Photoreceptor responses of patients with congenitalstationary night blindness
Rockefeller S. L. Young, James Price, James W. Walters, and Joseph M. Harrison
The present study examines the hypothesis that the electroretinogram (ERG) a-wave of patients withcongenital stationary night blindness with myopia (CSNB) is solely cone mediated. The subjects include fourpatients with x-linked recessive inheritance, two patients with no family history, and thirteen age-matchednormal subjects. Because normal subjects have relatively large b-waves (which can influence the measure-ment of the PIII component of the a-wave), the main response parameter studied was the slope of the a-wave.The results for the CSNB patients show that in the light adapted condition, the ratio of the responses tophotopically balanced blue and red flashes was nearly unity; whereas, in the dark-adapted condition, the ratiowas -3 times greater. The ratios for the normal subjects were similar to those of the CSNB patients. Theseresults lead to the conclusion that, in patients with CSNB, the ERG a-wave is not solely mediated by cones.
1. Introduction
This paper is concerned with congenital stationarynight blindness associated with myopia (CSNB).1ACSNB is believed to be a recessively inherited disor-der.2 56 Patients with this disorder are profoundlynight-blind even after 8 h of dark adaptation. Theirelectroretinograms (ERGs) have a well-known (Schu-bert-Bornschein-type) abnormality; the dark-adaptedrod b-wave appears preferentially attenuated. 47 8
The visual pigment concentration and the bleaching/regeneration kinetics of the rod photoreceptors appearto be normal. 9"l0
The most widely accepted view is that the nightblindness defect lies proximal to the rod outer seg-ments 3 9"10 as converging (but circumstantial) evidencesuggests that the electrical response of the rod photo-receptors may be normal. First, the amplitude of thedark-adapted a-wave in some patients was found to beas large as normal, 5 suggesting that the a-wave wascomposed of both rod and cone responses. Second,the electrooculogram (which is predominantly rod me-diated) was also found to be normal in some patients.9
James Walters is with University of Houston, College of Optome-try, Houston, Texas 77004; J. Harrison is with University of TexasHealth Science Center, Ophthalmology Department, San Antonio,Texas 78284-7779; the other authors are with Texas Tech HealthScience Center, Department of Ophthalmology & Visual Sciences,Lubbock, Texas 79430-0001.
Third, the pupil of CSNB patients was observed todilate in the dark after a full bleach with the same timecourse as the regeneration of rhodopsin.10" 1 In accor-dance with Alpern et al.,'0 the latter observation sug-gests that certain rod signals are preserved in thesepatients.
There is, however, one important observation thathas remained in discord with the widely accepted view.In 1954, Armington and Schwab'2 reported that thedark adapted a-wave of a night-blind subject (patient2) had the action spectrum of cones-not of a combina-tion of rods and cones as found in normal subjects.13
This patient, like CSNB patients described in otherstudies, had a long history of night blindness, wasmyopic, and had a Schubert-Bornschein-type ERGabnormality. More recently, others' 4 stated that theamplitude spectrum of the CSNB a-wave was alsoconsistent with that of cones alone. However, theevidence cannot be scrutinized as their data were notincluded in the publication. To our knowledge, noother study has examined the action spectrum of thedark-adapted a-wave in CSNB patients or, for thatmatter, has considered the possibility that the largedark-adapted a-wave in CSNB patients may be entire-ly cone mediated. Therefore, the purpose of thepresent study was to provide a necessary and sufficienttest of the hypothesis that the a-wave of CSNB pa-tients is solely cone mediated.
II. Materials and Methods
A. Human Subjects
Six patients with CSNB participated in this study.The diagnostic criteria used are as follows: (1) a histo-ry of night blindness that is congenital and stationary;
(2) a final dark-adapted threshold that is >100 timesnormal; (3) a family history inconsistent with autoso-mal dominant inheritance (the patient could have sim-plex, multiplex, or X-linked inheritance); (4) a Schu-bert-Bornschein-type ERG, i.e., the scotopic b/a ratiois markedly reduced but the photopic b/a ratio is nor-mal or nearly normal; and (5) aside from the usualmyopic changes such as a tilted disk and peripapillaryatrophy, the patient must not have significant fundusabnormalities. Specifically, the patient must not havefundus abnormalities that are consistent with retin-oschisis, fundus albipunctatus, Oguchi's disease, reti-nitis pigmentosa, or the like.
The patients' ages ranged from 8 to 74 (median =35.5) yr. Three of the men (P1, P2, and P4) belongedto the same x-linked recessive pedigree. A fourth man(P6) belonged to another x-linked recessive pedigree.A boy (P5) and a girl (P3) were isolated cases. Allpatients were myopic; the refractive error ranged from-5 to -15 (median = -7.25) diopters.
The normal subjects (n = 13) included staff mem-bers, normal relatives of patients, and persons recruit-ed from the general population (by newspaper adver-tisements). Their ages ranged from 10 to 69 (median= 28; mean = 35.5) yr. Informed consentwas obtainedfrom all subjects and patients after the nature of theprocedures had been fully explained.
B. ERG Recording Procedures
The subjects' pupils were dilated with 2.5% Neo-Synephrine and 1% Mydriacyl. The subjects werethen dark adapted for more than 20 min with a corneal(gold-foil) electrode inserted under the lower eyelid ofone eye.
The ERGs were recorded on a Nicolet Med-80 sys-tem. The signals were amplified, filtered (bandpass of1-1500 Hz), and also subjected to artifact rejection.The response for each subject was averaged 15 timeswith an interflash interval of 5 s. The averaged re-sponse was then stored on a floppy disk for off-lineanalysis.
The ERG stimulus was a 10-ps xenon flash projectedinto a LKC Ganzfeld sphere. The white I16 flash pro-jects -1.54-log photopic troland-s or 1.93-log scotopictroland-s for a subject with a 8-mm pupil. The red andblue flashes were photopically balanced using filterssimilar to those described by others.15 The photopicbackground was white illumination of 2.81-log scotopictrolands.
C. Analysis
We used the slope of the ERG a-wave as the bestindex of the photoreceptor response.16"17 In contrastto measuremnts ofthe a-wmevamplitude, the a-waveslope is much less influenced by the latency and ampli-tude of the subsequent b-wave. Therefore, compari-sons between the a-wave of CSNB patients and normalsubjects are justifiable, even though normal subjectshave large b-waves.
The a-wave slope (expressed in microvolts per milli-second) was computed from the time-average wave-
forms obtained from each patient and normal subject.The slope was measured off-line using a program writ-ten for the Med-80 system. The investigator placedcursors at the 10 and 90% points of the a-wave; theMed-80 computer assessed the amplitude and implicittime coordinates of each digital point along the a-waveand thereafter computed the slope using a regressionanalysis.
111. Results
Figure 1 shows waveforms of responses averagedacross six CSNB patients and across thirteen normalsubjects for several experimental conditions. Thesewaveforms are presented here to illustrate conciselydifferences and similarities found between the ERGresponses of the patients and normal subjects. TheERG responses to a white flash (Fig. 1, top row) for theCSNB and normal subjects are similar to those de-scribed by others.47,8
The main results (Table I) are the ratio of the a-waveslope for the blue and red flashes. In light-adaptedconditions (Table I, right column) the ratio for boththe normal subjects and CSNB patients was on theaverage about unity. In dark-adapted conditions (Ta-ble I, left column), the ratio was -3 times greater. Atwo-way analysis of variance indicates that the vari-ance associated with ADAPTATION (dark vs light) washighly significant (F = 88.08, p < 0.001 for df = 1/34).The effect of SUBJECTS (CSNB vs normal) and theinteraction effect of SUBJECTS X ADAPTATION were notsignificant. A correlated t-test confirms that the dif-ference between the dark- and light-adapted ratios forthe CSNB patients is significant (p < 0.005 for t = 5.13with df = 5).
Figure 2 illustrates differences in the a-waves elicit-ed by photopically balanced blue and red flashes over arange of flash intensities. One interesting observationis that certain oscillatory potential components (desig-nated by either a, and ap or 02) are not as apparent inthe CSNB responses as they are in the normal respons-es. This is consistent with that observed previous-ly. 4' 7' 8
IV. Discussion
If the a-wave of CSNB patients were only mediatedby cones, the ratio of a-wave slopes (elicited by photo-pically balanced blue and red flashes) should haveapproached unity in the dark adapted condition as itdoes in the light-adapted condition. Our results showthat for the dark-adapted a-waves, the slope for theblue flash was -3 times that for the red flash. Thisfinding is not likely to be attributable to the recruit-ment of blue (short-wavelength sensitive) cones in thedark, as blue cones contribute relatively-littleto theERG.'9-2' Additionally, this finding is not likely to beexplained by chromatic adaptation of a subpopulationof cones. Our background field was achromatic; thelight source was an unattenuated tungsten lamp with acolor temperature of -2800 K. The most probableexplanation of our results is that both rod and cone
100 msecFig. 1. Average electroretinogram for six CSNB patients (left) and thirteen normal subjects (right). The upper three rows show theresponses measured in the dark. The bottom two rows show the responses on a steady 2.81-log scotopic troland background field. The red
photoreceptors in CSNB patients mediate the ERG a-wave.
Although our conclusion differs from that of Arm-ington and Schwab,12 our ERG responses do not neces-sarily differ from those illustrated in their paper (theirsubject 2). In their Fig. 3, one can observe that ingeneral the a-waves elicited by short-wavelengthflashes (<515 nm) increased in amplitude when the eyewas dark adapted; but for long-wavelength flashes, thea-wave changed little with dark adaptation. Thus onemight infer that the a-wave of Armington's patient(like ours) was partly mediated by photoreceptors thatwere sensitive to short-wavelength flashes and exhibit-ed a large increase in sensitivity when dark adapted.
In the course of our analysis, we also noticed (asanother study reported4 ) that the photoreceptor re-sponse appears on the average smaller in the CSNBpatients than that of age-matched normal subjects.Analysis of the slopes of the a-waves elicited by thedifferent flash and adaptation conditions (Fig. 1, mid-dle and bottow rows) showed that the differences be-tween CSNB patients and normal subjects are statisti-cally significant (p < 0.01; two-way ANOVA F = 11.69for df = 1/68). The a-wave slope for normal subjectswas generally steeper than that for the CSNB patients.For example, for the dark-adapted blue flash condi-tion, the mean a-wave slope for the patient was -7.78,whereas for the normal subjects, it was -11.77 MV/ms.For the light-adapted red flash condition, the means
Fig. 2. Dark-adapted ERG responses as a function of flash intensity. The CSNB waveforms (left) were averaged across three patients (P1,
P2, and P4), the normal waveforms (right) were averaged across three normal subjects (N5, N7, and N13). The red and blue flashes were pho-
topically balanced. The wavelets labeled ap and a, refer to Armington's1 3 designation of the cone and rod a-wave components, respectively.
The wavelet labeled 02 refers to Lachapelle's 7 designation of the same feature of the ERG.
were -2.50 and -3.42 gV/ms for the patients andnormal subjects, respectively.
This reduction in the a-wave slope, however, cannotfully account for the severity of the patients' nightblindness. The subnormal a-wave response found inour CSNB patients can only explain a threefold loss ofnight vision sensitivity as the CSNB a-wave can besimulated by placing a 0.5 neutral density filter infront of the normal observers' eyes (Fig. 2). In con-trast, psychophysical measurements estimate the rod-mediated threshold of CSNB patients to be over 10OXhigher than normal.42223 A study of normal subjectsrecently suggested that individuals with high myopiagenerally have a subnormal a-wave amplitude. 2 4 Asmany of our normal subjects were emmetropic, thecomparatively smaller a-waves in CSNB patients mayrelate to their myopia rather than to their night blind-ness.
V. Conclusion
The present results support the widely acceptedview that the site of the defect lies proximal to the rodouter segments. Hypotheses attributing the underly-ing defect-partially or entirely-to the rod synapticprocesses,25 the horizontal cells,26 the amacrine/gan-glion cells,4 or structures that regulate the adaptationof rod signals'0 remain tenable.
Requests for reprints should be directed to R. S. L.Young, Department of Ophthalmology & Visual Sci-ence, Texas Tech Health Science Center, Lubbock,TX 79430-0001. We wish to thank Ben De La Rosaand Carmen Cano for technical assistance. The re-search was supported by the RP Foundation FightingBlindness, National Eye Institute grant EY05746, andan unrestricted grant from the Research to PreventBlindness, Inc., to the Department of Ophthalmology& Visual Sciences in Lubbock and the Department ofOphthalmology in San Antonio.
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Books continued from page 1362light of the birthplace and evolution of stars. Sandage then simplyintroduces the theoretical concepts needed to understand how starsevolve and shows how to construct color-magnitude diagrams (plotsof absolute brightness against color/temperature for a group of stars)for different stellar populations. By comparing the theoretical CMdiagrams to observations of the stars in our galaxy, a good under-standing of the ages and distances of star clusters can be obtained.These data provide important clues to the origin of our galaxy andserve as primary calibrators for the distances to nearby galaxies. InRecent Progress in the Understanding of Pulsars, Taylor and Stin-ebring review much of what we know about radio pulsars-radiosources which pulse with great regularity and which are thought tobe rapdily rotating neutron stars. After carefully discussing thegalactic distribution, the characteristics of the emission, and theevolution of pulsars, the authors review the mechanisms proposed toexplain how pulsars radiate. They make the interesting point thatalthough we know why pulsars pulse-rotation of a neutron star-we still have difficulty understanding why they shine. The authorsshow that there are still difficult theoretical problems with con-structing the standard model of a pulsar as an electromagneticengine driven by a rapidly rotating, magnetic neutron star. In ThePhysics of Supernova Explosions, Woosley and Weaver review ourtheoretical understanding of the two different classes of superno-vae-those which are end points of the evolution of massive stars(Type II) and those in which the progenitor object, an accretingwhite dwarf in a binary system, undergoes a thermonuclear explo-sion (Type I).
The ANNUAL REVIEW OF ASTRONOMY AND ASTRO-PHYSICS is ordinarily not read from cover to cover. Most astrono-mers, I believe, read the reviews quite selectively. So it was some-what of a surprise, after reading the entire volume, to notice itstotally illogical organization. The two reviews on pulsars are sepa-rated by hundreds of pages. The multiple discussions of the inter-stellar medium (Yorke; Cowie and Songaila), the structure of thegalaxy (Sandage; Bahcall; Sofue, Fujimoto, and Wielebinski), andthe atmospheres of cool stars (Tsuji; Dupree) are all also widelyseparated. Surely readers unfamiliar with the jargon found in thetitles will be quite confused about the material discussed. I wouldsuggest that the volumes be organized according to the simplescheme used to classify the reviews from the previous ten years.Such systematic organization of the reviews would provide an impor-tant service to general readers of the series.
STUART L. MUFSON
Sixth Conference on Atmospheric Radiation, May 1986.American Meteorological Society, Boston, 1986. 369 pp. $30.
One of the most active topical groups in the Optical Society is theTechnical Group on Atmospheric Optics, and their papers on atmo-spheric transmission, optical scattering by aerosols, lidar, remotesensing of the atmosphere, meteorological optics and optical propa-gation generally appear in either Applied Optics or JOSA A. Thereis also a similar topical group within the American MeteorologicalSociety, and from time to time this group assembles either for anational conference (sponsored by AMS) or for an internationalconference (generally sponsored by the Radiation Commission ofIUGG and WMO). The conference center at Williamsburg, VA, hasbeen a favorite site for these AMS atmospheric radiation meetings.We should add that many of the AMS participants are the very samepeople as the OSA participants, and their choice of society for a givenpaper is determined by whether the paper emphasizes the underly-ing optics, or instead the meteorology or climatology.
The present volume consists of the extended abstracts of 90 pa-pers (by 209 authors from some 60 different organizations). The
