Small fiber neuropathy (SFN) results from damage to the small nerve fibers of the peripheral nervous system. These nerves transmit sensations of pain and temperature and regulate automatic body functions such as heart rate, blood pressure, and sweating. Since SFN affects nerves not tested by routine neurological evaluations, it is often overlooked or misdiagnosed. Diagnosis relies on combining the patient’s clinical history with highly specific objective tests to confirm nerve damage.
Identifying the Clinical Indicators (Symptom Assessment)
Diagnosis begins with a detailed assessment of a patient’s symptoms and medical history. Physicians look for a pattern of discomfort that suggests small nerve involvement, which typically presents as sensory symptoms like burning, pins and needles, or electric shock sensations. This discomfort often starts in the feet and progresses upward toward the legs in a symmetrical, length-dependent distribution, sometimes described as a “stocking-glove” pattern.
Patients may also report heightened sensitivity, where normally non-painful stimuli cause pain, known as allodynia, or an exaggerated response to painful stimuli, which is hyperalgesia. Since these small fibers are responsible for pain and temperature perception, a patient might also have difficulty discerning between hot and cold temperatures. The physician will then perform a targeted physical examination to gather preliminary objective evidence.
The physical exam typically shows preserved muscle strength, normal deep tendon reflexes, and intact vibration and position sense. This is a significant clue, as these functions are carried by larger nerve fibers unaffected in pure SFN. Normal motor and large sensory function alongside characteristic pain and temperature symptoms raises a strong suspicion of SFN. However, symptoms alone are not sufficient for a definitive diagnosis, necessitating further specialized testing.
Specialized Diagnostic Testing
Once clinical suspicion is established, objective testing confirms the structural and functional integrity of the small nerve fibers. The gold standard for confirming SFN is a skin biopsy with quantification of the Intraepidermal Nerve Fiber Density (IENFD). This minimally invasive procedure involves taking a small, typically 3-millimeter, punch biopsy of skin, usually from the distal leg.
The tissue sample is processed and stained using a specific antibody, PGP 9.5, to make the nerve fibers visible under a microscope. Technicians then count the number of nerve fibers crossing the dermal-epidermal junction and compare this count to established normative values adjusted for the patient’s age and sex. A count significantly lower than the reference range indicates a loss of small nerve fibers, which provides definitive structural evidence of SFN.
Another functional test used to assess the sensory capacity of the small fibers is Quantitative Sensory Testing (QST). This non-invasive method precisely measures a patient’s threshold for detecting and tolerating controlled thermal stimuli, specifically warm and cold temperatures. QST determines the point at which the patient first perceives the stimulus (detection threshold) and the point at which the stimulus becomes painful (pain threshold). An abnormal result, such as an inability to detect temperature changes within a normal range, suggests impaired small fiber function.
If a patient reports symptoms related to the autonomic nervous system (e.g., lightheadedness upon standing, abnormal sweating, or digestive issues), specialized autonomic functional tests may be used. These include the Quantitative Sudomotor Axon Reflex Test (QSART), which evaluates sympathetic small fibers controlling sweat glands. Other assessments, such as heart rate variability tests or a tilt table test, help determine the extent of autonomic fiber damage. These objective measures, particularly the skin biopsy, confirm that clinical symptoms are due to physical damage to the small nerve fibers.
Distinguishing SFN from Other Neuropathies
A part of the diagnostic process involves ruling out other conditions that can cause similar symptoms, particularly large fiber neuropathies. This is achieved through electrodiagnostic studies, specifically Nerve Conduction Studies (NCS) and Electromyography (EMG). These tests measure the speed and strength of electrical signals traveling through the large, myelinated nerve fibers and the electrical activity within the muscles.
In cases of pure small fiber neuropathy, the NCS and EMG results will be normal because these tests do not assess the small, unmyelinated fibers. An abnormal finding on these tests, such as reduced conduction velocity or muscle denervation, would indicate a large fiber neuropathy, either exclusively or as part of a mixed neuropathy. The normal electrodiagnostic results in the presence of SFN symptoms and a positive skin biopsy are highly characteristic of an isolated small fiber condition.
Once SFN is confirmed and large fiber involvement is excluded, the final step involves comprehensive laboratory testing to identify any underlying causes. Common blood tests screen for conditions such as diabetes or pre-diabetes, B12 deficiency, thyroid dysfunction, and other systemic disorders known to damage small nerve fibers. Identifying the cause, which often includes impaired glucose tolerance, is necessary to guide effective management and treatment.