References And Further Reading

Ah-Song R, Sasco AJ. Tamoxifen and ocular toxicity. Rev Cancer Detect Prevent 21: 522–531, 1997.

Alwitry A, Gardner I. Tamoxifen maculopathy. Arch Ophthalmol 120: 1402, 2002. Ashford AR, et al. Reversible ocular toxicity related to tamoxifen therapy.

Cancer 61: 33, 1988.

Bradbury BD, Lash TL, Kaye JA, et al. Tamoxifen and cataracts: a null association. Breast Cancer Res Treat 87: 189–196, 2004.

Chang T, Gonder JR, Ventresca MR. Case report: Low-dose tamoxifen retinopathy. Can J Ophthalmol 27: 148–149, 1992.

Colley SM, Elston JS. Tamoxifen optic neuropathy. Clin Exp Ophthalmol. Eisner A, Incognito LJ. The color appearance of stimuli detected via short-

wavelength-sensitive cones for breast cancer survivors using tamoxifen. Vis Res 46: 1816–1822, 2006a.

Eisner A, Austin DF, Samples JR. Short wavelength automated perimetry and tamoxifen use. Br J Ophthalmol 88: 125–130, 2004.

Eisner A, O’Malley JP, Incognito LJ, et al. Small optic cup sizes among women using tamoxifen: assessment with scanning laser ophthalmoscopy. Curr Eye Res 31: 367–379, 2006b.

Fisher B, Costantino JP, Wickerham L, et al. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst 90: 1371–1388, 1998.

Gallicchio L, Lord G, Tkaczuk K, et al. Association of tamoxifen (TAM) and TAM metabolite concentrations with self-reported side effects of TAM in women with breast cancer. Breast Cancer Res Treat 85: 89–97, 2004.

Gianni L, Panzini I, Li S, et al. Ocular toxicity during adjuvant chemoendocrine therapy for early breast cancer. Cancer 106: 505–513, 2006.

Gorin MB, Day R, Costantino JP, et al. Long-term tamoxifen citrate use and potential ocular toxicity. Am J Ophthalmol 125: 493–501, 1998.

Gorin MB, Costantino JP, Kulacoglu DN, et al. Is tamoxifen a risk factor for retinal vaso-occlusive disease. Retina 25: 523–526, 2005.

Griffiths MFP. Tamoxifen retinopathy at low dosage. Am J Ophthalmol 104: 185–186, 1987.

Gualino V, Cohen SY, Dalyfer M-N, et al. Optical coherence tomography findings in tamoxifen retinopathy. Am J Ophthalmol 140: 757–758, 2005.

Heier JS, Dragoo RA, Enzenauer RW, et al. Screening for ocular toxicity in asymptomatic patients treated with tamoxifen. Am J Ophthalmol 117: 772–775, 1994.

Hollander DA, Aldave AJ. Drug-induced corneal complications. Curr Opin Ophthalmol 15: 541–548, 2004.

Imperia PS, Lazarus HM, Lass JH. Ocular complications of systemic cancer chemotherapy. Surv Ophthalmol 34(3): 209–230, 1989.

Kaiser-Kupfer MI, Kupfer C, Rodrigues MM. Tamoxifen retinopathy. A clinicopathologic report. Ophthalmology 88: 89, 1981.

Kalina RE, Wells CG. Screening for ocular toxicity in asymptomatic patients treated with tamoxifen. Am J Ophthalmol 119: 112–113, 1995.

McKeown CA, et al. Tamoxifen retinopathy. Br J Ophthalmol 65: 177, 1981. Nayfield SG, Gorin MB. Tamoxifen associated eye disease: a review. J Clin

Oncol 14: 1018–1026, 1996.

Paganini-Hill A, Clark LJ. Eye problems in breast cancer patients treated with tamoxifen. Breast Cancer Res Treat 60: 167–172, 2000.

Pavlidis NA, et al. Clear evidence that long-term, low-dose tamoxifen treatment can induce ocular toxicity. A prospective study of 63 patients. Cancer 69(12): 2961–2964, 1992.

Pugesgaard T, von Eyben F. Bilateral optic neuritis evolved during tamoxifen treatment. Cancer 58: 383, 1986.

Robinson E, Kimmick GG, Muss HB. Tamoxifen in postmenopausal women, a safety perspective. Review 8: 329–337, 1996.

Sadowski B, Kriegbaum C, Apfelstedt-Sylla E. Tamoxifen side effects, agerelated macular degeneration (AMD) or cancer associated retinopathy (CAR)? Eur J Ophthalmol 11: 309–312, 2001.

Tamoxifen and venous thromboembolism. WHO ADR Newslett 2: 3, 1999. Tang R, Shields J, Schiffman J, et al. Retinal changes associated with

tamoxifen treatment for breast cancer. Rev Eye 11: 295–297, 1997. Tsai D-C, Chen S-J, Chiou S-H, et al. Should we discontinue tamoxifen

in a patient with vision-threatening ocular toxicity related to low-dose tamoxifen therapy? Eye 17: 276–278, 2003.

Vinding T, Nielsen NV. Retinopathy caused by treatment with tamoxifen in low dosage. Acta Ophthalmol 61: 45, 1983.

Generic name: Thiotepa.

Proprietary name: Generic only.

Primary use

Systemic

This ethylenimine derivative is used in the management of ­carcinomas of the breast and ovary, lymphomas, Hodgkin’s ­disease and various sarcomas.

Ophthalmic

This topical agent is used to inhibit pterygium recurrence and possibly to prevent corneal neovascularization after chemical injuries.

Ocular side effects

Systemic administration (intravenous, intramuscular)

Certain

1.Eyelids or conjunctiva

a.Erythema

b.Angioneurotic edema

c.Urticaria

d.Periorbital depigmentation

Possible

1. Eyelids or conjunctiva – loss of eyelashes or eyebrows 2. Hyperpigmentation

3. Ocular teratogenic effects (intravenous, intramuscular only)

4. Subconjunctival or retinal hemorrhages secondary to drug-induced anemia

Local ophthalmic use or exposure

Certain

1. Irritation

2. Eyelids or conjunctiva

a.Allergic reactions

b.Conjunctivitis – non-specific

c.Depigmentation

d.Poliosis

3. Delayed corneal wound healing

4. Keratitis

5. Corneal edema

6. Occlusion of lacrimal punctum

Possible

1. Corneal ulceration

Clinical significance

Thiotepa is seldom given systemically because it has been replaced by more effective drugs. It is still used for mucosal ­neoplasia (i.e. bladder). The primary ocular side effect from systemic use is periorbital pigmentation (Horn et al 1989). While

­muscle palsies, internuclear opthalmoplegia, corneal anesthesia and lagophthalmos occuring in one form or another in up to 50% of the cases (Albert et al 1967). Lash et al (2004) and Toker et al (2004) reported reversible 6th nerve palsy associated with ­vincristine use. Müller et al (2004) reported the benefits of ­pyridoxine and pyridostigmine therapy to improve vincristineinduced ptosis. Optic neuropathy has been reported with ­vincristine, which can improve if the drug is discontinued in most cases (Sanderson et al 1976; Norton et al 1979). However, irreversible blindness has been reported (Margileth et al 1977). Retinal damage can occur based on autopsy findings (Sanderson et al 1976; Munier et al 1992). Transient cortical blindness has also been reported, with recovery in 1 to 14 days (Byrd et al 1981; Schouten et al 2003). The later case showed transient neuroradiological lesions in the occipital cortex. The ocular signs of gout that may occur include conjunctival hyperemia, uveitis, scleritis and corneal deposits or ulcerations. Ripps et al (1984) ­extensively studied a patient who developed night blindness ­after vincristine therapy. They felt that this drug interfered in the process of synoptic transmission between the photoreceptors and their second order neurons.

The accidental splashing of vinblastine causes a characteristic keratopathy, which includes microcystic edema, superficial punctate keratitis and corneal erosion with or without low-grade anterior uveitis. Corneal epithelial damage is usually apparent within the first few days along with decreased vision. The keratitis ­resolves within weeks to months. There is one report of increased astigmatism after inadvertent drug exposure. Most cases develop keratoconjunctivitis sicca and some show opacities in the area of Bowman’s layer - both of which appear to be permanent. ­Chowers et al (1996) postulated that sicca is caused by severe initial inflammation or vinblastine-induced neuropathy. Steroids experimentally had no effect on improving these toxic reactions.

References And Further Reading

Albert DM, Wong V, Henderson ES. Ocular complications of vincristine therapy. Arch Ophthalmol 78: 709–713, 1967.

Awidi AS. Blindness and vincristine. Ann Intern Med 93: 781, 1980. Birch J, et al. Acquired color vision defects. In: Congenital and Acquired

Color Vision Defects, Pokorny J, et al. Grune & Stratton, New York, p 243–350, 1979.

Byrd RL, et al. Transient cortical blindness secondary to vincristine therapy in childhood malignancies. Cancer 47: 37, 1981.

Chowers I, Frucht-Pery J, Siganos CS, et al. Vinblastine toxicity to the ocular surface. Anti-Cancer Drugs 7(7): 805–808, 1996.

Cohen RJ, et al. Transient left homonymous hemianopsia and encephalopathy following treatment of testicular carcinoma with cisplatinum, vinblastine, and bleomycin. J Clin Oncol 1: 392, 1983.

Elomaa I, Pajunen M, Virkkunen P. Raynaud’s phenomenon progressing to gangrene after vincristine and bleomycin therapy. Acta Med Scand 216: 323, 1984.

Holland JF, et al. Vincristine treatment of advanced cancer: a cooperative study of 392 cases. Cancer Res 33: 1258–1264, 1973.

Imperia PS, Lazarus HM, Lass JH. Ocular complications of systemic cancer chemotherapy. Surv Ophthalmol 34(3): 209–230, 1989.

Kaplan RS, Wiernik PH. Neurotoxicity of antineoplastic drugs. Semin Oncol 9: 103, 1982.

Lash SC, Williams CP, Marsh CS, et al. Acute sixth-nerve palsy after vincristine therapy. J Aapos 8: 67–68, 2004.

Margileth DA, Polplack DG, Tizzo PA, et al. Blindness during remission in two patients with acute lymphoblastic leukemia: a possible complication of multimodality therapy. Cancer 39: 58–61, 1977.

McLendon BF, Bron AJ. Corneal toxicity from vinblastine solution. Br J Ophthalmol 62: 97, 1978.

Müller L, Kramm C, Tenenbaum T. Treatment of vincristine-induced bilateral ptosis with pyridoxine and pyridostigmine. Pediatr Blood Cancer 42: 287–288, 2004.

Munier F, Uffer S, Herbort CP, et al. Loss of ganglion cells in the retina secondary to vincristine therapy. Klinische Monatsblatter fur Augenheilkunde 200(5): 550–554, 1992.

Norton SW, Stockman JA III. Unilateral optic neuropathy following vincristine chemotherapy. J Pediatr Ophthalmol Strabismus 16: 190, 1979.

Ripps H, et al. Functional abnormalities in vincristine-induced night blindness. Invest Ophthalmol Vis Sci 25: 787, 1984.

Sanderson PA, Kuwabara T, Cogan DG. Optic neuropathy presumably caused by vincristine therapy. Am J Ophthalmol 81: 146–150, 1976.

Schmid KE, Kornek GV, Scheithauer W, et al. Update on ocular complications of systemic cancer chemotherapy. Surv Ophthalmol 51: 19–40, 2006.

Schouten D, de Fraff SSN, Verrips A. Transient cortical blindness following vincristine therapy. Med Pediatr Oncol 41: 470, 2003.

Shurin SB, Rekate HL, Annable W. Optic atrophy induced by vincristine. Pediatrics 70: 288, 1982.

Spaeth GL, Nelson LB, Beaudoin AR. Ocular teratology. In: Ocular Anatomy, Embryology and Teratology, Jakobiec FA (ed), JB Lippincott, Philadelphia, p 955–975, 1982.

Teichmann KD, Dabbagh N. Severe visual loss after a single dose of vincristine in a patient with spinal cord astrocytoma. J Ocular Pharmacol 4: 149–151, 1988. Surv Ophthalmol 34: 149–150, 1989.

Toker E, Yenice O, Ogut MS. Isolated abducens nerve palsy induced by vincristine therapy. J Aapos 8: 69–71, 2004.

SECTION 12

Heavy Metal Antagonist and

Miscellaneous Agents

Class: Agents to Treat Alcoholism

Generic name: Disulfiram.

Proprietary name: Antabuse.

Primary use

This thiuram derivative is used as an aid in the management of chronic alcoholism.

References And Further Reading

Acheson JF, Howard RS. Reversible optic neuropathy associated with disulfiram. A clinical and electrophysiological report. J Neuroophthalmol 8: 175–177, 1988.

Bevilacqua JA, Diaz M, Diaz V, et al. Disulfiram neuropathy. Report of 3 cases. Rev Med Chil 130: 1037–1042, 2002.

Birch J, et al. Acquired color vison defects. In: Congenital and Acquired Color Vision Defects, Pokorny J et al. (eds), Grune & Stratton, New York, pp 243–350, 1979.

Gardner RJM, Clarkson JE. A malformed child whose previously alcoholic mother had taken disulfiram. N Z Med J 93: 184, 1981.

Geffray L, Dao T, Cevallos R, et al. Retrobulbar optic neuritis caused by disulfiram. Revue de Medecine Interne 16(12): 973, 1995.

Graveleau J, Ecoffet M, Villard A. Les neuropathies peripheriques dues au disulfirame. Nouv Presse Med 9: 2905, 1980.

Mokri B, Ohnishi A, Dyck PJ. Disulfiram neuropathy. Neurology 31: 730–735, 1981.

Morcamp D, Boudin G, Mizon JP. Complications neurologiques inhabituelles du disulfirame. Nouv Presse Med 10: 338, 1981.

Norton AL, Walsh FB. Disulfiram-induced optic neuritis. Trans Am Acad Ophthal Otol 76: 1263–1265, 1972.

Ocular side effects

Systemic administration – implantation

Certain

1. Decreased vision

2. Optic nerve

a.Hyperemia

b.Edema

c.Neuritis

d.Retrobulbar neuritis

e.Pallor

3. Scotomas – central or centrocecal

4. Problems with color vision – color vision defect, red-green defect 5. Eyelids or conjunctiva

a.Allergic reactions

b.Erythema

c.Urticaria

6. Visual hallucinations

Probable

1. Toxic amblyopia

Possible

1. Extraocular muscles – paresis or paralysis

Clinical significance

Disulfiram has been in use for over 55 years as a ‘psychological threat’ to treat alcoholism because of the severity of the disulfiramethanol interaction. When this interaction occurs, blurred vision may be marked, but serious adverse ocular side effects due to disulfiram are uncommon. Retrobulbar and optic neuritis have been well documented by numerous authors. In general, the vision loss secondary to retrobulbar or optic neuritis occurs 1–5 months after disulfiram is discontinued. These ocular side effects may be more common at higher dosages, in the elderly or in patients with impaired hepatic function. There are a few reports of optic disc hyperemia or optic nerve pallor. Neuropathy elsewhere occurs in 1 in 15 000 patients (Beveilacqua et al 2002) therefore optic nerve disorders are plausible. Other ocular side effects are reversible and seldom of importance. There is a case report in the National Registry of sisters on disulfiram who experienced transient repeating episodes of vertical diplopia. They were not related to time, day or activity and lasted only a matter of minutes then spontaneously resolved. Acheson and Howard (1988) reported a case of decreased and delayed visual evoked potential in a patient with bilateral optic neuropathy with recovery after 8 months off disulfiram.

Class: Calcium-Regulating Agents

Generic names: 1. Alendronate sodium; 2. disodium etidronate;­ 3. disodium pamidronate; 4. risedronate sodium; 5. sodium ibandronate; 6. tiludronate sodium; 7. zolendronic acid.

Proprietary names: 1. Fosamax; 2. Didronel; 3. Aredia; 4. Actonel; 5. Boniva; 6. Skelid; 7. Zometa.

Primary use

These biphosphonate calcium regulating agents are used primarily in the management of hypercalcemia of malignancy, metastasis bone pain, osteoporosis and Paget’s disease of bone.

Ocular side effects

Systemic administration (disodium pamidronate)

Certain

1. Blurred vision

2. Conjunctiva – transitory

a.Lacrimation

b.Hyperemia

c.Ocular pain

d.Burning sensation

e.Gritty sensation

f.Irritation

g.Angioneurotic edema 3. Anterior uveitis

4. Episcleritis

5. Scleritis

Possible

1. Visual hallucinations

2. Orbital inflammation

3. Color vision abnormalities

4. Eyelid or conjunctiva

a.Stevens-Johnson syndrome

b.Toxic epidermal necrolysis

Conditional/Unclassified

1. Optic neuritis

Clinical significance

It is rare in ophthalmology to get such a clear-cut positive rechallenge data of a drug-induced ocular side effect as with this class