Small-Fiber Degeneration in Alcohol-Related Peripheral Neuropathy

Alcohol-related peripheral neuropathy (ALN) is an under recognized and significant neurological complication that exacerbates the substantial morbidity caused by chronic alcoholism. The rate of ALN in alcoholic individuals has been estimated as high as 66% (Ammendola et al., 2001; Laker and Sullivan, 2009). Although excessive alcohol intake is clearly the critical variable in the development of ALN, the mechanisms of this disease process are not well understood; and therefore, effective treatments have not emerged. In the past, considerable attention was paid to the role of malnutrition, particularly thiamine deficiency (Abe and Itokawa, 1977; Fennelly et al., 1967; Frank et al., 1971; Hoyumpa, 1980; Hoyumpa et al., 1975; Leevy et al., 1965; Tomasulo et al., 1968). This concept had been challenged as several studies failed to show significant and specific associations between ALN and thiamine deficiency (Behse and Buchthal, 1977; Hilz et al., 1995; Koike et al., 2001, 2003; Zambelis et al., 2005) and clinical trials of vitamin supplementation alone did not reverse symptoms of ALN (Chopra and Tiwari, 2012). Additionally, experimental models indicated chronic high-dose ethanol administration, in the absence of nutritional deficiency, was sufficient to cause ALN (Mellion et al., 2013; Nguyen et al., 2012). ALN is generally regarded as a predominantly length-dependent axonal large-fiber polyneuropathy caused by thiamine deficiency (Behse and Buchthal, 1977; Blackstock et al., 1972; Dyck et al., 1968; Koike et al., 2003; Mawdsley and Mayer, 1965; Walsh and McLeod, 1970; Zambelis et al., 2005). However, the typical clinical presentation of ALN as a painful, burning neuropathy followed by motor and autonomic instability is suggestive of small-fiber involvement at the onset of disease that progresses to involve larger nerve fibers. Several studies of sural nerve biopsies have shown that patients with recent onset of ALN had associated small-fiber axonal loss, whereas those with long-standing disease had abundant regenerating fibers and marked axonal sprouting consistent with large-fiber damage (Behse and Buchthal, 1977; Koike et al., 2003; Zambelis et al., 2005). Furthermore, recent studies, also involving sural nerve biopsies, showed that small myelinated and unmyelinated fiber densities were more severely reduced than large myelinated fiber densities in the early stages of ALN (Koike et al., 2001, 2003). The observation of increased thermal thresholds in patients with ALN also supports the concept that small myelinated and unmyelinated nerve fibers may be selectively vulnerable to degeneration in ALN (Zambelis et al., 2005). Together, these studies suggest that small, unmyelinated nerve fibers are significantly affected (Koike et al., 2001). Until recently, damage to small nerve fibers was inferred by decreased thermal thresholds, abnormal autonomic testing, or axonal loss observed in sural nerve biopsies (Hilz et al., 1995; Zambelis et al., 2005). Nerve biopsies are invasive and can lead to significant morbidity due to loss of sensory function in the previously innervated structures. Skin biopsy is currently the standard approach in diagnosing small-fiber neuropathies, though no studies have been conducted to validate the use of skin biopsy in ALN (Ebenezer et al., 2007; Gibbons et al., 2006; McArthur et al., 1998; McCarthy et al., 1995). The primary objective of this pilot study is to demonstrate that ALN is associated with a small-fiber neuropathy and that this neuropathy can be diagnosed by skin biopsy in heavy alcohol drinking individuals with normal thiamine status. Skin biopsy is relatively benign, minimally invasive, repeatable over time, and could become an important tool in the study of the pathogenesis and assessment of the effectiveness of treatments in ALN.