Diagnosis and Treatment of Pain in Small Fiber Neuropathy
Causes of Small Fiber Neuropathy
Diabetes and prediabetes (including both impaired glucose tolerance and impaired fasting glucose) frequently are associated with pure small fiber neuropathy; however, concomitant large fiber involvement is seen more often . Nearly half of all subjects with idiopathic small fiber neuropathy have abnormal 2-hour glucose tolerance tests or abnormal fasting glucose levels [6, 7]. The abnormal glucose testing may be seen despite normal glycosylated hemoglobin. Several studies have also established a link between pain in small fiber neuropathy and abnormal glucose metabolism [8, 9]. There also is a large overlap between prediabetes and metabolic syndrome. The metabolic syndrome is comprised of hyperlipidemia, hypertension, and obesity in addition to abnormal glucose metabolism with insulin resistance. Each of these separate factors appears to convey an increased risk of developing a small fiber neuropathy . Individuals with diabetes and metabolic syndrome appear to have twice the risk of developing a small fiber neuropathy compared to those with diabetes alone . Recent reports now are suggesting that the single largest contributing factor to neuropathy development is hyperlipidemia [12•, 13••]. Some patients with diabetes also may experience an acute painful small fiber neuropathy associated with rapid glycemic control, also referred to as insulin neuritis or treatment-induced neuropathy [14•].
Other conditions associated with acquired small fiber neuropathy include HIV [15, 16], inflammatory neuropathies (such as Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy) [17, 18], celiac disease [19, 20], hepatitis C , restless legs syndrome , complex regional pain syndrome type I , paraproteinemia , neurotoxic drug use [25–27], systemic lupus erythematosus , Sjogren’s syndrome , abnormal thyroid function [2•], amyloidosis, and paraneoplastic syndromes [30, 31]. This list is not comprehensive and there are many case reports describing small fiber neuropathies in other diseases. In addition, there are inherited conditions which cause small fiber neuropathies, such as Fabry’s disease and the hereditary sensory and autonomic neuropathies.
Diagnosis of Small Fiber Neuropathy
The history and physical examination findings still are considered the gold standard against which all tests are compared when making a diagnosis of a small fiber neuropathy. A detailed review of the symptoms, rate of progression, and complaints suggestive of autonomic fiber involvement is necessary. Generally, if a patient presents with a compelling history for a small fiber neuropathy and an appropriate clinical exam, further testing to confirm the diagnosis may be unnecessary. This scenario is particularly likely in the context of an associated disease, such as diabetes. However, in many cases, the diagnosis may be less clear and ancillary testing may provide additional guidance. Patients should always be screened for other treatable causes of small fiber neuropathy. Recently, scoring examinations have been developed, and may aid in diagnosis of small fiber neuropathies [32•]. In addition, the specific types of pain experienced by patients with small fiber neuropathy may need to be characterized. The Neuropathic Pain Symptom Inventory differentiates various aspects of neuropathic pain, and may aid in selection of treatments as clinical trials begin to select specific aspect of neuropathic pain as targets .
Quantitative Sensory Testing
Quantitative sensory testing (QST) is an extension of the physical examination that can provide a threshold for detection of thermal sensation, thermal pain, and vibratory sensation. QST has been used in a number of longitudinal studies and clinical trials of neuropathy and is widely available . There are some well-recognized limitations to QST; abnormalities in either the central or peripheral nervous system can result in the same deficit. In addition, QST requires conscious integration from the patient, and in conditions of cognitive impairment (due to disease or medication), the reliability of the test results are in question. Finally, QST is unable to distinguish between feigned and true loss of sensation .
There are few trials utilizing QST in the study of isolated small fiber neuropathies, most trials include patients with large fiber involvement as well [34, 36]. Heat or heat-pain detection thresholds are considered the most useful and specific for evaluation of a small fiber neuropathy. Cold and cold-pain detection are transmitted through lightly myelinated Aδ fibers, while vibration detection thresholds are detected through large myelinated Aα and Aβ sensory fibers. Recent reports of contact heat evoked potentials (CHEPs), a device that provides rapid cycles of heat resulting in evoked potentials measured by electroencephalogram, show a linear correlation between CHEP amplitude and cutaneous nociceptive nerve fiber density . Further study is required to determine the utility of new variations of QST on the diagnosis of a small fiber neuropathy.