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1 Save Sight Institute, University of Sydney, Department of Ophthalmology, Sydney Eye Hospital, 8 Macquarie Street, Sydney 2000, Australia
2 Department of Ophthalmology, UC Davis Health System, University of California, Sacramento, CA 95817, USA
3 Save Sight Institute, University of Sydney, Department of Ophthalmology, Sydney Eye Hospital, 8, Macquarie Street, Sydney 2000, Australia
Correspondence to:
Sapna Sharan
Save Sight Institute, University of Sydney, Department of Ophthalmology, Sydney Eye Hospital, 8 Macquarie Street, Sydney 2000, Australia; sapnasd@yahoo.co.uk
Accepted for publication 1 January 2005
Keywords: BCG; autoimmune retinopathy; bladder carcinoma
Intravesical BCG is used as adjunctive immunotherapy for superficial carcinomas of the urinary bladder. Endophthalmitis and uveitis are the reported ocular complications.1–3 We report an unusual case of autoimmune retinopathy in a 58 year old man treated with intravesical BCG. The clinical features resembled CAR (cancer associated retinopathy) but there was no serum reaction to the CAR autoantigen.1 We believe that this is the first reported case of autoimmune retinopathy caused by BCG treatment.
Case report
A 58 year old white man was referred with reduced vision and photophobia for 4 months following a 6 week (one instillation per week) course of intravesical BCG immunotherapy for recurrent transitional cell bladder carcinoma. On examination, after 4 months of complaints, the visual acuity was 6/24 in each eye and N18 for near. Anterior segment evaluation revealed bilateral early nuclear cataracts. The anterior chamber and vitreous were quiet. The fundus examination showed mildly attenuated arterioles (RE>LE) with a mild pigmentary disturbance in the mid-periphery. Intraocular pressure was normal. Colour vision showed a protan-deutan axis in both eyes. There was no family history of colour blindness. Full field electroretinogram (ERG) amplitudes were subnormal for photopic and scotopic conditions in both eyes. Latency was normal. An electro-oculogram (EOG) was borderline normal in both eyes. Automated perimetry revealed bilaterally enlarged blind spots. Fundus fluorescein angiography showed narrowed arterioles. The choroid was normal. Serum analysis revealed no reaction to 23 kD CAR autoantigen.1 However, an unusual reaction which may represent a form of autoimmune degeneration was reported by the laboratory.
The photophobia increased over the next 2 months. A repeat full field ERG revealed that photopic responses were indistinguishable from noise in the right eye and just detectable in the left eye. On examination, visual acuity in each eye was 6/24. Oral prednisolone 20 mg daily was commenced. After a year it was decided to stop it as there was no improvement in vision. On his last follow up visit, the visual acuity was counting fingers in each eye and N36 at 10 cm. This had remained stable for 3 years. The photophobia was stable owing to dense cataracts and was well controlled with dark glasses. The fundus remained unchanged. The primary bladder carcinoma was unchanged and no secondaries were found.
Comment
BCG has been used for the treatment of bladder cancers for many years. Ocular toxicity caused by BCG resulting in granulomatous uveitis with vitiligo has been reported.1 The first case of endogenous endophthalmitis after use of BCG for metastatic bladder carcinoma was reported in 1988. The patient developed bilateral infiltrative retinitis and vitritis. Vitrectomy revealed Mycobacterium bovis.2
CAR is associated with melanomas, cancers of lung, cervix, colon, bladder, prostate, and breast. Progressive visual loss, night blindness with ring scotoma, and markedly abnormal ERG findings were described. Fundus revealed mild retinal pigmentation.2 Histopathology of CAR affected eyes revealed loss of retinal receptors and atrophic changes in the retinal pigment epithelium (RPE), most marked in the macula. An abnormal state of RPE hypersensitivity contributing to retinal degeneration has been reported. Grunwald et al, Kornguth et al and Keltner et al found antibodies to normal retina in serum of cancer patients with associated retinopathies.1,3 One key autoantigen was identified as a 23 kD photoreceptor component "recoverin," later found to be expressed by small cell carcinomas. Other CAR antigens have also since been identified.3,4 Corticosteroids, gamma globulin, and plasmapheresis do help in some cases.1
Induction of autoimmune reactions within the eye by extraocular diseases brings into question the possibility of a sensitisation involving the M bovis component of the BCG vaccine. The live attenuated mycobacterium of intravesical BCG infects normal and cancerous bladder epithelial cells. The infection then initiates a cascade of immune events including a rapid influx of CD4+ T cells, cytokine release (IL2, IFN-gamma and alpha) with an increase of gamma/delta T cells. These cells are not MHC type II restricted.5 We propose this is how activation of cellular immunity may lead to autoimmune phenomena in the eye.
Our case demonstrated the clinical features of an autoimmune retinopathy but the reaction to CAR antigen was absent. However, the unusual reaction reported suggests the presence of an immune mechanism which has the potential to cause a progressive type of retinopathy, the prognosis of which is unknown and which does not respond to steroids.
We may not have presented enough evidence to link the use of intravesical BCG with the ocular changes, although the temporal relation to the BCG therapy suggests that BCG is the most likely trigger of the autoimmunity. We suggest the bladder neoplasm is also a possibility. Ophthalmologists need to be aware of this rare possibility in order to improve their diagnostic yield in investigations of patients with similar clinical profiles. Patients also need to be warned of this rare but serious complication. This ocular complication in a previously normal patient necessitates regular ophthalmic screening in potential patients.
References
Ryan SJ. In: Retina. 2nd ed. St Louis: Mosby, 1994:894–6.
Lester H, Erdey RA, Fastenberg DM, et al. Bacillus Calmette-Guerin (BCG) endophthalmitis. Retina 1988;8:182–4.
Thirkill CE, Tait RC, Tyler NK, et al. The cancer associated retinopathy antigen is a recoverin-like protein. Invest Ophthalmol Vis Sci 1992;33:2768–72.
Thirkill CE. RPE hypersensitivity complicating paraneoplastic retinopathies. Ocul Immunol Inflamm 2000;8:25–37.
Bohle A, Brandau S. Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer. Urol 2003;170:964–9.