Sample J15 from J. W. C. Hagstrom et al., "Debilitating muscular weakness and steroid therapy," Archives of Neurology, 5 (1961), 60-65. A part of the XML version of the Brown Corpus2,013 words 13 (0.6%) quotes 2 symbols 1 formulaJ15

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J. W. C. Hagstrom et al., "Debilitating muscular weakness and steroid therapy," Archives of Neurology, 5 (1961), 60-65.

Typographical Error: 1949 [for 1959] [0640] 0010-1950

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Introduction Muscle weakness is now recognized as an uncommon though serious complication of steroid therapy , with most of the synthetic adrenal corticosteroids in clinical use . Although biopsies have shown structural changes in some of the reported cases of steroid-induced weakness , this case provides the only example known to us in which necropsy afforded the opportunity for extensive study of multiple muscle groups . The case described in this paper is that of an older man who developed disabling muscular weakness while receiving a variety of steroids for a refractory anemia .

Report of case This patient was a 65-year-old white male accountant who entered the New York Hospital for his fourth and terminal admission on June 26 , 1959 , because of disabling weakness and general debility .

In 1953 the patient developed an unexplained anemia for which 15 blood transfusions were given over a period of 4 years . Splenomegaly was first noted in 1956 , and a sternal marrow biopsy at that time showed `` scattered foci of fibrosis '' suggestive of myelofibrosis . No additional transfusions were necessary after the institution of prednisone in July , 1957 , in an initial dose of 40 mg. daily with gradual tapering to 10 mg. daily . This medication was continued until February , 1958 .

In February , 1958 , the patient suffered a myocardial infarction complicated by pulmonary edema . Additional findings at this time included cardiomegaly , peripheral arteriosclerosis obliterans , and cholelithiasis . The hemoglobin was 11.6 gm. . Therapy included digitalization and anticoagulation . Later , chlorothiazide and salt restriction became necessary to control the edema of chronic congestive failure .

Because of increasing anemia , triamcinolone , 8 mg. daily , was started on Feb. 23 , 1958 , and was continued until July , 1958 . In September , 1958 , the patient developed generalized weakness and fatigue which was concurrent with exacerbation of his anemia ; ; the hemoglobin was 10.6 gm. . In an attempt to reverse the downhill trend by stimulating the bone marrow and controlling any hemolytic component , triamcinolone , 16 mg. daily , was begun on Sept. 26 , 1958 , and continued until Feb. 18 , 1959 . At first the patient felt stronger , and the hemoglobin rose to 13.8 gm. , but on Oct. 20 , 1958 , he complained of `` caving in '' in his knees . By Nov. 8 , 1958 , weakness , specifically involving the pelvic and thigh musculature , was pronounced , and a common complaint was `` difficulty in stepping up on to curbs '' . Prednisone , 30 mg. daily , was substituted for triamcinolone from Nov. 22 until Dec. 1 , 1958 , without any improvement in the weakness . Serum potassium at this time was 3.8 mEq. per liter , and the hemoglobin was 13.9 gm. By Dec. 1 , 1958 , the weakness in the pelvic and quadriceps muscle groups was appreciably worse , and it became difficult for the patient to rise unaided from a sitting or reclining position . Triamcinolone , 16 mg. daily , was resumed and maintained until Feb. 18 , 1959 . Chlorothiazide was omitted for a 2-week period , but there was no change in the muscle weakness .

At this time a detailed neuromuscular examination revealed diffuse muscle atrophy that was moderate in the hands and feet , but marked in the shoulders , hips , and pelvic girdle , with hypoactive deep-tendon reflexes . No fasciculations or sensory defects were found . Electromyography revealed no evidence of lower motor neuron disease . Thyroid function tests yielded normal results . The protein-bound iodine was 6.6 mg. , and the radioactive iodine uptake over the thyroid gland was 46% in 24 hours , with a conversion ratio of 12% . A Schilling test demonstrated normal absorption of vitamin Af . In February , 1959 , during the second admission to The New York Hospital , a biopsy specimen of the left gastrocnemius showed striking increase in the sarcolemmal sheath nuclei and shrunken muscle fibers in several sections . Serial serum potassium levels remained normal ; ; the serum glutamic oxaloacetic transaminase was 10 units per ml. per min. . The clinical impression at this time was either muscular dystrophy or polymyositis .

On Feb. 12 , 1959 , purified corticotropin ( ACTH Gel ) , 20 units daily intramuscularly , was started but had to be discontinued 3 weeks later because of excessive fluid retention . From March 3 to May 1 , 1949 , the patient was maintained on dexamethasone , 3 to 6 mg. daily . In May 1959 , prednisone , 30 mg. daily , replaced the dexamethasone . Muscle weakness did not improve , and the patient needed first a cane , then crutches . In spite of normal thyroid function tests , a trial of propylthiouracil , 400 mg. daily for one week , was given but served only to intensify muscle weakness . Repeated attempts to withdraw steroids entirely were unsuccessful because increased muscle weakness resulted , as well as fever , malaise , anorexia , anxiety , and an exacerbation of the anemia . These reactions were interpreted as being manifestations of hypoadrenocorticism .

Severe back pain in June , 1959 , prompted a third hospital admission . Extensive osteoporosis with partial collapse of D8 was found . A high-protein diet , calcium lactate supplements , and norethandrolone failed to change the skeletal complaint or the severe muscle weakness .

The terminal hospital admission on June 27 , 1959 , was necessitated by continued weakness and debility complicated by urinary retention and painful thrombosed hemorrhoids . X-ray films of the vertebral column showed progression of the demineralization . On July 4 , 1959 , the patient developed marked abdominal pain and distension , went into shock , and died .

Findings at necropsy The body was that of a well-developed , somewhat debilitated white man weighing 108 lb. . There were bilateral pterygia and arcus senilis , and the mouth was edentulous .

The heart weighed 510 gm. , and at the outflow tracts the left and right ventricles measured 19 and 3 mm. , respectively . The coronary arteries were sclerotic and diffusely narrowed throughout their courses , and the right coronary artery was virtually occluded by a yellow atheromatous plaque 1.5 cm. distal to its origin . The myocardium of the posterior base of the left ventricle was replaced by gray scar tissue over a 7.5 cm. area . The valves were normal except for thin yellow plaques on the inferior surface of the mitral leaflets . Microscopically , sections from the posterior base of the left ventricle of the heart showed several large areas of replacement of muscle by fibrous tissue . In addition , other sections contained focal areas of recent myocardial necrosis that were infiltrated with neutrophils . Many of the myocardial fibers were hypertrophied and had large , irregular , basophilic nuclei . The intima of the larger coronary arteries was thickened by fibrous tissue containing fusiform clefts and mononuclear cells .

The intimal surface of the aorta was covered with confluent , yellow-brown , hard , friable plaques along its entire course , and there was a marked narrowing of the orifices of the large major visceral arteries . In particular , the orifices of the right renal and celiac arteries were virtually occluded , and both calcified common iliac arteries were completely occluded .

The lungs weighed together 950 gm. . On the surfaces of both lungs there were emphysematous blebs measuring up to 3 cm. in diameter . The parenchyma was slightly hyperemic in the apex of the left lung , and there were several firm , gray , fibrocalcific nodules measuring as large as 3 mm. . Microscopically , there was emphysema , fibrosis , and vascular congestion . Macrophages laden with brown pigment were seen in some of the alveoli , and the intima of some of the small arteries was thickened by fibrous tissue .

The firm red spleen weighed 410 gm. , and its surface was mottled by discrete , small patches of white material . The endothelial cells lining the sinusoids were prominent , and many contained large quantities of hemosiderin . Some of the sinusoids contained large numbers of nucleated red cells , and cells of the granulocytic series were found in small numbers . There were slight fibrosis and marked arteriolosclerosis .

The liver weighed 2,090 gm. , was brown in color , and the cut surface was mottled by irregular pale areas . Microscopically , there was hyperemia of the central veins , and there was some atrophy of adjacent parenchyma . Some liver cord cells contained vacuolated cytoplasm , while others had small amounts of brown hemosiderin pigment .

The gallbladder contained about 40 cc. of green-brown bile and 3 smooth , dark-green calculi measuring up to 1 cm. in diameter .

The mucosa of the stomach was atrophic and irregularly blackened over a 14 cm. area . The small and large intestines were filled with gas , and the jejunum was dilated to about 2 times its normal circumference . The small intestine and colon contained approximately 300 cc. of foul-smelling , sanguineous material , and the mucosa throughout was hyperemic and mottled green-brown . A careful search failed to show occlusion of any of the mesenteric vessels . Microscopically , the mucosa of the stomach showed extensive cytolysis and contained large numbers of Gram-negative bacterial rods . The submucosa was focally infiltrated with neutrophils . The mucosa of the jejunum and ileum showed similar changes , and in some areas the submucosa was edematous and contained considerable numbers of neutrophils . Some of the small vessels were filled with fibrin thrombi , and there was extensive interstitial hemorrhage . A section of the colon revealed intense hyperemia and extensive focal ulcerations of the mucosa , associated with much fibrin and many neutrophils . Cultures taken from the jejunum yielded Monilia albicans , Pseudomonas pyocanea , Aerobacter aerogenes , and Streptococcus anhemolyticus .

The kidneys were pale and weighed right , 110 gm. , and left , 230 gm. . The surfaces were coarsely and finely granular and punctuated by clear , fluid-filled cysts measuring up to 3 cm. in diameter . On the surface of the right kidney there were also 2 yellow , firm , friable raised areas measuring up to 2 cm. in diameter . Microscopically , both kidneys showed many small cortical scars in which there was glomerular and interstitial fibrosis , tubular atrophy , and an infiltration of lymphocytes and plasma cells . Occasional tubules contained hyaline casts admixed with neutrophils . Throughout , there were marked arteriolosclerosis and hyalinization of afferent glomerular arterioles . These changes were more marked in the atrophic right kidney than in the left . In addition , there were 2 small papillary adenomas in the right kidney .

The bone of the vertebral bodies , ribs , and sternum was soft and was easily compressed . The marrow of the vertebral bodies was pale and showed areas of fatty replacement . Microscopically , there were many areas of hypercellularity alternating with areas of hypocellularity . The cells of the erythroid , myeloid , and megakaryocytic series were normal except for their numbers . There was no evidence of fibrosis . The muscles of the extremities , chest wall , neck , and abdominal wall were soft , pale , and atrophic .

Microscopic studies of the gastrocnemius , pectoralis major , transversus abdominis , biceps brachii , and diaphragm showed atrophy as well as varying degrees of injury ranging from swelling and vacuolization to focal necrosis of the muscle fibers . These changes were most marked in the gastrocnemius and biceps and less evident in the pectoralis , diaphragm , and transversus .

In the gastrocnemius and biceps there were many swollen and homogeneous necrotic fibers such as that shown in Figure 2 . Such swollen fibers were deeply eosinophilic , contained a few pyknotic nuclei , and showed loss of cross-striations , obliteration of myofibrils , and prominent vacuolization . The necrosis often involved only a portion of the length of a given fiber , and usually the immediately adjacent fibers were normal . As shown in Figure 3 , the protoplasm of other fibers was pale , granular , or flocculated and invaded by phagocytes . Inflammatory cells were strikingly absent . In association with these changes in the fibers , there were striking alterations in the muscle nuclei . These were increased both in number and in size , contained prominent nucleoli , and were distributed throughout the fiber ( Figs. 2 - 5 ) . In contrast to the nuclear changes described above , another change in muscle nuclei was seen , usually occurring in fibers that were somewhat smaller than normal but that showed distinct cross-striations and myofibrillae . The nuclei of these fibers , as is shown in Figures 3 and 4 , showed remarkable proliferation and were closely approximated , forming a chainlike structure at either the center or the periphery of the fiber . Individual nuclei were usually oval to round , though occasionally elongated , and frequently small and somewhat pyknotic . At times , clumps of 10 to 15 closely-packed nuclei were also observed . Occasionally there were small basophilic fibers that were devoid of myofibrillae and contained many vesicular nuclei with prominent nucleoli ( Fig. 5 ) . These were thought to represent regenerating fibers . Trichrome stains failed to show fibrosis in the involved muscles . In all of the sections examined , the arterioles and small arteries were essentially normal .