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Cone and Rod Function in Vitamin a Deficiency with Chronic Alcoholism and in Retinitis Pigmentosa
CONE AND ROD FUNCTION IN VITAMIN A D E F I C I E N C Y WITH CHRONIC ALCOHOLISM AND IN RETINITIS PIGMENTOSA M I C H A E L A. S A N D B E R G , P H . D . , J O B. R O S E N , M.D., A N D E L I O T L. B E R S O N , M.D.
Boston, Massachusetts
A dietary deficiency of vitamin A has caused night blindness in humans with ele vated cone and rod thresholds 1-10 and re duced electroretinograms (ERGs). 5-7,11,12 Patients with cirrhosis of the liver, with or without obstructive jaundice, have exhib ited raised psychophysical thresholds 13 " 16 and reduced ERG amplitudes. 17-18 Their night blindness may have been caused by inadequate consumption19 or malabsorption15 of vitamin A, or alter natively, by impaired liver synthesis or release of the plasma proteins for trans port of vitamin A, or both.20 Laboratory investigations have shown that roddominated rats 21-25 and cone-dominated ground squirrels,26 fed vitamin Adèfìcient diets and maintained in light, developed photoreceptor malfunction and degeneration. Recovery of retinal function has been achieved in vitamin A-deficient humans, 1-5,11 patients with cirrhosis of the liver,14,15 and vitamin A-depleted rats21,24 by feeding them vita min A. Although patients with hereditary retinitis pigmentosa have also exhibited night blindness with elevated cone and rod thresholds 10,27 " 30 and reduced ERG amplitudes,31 such patients treated with vitamin A, even in large doses, have not From the Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Mas sachusetts. This work was supported in part by Research Grant EY00169 and Research Career De velopment Award EY70800 (Dr. Berson) from the National Eye Institute; and in part by grants from the National Retinitis Pigmentosa Foundation, Bal timore, Maryland, and the George Gund Founda tion, Cleveland, Ohio. Reprint requests to Michael A. Sandberg, Ph.D., Berman-Gund Laboratory, 243 Charles Street, Bos ton, MA 02114.
responded.32,33 Patients with retinitis pig mentosa have normal plasma levels of vitamin A34,35 and retinol-binding pro tein 36-38 ; but a local retinal deficiency of vitamin A has not been excluded.39,40 In this study, we evaluated cone and rod responses in two vitamin A-deficient patients with chronic alcoholism. After administering vitamin A to them, we compared their responses during stages of retinal function recovery with cone and rod responses in stages of retinal degener ation in patients with different genetic types of retinitis pigmentosa. CASE REPORTS Case 1—A 55-year-old white man had a five-year history of progressive night blindness that was so severe he needed a flashlight to see at dusk. He admitted to heavy beer drinking for at least 25 years, but also said he ate regular meals. He denied use of tobacco. Family history was noncontributory for ocular disease. On ocular examination, his visual acuity was 6/9 (20/30) in both eyes. Pertinent findings included slight conjunctival icterus and no evidence of xerophthalmia or keratomalacia. The ocular media were clear except for minimal cortical lens changes. The disk, macula, vessels, and periph eral fundus were unremarkable in each eye; no bone spicule pigmentation or white deposits were ob served in either fundus. Visual fields were full on the Goldmann perimeter with a I4 white test light. General physical examination revealed this pa tient had a palpable liver, 2+ pedal edema, and marked ascites. Serum showed total bilirubin, 7.6 mg/100 ml (normal, 0.0 to 1.0 mg/100 ml); direct bilirubin, 3.4 mg/100 ml (normal, 0.0 to 0.4 mg/100 ml); alkaline phosphatase, 96 Bodansky units (nor mal, 2 to 6 units); serum glutamic oxaloacetic trans aminase, 94 units/ml (normal, 10 to 40 units/ml); serum glutamic pyruvic transaminase, 42 units/ml (normal, 5 to 35 units/ml); total protein, 6.8 g/100 ml (normal, 6 to 8.4 g/100 ml); albumin, 2.8 g/100 ml (normal, 3.5 to 5 g/100 ml); globulin, 4 g/100 ml (normal, 2 to 3 g/100 ml); triglycérides, 101 mg/100 ml (normal, 40 to 150 mg/100 ml); and cholesterol, 139 mg/100 ml (normal, 150 to 280 mg/100 ml). Serum lipoprotein electrophoresis showed a normal beta fraction. Serum retinol-binding protein was nondetectable by a radial immunodiffusion tech-
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nique. 41 Serum zinc varied between 50 mg/100 ml and 68 mg/100 ml (normal, 80 to 160 mg/100 ml). Because plasma vitamin A42 was nondetectable this patient received 10,000 units of vitamin A orally per day for four weeks and three supplementary doses of 100,000 units each of vitamin A (Aquasol) orally on days 7,8, and 15 after initiation of therapy. Plasma vitamin A reached normal levels on day 8 (normal range, 0.15 to 0.6 μg/ml) and fluctuated thereafter within this range. During therapy, the patient stopped drinking beer, but his liver function measurements did not change. Case 2—A 38-year-old white man reported a oneyear history of night blindness and photophobia. He admitted to heavy beer drinking and poor nutrition for years. Family history was noncontributory for ocular disease. Visual acuity was R.E.: 6/9 (20/30), and L.E. : 6/6 (20/20), with a refractive error of +1.00 in both eyes; pertinent findings included clear cor neas, absence of xerosis and scierai icterus, clear media, and normal fundi. Visual fields on the Goldmann perimeter were within normal limits. This patient did not submit to a general physical examination or detailed psychophysical testing. His plasma vitamin A was initially nondetectable, so vitamin A tablets (10,000 units per day) were pre scribed. Plasma vitamin A was borderline normal on day 80; he received two oral doses of 100,000 units of vitamin A (Aquasol) under direct supervision on days 119 and 123 after his initial examination. Plasma vitamin A was normal on days 129 and 134. He continued to drink beer during the course of his therapy. Other cases—Psychophysical thresholds and ERGs from representative patients, ages 9 to 22 years, with the early stages of different genetic types of retinitis pigmentosa were compared with those from Cases 1 and 2. These patients with retinitis pigmentosa have been described previously.31 METHODS
Full-field ERGs were recorded by pre viously described methods. 43 Under these conditions, normal peak-to-peak ampli tudes (mean ± 2 S.D.) were 175 ± 50 μ ν for dim blue light, 425 ± 75 μν for white light, 75 ± 25 μ ν for flickering white light, and 95 ± 27 μν for single flashes of white light in the presence of a white background light. The interval between stimulus onset and the peak of the b-wave was considered for the measurement of implicit time. The normal range of im plicit times was 78 to 108 msec for rod b-wave responses to dim blue light, and 27 to 37 msec for cone b-wave responses to 30 cps flicker or white light with a background.
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Both patients were dark-adapted with a Goldmann-Weekers dark adaptometer modified to have automatic intensity con trol.44 Patients were dark-adapted for 30 to 45 minutes and tested with an 11degree white test light presented to the fovea or 20 to 25 degrees temporal to the fovea. Threshold measurements repre sented an average of five or six determina tions for each patient and varied within 0.3 log-unit on a given day. Rod (ΤΓ0), green cone (ir4), and blue cone (TT, and irj functions in the fovea, and rod and blue cone functions in the retina 10 degrees above the fovea were monitored with Stiles' two-color increment thresh old technique. 30 A 2.5-degree, 500-nm (10 nm half bandwidth) stimulus was flashed for 200 msec on a 68-degree, longwave (cut-on at 540 nm) background field of variable intensity. Additionally, darkadapted rod and cone functions were measured for Case 1 in the retina 10 degrees above the fovea on day 13 of vitamin A therapy. Two-and-one-half de gree, narrow-band (10 nm half band width) stimuli were flashed for 200 msec either after 30 minutes of dark adaptation for separating rod function, or within 3 to 11 minutes after termination of shortwave preadaptation (k < 470 nm) for separating green and red cone function. For studies of both increment thresholds and dark adapted thresholds, responses varied within ± 0.15 log-unit on repeat measure ments. RESULTS
Before vitamin A therapy, the ERGs in Case 1 demonstrated a nondetectable rod response to a dim blue light (Fig. 1). Dark-adapted responses to white light were reduced 95% below normal in am plitude. Cone responses to white light at 30 cps were reduced 75% below normal in amplitude and fell just within the nor mal range of b-wave implicit times. Dur ing the course of oral vitamin A therapy,
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DARK ADAPTED THRESHOLDS (Patitnt 1) 11" TEST SPOT Vit A today·
Normal
Vit A )3 dayt
i ί Patient 1 : Pre Vitamin A ;
Vitamin A 7 days
Vitamin A 13 days
Vitamin A 27 days
Fig. 1 (Sandberg, Rosen, and Berson). Full-field ERGs for a normal person and for the patient in Case 1 with chronic alcoholism, before and during vitamin A therapy, in response to single flashes of a dim blue (λ < 470 nm) light (left column), an 8 ft-L white light (middle column), and white light flicker ing at 30 cps (right column). Two or three consecu tive responses to the same stimulus are superim posed. The vertical lines denote stimulus onset.
ERG amplitudes returned to normal. Cone implicit times became slightly fast er and remained within the normal range. Before vitamin A therapy, ERGs in Case 2 (Fig. 2) were similar to those in Case 1. During the course òf oral vitamin A, rod and cone ERGs returned to borderline
Normal
Patient 2 Pre-Vitamin A
Vitamin A 130 days
Fig. 2 (Sandberg, Rosen, and Berson). Full-field ERGs for a normal person and for the patient in Case 2 with chronic alcoholism, before and during vitamin A therapy. For stimulus conditions, see Figure 1.
i ·■
* 2
i* • > Central Retina
» • 2 0 - 2 5 ° Temporal Retina
Fig. 3 (Sandberg, Rosen, and Berson). Progress of dark-adapted psychophysical thresholds in Case 1 with the patient looking directly at the white test light, or looking eccentrically to allow testing of the temporal retina.
normal amplitudes, and cone implicit times became slightly faster. Dark-adapted thresholds to an 11degree white test light were initially ele vated 5 log-units above normal in Case 1, and 3 log-units above normal in Case 2. The courses of recovery for the fovea and temporal retina (20 to 25 degrees from the fovea) are illustrated for Case 1 (Fig. 3); threshold in the central retina returned to normal more slowly than threshold in the peripheral retina. Increment thresholds in Case 1 on the 13th day of vitamin A therapy (Fig. 4) showed nondetectable rod (ιτ0) function, normal green cone (TTJ function, and bor derline normal blue cone (ττ, and ΤΓ3) func tion in the fovea; normal rod function and markedly elevated blue cone function were found 10 degrees above the fovea. Dark-adapted thresholds, obtained 10 de grees above the fovea in Case 1 on the same day, revealed normal rod thresholds and elevated green and red cone thresh olds (Fig. 5). On the 27th day of vitamin A therapy (Fig. 4), rod and cone functions were normal in both retinal areas. Incre ment thresholds in Case 2 were measured
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PATENTI
Fig. 4 (Sandberg, Rosen, and Berson). Psychophysical increment thresholds in the fovea and 10degree superior retina in Case 1 on days 13 and 27 of therapy. Solid lines designate average normal function mediated by rods (ττ0), green cones (ir4), and blue cones (ir, and ττ3).
Log Background Retinal Illuminance (Photopic Trolands)
on day 121 after initiation of vitamin A therapy; rod function was normal in the fovea and 10-degree superior retina; green cone and blue cone functions were normal in the fovea, while blue cone function was nondetectable 10 degrees above the fovea as tested. We compared ERGs from Case 1 with ERGs from representative cases of differ ent genetic types of retinitis pigmentosa l-,0 (Fig. 6). The case of dominant retinitis pigmentosa with reduced penetrance and the cases of recessive (autosomal or sexlinked) retinitis pigmentosa have reduc tions in full-field cone ERG amplitudes, but marked delays in cone ERG b-wave implicit times.31 In contrast, Case 1 shows normal ERG b-wave implicit times. Only the cone ERGs of the case of dominant retinitis pigmentosa with com plete penetrance resembled those of Case 900 6C 1. Psychophysical increment threshold Fig. 5 (Sandberg, Rosen, and Berson). Psychophysical thresholds in Case 1 on day 13 of vitamin A measurements distinguished Case 1 from therapy. Thresholds were obtained in the 10-degree cases of dominant retinitis pigmentosa superior retina to 2.5 degree stimuli of varying wavelengths flashed for 200 msec after 30 minutes with complete penetrance. Case 1 showed of dark adaptation (rod function), or from 3 to 11 the unusual combination of elevated fominutes after termination of shortwave preadapta- veal rod thresholds with normal perifotion when the cones had reached dark-adapted lev els (cone function). Solid lines designate normal veal rod thresholds during recovery on vi dark-adapted rod and cone levels. tamin A therapy (Fig. 4). In contrast, cases -2.0
Vitamin A - 1 3 Days n
C o m Function
o Rod Function
700
Wavelength (nm)
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of dominant retinitis pigmentosa with complete penetrance typically have shown rod thresholds that are less elevated in the fovea than in the perifovea, or nondetectable (Fig. 7) in both retinal areas.
CONE ERGs White OOcps) White ü Bkgd
Normal
Vitamin A deficient Dominant RP complete penetrance
\
SAAX
DISCUSSION
Both cases with chronic alcoholism and nondetectable plasma vitamin A had ele vated rod thresholds in dark adaptation testing, nondetectable rod ERGs, and cone ERGs reduced in amplitude b u t normal in b-wave implicit time. Normal cone ERG b-wave implicit times separat ed these cases from those with dominant retinitis pigmentosa with reduced pene trance, as well as those with Xchromosome linked and autosomal reces sive retinitis pigmentosa. The noncontributory family history for retinitis pig mentosa in both cases of chronic alcohol ism suggested they did not have domi nant retinitis pigmentosa with complete penetrance. During stages of recovery on vitamin A therapy, the psychophysical and ERG findings in the vitamin A deficient pa tients with chronic alcoholism were dif ferent from those observed in degenera tive stages of different types of hereditary retinitis pigmentosa. The vitamin A defi-
^TR^FF
:VW^
Dominant RP reduced penetrance
Recessive RP
NOVEMBER, 1977
-ttftt ^ ^
Fig. 6 (Sandberg, Rosen, and Berson). Full-field cone ERGs for a normal person, a patient with vitamin A deficiency and chronic alcoholism (Case 1), and three patients with the early stages of differ ent genetic types of retinitis pigmentosa. Arrows designate b-wave implicit times. Calibration symbol (lower right) is 100 μν vertically, and 50 msec and 25 msec horizontally for left and right columns, respectively.
DOMINANT RETINITIS PIGMENTOSA °°o
w
Λ"·\
Superior Retins
4y
Ì -10
. J
n
a
Fig. 7 (Sandberg, Rosen, and Ber son). Psychophysical increment thresholds for two siblings age 20 years (triangles) and 22 years (squares) who have dominant reti nitis pigmentosa with complete penetrance. Stimulus conditions were the same as in Figure 4.
i l n<
°
0
M
-
i—^—//■
i
Log Background Retinal Illuminance (Photopic Trolands)
i
i
i
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cient patients never showed delayed cone
b-wave implicit times, as seen in domi nant retinitis pigmentosa with reduced penetrance or recessive types of retinitis pigmentosa. Additionally, small field psy chophysical increment thresholds and dark-adapted thresholds showed the unu sual combination of elevated foveal rod thresholds with normal perifoveal rod thresholds during recovery on vitamin A therapy, a combination not seen in domi nant retinitis pigmentosa with complete penetrance or in other genetic types of retinitis pigmentosa. 28 · 30 A previous psychophysical study in normal persons suggested that rods and cones compete for available vitamin A during visual pigment regeneration. 45 In the cone-dominated fovea (central 2.5 de grees), regeneration of rod pigment after a bleaching light was retarded during the process of cone pigment regeneration; but, in the rod-dominated perifovea (15 degrees away), rod pigment regeneration after a bleaching light was unaffected by simultaneous cone pigment regeneration. Similarly, rod-cone rivalry for vitamin A provides an explanation for the slower recovery of rods in the fovea than 10 degrees above the fovea (Case 1). Addi tionally, the slower recovery of cones in the perifovea than in the fovea, observed in both cases, could also be caused by rod-cone competition for vitamin A in the perifovea. In early stages of vitamin A deficiency in the rat, before outer segment degenera tion begins, the concentration of opsin appears normal, while that of the chromophore (vitamin A aldehyde) is depleted 21 ; elevations of rod ERG thresholds were found logarithmically related to the amount of rhodopsin remaining in the retina. 22 In contrast, in patients with reti nitis pigmentosa elevations of rod psycho physical thresholds have been linearly correlated with the amount of rhodopsin remaining as measured by retinal densi-
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tometry. 29 This suggests that the pathogenetic mechanism in retinitis pig-
mentosa involves the loss of all the visual pigment molecule (opsin + chromophore), rather than a specific lack of the chromophore (vitamin A aldehyde). The present study also supports the idea that the pathogenetic mechanism in heredi tary retinitis pigmentosa does not involve a local deficiency of vitamin A in the retina. SUMMARY
Two vitamin A-deficient patients with chronic alcoholism and night blindness had elevated dark-adapted thresholds, nondetectable rod electroretinograms (ERGs), and cone ERGs that were re duced in amplitude with normal b-wave implicit time. During oral vitamin A ther apy, both patients regained normal plas ma vitamin A levels, normal rod thresh olds, and normal rod and cone ERG am plitudes. Psychophysical studies during stages of recovery revealed that, in the fovea, cone function returned to normal before rod function; but, in the perifovea, the opposite occurred. This finding can b e explained by rod-cone rivalry for vitamin A and regional differences in rod-cone densities. Stages of recovery of retinal function in vitamin A-deficient alcoholic patients differed from degenera tive stages described in various types of hereditary retinitis pigmentosa. REFERENCES 1. Wald, G., Jeghers, H., and Arminio, J.: An experiment in human dietary night blindness. Am. J. Physiol. 123:732, 1938. 2. McDonald, R., and Adler, F. H.: Effect of anoxemia on the dark adaptation of the normal and of the vitamin A-deficient subject. Arch. Ophthalmol. 22:980, 1939. 3. Wald, G., and Steven, D.: An experiment in human vitamin A-deficiency. Proc. Nati. Acad. Sci. 25:344, 1939. 4. Hecht, S., and Mandelbaum, J.: Dark adapta tion and experimental human vitamin A deficiency. Am. J. Physiol. 130:651, 1940. 5. Bornschein, H., and Bukovich, V.: Das Elek-
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troretinogram bei Mangelhemeralopie. Von Graefes Arch. Ophthalmol. 153:484, 1953. 6. Arden, G. B., and Kolb, H.: Electrophysiological investigations in retinal metabolic disease. Their range and application. Exp. Eye Res. 3:334, 1964. 7. Fells, P., and Bors, F.: Ocular complications of self-induced vitamin A deficiency. Trans. Ophthal mol. Soc. U.K. 89:221, 1969. 8. Norden, A., and Stigmar, G.: Measurement of dark adaptation in vitamin A deficiency by a new quantitative technique. Acta Ophthalmol. 47:716, 1969. 9. Levy, N. S., and Tockes, P. P.: Fundus albipunctatus and vitamin A deficiencv. Am. J. Ophthal mol. 78:926, 1974. 10. Sloan, L. L.: An apparatus for studying re gional differences in light sense. Arch. Ophthalmol. 22:233, 1939. 11. Dhanda, R. P.: Electroretinography in night blindness and other vitamin A deficiencies. Arch. Ophthalmol. 54:841, 1955. 12. Genest, A.: Vitamin A and the electroretinogram in humans. In François, J. (ed.): The Clinical Value of Electroretinography, ISCERG Symposi um, Ghent, 1966. Basel, S. Karger, 1968, pp. 250259. 13. Bailliart, P.: Les maladies de la rétine: l'hespéranopie (ou héméralopie) essentielle. Traite Ophtalmol. 5:368, 1939. 14. Haig, C , Hecht, S„ and Patek, Jr., A. J.: Vitamin A and rod-cone dark adaptation in cirrhosis of the liver. Science 87:534, 1938. 15. Patek, Jr., A. J., and Haig, C : The occurrence of abnormal dark adaptation and its relation to vitamin A metabolism in patients with cirrhosis of the liver. J. Clin. Invest. 18:609, 1939. 16. Parker, F . W., Jr.: Studies on dark adaptation in military personnel complaining of "night blind ness." Arch. Ophthalmol. 35:555, 1946. 17. Schmidt, B.: Electroretinographic investiga tions on dark adaptation in liver cirrhosis. In Fran çois, J. (ed.): The Clinical Value of Electroretinogr aphy, ISCERG Symposium, Ghent, 1966. Basel, S. Karger, 1968, pp. 267-272. 18. Cinotti, A., Stephens, G., and Kiebel, G.: The electroretinographic response and adaptation in chronic alcoholics. In Wirth, A. (ed.): Symposium on Electroretinography, ISCERG Symposium VIII, Pisa, Pacini, 1970, pp. 269-276. 19. Jayle, G. E., Ourgaud, A. G., Baisinger, L. F., and Holmes, W. J.: Night Vision. Springfield, Charles C Thomas, 1959, pp. 209-211. 20. Smith, F. R., and Goodman, D. S.: The effects of diseases of the liver, thyroid, and kidneys on the transport of vitamin A in human plasma. J. Clin. Invest. 50:2426, 1971. 21. Dowling, J. E., and Wald, G.: Vitamin A deficiency and night blindness. Proc. Nati. Acad. Sci. 44:648, 1958. 22. Dowling, J. E.: Chemistry of visual adapta tion in the rat. Nature 188:114, 1960. 23. Dowling, J. E., and Gibbons, I. R.: The effect of vitamin A deficiency on the fine structure of the retina. In Smelser, G. (ed.): The Structure of the Eye. New York, Academic Press, 1961, pp. 85-99.
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24. Noell, W. K., Delmelle, M. C , and Albrecht, R.: Vitamin A deficiency effect on retina. Depen dence on light. Science 172:72, 1971. 25. Herron, W. L., Jr., and Riegel, B. W.: Produc tion rate and removal of rod outer segment material in vitamin A deficiency. Invest. Ophthalmol. 13:46, 1974. 26. Berson, E. L.: Experimental and therapeutic aspects of photic damage to the retina. Invest. Oph thalmol. 12:35, 1973. 27. Mandelbaum, J.: Dark adaptation. Some physiologic and clinical considerations. Arch. Oph thalmol. 26:203, 1941. 28. Zeavin, B. H., and Wald, G.: Rod and cone vision in retinitis pigmentosa. Am. J. Ophthalmol. 42:253, 1956. 29. Highman, V. N., and Weale, R. A.: Rhodopsin density and visual threshold in retinitis pigmentosa. Am. J. Ophthalmol. 75:822, 1973. 30. Sandberg, M. A., and Berson, E. L.: Blue and green cone mechanisms in retinitis pigmentosa. In vest. Ophthalmol. & Visual Sci. 16:149, 1977. 31. Berson, E. L.: Retinitis pigmentosa and allied retinal diseases. Electrophysiological findings. Trans. Am. Acad. Ophthalmol. Otolaryngol. 81:659, 1976. 32. Chatzinoff, A., Nelson, E., Stahl, Ν,, and Clahane, A.: Eleven-cis vitamin A in the treatment of retinitis pigmentosa. A negative study. Arch. Ophthalmol. 80:417, 1968. 33. Bergsma, D., and Wolf, M.: A therapeutic trial of vitamin A in patients with pigmentary retinal degenerations. A negative study. In Landers, M. B., I l l , Wolbarsht, M. L., Dowling, J. E., and Laties, A. M. (eds.): Retinitis Pigmentosa. Clinical Implica tions of Current Research. New York, Plenum Press, 1977, pp. 197-209. 34. Krachmer, J. H., Smith, J. L., and Tocci, P. M.: Laboratory studies in retinitis pigmentosa. Arch. Ophthalmol. 75:661, 1966. 35. Massoud, W. H., Bird, A. C , and Perkins, E. S.: Plasma vitamin A and beta-carotene in retinitis pigmentosa. Br. J. Ophthalmol. 59:200, 1975. 36. Maraini, G.: The vitamin A transporting protein complex in human hereditary pigmen tosa retinal dystrophy. Invest. Ophthalmol. 13:288, 1974. 37. Futterman, S., Swanson, D., and Kalina, R. E.: Retinol in retinitis pigmentosa. Evidence that retinol is in normal concentration in serum and the retinol-binding protein complex displays unaltered fluorescence properties. Invest. Ophthalmol. 13:798, 1974. 38. Maraini, G., Fadda, G., and Gozzoli, F.: Serum levels of retinol-binding protein in different genetic types of retinitis pigmentosa. Invest. Oph thalmol. 14:236, 1975. 39. Gouras, P., and Chader, G.: Retinitis pigmen tosa and retinol-binding protein. Invest. Ophthal mol. 13:239, 1974. 40. Bergsma, D. R., Wiggert, B. N., Funahashi, M., Kuwabara, T., and Chader, G. J.: Vitamin A recep tors in normal and dystrophic human retina. Nature 265:66, 1977. 4 L Mancini, G., Carbonara, A. O., and Heremans,
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J. F.: Immunological quantitation of antigens by single radial immunodiffusion. Immunochemistry 2:235, 1965. 42. Natelson, S.: Micro-techniques of Clinical Chemistry. 2nd ed. Springfield, Charles C Thomas, 1961, pp. 451-454. 43. Rabin, A. R., and Berson, E. L.: A full-field
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system for clinical electroretinography. Arch. Ophthalmol. 92:59, 1974. 44. Gunkel, R. D., and Bornschein, H.: Automatic intensity control in testing dark adaptation. Arch. Ophthalmol. 57:681, 1957. 45. Ruston, W. A.: Rod/cone rivalry in pigment regeneration. J. Physiol. 198:219, 1968.
OPHTHALMIC MINIATURE
There is, of course, nothing new in the fact that the retinal arteries are small in Bright's disease; it has long been remarked as a common feature in albuminurie retinitis, and is shown plainly in the best illustrations of this change (as in those of Liebreich). But it is usually regarded as a consequence of the retinal change, and the points on which I would insist are that it occurs also quite independently of the retinal change, and stands commonly in direct relation to another condition—the blood-tension. William R. Gowers British Medical Journal, 1876
Boston, Massachusetts
A dietary deficiency of vitamin A has caused night blindness in humans with ele vated cone and rod thresholds 1-10 and re duced electroretinograms (ERGs). 5-7,11,12 Patients with cirrhosis of the liver, with or without obstructive jaundice, have exhib ited raised psychophysical thresholds 13 " 16 and reduced ERG amplitudes. 17-18 Their night blindness may have been caused by inadequate consumption19 or malabsorption15 of vitamin A, or alter natively, by impaired liver synthesis or release of the plasma proteins for trans port of vitamin A, or both.20 Laboratory investigations have shown that roddominated rats 21-25 and cone-dominated ground squirrels,26 fed vitamin Adèfìcient diets and maintained in light, developed photoreceptor malfunction and degeneration. Recovery of retinal function has been achieved in vitamin A-deficient humans, 1-5,11 patients with cirrhosis of the liver,14,15 and vitamin A-depleted rats21,24 by feeding them vita min A. Although patients with hereditary retinitis pigmentosa have also exhibited night blindness with elevated cone and rod thresholds 10,27 " 30 and reduced ERG amplitudes,31 such patients treated with vitamin A, even in large doses, have not From the Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Mas sachusetts. This work was supported in part by Research Grant EY00169 and Research Career De velopment Award EY70800 (Dr. Berson) from the National Eye Institute; and in part by grants from the National Retinitis Pigmentosa Foundation, Bal timore, Maryland, and the George Gund Founda tion, Cleveland, Ohio. Reprint requests to Michael A. Sandberg, Ph.D., Berman-Gund Laboratory, 243 Charles Street, Bos ton, MA 02114.
responded.32,33 Patients with retinitis pig mentosa have normal plasma levels of vitamin A34,35 and retinol-binding pro tein 36-38 ; but a local retinal deficiency of vitamin A has not been excluded.39,40 In this study, we evaluated cone and rod responses in two vitamin A-deficient patients with chronic alcoholism. After administering vitamin A to them, we compared their responses during stages of retinal function recovery with cone and rod responses in stages of retinal degener ation in patients with different genetic types of retinitis pigmentosa. CASE REPORTS Case 1—A 55-year-old white man had a five-year history of progressive night blindness that was so severe he needed a flashlight to see at dusk. He admitted to heavy beer drinking for at least 25 years, but also said he ate regular meals. He denied use of tobacco. Family history was noncontributory for ocular disease. On ocular examination, his visual acuity was 6/9 (20/30) in both eyes. Pertinent findings included slight conjunctival icterus and no evidence of xerophthalmia or keratomalacia. The ocular media were clear except for minimal cortical lens changes. The disk, macula, vessels, and periph eral fundus were unremarkable in each eye; no bone spicule pigmentation or white deposits were ob served in either fundus. Visual fields were full on the Goldmann perimeter with a I4 white test light. General physical examination revealed this pa tient had a palpable liver, 2+ pedal edema, and marked ascites. Serum showed total bilirubin, 7.6 mg/100 ml (normal, 0.0 to 1.0 mg/100 ml); direct bilirubin, 3.4 mg/100 ml (normal, 0.0 to 0.4 mg/100 ml); alkaline phosphatase, 96 Bodansky units (nor mal, 2 to 6 units); serum glutamic oxaloacetic trans aminase, 94 units/ml (normal, 10 to 40 units/ml); serum glutamic pyruvic transaminase, 42 units/ml (normal, 5 to 35 units/ml); total protein, 6.8 g/100 ml (normal, 6 to 8.4 g/100 ml); albumin, 2.8 g/100 ml (normal, 3.5 to 5 g/100 ml); globulin, 4 g/100 ml (normal, 2 to 3 g/100 ml); triglycérides, 101 mg/100 ml (normal, 40 to 150 mg/100 ml); and cholesterol, 139 mg/100 ml (normal, 150 to 280 mg/100 ml). Serum lipoprotein electrophoresis showed a normal beta fraction. Serum retinol-binding protein was nondetectable by a radial immunodiffusion tech-
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nique. 41 Serum zinc varied between 50 mg/100 ml and 68 mg/100 ml (normal, 80 to 160 mg/100 ml). Because plasma vitamin A42 was nondetectable this patient received 10,000 units of vitamin A orally per day for four weeks and three supplementary doses of 100,000 units each of vitamin A (Aquasol) orally on days 7,8, and 15 after initiation of therapy. Plasma vitamin A reached normal levels on day 8 (normal range, 0.15 to 0.6 μg/ml) and fluctuated thereafter within this range. During therapy, the patient stopped drinking beer, but his liver function measurements did not change. Case 2—A 38-year-old white man reported a oneyear history of night blindness and photophobia. He admitted to heavy beer drinking and poor nutrition for years. Family history was noncontributory for ocular disease. Visual acuity was R.E.: 6/9 (20/30), and L.E. : 6/6 (20/20), with a refractive error of +1.00 in both eyes; pertinent findings included clear cor neas, absence of xerosis and scierai icterus, clear media, and normal fundi. Visual fields on the Goldmann perimeter were within normal limits. This patient did not submit to a general physical examination or detailed psychophysical testing. His plasma vitamin A was initially nondetectable, so vitamin A tablets (10,000 units per day) were pre scribed. Plasma vitamin A was borderline normal on day 80; he received two oral doses of 100,000 units of vitamin A (Aquasol) under direct supervision on days 119 and 123 after his initial examination. Plasma vitamin A was normal on days 129 and 134. He continued to drink beer during the course of his therapy. Other cases—Psychophysical thresholds and ERGs from representative patients, ages 9 to 22 years, with the early stages of different genetic types of retinitis pigmentosa were compared with those from Cases 1 and 2. These patients with retinitis pigmentosa have been described previously.31 METHODS
Full-field ERGs were recorded by pre viously described methods. 43 Under these conditions, normal peak-to-peak ampli tudes (mean ± 2 S.D.) were 175 ± 50 μ ν for dim blue light, 425 ± 75 μν for white light, 75 ± 25 μ ν for flickering white light, and 95 ± 27 μν for single flashes of white light in the presence of a white background light. The interval between stimulus onset and the peak of the b-wave was considered for the measurement of implicit time. The normal range of im plicit times was 78 to 108 msec for rod b-wave responses to dim blue light, and 27 to 37 msec for cone b-wave responses to 30 cps flicker or white light with a background.
659
Both patients were dark-adapted with a Goldmann-Weekers dark adaptometer modified to have automatic intensity con trol.44 Patients were dark-adapted for 30 to 45 minutes and tested with an 11degree white test light presented to the fovea or 20 to 25 degrees temporal to the fovea. Threshold measurements repre sented an average of five or six determina tions for each patient and varied within 0.3 log-unit on a given day. Rod (ΤΓ0), green cone (ir4), and blue cone (TT, and irj functions in the fovea, and rod and blue cone functions in the retina 10 degrees above the fovea were monitored with Stiles' two-color increment thresh old technique. 30 A 2.5-degree, 500-nm (10 nm half bandwidth) stimulus was flashed for 200 msec on a 68-degree, longwave (cut-on at 540 nm) background field of variable intensity. Additionally, darkadapted rod and cone functions were measured for Case 1 in the retina 10 degrees above the fovea on day 13 of vitamin A therapy. Two-and-one-half de gree, narrow-band (10 nm half band width) stimuli were flashed for 200 msec either after 30 minutes of dark adaptation for separating rod function, or within 3 to 11 minutes after termination of shortwave preadaptation (k < 470 nm) for separating green and red cone function. For studies of both increment thresholds and dark adapted thresholds, responses varied within ± 0.15 log-unit on repeat measure ments. RESULTS
Before vitamin A therapy, the ERGs in Case 1 demonstrated a nondetectable rod response to a dim blue light (Fig. 1). Dark-adapted responses to white light were reduced 95% below normal in am plitude. Cone responses to white light at 30 cps were reduced 75% below normal in amplitude and fell just within the nor mal range of b-wave implicit times. Dur ing the course of oral vitamin A therapy,
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DARK ADAPTED THRESHOLDS (Patitnt 1) 11" TEST SPOT Vit A today·
Normal
Vit A )3 dayt
i ί Patient 1 : Pre Vitamin A ;
Vitamin A 7 days
Vitamin A 13 days
Vitamin A 27 days
Fig. 1 (Sandberg, Rosen, and Berson). Full-field ERGs for a normal person and for the patient in Case 1 with chronic alcoholism, before and during vitamin A therapy, in response to single flashes of a dim blue (λ < 470 nm) light (left column), an 8 ft-L white light (middle column), and white light flicker ing at 30 cps (right column). Two or three consecu tive responses to the same stimulus are superim posed. The vertical lines denote stimulus onset.
ERG amplitudes returned to normal. Cone implicit times became slightly fast er and remained within the normal range. Before vitamin A therapy, ERGs in Case 2 (Fig. 2) were similar to those in Case 1. During the course òf oral vitamin A, rod and cone ERGs returned to borderline
Normal
Patient 2 Pre-Vitamin A
Vitamin A 130 days
Fig. 2 (Sandberg, Rosen, and Berson). Full-field ERGs for a normal person and for the patient in Case 2 with chronic alcoholism, before and during vitamin A therapy. For stimulus conditions, see Figure 1.
i ·■
* 2
i* • > Central Retina
» • 2 0 - 2 5 ° Temporal Retina
Fig. 3 (Sandberg, Rosen, and Berson). Progress of dark-adapted psychophysical thresholds in Case 1 with the patient looking directly at the white test light, or looking eccentrically to allow testing of the temporal retina.
normal amplitudes, and cone implicit times became slightly faster. Dark-adapted thresholds to an 11degree white test light were initially ele vated 5 log-units above normal in Case 1, and 3 log-units above normal in Case 2. The courses of recovery for the fovea and temporal retina (20 to 25 degrees from the fovea) are illustrated for Case 1 (Fig. 3); threshold in the central retina returned to normal more slowly than threshold in the peripheral retina. Increment thresholds in Case 1 on the 13th day of vitamin A therapy (Fig. 4) showed nondetectable rod (ιτ0) function, normal green cone (TTJ function, and bor derline normal blue cone (ττ, and ΤΓ3) func tion in the fovea; normal rod function and markedly elevated blue cone function were found 10 degrees above the fovea. Dark-adapted thresholds, obtained 10 de grees above the fovea in Case 1 on the same day, revealed normal rod thresholds and elevated green and red cone thresh olds (Fig. 5). On the 27th day of vitamin A therapy (Fig. 4), rod and cone functions were normal in both retinal areas. Incre ment thresholds in Case 2 were measured
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PATENTI
Fig. 4 (Sandberg, Rosen, and Berson). Psychophysical increment thresholds in the fovea and 10degree superior retina in Case 1 on days 13 and 27 of therapy. Solid lines designate average normal function mediated by rods (ττ0), green cones (ir4), and blue cones (ir, and ττ3).
Log Background Retinal Illuminance (Photopic Trolands)
on day 121 after initiation of vitamin A therapy; rod function was normal in the fovea and 10-degree superior retina; green cone and blue cone functions were normal in the fovea, while blue cone function was nondetectable 10 degrees above the fovea as tested. We compared ERGs from Case 1 with ERGs from representative cases of differ ent genetic types of retinitis pigmentosa l-,0 (Fig. 6). The case of dominant retinitis pigmentosa with reduced penetrance and the cases of recessive (autosomal or sexlinked) retinitis pigmentosa have reduc tions in full-field cone ERG amplitudes, but marked delays in cone ERG b-wave implicit times.31 In contrast, Case 1 shows normal ERG b-wave implicit times. Only the cone ERGs of the case of dominant retinitis pigmentosa with com plete penetrance resembled those of Case 900 6C 1. Psychophysical increment threshold Fig. 5 (Sandberg, Rosen, and Berson). Psychophysical thresholds in Case 1 on day 13 of vitamin A measurements distinguished Case 1 from therapy. Thresholds were obtained in the 10-degree cases of dominant retinitis pigmentosa superior retina to 2.5 degree stimuli of varying wavelengths flashed for 200 msec after 30 minutes with complete penetrance. Case 1 showed of dark adaptation (rod function), or from 3 to 11 the unusual combination of elevated fominutes after termination of shortwave preadapta- veal rod thresholds with normal perifotion when the cones had reached dark-adapted lev els (cone function). Solid lines designate normal veal rod thresholds during recovery on vi dark-adapted rod and cone levels. tamin A therapy (Fig. 4). In contrast, cases -2.0
Vitamin A - 1 3 Days n
C o m Function
o Rod Function
700
Wavelength (nm)
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of dominant retinitis pigmentosa with complete penetrance typically have shown rod thresholds that are less elevated in the fovea than in the perifovea, or nondetectable (Fig. 7) in both retinal areas.
CONE ERGs White OOcps) White ü Bkgd
Normal
Vitamin A deficient Dominant RP complete penetrance
\
SAAX
DISCUSSION
Both cases with chronic alcoholism and nondetectable plasma vitamin A had ele vated rod thresholds in dark adaptation testing, nondetectable rod ERGs, and cone ERGs reduced in amplitude b u t normal in b-wave implicit time. Normal cone ERG b-wave implicit times separat ed these cases from those with dominant retinitis pigmentosa with reduced pene trance, as well as those with Xchromosome linked and autosomal reces sive retinitis pigmentosa. The noncontributory family history for retinitis pig mentosa in both cases of chronic alcohol ism suggested they did not have domi nant retinitis pigmentosa with complete penetrance. During stages of recovery on vitamin A therapy, the psychophysical and ERG findings in the vitamin A deficient pa tients with chronic alcoholism were dif ferent from those observed in degenera tive stages of different types of hereditary retinitis pigmentosa. The vitamin A defi-
^TR^FF
:VW^
Dominant RP reduced penetrance
Recessive RP
NOVEMBER, 1977
-ttftt ^ ^
Fig. 6 (Sandberg, Rosen, and Berson). Full-field cone ERGs for a normal person, a patient with vitamin A deficiency and chronic alcoholism (Case 1), and three patients with the early stages of differ ent genetic types of retinitis pigmentosa. Arrows designate b-wave implicit times. Calibration symbol (lower right) is 100 μν vertically, and 50 msec and 25 msec horizontally for left and right columns, respectively.
DOMINANT RETINITIS PIGMENTOSA °°o
w
Λ"·\
Superior Retins
4y
Ì -10
. J
n
a
Fig. 7 (Sandberg, Rosen, and Ber son). Psychophysical increment thresholds for two siblings age 20 years (triangles) and 22 years (squares) who have dominant reti nitis pigmentosa with complete penetrance. Stimulus conditions were the same as in Figure 4.
i l n<
°
0
M
-
i—^—//■
i
Log Background Retinal Illuminance (Photopic Trolands)
i
i
i
•
I
'
'
'
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CONE AND ROD FUNCTION
cient patients never showed delayed cone
b-wave implicit times, as seen in domi nant retinitis pigmentosa with reduced penetrance or recessive types of retinitis pigmentosa. Additionally, small field psy chophysical increment thresholds and dark-adapted thresholds showed the unu sual combination of elevated foveal rod thresholds with normal perifoveal rod thresholds during recovery on vitamin A therapy, a combination not seen in domi nant retinitis pigmentosa with complete penetrance or in other genetic types of retinitis pigmentosa. 28 · 30 A previous psychophysical study in normal persons suggested that rods and cones compete for available vitamin A during visual pigment regeneration. 45 In the cone-dominated fovea (central 2.5 de grees), regeneration of rod pigment after a bleaching light was retarded during the process of cone pigment regeneration; but, in the rod-dominated perifovea (15 degrees away), rod pigment regeneration after a bleaching light was unaffected by simultaneous cone pigment regeneration. Similarly, rod-cone rivalry for vitamin A provides an explanation for the slower recovery of rods in the fovea than 10 degrees above the fovea (Case 1). Addi tionally, the slower recovery of cones in the perifovea than in the fovea, observed in both cases, could also be caused by rod-cone competition for vitamin A in the perifovea. In early stages of vitamin A deficiency in the rat, before outer segment degenera tion begins, the concentration of opsin appears normal, while that of the chromophore (vitamin A aldehyde) is depleted 21 ; elevations of rod ERG thresholds were found logarithmically related to the amount of rhodopsin remaining in the retina. 22 In contrast, in patients with reti nitis pigmentosa elevations of rod psycho physical thresholds have been linearly correlated with the amount of rhodopsin remaining as measured by retinal densi-
663
tometry. 29 This suggests that the pathogenetic mechanism in retinitis pig-
mentosa involves the loss of all the visual pigment molecule (opsin + chromophore), rather than a specific lack of the chromophore (vitamin A aldehyde). The present study also supports the idea that the pathogenetic mechanism in heredi tary retinitis pigmentosa does not involve a local deficiency of vitamin A in the retina. SUMMARY
Two vitamin A-deficient patients with chronic alcoholism and night blindness had elevated dark-adapted thresholds, nondetectable rod electroretinograms (ERGs), and cone ERGs that were re duced in amplitude with normal b-wave implicit time. During oral vitamin A ther apy, both patients regained normal plas ma vitamin A levels, normal rod thresh olds, and normal rod and cone ERG am plitudes. Psychophysical studies during stages of recovery revealed that, in the fovea, cone function returned to normal before rod function; but, in the perifovea, the opposite occurred. This finding can b e explained by rod-cone rivalry for vitamin A and regional differences in rod-cone densities. Stages of recovery of retinal function in vitamin A-deficient alcoholic patients differed from degenera tive stages described in various types of hereditary retinitis pigmentosa. REFERENCES 1. Wald, G., Jeghers, H., and Arminio, J.: An experiment in human dietary night blindness. Am. J. Physiol. 123:732, 1938. 2. McDonald, R., and Adler, F. H.: Effect of anoxemia on the dark adaptation of the normal and of the vitamin A-deficient subject. Arch. Ophthalmol. 22:980, 1939. 3. Wald, G., and Steven, D.: An experiment in human vitamin A-deficiency. Proc. Nati. Acad. Sci. 25:344, 1939. 4. Hecht, S., and Mandelbaum, J.: Dark adapta tion and experimental human vitamin A deficiency. Am. J. Physiol. 130:651, 1940. 5. Bornschein, H., and Bukovich, V.: Das Elek-
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troretinogram bei Mangelhemeralopie. Von Graefes Arch. Ophthalmol. 153:484, 1953. 6. Arden, G. B., and Kolb, H.: Electrophysiological investigations in retinal metabolic disease. Their range and application. Exp. Eye Res. 3:334, 1964. 7. Fells, P., and Bors, F.: Ocular complications of self-induced vitamin A deficiency. Trans. Ophthal mol. Soc. U.K. 89:221, 1969. 8. Norden, A., and Stigmar, G.: Measurement of dark adaptation in vitamin A deficiency by a new quantitative technique. Acta Ophthalmol. 47:716, 1969. 9. Levy, N. S., and Tockes, P. P.: Fundus albipunctatus and vitamin A deficiencv. Am. J. Ophthal mol. 78:926, 1974. 10. Sloan, L. L.: An apparatus for studying re gional differences in light sense. Arch. Ophthalmol. 22:233, 1939. 11. Dhanda, R. P.: Electroretinography in night blindness and other vitamin A deficiencies. Arch. Ophthalmol. 54:841, 1955. 12. Genest, A.: Vitamin A and the electroretinogram in humans. In François, J. (ed.): The Clinical Value of Electroretinography, ISCERG Symposi um, Ghent, 1966. Basel, S. Karger, 1968, pp. 250259. 13. Bailliart, P.: Les maladies de la rétine: l'hespéranopie (ou héméralopie) essentielle. Traite Ophtalmol. 5:368, 1939. 14. Haig, C , Hecht, S„ and Patek, Jr., A. J.: Vitamin A and rod-cone dark adaptation in cirrhosis of the liver. Science 87:534, 1938. 15. Patek, Jr., A. J., and Haig, C : The occurrence of abnormal dark adaptation and its relation to vitamin A metabolism in patients with cirrhosis of the liver. J. Clin. Invest. 18:609, 1939. 16. Parker, F . W., Jr.: Studies on dark adaptation in military personnel complaining of "night blind ness." Arch. Ophthalmol. 35:555, 1946. 17. Schmidt, B.: Electroretinographic investiga tions on dark adaptation in liver cirrhosis. In Fran çois, J. (ed.): The Clinical Value of Electroretinogr aphy, ISCERG Symposium, Ghent, 1966. Basel, S. Karger, 1968, pp. 267-272. 18. Cinotti, A., Stephens, G., and Kiebel, G.: The electroretinographic response and adaptation in chronic alcoholics. In Wirth, A. (ed.): Symposium on Electroretinography, ISCERG Symposium VIII, Pisa, Pacini, 1970, pp. 269-276. 19. Jayle, G. E., Ourgaud, A. G., Baisinger, L. F., and Holmes, W. J.: Night Vision. Springfield, Charles C Thomas, 1959, pp. 209-211. 20. Smith, F. R., and Goodman, D. S.: The effects of diseases of the liver, thyroid, and kidneys on the transport of vitamin A in human plasma. J. Clin. Invest. 50:2426, 1971. 21. Dowling, J. E., and Wald, G.: Vitamin A deficiency and night blindness. Proc. Nati. Acad. Sci. 44:648, 1958. 22. Dowling, J. E.: Chemistry of visual adapta tion in the rat. Nature 188:114, 1960. 23. Dowling, J. E., and Gibbons, I. R.: The effect of vitamin A deficiency on the fine structure of the retina. In Smelser, G. (ed.): The Structure of the Eye. New York, Academic Press, 1961, pp. 85-99.
N O V E M B E R , 1977
24. Noell, W. K., Delmelle, M. C , and Albrecht, R.: Vitamin A deficiency effect on retina. Depen dence on light. Science 172:72, 1971. 25. Herron, W. L., Jr., and Riegel, B. W.: Produc tion rate and removal of rod outer segment material in vitamin A deficiency. Invest. Ophthalmol. 13:46, 1974. 26. Berson, E. L.: Experimental and therapeutic aspects of photic damage to the retina. Invest. Oph thalmol. 12:35, 1973. 27. Mandelbaum, J.: Dark adaptation. Some physiologic and clinical considerations. Arch. Oph thalmol. 26:203, 1941. 28. Zeavin, B. H., and Wald, G.: Rod and cone vision in retinitis pigmentosa. Am. J. Ophthalmol. 42:253, 1956. 29. Highman, V. N., and Weale, R. A.: Rhodopsin density and visual threshold in retinitis pigmentosa. Am. J. Ophthalmol. 75:822, 1973. 30. Sandberg, M. A., and Berson, E. L.: Blue and green cone mechanisms in retinitis pigmentosa. In vest. Ophthalmol. & Visual Sci. 16:149, 1977. 31. Berson, E. L.: Retinitis pigmentosa and allied retinal diseases. Electrophysiological findings. Trans. Am. Acad. Ophthalmol. Otolaryngol. 81:659, 1976. 32. Chatzinoff, A., Nelson, E., Stahl, Ν,, and Clahane, A.: Eleven-cis vitamin A in the treatment of retinitis pigmentosa. A negative study. Arch. Ophthalmol. 80:417, 1968. 33. Bergsma, D., and Wolf, M.: A therapeutic trial of vitamin A in patients with pigmentary retinal degenerations. A negative study. In Landers, M. B., I l l , Wolbarsht, M. L., Dowling, J. E., and Laties, A. M. (eds.): Retinitis Pigmentosa. Clinical Implica tions of Current Research. New York, Plenum Press, 1977, pp. 197-209. 34. Krachmer, J. H., Smith, J. L., and Tocci, P. M.: Laboratory studies in retinitis pigmentosa. Arch. Ophthalmol. 75:661, 1966. 35. Massoud, W. H., Bird, A. C , and Perkins, E. S.: Plasma vitamin A and beta-carotene in retinitis pigmentosa. Br. J. Ophthalmol. 59:200, 1975. 36. Maraini, G.: The vitamin A transporting protein complex in human hereditary pigmen tosa retinal dystrophy. Invest. Ophthalmol. 13:288, 1974. 37. Futterman, S., Swanson, D., and Kalina, R. E.: Retinol in retinitis pigmentosa. Evidence that retinol is in normal concentration in serum and the retinol-binding protein complex displays unaltered fluorescence properties. Invest. Ophthalmol. 13:798, 1974. 38. Maraini, G., Fadda, G., and Gozzoli, F.: Serum levels of retinol-binding protein in different genetic types of retinitis pigmentosa. Invest. Oph thalmol. 14:236, 1975. 39. Gouras, P., and Chader, G.: Retinitis pigmen tosa and retinol-binding protein. Invest. Ophthal mol. 13:239, 1974. 40. Bergsma, D. R., Wiggert, B. N., Funahashi, M., Kuwabara, T., and Chader, G. J.: Vitamin A recep tors in normal and dystrophic human retina. Nature 265:66, 1977. 4 L Mancini, G., Carbonara, A. O., and Heremans,
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J. F.: Immunological quantitation of antigens by single radial immunodiffusion. Immunochemistry 2:235, 1965. 42. Natelson, S.: Micro-techniques of Clinical Chemistry. 2nd ed. Springfield, Charles C Thomas, 1961, pp. 451-454. 43. Rabin, A. R., and Berson, E. L.: A full-field
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system for clinical electroretinography. Arch. Ophthalmol. 92:59, 1974. 44. Gunkel, R. D., and Bornschein, H.: Automatic intensity control in testing dark adaptation. Arch. Ophthalmol. 57:681, 1957. 45. Ruston, W. A.: Rod/cone rivalry in pigment regeneration. J. Physiol. 198:219, 1968.
OPHTHALMIC MINIATURE
There is, of course, nothing new in the fact that the retinal arteries are small in Bright's disease; it has long been remarked as a common feature in albuminurie retinitis, and is shown plainly in the best illustrations of this change (as in those of Liebreich). But it is usually regarded as a consequence of the retinal change, and the points on which I would insist are that it occurs also quite independently of the retinal change, and stands commonly in direct relation to another condition—the blood-tension. William R. Gowers British Medical Journal, 1876