Neuromuscular Disease Award funded by Alma May George, Michael Rogers Stirling and A. M. Cobden Estates
Pathophysiological insights into HIV and antiretroviral drug related neuropathy afforded by axonal excitability testing.
Dr Karl Ng
University of Sydney
Co-Investigators: Professor David Burke and Professor Bruce Brew
The human immunodeficiency virus affects approximately 40 million people worldwide, with a large socioeconomic and medical burden. Despite progress in patient longevity, painful peripheral neuropathy is prevalent and an estimated 36% are affected by peripheral neuropathy in those with advanced HIV using sensitive neurophysiological techniques. Most patients suffer a distal sensory polyneuropathy probably related to viral disease burden but there are many cases especially in the developing countries that are attributable to the older antiretroviral agents such as stavudine. Differentiation of these two aetiological groups can be difficult on clinical grounds, or even with laboratory methods.
The pathogenesis of HIV neuropathy is felt to be related to inflammatory processes centred on the dorsal root ganglion. Virus is mostly localised in the perivascular inflammatory cells here. The envelope glycoprotein, gp120, as well as inducing apoptosis in rat dorsal root ganglion, lowers the threshold for excitation in-vivo. Proinflammatory cytokines have been found in high concentrations in the dorsal root ganglion, and in animal models have been shown to lead to upregulation of sodium channels and neuronal hyperexcitability there. Prominent mitochondrial abnormalities have been seen in antiretroviral related neuropathy after exposure to offending drugs.
The purpose of this study is to use novel in-vivo techniques capable of studying neuronal voltage-gated ionic function to characterise the neuropathy of HIV polyneuropathy and ARV neuropathy. To our knowledge, this method has not been applied to this disease entity. These techniques provide a sophisticated insight into large fibre nodal and internodal ionic channel function. We intend to not only substantiate or refute in-vitro observations of Na channel upregulation in HIV polyneuropathy, but to see if there are features that distinguish a viral vs drug-induced neuropathic condition.