Small vs large fiber neuropathy
Small-fiber versus large-fiber neuropathy
Small-fiber neuropathy damages the thin unmyelinated nerves that carry pain, temperature and sweating, and these fibers are typically affected first; large-fiber neuropathy damages the myelinated nerves that carry vibration, position sense, strength and reflexes. Nerve conduction studies measure the large fibers, while small fibers are measured with sudomotor testing, sensory testing or skin biopsy.
If you have burning feet and a normal nerve conduction study, you were probably tested with the wrong instrument rather than reassured.
What is the difference between small and large fiber neuropathy?
Peripheral nerves come in two broad classes. Large myelinated fibers carry vibration, position sense, muscle power and reflexes. Small unmyelinated fibers carry pain, temperature, sweating and the control of blood vessels in the skin.
| Large myelinated fibers | Small unmyelinated fibers | |
|---|---|---|
| Carry | Vibration, position sense, strength, reflexes | Pain, temperature, sweating, skin blood flow |
| Measured by | Nerve conduction studies, electromyography | Sudomotor testing, quantitative sensory testing, skin biopsy |
| Typically affected | Later | Earlier |
| Symptoms | Numbness, weakness, unsteadiness, lost reflexes | Burning, tingling, temperature loss, sweat changes |
Why are small nerve fibers affected first?
They are long, thin and unmyelinated, which makes them metabolically expensive to maintain and dependent on a microcirculation that is itself vulnerable. Nerve injury associated with impaired glucose tolerance and metabolic syndrome preferentially affects them, and nerve conduction studies are relatively insensitive to that injury — which is why intraepidermal nerve fiber density on skin biopsy has traditionally been used to confirm the diagnosis.
Can you have neuropathy with a normal nerve conduction study?
A patient describes burning feet, worse at night. A nerve conduction study is ordered and comes back normal. The patient is told the nerves are fine. Two things have gone wrong: the instrument used cannot see the fiber population most likely to be affected, and the patient leaves believing nobody believes them.
The American Diabetes Association’s position statement on diabetic neuropathy notes that a substantial proportion of distal symmetric polyneuropathy is painless — so the reverse trap also exists. The people at highest risk of a foot injury are frequently the ones reporting the fewest symptoms.
How is small fiber neuropathy tested without a biopsy?
Electrochemical skin conductance measures sweat gland function, which is driven by small unmyelinated sympathetic cholinergic fibers. It takes about three minutes, uses a very low voltage, and requires nothing more than placing palms and soles on metal plates. A systematic review appraised the method against established reference tests including the quantitative sudomotor axon reflex test, sympathetic skin responses, the thermoregulatory sweat test and skin biopsy.
What does an abnormal small fiber test mean?
An abnormal small-fiber result is a reason to look for a driver — glucose intolerance, B12 deficiency, thyroid disease, alcohol, medication, autoimmune disease — and a reason to protect the feet, particularly if sensation is also reduced. It is not a diagnosis by itself. Peripheral neuropathy symptoms.
Frequently asked questions
What are the symptoms of large fiber neuropathy?
Large fiber neuropathy damages the myelinated nerves that carry vibration, position sense, strength and reflexes. The typical symptoms are numbness, weakness, unsteadiness and lost reflexes. These fibers are usually affected later than the small fibers, and they are the ones a nerve conduction study or electromyography measures.
What are the symptoms of small fiber neuropathy in the feet?
Small fiber neuropathy typically shows up as burning, tingling, loss of temperature sensation and changes in sweating, and burning feet are often worse at night. Some people have few or no symptoms at all, and they can be the ones at highest risk of a foot injury, because the usual warning signs are missing.
What test confirms small fiber neuropathy?
Skin biopsy measuring intraepidermal nerve fiber density has traditionally been used to confirm it. Small fibers can also be measured without a biopsy: sudomotor testing checks sweat gland function in about three minutes with your palms and soles resting on metal plates, and quantitative sensory testing is another option. A standard nerve conduction study cannot see these fibers.
References
- Cortez M, Singleton JR, Smith AG. Glucose intolerance, metabolic syndrome, and neuropathy. Handbook of Clinical Neurology. 2014;126:109–122. doi:10.1016/B978-0-444-53480-4.00009-6
- Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136–154. doi:10.2337/dc16-2042
- Novak P. Electrochemical skin conductance: a systematic review. Clinical Autonomic Research. 2019;29(1):17–29. doi:10.1007/s10286-017-0467-x
Related reading
Medically reviewed by Dr. Gurpreet Singh Padda, MD, MBA, MHP, medical director of Measura. Last reviewed .