Amiodarone-Induced Central Nervous System Toxicity in the Frail Geriatric Patient: A Case Report and Review of the Literature

The Case

A 91-year-old female was admitted to a transitional care unit after being discharged from a hospitalization for atrial fibrillation (AF) with rapid ventricular response. She initially presented to the hospital in mild acute heart failure and, following a transesophageal echocardiogram, underwent direct current (DC) cardioversion to sinus rhythm. Following DC cardioversion, however, she reverted to AF and was started on amiodarone at a dosage of 400 mg once daily. After a day on this medication she converted to sinus rhythm. Two days later, she was discharged to the transitional care unit on a reduced maintenance dosage of amiodarone of 200 mg once daily. She had no other medication changes at that time.

Five days after admission to the transitional care unit, the patient developed light-headedness, lethargy, and increased confusion over her baseline.

Her past medical history was significant for ischemic heart disease, prior coronary bypass surgery, hypertension, hyperlipidemia, hypothyroidism, mild dementia, and osteoarthritis. She also had a diagnosis of 3+ mitral regurgitation, which was felt during the hospitalization to be contributing to the heart failure. A cardiac surgery consultation in the hospital recommended attempting to convert her to sinus rhythm to see if that would help control her heart failure, and thereby obviate the need for valvular surgical repair.

Medications on admission to the transitional care unit, which were unchanged at the time the patient developed the new symptoms, were amiodarone 200 mg once daily, warfarin 2.5 mg once daily, furosemide 20 mg once daily, metoprolol 12.5 mg twice daily, aspirin 325 mg once daily, pravastatin 40 mg at bedtime, levothyroxine 125 mcg once daily, and donepezil 10 mg once daily.

On examination, the patient was noted to be oriented to person only; she was usually oriented to person, place, and month. She was slow to respond to queries and appeared sleepy. Blood pressure was 110/74, pulse was 44 and regular, respirations were 12 and relaxed, and temperature was 96.8 degrees F. Pulse oximetry was 96% on room air. Lungs were clear to auscultation, and cardiac exam revealed a 3/6 holosystolic blowing murmur heard loudest at the apex.

Laboratory study results were complete blood count and basic metabolic panel within normal limits, and thyroid-stimulating hormone (TSH) level was elevated at 11.4 mIU/L.

Amiodarone was discontinued, and dosages of the remaining medications were retained. Over the next five days, the patient's cognitive status gradually returned to baseline. Heart rate rose to 60-65 beats per minute and remained stable.

Introduction

Amiodarone is a unique and complex cardiac antiarrhythmic medication that is indicated for the treatment of recurrent ventricular fibrillation, hemodynamically unstable ventricular tachycardia, and rhythm control of AF. Amiodarone is a class III antiarrhythmic drug, indicating that it prolongs the QT interval; it also slows heart rate and AV nodal conduction and prolongs refractoriness.

Although amiodarone is a highly effective antiarrhythmic medication, it carries considerable risks of serious adverse reactions, including pulmonary disorders, particularly fibrosis and pneumonitis; thyroid disturbances; dermatologic, gastrointestinal, and neurologic adverse reactions; multiple eye disorders and, rarely, blindness; and elevation of hepatic enzymes.^1-10

The structure and pharmacology of the drug provide insight into some of these adverse effects. Amiodarone consists of a benzene ring containing two iodine molecules. Doses of 100 to 600 mg daily provide 37 to 222 mg of iodine.¹¹ These amounts are much greater than the recommended daily allowance of 0.15 mg of iodine. This large iodine load can lead to increased incidence of both hypo- and hyperthyroidism in patients taking amiodarone. Amiodarone also has a large volume of distribution and is markedly lipophilic, with a mean elimination half-life of 53 days.^12,13 As a result, amiodarone is slow to distribute to the tissues and requires long loading periods to get the drug to steady state in the body, resulting in adverse reactions that can continue long after discontinuation of the medication.

While older adults more frequently incur rhythm disturbances that might be responsive to amiodarone, this age group is the most susceptible to adverse drug events. As one ages from 20 to 79 years there is a sevenfold increase in overall adverse drug events.¹⁴ As people age, their body compositions change, resulting in increased fat and decreased water content.¹⁵ Due to the drug’s pharmacologic properties, such as high fatty tissue distribution and long half-life, one could presume that the physiological changes in an elderly person’s body composition could make them more prone to adverse events due to increased drug accumulation. In fact, there is evidence that amiodarone toxicities may be more frequent with elderly people.¹⁶

The case describes an elderly patient with complex comorbidities who developed adverse central nervous system (CNS) effects of lethargy, confusion, and light-headedness shortly after the initiation of amiodarone therapy for AF. Based on this patient’s complex medical history, including congestive heart failure (CHF) and recent attempt at cardioversion, the cause of these adverse CNS effects is uncertain. However, the possibility that these adverse effects were directly or secondarily caused by amiodarone will be evaluated in this article.

Literature Review and Discussion

A literature search was conducted to locate primary studies, meta-analyses, and case studies on CNS adverse reactions with amiodarone use. English language articles were searched in Ovid, MEDLINE, and PubMed using the search term amiodarone alone and combined with the following terms: CNS toxicity, neurological toxicity, tremor, ataxia, peripheral neuropathy, dementia, dizziness, lethargy, confusion, delirium, bradycardia, thyroid, and elderly or limited to greater than or equal to 65 years of age. Citations were rejected if adverse events were not documented. Relevant references were individually searched for and collected.

The Table^1-10,16-23 shows 18 studies located by the literature review that documented CNS adverse effects or other symptoms that could secondarily cause CNS symptoms, such as bradycardia and hypothyroidism. In these studies, conducted mostly in healthier, younger populations, the most common CNS adverse reactions were ataxia, tremor, and dizziness. One study reported short-term memory loss in 8.6% of subjects, but the dose of amiodarone was unusually high in this sample (600 mg/d).⁵

Although not reported in larger clinical studies, three case reports have described amiodarone-induced delirium.^24-26 Barry and Franklin²⁴ reported a case of a 54-year-old man with history of CHF and new-onset AF. The patient experienced depression, rambling speech, and paranoia after eight days on 800 mg/d of amiodarone. After a decrease in dose to 400 mg/day his symptoms initially improved, but then recurred with confusion and tangential thinking. After discontinuation of the drug, the patient returned to baseline, only to be restarted on 200 mg/day four days later. At this time he again became confused, agitated, and paranoid; after amiodarone was completely discontinued, the patient returned to baseline again.

Two other case reports concerned patients who were age 80 years and age 66 years, respectively, with no previous psychiatric history. In both cases, the patients developed delirium after a few days on amiodarone and returned to baseline functioning after discontinuation.^25,26

These data suggest that amiodarone may directly cause psychiatric effects and could have been the primary cause of confusion seen in the case report presented above. It is unlikely that medications other than amiodarone contributed to the patient’s CNS symptoms since she was determined to be euvolemic on furosemide, there was no evidence of a stroke on warfarin and aspirin, and metoprolol and furosemide were taken chronically at the same doses before and after the addition of amiodarone. While the patient in the case did not exhibit paranoia or agitation noted in previous cases, she did exhibit new symptoms of confusion and disorientation. It is also quite possible, however, that the CNS symptoms seen in this case report were indirectly caused by common adverse reactions of amiodarone, particularly hypothyroidism and bradycardia.

Hypothyroidism is a well-known adverse effect of amiodarone. One review found the incidence of hypothyroidism to be 1-22% among new users.²⁷ Studies composed of older subjects generally report higher rates of hypothyroidism.^1,16 Data from an amiodarone trial in men with a mean age of 67 years observed incidences of 26% for subclinical hypothyroidism (TSH range 4.5-10 mIU/L) and 5% for clinical hypothyroidism (TSH > 10 mIU/L) as compared to 7% and 0.3% in controls, respectively.²⁸ In the case presented above, the patient had pre-existing hypothyroidism that may have been exacerbated by amiodarone, contributing to the confusion, lethargy, and dizziness observed. It is also possible that she was simply underdosed with thyroid replacement; unfortunately, a pre-hospitalization TSH level was not available.

The symptoms in the case report may have also resulted secondary to amiodarone-induced bradycardia. The patient’s heart rate was 44 beats per minute. Bradycardia is a well-known effect of amiodarone. One study reported that 50% of the patients experienced more than a 10% decrease in heart rate with amiodarone use.³ Although a common adverse effect of amiodarone is decreased heart rate, symptomatic bradycardia is less frequent. Eleven of the eighteen studies presented in the Table reported an incidence of symptomatic bradycardia ranging from 0.5 to 2% (omitting placebo-controlled trials as they were not powered to test for significance). Most of these patients required the use of a pacemaker. One patient required a pacemaker after experiencing dizziness and lightheadedness after bradycardia induced by amiodarone.⁷ In the case report, while two of the patient’s other medications, metoprolol and, less commonly, donepezil, can cause bradycardia, her symptoms resolved despite continued therapy with the same doses of metoprolol and donepezil that were taken prior to hospitalization.

Employing the Naranjo Adverse Drug Reaction Probability Scale,²⁹ the CNS symptom of dizziness in this report was probably caused by amiodarone, and the symptoms of confusion and lethargy were assessed to be possibly caused by amiodarone.

Clinicians should be aware of the many forms of adverse CNS effects that can occur with amiodarone. This is especially true in older adults with multiple comorbidities, whose signs and symptoms may mask or mimic the adverse effects of medications. For example, tremor and ataxia, the most common adverse reactions of amiodarone, may be misinterpreted as uncontrolled disease symptoms in a patient with Parkinson’s disease, leading to overtreatment with antiparkinsonian agents and/or prolonged exposure to toxic levels of amiodarone. Amiodarone is most commonly prescribed for rhythm control of AF. While it is the most effective agent at maintaining sinus rhythm after conversion from AF, it also has the highest side-effect profile among antiarrhythmics.³⁰ One recommendation is that a strategy of rhythm control with antiarrhythmics be considered over rate control plus anticoagulation only in patients who have structural heart disease (left ventricular hypertrophy and moderate-to-severe mitral regurgitation) and troubling symptoms from AF.³¹ In such situations, when selecting an antiarrhythmic medication, the superior antifibrillatory effects of amiodarone need to be weighed against its higher incidence of adverse effects as compared to alternative antiarrhythmics such as propafenone and sotalol. This narrow indication for amiodarone therapy needs to be further tempered by its added propensity for adverse reactions, CNS and otherwise, when considered for use in elderly patients with multiple comorbidities.

Conclusion

Based on this review, it is possible that amiodarone may have directly resulted in the case patient’s confusion, lightheadedness, and lethargy. Larger-scale studies have reported patients experiencing dizziness and lethargy on amiodarone treatment. In addition, there are three case reports of patients experiencing delirium and confusion. As discussed above, however, the possibility that this patient’s symptoms were related to secondary bradycardia or hypothyroidism, both of which could have been caused or exacerbated by amiodarone, cannot be discounted. Clinicians caring for frail older adults with arrhythmias need to carefully consider the benefits and risks of amiodarone, including its potential for direct and indirect CNS effects.

The authors report no relevant financial relationships.