28 Suppressive Rod-Cone Interaction

.

R - - do not operate independently: conemediated pathways are tonically inhibited by dark-adapted rods. This latter phenomenon is referred to throughout this article as suppressive rod-cone interaction (SRCI), although other names have been used in the literature.

Background

SRCI was discovered by four independent psychophysical investigations of flicker.2,14,27,34 Sensitivity to cone-mediated flicker decreases during the rod-recovery phase of dark adaptation (e.g., see figure 28.1); similarly, cone-mediated flicker sensitivity increases as the illuminance of rod-stimulating backgrounds increases (e.g., see figure 28.2). Action spectra showed SRCI to reflect an influence of the dark-adapted state of rods upon cone-mediated vision.2,26 Furthermore, this effect clearly reflects a tonic inhibitory influence of darkadapted rods, not a facilitatory effect produced by lightadapted rods (see below).

SRCI has been documented by electroretinographic (ERG) procedures in normal humans.6 The technique is quite difficult, and psychophysical procedures are much more fruitful for clinical investigation. However, our knowledge of this effect is considerably enhanced by intracellular recordings in subhuman species. SRCI has been clearly documented in cat horizontal cells and has been observed in all types of neurons in the amphibian retina except rods and color-opponent cells.21,29,40 In the mud puppy, SRCI is blocked in all retinal neurons by divalent ions such as lead, which selectively block the rod input to second-order neurons, or by excitatory amino acid analogues such as - O-phosphoserine, which selectively block the light response of horizontal cells; in the presence of such agents, conemediated flicker responses are considerably enhanced.18,22 This strongly suggests that SRCI reflects a tonic inhibitory influence of dark-adapted rods upon cone pathways that is synaptically mediated by horizontal cells.

In the mud puppy, SRCI is seen in the cones themselves and is again blocked when horizontal cell responses are prevented pharmacologically, thus suggesting that SRCI must partially reflect a direct inhibitory influence upon cones. In amphibians, SRCI can be modified by the application of either agonists or antagonists of the putative neurotransmitter substances g-aminobutyric acid (GABA), glycine, or dopamine19,20,44; however, these substances do not really

mimic or totally block SRCI. In summary, the neurotransmitter(s) as well as the specifics of the neural pathway underlying this horizontal cell–mediated influence are at present unclear. It is clear that SRCI reflects one or several different rod-modulatory influences upon cone pathways within the retinal outer plexiform layer.

When using either psychophysical or neurophysiological procedures, SRCI has been shown to be limited by three parameters.10,21,27,40 First, SRCI is very small with lowfrequency flicker, but increases to a >1 log10 effect with flicker frequencies >15 Hz. Second, background enhancement of flicker increases with illuminance of the background field up to a limiting value. In the cat, human, and mud puppy, the limiting irradiance for a 500-nm background is about 1 nW/cm2, which corresponds to a retinal illuminance of about 1 troland (or under free viewing conditions with an unrestricted pupil, a luminance of about 1 cd/m2).

Third, the magnitude of SRCI decreases as the size of the flicker probe increases and generally cannot be observed with Ganzfeld stimuli.4,6,22,40 Pflug and Nelson40 and Frumkes and Eysteinsson22 have interpreted this to indicate that SRCI is limited by well-known electrical coupling properties of horizontal cells (e.g., see Lamb31 and Nelson38). SRCI is also largely attributed to the adapted state of rods in retinal areas adjacent to rather than within the area stimulated by the cone probe.26,27 This suggests that SRCI serves as the means for rods to modulate lateral inhibitory influences within the distal retina. As would be expected therefore, rod adaptation exerts as great an influence upon cone-mediated spatial (grating) acuity as on flicker.15,37 Flicker is preferred in most studies for its ease in experimentation.

Many other forms of rod-cone interaction are known in addition to SRCI, three of which are noteworthy. First, cone adaptation exerts an influence upon rod-mediated flicker.25 This phenomenon has not been studied by other psychophysicists, but a very similar effect has been described in the cat retina by electrophysiological procedures.39,41 When using ERG procedures, this “reverse effect” may have considerable clinical utility. Second, rod and cone signals summate together: depending upon their relative phase, the signals will either add together to produce a larger sensation or cancel one another out.16,35,46 Third, dark-adapted rods also exert an inhibitory effect upon a specific (correct color detection) threshold.32 Although much less is known about these other three types of rod-cone interaction, it is quite

F 28.1 Illuminance of a 2-degree, 20-minute sinusoidally flickered test stimulus presented 7 degrees parafoveally that produces just perceptible flicker as a function of time in the dark. Stimuli were presented in maxwellian view, and flicker was generated by either a red or green light-emitting diode and was either 5, 10, 15, or 20 Hz. Data represented by inverted open triangles were obtained with red and green flicker presented in counterphase and matched in scotopic illuminance. (From Goldberg SH, Frumkes TE, Nygaard RW: Science 1983; 221:180–182. Used by permission.)

F 28.2 Illuminance of a 2-degree, 20-minute-diameter red flickering test stimulus that produces just perceptible flicker as a function of the illuminance of a 28-degree continuously exposed adapting field of 512-nm wavelength. For the test stimulus, 1 photopic troland is equal to -1.3 log scotopic trolands. Other parameters are as listed in figure 28.1. (From Goldberg SH, Frumkes TE, Nygaard RW: Science 1983; 221:180–182. Used by permission.)

clear that they are all distinct from each other and from

SRCI.5,16,25

Clinical perspective

In most psychophysical and clinical studies of SRCI, the observer adjusts the intensity of a cone-stimulating probe until flicker is just perceived. The probe is flickered at a fixed frequency (usually between 15 and 25 Hz) and size (between 1 and 2.5 degrees). The magnitude of SRCI is assessed by determining the amount that cone flicker sensitivity is influenced by selective rod adaptation. Although SRCI can be seen with flicker probes placed at virtually any retinal position including the fovea,4,14,16 most investigators prefer to systematically vary rod adaptation and study at most a few retinal positions (e.g., figures 28.1 and 28.2). In contrast, Alexander and Fishman1–3 prefer to study only two levels of adaptation but to systematically vary retinal position, as shown in figure 28.3. I stress this methodological difference at the outset because their conclusions often differ strikingly from those reported by other groups, thus suggesting that sweeping generalizations may be unwarranted.

Night blindness

SRCI has been studied in a variety of night blindness conditions. Arden and his colleagues have reported three types of abnormalities in SRCI that are associated with retinitis pigmentosa (RP). First, SRCI is sometimes lacking or considerably reduced in retinal areas in which rod vision is absent10; this was confirmed by Alexander and Fishman.3 Second, in some patients with dominantly inherited RP, the amount of SRCI was carefully probed on both sides of the “cliff ” separating areas of the retina where rods were clearly affected from areas where they were functioning more normally. Obviously, SRCI is missing in the affected retinal areas, but this deficit extended several degrees into “unaffected” areas.11 Such a finding would be anticipated from a horizontal cell lateral inhibitory model. Third, in some patients in which rod dark adaptation measured by usual psychophysical threshold or fundus reflectometry procedures is slower than normal, the growth of rod inhibition upon cones nevertheless proceeds at a normal rate.10 A similar dissociation between the time course of rod threshold changes and the growth of inhibition of cones during dark adaptation has been seen also in patients with fundus flavimaculatus.42,45 In normals, the antiphosphodiesterase theophylline specifically influences the time course of inhibition upon cones during rod adaptation while having little influence upon rod threshold per se.30 Since cyclic nucleotides play so critical a role in rod phototransduction, this suggests that in patients with slowed dark adaptation there is some dissocia-

F 28.3 Luminance of a 1-degree, 44-minute-diameter square-wave flickering test probe of 25 Hz that was just perceived as flickering as a function of position on the retina. The stimuli were presented by means of a modified Tübinger perimeter and were presented in the dark (closed circles) or against a Ganzfeld background of 0.5 log cd/m2. Results are from three observers. (From Alexander KR, Fishman GA: Br J Ophthalmol 1984; 60:303–309. Used by permission.)

tion between photopigment bleaching and the release of neurotransmitter in the dark.

A number of studies have investigated patients with stationary night blindness. This condition is characterized by normal rod rhodopsin content and absent or considerably reduced rod sensitivity; sometimes the ERG has a fairly normal rod a-wave but a considerably reduced or absent rod b-wave. Two groups of investigators have found SRCI to be absent in the six patients they examined.8,10,28,43 On the other hand, Alexander and Fishman3,5 (also personal communication) have found normal SRCI in the three patients they examined. Although there remains the possibility that different groups are describing different diseases with similar symptoms, it is probable that these conflicting findings may reflect some unresolved methodological difficulty. Indeed, a third possible change in SRCI that is associated with this condition has recently been suggested by ERG procedures.36

In a much different vein, Arden and Hogg9 studied three individuals who appeared absolutely normal after even the most intense traditional clinical testing but who all complained of night vision difficulties: all refused to drive an automobile at night. In all three, the change in conemediated flicker sensitivity occurring during rod-dark adaptation was >2.5 log10 units as opposed to about 1 log unit in normals. Recall that SRCI exerts as big an influence upon cone-mediated spatial acuity as upon flicker.37 Apparently, too much rod inhibition upon cone pathways is a “new” cause for night blindness.

Disorders of color vision

SRCI has been studied in males with common X-linked forms of dichromacy, namely, deuteranopes and protanopes (respectively lacking normal green and red cones). SRCI is apparently normal in the two deuteranopes carefully investigated but is totally lacking in the four protanopes carefully investigated.13,22,26 Although these results have yet to be fully published, several results from the two protanopes investigated by the author prove particularly intriguing. Because inhibition upon cones is lacking, the flicker sensitivity of these individuals in the dark was considerably superior to normal (i.e., the sensitivity level of normals in the presence of an optimal rod-adapting field). One of these men was additionally studied using grating acuity procedures: rod suppression of cone grating acuity is lacking, and hence, his spatial vision is similarly supernormal in the dark. The other protanope studied by the author showed another form of rod-cone interaction involving the use of Stiles’ two-color increment threshold procedure.12,23 But Alexander and Fishman question the generality of these findings. That is, although they failed to find SRCI in two “extremely protanomalous” individuals,1 they have since found a normal pattern for SRCI in two protanopes (personal communication). More recently, they suggest that SRCI has little to do with the rod influence upon color perception.5

X-linked inherited conditions

SRCI is lacking in males with a number of X-linked conditions including protanopia and RP (see above). Although SRCI reflects distal retinal function, Arden and Hogg8,10 also find it to be missing in individuals with X-linked retinoschisis, a result again disputed by Alexander and Fishman3 (also personal communication). More recently, there have been several studies in female obligatory carriers who lack the phenotypical expression of this disease. Arden et al.7 fail to find SRCI in such women. Arden (personal communication) now has some evidence that SRCI might be similarly absent in carriers of X-linked RP. SRCI is also lacking in

individuals with choroideremia and reduced in others who are carriers for this condition.48

Newer developments

It is probable that SRCI has value for assessing visual functioning for a wide variety of other disease conditions. Lorenz and Zrenner33 have associated a number of the complaints of myopes to a reduction in rod inhibition upon cones! The use of SRCI for assessing function in more general conditions such as diabetic retinopathy is still unexplored.

The value of SRCI as a test of visual functioning can be vastly improved. Zrenner and his associates42,45,48 have found alterations in SRCI to be associated with alterations in color vision and particularly the phenomenon of transient tritanopia; Arden also has associated changes in SRCI with changes in color vision. This author can foresee several developments in the near future that will greatly expand the clinical usefulness of SRCI. First, SRCI should be more clearly related to horizontal cell functioning and lateral inhibition. Other than the Werblin-Westheimer procedure developed by Enoch,17 SRCI is probably the only known measure of lateral inhibitory effects in humans that is specifically attributable to the distal retina. Second, SRCI testing should be specifically associated with other types of rod-cone interaction. For example, Denny et al.16 have developed procedures for testing both a summation of rods and cones as well as SRCI in a single-sitting time period and show that the underlying mechanism must differ considerably. Their procedure should be of great value for studying individuals (RP or fundus flavimaculatus patients) in which the time course of rod threshold recovery and the growth of rod inhibition during dark adaptation are dissociated. If the claim by Alexander et al.5 for dissociation between SRCI and rod inhibition of color perception is replicated, this too should be of clinical value. Finally, it now seems probable, based upon neurophysiological findings in lower species,22,44,47 that SRCI possibly reflects a number of distinct mechanisms. If these can be teased apart by simple stimulus manipulation, their value for clinical investigation will be greatly enhanced.

Supported in part by National Eye Institute Grant EY05984 and grants from the National Science Foundation.

REFERENCES

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5.Alexander KR, Fishman GA, Derlacki DJ: Mechanisms of rod-cone interaction: Evidence from congenital stationary nightblindness. Vision Res 1988; 28:575–583.

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8.Arden GB, Hogg CR: Absence of rod-cone interaction in nyctalopia and retinoschisis. J Physiol 1984; 353:19.

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11.Arden GB, Hogg CR, Moore AT, Ernst WJK, Kemp CM, Bird AC: Abnormal rod-cone interaction in dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci 1987; 28 (suppl):235.

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13.Coletta NJ, Adams AJ: Loss of flicker sensitivity on dim backgrounds in normal and dichromatic observers. Invest Ophthalmol Vis Sci 1985; 26 (suppl):187.

14.Coletta NJ, Adams AJ: Rod-cone interactions in flicker detection. Vision Res 1984; 24:1333–1340.

15.Coletta NJ, Schefrin BE, Adams AJ: Rod adaptation influences cone spatial resolution. Invest Ophthalmol Vis Sci 1986; 27 (suppl):71.

16.Denny N, Frumkes TE, Goldberg SH: Differences between summatory and suppressive rod-cone interaction. Clin Vis Sci 1990; 5:27–36.

17.Enoch JM: Quantitative layer-by-layer perimetry. Invest Ophthalmol Vis Sci 1978; 17:208–257.

18.Eysteinsson T, Frumkes TE: Physiology and pharmacological analysis of suppressive rod-cone interaction in Necturus retina. J Neurophysiol 1989; 61:866–877.

19.Eysteinsson T, Frumkes TE, Denny N: The importance of horizontal cell coupling for rod-cone interaction. Invest Ophthalmol Vis Sci 1987; 28 (suppl):403.

20.Frumkes TE, Denny N, Sliwinski M, Eysteinsson T: The role of horizontal cell coupling for suppressive rod-cone interaction (abstract). Neuroscience 1987; 13:26.

21.Frumkes TE, Eysteinsson T: Suppressive rod-cone interaction in distal vertebrate retina: Intracellular records from Xenopus and Necturus. J Neurophysiol 1987; 57:1361–1382.

22.Frumkes TE, Eysteinsson T: The cellular basis for suppressive rod-cone interaction. Vis Neurosci 1988; 1:263–273.

23.Frumkes TE, Goldberg SH: Rod-cone interaction in dichromats and abnormal trichromats. J Opt Soc Am 1982; 72:1741–1742.

24.Frumkes TE, Naarendorp F, Goldberg SH: Abnormalities in retinal neurocircuitry in protanopes: Evidence provided by psychophysical investigation of temporal-spatial interactions (abstract). Invest Ophthalmol Vis Sci 1988; 29 (suppl):163.

25.Frumkes TE, Naarendorp F, Goldberg SH: The influence of cone stimulation upon flicker sensitivity mediated by adjacent rods. Vision Res 1986; 26:1167–1176.

26.Goldberg SH: Tonic suppression of cone flicker by darkadapted rods. Unpublished portions of a doctoral dissertation, City University of New York, 1983.

27.Goldberg SH, Frumkes TE, Nygaard RW: Inhibitory influence of unstimulated rods in human retina: Evidence provided by examining cone flicker. Science 1983; 221:180– 182.

28.Greenstein VC, Hood DC, Siegel IM, Carr RE: A possible use of rod-cone interaction in congenital stationary nightblindness. Clin Vis Sci 1988; 3:69–74.

29.Hassin G, Witkovsky P: Intracellular recording from identified photoreceptors and horizontal cells of the Xenopus retina. Vision Res 1983; 23:921–932.

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Fortschr Ophthalmol 1986; 83:602–608.

.

W number of retinal diseases where the electrophysiological test results are distinctive and often highly characteristic, the usual case undergoing evaluation needs to have other parameters assessed in order for a diagnosis to be reached. Typically, the diagnostic information considered includes the age of onset, inheritance pattern, symptoms, and morphological changes as seen on examination or in photographs; these are correlated with the results of electrophysiological and psychophysical testing.

One test that normally might not be thought to be of much value in electrodiagnosis is fluorescein angiography (FA) and fundus photography (FP). However, there are a number of situations where the FA and FP can strongly support or give the correct diagnosis. On occasion, additional information is learned about the disease process that may have clinical importance.

Basic principles of fluorescein angiography

Briefly, FA testing is based on the fact that blue light stimulates or excites fluorescein molecules to emit bright green light, which can be recorded selectively by the use of transmission filters on film or by video camera.2,18,19 The fluorescein is normally injected as a bolus in an antecubital vein and reaches the eye through the circulatory system in about 10 seconds. Since the fluorescein dye is blood borne and is a moderately large molecule, it normally does not leave retinal blood vessels because of the endothelial cells’ tight junctions. If the vessels are involved in an active inflammatory process, or have lost their tight junctions due to scarring, dye leaks or stains the tissue.

Since choroidal vessels do not have tight junctions, free passage of fluorescein takes place in the choroid, which contributes to the “choroidal flush” seen in the early transit phase of the FA. The confluent nature of the retinal pigment epithelial (RPE) monolayer, which also has tight junctions, prevents leakage of the fluorescein into the subretinal space.

If the RPE is damaged, it may diffusely or focally leak in recognizable patterns, or if the cells are filled with pigmented material, the choroidal flush is blocked and gives

what has been termed the “dark choroid effect.”1,5 Changes in the status of the retinal and choroidal vasculature systems are easily seen with FA. How quickly the fluorescein appears, what layer is affected, whether it is a diffuse slow active early leak or stain or late stain all give important diagnostic information.

Hereditary retinal diseases with distinctive fluorescein angiograms

C The choroideremia pattern is not always obvious on fundus examination, particularly in children or in patients who have more choroidal pigmentation. Visual physiological studies usually demonstrate a rod-cone loss pattern on the electroretinogram (ERG), elevation of the rod thresholds, and often ring scotomas or constricted fields.13,17 Usually an X-linked recessive inheritance pattern can be established.

The FA in choroideremia shows a distinctive scalloped loss of the choriocapillaris, which is hypofluorescent next to brightly hyperfluorescent patent choriocapillaris (figures 29.1A and 29.1B). With only the clinical history and ERG results, the diagnosis of X-linked retinitis pigmentosa (RP) might be made, yet this conclusion would miss the more precise diagnosis of choroideremia, which can be made by the examination of the fundus directly and confirmed by FA in cases where choroidal pigmentation masks the choriocapillaris/RPE dropout.

The appearance of lobular loss of RPE and choriocapillaris on FA that is confined primarily to the posterior pole can also be seen in Bietti’s crystalline retinal dystrophy (figures 29.2A and 29.2B). Pericentral RP will have selective loss of RPE and choriocapillaris at the edge of the posterior pole to the midequator, but there is also an associated pigmentary retinopathy.

C M S . E Cystoid macular edema is a known complication that may occur in a number of panretinal degenerations including RP. Occasionally a patient with the appearance of cystoid edema on direct

F 29.1 Choroideremia in a 22-year-old Japanese man from an X-linked recessive family pedigree. A, A red-free photograph, left eye, demonstrates choroidal pigmentation that almost masks an island of intact RPE in the macula. B, FA of the same area demon-

F 29.2 Bietti’s crystalline retinal dystrophy in a 45-year-old man with no family history; his visual acuity was OD 20/20, OS 20/25; the ERG was abnormal in a rod-cone pattern; and the light peak–dark trough ratio on the electro-oculogram (EOG) was 1.2. A, Wide-angle red-free photography shows cyrstalline dots

ophthalmoscopy will be found to have no accumulation of dye in the foveal area on late frames of the FA. Stereo observation will usually demonstrate a schisis-like breakdown of the retinal tissue that may look cystic. The most common conditions where this may occur are Goldmann-Favre disease, juvenile retinoschisis, and Usher’s syndrome. The lack of late macular staining in these cases can be most helpful in arriving at a better understanding of the patient’s visual acuity problems.

X-linked retinoschisis has a distinctive ERG, although severe cases can be confused with RP, particularly if older members in the family develop a pigmentary retinopathy.12,20 The negative waveform in the dark-adapted bright-flash

strates two islands of patent choriocapillaris in the macula and parapapillary area, with loss of choriocapillaris and small choroidal vessels outside the patent areas. The fovea is hypofluorescent, probably from thickened RPE.

throughout the posterior pole and more apparent choroidal circulation than usual. B, FA of the same area reveals lobule loss of choriocapillaris with retention of larger choroidal vessels. In Bietti’s dystrophy, the choriocapillaris loss is usually confined to the posterior pole.

ERG may be ignored in the face of concurrent poor photopic and scotopic rod tracings. However, the macular and, if present, the peripheral schisis changes can be distinctive although at times subtle. Red-free photography, which is part of the usual FA protocol, often gives the clearest demonstration of macular schisis, which is reinforced by no staining or leakage in the area, so that the changes are not mistaken for cystoid macular edema (figure 29.3). The presence of macular schisis on red-free photos in face of a negative wave would eliminate the diagnosis of congenital stationary night blindness, which also has a negative waveform (see table 49.3 and chapter 72).

The other common retinal dystrophy that occasionally has foveal schisis-like degeneration, i.e., a cystoid macular change without leakage, is Usher’s syndrome6 (figure 29.4). Many of these patients demonstrate cystic-like changes that look like cystoid edema but do not show leakage on FA.11 In these cases the macular cysts eventually degenerate and leave an atrophic macula.

Deutman reported five pedigrees with dominant cystoid macular edema in which the older individuals had atrophic macular degeneration while younger members had cystoid edema.3 Moderate to high hyperopia, astigmatism, strabismus, and punctate opacities in the vitreous were common. Capillaries of the posterior pole and disc were dilated; the ERG was normal, and the EOG was subnormal.

F 29.3 Juvenile retinoschisis. A red-free fundus photograph of a 38-year-old man demonstrates a stellate pattern in the macula. Red-free photography most clearly demonstrates the macular schisis pattern characteristic of this disorder.

F 29.4 Twenty-five-year-old man with Usher syndrome, type 1. A, A red-free photograph demonstrates cysticlike macular changes.

P D /RPE D FA is particularly useful in bringing out subtle lesions of the RPE and therefore can be quite useful in evaluating patients with hereditary macular dystrophies such as cone-rod, cone, or the pattern dystrophies.3 Similarly, more subtle cases of sector RP can be diagnosed because there is often a clear demarcation line between apparently unaffected (or functioning) retina and areas of nonfunctioning retina (figure 29.5). Wide-angle FA may be helpful in this documentation. While the FA would not be used alone in making the diagnosis, some carrier states might be identified such as choroideremia, X-linked ocular albinism, or RP. Early dominant type II RP will often show heavy granularity and focal dropout of the RPE and telangiectasia of the posterior pole and disc vessels before there are significant ERG changes.

P P - R P E

R P In 1981, Heckenlively described an autosomal recessive form of RP that, in more advanced states, is characterized by preserved para-arteriolar RPE (PPRPE) adjacent and under retinal arterioles; diffuse atrophy of surrounding RPE is necessary in order to observe the PPRPE pattern.8 Patients have been uniformly hypermetropic when typical RP patients are myopic, and the age of onset has usually been childhood to adolescent years. Many of the cases have had disc drusen. The ERG, when present, is in a rod-cone pattern, and the rod threshold on dark adaptometry is elevated. These patients tend to be severely affected by the time the PPRPE pattern is apparent.

FA is very effective in bringing out subtle cases of the PPRPE pattern (figure 29.6A), which may be difficult to distinguish on fundus examination alone. It should be noted that cases of diffuse retinal edema in advanced RP may occasionally show hypofluorescence next to arterioles, which could be confused with PPRPE (figure 29.6B).

B, FA shows no late leakage in the macular area. Careful inspection of the fovea with the 90-D lens showed irregular cystic disintegration.

F 29.5 Red-free photograph (A) and FA (B) of a 63-year- old woman with sector RP. The patient reported a 4-year history

F 29.6 A, FA in PPRPE in a 33-year-old lady with advanced RP from a family with consanguineous parents and presumed autosomal recessive inheritance. B, Autosomal dominant RP patient

D C E Bonnin et al. described a “silent choroid sign” in tapetoretinal degenerations that since has been termed the dark choroid effect or sign.1 Histopathological correlation by Eagle and associates in a case of fundus flavimaculatus with dark choroid demonstrated lipofuscin-like deposits filling the RPE, thereby blocking the choroidal fluorescence.4 The importance of this diagnostic sign was clarified by Fish et al. in 1981, who examined 91 patients with various types of hereditary macular disease with FA.5 Fortyseven patients in the study had retinal flecks, 34 of whom had a dark choroid effect. An additional 3 retinal dystrophy patients had the effect.

As suggested by the study of Fish et al., the most common retinal condition with dark choroid is fundus flavimaculatus (figures 29.7A and 29.7B), but occasionally recessive cone dystrophies or cases with inverse RP starting with posterior

of visual symptoms and superior field loss. The RPE loss is evident inferior to the vascular arcade on FA.

who does not have PPRPE but has severe posterior pole edema where perivascular hypofluorescent changes which mimic fluorescein changes seen in PPRPE RP.

pole flecks will show the dark choroid effect, particularly in areas surrounding the macular area, and the dark choroid helps to identify this group of diseases. Some patients with RP have hypofluorescent fovea centralis areas on FA that likely represent the same process as dark choroid, that is, blockage of choroidal flush by thickened or less transmissive RPE.

While patients with fundus flavimaculatus typically have only mild or subnormal ERG and EOG values, some more advanced cases may have macular atrophy with minimal flecks and cone-rod ERG patterns, and the FA finding of dark choroid and full peripheral visual fields helps to establish the correct diagnosis. Some of these latter patients may be diagnosed as having central areolar choroidal sclerosis, but if a dark choroid effect is present, then the diagnosis of fundus flavimaculatus is more likely.

F 29.7 Dark choroid effect in Stargardt’s disease. A, Red-free photography of a 22-year-old woman with 20/200 vision since 11 years of age demonstrates subtle macular

with a number of retinal degenerations since in advanced stages many will have diffuse retinal or macular edema. In other cases window defects may be seen that may not be obvious on clinical examination and indicate areas of atrophy or scarring. A nonspecific finding in a number of retinal dystrophies in early stages is telangiectasia of the optic nerve head and sometimes the macular area. This appears to occur more frequently in the cone-rod degeneration1 or cone degenerations. Some patients with retinal dystrophy will also have marked hyperfluorescent disc staining on late phases, which on an otherwise normal examination may be an indication to pursue a diagnosis with electrophysiological testing. Optic nerve temporal atrophy has been reported in a number of diseases and may be more easily seen in some patients by FA10,14,15 (figure 29.8).

Rarely patients with retinal dystrophy will have subretinal or retinal neovascularization, leaking or telangiectatic vessels giving retinal edema or even a Coats’ exudative reaction, all of which can be better understood with FA.9,21 Of particular importance to find are patients with RP and the Coats’ reaction, who should be treated with photocoagulation, since if present the retinal or subretinal neovascularization may hemorrhage and lead to severe scarring and even phthisis bulbi (figure 29.9).

Peripheral retinal telangiectasia is a prominent feature of facioscapulohumeral muscular dystrophy with deafness, an autosomal dominant disorder with variable expressivity.7 Likewise, dominant exudative vitreoretinopathy is a hereditary dystrophy that has prominent vascular changes.16 Retinal electrophysiological studies have not been reported in this disease.

atrophy and a few foveal flecks. B, FA shows profound hypofluorescence with only faint window defects in the macular area.

F 29.8 Temporal optic atrophy and disc telangiectasia in a 33-year-old woman with RP cone-rod degeneration. Temporal optic atrophy may be seen in cone dystrophy, cone-rod degenerations, and congenital stationary night blindness; it is a strong indication to do an ERG if other symptoms are present. Temporal atrophy may be difficult to distinguish from tilted discs of high myopia, but FA often shows papillary vessels in the area where disc tissue should be present.15

F 29.9 Coats’s reaction in a 32-year-old woman with advanced simplex RP. A, Red-free photography shows pigmentation, subretinal exudates, and dilated retinal vessels. B, FA demonstrates telangiectasia and neovascularization. Initially, she responded to xenon photocoagulation with regression for

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