Original Article
Mitochondrial Myopathy Caused by Long-Term Zidovudine Therapy
N Engl J Med 1990; 322:1098-1105April 19, 1990
- Abstract
- Abstract
Both infection with the human immunodeficiency virus type 1 (HIV) and zidovudine (formerly called azidothymidine [AZT]) cause myopathy. To identify criteria for distinguishing zidovudine-induced myopathy from that caused by primary HIV infection, we reviewed the histochemical, immunocytochemical, and electron-microscopical features of muscle-biopsy specimens from 20 HIV-positive patients with myopathy (15 of whom had been treated with zidovudine) and compared the findings with the patients' clinical course and response to various therapies. Among the zidovudine-treated patients, the myopathy responded to prednisone in four, to the discontinuation of zidovudine in eight, and to nonsteroidal anti-inflammatory drugs in two.
Numerous "ragged-red" fibers, indicative of abnormal mitochondria with paracrystalline inclusions, were found in the biopsy specimens from the zidovudine-treated patients but not in those from the other patients. The number of these fibers appeared to correlate with the severity of the myopathy. All the patients, regardless of whether they had been treated with zidovudine, had inflammatory myopathy characterized by degenerating fibers, cytoplasmic bodies, and endomysial infiltrates consisting of CD8+ cells (mean ±SD, 60.7±6.4 percent) and macrophages (39.2 ±6.4 percent) associated with Class I major histocompatibility complex (MHC-I) antigens (HLA-A, -B, and -C antigens) in the muscle fibers. The numbers and percentages of CD8+ cells and macrophages were similar in both the zidovudine-treated and the untreated HIV-positive patients. Specimens obtained on repeat muscle biopsy from two patients in whom the myopathy responded to the discontinuation of zidovudine showed remarkable histologic improvement.
We conclude that long-term therapy with zidovudine can cause a toxic mitochondrial myopathy, which coexists with a T-cell—mediated inflammatory myopathy that is restricted to MHC-I antigen, and is indistinguishable from the myopathy associated with primary HIV infection or polymyositis in HIV-seronegative patients. (N Engl J Med 1990; 322:1098–105.)
Media in This Article
Figure 1
Muscle-Biopsy Specimen from a Patient with Zidovudine-Associated Myopathy.Figure 2
Muscle-Biopsy Specimen from a Patient with Zidovudine-Associated Myopathy.Article Activity
- Article
THE myopathies associated with infection with the human immunodeficiency virus type 1 (HIV) are a histologically heterogeneous group of disorders that include inflammatory myopathy identical to polymyositis,1 2 3 4 5 noninflammatory destructive myopathy with granular fiber degeneration,4 5 6 7 nemaline (rod) myopathy,1 , 5 , 8 , 9 and some combination of these myopathies.4 Before 1986, when zidovudine (formerly called azidothymidine [AZT]) was introduced for the treatment of the acquired immunodeficiency syndrome (AIDS),10 11 12 the number of patients with HIV-associated myopathy was small, and myopathy was considered a rare complication of HIV infection.1 2 3 4 5 6 7 8 9 During the past two years, an increasing number of patients receiving long-term zidovudine therapy have had myopathic symptoms such as myalgia (in up to 8 percent of patients),12 elevated serum creatine kinase levels (in up to 15 percent),13 and muscle weakness. These symptoms generally improve when zidovudine is discontinued.13 14 15 16 17 18 The existence of zidovudine-related toxic myopathy has been debated,19 , 20 however, because no unique morphologic features that distinguish zidovudine-induced myopathy from that caused by primary HIV infection have been described. In the absence of such criteria, the discontinuation of zidovudine therapy in patients with AIDS who have myopathic symptoms has not been recommended.19 , 20 Furthermore, the fact that the myopathy has responded to corticosteroid therapy in some patients1 , 4 , 5 , 9 , 19 has created the dilemma of whether to discontinue zidovudine or add treatment with steroids.
We attempted to determine whether zidovudine does indeed cause myopathy and to distinguish such a myopathy from that caused by primary HIV infection by analyzing the morphologic and immunocytochemical changes in muscle-biopsy specimens from 20 HIV-positive patients who had myopathy either before receiving zidovudine or during long-term zidovudine therapy. Unlike HIV infection alone, zidovudine induced unique and probably reversible changes in the muscle mitochondria. In addition, all the patients, regardless of whether they had been treated with zidovudine, had an immune inflammatory myopathy that was mediated by suppressor—cytotoxic T cells and restricted to Class I major histocompatibility complex (MHC-I) antigen.
Methods
We performed muscle biopsies in 20 patients, 18 men and 2 women, 20 to 58 years old (mean age, 37.2 years), who had AIDS (n = 12) or AIDS-related complex (n = 8). Fifteen patients (who underwent a total of 17 biopsies) had received therapeutic doses of zidovudine, ranging from 1000 to 1200 mg daily for 3 to 24 months (mean, 12.8 months), and five patients had not received zidovudine (Table 1Table 1
Clinical and Histologic Features and Immunocytochemical Findings in Muscle-Biopsy Specimens in HIV-Positive Patients with Myopathy.*). The treated patients had received zidovudine either while participating in a clinical study approved by a National Institutes of Health clinical-research review committee or while being cared for by their physicians in the community after zidovudine was approved for the treatment of AIDS. Each patient gave written informed consent for the muscle biopsy. All the patients had proximal muscle weakness, myalgia, a two- to six-fold elevation of the serum creatine kinase level (measured by an enzymatic reaction), and evidence of myopathic changes in the electromyogram, all of gradual onset, as previously reported.1 2 3 4 Seventeen men were homosexuals, and 1 (Patient 11) had acute lymphoblastic leukemia and had received multiple blood transfusions; none abused drugs. One of the women (Patient 1) was a drug abuser, and the other (Patient 8) had received multiple transfusions. The myopathy was rated mild if the patient had only myalgia and minimal muscle weakness, moderate if proximal muscle strength was rated 4+/5 on the Medical Research Council (MRC) scale (the scale ranges from 0 to 5, with 5 denoting normal strength)21 but the patient was able to walk independently, and severe if the strength in certain proximal muscle groups was rated 3+/5 to 4−/5 on the MRC scale and the patient had muscle wasting and needed assistance with walking or carrying out daily activities. The muscle-biopsy specimens were fresh-frozen in isopentane that had been cooled to −70°C and processed for staining with the modified Gomori trichrome stain.22 The specimens from all the untreated patients and from 13 of the 15 zidovudine-treated patients were processed for electron microscopy.In the 15 zidovudine-treated patients, myopathy was managed by the discontinuation of zidovudine, the administration of prednisone or a nonsteroidal antiinflammatory drug, or both. Two patients (Patients 10 and 12) had a second biopsy four and two months after zidovudine was discontinued. The five patients who had myopathy that was unrelated to treatment with zidovudine (Table 1) subsequently received prednisone, zidovudine, or a nonsteroidal anti-inflammatory drug.
The muscle-biopsy specimens were coded and examined blindly and independently by two of us. This procedure was followed in order to avoid bias in correlating changes in the muscle-fiber cytoarchitecture and the number of endomysial cells with the response to treatment, as described below. Although there was no important variability between the two observers, the number of cells used in the analyses was based on the mean of the two readings.
We also processed all the muscle-biopsy specimens for immunocytochemical studies, in which we used a battery of monoclonal antibodies that identify surface markers on infiltrating lymphocytes. The immunocytochemical staining identified cells reacting with antibodies to CD4 (helper cells), CD8 (suppressor—cytotoxic T cells), CD11c, CD11b, and CD14 (macrophages), HLA-A, -B, and -C (MHC-I antigen), and HLA-DR (Class II major histocompatibility complex [MHC-II] antigen).23 The preparations were processed for staining with a single- or double-labeled avidin–biotin–immunoperoxidase or alkaline phosphatase technique and counterstained with 1 percent hematoxylin, as described previously.24 Because the cell population consisted predominantly of CD8+ cells and macrophages,23 with a few CD4+ cells, we counted only the CD8+ cells and macrophages on 4–μm-thick serial sections. The positive cells were stained dark brown with 3,3′-diaminobenzidine as the chromogen. The code was subsequently broken, and the histologic findings and cell counts were correlated with the patients' clinical course, the severity of the myopathy, the type of treatment, and the response to therapy. For comparison of lymphocyte counts, muscle-biopsy specimens from five HIV-negative patients with active polymyositis were immunostained with the same antibodies and processed simultaneously.
We counted CD8+ cells and macrophages on individually stained sections at a magnification of 25. Because certain areas of the muscle, even in the same biopsy specimen, contained mainly CD8+ cells and very few macrophages, or vice versa, counting was performed in two stages. In the first stage, we randomly selected three fields on the slides stained for CD8+ cells from each patient and counted scattered or clustered CD8+ cells; we then counted macrophages on the serial sections corresponding to the same fields on the slides stained for macrophages. In the second stage of cell counting, we randomly selected three additional fields on the slides stained for macrophages from the same patient and counted the macrophages; we then counted CD8+ cells on the serial sections corresponding to the same fields on the slides stained for CD8+ cells. We thus counted the CD8+ cells and macrophages in a total of six fields each and calculated the percentage of each cell type among all the immunostained cells counted.
Because we had earlier observed "ragged-red" fibers in the muscles of seven zidovudine-treated patients,25 we counted ragged-red fibers in three randomly selected fields at low magnification (×16) in all 22 biopsy specimens and calculated the percentage of ragged-red fibers among the total number of fibers counted. To ensure the specificity of ragged-red fibers in HIV-positive patients, we also counted ragged-red fibers in 25 muscle-biopsy specimens randomly selected from our large group of HIV-seronegative patients with polymyositis and dermatomyositis,26 using the same method and magnification.
Results
Histologic and Electron-Microscopical Findings
The muscle specimens of all 15 zidovudine-treated patients, but none of the 5 untreated patients, had unique morphologic features — namely, abundant ragged-red fibers (Fig. 1Figure 1
Muscle-Biopsy Specimen from a Patient with Zidovudine-Associated Myopathy.A) suggestive of abnormal mitochondria. Electron-microscopical study of 13 specimens confirmed the presence of strikingly abnormal mitochondria with marked proliferation in the subsarcolemmal spaces, enlargement, and abnormal paracrystalline inclusions (Fig. 1B). On blinded review of the muscle-biopsy specimens and electron micrographs, abnormal mitochondria were found only in the muscles of the patients who had received long-term zidovudine therapy; the patients with HIV-associated myopathy who had never received zidovudine had normal mitochondria. On the basis of these morphologic characteristics, we correctly identified the treatment of Patient 15, who was participating in a double-blind, placebo-controlled study of zidovudine; he was confirmed to be receiving zidovudine and not the placebo when the code was broken. The ragged-red fibers appeared identical to those that occur in mitochondrial myopathies,27 except that in the zidovudine-treated patients the fibers were more ragged and often smaller. The percentage of ragged-red fibers among the total number of fibers counted per muscle specimen (mean, 365; range, 190 to 696) ranged from 2.0 to 48.0 percent (Table 1). The number of ragged-red fibers appeared to correlate with the severity of the myopathy (Table 1), as described below. The percentage of ragged-red fibers in the 25 muscle-biopsy specimens from HIV-seronegative patients with polymyositis and dermatomyositis ranged from 0 to 2.9 percent (mean, 0.4 percent).All the specimens, including those with abnormal mitochondria from the zidovudine-treated patients, had histologic features of inflammatory myopathy characterized by varying degrees of necrotic muscle fibers, rod (nemaline) bodies (as previously reported),1 , 5 and cytoplasmic bodies in many fibers (confirmed by electron microscopy). The cytoplasmic bodies were large (Fig. 2Figure 2
Muscle-Biopsy Specimen from a Patient with Zidovudine-Associated Myopathy.), irregular, and prominent in the zidovudine-treated patients; the necrotic fibers with vacuoles were also prominent (Fig. 3Figure 3
Muscle-Biopsy Specimens from Patient 10, Who Had Zidovudine-Associated Myopathy.A). The perivascular or endomysial inflammation varied from mild to severe in the majority of patients but was not easily detectable in four zidovudine-treated patients (Patients 2, 7, 11, and 15; Table 1). In the immunocytochemical studies, however, CD8+ cells and macrophages were easily counted in the biopsy specimens from these four patients.Clinical Observations
In four zidovudine-treated patients, the myopathy improved with prednisone therapy (Table 1). In Patient 1, the mild muscle weakness that occurred before zidovudine treatment began continued to progress very slowly during 11 months of zidovudine therapy, in spite of improved immune function and an increased CD4 count in the circulation. The patient was unable to climb stairs or rise from her chair without assistance and had difficulty lifting objects weighing more than 4.5 kg (10 lb). When prednisone (40 mg daily) was added to her regimen, she improved remarkably, regaining muscle strength to the point of being able to resume normal activities of life. Patient 2 improved when zidovudine was discontinued and prednisone (60 mg daily) was started; his condition worsened when zidovudine was begun again and the dose of prednisone was reduced, but he improved after zidovudine was discontinued once again. The condition of Patient 3 worsened when zidovudine was discontinued, but his muscle strength improved when prednisone (40 mg daily) was begun and zidovudine was reinstituted; when the dose of prednisone was reduced to 20 mg daily he worsened, but he improved again when the dosage was increased to 40 mg daily while zidovudine was continued. No change was evident in Patient 4 when zidovudine was discontinued, but he improved when treatment with prednisone (60 mg daily) was begun; his strength did not decline when zidovudine was subsequently reinstated.
In seven other patients (Patients 8, 10, 11, 12, 13, 14, and 15), muscle strength improved and serum creatine kinase levels returned to normal from 7 to 10 days after zidovudine was discontinued (Table 1). Patients 8 and 12, whose muscle strength had greatly improved after zidovudine was discontinued, had myalgia and weakness when zidovudine was reinstituted at low doses (up to 400 mg daily) six months later. Both improved again when zidovudine was again discontinued. Analysis of the second biopsy specimen from Patient 12, obtained two months after zidovudine was withdrawn, showed remarkable improvement of muscle-fiber cytoarchitecture. Patient 10 had myopathy during combined treatment with interferon and zidovudine. He did not improve when interferon was discontinued; when zidovudine was discontinued and interferon begun again, however, his muscle strength improved. A second biopsy specimen, obtained four months later, showed remarkable histologic improvement (Fig. 3B). Patient 14 was initially treated with a nonsteroidal antiinflammatory drug without benefit; his muscle strength improved and his serum creatine kinase level returned to normal only after zidovudine was discontinued.
Patient 5 felt better and his serum creatine kinase level returned to normal when zidovudine was discontinued, but his strength did not increase substantially, and he died a few weeks later. Patient 9 worsened when zidovudine was discontinued; prednisone had no benefit, and he continued to worsen and died. Patient 13 did not respond to prednisone (60 mg daily) but improved when zidovudine was discontinued. Patient 6 improved when a nonsteroidal antiinflammatory drug was added to the zidovudine regimen, and Patient 7 improved when a nonsteroidal antiinflammatory drug was added to a reduced dose of zidovudine.
Of the five patients with HIV-associated myopathy who had not received zidovudine, two (Patients 16 and 19) responded to prednisone, one (Patient 17) did not and died two months after treatment began, one (Patient 18) worsened with prednisone therapy but improved with zidovudine, and another (Patient 20) responded to a nonsteroidal antiinflammatory drug (Table 1). These five patients had been HIV antibody—positive for a mean of only eight months before the biopsy, whereas the zidovudine-treated patients had been HIV antibody—positive for a mean of 27.2 months.
Correlation of Histologic and Immunocytochemical Findings with Clinical Observations
The muscle-biopsy specimens from the patients whose myopathy responded to prednisone were similar in appearance to those from the patients who responded to the discontinuation of zidovudine. Similarly, the specimens from the patients who did not respond to any therapy did not differ histologically from those of the patients who responded to treatment (Table 1). There was, however, a correlation between the number of ragged-red fibers and the severity of the myopathy. Patients in whom the ragged-red fibers made up more than 8 percent of the total number of fibers counted had more severe myopathy (Table 1). This was true for all the patients with moderate or severe myopathy except Patient 1, whose myopathy preceded zidovudine therapy but worsened during treatment with zidovudine. The two patients who responded to a nonsteroidal antiinflammatory drug (Patients 6 and 7) had mild histologic changes with less than 5 percent ragged-red fibers; Patient 15, who had the fewest ragged-red fibers, had the mildest myopathy. Similarly, in the second biopsy specimens from the two patients whose myopathy improved after the discontinuation of zidovudine, the proportion of ragged-red fibers dropped from 15.9 percent to 6.6 percent in Patient 10 and from 48.0 percent to 6.5 percent in Patient 12.
The predominant cells in all the muscle specimens were CD8+ cells, followed by macrophages. CD4+ cells were scarce, even in the muscles of zidovudine-treated patients. There was also no relation between the number of the circulating lymphocyte subsets, especially CD4+ cells, and the development of myopathy. For example, Patient 2 had no detectable CD4+ cells in the circulation, and Patient 3 had a CD4/CD8 ratio of 1 (Table 1). The muscle fibers in all specimens, regardless of whether the patient was treated with zidovudine and regardless of his or her response to a specific therapy, revealed strong expression of MHC-I antigen on the surface, as described previously for the inflammatory myopathies, including those due to HIV.23 , 28 , 29
The mean number of total cellular infiltrates in the untreated HIV-positive patients was 742 (range, 153 to 1311), in contrast with 436 (range, 83 to 1068) in the zidovudine-treated patients and 653 (range, 96 to 1579) in the HIV-seronegative patients with polymyositis (Table 2Table 2
Inflammatory Cells in Muscle-Biopsy Specimens from HIV-Positive Patients and HIV-Seronegative Patients with Polymyositis.*). These findings indicate that zidovudine-induced myopathy is also inflammatory, but the total number of cells in the zidovudine-treated patients tended to be lower than in the untreated HIV-positive patients and in the HIV-seronegative patients with polymyositis (P<0.1 by analysis of variance). Although the predominant lymphocyte subset was the CD8+ cells, the zidovudine-treated patients, as compared with the other two groups, had a slight but insignificant reduction in the percentage of CD8+ cells and a concomitant increase in the number of macrophages (P<0.1 by analysis of variance), suggestive of a more severe necrotizing process. There were no statistically significant differences in the total number of cells or in the percentage of CD8+ cells and macrophages between the zidovudine-treated patients who responded to prednisone and those who responded to the discontinuation of zidovudine. The two zidovudine-treated patients who improved when treated with a nonsteroidal anti-inflammatory drug had the least evidence of inflammation in their biopsy specimens, with percentages of CD8+ cells and macrophages similar to those in the untreated HIV-positive patients and the HIV-seronegative patients with polymyositis (Table 2). In the second biopsy specimens from Patients 10 and 12, the total number of infiltrating cells was reduced by 50 percent (Table 1). Patient 10 had a significant reduction in the percentage of infiltrating macrophages and a disproportionate increase in the percentage of CD8+ cells, as shown in representative sections in Fig. 4Figure 4
Serial Sections from Two Muscle-Biopsy Specimens from Patient 10, Who Had Zidovudine-Associated Myopathy.. This reflects a reduction in the percentage of scavenger-serving macrophages in association with both the normalization of the previously necrotic muscle fibers and the persistence of an inflammatory process mediated by CD8+ cells and macrophages.Discussion
The muscle-biopsy specimens from HIV-positive patients in whom myopathy developed during zidovudine therapy revealed the presence of a mitochondrial myopathy associated with endomysial inflammatory-cell infiltrates consisting of CD8+ cells and macrophages surrounding or invading muscle fibers expressing MHC-I antigen. The immunocytochemical characteristics of the biopsy specimens from the zidovudine-treated patients were similar to those in specimens from both the patients with HIV-positive myopathy who had not received zidovudine and the HIV-seronegative patients with polymyositis. There were no differences in the number and type of endomysial infiltrating cells between patients whose myopathy improved with prednisone and those in whom myopathy responded to the discontinuation of zidovudine. These findings suggest that the induction of abnormal mitochondria by zidovudine is only partially responsible for the observed muscle weakness and that immunopathologic mechanisms may also have an important role.
Because we found abnormal mitochondria only in the muscle specimens from zidovudine-treated patients and not in those from patients who had myopathy but had not received zidovudine, zidovudine —and not HIV — is likely to be responsible for these changes. Zidovudine, 3′–azido-3′–deoxythymidine, is a 2′,3′-dideoxynucleoside analogue that inhibits γ-DNA polymerase, an enzyme found solely in the mitochondrial matrix, and interferes with the replication of mitochondrial DNA.30 31 32 Zidovudine was apparently capable of inducing such changes after an average of 12.8 months of therapy (Table 1).
The clinical response of some zidovudine-treated patients to prednisone and not to the discontinuation of zidovudine, along with the immunocytochemical findings, suggests that the induction of abnormal mitochondria by zidovudine is not the only mechanism responsible for this myopathy. The muscle specimens from all the zidovudine-treated patients, regardless of whether their myopathy responded to prednisone or the discontinuation of zidovudine, showed similar inflammatory changes, as did the specimens from the untreated patients with HIV-positive myopathy23 and the HIV-seronegative patients with polymyositis26 , 28 , 29 , 33 , 34; these findings suggest that a T-cell—mediated, MHC-I—restricted cytotoxic process is a common mechanism in all these conditions. Whether the expression of MHC-I antigen in the muscle fibers is brought about by factors released by sensitized CD8+ T cells or by HIV antigens that occasionally occur within the infiltrating inflammatory cells1 , 3 , 23 , 35 is uncertain. The coexistence of an immune process in zidovudine-associated myopathy is further supported by the immunocytochemical findings in the second biopsy specimens obtained from two patients who responded to the discontinuation of zidovudine. These second specimens showed not only remarkable improvement in muscle-fiber cytoarchitecture, as expected in the case of a drug-induced toxic myopathy, but also the persistence of inflammation with a relative increase in the percentage of CD8+ cytotoxic T cells surrounding healthy muscle fibers and muscle fibers expressing MHC-I antigen (Table 1 and Fig. 4).
Because the number of ragged-red fibers correlated with the severity of the myopathic symptoms, it is quite likely that in the zidovudine-treated patients myopathy had a myotoxic component related to the zidovudine-induced abnormal mitochondria and an immune component in the form of T cell—mediated cytotoxicity related to the underlying disease. Subclinical inflammation occurs in the muscles of HIV-positive patients36 , 37; perhaps, in such patients, zidovudine may facilitate or exaggerate the overt expression of inflammatory myopathy by producing abnormalities in muscle mitochondria and impairing DNA replication. The prolonged survival of patients treated with zidovudine could also make their muscles more susceptible to a T-cell—mediated cytotoxic mechanism triggered by HIV or directly to HIV viral antigens, because in spite of bringing about a decrease in active viral replication, zidovudine has little or no effect on latent infection and the persistence of HIV reservoirs in several types of tissue.38 This hypothesis is consistent with the prolonged duration (mean, 27.2 months) of the HIV-positive state before the development of myopathy in the zidovudine-treated patients; in the patients who did not receive zidovudine, this period was shorter (mean, 8 months).
It is not known whether the zidovudine-induced myopathy is dose-related or whether the lower doses now recommended may prove to be less myotoxic, even with long-term therapy. It is of note, however, that two of our patients (Patients 8 and 12) had exacerbations of myopathy and increased serum creatine kinase levels when they were retreated with lower doses of zidovudine (up to 400 mg daily).
In this study the patients' responses to treatment varied, suggesting that the dual mechanisms of reversible zidovudine myotoxicity and immune-mediated muscle-fiber injury operate to varying degrees in different patients. This could explain why the myopathy responded only to prednisone in some patients, only to the discontinuation of zidovudine in others, to both drugs in some others, and to a nonsteroidal anti-inflammatory drug in still others. In a given patient, it is not clear which of the two is the predominant myopathic mechanism in zidovudine-associated myopathy. On the basis of our findings, we recommend the following empirical therapy in the management of HIV-associated myopathies, whether induced by zidovudine or not. Before prescribing prednisone, a potentially dangerous immunomodulating agent in patients with AIDS, a nonsteroidal antiinflammatory drug should be tried, with or without a reduction in the dosage of zidovudine. If this regimen is not effective, zidovudine should be discontinued for three to four weeks and the patient's level of strength monitored. (Serum creatine kinase levels may return to normal without an improvement in muscle strength.) If the patient's strength increases, zidovudine should be withheld and the patient given another antiretroviral agent, perhaps a 2′,3′-dideoxynucleoside analogue such as dideoxyinosine.30 If the patient's strength decreases or does not change, zidovudine should be reinstituted along with prednisone (40 to 60 mg daily).
Dr. Illa is the recipient of a fellowship from Hospital de Sant Pau, Barcelona, and Fondo de Investigaciones Sanitarias de la Seguridad Social, Spain.
We are indebted to Dr. Jordan Grafman for statistical assistance; to Ms. B.J. Hessie for editorial assistance; and to the following physicians, who allowed us to study their patients: Dr. Robert Yarchoan and Dr. Philip A. Pizzo of the National Cancer Institute and Dr. Lawrence Deyton of the National Institute of Allergy and Infectious Diseases, Bethesda, Md.; Dr. Peter Anderson of the Walter Reed Army Medical Center, Washington, D.C.; Dr. José Gutierrez of Andrews Air Force Base, Camp-Spring, Md.; Dr. Rütager Kratz of Georgetown University, Washington, D.C.; Dr. Barry Hafkin, Houston; Dr. Donald Poretz of Fairfax Hospital, Fairfax, Va.; Dr. Maie Herrick and Dr. Richard Tucker of Stanford University, Stanford, Calif; and Dr. Kenneth Cjesielka, Pittsburgh.
Source Information
From the Neuromuscular Diseases Section, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md. (M.C.D., I.I.); the Armed Forces Institute of Pathology, Washington, D.C. (G.H.P., J.L.G.); the Rheumatology Service, George Washington University School of Medicine, Washington, D.C. (J.P.L.); and the Neurology Service, Northwestern University, Chicago (B.C.). Address reprint requests to Dr. Dalakas at Bldg. 10, Rm. 4N248, NINDS, NIH, Bethesda, MD 20892.
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