Hypothesis on the pathogenesis of vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS
Neuromuscular Unit,
West London Centre and University Department of Clinical Neurosciences,
Charing Cross Hospital, London, UK
Correspondence to: Dr RJ Guiloff, Neuromuscular Unit (1st Floor Pilot Wing), Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. Telephone 0044 181 746 8319; fax 0044 181 746 8420; email r.guiloff{at}cxwms.ac.uk
Received 11 July 1997 and in revised form 20 January 1998;
Accepted 20 January
1998
Certain aspects of the clinical syndrome of dementia, cerebral
atrophy, predominantly sensory neuropathy, and vacuolar myelopathy in
AIDS resemble those seen in vitamin B12 deficiency. Pathologically, there are similarities not only in the changes in the spinal cord, but
also in the brain and peripheral nerves. The pathogenesis of vacuolar
myelopathy may be secondary to a combination of immune mediated myelin
and oligodendrocyte injury, and simultaneous impairment of repair
mechanisms due to a deficiency of S-adenosylmethionine (SAM). Products
derived from macrophages may interfere directly with the methyl
transfer cycle through the generation of reactive oxygen intermediates
and reactions involving nitric oxide and peroxynitrite which may limit
the supply of methionine for conversion to SAM, both by direct
interaction as well as through inhibition of methionine synthase.
Macrophage activation with secretion of cytokines and other
biologically reactive substances within the nervous system is sustained
in the late stages of HIV infection by the general effects of immune
depletion, including loss of T cells (with concomitant reduction of
macrophage regulatory molecules) and recurrent opportunistic
infections, and may be further augmented by the local presence of the
virus itself (or its surface glycoprotein gp120). This would account
for the common, but not exclusive, occurrence of vacuolar myelopathy in
AIDS. The ability of the virus and its products to stimulate macrophage
and microglial activation may also explain the association between
severity ofvacuolar myelopathy and the presence of HIV encephalitis. A
similar mechanism may underlie the pathogenesis of dementia, cerebral
atrophy, and peripheral neuropathy. Local factors or differential
susceptibility between the central and peripheral nervous system may
determine whether myelinotoxic or neurotoxic processes predominate; the prominence of myelin involvement in the spinal cord, and axonal involvement peripherally may reflect both ends of this range, with the
brain manifesting a more equal balance of both processes.
© 1998 by Journal of Neurology, Neurosurgery, and Psychiatry
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