Carcinoid
Myopathy
Serotonin-Induced Muscle Weakness in Man? Michael
Swash, MD, MRCP; Kathleen P. Fox, FILMT; Andrew R. Davidson, MB, MRCP
A myopathy, which improved with cyproheptadine hydrochloride therapy, developed in a patient with carcinoid syndrome of ten years' duration. Biopsy examination revealed advanced atrophy of type II muscle fibers, with type I fiber preponderance. Many of the small fibers had degenerated. Carcinoid myopathy may be due to excess circulating serotonin.
(Arch Neurol 32:572-574, 1975)
et al1 have described
Berryopathy
a my¬ associated with carcinoid syndrome in a patient with a metas¬ tatic ileal argentaifin tumor. We have studied a similar patient.
Report
excised. Several secondary deposits in the liver. Two years later, the patient was found to have tricuspid valve disease with right heart failure. Treatment with methysergide maléate (Sansert) was begun and her rash and diarrhea improved, but during the following eight years, her heart failure became increasingly difficult to control. During this time the urinary 5HIAA ex¬ cretion rate varied from 43 to 295 mg/24 hr. Myopathy.—In January 1974, the patient noticed progressive difficulty climbing was
were seen
stairs. In July, she could rise from a chair only with great difficulty. She reported oc¬ casional muscle cramps and some tender¬ ness in the shoulder muscles. On examination, there was severe, sym¬ metrical, proximal weakness. Affected muscles were mildly wasted and slightly tender to palpation. There was no fasciculation. The tendon reflexes were symmetri¬ cal and sensation was normal. Laboratory Data.—Electromyography of the right biceps and quadriceps muscles re¬ vealed a reduced interference pattern with numerous short duration, low amplitude,
Fig 1 .—Deltoid biopsy. Dark type II fibers are much smaller (ATPase pH 9.4x140, original magnification 140).
of a Case
Carcinoid Syndrome.—In 1964, a 41-yearold woman complained of headache, blue discoloration of her face, a feeling of facial swelling, and diarrhea. On examination, there was facial erythema and her liver was enlarged. The urinary 5 hydroxyindole acetic acid (5HIAA) excretion rate varied from 18 mg in 24 hours to 251 mg in 24 hours (normal 3 to 17 mg/24 hr). At laparotomy an ileal argentaifin carcinoma
Accepted for publication April 11, 1975. From the Department of Neurology, Section of Neurological Sciences, the London Hospital. Reprint requests to the Department of Neurology, the London Hospital, EL 1BB, United Kingdom (Dr. Swash).
Downloaded From: http://archneur.jamanetwork.com/ by a Monash University Library User on 06/19/2015
than
pale type I fibers.
Variability of Type I and Type II Fibers Variable Type I No. of fibers 120 58 Percentage of fibers Mean diameter, pm 48
Range SD
10-80 15.4
Type II 88 42 17 10-80 8.5
polyphasic potentials.
There was no evi¬ dence of denervation. The plasma creatine phosphokinase level was 127 mU/ml (nor¬ mal < 100 mU/ml) and the aldolase level was 3.4 mU/ml (normal 0.9 to 2.5 mU/ml). The erythrocyte sedimentation rate (ESR) was 7 mm/hr, and the plasma potassium measurement was 4.6 mEq/liter. The alka¬ line phosphatase measurement was 26.3 King-Armstrong units/100 ml plasma. There was no radiographie evidence of dis¬ seminated metastatic carcinoma. Muscle Biopsy.—A right deltoid biopsy was examined, using conventional histological, enzyme histochemical, and electron microscopical techniques.2 The ATPase (pH 9.4) method revealed type I fiber pre¬ dominance; 58% (120) of 208 fibers were type I. There was advanced type II fiber atrophy (Fig 1); 93% (82) of 88 type II fi¬ bers were less than 400/¿m in diameter. The atrophie type II fibers consisted of both type IIA and IIB fibers. There was no fi¬ ber type grouping and type II atrophy was not focally distributed. Both type I and type II fibers showed increased variability in size (Table). Although some atrophie type II fibers were unusually pointed in cross section (Fig 1), suggesting that they might be denervated, they did not stain darkly for nicotinamide adenine nucleotide dehy¬ drogenase (NADH) tetrazolium reducíase. Some of the smallest type II fibers con¬ tained prominent lipid droplets and cen¬ trally placed sarcolemmal nuclei (Fig 2). Many of the small, type II fibers were necrotic, but there were no inflammatory changes or basophilic fibers. Electron microscopy revealed advanced degenerative changes in the small (pre¬ sumedly type II) fibers (Fig 3). Most of the abnormal fibers contained many small lipid droplets. The larger fibers appeared nor¬ mal, except for an unusually wide separa¬ tion of their myofibrils. Progress.—Treatment with cypropheptadine (Periactin) hydrochloride, 24 mg daily, was begun and methysergide, digoxin, and diuretic therapy were continued. There was gradual improvement in strength. Six weeks later, she could again rise from a
Fig 2.—Deltoid biopsy. Small fibers are less granular than larger fibers. Central nuclei present in both small and large fibers (hemotoxylin-eosin, original magnification 560).
are
Fig 3.—Deltoid biopsy. Advanced degenerative changes have occurred in a small fi¬ ber. On either side, parts of nearby large fibers appear relatively normal (lead citrate,
original magnification
12,500).
Downloaded From: http://archneur.jamanetwork.com/ by a Monash University Library User on 06/19/2015
chair, dress herself, and complete light household tasks. However, the cardiac fail¬ ure worsened, and she died of bronchopneumonia four months later, 11 years after the first symptoms of carcinoid syn¬ drome. Permission for autopsy was re¬ fused.
krein.8 Although carcinoid myopathy could be due to one or more of these factors, the clinical1 and experimen¬ tal2'4"" evidence suggests that it re¬ sults from circulating serotonin. How¬ ever, the inhibitory action of sero¬ tonin on muscle is poorly under¬ stood." Cyproheptadine, a potent serotonin and histamine antagonist,1" improved muscle strength in both cases, when given in addition to methysergide. In the rat model,1 methysergide and cyproheptadine both prevented the weakness induced by serotonin infu¬ sion. Serotonin is normally removed from the circulation by the liver, lungs, and platelets.11 Myopathy may occur only when these regulatory mechanisms are overwhelmed and blood serotonin levels are greatly raised. In the case of Berry et al1 the blood serotonin concentration was nearly ten times the normal level, and in both cases the urinary 5HIAA ex¬ cretion levels had been increased for ten years before myopathy developed. Green et al12 described a patient who developed distal weakness, wast¬ ing, paresthesias, fasciculation, and muscular tenderness, three years af¬ ter resection of an ileal carcinoid tumor. A muscle biopsy showed in¬ flammatory changes and a diagnosis of carcinomatous neuromyopathy was suggested. The clinical and histological findings in this case clearly differ from those of carcinoid myopathy. In carcinoid syndrome, muscle weakness could also develop as part of a malabsorption syndrome due to in¬ testinal dysfunction, or as a result of hypercalcemia from bony métastases. These abnormalities were not found in either patient. In both, raised alka'"
COMMENT our patient, and in that of Berry al,1 symptoms of carcinoid syn¬
In et
drome
were
present for
more
than
ten years before muscular weakness developed. In both cases, the muscle
biopsy showed advanced atrophy of type II muscle fibers, some scattered necrotic fibers, and central nucleation. In our patient, type I fibers were also somewhat smaller than normal,
and the diameters of both type I and type II fibers were abnormally vari¬ able. These pathological findings, particularly the marked predilection for atrophy of type II fibers, are con¬ sistent with the observation of Pat¬ ten et al·' that, in a rat nerve-muscle preparation, serotonin infusion in¬ duced more severe weakness in the anterior tibial muscle (type II fi¬ bers) than in the soleus (type I fibers). In experimental studies, myopathie changes were induced by serotonin16 but type II atrophy was not de¬ scribed. Atrophy of type II fibers is not a specific feature of carcimatous my¬ opathy, since it also occurs in corticospinal tract disease, mental retar¬
collagen-vascular disease, myasthenia gravis, and disuse atro¬ phy.2 None of these problems were present in our patient. Functioning carcinoid tumors may dation,
release active substances other than serotonin, eg, histamine7 and kalli-
Downloaded From: http://archneur.jamanetwork.com/ by a Monash University Library User on 06/19/2015
line
phosphatase activity was consist¬ hepatic métastases. Finally, it seems that the occur¬ rence of a myopathy with such dis¬ tinctive clinical and pathological fea¬ tures in carcinoid syndrome makes it unlikely that circulating serotonin plays an important role in the patho¬ genesis of Duchenne dystrophy. ent with
References 1. Berry EM, Maunder C, Wilson M: Carcinoid myopathy and treatment with cyproheptadine
(Periactin). Gut 15:34-38, 1974. 2. Dubovitz V, Brooke MH: Muscle Biopsy: A
Modern Approach. Philadelphia, WB Saunders Co, 1973. 3. Patten BM, Oliver KL, Engel WK: Serotonin-induced muscle weakness. Arch Neurol 31:347-349, 1974. 4. Mendell JR, Engel WK, Derrer, EC: Duchenne muscular dystrophy: Functional ischaemia reproduces its characteristic lesions. Science 172:1143-1145, 1971. 5. Parker JM, Mendell JR: Proximal myopathy induced by 5 HT-imipramine simulates Duchenne dystrophy. Nature 247:103-104, 1974. 6. O'Steen WK, Barnard JL Jr, Yates RD: Morphologic changes in skeletal muscle induced by serotonin treatment: A light and electron microscopic study. Exp Mol Pathol 7:145-155, 1967. 7. Sandler M: The role of 5 hydroxyindoles in the carcinoid syndrome. Adv Pharmacol 6B:127\x=req-\ 142, 1968. 8. Oates JA, Melman K, Sjoerdsma A, et al: Release of a kinin peptide in the carcinoid syndrome. Lancet 1:514-517, 1964. 9. Rapport MM: Discussion of the possible mechanism of action of serotonin on molluscan muscle. Adv Pharmacol 6B:16-17, 1968. 10. Douglas WW: Histamines and antihistamines: 5 hydroxytryptamine and antagonists, in Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics, ed 4, New York, MacMillan Co, 1970, pp 645-662. 11. Vane JR: The release and fate of vaso-active hormones in the circulation. Br J Pharmacol 35:209-242, 1969. 12. Green D, Joynt RJ, Van Allen MW: Neuromyopathy associated with a malignant carcinoid tumor. Arch Intern Med 114:494-496, 1964.
Myopathy
Serotonin-Induced Muscle Weakness in Man? Michael
Swash, MD, MRCP; Kathleen P. Fox, FILMT; Andrew R. Davidson, MB, MRCP
A myopathy, which improved with cyproheptadine hydrochloride therapy, developed in a patient with carcinoid syndrome of ten years' duration. Biopsy examination revealed advanced atrophy of type II muscle fibers, with type I fiber preponderance. Many of the small fibers had degenerated. Carcinoid myopathy may be due to excess circulating serotonin.
(Arch Neurol 32:572-574, 1975)
et al1 have described
Berryopathy
a my¬ associated with carcinoid syndrome in a patient with a metas¬ tatic ileal argentaifin tumor. We have studied a similar patient.
Report
excised. Several secondary deposits in the liver. Two years later, the patient was found to have tricuspid valve disease with right heart failure. Treatment with methysergide maléate (Sansert) was begun and her rash and diarrhea improved, but during the following eight years, her heart failure became increasingly difficult to control. During this time the urinary 5HIAA ex¬ cretion rate varied from 43 to 295 mg/24 hr. Myopathy.—In January 1974, the patient noticed progressive difficulty climbing was
were seen
stairs. In July, she could rise from a chair only with great difficulty. She reported oc¬ casional muscle cramps and some tender¬ ness in the shoulder muscles. On examination, there was severe, sym¬ metrical, proximal weakness. Affected muscles were mildly wasted and slightly tender to palpation. There was no fasciculation. The tendon reflexes were symmetri¬ cal and sensation was normal. Laboratory Data.—Electromyography of the right biceps and quadriceps muscles re¬ vealed a reduced interference pattern with numerous short duration, low amplitude,
Fig 1 .—Deltoid biopsy. Dark type II fibers are much smaller (ATPase pH 9.4x140, original magnification 140).
of a Case
Carcinoid Syndrome.—In 1964, a 41-yearold woman complained of headache, blue discoloration of her face, a feeling of facial swelling, and diarrhea. On examination, there was facial erythema and her liver was enlarged. The urinary 5 hydroxyindole acetic acid (5HIAA) excretion rate varied from 18 mg in 24 hours to 251 mg in 24 hours (normal 3 to 17 mg/24 hr). At laparotomy an ileal argentaifin carcinoma
Accepted for publication April 11, 1975. From the Department of Neurology, Section of Neurological Sciences, the London Hospital. Reprint requests to the Department of Neurology, the London Hospital, EL 1BB, United Kingdom (Dr. Swash).
Downloaded From: http://archneur.jamanetwork.com/ by a Monash University Library User on 06/19/2015
than
pale type I fibers.
Variability of Type I and Type II Fibers Variable Type I No. of fibers 120 58 Percentage of fibers Mean diameter, pm 48
Range SD
10-80 15.4
Type II 88 42 17 10-80 8.5
polyphasic potentials.
There was no evi¬ dence of denervation. The plasma creatine phosphokinase level was 127 mU/ml (nor¬ mal < 100 mU/ml) and the aldolase level was 3.4 mU/ml (normal 0.9 to 2.5 mU/ml). The erythrocyte sedimentation rate (ESR) was 7 mm/hr, and the plasma potassium measurement was 4.6 mEq/liter. The alka¬ line phosphatase measurement was 26.3 King-Armstrong units/100 ml plasma. There was no radiographie evidence of dis¬ seminated metastatic carcinoma. Muscle Biopsy.—A right deltoid biopsy was examined, using conventional histological, enzyme histochemical, and electron microscopical techniques.2 The ATPase (pH 9.4) method revealed type I fiber pre¬ dominance; 58% (120) of 208 fibers were type I. There was advanced type II fiber atrophy (Fig 1); 93% (82) of 88 type II fi¬ bers were less than 400/¿m in diameter. The atrophie type II fibers consisted of both type IIA and IIB fibers. There was no fi¬ ber type grouping and type II atrophy was not focally distributed. Both type I and type II fibers showed increased variability in size (Table). Although some atrophie type II fibers were unusually pointed in cross section (Fig 1), suggesting that they might be denervated, they did not stain darkly for nicotinamide adenine nucleotide dehy¬ drogenase (NADH) tetrazolium reducíase. Some of the smallest type II fibers con¬ tained prominent lipid droplets and cen¬ trally placed sarcolemmal nuclei (Fig 2). Many of the small, type II fibers were necrotic, but there were no inflammatory changes or basophilic fibers. Electron microscopy revealed advanced degenerative changes in the small (pre¬ sumedly type II) fibers (Fig 3). Most of the abnormal fibers contained many small lipid droplets. The larger fibers appeared nor¬ mal, except for an unusually wide separa¬ tion of their myofibrils. Progress.—Treatment with cypropheptadine (Periactin) hydrochloride, 24 mg daily, was begun and methysergide, digoxin, and diuretic therapy were continued. There was gradual improvement in strength. Six weeks later, she could again rise from a
Fig 2.—Deltoid biopsy. Small fibers are less granular than larger fibers. Central nuclei present in both small and large fibers (hemotoxylin-eosin, original magnification 560).
are
Fig 3.—Deltoid biopsy. Advanced degenerative changes have occurred in a small fi¬ ber. On either side, parts of nearby large fibers appear relatively normal (lead citrate,
original magnification
12,500).
Downloaded From: http://archneur.jamanetwork.com/ by a Monash University Library User on 06/19/2015
chair, dress herself, and complete light household tasks. However, the cardiac fail¬ ure worsened, and she died of bronchopneumonia four months later, 11 years after the first symptoms of carcinoid syn¬ drome. Permission for autopsy was re¬ fused.
krein.8 Although carcinoid myopathy could be due to one or more of these factors, the clinical1 and experimen¬ tal2'4"" evidence suggests that it re¬ sults from circulating serotonin. How¬ ever, the inhibitory action of sero¬ tonin on muscle is poorly under¬ stood." Cyproheptadine, a potent serotonin and histamine antagonist,1" improved muscle strength in both cases, when given in addition to methysergide. In the rat model,1 methysergide and cyproheptadine both prevented the weakness induced by serotonin infu¬ sion. Serotonin is normally removed from the circulation by the liver, lungs, and platelets.11 Myopathy may occur only when these regulatory mechanisms are overwhelmed and blood serotonin levels are greatly raised. In the case of Berry et al1 the blood serotonin concentration was nearly ten times the normal level, and in both cases the urinary 5HIAA ex¬ cretion levels had been increased for ten years before myopathy developed. Green et al12 described a patient who developed distal weakness, wast¬ ing, paresthesias, fasciculation, and muscular tenderness, three years af¬ ter resection of an ileal carcinoid tumor. A muscle biopsy showed in¬ flammatory changes and a diagnosis of carcinomatous neuromyopathy was suggested. The clinical and histological findings in this case clearly differ from those of carcinoid myopathy. In carcinoid syndrome, muscle weakness could also develop as part of a malabsorption syndrome due to in¬ testinal dysfunction, or as a result of hypercalcemia from bony métastases. These abnormalities were not found in either patient. In both, raised alka'"
COMMENT our patient, and in that of Berry al,1 symptoms of carcinoid syn¬
In et
drome
were
present for
more
than
ten years before muscular weakness developed. In both cases, the muscle
biopsy showed advanced atrophy of type II muscle fibers, some scattered necrotic fibers, and central nucleation. In our patient, type I fibers were also somewhat smaller than normal,
and the diameters of both type I and type II fibers were abnormally vari¬ able. These pathological findings, particularly the marked predilection for atrophy of type II fibers, are con¬ sistent with the observation of Pat¬ ten et al·' that, in a rat nerve-muscle preparation, serotonin infusion in¬ duced more severe weakness in the anterior tibial muscle (type II fi¬ bers) than in the soleus (type I fibers). In experimental studies, myopathie changes were induced by serotonin16 but type II atrophy was not de¬ scribed. Atrophy of type II fibers is not a specific feature of carcimatous my¬ opathy, since it also occurs in corticospinal tract disease, mental retar¬
collagen-vascular disease, myasthenia gravis, and disuse atro¬ phy.2 None of these problems were present in our patient. Functioning carcinoid tumors may dation,
release active substances other than serotonin, eg, histamine7 and kalli-
Downloaded From: http://archneur.jamanetwork.com/ by a Monash University Library User on 06/19/2015
line
phosphatase activity was consist¬ hepatic métastases. Finally, it seems that the occur¬ rence of a myopathy with such dis¬ tinctive clinical and pathological fea¬ tures in carcinoid syndrome makes it unlikely that circulating serotonin plays an important role in the patho¬ genesis of Duchenne dystrophy. ent with
References 1. Berry EM, Maunder C, Wilson M: Carcinoid myopathy and treatment with cyproheptadine
(Periactin). Gut 15:34-38, 1974. 2. Dubovitz V, Brooke MH: Muscle Biopsy: A
Modern Approach. Philadelphia, WB Saunders Co, 1973. 3. Patten BM, Oliver KL, Engel WK: Serotonin-induced muscle weakness. Arch Neurol 31:347-349, 1974. 4. Mendell JR, Engel WK, Derrer, EC: Duchenne muscular dystrophy: Functional ischaemia reproduces its characteristic lesions. Science 172:1143-1145, 1971. 5. Parker JM, Mendell JR: Proximal myopathy induced by 5 HT-imipramine simulates Duchenne dystrophy. Nature 247:103-104, 1974. 6. O'Steen WK, Barnard JL Jr, Yates RD: Morphologic changes in skeletal muscle induced by serotonin treatment: A light and electron microscopic study. Exp Mol Pathol 7:145-155, 1967. 7. Sandler M: The role of 5 hydroxyindoles in the carcinoid syndrome. Adv Pharmacol 6B:127\x=req-\ 142, 1968. 8. Oates JA, Melman K, Sjoerdsma A, et al: Release of a kinin peptide in the carcinoid syndrome. Lancet 1:514-517, 1964. 9. Rapport MM: Discussion of the possible mechanism of action of serotonin on molluscan muscle. Adv Pharmacol 6B:16-17, 1968. 10. Douglas WW: Histamines and antihistamines: 5 hydroxytryptamine and antagonists, in Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics, ed 4, New York, MacMillan Co, 1970, pp 645-662. 11. Vane JR: The release and fate of vaso-active hormones in the circulation. Br J Pharmacol 35:209-242, 1969. 12. Green D, Joynt RJ, Van Allen MW: Neuromyopathy associated with a malignant carcinoid tumor. Arch Intern Med 114:494-496, 1964.
