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An Elderly Woman with a Progressive Neuropathy
Case 67
An Elderly Woman with a Progressive Neuropathy
A 75-year-old woman with congestive heart failure and coronary artery disease was evaluated for progressive numbness and weakness in the feet and legs for the past 3 months. She had been on lanoxin, furosemide, and amiodarone. Past medical and family histories were unremarkable, and she did not smoke or drink. Gait was normal; the rest of the neurologic examination was unremarkable. Examination revealed normal mentation and gross cognitive function. Cranial nerves were normal. There was 4 to 4+/5 weakness in all extremities; the iliopsoas and glutei were 3 to 4−/5 bilaterally; quadriceps, adductors, and hamstrings were 5−/5; foot dorsiflexors 4/5; evertors 4/5; flexors 5−/5. There was decreased pinprick in a stocking distribution up to the midarm and midcalf. She was areflexic, and her toes were downgoing.
WHAT IS THE DIFFERENTIAL DIAGNOSIS? This woman presented with progressive motor and sensory neuropathy. There was no history of diabetes or renal
disease, but she had congestive heart failure and a negative family history. Other conditions such as connective tissue disorder, an autoimmune polyneuropathy, a toxic neuropathy, or a neuropathy associated with carcinoma needed to be considered. The congestive heart failure could also suggest amyloidosis. The patient was on amiodarone which could cause a peripheral neuropathy.
WHAT SHOULD BE DONE? A complete metabolic panel was normal except for mildly elevated sugar of 182 mg/dL (normal, <110 mg/dL). Erythrocyte sedimentation rate was 52 mm/hour (normal, <30 mm/hour) and when repeated was 39 mm/hour. Fluorescent antinuclear antibody was positive 1:80. C3, C4 complement, and extractable nuclear antibody titers were normal.
AN EMG TEST WAS PERFORMED Motor Nerve Studies
Motor Nerve Studies—cont’d
Nerve and Site
Latency (ms)
Amplitude (mV)
Conduction Velocity (m/s)
Peroneal Nerve L.
Normal £ 5.7
Normal ≥4
4.6 10.9 12.4
2 2 2
Ankle Fibular head Knee
This case was evaluated with Dr. Thomas Arnold.
Nerve and Site
Latency (ms)
Amplitude (mV)
Conduction Velocity (m/s)
Normal ≥ 40
Tibial Nerve L.
Normal £ 5.3
Normal ≥4
Normal ≥ 40
— 37 39
Ankle Pop. fossa
4.4 12.6
3 2
— 37
Median Nerve L.
Normal £ 3.6
Normal ≥8
Normal ≥ 50
2.7 6.3
7 7
— 49
Wrist Elbow
429
430
Case 67
F-wave and Tibial H-reflex Studies Nerve
Latency (ms)
Normal Latency £ (ms)
51.5 52.8 28.9 NR NR
54 54 30 34 34
Peroneal nerve L. Tibial nerve L. Median nerve L. H-reflex L. H-reflex R.
Sensory Nerve Studies Nerve
Peak Latency (ms)
Normal Peak Latency £ (ms)
Amp (mV)
Normal Amp ≥ (mV)
NR NR NR
4.0 4.0 3.1
NR NR NR
11 8–10 13
Sural nerve L. Superficial peroneal nerve L. Median nerve L.
EMG Data Muscle
Insrt Activity
Fibs
Pos Waves
Fasc
Amp
Dur
Poly
Pattern
Vastus lateralis L. Tibialis anterior L. Peroneus longus L. Gastrocnemius L. Vastus lateralis R. Tibialis anterior R. Gastrocnemius R. 1st dorsal interosseous L. Flexor carpi ulnaris L.
Norm Norm Inc Inc Norm Inc Inc Norm Norm
None None None None None None None None None
None None None 1+ None None 1+ None None
None None None None None None None None None
Norm Lg Norm Lg Lg Lg Norm Lg Norm
Norm Inc Norm Inc Inc Inc Norm Inc Norm
None None None None None None None None None
Full Red Full Red Red Red Full Red Full
WHAT WERE THE EMG FINDINGS? These electrophysiologic studies revealed mild slowing of nerve conduction velocities with low-amplitude median and peroneal CMAPs; all tested SNAPs were absent. There was mild denervation in the distal legs. It was concluded that this patient had a mild demyelinating and axonal polyneuropathy. A nerve biopsy showed some axonal degeneration, segmental demyelination, and osmiophilic inclusions in the endoneural area (Fig. 67-1). The patient was diagnosed having an amiodaroneinduced neuropathy, and the drug was discontinued. She was treated with physical therapy and slowly improved.
DISCUSSION This elderly woman presented with a polyneuropathy that was thought to be caused by amiodarone, and she improved after discontinuing this drug. Other medications that could cause a neuropathy are summarized in Table 67-1.
Amiodarone is a diodated benzoforfuran derivative used in the treatment of cardiac arrhythmias. The drug can cause several systemic side effects, such as thyroid disease, skin rash, pulmonary fibrosis, and corneal disease.1,2 It could also cause neurologic problems, which occur in about 54% of the cases. Most frequently, this consists of tremors, ataxia, and, rarely, optic neuropathy.3,4 Amiodarone also can cause a peripheral neuropathy,4–8 myopathy,9 or neuromyopathy.10–12 Amiodarone neuropathy could be predominantly demyelinating, axonal, or both EMGs could show signs of denervation as well, but also small, polyphasic motor unit action potentials. Some patients could have elevated serum creatine kinase. The muscle biopsy shows atrophy10,11 or some vacuolization with lipidlike inclusions10–12; a necrotizing myopathy has also been reported.9 Nerve biopsies demonstrate loss of myelinated axons with degeneration6,10 and demyelination.12 The characteristic finding is the presence of electron-dense inclusions in the Schwann cells, endoneural cells, and interstitial cells.6,10 These osmophilic inclusions can also be caused by other
431
An Elderly Woman with a Progressive Neuropathy
Table 67-1. Drug-induced Neuropathies: Anatomical Site of Disease
FIGURE 67-1 Electromicroscopy on sural nerve biopsy showing osmiophilic inclusions in cytoplasm of Schwann cells (arrows) (×10,000).
amphiphilic drugs and are likely of lysosomal origin.13 The demyelination is believed to be produced by Schwann cell dysfunction with secondary axonal degeneration.12 The long half-life of the drug is likely predisposed to its tissue accumulation.10,14 The treatment of the neurologic manifestations of amiodarone toxicity includes discontinuation of the drug and physical therapy.
Axonopathy Almitrine Amiodarone Amitriptyline Carbamide Chloramphenicol Chloroquine Clioquinol Colchicine Cyanate Disopyramide Disulfiram Ethambutol Ethionamide Hydralazine Gold Glutethimide Isoniazid Lithium Methaqualone Metronidazole Misonidazole Nitrofurantoin
Axonopathy—cont’d Nitrous oxide Phenytoin Sulfapyridine Sulfasalazine Statins Thalidomide Vancomycin Anterior Horn Cell Dapsone Dorsal Root Ganglion Pyridoxine Schwann Cell Allopurinol Amiodarone Indomethacin Perhexiline Suramin Zimeldine Gentamicin Streptokinase Eosinophilia-myalgia syndrome
Reprinted with permission from Brown WF, Bolton CF, Aminoff MJ (eds): Drug-Related Neuropathies from Neuromuscular Function and Disease, vol 2. Philadelphia, WB Saunders, 2002, p. 1128.
REFERENCES SUMMARY This elderly woman presented with a severe peripheral neuropathy. Her nerve biopsy showed accumulation of osmiophilic occlusions in several areas of the nerve. This was thought to be caused by amiodarone toxicity. She improved upon withdrawal of the drug.
IMPORTANT POINTS • The neurologic manifestations of amiodarone toxicity include tremor, ataxia, a neuropathy, and a myopathy. • Amiodarone neuropathy can be axonal, demyelinating, or both. • The characteristic finding of a nerve biopsy of amiodarone neuropathy is the presence of osmiophilic bodies within the Schwann cells and other areas of the peripheral nerve. • The treatment consists of discontinuation of the drug and management of contributing factors.
1. Hilleman D, Miller MA, Parker R, et al: Optimal management of amiodarone therapy: Efficacy and side effects. Pharmacotherapy 18:138S–145S, 1998. 2. Dovie JM, Gurwood AS: Acute onset of halos and glare: Bilateral corneal epithelial edema with cystic eruptions: Atypical presentation of amiodarone keratopathy. Optometry 77(2):76–81, 2006. 3. Charness ME, Morady F, Scheinman MM: Frequent neurologic toxicity associated with amiodarone therapy. Neurology 34:669–671, 1986. 4. Azzam I, Tov N, Elias N, Naschitz JE: Amiodarone toxicity presenting as pulmonary mass and peripheral neuropathy: The continuing diagnostic challenge. Postgrad Med J 82(963): 73–75, 2006. 5. Martinez-Arizala A, Sobol SM, McCarty GE, et al: Amiodarone neuropathy. Neurology 33:643–645, 1983. 6. Pellissier JF, Pouget J, Cros D, et al: Peripheral neuropathy induced by amiodarone chlorohydrate: A clinicopathological study. J Neurol Sci 63:251–266, 1984. 7. Lemaire JF, Autret A, Biziere K, et al: Amiodarone neuropathy: Further arguments for human drug-induced neurolipidosis. Eur Neurol 21:65–68, 1982.
432
Case 67
8. Fraser AG, McQueen IN, Watt AH, et al: Peripheral neuropathy during long-term high dose amiodarone therapy. J Neurol Neurosurg Psychiatry 48:576–578, 1985. 9. Clouston PD, Donnelly PE: Acute necrotizing myopathy associated with amiodarone therapy. Aust N Z J Med 19:483– 485, 1989. 10. Miere C, Kauer B, Muller U, et al: Neuromyopathy during chronic amiodarone treatment: A case report. J Neurol 220:231–239, 1979. 11. Roth RF, Itabashi H, Louie J, et al: Amiodarone toxicity: Myopathy and neuropathy. Am Heart J 119:1223–1225, 1990.
12. Pulipaka U, Lacomis D, Omalu B: Amiodarone-induced neuromyopathy: Three cases and a review of the literature. J Clin Neuromusucul Dis 3:97–105, 2002. 13. Lullmann H, Lullmann-Rauch R, Wasserman O: Lipidosis induced by amphiphilic cationic drugs. CRC Crit Rev Toxicol 4:185–218, 1975. 14. Adams PC, Holt DW, Storey GC, et al: Amiodarone and its desethyl metabolite: Tissue distribution and morphologic changes. Circulation 72:1064–1075, 1985.
An Elderly Woman with a Progressive Neuropathy
A 75-year-old woman with congestive heart failure and coronary artery disease was evaluated for progressive numbness and weakness in the feet and legs for the past 3 months. She had been on lanoxin, furosemide, and amiodarone. Past medical and family histories were unremarkable, and she did not smoke or drink. Gait was normal; the rest of the neurologic examination was unremarkable. Examination revealed normal mentation and gross cognitive function. Cranial nerves were normal. There was 4 to 4+/5 weakness in all extremities; the iliopsoas and glutei were 3 to 4−/5 bilaterally; quadriceps, adductors, and hamstrings were 5−/5; foot dorsiflexors 4/5; evertors 4/5; flexors 5−/5. There was decreased pinprick in a stocking distribution up to the midarm and midcalf. She was areflexic, and her toes were downgoing.
WHAT IS THE DIFFERENTIAL DIAGNOSIS? This woman presented with progressive motor and sensory neuropathy. There was no history of diabetes or renal
disease, but she had congestive heart failure and a negative family history. Other conditions such as connective tissue disorder, an autoimmune polyneuropathy, a toxic neuropathy, or a neuropathy associated with carcinoma needed to be considered. The congestive heart failure could also suggest amyloidosis. The patient was on amiodarone which could cause a peripheral neuropathy.
WHAT SHOULD BE DONE? A complete metabolic panel was normal except for mildly elevated sugar of 182 mg/dL (normal, <110 mg/dL). Erythrocyte sedimentation rate was 52 mm/hour (normal, <30 mm/hour) and when repeated was 39 mm/hour. Fluorescent antinuclear antibody was positive 1:80. C3, C4 complement, and extractable nuclear antibody titers were normal.
AN EMG TEST WAS PERFORMED Motor Nerve Studies
Motor Nerve Studies—cont’d
Nerve and Site
Latency (ms)
Amplitude (mV)
Conduction Velocity (m/s)
Peroneal Nerve L.
Normal £ 5.7
Normal ≥4
4.6 10.9 12.4
2 2 2
Ankle Fibular head Knee
This case was evaluated with Dr. Thomas Arnold.
Nerve and Site
Latency (ms)
Amplitude (mV)
Conduction Velocity (m/s)
Normal ≥ 40
Tibial Nerve L.
Normal £ 5.3
Normal ≥4
Normal ≥ 40
— 37 39
Ankle Pop. fossa
4.4 12.6
3 2
— 37
Median Nerve L.
Normal £ 3.6
Normal ≥8
Normal ≥ 50
2.7 6.3
7 7
— 49
Wrist Elbow
429
430
Case 67
F-wave and Tibial H-reflex Studies Nerve
Latency (ms)
Normal Latency £ (ms)
51.5 52.8 28.9 NR NR
54 54 30 34 34
Peroneal nerve L. Tibial nerve L. Median nerve L. H-reflex L. H-reflex R.
Sensory Nerve Studies Nerve
Peak Latency (ms)
Normal Peak Latency £ (ms)
Amp (mV)
Normal Amp ≥ (mV)
NR NR NR
4.0 4.0 3.1
NR NR NR
11 8–10 13
Sural nerve L. Superficial peroneal nerve L. Median nerve L.
EMG Data Muscle
Insrt Activity
Fibs
Pos Waves
Fasc
Amp
Dur
Poly
Pattern
Vastus lateralis L. Tibialis anterior L. Peroneus longus L. Gastrocnemius L. Vastus lateralis R. Tibialis anterior R. Gastrocnemius R. 1st dorsal interosseous L. Flexor carpi ulnaris L.
Norm Norm Inc Inc Norm Inc Inc Norm Norm
None None None None None None None None None
None None None 1+ None None 1+ None None
None None None None None None None None None
Norm Lg Norm Lg Lg Lg Norm Lg Norm
Norm Inc Norm Inc Inc Inc Norm Inc Norm
None None None None None None None None None
Full Red Full Red Red Red Full Red Full
WHAT WERE THE EMG FINDINGS? These electrophysiologic studies revealed mild slowing of nerve conduction velocities with low-amplitude median and peroneal CMAPs; all tested SNAPs were absent. There was mild denervation in the distal legs. It was concluded that this patient had a mild demyelinating and axonal polyneuropathy. A nerve biopsy showed some axonal degeneration, segmental demyelination, and osmiophilic inclusions in the endoneural area (Fig. 67-1). The patient was diagnosed having an amiodaroneinduced neuropathy, and the drug was discontinued. She was treated with physical therapy and slowly improved.
DISCUSSION This elderly woman presented with a polyneuropathy that was thought to be caused by amiodarone, and she improved after discontinuing this drug. Other medications that could cause a neuropathy are summarized in Table 67-1.
Amiodarone is a diodated benzoforfuran derivative used in the treatment of cardiac arrhythmias. The drug can cause several systemic side effects, such as thyroid disease, skin rash, pulmonary fibrosis, and corneal disease.1,2 It could also cause neurologic problems, which occur in about 54% of the cases. Most frequently, this consists of tremors, ataxia, and, rarely, optic neuropathy.3,4 Amiodarone also can cause a peripheral neuropathy,4–8 myopathy,9 or neuromyopathy.10–12 Amiodarone neuropathy could be predominantly demyelinating, axonal, or both EMGs could show signs of denervation as well, but also small, polyphasic motor unit action potentials. Some patients could have elevated serum creatine kinase. The muscle biopsy shows atrophy10,11 or some vacuolization with lipidlike inclusions10–12; a necrotizing myopathy has also been reported.9 Nerve biopsies demonstrate loss of myelinated axons with degeneration6,10 and demyelination.12 The characteristic finding is the presence of electron-dense inclusions in the Schwann cells, endoneural cells, and interstitial cells.6,10 These osmophilic inclusions can also be caused by other
431
An Elderly Woman with a Progressive Neuropathy
Table 67-1. Drug-induced Neuropathies: Anatomical Site of Disease
FIGURE 67-1 Electromicroscopy on sural nerve biopsy showing osmiophilic inclusions in cytoplasm of Schwann cells (arrows) (×10,000).
amphiphilic drugs and are likely of lysosomal origin.13 The demyelination is believed to be produced by Schwann cell dysfunction with secondary axonal degeneration.12 The long half-life of the drug is likely predisposed to its tissue accumulation.10,14 The treatment of the neurologic manifestations of amiodarone toxicity includes discontinuation of the drug and physical therapy.
Axonopathy Almitrine Amiodarone Amitriptyline Carbamide Chloramphenicol Chloroquine Clioquinol Colchicine Cyanate Disopyramide Disulfiram Ethambutol Ethionamide Hydralazine Gold Glutethimide Isoniazid Lithium Methaqualone Metronidazole Misonidazole Nitrofurantoin
Axonopathy—cont’d Nitrous oxide Phenytoin Sulfapyridine Sulfasalazine Statins Thalidomide Vancomycin Anterior Horn Cell Dapsone Dorsal Root Ganglion Pyridoxine Schwann Cell Allopurinol Amiodarone Indomethacin Perhexiline Suramin Zimeldine Gentamicin Streptokinase Eosinophilia-myalgia syndrome
Reprinted with permission from Brown WF, Bolton CF, Aminoff MJ (eds): Drug-Related Neuropathies from Neuromuscular Function and Disease, vol 2. Philadelphia, WB Saunders, 2002, p. 1128.
REFERENCES SUMMARY This elderly woman presented with a severe peripheral neuropathy. Her nerve biopsy showed accumulation of osmiophilic occlusions in several areas of the nerve. This was thought to be caused by amiodarone toxicity. She improved upon withdrawal of the drug.
IMPORTANT POINTS • The neurologic manifestations of amiodarone toxicity include tremor, ataxia, a neuropathy, and a myopathy. • Amiodarone neuropathy can be axonal, demyelinating, or both. • The characteristic finding of a nerve biopsy of amiodarone neuropathy is the presence of osmiophilic bodies within the Schwann cells and other areas of the peripheral nerve. • The treatment consists of discontinuation of the drug and management of contributing factors.
1. Hilleman D, Miller MA, Parker R, et al: Optimal management of amiodarone therapy: Efficacy and side effects. Pharmacotherapy 18:138S–145S, 1998. 2. Dovie JM, Gurwood AS: Acute onset of halos and glare: Bilateral corneal epithelial edema with cystic eruptions: Atypical presentation of amiodarone keratopathy. Optometry 77(2):76–81, 2006. 3. Charness ME, Morady F, Scheinman MM: Frequent neurologic toxicity associated with amiodarone therapy. Neurology 34:669–671, 1986. 4. Azzam I, Tov N, Elias N, Naschitz JE: Amiodarone toxicity presenting as pulmonary mass and peripheral neuropathy: The continuing diagnostic challenge. Postgrad Med J 82(963): 73–75, 2006. 5. Martinez-Arizala A, Sobol SM, McCarty GE, et al: Amiodarone neuropathy. Neurology 33:643–645, 1983. 6. Pellissier JF, Pouget J, Cros D, et al: Peripheral neuropathy induced by amiodarone chlorohydrate: A clinicopathological study. J Neurol Sci 63:251–266, 1984. 7. Lemaire JF, Autret A, Biziere K, et al: Amiodarone neuropathy: Further arguments for human drug-induced neurolipidosis. Eur Neurol 21:65–68, 1982.
432
Case 67
8. Fraser AG, McQueen IN, Watt AH, et al: Peripheral neuropathy during long-term high dose amiodarone therapy. J Neurol Neurosurg Psychiatry 48:576–578, 1985. 9. Clouston PD, Donnelly PE: Acute necrotizing myopathy associated with amiodarone therapy. Aust N Z J Med 19:483– 485, 1989. 10. Miere C, Kauer B, Muller U, et al: Neuromyopathy during chronic amiodarone treatment: A case report. J Neurol 220:231–239, 1979. 11. Roth RF, Itabashi H, Louie J, et al: Amiodarone toxicity: Myopathy and neuropathy. Am Heart J 119:1223–1225, 1990.
12. Pulipaka U, Lacomis D, Omalu B: Amiodarone-induced neuromyopathy: Three cases and a review of the literature. J Clin Neuromusucul Dis 3:97–105, 2002. 13. Lullmann H, Lullmann-Rauch R, Wasserman O: Lipidosis induced by amphiphilic cationic drugs. CRC Crit Rev Toxicol 4:185–218, 1975. 14. Adams PC, Holt DW, Storey GC, et al: Amiodarone and its desethyl metabolite: Tissue distribution and morphologic changes. Circulation 72:1064–1075, 1985.