A C TA 0 P H T H A L M 0 L O G I C A
70 (1992) 693-697
CASE REPORT
Birdshot retinochoroidopathy in monozygotic twins Marianne Fich and Thomas Rosenberg The National Eye Clinic for the Visually Impaired, Copenhagen,Denmark
Abstract. Birdshot retinochoroidopathy is a rare ocular disorder which was named and delineated as a separate clinical entity by Ryan & Maumenee in 1980. We diagnosed birdshot retinochoroidopathy in a monozygotic pair of twins, who were affected with a time interval of 12 years, respectively. These are the first with birdshot retinochoroidopathy to be reported from the Nordic countries and the first report on this disorder in monozygotic twins. Due to night-blindness, visual field defects and a severely affected electroretinogram one of our cases initially was diagnosed as a choroidoretinaldystrophy. Birdshot retinochoroidopathy should be kept in mind as a differential diagnosis in retinitis pigmentosa-like disorders with widespread choroidal involvement. Our cases substantiated the evidence of a strong correlation with the presence of HLA-A29 antigen. Key words: birdshot retinochoroidopathy - monozygotic twins - HLA-A29 - choroidoretinal dystrophy.
In 1980 birdshot retinochoroidopathy (BSRC) was for the fist time described as a specific intraocular inflammation by Ryan & Maumenee (1980). The name birdshot was chosen because of the multiple small white lesions resembling birdshot scatter from a shotgun. Birdshot choroidopathy is characterized by multiple white spots either confluent or radiating from the optic nerve in the retinal pigment epithelium and choroid. The disorder resembles other types of posterior uveitis in not being painful, rarely affecting the anterior part of the eye, having inflammatory reactions in the vitreous and retinal vascular leakage leading to cystoid mauclar oedema and papilloedema. Retinal function studies (Priem et al. 1988; Hirose et al. 1991) have shown abnormalities in dark adaptation, colour vision, electrooculography, electroretinography,visual field and visual-evoked
cortical potentials suggested to be related to changes of the inner retina. Other authors have described subretinal new vessels (Brucker et al. 1985; Soubrane et al. 1990) and optic atrophy (De Laey & Priem 1981). BSRC is a rare disease.In a European study from 14 eye clinics, 102 cases were collected during the period 1980-1986 (Priem & Oosterhuis 1988). In a material of 600 patients from a specialized uveitis clinic (Henderly et al. 1987),7 cases (1.2%)of BSRC were found. More women than men seem to be affected, and all published cases have been Caucasian (Priem & Oosterhuis 1988). BSRC is thought to be an initially slowly progressive but usually self-limited disease (Gass 1981). Nevertheless, some patients are left with severe visual impairment (Hirose et al. 1991). Treatment with steroids has proved less efficient, but good results were reported from treatments with cyclosporine A (Le Hoang et al. 1988; Hemady et al. 1991). In 1982 Nussenblatt and associatesreported that birdshot choroidopathy was strongly associated with the antigen HIAA29, as 80%of their patients were HLA-A29 positive. Priem et al. (1988) found an even stronger correlation of 95.9%representing a relative risk of approximately 200.
Case Reports Twin A In 1974 a Caucasianmale aged 49 years experienced a sudden onset of night-blindness followed by a more insidous loss of central vision. He did not receive ophthalmic care until 1976 when an ophthalmic examination elsewhere demonstrated a visual acuity of the right eye (RE): < 6/12 -0.50 sph, left eye (LE): < 6/12 -1.00 sph. Vitreous 693
a
b
Fig.I. Fundus pictures from twin brothers with sequelae from birdshot retinochoroidopathy. a) Twin A, right eye: Fundus photography from 1991,17 years after the debut of BSRC. Besides the characteristic spotted pattern, narrowing of the retinal arterioles, optic atrophy and peripheral pigment aggregations are noted. b) Same: Fluorescein angiography.Midvenous phase, 1min after injection. The atrophic spots are seen as filling defects exposing some larger choroidal vessels. The surrounding areas 694
demonstrate the filling of the choroidocapillary layer. c) Same: Fluorescein angiography.Late phase, 15 m h after injection. The dark vessels of the retinal and choroidal vascular system are contrasted against the scleral hyperfluorescence. d) Twin B. Left eye: Fundus photography 1% years after the debut of BSRC. A slight vitreous haze was still present. The optic nerve head and the retinal vessels show retinitis pipentosa-like alterations. Birdshot pattern and flame shaped pigment epithelium atrophy are present.
695
floaters, vitreous flare, irregularity of the retinal veins, and attenuated retinal arterioles were described. The anterior segments of both eyes and the optic disks were unremarkable. The visual fields initially were normal. Treatment with oral steroids was initiated with some temporary improvement in the condition, but recurrent inflammatory episodes occurred and the treatment was discontinued after 6 months. In 1978 a reexamination took place at our clinic due to diagnostic uncertainty and a request from the patient for genetic councelling. Visual acuity RE: 6/18 L E 619 + 0.50 sph, LE: 6/12 +0.50 sph. Anterior segments were normal, but the vitreous demonstrated inflammatory haze. The optic nerve heads were pale and marked attenuated retinal arterioles were noticed. Outside the vascular arcades scattered cream-yellow round lesions and flame shaped areas of atrophy of the choroidocapillary layer and the pigmentepithelium were seen (Fig. Id). The visual fields measured with Goldmann perimetry demonstrated small residual central islands, complete ring scotomas and preserved temporal islands on both eyes. Dark adaptation was impaired with a 4 log elevation of final threshold. Electroretinography gave no reactions to high intensity flashes under d&k adapted condition, and the photopic responses were severely reduced with delayed implicit times. In March 1991 the visual field defects showed slight progression. Zygosity examination
No information was available with regard to the placental conditions of the twins. The brothers were very alike and even their children had experienced difficulty in descerning who was who. A zygosity test was carried out by the University Institute of Forensic Genetics in Copenhagen and demonstrated complete concordance with respect to the following blood, serum, enzyme and HLAtypes: OMNS-s+ C-Cw-D+E+C+e+ K Le(a-b+) Hp 2H-2H Gc 2-1F Tf 1-1 Gm(a-x-b+f+) Inv- PGM 2f-1s S P A GPT 2-2 EsD 1- 1 GLO 1- 1 HLA-Al, A29; B41, B45.
Discussion The complete concordance in typing makes it reasonable to assume that the two brothers are monozygotic twins. Although the clinical examinations took place at different and relatively late stages of BSRC both patients fulfil the diagnostic criteria established by Priem & Oosterhuis (1988). The following criteria were present: Characteristic fundus pattern combined with vitritis, arteriolar narrowing and irregularity of veins, optic atrophy, night-blindness, and severely affected ERG. The fact that the patients carried the relatively uncommon HLA-A29 antigen, which occurs with a gene frequency of 2.9% among Caucasians (Baur et al.
1984), represents a further, but indirect evidence for a diagnosis of BSRC. The fundus of twin A who developed BSCR about 1978, had late stage lesions with very sharp margins and hyperpigmentated areas in between, whereas twin B, who developed BCSR in 1990, had more ill-marked lesions and no hyperpigmentation. Both had atrophic optic nerve heads, attenuated vessels and vitreous flare together with only a residual central vision and marked night-blindness. The clinical appearance of BSRC seems to indicate an immunemediated pathogenesis (Gass 1981). This assumption was supported with the finding of a unique association with the HLA-system and in vitro responsiveness to retinal S-antigen (Nussenblatt et al. 1982). The therapeutic effect of cyclosporine A gives further support to the immunological nature of BSRC. Nevertheless, the aetiology in the sense of a specific trigger mechanisms is obscure. A number of systemic disease conditions have been associated with the evolution of BSRC, but only vascular disorders seem to occur with a high prevalence (Priem & Oosterhuis 1988). On the other hand, this is not surprising considering the age predilection of BSRC. Our patients lived in different part of the country and had little physical contact with each other. Neither the medical history nor the habits of the twin borthers gave a hint to any common triggering mechanism for the immune reaction, no more than any explanation for the 12-year interval between the debuts. Both brothers were moderately hearing impaired due to middle ear infections in childhood. In addition, case B suffered from a mild hypertension and walking difficulties of claudicatio intermittens type. Despite the characteristic clinical pattern, the similarity between BSRC and a choroidoretinal dystrophy was striking. In fact, our cases f u m e d the inclusion criteria of ‘The Danish Retinitis Pigmentosa Register’ (Haim et al. 1992). Possibly a reevaluation of atypical cases of retinitis pigmentosa diagnosed some years ago might reveal cases of undiagnosed BSRC.
In:Albert E D, Baur M P & Mayr W R (eds).Histocompatibility Testing 1984. Springer Verlag, Berlin, Heidelberg, New York, Tokyo. Brucker A J, Deglin E A, Bene C & Hoffman ME (1985): Subretinal choroidal neovascularization in birdshot retinochoroidopathy. Am J Ophthalmol99: 40-44. De Laye J J & Priem H (1981): Birdshot chorioretinopathy: an etiological problem. Bull SOCBelge Ophthalmol 193: 131-136. GassJ D M (1981):Vitiliginous chorioretinitis. Arch Ophthalmol 99: 1778-1787. Haim M, Holm N & Rosenberg T (1992): Population survey of retinitis pigmentosa and allied disorders in Denmark. Completeness of registration and quality of data. Acta Ophthalmol (Copenh) 70: 165-177. Hemady R, Tauber J & Foster C S (1991): Immunosuppressive drugs in immune and inflammatory ocular disease. SUN Ophthalmol 35: 369-385. Henderly D E, Genstler A J, Smith R E & Rao N A (1987): Changing patterns of uveitis. Am J Ophthalmol 103: 131-136. Hirose T, Katsumi 0, Pruett R C, Sakaue H & Mehta M (1991): Retinal function in birdshot retinochoroidopathy. Acta Ophthalmol (Copenh) 69: 327-337. Le Hoang P, Girard B, Le Minh H, De Kozak Y, Thillaye B, Faure J P & Rousselie F (1988): Cyclosporine in the treatment of birdshot retinochoroidopathy. Transplant Proc 20 (Suppl4): 128-130. Nussenblatt R B, Mittal K K, Ryan S, Green W R & Maumenee A E (1982): Birdshot retinochoroidopathy associated with HLA-A29 antigen and immune responsiveness to retinal S-antigen. Am J Ophthalmol 94: 147-158. Priem H A, De Rouck A, De Laey J J & Bird A C (1988): Electrophysiologic studies in birdshot chorioretinopathy. Am J Ophthalmol 106: 430-436. Priem H A, Kijlstra A, Noens L, Baarsma G S, De LaeyJ J & Oosterhuis J A (1988): HLA typing in birdshot chorioretinopathy. Am J Ophthalmol 105: 182-185. Priem H A & Oosterhuis J A (1988): Birdshot chorioretinopathy: clinical characteristics and evolution. Br J Ophthalmol72: 646-659. Ryan SJ & Maumenee A E (1980):Birdshot retinochoroidopathy. Am J Ophthalmol89: 31-45. Soubrane G, Bokobza R & Coscas G (1990): Late developing lesions in birdshot retinochoroidopathy. Am J Ophthalmol 109: 204-210.
Received on December 9th, 1991. Author’s address:
References Baur M P, Neugebauer M, Deppe H, Sigmund H, Luton T, Mayr W R & Albert E D (1984):Population analysis on the basis of deduced haplotypes from random families.
Marianne Fich and Thomas Rosenberg, National Eye Clinic for the Visually Impaired, 1 Rymarksvej, DK-2900 Hellerup, Denmark.
697
70 (1992) 693-697
CASE REPORT
Birdshot retinochoroidopathy in monozygotic twins Marianne Fich and Thomas Rosenberg The National Eye Clinic for the Visually Impaired, Copenhagen,Denmark
Abstract. Birdshot retinochoroidopathy is a rare ocular disorder which was named and delineated as a separate clinical entity by Ryan & Maumenee in 1980. We diagnosed birdshot retinochoroidopathy in a monozygotic pair of twins, who were affected with a time interval of 12 years, respectively. These are the first with birdshot retinochoroidopathy to be reported from the Nordic countries and the first report on this disorder in monozygotic twins. Due to night-blindness, visual field defects and a severely affected electroretinogram one of our cases initially was diagnosed as a choroidoretinaldystrophy. Birdshot retinochoroidopathy should be kept in mind as a differential diagnosis in retinitis pigmentosa-like disorders with widespread choroidal involvement. Our cases substantiated the evidence of a strong correlation with the presence of HLA-A29 antigen. Key words: birdshot retinochoroidopathy - monozygotic twins - HLA-A29 - choroidoretinal dystrophy.
In 1980 birdshot retinochoroidopathy (BSRC) was for the fist time described as a specific intraocular inflammation by Ryan & Maumenee (1980). The name birdshot was chosen because of the multiple small white lesions resembling birdshot scatter from a shotgun. Birdshot choroidopathy is characterized by multiple white spots either confluent or radiating from the optic nerve in the retinal pigment epithelium and choroid. The disorder resembles other types of posterior uveitis in not being painful, rarely affecting the anterior part of the eye, having inflammatory reactions in the vitreous and retinal vascular leakage leading to cystoid mauclar oedema and papilloedema. Retinal function studies (Priem et al. 1988; Hirose et al. 1991) have shown abnormalities in dark adaptation, colour vision, electrooculography, electroretinography,visual field and visual-evoked
cortical potentials suggested to be related to changes of the inner retina. Other authors have described subretinal new vessels (Brucker et al. 1985; Soubrane et al. 1990) and optic atrophy (De Laey & Priem 1981). BSRC is a rare disease.In a European study from 14 eye clinics, 102 cases were collected during the period 1980-1986 (Priem & Oosterhuis 1988). In a material of 600 patients from a specialized uveitis clinic (Henderly et al. 1987),7 cases (1.2%)of BSRC were found. More women than men seem to be affected, and all published cases have been Caucasian (Priem & Oosterhuis 1988). BSRC is thought to be an initially slowly progressive but usually self-limited disease (Gass 1981). Nevertheless, some patients are left with severe visual impairment (Hirose et al. 1991). Treatment with steroids has proved less efficient, but good results were reported from treatments with cyclosporine A (Le Hoang et al. 1988; Hemady et al. 1991). In 1982 Nussenblatt and associatesreported that birdshot choroidopathy was strongly associated with the antigen HIAA29, as 80%of their patients were HLA-A29 positive. Priem et al. (1988) found an even stronger correlation of 95.9%representing a relative risk of approximately 200.
Case Reports Twin A In 1974 a Caucasianmale aged 49 years experienced a sudden onset of night-blindness followed by a more insidous loss of central vision. He did not receive ophthalmic care until 1976 when an ophthalmic examination elsewhere demonstrated a visual acuity of the right eye (RE): < 6/12 -0.50 sph, left eye (LE): < 6/12 -1.00 sph. Vitreous 693
a
b
Fig.I. Fundus pictures from twin brothers with sequelae from birdshot retinochoroidopathy. a) Twin A, right eye: Fundus photography from 1991,17 years after the debut of BSRC. Besides the characteristic spotted pattern, narrowing of the retinal arterioles, optic atrophy and peripheral pigment aggregations are noted. b) Same: Fluorescein angiography.Midvenous phase, 1min after injection. The atrophic spots are seen as filling defects exposing some larger choroidal vessels. The surrounding areas 694
demonstrate the filling of the choroidocapillary layer. c) Same: Fluorescein angiography.Late phase, 15 m h after injection. The dark vessels of the retinal and choroidal vascular system are contrasted against the scleral hyperfluorescence. d) Twin B. Left eye: Fundus photography 1% years after the debut of BSRC. A slight vitreous haze was still present. The optic nerve head and the retinal vessels show retinitis pipentosa-like alterations. Birdshot pattern and flame shaped pigment epithelium atrophy are present.
695
floaters, vitreous flare, irregularity of the retinal veins, and attenuated retinal arterioles were described. The anterior segments of both eyes and the optic disks were unremarkable. The visual fields initially were normal. Treatment with oral steroids was initiated with some temporary improvement in the condition, but recurrent inflammatory episodes occurred and the treatment was discontinued after 6 months. In 1978 a reexamination took place at our clinic due to diagnostic uncertainty and a request from the patient for genetic councelling. Visual acuity RE: 6/18 L E 619 + 0.50 sph, LE: 6/12 +0.50 sph. Anterior segments were normal, but the vitreous demonstrated inflammatory haze. The optic nerve heads were pale and marked attenuated retinal arterioles were noticed. Outside the vascular arcades scattered cream-yellow round lesions and flame shaped areas of atrophy of the choroidocapillary layer and the pigmentepithelium were seen (Fig. Id). The visual fields measured with Goldmann perimetry demonstrated small residual central islands, complete ring scotomas and preserved temporal islands on both eyes. Dark adaptation was impaired with a 4 log elevation of final threshold. Electroretinography gave no reactions to high intensity flashes under d&k adapted condition, and the photopic responses were severely reduced with delayed implicit times. In March 1991 the visual field defects showed slight progression. Zygosity examination
No information was available with regard to the placental conditions of the twins. The brothers were very alike and even their children had experienced difficulty in descerning who was who. A zygosity test was carried out by the University Institute of Forensic Genetics in Copenhagen and demonstrated complete concordance with respect to the following blood, serum, enzyme and HLAtypes: OMNS-s+ C-Cw-D+E+C+e+ K Le(a-b+) Hp 2H-2H Gc 2-1F Tf 1-1 Gm(a-x-b+f+) Inv- PGM 2f-1s S P A GPT 2-2 EsD 1- 1 GLO 1- 1 HLA-Al, A29; B41, B45.
Discussion The complete concordance in typing makes it reasonable to assume that the two brothers are monozygotic twins. Although the clinical examinations took place at different and relatively late stages of BSRC both patients fulfil the diagnostic criteria established by Priem & Oosterhuis (1988). The following criteria were present: Characteristic fundus pattern combined with vitritis, arteriolar narrowing and irregularity of veins, optic atrophy, night-blindness, and severely affected ERG. The fact that the patients carried the relatively uncommon HLA-A29 antigen, which occurs with a gene frequency of 2.9% among Caucasians (Baur et al.
1984), represents a further, but indirect evidence for a diagnosis of BSRC. The fundus of twin A who developed BSCR about 1978, had late stage lesions with very sharp margins and hyperpigmentated areas in between, whereas twin B, who developed BCSR in 1990, had more ill-marked lesions and no hyperpigmentation. Both had atrophic optic nerve heads, attenuated vessels and vitreous flare together with only a residual central vision and marked night-blindness. The clinical appearance of BSRC seems to indicate an immunemediated pathogenesis (Gass 1981). This assumption was supported with the finding of a unique association with the HLA-system and in vitro responsiveness to retinal S-antigen (Nussenblatt et al. 1982). The therapeutic effect of cyclosporine A gives further support to the immunological nature of BSRC. Nevertheless, the aetiology in the sense of a specific trigger mechanisms is obscure. A number of systemic disease conditions have been associated with the evolution of BSRC, but only vascular disorders seem to occur with a high prevalence (Priem & Oosterhuis 1988). On the other hand, this is not surprising considering the age predilection of BSRC. Our patients lived in different part of the country and had little physical contact with each other. Neither the medical history nor the habits of the twin borthers gave a hint to any common triggering mechanism for the immune reaction, no more than any explanation for the 12-year interval between the debuts. Both brothers were moderately hearing impaired due to middle ear infections in childhood. In addition, case B suffered from a mild hypertension and walking difficulties of claudicatio intermittens type. Despite the characteristic clinical pattern, the similarity between BSRC and a choroidoretinal dystrophy was striking. In fact, our cases f u m e d the inclusion criteria of ‘The Danish Retinitis Pigmentosa Register’ (Haim et al. 1992). Possibly a reevaluation of atypical cases of retinitis pigmentosa diagnosed some years ago might reveal cases of undiagnosed BSRC.
In:Albert E D, Baur M P & Mayr W R (eds).Histocompatibility Testing 1984. Springer Verlag, Berlin, Heidelberg, New York, Tokyo. Brucker A J, Deglin E A, Bene C & Hoffman ME (1985): Subretinal choroidal neovascularization in birdshot retinochoroidopathy. Am J Ophthalmol99: 40-44. De Laye J J & Priem H (1981): Birdshot chorioretinopathy: an etiological problem. Bull SOCBelge Ophthalmol 193: 131-136. GassJ D M (1981):Vitiliginous chorioretinitis. Arch Ophthalmol 99: 1778-1787. Haim M, Holm N & Rosenberg T (1992): Population survey of retinitis pigmentosa and allied disorders in Denmark. Completeness of registration and quality of data. Acta Ophthalmol (Copenh) 70: 165-177. Hemady R, Tauber J & Foster C S (1991): Immunosuppressive drugs in immune and inflammatory ocular disease. SUN Ophthalmol 35: 369-385. Henderly D E, Genstler A J, Smith R E & Rao N A (1987): Changing patterns of uveitis. Am J Ophthalmol 103: 131-136. Hirose T, Katsumi 0, Pruett R C, Sakaue H & Mehta M (1991): Retinal function in birdshot retinochoroidopathy. Acta Ophthalmol (Copenh) 69: 327-337. Le Hoang P, Girard B, Le Minh H, De Kozak Y, Thillaye B, Faure J P & Rousselie F (1988): Cyclosporine in the treatment of birdshot retinochoroidopathy. Transplant Proc 20 (Suppl4): 128-130. Nussenblatt R B, Mittal K K, Ryan S, Green W R & Maumenee A E (1982): Birdshot retinochoroidopathy associated with HLA-A29 antigen and immune responsiveness to retinal S-antigen. Am J Ophthalmol 94: 147-158. Priem H A, De Rouck A, De Laey J J & Bird A C (1988): Electrophysiologic studies in birdshot chorioretinopathy. Am J Ophthalmol 106: 430-436. Priem H A, Kijlstra A, Noens L, Baarsma G S, De LaeyJ J & Oosterhuis J A (1988): HLA typing in birdshot chorioretinopathy. Am J Ophthalmol 105: 182-185. Priem H A & Oosterhuis J A (1988): Birdshot chorioretinopathy: clinical characteristics and evolution. Br J Ophthalmol72: 646-659. Ryan SJ & Maumenee A E (1980):Birdshot retinochoroidopathy. Am J Ophthalmol89: 31-45. Soubrane G, Bokobza R & Coscas G (1990): Late developing lesions in birdshot retinochoroidopathy. Am J Ophthalmol 109: 204-210.
Received on December 9th, 1991. Author’s address:
References Baur M P, Neugebauer M, Deppe H, Sigmund H, Luton T, Mayr W R & Albert E D (1984):Population analysis on the basis of deduced haplotypes from random families.
Marianne Fich and Thomas Rosenberg, National Eye Clinic for the Visually Impaired, 1 Rymarksvej, DK-2900 Hellerup, Denmark.
697
