Retinitis pigmentosa

SURVEY OF OPHTHALMOLOGY

VOLUME 20

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NUMBER 5

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MARCH-APRIL

1976

REVIEW Retinitis

Pigmentosa

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

Hadassah

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,

1976)

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

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

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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.

corpuscle”

changes

pigment

and

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.‘@

Panteleevas62**

Jay”’

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.

RETlNlllS PIGMENTOSA

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

AMAUROSIS

MERIN,

1976

AUERIACH

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

CONE-ROD DEGENERATION

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. ~33.157.170.231.93~ 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 reported.ls 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.

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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

RETINITIS

PIGMENTOSA

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

PIGMENTOSA

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.

ASSOCIATED OCULAR ABNORMALITIES

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

Cataract

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-

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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.

RETINITISPIGMENTOSA

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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

Aspects

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 measurements.as~zs~61~‘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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J

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 times.ss 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

RfilNltlS

313

PIGME~OSA

pigment kinetics. disagreehBO

Berson

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.

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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

RLTINITISPIGMCNTOSA

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

Idiocy

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

Syndrome

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

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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

(MPS I-S)

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

(MPS II)

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

AFFECTING THE CENTRAL SYSTEM (CNS)

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

(LMBB)

Syndrome

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

Syndromes

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

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317

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. 1.74.140.218.236.307,S21,356,3S9,39S,403

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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.)

RETlNlTlSPIOMRNTOSA

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

319

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-

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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 al.gs~ss 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

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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.“’

RETINITISPIGMENTOSA

. 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 Orzalesi.sg “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-

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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

-

AGMENT EPITHEUUM

-OUTER

-INNER

SEGMENTS

SEGMENTS

LAYER

3

OF

RODS

OUTER NUCLEAR IAYER

s -

PIGMENT EPITHELIUM

DISORGANIZED -OUTER SEGMENT MATERIAL -OUTER -INNER

LAYER OF

SEGMENTS SEGMENTS

RODS

-EXTERNAL LIMITING MEMBRANE OUTER NUCLEAR LAYER

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.)

RCTINITIS

PIGMCNTOSA

T

.5hr

325 Id

fd

3d

A

15

18

T

.5hr

3d

WISTAR

7d

20

1 Id

43d r--T

111111 18

20

RCS

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

Hereditary

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

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1976

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.

PAtHOGENESiS

PIGMENTOSA

AUERBACH

OF HUMAN RETINITIS

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

RETINITIS

PIGMENTOSA

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.

329

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

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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 available.ss 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

MRRIN, AUERRACH

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.

RRTINITISPIGMENTOSA

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

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I. Definition and nomenclature I I. Prevalence

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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

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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

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