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Respiratory muscle weakness and ventilatory failure in AL amyloidosis with muscular pseudohypertrophy
Respiratory Muscle Weakness and Ventilatory Failure in AL Amyloidosis with Muscular Pseudohypertrophy
RAFAEL M. SANTIAGO, MAJ., U.S.A.F., M.C. DAVID SCHARNHORST, M.D. GARY RATKIN, M.D. EDMOND C. CROUCH, M.D., Ph.D. St. Louis, Missouri
Generalized muscle weakness culminating in ventilatory failure developed in a 59-year-old man with kappa light chain multiple myeloma. Physical examination demonstrated skeletal muscle enlargement, severe proximal muscle weakness, and macroglossia, consistent with amyloid-associated muscle pseudohypertrophy. Pulmonary function studies revealed a severe restrictive abnormality with a low maximal inspiratory pressure and maximal voluntary ventilation. Arterial blood gas values and chest radiographic results were normal. There was no clinical evidence of cardiac or central nervous system disease. At autopsy, skeletal muscles and diaphragm were diffusely infiltrated by amyloid. There was also multifocal deposition of amyloid in alveolar septae, esophagus, and subendocardium. This report suggests that ventilatory failure may occur as a complication of myeloma-associated (AL) amyloidosis involving the respiratory muscles. Generalized amyioidosis complicates the course of some patients with multiple myeloma. In this setting, amyloidosis most commonly involves the gastrointestinal tract, skeletal muscles, heat-t, peripheral and autonomic nerves, and kidneys [l-7]. Although respiratory tract involvement appears to be relatively common [8-lo], amyloidosis has rarely been implicated as a cause of respiratory failure. This report describes a patient with kappa light chain multiple myeloma in whom extensive amyloid infiltration of muscle was associated with generalized weakness and ventilatory failure.
CASE REPORT Clinical Course. A 59-year-old
white man was transferred to the Jewish Hospital (St. Louis) on September 11, 1984, for evaluation of renal failure and hypercalcemia. The patient had undergone resection of a colonic cancer in 1978 but had remained in good health until one month prior to admission, when malaise, atthralgias, anorexia and a 15pound weight loss developed. At ttie outside hospital, he was found to have an elevated serum
From the Respiratory and Critical Care Division and Hematology Oncology Division, Department of Medicine, and the Department of Pathology, Jewish Hospital, Washington University Medical Center, St. Louis, Missouri. Dr. Santiago is an Air Force-sponsored Pulmonary Fellow at Washing1ton University Medical Center. Requests for reprints should be addressed to Dr. Edmond C. Crouch, Department of Pathology, Jewish Hospital, Washington University Medical Center, 216 South Kingshighway, St. Louis, Missouri 63110. Manuscript submitted August 29, 1986, and accepted October 24, 1986.
creatinine
concentration,
a low
creatinine
clearance,
marked
proteinuria,
and a serum calcium level of 11.3 mg/dl. Ultrasound study of the kidneys and bone and liver-spleen scanning revealed no abnormalities. A compression fracture of the second lumbar vertebra was found on lumbar-sacral spine radiography. Results of computed tomographic scanning of the abdomen and upper and lower gastrointestinal series were reported as normal. Physical examination revealed a well-developed muscular man in no acute distress. His temperature was normal, blood pressure was 190/100 mm Hg, pulse was 84/minute and regular, and respiratory rate was 161 minute, unlabored. His tongue was enlarged. Cardiac examination revealed normal heart sounds, no murmurs, and a regular rhythm. No jugular venous distention was present. Lung examination showed distant breath sounds but
July
1987
The American
Journal
of Medicine
Volume
83
175
VENTILATORY
FAILURE
AND
AMYLOIDOSIS-SANTIAGO
ET AL
ic ST-T wave changes. Echocardiography, M-mode and two-dimensional, showed mild left ventricular concentric hypertrophy with normal wall motion and a calculated ejection fraction of 82 percent. Further work-up showed a creatinine clearance of 28 ml/minute and a 24-hour protein excretion of 23.4 g; the urine contained no myoglobin. Serum protein electrophoresis showed no evidence of a monoclonal spike. However, serum immunoelectrophoresis revealed a kappa light chain paraprotein with marked reduction of IgG and IgA levels and no detectable IgM. Lambda light chain values were also markedly decreased. Urine immunoelectrophoresis revealed large amounts of kappa light chains with trace amounts of IgG and small amounts of albumin. Bone marrow aspiratipn and biopsy showed more than 50 percent replacement with atypical plasmacytoid cells. Thus, the patient was thought to have kappa light chain multiple myeloma, and his renal failure and proteinuria were attributed to myeloma kidney. Hypercalcemia was corrected with furosemide, corticosteroids, and hydration. The patient was treated with vincristine, carmustine (BCNU), and prednisone. At time of discharge on September 28, 1984, the patient still had significant upper and lower extremity muscle weakness. The patient was readmitted on October 14, 1984, after five days of progressive muscular weakness, inability to walk, dyspnea at rest, and dysphagia. On physical examination, vital signs were normal; his tongue was markedly enlarged, making it difficult for the patient to close his mouth. His speech was slurred, and he was markedly weak despite his apparent well-developed musculature. Except for mildly decreased tendon reflexes, his neurologic results were normal. His lung and cardiac examinations were unremarkable. As before, chest radiography showed no evidence of acute cardiac or pulmonary disease. Electrocardiography showed a normal sinus rhythm with normal voltage and nonspecific ST-T wave changes. The serum calcium level was 12.7 mg/dl, serum electrolyte values were normal, and the creatinine concentration was 2.9 mg/dl. Biopsy of the tongue confirmed the diagnosis of amyloidosis. Pulmonary function studies revealed a forced vital capacity of 1.5 liters (29 percent of predicted), one-second forced expiratory volume of 1.1 liters/second (31 percent of predicted), maximal inspiratory pressure of -45 cm H20, maximal voluntary ventilation of 27.8 liters (19 percent of predicted), minute ventilation of 11.7 liters, and tidal volume of 829 ml. Measurement of arterial blood gas values while the patient was breathing room air showed a pH of 7.40, carbon dioxide tension of 40 mm Hg, and oxygen tension of 77 mm Hg. Despite treatment with high-dose methylprednisolone, progressive ventilatory impairment developed, with a decrease in vital capacity to 0.9 liters and maximal inspiratory pressure to -15 cm H20, at which time intubation was carried out. Therapeutic efforts consisting of plasmapheresis and chemotherapy with cyclophosphamide, BCNU, and prednisone failed to improve muscle strength enough to allow discontinuation of ventilatory support. The remainder of his hospital course was complicated by pancytopenia, pneumonia, sepsis, gastrointestinal bleeding, cardiac arrhythmias, and azotemia. He died 20 days after admission. Pathologic Study. At autopsy, the skeletal muscles were firm and tan, and appeared hypertrophic. The diaphragm
Figure 1. Section of thickened diaphragm obtained at autopsy showing atrophy and distortion of muscle fibers with infiltration of interstitium by amorphous eosinophilic material. Short arrow identifies a distorted muscle fiber in cross-section; long arrow identifies amorphous interstitial material (hematoxylin and eosin stain; original magnification X 320, reduced by 25 percent).
otherwise was clear to auscultation and percussion. Liver span was normal by percussion, and the spleen was not palpable. He showed increased muscle tone and apparent muscular hypertrophy with severe upper and lower extremity proximal muscle weakness. Findings on neurologic examination were normal, with preservation of sensory function and deep tendon reflexes. Laboratory values included normal serum electrolyte levels, blood urea nitrogen 59 mg/dl, creatinine 4.0 mg/dl, uric acid 9.8 mg/dl, serum calcium 11.0 mg/dl, phosphate 5.0 mg/dl, total protein 5.8 g/dl, albumin 3.7 g/d& creatine phosphokinase 484 units/ liter and cholesterol 15 1 mg/dl. Urinalysis showed a specific gravity of 1.02, pH of 5 with 4+ protein, one to three red blood cells per high-power field, one to two white blood cells/per high-power field, and three to four hyaline casts. The white blood cell count was 9,800/mm3, hemoglobin 10.1 g/dl, hematocrit 30.1 percent, mean corpuscular volume 93 p3, with normal differential. The platelet count was 572,000/mm3, and the erythrocyte sedimentation rate was 85 mm/hour. Chest radiography revealed no evidence of cardiac or pulmonary disease. Electrocardiography revealed normal sinus rhythm, normal voltage, and nonspecif176
July
1967
The
American Journal
of Medicine
Volume
63
VENTILATORY
was approximately 1 cm thick (three to five times normal). The tongue was also firm and enlarged. The liver, spleen, heart, peripheral nerves, and central nervous system were unremarkable. On cut section, the vertebral bodies showed several small bony defects containing soft, red, and gelatinous tissue. The kidneys were pale and slightly enlarged. The lungs were heavy, each weighing approximately 2,000 g (normal, 300 to 400 g), and diffusely consolidated consistent with confluent bronchopneumonia. By light microscopy, the diaphragm and psoas muscles showed variable myofiber atrophy, focal myofiber degeneration, and diffuse infiltration of perivascular connective tissue by amorphous eosinophilic material (Figure 1). This material stained with Congo red and showed “apple-green” birefringence by polarization microscopy, consistent with amyloid (Figure 2). Group atrophy of muscle fibers, as usually occurs with degeneration, was not observed. Significant amyloid deposits were also identified between cardiac muscle fibers in the subendocardium and within the muscularis of the esophagus. There was patchy interstitial deposition of amyloid in alveolar septae. There was no identifiable amyloid in sections of liver, spleen, adrenal glands, peripheral nerves, or brain. The vertebral bone defects showed diffuse infiltrates of immature plasma cells. The kidneys showed changes consistent with myeloma kidney, including numerous homogeneous eosinophilic casts within the distal con-
voluted tubules and collecting ducts. In some areas, casts were associated with multinucleated giant cells. The renal medulla showed mild tubular atrophy and interstitial fibrosis. Glomeruli were unremarkable except for focal increases in mesangial matrix. The lungs showed diffuse acute and organizing bronchopneumonia and purulent tracheobronchitis. COMMENTS Amyloidosis
is a disorder
in which organs are infiltrated
by
extracellular proteinaceous material. This material is histochemically characterized by green birefringence when stained with Congo red and examined by polarization microscopy. It is now established that monoclonal immunoglobulin light chains or amino-terminal light chain fragments are the major comoonents of amyloid in cases of primary and myeloma-as ociated amyloidosis [ 11-I 31. Organ dysfunction apparently occurs as a result of excess deposition and/or defective degradation of this material. Generalized amyloidosis occurs in 5 to 15 percent of patients with multiple myeloma, and patients with light chain myeloma have a reported incidence of 20 to 24 percent [ 1,141. The disease predominantly affects the kidneys, heart, gastrointestinal tract, and peripheral and autonomic nerves, with nephrotic syndrome, congestive heart failure, peripheral neuropathy, carpal tunnel syndrome, and orthostatic hypotension being the most common clinical presentations [3,5-71. In a recent series of 187 patients, death was due to cardiac failure and renal failure in 40 percent and IO percent, respectively [3]. Involvement of the respiratory tract is common in primary and myeloma-associated amyloidosis, occurring in 36 to 90 percent of patients with generalized disease
FAILURE
AND
AMYLOIDOSIS-SANTIAGO
ET AL
FIgure 2. Top, section of diaphragm stained with Congo red. Long arrow identifies perivascular congophilic material; short arrow identifies muscle fiber. Boffom, same field viewed under partially polarized light. Congophilic material showed “apple-green” birefringence consistent with amyloid (original magnification X 128, reduced by 35 percent).
[3,10,15]. The most common pattern of respiratory involvement in this setting is diffuse deposition of amyloid in alveolar septae. Multifocal perivascular or tracheobronchial deposits may also be observed [8- 10,16,17]. Several reports have described patients with progressive muscular weakness, dysphonia, dysphagia, and a prominent athletic appearance secondary to amyloid infiltration of skeletal muscles. This constellation of findings has been termed amyloid-muscle pseudohypettrophy [ 18,191. In some of these patients, pulmonary function studies demonstrated combined restrictive and obstructive defects. It was unclear, however, whether the pulmonary function abnormalities noted were secondary to underlying chronic lung disease, congestive heart failure, or a component of respiratory muscle weakness. Diaphragmatic muscles were not examined in these studies. Our patient fits the description of muscle pseudohypertrophy due to amyloid. In addition, serial pulmonary functions documented a decrease in forced vital capacity and maximal inspiratory pressure leading to respiratory failure in the absence of overt complicating cardiac or parenchymal pulmonary disease. Thus, it seems likely that amyloid infiltration of respiratory muscles and resulting respiratory muscle weakness contributed to the development of ventilatory failure. Streeten et al [20] recently described a July 1987
The American Journal of Medicine
volume 83
177
VENTILATORY
FAILURE
AND
AMYLOIDOSIS-SANTIAGO
ET AL
thy of primary amyloidosis is characteristically of the sensory-motor type with prominent autonomic features and symmetric distal muscle weakness [24]. We suggest that diffuse myofiber atrophy resulted from si compartment syndrome produced by the interstitial amyloid deposits. We cannot, however, exclude the possibility that prolonged mechanical ventilation contributed to the observed diaphragmatic changes. Vincristine or hypercalcemia may have exacerbated this patient’s muscle weakness. However, it is doubtful that they played a significant role since marked muscle weakness antedated treatment with vincristine and persisted after the serum calcium concentration was normafized. The respiratory muscles, especially the diaphragm, play crucial roles in ventilation. Respiratory muscle dysfunction and diaphragmatic fatigue contribute significantly to the development of ventilatory failure in various clinical settings [2 I]. Thus, this patient most likely had ventilatory failure secondary to muscular weakness caused by amyloid infiltration of his diaphragm and other muscles of. respiration. Ventilatory failure should therefore be considered a possible complication of generalized amyloidosis.
patient without myeloma who died with respiratory failure secondary to amyloid infiltration of the diaphragm. Although there was amyloid deposition in the tongue, there was no other evidence of skeletal muscle involvement. As in previous reports, infiltration of muscle by amyloid was most prominent in the perivascular connective tissue and was not observed within the sarcolemma of individual muscle fibers [ 18,191. Ringel and Claman [ 191 have suggested that this deposition interferes with normal propagation of action potentials along the sarcolemmal membrane leading to an effective denervation of individual muscle fibers. Alternatively, deposition of amyloid may have interfered with the mechanical properties of the muscle, altering length-tension properties of its fibers, and contributing to muscle dysfunction [2 11. Marked infiltration of intercostal muscles may have also altered the elastic properties of the chest wall, decreasing its compliance and increasing the work of breathing [22,23]. Finally, macroglossia may have contributed to increased work of breathing by increasing inspiratory resistance of the upper airways. In contrast to previously reported cases of amyloid muscle pseudohypertrophy, we observed significant muscle fiber atrophy in addition to interstitial amyloid deposition. The myofiber atrophy was probably not secondary to neural involvement, since there was no clinical evidence of neuropathy and no histologically evident deposition of amyloid in peripheral nerves. Furthermore, the neuropa-
ACKNOWLEDGMENT We would like tothank Dr. Robert M. Senior for his critical review of this manuscript and Rose M. Scego for her secretarial assistance.
REFERENCES 1. 2.
3.
4.
5. 6. 7. 8. 9. 10.
11.
12.
178
Stone MJ, Frenkel EP: The clinical spectrum of light chain myeloma. Am J Med 1975; 58: 601-618. Pruzanski W, Katz A: Clinical and laboratory findings in primary generalized and multiple-myeloma related amyloidosis. Can Med Assoc J 1976; 114: 906-909. Kyle R, Greipp P: Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clin Proc 1983; 58: 665683. Alexanian R, Fraschini G, Smith L: Amyloidosis in multiple myeloma or without apparent cause. Arch Intern Med 198;4; 144: 2158-2160. Glenner G, Terry W, lsersky C: Amyloidosis: its nature and pathogenesis. Semin Hematol 1973; 10: 65-86. Barth WF, Willerson JT, Waldmann TA, Decker JL: Primary amyloidosis. Am J Med 1969; 47: 259-273. Kyle R, Bayrd ED: Amyloidosis: review of 236 cases. Meditine (Baltimore) 1975; 54: 271-299. Thompson PJ, Citron KM: Amyloid and the lower respiratory tract. Thorax 1983; 38: 84-87. Poh SC, Tjia TS, Seah HC: Primary diffuse alveolar septal amyloidosis. Thorax 1975; 30: 186-191. Celli BR, Rubinow A, Cohen AS, Brody J: Patterns of pulmonary involvement in systemic amyloidosis. Chest 1978; 74: 543-547. Glenner GC: Amyloid deposits and amyloidosis. The ,&fibrilloses (parts 1 and 2). N Engl J Med 1980; 302: 12831292,1333-1343. Glenner GC, Harbaugh J, Ohms JI, Harada M, Cuatrecasas P: An amyloid protein: the amino-terminal variable fragment of an immunoglobulin light chain. Biochem Biophys Res Commun 1970; 41: 1287-1289.
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1987
The American
Journal
of Medicine
Volume
13.
14. 15. 16. 17.
18.
19. 20.
21. 22. 23.
24.
83
Glenner GC, Terry W, Harada M, lsersky C, Page D: Amyloid fibril proteins: proof of homology with immunoglobulin light chains by sequence analyses. Science 1971; 172: 1150-1151. Calkins E, Cohen AS: Diagnosis of amyloidosis. Bull Rheum Dis 1966; 10: 215-218. Mathews WH: Primary systemic amyloidosis. Am J Med Sci 1954; 288: 317-333. Gonzales-Cueto DM, Rigoli M, Gioseffi LM; et al: Diffuse pulmonary amybidosis. Am J Med 1970; 48: 668-670. Lewinsohn G, Bruderman I, Bohanada A: Primary diffuse pulmonary amyloidosis with monoclonal gammopathy. Chest 1976; 69: 682-685. Whitaker JN, Hashimoto K, Quinones M: Skeletal muscle pseudohypertrophy in primary amyloidosis. Neurology 1977; 27: 47-54. Ringel SP, Claman HN: Amyloid-associated muscle pseudohypertrophy. Arch Neurol 1982; 39: 413-417. Streeten EA, de la Monte SM, Kennedy TP: Amyloid infiltration of the diaphragm as a cause of respiratory failure. Chest 1986; 89: 760-762. Roussos C, Macklem P: The respiratory muscles. N Engl J Med 1982; 307: 786-797. Lute J: Respiratory complications of obesity. Chest 1980; 48: 626-631. Naimark A, Cherniack RM: Compliance of the respiratory system and its components in health and obesity. J Appl Physiol 1964 19: 959-966. KellyJJ, Kyle RA, O’Brien PC, Dyck PJ: The natural history of peripheral neuropathy in primary systemic amyloidosis. Ann Neurol 1979 6: l-7.
RAFAEL M. SANTIAGO, MAJ., U.S.A.F., M.C. DAVID SCHARNHORST, M.D. GARY RATKIN, M.D. EDMOND C. CROUCH, M.D., Ph.D. St. Louis, Missouri
Generalized muscle weakness culminating in ventilatory failure developed in a 59-year-old man with kappa light chain multiple myeloma. Physical examination demonstrated skeletal muscle enlargement, severe proximal muscle weakness, and macroglossia, consistent with amyloid-associated muscle pseudohypertrophy. Pulmonary function studies revealed a severe restrictive abnormality with a low maximal inspiratory pressure and maximal voluntary ventilation. Arterial blood gas values and chest radiographic results were normal. There was no clinical evidence of cardiac or central nervous system disease. At autopsy, skeletal muscles and diaphragm were diffusely infiltrated by amyloid. There was also multifocal deposition of amyloid in alveolar septae, esophagus, and subendocardium. This report suggests that ventilatory failure may occur as a complication of myeloma-associated (AL) amyloidosis involving the respiratory muscles. Generalized amyioidosis complicates the course of some patients with multiple myeloma. In this setting, amyloidosis most commonly involves the gastrointestinal tract, skeletal muscles, heat-t, peripheral and autonomic nerves, and kidneys [l-7]. Although respiratory tract involvement appears to be relatively common [8-lo], amyloidosis has rarely been implicated as a cause of respiratory failure. This report describes a patient with kappa light chain multiple myeloma in whom extensive amyloid infiltration of muscle was associated with generalized weakness and ventilatory failure.
CASE REPORT Clinical Course. A 59-year-old
white man was transferred to the Jewish Hospital (St. Louis) on September 11, 1984, for evaluation of renal failure and hypercalcemia. The patient had undergone resection of a colonic cancer in 1978 but had remained in good health until one month prior to admission, when malaise, atthralgias, anorexia and a 15pound weight loss developed. At ttie outside hospital, he was found to have an elevated serum
From the Respiratory and Critical Care Division and Hematology Oncology Division, Department of Medicine, and the Department of Pathology, Jewish Hospital, Washington University Medical Center, St. Louis, Missouri. Dr. Santiago is an Air Force-sponsored Pulmonary Fellow at Washing1ton University Medical Center. Requests for reprints should be addressed to Dr. Edmond C. Crouch, Department of Pathology, Jewish Hospital, Washington University Medical Center, 216 South Kingshighway, St. Louis, Missouri 63110. Manuscript submitted August 29, 1986, and accepted October 24, 1986.
creatinine
concentration,
a low
creatinine
clearance,
marked
proteinuria,
and a serum calcium level of 11.3 mg/dl. Ultrasound study of the kidneys and bone and liver-spleen scanning revealed no abnormalities. A compression fracture of the second lumbar vertebra was found on lumbar-sacral spine radiography. Results of computed tomographic scanning of the abdomen and upper and lower gastrointestinal series were reported as normal. Physical examination revealed a well-developed muscular man in no acute distress. His temperature was normal, blood pressure was 190/100 mm Hg, pulse was 84/minute and regular, and respiratory rate was 161 minute, unlabored. His tongue was enlarged. Cardiac examination revealed normal heart sounds, no murmurs, and a regular rhythm. No jugular venous distention was present. Lung examination showed distant breath sounds but
July
1987
The American
Journal
of Medicine
Volume
83
175
VENTILATORY
FAILURE
AND
AMYLOIDOSIS-SANTIAGO
ET AL
ic ST-T wave changes. Echocardiography, M-mode and two-dimensional, showed mild left ventricular concentric hypertrophy with normal wall motion and a calculated ejection fraction of 82 percent. Further work-up showed a creatinine clearance of 28 ml/minute and a 24-hour protein excretion of 23.4 g; the urine contained no myoglobin. Serum protein electrophoresis showed no evidence of a monoclonal spike. However, serum immunoelectrophoresis revealed a kappa light chain paraprotein with marked reduction of IgG and IgA levels and no detectable IgM. Lambda light chain values were also markedly decreased. Urine immunoelectrophoresis revealed large amounts of kappa light chains with trace amounts of IgG and small amounts of albumin. Bone marrow aspiratipn and biopsy showed more than 50 percent replacement with atypical plasmacytoid cells. Thus, the patient was thought to have kappa light chain multiple myeloma, and his renal failure and proteinuria were attributed to myeloma kidney. Hypercalcemia was corrected with furosemide, corticosteroids, and hydration. The patient was treated with vincristine, carmustine (BCNU), and prednisone. At time of discharge on September 28, 1984, the patient still had significant upper and lower extremity muscle weakness. The patient was readmitted on October 14, 1984, after five days of progressive muscular weakness, inability to walk, dyspnea at rest, and dysphagia. On physical examination, vital signs were normal; his tongue was markedly enlarged, making it difficult for the patient to close his mouth. His speech was slurred, and he was markedly weak despite his apparent well-developed musculature. Except for mildly decreased tendon reflexes, his neurologic results were normal. His lung and cardiac examinations were unremarkable. As before, chest radiography showed no evidence of acute cardiac or pulmonary disease. Electrocardiography showed a normal sinus rhythm with normal voltage and nonspecific ST-T wave changes. The serum calcium level was 12.7 mg/dl, serum electrolyte values were normal, and the creatinine concentration was 2.9 mg/dl. Biopsy of the tongue confirmed the diagnosis of amyloidosis. Pulmonary function studies revealed a forced vital capacity of 1.5 liters (29 percent of predicted), one-second forced expiratory volume of 1.1 liters/second (31 percent of predicted), maximal inspiratory pressure of -45 cm H20, maximal voluntary ventilation of 27.8 liters (19 percent of predicted), minute ventilation of 11.7 liters, and tidal volume of 829 ml. Measurement of arterial blood gas values while the patient was breathing room air showed a pH of 7.40, carbon dioxide tension of 40 mm Hg, and oxygen tension of 77 mm Hg. Despite treatment with high-dose methylprednisolone, progressive ventilatory impairment developed, with a decrease in vital capacity to 0.9 liters and maximal inspiratory pressure to -15 cm H20, at which time intubation was carried out. Therapeutic efforts consisting of plasmapheresis and chemotherapy with cyclophosphamide, BCNU, and prednisone failed to improve muscle strength enough to allow discontinuation of ventilatory support. The remainder of his hospital course was complicated by pancytopenia, pneumonia, sepsis, gastrointestinal bleeding, cardiac arrhythmias, and azotemia. He died 20 days after admission. Pathologic Study. At autopsy, the skeletal muscles were firm and tan, and appeared hypertrophic. The diaphragm
Figure 1. Section of thickened diaphragm obtained at autopsy showing atrophy and distortion of muscle fibers with infiltration of interstitium by amorphous eosinophilic material. Short arrow identifies a distorted muscle fiber in cross-section; long arrow identifies amorphous interstitial material (hematoxylin and eosin stain; original magnification X 320, reduced by 25 percent).
otherwise was clear to auscultation and percussion. Liver span was normal by percussion, and the spleen was not palpable. He showed increased muscle tone and apparent muscular hypertrophy with severe upper and lower extremity proximal muscle weakness. Findings on neurologic examination were normal, with preservation of sensory function and deep tendon reflexes. Laboratory values included normal serum electrolyte levels, blood urea nitrogen 59 mg/dl, creatinine 4.0 mg/dl, uric acid 9.8 mg/dl, serum calcium 11.0 mg/dl, phosphate 5.0 mg/dl, total protein 5.8 g/dl, albumin 3.7 g/d& creatine phosphokinase 484 units/ liter and cholesterol 15 1 mg/dl. Urinalysis showed a specific gravity of 1.02, pH of 5 with 4+ protein, one to three red blood cells per high-power field, one to two white blood cells/per high-power field, and three to four hyaline casts. The white blood cell count was 9,800/mm3, hemoglobin 10.1 g/dl, hematocrit 30.1 percent, mean corpuscular volume 93 p3, with normal differential. The platelet count was 572,000/mm3, and the erythrocyte sedimentation rate was 85 mm/hour. Chest radiography revealed no evidence of cardiac or pulmonary disease. Electrocardiography revealed normal sinus rhythm, normal voltage, and nonspecif176
July
1967
The
American Journal
of Medicine
Volume
63
VENTILATORY
was approximately 1 cm thick (three to five times normal). The tongue was also firm and enlarged. The liver, spleen, heart, peripheral nerves, and central nervous system were unremarkable. On cut section, the vertebral bodies showed several small bony defects containing soft, red, and gelatinous tissue. The kidneys were pale and slightly enlarged. The lungs were heavy, each weighing approximately 2,000 g (normal, 300 to 400 g), and diffusely consolidated consistent with confluent bronchopneumonia. By light microscopy, the diaphragm and psoas muscles showed variable myofiber atrophy, focal myofiber degeneration, and diffuse infiltration of perivascular connective tissue by amorphous eosinophilic material (Figure 1). This material stained with Congo red and showed “apple-green” birefringence by polarization microscopy, consistent with amyloid (Figure 2). Group atrophy of muscle fibers, as usually occurs with degeneration, was not observed. Significant amyloid deposits were also identified between cardiac muscle fibers in the subendocardium and within the muscularis of the esophagus. There was patchy interstitial deposition of amyloid in alveolar septae. There was no identifiable amyloid in sections of liver, spleen, adrenal glands, peripheral nerves, or brain. The vertebral bone defects showed diffuse infiltrates of immature plasma cells. The kidneys showed changes consistent with myeloma kidney, including numerous homogeneous eosinophilic casts within the distal con-
voluted tubules and collecting ducts. In some areas, casts were associated with multinucleated giant cells. The renal medulla showed mild tubular atrophy and interstitial fibrosis. Glomeruli were unremarkable except for focal increases in mesangial matrix. The lungs showed diffuse acute and organizing bronchopneumonia and purulent tracheobronchitis. COMMENTS Amyloidosis
is a disorder
in which organs are infiltrated
by
extracellular proteinaceous material. This material is histochemically characterized by green birefringence when stained with Congo red and examined by polarization microscopy. It is now established that monoclonal immunoglobulin light chains or amino-terminal light chain fragments are the major comoonents of amyloid in cases of primary and myeloma-as ociated amyloidosis [ 11-I 31. Organ dysfunction apparently occurs as a result of excess deposition and/or defective degradation of this material. Generalized amyloidosis occurs in 5 to 15 percent of patients with multiple myeloma, and patients with light chain myeloma have a reported incidence of 20 to 24 percent [ 1,141. The disease predominantly affects the kidneys, heart, gastrointestinal tract, and peripheral and autonomic nerves, with nephrotic syndrome, congestive heart failure, peripheral neuropathy, carpal tunnel syndrome, and orthostatic hypotension being the most common clinical presentations [3,5-71. In a recent series of 187 patients, death was due to cardiac failure and renal failure in 40 percent and IO percent, respectively [3]. Involvement of the respiratory tract is common in primary and myeloma-associated amyloidosis, occurring in 36 to 90 percent of patients with generalized disease
FAILURE
AND
AMYLOIDOSIS-SANTIAGO
ET AL
FIgure 2. Top, section of diaphragm stained with Congo red. Long arrow identifies perivascular congophilic material; short arrow identifies muscle fiber. Boffom, same field viewed under partially polarized light. Congophilic material showed “apple-green” birefringence consistent with amyloid (original magnification X 128, reduced by 35 percent).
[3,10,15]. The most common pattern of respiratory involvement in this setting is diffuse deposition of amyloid in alveolar septae. Multifocal perivascular or tracheobronchial deposits may also be observed [8- 10,16,17]. Several reports have described patients with progressive muscular weakness, dysphonia, dysphagia, and a prominent athletic appearance secondary to amyloid infiltration of skeletal muscles. This constellation of findings has been termed amyloid-muscle pseudohypettrophy [ 18,191. In some of these patients, pulmonary function studies demonstrated combined restrictive and obstructive defects. It was unclear, however, whether the pulmonary function abnormalities noted were secondary to underlying chronic lung disease, congestive heart failure, or a component of respiratory muscle weakness. Diaphragmatic muscles were not examined in these studies. Our patient fits the description of muscle pseudohypertrophy due to amyloid. In addition, serial pulmonary functions documented a decrease in forced vital capacity and maximal inspiratory pressure leading to respiratory failure in the absence of overt complicating cardiac or parenchymal pulmonary disease. Thus, it seems likely that amyloid infiltration of respiratory muscles and resulting respiratory muscle weakness contributed to the development of ventilatory failure. Streeten et al [20] recently described a July 1987
The American Journal of Medicine
volume 83
177
VENTILATORY
FAILURE
AND
AMYLOIDOSIS-SANTIAGO
ET AL
thy of primary amyloidosis is characteristically of the sensory-motor type with prominent autonomic features and symmetric distal muscle weakness [24]. We suggest that diffuse myofiber atrophy resulted from si compartment syndrome produced by the interstitial amyloid deposits. We cannot, however, exclude the possibility that prolonged mechanical ventilation contributed to the observed diaphragmatic changes. Vincristine or hypercalcemia may have exacerbated this patient’s muscle weakness. However, it is doubtful that they played a significant role since marked muscle weakness antedated treatment with vincristine and persisted after the serum calcium concentration was normafized. The respiratory muscles, especially the diaphragm, play crucial roles in ventilation. Respiratory muscle dysfunction and diaphragmatic fatigue contribute significantly to the development of ventilatory failure in various clinical settings [2 I]. Thus, this patient most likely had ventilatory failure secondary to muscular weakness caused by amyloid infiltration of his diaphragm and other muscles of. respiration. Ventilatory failure should therefore be considered a possible complication of generalized amyloidosis.
patient without myeloma who died with respiratory failure secondary to amyloid infiltration of the diaphragm. Although there was amyloid deposition in the tongue, there was no other evidence of skeletal muscle involvement. As in previous reports, infiltration of muscle by amyloid was most prominent in the perivascular connective tissue and was not observed within the sarcolemma of individual muscle fibers [ 18,191. Ringel and Claman [ 191 have suggested that this deposition interferes with normal propagation of action potentials along the sarcolemmal membrane leading to an effective denervation of individual muscle fibers. Alternatively, deposition of amyloid may have interfered with the mechanical properties of the muscle, altering length-tension properties of its fibers, and contributing to muscle dysfunction [2 11. Marked infiltration of intercostal muscles may have also altered the elastic properties of the chest wall, decreasing its compliance and increasing the work of breathing [22,23]. Finally, macroglossia may have contributed to increased work of breathing by increasing inspiratory resistance of the upper airways. In contrast to previously reported cases of amyloid muscle pseudohypertrophy, we observed significant muscle fiber atrophy in addition to interstitial amyloid deposition. The myofiber atrophy was probably not secondary to neural involvement, since there was no clinical evidence of neuropathy and no histologically evident deposition of amyloid in peripheral nerves. Furthermore, the neuropa-
ACKNOWLEDGMENT We would like tothank Dr. Robert M. Senior for his critical review of this manuscript and Rose M. Scego for her secretarial assistance.
REFERENCES 1. 2.
3.
4.
5. 6. 7. 8. 9. 10.
11.
12.
178
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