Volume 119
Number 5
Amiodarone toxicity: Myopathy and neuropathy R. Fernando Roth, MD, Hideo Itabashi, MD, James Louie, MD, Thomas Anderson, MD, and Kenneth A. Narahara, MD.
Los Angeles and Torrance, Calif.
Common neurologic side effects of the drug amiodarone include tremor, ataxia, and a peripheral neuropathy. NeuFrom the Departments of Medicine, Pathology, and Neurology, University of California at Los Angeles School of Medicine; and the Division of Cardiology, Department of Medicine, Harbor-UCLA Medical Center. Reprint requests: Kenneth A. Narahara, MD, Division of Cardiology, F-9, Harbor-UCLA Medical Center, 1000 W. Carson St., Torrance, CA 90509. 4/4/19131
Fig. 1. Initial muscle biopsy showing a representative area of vacuolar myopathy with an extreme range of muscle fiber diameters. Some fibers have focal rarefaction or myofibrillar loss. (Hematoxylin and eosin stain; original magnification •
Brief Communications
1223
rologic complications have been described as early as 1 week after the initiation of therapy and are usually dosedependent in these early stages. We report a patient taking amiodarone for i month who developed a severe myopathy in combination with a peripheral neuropathy. A 62-year-old man with a history of recurrent sustained ventricular tachycardia, hypertension, and gout was hospitalized complaining of severe generalized weakness, particularly in the proximal extremities. His medications included allopurinol, 150 mg daily, and colchicine, 0.5 mg daily, for 7 years. He had been receiving amiodarone, 400 mg daily, for 1 month. The patient had a normal mental status and cranial nerve examination. The proximal muscle weakness was rated as 1 to 2+/5 (by the Medical Research Council system). Reflexes were reduced throughout and decreased sensation was noted distally to all modalities. The patient had a normal cerebrospinal fluid examination. Creatine kinase blood levels were elevated to 8000 mU/ml (normal 45 to 235 mU/ml) with a negative MB fraction. A technetium pyrophosphate scan was negative. Slow nerve conduction velocities were found, as were signs of muscle membrane irritability on electromyogram (EMG) examination (positive sharp waves and fibrillation potentials). These electrical findings were attributed to an acute neuropathy. Light microscopic examination of a deltoid muscle biopsy showed a severe vacuolar myopathy with fibers containing single large and numerous small vacuoles (Fig. 1). There was abnormal variability of muscle fiber size. Many muscle fibers were large and rounded; fewer fibers were small, with basophilia reminiscent of regenerating fibers. Periodic acid-Schiff (PAS) stain revealed randomly scattered muscle fibers with dense aggregates of PAS-positive material not seen after diastase digestion. Adenosine triphosphatase (ATPase) showed that the vacuoles were present in both type 1 and type 2 fibers. No inflammation was seen. Electron microscopy demonstrated that the vacuoles Seen by light microscopy corresponded to autophagic vacuoles of varied sizes. Larger vacuoles often contained degenerating mitochondria as well as other granular and vesicular debris. Myofibrils adjacent to the larger vacuoles consistently showed significant myofibrillar disorganization. Other regions of degenerating muscle fibers contained long arrays of Z-band streaming, as shown in Fig. 2. Flecainide, 50 mg twice daily, was substituted for amiodarone. A second muscle biopsy obtained 8 months later demonstrated a total disappearance of the previous microscopic picture of vacuolar myopathy. In general, muscle fiber diameters were 25 % larger in the later biopsy (Fig. 3). The patient was without symptoms and had regained his former strength at this time. Amiodarone-induced peripheral neuropathy is well documented, 1 while only a few instances of a myopathy have been reported. 2 Meier et al. 2 described a patient requiring chronic amiodarone therapy who developed what they called a neuromyopathy. In their case, like ours, a myopathy developed in concert with a neuropathy. The
1224
Brief Communications
May 1990 American Heart Journal
Fig. 2. Electron micrograph of a segment of muscle fiber showing commonly observed Z-band streaming in areas of marked myofibrillar disassembly. (Original magnification •
muscle biopsy in their patient revealed myopathic changes and "vacuolar degeneration" of single fibers. Ultrastructural examination revealed membrane-bound cisterns with many dense bodies. Lysosomal inclusion bodies have been described in tissues of many patients taking amiodarone. 3, 4 One of these patients had proximal weakness with inclusion bodies in lymphocytes, plasma cells, granulocytes, and hepatocytes, but a muscle biopsy was not performed. Other causes of vacuolar myopathy include toxic myopathies from chloroquine and colchicine, 5 acid maltase deficiency, polymyositis, and periodic paralysis. Our patient took colchicine for 7 years prior to the development of his weakness and was still taking colchicine when his myopa-
thy resolved both clinically and microscopically. We conclude that his myopathy was caused predominantly by ingestion of amiodarone. However, the concomitant administration of colchicine may have predisposed the patient to develop an amiodarone-induced myopathy. This case was initially diagnosed as an amiodaroneinduced neuropathy. However, due to the high creatine kinase level, muscle biopsies were obtained that documented a reversible vacuolar myopathy in addition to the neuropathy. The neuromyopathy occurred despite a relatively low dose and short duration of amiodarone therapy. The possibility of a concurrent myopathy and neuropathy should be considered in patients taking amiodarone.
Volume 119
Number S
Brief Communications
1225
Exercise-induced T wave normalization is not specific for myocardial ischemia detected by perfusion scintigraphy Michael A. Frais, MD, and R o b e r t J. Hoeschen, MD. Winnipeg, Manitoba, Canada
Fig. 3. Second muscle biopsy performed 8 months later showing resolution of the vacuolar change and a general normalization. However, atrophic fibers persist and a striking moth-eaten change in type I fibers is present. (Reduced nicotinamide adenine dinucleotide-tetrazolium reduction stain; original magnification x150.)
REFERENCES
1. Heger JJ, Prystowsky EN, Jackman WM, et al. Amiodarone, clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981;305:539-45. 2. Meier C, Kauer B, Muller U, Ludin HP. Neuromyopathy during chronic amiodarone treatment. J Neurol 1979;220: 231-9. 3. Adams PC, Holt DW, Storey GCA, Morley AR, Callaghan J, Campbell RWF. Amiodarone and its desethyl metabolite: tissue distribution and morphologic changes during long-term therapy. Circulation 1985;72:1064-75. 4. Dake MD, Madison JM, Montgomery CK, et al. Electron microscopic demonstration of lysosomal inclusion bodies in lung, liver, lymph nodes, and blood leukocytes of patients with amiodarone pulmonary toxicity. Am J Med 1985;78:504-12. 5. Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, Peper M. Colchicine myopathy and neuropathy. N Engl J Med 1987;316:1562-8.
T wave flattening or inversion on the resting electrocardiogram (ECG) t h a t becomes upright during exercise (T wave normalization) has been described as a marker of exerciseinduced ischemia 14 and as a nonspecific finding. 5-9 The purpose of this study was to determine the relationship between T wave normalization and scintigraphic evidence of exercise-induced myocardial ischemia. We prospectively studied all patients who underwent 2~ stress perfusion scintigraphy for the investigation of chest pain in our laboratory between October 1987 and October 1988. Treadmill (Quinton 4000 series, Quinton I n s t r u m e n t Co., Seattle, Wash.) exercise testing was performed according to a modified Balke protocol. T h e grade and speed were adjusted, so t h a t each patient exercised for approximately 6 minutes before developing limiting cardiac symptoms or achieving the target heart rate (> 85 % age-predicted maximum heart rate). The heart rate and r h y t h m were monitored by a continuous three-lead E C G display. The 12-lead ECG was recorded at rest, following hyperventilation, int e r m i t t e n t l y during exercise, and at peak exercise. 2~ 2.0 mCi, was injected intravenously 1 minute before the termination of exercise. Patients were imaged within 5 minutes and 3 to 4 hours later in three planar views (anterior, left anterior oblique 45-degree, and left anterior oblique 70-degree) using a Picker mobile Dynacamera 4 (Picker International, Inc., Highland Heights, Ohio) or E1scint Apex 409AG camera (Elscint I n c , Boston, Mass.) with a multipurpose collimator, interfaced to a MedtronicMedical Data Systems A3/A 2 (Medtronic-Medical Data Systems, Inc., Ann Arbor, Mich.) or Elscint Apex 009 computer. The d a t a were interpreted by at least two experienced observers blinded to the results of the exercise test from the raw and computer-enhanced planar images and computer-generated radial count profiles. T wave normalization was defined as inverted T waves at rest t h a t became upright during exercise in at least two adjacent leads. Cases in which these T wave changes were associated with a shift in the QRS axis corresponding to the shift in the T wave axis, or where the resting T wave abnormalities were secondary to a ventricular conduction disturbance or ventricular hypertrophy, were excluded from analysis. From the Sectionof Cardiology,Universityof Manitoba,St. BonifaceGeneral Hospital. Reprint requests: Michael A. Frais, MD, C5009--Section of Cardiology, Department of Medicine, St. Boniface General Hospital, 409 Tache Ave., Winnipeg, Manitoba, Canada R2H 2A6. 4/4/19129
Number 5
Amiodarone toxicity: Myopathy and neuropathy R. Fernando Roth, MD, Hideo Itabashi, MD, James Louie, MD, Thomas Anderson, MD, and Kenneth A. Narahara, MD.
Los Angeles and Torrance, Calif.
Common neurologic side effects of the drug amiodarone include tremor, ataxia, and a peripheral neuropathy. NeuFrom the Departments of Medicine, Pathology, and Neurology, University of California at Los Angeles School of Medicine; and the Division of Cardiology, Department of Medicine, Harbor-UCLA Medical Center. Reprint requests: Kenneth A. Narahara, MD, Division of Cardiology, F-9, Harbor-UCLA Medical Center, 1000 W. Carson St., Torrance, CA 90509. 4/4/19131
Fig. 1. Initial muscle biopsy showing a representative area of vacuolar myopathy with an extreme range of muscle fiber diameters. Some fibers have focal rarefaction or myofibrillar loss. (Hematoxylin and eosin stain; original magnification •
Brief Communications
1223
rologic complications have been described as early as 1 week after the initiation of therapy and are usually dosedependent in these early stages. We report a patient taking amiodarone for i month who developed a severe myopathy in combination with a peripheral neuropathy. A 62-year-old man with a history of recurrent sustained ventricular tachycardia, hypertension, and gout was hospitalized complaining of severe generalized weakness, particularly in the proximal extremities. His medications included allopurinol, 150 mg daily, and colchicine, 0.5 mg daily, for 7 years. He had been receiving amiodarone, 400 mg daily, for 1 month. The patient had a normal mental status and cranial nerve examination. The proximal muscle weakness was rated as 1 to 2+/5 (by the Medical Research Council system). Reflexes were reduced throughout and decreased sensation was noted distally to all modalities. The patient had a normal cerebrospinal fluid examination. Creatine kinase blood levels were elevated to 8000 mU/ml (normal 45 to 235 mU/ml) with a negative MB fraction. A technetium pyrophosphate scan was negative. Slow nerve conduction velocities were found, as were signs of muscle membrane irritability on electromyogram (EMG) examination (positive sharp waves and fibrillation potentials). These electrical findings were attributed to an acute neuropathy. Light microscopic examination of a deltoid muscle biopsy showed a severe vacuolar myopathy with fibers containing single large and numerous small vacuoles (Fig. 1). There was abnormal variability of muscle fiber size. Many muscle fibers were large and rounded; fewer fibers were small, with basophilia reminiscent of regenerating fibers. Periodic acid-Schiff (PAS) stain revealed randomly scattered muscle fibers with dense aggregates of PAS-positive material not seen after diastase digestion. Adenosine triphosphatase (ATPase) showed that the vacuoles were present in both type 1 and type 2 fibers. No inflammation was seen. Electron microscopy demonstrated that the vacuoles Seen by light microscopy corresponded to autophagic vacuoles of varied sizes. Larger vacuoles often contained degenerating mitochondria as well as other granular and vesicular debris. Myofibrils adjacent to the larger vacuoles consistently showed significant myofibrillar disorganization. Other regions of degenerating muscle fibers contained long arrays of Z-band streaming, as shown in Fig. 2. Flecainide, 50 mg twice daily, was substituted for amiodarone. A second muscle biopsy obtained 8 months later demonstrated a total disappearance of the previous microscopic picture of vacuolar myopathy. In general, muscle fiber diameters were 25 % larger in the later biopsy (Fig. 3). The patient was without symptoms and had regained his former strength at this time. Amiodarone-induced peripheral neuropathy is well documented, 1 while only a few instances of a myopathy have been reported. 2 Meier et al. 2 described a patient requiring chronic amiodarone therapy who developed what they called a neuromyopathy. In their case, like ours, a myopathy developed in concert with a neuropathy. The
1224
Brief Communications
May 1990 American Heart Journal
Fig. 2. Electron micrograph of a segment of muscle fiber showing commonly observed Z-band streaming in areas of marked myofibrillar disassembly. (Original magnification •
muscle biopsy in their patient revealed myopathic changes and "vacuolar degeneration" of single fibers. Ultrastructural examination revealed membrane-bound cisterns with many dense bodies. Lysosomal inclusion bodies have been described in tissues of many patients taking amiodarone. 3, 4 One of these patients had proximal weakness with inclusion bodies in lymphocytes, plasma cells, granulocytes, and hepatocytes, but a muscle biopsy was not performed. Other causes of vacuolar myopathy include toxic myopathies from chloroquine and colchicine, 5 acid maltase deficiency, polymyositis, and periodic paralysis. Our patient took colchicine for 7 years prior to the development of his weakness and was still taking colchicine when his myopa-
thy resolved both clinically and microscopically. We conclude that his myopathy was caused predominantly by ingestion of amiodarone. However, the concomitant administration of colchicine may have predisposed the patient to develop an amiodarone-induced myopathy. This case was initially diagnosed as an amiodaroneinduced neuropathy. However, due to the high creatine kinase level, muscle biopsies were obtained that documented a reversible vacuolar myopathy in addition to the neuropathy. The neuromyopathy occurred despite a relatively low dose and short duration of amiodarone therapy. The possibility of a concurrent myopathy and neuropathy should be considered in patients taking amiodarone.
Volume 119
Number S
Brief Communications
1225
Exercise-induced T wave normalization is not specific for myocardial ischemia detected by perfusion scintigraphy Michael A. Frais, MD, and R o b e r t J. Hoeschen, MD. Winnipeg, Manitoba, Canada
Fig. 3. Second muscle biopsy performed 8 months later showing resolution of the vacuolar change and a general normalization. However, atrophic fibers persist and a striking moth-eaten change in type I fibers is present. (Reduced nicotinamide adenine dinucleotide-tetrazolium reduction stain; original magnification x150.)
REFERENCES
1. Heger JJ, Prystowsky EN, Jackman WM, et al. Amiodarone, clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981;305:539-45. 2. Meier C, Kauer B, Muller U, Ludin HP. Neuromyopathy during chronic amiodarone treatment. J Neurol 1979;220: 231-9. 3. Adams PC, Holt DW, Storey GCA, Morley AR, Callaghan J, Campbell RWF. Amiodarone and its desethyl metabolite: tissue distribution and morphologic changes during long-term therapy. Circulation 1985;72:1064-75. 4. Dake MD, Madison JM, Montgomery CK, et al. Electron microscopic demonstration of lysosomal inclusion bodies in lung, liver, lymph nodes, and blood leukocytes of patients with amiodarone pulmonary toxicity. Am J Med 1985;78:504-12. 5. Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, Peper M. Colchicine myopathy and neuropathy. N Engl J Med 1987;316:1562-8.
T wave flattening or inversion on the resting electrocardiogram (ECG) t h a t becomes upright during exercise (T wave normalization) has been described as a marker of exerciseinduced ischemia 14 and as a nonspecific finding. 5-9 The purpose of this study was to determine the relationship between T wave normalization and scintigraphic evidence of exercise-induced myocardial ischemia. We prospectively studied all patients who underwent 2~ stress perfusion scintigraphy for the investigation of chest pain in our laboratory between October 1987 and October 1988. Treadmill (Quinton 4000 series, Quinton I n s t r u m e n t Co., Seattle, Wash.) exercise testing was performed according to a modified Balke protocol. T h e grade and speed were adjusted, so t h a t each patient exercised for approximately 6 minutes before developing limiting cardiac symptoms or achieving the target heart rate (> 85 % age-predicted maximum heart rate). The heart rate and r h y t h m were monitored by a continuous three-lead E C G display. The 12-lead ECG was recorded at rest, following hyperventilation, int e r m i t t e n t l y during exercise, and at peak exercise. 2~ 2.0 mCi, was injected intravenously 1 minute before the termination of exercise. Patients were imaged within 5 minutes and 3 to 4 hours later in three planar views (anterior, left anterior oblique 45-degree, and left anterior oblique 70-degree) using a Picker mobile Dynacamera 4 (Picker International, Inc., Highland Heights, Ohio) or E1scint Apex 409AG camera (Elscint I n c , Boston, Mass.) with a multipurpose collimator, interfaced to a MedtronicMedical Data Systems A3/A 2 (Medtronic-Medical Data Systems, Inc., Ann Arbor, Mich.) or Elscint Apex 009 computer. The d a t a were interpreted by at least two experienced observers blinded to the results of the exercise test from the raw and computer-enhanced planar images and computer-generated radial count profiles. T wave normalization was defined as inverted T waves at rest t h a t became upright during exercise in at least two adjacent leads. Cases in which these T wave changes were associated with a shift in the QRS axis corresponding to the shift in the T wave axis, or where the resting T wave abnormalities were secondary to a ventricular conduction disturbance or ventricular hypertrophy, were excluded from analysis. From the Sectionof Cardiology,Universityof Manitoba,St. BonifaceGeneral Hospital. Reprint requests: Michael A. Frais, MD, C5009--Section of Cardiology, Department of Medicine, St. Boniface General Hospital, 409 Tache Ave., Winnipeg, Manitoba, Canada R2H 2A6. 4/4/19129
