Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy

Polydefkis, Michael; Yiannoutsos, Constantin T.; Cohen, Bruce A.; Hollander, Harry; Schifitto, Giovanni; Clifford, David B.; Simpson, David M.; Katzenstein, David; Shriver, S.; Hauer, Peter; Brown, Amanda; Haidich, Anna Bettina; Moo, Lauren; McArthur, Justin C.

doi:10.1212/wnl.58.1.115

Cited by 278 publications

(181 citation statements)

References 16 publications

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“…19,29 Alterations in ENF density are consistent with our report of impaired ENF regeneration postaxotomy in SIV-infected macaques. 43 In nerves, SIV-induced damage is first apparent in the most distal innervation territory (skin) and only at later stages of the disease at more proximal sites (sural nerve).…”

Section: Discussionsupporting

confidence: 90%

“…8,19,20,[27][28][29] Previous studies of skin biopsies taken from HIV-infected patients have shown a close correlation between epidermal nerve fiber (ENF) densities measured at the distal leg region and the presence of neuropathic pain. In those studies, reduced ENF density at the distal leg was associated with increased neuropathic pain, lower CD4 counts, and higher plasma viral loads.…”

Section: Epidermal Nerve Fiber Density Declines With Siv Infectionmentioning

confidence: 99%

“…In those studies, reduced ENF density at the distal leg was associated with increased neuropathic pain, lower CD4 counts, and higher plasma viral loads. 29 To determine whether epidermal nerve fiber density loss occurred with SIV infection, epidermal nerve fiber densities in footpad samples from SIV-infected macaques were immunostained for PGP9.5, and then were compared with ENF density in uninfected control animals ( Figure 1). Immunostaining to detect PGP9.5, a pan-neuronal marker present as a cytoplasmic protein in peripheral nerves, is currently the most consistent method to visualize ENF.…”

Section: Epidermal Nerve Fiber Density Declines With Siv Infectionmentioning

confidence: 99%

See 2 more Smart Citations

Macrophage-Mediated Dorsal Root Ganglion Damage Precedes Altered Nerve Conduction in SIV-Infected Macaques

Laast

Shim

Johanek

et al. 2011

The American Journal of Pathology

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Section: Discussionsupporting

confidence: 90%

Section: Epidermal Nerve Fiber Density Declines With Siv Infectionmentioning

confidence: 99%

Section: Epidermal Nerve Fiber Density Declines With Siv Infectionmentioning

confidence: 99%

See 1 more Smart Citation

Macrophage-Mediated Dorsal Root Ganglion Damage Precedes Altered Nerve Conduction in SIV-Infected Macaques

Laast

Shim

Johanek

et al. 2011

The American Journal of Pathology

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“…One manifestation of this is the loss of intraepidermal nerve fiber density, which we have shown is correlated with damage to the DRG, 22 whereas others have shown it is correlated with pain. 23 Natalizumab treatment resulted in decreased numbers of recently recruited M1-like MAC387 þ BrdU þ monocytes, decreased CD68 þ macrophages, and fewer productively SIV-infected macrophages in DRGs, suggesting that these all relate to DRG pathology. These results demonstrate that by blocking a4-integrins and, thus, traffic of monocytes to DRGs, subsequent histopathology is diminished and suggests that monocyte traffic, viral replication, and macrophage activation have causative roles in perpetuating neuronal damage, and are not simply correlative.…”

Section: Discussionmentioning

confidence: 97%

α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy

Lakritz

Thibault

Robinson

et al. 2016

The American Journal of Pathology

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Traffic of activated monocytes into the dorsal root ganglia (DRG) is critical for pathology in HIV peripheral neuropathy. We have shown that accumulation of recently recruited (bromodeoxyuridine þ MAC387 þ ) monocytes is associated with severe DRG pathology and loss of intraepidermal nerve fibers in SIV-infected macaques. Herein, we blocked leukocyte traffic by treating animals with natalizumab, which binds to a4-integrins. SIV-infected CD8-depleted macaques treated with natalizumab either early (the day of infection) or late (28 days after infection) were compared with untreated SIV-infected animals sacrificed at similar times. Histopathology showed diminished DRG pathology with natalizumab treatment, including decreased inflammation, neuronophagia, and Nageotte nodules. Natalizumab treatment resulted in a decrease in the number of bromodeoxyuridine þ (early), MAC387 þ (late), CD68 þ (early and late), and SIVp28 þ (late) macrophages in DRG tissues. The number of CD3 þ T lymphocytes in DRGs was not affected by natalizumab treatment. Vascular cell adhesion molecule 1, an adhesion molecule that mediates leukocyte traffic, was diminished in DRGs of all natalizumab-treated animals. These data show that blocking monocyte, but not T lymphocyte, traffic to the DRG results in decreased inflammation and pathology, supporting a role for monocyte traffic and activation in HIV peripheral neuropathy. The primary mechanisms of HIV peripheral neuropathy include immune damage secondary to viral infection and mitochondrial toxicity from the antiretrovirals. Because HIV and SIV do not productively infect neurons or Schwann cells, damage to the dorsal root ganglia (DRG) in peripheral neuropathy is believed to be, in part, because of infected and activated macrophages. In vitro and in vivo studies suggest that both viral proteins and systemic inflammation secondary to the viral infection may damage neurons and axons. 1 Using a CD8-depleted SIV-infected rhesus macaque model of peripheral neuropathy, we have shown that accumulation of recruited [bromodeoxyuridine (BrdU) þ MAC387 þ ] monocytes/macrophages was associated with severe DRG pathology. 2 The number of BrdU þ monocytes correlated with DRG histopathology, which included neuronophagia, satellitosis, and Nageotte nodules. 2 Our data demonstrate that newly recruited MAC387 þ BrdU þ macrophages play a significant role in DRG pathogenesis.

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“…Image analysis An image analysis camera (Sony 2CCD, CCD-IRIS; Weybridge, Surrey, UK) and suitable computer program (Leica QWin Standard V2.4; Leica Microsystem Imaging, Cambridge, UK) were used to quantify IENFD (number of fibres per mm of basement membrane) as previously described [15].…”

Section: Methodsmentioning

confidence: 99%

The Neuropad test: a visual indicator test for human diabetic neuropathy

et al. 2008

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Aims/hypothesis The commercially available Neuropad test was developed as a simple visual indicator test to evaluate diabetic neuropathy. It uses a colour change to define the integrity of skin sympathetic cholinergic innervation. We compared the results of Neuropad assessment in the foot with established measures of somatic and autonomic neuropathy. Methods Fifty-seven diabetic patients underwent Neuropad assessment, quantitative sensory and autonomic function testing, and evaluation of intra-epidermal nerve fibre density in foot skin biopsies. Results Neuropad responses correlated with the neuropathy disability score (r s =0.450, p<0.001), neuropathic symptom score (r s =0.288, p=0.03), cold detection threshold (r s = 0.394, p=0.003), heat-as-pain perception threshold visual analogue score 0.5 (r s =0.279, p=0.043) and deep-breathing heart rate variability (r s =−0.525, p<0.001). Intra-epidermal nerve fibre density (fibres/mm) compared with age-and sexmatched control subjects (11.06±0.82) was non-significantly reduced (7.37±0.93) in diabetic patients with a normal Neuropad response and significantly reduced in patients with a patchy (5.01±0.93) or absent (5.02±0.77) response (p= 0.02). The sensitivity of an abnormal Neuropad response in detecting clinical neuropathy (neuropathy disability score ≥5) was 85% (negative predictive value 71%) and the specificity was 45% (positive predictive value 69%). Conclusions/interpretation The Neuropad test may be a simple indicator for screening patients with diabetic neuropathy.

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Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy

Abstract: IENF loss at the distal leg is associated with increased neuropathic pain, lower CD4 counts, and higher plasma viral load in HIV-SN. The robustness of the longitudinal measurement of IENF density supports its use in future longitudinal studies and clinical trials.

Cited by 278 publications

References 16 publications

Macrophage-Mediated Dorsal Root Ganglion Damage Precedes Altered Nerve Conduction in SIV-Infected Macaques

Macrophage-Mediated Dorsal Root Ganglion Damage Precedes Altered Nerve Conduction in SIV-Infected Macaques

α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy

The Neuropad test: a visual indicator test for human diabetic neuropathy

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