Peripheral neuropathy is a frequent neurological complication of chronic alcoholism. Most studies evaluated large-fiber involvement by nerve conduction studies (NCS). Since previous studies document the predominant injury of small myelinated and unmyelinated fibers in patients with alcoholic neuropathy, it will be imperative to know their prevalence and clinical significance. Moreover, the pathogenesis of alcoholic neuropathy, especially the roles of ethanol and its metabolites and thiamine, remains elusive. This proposal will be designed to understand the extent and clinical significance of cutaneous nerve degeneration in the skin of alcoholic patients and to investigate its pathogenesis. We will investigate cutaneous innervation by 3 mm punch skin biopsies with immunohistochemistry for protein gene product 9.5 and quantifying epidermal nerve density (END) in alcoholic patients. Patients will undergo clinical evaluation, quantitative sensory testing (QST), nerve conduction studies (NCS), and tests of sympathetic skin response (SSR) and beat-to-beat RR interval variability (RRIV). The prevalence of peripheral neuropathy in chronic alcoholic patients with emphasis on small-fiber involvement will be first evaluated. The sensitivity of punch skin biopsy, QST, SSR and RRIV tests, and NCS will be compared, and the correlations between END and psychophysic and electrodiagnostic parameters will be discussed. Subsequently, we will elucidate the clinical significance of END reduction in alcoholic patients. Patients with evidences of involvement of central nervous system will be excluded, and END will be correlated with clinical manifestations and neurological deficits. Finally, the role of ethanol and thiamine in alcoholic neuropathy will be further studied. To clarify the role of thiamine in alcoholic neuropathy, we will examine whether it has influences on small-fiber degeneration. This may provide important information in understanding the pathogenesis and designing optimal treatment for alcoholic neuropathy.