailey, R.W. 1982 Human Performance Engineering: A Guide for System Designers. Englewood Cliffs, N.J.: Prentice-Hall. Barlow, H.B. 1956 Retinal noise and absolute threshold. Journal of the Optical Society of America 46:634-639. 1962 A method for determining the over-all quantum efficiency of visual discriminations. Journal of Physiology 141:337-350. 1977 Retinal and central factors in human vision limited by noise. Pp. 337-358 in H.B. Barlow and P. Fatt, eds., Vertebrate Photoreception. New York: Academic Press. Barlow, H.B., and J.M.B. Sparrock 1964 The role of afterimages in dark adaptation. Science 144:1309-1314. Baylor, D.A., B.J. Nunn, and J.L. Schnapf 1984 The photocurrent, noise and spectral sensitivity of rods of the monkey Macaca fascicularis. Journal of Physiology 357:575-607. Crawford, B.H. 1947 visual adaptation in relation to br ief conditioning stimuli . Proceedings of the Royal Society (London) B134 :283-302. Denton, E.J., and M.H. Pirenne 1954 The absolute sensitivity and functional stability of the human eye. Journal of Physiology 123: 417-442. de Vries, H. 1943 The quantum character of light and its bear ing upon threshola of vision, the differential sensitivity ana visual acuity of the eye. Physica 10: 553-564 . Geisler, W.S. 1984 Physical limits of acuity and hype racu ity. Journal of the Optical Society of America A 1: 775-782 . Geisler, W.S., and K.D. Davila 1985 Ideal d iscriminators in spatial vis~on: Tw~ point stimuli. Journal of the Optical Society of America A 2 :1483-1497.

74 Geisler, W.S., and D.B. Hamilton 1986 Sampling-theory analysis of spatial vision. Journal of the Optical Society of America A 3 :62-70. Hallett, P .E . 1969 Quantum eff iciency and false positive rate. Journal of Physiology 202: 4 21-43 6 . Hecht, S., S. Shlaer, and M.H. Pirenne 1942 Energy, quanta, and vision. Journal of General Physiology 25: 819-840. Kaufman, J .E ., and J .F . Chr istensen, eds. 1972 IES Lighting Handbook, 5th ed. New York: Illuminating Engineer ing Society. Kelly, D.H. 1972 Flicker. Pp. 273-302 in D. Jameson and L.M. Hurvich, eds., Handbook of Sensory Physiology: Visual Psychophysics. New York: Springer. Krauskopf, J., and A. Reeves 1980 Measurement of the effect of photon noise on detection. Vision Research 20 :193-196. . . MacLeod, D.I .A., D.R. Williams, and W. Makous 1985 Difference frequency gratings above the resolution limit. Investigative Ophthalmology and Visual Science 26(Suppl.) :11. Makou s, W., D . Telle r , and R. Boothe 1976 E3 inocular interaction in the dark. Vision Research 16 :473-476. Makous, W., D.R. Williams, and D.I.A. MacLeod 1985 Nonlinear transformation in human vision. Annual Meeting, Optical Society of Amer~ca, Digest of Technical Papers 2 :90. Nachmia s, J . 1972 Signal detection theory and its application to problems in vision. Pp. 56-77 in D. Jameson and L.M. Hurvich, eds., Handbook of Sensory Physiology: Visual Psychophysics. New Yor k: Spr inge r . Pell i, D .G . 1985 Uncertainty explains many aspects of visual contrast detec- tion and discr imination. Journal of the Optical Society A 2: 1508-1532. Peterson, W.W., T.G. Birdsall, and W.C. Fox 1954 Theory of signal detectability. IRE Transactions on Infor- mation Theory PGIT-4 :171-212. Pirenne, M.H., and F.H.C. Marriott 1959 The quantum theory of light and the psychophysiology of vision. Pp. 288-3 61 in S . Koch, ea., Psychology : A Study of a Science. New York: McGraw-Hill. - Pulos, E., and W. Makous 1982 Changes of visual sensitivity caused by on- and off transients. Vision Research 22 :879-887. Rose, A. 1948 The sensitivity performance c~f the human eye on an abso'ute scale. Journal of the Optical Society of America 38 :196-208.

75 Rushton, W.A.H. 1963 1965 Increment threshold and dark adaptation. Journal of the Optical Society of America 53:104-109. The sensitivity of rods under illumination. Journal of Physiology 178:141-160. Sakitt, B. 1971 Configuration dependence of scotopic spatial summation. Journal of Physiology 216:513-529. 1972 Counting every quantum. .~, anal of Phvsioloav 223:131-150 Valeton, J.M., and D. van Norren 1983 Light adaptation of primate cones: An analysis based on extracellular data. Vision Research 23:1539-1547. Van Cott, H.P., and R.G. Kinkade 1972 Human Engineering Guide to Equipment Design. New York: McGraw-H ill. van Meeteren, A. . . 1978 On the detective quantum eff iciency of the human eye. Vision Research 18: 257-26 7. - van Meeteren, A., and J.J. Vos 1972 Resolution and contrast sensitivity at low luminances. Vision Research 12: 825-833 . Wood son, W.E. 1981 Human Factors Design Handbook. Wyszecki, G., and W.S. Stiles 1982 Color Sc fence: Formulas. New York: Zacks, J.L. 1970 New York: ~IcGraw-Hill. Concepts and Methods, Quantitative Data and John Wiley & Sons. Temporal summation phenomena at absolute coresnoxc~: Their relation to visual mechanisms. Science 170:197-199. Zuidema, P., W. Roest, M.A. Bouman, and J.J. Koenderink 1984 Detection of light and flicker at low luminance levels in the human peripheral visual system. I. Psychophysical experi- ments. Journal of the Optical Society A 1:764-774 . . ~. . . ~. ~ .

GENERAL DISCUSSION BERSON: Does anyone feel that normal rod function would be enhanced by taking vitamin A every day? PITTS: The work that has been done on this shows that if a person has sufficient amounts of vitamin A, additional amounts of vitamin A are not going to help them. But we do know that if vitamin A is not in their diets, they're going to get an elevated threshold. A. MENENDEZ: I 'm with Technology Incorporated. It has come to our attention that the Air Force Office of Scientific Research is inter- ested in funding ways to improve normal vision through pharamacolog ical research--"super-vision," as we call it. That raises the question of whether normal vision is limited not so much by the physiological prom cess as by the actual quantum nature of light. If we believe in the doctrine of quantum limitation, then it seems that normal vision could not be improved and that the limiting factor is the physics of the light involved. I think that's related to the question of vitamin A in a general sense. BERSON: Dr. Copenhagen, would you like to comment on that? Do you think we have the most visually efficient system we could possibly have? COPENHAGEN: I would think selective evolutionary pressures would make it optimal. There is some dispute still over whether we are photon-limited at the absolute threshold. But the point is that you cannot get any better from the physics of the light. That's what the ideal observer can do. So you can build no machine that's better than that. There's no drug that you can take that's going to somehow change the physical properties of light. That's as far as we can go. So if that's super-vision, that would be the definition of super-vision. MACLEOD: I'd like to mention one interesting experiment concerned with super-vision and dietary vitamin A deprivation. One way to improve vision--even if the vision system is currently quantum-limited--is to absorb more quanta. I understand that during the war an effort was made to develop super-vision in the infrared by substituting vitamin A2 for vitamin Al in the diet, which should give a redward shift in the visual pigment absorption spectra. Experiments were done in Britain during World War II, but the project turned out to be infeasible with humans because it was difficult to induce sufficient vitamin A depriva- tion without endangering the general health of the observer. The ex- periment, however, has been made successfully using rats (S. Yoshikami, J . Pearlman, and F . Crescitelli, Vision Research 9: 633-646, 1969) . 76

77 MAKOUS: I do want to add one thing to that. When we talk about "optimum," it depends on what "optimum" you're talking about. At abso- lute threshold, detecting quanta is certainly what the organism needs to do, but at high levels of illumination, it is more important to make discriminations of fine differences in the environment than simply to detect quanta. It is important to keep in mind what "optimum" you're comparing performance against. JOHNSON: I'd like to introduce the subject of individual differ- ences, particularly with regard to the ideal observer and the limiting factors on vision. There are considerable individual differences in the normal population. I was wondering if any of you would like to comment upon these individual differences. I'd also like to ask how the various clinical and psychological measures of photopic and sco- topic visual function compare in terms of the individual variations. What kind of correlations do you find among the various tests in normal individuals? MAKOUS: Crawford measured dark adaptation among 26 nonclinical subjects and found that the standard deviation of their time to a given point in dark adaptation was about 60 percent of the mean, which I would consider substantial variation among a nonclinical population. Another issue has to do with the relationship between cone dark adaptation and rod dark adaptation, but I don't have any data on it. I expect from our research that rod adaptation wouldn't tell you much about cone sensitiv- ity, or rate of cone dark adaptation or vice versa. They are factors that would tend to make the two systems competitive, and other factors would lead to independence of the two estimates. MASSOF: I want to respond to Chris's fJohnson] question on individ- ual differences. We've been doing studies with the electroretinogram [ERG] in normals to look at sources of variability. If you look across normal observers with the electroretinogram and look at a number of dif- ferent intensities so you're varying the amplitude across observers, the standard deviation of the between-observer distribution is a constant proportion of the mean amplitude. And the proportionality constant, the coefficient of variation, is 18 percent. So what that means is that across the normal population you expect to see a standard deviation of approximately 18 percent on the amplitude of the electroretinogram, on the dark-adapted eye. However, the within-observer coefficient of var~- ation is approximately 11 percent. So a large portion of the between- observer variability can be attributed to within-observer variability. The cetween-eye variables' coefficient of variation--recording the res- ponses of both eyes to the same flash--is about 3 percent. FISHMAN: Regarding visual f ield reproducibility, we have had the opportunity to look at it in the same individual repeated three times over a per lad of approximately 3 weeks. The visual field reproducibil- ity can be extremely poor, particularly in patients with ocular disease. In some patients with retinitis pigmentosa, the visual field area can vary by as much as 50 percent on short-term retest. BERSON: We found that the intervisit variation for 24 patients with retinitis pigmentosa was such that one had to have a change of greater than 33 percent in the ERG response to a single flash of white light to be certain with 99 percent confidence that the change had

78 really occurred. We have not done intervisit variability of normals. But we have done yearly follow-ups of normals and find that they are not varying too much. MASSOF: I'd like to add to your comment, Jerry [Fishman], that the ERG numbers I'm using apply to Ganzfeld stimulation, so you're integrating over the entire retina. To talk about individual dark adaptation curves or individual measures of points, you have to add to that sampling errors and inhomogeneity of thresholds in terms of dis- tribution of sensitivity across the retina, so you would expect varia- bility to be higher. HARVEY: There really Is more to vision than detecting light. A lot of the uses that people want to optimize are not detecting small spots for which the ideal observer can be fairly well defined. So in tasks that require pattern observation there really is not a good theory of an ideal observer. It is really difficult to know whether there is not some sort of observable physical limit on an ideal observer for identi- fying or recognizing the target, rather than just detecting it. And since there are at least two psychological processes that go on, one involving sensory representations and the other involving decision, it would seem to me to be an open question whether you could have training strategies or some sort of intervention strategy that would lead to a substantive improvement. This is a possibility that should not be ruled out on theoretical grounds alone. MAKOUS: I'd like to comment on that. Bill Geisler has recently published two papers for which he's described an ideal observer for more complex tasks such as localization and Vernier acuity. I'd like to add a comment about dark adaptation, ERG variability, and psychophysical var lability. Of course, the ERG is of enormous value in clinical evaluations, but it' s hard to go directly f rom the variability of an ERG to variability of a psychophysical process such as afar k adaptation. MASSOF: I'd like to add to what Walt [Makous] just said. The ERG numbers I just gave you apply to the amplitude of the ERG, which is of course in all cases a suprathreshold stimulus. The other way you can look at the ERG is to take an intensity ser. ies. I f you plot amplitude versus log intensity and then look at the half-saturation constant, the variability across observers on that half-saturation constant is comparable to what you would get psychophysical. MACLEOD: I'd like to raise a question about the reproducibility of the course of dark adaptation for a given observer. I am very struck that in the lab when we try to measure dark adaptation curves of normal individuals, they are really disappointing in their reproducibility. Other psychophysical functions reproduce very well. Dark adaptation curves reproduce very poorly by comparison. There must be an underlying reason for that, in terms of a fluctuation over time and the dynamics of a given individual's dark adaptation process. I think it would be very interesting to try to do some analytical work on the systemic fac- tors that underlie this fluctuation with time in a given individual's dark adaptation characteristics, whether it's related to eating pat- terns, caffeine, or diurnal rhythms and body temperature, and in the latter case, whether sensitivity is optimal during the night phase or during the daytime phase when body temperature is higher.

79 MONACO: I'd like to digress to what General Doppelt said and what I interpreted as him asking: What are the kinds of tests that are cur- rently available--diagnost~c tests, screening tests--that will answer some of the questions that the military has about operating under re- duced levels of illumination. FISHMAN: I'm not clear whether to make the screening procedures more efficient so that you could administer them to the 750,000 recruits that need to be screened for night-blinding disorders or whether you want to qualitatively improve the tests to discern the difference be- tween ~better" and "best" for a group of normal recruits, so that some could be optimized for night vision tasks while the rest would be deter- mined as adequate to perform the majority of night vision tasks. If the latter case is the goal, I think that's very difficult because I don't know how to solve it with any clinical techniques that are currently available; in other words, how to discern the individual that would be superlative at a potentially critical task done under dim illumination as opposed to other individuals that would be considered "good." TREDICI: That's one of the reasons we set up this conference. Yes, we need to know the true pathologic ones and separate those out at the very beginning. We do have methods for that, which you've all done. The other aspect, I understand, would be difficult. BERSON: I'd like to make one comment: The family history and a history of symptoms of cliff faulty with adaptation are, o' course, important in deciding which individuals should have an ERG to see if they have retinitis pigmentosa. I would also like to suggest for your consideration that the optics of the patient--the pair of glasses that they're wearing--should be a red flag, particularly if there's astig- matism. We analyzed the patients with ret~nitis pigmentosa and their normal relatives -with 20/20 to find out if the refractive errors in the retinitis pigmentosa patients differed from those in their normal rela- tives. We found that astigmatism of two or more diopters in the less astigmatic eye was seen in a sample of approximately 10 percent of 160 patients who had retinitis pigmentosa. When we compared this to the normal relatives, we found that only 1 to 2 percent of normal relatives had this refractive error and 20/20. I'm confining my remarks now to patients who have 20/20, for if their acuity is reduced, which is more often the case when they come to our hospital, that's a separate issue. If you want to obtain a higher yield of people who might have retinitis pigmentosa, we would suggest ERG testing of individuals who have two or more diopters of astigmatism. We suspect that the yield per examination of patients with retinitis pigmentosa would be greater for those with this refractive error. JOHNSON: Just a comment relative to rapid screen tests. Everybody wants a quick test that will give them all the answers. With a quick test you have very limited information. Since very little is presently known about the relative parameters of night vision for job performance, I think that a quick screening test is a bit preliminary. In order to establish a relationship between task performance and visual parameters, a great deal of work must be done. Only after these relationships have been established and the visual parameters have been fully characterized should a rapid screening test be contemplated.

80 BERSON: I'd like to state that most of the disease states are symmetrical in both eyes. In terms of economy of time and effort, a patient can be dilated and dark-adapted in the waiting room with a patch over one eye and can do other tasks with the other eye, whether it's questionnaires or whatever. The patient can be led into the room to record a dark adaptation threshold, then have an ERG lens placed on the topically anesthetized cornea, have a few flashes of light adminis- tered, thus doing a very comprehensive and definitive examination in 10 or 15 minutes. So I think screening programs could be very definitive and run in a short period of time. The advantage of doing the testing this way also is that if the person is normal by ERG testing, our avail- able evidence is that they're not going to develop these diseases later. If you're going to pass someone, it would be helpful to know that they are going to be normal for the next 20 years. Therefore, it seems if you have a high-risk individual--high astigmatism, symptoms of night blindness or difficulty with adaptation, positive family history of retinitis pigmentosa--I would do ERG testing even though it may take an extra few minutes. I think this will be cost-effective in the end.

Next: Oculomotor and Spatial Orientation Factors »
Night Vision: Current Research and Future Directions, Symposium Proceedings Get This Book
×
Buy Paperback | $100.00
MyNAP members save 10% online.
Login or Register to save!
  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  6. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  7. ×

    View our suggested citation for this chapter.

    « Back Next »
  8. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!