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evidence of autonomic dysfunction. These patients do not meet the current definition of CRPS and have been termed ‘‘post-traumatic neuralgia’’ [17]; their autonomic functions have not been well studied.

Skin biopsy

For the past decade the histological study of unmyelinated nerve fibers in the skin has grown in importance in the diagnosis of peripheral nerve disorders, both generalized and focal, including those associated with neuropathic pain. When a skin punch biopsy is fixed with certain anti- bodies, most frequently protein gene product (PGP) 9.5, epidermal fibers can be stained and visualized [18,19]. Epidermal nerve fiber density and morphology, eg, tortuosity, complex ramifications, clustering, and axon swellings, can be quantified [18,19] and compared with control values [20]. A reduced density of epidermal nerve fibers is seen in small-fiber neuropathies [21], diabetic neuropathy, and impaired glucose tolerance neuropathy [22], each of which is associated with neuropathic pain. In a subgroup analysis of one such study, the skin biopsy findings were found to be a more sensitive measure than QSART or QST in diagnosing neuropathy in patients with burning feet and normal NCVs [23]. Con- versely, disorders with severe loss of pain sensation such as congenital in- sensitivity to pain with anhidrosis (hereditary sensory and autonomic neuropathy IV; HSAN IV) and familial dysautonomia with sensory loss (Riley-Day; HSAN III) also have severe loss of epidermal fibers, as does a predominantly large fiber neuropathy, Friedreich’s ataxia, in which pain is unusual [18,19]. Thus, the loss of epidermal small fibers is not specific for the presence of neuropathic pain.

Additional tests that may be of value in patients with neuropathic pain, particularly in focal pain syndromes such as CRPS, are bone scintigraphy, bone densitometry, and nerve or sympathetic ganglion blockade. Serum im- munoelectrophoresis can be helpful in painful polyneuropathies associated with monoclonal gammopathies and acquired amyloid polyneuropathy. Specific serum antibody tests are valuable in painful neuropathies associated with neoplasia, celiac disease, and human immunodeficiency virus [24].


Determining the causes of neuropathic pain is more than an epistemolog- ical exercise. At its essence, it is a quest to delineate mechanisms of dysfunc- tion through which treatment strategies can be created that are effective in reducing, ameliorating, or eliminating symptomatology. To date, predictors of which patients will develop neuropathic pain or who will respond to spe- cific therapies are lacking, and present therapies have been developed mainly through trial and error [25]. Our current inability to make therapeutically

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