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.