Abstract
Small fibres in the skin are vulnerable to damage in metabolic or toxic conditions such as diabetes mellitus or chemotherapy resulting in small fibre neuropathy and associated neuropathic pain. Whether injury to the most distal portion of sensory small fibres due to a primary dermatological disorder can cause neuropathic pain is still unclear. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare condition in which mutations of proteins of the dermo-epidermal junction lead to cycles of blistering followed by regeneration of the skin. Damage is exclusive to the skin and mucous membranes, with no known direct compromise of the nervous system. It is increasingly recognized that most RDEB patients experience daily pain, the aetiology of which is unclear but may include inflammation (in the wounds), musculoskeletal (due to atrophy and retraction scars limiting movement) or neuropathic pain. In this study we investigated the incidence of neuropathic pain and examined the presence of nerve dysfunction in RDEB patients. Around three quarters of patients presented with pain of neuropathic characteristics, which had a length-dependent distribution. Quantitative sensory testing of the foot revealed striking impairments in thermal detection thresholds combined with an increased mechanical pain sensitivity and wind up ratio (temporal summation of noxious mechanical stimuli). Nerve conduction studies showed normal large fibre sensory and motor nerve conduction; however, skin biopsy showed a significant decrease in intraepidermal nerve fibre density. Autonomic nervous system testing revealed no abnormalities in heart rate and blood pressure variability however the sympathetic skin response of the foot was impaired and sweat gland innervation was reduced. We conclude that chronic cutaneous injury can lead to injury and dysfunction of the most distal part of small sensory fibres in a length-dependent distribution resulting in disabling neuropathic pain. These findings also support the use of neuropathic pain screening tools in these patients and treatment algorithms designed to target neuropathic pain.
Highlights
Small nerve fibres that innervate the skin are especially susceptible to damage and degeneration in several systemic diseases such as diabetes mellitus and toxin exposure
The severity of RDEB can vary between patients, so we used the Birmingham Epidermolysis Bullosa Severity (BEBS) score (Moss et al, 2009) to
We found that loss in cold and warm detection thresholds and thermal sensory limen inversely correlated with RDEB severity score (Fig. 2A–C)
Summary
Small nerve fibres that innervate the skin are especially susceptible to damage and degeneration in several systemic diseases such as diabetes mellitus and toxin exposure. Whether injury to the most distal portion of sensory small fibres due to a primary dermatological disorder can cause neuropathic pain is still unclear. Based on the site of skin cleavage, epidermolysis bullosa is classified into four major types: epidermolysis bullosa simplex (EBS, cleavage plane within the epidermis), junctional epidermolysis bullosa (JEB, cleavage plane in the lamina lucida), dystrophic epidermolysis bullosa (DEB, cleavage plane below the lamina densa), and Kindler syndrome (multiple cleavage planes) (Fine et al, 2008). DEB is inherited in both an autosomal dominant or DDEB (milder form) and an autosomal recessive manner or RDEB (severe form), both of which result from mutations in the type VII collagen gene (COL7A1) (Dang and Murrell, 2008). Type VII collagen is a major component of the anchoring fibril located below the basement membrane in the upper dermis, providing stable dermal–epidermal adhesion (Shinkuma et al, 2011)
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