New Research Sets the Stage for Noninvasive Monitoring of HIV-Induced Peripheral Neuropathy

Corneal nerve fiber assessment proposed for managing patients with HIV-induced peripheral neuropathy, according to The American Journal of Pathology

Philadelphia, PA, May 12, 2014

Corneal nerve fiber assessment has great potential as a tool to diagnose and monitor peripheral neuropathy induced by HIV, say scientists at the Johns Hopkins University School of Medicine. The results of their study are published in The American Journal of Pathology.

Although corneal nerve assessments have shown increasingly valuable as a replacement for epidermal nerve fiber evaluation in diabetic peripheral neuropathy, the evaluation of corneal alterations in tracking HIV-induced neuropathy has yet to be explored.

“The cornea is the most densely innervated tissue in the body, so corneal nerve assessment is extremely sensitive for detecting small sensory nerve fiber damage as compared to other tests including measurement of intra-epidermal nerve fibers in the skin,” notes lead investigator Joseph L. Mankowski, DVM, PhD, who is Professor of Molecular and Comparative Pathobiology, Pathology, and Neurology at the Johns Hopkins University School of Medicine, Baltimore, MD.

Although not life threatening, HIV-induced peripheral neuropathy greatly compromises patient quality of life. Currently, skin biopsy is the accepted standard for measuring the loss of small, unmyelinated C fibers in the epidermis, one of the earliest detectable signs of peripheral nerve damage. However, skin biopsy is an invasive procedure, and ongoing assessment requires repeated surgical procedures. Electrophysiological testing to measure peripheral nerve conduction properties is not a viable alternative because current methods lack the sensitivity required to detect damage to small, unmyelinated fibers, especially in early stages of disease. Therefore, new sensitive, noninvasive methods of assessing small fiber nerve damage are urgently needed to detect and monitor peripheral neuropathy in HIV-infected individuals.

To study the pathogenesis of HIV-induced PNS disease, Jamie Dorsey, Research Technologist, and the research team led by Dr. Mankowski developed a simian immunodeficiency virus (SIV)-infected macaque model that closely reflects key peripheral nervous system (PNS) alterations seen in HIV patients with peripheral neuropathy. They sought to determine whether SIV infection leads to decreases in corneal nerve fiber density, and whether corneal nerve fiber density correlates with epidermal nerve fiber length counts, thereby setting the stage for follow-up investigation using corneal confocal microscopy.

“Moving to non-invasive and repeatable methods of nerve fiber measurements such as in vivo corneal confocal microscopy would enhance study of peripheral neuropathy by enabling early detection of damage, progression of nerve fiber deterioration, and enable assessment of therapeutic strategies in the SIV/macaque model,” explains Dr. Mankowski. “Furthermore, adapting in vivo corneal confocal microscopy for use in tracking HIV-induced PNS damage in patients may be of great value to identify early PNS damage independent of performing skin biopsies.”

To determine whether SIV infection leads to corneal nerve fiber loss, the researchers immunostained corneas for the nerve fiber marker βIII tubulin. They developed and applied both manual and automated methods developed by Jonathan Oakley, PhD, of Voxeleron to measure nerves in the corneal sub-basal plexus. These counting methods independently demonstrated significantly lower sub-basal corneal nerve fiber density among SIV-infected animals that rapidly progressed to AIDS as compared to slow progressors. Corneal nerve fiber density was also directly correlated with epidermal nerve fiber length.

Besides decreased corneal nerve fiber density, rapid SIV progressors had increased levels of SIV RNA, CD68-positive macrophages, and GFAP expression by glial satellite cells in the trigeminal ganglia, the location of the neuronal cell bodies of corneal sensory nerve fibers.

Together, these findings demonstrate that emerging noninvasive techniques to measure corneal nerve fiber alterations such as in vivo corneal confocal microscopy may be useful clinical tools to screen for and monitor progression of peripheral neuropathy in HIV-infected patients.

---

Notes for editors
“Loss of Corneal Sensory Nerve Fibers in SIV-infected Macaques: An Alternate Approach to Investigate HIV-induced PNS Damage,” by Jamie L. Dorsey, Lisa M. Mangus, Jonathan D. Oakley, Sarah E. Beck, Kathleen M. Kelly, Suzanne E. Queen, Kelly A. Metcalf Pate, Robert J. Adams, Carl F. Marfurt, and Joseph L. Mankowski (DOI: http://dx.doi.org/10.1016/j.ajpath.2014.02.009), The American Journal of Pathology, Volume 184, Issue 6 (June 2014) published by Elsevier.

Full text of the article is available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com. Journalists wishing to interview the authors should contact Shawna Williams, Communications Manager, Johns Hopkins Medicine, at +1 410 955 8236 (office), +1 443 903 7607 (mobile), or Shawna@jhmi.edu.

This work was supported by NIH NS055651, NIH MH070306, NIH NS077869, and NCRR and the Office of Research Infrastructure Programs P40 OD013117 and NIH T32 OD011089.

About The American Journal of Pathology
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.

The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – over 38,000 cites in 2012 – with an Impact Factor of 4.522 and Eigenfactor of 0.07599 according to the 2012 Journal Citation Reports®, Thomson Reuters, and an h-index of 181 according to the 2011 SCImago Journal and Country Rank.

About Elsevier

Elsevier is a world-leading provider of information solutions that enhance the performance of science, health, and technology professionals, empowering them to make better decisions, deliver better care, and sometimes make groundbreaking discoveries that advance the boundaries of knowledge and human progress. Elsevier provides web-based, digital solutions — among them ScienceDirect, Scopus, Elsevier Research Intelligence,and ClinicalKey—and publishes over 2,200 journals, including The Lancet and Cell, and over 25,000 book titles, including a number of iconic reference works.

The company is part of Reed Elsevier Group PLC, a world leading provider of professional information solutions in the Science, Medical, Legal and Risk and Business sectors, which is jointly owned by Reed Elsevier PLC and Reed Elsevier NV. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).

Media contact
Eileen Leahy
Elsevier
+1 732 238 3628
ajpmedia@elsevier.com

Dr. Chhavi Chauhan
Scientific Editor
The American Journal of Pathology
+1 301 634 7953
cchauhan@asip.org