Amiodarone-induced ocular and extra-ocular toxicity: a retrospective cohort study

Amiodarone (AMD) is a largely employed anti-arrhythmic agent for the treatment of recurrent supraventricular and ventricular tachyarrhythmias. Because of its lipophilic properties, prolonged half-life and prevailing biliary excretion, it is not rarely responsible for potentially severe adverse events that can involve one or more organs with a prevalence ranging from 15% in the first year of drug intake to 50% in patients treated for a longer time. In addition to pro-arrhythmia effects, AMD toxicity may result in a variable combination of clinical manifestations, including visual impairment, thyroid dysfunctions, pulmonary diseases, liver injury, neutropenia or thrombocytopenia. We aimed to describe the AMD-induced ophthalmologic and non-ophthalmologic side effects observed in a longitudinal cohort of patients. Seventeen Caucasian patients, who were on amiodarone therapy for a variable period, were enrolled in this retrospective, cross-sectional, observational study. All of them were referred to the Department of Ophthalmology and Neuroscience of the University of Bari, Italy, because of visual disturbances of variable severity. Three patients were given 3 intravenous boluses of 150 mg AMD followed by progressively decreasing oral doses, whereas 14 patients received a loading daily dose of 600-1200 mg orally, reduced after 2-3 weeks to a maintenance daily dose of 200-400 mg. All patients underwent complete clinical and laboratory assessments, according to a standard protocol. Ophthalmologic examination included intraocular pressure, ocular motility, visual field testing, angiography, optical coherence tomography, best-corrected visual acuity (BCVA) and grading of AMD-induced keratopathy by slit-lamp biomicroscopy. At diagnosis, eye disorders ranging from blurred vision and deterioration of visual acuity to eye redness and progressive glare were reported in 14 patients and lasting photophobia in the remaining 3 patients. Verticillate keratopathy (VK), stage 1-4, was diagnosed in all of them. Following AMD cessation, the patients were checked after a mean of 94 days and clear corneas were found in 12 of them, whereas lower-stage VK persisted in 5 patients. A 20/40 visual outcome or better was detected in 29 of 34 eyes (85.3%). Bilateral optic disk edema was found in 3 patients. Fundoscopic examination performed 23 months after AMD discontinuation showed that optic disk edema was reduced in all 3 patients, though to a variable extent. Optic neuropathy with protracted disk edema was diagnosed in a single patient who complained of progressive visual loss. Almost 2 months after AMD cessation, disk edema was reduced in OD > OS and BCVA partially improved. Extra-ocular manifestations included poorly symptomatic hypothyroidism in 2 patients, and overt myxedema, cholestatic liver injury, pancytopenia and interstitial pneumonitis associated with subclinical hypothyroidism in one patient each. A point stemming from our study and not clearly emphasized in the literature is that while a higher maintenance dose of AMD for a longer time was responsible for the most advanced grade 4 VK, no correlation was found between the occurrence of extra-ocular manifestations and the severity of ophthalmological signs or complaints. Patients assuming AMD should undergo close monitoring by specialist clinicians of a multidisciplinary team with the aim of an early recognition of eye, thyroid, liver and lung toxicities, thus preventing more serious complications.