Ocular Motility Dysfunction Associated With Chemotherapeutic Agents David T. Wheeler, MD, and Frederick W. Fraunfelder, MD wo articles in this issue discuss strabismus associated with vincristine. Chemotherapeutic toxicity is an uncommon cause of ocular motility disturbance and one that could easily be overlooked by oncologists, strabismus surgeons, and primary care providers alike. In addition, ophthalmologists use chemotherapeutic agents infrequently, and drug-induced ocular side effects related to their use are uncommon. Still, it is important to be aware of potential ocular side effects from this class of medication. Reported here is a summary of reports of ocular motility disorders caused by chemotherapeutic agents. It is hoped that clinicians will recognize this association in select patients and diagnose the condition and treat their patients accordingly. We reviewed information from the National Registry of Drug-Induced Ocular Side Effects (NR) at Casey Eye Institute (Portland, Oregon), as well as the World Health Organization’s (WHO; Uppsala, Sweden) database of adverse drug reactions. We also performed a literature search for articles describing ocular motility dysfunction in this setting.1-5 We included reports of diplopia, strabismus, ptosis, and myasthenia-like effects, but we speciﬁcally excluded nystagmus because this condition is both frequently reported and poorly characterized throughout the literature. Most reports of strabismus or diplopia were associated with extraocular muscle paresis, although several drugs are known speciﬁcally to be myotoxic. Similarly, strabismus and diplopia normally occurred together but are sometimes reported independently. Our ﬁndings are presented in Tables 1 and 2. In this review, we distinguish between drug effects reported to the NR or the WHO and those reported in the scientiﬁc literature. Furthermore, the adverse drug reactions contained in these databases have been reviewed to determine the strength of the association. It is often unclear whether an observed side effect can be attributed to a speciﬁc agent or whether it could have been caused by
Supported in part by an unrestricted grant from Research to Prevent Blindness, New York, NY. Submitted July 23, 2003. Revision accepted October 31, 2003. Reprint requests: David T. Wheeler, MD, Casey Eye Institute, 3375 SW Terwilliger Blvd, Portland, OR 97239-4197. J AAPOS 2004;8:15-17. Copyright © 2004 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2004/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2003.10.009
Journal of AAPOS
TABLE 1. Chemotherapeutic drugs reportedly associated with ocular motility dysfunction Drug 5-flourouracil*,† ATRA* Bleomycin Chlorambucil*,† Cisplatin† Corticosteroid* Cyclophosphamide† Cyclosporine* Cytarabine† Dactinomycin Daunorubicin† Doxorubicin†,‡,§ Fludarabine* Methotrexate* Mitotane* Nitrosureas*,‡ Procarbazine* Vinblastine*,† Vincristine†
⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫
⻫ ⻫ ⻫ ⻫
⻫ ⻫ ⻫ ⻫ ⻫
⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫ ⻫
ATRA: all-trans-retinoic acid; MG: myasthenia gravis. *Cited in the literature. †Strabismus attributed to neurogenic origin. ‡Strabismus attributed to myogenic origin. §Studied as an agent for blepharospasm because of myotoxicity.5
the underlying condition, by concurrent drug use, or by coincidence. This concern is particularly relevant in the setting of cancer treatment, and we have attempted to address this issue by reporting dechallenge and rechallenge data. A positive dechallenge test involves resolution of the reported side effect after discontinuation of the drug thought to be its cause, whereas a positive rechallenge test involves reappearance of the side effect on resumption of treatment with the same drug. These data substantially increase the likelihood of a cause-and-effect association, whereas the lack of such data leaves the possibility open that the reaction is being caused by another mechanism.6,7 Table 1 lists the chemotherapeutic drugs and their associated toxicities. More than half (11 of 19) of these drugs are cited in the literature but have not been reported to an organized registry. A full discussion of these agents’ mechanism of action, and of the possible etiology of ocular motility dysfunction, is beyond the scope of this editorial. However, it is likely that toxicity is related to the same drug properties responsible for the therapeutic beneﬁt. In the case of vincristine, for example, the drug produces mitotic arrest by interfering with microtubule synthesis. At therapeutic levels, axonal degeneration occurs in both February 2004
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TABLE 2. Chemotherapeutic drugs reported to the NR or WHO as potentially causing ocular motility dysfunction Drug Cases Concurrent Chemotherapy Drugs Dechallenge Bleomycin Cisplatin Cyclophosphamide Cytarabine Dactinomycin Daunorubicin Doxorubicin Vincristine
1 9 2 12 1 2 1 9
None Cyclophosphamide, doxorubicin, etoposide, 5-fluorouracil, methotrexate, vincristine Carmustine, cytarabine, etoposide, prednisone, vincristine Cyclosporine, daunorubicin, prednisone, thioguanine, vincristine Cyclophosphamide Cytarabine, thioguanine None Cisplatin, cyclophosphamide, cytarabine, doxorubicin, methotrexate, prednisone, procarbazine
Not reported 1 positive
Not reported 1 positive
Not reported 5 positive Not reported 1 positive 1 positive 1 positive
1 negative 1 positive 2 negative Not reported 1 positive 1 negative 1 negative
NR: National Registry of Drug-Induced Ocular Side Effects; WHO: World Health Organization.
Table 3. Reported cases of ocular motility dysfunction associated with vincristine Age Ocular Side (yr) Gender Effect 2 2 10 27 28 29 31 35 48
F M M F M F F M M
Strabismus Strabismus, ptosis Diplopia Diplopia Strabismus Diplopia Diplopia Diplopia Diplopia
Concurrent Drugs Asparaginase, cytarabine, methotrexate, prednisolone Cyclophosphamide, cytarabine, prednisone Chlormethine, prednisone, procarbazine Cyclophosphamide, doxorubicin, prednisone Cytarabine, hydrocortisone, methotrexate Codeine, diazepam, levothyroxine, prednisone, secobarbital Cisplatin, methotrexate, ondansetron Indocin*
*Concurrent radiation therapy.
large and small nerve ﬁbers. Dose-limiting neurotoxicity is common and results in paralytic strabismus, ptosis, lagophthalmos, corneal hypesthesia or internal ophthalmoplegia when associated cranial nerves are affected. Table 2 lists only those drugs reported to the NR or WHO and provides additional information. Eight chemotherapeutic drugs in a total of 35 cases have been implicated in these reports. Four of these 8 drugs have been associated with a positive dechallenge and 3 with a positive rechallenge. All but 2 drugs were given in combination with other chemotherapy agents; a total of 14 other agents were used concurrently, and 6 of these 14 are included in this table. Five of the remaining 8 drugs have been reported to cause ocular motility dysfunction (Table 1). Concurrent medications other than chemotherapy drugs have also been reported as possibly being associated with ocular motility disorders; however, these drugs are not included in Table 2, which lists only concurrent chemotherapeutics. Other agents may be relevant in cases when dechallenge and rechallenge data are negative or not available. Table 3 provides additional detail regarding 9 patients reported to suffer ocular motility dysfunction associated with vincristine. Two case reports are included in this issue. Strabismus was reported to resolve in only 1 patient after vincristine was discontinued (positive dechallenge), but no data were provided regarding further treatment with this drug. In another case, diplopia failed to recur
after vincristine was readministered (negative rechallenge), but data are lacking regarding the initial response to removal of the drug. Therefore, evidence for a causative association between ocular motility dysfunction and vincristine is fairly weak despite the frequent reporting of this ﬁnding in the literature and the existence of a potential mechanism of action to explain the side effect. As with vincristine, many chemotherapeutic drugs have been associated with ocular side effects, but relatively few reports strongly infer causality. Voluntary postmarketing surveillance systems suffer from under-reporting, incomplete information, and lack of follow-up. However, because they contain rechallenge and dechallenge data and a record of temporal relations, such databases may provide early signals indicating a possible or probable adverse drug event. When ocular motility dysfunction occurs in the setting of chemotherapy, the possibility of an adverse drug reaction should be considered and discussed with the oncologist. Treatment may include stopping the medication or changing to alternate therapy after consultation with the care team. In addition, temporizing measures—such as monocular occlusion, the use of prisms, and possibly the administration of Botox in selected patients—should be adopted before attempting surgical management because many of these cases resolve when the suspect drug is discontinued or when another is substituted. Filing a report with the National Registry (www.eyedrugregistry.
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com) will add to the body of knowledge available to clinicians and help lead to a better understanding of the relationship between chemotherapy and ocular motility dysfunction. The authors are indebted to the national centers mentioned in this study that contributed data. The opinions and conclusions, however, are not necessarily those of the National Registry of Drug-Induced Ocular Side Effects or the World Health Organization. References 1. Imperia PS, Lazarus HM, Lass JH. Ocular complications of systemic cancer chemotherapy. Surv Ophthalmol 1989;34:209-30.
2. Chen HY, Tsai RK, Huang SM. ATRA-induced pseudotumor cerebri— one case report. Kaohsiung J Med Sci 1998;14:58-60. 3. Oster MW. Ocular side effects of cancer chemotherapy. In: Perry MC, Yarbro JW, editors. Toxicity of chemotherapy. New York: Grune & Stratton; 1984. p. 181-92. 4. Goldberg ID, Bloomer WD, Dawson DM. Nervous system toxic effects of cancer therapy. JAMA 1982;247:1437-41. 5. Baker L, Wirtschafter JD. Experimental doxorubicin myopathy: a permanent treatment for eyelid spasms? Arch Ophthalmol 1987;105: 1265-8. 6. Edwards R, Biriell C. Harmonisation in pharmacovigilance. Drug Saf 1994;10:93-102. 7. Fraunfelder FT, Fraunfelder FW. Drug-induced ocular side effects. 5th ed. Woburn (MA): Butterworth-Heinemann; 2001.
An Eye on the Arts – The Arts on the Eye
The Great Seal is reproduced on the back of the modern dollar bill. It has been there for almost seventy years. Some still ﬁnd its design disturbing; it is certainly unique. Paper money around the world tends to portray famous people, landmarks, kings, queens, splendid new dams, characteristic animals, or funky graphics, rather as though it was produced by the local tourist board. The dollar, on the contrary, glories in its weirdness. The Great Seal shows an eagle carrying a shield on one side, and an unﬁnished pyramid below a blazing eye on the other. The eye is generally taken to be the eye of God; but perhaps it is really the eye of the people—an unblinking, all-seeing eye that penetrates through conspiracies of power and warns the republic of threats to its liberty. It ﬁrst appeared on the back of the dollar bill in 1935, when Roosevelt’s New Deal was being put together to drag America out of the Great Depression. Secretary of Agriculture Henry A. Wallace was idly contemplating a picture of the seal one day when the phrase Novus Ordo Seclorum struck him as meaning the New Deal of the Ages. He took the picture to President Roosevelt, who “was ﬁrst struck by the representation of the ‘All-Seeing Eye,’ a Masonic representation of The Great Architect of the Universe,” Wallace recalled. —Jason Goodwin (from Greenback: The Almighty Dollar and the Invention of America)