Full text of DOI:10.1017/S0317167100002286

CASE REPORT
AZT Myopathy and HIV-1 Polymyositis:
One Disease or Two?
Kimberley Walsh, Kathy Kaye, Bart Demaerschalk, Sarah Stewart, Jeff Crukley,
Robert Hammond
ABSTRACT: Purpose: This paper discusses the association between inflammatory and mitochondrial
pathologies in patients with HIV-1/AIDS treated with zidovudine (AZT). Methods: We present the
clinical and pathological details of a 52-year-old HIV-1 positive male who presented with progressive
muscle weakness. We also review the current literature and address the debated pathogenesis of the
inflammatory pathology. Results: Muscle biopsy revealed evidence of both HIV-1 polymyositis and
AZT myopathy. Six months after initiation of corticosteroid therapy and discontinuation of AZT, the
patient’s symptoms had greatly improved. The biopsy was repeated to show that both pathologies had
resolved. Conclusions: The perceived overlap in the pathological spectra of HIV-1 polymyositis and
AZT myopathy has produced some debate on causation and treatment. Unfortunately, there have been
very few reports where a repeat biopsy following a drug washout period confirmed resolution of the
pathology. Furthermore, affected patients have not been treated in a uniform fashion. Whether this
represents one disease or two remains uncertain. The clinical relevance of this issue lies in the potential
for harm from the unnecessary use of corticosteroids. This question may be best addressed by a
randomized clinical trial.
RÉSUMÉ: Myopathie à l’AZT et polymyosite à VIH-1: une ou deux maladies? Objectif: Cet article discute de
l’association de pathologies inflammatoires et mitochondriales chez des patients atteints du VIH-1/SIDA qui sont
traités par la zidovudine (AZT). Méthodes: Nous présentons les observations cliniques et anatomopathologiques à
propos d’un patient de 52 ans, VIH-1 positif, qui a consulté pour faiblesse musculaire progressive. Nous revoyons
également la littérature et la pathogenèse de la pathologie inflammatoire. Résultats: La biopsie musculaire a montré
des signes de polymyosite à VIH-1 et de myopathie à l’AZT. Six mois après avoir commencé la corticothérapie et
avoir cessé l’AZT, les symptômes du patient s’étaient améliorés considérablement. Une nouvelle biopsie a montré
que les signes des deux pathologies étaient disparus. Conclusions: Le chevauchement des spectres
anatomopathologiques de la polymyosite à VIH-1 et de la myopathie à l’AZT a engendré une controverse sur
l’étiologie et le traitement. Malheureusement, il existe peu de cas rapportés où des biopsies avant et après le retrait
du médicament ont confirmé la résolution des signes anatomopathologiques. De plus, les patients atteints n’ont pas
tous été traités de la même façon. On ne sait pas s’il s’agit d’une ou de deux maladies. La pertinence clinique de
cette question est liée au préjudice potentiel causé par la prise de corticostéroïdes. Un essai clinique randomisé serait
la meilleure façon de répondre à cette question.
Can. J. Neurol. Sci. 2002; 29: 390-393
Infection with HIV-1 is associated with a variety of central
and peripheral nervous system diseases. Although many are due
to opportunistic infections and neoplasms many others are
putatively mediated directly or indirectly (through immune
dysfunction or toxin production) by HIV-1 itself. Prime
examples of the latter are the HIV-1 associated dementia
complex1,2 and a distal symmetric polyneuropathy.3-5
presence of inflammation, necrosis and phagocytosis in muscle
biopsy material.8 Creatine kinase levels are typically elevated.
The diffuse symmetrical myopathy associated with AZT is
thought to be due to the drug’s interference with mitochondrial
Myopathy in the setting of HIV-1 infection is commonly due
to HIV-1 polymyositis and zidovudine (AZT) effect.6-16
Hallmarks of HIV-1 polymyositis include symmetrical proximal
muscle weakness, increased creatine kinase (CK) levels, and the
From the Department of Pathology, LHSC-UC, London, Ontario, Canada.
RECEIVED MARCH 12, 2002. ACCEPTED IN FINAL FORM JUNE 12, 2002.
Reprint requests to: Robert R. Hammond, Department of Pathology, LHSC-UC, 339
Windermere Rd., London, Ontario, Canada, N6A 5C1
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Figure 1:
a) Inflammatory myopathy with
increased fibre size variation
and mononuclear endomysial
infiltrates (arrows),
Hematoxylin-Phloxine-Saffron
(HPS), bar = 100 µm.
b) Ragged-red fibres (arrows),
Gomori trichrome,
bar = 100 µm.
c) Ragged-red equivalent fibres
(arrows) (enzymatic
discordance), succinic acid
dehydrogenase (SDH),
bar = 100 µm.
d) Mitochondrial and cristal
pleomorphism and atypia,
Electron microscopy,
bar = 0.5 µm.
DNA-polymerase function.10 The pathological hallmark is the
presence of ragged red fibres (RRFs), which signify
accumulations of abnormal mitochondria.7 Creatine kinase levels
may or may not be altered in AZT myopathy. In a large collection
of cases, Dalakas et al9 proposed that mononuclear inflammatory
infiltrates could be ascribed to AZT and not necessarily represent
concurrent polymyositis.
We report the additional case of a 52-year-old HIV-1 positive
male presenting with progressive muscle weakness. His initial
biopsy identified HIV-1 polymyositis and AZT myopathy. Six
months after stopping AZT and beginning corticosteroids, a
repeat biopsy confirmed that both pathologies had resolved. Few
cases have been reported in which a second biopsy was
performed after discontinuing AZT to demonstrate the resolution
of pathological findings. This case again raises the issue of
whether or not such instances represent one pathological process
or two and whether or not corticosteroids are necessary.
CLINICAL HISTORY
A 52-year-old male developed slowly progressive proximal muscle
weakness of his arms and legs beginning in September of 1999. He was
known to be HIV-1 positive since 1996, which was acquired through
unprotected intravenous drug use. He was treated with 200mg of AZT
twice daily in 1996. He had a remote history of hepatitis C which was
inactive, a positive tuberculin skin test in 1998, with an abnormal chest
x-ray showing small granulomas in his right lung base, in addition to
granulomatous calcifications in his right hilum and mediastinum. He
received a course of isoniazid and pyridoxine beginning July of 1999.
He began to complain of myalgias in his thighs and calves with
occasional burning pain in his feet and palms in the fall of 1999. This
was accompanied by weakness in his lower extremities, which
progressed to involve his upper extremities and facial muscles over the
next several months.
By January of 2000, he was unable to climb stairs and had difficulty
sitting up in bed. There was mild weakness of his peri-ocular and peri-oral
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Figure 2:
a) Fibre size variation (bi-
modal) without inflammation,
HPS, bar = 100 µm.
b) Resolution of ragged-red
fibres, Gomori trichrome,
bar = 100 µm.
c) Resolution of ragged-red
equivalent fibres (enzymatic
discordance). A few very
atrophic fibres showed
increased SDH staining
(arrows) but preserved
cytochrome oxidase (COX)
expression and normalized
mitochondrial ultrastructure,
SDH, bar = 100 µm.
d) Selective type II fibre atrophy
(darkly stained fibres are
type II). ATPase at pH 9.4,
bar = 100 µm.
muscles, mild neck flexor weakness, and proximal greater than distal
weakness of his arms and legs in a symmetrical fashion. Power was graded
at MRC grade 4/5 in his arms, grade 3/5 in his hip flexors, quadriceps and
hamstrings, and grade 4 elsewhere in his legs. Deep tendon reflexes were
grade 2 in his arms and absent in his lower extremities.
His AZT was discontinued. A muscle biopsy was performed which
revealed an inflammatory myopathy with endomysial and perimysial
mononuclear infiltrates (Figure 1a). Partially invaded muscle fibres were
present, as well as degenerating fibres. Many fibres showed basophillic
subsarcolemmal accumulations and ragged red pathology on Gomori
preparations (Figure 1b). Histochemical staining for cytochrome oxidase
(COX), and succinic acid dehydrogenase (SDH) displayed numerous
examples of enzymatic discordance (ragged red fibre equivalents)
affecting approximately 25% of fibres, especially the type I
subpopulation (Figure 1c). Ultrastructural examination revealed large
accumulations of atypical mitochondria within muscle fibres. The
mitochondria were enlarged, misshapen and contained unusual
redundant cristae (Figure 1d). Many of the abnormal mitochondria also
contained irregular dense accumulations of granular osmiophilic
material. Paracrystalline inclusions were not seen. Excessive lipid and
focal collections of Z-band material (nemaline rod-like deposits) were
also noted, particularly in severely affected fibres.
Medications included AZT 200mg BID, ritonivir 400mg BID,
indinavir 400mg BID, naproxen 250mg TID, 3TC 150mg BID,
pyridoxine 25mg OD, isoniazid 300mg OD, and ranitidine 150mg BID.
Laboratory investigations upon admission revealed that his CD4
count was moderately decreased at 330 cells/mm3 with an HIV-1 viral
load of 11403. His CK level was 66 (normal range 38-174) U/L.
Electromyography revealed some large amplitude motor units in his
right quadriceps and gluteus medius with decreased recruitment, but no
fibrillations or positive sharp waves. Electromyogram studies of his right
tibialis anterior, psoas, gastrocnemius, deltoid, biceps, triceps,
brachioradialis and first dorsal interosseus muscles were normal. Motor
and sensory nerve conductions in his right arm and leg were within
normal limits.
The patient was subsequently started on 100mg of prednisone OD for
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one month, which resulted in improved strength by March of 2000. He
was able to ambulate with a walker with at least grade 4 power in all
muscle groups.
disease. On the basis of current evidence, the two entities are not
necessarily mutually exclusive. This dilemma requires the
scrutiny of a prospective randomized clinical trial to clarify the
mechanism of disease and to address the appropriateness of
corticosteroid therapy in such patients for whom this poses a
number of additional risks.
His strength continued to improve and a second muscle biopsy was
performed (six months after the first biopsy) showing resolution of the
inflammatory myopathy (Figure 2a) and ragged red fibre pathology
(Figures 2b and 2c). Selective type II fibre atrophy was noted, and this
was felt to be secondary to his corticosteroid use (Figure 2d). Occasional
atrophic fibres were hyperstaining on NADH and SDH preparations, but
were not COX negative nor did they reveal mitochondrial abnormalities
by electron microscopy.
ACKNOWLEDGMENTS
The authors thank Dr. George Karpati for helpful consultation and
advice. We also thank Deb Reade, June Janzen, and Debbie Newman for
their technical expertise. RH was supported by the Ontario HIV
Treatment Network.
DISCUSSION
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