AC TA 0 P H T H A L M 0 L 0 G I CA 71 (1993) 246-255

Retinal cone dysfunction of supernormal rod ERG type

Five new cases

Thomas Rosenberg and Svend Erik Simonsen

National Eye Clinic for The Visually Impaired, Hellerup, Denmark

Abstract. Five patients, not related to each other, showed clinical signs, including electroretinograms, of a retinal dysfunction which mainly affected the cone sys- tem, but also involved the rod responses in a peculiar way. ERG b-wave threshold under dark adapted condi- tions was elevated. In contrast, rod b-wave sensitivity was enhanced with medium to high intensity flash stimula- tion. Furthermore, all patients had a severe reduction of the oscillatory potentials. The findings are discussed with special emphasis on a hypothetical disturbance in the cyclic guanosine monophosphate metabolism, invol- ving both photoreceptors and cells of the inner plexi- form layer responsible for retinal feedback mechanisms.

Key words: cGMP - cone dystrophy - cone dysfunction - ERG - Muller cell - oscillatory potential - retinal feed- back - supernormal rod response.

In 1983 Gouras and co-workers described a new type of retinal cone dystrophy. The disorder, in ad- dition to a progressive degeneration of the cone photoreceptors, was associated with characteristic alterations in the rod mediated electroretinogra- phic pattern. Rod sensitivity to weak flashes was reduced, but with high levels of flash stimulation the responses were extraordinarily large. Another characteristic feature was a considerable delay in b-wave implicit time with all stimulus intensities. These patients also had photophobia and a mild nyctalopia.

Subsequently, Alexander & Fishman (1984), Yagasaki et al. (1986), Sandberg et al. (1990), and Foerster et al. (1990) published descriptions of an

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additional 9 patients with the same pattern of supernormal dark-adapted b-waves to high intens- ity flashes, in retinal disorders that primarily af- fected the cone photoreceptors. Some of these pa- tients differed from the original description by Gouras et al. (1983) by being probably congenital and non-progressive, having absence of night blindness and various degrees of photophobia, and in presenting normal or elevated dark adapted b-wave thresholds, different types of col- our deficiency, and distinct fundoscopic findings.

Prior to the above mentioned reports, Francois et al. (1974) reported on a sister and brother with progressive generalized cone dysfunction and supernormal ERG, and Abraham & Sandberg (1977) described supernormal 'photopic domi- nated' ERGS in two young members of a family with autosomal dominant foveal dystrophy, while the responses were subnormal in the parent gener- ation.

Gouras et al. (1983) proposed an elevated intra- cellular level of cyclic guanosine monophosphate (cGMF') as a possible pathogenetic mechanism. This hypothesis was firmly supported by Sandberg et al. (1987) who demonstrated similar ERG re- sponses in isolated cat eyes perfused with isobutyl- methylxanthine (IBMX), a phospho-diesterase (PDE) inhibitor that results in elevated retinal cGMP.

Foerster et al. (1990) pointed out that the pa- tients seemed to have in common a postreceptoral transmission abnormality of the rod potentials.

We describe five patients with cone dysfunctions and profound alteration in the stimulus-response relationship of the scotopic b-wave of the ERG. We also found a severe reduction of the oscillatory potentials in all our patients. ERG findings might in part be interpreted as a defect in feedback neur- onal circuits of the inner retina.

Methods

Routine ophthalmological examinations included visual acuity measurements, objective and subjec- tive refraction, slit-lamp inspection and direct as well as indirect ophthalmoscopy in cycloplegia.

Visual field measurements were obtained with a Goldmann perimeter (Haag-Streit) and dark adap- tation curves were recorded with a Haag-Streit in- strument using the method of integral technique as described in the manual.

Binocular colour vision testing was performed in artificial light using 4 roof-mounted Osram L 36 W/72 Biolux fluorescent lamps. We used the fol- lowing tests in various combinations: Danish Stan- dard Colours (DS 735, Copenhagen 1982), Ishihara pseudoisochromatic tables (Kanehara & Co, Tokyo 1986), American Optical H-R-R Pseudoisochro- matic plates (American Optical Corp. 1957), Tritan Album of Lanthony (Luneau, Paris 1985), Farn- sworth-Munsell 15 Hue saturated and desaturated version, Roth 28 Hue (Luneau, Paris), Blue cone monochromatism plates (Harvard Medical School), and Nagels anomaloscope. Our anomalos- cope (Schmidt Haensch, Berlin No. 738) was tested on 20 colournormal young women and had a ‘nor- mal’ value of 42/14.

Corneal ERGs were obtained with a Burian- Allen monopolar electrode wetted with methylcel- lulose, usually from one eye only. Mydriasis was obtained with 1% cyclopentolate. Local corneal anaesthesia was obtained with 1% tetracaine. The indifferent electrode was a silver-disc, placed on the middle of the forehead, and the ground elec- trode was placed on the ipsilateral earlobe. The examination was done with the patient in horizon- tal position.

Light flashes were produced by a Grass PS22C photostimulator illuminating a LKC Ganzfeld 2503 bowl equipped with a weak central red fixa- tion diode. Flash intensities and background il- lumination were measured with a ‘Mastersix‘ sys-

tem exposure meter (Gossen, Erlangen) (ISCEV newsletter, February 1991). The ERGs were re- corded by a 4-channel averager system (Dantec Evomatic 4000) with digital X-Y plotter.

The fi-equency range was 0.2-1000 Hz, except for recording oscillatory potentials, where the range was 100-1000 Hz (analog filter, -3 dB).

The following ERG recordings were done: 1) Scotopic recordings (after 30 min dark adap-

tation) as a function of flash intensity (white). From below b-wave threshold and in steps of 0.5-1.0 log (Kodak neutral density filters) to the maximum available intensity of Grass step 16, equivalent to 5.0 cds/m2. Flash intervals were 5 sec with weak flashes increasing to 20 sec with the highest inten- sities. 3-5 responses were averaged for every in- tensity step.

2) Photopic recordings (white background il- lumination 17 cd/m2 as preadaptation for 10 min) with a) single white flashes, (5-10 averaged respon- ses to Grass step 4 flashes, 1.0 cds/m2), and b) 32 Hz white flicker (1.0 cds/m2, 20 series averaged after discarding the first responses).

3) Responses as a function of increasing dark adaptation (15, 30 sec, 1, 2, 5, 10, 15, 20, 30 min after switching off the background illumination, 17 cd/m2, applied for 10 min). Single white flashes Grass step 4 (1.0 cds/m2).

4) Oscillatory potentials (after 30 min dark adaptation), white flashes, Grass step 4 (1.0 cds/m2), 5 averaged responses after having discarded the first 2 responses. Flash intervals were 15 sec. Fre- quency range was 100-1000 Hz (analog filter, -3 dB) .

Twenty-one subjects with normal eyes aged 15 to 67 served as controls for the intensity-response measurements, and for establishment of the time- response relationship of dark adaptation. Fourty- two subjects with normal eyes aged 13-42 served as controls for light adapted single flash recording and 32 Hz flicker response. Informed consent was obtained from both patients and controls.

Patients Case 1 Male, SKH born 1928. No family history of eye dis- orders. The patient stated that he had ‘always’ had low vision and nystagmus. In addition, he com- plained of moderate photophobia as well as night-

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blindness. Best visual function was experienced in twilight. We first examined him at the age of 54, and again at 62 and 63 years. We found a visual acuity of 0.125 and 0.2 and refractive error of +2.0 sph. and +2.0 sph. -1.0 cyl. X 130 in the right and left eye, respectively. A faint, irregular nystagmus was seen. Colour vision tests demonstrated a severe red-green defect, and visual field meas- urements showed bilateral central scotomas. There was moderate night-blindness with a 2 log unit elevation of the dark adaptation threshold. Ophthalmoscopy revealed a fine, grainy appear- ance of the macular regions without demarcated defects of the pigment epithelium. The optic nerve heads had slight temporal pallor. In the equatorial regions, scattered point-shaped pigment epithe- lium atrophies with hyperpigmented borders were seen. Otherwise the fundus looked normal. The condition was considered stationary.

Case 2 Female, EVP born 1970. The only one affected in a halfsibship of 2. No colour vision defects were pres- ent among her near relatives. Her mother’s brother had congenital cataract and nystagmus, and her maternal grandmother’s brother had re- tinitis pigmentosa.

From the age of 4 the patient was seen re- peatedly at various eye departments, and she was examined at our clinic eight times between the age of 10 and 21. There was low vision between 0.2 and 0.4 and slight nystagmus, together with a red- green colour vision defect characterized as ex- treme protanomaly. Insignificant hyperopia (+0.75 sph.) and astigmatism (-0.5 cyl.) was present. There was discrete pigment irregularity in the cen- tral fundus with preserved foveal reflexes. Neither photophobia nor night blindness was present.

Case 3 Male, PWS born 1966. Eldest of two siblings. The family history was negative, and parental consan- guinity denied. Nystagmus was noted at age seven months. At the age of 3 glasses were prescribed for myopia, -4.5 and -5 D. Between age 6 and 12 he was examined elsewhere by several ophthalmolog- ists. From age 12 to 25 the patient was controlled annually at our clinic. Visual acuity measurements varied between 0.3 and 0.1 in the right eye, and be- tween 0.1 and 0.05 in the left eye, where a small

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exotropia and hypertropia was found. Colour vi- sion was severely affected and characterized as in- complete achromatopsia with preserved blue cone function. Goldmann perimetry revealed slight constriction of peripheral borders of the left eye, and a centrocoecal scotoma on the same eye, while the visual field in the right eye was normal. Dark adaptation was deficient with a 2 log unit elevation of the rod threshold. There was photophobia. Ophthalmoscopy &owed a central pigment pow- dering, and in the inferior equatorial regions band-shaped pigment epithelial atrophy with coarse hyperpigmentations were seen. Apart from fluctuations, visual acuity was stationary over an 18-year period.

Case 4

Male, KS born 1979. Youngest in a sibship of two. No known family history of eye disorders, parental consanguinity was denied. Nystagmus was noticed from birth. Three years old an eye examination performed elsewhere demonstrated visual acuity 3/60, slight hyperopia, and astigmatism. We exam- ined the boy at age 4 and 11. Visual acuity was 0.08 on both occasions. A high frequency, low ampli- tude horizontal nystagmus was still present. The fundus was unremarkable apart from slight macu- lar mottling. Colour vision tests demonstrated a severe red-green defect with achromatopsic char- acteristics. This patient was not night blind, but ex- perienced photophobia.

Case 5 Female, NMT born 1981. She had a younger sister, the family history was negative with respect to eye disorders, and her parents were unrelated.

Reduced visual acuity and night-blindness was suspected from age 2 to 3. A year later, difficulties with colour discrimination was noticed. Eye exam- ination performed elsewhere at age 4% demon- strated visual acuity 0.15 +3.00 sph. in both eyes, and slightly irregular pigmentation of the foveal regions. Follow-up examinations at age 7,8, and 9 showed moderate improvement of visual acuity, and severely affected colour vision. Nine years old she was referred to our clinic. Visual acuity of both eyes and binocularly was 0.3. An alternating exo- tropia and impaired accommodative convergence, and a red-green colour vision defect was found. There was moderate photophobia. Ophthalmos- copy revealed macular regions with a grainy, struc-

Table 1. Symptoms were graded from 0 to ++. emm = emmetropia, ND = No Data. Colour vision tests (see text) were abbrevi- ated A = AOHRR, B = Blue cone test, F = Farnsworth D15, I = Ishihara, N = Nagel, R = Roth 28 Hue, S = Standard

colour plates, T = Tritan album.

Night- Colour Age Pho tophobia Case

No. last exam. blindness difEcult. Nystagmus

1 63 + + + 2 21 0 + 0 3 25 + + + 4 11 0 + ++ 5 9 ++ + +

Case Vis. acuity Refraction Darkadapta tion No. rightlleft rightfleft thresholds

Colour tests

0.125 0.2 0.25 0.3 0.2 0.1 0.08 0.08 0.3 0.3

+2.0 3x10-4 cd/m2 A, I, S

+1.75 -1.OX130 ND A, B, F, 1, +2.0 -1.OX40 R, S, T -6.5 3 X 10-4 cd/m' A, B, F, 1, -7.0 N, R, S -1.oxo ND B, F, N, S +1.0 -1.oxo emm ND F, I, T emm

+2.0 -1.OX130

tureless appearance. The optic nerve heads, the re- tinal vessels, and peripheral fundi looked normal.

Results

The five patients presented here had some charac- teristics in common pointing towards a cone dys- function: congenital or early affection of visual acuity, a nearly stationary course, and significant colour vision deficiency. Four patients had con- genital nystagmus, four patients suffered from moderate photophobia and three patients com- plained of night-blindness, which in case 1 and 3 was substantiated by the finding of an elevated h a l threshold by dark adaptation. Ophthalmos- copy revealed only slight morphological devia- tions in the macular regions. Four patients had low refractive errors, and one patient had a medium grade myopia.

Some of the clinical findings are summarized in Table 1. It is apparent that ERG is crucial for the

categorization of these cases under a common heading.

With high intensity flashes our patients exhibit b-wave amplitudes that are supernormal or at the upper normal limit (Fig. 1). But, as can be seen, if the flashes are weakened, the b-wave amplitude gradually becomes significantly subnormal, and the threshold for all five cases is about 1 log higher than for the normal material (Figs. 1 and 2). Thus, the intensity-response curve is much steeper and more linear than for the normal material. The b-wave implicit times are abnormally increased for all intensities, most pronounced with weaker flashes (Fig. 2).

In the case of a-wave amplitudes (rod-domi- nated), they are generally inside the normal range, but implicit times are significantly increased, espe- cially for relatively weak flashes (Fig. 1).

Oscillatory potentials are not apparent in our patients' recordings with the fi-equency range 0.2- 1000 Hz, while they are clearly visible in the nor- mal ERG (Fig. 1). With frequency range 100-1000 Hz s m a l l remnants of OPs are seen in all cases (Fig.

249

Normal

L -5.0 -

400 pV Case 1

60 msec

-4.0 - Case 2

- -3.0 - - -

c a E

-1.0

160 - E .- E" 120

E 8 0 -

c. + .- u .- - - Q > F 4 0 - n

Fig. 1. Dark adapted ERGS as function of intensity of white Ganzfeld flashes from a typical, normal subject, and from two of our cases. Note especially the pathological super- normal b-wave amplitude with high intensity flashes, in contrast to the elevated b-wave threshold with weak flashes. Furthermore, the implicit times both for a-waves and b-waves are increased, and the OPs are missing or

highly reduced.

-

-

4A). OP amplitudes are significantly reduced and implicit times increased about 30%, while their in- tervals seem unchanged.

Photopic recordings with 32 Hz white flicker (Fig. 4B) all show significantly reduced amplitudes between 20 and 62 pV (Normal: Median 107 pV with 5th to 95th interpercentile range 63-199 pv), and significantly prolonged implicit times, be- tween 37 and 39 msec (Normal: Median 26 msec with 5th to 95th interpercentile range 24-30 msec).

In Fig. 3, ERG responses during dark adaptation for case 1 are compared with those of a typical, normal observer. The light adapted cone respon- ses to single, white flashes and 32 Hz flicker are re- duced and implicit times enhanced.

During dark adaptation the normal ERG shows moderate increase of the a-wave amplitude, marked by increasing negative A2-wave, while its implicit time is unchanged. During the first minutes the b-wave is photopic dominated, super- imposed with an 'W-wave (Nagata 1963), a compli-

250

1 OO(

Case 1 Case 2 Case 3 - Case 4

.-. Case5

--- ..-- -

/

-5.0 log -4.0 -3.0 -2.0 -1.0 log 0 (5.0 c d d m z

2oo r

f It case 1 case 2 Case 3 Case 4 Case 5

0 L , I I 1 I I

-5.0 log -4.0 -3.0 -2.0 -1.0 log 0

(5.0 Cdslmz Log Relative Flash Intensity

Fig. 2 Diagrams showing relation between log relative flash in- tensity and b-wave amplitude (top), and b-wave implicit time (bottom). Normal values (N = 21) are shown as mean f SD. Note that our five cases at high intensities show b-wave amplitudes that are supernormal or at the upper normal limit; while their thresholds are significantly in- creased. The b-wave implicit times for our five cases are increased for all flash intensities, especially the lower

ones.

cated interaction between on and off OPs. With in- creasing dark adaptation the b-wave amplitude in- creases, becoming gradually dominated by the slower scotopic rod component while the off-OPs disappear, leaving small, pure on- oscillations on the ascending slope of the b-wave.

Normal Case 1

30 sec

1 min - 2 min .- : 8 2

5 min 3 10 min

0 15 min c .O 20 min

!! a 0 30 min

r

c

400 p V I 40OpVl

60 msec 60 msec

Fig. 3. ERGs from a normal subject (same as in Fig. 1 and Fig. 4) and our case 1 compared during dark adaptation. All ERGs are elicited by Grass step 4 flash (1 cds/m'). Light adapted pure cone ERGs (background 17 cd/m', 10 min, 32 Hz white flicker and single white flash) are shown at the top. After switching off the background light (dashed line), single flash recordings during 30 min dark adapta- tion are shown. The ERG of case 1 turns gradually into an apparently pure rod type without visible remnants of A,-wave or photopic b-wave, and eventually becomes hypernormal with increased implicit times. No OPs are visible.

The corresponding ERGs from case 1 (Fig. 3) present a different pattern. Implicit times for both a- and b-waves are clearly increased, though less marked during the first minutes of dark adapta- tion because of relatively higher influence of the faster cone components. After 30 min of dark adaptation the ERG is completely dominated by the slower rod components, and the rod b-wave has become supernormal in amplitude. Neither on- nor off- OPs are visible with this frequency range (0.2-1000 Hz).

A B

Case

Case

Case

Case

Case

L

E 60 msec 60 msec

Fig. 4. A. Dark adapted OPs (frequency range 100-1000 Hz) and B. 32 Hz light adapted white flicker from a typical nor- mal subject and from our five cases. The OPs are heavily reduced in amplitude with increased implicit times, but apparently normal intervals. The 32 Hz cone flicker re- sponses are all significantly reduced in amplitude and in-

creased in implicit time.

Discussion

Several authors have emphasized the importance of electroretinography for the taxonomic classifi- cation of hereditary retinal disorders, a.0. Krill & Deutman (1972), and Francois et al. (1974). Never- theless, the clinical delineation of specific noso- logical entities is based on a spectrum of symp- toms, signs, hereditary pattern, and a number of phychophysical and biophysical tests.

A considerable number of diseases, mainly or in- itially affecting the cone photoreceptors have been described. In progressive cases the term 'cone dys- trophy' has gained wide acceptance, since this name was coined by i.a. Deutman (1971) and Krill & Deutman (1972). In stationary cases, e.g. achro- matopsia and blue cone monocromacy the term 'dystrophy' is incorrect, 'cone dysfunction disor-

251

der' being more appropriate. Simultaneous occur- rence of a cone dystrophy or a cone dysfunction disorder and impaired night vision has been ob- served in a number of quite different entities, i.e. imcomplete night blindness (Miyake et al. 1986), hand eye disease (Rosenberg et al. 1990), cone-rod dystrophies (Yagasaki &Jacobson 1989), enhanced S cone syndrome (Marmor et al. 1990), and a cone dystrophy with supernormal rod responses de- scribed by Gouras et al. (1983). The latter condi- tion closely resembles our cases.

Regarding some of our patients, it took years and a large number of examinations to arrive at the present diagnosis. This is partly because earlier ERG techniques did not separate cone and rod functions, and did not include different flash in- tensities. Prior diagnoses were infantile or juvenile macular dystrophy, Stargardt disease, incomplete achromatopsia, congenital nystagmus, incomplete congenital stationary night-blindness, cone-rod dystrophy, retinitis pigmentosa, or unspecified am- blyopia.

Within the expanding group of cone dysfunc- tions the supernormal rod response type holds a significant position. Still, it remains to be estab- lished whether this cone dysfunction represents a single disease or merely a group of retinal disor- ders with a common pathophysiological mechan- ism.

The condition also represents a subunit of a larger entity with congenital nystagmus and chiefly normal hndus, and therefore is a differen- tial diagnosis in relation with a.0. Leber congenital amaurosis, achromatopsia, congenital stationary night blindness, and hand eye disease. For that reason, this paper also underlines the necessity for complete ERG examination in cases with unex- plained congenital nystagmus.

Hypernormal ERG b-waves are found in a num- ber of conditions (Wirth 1979). Of special interest to our cases are those conditions in which hyper- normal scotopic b-wave responses to high flash in- tensity are combined with a prolonged implicit time, possibly with an elevated b-wave threshold and lost or severely reduced OPs. In experiments with low dose barbiturates using only strong light flashes, Yonemura et al. (1966), Winkler (1972), and Morita (1970) found hypernormal b-waves, pro- longed implicit times, and a significant reduction in OPs. Yet, as early as 1956, in addition to the hypernormal responses, Wohlzogen found a re-

252

duced amplitude with weak flashes. The author as- cribed these findings to the activity of internuncial neurones, e.g. horizontal cells or amacrines.

Similar ERG alterations have been reported to be due to early acute ischaemia (Brunette et al. 1983), early siderosis (Good & Gross 1988), and cer- tain drugs, e.g. Diphenylhydantion (Honda et al. 1973), and LSD (Krill et al. 1960). Changes in the extracellular ionic composition in isolated rat re- tina including elimioation of Ca++ or increase of K', produced the same type of ERG changes (Win- kler 1973). It seems probable that either amacrines, bipolars or Miiller cells are the target cells in these experiments.

Gouras et al. (1983) hypothesized a disturbance of cGMP metabolism as a possible pathophysio- logical mechanism, either primary or secondary to the cone dystrophy. This theory was based on ex- periments in which changes in intracellular rod re- sponses were induced by elevated intracellular cGMP, either through an inhibition of rod phos- phodiesterase (Lipton et al. 1977), by injection of cGMP into rods (Nicol & Miller 1978), or by reduc- ing the concentration of intracellular rod Cat+ ions leading to a rise in rod cGMP (Cohen et al. 1978). Later, this hypothesis was supported by ERG experiments on isolated perfused cat eyes (Sand- berg et al. 1987; Pawlyk et al. 1991), in which isobu- tyl-methylxanthine (IBMX), an inhibitor of cGMP- phosphodiesterase, gave rise to elevated intracel- lular cGMP. Following administration of small doses IBMX, a raised scotopic b-wave threshold was observed, whereas strong flashes elicited hypernormal b-wave amplitudes with prolonged implicit times. These experimental findings were identical to the findings in their patients (Sand- berg et al. 1990).

Our five patients demonstrate the following common characteristic ERG abnormalities: 1. A significant reduction in amplitude and a pro- longed implicit time of photopic cone responses, 2. Elevated rod b-wave threshold in contrast to hypernormal b-wave amplitude following high in- tensity flashes, 3. Reduced amplitude and pro- longed implicit times of oscillatory potentials. Ac- cordingly, any pathogenic hypothesis should ac- count for the above mentioned ERG findings, in- volving both a cone cell abnormality, a rod cell dys- function and a postreceptoral disturbance.

cGMP is mostly located in receptor cells (both rods and cones) (Lolley & Lee 1990; Pugh & Cobbs

1986), but also in middle and inner retinal layers (de Azeredo et al. 1979; Shiells & Falk 1990; Ahmad et al. 1992). Lolley et al. (1977) demonstrated photoreceptor degeneration simulating inherited disease in experimentally induced cGMP accumu- lation.

Ad 1. Cones: Experiments on ground squirrels with cone dominated retinas demonstrated histological changes after a few hours’ elevation of cGMP to 3-4 times physiological levels (Farber et al. 1983). -A similar effect might explain the general reduction in cone ERG amplitudes in our patients. Pro- longed cone implicit time secondary to the admin- istration of a PDE-inhibitor was demonstrated in animal experiments by Schneider & Zrenner (1986).

Ad 2. Rods: Intracellular recordings from rods of dark adapted retinas following light flashes after application of IBMX demonstrated prolonged im- plicit time of the rod response and a moderate rise in amplitude (Lipton et al. 1977). This might ex- plain the prolonged implicit time of the ERG b-wave in our patients. However, our patients dem- onstrated only insignificant changes in the nega- tive rod a-wave amplitude, leaving the hypernor- mal ERG b-wave amplitude with increased light in- tensity unexplained.

Ad 3. Postreceptoral cells: The rod b-wave of the ERG generally is considered to be generated through the Miiller cells’ reaction to K+ release from depolarizing rod-on-bipolars (Dick et al. 1985; Stockton & Slaughter 1989). It therefore seems reasonable to assume some additional ab- normality in these cells or their function.

The origin of OPs is not definitely established. Indeed, according to the most accepted view, OPs are generated in connection with negative feed- back from amacrines to depolarizing on-bipolars (Karwoski & Kawasaki 1991; Speros & Price 1981; Wachtmeister & Dowling 1978), possibly represent- ing a network adaptation mechanism (Steinberg 1966; Knave 1970). Intracellular responses from rabbit amacrines have demonstrated typical OPs with close similarity to the OPs of ERG (Dacheux & Raviola 1986). Corresponding oscillations from other retinal neurons have not been reported. A significant reduction in OPs would imply a re- duced negative feedback, which, through a larger K+ outflow from depolarizing on-bipolars, might

induce an elevated Miiller cell generated b-wave amplitude.

According to several investigators (Dowling & Boycott 1965; Nelson & Kolb 1984; Freed et al. 1987; Daw et al. 1990), a positive feedback from amacrines to depolarizing bipolars may exist as well.

A single amacrine cell may possess both excita- tory and inhibitory transmitter substances (Shep- herd 1990; Miller 1988). A drop in positive feed- back might imply a reduced K+ outflow from rod bipolars, resulting in a reduction in ERG b-wave of the Miiller cell.

Hypothetically, an amacrine-bipolar system like this with the possibility of negative feedback at high stimulus intensities and positive feedback at low stimulus intensities, would explain the clinical findings and represent a biologically appropriate system of gain control.

It seems that no systematic investigation of the retinal cellular localization of cGMP has been per- formed so far. Meanwhile, it may be of significance that in the brain, cGMP is mainly found in glial cells (Somjen 1981; Barres 1991; Fried1 et al. 1989) and especially in the Miiller cell-like Bergman glia in cerebellum (de Vente et al. 1989). In these neu- roglial cells cGMP is found both in the cell mem- brane and in the cytoplasma (Chan-Palay & Palay 1979). It is possible that a primarily glial cell re- lated pathophysiological process might explain the electrophysiological data in our patients.

Yet, the possible pathogenetic role of cGMP still remains to be elucidated. Among the questions that need to be addressed is why a possible defect in cGMP metabolism primarily affects cones and not rods, and whether a single metabolic defect wiU account for all the varied effect upon different retinal cell types.

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Received on October 19th. 1992.

Authors’ address:

Thomas Rosenberg, Svend Erik Simonsen, National Eye Clinic, 1 Rymarksvej, DK-2900 Hellerup, Denmark.

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