Small-fiber versus large-fiber neuropathy
If you have burning feet and a normal nerve conduction study, you were probably tested with the wrong instrument rather than reassured.
Two kinds of nerve, failing in a predictable order
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 the small ones go 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.
The clinical trap
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 small fibers are measured 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 to do with the answer
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.
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 .