European Journal of Ophthalmology / Vol. 11 no. 3, 2001 / pp. 309-312

PURPOSE. Differential diagnosis of maculopathies can be difficult but is important if patientsalso suffer from other diseases such as breast cancer treated with antiestrogens. The mainpossible diagnoses, especially in the elderly, are age-related macular degeneration, tamoxifenand cancer-associated retinopathy (CAR).METHODS. We describe an 84-year-old patient with breast and colon cancer, who complainedof a decrease in visual acuity after treatment with low-dose antiestrogens. She underwenta general ophthalmological investigation, perimetry and electroretinographic examinationwith multifocal (m-ERG) and flash-electroretinogram (flash-ERG). RESULTS. Visual acuity was reduced to 1/50 and 0.3. The ophthalmological examination wasnormal, except for extensive bilateral maculopathy with shining crystalline deposits, cen-tral and peripheral visual field defects, slightly affected scotopic and photopic potentialsin the flash-ERG, and an abnormal m-ERG. CONCLUSIONS. The findings are expected with age-related macular degeneration with crys-talline drusen, but also with CAR. Even if the single and total dosage of antiestrogens giv-en to the patient is sufficient to cause tamoxifen retinopathy, this diagnosis can be excludedbecause, in tamoxifen retinopathy unlike in the case presented here, the deposits are notdistributed in all retinal layers. (Eur J Ophthalmol 2001; 11: 309-12)

KEY WORDS. Age-related macular degeneration, Antiestrogen, CAR (cancer-associated retino-pathy), Drusen, Tamoxifen

Accepted: April 18, 2001

Tamoxifen side effects, age-related maculardegeneration (AMD) or cancer associated retinopathy (CAR)?

INTRODUCTION

Tamoxifen retinopathy is an adverse effect of high-dose tamoxifen treatment. This non-steroidal oral anti-estrogen binds to estrogen receptor proteins in thecytoplasm. Antiestrogens are beneficial in the treat-ment of metastatic breast cancer and are used as ad-juvant therapy in the early stages of the disease todelay relapses (1, 2). Side effects in the eye, retinopa-thy and corneal changes, have been reported, espe-cially in patients treated with high doses (60 or 100mg/m2/day) for at least a year (3). The changes con-

sist of macular edema, refractile macular and para-macular, whirl-like subepithelial corneal opacities, anddecreased visual acuity (4). Low doses (20 or 30 mg/day)may also damage the eye and cause papillary edemaand superficial retinal hemorrhages (5), corneal andretinal alterations (4, 6), only retinal changes (7-9) orbilateral optic neuritis (10). Differential diagnosis ofother macular alterations such as drusen and age-re-lated macular degeneration can be difficult (11), es-pecially if the patient is elderly and needs tamoxifenor other antiestrogens. Senile macular degenerationis characterised by disturbances of the retinal pig-

B. SADOWSKI, C. KRIEGBAUM, E. APFELSTEDT-SYLLA

Dept. of Neuro-Ophthalmology and Pathophysiology of Vision, University Eye Hospital, Tuebingen, Germany

1120-6721/309-04$02.00/0© by Wichtig Editore, 2001

Tamoxifen side effects, AMD or CAR?

310

ment epithelium within the macular area and a de-crease in visual acuity (12). A decrease of central vi-sion in the elderly can also be due to mostly bilater-al lesions, called drusen, which are deposits of ab-normal material in Bruch’s membrane, deriving fromthe retinal pigment epithelium (13-15).

Calcification may occur around drusen; their appearancethen changes from yellowish to refractile, with a crys-talline look mostly due to cholesterol, which makesdifferential diagnosis even more difficult (16). How-ever, cancer itself can also cause retinopathy (CAR =cancer-associated retinopatny) and has to be con-sidered another possible diagnosis (17).

Here we present the ophthalmological findings ofa patient treated with tamoxifen for about tenmonths, to il lustrate the difficulty of differential di-agnosis.

METHODS

The patient underwent an extensive ophthalmolog-ical examination, which included measurement of vi-sual acuity, neuro-ophthalmological investigation,slit-lamp examination, dilated pupil funduscopy, fun-dus photography, perimetry (Tübingen hand perime-ter), a flash electroretinogram (flash-ERG) according

to the ISCEV standard (18) and multifocal elec-troretinogram (m-ERG, 19). For the m-ERG, ampli-tude and peak time responses were grouped by ec-centricity (group 1 – foveal response, group 2 – mac-ular response: 1.8 – 7°, group 3: 5 – 13°, group 4:10.5 – 22°, group 5: 17– 30.5°).

RESULTS

An 84-year-old woman presented at our low visionclinic to obtain a reading device because of inabili-ty to read newspaper print. Two years earlier, breastcancer had been diagnosed and treatment had start-ed with antiestrogens. One year before the exami-nation, the patient had been operated for a metasta-tic colon carcinoma; no further diseases were known.The patient never had problems with her eyes untilone year before, when she noticed a decrease in vi-sual acuity.

At the time of ophthalmological examination she wastaking antiestrogens (anastrozol) and vitamins. Twoyears before the examination the patient had beentreated with tamoxifen for ten months (30 mg/d), fol-lowed by Lentaron (formestan) for six months and Arim-idex (anastrozol) for nine months. The total tamoxifendosage was about 900 mg in ten months.

Fig. 1 - Macula in the right and left eyes of the patient with crystalline drusen and pigmentary atrophy.

Sadowski et al

311

Ophthalmological data

Visual acuity was 1/50 (+2.0 sph –0.5 cyl / 90°) righteye and 0.3 (+1.0 sph –0.5 cyl / 80°) left eye. Age -related signs in the anterior segments had been ob-served, with slight lens opacities and arcus senilis.The funduscopy showed regular optic discs and thecrystalline deposits in the maculae. The right eye hada large area of retinal pigment epithelial geographicatrophy (Fig. 1). Extensive central scotomas extend-ing to the left peripheral visual field were seen in perime-try (10°, 1000 asb stimulus, Tübingen perimeter). Elec-troretinographic findings (flash-ERG) included rod, coneand oscillatory potential amplitudes in the lower nor-mal range (± 2 SD); all peak times were slightly pro-longed in the multifocal ERG (mf-ERG) foveal responses(group 1) of the left eye and macular responses of theright eye (group 1-2) were undetectable. Peripheral-ly to these areas, amplitudes increased with eccen-tricity, but failed to reach normal levels even in theoutermost ring (group 5). Peak times were slightly de-layed in groups 2 and 3, but within the normal rangein the outer rings (groups 4 and 5).

DISCUSSION

The patient’s advanced age and her medical con-ditions under treatment complicated and limited theinvestigations needed to ascertain the diagnosis, afrequent clinical situation. The patient refused furtherexamination, such as dark adaptation, fluorescein an-giography and magnetic resonance tomography(MRT) or cranial computer tomography (CCT). The pa-tient suffered from colon and breast cancer and hadtherefore been treated with tamoxifen and other anti-estrogens for long periods. She had noticed a de-crease of visual aculty, and the ophthalmological in-vestigation also showed visual field scotomata andabnormal flash and multifocal electroretinograms. Theseproblems could have been caused by various mech-anisms or diseases which would have different im-plications for monitoring and therapeutic strategies.

Because of her age, however, the most likely reti-nal disease is age-related maculopathy, other diag-noses being rare.

The deposits in the macula did not include all reti-nal layers. The macula showed atrophic areas with

pigment alterations and drusen in their typical loca-tion, the Bruch’s membrane (13, 15), which lookedglittering if calcium was also present. Von Ruckmannet al (20) found no fundus autofluorescence of age-related drusen. However, Holz and Pauleikhoff (16)mention the possibility of cholesterol-containingdrusen which have a crystalline appearance. This canconfound the diagnosis of tamoxifen retinopathy, whichwould be distributed in all retinal layers.

In the literature, the intake of tamoxifen followed byretinopathy ranges from 6.0 g to 81.0 g for patientswith retinopathy to less than 1 g for a patient with op-tic neuropathy. Heier et al (9) reviewed high- and low-dose therapy with tamoxifen, its side-effects and pos-sibility of recovery. They conclude that the main dif-ference between high- and low-dose toxicity is thereversibility after discontinuation of treatment. Theydid not find toxicity in patients with a total dosage ofless than 10 g. Vinding and Nielsen (4) never diag-nosed tamoxifen retinopathy below a total dosage of8.1 g. This is contrary to Tang et al (21) who put thelower limit of antiestrogen-induced retinopathy at 23.7g. Lazzaroni et al (11) confirm the possibility of low-dose tamoxifen retinopathy, but none of their patientshad visual symptoms.

The total tamoxifen intake by our patient (about 900mg) renders the diagnosis of toxic retinopathy unlikely.She had been treated with different antiestrogens: anas-trozol, formestan and tamoxifen dihydrogen citrate. Evenif all those therapeutics are antiestrogens, ocular sideeffects are described only for tamoxifen and consist ofretinopathy and corneal changes. If discovered in time,the retinal and corneal lesions are potentially reversible,with a fair visual prognosis, challenging the ophthalmologistto be aware of ocular tamoxifen side effects and to keepthe differential diagnosis in mind.

Another diagnosis to be considered is CAR. Patientswith CAR show clinical and electrophysiological evi-dence of both cone and rod dysfunction (14, 22). Theslightly prolonged implicit times in the flash-ERG ofour patient and the effect on the peripheral visual fieldshown in the mf-ERG traces, indicate that retinal func-tion loss was not confined to the macular area. Con-sideration of this patient’s history, with this finding,could implicate CAR.

Bietti’s crystalline retinopathy also causes reducedscotopic and photopic ERG responses (23, 24). How-ever, this inherited disease is usually diagnosed in

Tamoxifen side effects, AMD or CAR?

312

young or middle-aged adults and, besides glitteringcrystals in the macula, limbal crystalline dystrophy ofthe cornea is one of the main features and an impor-tant diagnostic criteria. Because of the widespreadpossibilities of differential diagnoses, screening andmonitoring of patients is necessary. As Ah Song andSasco (25) suggested, the m-ERG should be part ofthe screening examinations. With its high resolutionthe m-ERG can detect small areas of retinopathy andis therefore a sensitive tool for the detection and moni-toring of early macular alterations (26).

Reprint requests to:Bettina Sadowski, MDUniversity Eye HospitalDept. of Neuro-Ophthalmology and Pathophysiology of VisionSchleichstr 12D-72076 Tuebingen, Germany

REFERENCES

1. Heel RC, Brogden RN, Speight TM, Avery GS. Tamoxifen:a review of pharmacological properties and therapeutic usein the treatment of breast cancer. Drugs 1978; 16: 1 –24.

2. Nayfield SG, Gorin MB. Tamoxifen-associated eye dis-ease. A review. J Clin Oncol 1996; 14: 1018-26.

3. Kaiser-Kupfer Ml, Lippmann M. Tamoxifen retinopathy.Cancer Treat Rep 1978; 62: 315-20.

4. Vinding T, Nielsen NV. Retinopathy caused by treatmentwith tamoxifen in low dosage. Acta Ophthalmol 1983; 61:45-50.

5. Ashford AR, Donev I, Tiwari RP, Garrett TJ. Reversibleocular toxicity related to tamoxifen therapy. Cancer 1988;61: 33-5.

6. Pavlidis NA, Petris C, Briassoulis E, et al. Clear evidencethat long-term, low-dose tamoxifen treatment can induceocular toxicity. A prospective study of 63 patients. Can-cer 1992; 69: 2961-64.

7. Chern S, Danis RP. Retinopathy associated with low-dosetamoxifen (Letter). Am J Ophthalmol 1993: 116: 372-3.

8. Gliffiths MFP. Tamoxifen retinopathy at low dosage (Let-ter). Am J Ophthalmol 1987; 104: 185-6.

9. Heier JS, Dragoo RA, Enzenauer RW, Waterhouse WJ. Screen-ing for ocular toxicity in asymptomatic patients treatedwith tamoxfen. Am J Ophthalmol 1994; 117: 772-5.

10. Pugesgaard T, Von Eyben FE. Bilateral optic neuritis evolvedduring tamoxifen treatment. Cancer 1986; 58: 383-6.

11. Lazzaroni F, Scorolli L, Pizzoleo CF, Savini G, De NigrisA, Giosa F, Meduri RA. Tamoxifen retinopathy: does it really exist? Graefes Arch Clin Exp Ophthalmol 1998; 236:669-73.

12. Framingham Eye Study. Vl. Macular degeneration. SurvOphthalmol 1980; 24 (Suppl): S428.

13. Barondes M, Pauleikhoff D, Chisholm IC, Minassian D,Bird AC. Bilaterality of drusen. Br J Ophthalmol 1990;74: 180-2.

14. Holz FG, Wolfensberger TJ, Piquet B, et al. Bilateral mac-ular drusen in age-related macular degeneration. Oph-

thalmology 1994; 101: 1522-8. 15. Pauleikhoff D. Drusen in der Bruchschen Membran. Oph-

thalmologe 1992; 89: 363-86.16. Holz FG, Pauleikhoff D. Altersabhängige Makuladegen-

eration. Berlin, Heidelberg, New York: Springer Verlag,1997; 199: 66.

17. Holz FG, Bellmann C, Steffen H. KarzinomassoziierteRetinopathie (CAR) bei Mammakarzinom und Karzinoid.Ophthalmologe 1997; 94: 337-42.

18. Marmor MF, Zrenner E. Standard for clinical elec-troretinography (1994 upgrade). Doc Ophthalmol 1995;89: 199-210.

19. Kretschmann U, Gendo K, Seeliger M. Zrenner E. Multi-focal ERG recording by the VERIS technique and its clin-ical applications. In: Wiedemann P, Kohen L, eds. Mac-ular and retinal diseases. Dev Ophthalmol, Basel: Karger,1997; 29: 8-14.

20. Von Rückmann A, Schmigt K-G Fitzke FW, Jacobi KW.Fundus-Autofluoreszenz bei Patienten mit vererbtenMakuladystrophien, Malattia leventinese, familiär domi-nanten und altersbedingten Drusen. Klin Monatsbl Au-genheilkd 1998; 213: 81-6.

21. Tang R, Shields J, Schiffman J, et al. Retinal changes as-sociated with tamoxifen treatment for breast cancer. Eye1997: 11: 295-7.

22. Jacobson DM, Wis M, Thirkill Ch E, Calif S. Paraneo-plastic cone dysfunction: an unusual visual remote ef-fect of cancer. Arch Ophthalmol 1995; 113: 1580-2.

23. Kaiser-Kupfer Ml, Chan C, Markello TC, et al. Clinicalbiochemical and pathologic correlations in Bietti's crys-talline dystrophy. Am J Ophthalmol 1994; 118: 569-82.

24. Kretschmann U, Usui T, Ruether K, Zrenner E. Elec-troretinographic campimetry in a patient with crystallineretinopathy. German J Ophthalmol 1997; 5: 399-403.

25. Ah Song R, Sasco AJ. Tamoxifen and ocular toxicity. Can-cer Detect Prev 1997; 21: 522-31.

26. Palmowski AM, Sutter EE, Bearse MA, Wayne F. Mul-tifocal electroretinography (MF-ERG) in age-related mac-ular degeneration. Ophthalmologe 1999; 96: 166-73.