Br J Ophthalmol: first published as 10.1136/bjo.68.10.727 on 1 October 1984. Downloaded from

British Journal of Ophthalmology, 1984, 68, 727-731

Yellowish flecks in Leber's congenital amaurosis

E. CHEW,' A. DEUTMAN,2 A. PINCKERS,2 AND A. AAN DE KERK' From the 'Hospital for Sick Children, Toronto, Canada, and the 'Institute of Ophthalmology, University of Nijmegen, Nijmegen, The Netherlands

SUMMARY The fundus abnormalities of Leber's congenital amaurosis are extremely variable, from normal to salt-and-pepper changes to typical retinitis pigmentosa. A less commonly seen appearance is that of multiple, irregular shaped, yellowish white flecks deep in the midperipheral retina in a periarteriolar distribution. The nasal fundus as well as the posterior pole are spared. Such a case is presented along with a four-year follow-up together with the fluorescein angiographic findings. The flecks appear to be specific for this entity.

In 1896 Leber originally described a syndrome of been described, are presented. The diagnostic ERG congenital blindness with nystagmus, poor pupillary and the awareness of the polymorphism of the response, and funduscopic findings of tapetoretinal fundus appearances are emphasised. degeneration.' In 1954 Franceschetti and Dieterle2 emphasised the importance of a markedly abnormal Case report or extinct electroretinogram (ERG) in the diagnosis of the syndrome complex now known as Leber's The patient, a boy born in 1970 and enrolled in an congenital amaurosis. Other findings of this institute for the partially sighted, was referred to the autosomal recessive inherited disease include photo- University of Nijmegen Ophthalmology Depart- phobia, digito-ocular sign, and subsequent sunken ment because of unusual fundus lesions noted by his eyeballs. There may be associated ocular and school ophthalmologist in 1978. He was a product of systemic abnormalities such as keratoconus, kerato- a full-term pregnancy complicated by measles http://bjo.bmj.com/ globus, cataract, strabismus, mental retardation, during the seventh month of gestation. The peri- deafness, renal dysgenesis, and neurological deficits. natal history was uneventful. He was noted to have The modern nomenclature of Leber's congenital nystagmus and an inability to follow objects at 3 amaurosis has been challenged by some '; estiga- months of age. ERG and EOG performed at tors as to its representation of the views of the another institute at age of 6 months were reported as original author.' unrecordable and flat, respectively. He displayed

The fundus changes in this syndrome are ex- the digito-ocular sign. His milestone development on October 1, 2021 by guest. Protected copyright. tremely variable4 from normal' to salt-and-pepper was delayed with sitting up at 12 months and changes to typical retinitis pigmentosa," and walking at 19 months. No neurological deficits were occasionally the changes may resemble choroid- present. He is at present reported to have slight eraemia.7 Commonly the ophthalmoscopic picture learning disability. His parents, who are third may be quite polymorphic.7 Rarely the fundus cousins, had normal eyes on examination. His only abnormalities may include macular colobomas' and sib was also normal. optic disc oedema.49 A less commonly known fundus On examination in 1978 his visual acuity was poor presentation of Leber's congenital amaurosis is the light perception bilaterally. Searching nystagmus appearance of multiple, irregular shaped, yellowish was present. He displayed enophthalmos, while slit- white flecks deep in the peripheral retina. The lamp examination revealed entirely normal anterior purpose of this paper is to emphasise this variant of segment. The pupils were 5 mm in diameter with a the fundus appearance in this entity. Fluorescein very slight, sluggish reaction to light. Ophthal- angiography findings, which have not previously moscopy revealed optic discs of normal size and colour, with no evidence of disc oedema. Foveal Corrcspondencc to E. Chew, MD, Hospital for Sick Childrcn, Departmcnt of Ophthalmology, 555 Univcrsity Avenue, Toronto, reflexes were normal and the arterioles were Ontario M5G-lX8, Canada. attenuated. Yellowish white flecks, with well 727 Br J Ophthalmol: first published as 10.1136/bjo.68.10.727 on 1 October 1984. Downloaded from

728 E. Chew, A. Deutman, A. Pinckers, and A. Aan de Kerk

...... http://bjo.bmj.com/ Fig. 1 Yellowish flecks in the mid periphery in a periarteriolar distribution seen on initial examination in 1978.

defined borders but becoming more confluent pepper retinal changes. There was also leakage from peripherally were found in a periarteriolar distribu- the peripheral vessels over the areas of the flecks tion in the midperiphery (Fig. 1). The nasal fundus (Fig. 5). as well as the posterior pole and the far periphery fundus adjacent to the ora serrata were spared. In Discussion on October 1, 2021 by guest. Protected copyright. this spared peripheral zone salt and pepper changes were seen. These lesions were remarkably sym- In addition to these unusual yellowish white flecks in metrical bilaterally. the midperiphery of the fundus our patient pre- In October 1982 a follow-up examination revealed sented with nystagmus, digito-oculo sign, con- essentially unchanged ocular status. These lesions, genital blindness, and an unrecordable ERG, however, appeared more greyish in the peripheral confirming the diagnosis of Leber's congenital aspects and the far peripheral pigmentation was amaurosis. This striking fundus appearance is a rare more evident. The lesions appeared to have picture seen in the syndrome complex of Leber's diminished in size in the peripheral margin (Figs. congenital amaurosis. It was first described by 2B, 3B) as compared with comparable areas seen in Franceschetti and Forni "' as 'marbilized fundus' with 1978 (Figs. 2A, 3A). A fluorescein angiogram its unusual mosaic pattern and periarteriolar dis- showed hypofluorescence corresponding to the tribution of well-demarcated yellowish lesions yellowish white flecks (Fig. 4). No staining or located deep to the retinal vessels. Other authors leakage of fluorescein resulted from these lesions, reported on this unusual fundus variant of Leber's while hypofluorescence and window defects corres- congenital amaurosis.1'-'6 ponded with hyper/hypopigmentation of the salt and The age of onset of these fundus lesions was Br J Ophthalmol: first published as 10.1136/bjo.68.10.727 on 1 October 1984. Downloaded from

Yellowish flecks in Leber's congenital amaurosis 729

Fig. 2A Fig. 3A http://bjo.bmj.com/ on October 1, 2021 by guest. Protected copyright.

Fig. 2B Fig. 3B Figs. 2A and 3A The extensive distribution oftheseflecks are reduced in size and colourafterfouryears offollow-up (Figs. 2B and3B). unknown in our patient. Two patients described in graphs were not shown but had a clinical description the literature'2"' were initially reported to have a which resembled the lesions found in our patient; normal appearing fundus and later found to have the other patient had a different fundus affection of these lesions at the age of 21 months and 4 years multiple white spots scattered throughout the entire when follow-up examinations were performed. It is fundus except for the macular area. Pathological unclear what these lesions, which appear to be deep study of the latter case revealed changes of the to the retina, represent histologically. Mizuno et al. 14 entire photoreceptor layer, with the outer segments reported on two patients, one whose fundus photo- of the cones either shortened and disorganised or Br J Ophthalmol: first published as 10.1136/bjo.68.10.727 on 1 October 1984. Downloaded from

730 E. Chew, A. Deutman, A. Pinckers, and A. Aan de Kerk

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.:X.c.Ut'.. ...', \.e. r...: .... :c.'re .: X ... '. :..,, .... :..: ::: Fig. 4 Blockage offuorescence by the yelZowish white Fig. 5 Leakage offluorescein from the peripheral vessels flecks. '..,:..::: .-.....: ..' ..:::...... :.S;', : .;Rs1^,.,,U'.. : e ;.., u 'o.:i9:fE .5.:S.,.,,;,.. ..-"';0 -g.O over the areas oftheflecks. completely absent. Lack of cellular differentiation Leakage of fluorescein from the peripheral vessels was observed .. .. outer to fromyidknthe ebi#: nuclear ...... !ip the * ' !'.,,> ... :.. ,..,ci' layer in Leber's congenital amaurosis has not been pigment epithelial layer. The most striking patholo- described before. It is not a surprising finding, as an gical feature was the presence of large deposits association between retinal dystrophies and retinal between the retina and the retinal pigment epithelial vascular disease had been noted previously."'2' An layer. They corresponded to the white spots and appearance like Coats's disease has been associated consisted of fragments of inner segments, apical with retinitis pigmentosa.' Witschel22 has suggested processes of pigment epithelial cells, and macro- that a toxic substance may be released by this http://bjo.bmj.com/ phages. It is difficult to conclude that the same degenerative process of the retina in retinitis pig- pathological lesions occurred in our patient, as mentosa, thus causing vascular leakage and a Mizuno et al.'4 described a different clinical picture Coats's-disease-like picture. in the fundus. The clinical presentation of such flecks may Previous reports of Leber's congenital amaurosis confuse the clinician.'2 They appear to be more or showed the pathology to be as variable as the clinical less specific for this disease and may be diagnostic of

appearance of the fundus. Complete disorganisation a special subgroup of Leber's congenital amaurosis. on October 1, 2021 by guest. Protected copyright. of all retinal layers has been reported,'7 as have Other flecked retina patterns such as fundus flavi- normal inner retinal layers, with disorganisation of maculatus, retinitis punctata albescens, fundus albi- the photoreceptor cell layer and external granular punctatus, drusen,2 crystalline retinopathy,24 layer. '" '9 Mizuno et al. '4 postulated that the patholo- vitamin A deficiency,25 and Kandori's flecked retina 23 gical lesion represents a primary dystrophic are generally easily distinguished from Leber's disorder, as lack of cellular differentiation was congenital amaurosis. A flecked pattern in a prominent. A secondary degenerative process palisade distribution appears quite similar; however, resulted in cellular debris and macrophages in the the location is confined to the posterior pole.26 The subretinal layer. This may be the case, as the larger, yellowish, fleck-like patterns such as are degenerative process is seen as spots or flecks found in multiple vitelliform disease are clearly developing after birth. different.27 Fluorescein angiography of these yellowish white lesions showed hypofluorescence without leakage or References staining. Mizuno et al."' described a patient with a similar clinical appearance in the fundus, but I Lcber T. Uber Retinitis pigmcntosa und angeborcnc Amaurosc. Arch Ophthalmot 1869; 15: 1-25. fluorescein angiography showed fluorescence during 2 Franccschetti A, Dictcric P. L'importancc diagnostiquc dc the choroidal phase without leakage or staining. l'ERG dans Ics d6g6ndrcsccnccs tap6to- rctinicnncs avec Br J Ophthalmol: first published as 10.1136/bjo.68.10.727 on 1 October 1984. Downloaded from

Yellowish flecks in Leber's congenital amaurosis 731

r6tr6cissement du champ visuel et h6m6ralopie. Confin Neurol spective study of 33 cases and a histopathological study of 1 1954; 14: 184-6. case. Arch Ophihalmol 1978; 96: 818-21. 3 Pinckers AJL. Leer's congenital amaurosis as conceived by 16 Dekaban A, Carr R. Congenital amaurosis of retinal origin. Lcher. Ophihalmologica 1979; 179: 48-51. Arch Neurol 1966; 44: 294-301. 4 Schappert-Kimmijser J, Henkes HE, van den Bosch J. 17 Sorsby A, William CF. Retinal aplasia as a clinical entity. Br Amaurosis congenita (Leber). Arch Ophthalmol 1959; 61: MedJ 1960; i: 293-7. 211-8. 18 Franqois J, Hanssens M. Etude histo-pathologique de deux cas 5 Winkelman JE, Horstein GPM. Congenital blindness in the de ddg6nerdscence tapeto-retinienne congdnitale de Leber. Ann presence of a normal fundus. Ophthalmologica 1959; 137: Oculist (Paris) 1969; 202: 127-55. 423-5. 19 Kroll AJ, Kuwabara T. Electron microscopy of a retinal 6 Francois J. Leber's congenital tapctoretinal degeneration. Int abiotrophy. Arch Ophthalmol 1964; 71: 683-90. Ophthalmol Clin 1968; 8: 931-47. 20 Grizzard WS, Deutman AF, Pinckers AJLG. Retinal 7 Franceschetti A, Francois J, Babel J. Chorioretinal heredo- dystrophies associated with peripheral retinal vasculopathy. Br degenerations. Springfield: Thomas, 1974. J Ophthalmol 1978; 62: 188-94. 8 Margolis S, Scher, BM, Carr, RE. Macular colobomas in 21 Notting JGA, Deutman AF. Leakage from retinal capillaries in Leber's congenital amaurosis. Am J Ophthalmol 1977; 83: hereditary dystrophies. In: DeLaey, JJ, ed. International 27-31. Symposium on Fluorescein Angiography, Ghent, 1976. Doc 9 Flynn JT, Cullen RF. Disc oedema in congenital amaurosis of Ophthalmol Proc 1976; 9: 439-47. Leber. Br J Ophthalmol 1975; 59: 497-5t)2. 22 Witschel H. Retinopathia pigmentosa und Morbus Coats'. Klin 1t) Franceschetti A, Forni S. Degenerescence tap6tor6tinienne Monatsbl Augenheilkd 1974; 164: 405-1 1. (type Leber) avec aspect marbre du fond de l'oeil periphcrique. 23 Krill AE, Klein BA. Flecked retina syndrome. Arch Ophthal- Ophthalmologica 1958; 135: 610-8. mol 1965; 74: 496-508. 11 Krill AE. Congenital anomalies of the eye. St Louis: Mosby, 24 Grizzard WS, Deutman AF, Nijhuis F, Aan de Kerk A. 1968. Crystalline retinopathy. Am J Ophthalmol 1978; 86: 81-8. 12 Edwards WC, Price WD, Macdonald R. Congenital amaurosis 25 Bors F, Fells P. Reversal of the complications of self-induced of retinal origin (Leber). Am J Ophthalmol 1971; 72: 724-8. vitamin A deficiency. Br J Oplhthalmol 1971; 55: 210-4. 13 Hirosc T, Wand 0. Amaurosis congenita (Leber). Ann 26 Krogh E, Reersted, K. Flecked retina syndrome with palisade Ophthalmol 1975; 7: 59-63. appearance of the periphery. Int Ophthalmol 1980; 2: 77-8(0. 14 Mizuno K, Takei Y, Sears ML, Peterson WS, Carr RE, Jampol 27 Deutman AF. Retinal dystrophies with unusually large LM. Leber's congcnital amaurosis. Am J Ophthalmol 1977; 83: yellowish flecks. In: Shimizu K, ed. International Congress No. 32-42. 450, Kyoto, 1978. Concilium Ophthalmologicum XXIII:758. 15 Nobic KG, Carr RE. Lebcr's congenital amaurosis. A retro- Amsterdam-Oxford: Excerpta Medica, 1978. http://bjo.bmj.com/ on October 1, 2021 by guest. Protected copyright.