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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 c ompletely

after cessation of tamoxifen therapy. This

case

suggests that tamoxifen has the potential for causing

serious ophthalm ologic toxicity which may be reversible if recognized early.

Cancer

61:33-35. 1988.

AMOXIFEN

is a nonsteroidal antiestrogen widely

T

used in the treatm ent of breast cancer. It has rela-

tively few serious side effects and ophthalm ologic com-

plications are particularly uncommon. Ocular toxicity

has been reported in eight patients.'-'

All

were treated

with tamoxifen at high doses and/ or for prolonged pe

nods of time.

A

patient with breast cancer developed

striking eye findings and visual impa irment sho rtly after

starting therapy with low-dose tamoxifen. Neurologic

evaluation failed to provide an explanation for the ab-

normalities and the findings resolved after tamoxifen

was discontinued. The clinical course suggests that this

was a toxic effect of tamoxifen.

Case Report

A 42-year-old gravida

I I

para

I

Hispanic woman presented

to the Oncology Clinic in September 1986. She had undergone

a left radical mastectomy for breast cancer in Janu ary, 1984 at

a hospital in the D ominican Republic. She received postopera-

tive radiation therapy and was asymptomatic until August

1986 when she noticed an enlarged

left

supraclavicular lymph

node which was biopsied and co ntained adenocarcinom a.

Skeletal x-rays showed evidence

of

metastases to th e lum bar

spine and pelvic bones. A chest x-ray was normal.

On

initial evaluation at Harlem Hospital Center, the pa-

tient's sy mp tom s included mild bone pain, insomnia, and par-

oxysms

of

flushing, sweating, and palpitations. She had

no

headache or visual complaints. T he physical exam inatio n was

normal except for moderate obesity. The hematocrit was 34%,

the white blood cell cou nt was 14,63O/pl, an d th e platelet

count was

95 000/pl.The

blood smear showed

a

leukoeryth-

From the Departm ents of Medicine and Ophthalmology, Harlem

Hospital Center,

New

York,

nd

Columbia

Univers i ty,

College

of

Physicians and Surgeons, New York,

New

York.

Address for reprints: Alfred

R.

Ashford, MD, Department

of

Medi-

cine, Harlem

Hospital

Center,

5 6

Lenox Avenue,

New

York,

N Y

10037

Accepted

for

publication July

10.

1987.

roblastic picture. A bo ne scan showed widespread skeletal me-

tastases. Liver function tests were normal.

Treatment with tamoxifen (Nolvadex, Stuart Pharmaceuti-

cals, Wilm ington,

DE)

10 mg twice daily was begun S eptember

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 head-

aches. Fundoscopic examination showed bilateral optic disc

swelling and diffuse hemorrhages. The blood pressure was

130/88 and a neurologic examination showed no abnormali-

ties. She was admitte d

to

the hospital on October 16,

1986.

A

T

scan

of

the head with contrast showed n o abnormalities of

the skull or brain. A detailed ophthalmologic evaluation

showed that t he 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 hy peremia an d blurred mar-

gins (Fig.

l).

Superficial hemorrhages were present in th e

su-

peronasal area. The retina was diffusely edematous with di-

lated veins. Scattered hard ex udates were seen aroun d th e disc

with sparing

of

the macula.

A

similar bu t 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

norm l

to confrontation and kinetic perimetry.

A

lum bar pun cture yielded clear cerebrospinal fluid with a pro-

tein of

28

m ad ], a glucose of 67 mg/dl,

3

lymphocytes/pl, and

3 erythrocytes/pl. Cytologic examin ation was negative for

ma-

lignan t cells. Tech nical difficulties prevented an accur&@F

pressure measurement on the first lumbar puncture, but a

second three days later had an o pening pressure

of

160 mm of

water. Cerebrospinal fluid samples obtained from three addi-

tional lum bar 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 adeno-

carcinoma w as demonstrated on needle biopsy.

Tamoxifen was discontinued

on

admission and two weeks

later the visual symptoms subsided. Acetaminophen with co-

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4

CANCER

anuary

I 1988 Vol. 61

FIG Fundosco pic 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 m onth

later and the corrected visual acuity was 2 0/2 5. Tre atmen t

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 pha se)of the right eye

showing optic nerve sw elling and blockage of fluorescein in the area

of

hemorrhage.

cycles of treatmen t. On M ay 28, 1987 the patient was asymp-

tomatic; physical examina tion showed no abnormalities.

Discussion

Th e temporal relationship between tamoxifen therapy

and ocular abnormalities in this patient appears to be

more than coincidental and suggests that ophthalmo-

logic toxicity was due to the medication. Since a cause

and effect relationship cannot be established with

cer

tainty, it is necessary to consider other explanations for

the d evelopment of optic disc swelling and retinal hem -

orrhages in this patient. Th e m ultiple n ormal samples of

cerebrospinal fluid with no malignant cells and the pa-

tient's subsequent clinical course make carcinomatous

meningitis Similarly, the lumb ar 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 du e to metastases or a

remo te effect of cancer has occ urred in a ssociation with

breast cancer as well as other solid tumors a nd he mato -

logic malignancies. However, a total lack of focal neuro-

logic findings

or

cerebral dysfunction would

be

an ex-

ceedingly rare occ urence, at least in a dults with this dis-

order. -13 Eye changes have occurred in association

with many drugs, but not with acetaminophen w ith co-

deine, the o nly m edication besides tamoxifen that this

patient was receiving.

Although uncom mon , direct ocular toxicity has been

related to tamoxifen therapy. K aiser-Kupfer and Lipp-

man described four patients who developed refractile

opacities, primarily in the macular and paramacular re-

gions.l'2 Three of the four also had a peculiar kerato-

pathy. Visual

loss

was progressive in at least two pa-

tients. McK eown l

al.

described one patient w ith a sim-

i l a r r e t i n ~p a t h y . ~hese 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 mo nths of therapy. T he optic nerve head was edema-

t ou s b u t t he re tin a was n ~ r m a l . ~inding

et aL

de-

scribed two patients. One had decreased visual acuity

and on examination there were retinal changes consis-

tent with those previously described' as well as a single

retinal hemorrha ge. Th is patient had received tamoxifen

for 9 months. T he second patient had been treated with

tamoxifen for 14 months. Her visual acuity was un-

changed but she had pigmentary changes and yellowish

refractile dots in the retina.

The mechanism of tamoxifen ocular toxicity is un-

known. In a case of retinopathy described pathologi-

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No. 1 TAMOXIFENCULAROXICITY

Ashford

et

al.

35

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 op tic nerve heada2

The clinical and autopsy observations in this case sug-

gested that the damage t o th e retina was irreversible in

contrast to the lens changes which resolved completely.

In the one case of optic neuritis reported, partial im-

provement occurred when tamoxifen was withdrawn

two to three weeks after the onset of ocular symptoms.

The swift resolution of sym ptom s and eye findings in

ou r patient may hav e been related to the relatively sma ll

cumulative dose and/or the pro mpt cessation of tamox-

ifen therapy.

Th e previously published cases, as well as the present

report, suggest that tamoxifen has the potential for

causing serious ophthalmologic toxicity and that abnor-

malities of the lens, retina, an d optic nerv e may

be

seen.

Tamoxifen should be included in the list

of

causes for

the development of visual symptom s and signs in a pa-

tient receiving this m edication.

In

view

of

the extensive

use of tamo xifen in treating patients with e arly as well as

advanced breast cancer and the limited information

abou t the frequency of ophthalm ologic side effects with

this drug,I4 the need for periodic ocula r evaluation

should be reassessed. Certainly the prese nce of even sub-

tle ocular symptoms in patients receiving tamoxifen

should prompt a thorough op hthalmologic evaluation.

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Cancer Treat Rep 1978; 2:3 15-320.

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