Small fiber neuropathy

Ross Hauser, MD

Some patients with connective tissue pain disorders, including fibromyalgia and EDS, have small fiber neuropathy that can be documented through a small skin punch biopsy. Studies have shown that about 50% of patients diagnosed with fibromyalgia have small fiber neuropathy. It is believed that small fiber neuropathy is likely to contribute to some of the pain symptoms of fibromyalgia.

Doctors at the Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Harvard Medical School give an excellent summary in their research paper published in the medical journal Current Pain and Headache Reports (1) of the problems of Small fiber neuropathy.

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In summary, the Harvard researchers write:

Small fiber neuropathy manifests in a variety of different diseases and often results in symptoms of burning pain, shooting pain, allodynia (over sensitization to pain and pain from stimuli that should not cause pain), and hyperesthesia (over the sensation of the skin).
Diagnosis of small fiber neuropathy is determined primarily by the history and physical exam, but functional neurophysiologic testing and skin biopsy evaluation of intraepidermal nerve fiber density can provide diagnostic confirmation. Intraepidermal nerve fiber density testing is a skin biopsy where the visual examination of the number or density of nerve fibers is performed.
Management of small fiber neuropathy depends on the underlying etiology with concurrent treatment of associated neuropathic pain.
- A variety of recent guidelines propose the use of antidepressants, anticonvulsants, opioids, topical therapies, and nonpharmacologic treatments as part of the overall management of neuropathic pain.
- Unfortunately, little data about the treatment of pain specifically in small fiber neuropathy exist because most studies combine mixed neuropathic pain syndromes in the analysis. Additional studies targeting the treatment of pain in small fiber neuropathy are needed to guide decision-making.

The above report was published in June 2011. Six years later, publishing in July 2017, (2) doctors writing in the medical journal Current opinion in pulmonary medicine discuss the challenges of the cause, clinical manifestations, diagnostics, and treatment of small fiber neuropathy. They also suggest the diagnosis is difficult and can be easily missed.

In their paper, the team led by Dutch researchers described small fiber neuropathy as a condition causing significant and disabling symptoms and impact on quality of life. They speculate that patients may benefit from being diagnosed with small fiber neuropathy, even if no underlying cause is identified and no specific treatment is yet available. (In other words, the patient is given a diagnostic tag and categorized).

Clinical diagnostic criteria have been proposed for small fiber neuropathy, but no gold standard exists.

Clinical diagnostic criteria have been proposed for small fiber neuropathy, but no gold standard exists, and each test has its limitations, as pointed out by the Harvard team above. The diagnosis requires a combination of typical symptoms, abnormal neurologic findings, and the absence of large fiber involvement (large fibers control motor function). Clinicians should be aware of overlapping symptoms of small fiber neuropathy and fibromyalgia.

Treatment is often difficult, even when the underlying cause is identified and appropriately treated. Usually, only symptomatic relief of complaints is available. (Unfortunately, doctors admit that they cannot get to or even find the root of the problem to determine a curative treatment, they can only treat the symptoms.)

A paper published in the French language journal La Revue De Médecine Interne (The Journal of Internal Medicine), (3) also cited the difficulty in figuring out what small fiber neuropathy is. They write:

Small fiber neuropathy is still unknown. Characterized by neuropathic pain and can lead to paresthesia (numbness or a feeling of pins and needles in the skin) and autonomic dysfunction which could lead to problems of unregulated heart rate, body temperature, problems with digestion, breathing, and sensation. For some burning mouth syndrome will develop.

Small fiber neuropathy can be caused by diabetes, impaired glucose metabolism, vitamin deficiency, alcohol, auto-immune disease, sarcoidosis, etc.

Treatment is based on multidisciplinary management, combining symptomatic treatment, psychological management, and treatment of an associated etiology.

It should be clear that these three sample studies of many published reports outline that there are symptoms, doctors are not sure what is causing them, they are not sure how to treat the symptoms but can offer little else.

Diagnosing small fiber neuropathy remains a challenge

Even so, a 2021 paper published in the Journal of Neuromuscular Diseases (4) found: “Diagnosing small fiber neuropathy remains a challenge. While small fibers have a wide range of functions, current diagnostic tools only focus on specific areas. Therefore, small fiber neuropathy in areas outside of the diagnostic test range might be missed. Moreover, tools focusing on different areas do not correlate with each other. A reliable test that examines all parts of the small fiber system has yet to be developed. In the absence of a true gold standard, the most reliable diagnosis of small fiber neuropathy in daily clinical practice is made using a combination of tests based on structural and sensory function tests of the small fiber nerves.”

Fibromyalgia and small fiber neuropathy

Fibromyalgia and small fiber neuropathy are two medical conditions that are often tied together and both can have an upper cervical instability etiology. Fibromyalgia has been described as a clinical syndrome without any specific pathological findings to confirm the diagnosis. It is made when a person has widespread musculoskeletal pain, fatigue, poor sleeping patterns, and multiple tender points occurring in precise, localized areas, particularly in the neck, spine, shoulders, and hips. The severity of fibromyalgia symptoms varies from person to person. For some women, pain or other symptoms can be so intense that they interfere with daily activities. For others, symptoms may cause discomfort but are not incapacitating. People with fibromyalgia may experience morning stiffness, fatigue, increased headaches or facial pain, irritable bowel syndrome, depression, anxiety, heightened sensitivity, and cognitive symptoms (trouble with concentration, short-term memory, and handling multiple tasks). About 50 percent of people with fibromyalgia report being sensitive to odors, noises, bright lights, various foods, and changes in weather conditions.

Fibromyalgia ranks among the most enigmatic and prevalent chronic pain conditions, as no underlying cause has been found. It is clear, though, that some patients with Fibromyalgia have small fiber neuropathy that is easily documentable through a small skin punch biopsy. This was demonstrated in a December 2015 study in the journal Current Pain and Headache Reports. (5) The 3-mm skin punch biopsy technique is a safe and minimally invasive procedure that is typically done in the shin area on both lower extremities. The skin biopsy test can reliably demonstrate the loss of epidermal nerve fibers, and when the number of nerve fibers counted on the specimen is less than 7/mm, the person is diagnosed with small fiber neuropathy. Several studies have documented that about 50% of patients diagnosed with fibromyalgia have small fiber neuropathy. This was recently discussed in a July 2021 study from researchers at the University of Genova, Italy, published in the medical journal Joint Bone Spine (6). In this paper the research team noted:

“Recent studies have highlighted that about 50% of fibromyalgia patients have a neuropathy of small- and/or large-fibers which could partially explain the puzzling symptoms of fibromyalgia.” What the researchers here hoped to achieve was an updated estimated prevalence of self-reported (by patients) neuropathic pain and small-fiber neuropathic symptoms indicative of the presence of small-fiber pathology in fibromyalgia patients.
57.3% of patients indicated severe neuropathic pain
Around 46% of patients presented three or more small-fiber neuropathic symptoms that could be suggestive of small fiber pathology, the most frequent being dry eyes/mouth, allodynia (high sensitivity to pain), and dyshidrosis (skin blisters).
There was a strong association based on standard testing of with disability, pain, stiffness level, number of painful sites, and small-fiber neuropathic symptoms.

What these researchers wanted to point out was: “Despite the high prevalence of neuropathic pain and other symptoms attributable to potential small and/or large fibers pathology, neurophysiologic investigations were performed in 43.6% of cases and skin punch biopsy only in 1.9% of patients enrolled, as well as the assumption of anti-neuropathic pain drugs (13.2%).”

In other words, it is assumed that these patients have these problems based on symptoms and medication usage. This can make it difficult for some patients to understand the true problem. It is believed that small fiber neuropathy is likely to contribute to some of the pain symptoms of fibromyalgia.

Classic symptoms of small fiber neuropathy

Classic symptoms of small fiber neuropathy are burning, stabbing, and tingling, in contrast to the typical deep muscular and aching pain seen in fibromyalgia. Other symptoms of small fiber neuropathy include vague disturbances of sensation in the feet though some can have full-blown numbness. It is clear that small fiber neuropathy does not explain all the symptoms of fibromyalgia, but it could explain the hyperalgesia, allodynia, and autonomic dysfunction that are seen in some patients. Some of the autonomic symptoms include dry eyes, dry mouth, postural lightheadedness, dizziness, abnormal sweating, constipation, nocturia, and urinary frequency.

While fibromyalgia has no known cause, small fiber neuropathy is most commonly caused by diabetes and other glucose dysregulation syndromes, vitamin and hormonal deficiencies, medications such as chemotherapy, and various toxins, infections, and genetic disorders. What isn’t appreciated as much as it should be is the concept that small fiber neuropathy could be caused by ligament laxity. Consider one study published in 2016 in the medical journal Neurology (7) where 20 adults with joint hypermobility or Ehlers-Danlos Syndrome were given a skin biopsy and all 20 had a decrease in epidermal nerve fiber density consistent with small fiber neuropathy.

A clear association between fibromyalgia and trauma including whiplash

While small fiber neuropathy is found in a subset of fibromyalgia patients, many times the cause of the small fiber neuropathy is said to be idiopathic or unknown. However some researchers find a clear association between fibromyalgia and trauma including whiplash, and most physicians believe that post-traumatic fibromyalgia definitely exists. A study in The Journal of Rheumatology (8) found that among medical school graduates, 83% of rheumatologists were more likely to agree with the fibromyalgia diagnosis as opposed to only 28.8% of orthopedists. This paper was published in 2000.

However, skepticism remained among orthopedists, Thirteen years later in 2013, rheumatologists publishing in the journal Rheumatology International (9) suggested “The awareness and knowledge among orthopedists regarding fibromyalgia need to be improved. ” In 2021 a paper reported on the continued skepticism that patients had about physician awareness of fibromyalgia leading to a mistrust of medical services. The paper noted (10): “Fibromyalgia is a complex pain condition that affects mostly women. Given the disease’s lack of understanding, patients report poor adherence to medication and mistrust of medical services.”

A December 2021 study – Fibromyalgia and small fiber neuropathy are two diseases leading to chronic widespread pain, and it is difficult to differentiate them in order to provide appropriate care.

In Paris, Dr. Florian Bailly published this update in December 2021 in the journal Joint Bone Spine (11)

“Fibromyalgia and small fiber neuropathy are two diseases leading to chronic widespread pain, and it is difficult to differentiate them in order to provide appropriate care. . . In fibromyalgia, pain is increased by dysregulation of central pain processing while small fiber neuropathy pain is related to loss or dysfunction of intraepidermal small nerve fibers.

Higher pain intensity; stabbing pain and paraesthesia; allodynia; dry eyes/mouth; the changed pattern or sweating on the body; skin color alterations/modifications; reduced hair/nail growth on lower extremities; warm or cold hypoesthesia could be more common in small fiber neuropathy whereas headache or temporomandibular disorder point toward fibromyalgia. Length-dependent distribution of pain is common in small fiber neuropathy but can also affect the whole body.

Anxiety or depression are common in these two diseases, but post-traumatic stress disorder and physical or sexual abuse in childhood or adulthood suggest fibromyalgia.

Inflammatory disease or musculoskeletal disease is frequently reported with fibromyalgia whereas metabolic disorders (especially diabetes mellitus), neurotoxic exposure, Sjogren’s syndrome, sarcoidosis, HIV are the main diseases associated with small fiber neuropathy. Skin biopsy, quantitative sensory testing, laser evoked potentials, confocal corneal microscopy or electrochemical skin conductance can help to discriminate between fibromyalgia and small fiber neuropathy.”

Small fiber neuropathy can also be caused by cervical ligament laxity

When we have a difficult to determine or are treating a problem such as small fiber neuropathy, we look for a solution. A possible solution may be cervical ligament laxity or simply, neck instability. If the cervical vertebrae are hypermobile they can press down and disrupt sensitive blood and nerve pathways. This problem is typically seen in patients exhibiting the symptoms described above in addition to a few other symptoms we see including dry eyes, dry mouth, postural lightheadedness, and dizziness. These are typical symptoms of a patient suffering from cervical neck instability. These are also symptoms of autonomic dysfunction a common problem in cervical instability.

Cervical instability can be responsible for many head, neck, and facial pains, it can also be responsible for many systemic conditions such as fibromyalgia, movement disorders, small fiber neuropathy, and possibly be associated with multiple sclerosis and Parkinson’s disease.

Prolotherapy treatment for cervical ligament laxity

The ligaments that hold the cervical vertebrae in alignment can be damaged via a sudden trauma, such as whiplash or concussion, or through the slow stretching of ligaments, known as creep. This can be attributed to extended hours of poor posture in front of a computer or smartphone, or other position that slowly stretches the neck ligaments.

Cervical instability causes the cervical facet joints (the joints that allow the spine to bend) to become hypermobile and unstable. When this condition occurs pinched nerves, headaches, vertigo, drop attacks, and small fiber neuropathy can develop.

Prolotherapy has been shown to be a safe and effective treatment for chronic neck pain and instability because it strengthens the ligaments that are weak and causing the pain. The injections restart the body’s natural healing cascade to the weakened structures that otherwise have a poor blood supply and have ceased being able to repair on their own. Each treatment builds upon itself, and as the tissue strengthens the patient notices fewer symptoms and increased stability.

Prolotherapy to the Cervical Facet Joints

Prolotherapy can be an effective treatment when cervical instability is suspected of causing a myriad of neurological-like problems including small fiver neuropathy. By stabilizing the vertebral motion, Prolotherapy resolves the impingement of the cervical sympathetic ganglion and the resultant symptoms.

Questions about Cervical Neck Pain and Instability?
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This article was updated January 11, 2022