PROGRESSIVE E X T E R N A L O P H T H A L M O P L E G I A ASSOCIATED W I T H RETINAL PIGMENT EPITHELIOPATHY SALVATORE DANIELE, M.D.,
CARLO CIANCHETTI, M.D.,
AND ANTONIO CAO,
M.D.
Perugia, Italy Visual acuity was 20/20 in each eye. The pupils were normal. Visual fields were normal. On ophthalmoscopic examination, the optic disk and the caliber of the retinal vessels appeared to be normal. There was a nasal peripapillary crescent of atrophic pigment epithelium. The maculae, particularly the left, had a slight salt-and-pepper appearance but no pigment clumping was present (Fig. 2). On redfree ophthalmoscopy, there seemed to be some depigmentation of the retinal pigment epithelium, par ticularly in the peripapillary areas. Laboratory studies of the blood and urine, skull and chest x-ray films, and electroencephalography revealed no ab normalities.
Progressive external ophthalmoplegia is a syndrome characterized by occurrence in either sex at any age, most frequently dur ing the second decade, by slow progression, and bilateral weakness of the extraocular muscles of each ey**, Thy Watnr palpebrae superioris muscles rarely are solely affected. The condition is inherited as an autosomal dominant trait with incomplete penetrance. Progressive external opntnaimopiegia may be associated with other pathologic condi tions, such as hvnoyonadism.1 rerehellar ataxia,2 cardiopathy,3 spastic tetraparesis,* anal'sphincter insufficiency,5 and retinal pig mentary dystrophy. Forty-two cases of pro gressive external ophthalmoplegia associated with pigmentary dystrophy of the retina have been described.6"28 We document an additional case of pro gressive external ophthalmoplegia associated with atypical retinal dystrophy that we studied in detail, principally by means of retinal fluorescein angiography.
RESULTS
Electromyography—In the concentric nee dle electrode examination of eye, face, neck, shoulder, and limb muscles, there was no resting activity in any muscle. Voluntary
CASE REPORT
A 20-year-old man had no family history of neuromuscular or eye disease. At 11 years of age, he developed progressive bilateral blepharoptosis. He was underweight and underdeveloped. There was marked, slightly asymmetrical bilateral bleph aroptosis with secondary frontalis musculature compensatory overaction. Movements of both eyes were severely limited, particularly on upward gaze. The face was hypomimic. The musculature of the head, neck, and upper half of the trunk (Fig. 1) was thin. Slight hypotonia, hyposthenia, and proprioceptive hyporefiexia were observed. The lower limbs and gait were normal. There was neither ataxia nor cerebellar or pyramidal signs. The intelligence quo tient was 82. From the Institutes of Ophthalmology (Dr Daniele), Neurology (Dr. Cianchetti), and Pedia trics (Dr. Cao), University of Perugia School of Medicine, Perugia, Italy. Reprint requests to Salvatore Daniele, M.D., Clinica Oculistica, Policlinico Monteluce, 06100 Perugia, Italy.
Fig. 1 (Daniele, Cianchetti, and Cao). Ocular myopathy. Note the thin musculature of the head and neck, the hypomimic face, and bilateral bleph aroptosis. Impairment of the extraocular move ments was marked.
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Fig. 2 (Daniele, Cianchetti, and Cao). Ophthalmoscopic aspect of the fundus of the left eye show ing a temporal crescent of peripapillary atrophy. The diffuse abnormality of the pigment epithelium is not prominent. There is clumping of dustlike pig ment in the macular area.
activity was not detectable from the left superior rectus muscle. The left levator palpebrae superioris muscle showed a vari able pattern, slightly reduced in some detec tion areas (Fig. 3, a ) , but near to inter ference in others (Fig. 3, b), contrasting with the almost missing eyelid elevation; there was low amplitude, and spikes were frequently irregular. There were interference and subinterference patterns with short and irregular
OCTOBER, 1975
potentials in the left orbicularis oculi muscle, left sternocleidomastoideus muscle, and left and right deltoideus muscles (Fig. 3, c and d). There were fewer abnormalities in the right palmaris magnus muscle and the right and left adductor pollicis muscles; the right tibialis anterior muscle was normal. Maximal motor conduction of the ulnar and median nerves was normal. Tetanic stimulation was 50 c/sec, and Desmedt's test showed no changes in the amplitude of the evoked potentials in the ulnar nerve with detection from the adductor pollicis muscle. There was primary myopathy with maxi mum severity in the extraocular muscles (loss of parenchyma in the superior rectus muscle, followed by parenchymal loss in the muscles of the face, neck, and shoulders). The following studies showed normal or negative values: prostigmine test (2 mg intramuscularly), dark adaptation, Farnsworth-100 color vision hue test, electroretinogram (b-wave, —0.35 mV), and an electro-oculogram. Retinal fluorescein angiography—Angiograms disclosed clear signs of alterations in the entire pigment epithelial layer, signs not seen ophthalmoscopically. The most precocious finding was an early, diffuse choroidal hyperfluorescence, more marked
Fig. 3 (Daniele, Cianchetti, and Cao). The electromyograph of the left levator pal pebrae muscle was slightly reduced (a) in some detection areas but near to interference (b) in others (0.1 mV/100 msec). Interference and subinterference patterns (c and d) had short and irregular potentials in the left orbicularis oculi muscle, left sterno cleidomastoideus muscle, and left and right deltoideus muscles (0.2 mV/100 msec).
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along the main retinal vessels whose caliber appeared to be normal. The underlying choroidal and retinal circulation appeared nor mal. There was general thinning of the pig ment epithelium with a nasal peripapillary area of atrophy, and widespread patches of rarefaction that revealed multiple, discrete, nonleaking areas of hyperfluorescence due to a reduced filter effect of the pigment layer. These hyperfluorescent areas remained con stant in size and configuration, varying only in brightness throughout the angiography study. The fluorescence observed earlier in the retinal arterial phase persisted beyond the retinal venous phase of angiography. The filter effect was almost lost in the macular
587
area. A long-lasting scleral fluorescence per sisted abnormally. The findings were similar in each eye (Fig. 4 ) . DISCUSSION
Our patient belongs to the group of un common cases of progressive external ophthalmoplegia associated with pigment dys trophy of the retina. Electromyography diagnosed an ocular myopathy that extended to the muscles of the face, neck, and shoulder girdle. Normal values of muscle enzymes in blood serum are compatible with slowly progressive disease and limited extension of macular changes.26 In the cases that have been reported, reti nal changes have always been described as forms of "atypical" retinal pigment dys-
Fig. 4 (Daniele, Cianchetti, and Cao). Retinal fluorescein angiography of the same eye as in Fig ure 2. The diffuse pigment changes, unappreciated ophthalmoscopically, are apparent. Top left, Arterial phase. Areas of damage to the pigment epithelium, already diffusely fluorescent in the early phase of the angiography, demonstrate that the choriocapillaris is intact. Top right, Arteriovenous phase. The pigment epithelium is generally thinned. The tem poral area of peripapillary atrophy and the wide spread, nonleaking areas of hyperfluorescence occur because the filter effect of the pigment layer is re duced. Bottom left, Late venous phase. The fluores cence seen initially in the arterial phase persists beyond the retinal venous phase of the angiography.
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trophy, characterized by good visual func tion, absence of optic atrophy, and attenua tion of the retinal vessels. However, there has been heterogeneity of the ophthalmoscopic findings, similar to but never specific for retinitis pigmentosa. The reported find ings vary in fact from those found in classic tapetoretinal bone-corpuscle pigmentation to granular, clumped, or fine dustlike pig mentary disturbances detectable at the pos terior pole, at the equator, or in the ex treme periphery of the fundus. In other words, a case of true tapetoretinal degenera tion associated with ocular myopathy has not been reported to our knowledge. Even in Kearns's 21 patient, the only case studied histopathologically, the diagnosis of retinitis pigmentosa was impossible. Prior reports never considered the appearance of the fundus other than the contextual retinal al terations that manifested generalized abiotrophic processes of ocular myopathy.18'15'19'80 The suggested diagnosis of primary ret inal pigment epitheliopathy in our case is supported by: (1) the lasting normality of the retinal function. The integrity of the peripheral neurons and of the neuroepithelium persisted despite the progressive wors ening of the function of the muscles affected by the degenerative process; and (2) the findings of retinal fluorescein angiography. When histologic study is impossible, retinal angiography discloses the extent and severity of the abiotrophic or degenerative changes, unappreciated or misinterpreted by ophthalmoscopy. In our patient, the early fluorescence pres ent in the arterial phase and persisting be yond the venous phase without changing size indicated a defective pigment epithelium rather than a leakage. When the patient was examined ophthalmoscopically, even with red-free light, the less-extended visible * changes were fewer than with fluorescein angiography. The changes seemed to spread all over the fundus, diffuse beyond the ophthalmoscopic limits, giving the impression of a global process. This discrepancy is an angiographic
OCTOBER, 1975
peculiarity of the pigment epitheliopathies alone.81'32 When the choriocapillaris or Bruch's membrane are affected, a more pre cise regional topography, more irregular borders, and dense and localized plaques of hyperfluorescence characterize the fundus changes. It is more difficult in the case of pig ment epitheliopathy to establish whether the background mottling of the fundus is due to increased transparency of the altered pig ment epithelium or to impregnation of the pigment cells by the stain. Pigment epi thelium is not just a simple support for the photoreceptors or a filter for the light energy required by the photoreceptors. It is a layer of complex cells whose specific functions include transmission of nutrients from the choriocapillaris to other parts of the retina, storage of vitamin A and its conversion to forms suitable for the synthesis of rhodopsin, some mucoprotein synthesis, phagocitosis, and digestion of the rod-segment disks and of other substances from the neuroretina. 83-38 Failure of the pigment epithelium to func tion properly is responsible for some types of maculopathies, as well as changes in Bruch's membrane secondary to disease of the pigment epithelium that augments the progress of retinal degeneration.39 Fundus flavimaculatus and Best's or Stargardt*slBsease are caused by damage of the retinal pigment epithelium, probably due to a failure of the enzymatic system within the pigment cells.31-*0'" According to Klien and Krill, 81 fundus flavimaculatus, a retinal affection whose fluorescein angiographic features re semble those of our case, should be con sidered the consequence of a genetic disorder responsible for a primary defect in the pig ment epithelium. Rodrigues and associates'42 report of a case of defective pigment epi thelium alone in a boy with a trisomy-18 syndrome, adds interest to the observation of interrelationship between genetic dis orders and retinal changes confined to the pigment layer alone. These findings suggest that the atypical forms of retinal dystrophies associated with
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ocular myopathy could be clinical expres sions of a unique, original genetic defect confined to the pigment epithelium layer. This view is supported by Gass's48 report of a 16-year-old girl with Kearns-Sayre syndrome who revealed definite but not ophthalmoscopically prominent alterations of the pigment layer, exactly as those that occurred in our patient. Therefore, there is no relationship between true retinitis pigmentosa and primary retinal pigment epitheliopathy in the course of ocular myopathy since histopathologic studies of retinitis pigmentosa indicate that the first step in the dystrophic process is always a primary de generation of the photoreceptors.44 Further anatomic and functional changes follow thereafter. The most likely explanation for damage to the pigment epithelium during the course of ocular myopathy is that the muscular dystrophy gene has pleiotropic effects or different degrees of penetrance. In addition to the effect on the muscle tissue, primary or secondary biochemical changes could dam age the development and functions of the retinal pigment epithelium. Depending on the severity and extent of the original dam age to the epithelial cells, retinal changes can follow the primary epitheliopathy and account for the atypical and irregular dis orders so far reported. Even though narrow ing of the vessels and pallor of the optic disk may occasionally be present, such func tional disturbances as hemeralopia, dischromatopsia, annular scotomas, or peripheral contraction of the visual fields, which always characterize the true tapetoretinal degenera tions, are practically absent in the retinal alterations associated with ocular myop athy.45 SUMMARY
The diagnosis of ocular myopathy associ ated with a primary retinal pigment epi theliopathy in. a 20-year-old man was based on the integrity of the retinal functions, despite progressive worsening of muscular activity in the systems affected by the dis
589
ease, and on the results of retinal fluorescein angiography. Although the changes in the pigment epithelium were not prominent ophthalmoscopically, they were clearly visible angiographically. Atypical forms of retinal pigment dys trophy occurring during the course of ocular myopathy appear to be clinical expressions of a unique genetic defect confined to the pigment epithelial layer. We assume that the gene is capable of inducing a pleiotropic effect. REFERENCES
1. Lundberg, P. D.: Ocular myopathy with hypogonadism. Acta Neurol. Scand. 38:142, 1962. 2. Stephens, J., Hoover, M. L., and Denst, Y.: On familial ataxia, neural amyotrophy, and their t association with progressive external ophthalmoplegia. Brain 81 :S56, 1958. 3. Kearns, T. P., and Sayre, G. P.: Retinitis pigmentosa, external ophthalmoplegia, and complete heart block. Unusual syndrome with histologic study in one of two cases. Arch. Ophthalmol. 60: 280, 1958. 4. Drachman, D. A.: Experimental denervation of ocular muscles. Arch. Neurol. 21:170, 1969. 5. Teasdall, R. D., Schuster, M. M., and Walsh, F. B.: Sphincter involvement in ocular myopathy. Arch. Neurol. 10:446, 1964. 6. MacMullen, W. H., and Hine, M. L.: Chronic progressive ophthalmoplegia externa or "infantile nuclear atrophy" (Mobius). Br. J. Ophthalmol. 5: 337, 1921. 7. Barnard, R., and Scholz, R. O.: Ophthalmo plegia and retinal degeneration. Am. J. Ophthalmol. 27:621, 1944. 8. Chamlin, M., and Billet, E.: Ophthalmoplegia and pigmentary degeneration of the retina. Arch. Ophthalmol. 43:217, 1950. 9. De Ruyter, J.: Progressive chronic external ophthalmoplegia with disorders of retinal pigmen tation. Ophthalmologica 132:298, 1956. 10. Alfano, J. E., and Berger, J. P . : Retinitis pigmentosa, ophthalmoplegia, and spastic quadriplegia. Am. J. Ophthalmol. 43:231, 1957. 11. Erdrink, W. L.: Ocular myopathy associated with retinitis pigmentosa. Arch. Ophthalmol. 57: 335, 1957. 12. Lux, P.: Ophthalmoplegia chronica progres sive externa mit atypischer Pigmentdegeneration der Netzhaut. Klin. Monatsbl. Augenheilkd. 134: 122, 1959. 13. Thorson, J. C, and Bell, W. E.: Progressive dystrophic external ophthalmoplegia with abiotrophic fundus changes. Arch. Ophthalmol. 62:833, 1959. 14. Teasdall, R. D., and Sears, M. L.: Ocular myopathy. Ginical and electromyographical con siderations. Arch. Neurol. 2:281, 1960.
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15. Davidson, S. J.: Abiotrophic ophthalmoplegia externa. Br. J. Ophthalmol. 44:590, 1960. 16. Jager, B. V., Fred, H. L., Butler, R. B., and Carnes, W. H.: Occurrence of retinal pigmenta tion, ophthalmoplegia, ataxia, deafness and heart block. Report of a case with fundus at autopsy. Am. J. Med. 29:888, 1960. 17. Jampel, R. S., Okazaki, H., and Bernstein, H.: Ophthalmoplegia and retinal degeneration as sociated with spinocellular ataxia. Arch. Ophthal mol. 66:247, 1961. 18. Harenko, H., and Lappalainen, A.: Progres sive external ophthalmoplegia. Nord. Med. 67:24, 1962. 19. Thomas, C, Cordier, J., Tridon, P., and Saudax, E. r Myopathie oculaire et retinopathie pigmentaire atypique. Rev. Otoneuroophtalmol. 35:5, 1963. 20. Guerci, O., and Reny, A.: Progressive ex terna ophthalmoplegia and pigmentary pseudoretinitis. Bull. Soc. Ophtalmol. Fr. 64:82, 1964. 21. Kearns, T. P.: Externa ophthalmoplegia, pigmentary degeneration of the retina and cardiomyopathy. A newly recognized syndrome. Trans. Am. Ophthalmol. Soc. 63:552, 1965. 22. Malbran, E. S.: Myopathie ophthalmoplegia externa. Int. Ophthalmol. Clin. 6:711, 1966. 23. Shy, G. M., Silberberg, D. H., Appel, S. H., Mishkin, M. M., and Godfrey, E. H.: A generalized disorder of nervous system, skeletal muscle and heart resembling Refsum's disease and Hurler's syndrome. Am. J. Med. 42:163, 1967. 24. Drachman, D. A.: Ophthalmoplegia plus. The neurodegenerative disorders associated with progres sive external ophthalmoplegia. Arch. Neurol. 18: 654, 1968. 25. Rosenberg, R. N., Schotland, D. L., Love lace, R. E., and Rowland, L. B.: Progressive oph thalmoplegia. Report of cases. Arch. Neurol. 19: 362, 1968. 26. Walsh, F. B., and Hoyt, W. F.: Qinical Neuro-Ophthalmology. Baltimore, Williams and Wilkins, 1969, p. 1259. 27. Mills, P. V., Bowen, D. J., and Thomson, D. B.: Chronic progressive ophthalmoplegia. Br. J. Ophthalmol. 55:302, 1971. 28. Koerner, F., and Schlote, W.: Chronic pro gressive external ophthalmoplegia associated with retinal pigmentary changes and evidence in favor of ocular myopathy. Arch. Ophthalmol. 88:155, 1972. 29. Magora, A., and Zauberman, H.: Ocular myopathy. Arch. Neurol. 20:1, 1969. 30. Cogan, D. G., Kuwabara, T., and Richardson,
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E. P.: Pathology of abiotrophic ophthalmoplegia externa. Bull. Johns Hopkins Hosp. 14:42, 1962. 31. Klien, B. A., and Krill, A. E.: Fundus flavimaculatus. Qinical, functional, and histopathologic observations. Am. J. Ophthalmol. 64:3, 1967. 32. Amalric, P.: Les epitheliopathies. Minerva Oftalmol. 13:86, 1971. 33. Zimmerman, L. E., and Eastham, A. B.: Acid mucopolysaccharide in the retinal pigment epithe lium and visual cell layer of the developing mouse eye. Am. J. Ophthalmol. 47:488, 1959. 34. Young, R. W., and Bock, D.: Autoradiographic studies on the metabolism of the retinal pig ment epithelium. Invest. Ophthalmol. 9:524, 1970. 35. Spitznas, M., and Hogan, M. J.: Outer seg ments of photoreceptors and retinal pigment epi thelium. Interrelationship in the human eye. Arch. Ophthalmol. 84:810, 1970. 36. Ishikawa, T., and Yamada, E.: The degrada tion of the photoreceptor outer segment within the pigment epithelium cell of rat retina. J. Electron Microsc. 19:85, 1970. 37. Herron, W. L., Riegel, B. W., and Rubin, M. L.: Outer segment production and removal in the degenerating retina of the dystrophic rat. Invest. Ophthalmol. 10:54, 1971. 38. Young, R. W.: The renewal of rod and eone outer segments in the rhesus monkey. J. Cell. Biol. 49:303, 1971. 39. Hogan, M. J.: Role of the retinal pigment epithelium in macular disease. Trans. Am. Acad. Ophthalmol. Otolaryngol. 76:64, 1972. 40. Krill, A., Newell, F. W., and Chishti, M. I.: Fluorescein studies in diseases affecting the retinal pigment epithelium. Am. J. Ophthalmol. 66:470, 1968. 41. Morse, P. H., and MacLean, A. L.: Fluo rescein fundus studies in hereditary vitelliruptive macular degeneration. Am. J. Ophthalmol. 66:485, 1968. 42. Rodrigues, M. M., Punnet, H. H., Dapena, M. V., and Martin, L. J.: Retinal pigment epithe lium in a case of trisomy 18. Am. J. Ophthalmol. 76:265, 1973. 43. Gass, J. D. M.: Stereoscopic Atlas of Macu lar Diseases. St. Louis, C. V. Mosby, 1970, p. 117. 44. Cogan, D. G.: Symposium on primary chorioretinal aberrations with night blindness, pathology. Trans. Am. Acad. Ophthalmol. Otolaryngol. 54:629, 1950. 45. Duke-Elder, S., and Dobree, J. H.: Diseases of the Retina. In Duke-Elder, S. (ed.) : System of Ophthalmology, vol. 10. London, Henry Kimpton, 1967, p. 615.
CARLO CIANCHETTI, M.D.,
AND ANTONIO CAO,
M.D.
Perugia, Italy Visual acuity was 20/20 in each eye. The pupils were normal. Visual fields were normal. On ophthalmoscopic examination, the optic disk and the caliber of the retinal vessels appeared to be normal. There was a nasal peripapillary crescent of atrophic pigment epithelium. The maculae, particularly the left, had a slight salt-and-pepper appearance but no pigment clumping was present (Fig. 2). On redfree ophthalmoscopy, there seemed to be some depigmentation of the retinal pigment epithelium, par ticularly in the peripapillary areas. Laboratory studies of the blood and urine, skull and chest x-ray films, and electroencephalography revealed no ab normalities.
Progressive external ophthalmoplegia is a syndrome characterized by occurrence in either sex at any age, most frequently dur ing the second decade, by slow progression, and bilateral weakness of the extraocular muscles of each ey**, Thy Watnr palpebrae superioris muscles rarely are solely affected. The condition is inherited as an autosomal dominant trait with incomplete penetrance. Progressive external opntnaimopiegia may be associated with other pathologic condi tions, such as hvnoyonadism.1 rerehellar ataxia,2 cardiopathy,3 spastic tetraparesis,* anal'sphincter insufficiency,5 and retinal pig mentary dystrophy. Forty-two cases of pro gressive external ophthalmoplegia associated with pigmentary dystrophy of the retina have been described.6"28 We document an additional case of pro gressive external ophthalmoplegia associated with atypical retinal dystrophy that we studied in detail, principally by means of retinal fluorescein angiography.
RESULTS
Electromyography—In the concentric nee dle electrode examination of eye, face, neck, shoulder, and limb muscles, there was no resting activity in any muscle. Voluntary
CASE REPORT
A 20-year-old man had no family history of neuromuscular or eye disease. At 11 years of age, he developed progressive bilateral blepharoptosis. He was underweight and underdeveloped. There was marked, slightly asymmetrical bilateral bleph aroptosis with secondary frontalis musculature compensatory overaction. Movements of both eyes were severely limited, particularly on upward gaze. The face was hypomimic. The musculature of the head, neck, and upper half of the trunk (Fig. 1) was thin. Slight hypotonia, hyposthenia, and proprioceptive hyporefiexia were observed. The lower limbs and gait were normal. There was neither ataxia nor cerebellar or pyramidal signs. The intelligence quo tient was 82. From the Institutes of Ophthalmology (Dr Daniele), Neurology (Dr. Cianchetti), and Pedia trics (Dr. Cao), University of Perugia School of Medicine, Perugia, Italy. Reprint requests to Salvatore Daniele, M.D., Clinica Oculistica, Policlinico Monteluce, 06100 Perugia, Italy.
Fig. 1 (Daniele, Cianchetti, and Cao). Ocular myopathy. Note the thin musculature of the head and neck, the hypomimic face, and bilateral bleph aroptosis. Impairment of the extraocular move ments was marked.
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Fig. 2 (Daniele, Cianchetti, and Cao). Ophthalmoscopic aspect of the fundus of the left eye show ing a temporal crescent of peripapillary atrophy. The diffuse abnormality of the pigment epithelium is not prominent. There is clumping of dustlike pig ment in the macular area.
activity was not detectable from the left superior rectus muscle. The left levator palpebrae superioris muscle showed a vari able pattern, slightly reduced in some detec tion areas (Fig. 3, a ) , but near to inter ference in others (Fig. 3, b), contrasting with the almost missing eyelid elevation; there was low amplitude, and spikes were frequently irregular. There were interference and subinterference patterns with short and irregular
OCTOBER, 1975
potentials in the left orbicularis oculi muscle, left sternocleidomastoideus muscle, and left and right deltoideus muscles (Fig. 3, c and d). There were fewer abnormalities in the right palmaris magnus muscle and the right and left adductor pollicis muscles; the right tibialis anterior muscle was normal. Maximal motor conduction of the ulnar and median nerves was normal. Tetanic stimulation was 50 c/sec, and Desmedt's test showed no changes in the amplitude of the evoked potentials in the ulnar nerve with detection from the adductor pollicis muscle. There was primary myopathy with maxi mum severity in the extraocular muscles (loss of parenchyma in the superior rectus muscle, followed by parenchymal loss in the muscles of the face, neck, and shoulders). The following studies showed normal or negative values: prostigmine test (2 mg intramuscularly), dark adaptation, Farnsworth-100 color vision hue test, electroretinogram (b-wave, —0.35 mV), and an electro-oculogram. Retinal fluorescein angiography—Angiograms disclosed clear signs of alterations in the entire pigment epithelial layer, signs not seen ophthalmoscopically. The most precocious finding was an early, diffuse choroidal hyperfluorescence, more marked
Fig. 3 (Daniele, Cianchetti, and Cao). The electromyograph of the left levator pal pebrae muscle was slightly reduced (a) in some detection areas but near to interference (b) in others (0.1 mV/100 msec). Interference and subinterference patterns (c and d) had short and irregular potentials in the left orbicularis oculi muscle, left sterno cleidomastoideus muscle, and left and right deltoideus muscles (0.2 mV/100 msec).
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along the main retinal vessels whose caliber appeared to be normal. The underlying choroidal and retinal circulation appeared nor mal. There was general thinning of the pig ment epithelium with a nasal peripapillary area of atrophy, and widespread patches of rarefaction that revealed multiple, discrete, nonleaking areas of hyperfluorescence due to a reduced filter effect of the pigment layer. These hyperfluorescent areas remained con stant in size and configuration, varying only in brightness throughout the angiography study. The fluorescence observed earlier in the retinal arterial phase persisted beyond the retinal venous phase of angiography. The filter effect was almost lost in the macular
587
area. A long-lasting scleral fluorescence per sisted abnormally. The findings were similar in each eye (Fig. 4 ) . DISCUSSION
Our patient belongs to the group of un common cases of progressive external ophthalmoplegia associated with pigment dys trophy of the retina. Electromyography diagnosed an ocular myopathy that extended to the muscles of the face, neck, and shoulder girdle. Normal values of muscle enzymes in blood serum are compatible with slowly progressive disease and limited extension of macular changes.26 In the cases that have been reported, reti nal changes have always been described as forms of "atypical" retinal pigment dys-
Fig. 4 (Daniele, Cianchetti, and Cao). Retinal fluorescein angiography of the same eye as in Fig ure 2. The diffuse pigment changes, unappreciated ophthalmoscopically, are apparent. Top left, Arterial phase. Areas of damage to the pigment epithelium, already diffusely fluorescent in the early phase of the angiography, demonstrate that the choriocapillaris is intact. Top right, Arteriovenous phase. The pigment epithelium is generally thinned. The tem poral area of peripapillary atrophy and the wide spread, nonleaking areas of hyperfluorescence occur because the filter effect of the pigment layer is re duced. Bottom left, Late venous phase. The fluores cence seen initially in the arterial phase persists beyond the retinal venous phase of the angiography.
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trophy, characterized by good visual func tion, absence of optic atrophy, and attenua tion of the retinal vessels. However, there has been heterogeneity of the ophthalmoscopic findings, similar to but never specific for retinitis pigmentosa. The reported find ings vary in fact from those found in classic tapetoretinal bone-corpuscle pigmentation to granular, clumped, or fine dustlike pig mentary disturbances detectable at the pos terior pole, at the equator, or in the ex treme periphery of the fundus. In other words, a case of true tapetoretinal degenera tion associated with ocular myopathy has not been reported to our knowledge. Even in Kearns's 21 patient, the only case studied histopathologically, the diagnosis of retinitis pigmentosa was impossible. Prior reports never considered the appearance of the fundus other than the contextual retinal al terations that manifested generalized abiotrophic processes of ocular myopathy.18'15'19'80 The suggested diagnosis of primary ret inal pigment epitheliopathy in our case is supported by: (1) the lasting normality of the retinal function. The integrity of the peripheral neurons and of the neuroepithelium persisted despite the progressive wors ening of the function of the muscles affected by the degenerative process; and (2) the findings of retinal fluorescein angiography. When histologic study is impossible, retinal angiography discloses the extent and severity of the abiotrophic or degenerative changes, unappreciated or misinterpreted by ophthalmoscopy. In our patient, the early fluorescence pres ent in the arterial phase and persisting be yond the venous phase without changing size indicated a defective pigment epithelium rather than a leakage. When the patient was examined ophthalmoscopically, even with red-free light, the less-extended visible * changes were fewer than with fluorescein angiography. The changes seemed to spread all over the fundus, diffuse beyond the ophthalmoscopic limits, giving the impression of a global process. This discrepancy is an angiographic
OCTOBER, 1975
peculiarity of the pigment epitheliopathies alone.81'32 When the choriocapillaris or Bruch's membrane are affected, a more pre cise regional topography, more irregular borders, and dense and localized plaques of hyperfluorescence characterize the fundus changes. It is more difficult in the case of pig ment epitheliopathy to establish whether the background mottling of the fundus is due to increased transparency of the altered pig ment epithelium or to impregnation of the pigment cells by the stain. Pigment epi thelium is not just a simple support for the photoreceptors or a filter for the light energy required by the photoreceptors. It is a layer of complex cells whose specific functions include transmission of nutrients from the choriocapillaris to other parts of the retina, storage of vitamin A and its conversion to forms suitable for the synthesis of rhodopsin, some mucoprotein synthesis, phagocitosis, and digestion of the rod-segment disks and of other substances from the neuroretina. 83-38 Failure of the pigment epithelium to func tion properly is responsible for some types of maculopathies, as well as changes in Bruch's membrane secondary to disease of the pigment epithelium that augments the progress of retinal degeneration.39 Fundus flavimaculatus and Best's or Stargardt*slBsease are caused by damage of the retinal pigment epithelium, probably due to a failure of the enzymatic system within the pigment cells.31-*0'" According to Klien and Krill, 81 fundus flavimaculatus, a retinal affection whose fluorescein angiographic features re semble those of our case, should be con sidered the consequence of a genetic disorder responsible for a primary defect in the pig ment epithelium. Rodrigues and associates'42 report of a case of defective pigment epi thelium alone in a boy with a trisomy-18 syndrome, adds interest to the observation of interrelationship between genetic dis orders and retinal changes confined to the pigment layer alone. These findings suggest that the atypical forms of retinal dystrophies associated with
VOL. 80, NO. 4
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA
ocular myopathy could be clinical expres sions of a unique, original genetic defect confined to the pigment epithelium layer. This view is supported by Gass's48 report of a 16-year-old girl with Kearns-Sayre syndrome who revealed definite but not ophthalmoscopically prominent alterations of the pigment layer, exactly as those that occurred in our patient. Therefore, there is no relationship between true retinitis pigmentosa and primary retinal pigment epitheliopathy in the course of ocular myopathy since histopathologic studies of retinitis pigmentosa indicate that the first step in the dystrophic process is always a primary de generation of the photoreceptors.44 Further anatomic and functional changes follow thereafter. The most likely explanation for damage to the pigment epithelium during the course of ocular myopathy is that the muscular dystrophy gene has pleiotropic effects or different degrees of penetrance. In addition to the effect on the muscle tissue, primary or secondary biochemical changes could dam age the development and functions of the retinal pigment epithelium. Depending on the severity and extent of the original dam age to the epithelial cells, retinal changes can follow the primary epitheliopathy and account for the atypical and irregular dis orders so far reported. Even though narrow ing of the vessels and pallor of the optic disk may occasionally be present, such func tional disturbances as hemeralopia, dischromatopsia, annular scotomas, or peripheral contraction of the visual fields, which always characterize the true tapetoretinal degenera tions, are practically absent in the retinal alterations associated with ocular myop athy.45 SUMMARY
The diagnosis of ocular myopathy associ ated with a primary retinal pigment epi theliopathy in. a 20-year-old man was based on the integrity of the retinal functions, despite progressive worsening of muscular activity in the systems affected by the dis
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ease, and on the results of retinal fluorescein angiography. Although the changes in the pigment epithelium were not prominent ophthalmoscopically, they were clearly visible angiographically. Atypical forms of retinal pigment dys trophy occurring during the course of ocular myopathy appear to be clinical expressions of a unique genetic defect confined to the pigment epithelial layer. We assume that the gene is capable of inducing a pleiotropic effect. REFERENCES
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