Important note: Information in this article was accurate in July 2002. The state of the art may have changed since the publication date.
In the last three years a new form of HIV associated neurological disease has been described, often occurring in association with lactic acidosis in patients with prolonged use of stavudine (d4T, Zerit). While the clinical and pathological features are still being defined, the severity of this syndrome and its apparent high mortality rate warrant a discussion of what we know now.
The FDA adverse events reporting system identified 25 cases of this syndrome, with a fatal outcome in seven. Twenty-two of the 25 reported were on d4T, making this agent the leading, but not the only, culprit [Marcus K, 9th CROI 2002, Abstract LB14]. The neurological features include ascending paresis, areflexia, and development of cranial neuropathies. These features overlap with those of Guillain-Barré syndrome (acute inflammatory demyelinating polyneuropathy), and some patients develop severe neuropathic limb pains and myopathic weakness. The differential diagnosis includes transverse myelitis, the neuromuscular weakness accompanying West Nile encephalitis, and botulism. Serum CPK and lactate are usually elevated,
and EMG/nerve conduction studies show a mixed pattern with both axonal neuropathy and myopathy.
The ACTG Neurology group is attempting to collect prospective information on this new syndrome from ACTG trials and clinical cases. A proposed case definition is included below, and clinical details can be sent to this author at jm@jhmi.edu. The full extent of the syndrome is unclear, and the patho-physiological mechanisms are currently unknown. Therapy is confined to discontinuation of the offending agent. Since the dideoxynucleoside analogues are known to inhibit mitochondrial DNA polymerase [Kakuda T, Clin Ther 2000 Jun;22(6):685-708; Chen C-H, Vazquez-Padua M, Y-C C, Mol Pharmacol 1991 May;39(5):625-8]), the enzyme that maintains DNA, their prolonged action might lead to energy failure. Recently techniques to
assay mitochondrial DNA levels have been developed, and several studies have now shown that levels are suppressed either in PBMCs or subcutaneous fat after prolonged exposure to dideoxynucleosides (ddx) [Cote HC, Brumme ZL, Craib KJ, et al., N Engl J Med 2002 Mar 14;346(11):811-20; Shikuma CM, Hu N, Milne C, et al., AIDS 2001 Sep 28;15(14):1801-9; Cherry C, 2002 in press.] In collaboration with colleagues at the Alfred Hospital in Melbourne, we have used the simple technique of punch skin biopsies to quantify mitochondrial DNA in subcutaneous fat. Levels of mtDNA were significantly lower in individuals who were using ddx agents. Prospective evaluation of subjects at both institutions is underway through clinical questionnaires and physiological testing and measurement of the density of unmyelinated nerve fibers in the epidermis to
examine whether the measurement of mtDNA in this way can predict sensory neuropathy associated with antiretroviral toxicity.
Proposed Case Definition for Acute Neuromyopathy and Lactic Acidosis Syndrome
[Prepared by Justin McArthur MBBS, M.P.H., David Simpson M.D., and the ACTG Neuropathy Working Group]
20020701
JH20020703
©1997,1998,1999,2000,2001, 2002. The Johns Hopkins University AIDS Service, Division of Infectious Diseases. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to Sharon McAvinue, Managing Editor. Website: Johns Hopkins AIDS Service.
AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2002. This material is designed to support, not replace, the relationship that exists between you and your doctor.
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1980, 2002. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content.
