Scientific Rationale: This is a proposal to continue the research of a Harvard team with a strong track record of medical detective work discovering the underlying causes of "mystery" illnesses. We particularly focus on a type of peripheral nerve cell known as "small-fibers." These cells do many jobs, including sensing pain, regulating blood pressure and heart rate, and controlling digestion and urination. If small-fibers are damaged, people notice problems with these functions, and unexpectedly, sometimes even develop problems with frequent headaches and poor sleep and thinking. Most doctors are not familiar with small-fibers, so most patients who develop small-fiber polyneuropathy (SFPN) remain undiagnosed. This is unfortunate because when SFPN is diagnosed, its causes can often be identified and treated, allowing the small fibers to begin to grow back and patients' symptoms to fade away. Two special tests are available to diagnose SFPN. One involves removing a tiny skin biopsy from the leg under local anesthesia, and counting the number of small-fiber nerve cells within it to see if cell counts are low. The other, called autonomic function testing (AFT), involves looking for abnormalities in heart rate, blood pressure, and sweating, all autonomic functions that can go awry in SFPN.

During our first Gulf War Illness grant, these tests allowed us to discover that even teenagers and young adults at the age of military service can develop small-fiber neuropathy. Before, it was thought that only much older people got SFPN, from diabetes or cancer for instance. We also figured out that this "early onset small-fiber polyneuropathy" or eoSFPN is usually caused by autoimmunity, a type of illness where people's immune cells mistakenly attack other cell types in their own body. Treatments are already available for autoimmune diseases, and we found that treating eoSFPN patients with immunosuppressant drugs such as steroids caused rapid improvement in their "mystery" symptoms as their small-fibers began to heal and function again.

We next studied fibromyalgia, a common "mystery" illness, and found that almost half of those we studied had skin biopsy results showing that they had small-fiber neuropathy. This discovery made news on television, in newspapers such as USA Today, and in magazines such as Scientific American Mind. We next began to test Veterans with Gulf War Illness, and so far 47% of them also have evidence of eoSFPN, which they got during the Gulf War and still have. This is exciting because so far it looks like even people with undiagnosed eoSFPN for 10 or 20 years can still improve if they are correctly diagnosed and treated. But Department of Veterans Affairs (VA) hospitals don't yet offer skin biopsy and AFT tests for eoSFPN, and they don't yet have the expertise to diagnose SFPN.

What research is planned now and how would it help Veterans with Gulf War Illness?

This project is intended to develop easier and cheaper tests for diagnosing eoSFPN in Veterans aged 40 to 70 who have had symptoms for more than 20 years. As soon we figure out what the best tests are, hospitals could start testing Veterans suffering from Gulf War Illness for eoSFPN, and patients with similar conditions such as fibromyalgia could get tested as well. Patients who test positive for eoSFPN could immediately be treated with drugs already on the market, such as steroids or immunoglobulins. Our work finds that these treatments help more than half of treated patients. Aim 1 will develop a new screening questionnaire for patients with Gulf War Illness to fill out and find out if their symptoms suggest whether they have SFPN or not. Once final, this could be put on government websites for free use by Veterans. We will also develop a checklist that doctors and nurses could immediately start using to better detect signs of SFPN during yearly medical examinations. We will perfect these forms by testing them with civilians and Veterans age 40-70 who have had skin biopsies and AFT to prove who does or does not have eoSFPN. Then we can improve these forms to include the items that work the best to predict who does or does not have eoSFPN. Aim 2 will evaluate new biotechnology devices that show promise for improving SFPN diagnosis. We will test a new non-invasive device already on the market that senses reduced sweating in the hands and feet, and another device that picks up abnormally dilated eyes. Both problems are common in SFPN, and if the devices work, VA hospitals could buy and use them right away as both are no-risk tests. Aim 3 involves working with Harvard's neurogeneticists to develop tests for mutations in the 16 genes shown to occasionally have mutations that might increase a person's risk for developing SFPN. Fifty Veterans with Gulf War Illness proven to have eoSFPN will then have these genes tested for mutations. If this proves useful, future military enlistees could be tested for genetic risk factors at enlistment to keep those with high risk for SFPN from being exposed to nerve toxins, as during the Gulf War.

All told, these are very low risk studies designed to help physicians recognize and diagnose SFPN sooner when it is the underlying cause of Gulf War Illness. This study is being conducted in a collaboration between Harvard and the New Jersey War Related Injury and Illness Center (WRIISC), where they will be offered to registered Veterans with Gulf War Illness. The impact on Veteran health should be immediate, as Veterans with Gulf War Illness found to have eoSFPN should then be able to get effective treatment for the first time.