Retinitis pigmentosa

Retinitis pigmentosa


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REVIEW Retinitis


S. MERIN, M.D. AND E. AUER6ACH, M.D. Vision Research Laboratory and the Department of Ophthalmology. University Hospital and Medical School, Jerusalem, Israel


Abstract. The authors review the symptomatic and genetic aspects of the various entities of isolated retinitis pigmentosa (R.P.), both in its typical form and in the forms associated with the affection of other ocular tissues. Syndromes in which R. P. is associated with the affection of other organs and systemic disorders are also considered. Origin, diagnosis and the course of the disease are discussed with regard to electrophysiology, histopathology, fluorescein angiography and biochemistry. Animal research has provided new realizations about the ultrastructure and physiological mechanisms of retinal photoreceptors, and better understanding of abnormal changes. The possible pathogenesis of the human disease, based on research findings, is considered. Although R.P. is generally thought to be an “untreatable” disease, therapy may be effective in several pathological entities. Methods and results of therapy with vitamins, light deprivation and vision aids are discussed. (!3un Ophthrlmol 20: 303-346,


centrat nervous system * Key Words: electrophysiology lipid disorders - photoreceptors retinal dystrophy retinitis pigmentosa - isolated, pseudo-, retinopathy review l



cone-rod degeneration mucopolysaccharidoses * sector, typical, unilateral *



n the last 25 years, retinitis pigmentosa (R.P.) has been the subject of

more than 1000 articles, one extensive book’62 and two symposia.4s’~4S2Nevertheless, many unsolved questions remain, including even such basic ones as nomenclature and definition. Of all human hereditary diseases known to be transmitted by single genes and causing blindness, R.P. is the most common.‘13 As an unpreventable and untreatable hereditary disease, R.P. is becoming increasingly recognized as an important public health problem. Methods of prevention and treatment of R.P. may be developed in the foreseeable future because of our better understanding of its pathogenesis, based on

animal experiments in the last decade, and because of recent advances in the prevention of hereditary diseases. Definition

and Nomenclature

Retinitis pigmentosa was the term given by Donders in 1857 to a form of night blindness. It is now understood to be a progressive disease of the retina, characterized by early and diffuse functional retinal abnormalities, a subnormal or “extinct” (non-recordable) electroretinogram, early involvement of the retinal pigment epithelium and visual receptors, and an outcome of severely impaired vision or blindness. Usually, pigmentary changes in the ocular fundus are conspicuous, 303


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but other changes (as in retinitis punctata albescens) are possible. Many different names were given to this disease once it was realized that it is not an inflammatory disease of the retina and that the suffix “itis” is not justified. It has been called retinopathia pigmentosa (pigmentary retinopathy), pigmentary retinal dystrophy, peripheral tapeto-retinal degeneration, and peripheral tapeto-retinal dystrophy. Different subgroups and “atypical” forms received additional names. It seems to us that, at least until the biochemical basis of the disease is known, the name “retinitis pigmentosa,” being the most commonly used, should remain, even though it is a misnomer. In this review, the term retinitis pigmentosa will be used in the broad sense of the above definition. However, different morphological, genetic and clinical entities will be named according to their commonly used terms. Retinitis pigmentosa in its narrow sense, a disease not associated with any systemic changes and showing the well known clinical picture, will be discussed under the heading of “typical retinitis pigmentosa.” Prevalence No incidence studies have been performed for R.P. Ammann et al.‘* found its prevalence to be 1:7,OOClof the general population in Switzerland. In Israel, the number was estimated on the basis of a statistical study to be about 1:4,500.138 R.P. was found to be much more common in communities with a high rate of cosanguineous marriages.1se We estimate that in such communities the prevalence of R.P. is around 1:2,000.

FIG. 1. Early ophthalmoscopic changes consisting of a “tapetal” reflex and tine whitish dots spread over the fundus. progressive nature of the disease. In our experience, there is little objective basis for improvements or even temporary remissions, although subjectively this may sometimes be the patient’s impression. Occasionally, other symptoms may be predominant, masking the more specific symptoms of R.P. For instance, Harcourt has described four children in whom the prevailing symptom was a behavioral disturbance,210 which was due to the visual handicap resulting from an unrecognized R.P. THE FUNDUS PICTURE

The classical triad of findings in the fundus of an R.P. patient consists of scattered lumps of pigment resembling bone corpuscles, attenuated blood vessels, and a waxy-pale Clinical Findings in Typical Retinitls disc.las Of the 300 R.P. patients analyzed in Pigmentosa our laboratory before 1970 (more than 250 SYMPTOMS have been examined since), 93% had pigmenThe two most common symptoms of R.P. tary changes of some sort, 35% had typical 87% had attenuated are night-blindness and progressive constric“bone corpuscles,” tion of the peripheral visual field, terminating vessels, and 65% had disc abnormalities.1se in the loss of central vision. A midperipheral Using stereoscopic methods of fundus exring scotoma may also be caused by R.P. amination, including stereoscopic fluorescein These symptoms usually become apparent angiography, Adams et al.* found that the during the second decade of life, but pigment epithelium is the layer primarily sometimes are present in early childhood. showing morphological abnormalities, but Prior to the involvement of central vision, the that in the final stages of the disease all layers patient may be aware of deterioration of of the retina and choroid are involved. The color vision. All these symptoms become pigment epithelium shows three types of gradually more pronounced, indicating the changes: whitish spots (possibly thickening or

FIG. 2. Intermediate ophthalmoscopic changes consisting of fine and coarse whitish dots and of pigmentary changes in form of fine dots and blots.

roughening of the surface of the pigment epithelial cells), areas of reddish change and areas of depigmentation. In our experience, these pigment epithelium changes are responsible for the “tapetal” or edematous reflexes from the fundus of practically every R.P. patient, even at a stage when no other abnormality is apparent. The neural retina shows progressively increasing pigmentary changes. Initially, line pigmentary stippling is seen. This is due to accumulation of pigment granules in the outer layers of the retina stemming from the pigment epithelium. Later, they spread throughout the neural retina and finally form bone-corpuscle-like lumps and large pigment clumps in the innermost layers, mainly in the equatorial area. Later, they cause vascular pigmentary sheathing. Adams et al.6 suggest that the pigment migration and the formation of these typical figures are due to their spread along Miller fibers. A parallel finding is vascular narrowing. In advanced cases the whole retina becomes very thin. Choroidal changes are secondary and include disappearance of the choriocapillaris and, in advanced cases, of the larger choroidal vessels as well. The choroidal pigment which remains in the presence of the choriocapillaris and pigment epithelium abnormality gives a greenish funduscopic appearance, which adds to the abnormal “tapetal” reflex. A constant and typical finding for R.P. is the development of symmetrical, retinal pigmentation.79 Michaelson and Yankosz8

FIG. 3. Advanced ophthalmoscopic consisting of “bone narrow vessels.





claimed that the development of retinal pigmentation could be divided into live stages: 1) functional disability without fundal changes, 2) pigmentary stippling, 3) pigment resembling bone corpuscles in the equatorial 4) vascular sheathing in the zone, midperiphery, and 5) vascular sheathing up to the disc. These authors suggested that each stage takes 5 to 10 years for completion. In our experience, however, the progress of the morphologic changes of the fundus depends upon the genetic entity and varies in different types of R.P. (Figs. l-3). Ziv and Dunphy’80 described R.P. patients in whom the earliest fundus finding consisted of pigmented arteries. FUNCTIONAL ABNORMALITIES

Abnormalities of the visual function may include changes in the visual field, visual acuity, color vision, and light sense (dark adaptation). (Characteristic functional abnormalities revealed by bioelectrical examination will be discussed later.) Functional abnormalities are found early in the disease, often before any ophthalmoscopic changes are detectable. These abnormalities become progressively worse until the final stage of total loss of vision (no light perception) is reached. Visual Fields

The typical finding is a gradually progressing constriction of the visual field





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which produces ever decreasing tubular vision as the disease progresses. The equatorial area is generally first affected by the pigmentary changeslss resulting, in moderately advanced cases, in a ring scotoma. Usually, this starts in the lower temporal quadrant as an arcuate field loss. However, sector defects including quadrantanopsia and hemianopsia can sometimes be found.‘62 The visual fields show greater defects if examined under mesopic or scotopic conditions than under the customary photopic ones. Visual Acuity

Because the macular area becomes involved late in the degenerative process, visual acuity of R.P. patients is often preserved until late in the course of the disease. However, this depends on the specific clinical entity. For instance, in autosomal dominant R.P., visual acuity is often reasonably good even after the age of 50 or 60 years. Color Vision

While most R.P. patients have normal color vision in early childhood, defects develop progressively. Sixty-three percent of R.P. patients examined by us had acquired color vision defects. Other studies report percentages of 44, 48 and 76.175J04*448 Most likely, the difference in these reports is due to the age of the patients examined. The typical color defect shows a tendency to tritanopia, although it differs slightly from congenital tritanopia as displayed by the Farnsworth panel D-15 test and other tests.16SThe tendency to tritanopia is sometimes found even in early stages of the disease.202

Deficient rod vision can be detected by scanning from the center to the periphery of the retina. With progress of the disease, the scotopic threshold becomes gradually higher. In advanced stages, the dark adaptation curve becomes monophasic.152 In all stages, the photopic threshold in the periphery and in the fovea is usually raised as well. This can often be detected even in early cases by reduced flicker responses associated with reduced scotopic ERGsle7 and by elevated thresholds to both red and blue stimuli in testing retinal proIiles.lB1 The diminution of visual function in R.P. patients is related to a loss of rhodopsin. It was found22S that there is a high correlation between the reciprocal of the threshold and the density of rhodopsin. Moreover, the diminution of rhodopsin is attributed to loss of rods and not primarily to a change in rhodopsin regeneration, which was found to be normal in R.P. patients.1’B~225 The Clinical and Genetic Entities of isolated Retinitir Pigmentosa and their Characteristics Typical R.P. and most of the nontypical forms are hereditary diseases. The transmission in all cases occurs by single pathologic genes and no multifactorial inheritance has been described. R.P. may appear as an isolated disease or in association with other systemic abnormalities; in either case, the morphological changes in the fundus may be typical or atypical. TYPICALRETINITISPIGMENTOSA

The disease can be transmitted by the autosomal recessive, the autosomal dominant or the sex-linked mode. Table 1 shows the light Sense and Dark Adaptation relative frequency of the different genotypes The first detectable sign of R.P. is reduced as reported from various countries. The light sensitivity in localized retinal areas.427 autosomal recessive mode is usually the most

TABLE 1 Relative Frequency

of Different Genotypes of Retinitis Pigmentosa

Voipio et al.‘60 Autosomal recessive Autosomal dominant Sex-linked recessive Sporadic

:: 4.5 38.5

Ammann et al.‘@



90 9 1

21.9 12.7 1.1 41

15 39 25 21

*Autosomal recessive includes sporadic. **Since the percentage values do not equal 100, it is assumed that some cases did not iit into any of the designated groups.


frequent form,155 especially if sporadic cases, undoubtedly of recessive nature, are included. Interestingly, in Britain the autosomal dominant genotype was found most frequently.242 It is fortunate that the sex-linked recessive genotype is the least frequent form,‘55 as it is considered the most severe mode; the autosomal recessive is next in severity and the autosomal dominant is the mildest form. In the recessive forms, progression of the disease is fast and the affected person becomes blind early in life, while in the dominant form central vision may be preserved much longer. Some of our R.P. patients with the autosomal dominant mode preserve enough sight to work satisfactorily at the age of 60. JayZ4Z found that the majority of such patients had visual acuity of 6/ 18 or better at the age of 50. It is probable that more than one gene is responsible for each of the two autosomal modes of the disease. The typical autosomal dominant R.P. has complete penetrance in most reported pedigrees. However, dominant R.P. with reduced penetrance has been reported” and may be a different genetic entity. The different clinical appearance of the autosomal recessive disease in different families may also indicate two or more genetic entities. The frequency of the recessive gene or genes in Switzerland was calculated by Ammann et a1.16to be 1:84. Several linkage studies were performed to detect the relative position of the locus for the abnormal gene in X-linked R.P. This locus is far from the loci Xg blood group,26o color blindness,456 and both Xg blood group and deuteranomaly.203~204It was estimatecY5 that it lies at a distance of at least 27 map units from the Xg blood group. In genetic counseling, it is important to recognize the female carrier of the disease in cases of sex-linked R.P.155~238~2”~37’~3eo The carrier may show abnormal fundus reflexes, sometimes called the reverse Mizuo phenomenon, consisting of speckled, golden, shimmering dots in darkness; they disappear with dazzling. Pigmentary changes may be in the form of isolated present 236.277~390.459 scanty pigment dots or “bone corpuscles.” The fundus findings are similar in both eyes, but there are large intrafamilial differences.‘@ Visual fields may be normal or show slight peripheral constriction to blue light.23* The ERG may be normals3*7*or slightly subnormal.277 The EOG is usually more affected.

FIG. 4. Ophthalmoscopic picture of an eye with retinitis punctata albescens. Fluorescein angiography may indicate pigment epithelium involvement similar to that seen in affected individuals.236 Dark adaptation may be affected, but retinal profile studies have shown that rod function is completely normal in some areas of the retina and abnormal in others.63 All these abnormalities or any combination of them may be present. However, there may be established carriers without any of these signs. Bird and Hyman7* claim that the most useful method to detect such heterozygotes is by fundus reflectometry. In all of their six cases the rhodopsin content was found to be low, ranging from 43% to 66% of normal. Sporadic cases might be due to a mutation which may manifest itself as a dominant gene or as a sex-linked gene.15’ RETINITIS PUNCTATA ALRESCENS

Lauber289 made a clear distinction between this progressive disease and a stationary disease which he called fundus albipunctatus. The former is a tapetoretinal dystrophy; in the latter the only complaint is night blindness. Such a distinction is necessary, as both diseases show multiple white dots in the fundus. In retinitis punctata albescens, the functional abnormalities of the retina are similar to those of any retinitis pigmentosa, but the ophthalmoscopic findings are different. The fundus shows multiple, diffusely scattered whitish dots together with abnormal fundal reflexes (Fig. 4). The disease is slowly progressive and the ERG becomes


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finally extremely small or extinct.151 There is evidence that retinitis punctata albescens is not a separate genetic entity but is transmitted by the same autosomal recessive gene that causes typical R.P. In one family under our care, one of two affected siblings had “bone corpuscles” and the other had whitish dots. Usually, retinitis punctata albescens is a stage in the progressive development of R.P. in which the pigmentary changes are not yet pronounced. It should be mentioned that characteristics similar to those seen in retinitis punctata albescens were seen in patients with vitamin A deficiency due to malnutrition44’8 and in vitamin A depleted squirrels.5s LERER’S CONGENITAL





tiates the existence of a common genetic basis for Leber’s amaurosis and other tapetoretinal degenerations, as was suggested after a study in the Aland Islands,148 and, in fact, Leber’s amaurosis seems to be quite different from other tapetoretinal degenerations. PROGRESSIVE


This form of R.P. has to be distinguished from heredo-macular degenerations which may present a similar clinical picture. It is characterized by the early affection of the macular area and the photopic system followed by, or together with, peripheral pigmentary retinal degeneration.“’ The disease is slowly progressive and, at a more developed stage, predominant loss of cone function with color vision abnormalities is found with relatively smaller involvement of rod function.6Z*331It is probable that the disease belongs to the clinical entity of central and pericentral pigmentary retinopathy or intwo verse R.P. ~ Genetically, varieties have been described, an autosomal recessive and an autosomal dominant form.62*331

This is the congenital form of R.P., transmitted by autosomal recessive genes. Leber’s amaurosis was little known and often not properly diagnosed until studies in SwedenI and in HollandSQ1 showed it to be relatively common. In Sweden, it was found to be responsible for 10% of all cases of blindness, and, in Holland, for 18% of all blindness in children. Affected children are born blind or almost so. The ERG is extinct, SECTOR RETINITIS PIGMENTOSA This condition first described by Bietti7E even when done at an early age. The fundus is initially normal, or may show abnormal has been reviewed extensively by Bisantis.8* “tapetal” reflexes or pigmentary changes at Generally, in this condition a sector of the the macula or it may reveal a picture of retina is bilaterally and symmetrically retinitis punctata albescens.‘s6J64~415Later in affected by R.P. The lower quadrants are life, the fundus becomes more and more usually involved,“Jol but the upper nasaLsee pigmented until the picture typical for R.P. the nasal part,ee or the temporal quadrants’* appears, displaying “bone corpuscles” and may be affected instead. The fundus picture is attenuated vessels. variable, as in diffuse R.P. It may vary from The frequent association of Leber’s small greyish-white spots and tine granular amaurosis with keratoconus and/or cataract pigmentation to typical “bone corpuscles.“2o6 was stressed in numerous reports.19~‘36+248 In The visual field defects are coincident with some countries, a large proportion of children the affected sectors. These often simulate with Leber’s amaurosis have associated neurological defects such as altitudinal neurological or psychiatric disturbances in- hemianopsia or bitemporal hemianopsia. The cluding mental retardation,‘20~*21,136,154,416disease is sometimes stationary, but it may be while in others, for instance Sweden, this was slowly progressive, eventually involving all not four quadrants in old age. A large number of Leber’s amaurosis is frequent in com- familial cases have been described214~Z64~2BZ and munities with a high rate of consanguineous it has been suggestedso~201that a large permafriages.147 At least two autosomal centage of the reported cases have a recessive genes are involved in the disease per hereditary basis. It is probably a separate se 454 and at least one other gene causes genetic entity from typical R.P. and Ldber’s amaurosis associated with mental transmitted by the autosomal dominant retardation. There seems to be a high rate of mode.206,279 One patient reported to have secconcordance in twins.“’ An autosomal domi- toral R.P. and achromatopsia congenita497*488 nant variety may also exist, although only one probably had a fortuitous combination of two such family was reported.416 Nothing substan- separate genetic diseases.



Combined clinical, psychophysical and electrophysiological examinations of the visual systems of two patients showed that in one patient during 5 years of observation the disease remained stationary, while in the other patient 12 years of observation revealed slight clinical change, but marked deterioration of the ERGS3 Fluorescein angiography revealed larger retinal defects than were ophthalmoscopically visible.’ UNILATERAL



In this fairly rare condition (about onehundred cases reported), one eye has all the functional and morphological changes of R.P. while the other eye is normal. The patient has normal vision in both eyes until visual deterioration develops gradually320 or, more often, suddenly in the affected eye. The fundus shows the whole scale of findings of typical R.P., including “bone corpuscle” pigment, attenuated vessels and pale optic disc. As in typical hereditary R.P., central vision may be kept while vision becomes gradually tubular, central vision remaining longest. The ERG is extinct and the dark adaptation curve is monophasic.‘” The onset may be at any age (even in childhood as observed by us), but most reported cases occur at age 45-50. The apparently normal eye sometimes shows other abnormalities or it may be involved by R.P. at a stage not yet visible ophthalmoscopically, as was seen in three young patients with unilateral R.P.‘l. It was shown by EOG and ERG22*2’0in four cases of unilateral R.P. that the pigment epithelium and the outer segments of the receptors were involved in the clinically normal eye. The etiology of this condition is in many cases obscure.4s3 The suggestion that unilateral R.P. is an example of a “genotypic asymmetry”283 is not valid because none of the patients reported belongs to a family with bilateral hereditary R.P. of any of the known genetic types.212~2g0~453 Chromosomal analysis revealed a normal karyotype. Some evidence in favor of a vascular origin of unilateral R.P. has been reported in recent years. Based on X-rays of the skull and cerebral angiography, Kandori et al.247found evidence to claim that unilateral R.P. is caused by ischemic changes due to complete or partial closure of the ophthalmic artery or its branches. It developed in one patient with temporal arteritis’O and in patients with clear occlusion of the ophthalmic artery.lO’ The ophthal-

modynamometric pressures were found to be lower in the affected eye than in the good eye.429In summary, the latest evidence seems to suggest that unilateral R.P., at least in some cases, is caused by vascular occlusion and is thus nonhereditary; it may belong to the group of pseudo-retinitis pigmentosa or secondary R.P. PSEUDO-RETINITIS


This is a general term given to an R.P.-like disease affecting one or both eyes and caused by a known external factor such as a virus363 or another infection, trauma”’ or drugs.257.449 These cases should not be confused with widespread chorioretinal pigmentation secondary to multiple foci of chorioretinitis. The latter have a normal or a reduced ERG which is relative to the amount of damage to the photoreceptors. Their morphological changes do not look like those of R.P. and should not be considered pseudo-R.P. Now that syphilis is rarely seen, the most commonly reported infective cause of pseudoR.P. is measles.86~2’3It has even been reported after maternal measles in the third month of pregnancy. 328The fundus picture may show a disseminated pigmentary stippling with whitish spots and, still later, the “bonetype of retinal pigmentacorpuscle” tion.a2~217~3gs The ERG is very reduced or even extinct. The disease is bilateral and may thus be difficult to distinguish from hereditary R.P. Typically, visual loss is acute. Initially ophthalmoscopy reveals narrowing of the arteries and small whitish dots.217 Several weeks later, granular pigmentation replaces these dots and still later “bone-corpuscles” appear. At least one patient” showed a typical clinical picture of central retinal artery occlusion, which later developed into a pseudo-retinitis pigmentosa. It is possible that the etiology of some or most of these cases is vascular, as in patients with unilateral R.P. It was suggested that the viral infection causes a spasmodic temporary occlusion of the retinal and choroidal arteries.“’ This may explain the initial loss of vision (sometimes even of light perception) and subsequent slow improvement.39Z Cogan’og suggested that in R.P. secondary to trauma, the loss of photoreceptors is secondary to release of lytic enzymes from the pigment epithelium. Drug-induced R.P. and the pathology of pseudo-R.P. are discussed separately.


R.P. may be associated with an affection of other tissues inside the eyeball. These other ocular abnormalities are quite frequent. They represent either changes secondary to the retinal degeneration or genetic entities.

moscopic sign of an existing R.P. However, it may be also a transient phenomenon which later disappears. CentraI vision is affected to various degrees. Coats’ Syndrome

Several cases of R.P. associated with bilateral Coats’ syndrome have been In all these cases, the Keratoconus, or keratoglobus, is found described. 232*338~3*8*387~388 more frequently in R.P. patients,“” but it is affection was bilateral, contrary to the especially common in Leber’s congenital generally unilateral sporadic appearance of amaurosis. The incidence of keratoconus in Coats’ syndrome. The R.P. has all the this condition increases with age, and in one features of the isolated disease including imstudy it was reported to be 57% in the group paired dark adaptation, peripheral visual field loss, and nearly extinct ERG.33g The comover 15 years of age.24g R.P. with keratoconus is probably not a bination of Coats’ syndrome with R.P. is separate genetic entity. We suggest that the probably a separate genetic entity; two cases keratoconus is secondary to the pressure on were described in one family.397 However, the the eyes. This is often seen in affected possibility that the exudative retinal detachchildren in the form of Franceschetti’s digito- ment is the cause of a secondary R.P. cannot, ocular sign. This would be similar to the as yet, be entirely excluded. development of keratoconus in children with Drusen of the Optic Disc vernal catarrh who persistently rub their eyes. R.P. in association with drusen of the optic Marginal Cornea1 Dystrophy disc has been reported in about 50 cases.3o’ It Several cases of marginal cornea1 may be one or two separate genetic entities, dystrophy associated with R.P. have been transmitted by either autosomal recessive”O described.98,36sThe cornea1 changes consist of or autosomal dominant”’ genes. It has been sparkling yellowish-white spots in the super- claimedSBothat in some of these cases it is not ficial parenchyma of the limbus. It has been drusen (laminated acellular basophilic exsuggested that it is a separate clinical and genetic entity and the name of “Bietti’s tapetoretinal degeneration with marginal corneal dystrophy” has been given to this disease.38 Keratoconus


R.P. patients often develop cataracts at a much younger age than does the general population. It is relatively more common in the autosomal dominant than in the autosomal recessive types. Sorsby”’ claimed that dominant R.P. with cataract is a genetic entity and that the same may be true for some recessive forms. However, it is possible that the premature cataract is a secondary phenomenon appearing as a consequence of vitreous abnormalities seen frequently in R.P. A recent study by Pruett (Arch Ophthalmol 93:603608, 1975) confirms our observation on frequently occurring vitreous abnormalities in R.P. Macular Cystoid Degeneration

Macular cystoid degeneration may be observed in early cases of R.P. at a stage before “bone-corpuscle” pigment develops. 144~1’1*323 It may be the first ophthal-



25 msec FIG. 5. The ERGS recorded by computer of average transients (CAT) (upper row: right eye, lower row: left eye) from a 58-year-old patient with retinitis pigmentosa. The fundi were about equally affected and showed the typical “bone-corpuscle” pigment, attenuated vessels and pale discs. The visual fields were constricted to 10”. Visual acuity: O.D. 6/18, O.S. 6/24. Both responses were very small, but differed significantly. The right eye showed an extremely small pattern with a scotopic positive wave of less than 10 microvolt, while the left eye had a positive wave of about 35 microvolt. The traces would not be measurable by the conventional recording method using single stimuli.



cretions), but hamartomas (calcified proliferations of astrocyte cells) that are situated superficially in the retina and optic nerve. Other Ocular Associations

It has been claimed that glaucoma is often found in association with R.P.,ls3 but the statistics do not seem convincing, and our own experience does not support this view. Myopia and other ametropias are more common in R.P. than they are in some other retinal, degenerative hereditary diseases. Angioma of the choroid and the SturgeWeber syndrome have been described in association with R.P.,50.124but are probably fortuitous associations. Arrested or resolved cases of congenital retinoschisis may simulate R.P. ophthalmoscopically and electroretinographically, and they may even exhibit night blindness. However, congenital retinoschisis is transmitted as a sex-linked recessive trait and is stationary.27s Electrophysiologic


A number of electrophysiological tests can be employed to diagnose R.P. and further elucidate its nature.2’ These include the electroretinogram (ERG), the early receptor potential (ERP), the electro-oculogram (EOG), and the evoked responses from the brain. It has been [email protected] that the retinal functions expressed by the ERG, the EOG, and the ERP are equally affected in R.P. but this has been contradicted.‘6g THE ELECTROREtlNOGRAM

A very important single test for the diagnosis of R.P. is the ERGe2’ It has been employed for years to diagnose R.P. in children274*‘24even before fundus changes appear in atypical cases,426and to distinguish between retinitis punctata albescens, which is progressive, and fundus albipunctatus with nyctalopia, which is stationary.433 A nonrecordable retinal response (an “extinct” ERG) was once considered a specific sign of R.P. With progress in technology and the introduction of computer averaging, it was shown that proportionate to the severity of the disease, all stages of subnormal ERGS can be recorded down to virtual extinction in the most advanced cases of R.P.27*ae6In short, in most cases, the ERG is just very subnormaPea and can be elicited by a very strong light source”’ or by using averaging techniques.23 Averaging techniques are now employed by

us as standard procedure (Figs. 5-7). The FI?G reflects only retinal function (excluding the ganglion cells). Since adaptation is a function of the retina, the ERG yields information about the dynamics of photopic and scotopic activity, which can also be demonstrated and compared by psychophysical‘8L~1B4 The ERG recorded in R.P. depends on the stage of the disease, which depends mostly on the age of the R.P. patient and on the genetic trait. Rubino and Ponte3*’ published a report of R.P. patients displaying impaired ERGS without nyctalopia. We have never encountered such a case. Use of the ERG enables one to separate photopic (cone) and scotopic (rod) activity. Photopic activity is recorded under conditions of light adaptation, high intensity stimuli and/or red light. Scotopic activity is recorded under conditions of dark adaptation, low intensity stimuli and/or blue light.2e*6’~Ls’ The earliest defect detectable in R.P. is diminished rod function. The psychophysical dark adaptation curve shows a raised threshold together with a parallel subnormality of the scotopic component of the ERG.lg7 Similar data were obtained in cases of asymmetric R.P. and unilateral R.P.3’ Slight abnormalities in cone function can sometimes be detected also, even before pathognomonic fundal changes appear. The cone ERG has been found to be delayed, but of normal amplitude, in early cases of dominant R.P. with reduced penetrance,64+65 although it has also been reported to remain normal while rod function is reduced.6’ In sex-linked R.P. both cone and rod responses have been found to be delayed and subnormal in early cases,67 while in a young child with autosomal recessive transmittance, the cone ERG was subnormal and delayed prior to rod abnormality.” In early cases of central R.P. or progressive cone-rod degeneration, cone function is affected while rod function is normal. Only later does rod function become reduced, although there is always a predominant loss of cone function.62,2s1As the disease involves increasingly larger retinal regions, the ERG amplitude decreases correspondingly. Is6 It must be stressed that in advanced R.P. and older patients with any of these forms, both the scotopic and photopic systems are always affected. In Leber’s congenital amaurosis no ERG is


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25 msec FIG. 6. The ERGS from a 55-year-old patient with advanced R.P., recorded by CAT. The response of the better right eye [upper trace (visual acuity: 6/18)] was very subnormal at the steady state of dark adaptation but far better than that in the more affected left eye [lower trace (visual acuity: 6/24)]. Subsequent examinations during the following years revealed a deterioration of both electrical responses and visual functions. The one of the left eye was extinct two years later. Both visual fields were constricted to 10” and the fundi showed pale discs, attenuated vessels and “bone corpuscle” pigmentation. The two cases illustrated in Figs. 5 and 6 contrast with the majority of our patients in whom the two eyes had a symmetrically abnormal ERG.

In sector R.P., the ERG was THE EARLY RECEPTOR POTENTIAL found to be subnormal in practically all reported patients, the degree of subnormality Shortly after the discovery of the ERP by depending on the area of retina affected.240~2’8 Brown and MurakamY and by Cone,“’ it The amplitude of both cone and rod responses was introduced into clinical use. Like the was subnormal, but there was no delay in ERG, the ERP is very small or not detectable their implicit in advanced cases of R.P.16* In early cases it is In unilateral R.P., the ERG is subnormal affected less than the ERGlB8 because cones, or absent in the affected eye and has been which account for 60%80% of the human reported to be normal in the other eye (Fig. ERP,“’ are better preserved than rods in Q3’0 Sometimes, however, the other eye has most cases of R.P. The amplitude of the ERP been found to have a subnormal ERG,2’o its becomes smaller with age, as cone function amplitudes becoming smaller in the course of deteriorates. years.31~216 In one case, the positive wave was Berson and Goldstein reported6’J8~5ethat in grossly supernormal in the “good” eye with R.P. patients the ERP recovers after flash normal visual acuity, and it has remained so bleaching at a much faster than normal rate. for the last 14 years, while the ERG has been They concluded that this recovery rate of the absent in the affected eye.‘l It is possible that ERP points to anomalous cone pigment these abnormalities in the good eye are kinetics in R.P. patients. It can be caused by some disturbance in blood flow, as demonstrated at a stage when no other is the case in the affected eye. It has been method indicates cone abnormality. Their shown that insufficient retinal blood supply conclusions are, however, strongly contested affects the ERG by decreasing its by Weale,48o who considers the ERP recovamplitude.‘00,‘0~.~88 ery in R.P. patients to reflect correct cone recordable.92




pigment kinetics. disagreehBO


and Goldstein

THE [email protected]

The EOG is irt many cases a useful tool for the study of retinal disease, because it is produced by retinal functions and regions different from those producing the ERG. It is a measure of the standing potential whose dependence on light and dark is a function of two non-neural processes largely generated in the pigment epithelium and in the receptor cellszo In various forms of R.P., the EOG is severely impaired or even absent,216 as is the ERG. In addition to subnormality, the light peak appears earlier than is normal.“’ In the opinion of Arden and Kolb,22 who studied 74 R.P. patients, the EOG is a more sensitive test than the ERG, an opinion which is not entirely in keeping with our experience; the tests complement each other. They permit localization of the damage produced by R.P. in the pigment epithelium as well as in the FIG. 7. The ERGS of an eye affected by retinitis visual receptors. pigmentosa, showing progression of the disease. BRAIN POTENTIALS

The visual evoked potential (VEP) recorded with scalp electrodes is so attenuated by intervening tissues that in order to obtain useful records, averaging techniques must be used. The VEP is usually better preserved than the ERG in R.P. patients, despite its much more complex wave pattern (Fig. 9). This is because the macular area, which is responsible for the major part of the VEP,‘= is generally preserved or only moderately damaged, until late in the development of the disease. The electrically evoked response (EER) was found to be even better preserved than the VEP in some R.P. patients, but generally there is good parallelism between VEP and EER.362 This suggests that the receptors, presumably stimulated to produce the VEP, and the more central sight to produce the EER, are both damaged in advanced R.P. Electra-encephalographic (EEG) changes have been frequently reported in R.P. patients, but they are not suf~ciently understood. They are nonspecific and probably of little clinical value.“’ In associated R.P. they have been reported in healthy relatives of patients.‘72

Upper trace recorded in 1960 (superimposition of 70 responses on one frame of the film): the wave pattern is suggestive of congenital nyctalopia of the Schubert-Bornschein type. Lower trace recorded in 1964 by CAT shows extinction of the response. Patient was 8 years old in 1960. The visual acuity of this eye was 619, the visual field was constricted to So and the fundus showed a pale and waxy disc, attenuated vessels and “bone corpuscle” pigmentation. Already, in 1961, the

20 msec

FIG. 8. The ERGS from both eyes in unilateral R.P. to single stimuli. This 25year-old patient had a visual acuity of 6/6 and normal visual field and fundus in the normal eye (upper trace). The visual acuity of the affected eye (lower trace) was 6/12, the visual field constricted to 7’-10” with a small The Clinical and Genetic Entities of island in the upper temporal quadrant and the funAssociated Retinitis Pigmentosa dus exhibited a waxy disc with attenuated vessels There are many syndromes in which R.P. is and heavy “bone corpuscle” pigmentation.



20 (5) March-April



the coeliac syndrome, crenated erythrocytes (acanthocytosis), highly raised visual threshold and R.P. Neurological abnormalities such as ataxia, voluntary tremor, lack of deep reflex and pathological pyramidal reflexes are also present. The eye symptoms start with night blindness, proceed with a deterioration of day vision and constriction of the visual fields. The fundus changes are typical of R.P., but they progress so slowly that the name, “atypical retinitis pigmentosa,” is often given to these changes. In early childhood the fundus may be normal and the only obvious sign of retinal disease is an abnormal ERG.S57 Later, multiple white dots resembling those in retinitis punctata 1 albescensssO or tine scattered pigmentary 50 msec stippling are noted. Sometimes early macular involvement can also be seen. Still later, the FIG. 9. The VEPs recorded by CAT (upper trace: stimulation of the more affected right eye; typical “bone corpuscles” appear and a color lower trace: stimulation of the left eye). Same vision defect for yellow-blue is acquired.“’ patient as described in Fig. 5. Note the longer All these changes are age-dependent.” latency and smaller amplitude of the upper trace. In the early 1960’s, three independent The wave pattern of the lower trace is also very groups of investigators286~30s.587 showed that in abnormal, but more information reaches the visual this disease, beta-lipoproteins are absent in cortex. the serum. At the same time, there is a low associated with the affection of another organ level of carotenoids and vitamin A, which are or with a systemic syndrome. These include carried in the serum of the beta-lipoprotein several groups of diseases such as lipid fraction. This gave some clue as to the spino- pathogenesis of the R.P. in this condition and disorders, mucopolysaccharidoses, cerebellar degenerations and other seemingly to its treatment. These abnormalities will be unrelated disorders. Although all these are discussed later. The disease is rare, and only 32 cases had supposed to be genetically determined, there as of 1972. There is little is apparently no common basis. Why they all been reported83~asz~2’2 have R.P. in common is a question still to be doubt that it is genetically determined and answered, but the study of the pathogenesis of transmitted by an autosomal recessive gene. R.P. in each of these entities may give insight One third of the cases stem from coninto the nature of the disease. The long list of sanguineous matings.4E8 these syndromes will be discussed under Refsum’s syndrome several headings. Refsum described374,376the basic features of LIPID DISORDERS this syndrome, consisting of chronic polydissociation The clinical and biochemical aspects of neuritis, albumino-cytologic [high cerebra-spinal fluid (CSF) albumin with R.P. in lipid disorders were recently reviewed.51*gz4This group includes the only a small number of cells], ataxia and various cases of R.P. which are, under certain cir- other cerebellar phenomena and a R.P. “sine cumstances, practically preventable. It was pigmento.” Except in rare cases,‘02 mental recently suggested that the high content of retardation is not a part of Refsum’s synlipids in the rod outer segments6 may be the drome. Muscle weakness may develop into common cause for the frequent association of paralysis of all four limbs. R.P. with lipid disorders.43 All patients have an associated R.P. which progresses very slowly. Night blindness is an A-Beta-Lipoproteinemto early sign. The fundus may show fine This syndrome, described by Bassen and granular pigmentation without “bone corKornzweig43*273in 1950 appears in early child- puscle” formation even in the fourth decade hood’” and consists of diarrhea resembling of life.‘ls Cataracts are found in 80% of the


patients and miosis in 94%~~~~The ERG is The disease is caused by an inborn error of lipid metabolism causing storage of phytanic acid (3,7,11,15tetramethyl hexadecanoid acid) in various tissues of the body245,263 and in plasma.42o The disease is rare and is transmitted by an autosomal-recessive gene.379 Juvenile Amaurotic


This hereditary group of diseases is known under several names, such as Batten’s disease, Batten-Mayou, Sjiigren’s disease, Spielmeyer-Vogt disease, Batten-Vogt, SpielmeyerSjijgren, and others. Although the age of onset of several similar diseases used to be a basis for classification among the different diseases of the group, a better classification would be based on the biochemical background. Recently, the term neuronalceroid lipofuscinosis was introduced and Zeman and co-workers reviewed the subject critically.479 In the Spielmeyer-SjSgren or Batten-Mayou syndromes, the ocular Iindings are an atypical R.P. with an early affection of the macular area. Pigmentation in the form of fine dust turns into “bone corpuscles” in the periphery toward the end of the second decade of life. The ERG is “extinct.“26’ Neurological signs consist of seizures of the grand ma1 type, spasticity, pyramidal and cerebellar dysfunction, becoming progressively worse. Finally, mental retardation and personality changes occur. The peripheral blood shows abnormal vacuolation or inclusions in the lymphocytesS6e*467 and azurophilic hypergranulation of the polymorphonuclear cells.‘25~425 The disease is genetically determined by the autosomal recessive mode and is found frequently in the Scandinavian countries. Recently, an accumulation of both ceroid and lipofuscin particles has been found in this disease in neurons, leukocytes and some ocular tissues including pigment epithelium, cones and rods, outer nuclear layer and ganglion cells.‘*1 Lipofuscin, which normally accumulates in aging cells, is here stored in much higher quantities. Both lipofuscin and ceroid are pigments, probably containing a polymerized, unsaturated fatty acid. A peroxidase deficiency was recently found in various cells of patients suffering from this disease.24.25

315 Cockayne’s


This condition described by Cockayne in 1936’06is characterized by dwarfism, microcephaly prematurely-aged appearance, d ea fness: mental retardation and “atypical” R.P.288.382Ocular findings include a slowly progressive R.P eventually with typical “bone corpuscles;” a developing cataract and cornea1 opacification1’1’355 which may be secondary to the lack of tears. The ERGS in three siblings examined by us were found extinct in their third decade of life. The disease is transmitted by an autosomal recessive gene. Most reported patients are of Anglo-Saxon origin and the disease is probably due to a single mutation.35’ Hyperlipoproteinemia has been described in some cases.‘85*358 O,her Lipid Dizorde,z Isolated cases of three other syndromes with R.P. associated with a lipid disorder have been described. Alstr8m12 noted R.P. with obesity, diabetes and neurogenic In this syndrome, elevated deafness. triglycerides and [email protected] were found. Five additional cases were recently Hooft’s disease158,233 consists of reported. 1*6~258 R.P. with psychomotor retardation, erythematous eruption on the face and hypolipidemia. Durand13’ described a patient with R.P., nephronophthisis, deafness, severe mental deficiency and obesity. Hyperlipemia was found with storage of lipids in tissues, MUCOPOLYSACCHARIDOSES

The mucopolysaccharidoses (MPS) are a group of storage diseases characterized by examounts of urinary glycocessive saminoglycans (acid mucopolysaccharides) and in most cases cornea1 clouding. In some cases, retinal degeneration in the form of a slowly progressive R.P. was described. Their classification is based on the clinical defect.318 The mucopolysaccharides are an integral part of the retina and are essential both for structural integrity and normal function. They are synthesized in the myoid region of the inner segment of the visual cells and possibly, in part, by the pigment epithelium.207 They occupy, together with proteins as a homogenous mass, the interstitial space between the pigment epithelium and photoreceptors.146,207 Their physiological significance in the eye and the whole



Surv Ophthalmol 20 (5) March-April 1976

organism is emphasized by the large range of genetically determined physical and mental degenerations which are produced by a disturbance of their metabolism. Hurler’s Disease (MPS I-H)

Of the six recognized mucopolysaccharidoses, the ERG was found to be abnormal in four.2gs In Hurler’s disease (MPS I-H), characterized by severe cornea1 cloudiness, the ERG was found to be abnormal in all examined cases.178*2g6 Re-examination of the patients after several years showed progressive deterioration”’ and even extinction.lso Retinal pigmentation was described.ls8 Late in life, vision may be reduced to light perception due to both the cornea1 and retinal conditions. Scheie Syndrome


Night blindness, narrow visual fields, subnormal or extinct ERG and retinal pigmentary changes have been described in this disease.2vs It is similar to MPS I-H, but the systemic abnormalities are much milder. Hunter Syndrome


This syndrome is transmitted as a sexlinked recessive disease; 11 other mucopolysaccharides display autosomal recessive inheritance. The cornea is generally clear or slight cornea1 cloudiness may appear late in life.‘*’ R.P. has been reported and confirmed histologically.‘84~186The retinal degeneration is slowly progressive, obvious ophthalmoscopic changes appearing only late in life. The ERG was normal in four of the five cases studied.2~178~288 However, it generally deteriorates over several years, 2*248 even when the fundus remains normal. The EOG may be normal or subnormal. In one report,“” a patient with constricted visual fields, retinal pigmentation and nyctalopia had a reduced ERG and a flat EOG. In two other patients,2 the fundi were normal, the ERGS were subnormal and the EOGs were normal in one patient and abnormal in the other.

a quarter of the normal. reported extinct ERGS. DfSORDERS NERVOUS

Leung et al.zss


In this group, R.P. is part of a syndrome affecting many organs of the body with an obvious predilection for the brain. There seems to be no pathogenetic relationship between the different diseases of this group. Laurence-Moon-Bardet-Biedl



The five principal signs of this syndrome are mental retardation, obesity, hypogenitalism, poly- or syndactyly and R.P. In addition, congenital heart disease, deafness, strabismus, and other neurological and renal involvements can be found. The syndrome seems to be caused by a rare autosomal recessive gene. The frequency of consanguinity among parents of affected individuals is expectedly high.lV466 The syndrome has been studied in several countries.1’~1s6~26e~42s The fundus displays a relatively slowly progressing R.P. and pigmentary “bone corpuscles” are found only late in life.‘3e Electrophysiological examinations showed the ERG to be extremely subnormal or even extinct, and the flicker ERG to be extinct in the range of 5-70 cps in all cases. The VEP was measurable only when central vision was still preserved.1SE The LMBB syndrome is rare. It was estimated that about one in 160,000 of the population in Switzerland suffers from this disease25e and a similar figure was found in Israel.1s6 Ataxia,

Epilepsy or Diencephalic


The subject of R.P. associated with spinocerebellar degeneration was recently reviewed by Francois16e and Klein.2S8 The familial appearance of R.P. and heredo-ataxia” due to a hereditary olivopontocerebellar degeneration is a well recognized, distinct nosological entity.97*S86*4e1 The R.P. associated with this condition shows characteristically early Sanfilippo Syndrome (MPS III) macular involvement. The association of R.P. In this condition, mental retardation is with degeneration of basal ganglia,a1’*981~46’ severe. The cornea is clear. ERG abnor- Friedreich’s ataxia158 and progressive malities were reported in all cases examined, myoclonic epilepsyze2 have also been even at the stage of a still normal fundus.178*29s described. Various reports on R.P. with ataxIn one patient examined in our laboratory, ia and other abnormalities,1B7~400deafness, the amplitude of the positive wave was about myoclonus and mental retardation,814



deafness and hypogenitalism,s76 mental retar- various differences, the renal pathology has dation and microcephaly,sS9~sg4have also been consisted in most families of nephronophthisis published. The whole group is poorly manifested clinically by the failure to concenclassified and the exact relationships of the trate and acidify the urine. The fundus shows different syndromes are not clear. It is only minor abnormalities in younger probable that some are variants of the same patients40s and typical “bone corpuscles” in clinical and genetical entity. the older ones.s21 The ERG was extinct The possibility has been considered that a or extremely subnormal in the examined except in one patient diencephalo-hypophyseal lesion may cause cases 1.74.235,S07.321.393.103 R.P. as a secondary phenomenon; however, whose ERG was enhanced and whose EOG the few reports on such an associations5’*“’ was abnorma1.s5” The term “hereditary renalare inconclusive. retinal dysplasia” may be used for this combination of symptoms.s93 It is not clear MUSCULAR INVOLVEMENT whether the families renorted to be afflicted Progressive External Ophthalmoplegia by this syndrome possess the same or The age of onset of this well defined different genes. Also unclear is their relasyndrome varies, but it usually appears dur- tionship to familial juvenile nephronophing the second decade of life. It starts with thisis, described in 1951 by Fanconi et al.“’ weakness of various which The combination of Leber’s amaurosis conmuscles, progresses to cause ptosis, external ophthal- genita with polycystic kidneys and cerebral malformation has also been reported.‘*O moplegia and weakness of the orbicularis oculi muscle.2ss~sszIt is often associated with DEAFNESS complete heart block.251~z69About 50 cases The association of R.P. with deaf-mutism have been reported.2sa In some of these, ERGS were performed and found to be ex- in a patient otherwise normal is tragic and, relatively common. About tinct. The muscular involvement is most unfortunately, probably due to a myopathic rather than to a 10% of all R.P. patients have been reported to while neuropathic process. 25s,267Widespread mito- have considerable hearing 10ss,‘~~~~~ chondrial abnormalities were found in audiometric abnormalities were reported to skeletal muscle cells and in sweat glands of be even more frequent.286 In schools for the the skin.251 Two serum enzymes, creatine deaf, patients with R.P. are often found.“’ This is true only for the progressive type of phosphokinase and alpha-hydroxy-butyric dehydrogenase,267 were found to be R.P. and not for the congenital type (Leber’s amaurosis), which is not associated with significantly increased. deafness.25o Myotonic Dystrophy Various names have been given to the Myotonic dystrophy is known to be genetic syndrome of R.P. and deafness. These associated with retinal pigmentary changes. include Hallgren’s syndrome, Usher-Hallgren Sometimes, these take the form of peripheral syndrome, retinitis pigmentosa-dysacusis pigmentary stippling, at other times there are syndrome and dystrophia retinae dysacusis macular pigmentary changes, and in still syndrome. However, the most widely used other cases the fundus may be norma1.s5~g4~244term is Usher’s syndrome, named after the Pigmentary proliferation in the retina may, person who described several cases in 1914.“’ however, be marked in this synd,rome.7s~2s4*so8Studies performed in Denmark,So1 Sweden,20* The ERG is very subnormal or extinct even in Switzerland1s and Finlands4g found the patients with normal fundi.‘“,” It has been prevalence of Usher’s syndrome to vary suggested7s that the retinal degeneration is between 1.8 and 3.5 per 100,000 population. secondary to the ingestion of large amounts It was estimated447 that 2/3 of all blind-deaf of quinine given to these patients for treat- people in the United States suffer from ment; quinine is known to affect the pigment Usher’s syndrome. The greatest concentration of these patients is in southwestern epithelium. Louisiana where a large genetic isolate exRENAL INVOLVEMENT ists.265 Cases are also reported in other regions of the U.S.,‘05 Israe1,s25~400and The association of R.P. and hereditary nephritis has been the subject of many Poland.248 Usher’s syndrome has been considered to Despite reports.,S21,356,3S9,39S,403


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20 (5) March-April



Type I. It is not clear whether they are also be caused in all cases by a single autosomal recessive gene.‘6~20B~301 However, Nuutila348 separate genetic entities. Electroencephalodisputes this. A study performed by ussz6 on graphic abnormalities are common,43B as is 35 patients belonging to 20 families indicated often found in R.P. patients. The degree of ocular, audiologic and that there are four clinical types of Usher’s syndrome. In Usher’s syndrome Type I, R.P. vestibular affection is the same in all affected members of one family.11e Heterozygotes may is associated with congenital neurosensory sometimes be distinguished. It has been complete deafness, with blindness occurring claimed that in some carriers, gyrate atrophy during adolescence. This type is transmitted by an autosomal recessive gene, the same of the fundus occurs,23o and that the EOG and gene that determines all cases described in the the dark adaptation curve are often subnorgenetic isolate in the U.S.A.,265 most of the mal. and most of our Israeli cases in Finland,348~34D patients.325 In Usher’s syndrome Type II, ASSOCIATIONWITHOTHERDISORDERS R.P. is associated with a progressive hearing R.P. has been described in association with defect which is never as severe as that found oculodermal melanocytosis,‘82 Ehlers-Danlosin Type I. Moreover, the retinal changes in like syndrome,S”’ Klinefelter syndrome,33’ Type II are much milder than in Type I;14g~348ocular albinism,22e lymphocytic leukemia,“’ some patients were reported to have good and Marfan syndrome.33 All these are most central vision beyond the age of 50.325Usher’s probably non-genetic fortuitous associations. syndrome Type II is caused by a distinct Pathology and Pathogene8ir of autosomal recessive gene different from the Retinitir Pigmento8a one causing Type I. 325 Usher’s syndrome Type III (Hallgren’s syndrome) comprises HISTOPATHOLOGY R.P. with complete congenital deafness and vestibular ataxia. This type is common in Isolated Retinltis Plgmentosa Most of the cases of R.P. studied Sweden,2o8 but it has been described to occur elsewhere.301~318~325 In Usher’s syndrome Type histologically during the last 100 years have IV, R.P. is associated with complete con- been advanced cases. The main changes genital deafness and mental retardation. The found have been in the layer of the neuroR.P. and hearing loss that characterize Types epithelium, showing absence of rods and III and IV are indistinguishable from those in cones, and in the layer of the pigment epi-

FIG. 10. Histology of an eye of a patient with advanced autosomal dominant retinitis pigmentosa. Cones in the center of the fovea (left) are relatively normal. In the fovea1 slope (right) the cones are abnormal and the outer segment is missing. Outside this area no photoreceptors were found. (Reprinted from Kolb H and Gouras P*‘l with permission of the authors and publishers.)


thelium, which is absent or destroyed in some areas.133 The retinal and choroidal vessels were occluded and pigment migration through all layers of the retina can be seen. It has been suggested that this pigment migrates along Milller’s fibers.’ The whole retina is much thinner than normal and shows gliosis to various degrees.133 Little has been added to these findings by light microscopy in the last ten years. In the first electron microscopic study of two advanced cases of R.P.,33e several interesting points were discovered. However, an electron-microscopic study of the normal pigment epithelium-photoreceptor relationship in two human eyes”’ should be mentioned first. The pigment epithelium sends out finger-like or fringe-like villi into the matrix which fills the spaces between the outer segments, and broad rampart-like cytoplasmic sheets which intimately surround the tips of the outer segments. These sheets are not only important for the normal cohesion between neuroretina and pigment epithelium, but also for their ability to phagocytize the tips of the outer segments. Electron microscopic study of R.P. eyes”’ showed the visual cells and the pigment epithelium to be abnormal. In the periphery of the retina only some degenerated rod inner segments mixed with melanin granules could be seen. In the posterior pole, the cone outer segments showed irregular lamellae and the formation of “linger-print” structures, which were in some places encapsulated. The basement membrane of the pigment epithelium was thickened and fragmented. The cytoplasm of these cells contained normal organelles with unusually large melanin granules. The epithelial processes were abnormally elongated and they protruded like strands into the area of the visual cells. In R.P. eyes, abnormal large vacuolated mitochondria were seen in some pigment epithelial cells and in some inner segments of the photoreceptors. It was concluded that the degeneration of the photoreceptors coincides with pathologic changes in the membrane of the basal infoldings and the epithelial processes of the pigment epithelium. The choroid was found to be norma1.338 In another electron microscopic study of human R.P., the eye of a 68-year-old female with autosomal dominant R.P. was examined.2” Only a few abnormal cones were found at the fovea. The pigment epithelium


was abnormal; in the macular area these cells contained lipofuscin granules, while in the periphery they looked like uveal melanocytes and contained only melanin granules. These same melanin-bearing cells seemed to carry the pigment of the “bone corpuscles” into the neural retina (Figs. 10-l 1). Leber’s Amauroris

Extensive degeneration of the neuroepithelium with complete loss of the photoreceptors, intraretinal pigment migration, gliosis and destruction of Bruch’s membrane were described in this disease.34**‘8 The choroid was found normal in one study’7Band atrophic in another. 34Furthermore, abnormal short inner segments of the cones were all that remained of the photoreceptors. The pigment epithelium contained large inclusion bodies with fragments of pigment. These changes were similar to those found in avitaminosis A. AssociatedRetinitis PiRmentosa

Essentially, the histologic findings in these cases resemble those found in isolated R.P. However, in many syndromes additional tindings suggest the possible pathogenesis of the disease. One case of a-beta-lipoproteinemia showed changes typical of R.P.462 and also abnormal PAS-positive, alcian-blue positive deposits in the optic nerve. In Refsum’s syndrome, visual receptors were found in the posterior pole while they were missing in the periphery. A sudanophilic substance, most probably phytanic acid, was found to accumulate mainly in the pigment epithelium cells, but also in other layers of the retina.2*8~443 Pigment-laden macrophages were seen throughout all layers of the retina. In juvenile amaurotic idiocy (neuronal ceroid lipofuscinosis) the external retinal layers were totally absentslo or only a few cones and rods remained in the posterior pole.1g3 Degenerative and proliferative changes were found in the pigment epithelium, and the ganglion cells were swollen due to storage of granular SSBand PAS-positive material. In one electron microscopic study, the outer layers of the neural retina were practically absent, the RPE layer was atrophic and the ganglion cells contained stored material in the form of curvilinear and fingerprint bodies.‘!” In Hunter’s syndrome, a histological picture typical of R.P. was found,lB4 but in the ganglion cells, membranous lamellar vacuoles were seen.

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E:IG. 11. Ultrastructure of the same eye as in Figure 10. Cells of a bone corpuscular pigmentat ion con.tain pigment similar in type to that of peripheral pigment epithelium cells and are joined to neight ror-

inn cells by zonulae adherens and aan iunctions. (Reprinted from Kolb H and Gouras P2’l with pern nission of the authors and publisher;)’ _

Loss of pigment granules in the remaining pigment epithelial cells, and pigment deposits within migrating pigment epithelium cells or macrophages completed this picture. The choroid was normal. In R.P. associated with external ophthalmoplegia few ocular pathology reports are available.a69 In the skeletal muscle cells and in sweat glands of the skin, widespread mitochondrial pathology was found.251 In R.P. associated with myotonic dystrophy, three separate reportsas~2s4~aoe showed similar lindings: atrophy of the external retinal layers with extensive proliferation of the pigment epithelium forming infoldings which contain

hyaline material. Occlusion of choroidal and retinal vessels was evident. A pathology similar to that of classical R.P. was also found in cases of R.P. associated with nephropathy.‘0’~40a OCULAR HEMODYNAMICS AND FLUORESCEIN ANGIOGRAPHY

During the last ten years, fluorescein angiography has been used to study the retinal and choroidal vasculature, their relative perfusion pressures and the effect of changes in the pigment epithelium in R.P. The retinal vasculature has been found to be consistently abnormal. The arteries are narrow, con-



taining dye in a lower than usual concentraother organs of the body. Only 0.005% of the tion and there is delay in tilling of the total body vitamin A is found in the eyes;38* arteries278 and veins.“6 Krill et a1.278found however, it is essential for the normal functhree early fluorescein angiographic signs of tion of the visual receptors. For a long time it R.P.: diffuse mottled hyperpigmentation, ab- was theorized”” that R.P. patients might be normalities of retinal vasculature (as unable to utilize vitamin A, but this was never described above), and, in some areas, ex- proved. An investigation of 28 patients inposure of the large choroidal vessels. In ad- dicated that the absorption of beta-carotene vanced cases, the retinal capillaries show in- and its conversion to vitamin A is abnormally creased permeability or are not seen at a11.237 low in R.P.‘O’ Similarly, Campbell et Histological studies442 confirmed these lind- suggested that the blood levels of vitamin A ings, indicating the presence of occlusive are low in most R.P. patients. The average hyalization of many capillaries and the for- serum level of vitamin A was found to be 82 mation of vascular shunts. I.U. (International Units) per 100 ml in R.P. The perfusion pressure of the retinal patients instead of 120 I.U./lOO ml found in arteries was found to be normal in R.P. normals. This claim was denied by others, patients with normal retinal blood vessels, but who found normal vitamin A blood values in low in patients with attenuated retinal arteries all patients examined.275 and advanced R.P.“,” It was concluded71 If the vitamin A content in the body is northat this change in hemodynamics is of a mal, the question arises whether in R.P. it secondary nature. Most investigators have might fail to reach its target cell in the eye shown that in early cases of R.P. the chorio- because of a fault in its transportation or an capillaris fills normally. At a later stage, inability of the retina to utilize vitamin A. there is a slight delay in filling and The question of whether a specific carrier for in advanced cases the delay is very vitamin A exists in the plasma was raised in The large choroidal vessels 1964,180and data obtained in rats confirmed marked. 1*~174~238*237 remain normal until late in the disease.174,23e the existence of a protein carrier for vitamin However, Weinstein et al.4ez believe that the A.24E,446It was shown that the vitamin A choriocapillaris is affected early and that transport to the ocular tissues involves inthese vascular abnormalities together with teraction of two carrier proteins. Retinol, associated changes in the pigment epithelium which is the metabolized carotene, interacts are the primary disease, photoreceptor de- in the plasma with specific “retinol-binding generation being secondary. proteins” (RBP) of a molecular weight of The study of the pigment epithelium layer 21,000-22,000. The concentration of this by fluorescein angiography seems most complex in the plasma is 3-4 mg%. They cirrewarding since minimal lesions in these cells culate in the human plasma bound to a larger can be detected by this method long before protein of the prealbumin group (PA). RBPs they appear ophthalmoscopically. Pigment solubalize retinol and protect it during the epithelium disturbances have been reported in transport to the tissues including the eyes. all studies and they can be seen in the early The Retinol-RBP complex and the Retinolstages of the disease.4~14~‘B~159~226 The white RBP-PA complex seem essential for the dots seen in retinitis punctata albescens show mechanism responsible for the retinol early and increased fluorescence. This is at- transport in the plasma2”j and they form tributed to defects in the pigment epithelium a molecule with a weight of approximately layer.173,308However, the gradual increase in 85,000. the RBP by imthe stain and its persistence after the RahiSs7 measured choroidal phase may indicate an active up- munological methods in 51 adult R.P. patients. Using an anti-RBP serum, he found take of fluorescein by these dots.’ the RBP to be abnormally low in most of his BIOCHEMISTRY OF ISOLATED RETINITIS patients, a finding not confirmed in other PIGMENTOSA studies.200.3” In addition, Maraini3’l found that in the interaction between RBP and Relatively few studies on the biochemical changes in R.P. have been performed in prealbumin and its capacity to carry retinol humans. Most of them dealt with vitamin A, was the same in R.P. patients and normals. The possibility still exists that the utilizaits absorption, circulation _ . and_. metabolism. __ _ . Vitamin A is found in the liver, blood and tion and absorption of retinol by the retina in



20 (5) March-April



membrane discs (in the frog, 1,800) which are arranged perpendicular to the axis of the outer segment. According to Heller et a1.21s these are in the frog free-floating membranous organelles with an inside space separate and distinct from the rod’s intracellular At least 80 per cent, and space. 122,aW.456 possibly more, of the protein of the discs is that of visual pigment?’ the 1 1-cis retinal of which closely fits into a “pocket” of its protein opsin. Rhodopsin seems to float in a matrix of fatty acid chains of phospholipids within the disc membranesB2~11sbut it has also been claimed that it is present in the plasma membrane of the outer segment.*l By means of autoradiography combined with electron microscopy, protein synthesized from labeled amino acids in the inner segment of the photoreceptors was found to become incorporated through the connecting cilium into the discs of the outer segment of the rods.1s1*‘32*‘71 In other words, the visual pigment is steadily delivered to the discs and represents most of their membrane protein. The autoradiographic method led to the discovery of the continual restoration of new discs at the proximal base of the rod outer segments and their steady and continuous displacement into the pigment epitheliThe renewal rate of the discs urn. 132~4’o~4’4~4’7 differs among species.206*4’8 In primates (rhesus monkey), each rod outer segment produces 80-90 discs per day, replenishing its HEREDITARY PIGMENTARY DYSTROPHY OF entire capacity every 9-13 days.‘16 RhodopTHE RETINA IN ANIMALS sin, as long as the disc membranes are intact Several animal species are known to suffer within the rods, is very stable and apparently from a hereditary pigmentary degeneration of is not renewed.2os the retina which, in many respects, is similar In contrast to the continual formation of to human R.P. For this reason, these animals new membranous discs in the rods, there is no were used to study the early pathology, the clear evidence of disc renewal in the cones, electron microscopic changes, and the which differ morphologically from the pathogenesis of pigmentary retinopathy. rods.47a In the cones, the protein becomes difRetinal dystrophy has been described in rats, fusely distributed in the layers of the outer mice, dogs, and sheep. In ah, except sheep, segment. Hence, the continual replacement of the disease is transmitted by autosomal old discs by new ones is typically a rod recessive genes. Before describing these phenomenon. In cones, a small proportion of dystrophic strains, the pertinent ultra- the protein is similarly displaced to the outer microscopic findings in normal animals will segment, but uniformly distributed, and no be discussed. Auerbach has recently new discs are formed after growth is compublished a critical review of the phenomena plete.47a This essential difference, as well as occurring in the normal rod outer segments the differences in form and size, may be and their pathologic implications,** reflected in the predisposition of rods and cones to different pathologies (Fig. 12).472 The Outer Segments of Photoreceptors Because of the continual disc production of The membranous outer segments of rods the rod outer segment proximal end, removal contain stacks of about a thousand double- of the discs is necessary. The membranous R.P. patients is impaired or faulty. It has been shown288 that two retinol dehydrogenase isoenzymes and one alcohol dehydrogenase isoenzyme found in the retina are different from these isoenzymes found in the liver. These “eye-type” isoenzymes are specific; they are absent from the liver and could be abnormal in R.P. patients. R.P. patients have normal blood values for various lipid and protein components2ss~27” and normal urinary amino acids. One report18B claims that the activity of serum lactic dehydrogenase is significantly higher than normal in R.P. patients. In another study,* a mecholyl injection, which in normals causes a moderate decrease in blood pressure followed by an increase, caused in R.P. patients significantly lower blood pressure followed by a significantly higher increase. The regeneration of rhodopsin is normal in R.P. patients as shown by densitometric methods.226 This has been confirmed by psychophysical and electrophysiological studies*’ which indicate that the visual disability of R.P. patients is associated with a decrease in the amount of rhodopsin (due to a loss of rods) and not to a change in the quality or function of rhodopsin. A detailed review of the biochemical changes of R.P. with lipidoses has recently been published.“’


. 12. The difference in the distribution of labelled protein in the rod outer segment (left) and the outer segment (right). (Reprinted from Young RW”2 with permission of the auth ors and publishers.)

discs move steadily to the rod distal end, are monkeys this phagocytosis destroys 2000 to eventually shed into the pigment epitheli- 4000 discs per day by each epithelial cell:475 urn 39~~7’*478~4” and so the entire rod outer seg- The pigment epithelium must possess an exmeht undergoes a constant renewal.‘70~476 traordinarily effective phagocytic-lysosomal There is then a continuous turnover of visual system in order to be functional for a lifetime. pigment in rods, which occurs more slowly in What finally happens to the phagosomes is the dark and in cool temperatures than in the still unclear, but acid phosphatase of primary light and in warm temperatures.8°*470The con- lysosomes may participate in the enzymatic tinuous disc shedding may be considered a digestion of the disc material.3’7 The first inwho not only observed the mechanism to preserve structure during the vestigators life of the individual. phenomenon in the human pigment epiThe detached discs are ingested in the pig- thelium but also recognized their true signifment epithelium; these bodies were called icance, were Bairati and “phagosomes” by Young.47e This process is Hereditary Retinal Dystrophy in the Rat equivalent to the fusion of the exogenous The discovery of a strain of rats suffering material, the former discs, with primary from a hereditary retinal dystrophyss.8g lysosomes. Lysosomes, the so-called vacuolar opened the way for a larger number of studies apparatus, are small particles which represent a highly organized intracellular digestive on pigmentary retinopathy in animals. These system by means of their association with rats, the RCS (Royal College of Surgeons) specific enzymes. They are phagocytized in strain of dystrophic rats, are homozygotic for the cytoplasm of the pigment epithelial cells an autosomal recessive gene rd, and present and eventually disappear.“0~‘a2~“o~477 In rhesus many similarities to human R.P. Ophthal-



Surv Ophthalmol 20 (5) March-April 1976

moscopically, progressive changes are noted, starting with abnormal fundal reflexes and ending with pigment c1umps.2*2The ERG is normal until the 18th day of life; it then begins to decrease gradually until extinction on the 60th day.‘28~22SHistological examinations in advanced cases revealed findings similar to those of human R.P.128.22’ An analysis of retinal function using the ERG, rhodopsin concentration measurement, light and electron microscopy, and autoradiographic methods have shown that the early stages of the disease in these dystrophic rats is characterized by an accumulation of rhodopsin and not by a primary defect of vitamin A or rhodopsin metabolism.‘28~2es Starting on day 12, outer segment discs accumulate in the space between the outer segments and the pigment epithelium,‘28~2aJwhich seems to have lost the ability to phagocytize and to remove the discarded discs (Figs. 13, 14). By day 20, the amount of rhodopsin has increased to twice the normal amount, even at a stage when the outer segments are still increasing in size. Later, in spite of new disc production, the degeneration of the outer segments continues until finally the bipolar cells are adjacent to the pigment epithelium. On day 60, no rhodopsin can be detected.222-P2’Keeping the rats in darkness slows the process.12T The rhodopsin is qualitatively norma1128 as in human R.P. The ERP is supernormal, due to the increased disc material, up to the age of

20-21 days when the ERG is already subnormal due to the functionally abnormal and possibly degenerated outer segments.2l By means of autoradiography,84~86~222-224 Dowling and Sidman’slZB results were confirmed and elaborated. The dystrophy is likely to be a disease of the pigment epithelium. The inability to remove the shed material may be caused by an enzymatic deficiency in the pigment epithelium, and the death of the visual cell may be due to poor nutritional supply from the choroid,22s caused by the excessive amount of debris in the intercellular space. LaVail et al.ass noted that the disorganized extralamellar material appeared to be derived from both the rod outer segments and pigment epithelium processes. In a strain of rats in which pigmentation possibly affords some protection to the eye from light, the onset and progression of the process was delayed by one week compared to albino RCS rats.46g Worth reading is the editorial by Feeney.*42 The author describes the phagolysosomal system of the pigment epithelium, indicating that the phagocytosis of its cells may be similar to that of leukocytes and macrophages, and may be the key to retinal diseases. Studies of the blood circulation showed no difference in uptake of fluorescein by the choroid in normal and dystrophic rats except that resulting from the lack of the screening effect of the pigment epithelium.412 The












s -







FIG. 13. Histologic appearance (left) and diagrammatic representation (right) of outer retinal layers in control (A) and dystrophic rats (B). (Reprinted from Herron WL et a1.213with permission of the authors and publishers.)





325 Id












1 Id

43d r--T

111111 18



FIG. 14. Diagram comparing the movement of labelled amino acid in control (Wistar) rats and in RCS rats. The area covered by irregular lines represents the extracellular debris found in RCS rats.

(Reprinted from Herron WL et al.“’ with permission of the authors and publishers.) degeneration of retinal capillaries was thought to be the result of the vasdconstrictive effect of oxygen, having increased tension in the retina due to lack of visual receptors.175 Several biochemical studies were performed on the retinas of dystrophic rats. The activity of the enzyme lactic dehydrogenase has been found to decrease progressively and rapidly,*’ after having been normal up to the 20th day of life.97a The glucose metabolism (aerobic and anaerobic) is initially normal, and then decreases.a7a The hexose monophosphate shunt shows a considerably higher than normal activity, starting on the 6th or 7th day of life, after which it decreases.371 The decrease in synthesis and breakdown of protein in photoreceptors is noted several days before dystrophic changes can be seen. After bleaching, RCS rats show higher than normal amounts of retinol in the pigment epithelium and a greater than normal depletion of retina1.371+a72 The lysosomes of the pigment epithelium of dystrophic rats were found to be relatively unstable.ea Their total enzyme activity was found to be significantly increased, increasing even more with the progression of the disease. It was suggested that this lytic enzyme originating in the pigment epithelium may cause the degeneration of the visual cells.8a


Retinal Dystrophy

in the Mouse

This was first described in the house mouse, 171u.smusculus, in 1927.25’ It is an autosomal recessive disease, similar to the dystrophy found in RCS rats. However, it appears earlier and progresses more rapidly, and the associated cataracts seen in RCS rats are not found.2B1This strain, as well as others, have been studied.292.410Glutamine synthetase activity was found to decrease in dystrophic mice after the 18th day of life.‘a8 Studies have shown that ATP-ase activity, RNA and DNA302.303 are not involved in the etiology of the retinal dystrophy, but merely reflect cellular death. Hereditary

Retinal Dystrophy

in the Dog

Many different hereditary retinal degenerations exist in the dog” and they cannot all be mentioned here. A slowly progressive pigmentary retinal dystrophy was described in the Irish Setter.306~a6a The affected dog suffers predominantly from night blindness between the 2nd and 9th month of life. Day

vision begins to deteriorate in about the 3rd month of life, leading to blindness at about the age of 2 years. Pathologically, it starts as an atrophy of the rods and progresses until all pigment epithelium and neuroepithelium cells disappear.“’ The ERG is then extinct and

cataracts are usually present. The disease has also been described in other dogs.” Pigmentary Retinopathy in the Sheep

This retinopathy, causing a disease called Bright Blindness, is histologically similar to the hereditary dystrophy of the RCS rats.“’ It was thought to be hereditary in origin, but it is now clear that it is an acquired disease caused by grazing on bracken.42 It is an irreversible primary retinal degeneration with no associated cataracts.287 INDUCEDRETINOPATHIESIN MAN AND ANIMALS

Pigmentary retinopathies with many similarities to human R.P. were experimentally produced in animals by deficient nutrition, strong light and a series of toxic agents. In man, a similar retinopathy can be produced iatrogenically as a side effect of the use of drugs or deficient nutrition. All these may be important for our understanding of the pathogenesis of human R.P. Nutritional Deficiency Retinopathy

Most studies of the effects of vitamin A deficiency on the retina were made in the rat. It is probable that the rat is especially sensitive to vitamin A deficiency. One reason may be that its retina is predominantly built of rods. Rods appear to be more sensitive to vitamin A deficiency than cones. When vitamin A is in short supply, the cone pigments are less affected since they are synthesized more rapidly than rod pigments.‘30 Vitamin A deficient rats showed pathological changes resembling those of human R.P., starting with swelling and fragmentation of the outer segments, then of the inner segments, and finally of the outer nuclear layer.“’ Dowling,12eJ2’ however, by means of the ERG and visual pigment studies, showed major differences between this nutritional retinopathy and the hereditary retinal dystrophy of the rat. In the former, the ERG a-wave and the production of rhodopsin decrease in the initial stages because the outer segment is affected in the earliest stage and, with it, the production of rhodopsin. In hereditary dystrophy, the ERG b-wave decreases before the a-wave and rhodopsin increases initially; perhaps this can be attributed to the accumulation of normally produced rhodopsin because the shed discs are not phagocytized. In contrast, Amemiya16 claimed that the earliest change in vitamin A deficiency occurs in the pigment epithelium.

With supply of vitamin A in the early stages of nutritional retinopathy, regeneration also starts in the pigment epithelium as evidenced by renewed activity of alcohol dehydrogenase.16 It was theorized that the pigment epithelium could be directly affected by the lack of vitamin A or indirectly through structural changes in the collagen of Bruch’s membrane converting it to a barrier impermeable to passage of metabolites from the choriocapillaris to the pigment epithelium cells. Changes in the ERG c-wave precede those in a- and b-waves, suggesting that the pigment epithelium is primarily involved in nutritional retinopathy of the rat.435 In albino rats, the curve relating amplitude of ERG b-wave to stimulus intensity was practically the same in protein-deficient rats as in rats fed on a vitamin A-free diet.3o In another study,208 it was suggested that the degeneration of the visual cells is due to a faulty synthesis of protein resulting from the vitamin A deficiency and not from a primary degeneration and fragmentation of the discs in the outer segment. Herron and Riege1220v221 showed that there is a decreased rate of outer segment production in nutritional retinopathy. At the same time, there is a decrease in effective phagocytic removal, simply because there is less to phagocytize. It takes ten days for a normal outer segment to be phagocytized and this is not changed in nutritional retinopathy, indicating that the mechanism of phagocytosis is not primarily affected. This was recently confirmed by a study which showed that phagocytosis takes place in the retina of vitamin A deficient monkeys.211 The same study revealed the interesting, and as yet unexplained, fact that cones are affected earlier than rods in this nutritional retinopathy of the monkey. Deficiency of some essential fatty acids such as linoleic and linolenic acids also cause an alteration in the formation of the outer segment discs in the ratas’ Nutritional blindness in the cat was produced as a result of a diet based on casein which led to defective utilization and storage of vitamin A. The retina showed progressive destruction of the visual receptors with disappearance of the outer nuclear layer.40**402 Interestingly, cataracts were found in some animals, as is often seen in hereditary R.P. More recently, a retinopathy resembling “progressive cone-rod degeneration” was produced in cats fed on a specific semipurified diet.364 Vitamin A deficiency in the squirrel caused

abnormal deposits of a white, amorphous substance at the photoreceptor pigment epithelium level resembling human retinitis punctata albescens.5e

retinal image and a I set exposure was 3.2 Cal/cm2 in brown-eyed persons and about twice this value in blue-eyed persons.

Light-induced Retlnopathy

Experimental Toxic Retinopathy in Animals

Strong and prolonged light exposure causes irreversible damage to the retina of both albino and pigmented rats.‘0a~s4sThe resulting retinopathy resembles human R.P. in that the ERG is reduced and the visual cells and the pigment epithelium are deteriorated. The earliest change, occurring after one hour of exposure to strong light, consists in a separation of some disc membranes to form small vesicles.‘*’ Later, the membranes of outer segments become separated and vacuolated and the cytoplasm of the pigment epithelium shows an increased number of lysosomes (possibly involved in increased phagocytosis). After two to seven days, the outer segments become distorted, separated from the inner segments and mostly buried in increased microvilli of the pigment epithelium. After 2-3 weeks the cellular degeneration is irreversible.284 Two or more weeks after the degeneration of the pigment epithelium and visual receptors, retinal capillaries degenerate.1’6 After 130 days of light exposure, there is degeneration of rod cells in rats but their vision is, amazingly, not severely affected, as tested by means of intensity discrimination’O and pattern discrimination.18 Darkness was found to protect vitamin A depleted rats from nutritional retinopathy.s45 As mentioned previously, Dowling observed that in vitamin A deficiency and in dystrophic rats, degeneration can largely be prevented by keeping the animals in darkness.127*128 Noel1 and Albrechts4’ suggested four possible causes of damage by light: thermal injury, photosensitized oxidation of cell components, electrolyte changes due to light stimulation, and injury by some unknown toxic photoproduct. It has been shownzg4 that this damage is directly related to the amount of energy absorbed by the visual receptor and not to its wavelength. Rodents are especially sensitive to strong light. In rabbits, the threshold for light damage is much higher than in rats.“’ Light can also cause damage to the retina in man.“’ The threshold for retinal damage by white light has recently been studied by means of a light coagulator in six human volunteers prior to enucleation for ocular tumor.lo*a The minimum energy to produce an ophthalmoscopically visible lesion for a 3” diameter

Studies on retinopathy experimentally produced by sodium iodate or iodoacetate were extensively performed more than 20 years ago by Noell.342*s43 They have been continued in the last ten years, mainly in Japan. Noel1 found that sodium iodate is primarily toxic to the pigment epithelium while iodoacetate destroys the photoreceptors. However, Francois et al.ls2 were unable to determine whether the pigment epithelium or the photoreceptors were the tissues primarily affected by iodate. Suyama428 injected sodium iodate intravenously in rabbits and noticed, after 7 days of daily injections, white flecks and edema in the fundus, and after 17 days attenuated retinal vessels and pigment flecks. It was shown by electron-microscopy that Mliller and other glial cells actively phagocytize the pigment. Six hours after sodium iodate injection, morphological changes in the basal infoldings of the pigment epithelium and a reduction in the activity of ATP-ase could be seen.316 Dopa-oxidase activity increases after iodate injection parallel to the increase in pigmentation and it has been postulated that this indicates damage to the blood-retina barrier, caused by the iodate. 334*335 Alcohol dehydrogenase activity in the retina decreases rapidly after iodate injections.34’ Ponte and Lauricella360 have administered iodoacetic acid to rats, and shown that rats of the RCS strain heterozygous for yd gene (phenotypically normal) have greater susceptibility to retinal damage from iodoacetic acid than do normal rats. A pigmentary retinopathy has also been produced in various animals by urethan,48*434 para-chloromercurobenzoate,“” N-methylN-nitrosourea,219 and other toxic agents. N-methyl-N-nitrosourea initially produced changes in the pigment epithelium and the inner nuclear layer in hamsters. In the second stage, destruction of the rods and cones was seen, and finally total destruction of the photoreceptor cell occurred.218 Toxic Retinopathy in Man

Since the discovery of a retinopathy following chloroquine therapy in 195922’ (isolated cases were described as early as in


SW Ophthalmol

20 (5) March-April



1957), a series of drugs was found to cause a similar toxic retinopathy. It is beyond the scope of this review to mention the hundreds of patients reported in the literature. Chloroquine retinopathy may appear in a patient who receives more than 100 gm of this drug over a period of one year.44g This retinopathy has much in common with R.P. including clumps and “bone corpuscle” pigment, attenuated retinal vessels and a reduced or extinct ERG. There are, however, differences: the macular area is affected early, there is greater cone than rod loss, and dark adaptation is affected relatively late.350On the other hand, there are findings that the scotopic ERG components are more affected than the photopic.SQ6A retinopathy similar in many aspects to chloroquine retinopathy was described in patients receiving large quantities of phenothiazines, mainly chlorpromazine, thioridazine and NP 207.261 Several clinical facts and experimental studies point to the pigment epithelium as the primary tissue involved in these retinopathies. Chloroquine has an increased affinity to melanin where its concentration may be 80 times greater than in other tissues.62*6SAlso, phenothiazine concentrates in pigmented tissues.981 The electro-oculogram, which records the resting potential in the pigment epithelium is affected early in patients with chloroquine retinopathy, suggesting the involvement of this tissue layer.2Bs It has been claimed that the chloroquinemelanin complex interferes with the metabolism of the pigment epithelium, leading to atrophy of the rods and cones.52 A chloroquine retinopathy produced experimentally in cats322 showed in the early stages an extensive enlargement of the pigment epithelium cells with a decrease of enzymatic activity. It was concluded that a gradual loss of rods and cones is secondary to this. Electron microscopic studie$‘O demonstrated the presence of membranous and granular cytoplasmic inclusion bodies in a variety of epithelial cells in chloroquine poisoning. These are degenerated lysosomes. In this respect, it is also known that chloroquine concentrates in the lysosomes of cells” and that it tends to “stabilize” the lysosomal membrane by interference with the normal phagocytic function of the cell.“j’ In one study,18* however, chloroquine in high concentrations was shown to inhibit protein synthesis in pigment epithelial cells.





The pathogenesis of R.P. in man is not known. However, present knowledge of pathology, electrophysiology, fluorescein angiography and biochemical abnormalities in human R.P., animal models and experimental retinopathies, provide evidence that in hereditary R.P. the retinal pigment epithelium may be the tissue primarily affected. Most of this evidence has been outlined in this review. A normal pigment epithelium-visual receptor relationship is needed to enable the pigment epithelium to perform two functions: to remove waste products of the photoreceptors, and to provide the photoreceptors with necessary metabolites. In the normal human retina, the discs shed from the tips of the rod outer segments are constantly phagocytized in the pigment epithelium.sQ~228~41’ However, there is evidence that in dystrophic RCS rats, this phagocytosis does not take place.223 In human R.P., as in RCS rats, the defect may be in the recognition of the waste material (the shed discs) by the “recognition site” of the pigment epithelium processes.142 Later, the accumulation of a thick layer of waste products between the pigment epithelium and photoreceptors interferes with the normal metabolic exchange between these two structures and causes death of the neural cells. Secondary and late changes follow in the form of atrophy of the neural retina, retinal vascular changes, migration of pigment-bearing cells, and atrophy of the optic nerve with death of the nerve fibers. There is other evidence in favor of this theory. If the photoreceptors were primarily affected, one might expect the regeneration of the rhodopsin to be abnormal; however, this is contrary to what has been found.226 Also, electrodiagnostic tests have indicated that the pigment epithelium is affected early in human R.P.22 No pathological reports of early cases of human R.P. are available, but electronmicroscopic studies of late cases have indicated a severe pathology in the pigment epithelium.a’lJss Fluorescein angiography provides evidence that the pigment epithelium is always involved in the early stages.18 However, the main body of evidence in favor of this theory lies in the animal models of R.P., particularly the RCS dystrophic rats. Considering the various syndromes of associated R.P., it is conceivable that there is



no common denominator pointing to the pathogenesis of R.P.28 In the storage diseases, the accumulation of the storage material within pigment epithelial cells might interfere with the metabolic function of these cells.255 In a-beta-lipoproteinemia, R.P. could be caused either by the absence of beta-lipoprotein causing direct ocular and neurological lesions15oor, more likely, by the low levels of vitamin A causing a deficiency retinopathy which, as outlined above, bears many similarities to human R.P.


Our longterm followup with repeated ERG recordings of six patients treated with Adaptinol’nl [helenien equal to xanthophyll dipalmitate (Bayer)] indicated no effect of the drug.28 The speculation of Herron et al.,223which is based on the histological similarity of the retina in the dystrophic rat and the retinitis seen in advanced human R.P. should be mentioned again. If the pathogenesis in rats is similar to that in man, the production of discs may be slowed down by induced relative vitamin A deficiency (which is in direct conTherapy trast to the treatment suggested by Campbell The widely accepted view that no treatment et a1.B6).If this is true, vitamin A given to is available for R.P.‘* is true only in a “cure” R.P. may have the opposite effect. In qualified sense. Treatment should be con- other words, there is no evidence for a benesidered in several pathological entities. In ficial effect of vitamin A or its derivatives on order to try to prevent, or at least to diminish, isolated R.P., and it is possible that this treatthe destructive, irreversible sequelae of the ment even has a deleterious effect. Herron disease on the neural retina, such treatment and Riege12*"J21 suggest4 a clinical applicashould be initiated as early as possible, when tion of their findings in rats by producing retinal function is still practically norma1.54 vitamin A deficiency in R.P. patients by apVarious forms of treatment have been propriate diet; it may then be possible to suggested; however, many of these have decrease the rate of rod outer segment proved inefficient, or apparently have not production and to prolong the life of photobeen founded on rational bases. We will limit receptors by restoring a better relationship our discussion mainly to suggestions raised in between production of outer segments and the last decade. Reports of earlier un- their phagocytosis. This has not yet been successful attempts at treatment have been attempt4 clinically_ published.133 Contrary to isolated R.P., in a-betalipoproteinemia (Bassen-Kornzweig synVITAMINS drome) vitamin A therapy is helpful. It is conVitamin A administered orally or by ceivable that it may prevent the appearance of injection has been used for many years as retinal dystrophy if it is administered early therapy for R.P. Campbell et al. 96found the enough. Vitamin A treatment for this disVitamin A and carotenoid content in the order was attempted in 1964 by Wolff et al.“* blood of R.P. patients subnormal, and con- However, these investigators were unable to eluded that R.P. patients are unable to store prevent the development of R.P. although a vitamin A. They claimed improvement in normal vitamin A level could be maintained. visual fields, and in rod and cone thresholds, More recently, it has been shown that the in most of their patients treated daily with ERG may improve”’ or even return to nor24,000 I.U. of vitamin A. This has not been males with the rise of serum vitamin A levels. The ERG recovery reflects both cone and rod confirmed by others. Shearer has suggested4o6 that R.P. may be function, the former improving more caused by failure of the pigment epithelium rapidly. Is8 In order to reverse the process of to esterify serum vitamin A or to replenish pigmentary degeneration in this disease, I l-cis-retinol for regeneration. He found ab- vitamin A must be given early.‘B6 It is given as sorption and conversion of B-carotene to be ab- vitamin A palmitate, 200,000 I.U. orally, or monthly intramuscular injections of 100,ooO normally low in R.P. patients. Subliminal doses of il-cis vitamin A in nutritional I.U. each. Vitamin E (Tocopherol) has been used as retinopathy of newborn rats seemed to protect the retina from the effects of vitamin treatment for R.P. with the rationale that it A deficiency and seemed very promising.lo3 serves as a vitamin A “sparer” and that in it was found to be However, a double-blind study on 71 R.P. a-beta-lipoproteinemia 10w.‘~~However, the nutritional retinopathy patients did not fulfill this promise.‘o4


Surv Ophthalmol

20 (5) March-April


produced in monkeys by vitamin E deficiency is very different from R.P.pll and its clinical trial in 21 patients with Leber’s amaurosis yielded negative results.82 LIGHT DEPRIVATION

Berson suggested that a patient in an early stage of R.P. may benefit from monocular complete light deprivation.66*66This is done in patients old enough not to risk acquiring amblyopia. His hypothesis is based essentially on Dowling and Sidman’sLZ8 observation that the decline of rhodopsin in dystrophic and vitamin A deficient rats can be prevented and the degenerative changes slowed down when the animals are kept in the dark. Berson suggested that one eye of the patient should be covered by a flush-fitting, opaque scleral contact lens. This could double the patient’s visual lifetime if, indeed, the retina does not deteriorate (or does so very slowly) when it is occluded from light. Berson used regular ERG recordings to determine retinal function. It is premature to form an opinion of this treatment since only one patient has been reported to have been treated in this way and no longterm clinical results are It should be kept in mind that the retina of the rat is known to be extremely sensitive to light; therefore, the effect of light on the rat can be compared only in a qualified way to that in man and other species. Furthermore, rat rhodopsin is said to be atypical among mammals in that, among other things, 1I-cis retinol is not stored in the pigment epithelium and rhodopsin regeneration is a very slow process.4s TREATMENT OF ASSOCIATED RETJNITIS PIGMENTOSA

In addition to vitamin A therapy in a-betalipoproteinemia, dietary therapy has been suggested for the systemic condition in Refsum’s syndrome.208*‘21,422 It is conceivable that restriction of phytol and phytanic acid in the diet may prevent the accumulation of the fatty deposits in the pigment epithelium and neural retina. If started early, this dietary restriction may possibly prevent the development of R.P., making Refsum’s syndrome another preventable retinal dystrophy. There is no clear evidence about the potential for reducing the accumulation of intracellular storage substances in the mucopolysaccharidoses and improving the retinal


dystrophy by administration of retinol (vitamin A which is a primary alcoho1)115or fresh frozen plasma.1a8 MISCELLANEOUS

As might be expected with an “untreatable” disease, many drugs, operations and bizarre procedures for treatment of R.P. have been suggested. These anticoagulants,s2’~38s complamine include (xanthinol nicotinate)“’ and other vasodilatot-s, RNA,‘O’ retrobulbar injections of hyaluronidase and acid phosphates,soo and even subconjunctival injections of peat distillate.2*1 Transplantation of human placenta 146used for many years, continues to be uskd by some.4o” Surgical transplantation of strips of extraocular muscles has been suggested to improve choroidal blood flow? It has been reported that R.P. patients responded favorably to exposure to ultrasonics312*91s and to acupuncture.‘08 However, reliable evidence of the success of any of the treatments mentioned above is not available. VISUAL AIDS

Many R.P. patients have associated refractive errors, the correction of which often improves central vision. A night vision device based on an image intensifier has recently been suggested to improve vision in darkness of R.P. patients.68*6eIt has not yet been used widely enough to warrant comment. We are experimenting with devices to widen the visual field of R.P. patients and the results are, so far, enc0uraging.s2s R.P. patients should be treated for ocular defects in addition to retinal dystrophy. Most surgeons report good results from cataract removal in R.P. patients, even in cases where the preoperative ERG is extinct or very 1ow.385~4s1 Such patients still have central vision which, although not reflected by the ERG, is clearly demonstrable by the visual evoked response.27*‘2s While we possess a great deal of information about R.P., related syndromes, and animal conditions apparently simulating the human pathological condition, .we do not know yet where future endeavors will lead us. Studies from animal experiments and induced retinopathies, and the use of modern technology in the study of human tissue, may provide the first leads toward future understanding of the pathogenesis of R.P.


However, we should not deceive ourselves; the root causes of this disease are still unknown. References 1. Abraham

FA, Yanco L, Licht A, Viskoper RJ: Electrophysiological study of the visual system in familial juvenile nephronophthisis and tapetoretinal dystrophy. Am J Ophthalmol 78:591-597, 1974 2. Abraham FA, Yatziv S, Russell A, Auerbach E: Electrophysiological and psychophysical findings in Hunter Syndrome. Arch Ophthalmol 91:181-186, 1974 3. Abraham FA: Sector retinitis pigmentosa. Electrophysiological and psychophysical study of the visual system. Dot Ophthalmol 39:13-28, 1975 4. Abraham FA, Ivry M, Tsvieli R: Sector retinitis pigmentosa. A fluorescein angiographic study. Ophthalmologica 172:287-297, 1976 5. Abrahamson EW, Wiesenfeld JR: The structure, spectra and reactivity of visual pigments, in Dartnall HJA (ed): Handbook of Sensory Physiology, Vol. VII/l, Photochemistry of Vision. Berlin, Springer-Verlag, 1972. pp 69-121 6. Adams A, Aspinall P, Hayreh SS: Primary retinal pigmentary degeneration. Trans Ophthalmol Sot UK 92:233-249, 1972 7. Agarwal LP, Malik SRK, Mohan M, Karwal PR: Retinitis pigmentosa. A new therapeutic approach. Br J Ophthalmol 47:144-148, 1963 8. Akabane N: Mecholyl test in retinitis pigmentosa. Acta Sot Ophthalmol Jap 70:1299-1310, 1966 9. Albert DM, Geltzer AI: Retinitis punctata in a Negro child studied with fluorescein angiography. Arch Ophthalmol 81:170-176, 1969 10. Alezzandrini AA: Retinitis pigmentosa en sectores simetricos. Arch Oftalmol (B Aires) 40:72-75, 1965 11. Allison AC, Young MR: Uptake of dyes and drugs by living cells in culture. Life Science 3:1407, 1964 12. Alstriim CH, Hallgren B, Milsson LB, Asander H: Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness. Acta Psychiat Stand 34: Suppl 129: l-35, 1959 13. Alstriim CH, Olson 0: Heredo-retinopathia congenitalis recessiva monohybrida autosomalis. Hereditas 43: 1, 1957 14. Amalric P: In&et du test a la fluoresceine dans l’bude de certaines degentrescences taptto-retiniennes et en particulier dans le fundus flavimaculatus. Ophthalmologica 154:367-372, 1967 15. Amemiya T: Vitamin A and the retina. Eye Ear Nose Throat Mon 50:341-346, 1971


16. Ammann F, Klein D, Franceschetti A: Genetic and epidemiological investigations on pigmentary degeneration of the retina and allied disorders in Switzerland. J Neural Sci 2:183-196, 1965 17. Ammann F, Klein D, Prader A, Hauser A: Deux grands arbres gtnealogiques de syndrome de Bardet-Biedl provenent de la Suisse Centrale. Contribution a l’etude des isolats. Arch Julius Klaus Stift Vererbungsforsch 41:67-81, 1966 18. Anderson KV, O’Steen WK: Black-white and pattern discrimination in rats without photoreceptors. Exp Neurol 34~446-454. 1972 19. Archer DB, Krill AE, Ernest JT: Choroidal vascular aspects of degenerations of the retinal pigment epithelium. Trans Ophthalmol Sot UK 92:187-207, 1972 20. Arden GB, Fojas MR: Electrophysiological abnormalities in pigmentary degenerations of the retina. Assessment of value and basis. Arch Ophthalmol 68:369-389, 1962 21. Arden GB, lkeda H: Effects of hereditary degeneration of the retina on the early recep tor potential and the cornea-fundal potential of the rat eye. Vis Res 6:171-184, 1966 22. Arden GB, Kolb H: Electrophysiological investigations in retinal metabolic disease: Their range and application. Exp Eye Res 3:334-347, 1964 23. Armington JC, Gouras P, Tepas DI, Gunkel R: Detection of the electroretinogram in retinitis pigmentosa. Exp Eye Res 1:74-80, 1961 24. Armstrong D, Dimmitt S, Van Wormer D: Studies in Batten Disease. 1. Peroxidase deficiency in granulocytes. Arch Neurol 30:144-152, 1974 25. Armstrong D, Van Wormer D, Neville H, et al: Thyroid peroxidase deficiency in BattenSpielmeyer-Vogt disease. Arch Pathol 99:430-435, 1975 26. Auerbach E: The human electroretinogram in the light and during dark adaptation. Dot Ophthalmol 22:1-71, 1967 27. Auerbach E: Clinical application of bioelectrical tests, in Ballantyne AJ, Michaelson IC (ed): Textbook of the Fundus of the Eye. Edinburgh, London, E. & S. Livingstone, 1970, ed 2. pp 512-542 28. Auerbach E: The rod outer segment, Its pathology and clinical implications. Dot Ophthalmol Proc Series, 1974, pp 1l-35 29. Auerbach E, Burian H: Studies on the photopic-scotopic relationships in the human electroretinogram. Am J Ophthalmol 40, Part II:42-59, 1955 30. Auerbach E, Guggenheim K, Kaplansky J, Rowe H: Effect of protein depletion on the electric response of the retina in albino rats. J Physiol 172:4 17-424, 1964


Surv Ophtholmol

20 (5) March-April

31. Auerbach E, Rowe H: The “good” eye in unilateral retinitis pigmentosa. OphthalmoIogica 155:98-l 16, 1968 32. Avanza C: L’amaurosi

o degenerazione tappetoretinica congenita o infantile di Leber. Boll Ocul 41:635-673, 1962 33. Avedikian H: Marfan-Syndrom und Retinopathia pigmentosa. Klin Monatsbl

Augenheilkd W&704-707, 1971 34. Babel J: Constations histologiques

dans l’amaurose infantile de L&ber et dans diverses formes d’hbmeralopie. Ophthalmologica 145:399-402, 1963 35. Babel J, Tsacopoulos M: Les l&ions retiniennes de la dystrophie myotonique. &de clinique. Ann Ocul 203: 1049- 1065, 1970 36. Bach

G, Berman ER: Amino sugarcontaining compounds of the retina. I. Isolation and identi~cation. Biockim Biophys Acta

252:461, 1971 37. Bach G, Berman

ER: Amino sugar containing compounds of the retina. II. Structural studies. Biochim Biophys Acta 252:461-471, 1971 38. Bagolini B, Ioli-Spada G: Bietti’s tapetoretinal degeneration with marginal cornea1 dystrophy. Am J OphthaImol 65:53-60,


39. Bairati A, Orzalesi N: The ultrastructure

of the pigment epithelium and of the photoreceptor-pigment epithelium junction in the human retina. J Ultrastruct Res 9:484-496,

1963 40. Bank





H, Pasco M, Godel V: Rttiniti: pigmentaire unilattrale et arttrite temporale. Arch Opht~mol (Paris) 32:213-216, 1972 Barnett KC: Primary tapeto-retinal degeneration in dogs, in Graham-Jones 0 (ed): Aspects of Comparative Ophthalmology. New York, Pergamon Press, 1966. pp 77-87 Barnett KC, Blakemore WF, Mason J: Bracken retinopathy in sheep. Trans Ophthalmoi Sot UK 92:741, 1972 Bassen FA, Kornzweig AL: Malformations of the erythrocytes in a case of atypical retinitis pigmentosa. Blood 5:381-387, 1950 Batra DV: Bilateral symmetrical sectoral retinal pigmentation. Br J Ophthalmol 50:734-735,


45. Baumann Ch: The regeneration and renewal of visual pigment in vertebrates, in Dartnall HJA (ed): Hb. of Sensory Physiology, Vol. VII/l, Berlin, Heidelberg, New York, Springer-Verlag, 1972. pp 395-4 16 46. Becroft DMO, Costello JM, Scott PJ: Abeta-lipoproteinemia (Bassen-Kornzweig syndrome). Report of a case. Arch Dis Child 40~40-46, 1965 47. Bell J: Retinitis



pigmentosa and allied diseases. The Treasury of Humaa Inheritance.


2:1, 1933 48. BelIhorn RE, BelIhorn M, Friedman AH, Henkind P: Urethan-induct retinopathy in pigmented rats. Invest Ophthalmol 12:65-76, 1973 49. Bennett MH,

Dyer RF, Dunn JD: Visual deficit following long-term continuous light exposure. Exp Neural 38:80-89, 1973 50. Berkow JW: Retinitis pigmentosa associated with Sturge-Weber syndrome. Arch

Ophthalmol 75:72-76, 1966 5 1. Berman ER: Tapeto-retinal

and disorders

degenerations of lipid metabolism. Acta

Cenet Med Gemell 23:33-47, 1974 52. Bernstein H, Ginsberg J: The pathology of chloroquine retinopathy. Arch Ophthalmol 71:238-248, 1964 53. Bernstein H, Zvaifler N, Rubin M, Mansour

S: The ocular


of ~hloroquine.

Invest Ophth~mol 2:384-392,

1963 54. Berson EL: Retinitis pigmentosa without pigment (Editorial). Arch Ophthalmol 81:453, 1969 55. Berson EL: Light deprivation for early retinitis pigmentosa. A hypothesis. Arch Ophthalmol 85:521-529, 1971 56. Berson EL: Experimental and therapeutic

aspects of photic damage to the retina. Invest Ophthalmol 12:35-44,


57. Berson EL, Goldstein

EB: Recovery of the human early receptor potential during dark adaptation in hereditary retinal disease. Vis Res 10: 219-226, 1970 58. Berson EL, Goldstein EB: Early receptor potential in dominantly inherited retinitis pigmentosa. Arch Ophthalmol 83:4 12-420, 1970 59. Berson


EL, Goldstein EB: Early receptor in sex-linked retinitis pigmentosa.

Invest Ophthalmol 9:58-63, 1970 60. Berson EL, Goldstein EB: Cone

pigment regeneration, retinitis pigmentosa and light deprivation. Vis Res 12:749-752, 1972 61. Berson EL, Gouras P, Gunkel RD: Rod responses in retinitis pigmentosa, dominantly inherited. Arch Ophthalmol 80~58-67, 1968 62. Berson EL, Gouras P, Gunkel RD: Progressive cone-rod degeneration. Arch Ophthalmol 80:68-76, 1968 63. Berson EL, Gouras P,

Gunkel RD, Myrianthopoulos N: Rod and cone responses in sex-linked retinitis pigmentosa. Arch Ophthalmol 81:2 1S-225, 1969 64. Berson EL, Gouras P, Gunkel RD, Myrianthopoulos N: Dominant retinitis pigmentosa with reduced penetrance. Arch Ophthalmol 81:226-234, 1969 65. Berson EL, Gouras P, Hoff M: Temporal

aspects of the electroretinogram. Arch Ophthalmol l&207-2 14, 1969 66. Berson EL, Howard J: Temporal aspects of


the electroretinogram in sector retinitis pigmentosa. Arch Ophthalmol f&653-665, 1971 67. Berson EL, Kanters L: Cone and rod responses in a family with recessively inherited retinitis pigmentosa. Arch Ophthalmol 84:288-297, 1970 68. Berson EL, Mehaffey L, Rabin AR: A night vision device as an aid for patients with retinitis pigmentosa. Arch Ophthalmol 90:112-116, 1973 69. Berson EL, Rabin AR, Mahaffey L: Advances in night vision technology. A pocketscope for patients with retinitis pigmentosa. Arch Ophthalmol 90:427-43 1, 1973 70. Best M, Galin MA, Blumenthal M, Toyofuku H: Fluorescein angiography during induced ocular hypertension in retinitis pigmentosa. Am J Ophthalmol 71:1226-1230, 1971 71. Best M, Toyofuku H, Galin MA: Ocular hemodynamics in retinitis pigmentosa. Arch Ophthal g&123-130, 1972 pigmentosa. Dtsch 72. Best W: Retinopathia Med Wochenschr 98:2489, 1973 73. Betten MG, Bilchik RC, Smith ME: Pigmentary retinopathy of myotonic dystrophy. Am J Ophthalmol 72:720-723, 1971 74. Betts PR, Forrest-Hay I: Juvenile nephronophthisis. Lancet 2:475-478, 1973 75. Bider E: Zur Kenntnis des “Refsum’schen Retinopathia pigmentosa bei Syndroms”: hereditarer Enzymopathie des Fettstoffwechsels. Ophthalmologia 152:356-363, 1966 76. Bietti GB: Su alcune forme atipiche o rare di degenerazione retinica. Bull Ocul 16: 1159-1244, 1937 77. Bigorgne J, Halot-Boyer R, Hermann P: Degentrescence tap&to-retinienne et hiredoataxie (A propos d’une famille). Bull Sot Ophtalmol Fr 71:361-364, 1971 78. Bird AC, Hyman V: Detection of heterozygotes in families with x-linked pigmentary retinopathy by measurement of retinal rhodopsin concentration. Trans Ophthalmol Sot UK 92:221-229, 1972 79. Biro I: Symmetrical development of pigmentation as a specific feature of the fundus pattern in retinitis pigmentosa. Am J Ophthalmol 55: 1176- 1179, 1963 80. Bisantis C: La retinopathie pigmentaire en secteur de G.B. Bietti; contribution a la connaissance de ses divers aspects cliniques. Ann Ocul 204:907-954, 197 1 81. Blasie JK, Worthington CR, Dewey MM: Molecular localization of frog retinal receptor photopigment by electron microscopy and low angle X-ray diffraction. J Molec Biol 39:407-416, 1969 82. Blasie JK, Worthington CR: Planar liquid-

like arrangement of photopigment molecules in frog retinal receptor disk membranes. J Molec Biol 39:417-439, 1969 83. Bohlmann HG, Thiede H, Rosenstiel K, et al: A+lipoproteinlmie bei drei Geschwistern. Dtsch Med Wschr 97:892-896, 1972 84. Bok D, Hall MO: The etiology of retinal dystrophy in RCS rats. Invest Ophthalmol 8:649-650, 1969 85. Bok D, Hall MO: The role of the pigment epithelium in the etiology of inherited retinal dystrophy in the rat. J Cell Biol49:664-682, 1971 86. Bonamour MG, Bonnet M: RCtinite grave post-morbilleuse. Bull Sot Ophtalmol Fr 65:5 17-523, 1965 87. Bonavita V, Ponte F, Amore G: Neurochemical studies on the inherited retinal degeneration of the rat. Vis Res 3:271-280, 1963 88. Bourne MC, Campbell DA, Tansley K: Hereditary degeneration of the rat retina. Br J Ophthalmol 22:6 13-623, 1938 89. Bourne MC, Grtineberg H: Degeneration of the retina and cataract, a new recessive gene in the rat (Rattus norvegicus). J Hered 30: 130, 1939 90. Bridges CDB, Yoshikami S: Personal communication to Arden GB: The excitation of photoreceptors. Prog Biophys Molec Biol 19: Part 2, 273-421, 1969 91. Brown KT, Murakami M: A new receptor potential of the monkey retina with no detectable latency. Nature (London) 201: 626-628, 1964 92. Biicklers M: Erblindung bei Masern mit nachfolgender Pigmententartung der Ophthalmologica 159:274-294, Netzhaut. 1969 93. Burden EM, Yates CM, Reading HW, et al: Investigation into the structural integrity of lysosomes in the normal and dystrophic rat retina. Exp Eye Res 12:159-165, 1971 94. Burian HM, Burns CA: Ocular changes in myotonic dystrophy. Am J Ophthalmol 63~22-34, 1967 95. Campbell DA, Harrison R, Tonks EL: Retinitis pigmentosa vitamin A serum levels in relation to clinical findings. Exp Eye Res 3:412-426, 1964 96. Campbell DA, Tonks EL: Biochemical tindings in human retinitis pigmentosa with particular relation to vitamin A deficiency. Br J Ophthalmol 46:151-164, 1962 97. Carpenter S, Schumacher GA: Familial infantile cerebellar atrophy associated with retinal degeneration. Arch Neurol 14:82-94, 1966 98. Carr RE: Vitamin A therapy may reverse degenerative retinal syndrome. Clia Trends 8:8, 1970




20 (5) March-April


99. Carr RE: Symposium: Pigmentary retinopathy summing-up. Trans Ophthalmol Sot UK 92:289-301, 1972 100. Carr R, Siegel I: Electrophysiologic aspects of several retinal diseases. Am J Ophthalmol S&95-107, 1964 101. Carr RE, Siegel IM: Unilateral retinitis pigmentosa. Arch Ophthalmol W:21-26, 1973 101a. Cavonius CR, Elgin S, Robbins DO: Thresholds for damage to the human retina by white light. Exp Eye Res 19:543-548, 1974 102. Chaptal J, Jean R, Crastes A, et al: Polyntvrite chronique, rttinite pigmentaire et hyperprottinorachie chez un garcon de 5 ans: Maladie de Refsum? Pediatrie 23:580-58 1, 1968 103. Chatzinoff A, Millmann N, Oroshnik W, Rosen F: 1I-cis vitamin A in the prevention of retinal rod degeneration. An animal study. Am J Ophthalmol 46:205-210, 1958 104. Chatzinoff A, Nelson E, Stahl N, Cahane A: 1I-cis vitamin A in the treatment of retinitis A negative study. Arch pigmentosa. Ophthalmol 80:417-419, 1968 105. Cherry PM: Usher’s syndrome. Ann Ophthalmol 5:743-752, 1973 106. Cockayne EA: Dwarfism with retinal atrophy and deafness. Arch Iiis Child ll:l-8, 1936 107. Cogan DG: Symposium: Primary Chorioretinal aberrations with night blindness. Trans Am Acad Ophthalmol Otolaryngol 54:629-661, 1950 108. Cogan DG: Lighting and health hazards (Editorial). Arch Ophthalmol 79:2, 1968 109. Cogan DG: Pseudoretinitis pigmentosa. Report of 2 traumatic cases of recent origin. Arch Ophthalmol 81:45-53, 1969 110. Cohen AI: Vertebrate retinal cells and their organization. Biol Rev 38:427-459, 1963 I1 1. Coles WH: Ocular manifestations of Cockayne’s syndrome. Am J Ophthalmol 67:762-764, 1969 112. Cone RA: Early receptor potential of the retina. vertebrate Nature (London) 204:736-740, 1964 113. Cone RA: Rotational diffusion of rhodopsin in the visual receptor membrane. Nature (New Biol) 236:39-43, 1972 114. Cox J: Color vision defects acquired in diseases of the eye. Br J Physiol Opt 18:3, 67, 1961 115. Danes BS, Bearn AG: Hurler syndrome: Effect of retinol (vitamin A alcohol) on cellular mucopolysaccharides in cultured human skin fibroblasts. J Exp Med 124: 118 1, 1966 116. Dantzker DR, Gerstein DD: Retinal vascular changes following toxic effects on visual cells


and pigment epithelium. Arch Ophthalmol 81:106-l 14, 1969 117. Dayton GO Jr, Jones MH, Kelly W, et al: The electro-oculogram as a diagnostic tool in retinitis pigmentosa, J Pediat Ophthalmol 1:9-14, 1964 118. DeDecker W, Horn C: Ophthalmologische Befunde bei Hiirgeschldigten. Alhrecht von Craefes Arch Ophthalmol 182:341-350, 1971 119. De Haas EBH, van Lith GHM, Rijnders J, et al: Usher’s syndrome. With special reference to heterozygous manifestations. Dot Ophthal t&166-190, 1970 120. Dekaban AS: Hereditary syndrome of congenital retinal blindness (Leber), polycystic kidneys and maldevelopment of the brain. Am J Ophthalmol 68:1029-1037, 1969 121. Dekaban A, Carr R: Congenital amaurosis of retinal origin. Frequent association with neurological disorders. Arch Neurol 14:294-301, 1966 122. Denton EJ: The contribution of the oriented photosensitive and other molecules to the absorption of the whole retina. Proc Roy Sot B 150:78-94, 1959 123. DeVoe RG, Ripps H, Vaughan HG Jr: Cortical responses to stimulation of the human fovea. Vis Res 8:135-147, 1968 124. Dhermy P, Raynaud G, Coscas G: Angioma de la choroide et pseudo-rCtinite pigmentaire. Arch Ophtalmol (Paris) 31:845-858, 1971 125. Donahue S, Watanabe I, Zeman W: Morphology of leukocytic hypergranulation in Batten’s disease. Ann NY Acad Sci 155:847-859, 1968 126. Dowling JE: Night blindness, dark adaptation and the electroretinogram. Am J Ophthalmol 50:875-889, 1960 127. Dowling JE: Nutritional and inherited blindness in the rat. Exp Eye Res 3:348-356, 1964 128. Dowling JE, Sidman RL: Inherited retinal dystrophy in the rat. J Cell Biol 14:73-109, 1962 129. Dowling JE, Wald G: Vitamin A and night blindness. Proc Nat Acad Sci 44:648-661, 1958 130. Dowling JE, Wald G: The biological function of vitamin A acid. Proc Nat Acad Sci US 46:587-608, 1960 131. Droz B: Synthesis and migration of proteins in the visual cells of rats and mice. Anat Rcc 139:222, 1961 132. Droz B: Dynamic condition of proteins in the visual cells of rats and mice as shown by radioautography with labeled amino acids. Anat Ret 145:157-167, 1963 133. Duke-Elder S, Dobree JH: System of Ophthalmology, Vol. X, London, Kimpton, 1967. pp 598-602 134. Durand P, Bugiani 0, Palladini G. et al:


Ntphropathie tubule-interstitielle chronique, dCgtntrescence tap&o-rttinienne et lipidose g&ralis&e. Analyse d’une observation anatomo-clinique. Arch Fr Pediat 28~915-927, 1971 135. Edwards WC, Price WD, MacDonald R: Congenital amaurosis of retinal origin (Leber). Am J Ophthaimoi 72:724-728, 1971 136. Ehrenfeld EN, Rowe H, Auerbach E: Laurence-Moon-Bardet-Biedl Syndrome in Israel. Am J Opbthnlmoi 70:524-532, 1970 137. Einaugler RB, Finkelstein D, Brown CH, Collins EA: Retinitis pigmentosa and lymphocytic leukemia. Arch Ophthnimoi 85:699-702, 197 1 138. Erickson RP, Sandman R, Robertson WB, Epstein CJ: Inefficacy of fresh frozen plasma therapy of mucopolysaccharidosis. Pediatrics 50:693-701, 1972 139. Faber J: Retinitis pigmentosa in Israel. Statistical-clinical survey. (MD Thesis) Hebrew University, Vision Research Laboratory, Jerusalem, 1970 140. Fairly KF, Leighton PW, Kincaid-Smith P: Familial visual defects associated with polycystic kidney and medullary sponge kidney. Br Med J 1:1060, 1963 141. Fanconi G, Hanhart E, von Albertini A, et al: Die famili3ire juvenile Nephronophthise (die idiopathische parenchymatose Schrumpfniere). Heiv Paediat Acta 6: 1, 195 I 142. Feeney L: The phagolysosomal system of the pigment epithelium. A key to retina1 disease. invest Ophthaimol 12:635-638, 1973 143. Felgenhauer WR, Boreux G: Concordances multiplex chtz deux jumeaux bivitellins atteints de dCg&rescence tap&o-rttinienne infantile de Leber. J Gen Hum 18:135-168, 1970 144. Ffytche TJ: Cystoid maculopathy in retinitis pigmentosa. Trans Ophthaimol Sot UK 92:265-283, 1972 145. Filatov VP: Keratoplasty and tissue therapy. State Publications of Medical Literature, Moscow, 1945 146. Fine BS, Zimmerman LE: Observations on the rod and cone layer of the human retina; a light and electron microscopic study. Invest Ophthaimol 2:446-459, 1963 147. Firat T: Clinical and genetic investigations in Leber’s tapetoretinal dystrophy. Ann Ophthaimol 2:664, 1970 148. Forsius H, Eriksson A: Tapeto-retinal degenerations with varying clinical features in Aland islanders. J Med Genet 7:200, 1970 149. Forsius H, Eriksson A, Nuutila A, et al: A genetic study of three rare retinal disorders: dystrophia retinae dysacusis syndrome, Xchromosomal retinoschisis and grouped pigments of the retina. Birth Defects: Original Article Series, 7(3):83-98, 1971

150. Forsyth CC, Lloyd JK, Fosbrooke AS: Abeta-lipoproteinemia. Arch Dis Child 40:47, 1965 151. Franceschetti A: La rktinopathie ponctuh albescente. Bull Mem Sot Fr Ophtaimoi 76:14-19, 1963 152. Franceschetti A, Franqois J, Babel J: Les H&do-DCg&nCrescences Chorio-Rktiniennes ( DCgbnerescences tap&to&tiniennes), Vol. I & 2. Paris, Massoh. 1963 153. Franceschetti A, Klein D: Weitere BeitrSige zur Frage der genetischen Beziehungen zwischen der Friedreich’schen Ataxie und den verschiedenen Formen der tapetoretinalen Degenerationen. Arch Julius KlausStift Vererbungsforsch 22:93, 1947 154. FranGois J: La dtgtntrescence tapttoritinienne congknitale de LCber. Bull Mem Sot Fr Ophtaimol 76:1-13, 1963 155. Francois J: Counseling in hereditary eye disorders, in Bellows JG (ed): Contemporary Ophthalmology, Baltimore, Williams & Wilkins, 1972. pp 459-471 156. FranGois J: Tapetoretinal degenerations and spinocerebellar degenerations. Acta Genet Med Gemeli 23~3-24, 1974 157. FranGoisJ, De Rouck A, Cambie E, De Laey JJ: Visual functions in pericentral and central pigmentary retinopathy. Ophthalmologica 165:38-61, 1972 158. FranGois J, De Blond R: DegCnCrescence tap&o-rbtinienne associk B un syndrome hypolipidCmique. Acta Genet Med Gemeii 12:145-157, 1963 159. Frangois J, DeLaey JJ: Les aspects fluoroangiographiques de la ritinopathie pigmentaire pkriphtrique. Ann Ocul (Paris) 205: 17-34, 1972 160. FranGois J, De Rouck A: L’tlectro-rttinoenctphalographie dans la maladie de Hurler. Ophthalmologica 139:45-55, 1960 161. Francois J, Hanssens M: Histopathological examination of a congenital tapeto-retinal degeneration associated with keratoconus and nephropathy. Bull Sot Belge Ophtaimoi 147:41 l-426, 1967 162. FranGois J, Szmigielski M, De Rouck A, Hanssens M: etude &ctrophysiologique et histologique de la d&gentrescence tapttorttinienne exptrimentale par l’iodate de sodium. II. &ude histologique. Ophthaimoiogica 152:219-240, 1966 163 Frangois J, Verriest G: Les dyschromatopsies acquises. Ann Ocul (Paris) 190:713, 812, 893, 1957 164. FranCois J, Verriest G: Etude biometrique de la rktinopathie pigmentaire. Ann Ocui (Paris) 195:937-95 1, 1962 165. Fujimoto WY, Greene ML, Seegmiller JE: Cockayne’s syndrome: Report of a case with


Surv Ophthalmol

20 (5) March-April



hyperlipoproteinemia, hyperinsulinemia, renal disease and normal growth hormone. .J Pediat 75:881-884, 1969 166. Fujiwara H, Nasu K: Retinitis pigmentosa and lactate metabolism. Acte Sot Ophthalmol Jap 70: 1285- 1290, 1966 167. Furukawa T, Takagi A, Nakao K, et al: Hereditary muscular atrophy with ataxia, retinitis pigmentosa and diabetes mellitus. Neurology l&942-947, 1968 168. Galloway NR: Early receptor potential in the human eye. Br J Ophthalmol 51:261-264, 1967 169. Galloway NR: The value of electrodiagnostic tests in pigmentary retinopathy. Trans Ophthalmol Sot UK 92:209-220, 1972 170. Garston JB, Strachan IM: Two families with tapetoretinal degeneration having unusual features. Trans Ophthalmol Sot UK 90: 195-206, 1970 171. Gass JDM: Stereoscopic Atlas of Macular Diseases. A Fundoscopic and Angiographic Presentation. Mosby, St Louis, 1970. p. 154 172. Gedda L, Restivo-Manfridi ML, Romei L: Electroencephalographic picture in a family with two brothers affected by pigmentary retinopathy, hypoacusia and polydactylia. Acta Genet Med 16:350-364, 1967 173. Gelber P, Shah A: Fluorescein study of albipunctate dystrophy. Arch Ophthalmol 81:164-169, 1969 174. Geltzer AI, Berson EL: Fluorescein angiography of hereditary retinal degeneration. Arch Ophthalmol 81:776-782, 1969 175. Gerstein DD, Dantzker DR: Retinal vascular changes in hereditary visual cell degeneration. Arch Ophthalmol 81:99-105, 1969 176. Gillespie FD: Congenital amaurosis of Leber. Am J Ophthalmol 61:874-880, 1966 177. Gillespie FD, Dohogne VZ: Electroencephalograms in retinitis pigmentosa. Am J Ophthalmol 57:1045-1050, 1964 178. Gills JP, Hobson R, Hanley WB, et al: Electroretinography and fundus oculi findings in Hurler’s disease and allied mucopolysaccharidoses. Arch Ophthalmol 74:596-603, 1965 179. Gloster J, Greaves DP: A study of bleaching of the fundus degenera_ _..~ ^ . oculi. in pigmentary tlon of the retina. Br J Ophthalmol 48:260-273, 1964 180. Glover J, Walker RJ: Absorption and transport of Vitamin A. Exp- Eye Res 3:374-382, 1964 181. Goebel HH, Fix JD, Zeman Q: Retina in ceroid-lipofuscinosis. Am J Ophthalmol 77:25-39, 1974 182. Gold DH, Henkind P, Sturner WQ, Baden M: Oculodermal melanocytosis and retinitis pigmentosa. Am J Ophthalmol 63:271-279, 1967

183. Goldberg MF: A review of selected inherited cornea1 dystrophies associated with systemic diseases, Birth Defects: Original Article Series 7(3):13-25, 1971 184. Goldberg MF, Duke JR: Ocular histopathology in Hunter’s syndrome. Arch Ophthalmol 74:516-520, 1965 185. Goldberg MF, Duke JR: Ocular histopathology in Hunter’s syndrome. Systemic mucopolysaccharidosis type II. Arch Ophthalmol 77:503-5 12, 1967 186. Goldstein JL: The Alstrijm syndrome. Report of three cases with further delineation of the clinical, pathophysiological and genetic aspects of the disorder. Medicine 52:53-71, 1973 187. Goldstein EB, Berson EL: Rod and cone contributions to the human early receptor potential. Vis Res 10:207-218, 1970 RB, d’Amico RA: A typical 188. Gollance mucopolysaccharidosis successful and keratoplasty. Am J OphthaImol 64:707-7 16, 1967 189. Gonasun LM, Potts AM: In vitro inhibition of protein synthesis in the retinal pigment epithelium by chloroquine. Invest Ophthalmol 13:107-l 15, 1974 190. Goode RL, Rafaty FM, Blair F: Hearing loss in retinitis pigmentosa. Pediatrics 40:875-880, 1967 191. Goodman G, Gunkel RD: Familial electroretinographic and adaptometric studies in retinitis pigmentosa. Am J Ophthalmol 46:142-172,


192. Corn RA, Kuwabara T: Retinal damage by visible light. Arch Ophthalmol 77: 115-l 18, 1967 W, Minauf M: Netzhautver193 Gijttinger lnderungen bei juveniler amaurotischer Idiotie. Ophthalmoskopische und histopathologische Befunde. Klin Monatsbl Augenheilkd 159:532-538, 1971 194. Gouras P: Rod and cone independence in the electroretinogram of the dark-adapted monkey’s perifovea. J Physiol 187:455-464, 1966 195. Gouras P: Electroretinography: some basic principles. Invest Ophthalmol 9:557-569, 1970 196. Gouras P, Armington JC, Kropfl WJ, Gunkel RD: Electronic computation of human retinal and brain responses to light stimulation. Ann NY Acad Sci 115:763-775, 1964 197. Gouras P, Carr RE: Electrophysiological studies in early retinitis pigmentosa. Arch Ophthalmol 72:104- 110, 1964 198. Gouras P, Carr RE: Light induced DC responses on monkey retina before and after central retinal artery interruption. Invest Ophthalmol 4:310-317, 1965




Gouras P, Carr RE, Gunkel RD: Retinitis pigmentosa in A-beta-lipoproteinemia: Effects of vitamin A. Invest Ophthnlmol 10:784-793, I97 1 200. Gouras P, Chader G: Retinitis pigmentosa and retinol-binding protein. Invest Ophthal-


Henkes HE, Verduin PC: Dysgenesis or abiotrophy? A differentiation with the help of the electroretinogram (ERG) and electrooculogram (EOG) in Leber’s congenital amaurosis. Ophthalmologica 145: 144- 160,

mol 13:239-242, 1974 201. Graham MV: Bilateral


Hentsch R, Ktilz J: Beitrag zur sekundlren Pigmentdegeneration der Netzhaut nach Klin Monatsbl Augenheilkd Masern.




symmetrical sectoral of the retina. Br J




Griitzner P: Functional abnormalities, particularly of an acquired color blindness in a pigment-poor form of diffuse tapetoretinal degeneration. Albrecht von Graefes Arch Klin


Griitzner P, Sanger R, Spivey BE: Linkage studies in X-linked retinitis pigmentosa.

Exp Ophthalmol




14: 155-158,




Arch. (Zellpathol)



Harcourt B, Hopkins D: Tapetoretinal degeneration in childhood presenting as a disturbance of behavior. Br Med J 1:202-205,


Herron WL, Riegel BW, Brennan E, Rubin ML: Retinal dystrophy in the pigmented rat.


Invest Ophthalmol 223.



Herron WL, Riegel BW, Myers OE, Rubin ML: Retinal dystrophy in the rat - A pigment epithelial disease. Invest Ophthalmol 8:595-604,


Herron WL, Riegel BW, Rubin ML: Outer segment production and removal in the degenerating retina of the dystrophic rat. Invest Ophthalmol 10:54-63, 197 I 225. Highman VN, Weale RA: Rhodopsin density and visual threshold in retinitis pigmentosa. Am J Ophthalmol

Hayes KC: Retinal degeneration in monkeys induced by deficiencies of vitamin E or A. Invest Ophthalmol 13:499-510, 1974 212. Heilig P, Thaler A, Slezak H: Einseitige Pigmentdegeneration der Netzhaut. Klin Augenheilkd



Heller J, Ostwald TJ, Bok D: The osmotic behavior of rod photoreceptor outer segment disks. J Cell Biol 48:633-649, 1971 214. Hellner KA, Rickers J: Familiary bilateral segmental retinopathia pigmentosa. Oph-

Lancet 2:478-480,











of the Human Eye: An Atlas and Philadelphia, WB Saunders. 197 I.

pp 420-430 229. Holland MG, Cambie E: Une association de stigmates d’albinisme oculaire et d’amaurose congenitale de Ltber. Rapport clinique. Ophthalmologica 161:425-436, 1970 Holland MG, Cambie E, Kloepfer

W: An evaluation of genetic carriers of Usher’s syndrome. Am J Ophthalmol 74:940-947, 1972 23 1. Hommer K: Das Elektroretinogramm bei der zentralen Retinitis pigmentosa. Albrecht von


Graefes Arch 30-43, 1969

Henkes HE: Does unilateral retinitis pigmentosa really exist? Ophthalmologica 149:202-203,

Hogan Histology Textbook.




Hill DW: Fluorescence angiography and inherited degeneration of the fundus oculi. J Med Genet 7:285-288, 1970 227. Hobbs HE, Sorsby A, Freedman A: Retinopathy following chloroquine therapy.


2 1 I.



Herron WL, Riegel BW: Vitamin A deficiency-induced “rod thinning” to permanently decrease the production of rod outer segment material. Invest Ophthalmol






1969 Hallgren

Virchows 210.



B: Retinitis pigmentosa combined with congenital deafness; with vestibulocerebellar ataxia and mental abnormality in a proportion of cases. A clinical and geneticostatistical study. Acta Psychiat Neurol Stand 34: Suppl. 138, 1959 209. Hansson HA: Scanning electron microscopy of the retina in vitamin A-deficient rats.



Herron WL, Riegel BW: Production rate and removal of rod outer segment material in vitamin A deficiency. Invest Ophthalmol



Hall MO, Bok D, Bacharach ADE: Biosynthesis and assembly of the rod outer segment membrane system. Formation and fate of visual pigment in the frog retina. J Molec Biol 45:397-406, 1969 207. Hall MO, Heller J: Mucopolysaccharides of the retina. UCLA Forum Med Sci 8:2 I l-224,



Arch Ophthalmol 220.


Griitzner P, Spivey BE, Sanger R: Linkage studies in X-linked retinitis pigmentosa. Monogr Hum Genet 6:195, !!I72 205. Haase W, Hellner KA: Uber familiIre bifaterale sektorenfiirmige retinopathia pigmentosa. Klin Monatsbl Augenheilkd

154:706-712, Herdman

RC, Good RA, Vernier RL: Medullary cystic disease in two siblings. Am J Med 43:335, 1967 2 19. Herrold K: Pigmentary degeneration of the retina induced by N-methyl-N-nitrosourea. 218.





H: Extensive




of senile
















Surv Ophthalmol

20 (5) March-April


bilateral cystic degeneration of the macula with spreading over the entire retina and terminal degeneration proliferation and serous detachment (similar to Coats’ Disease). Ber Deutch Ophthalmol Ges 67:457-460, 1966 Hooft C, De Laey P, Herpol J, et al: Familial hypolipidaemia and retarded development without steatorrhoea. Another inborn error of metabolism? Helv Paediatr Acta 17: l-23, 1962 Houbert JP, Babel J: Les lesions uveoretiniennes de la dystrophie myotonique. Etude histologique. Ann Ocul (Paris) 203:1067-1076, 1970 Hussels IE: Connenital amaurosis and nephronophthisis: x new syndrome. Birth Defects 7:199, 1971 Hyvlrinen L, Maumenee AE, George T, Weinstein GW: Fluorescein angiography of the choriocapillaries. Am .I Ophthalmol 67:653-666, 1969 Hyvlrinen L, Maumenee AE, Kelley J, Cantollino S: Fluorescein angiographic findings in retinitis pigmentosa. Am J Ophthalmol 71:17-26, 1971 Imaizumi K, Takahashi R, Tazawa Y, et al: Clinical and eiecfrophysiological observations on genetic carriers of retinitis pigmentosa in a family (pedigree Tt) showing intermediate sex linked inheritance. Vis Res 11:1215-1216, 1971 Ioli-Spada G, Mazzella G: Serum proteins and lipids in patients with primary pigmentary degeneration of the retina. Boll Ocul 43:562-568, 1964 Ivandic T: Sektorenfdrmige tapetoretinale Degenerationen. Klin Monntshl Augenheilkd 160:98-103, 1972 Jacobson JH, Stephens G: Unilateral retinitis pigmentosa sine pigmento. Arch Ophthalmol 67:456-458, 1962 Jay B: Hereditary aspects of pigmentary retinopathy. Trans Ophthalmol Sot UK 92:173-178, 1972 Jiinemann G, Damaske E: Pseudoretinopathia pigmentosa nach Masern. Med Klin 63:1687-1690, 1968 Junge J: Ocular changes in dystrophia myotonica, paramyotonia and myotonia congenita. Dot Ophthaimol 21:1-l 15, 1966 Kahlke W, Richterich R: Refsum’s Disease (Heredopathia atactica Polyneuritiformis): An inborn error of lipid metabolism with storage of 3, 7, 11, 15-tetramethyl hexadecanoic acid. II. Isolation and identification of the storage product. Am J Med 39:237-24 1, 1965 Kanae M, Raz A, Goodman DS: Retinolbinding protein: the transport protein for vitamin A in human plasma. J Clin Invest 47~2025-2044, 1968


247. Kandori F, Tamai A, Watanabe T, Kurimoto S: Unilateral pigmentary degeneration of the retina. Report of 2 cases. Am J Ophthalmol 66:1091-I 101, 1968 248. Kapuscinski WJ, Uher M, Ogielska E: Syndrome d’llsher. Description de trois cas. Bull Mem Sot Fr Ophtalmol 82:147-154, 1969 249. Karel I: Keratoconus in congenital diffuse tapetoretinal degeneration. Ophthalmologica 155:8-15, 1968 250. Karel I, Sedlackova E: Audiometric and phoniatric findings in congenital diffuse tapetoretinal degeneration. Acta Ophthalmol 45:42-48, 1967 251. Karpati G, Carpenter S, Larbrisseau A, LaFontaine R: The Kearns-Shy syndrome. A multisystem disease with mitochondrial abnormality demonstrated in skeletal muscle and skin. J Neurol Sci 19:133-151, 1973 252. Kayden HJ: A-beta-lipoproteinemia. Annu Rev Med 23:285-296, 1972 253. Kearns TP, Sayre GP: Retinitis pigmentosa, external ophthalmolegia and complete heart block: Unusual syndrome with histologie study in one of two cases. Arch Ophthalmol 603280-289, 1958 254. Keeler CE: Rodless retina, an ophthalmic mutation in the house mouse, mus musculus. J Exp Zoo1 46:355, 1927 255. Kenyon KR: Ocular ultrastructure of inherited metabolic disease, in Goldberg MF (ed): Genetic and Metabolic Eye Disease. Boston, Little Brown, 1974. pp 139-185 256. Khachadurian AK, Freyha R, Schammaa MM, Baghdassarian SA: A-,%lipoproteinaemia and colour-blindness. Arch Dis Child 46:871-873, 1971 257. Kjaer GC: Retinopathy associated with phenothiazine administration. Dis New Sys 29:316-319, 1968 258. Klein D: Genetic approach to the nosology of retinal disorders. Birth Defects, Original Article Series 7(3):58-82, 1971 259. Klein D, Ammann F: The syndrome of Laurence-Moon-Bardet-Biedl and allied diseases in Switzerland. J Neurol Sci 9:479-5 13, 1969 260. Klein D, Franceschetti A, Hussels I, et al: Xlinked retinitis pigmentosa and linkage studies with the Xg blood groups. Lrncet 1:974-975, 1967 261. Klein D, Hussels I: Cas observd: Une famille atteinte d’idiotie amaurotique juvenile (VogtSpielmeyer) Detection des porteurs heterozygotes. J Genet Hum 16:226-231, 1967 262. Klein D, Mumepthaler M, Kraus-Ruppert R, Rallo E: Une grande famille valaisanne atteinte d’epilepsie myoclonique progressive et de retinite pigmentaire. Humaugenetlk 6:237-252, 1968 263. Klenk E, Kahlke W: Uber das Vorkommen



der 3, 7, 1 I, 15tetramethylhexadecanslure (PhytansPure) in den Cholesterinestern und anderen Lipoidfraktionen der Organe bei einem Krankheitsfall unbekannter Genese (Verdacht auf Refsum-Syndrom). Z Physiol Chem 333:133-139, 264.



Kloepfer HW, Laguaaite JK, McLaurin JW: The hereditary syndrome of congenital deafness and retinitis pigmentosa (Usher’s syndrome). Laryngoscope 76:850, 1966 266. Koen AL, Shaw CR: Retinal and alcohol dehydrogenases in retina and liver. Biochim


Biophys Acta


retinitis 280.



Kolb H, Gouras P: Electron microscopic observations of human retinitis pigmentosa dominantly inherited. Invest Ophthalmol










Kornzweig AL: Bassen-Kornzweig syndrome; Present status. J Med Genet 7:27 l-296, 1972 273. Kornzweig AR, Bassen FA: Retinitis pigmentosa, acanthocytosis and heredodegenerative neuromuscular disease. Arch Ophthalmol 58:183-187, 1957 274. Kosel K: ERG-Untersuchnugen bei Kindern zum Ausschluss einer tapetoretinalen Degeneration. Klin Monatsbl Augenheilkd



159:645-649, Krachmer



Arch Ophthalmol Kraushar MF,


136:97-102, 1960 Kiiper J, Miiller-Limmroth


W, Dieckhues B: pigmentosa. Klin

Monatsbl Augenheilkd 141:697-700, 1963 Kuwabara T, Gorn RA: Retinal damage

by visible light. An electron microscopic study. 79:69-78,


Lamy M, Frezal J, Polonovski J, Rey J: L’absence congtnitale de beta-lipoprottines. Presse Med 69:1511-1514, 1961 Landau J, Feinmesser M: Audiometic and vestibular examinations in retinitis pigmentosa. Br J Ophthalmol 40:4O-44, 1956 Landis DJ, Dudley PA, Anderson RE: Alteration of disc formation in photoreceptors of rat retina. Science 182:1144, 1973 Lanning M, Simila S: Cockayne’s syndromes, Report of a case with normal intelligence. Z Kinderheilkd 109:70-75, 1970 Lauber H: Die sogenannte Retinitis punctata albescens. Klin Monatsbl Augenheilk 48: 133, 1910

Lauring L: Chromosomal mosaicism and unilateral retinitis pigmentosa. A negative study. J Pediatr Ophthalmol 7:33-36, 1970 29 1. La Vail MM, Reif-Lehrer L: Glutamine synthetase in the normal and dystrophic mouse retina. J Cell Biol 51:348-354, 1971 292. La Vail MM, Sidman RL: C 57BL/6J Mice with inherited retinal degeneration. Arch 290.





La Vail MM, Sidman RL, O’Neil D: epithelial cell Photoreceptor-pigment relationships in rats with inherited retinal degeneration. Radioautographic and electron microscope evidence for a dual source of extralamellar material. J Cell Biol 53: 185-209.


Lawwill T: Effects of prolonged exposure of rabbit retina to low-intensity light. invest

JH, Smith JL, Tocci PM: studies in retinitis pigmentosa. 1966

Schepens CL, Kaplan JA, Freemen HM: Congenital retinoschisis in Bellows JG (ed): Contemporary Ophthalmology. Baltimore, Williams & Wilkins, 1972, pp 265-290 277. Krill AE: Observations of carriers of Xchromosomal linked chorioretinal degenerations. Do these support the “inactivation hypothesis”? Am J Ophthalmol 64:1029-1040, 1967 278. Krill AE, Archer D, Newell FW: Fluorescein angiography in retinitis pigmentosa. Am J


Kiiper J: Famililre sektorenfdrmige Retinitis pigmentosa. Klin Monatsbl Augenheilk

Arch Ophthalmol 285.




1966 282.


Kolb H, Galloway NR: Three cases of unilateral pigmentary degeneration. Br J


Kroll A, Kuwabara T: Electron microscopy of a retinal abiotrophy. Arch Ophthalmol




I. Kulesh AP: On the problem of the clinical picture and treatment of pigmental degeneration of the retina. Oftalmol Zh 21:346-349.


Koerner F: Pigmentary retinopathy in cases of chronic progressive external ophthalmoplegia. Visual sensory aspects. Trans Ophthalmol Sot UK 92:251-263, 1972 268. Koerner R, Schlote W: Chronic progressive external ophthalmoplegia. Association with retinal pigmentary changes and evidence in favor of ocular myopathy. Arch Ophthalmol g&155-166, 1972 269. Kolb H: Electra-oculogram findings in patients treated with anti-malarial drugs. Br


Archer D, Martin D: Sector pigmentosa. Am J Ophthalmol

71:683-690, 28


J Ophthalmol

Ophthalmol Krill AE, 69:977-987,


Klier A: Zur Kenntnis der sektorenfdrmigen Retinopathia pigmentosa. Klin Monatsbl Augenheilkd




Ophthalmol 12:45-5 1, 1973 Lehnert W: Das Elektroretinogramm

bei der Retinitis pigmentosa nach Blitzreizen hoher Intensitlt. Albrecht von Graefes Arch Klin

Exp Ophthalmol 296.

165:5 19-523,


Leung L-SE, Weinstein GW, Hobson RR: Further electroretinographic studies of



298. 299.


301. 302.









3 11.



Surv Ophthalmol

20 (5) March-April


patients with mucopolysaccharidoses. Birth Defects: Original Article Series 7(3):32-40, 1971 Levene J: Similarity between progressive retinal degeneration in sheep and retinitis pigmentosa in man. Vet Ret 92:79, 1973 Levy IS: Refsum’s syndrome. Trans Ophthalmol Sot UK 90:181-186, 1970 Levy IS: Pigmentary retinopathy associated with metabolic defects. Tram Ophthalmol Sot UK 92:285-287, 1972 Lijo Pavia J, Mogort L: Retinitis pigmentosa: prognosis and treatment. Arch Oftalmol B Aires 38:399-403, 1963 Lindenov H: The Etiology of Deaf-Mutism. Copenhagen, 1945 Lolley RN: RNA and DNA in developing retinae: comparison of a normal with the degenerating retmae of C3H mice. J Neurothem 20:175-182, 1973 Lolley RN, Racz E: Changes in levels of ATP-ase activity in developing retinae of normal (DBA) and mutant (C3H) mice. Vis Res 12:567-57 1, 1972 Lorentzen SE: Drusen of the Optic Disc: A Clinical and Genetic Study. Copenhagen, Ejnar Munksgaards Forlag, 1967 Lucas DR: Retinal dystrophy in the Irish setter. I. Histology. J Exp ZooI 126:537, 1954 Mabry CC, Digeorge AM, Auerbach VH: Studies concerning the defect in a patient with acanthocytosis. Clin Res 8:371, 1960 Mainzer F, Saldino RM, Ozonoff MB, Minagi H: Familial nephropathy associated with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities. Am J Med 49:556-562, 1970 Makabe R: Retinitis punctata albescens eine Beobachtung mit Fluoreszens-FundusAngiographie. Klin Monatsbl Augenheilkd 157:114-l 18, 1970 Manschot WA: Histological findings in a case of dystrophia myotonica. Ophthalmologica 155:294-296, 1968 Manschot WA: Retinal histology in amaurotic idiocies and tapeto-retinal degenerations. Ophthalmologica 156:28-37, 1968 Maraini G: The vitamin A transporting protein complex in human hereditary pigmentous retinal dystrophy. Invest Ophthalmol 13:288-290, 1974 Marmur RK: Ultrasonic therapy of patients with pigment degeneration of the retina and partial atrophy of the optic nerve. Oftalmol Zh 24:192-196, 1969 Marmur RK, Skorodinskaya VV: Ultrasonics in a complex therapy of pigment degeneration of the retina. Oftalmol Zh 22:207-210, 1967


314. Martin L, Martin JJ, Guazzi GC, et al: Degtnerescence tapeto-rttinienne, surdite, myoclonies, dtmence, epilepsie avec presence d’acide a-amino-n-butyrique en exces. Contribution a l’ttude des angiomatoses leptomtningees avec leucodystrophie soudanophile et abiotrophies complexes. J Neurol Sci 6:217-236, 1968 315. Maumenee IH: Genetic Counselling, in Goldberg MF (ed.): Genetic and Metabolic Eye Disease. Boston, Little Brown, 1974. p 614 316. Mazima T: Studies on retinitis pigmentosa. Acta Sot Ophthalmol Jap 70:1424-1441, 1966 3 17. McDonald WI: Neurological associations of pigmentary retinopathy. Trans Ophthalmol Sot UK 92:179-186, 1972 3 18. McKusick VA: The nosology of the mucopolysaccharidoses. Am J Med 47:730-747, 1969 319. McLeod AC, McConnell FE, Sweeney A, et al: Clinical variation in Usher’s syndrome. Arch Otolaryngol 94:321-334, 197 1 320. Mehra KS: Unilateral retinitis pigmentosa. Br J Ophthalmol 46:310, 1962 321. Meier DA, Hess JW: Familial nephropathy with retinitis pigmentosa. A new oculorenal syndrome in adults. Am J Med 39:58-69, 1965 322. Meier-Ruge W: Experimental investigation of the morphology of chloroquine retinopathy. Arch Ophthalmol73:540-544, 1965 323. Merin S: Macular cysts as an early sign of peripheral tapeto-retinal degeneration. J Pediatr Ophthalmol 7:225-228, 1970 324. Merin S: Tapetoretinal degenerations and disorders of lipid metabolism; clinical, genetic, pathological and therapeutic aspects. Acta Genet Med Gemell 23:25-3 1, 1974 325. Merin S, Abraham F, Auerbach E: Usher’s and Hallgren’s syndromes. Acta Cenet Med Gemell 23:49-55, 1974 326. Merin S, Weinreb A, Levinger E: Widening the visual fields. (in preparation) 327. Merz MO, Piotrowski A: Dicoumarin compounds in the treatment of pigmentary degeneration of the retina. Ophthalmologica 145:249-256, 1963 328. Metz HS, Harkey ME: Pigmentary retinopathy following maternal measles (morbilli) infection. Am J Ophthalmol 66:1107-l 110, 1968 329. Michaelson IC, Yanko L: Histo-ophthalmoscopy: The use of the Ophthalmoscope in Histology, in Bellows JG (ed): Contemporary Ophthalmology. Baltimore, Williams 8~ Wilkins, 1972 330. Mier M, Schwartz SO, Boshes B: Acanthocytosis, pigmentary degeneration of the retina and ataxic neuropathy: A genetically


determined syndrome with associated metabolic disorder. Blood 16:1586-1608, 1960 33 I. Miglior M, Spinelli D, Castellani F: La rttinopathie pigmentaire pericentrale. Rapport clinique. Ann Ocul (Paris) 202:447-456, 1969 332. Mills PV, Bowen DI, Thomson DS: Chronic progressive external ophthalmoplegia and pigmentary degeneration of the retina. Br J Ophthalmol 55:302-311, 1971 333. Mirhosseini SA, Holmes LB, Walton DS: Syndrome of pigmentary retinal degeneration, cataract, microcephaly and severe mental retardation. J Med Genet 9:193-196, 1972 334. Miyata M: Retinal pigmentation in experimental retinitis pigmentosa. Acta Sot Ophthalmol Jap 66:704-713, 1962 335. Miyata M, Mizuno K: On the nature of the pigment in experimental retinitis pigmentosa. Jap J Ophthalmol 7:20-29, 1963 336. Mizuno K, Nishida S: Electron microscopic studies of human retinitis pigmentosa. Part I: Two cases of advanced retinitis pigmentosa. Am J Ophthalmol 63:791-803, 1967 337. Molnar L: Gleichzeitiges Vorkommen von Klinefelter-Syndrom und degeneratio pigmentosa retinae. Kim Monatsbl Augenheilkd 157:663-667, 1970 338. Moore T: Systemic action of vitamin A. Exp Eye Res 3:305-315, 1964 339. Morgan WE, Crawford JB: Retinitis pigmentosa and Coats’ disease. Arch Ophthalmol 79:146-149, 1968 340. Niemeyer G: Einseitige Tapetoretinale Degeneration. Bericht ilber eine einjlhrige Verlaufs-Kontrolle. Ophthalmologica 156: 337-345, 1968 341. Niwa T: Alcohol dehydrogenase and experimental retinitis pigmentosa. Acta Sot Ophthalmol Jap 69:1283-1289, 1965 342. Noel1 WK: Experimentally induced toxic effects in structure and function of visual cells and pigment epithelium. Am J Ophthalmol 36: Part II, 103-114, 1953 343. Noel1 WK: Studies on the electrophysiology and the metabolism of the retina. U.S. Air Force, SAM Project 21-1201-0004, 1953 344. Noel1 WK, Albrecht R: Irreversible effects of visible light on the retina: Role of vitamin A. Science 172:76-80, 1971 345. Noel1 WK, Delmelle MC, Albrecht R: Vitamin A deficiency effect on the retina: Dependence on light. Science 172:72-76, 1971 346. Noel1 WK, Walker VS, Kang BS, Berman S: Retinal damage by light in rats. Invest Ophthalmol 5:450-473, 1966 347. Novikoff AB: Lysosomes and related particles, in Brachet J, Minsky AE (ed): The Cell, Vol 2, Cells and their Compooent Parts.








New York, Academic Press, 1961. pp 423-488 Nuutila A: Retinitis pigmentosa-dysacusis syndrome. Preliminary report. Acta Near01 Stand 43 Suppl 31:68-69, 1967 Nuutila A: Dystrophia retinae pigmentosadysacusis syndrome (DRD): A study of the Usher or Hallgren syndrome. J Cenet Hum l&57-88, 1970 Okun E, Gouras P, Bernstein H, von Sallman L: Chloroquine retinopathy. Arch Ophthalmol 69:59-7 1, 1963 Paddison RM, Moosy J, Derbes VK: Cockayne’s syndrome. Dermatol Int 2:195-203, 1963 Panteleeva OA: On hereditary tapeto-retinal degenerations (Russian). Vestn Oftalmol 82:53-56, 1969 Parry HB: Degenerations of the dog retina. II. Generalized progressive atrophy of heriditary origin. Br J Ophthalmol 37:487, 1953

Paufique L, Charleux J, Pommier J: Retinite pigmentaire et lesions diecephalohypophysaires. Bull Sot Ophthal Fr 63:850-853, 1963 355. Pearce WG: Ocular and genetic features of Cockayne’s syndrome. Can J Ophthalmol


7~435-444, 356.







Perdriel G, Masbernard A, Andre JM_, Vatiadis S: Anomalies retiniennes associees a la nephronophthise. Bull Sot Ophthalmol Fr 70:659, 1970 Perdriel G, Rey J, Aron JJ: Absence congtnitale de beta-lipoprottines et abiotrophie tap&o-retinienne infra-clinique. Ann Ocul (Paris) 1%:388-395, 1963 Pfeiffer RA, Bachmann KD: An atypical case of Cockayne’s syndrome. Clin Genet 4:28-32, 1973 Pinckers A: A family pedigree with cornea1 dystrophy, tapetoretinal degeneration and albinism. Acta Ophthalmol 51:445-460, 1973 Ponte F, Lauricella M: Effects of retinotoxic drugs on rats heterozygotic for recessive retinitis pigmentosa. Vis Res 11:1211-1212, 1971 Potts AM: The concentration of phenothiazines in the eye of experimental animals. Invest Ophthalmol




Potts AM, Inoue J: The electrically evoked response (EER) of the visual system II. Effect of adaptation and retinitis pigmentosa. Invest Ophthalmol



Puscariu E: Heredity of the heredo-familial syndromes. Retinitis pigmentosa caused by medication or following viral disease. Arch Ophthalmol 22:253-258, 1962 364. Rabin AR, Hayes KC, Berson EL: Cone and rod responses in nutritionally induced retinal degeneration in the cat. Invest Ophthalmol



Surv Ophthcdmol

20 (5) March-April


12:694-704, 1973 365. Radian AB, Radian AL: Cataract extraction in eyes with retinitis pigmentosa. Ann Ocul 206:405-408, 1973 366. Ragneti E: Su di una forma atipica di retinosi pigmentosa. Boll Ocul 41:617-626, 1962 367. Rahi AHS: Retinol-binding protein (RBP) and pigmentary dystrophy of the retina. Br J Ophthalmol 56:647-65 1, 1972 368. Rahn EK, Falls HF, Knaggs JG, Proux DJ: Leber’s congenital amaurosis with an EhlersDanlos-like syndrome. Arch Ophthalmol 79:135-141, 1968 369. Rayner S: Juvenile amaurotic idiocy in Sweden. institute for Medical Genetics, Univ. of Uppsala, Uppsala, Sweden, 1962 370. Read W, Bay D: Basic cellular lesions in chloroquine toxicity. Lab Invest 24~246259, 1971 371. Reading HW: Activity of the hexose monophosphate shunt in the normal and dystrophic retina. Nature 203:491-492, 1964 Retinal and retinol 372. Reading HW: metabolism in hereditary degeneration of the retina. Biochem J 100:34-35, 1966 373. Reading HW: Biochemistry of retinal dystrophy. J Med Genet 7:277-284, 1970 374. Refsum S: Heredataxia hemeralopica polyneuritiformis. Nord Med 28:2682-2691, 1945 375. Refsum S: Henedopathia atactica polyneuritiformis. A familial syndrome not hitherto described. Acta Psychiatr Neurol Stand Suppl 38, 1946 376. Reinstein NM, Chalfin Al: Inverse retinitis pigmentosa, deafness and hypogenitalism. Am J Ophthalmol 72:332-341, 1971 377. Ricci A, Ammann F, Franceschetti A: Reversible tapetoid reflex (reversed phenomenon of Mizuo) in carriers of recessive type of pigmentary retinopathy found in one sex. Bull Sot Fr Ophtalmol 76:31-35, 1963 378. Richterich R, Moser H, Rossi E: Refsum’s disease (Heredopathia atactica polyneuritiformis): A review of the clinical findings. Humangenetik 1:322-332, 1965 379. Richterich R, Rosin S, Rossi E: Refsum’s disease (Heredopathia atactica polyneuritiformis). Formal genetics. Humangenetik 1:333-336, 1965 380. Robertson DM: Hamartomas of the optic disk with retinitis pigmentosa. Am J Ophthalmol 74:526-53 1, 1972 381. Roth AM, Hepler RS, Mukoyama M, et al: Pigmentary retinal dystrophy in Hallervorden-Spatz disease: clinicopathological report of a case. Surv Ophthalmol 16: 24-35, 1971 382. Rowlatt U: Cockayne’s syndrome. Report of a case with necropsy findings. Acta Neuropathol 14:52-6 1, 1969



383. Rubino A, Ponte F: The role of electroretinography in the diagnosis and prognosis of retinitis pigmentosa. Acta Ophthalmol Suppl 70:232-237, 1962 384. Rubino A, Ponte F: Cases of retinitis pigmentosa without hemeralopia and with impairment of the ERG. G Itai Oftalmol 17:193-211, 1964 385. Ruiz Barranco F: Problems of tapetoretinal degeneration. Arch SW Oftalmol Hisp-Am 23:193-203, 1963 386. Ryan SJ, Smith RE: Retinopathy associated with hereditary olivopontocerebellar degeneration. Am J Ophthalmol 71:838-843, 1971 387. Salt HB, Wolff OH, Lloyd JK, et al: On having no beta-lipoprotein. A syndrome comprising A-beta-hpoproteinemia, acanthocytosis and steatorrhea. Lancet 2:325-329, 1960 388. Santino D: A form of Coats’ retinitis superimposed upon retinitis pigmentosa. Arch Ottalmol 66:153-165, 1962 389. Sarles HE, Rodin AE, Poduska PR, et al: Hereditary nephritis, retinitis pigmentosa and chromosomal abnormalities. Am J Med 45:312-321, 1968 390. Schappert-Kimmijser J: Les d&g&terescences tap&to-retiniennes du type X chromosomal aux Pays-Bas. Bull Sot Fr Ophtalmol 76:122-129, 1963 39 1. Schappert-Kimmijser J, Henkes HE, van den Bosch J: Amaurosis congenita (Leber). Arch Ophthalmol 61:211-218, 1959 392. Scheie HG, Morse PH: Rubeola Retinopathy. Arch Ophthalmol88:341-344, 1972 393. Schimke RN: Hereditary renal-retinal dysplasia. Ann Intern Med 70:735-744, 1969 394. Schmidt B, Jaeger W, Neubauer H: Ein Mikrozephalie-Syndrom mit atypisdher tapeto-retinaler Degneration bei 3 Geschwistern. Monatsbl Augenheilkd Klin E&188-196, 1967 395. Schmidt B, Miller-Limmroth W: Electroretinographic examinations following the application of chloroquine. Acta Ophthalmol Suppl 70~245-25 1, 1962 396. Schmidt B, Straub W: Disseminierte tapetoretinale Degeneration oder pseudoretinitis pigmentosa? Klin Monatsbl Augenheilkd 150:180-187, 1967 397. Schmidt D: Familiares Vorkommen von Coats-Syndrom kombiniert mit retinopathia pigmentosa. Klin Monatsbl Augenheilkd 160:158-163, 1972 398. Schmidt D, Faulborn J: Retinopathia pigmentosa mit Coats Syndrom. Klin Monatsbl Augenheilkd 157:643-652, 1957 399. Schmidt WJ: Polarisationsoptische Analyse eines Eiweiss-Lipoid-Systemes, erlZiutert am Aussenglied der Sehzellen. Kolloid-Z. 85:137-148, 1938


400. Scialdone D, Artifone E: An unusual syndrome of pigmentary dermatopathy associated with retinitis pigmentosa, congenital deafness, oligophrenia and cerebellar ataxia. C Itd Oftalmol 17:49-60, 1964 401. Scott PP, Greaves JP: Retinal degeneration and other signs of vitamin A deficiency in the cat. Proc Nutr Sot 23:34-35, 1964 402. Scott PP, Greaves JP, Scott MC: Nutritional blindness in the cat. Exp Eye Res 3:357-W, 1964 403. Senior B, Friedmann AI, Bravdo JL: Juvenile familial nephropathy with tapetoretinal degeneration. A new oculorenal dystrophy. Am J Ophthalmol 52:625-633, 1961 404. Setogawa T: ERG of experimental pigmentary degeneration of the retina. Yonago Acta Med 11:262-269, 1967 405. Setogowa T: Results of clinical examinations after transplantation of human placenta in patients with pigmentary degeneration of the retina. Folia Ophthalmol Jap 18: 11 lO- 1120, 1967 406. Shearer ACI: Absorption of p-carotene in human retinitis pigmentosa. Exp Eye Res 3~427-438, 1964 407. Shershevskaya SF, Fuks BB, Potapova LN, et al: Experience with the use of RNA in a complex treatment of tapetoretinal degeneration. Vestn Oftalmol I&4(3):59-63, 1971 408. Schevchuk IY: Reflex therapy of pigment degeneration of the retina. Oftal Zh 24:122-124, 1969 409. Sidi Z, Liberman A: Usher’s syndrome Nerve deafness with retinitis pigmentosa in children. Harefuah 83:198, 1972 410. Sidman RL, Green MC: Retinal degeneration in the mouse. J Hered 56:23, 1965 4 11. Smail JM: Primary pigmentary degeneration of the retina and acromegaly in a case of pituitary adenoma. Br J Ophthalmol 56:25-3 1, 1972 412. Sollom AW, Adlakha D: Fluorescein staining in primary pigmentary degeneration of the retina. A histological study in rats. Exp Eye Res 7:l-3, 1968 413. Sorsby A: Annual Report of the Chief Medical Officer for 1960. London, H.M. Stationery Office. (Cited by Sorsby A: Modern Ophthalmology, Vol. I., London, Butterworths, 1963, p 506) 414. Sorsby A: Ophthalmic Genetics. London, Butterworths, 1970, pp 136-138 415. Sorsby A, Williams CE: Retinal aplasia as a clinical entity. Br Med J 1:293-296, 1960 416. Sperling MA, Hiles DA, Kennerdell JS: Electroretinographic responses following vitamin A therapy in A-beta-lipoproteinemia. Am J OphthaImol 73:342-351, 1972


417. Spirxnas M, Hogan MJ: Outer segments of photoreceptors and the retinal pigment epithelium. interrelationship in the human eye. Arch Ophthrlmol 84:810-819, 1970 418. Stanka P: Komplizierte Heterochromie der Drusenpapille und tapetoretinale Iris, Heredodegeneration in einer Familie. Klin Monatshl Augenheilkd 148:574-579, 1966 419. Steinberg D, Vroom FQ, Engel WK, et al: Refsum’s disease, a recently characterized lipidosis involving the nervous system. (Combined Clinical staff conference at the National Institutes of Health), Ann Int Med 66:365-395, 1967 420. Steinberg D: Phytanic acid storage disease: Refsum’s syndrome, in Stanbury JB, Wyngaarden JB, Frederickson DS (ed): The Metabolic Basis of Inherited Disease. New York, McGraw Hill, ed 3, 1972 421. Steinberg D, Mize CE, Herndon JH, et al: Phytanic acid in patients with Refsum’s syndrome and response to dietary treatment. Arch Intern Med 125:75-87, 1970 422. Steinberg D, Vroom FQ, Engel WK, et al: Refsum’s disease, a recently characterized lipidosis involving the nervous system (Clinical Staff Conference). Ann Intern Med 66:365-395, 1967 423. Stigglebout W: The (Laurence-Moon) Bardet-Biedl Syndrome. van Gorcum, Amsterdam, 1969 424. Straub W, Schmidt B: Le diagnostic des degenerescences tapeto-rttiniennes chez l’enfant. Bull Mem Sot Fr Ophtalmol 82: 5-11, 1969 425. Strouth JC, Zeman W, Merrit AD: Leukocyte abnormalities in familial amaurotic idiocy. N Engl J Med 274:36-38. 1966 426. Sulli R, Stirpe M: L’Elettroretinografia nelle retiniti pigmentose atapiche. Bull Ocul 44:891-908, 1965 427. Sunga RN, Sloan LL: Pigmentary degeneration of the retina: Early diagnosis and natural history. Invest Ophthalmol 6:309-325, 1967 428. Suyama T: Electron microscopic study on experimental retinal degeneration induced by sodium iodate injection. Yonago Acta Med 11:222-231, 1967 429. Sveiak J, Peregrin J, Vrabec J: Die einseitige Pigmentdegeneration der Retina. Klinische und elektrophysiologische Beobachtungen. Arch Klin Exp Ophthaimol 174:221-230, 1968 430. Sweasey D, Patterson DSP, Terlecki S: Lactate dehydrogenase (LHD) isoenzymes in the retina of the sheep and changes associated with progressive retinal degeneration. (Bright blindness). Exp Eye Res 12:60-69, 1973 Chorioretinal Primary 43 1. Symposium: aberrations with night blindness. Trans Am


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Acad Ophthalmol Otolaryngol 54:589, 1950 432. Symposium: Pigmentary Retinopathy. Trans Ophthalmol Sot UK 92: 173-301, 1972 433. Tami A, Setogawa T, Kandori F: Electroretinographic studies in retinitis punctata albescens. Am J Ophthalmol 62:125-131, 1966 434. Tamake S: ERG studies on the experimental hypervitaminosis A and vitamin A deliciency. II. ERG normal and influence of urethane. Acta Sot Ophthalmol Jap 71:2095, 1967 435. Tamaki S: Electroretinographic studies on experimental hypervitaminosis A and vitamin A deficiency. IV. The influence of vitamin A deficiency and light adaptation on the ERG. Acta Sot Ophthalmol Jap 72:1209-1217, 1968 436. Tansley K: Hereditary degeneration of the mouse retina. Br J Ophthalmol X:573, 195 1 437. Thaler A, Heilig P: ERG in a case of achromatopsia congenita and sectoral retinopathia pigmentosa. Vis Res 11:1217, 1971 438. Thaler A, Heilig P, Slezak H: Konbination einer angeborenen Achromatopsie mit sektorenfirmiger Degeneratio pigmentosa retinae. Albrecht von Graefes Arch Klin Ophthalmol 183:3 10-3 16, 1972 439. Toivakka E, Nuutila A: EEG findings in syndrome. retinitis pigmentosa-dysacusis Acta Neural Stand 43: Suppl31:70-71, 1967 440. Topping TM, Kenyon KR, Goldberg MF, Maumenee AE: Ultrastructural ocular pathology of Hunter’s syndrome: Systemic mucopolysaccharidosis type II. Arch Ophthalmol 86:164-177, 1971 441. Tosello P: Treatment of retinitis pigmentosa with complamine. Arch Oftalmol B Aires 40~223-225, 1965 442. Toussaint D: Histological alterations of the blood vessels in retinitis pigmentosa. Bull Sot Belge Ophtalmol 137:347-360, 1964 443. Toussaint D, Danis P: An ocular pathologic study of Refsum’s syndrome. Am J Ophthalmol 72:342-347, 1971 444. Usher CH: On the inheritance of retinitis pigmentosa, with notes of cases. Roy London Ophthalmol Hosp Rep 19:130, 1914 444a. Uyemura M: Ober eine Merkwiirdige Augenhintergrund-Verandrung bei zwei FIllen von idiopathischer Hemeralopie. Klin Monatsbl Augenheilkd 81:471-473, 1928 445. Vannas S, Raitta C, Vannas A: Fluoreszeinangiographie bei Dystrophia retinae pigmentosa. Klin Monatsbl Augenheilkd 155:673-680, 1969 446. Veen MJ, Beaton GH: Vitamin A transport in the rat. Can J Physiol Pharmacol 44:521-527, 1966 447. Vernon M: Usher’s syndrome - deafness

















464. 465.


and progressive blindness. Clinical cases, prevention, theory and literature survey. J Chronic Dis 22:133-151, 1969 Verriest G: Further studies on acquired deficiency of colour discrimination. J Opt Sot Am 53:185, 1963 Voipio H: Incidence of chloroquine retinopathy. Acta Ophthalmol 44:349-354, 1966 Voipio H, Grippenburg U, Raitta C, Horsmanheimo A: Retinitis pigmentosa: a preliminary report. Hereditas 52:247, 1964 Voisin G, Bertrand JJ: Conservation d’une acuitt visuelle partielle chez certains malades avec trace 6lectror&nographique &eint. Bull Sot Ophthalmol 6&1025-1027, 1968 von Sallmann L, Gelderman AH, Laster L: Ocular histopathologic changes in a case of A-beta-lipoproteinemia (Bassen-Kornzweig syndrome). Dot Ophthalmol 26:45 l-460, 1969 Waardenburg PJ: Discussion of Henkes HE: Does unilateral retinitis pigmentosa really exist? Ophthalmologica 149:203, 1965 Waardenburg P, Schappert-Kimmijser J: On various recessive biotypes of Leber’s congenital amaurosis. Acta Ophthalmol 41:317-320, 1963 Wald G, Brown PK, Gibbons IR: Visual excitation: a chemoanatomical study. Symp Sot Exp Biol l&32-57, 1962 Wallis K, Gross M, Zaidman JL, et al: Tocopherol therapy in acanthocytosis. Pediatrics 48:669-67 1, 197 1 Walsh FB, Hoyt WF: Clinical Neuroophthalmology. Baltimore, Williams & Wilkins, 1969. pp 849-850 Warburg M: Random inactivities of the xchromosome in intermediate X-linked retinitis pigmentosa. Trans Ophthalmol Sot UK 91:553-560, 1971 Warburg M, Simonsen SE: Sex-linked pigmentosa. Acta retinitis recessive Ophthalmol 46: 1029, 1968 Weale RA: Cone pigment regeneration, retinitis pigmentosa and light deprivation. Vis Res 12~747-748, 1972 Weiner LP, Konigsmark BW, Stall J, Magladery JW: Hereditary olivopontocerebellar degeneration. Am J Ophthalmol 71:838-876, 1967 Weinstein GW, Maumenee AE, Hyvlrinen, L: On the pathogenesis of retinitis pigmentoss. Ophthalmologica 162:82-97, 1971 Weiss JF, Nicholl RJ: Nonsyphilitic uniretinitis pigmentosa. Am J lateral Ophthalmol 65:573-574, 1968 Wiessman G: Labilization and stabilization of lysosomes. Fed Proc 23: 1038, 1964 Williams RH: Textbook of Endocrinology. Philadelphia, WB Saunders, ed 4, 1968. p


1152 466. Wirth A, Apollonio A: High intensity ERG in retinitis pigmentosa. Acta Ophthalmol Suppl 70:230-23 1, 1962 467. Witzleben CL, Smith K, Nelson JS, et al: Ultrastructural studies in late-onset amaurotic idiocy: lymphocyte inclusions as a diagnostic marker. J Pediatr 79:285-293, 1971 468. Wolff OH, Lloyd JK, Tonks EL: A-/% lipoproteinaemia with special reference to the visual defect. Exp Eye Res 3:439-442, 1964 469. Yates CM, Dewar AJ, Wilson H, et al: Histological and biochemical studies on the retina of a new strain of dystrophic rat. Exp Eye Res l&119-133, 1974 470. Young RW: The renewal of photoreceptor cell outer segments. J Cell Biol 33:61-72, 1967 47 1. Young RW: Passage of newly formed protein through the connecting cilium of retinal rods in the frog. J Ultrastruct Res 23:462-473, 1968 472. Young RW: A difference between rods and cones in the renewal of outer sement protein. Invest Ophthalmol 8:222-23 1, 1969 473. Young RW: An hypothesis to account for a basic distinction between rods and cones. Vis Res ll:l-5, 1971 474. Young RW: Shedding of discs from rod outer segments in the rhesus monkey. J Ultrastruct Res 34: 190-203, 197 1 475. Young RW: The renewal of rod and cone outer segments in the rhesus monkey. J Cell Biol 49:303-318, 1971 476. Young RW, Bok D: Participation of the retinal pigment epithelium in the rod outer segment renewal process. J Cell Biol 42~392-403, 1969 477. Young RW, Bok D: Autoradiographic studies on the metabolism of the retinal pigment epithelium. Invest Ophthalmol 9:524-536, 1970 478. Young RW, Droz B: The renewal of protein in retinal rods and cones. J Cell Biol 39:169-184, 1968 479. Zeman W, Donahue S, Dyken P, Green J: The neuronal ceroid-lipofuscinoses (BattenVogt syndrome), in Vinken PJ, Bruyn GW (ed): Handbook of Clinical Neurology, Vol 10. Amsterdam, North Holland Publishing co, 1970 480. Ziv B, Dunphy EB: Pigmented retinal arteries in retinitis pigmentosa. Am J Ophthalmol 57:132-133, 1964 Outline

I. Definition and nomenclature I I. Prevalence


III. Clinical findings in typical retinitis pigmentosa A. Symptoms B. The fundus picture C. Functional abnormalities 1. Visual fields 2. Visual acuity 3. Color vision 4. Light sense and dark adaptation IV. The clinical and genetic entities of isolated retinitis pigmentosa and their characteristics A. Typical retinitis pigmentosa B. Retinitis punctata albescens C. Leber’s congenital amaurosis D. Progressive cone-rod degeneration E. Sector retinitis pigmentosa F. Unilateral retinitis pigmentosa G. Pseudo-retinitis pigmentosa H. Associated ocular abnormalities 1. Keratoconus 2. Marginal cornea1 dystrophy 3. Cataract 4. Macular cystoid degeneration 5. Coats’ syndrome 6. Drusen of the optic disc 7. Other ocular associations V. Electrophysiologic aspects A. The electroretinogram B. The early receptor potential C. The electro-oculogram D. Brain potentials VI. The clinical and genetic entities of associated retinitis pigmentosa A. Lipid disorders 1. A-beta-lipoproteinemia 2. Refsum’s syndrome 3. Juvenile amaurotic idiocy 4. Cockayne’s syndrome 5. Other lipid disorders B. Mucopolysaccharidoses 1. Hurler’s disease (MPS I-H) 2. Scheie syndrome (MPS I-S) 3. Hunter syndrome (MPS II) 4. Sanfilippo syndrome (MPS III) C. Disorders affecting the central nervous system (CNS) 1. Laurence-Moon-Bardet-Biedl (LMBB) syndrome 2. Ataxia, epilepsy or diencephalic syndrome D. Muscular involvement 1. Progressive external ophthalmoplegia 2. Myotonic dystrophy E. Renal involvement F. Deafness G. Association with other syndromes VII. Pathology and Pathogenesis A. Histopathology 1. Isolated retinitis pigmentosa 2. Leber’s amaurosis 3. Associated retinitis pigmentosa


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B. Ocular hemodynamics and fluorescein angiography C. Biochemistry of isolated retinitis pigmentosa D. Hereditary pigmentary dystrophy of the retina in animals 1. The outer segments of photoreceptors 2. Hereditary retinal dystrophy in the rat 3. Hereditary retinal dystrophy in the mouse 4. Hereditary retinal dystrophy in the dog 5. Pigmentary retinopathy in the sheep E. Induced retinopathies in man and animals 1. Nutritional deficiency retinopathy 2. Light-induced retinopathy 3. Experimental toxic retinopathy in



animals 4. Toxic retinopathy in man F. Pathogenesis of human retinitis mentosa VIII. Therapy A. Vitamins B. Light deprivation C. Treatment of associated retinitis mentosa D. Miscellaneous E. Visual aids



Reprint requests should be addressed to: Dr. Edgar Auerbach, Vision Research Laboratory, Hadassah University Hospital and Medical School, P.O. Box 499, Jerusalem, Israel.