Reversible Ocular Toxicity Related to Tamoxifen Therapy

ALFRED R. ASHFORD, MD, IRlNA DONEV, MD, RAM P. TIWARI, MD, AND T. J. GARRETT, MD, FRCP(C), FACP

A 42-year-old woman with metastatic breast cancer developed bilateral optic disc swelling, retinal
hemorrhages, and visual impairment three weeks after starting treatment with low doses of tamoxifen.
Neurologic evaluation failed to provide an explanation for the ocular findings which resolved completely
after cessation of tamoxifen therapy. This case suggests that tamoxifen has the potential for causing
serious ophthalmologic toxicity which may be reversible if recognized early.
Cancer 61:33-35. 1988.

is a nonsteroidal antiestrogen widely

used in the treatment of breast cancer. It has relatively few serious side effects and ophthalmologic complications are particularly uncommon. Ocular toxicity
has been reported in eight patients.'-' All were treated
with tamoxifen at high doses and/or for prolonged penods of time. A patient with breast cancer developed
striking eye findings and visual impairment shortly after
starting therapy with low-dose tamoxifen. Neurologic
evaluation failed to provide an explanation for the abnormalities and the findings resolved after tamoxifen
was discontinued. The clinical course suggests that this
was a toxic effect of tamoxifen.
AMOXIFEN

Case Report
A 42-year-old gravida II para I1 Hispanic woman presented
to the Oncology Clinic in September 1986. She had undergone
a left radical mastectomy for breast cancer in January, 1984 at
a hospital in the Dominican Republic. She received postoperative radiation therapy and was asymptomatic until August
1986 when she noticed an enlarged left supraclavicular lymph
node which was biopsied and contained adenocarcinoma.
Skeletal x-rays showed evidence of metastases to the lumbar
spine and pelvic bones. A chest x-ray was normal.
On initial evaluation at Harlem Hospital Center, the patient's symptoms included mild bone pain, insomnia, and paroxysms of flushing, sweating, and palpitations. She had no
headache or visual complaints. The physical examination was
normal except for moderate obesity. The hematocrit was 34%,
the white blood cell count was 14,63O/pl, and the platelet
count was 95,000/pl. The blood smear showed a leukoeryth-

From the Departments of Medicine and Ophthalmology, Harlem

Hospital Center, New York, and Columbia University, College of
Physicians and Surgeons, New York, New York.
Address for reprints: Alfred R. Ashford, MD, Department of Medicine, Harlem Hospital Center, 506 Lenox Avenue, New York, NY
10037.

Accepted for publication July 10. 1987.

roblastic picture. A bone scan showed widespread skeletal metastases. Liver function tests were normal.
Treatment with tamoxifen (Nolvadex, Stuart Pharmaceuticals, Wilmington, DE) 10 mg twice daily was begun September
25, 1986. Acetaminophen with codeine was also prescribed.
Three weeks later the bone pain decreased dramatically but
she complained of seeing black spots in front of her eyes and
had experienced one episode of vomiting. She denied headaches. Fundoscopic examination showed bilateral optic disc
swelling and diffuse hemorrhages. The blood pressure was
130/88 and a neurologic examination showed no abnormalities. She was admitted to the hospital on October 16, 1986. A
CT scan of the head with contrast showed no abnormalities of
the skull or brain. A detailed ophthalmologic evaluation
showed that the best corrected vision in the right eye was 20/40
and in the left eye 20/25. External examination was normal
and the extraocular movements were full without nystagmus.
There were no abnormalities in the anterior segment. The
right optic disc was swollen with hyperemia and blurred margins (Fig. l). Superficial hemorrhages were present in the superonasal area. The retina was diffusely edematous with dilated veins. Scattered hard exudates were seen around the disc
with sparing of the macula. A similar but less extensive picture
was seen in the left eye. Fluorescein angiography confirmed
the impression of bilateral optic nerve swelling (Fig. 2). There
was a blockage of fluorescein in the area of hemorrhage. Late
pictures showed leakage of the dye around the disc. Visual
fields were normal to confrontation and kinetic perimetry. A
lumbar puncture yielded clear cerebrospinal fluid with a protein of 28 mad], a glucose of 67 mg/dl, 3 lymphocytes/pl, and
3 erythrocytes/pl. Cytologic examination was negative for ma-,
lignant cells. Technical difficulties prevented an accur&@F
pressure measurement on the first lumbar puncture, but a
second three days later had an opening pressure of 160 mm of
water. Cerebrospinal fluid samples obtained from three additional lumbar punctures during the course of the one month
all had normal composition and were cytologically negative
for malignant cells. Infiltration of the bone marrow by adenocarcinoma was demonstrated on needle biopsy.
Tamoxifen was discontinued on admission and two weeks
later the visual symptoms subsided. Acetaminophen with co-

34

CANCERJanuary I 1988

Vol. 61

cycles of treatment. On May 28, 1987 the patient was asymptomatic; physical examination showed no abnormalities.

Discussion

FIG. I . Fundoscopic appearance of the right eye with marked optic

nerve swelling. retinal edema, and hemorrhages.

deine was continued whenever necessary. Within three

months the fundoscopic examination was normal except for a
few exudates in the right eye. It was entirely normal one month
later and the corrected visual acuity was 20/25. Treatment of
the breast cancer with a combination of cyclophosphamide.
adriamycin. and 5-fluorouracil was initiated on October 29,
1986. Thrombocytopenia and bone pain resolved after two

FIG.2. Retinal fluorescein angiography (early phase) of the right eye

showing optic nerve swelling and blockage of fluorescein in the area of
hemorrhage.

The temporal relationship between tamoxifen therapy

and ocular abnormalities in this patient appears to be
more than coincidental and suggests that ophthalmologic toxicity was due to the medication. Since a cause
and effect relationship cannot be established with certainty, it is necessary to consider other explanations for
the development of optic disc swelling and retinal hemorrhages in this patient. The multiple normal samples of
cerebrospinal fluid with no malignant cells and the patient's subsequent clinical course make carcinomatous
meningitis
Similarly, the lumbar puncture
findings do not support the diagnosis of pseudotumor
cerebri.'.'' The computerized tomogram did not show
evidence of intracranial metastasis or hydrocephalus.
Superior sagittal sinus thrombosis due to metastases or a
remote effect of cancer has occurred in association with
breast cancer as well as other solid tumors and hematologic malignancies. However, a total lack of focal neurologic findings or cerebral dysfunction would be an exceedingly rare occurence, at least in adults with this disorder."-13 Eye changes have occurred in association
with many drugs, but not with acetaminophen with codeine, the only medication besides tamoxifen that this
patient was receiving.
Although uncommon, direct ocular toxicity has been
related to tamoxifen therapy. Kaiser-Kupfer and Lippman described four patients who developed refractile
opacities, primarily in the macular and paramacular regions.l'2 Three of the four also had a peculiar keratopathy. Visual loss was progressive in at least two patients. McKeown el al. described one patient with a similar retin~pathy.~
These five patients were all treated
with tamoxifen at high doses and for greater than one
year. Retinal toxicity developing with tamoxifen at low
daily doses (30 mg or less daily) has been reported in
three patients. One patient developed optic neuritis after
7 months of therapy. The optic nerve head was edematous but the retina was n ~ r m a l Vinding
.~
et aL4 described two patients. One had decreased visual acuity
and on examination there were retinal changes consistent with those previously described' as well as a single
retinal hemorrhage. This patient had received tamoxifen
for 9 months. The second patient had been treated with
tamoxifen for 14 months. Her visual acuity was unchanged but she had pigmentary changes and "yellowish
refractile dots" in the retina.
The mechanism of tamoxifen ocular toxicity is unknown. In a case of retinopathy described pathologi-

No. 1

TAMOXIFEN
OCULAR
TOXICITY Ashford et al.

cally, the lesions were confined to the nerve fiber and

inner plexiform layers and had electron microscopic
features suggestive of axonal degeneration. A relative
paucity of lesions were noted on the optic nerve heada2
The clinical and autopsy observations in this case suggested that the damage to the retina was irreversible in
contrast to the lens changes which resolved completely.
In the one case of optic neuritis reported, partial improvement occurred when tamoxifen was withdrawn
two to three weeks after the onset of ocular symptoms.
The swift resolution of symptoms and eye findings in
our patient may have been related to the relatively small
cumulative dose and/or the prompt cessation of tamoxifen therapy.
The previously published cases, as well as the present
report, suggest that tamoxifen has the potential for
causing serious ophthalmologic toxicity and that abnormalities of the lens, retina, and optic nerve may be seen.
Tamoxifen should be included in the list of causes for
the development of visual symptoms and signs in a patient receiving this medication. In view of the extensive
use of tamoxifen in treating patients with early as well as
advanced breast cancer and the limited information
about the frequency of ophthalmologic side effects with
this drug,I4 the need for periodic ocular evaluation
should be reassessed. Certainly the presence of even subtle ocular symptoms in patients receiving tamoxifen
should prompt a thorough ophthalmologic evaluation.

35

REFERENCES
I . Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy.
Cancer Treat Rep 1978;62:3 15-320.
2. Kaiser-Kupfer MI, Kupfer C, Rodrigues MM. Tamoxifen retinopathy: 1. A clinicopathologic report. Ophthalmology 198 I ; 883993.
3. McKeown CA, Swam M, Blom J, Maggiano JM. Tamoxifen
retinopathy. Br J Ophthalmol198 1 ; 65:177- 179.
4. Vinding T. Nielsen NV. Retinopathy caused by treatment with
tamoxifen in low dosage. Acta Ophthalmol (Copenh) 1983;6 1:45-50.
5. Pugesgaard T, Von Eyben FE. Bilateral optic neuritis evolved
during tamoxifen treatment. Cancer 1986;58:383-386.
6. Olson ME, Chernik NL, Posner JB. Infiltration of the leptomeninges by systemic cancer: A clinical and pathologic study. Arch Neurol
1974; 30122-137.
7. Yap HY, Yap BS, Tashima CK, DiStefano A, Blumemschein
GR. Meningeal carcinomatosis in breast cancer. Cancer 1978;
421283-286.
8. Wasserman WR, Glass JP, Posner JB. Diagnosis and treatment
of leptomeningeal metastases from solid tumors: Experience with 90
patients. Cancer 1982;491759-772.
9. Ahlskog JE, ONeill BP. Pseudotumor cerebri. Ann Int Med
1982:97:289-256.
10. Johnson I, Patenon A. Benign intracranial hypertension: 11.
Brain 1974; 97:301-312.
1 1. Sigsbee B, Deck MDF, Posner JB. Nonmetastatic superior sagittal sinus thrombosis complicating systemic cancer. Nezrrologv 1979;
29:130- 146.
12. Hickey WF, Garnick MB, Henderson IC, Dawson DM. Primary cerebral venous thrombosis in patients with cancer: A rarely
diagnosed paraneoplastic syndrome. Report of three cases and review
of the literature. Am J Med 1982;73:740-750.
13. Graus F,Rogers LR. Posner JB. Cerebrovascular complications
in patients with cancer. Medicine 1985;64:16-35.
14. Beck M, Mills PV. Ocular assessment of patients treated with
tamoxifen. Cancer Treat Rep 1979;63:1833- 1834.