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From the Departments of Neurology (L.Z., P.H., S.R., G.J.E., J.C.M.) and Pathology and Epidemiology (J.C.M.), Johns Hopkins University, Baltimore, MD; Harvard University (D.W.K., S.R.E.), Cambridge, MA; University of Hawaii (M.G., V.V.); University of Washington (C.M.M.); University of Texas at Southwestern (R.D.-A.); University of Miami (K.G.); Frontier Science and Technology Research Foundation (L.M.); ACTG Operations Center (S.S.); University of California Davis Medical Center (D.M.A.); Washington University (D.B.C.); and Department of Neurology (D.M.S.), Mount Sinai School of Medicine. L. Zhou is currently affiliated with Department of Neurology, Cleveland Clinic, OH.
Address correspondence and reprint requests to Justin C. McArthur, Professor of Neurology, Pathology, and Epidemiology, Interim Chair, Department of Neurology, Johns Hopkins University, 600 N. Wolfe Street/Meyer 6-109, Baltimore, MD 21287-7609 jm{at}jhmi.edu
Objective: To demonstrate the relationship between epidermal nerve fiber density (ENFD) in the leg and the phenotype of HIV-associated distal sensory polyneuropathy (HIV-DSP) in a multicenter prospective study (ACTG A5117).
Methods: A total of 101 HIV-infected adults, with CD4 cell count <300 cells/mm3 and who had received antiretroviral therapy (ART) for at least 15 consecutive weeks, underwent standardized clinical and electrophysiologic assessment. All 101 subjects were biopsied at the distal leg (DL) and 99 at the proximal thigh (PT) at baseline. ENFD was assessed by skin biopsy using PGP9.5 immunostaining. Associations of ENFD with demographics, ART treatment, Total Neuropathy Score (TNS), sural sensory nerve action potential (SNAP) amplitude and conduction velocity, quantitative sensory testing (QST) measures, and neuropathic pain were explored.
Results: ENFD at the DL site correlated with neuropathy severity as gauged by TNS (p < 0.01), the level of neuropathic pain quantified by the Gracely Pain Scale (GPS) (p = 0.01) and Visual Analogue Scale (VAS) (p = 0.01), sural SNAP amplitude (p < 0.01), and toe cooling (p < 0.01) and vibration (p = 0.02) detection thresholds. ENFD did not correlate with neurotoxic ART exposure, CD4 cell count, or plasma HIV-1 viral load.
Conclusions: In subjects with advanced HIV-1 infection, epidermal nerve fiber density (ENFD) assessment correlates with the clinical and electrophysiologic severity of distal sensory polyneuropathy (DSP). ENFD did not correlate with previously established risk factors for HIV-DSP, including CD4 cell count, plasma HIV-1 viral load, and neurotoxic antiretroviral therapy exposure.
Supported by the Adult AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases, AI38858, AI34853, and the Neurological AIDS Research Consortium funded by the National Institute of Neurological Diseases and Stroke, NS32228, NS44807, NS02253, K24 NS002253, and GCRC Units funded by the NCRR, RR00071, and RR16467. Support for the development of the skin biopsy technique was initially provided by the W.W. Smith Charitable Trust (J.C.M.).
Disclosure: The authors report no conflicts of interest.
Received April 24, 2006. Accepted in final form February 8, 2007.
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