Background: Revision of the guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy, published in 2005, has become appropriate owing to publication of more relevant articles. Most of the new studies focused on small fiber neuropathy (SFN), a subtype of neuropathy for which the diagnosis was first developed through skin biopsy examination. This revision focuses on the use of this technique to diagnose SFN. Methods: Task force members searched the Medline database from 2005, the year of the publication of the first EFNS guideline, to June 30th, 2009. All pertinent articles were rated according to the EFNS and PNS guidance. After a consensus meeting, the task force members created a manuscript that was subsequently revised by two experts (JML and JVS) in the field of peripheral neuropathy and clinical neurophysiology, who were not previously involved in the use of skin biopsy. Results and Conclusions: Distal leg skin biopsy with quantification of the linear density of intraepidermal nerve fibers (IENF), using generally agreed upon counting rules, is a reliable and efficient technique to assess the diagnosis of SFN (Recommendation Level A). Normative reference values are available for bright-field immunohistochemistry (Recommendation Level A) but not yet for confocal immunofluorescence or the blister technique. The morphometric analysis of IENF density, either performed with bright-field or immunofluorescence microscopy, should always refer to normative values matched for age (Recommendation Level A). Newly established laboratories should undergo adequate training in a well-established skin biopsy laboratory and provide their own stratified for age and gender normative values, intra-and interobserver reliability, and interlaboratory agreement. Quality control of the procedure at all levels is mandatory (Good Practice Point). Procedures to quantify subepidermal nerve fibers and autonomic innervated structures, including erector pili muscles, and skin vessels, are under development but need to be confirmed by further studies. Sweat gland innervation can be examined using an unbiased stereologic technique recently proposed (Recommendation Level B).

ObjectiveTo determine outcome in diabetic pancreas transplant recipients according to risk factors and the surgical techniques and immunosuppressive protocols that evolved during a 33-year period at a single institution. Summary Background DataInsulin-dependent diabetes mellitus is associated with a high incidence of management problems and secondary complications. Clinical pancreas transplantation began at the University of Minnesota in 1966, initially with a high failure rate, but outcome improved in parallel with other organ transplants. The authors retrospectively analyzed the factors associated with the increased success rate of pancreas transplants. MethodsFrom December 16, 1966, to March 31, 2000, the authors performed 1,194 pancreas transplants (111 from living donors; 191 retransplants): 498 simultaneous pancreas-kidney (SPK) and 1 simultaneous pancreas-liver transplant; 404 pancreas after kidney (PAK) transplants; and 291 pancreas transplants alone (PTA). The analyses were divided into five eras: era 0, 1966 to 1973 (n ϭ 14), historical; era 1, 1978 to 1986 (n ϭ 148), transition to cyclosporine for immunosuppression, multiple duct management techniques, and only solitary (PAK and PTA) transplants; era 2, 1986 to 1994 (n ϭ 461), all categories (SPK, PAK, and PTA), predominately bladder drainage for graft duct management, and primarily triple therapy (cyclosporine, azathioprine, and prednisone) for maintenance immunosuppression; era 3, 1994 to 1998 (n ϭ 286), tacrolimus and mycophenolate mofetil used; and era 4, 1998 to 2000 (n ϭ 275), use of daclizumab for induction immunosuppression, primarily enteric drainage for SPK transplants, pretransplant immunosuppression in candidates awaiting PTA. ResultsPatient and primary cadaver pancreas graft functional (insulinindependence) survival rates at 1 year by category and era were as follows: SPK, era 2 (n ϭ 214) versus eras 3 and 4 combined (n ϭ 212), 85% and 64% versus 92% and 79%, respectively; PAK, era 1 (n ϭ 36) versus 2 (n ϭ 61) versus 3 (n ϭ 84) versus 4 (n ϭ 92), 86% and 17%, 98% and 59%, 98% and 76%, and 98% and 81%, respectively; in PTA, era 1 (n ϭ 36) versus 2 (n ϭ 72) versus 3 (n ϭ 30) versus 4 (n ϭ 40), 77% and 31%, 99% and 50%, 90% and 67%, and 100% and 88%, respectively. In eras 3 and 4 combined for primary cadaver SPK transplants, pancreas graft survival rates were significantly higher with bladder drainage (n ϭ 136) than enteric drainage (n ϭ 70), 82% versus 74% at 1 year (P ϭ .03). Increasing recipient age had an adverse effect on outcome only in SPK recipients. Vascular disease was common (in eras 3 and 4, 27% of SPK recipients had a pretransplant myocardial infarction and 40% had a coronary artery bypass); those with no vascular disease had significantly higher patient and graft survival rates in the SPK and PAK categories. Living donor segmental pancreas transplants were associated with higher technically successful graft survival rates in each era, predominately solitary (PAK and PTA) in eras 1 and 2 and SPK in eras 3 and 4. Diabetic seconda...

We describe methods to quantify epidermal nerve fibers (ENFs) in skin biopsy specimens from diabetic candidates for pancreas transplantation and control subjects. ENFs and the dermal-epidermal basement membrane were stained by immunohistochemical methods, imaged with a confocal microscope, and quantified using a neuron tracing system. The number of ENFs per surface of epidermis was diminished in diabetic subjects. ENF number and summed length of all ENFs per volume of epidermis examined were also decreased. Length and number of branch points of single surviving ENFs were similar in skin of control and diabetic subjects. The methods and results constitute a basis for continued study of the effects of the euglycemia that attends successful pancreas transplantation and the effects of therapy in patients with various types of polyneuropathy.

Capsaicin applied topically to human skin produces itching, pricking and burning sensations due to excitation of nociceptors. With repeated application, these positive sensory responses are followed by a prolonged period of hypalgesia that is usually referred to as desensitization, or nociceptor inactivation. Consequently, capsaicin has been recommended as a treatment for a variety of painful syndromes. The precise mechanisms that account for nociceptor desensitization and hypalgesia are unclear. The present study was performed to determine if morphological changes of intracutaneous nerve fibers contribute to desensitization and hypalgesia. Capsaicin (0.075%) was applied topically to the volar forearm four times daily for 3 weeks. At various time intervals tactile, cold, mechanical and heat pain sensations were assessed in the treated and in contralateral untreated areas. Skin blisters and skin biopsies were collected and immunostained for protein gene product (PGP) 9.5 to assess the morphology of cutaneous nerves and to quantify the number of epidermal nerve fibers (ENFs). Capsaicin resulted in reduced sensitivity to all cutaneous stimuli, particularly to noxious heat and mechanical stimuli. This hypalgesia was accompanied by degeneration of epidermal nerve fibers as evidenced by loss of PGP 9.5 immunoreactivity. As early as 3 days following capsaicin application, there was a 74% decrease in the number of nerve fibers in blister specimens. After 3 weeks of capsaicin treatment, the reduction was 79% in blisters and 82% in biopsies. Discontinuation of capsaicin was followed by reinnervation of the epidermis over a 6-week period with a return of all sensations, except cold, to normal levels. We conclude that degeneration of epidermal nerve fibers contributes to the analgesia accredited to capsaicin. Furthermore, our data demonstrate that ENFs contribute to the painful sensations evoked by noxious thermal and mechanical stimuli.