Press Release and Letter - Another Veteran Resigns Over Scocos Nomination

Press Release and Letter - Another Veteran Resigns Over Scocos Nomination

Haley Study finds chronic abnormal brain blood flow in Gulf War veterans

Editor's Note: Dr. Robert Haley's research was methodically defunded by VA officials in 2009.  See the 91outcomes original coverage of the issue.  It is time for Congressional and Obama Administration officials to relook at how to restore funding to this groundbreaking research.

--Anthony Hardie, Madison, Wis.

================

Contact: Linda Brooks
Radiological Society of North America

Study finds chronic abnormal brain blood flow in Gulf War veterans

OAK BROOK, Ill. – Blood flow abnormalities found in the brains of veterans with Gulf War illness have persisted 20 years after the war, and in some cases have gotten worse, according to a new study published online in the journal Radiology.

"We confirmed that abnormal blood flow continued or worsened over the 11-year span since first being diagnosed, which indicates that the damage is ongoing and lasts long term," said principal investigator Robert W. Haley, M.D., chief of epidemiology in the Departments of Internal Medicine and Clinical Sciences at the University of Texas (UT) Southwestern Medical Center in Dallas. "We also identified a special MRI procedure that better diagnoses and distinguishes between the three main types of Gulf War illness."

Gulf War illness is a poorly understood chronic condition associated with exposure to neurotoxic chemicals and nerve gas. It affects an estimated 25 percent of the 700,000 military personnel deployed to the 1991 Persian Gulf War, according to the U.S. Department of Veterans Affairs' scientific advisory committee [RAC-GWVI].

There are three main syndromes associated with Gulf War illness, producing a variety of symptoms, including fatigue, neuropathic pain, memory and concentration deficits, balance disturbances and depression.

The hippocampus is the part of the brain responsible for forming long-term memories and helping with spatial navigation. Many Gulf War illness neurological symptoms, such as memory loss, confusion, irritability and disorders in motion control suggest impairment of the hippocampus.
In 1998, Dr. Haley's research team published a study using single photon emission computed tomography (SPECT) to assess hippocampal blood flow in veterans with Gulf War Syndrome. For the current study, the researchers used a novel technique called arterial spin labeled (ASL) MRI to assess hippocampal regional cerebral blood flow (rCBF) in 13 control participants and 35 patients with Gulf War syndromes 1 (impaired cognition), 2 (confusion-ataxia) and 3 (central neuropathic pain).

Each patient received intravenous infusions of saline in an initial session, and physostigmine in a second session 48 hours later. Physostigmine is a short-acting cholinesterase inhibitor, used to test the functional integrity of the cholinergic system, a neurotransmitter system involved in the regulation of memory and learning.

"ASL scanning after giving this medication is particularly well suited to diagnosing Gulf War illness, because it picks up brain abnormalities too subtle for regular MRI to detect," said co-author Richard W. Briggs, Ph.D., professor of radiology at UT Southwestern. "This allows us to make the diagnosis in a single two-hour session without the need for exposure to ionizing radiation."

The findings replicated the results of the initial SPECT study of largely the same group of veterans. The results showed that abnormal hippocampal blood flow persisted and may have progressed 11 years after initial testing and nearly 20 years after the Gulf War, suggesting chronic alteration of hippocampal blood flow.

Physostigmine significantly decreased rCBF in control participants and veterans with syndrome 1, but significantly increased rCBF in the right hippocampus of veterans with syndrome 2 in the original study. The abnormal increase in rCBF was now found to have progressed to the left hippocampus with syndrome 2 and to both hippocampi of the veterans with syndrome 3.

"Having an objective diagnostic test allows researchers to identify ill veterans for future clinical trials to test possible treatments," Dr. Haley said. "It is also critical for ongoing genomic studies to see why some people are affected by chemical exposures, and why others are not."

"Hippocampal Dysfunction in Gulf War Veterans: Investigation with ASL Perfusion MR Imaging and Physostigmine Challenge." Collaborating with Drs. Haley and Briggs on this paper were Xiufeng Li, Ph.D., Jeffrey S. Spence, Ph.D., David M. Buhner, M.D., M.S., John Hart Jr., M.D., C. Munro Cullum, Ph.D., Melanie M. Biggs, Ph.D., Andrea L. Hester, Ph.D., Timothy N. Odegard, Ph.D., and Patrick S. Carmack, Ph.D. The study was funded by a federal research contract administered by the Department of Veterans Affairs Medical Center, Dallas, Texas, and grants from the U.S. Army Medical Research and Materiel Command and the National Institutes of Health.

Radiology is edited by Herbert Y. Kressel, M.D., Harvard Medical School, Boston, Mass., and owned and published by the Radiological Society of North America, Inc. (http://radiology.rsna.org/)
RSNA is an association of more than 46,000 radiologists, radiation oncologists, medical physicists and related scientists committed to excellence in patient care through education and research. The Society is based in Oak Brook, Ill. (RSNA.org)

For patient-friendly information on magnetic resonance imaging (MRI), visit RadiologyInfo.org.

Possible Fibromyalgia Drug Moves Forward

ORIGINAL About.com article: http://chronicfatigue.about.com/b/2011/09/12/possible-fibromyalgia-drug-moves-forward.htm 

Possible Fibromyalgia Drug Moves Forward

By Adrienne Dellwo, About.com Guide  

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 NEWSBRIEF: The U.S. Patent Office has issued a new patent to Chelsea Therapeutics for its drug droxidopa as a fibromyalgia treatment, according to the company. The patent is based on positive results of previous trials and would give Chelsea exclusive rights to produce the drug for a certain period of time, if it receives FDA approval.

Chelsea says it is gearing up to start its second phase 2 trial of droxidopa and has enrolled 120 fibromyalgia patients. The company expects to release preliminary results by the end of 2011.

What is Droxidopa?

Droxidopa is a synthetic version of a substance your body uses to make the neurotransmitter/hormone norepinephrine. Norepinephrine performs several important functions, and your body also uses it to produce dopamine, another important neurotransmitter. Studies have shown that this drug can improve fatigue, weakness, concentration, and orthostatic hypotension (blood pressure drop upon standing, which causes dizziness) in several conditions.

The drug is not yet approved in the U.S. for any use. However, it is currently in phase 2 trials for chronic fatigue syndrome and phase 3 trials for orthostatic hypotension in Parkinson's disease.
Based on typical timelines for drug testing and approval, this drug could be on the market in 3 to 5 years, if current trials are successful.

More Information:

• Positive Results With Droxidopa for Fibromyalgia
• Droxidopa Investigated for Chronic Fatigue Syndrome
• Neurotransmitter Dysregulation in Fibromyalgia & Chronic Fatigue Syndrome

UK: Hull hospital pioneers Gulf War Syndrome treatment

Original BBC news story: http://www.bbc.co.uk/news/uk-england-humber-14685953

Hull hospital pioneers Gulf War Syndrome treatment

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Shaun Rusling talks to Look North's Phil Connell about the treatment

Continue reading the main story

Related Stories

• Battle continues over Gulf War Syndrome
• Veteran wins Gulf War ruling

Researchers at the University of Hull believe they have found a treatment for people with Gulf War Syndrome.

Thousands of former service personnel claim to be affected by the illness, with reported symptoms including fatigue and depression.

Scientists at a research unit at Hull Royal Infirmary are using injections of hormones to treat the condition.

The syndrome is controversial with many medical experts refusing to accept that it exists.

Many military veterans link their illness to vaccinations given prior to their deployment to the Gulf in 1991.
'Testosterone and thyroxin'
Prof Stephen Atkins and his team at the Hull York Medical School introduced the treatment after a number of patients were referred to his department by their GPs.

Of the 11 people with Gulf War Syndrome sent to Prof Atkins, nine were diagnosed with a rare problem with their pituitary gland which led to a deficiency of certain hormones, such as testosterone and thyroxin.

Professor Atkins has put patients on injections of hormones

The patients are now undergoing therapy with injections to replace the missing hormones.

Prof Atkins said the initial results were encouraging: "Of the veterans that we've actually treated with hormone problems, they've all responded to a greater or lesser degree. And therefore their quality of life has generally improved."

One patient undergoing the treatment is 52-year-old Shaun Rusling from Hull.
'Transformed life'
Mr Rusling said he became ill after serving as a medic with the Parachute Regiment during the conflict.

He said the therapy had transformed his life: "It's simply like switching a light back inside your head. I had lost complete interest in everything, friends and family, relationships. I had total dysfunction. To explain it simply, I existed."

Prof Atkins said that all service veterans with Gulf War Syndrome should be tested for pituitary problems. He called for a full-scale clinical trial.

"It's very rare. Pituitary hypophysitis is approximately about one in a million," he said.

"So what we are not saying that is this is causing Gulf War Syndrome. What we're saying perhaps that there are some patients out there with Gulf War Syndrome who may have this."

More on This Story

Related Stories

• Battle continues over Gulf War Syndrome 16 JANUARY 2011, UK
• Veteran wins Gulf War ruling 13 JUNE 2003, HEALTH

ME-CFSCommunity.com Update

ME-CFSCommunity.com A message to all members of ME-CFSCommunity.com The new "Myalgic Encephalomyelitis: International Consensus Criteria" has been released and available for downloading.                                 Exercise & ME/CFS: Post VO2 Max Testing Consult "Brilliant." was the first comment posted on this second in the series on Exercise & ME/CFS. It focuses on the application of the VO2 Max testing results in the development of an exercise program for those afflicted with ME/CFS. One which will not over tax the body and result in a crash. Dr Nancy Klimas explains the basic elements of the testing. Physiologist, Connie Sol conducts the post-testing consult and explains the design of a patient-specific exercise program.            The first video in the series "Exercise & ME/CFS: VO2 Max Testing Procedure" has garnered rave reviews from around the world To view the videos go to: The Exercise Group.            As of July 29th, the Whittemore Peterson Institute ranks 6th overall and 1st within its region with 45,453 votes. They are currently 74,447 votes behind the leader and it would seem unlikely at this point that they can overcome that lead and win the first prize of $250,00. They are, however, well ahead of the second place organization and seem assured of winning the $100,000 regional award. Currently, The National ME/FM Action Network ranks 3rd within its region with 6,908 votes. The first place award of $100,000 in their region appears attainable if they get the full, daily support of those afflicted with ME/CFS.        Please help us to help you. We can only continue producing the ME-CFSCommunity and its services and videos including our Expert Assistance series with your financial support. A contribution of just $5 from you would be gratefully appreciated and allow us to continue our efforts to help you cope with this dreaded affliction.              Visit ME-CFSCommunity.com at: http://cfsknowledgecenter.ning.com/?xg_source=msg_mes_network

GULF WAR SYNDROME II: Burn Pits

Research shows burn pits can lead to deadly illnesses

Posted at: 07/21/2011 7:31 PM
By: Heather Mills, KOB Eyewitness News 4

Men and women in the armed forces are coming back from war with mysterious illnesses. Large pits, where a variety of hazardous materials are burned, have been blamed for a rare lung disease. Now new research backs that up.

One New Mexico soldier has come forward talking about the battle since his return.

Master Sergeant Jessey Baca says the burn pits in Iraq are killing him. He says each day is progressively worse. He looks normal, but he's suffering, a lot. "It's a cough that never goes away, your sinuses are burning, your eyes are burning, all of a sudden you get a fever." Next he says come cold sweats, swollen and painful lymph nodes in grape-like clusters and tumors. Baca calls it the new "Agent Orange," the burn pits in Iraq and Afghanistan.

"{It's} the most putrid, smelliest smell you've ever smelled in your life. It burns your nose. It burns your eyes constantly and it never goes away."

Baca served two tours in Iraq, both times he was stationed at Balad Airbase, the site of one of the largest burn pits. He says it was about 10-acres in size. "Anything that can be thrown away, is thrown away, whether it's tires, vehicles or destroyed equipment." That includes hospital waste and human waste.

Baca says he first started feeling sick after his first tour ended in 2003 and he searched for answers. "Everywhere you turn, 'I don't know, we don't know. We can't figure it out. We don't know what to do.' You tell them all your symptoms and they look at your kind of strangely."

Baca visited dozens of doctors in New Mexico. He and his wife Maria finally got answers at Vanderbilt University Medical Center in Nashville. He's been diagnosed with chemically induced asthma, constrictive bronchiolitis, mesophelial hyperplasia; among a long list of other things.

Maria said, "You know when you spits up blood, we don't even know what it is anymore. There's just pieces of him coming out."

Faced with a stack of medical bills, the Baca family is focusing on Jessey's bucket list and managing his symptoms. Maria said, "Yeah, my husband has both his limbs, he has his hands, he has his arms, he doesn't have hole coming out of his head, but try living with being eaten inside by poison."

KOB Eyewitness News 4 talked to a physician with the VA in Albuquerque, Dr. Dona Upson. She says more than 2 million troops have been exposed to the burn pits, and they're still burning. She says constrictive bronchiolitis is terminal, that the only possible treatment option right now is a lung transplant, but doctors still have a lot to learn since this has just come to light. Upson says it's a problem she expects to see much more of.

-----

SOURCE:  

http://www.kob.com/article/stories/S2209428.shtml?cat=516

Small fiber neuropathy: A burning problem

1. JINNY TAVEE, MD

+Author Affiliations

1. Neuromuscular Disease Center, Neurological Institute, Cleveland Clinic

1. LAN ZHOU, MD, PhD

+Author Affiliations

1. Director, Cleveland Clinic Cutaneous Nerve Laboratory, Neuromuscular Disease Center, Neurological Institute, Cleveland Clinic

1. ADDRESS: Lan Zhou, MD, PhD, Neuromuscular Disease Center, Neurological Institute, S90, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail zhoul2@ccf.org.

 

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Abstract

Small fiber neuropathy is increasingly being recognized as a major cause of painful burning sensations in the feet, especially in the elderly. Although strength remains preserved throughout the course of the disease, the pain and paresthesias are often disabling. Diabetes mellitus is the most common identifiable cause of small fiber neuropathy, and impaired oral glucose tolerance and individual components of the metabolic syndrome are often associated with it. Some cases, however, are idiopathic. Skin biopsy (with an evaluation of the density of intraepidermal nerve fibers) and tests of autonomic nerve function are useful for the diagnosis. Management involves controlling pain and identifying and aggressively treating the underlying cause.

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Key points Symptoms of small fiber neuropathy typically start with burning feet and numb toes.

Key points Causes and associated conditions can be found in over 50% of cases. These include glucose dysmetabolism, connective tissue diseases, sarcoidosis, dysthyroidism, vitamin B₁₂ deficiency, paraproteinemia, human immunodeficiency virus infection, celiac disease, neurotoxic drug exposure, and paraneoplastic syndrome.

Key points Findings on routine nerve conduction studies and electromyography are typically normal in this disease.

Key points Management includes aggressively identifying and treating the underlying cause, advising lifestyle modifications, and alleviating pain.

AN ESTIMATED 15 to 20 million people in the United States over age 40 have some type of peripheral neuropathy.¹ In many, the impairment is purely or predominantly in small nerve fibers, and the clinical presentation consists of pain, burning, tingling, and numbness in a length-dependent or stocking-glove distribution. (“Length” refers to distance from the trunk; distal fibers are affected first.) Symptoms typically begin in the feet and slowly ascend to the distal legs, at which point the hands may also be affected (FIGURE 1).

In many of these patients, the findings on neurologic examination, nerve conduction studies, and electromyography are normal, although some may show signs of mild distal sensory loss on physical examination. The lack of objective findings on routine nerve conduction studies and electromyography may lead many physicians to attribute the symptoms to other disorders such as plantar fasciitis, vascular insufficiency, or degenerative lumbosacral spine disease.

The past 2 decades have seen the development of specialized tests that have greatly facilitated the diagnosis of small fiber neuropathy; these include skin biopsy to evaluate the density of nerve fibers in the epidermis and studies of autonomic nerve function. Common etiologies have been identified for small fiber neuropathy and can be specifically treated, which is critical for controlling progression of the disease. Pain management is becoming easier with more available options but is still quite challenging.

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WHAT IS SMALL FIBER NEUROPATHY?

Small fiber neuropathy is a disorder of the peripheral nerves that primarily or exclusively affects small somatic fibers, autonomic fibers, or both, resulting in sensory changes and autonomic dysfunction when both types are involved (FIGURE 2).²

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FIGURE 1.

Symptoms are pain, burning, numbness, and autonomic dysfunction (lack of sweating) in the hands and feet in a stocking-glove distribution. Strength is not affected. Tendon reflexes are normal, as are nerve conduction studies.

Peripheral nerve fibers can be classified according to size, which correlates with the degree of myelination.

• Large nerve fibers are heavily myelinated and include A-alpha fibers, which mediate motor strength, and A-beta fibers, which mediate vibratory and touch sensation.
• Medium-sized fibers, known as A-gamma fibers, are also myelinated and carry information to muscle spindles.
• Small fibers include myelinated A-delta fibers and unmyelinated C fibers, which innervate skin (somatic fibers) and involuntary muscles, including cardiac and smooth muscles (autonomic fibers). Together, they mediate pain, thermal sensation, and autonomic function.

Small fiber neuropathy results from selective impairment of small myelinated A-delta and unmyelinated C fibers.

Sensory symptoms: Pain, burning, tingling, numbness

Damage to or loss of small somatic nerve fibers results in pain, burning, tingling, or numbness that typically affects the limbs in a distal-toproximal gradient. In rare cases, small fiber neuropathy follows a non-length-dependent distribution in which symptoms may be manifested predominantly in the arms, face, or trunk.

Symptoms may be mild initially, with some patients complaining of vague discomfort in one or both feet similar to the sensation of a sock gathering at the end of a shoe. Others report a wooden quality in their feet, numbness in their toes, or a feeling as if they are walking on pebbles, sand, or golf balls. The most bothersome and fairly typical symptom is burning pain in the feet that extends proximally in a stocking-glove distribution and is often accompanied by stabbing or aching pains, electric shock-like or pins-and-needles sensations, or cramping of the feet and calves.

Symptoms are usually worse at night and often affect sleep. Some patients say that their feet have become so exquisitely tender that they cannot bear having the bed sheets touch them, and so they sleep with their feet uncovered. A small number of patients do not have pain but report a feeling of tightness and swelling in their feet (even though the feet appear normal).

Examination often reveals allodynia (perception of nonpainful stimuli as being painful), hyperalgesia (perception of painful stimuli as being more painful than expected), or reduced pinprick and thermal sensation in the affected area. Vibratory sensation can be mildly reduced at the toes. Motor strength, tendon reflexes, and proprioception, however, are preserved because they are functions of large nerve fibers.

Autonomic symptoms

When autonomic fibers are affected, patients may experience dry eyes, dry mouth, orthostatic dizziness, constipation, bladder incontinence, sexual dysfunction, trouble sweating, or red or white skin discoloration.² Examination may show orthostatic hypotension and skin changes. The skin over the affected area may appear atrophic, dry, shiny, discolored, or mildly edematous as the result of sudomotor and vasomotor abnormalities.

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FIGURE 2

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WHAT CAUSES SMALL FIBER NEUROPATHY?

Small fiber neuropathy has been associated with many medical conditions, including glucose dysmetabolism,³ connective tissue disease,^4,5 dysthyroidism,⁶ vitamin B₁₂deficiency, paraproteinemia, human immunodeficiency virus (HIV) infection,⁷ hepatitis C virus infection, celiac disease,⁸ restless legs syndrome,⁹ neurotoxic drug exposure, hereditary diseases, and paraneoplastic syndrome. While most of these conditions cause a length-dependent small fiber neuropathy, others (Sjögren disease, celiac disease, and paraneoplastic syndrome) can cause a form of small fiber neuropathy that is not length-dependent.^4,8,10

Diabetes and prediabetes

Glucose dysmetabolism, including diabetes and prediabetes with impaired oral glucose tolerance (a glucose level 140–199 mg/dL 2 hours after a 75-g oral dextrose load), is the most common identifiable associated condition, present in about one-third of patients with painful sensory neuropathy¹¹ and in nearly half of those with otherwise idiopathic small fiber neuropathy.^12–14

Research findings strongly suggest that even prediabetes is a risk factor for small fiber neuropathy, and that so-called “impaired glucose tolerance neuropathy” may represent the earliest stage of diabetic neuropathy. Several recent studies have found a high prevalence of impaired glucose tolerance in patients with sensory peripheral neuropathy,^12–14 with a rate of up to 42% in cases initially thought to be idiopathic¹⁴compared with 14% in the general population.¹⁵ Also, a dose-response relationship between the severity of hyperglycemia and the degree of neuropathy was demonstrated in one study, in which patients with impaired glucose tolerance more often had small fiber neuropathy, whereas those with diabetes more often had polyneuropathy involving both small and large fibers.¹⁴ And studies in animals and cell cultures have shown that intermittent hyperglycemia, which can be seen in patients with impaired glucose tolerance, caused sensory neuron and nerve fiber damage and increased spontaneous C-fiber firing, resulting in neuropathic pain.^8,16,17

Metabolic syndrome

Insulin resistance with prediabetes and diabetes is a part of the metabolic syndrome, which also consists of hypertension, hyperlipidemia, and obesity. The individual components of the metabolic syndrome have been implicated as risk factors not only for cardiovascular and cerebrovascular disease but also for small fiber neuropathy.

One study in 548 patients with type 2 diabetes showed that those with the metabolic syndrome were twice as likely to have neuropathy as those without.¹⁸ Another study showed that in 1,200 patients with type 1 diabetes without neuropathy at baseline, hypertension, hyperlipidemia, and increased body mass index were each independently associated with a higher risk of developing neuropathy.¹⁹

A recent study of 219 patients with idiopathic distal symmetrical peripheral neuropathy and 175 diabetic patients without neuropathy found a higher prevalence of metabolic syndrome in patients with neuropathy than in normal populations. The prevalence of dyslipidemia (high levels of total and low-density lipoprotein cholesterol and triglycerides and low levels of high-density lipoprotein cholesterol), but not hypertension or obesity, was higher in patients with neuropathy than in patients with diabetes but no neuropathy.²⁰The findings linked dyslipidemia to neuropathy and showed the need for further studies of the potential pathogenic role of dyslipidemia in neuropathy.

Hereditary causes

Hereditary causes of small fiber neuropathy are rare and include Fabry disease, Tangier disease, hereditary sensory autonomic neuropathy, and hereditary amyloidosis.

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HOW DO YOU EVALUATE PATIENTS WITH SUSPECTED SMALL FIBER NEUROPATHY?

A thorough history should be taken to obtain details regarding onset and features of neuropathy symptoms, exacerbating factors, and progression. It is also important to ascertain whether the patient has any associated conditions as mentioned above, a family history of neuropathy, risk factors for HIV or hepatitis C virus infection, or a history of neurotoxic drug exposure.

Clinical suspicion of small fiber neuropathy should be high if a patient presents with predominant small fiber symptoms and signs with preserved large fiber functions.

Nerve conduction studies and electromyography

For diagnostic testing, routine nerve conduction studies and electromyography assess the function of large nerve fibers only and are thus normal in small fiber neuropathy. These tests should still be ordered to rule out subclinical involvement of large fibers, which may affect the diagnostic evaluation, prognosis, and treatment plan. However, if the results of these tests are normal, specialized studies are needed to evaluate small fibers.

Although several tests are available to evaluate somatic and autonomic small fibers, the two that have the highest diagnostic efficiency for small fiber neuropathy and that are used most often are skin biopsy, to evaluate intraepidermal nerve fiber density, and quantitative sudomotor axon reflex testing (QSART), to assess sudomotor autonomic function.^21–23

Skin biopsy

Skin biopsy is a minimally invasive procedure in which 3-mm-diameter punch biopsy specimens are taken from the distal leg, distal thigh, and proximal thigh of one lower limb. The procedure takes only 10 to 15 minutes.

Biopsy specimens are immunostained using an antibody against protein gene product 9.5, which is a panaxonal marker. Small nerve fibers in the epidermis are counted under a microscope, and intraepithelial nerve fiber densities are calculated and compared with established normative values. The diagnosis of small fiber neuropathy can be established if the intraepidermal nerve fiber density is lower than normal (FIGURE 1). Nerve fiber density may be normal in the early stage of small fiber neuropathy, but in this setting skin biopsy often shows abnormal morphologic changes in the small fibers, especially large swellings,²⁴ and repeat biopsy in 6 to 12 months may be considered.

The diagnostic efficiency of skin biopsy is about 88%.^21,23 For diagnosing small fiber neuropathy, it is more sensitive than quantitative sensory testing^21,25 and more sensitive and less invasive than sural nerve biopsy.²⁶ Intraepidermal nerve fiber density also correlates well with a variety of measures of severity of HIV distal sensory neuropathy and thus may be used to measure the severity and treatment response of small fiber neuropathy.²⁷

Quantitative sudomotor axon reflex testing

QSART is an autonomic study that measures sweat output in response to acetylcholine, which reflects the function of postganglionic sympathetic unmyelinated sudomotor nerve fibers. Electrodes are placed on the arms and legs to record the volume of sweat produced by acetylcholine iontophoresis, in which a mild electrical stimulation on the skin allows acetylcholine to stimulate the sweat glands. The output is compared with normative values.

One prospective study showed that 67 (72.8%) of 92 patients with painful feet had abnormal results on QSART, ie, low sweat output.²⁸ A retrospective study found that 77 (62%) of 125 patients with clinical features of distal small fiber neuropathy had a length-dependent pattern of QSART abnormalities.²² QSART abnormalities were detected in some patients without autonomic symptoms.

If these tests are not available

Skin biopsy and QSART are objective, reproducible, sensitive, and complementary in diagnosing small fiber neuropathy. One or both can be ordered, depending on whether the patient has somatic symptoms, autonomic symptoms, or both. However, these two tests are not widely available. Only a few laboratories in the country can process skin biopsy specimens to evaluate intraepidermal nerve fiber density. Nevertheless, it is easy to learn the skin punch biopsy procedure, and primary care physicians and neurologists can perform it after appropriate training. (A concern is avoiding damage to the epidermis.) They can then send specimens to one of the cutaneous nerve laboratories (but not to a routine reference laboratory).

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TABLE 1

Drugs for pain control in small fiber neuropathy

A special technique, including unique fixative and cryoprotectant, is used to fix and process the biopsy specimens, because routine techniques for processing dermatologic punch biopsy specimens often result in lower intraepidermal nerve fiber densities. Therefore, it is very important to contact the laboratory regarding fixative and processing before performing a biopsy.

QSART requires specialized equipment and must be performed on site. In addition, the test is very sensitive to drugs that can affect sweating, such as antihistamines and antidepressants, and such drugs must be discontinued 48 hours before the study.

Basic laboratory tests to find the cause

Once the diagnosis of small fiber neuropathy is established, the next important step is to order a battery of laboratory tests to search for an underlying cause. The tests should include the following:

• Complete blood cell count
• Comprehensive metabolic panel
• Lipid panel
• Erythrocyte sedimentation rate
• Thyroid-stimulating hormone level
• Free thyroxine (T4) level
• Antinuclear antibody
• Extractable nuclear antigens
• Angiotensin-converting enzyme (ACE) level
• Serum and urine immunofixation tests
• Vitamin B₁₂ level
• 2-hour oral glucose tolerance test.

Oral glucose tolerance testing is much more sensitive than measuring the hemoglobin A_1c and fasting glucose levels in detecting diabetes and prediabetes. These two conditions were detected by oral glucose tolerance testing in more than 50% of patients with otherwise idiopathic sensory-predominant peripheral neuropathy and normal hemoglobin A_1c and fasting glucose levels.^13,14 Therefore, every patient with small fiber neuropathy without a known history of diabetes or prediabetes should have an oral glucose tolerance test.

Special laboratory tests in special cases

• If there is a history of gastrointestinal symptoms or herpetiform-like rash, then testing for gliadin antibody and tissue transglutaminase antibodies as well as small-bowel biopsy may be pursued to evaluate for celiac sprue.
• Serologic tests for HIV or hepatitis C should be ordered if the patient has risk factors.
• If there is a significant family history, further genetic testing should be considered.
• Lip biopsy or bone marrow biopsy should be considered if clinical suspicion is high for Sjögren disease, seronegative sicca syndrome, or amyloidosis.
• The serum ACE level has a low sensitivity and specificity; therefore, if sarcoid is suspected clinically, additional confirmatory testing, such as computed tomography of the chest, should be ordered despite a normal ACE value.

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HOW DO YOU TREAT SMALL FIBER NEUROPATHY?

Treatment of small fiber neuropathy should target the underlying cause and neuropathic pain. Cause-specific treatment is a key in preventing small fiber neuropathy or slowing its progression.

Glucose control, weight control, and regular exercise

As glucose dysmetabolism is the condition most often associated with small fiber neuropathy (and since individual components of the metabolic syndrome are potential risk factors for it), tight glycemic control and lifestyle modification with diet control, weight control, and regular exercise are of paramount importance in patients with these conditions.

The Diabetic Prevention Program,²⁹ a study in 3,234 people with prediabetes, found that diet and exercise were more effective than metformin (Glucophage) in preventing full-blown diabetes. At an average of 2.8 years of follow-up, the incidence of diabetes was 11.0 cases per 100 patient-years in a group assigned to receive placebo, compared with 7.8 in those assigned to receive metformin (31% lower), and 4.8 (58% lower) in those who were assigned to undergo a lifestyle intervention that included at least 150 minutes of physical activity per week with a weight-loss goal of 7%. Put another way, to prevent one case of diabetes over 3 years, 6.9 patients would have to undergo the lifestyle intervention program, or 13.9 would have to receive metformin. Since impaired glucose tolerance neuropathy may represent the earliest stage of diabetic neuropathy, the neuropathy at this stage may be reversible with lifestyle intervention and improvement of impaired glucose tolerance.

This concept is supported by a 3-year study in 31 people, which showed that lifestyle intervention significantly improved impaired glucose tolerance, reduced the body mass index, and lowered total serum cholesterol levels.³⁰ Changes in these metabolic variables were accompanied by significant improvement of neuropathy as evidenced by significantly increased intraepidermal nerve fiber density, increased foot sweat volume, and decreased neuropathic pain.³⁰

Treatment of other diseases

It has also been reported that treatment of sarcoidosis, autoimmune diseases, and celiac disease improved the symptoms of small fiber neuropathy resulting from these conditions.^8,31 Therefore, it is important to identify the cause and treat it to prevent and slow the progression of small fiber neuropathy, and doing so may improve the disease in some mild cases.

Pain management

Pain management is crucial in the treatment of small fiber neuropathy, as neuropathic pain can be debilitating and can cause depression. Pain management often requires a multidisciplinary team, including a primary care physician, a neurologist, a pain specialist, and a psychiatrist. Medications include antidepressants, anticonvulsants, and topical anesthetics (TABLE 1) as well as narcotic and non-narcotic analgesics and antiarrhythmics. Nonpharmacologic management includes transcutaneous electrical nerve stimulation (TENS), heat, ice, and massage of painful areas (reviewed by Chen et al³²and Galluzzi³³).

First-line choices of pain medications are the anticonvulsants gabapentin (Neurontin) and pregabalin (Lyrica), the tricyclic antidepressants amitriptyline (Elavil) and nortriptyline (Aventyl), a 5% lidocaine patch (Lidoderm), and the semisynthetic opioid analgesic tramadol (Ultram). These can be used alone or in combination.

Gabapentin is relatively well tolerated, but drowsiness can occur, especially with high starting doses. We usually start with 300 mg daily and increase it by 300 mg every week up to 1,200 mg three times a day as tolerated. Most patients need 600 to 900 mg three times a day.

Pregabalin is a newer antiepileptic drug, similar to gabapentin but less sedating. It can be started at 75 mg twice a day and gradually increased to 300 mg twice a day as needed. Weight gain and, rarely, swelling of the lower extremities may limit the use of both of these drugs.

Tricyclic antidepressants, such as amitriptyline, nortriptyline, and desipramine (Norpramin), are proven effective in controlling neuropathic pain, although no response with amitriptyline was seen in patients with painful HIV distal sensory neuropathy.³⁴

Lidocaine patch is preferred if the painful area is small. Patients should be instructed to use the patch to cover the painful area 12 hours on and 12 hours off. If it does not provide relief within 1 week, it should be discontinued.

Tramadol is also helpful in treating neuropathic pain. It can be started at 50 mg two to four times a day as needed.

Nonsteroidal anti-inflammatory drugs and selective serotonin reuptake inhibitorsare typically less effective than the other drugs mentioned.

Opioids should be reserved for refractory cases, given the potential for addiction, but they are sometimes necessary in patients with disabling pain that does not respond to other drugs.

TENS may be of benefit. The patient controls a pocket-size device that sends electrical signals to leads placed on affected areas.

Alternative therapies for small fiber neuropathy, such as meditation, yoga, and acupuncture, have yet to be studied.

It is also important to explain to patients that the typical course of small fiber neuropathy is relatively benign, as many patients worry about developing weakness and eventually not being able to walk. These concerns and fears can aggravate pain and depression, which can make treatment difficult.

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WHAT IS THE PROGNOSIS OF SMALL FIBER NEUROPATHY?

Most patients with small fiber neuropathy experience a slowly progressive course, with symptoms and signs spreading proximally over time.

In one study, only 13% of 124 patients with small fiber neuropathy showed evidence of large-fiber involvement over a 2-year period. ²¹ None went on to develop Charcot joints, foot ulcers, weakness, or sensory ataxia, as is often seen in patients with long-standing or severe large fiber neuropathy. Neuropathic pain worsened in 30% and resolved spontaneously in 11%.²¹

Most patients with small fiber neuropathy require chronic pain management. Again, treatment of the underlying cause is important and can improve the prognosis.

We believe that the overall progression of small fiber neuropathy is slow. A longitudinal study with a follow-up longer than 2 years would be useful to confirm this.

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TAKE-HOME POINTS

As the population continues to age and as more patients develop diabetes and the metabolic syndrome, the prevalence of small fiber neuropathy will rise. Patients who present to their primary care physicians with painful, burning feet require a thorough diagnostic evaluation, which may include referral for specialized neurodiagnostic testing. Aggressive cause-specific treatment, lifestyle modification, and pain control are key elements of a team approach to managing small fiber neuropathy.

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Footnotes

• EDUCATIONAL OBJECTIVE: Readers will recognize the symptoms of small fiber neuropathy, list its causes, and formulate a plan for treating it
• Copyright© 2009 The Cleveland Clinic Foundation