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Underlying Causes of Small Fiber Neuropathies

In the past decade, SFN has become linked increasingly with an expanding number of medical conditions; what clinicians need to know about advances, pathophysiology, diagnosis, and treatments. A PAINWeek 2018 highlight with Charles Argoff, MD.


Peripheral neuropathy, experienced by about 40 million people in the United States, actually may include mixed neuropathies, with both large fiber and small fiber involvement, according to Charles E. Argoff, MD, professor of neurology at Albany Medical College and director of the Comprehensive Pain Center at Albany Medical Center in New York.

Over the past few years, the specific involvement of these small myelinated or unmyelinated fibers is being increasingly recognized, Dr. Argoff told those attending his 2018 PAINWeek talk, "Big News in Small Fiber Neuropathies."1

"We now think [of the possibility of] small fiber neuropathy (SFN) in almost anyone who comes to us with widespread pain," he said. "Years ago, we didn't think that way, even two or three years ago." Among those affected, he added, are people told by their physician they do not understand why they are experiencing pain, and those suspected of drug seeking.

Defining SFN

Neuropathic pain arises as a direct consequence of disease affecting the somatosensory system, Dr. Argoff reminded attendees—that is, pain originating from nerves, spinal cord or brain, not bones, muscles or organs. SFNs result from damage to the peripheral nerves, affecting small myelinated A-Delta and unmyelinated C fiber. Large fibers are heavily myelinated and involved in muscle control, he explained, as well as touch, vibration and position sense.

What is not well understood, he added, is the pathogenesis of injury to small fibers. Genetic mutations are thought to play a role. SFN may progress and involve large fibers, as well.1

Sodium channel mutations may help explain the condition, Dr. Argoff said, and experts at the National Institutes of Health (NIH) seem to agree. According to the NIH Genetics Home Reference, the mutations involve SCN9A and SCN10A genes. These lead to sodium channels that do not close completely (SCN9A) or open more easily (SCN10), and these changes may lead to enhanced transmission of pain signals, among other consequences.2

Hopefully, this emerging information will lead to new treatments, Dr. Argoff said. For now, however, there is an increasing focus on how to diagnose the condition and on the growing list of conditions linked with SFN, he noted.

Diagnosing SFN

"Small fiber patients often talk about burning pain, a pinprick [feeling], a stabbing pain," Dr. Argoff told the audience.  Muscle cramps may be a complaint as well.3 Symptoms vary in severity, with patients often describing a gradual onset of vague sensory disturbances, such as a feeling of sand in the shoe or socks with pebbles. Restless leg syndrome is often linked with SFN as well. The condition affects both adults and children.

On a physical exam, everything may appear normal or nearly so, Dr. Argoff explained. However, in some patients, there can be decreased pinprick reaction, hyperalgesia, diminished thermal sensation or dry skin.3

Skin biopsy, using a 3-mm skin punch from any location on the body, has become a widely accepted way to diagnose SFN. "The procedure takes 15 to 20 minutes, a half hour if you are new to it," Dr. Argoff said, who said his practice typically takes “two or three samples depending on the lab's requirement or request. [The site] heals in a week or two" with results typically returned in about a week and expressed as the number of intraepidermal fibers per millimeter. When analyzing results for SFN, sensitivity (78 to 92%) and specificity (65 to 90%) are usually fairly high.3

Related Conditions

The incidence of small fiber neuropathy is not known, but epidemiologic data from The Netherlands suggests a minimum of 12 per 100,000.3 Over the past few years, the list of disorders linked with SFN has grown greatly, Dr. Argoff said. Among them:

  • Diabetes
  • Impaired glucose tolerance
  • Fibromyalgia
  • Metabolic syndrome
  • Celiac Disease
  • Rheumatoid arthritis
  • Hepatitis C
  • Restless leg syndrome
  • Parkinson disease
  • Fragile X
  • Chronic renal disease3
  • Plus: use of chemotherapy medications, alcohol, and statins.

SFN Treatment

First, look for an underling cause, Dr. Argoff said. If the underlying cause—diabetes, restless leg syndrome, Parkinson’s, for example, can be treated, that may lessen the SFN symptoms.Few studies and no guidelines address the pharmacologic treatment of SFN-associated pain, he pointed out, but some research has found efficacy with gabapentin and tramadol.3

An emerging treatment may be intravenous immunoglobulin, or IVIG. Among several studies cited by Dr. Argoff, patients with sarcoidosis receiving an initial dose of 2g/kg and subsequent doses of 1g/kg experienced substantial resolution of pain and autonomic symptoms.4

As research continues, and the mechanism or mechanisms of SFN become more completely understood, improved treatment may occur. In the meantime, the best advice from Dr. Argoff is to "Listen to your patient. Don't blow them off. This is not an uncommon problem. We are still learning about it."

With colleagues, Dr. Argoff has written a book, "Small Nerves, Big Problems." It was published in 2017 by Hilton Press and is available on the publisher's site.

Dr. Argoff disclosed that he is a consultant for Pfizer, Lilly, Regneron, Teva, US World Meds, Collegium, Kaleo, Quest, Vertex and Novartis. He is a stock shareholder with Depomed and Pfizer.



1Arnoff C. “Big News in Small Fiber Neuropathies,” presented at PAINWeek 2018, September 4-8, in Las Vegas, Nevada

2 US National Library of Medicine: Genetics Home Reference—Small fiber neuropathy. NIH. August 28, 2018. Available at  https://ghr.nlm.nih.gov/condition/small-fiber-neuropathy. Accessed September 12, 2018.

3Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small Fiber Neuropathy. Curr Pain Headache Rep. 2011:15(3);193-200.

4Parambil JG, et al. Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. Respir Med. 2011:105(1):101-105.

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