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Introduction
Hill Criteria
Studies
Summary
References

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 Neuro-Ophthalmology

Amiodarone Optic Neuropathy

Andrew G. Lee, MD

Introduction

Despite numerous reports in the literature, amiodarone optic neuropathy remains a controversial subject.1-19 Issues associated with amiodarone optic neuropathy have medicolegal and medical implications. In February 1997, an Oregon court awarded to a plaintiff with visual loss from amiodarone a $20 million judgment from Wyeth-Ayerst Laboratories.1 Explicit causality criteria may be useful to determine the validity of the association between amiodarone and optic neuropathy.

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Hill Criteria

Austin Bradford Hill, a British medical statistician, proposed criteria to define causality.20 The Hill criteria include:

  • Temporal relationship between cause and effect
  • Strength of association
  • Dose-response relationship (i.e., increasing amount of exposure increases risk and vice versa)
  • Consistency (e.g., reproducibility of effect in multiple studies)
  • Biologic plausibility
  • Consideration and elimination of alternate explanations
  • Experiment (i.e., the condition can be altered by an appropriate experimental regimen of rechallenge or recovery after discontinuation of the cause)
  • Specificity of effect (e.g., bull's eye maculopathy in choroquine toxicity)
  • Coherence with existing medical theory and current knowledge (e.g., analogy from previous work with humans or animals)

Comparing the application of the Hill criteria for amiodarone corneal deposits (verticellata) with amiodarone optic neuropathy may be useful. In clinical and preclinical studies of amiodarone, a clear temporal relationship existed between the use of the drug and the development of the keratopathy. The strength of the association of verticellata and amiodarone is high (up to 95%) and is consistent across multiple studies and multiple prospective observations.2-6 The hypothesis that deposition of the drug in the cornea causes the keratopathy is biologically plausible and has been confirmed by experimental testing of the conjunctiva and corneal epithelium.

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Studies

D’Amico and colleagues4 studied eight patients and documented the formation of vortex-like figures within the anterior cornea. Light-microscopy and transmission electron microscopy revealed complex lipid deposits within lysosome-like intracytoplasmic inclusions in corneal, conjunctival, and lens epithelium; conjunctival fibrocytes; and conjunctival vascular endothelium. Vortex keratopathy is a specific finding for deposition of drug or other substances in the corneal epithelium and few other conditions (e.g., chorlorquine toxicity) could produce the clinical picture.

Orlando and colleagues2 prospectively followed 18 patients on amiodarone and 17 patients (94%) developed characteristic epithelial keratopathy in at least one eye within 3 months of the therapy. The corneal effect is dose-related. Kaplan and colleagues3 reviewed 27 patients and reported that the keratopathy correlated with dosage and duration of treatment and that after discontinuation of the drug there was regression of the deposits.

In contrast to amiodarone keratopathy, the data on amiodarone optic neuropathy are less convincing for causality using the Hill criteria. Although some temporal relationship exists between drug onset and optic neuropathy, in many cases the visual loss does not occur until weeks or months after beginning treatment.7-19

The half-life of amiodarone is reported to be 3.2 to 79.7 hours, but the half-life after long-term treatment may be as long as 100 days.6 A toxic effect is difficult to support for the cases of amiodarone optic neuropathy resembling typical anterior ischemic optic neuropathy. It does not seem biologically plausible that an acute ischemic event would be related to drug toxicity. On the other hand, it is plausible that drug deposition could occur over time in the patients with more insidious and bilateral onset.

Mansour and colleagues18 reported the histopathologic findings of an optic nerve obtained from an asymptomatic subject on amiodarone. Lamellar inclusions were selectively found in the large axons. The researchers postulated that amiodarone may have a chronic neurotoxic effect on the optic nerve via a drug-induced lipidosis, but the linkage to a clinical presentation of anterior ischemic optic neuropathy was not defined.

The strength of the association between optic neuropathy and amiodarone is relatively weak compared with amiodarone keratopathy. Amiodarone vortex keratopathy occurs in up to 95% of patients treated. In contrast, Feiner and colleagues7 followed 447 patients taking amiodarone and 13 developed optic neuropathy with an incidence of 1.79%. This figure is higher than would be expected for anterior ischemic optic neuropathy in the general population, but the true incidence of anterior ischemic optic neuropathy in an age-matched vasculopathic population is not well defined. In addition, a dose-response relationship between the optic neuropathy and the duration, dose, or levels of amiodarone is not imminent.

Variable consistency is found in the clinical features of the optic neuropathy across the case reports and series due to the lack of widely accepted diagnostic criteria for amiodarone optic neuropathy and the lack of an objective confirmatory test for the diagnosis. In addition, little rechallenge data exist. Although cases of visual recovery after discontinuation of the medication exist, this may reflect the natural history of non-arteritic anterior ischemic optic neuropathy. Almog and Goldstein17 reviewed 23 patients with asymptomatic disc edema and followed them for the development of anterior ischemic optic neuropathy. The conversion rate to anterior ischemic optic neuropathy was 40% in patients with prior anterior ischemic optic neuropathy in the fellow eye, 31% in patients with diabetes, 43% in patients with diabetic retinopathy, and 0% in the four patients treated with amiodarone.

Slide 1

SLIDE 1View full size slide

The specificity of the effect, unlike corneal deposits from amiodarone, is also weak and many of the reported cases are indistinguishable from "garden variety" non-arteritic anterior ischemic optic neuropathy. In addition, many of these patients are on amiodarone for a cardiac condition and usually have other vasculopathic risk factors that might predispose them to the development of anterior ischemic optic neuropathy. Whether amiodarone produces typical anterior ischemic optic neuropathy due to hypotension from its antihypertensive effect has not been critically studied.

Macaluso and colleagues12 described 73 patients with an optic neuropathy while taking amiodarone. The patients had an insidious onset, slow progression, were bilateral, and showed protracted disc swelling that resolved within several months after discontinuing the medication. Nagra and colleagues15 reported three patients with loss of visual acuity and visual field, and bilateral optic disc swelling that slowly improved after discontinuation of the drug. These cases seem clinically distinct from typical anterior ischemic optic neuropathy.12

Finally, optic nerve toxicity from other agents (e.g., ethambutol) does not resemble the clinical presentation and course of presumed amiodarone optic neuropathy. In ethambutol toxicity, the condition is dose related, slowly progressive, not associated with optic disc edema, bilateral and simultaneous, and characterized by a central or cecocentral scotoma.

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Summary

Amiodarone keratopathy is temporally associated with drug onset, a dose-dependent effect seen in the majority of patients on the drug, produces a characteristic and specific corneal appearance that cannot be attributed to alternative etiologies, has been pathologically proven to be due to drug deposition in the epithelium, and typically resolves after discontinuation of the drug.

Slide 2

SLIDE 2View full size slide

In contrast, amiodarone optic neuropathy is not a dose-dependent phenomenon, is seen in a minority of patients on the drug, has no proven pathogenic mechanism, produces a picture that sometimes is clinically indistinguishable from non-arteritic anterior ischemic optic neuropathy (Slide 1 and Slide 2), occurs in patients with alternative vasculopathic risk factors for anterior ischemic optic neuropathy, and sometimes does not resolve even after discontinuation of the drug.

The most convincing cases of amiodarone optic neuropathy are those with an insidious, bilateral onset (months) and chronic disc edema (months) that resolves after discontinuation of the drug. The least convincing cases resemble typical non-arteritic ischemic neuropathy with an acute and unilateral onset and shorter lasting (weeks) disc edema that resolves to optic atrophy. The risk to benefit ratio for continuing or discontinuing treatment should be discussed with the patient and the physician prescribing the amiodarone.

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References

  1. Mindel JM. Editorial: Amiodarone and optic neuropathy — a medicolegal issue. Surv Ophthalmol. 1998;42:358-359.

  2. Orlando RG, Dangel ME, Schaal SF. Clinical experience and grading of amiodarone keratopathy. Ophthalmology. 1984;91:1184-1187.

  3. Kaplan LJ, Cappaert WE. Amiodarone-induced corneal deposits. Ann Ophthalmol. 1984;16:762-766.

  4. D'Amico DJ, Kenyon KR, Ruskin JN. Amiodarone keratopathy: Drug-induced lipid storage disease. Arch Ophthalmol. 1981;99:257-261.

  5. Mantyjarvi M, Tuppurainen K, Ikaheimo K. Ocular side effects of amiodarone. Surv Ophthalmol. 1998;42:360-366.

  6. Latini R, Tognoni G, Kates RE. Clinical pharmacokinetics of amiodarone. Clin Pharmacokinet. 1984;9:136-156.

  7. Feiner LA, Younge BR, Kazmier FJ, Stricker BH, Fraunfelder FT. Optic neuropathy and amiodarone therapy. Mayo Clin Proc. 1987;62:702-717.

  8. Borruat F, Regli F. Pseudotumor cerebri as a complication of amiodarone therapy. Am J Ophthalmol. 1993;116:776-777.

  9. Seemongal-Dass RR, Spencer SR. Bilateral optic neuropathy linked with amiodarone. Eye. 1998;12:474-477.

  10. Gittinger JW, Asdourian GK. Papillopathy caused by amiodarone. Arch Ophthalmol. 1987;105:349-351.

  11. Nazarian SM, Jay WM. Bilateral optic neuropathy associated with amiodarone therapy. J Clin Neuro-ophthalmol. 1988;8:25-28.

  12. Macaluso DC, Shults WT, Fraunfelder FT. Features of amiodarone-induced optic neuropathy. Am J Ophthalmol. 1999;127:610-612.

  13. Gittinger JW, Asdourian G. Amiodarone-related optic neuropathy. Mayo Clin Proc. 1988;63:210.

  14. Sedwick LA. Getting to the heart of visual loss: When cardiac medication may be dangerous to the optic nerves. Surv Ophthalmol. 1992;36:366-372.

  15. Nagra PK, Foroozan R, Savino PJ, Castillo I, Sergott RC. Amiodarone induced optic neuropathy. Br J Ophthalmol. 2003;87:420-422.

  16. Leifert D, Hansen LL, Gerling J. Amiodarone-associated optic neuropathy: An independent syndrome? Three patients with bilateral optic neuropathy. Klin Monatsbl Augenheilkd. 2000;217:171-177.

  17. Almog Y, Goldstein M. Visual outcome in eyes with asymptomatic optic disc edema. J Neuroophthalmol. 2003;23:204-207.

  18. Mansour AM, Puklin JE, O'Grady R. Optic nerve ultrastructure following amiodarone therapy. J Clin Neuro-ophthalmol. 1988;8:231-237.

  19. Colin Lizalde LJ, Febles Palenzuela T, et al. A retrospective study for the analysis of collateral effects of amiodarone. Arch Inst Cardiol Mex. 1990;60:455-460.

  20. Morabia A. On the origin of Hill’s causal criteria. Epidemiology. 1991;2:367-369.

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