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Show VIEWPOINT Amiodarone and Optic Neuropathy: The Heart of the Matter Marjorie A. Murphy, MD and John F. Murphy, MD, FACC Abstract: Amiodarone is one of the most effective antiarrhythmic drugs currently available. Although a subject of intense controversy, a causal link between amiodarone and optic neuropathy has never been firmly established. Indications for treatment with amiodarone are outlined, and features of the optic neuropathy in patients on amiodarone are compared with those of nonarteritic anterior ischemic optic neuropathy. An approach to patients treated with amiodarone who present with optic neuropathy is outlined, and suggestions for a registry and prospective study of such patients are presented. ( J Neuro- Ophthalmol 2005; 25: 232- 236) Heart disease is the leading cause of death in the United States, and more than 60 million Americans have some form of cardiovascular disease. Advances in antiarrhythmic therapy over the past several decades have nonetheless contributed greatly to a downward trend in the death rate from cardiac disease and have prolonged the lives of many with life- threatening cardiac arrhythmias. Amiodarone is currently one of the most effective anti- arrhythmic drugs in the treatment of both ventricular and supraventricular arrhythmias. Although reports of amiodarone- related optic neuropathy first began surfacing in the 1980s ( 1,2), a causal link between amiodarone treatment and optic neuropathy has never been firmly established. Even so, a $ 20 million judgment was rendered against Wyeth Ayerst in 1997 for not including blindness as a potential adverse effect in the package insert. A search of the Internet reveals that there is an abundance of so- called " amiodarone attorneys" willing to sue for blindness resulting from the drug. The web site amiodaronelawyer. com notes that " Cases of optic neuropathy, and/ or optic neuritis, resulting in visual impairment, have been common. The condition gives rise to symptoms such as visual halos or blurred vision and can progress to Departments of Ophthalmology ( MAM) and Cardiology ( JFM), Rhode Island Hospital, Brown Medical School, Providence, RI. Address correspondence to Marjorie A. Murphy, Rhode Island Hospital, Department of Ophthalmology, APC- 7, 593 Eddy Street, Providence, RI 02903; E- mail: margiemurphy@ cox. net permanent blindness.... If you or a loved one has been injured by amiodarone side effects, contact us today for a free consultation that will help you understand your rights." The concern about a link between amiodarone and optic neuropathy has caused many neuro- ophthalmologists to suggest that the medication be discontinued in patients with newly discovered optic neuropathy. Some have suggested that such patients can do without the drug and that it is overused. However, we are far more certain of how helpful amiodarone is from a cardiac standpoint than we are of how harmful it may be from an ophthalmologic standpoint. It is therefore important for ophthalmologists to understand all the data to make informed recommendations in patients who are using the drug and who present with visual symptoms. ANTI- ARRHYTHMIC THERAPY A brief review of antiarrhythmic therapy is helpful to gain a perspective on the current indications for prescribing amiodarone. The 1970s saw the appearance of beta blockers like propranolol, potassium- channel blockers like amiodarone, and calcium antagonists like verapamil for anti- arrhythmic therapy. Anti- arrhythmic research in the 1980s focused on finding more potent class I sodium channel- blocking agents, which include flecainide and encainide. This trend abruptly ceased after the revelation of their widespread proarrhythmic toxicity with the publication of the landmark Cardiac Arrhythmia Suppression Trial ( CAST) studies ( 3). The 1990s then saw a re- emergence of class III agents such as amiodarone and sotalol and a focus on developing new agents in this class ( 4). None of the classes of anti- arrhythmic agents is without toxicity ( 5). Many newer class I agents reduced some of these toxicities, but ironically, it was the recognition of their pro- arrhythmic effect that proved to be the critical toxicity limiting their use ( 4). As a result, agents with class III properties such as amiodarone and sotalol and newer pure class III compounds are undergoing a great increase in use. It is extremely rare for amiodarone to be associated with pro- arrhythmic effects found even with other class III agents ( 4). More importantly, amiodarone is still the most effective anti- arrhythmic agent available. There are currently four primary clinical uses for amiodarone: 1) the short- term and 2) long- term management 232 J Neuro- Ophthalmol, Vol. 25, No. 3, 2005 Amiodarone and Optic Neuropathy: The Heart of the Matter J Neuro- Ophthalmol, Vol. 25, No. 3, 2005 of ventricular tachycardia/ ventricular fibrillation, and 3) the short- term and 4) long- term management of atrial fibrillation. Amiodarone is indicated in the acute setting for ventricular fibrillation, sustained ventricular tachycardia, hemodynamically significant ventricular tachycardia, and symptomatic ventricular tachycardia. It is prominently recommended in the Advanced Cardiac Life Saving algorithms, and it is routinely relied on because of its clinical effectiveness ( 6). The long- term management of ventricular arrhythmias continues to evolve. Implantable cardioverter defibrillators ( ICD) are the first- line therapy for both primary and secondary prevention ( 7,8). There may be a misperception that these devices have eliminated the need for medical management of arrhythmias. The reality is that 40% to 70% of patients with ICDs require concomitant drug therapy ( 9,10) to: 1) reduce the frequency of sustained ventricular arrhythmias, which cause both symptoms and shocks; 2) slow the rate of ventricular tachycardia, which promotes anti- tachycardic pacing over shock therapy; 3) treat atrial fibrillation, which can cause serious problems in patients with devices; 4) promote device longevity; and 5) promote patient comfort. Amiodarone is frequently used for the management of atrial fibrillation in the acute, particularly inpatient, setting. Patients may have atrial fibrillation complicating surgery, pneumonia, or other infections. Stabilization often requires establishing and maintaining sinus rhythm, and amiodarone is the most effective medication for maintaining sinus rhythm. It is sometimes standard therapy for post-cardiac surgery prophylaxis against atrial fibrillation ( 11). The long- term use of amiodarone for atrial fibrillation is diminishing as a result of recent literature showing that rate control and anticoagulation do not have a higher risk of thromboembolization than rhythm control ( 12). Nonetheless, there are several indications for anti- arrhythmic therapy: 1) symptomatic relief, 2) prevention of tachycardia-mediated cardiomyopathy, 3) prevention of heart failure, and 4) prevention of thromboembolism, particularly in patients with contraindications to anticoagulation ( 13). Amiodarone is the most effective anti- arrhythmic for maintaining sinus rhythm ( 14). Additionally, it can be used in patients who cannot use other anti- arrhythmics because they have renal insufficiency, coronary artery disease, or structural heart disease. PROPERTIES OF AMIODARONE Amiodarone is an iodinated derivative of benzofuran highly bound by both lipid and protein. The amphophilic nature of the drug causes it to be widely distributed throughout body tissues, including the eye. Like other cationic amphophilic compounds, amiodarone interferes with the movement of phospholipids across intracellular membranes, leading to accumulation in high concentrations of phospholipid- bound drug in membrane- rich structures such as lysosomes. OPHTHALMIC HISTOPATHOLOGIC EFFECTS OF AMIODARONE With electron microscopy, lysosome- like intracyto-plasmic membranous lamellar bodies have been found in extraocular muscle fibers; corneal epithelial, stromal, and endothelial cells; conjunctival epithelium; sclera; lens epithelium; iris; ciliary body; choroid; retina ( particularly the retinal pigment epithelium and ganglion cells); large-diameter axons of the optic nerve; and the endothelium of all ocular blood vessels ( 15- 17). Despite the fact that ultra-structural changes have been observed in nearly all ocular tissues in patients taking amiodarone, most patients treated with the drug do not develop visual symptoms. OPHTHALMIC CLINICAL EFFECTS OF AMIODARONE Although nearly 100% of patients on amiodarone develop a verticillate keratopathy, this finding only infrequently produces symptoms of glare, halos, or blurred vision ( 4,18). Of greater concern is the fact that amiodarone is implicated in causing an optic neuropathy with optic disc swelling and hemorrhages, findings that are indistinguishable from those of nonarteritic anterior ischemic optic neuropathy ( NAION). Amiodarone has also been reported to cause an optic neuropathy in the absence of any visible disc changes ( 19- 21). Whether there is a causal relationship between amiodarone and optic neuropathy is a subject of intense controversy ( 18,22,23), and the pathophysiology is unknown. It is unclear whether the optic neuropathy is the result of a toxic effect of the drug ( 24), whether it is simply a variant of NAION in which resolution of disc swelling is prolonged, or whether it is an independent risk factor for NAION. OPTIC NEUROPATHY IN AMIODARONE- TREATED PATIENTS The incidence of optic neuropathy in patients receiving amiodarone is unknown, and it is unclear whether it is higher than the incidence of NAION in patients with similar cardiac arrhythmias. The incidence of amiodarone- related optic neuropathy was estimated by Feiner et al ( 2) at 1.76% over the preceding 10 years versus 0.3% in an age- matched population not using the drug. However, several confounding variables contribute to the possibility that the 1.76% figure is an overestimate. Of the 13 amiodarone- treated patients noted to have an optic neuropathy, three had 233 J Neuro- Ophthalmol, Vol. 25, No. 3, 2005 Murphy and Murphy asymptomatic disc swelling and one had normal- appearing discs and an abnormal visual evoked potential as the only support for an optic neuropathy. Five of the amiodarone - treated patients also had diabetes or hypertension, both of which are risk factors for NAION. The risk factor profile of the age- matched control group was not reported. Because there are no data on the incidence of NAION in an age-matched and disease- matched population, it is quite possible that the incidence of NAION is higher in a group of patients with severe cardiovascular disease who are treated with amiodarone. A wide spectrum of optic nerve involvement has been reported in patients taking amiodarone, including asymptomatic optic disc edema ( 1,2,25), unilateral optic neuropathy ( 2,25,26), and bilateral simultaneous ( 2,19,24,25,27) or sequential ( 28,29) optic neuropathy. Normal visual function ( 1,2) and visual loss ranging from mild ( 2,19,27) to severe ( 2,26,28,29) have been reported in association with the optic neuropathy. Likewise, the onset of visual loss has been noted to be acute in some cases ( 2,26,28) and insidious in others ( 21,27). Johnson et al ( 25) recently reported a clinical spectrum of amiodarone- induced optic neuropathy based on an observational case series involving two clinical neuro-ophthalmology practices and a Medline literature review of patients with optic neuropathy in association with amiodarone use. Based on their review of 55 patients, they stated that amiodarone- induced optic neuropathy can be classified into five distinct forms: insidious onset ( 43%), acute onset ( 28%), raised intracranial pressure ( 8%), and delayed- progressive onset ( 8%). They noted that, in contrast to visual acuity, visual field loss is permanent despite cessation of amiodarone. These findings are consistent with other reports showing that when visual loss has occurred in patients taking amiodarone, it has usually been permanent ( 2,23,24,26, 28,29) and that the disc edema has gradually turned to optic disc pallor. Others have noted that the optic neuropathy may improve in some patients after the discontinuation of amiodarone ( 19), but the improvement in visual fields is modest at best and not clearly better than that seen in patients with typical NAION who are not taking amiodarone. AMIODARONE- ASSOCIATED VERSUS NON- AMIODARONE- ASSOCIATED NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY Several authors have attempted to distinguish amiodarone- associated optic neuropathy from the NAION that occurs in patients not taking amiodarone. The disc swelling in patients who develop an optic neuropathy while taking amiodarone has been reported to resolve over months, more slowly than is seen in typical NAION ( 27). It is important to note that disc swelling resolves over a similar time course whether or not the drug is stopped ( 1,2,27,19,24,29). It is therefore quite possible that the optic neuropathy in patients taking amiodarone is simply an NAION in which disc swelling takes longer to resolve because of ultrastructural changes in the nerve. Selective accumulation of intracytoplasmic lamellar inclusions in large optic nerve axons may mechanically or biochemically decrease axoplasmic flow ( 17). However, the optic neuropathy itself and the intracytoplasmic inclusions may be unrelated. The fact that amiodarone induces subclinical structural change affecting the optic nerve does not mean that it is the cause of the optic nerve head swelling or the visual loss in optic neuropathy ( 22). Additional features are said to distinguish amiodarone-related optic neuropathy from NAION. It has been noted that some patients have " significant cup- to- disc ratios" ( 2), but whether this incidence is higher than that seen with NAION is unknown, because precise data regarding cup- to-disc ratios are generally lacking in reports of amiodarone-associated NAION ( 30,31). While some patients with an optic neuropathy on amiodarone have been noted to have improvement in vision when the drug is stopped ( 19), visual improvement has also been noted in patients in whom the drug is continued ( 1). Conversely, patients with asymptomatic disc swelling have been noted to have progression to an optic neuropathy even after the drug has been discontinued ( 2,19,29). This situation is analogous to the finding that asymptomatic disc swelling may precede visual loss in NAION by weeks to months ( 32). OPHTHALMIC SCREENING OF PATIENTS USING AMIODARONE If regular ophthalmic screening of patients taking amiodarone is advocated, what should be done for those patients who develop asymptomatic optic disc swelling with no visual compromise? The finding of asymptomatic optic disc edema is not unique to patients on amiodarone. Almog et al ( 33) studied the visual outcome in 23 patients with asymptomatic optic disc edema and no signs of optic nerve dysfunction in whom the disc edema had been incidentally discovered on routine ophthalmoscopic examination performed for diabetes, hypertension, or in follow up of patients who had developed NAION in one eye. In nine ( 36%) eyes, optic disc edema progressed to overt NAION with a mean latency of 16.8 weeks. In 16 ( 64%) eyes, optic disc edema resolved without loss of vision with a mean latency of 15.5 weeks. The conversion rate to NAION was 40% o in patients who had NAION in the fellow eye, 31% in patients with diabetes, 43% in patients with diabetic retinopathy, and 0% in four amiodarone- treated patients. Their study therefore concluded that asymptomatic optic disc edema generally resolves with no visual loss, but one 234 © 2005 Lippincott Williams & Wilkins Amiodarone and Optic Neuropathy: The Heart of the Matter J Neuro- Ophthalmol, Vol. 25, No. 3, 2005 third of patients progress to full- blown NAION. If, as suggested by the study of Almog et al ( 33), the conversion rate to optic neuropathy in eyes with asymptomatic optic disc edema is actually higher in patients not using amiodarone than in those using it, we cannot uniformly recommend that the amiodarone be stopped in those with asymptomatic disc edema. What should be done for those patients taking amiodarone who develop optic neuropathy in one eye and asymptomatic disc edema in the other eye? Patients have been noted to progress to optic neuropathy more than a month after the drug has been discontinued ( 2,19,29). Therefore, stopping the drug is not necessarily protective. Finally, what should be done for patients who develop bilateral optic neuropathy while taking amiodarone? Given that visual deficits have been noted to be permanent in some patients and to improve in others when the drug stopped and when it is continued, the answer is unclear. DISCONTINUING AMIODARONE When evaluating patients who develop asymptomatic disc swelling or an optic neuropathy while taking amiodarone, one should be mindful of the far more serious reasons for which the patient is taking the medication. It is prudent to consult the cardiologist regarding the feasibility of discontinuing the drug. In our initial discussion with the patient, we believe it is important to note the findings and point out a potential causal relationship between optic neuropathy and amiodarone rather than to definitively implicate the drug as causing the disorder given the significant overlap in clinical appearance and behavior with NAION and our uncertainty regarding the exact incidence and pathogenesis of the optic neuropathy in patients on amiodarone. Otherwise, we risk that patients who fear that amiodarone may cause visual loss or blindness will discontinue the medication on their own and put their lives at risk. Many patients cannot stop the drug without significant morbidity or even death. The decision regarding the safety of discontinuing the amiodarone is best left to the cardiologist. It seems prudent to consider amiodarone a potential risk factor rather than a direct cause of optic neuropathy, especially given the low incidence of optic neuropathy, which is not rigorously established as higher than that of NAION in an age- matched and health- matched population. Just as symptoms of dyspnea and cough in arrhythmia patients on amiodarone are most often related to underlying cardiopulmonary abnormalities and congestive heart failure rather than to the relatively rare amiodarone pulmonary toxicity, asymptomatic optic disc edema and optic neuropathy in a patient taking amiodarone may be unrelated to drug therapy and simply represent NAION. FURTHER STUDY It would be helpful to establish a registry of patients who develop optic neuropathy while taking amiodarone to help answer the following questions for which there is still insufficient data: 1. Is the natural history of asymptomatic disc swelling and of optic neuropathy in patients taking amiodarone better when the drug is stopped than when it is continued? 2. If amiodarone is associated with optic neuropathy, is it dose- related, and would reducing the dose be as effective as stopping it? 3. Can the drug be restarted at a later time without cardiac or optic neuropathy risk? 4. What is the incidence of crowded optic discs in patients who develop optic neuropathy while taking amiodarone? It has been stated that there is no " control group" of patients with similar refractory cardiac arrhythmias who are not treated with amiodarone in whom the incidence of NAION could be compared with patients using amiodarone ( 2,34). This is not the case. 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