Journal of Neuro-Ophthalmology, December 1988, Volume 8, Issue 4

Optic nerve ultrastructure following amiodarone therapy.

Amiodarone has been implicated in the pathogenesis of optic neuropathy in several cases. However, that relationship is unclear, as subjects placed on amiodarone represent a high-risk group for various vasoocclusive accidents. In order to investigate the effect of amiodarone on the optic nerve, we examined histopathologically sections of the retrobulbar optic nerve obtained from an asymptomatic subject taking amiodarone. Lamellar inclusions were selectively found in the large axons. Amiodarone may have a chronic neurotoxic effect on the optic nerve via a drug-induced lipidosis. This neurotoxicity may be related to some of the acute forms of optic neuropathy described in the literature.

Journal of Clinical NeuTo-ophthalmology 8(4):231-237, 1988. Optic Nerve Ultrastructure Following Amiodarone Therapy Ahmad M. Mansour, M.D., James E. Puklin, M.D., and Richard O'Grady, M.D. © 1988 Raven Press, Ltd., New York Amiodarone has been implicated in the pathogenesis of optic neuropathy in several cases. However, that rela­tionship is unclear, as subjects placed on amiodarone represent a high-risk group for various vasoocclusive ac­cidents. In order to investigate the effect of amiodarone on the optic nerve, we examined histopathologically sec­tions of the retrobulbar optic nerve obtained from an asymptomatic subject taking amiodarone. Lamellar in­clusions were selectively found in the large axons. Ami­odarone may have a chronic neurotoxic effect on the optic nerve via a drug-induced lipidosis. This neurotox­icity may be related to some of the acute forms of optic neuropathy described in the literature. Key Words: Amiodarone-Optic nerve-Optic neurop­athy- Neurotoxicity. From the Department of Ophthalmology, University of Texas Medical Branch, Galveston, Texas (A.M.M.), and the Depart­ment of Ophthalmology, Northwestern University Medical SchooL Chicago, Illinois (J.E.P., R.O'G.), U.S.A. Address correspondence and reprint requests to Ahmad M. Mansour, M.D., Department of Ophthalmology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77550, U.S.A. 231 Amiodarone was introduced for clinical use in 1964 as a vasodilator with antianginal and antihy­pertensive properties (1). More recently, studies have documented its efficacy in the treatment of arrhythmias, notably supraventricular and ventric­ular tachycardia, as well as symptomatic and re­fractory atrial fibrillation (2,3). Serious systemic ad­verse effects have included alteration of serum thy­roid hormones, interstitial pneumonitis, tremor, and peripheral neuropathy (2,4), Ocular side effects of amiodarone are usually not sight-threatening. However, several reports have recently linked the occurrence of an optic neurop­athy to amiodarone intake (5-7), Evidence for that association has remained circumstantial. We present the first histopathological findings of the retrobulbar optic nerve in a subject taking amio­darone. CASE REPORT A 57-year-old asymptomatic white man was found to have atrial fibrillation in June 1985. He FIG. 1. Whorl-like distribution of epithelial lesions of the right cornea. 232 A. M. MANSOUR ET AL. FIG. 2. Cornea verticillata of the left eye. was started on digoxin, followed by Coumadin and verapamil. Due to inadequate control, vera­pamil was replaced by amiodarone at a starting daily oral dose of 600 mg. He was then maintained on 400 mg of amiodarone every other day. Routine eye examination then revealed a moderate-sized choroidal melanoma in the right eye. Eighteen months later, the patient was referred for enucle­ation of the right eye because of growth of the melanoma. Upon admission, visual acuities were 20/20 in both eyes. The patient had bilateral cornea verticillata (Figs. 1 and 2). A 7DD x 300 x 100 fusiform creamish-grayish choroidal lesion was present along the inferotemporal arcade of the right eye, with an overlying neurosensory retinal detachment (Fig. 3). The optic discs were normal looking, with surrounding peripapillary atrophy and a cup/disc ratio of 0.3 in the right eye and 0.4 in the left eye (Figs. 4 and 5). Fluorescein angio­graphy revealed normal filling of the optic disc vasculature (Figs. 4 and 5) and several transmis- FIG. S. Inferior equatorial fusiform choroidal leSion (arrows) reaching the inferior arcade in the right eye. • './ jQS3 FIG. 4. (A) Posterior pole of the right eye shows peri­papillary atrophy and hypopigmented areas of retinal epithelium nasal to the macula (arrowheads). (8) These areas transmit fluorescence during the arterio­venous phase. sion defects corresponding to several hypopig­mented retinal lesions. Enucleation was consented. The eyeball was cut into calotles. The calotles were placed in formaldehyde (as part of the National Mel­anoma Study protocol), and light microscopy re­vealed a spindle cell choroidal melanoma. The optic nerve stump measured 4 mm in length and was im­mersed in a 3% glutaraldehyde solution. The distal 2-mm portion of the optic nerve was disregarded, and the portion behind the globe was cut into a l-lJ.m section (Fig. 6), as well as being processed for trans­mission electron microscopy. All of the nerve axons appeared to be myelinated (Fig. 7). The oligodendro­cytes (Fig. 8) and astrocytes (Fig. 9) did not contain intracytoplasmic membrane-bound bodies. Several large axons had multiple lamellated inclusion bodies (Fig. 10). There was no apparent loss of large axons, as the size distribution ofaxons appeared to be nor­mal. OPTIC NERVE AFTER AMIODARONE 233 FIG. 5. (A) Posterior pole of the left eye demonstrates peripapillary atrophy and multiple areas of hypopig­mented retinal pigment epithelium (arrowhead). (8) These areas correspond to transmission defects on fluorescein angiography. DISCUSSION Amiodarone-induced intracytoplasmic mem­brane- bound bodies have been detected in several ocular tissues: corneal epithelium (8-12), corneal fibroblasts (8,10), corneal endothelium (8,9), con­junctival fibrocytes and vascular endothelium (8,9), eyelid (13), lens epithelium (8,9,14), retinal pigment epithelium (8,15,16), retinal ganglion cells (8,16), Mueller cells (16), extraocular muscles (16), uveal fibrocytes, scleral fibrocytes, and pigment epithelium of iris and ciliary body (8,16). Visual disturbances are uncommon following amio­darone intake. Amiodarone keratopathy is an in­nocent reversible side effect and does not usually affect visual acuity (17). Amiodarone-induced cor­neal changes usually appear within 8 months after intake of the drug and disappear within 7 months after cessation of the drug (12,18). The prevalence of corneal changes varied between different series to include values such as 41.3% (19), 70% (17), 78% (20), 82.5% (11), 90% (21), 94% (22), 95% (10), 98% (18,23), and 100% (24). The severity of the cornea verticillata is correlated with the total dose of ami­odarone as well and with the duration of treatment (17). Amiodarone is known to cause peripheral neu­ropathy in humans (2,4,25-31) and in experimental studies in rats and mice (15). Most patients have presented with signs and symptoms of sensori­motor polyneuropathy of the four limbs without cranial or autonomic neuropathy. Histopathologi­cally, the amiodarone-induced peripheral neurop­athy has consisted of varying degrees of demye­lination, axonal loss, and presence of numerous lysosomal inclusions in Schwann cells and other cell types. There is selective loss of the large axons (30,31). Similar findings have been reported in neuropathies induced by perhexiline maleate (de­myelination from toxicity of Schwann cells) and in drug-induced lipidosis (lamellar inclusions) (25). Ultrastructural findings in our case were com­pared to findings in normal optic nerves reported elsewhere (32,33). Our case demonstrated a selec­tive accumulation of intracytoplasmic lamellar in­clusions in the large axons. It is inferred that a likely mechanism of optic nerve damage in amio­darone- related optic neuropathy is a primary lipi­dosis. Amiodarone chlorhydrate is a triiodated ben­zofuran derivative. The drug is a cationic ampho­philic drug possessing neighboring hydrophilic and hydrophobic groups that allow the drug to interact with polar lipids. The resulting complexes accumulate in lysosomes as lamellated inclusion bodies. Amiodarone has a long elimination half­life of 41 days (34,35). Other amphophilic drugs, like perhexiline, iodochlorhydroxyquin, and di­iodohydroxyquin, have been reported to cause, re­spectively, asymptomatic optic disc swelling (36), subacute myelooptic neuropathy (37), and optic at­rophy (38). Visual loss, visual field loss, and optic disc swell­ing have been described in 17 patients taking ami­odarone. Chew et a1. (10) mentioned briefly the occurrence of ischemic optic neuropathy in one pa­tient with amiodarone keratopathy. Gittinger and Asdourian (5) reported two subjects with optic nerve head swelling. The first subject was asymp­tomatic and developed disc edema 8 months fol­lowing amiodarone intake; the second subject had bilateral disc involvement with mild decrease in visual acuity in one eye 8 months following amio­darone intake. Feiner et a1. (6) collected 13 cases of J Clin Neuro-ophthalmol, Vol. 8, No.4. 1988 FIG. 6. Cross-section of the retrobulbar optic nerve showing septae (arrows) sepa­rating bundles ofaxons (paraphenylenediamine stain, x 100). FIG. 7. Transmission electron micrograph of a cross-section of the retrobulbar optic nerve showing uniform myelination of the nerve fibers (x 1ADO). The nerve fibers show considerable variation in diameter. Intrafascicular astrocytes are noted in the " "I thp figure '~I'rows). FIG. 8. Electron micrograph of a cross-section of the retrobulbar portion of the optic nerve showing an oligodendrocyte (x10,500). Note the dense cytoplasm packed with rough endoplasmic reticulum (arrowheads) and free ribosomes. FIG. 9. Transmission electron micrograph of an intrafascicular astrocyte in the ret­robulbar portion of the optic nerve (x 10,500). The karyoplasm shows the coarse chromatin clumps within a relatively light karyoplasm. The cytoplasm is pale. An intracytoplasmic cilium is noted (arrowhead). A neighboring astrocyte is present (dark arrows). Membrane-bound inclusion bodies (lipofuscin) are present outside the as­trocytic processes (open arrows). 236 A. M. MANSOUR ET AL. FIG. 10. Electron micrograph of a cross-section of the retrobulbar optic nerve (x7,OOO). Centrally, a large axon has mitochondria (arrow), endoplasmic reticulum, and multiple lamellated inclusion bodies (arrowheads). optic neuropathy in subjects receIvmg amio­darone. Visual loss occurred from 1 to 72 months following amiodarone therapy. All subjects but one had swelling of the optic disc. Two patients in that series had normal visual acuities and visual fields (asymptomatic disc swelling), whereas the remaining patients had mild to moderate loss of visual acuity or visual fields. Nazarian and Jay (7) reported a patient with bilateral disc swelling and visual loss 4 weeks following initiation of amio­darone therapy. These 17 case reports may repre­sent a mixture of anterior ischemic optic neuropa­thy on one side, and optic neuropathy related to amiodarone on the other side. The amiodarone­related optic neuropathy is typically milder in se­verity than anterior ischemic optic neuropathy. Duff and Fraser reported the impairment of color vision in patients on amiodarone therapy (24). The impairment correlated with the severity of amiodarone keratopathy. These authors attrib­uted the disturbance in color discrimination to the keratopathy. We propose that these color defects are likely to be a result of a mild subacute form of >,r, 4. 1988 amiodarone-induced optic neuropathy. Testing of color vision, visual fields, and visual evoked re­sponses may be helpful in detecting otherwise asymptomatic cases of amiodarone optic neuropa­thy. Moreover, our case raises the possibility of a common, subclinical, chronic type of mild axonal degeneration secondary to amiodarone-induced lipidosis, in contrast to the acute and less common form of neuropathy detailed in the literature (5-7). This acute form could be related to a neurotoxic effect of the drug. REFERENCES 1. Miller MH-A. Keratopathic consecutive au traitement par cordarone (chlorhydrate d'amiodarone). Bull Soc Fr Ophtal­mol 1969;69:1059-65. 2. Nademanee K, Singh BN, Cannom OS, Weiss J, Feld G, Stevenson WG. Control of sudden recurrent arrhythmic deaths: role of amiodarone. Am Heart / 1983;106:895-901. 3. Blevius Roger 0, Kerin NZ, Benaderet 0, Frumin H, Faitel K, Jarandilla R, Rubenfire M. Amiodarone in the manage­ment of refractory atrial fibrillation. Arch Intern Med 1987;147:1401~. 4. McGovern B, Garan H, Ruskin IN. Serious adverse effects of amiodarone. Clin Cardiol 1984;7:131-7. OPTIC NERVE AFTER AMIODARONE 237 5. Gittinger JW, Asdourian GK. 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