Diagnosis and Treatment of Pain in Small Fiber Neuropathy
Quantitative Sudomotor Axon Reflex Testing
There are a variety of methods to quantify sudomotor function. The most frequently utilized and well-known test is quantitative sudomotor axon reflex testing (QSART), a measure of postganglionic sympathetic cholinergic function. Local sweating is produced through iontophoresis of acetylcholine; this method uses a mild electrical current to draw acetylcholine (a charged substance) into the skin, causing activation of local sweat glands. The stimulation also triggers an axon reflex resulting in neighboring sweat glands, not stimulated by acetylcholine, to produce sweat. The axon reflex–mediated sweat output is detected by passing dry gas over the nonstimulated region and quantifying the change in humidity of the gas. A study of patients with small fiber neuropathy revealed that QSART was abnormal in 74% of patients, and that sudomotor dysfunction may be the earliest manifestation of a distal small fiber neuropathy . Another study reported QSART to be abnormal in 73% of patients with painful feet from a small fiber neuropathy. A variety of other tests, including sweat imprint tests, thermoregulatory sweat testing, and quantitative direct and indirect sudomotor testing, also detect abnormalities in patients with a small fiber neuropathy. To date, no prospective controlled study has evaluated the ability of these tests to diagnose a small fiber neuropathy.
Skin biopsy has become a widely accepted technique to investigate the structural integrity of small nerve fibers . A standard 3-mm dermatologic punch biopsy can be taken from any location on the body, but typically is performed on sites of interest in evaluation of a distal small fiber neuropathy (the lateral distal leg, the lateral distal thigh, and the lateral proximal thigh to look for a length-dependent pattern). For clinical investigation, bright field immunohistochemistry is used with antibodies against protein gene product 9.5, a marker for all peripheral nerve fibers. The number of fibers crossing the dermal/epidermal junction is quantified through standardized means, and results are expressed as the number of intraepidermal nerve fibers per millimeter. Recently revised consensus statements have highlighted the utility of skin biopsy in the evaluation of small fiber neuropathy [40•]. The sensitivity (78%–92%) and specificity (65%–90%) of skin biopsy for diagnosing a small fiber neuropathy is fairly high across all studies. In early or mild cases of small fiber neuropathy, morphologic abnormalities of nerve fibers may aid in diagnosis if nerve fiber density is not reduced . Unfortunately, there are no data on the utility of skin biopsy to diagnose the etiology of the small fiber neuropathy.
Electromyography and Nerve-conduction Studies
Electromyography and nerve-conduction studies are well-established neurophysiologic techniques used to assess the integrity of larger myelinated sensory and motor fibers. These studies often are normal in pure small fiber neuropathies. If there is question of possible larger fiber involvement causing symptoms or occurring concomitantly with a small fiber neuropathy, these studies can clarify if larger sensory and/or motor nerve fibers are involved.
Treatment of Pain in Small Fiber Neuropathy
Treatment of any underlying causative etiology of a small fiber neuropathy is likely to be the most effective treatment of pain, when possible. Many cases of small fiber neuropathy will remain idiopathic, or will still require treatment of pain. There is very limited evidence for specific medications in the treatment of pain from small fiber neuropathies. Most clinical studies have examined drugs in the treatment of many neuropathic pain syndromes (such as postherpetic neuralgia and painful diabetic neuropathy). In some trials, the spectrum of neuropathic pain can be broad and include diagnoses such as central neuropathic pain, radiculopathy, or carpal tunnel syndrome. These disorders may respond to treatment differently than pain from small fiber neuropathy. This is a challenge when developing treatment recommendations for small nerve fiber pain because comparative effectiveness across different pain states is not known.
This issue is further complicated by evidence suggesting that some diseases causing neuropathic pain respond differently to the same medications. Neither HIV nor chemotherapy-related neuropathic pain respond to treatments that are effective for other forms of neuropathic pain. It is unclear if these discrepancies are methodological or due to differences in the underlying disease state. In addition, head-to-head trials of medications and long-term outcome data for small fiber neuropathies are lacking. When possible, disease-specific treatment guidelines should be selected for management of pain in small fiber neuropathy (eg, diabetes, HIV, or chemotherapy).