Small Fiber Neuropathy is a disabling form of peripheral neuropathy that is increasing in prevalence among young non-diabetic patients. The peripheral nerves, which includes all nerves outside of the central nervous system (the brain and spinal cord), support motor, autonomic, and sensory functions for the limbs and organs of the body. Peripheral neuropathies common among aging and diabetic patients, arise most frequently as a result of damage from uncontrolled blood sugars and vitamin deficiencies. Research has been able to demonstrate that neuropathy symptoms  are associated with loss of the smallest nerves present at the surface of the skin and organs. Most peripheral neuropathies are of an unknown origin though most research is pointing toward chronic inflammation as a root cause. Diabetes is no longer the leading cause of peripheral neuropathies. 

Nerve Types

The symptoms of peripheral and small fiber neuropathies are very diverse. To understand why that is, it may help to appreciate the types of nerves that are affected. The peripheral nerves are divided into 3 major functions or types. 

Motor Nerves

• The motor nerves send impulses from the brain and spinal cord to all of the muscles in the body.
• Motor nerve loss or damage results in muscle weakness, muscle cramps and spasms, and difficulty with ambulation.

Sensory Nerves

• The sensory nerves send messages from the periphery back to the spinal cord and brain. Sensory nerves are located superficially in the skin and deeply throughout the body and evaluate pressure, temperature, and motion. 
• Sensory nerve loss or damage results in tingling, numbness, pain, and extreme sensitivity to touch.

Autonomic Nerves

• The autonomic nerves control the involuntary functions of the body such as heart rate, blood pressure, digestion, and sweating. 
• Autonomic nerve loss or damage results in tachycardia, bradycardia, hyperhidrosis, anhidrosis, dysphagia, nausea, vomiting, diarrhea, constipation, difficulty with urination, abnormal pupil size, and sexual dysfunction. 

Peripheral neuropathies result from loss of both sensory and autonomic nerves. The nerves most affected are the smallest and most vulnerable nerves located distally in the skin. Amongst the sensory nerve fibers are included the lightly myelinated A-delta nerve fibers, and the unmyelinated Group C nerve fibers. And among the autonomic nerve fibers are the unmyelinated Group C nerve fibers.

Unmyelinated Group C Nerve Fibers

• The unmyelinated Group C nerve fibers are the leading peripheral sensory nerve fiber type. These include postganglionic fibers in the Autonomic Nervous System, and nerve fibers at the dorsal roots. 
• The purpose of these polymodal (multiple stimuli) nerves are to react to changes, such as thermal (hot or cold), mechanical(pressure and touch), or chemical in nature(hypoxia, osmolarity, hypoglycemia, toxicity).
• It is the loss of these unmyelinated Group C fibers that causes the burning, warmth, itching, and cramping pain.

Aδ-(Delta) Nerve Fibers 

• The other nerve fiber leading to various forms of peripheral neuropathy includes the myelinated A-Delta fibers. 
• Because they are myelinated the conduction velocity is faster than the C fibers. 
• These A-delta axons respond to sharp and stinging pain.

Small Fiber Neuropathy

Small fiber neuropathy is a type of peripheral neuropathy resulting from damage or loss of the lightly myelinated A-delta and the unmyelinated Group C nerve fibers.

The final result of nerve loss includes both sensory and autonomic fibers and thus causes both sensory and autonomic symptoms. Review both sensory and autonomic symptom lists below. If you have symptoms on both sides of the chart you may have small fiber neuropathy.

AUTONOMIC SYMPTOMS

• Hyperhidrosis and Anhidrosis
• Palpitations
• Dizziness
• Vertigo
• Vestibular Neuritis
• Headaches
• “Brain Fog”
• Tachycardia
• Hypoadrenergic POTS
• Hyperadrenergic POTS
• Sleep disturbance
• Paresthesias

SENSORY SYMPTOMS

• Numb sensation as if wearing an invisible “glove” or “sock”
• Prickling or tingling in the toes, feet, face, hands, or fingers
• Sharp, shooting, jabbing, burning, throbbing, or electric-like pain
• Extreme sensitivity to touch
• Loss of balance and coordination
• Muscle weakness in limbs
• Muscle cramping/twitching (fasciculations)
• Pain disruptive to sleep
• Usually bilateral

The gold standard for diagnosing small fiber neuropathy is an epidermal nerve fiber density (ENFD) biopsy to evaluate the number of nerves within a specified range along the lateral edge of either leg. The absence or loss of fibers is diagnostic for small fiber neuropathy. Due to the loss of the autonomic nerve fibers other tests such as the tilt table test and sweat test (QSART) may also confirm or raise suspicion of small fiber loss. Generally the large nerve fibers are normal when evaluated with EMG testing and CNS exams.

Causes of Small Fiber Neuropathy 

The diagnosis of small fiber neuropathy is all too often neglected in primary medicine. Once a diagnosis is made it is even more difficult to discover the root cause of small fiber nerve loss. Fifty percent of peripheral neuropathy cases are considered idiopathic, meaning no known underlying or definable cause. An approximate 54 types are inherited, and 8 causes arise from known mitochondrial disorders. Diabetes and metabolic syndrome have been clearly established and the assumed leading causes, but they represent only a small fraction of the root aggravators. 

One of the easier causes to evaluate includes vitamin B12 deficiency, easily discovered with lab testing. In the literature we also find peripheral neuropathies arising from infections such as Lyme disease, viruses, and more recently even COVID. Drug toxicities such as chemotherapeutics and treatments for Hepatitis C, such as Harvoni, have also induced small fiber neuropathies.

Another common form that can be evaluated through specialty nerve labs is autoimmune neuropathy. Two rare antibodies, immunoglobulin G (IgG) vs fibroblast growth factor receptor-3 (FGFR-3), and immunoglobulin M (IgM) vs trisulfated heparan disaccharide (TS-HDS) are found in 50% of confirmed small fiber neuropathy cases by biopsy, indicating some type of immune disorder. In some cases, labs and symptoms may also suggest the presence of Lupus or Sjogren’s. All of this gives strong evidence that inflammation is present and an underlying instigator and promoter of small fiber neuropathy.

Inflammation

As we have evaluated and treated patients diagnosed with various types of small fiber neuropathies, we have observed that each patient’s root causes are uniquely different. The symptoms are often similar, but when it comes to laboratory diagnosis, labs may not be enough. One type of lab stands out for sure in regards to being common amongst all patients we have evaluated, and that is HLA typing for biotoxin illness. This is also known as mold toxicity or chronic inflammatory response syndrome (CIRS). Patients who present with these labs have difficulty eliminating biotoxins such as mold toxins, and produce significant inflammation when exposed to these toxins. Our results show that most, if not all, patients are multi-susceptible to mold and many other known, and some yet to be discovered, living toxins. This patient group also often presents with antibodies to IgG vs FGFR3 and IgM vs TS-HDS indicating some form of inflammation or autoimmunity. The epidermal skin biopsy is diagnostic, but the labs for antibodies and mold reactivity are telling of the root immune disturbance that leads to the loss of the small fiber nerves. 

Current allopathic treatment includes treating any underlying known or newly diagnosed causes such as diabetes, metabolic syndrome, autoimmunity, hyperhomocysteinemia etc; The goal for treatment is to manage the pain with a goal of having >50% reduction overall. The most commonly prescribed medications for nerve pain include the Tricyclic Antidepressants (lower doses), Serotonin Norepinephrine Reuptake Inhibitors (higher doses), Gabapentin, and Lyrica. A small percentage of patients may favorably respond to topical lidocaine or capsaicin patches. Insurance may approve IVIg therapy for which 10% of patients respond with confirming labs for IgM vs TS-HDS or IgG vs FGFR3. 

Sadly for a majority of patients, the realization of the root cause or trigger, or the resolution of pain with medications fails much too often. Small fiber neuropathies studies are growing slowly over time, but still lack any effective consensus on why it presents and how to reduce or eliminate the symptoms. Medications help some but are ripe with undesirable side effects and risks. Too many patients fail prescription trials and are denied IVIg therapy or can’t afford the therapy.

Chronic Inflammatory Response Syndrome

Because of the consistent findings associated with CIRS between various patients, we have found success by treating SFN as if it is a symptom of biotoxin illness. We recommend our patients start a Candida Diet, Keto Diet, Carnivore Diet, Intermittent fasting, or mix of all the diets. These diets tend to call for elimination of grains, refined carbohydrates, and refined sugars, for which most individuals notice some improvement in energy, and less neuropathic pain when they strictly avoid them. This is proof that our food is hurting more and more of us.  We also recommend and find great benefit with a trial of Diflucan once daily for 30-90 days. Some patients report seeing a decline in nerve pain within just a few days of starting the mold and yeast cleanser fluconazole. As it appears mold may be a trigger, a personal mycotox panel or home testing can provide confirmation of a current or recent mold exposure. We often add natural  binders during this time to reduce circulating burden, thereby reducing strain on detox organs such as the liver and intestines.

Methyl B12, Folic acid, and Vitamin B6 Supplementation

As far back as 2010 published studies have shown the benefit of specific B vitamins in reducing neuropathy symptoms. In one study, eleven Type 2 symptomatic diabetic peripheral neuropathy patients confirmed by calf biopsy, were placed on twice daily oral-combination high dose B12, B6, and folic acid.(1) At the end of 6 months of their treatment, follow up biopsy showed 73% of patients had an increase in calf epidermal nerve fiber density (ENFD) when compared to baseline. Just as astounding, 82% of patients experienced both reduced frequency and intensity of paresthesias and/or dysesthesias. 

L-Arginine

One described effect of the high dose B vitamin regimen is an increase in Nitric Oxide. L-Arginine, an amino acid, is also well known to increase Nitric Oxide. In studies with L-Arginine, supplementation prevented the development of mechanical hyperalgesia(pain with movement and pressure) and reduced tactile and thermal allodynia (less pain with touch and change in temperature).(2) In another finding, L- Arginine lead to an increase in agmatine sulfate production which has been studied also to have benefit in small fiber neuropathy.

Agmatine Sulfate

Agmatine Sulfate is a metabolite of L-Arginine. L-Arginine converts to citrulline which then converts to Agmatine Sulfate. In studies of Agmatine Sulfate on confirmed small fiber neuropathy patients, pain symptoms reduced 46.4% overall compared to baseline.(3) Agmatine is known to modulate key neurotransmitter receptors like nicotine, N-methyl-D-aspartate (NMDA), imidazoline and α2-adrenoceptors. In addition Agmatine is know to also modulate ionic channels (including potassium and calcium channels), cell signaling pathways (by inhibiting ADP-ribosylation of proteins), nitric oxide (NO) synthesis, and polyamine metabolism and extracellular protein modifications (by inhibiting matrix metalloproteinases and advanced glycation end (AGE)-product formation). The net result is less inflammation,  new growth of small fiber nerves, and reduction in neuropathy symptoms.

Phosphodiesterase-5 (PDE-5) Inhibitors(TADALAFIL)

In the early studies of PDE-5 Inhibitors, two side effects were observed. The first is well known. It improved erectile function. The other less known observed effect with regular use was a reduction in neuropathy symptoms. PDE-5 Inhibitors are known to increase intraepidermal nerve fiber density, significantly improve motor and sensory conduction velocities in the sciatic nerve, improve peripheral thermal sensitivity, increase local blood flow in the sciatic nerve, and reverse diabetes-induced axon (nerve) damage.(4)

Hyperbaric Oxygen Therapy (HBOT)

Though we lack a perfect understanding of the exact local features that lead to loss of small fiber nerves, we know that inflammation, swelling, and poor oxygen transport are local and systemic factors. Hyperbaric Oxygen Therapy serves to increase oxygen, reduces inflammation, and resolves local edema. HBOT therapy is known to raise the production of oxygen and nitrogen reactive species which serve as pain signaling molecules as well as inducing nitric oxide-dependent release of opioid peptides. In animal models HBOT has been shown to have antinociceptive and analgesic effects, and have positive benefits with inflammatory, neuropathic, and chronic pain syndromes. Human study participants report reduced pain scores and symptoms along with an improved quality of life.(5)

Acupuncture

Acupuncture is an ancient eastern medicine model for treatment showing great promise against the rise of modern disease. Treatment of neuropathic pain with acupuncture following the structural and dermatome patterns associated with the neuropathy, have been reported by patients to be extremely beneficial and if some cases were known to completely abolish the symptoms.(6)

Treatment Goals and Protocols

The overall success of managing and resolving the chronic disability of small fiber neuropathy is still a great struggle. Modern medicines’ best attempts to manage the pain symptoms still leave too many struggling with side effects and ongoing disability. Our approach is not to replace the current medicines and treatments, but to provide natural, low risk, effective, and synergistic therapies to reduce pain greater than 50 percent and restore mental and physical function greater than 75 percent. Please contact our office to learn how we can help you find the right therapies for your small fiber neuropathy.

References

1. Hanna Shevalye et al. Metanx alleviates multiple manifestations of peripheral neuropathy and increases intraepidermal nerve fiber density in Zucker diabetic fatty rats. Diabetes. 2012 Aug;61(8):2126-33.
2. Lusliany J Rondón et al. L-Arginine supplementation prevents allodynia and hyperalgesia in painful diabetic neuropathic rats by normalizing plasma nitric oxide concentration and increasing plasma agmatine concentration. Eur J Nutr. . 2018 Oct;57(7):2353-2363.
3. L Rosenberg et al. Evidence for Dietary Agmatine Sulfate Effectiveness in Neuropathies Associated with Painful Small Fiber Neuropathy. A Pilot Open-Label Consecutive Case Series Study. Nutrients. . 2020 Feb 23;12(2):576.
4. Lei Wang, Michael Chopp, Zheng Gang Zhang. PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice. Neural Regen Res. 2017 Feb;12(2):218-219.
5. Simone Schiavo et al. Mechanistic Rationale and Clinical Efficacy of Hyperbaric Oxygen Therapy in Chronic Neuropathic Pain: An Evidence-Based Narrative Review. Pain Res Manag. 2021 Apr 22;2021:8817504
6. Dimitrova A, Murchison C, Oken B. Acupuncture for the Treatment of Peripheral Neuropathy: A Systematic Review and Meta-Analysis. J Altern Complement Med. 2017 Mar;23(3):164-179.