What Are the Causes of Small Fiber Neuropathy?

The pathogenesis (the process by which a disease develops) of small fiber neuropathy (SFN) is poorly understood. However, diseases such as diabetes mellitus, impaired glucose tolerance, Sjögren syndrome, sarcoidosis, and various other disorders can lead to small fiber neuropathy. Other causes are associated with sodium channel gene variants and vitamin B12 deficiency. It has been reported that 50% of patients experience SFN due to unknown or “idiopathic” etiology. Certain ailments cause injury to thinly myelinated (Aδ) nerve fibers and small unmyelinated C fibers, leading to neuropathic pain. The main cause of neuropathic pain is the damage that occurs to the small unmyelinated peripheral nerves that mediate autonomic activities and send the skin signals for pain and temperature.  

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Diabetes is the most typical cause of small fiber neuropathy. SFN can occur in people with prediabetes as well. Small fiber neuropathy typically develops as a result of underlying illnesses like diabetes. According to a recent study, small fiber neuropathy can occur in up to 50% of persons with diabetes or prediabetes.

Small fiber neuropathy can also be caused by mutations in sodium channel gene variants According to the National Institutes of Health (NIH) these genes are known as SCN9A and SCN10A. Mutations in the SCN9A and SCN10A genes cause small fiber neuropathy. Physiologically, sodium channels have the ability to generate and transmit electrical signals throughout the body. However, when there is a mutation in the gene, sodium channels do not completely turn off, leading to the enhancement of pain signals. Mutations in SCN9A make up about 30% of cases of SFN, in contrast to the mutations in SCN10A, which make up about 5% of cases. 

The following are examples of medical conditions that can result in small fiber neuropathy:

• HIV
• Fibromyalgia
• Lupus
• Sarcoidosis
• Fabry disease
• Familial amyloidosis
• Primary systemic amyloidosis
• Sjogren’s syndrome
• Celiac disease
• Metabolic and endocrine disorders

Other causes include:

• Illicit or prescription drug use
• Physical injuries
• Exposure to chemotherapy
• Alcohol use disorder
• Vitamin B-12 deficiency

If no underlying condition is found, a patient may be diagnosed with idiopathic small fiber neuropathy. A study was conducted in 2018 on 921 people who suffer from small fiber neuropathy. Of the 921 participants, 53% did not suffer from an underlying ailment. 

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Risk factors

The most prevalent risk factor for SFN is diabetes. Research indicates that approximately 50% of people with diabetes will develop diabetic neuropathy during their lifetime. Small fiber neuropathy is less prevalent than other forms of diabetic neuropathy, but it remains a cause for concern.

In addition, research has shown that patients with idiopathic small fiber neuropathy have a higher prevalence of impaired glucose tolerance compared to the general population. Insensitivity to the effects of glucose is linked to the development of prediabetes. It’s possible that small fiber neuropathy is one of the earliest warning signs of prediabetes.

Age is an additional risk factor. Over the age of 65, small fiber neuropathy is more prevalent than in younger individuals. It may also be more prevalent in men.

REFERENCES:

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2. Levine TD. Small Fiber Neuropathy: Disease Classification Beyond Pain and Burning. J Cent Nerv Syst Dis. 2018 Apr 18;10:1179573518771703. doi: 10.1177/1179573518771703. PMID: 29706768; PMCID: PMC5912271.
3. de Greef BTA, Hoeijmakers JGJ, Gorissen-Brouwers CML, Geerts M, Faber CG, Merkies ISJ. Associated conditions in small fiber neuropathy – a large cohort study and review of the literature. Eur J Neurol. 2018 Feb;25(2):348-355. doi: 10.1111/ene.13508. Epub 2017 Dec 18. PMID: 29112785; PMCID: PMC5814938.
4. Juster-Switlyk K, Smith AG. Updates in diabetic peripheral neuropathy. F1000Res. 2016 Apr 25;5:F1000 Faculty Rev-738. doi: 10.12688/f1000research.7898.1. PMID: 27158461; PMCID: PMC4847561.
5. Brouwer BA, de Greef BT, Hoeijmakers JG, Geerts M, van Kleef M, Merkies IS, Faber CG. Neuropathic Pain due to Small Fiber Neuropathy in Aging: Current Management and Future Prospects. Drugs Aging. 2015 Aug;32(8):611-21. doi: 10.1007/s40266-015-0283-8. PMID: 26239827; PMCID: PMC4548010.