New Tool to Diagnose and Monitor HIV-related Peripheral Neuropathy

 

Corneal nerve fiber assessment less invasive than skin biopsy

 Scientists at the Johns Hopkins University School of Medicine have discovered that corneal nerve fiber assessment has great potential as a tool to diagnose and monitor peripheral neuropathy induced by HIV, according to the results of their study published in the American Journal of Pathology.

Although corneal nerve assessments have become 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.

Although not life threatening, HIV-induced peripheral neuropathy greatly affects the quality of life for HIV-positive people. 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. Therefore, new sensitive, noninvasive methods of assessing small fiber nerve damage are urgently needed to detect and monitor peripheral neuropathy in those living with HIV.

To study the pathogenesis of HIV-induced peripheral nervous system (PNS) disease, Jamie Dorsey, research technologist, and the team led by Dr. Mankowski studied macaques that were infected with SIV, the simian (monkey) immunodeficiency virus that closely reflects key 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.

Use of such a method involves a single point of tissue being illuminated by a point light source and simultaneously imaged by a camera in the same plane. This produces an image with a very high resolution but virtually no field of view due to the single point of illumination and detection. To solve this problem, the instrument instantaneously illuminates and synchronously scans a small region of tissue with thousands of tiny spots of light which are reconstructed to create a usable field of view with high resolution and magnification.

“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 to measure nerves in the cornea. 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 and other significant signs of advanced disease and its affect on corneal sensory nerve fibers.

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

 

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HIV Signs and Symptoms

Many people don’t have any symptoms when they first become infected with HIV. Some have a flu-like illness, called HIV sero-conversion syndrome, a month or two after exposure to the virus. This illness may cause a variety of symptoms, including:
  • Diarrhea
  • Enlarged liver or spleen
  • Fever
  • Enlarged or swollen lymph nodes
  • Headache
  • Muscle pain
  • Nausea and vomiting
  • Neurologic symptoms
  • Rash on the abdomen, arms and legs and face
  • Sore throat
  • Thrush, a common fungal infection of the mouth caused by Candida, a yeast-like fungus

These symptoms usually disappear in a week to a month and may be mistaken for other viral infections. During this period, people are very infectious and HIV is present in large quantities in genital fluids.

An infected person may not experience severe symptoms for eight to 10 years or more. This period — called the asymptomatic period — varies in length for each person. Some people may have symptoms within a few months and others may be symptom-free for years.

Children born with HIV usually have symptoms within two years of birth. Children may grow slowly or become sick frequently.

As the immune system weakens, other complications may occur. For many people, the first signs of infection are large lymph nodes or swollen glands that may be enlarged for more than three months. Other symptoms before the onset of AIDS include:

  • Fevers and sweats
  • Herpes infections that cause severe mouth, genital or anal sores
  • Lack of energy
  • Pelvic inflammatory disease in women that does not respond to treatment
  • Persistent skin rashes or flaky skin
  • Shingles, a painful nerve disease often accompanied by a rash or blisters
  • Short-term memory loss
  • Weight loss