Eur J Dermatol 2014; 24(2): 147-153
Review article Laurent MISERY1,2,3 Céline BODERE1,4 Steeve GENESTET2,5 Fabien ZAGNOLI1,2,6 Pascale MARCORELLES1,2,7 1
University of Western Brittany, Laboratory of Neurosciences of Brest, Brest, France 2 Breton Competence Centre of Rare Neuro-Muscular Diseases and Neuropathies with Cutaneous-Mucosal Symptoms, Brest, France 3 Department of dermatology, 4 Department of odontology, 5 Department of clinical neurophysiology, 6 Department of neurology, Armed Forces Instruction Hospital Clermont-Tonnerre, Brest, France 7 Department of pathology, University Hospital of Brest, 29609 Brest, France
Reprints: L. Misery
Small-fibre neuropathies and skin: news and perspectives for dermatologists Small-fibre neuropathies (SFNs) can be defined as diseases of small nerve fibres. Because their symptoms are mainly located in the skin in the initial stages, dermatologists may frequently be confronted with these diseases. Moreover, skin biopsies and the subsequent measurement of intraepidermal nerve fibre density have become a widely accepted technique to investigate the structural integrity of small nerve fibres. The pathogenesis of injury to small nerve fibres is poorly understood. It probably depends on the cause. SCN9A-gene variants have been reported. Diabetes mellitus is one of the main causes of SFNs. Some causes of SFNs are very well-known to dermatologists: Gougerot-Sjögren syndrome, lupus, sarcoidosis and Fabry disease. We also discuss erythermalgia, prurigo nodularis, nummular eczema, burning mouth syndrome and sensitive skin as SFNs. Key words: small-fibre neuropathy, PGP9.5, nerve, Gougerot-Sjögren syndrome, sarcoidosis, Fabry disease, erythermalgia, pruritus, burning mouth syndrome, sensitive skin
Article accepted on 8/24/2013
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any dermatologists have met patients suffering from pruritus, pain, stinging, tingling, chaffing, burning, prickling or other abnormal skin sensations that predominate on the hands and feet. Often these sensations are atypical and nerve conduction studies do not show abnormalities; therefore, a diagnosis of ‘idiopathic’ or ‘psychogenic’ paraesthesia is common. However, SFN may be a more appropriate diagnosis. Small-fibre neuropathies have been recently described [1] and are one of the main causes of neuropathic itch [2].
that typically affects the limbs in a distal-to-proximal gradient) [9]. More recently, a diminution of intraepidermal nerve fibre (IENF) density became a major diagnostic criterion [10]. New diagnostic criteria can be proposed (table 1).
Causes SFNs are frequently idiopathic [11]. The main medical conditions associated with SFNs are summarized in table 2.
doi:10.1684/ejd.2013.2189
Definition Small nerve fibres are numerous in the skin and mucosa and they include myelinated A␦ fibres and unmyelinated C fibres. In addition, the presence of nerve fibres in the epidermis can be identified with the use of immunostaining for neurofilaments [3] with PGP9.5 [4] and electron microscopy [5]. Small-fibre neuropathies (SFNs) are defined as diseases of small nerve fibres but conclusive diagnostic criteria are not yet available [6-8]. However, the following diagnostic criteria are generally accepted: normal sural nerve conduction (NCS), clinical symptoms and signs considered suggestive of SFN and/or altered quantitative sensory testing (QST) [6, 7]. Clinical symptoms include autonomic symptoms (i.e., dry eyes, dry mouth, dizziness, constipation, bladder incontinence, sexual dysfunction, sweating troubles, red or white skin discoloration) and sensory symptoms (i.e., pain, pruritus, burning, tingling, or numbness EJD, vol. 24, n◦ 2, March-April 2014
Table 1. Diagnostic criteria of small-fibre neuropathies, according to Devigili [10]. At least two of the following examinations: - clinical signs of small fibre impairment (pinprick and thermal sensory loss and/or allodynia and/or hyperalgesia), the distribution of which is consistent with peripheral neuropathy (length or non-length dependent neuropathy) - abnormal warm and/or cooling threshold in the foot, assessed by QST - reduced IENF density in the distal leg. Ruled out in the presence of: - any sign of large fibre impairment (light touch and/or vibratory and/or proprioceptive sensory loss and/or absent deep tendon reflexes) - any sign of motor fibre impairment (muscle waste and/or weakness); - any abnormality on sensorimotor NCS.
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To cite this article: Misery L, Bodere C, Genestet S, Zagnoli F, Marcorelles P. Small-fibre neuropathies and skin: news and perspectives for dermatologists. Eur J Dermatol 2014; 24(2): 147-153 doi:10.1684/ejd.2013.2189
Table 2. Diseases associated with small-fibre neuropathies. Glucose dysmetabolism (diabetes and pre-diabetes) Systemic lupus erythematous Gougerot-Sjögren disease Sarcoidosis Paraproteinemia, amyloidosis Dysthyroidism Alcoholism Vitamin B12 deficiency HIV or hepatitis C infection Celiac disease Restless legs syndrome Neurotoxic drug exposure (metronidazole, linezolide, bortezomid. . .) Complex regional pain syndrome type I Hereditary diseases (Fabry disease, autosomal recessive hereditary neuropathy, familial amyloidosis, Friedreich’s ataxia, hereditary sensory and autonomic neuropathy, Ross syndrome, Tangier disease) Paraneoplastic syndromes
Diagnosis Patient history and physical examination are considered important for diagnosing SFN. If a patient presents with a compelling history for a SFN and an appropriate clinical examination, further testing to confirm the diagnosis may be unnecessary [11]. This scenario is particularly likely in the context of an associated disease, such as diabetes. However, in many cases, the diagnosis may be less clear, and ancillary testing may provide additional guidance. Scoring examinations have been developed and may aid in the diagnosis of SFN [12]. The Neuropathic Pain Symptom Inventory (NPSI) and the Douleur Neuropathique-4 (DN4) differentiate various aspects of neuropathic pain [13, 14]. Quantitative sensory testing (QST) is an extension of the physical examination and can provide thresholds of detection for thermal sensation, thermal pain and vibratory sensation [15]. QST is frequently used in the diagnosis of SFNs; however, further study is required to determine the utility of new variations of QST in the diagnosis of SFN [11]. There are a variety of methods to quantify sudomotor function that could be used to help in the diagnosis of SFN. The most frequently utilised and well-known is the quantitative sudomotor axon reflex test (QSART), which is a measure of postganglionic sympathetic cholinergic function [16].
Specific role of dermatologists in the diagnosis Impairment of water-induced skin wrinkling (WISW) was found to correlate with low IENF density in patients with foot and hand dysaesthesia [17]. The Neuropad® is marketed as an inexpensive and easy test of sudomotor function,
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to screen for early peripheral neuropathy in patients with diabetes mellitus. In SFN, the sensitivity of the Neuropad® was 29% and its specificity 93%. The sensitivity of WISW was 66% and its specificity 70%. Regarding abnormality in at least one test to define the combination as abnormal yielded a sensitivity of 71% and specificity 67%. When both tests had to be abnormal to judge the combination abnormal, sensitivity was 23% and specificity 97%. Hence, the Neuropad® has a high specificity, so an abnormal result can be used to confirm SFN. WISW has a moderate sensitivity and specificity. Combining these two tests can be helpful: when both tests are abnormal the diagnosis of SFN is highly likely [18]. Skin biopsies have become a widely accepted technique to investigate the structural integrity of small nerve fibres [11]. In addition, there is international consensus to use a skin biopsy examination for the diagnosis of SFNs. Guidelines have been established for the measurement of IENF density in the diagnosis of SFN; however, this approach cannot measure the severity [6, 7]. The diagnostic value of skin biopsy has been evaluated at approximately 90% [9] and measurement of the IENF density could replace all other possibilities for diagnostic testing. However, normal IENF density does not exclude SFN and reduced IENF density does not prove it [10]. Performed under local anaesthesia, skin biopsies using a 3 mm punch diameter are taken from the distal leg (10 cm above the lateral malleolus) in the territory of the sural nerve and from the proximal lateral thigh to control for length-dependent pathology [7, 19]. The biopsies must be immediately fixed in 4% paraformaldehyde (PFA) for 12-24 hours, submerged in 10% sucrose for another 12-24 hours, cryopreserved at -80 ◦ C and subsequently sectioned into sections with a thickness of 30 m [20]. In order to avoid skin biopsies, a suction skin blister method has been proposed and no systematic differences in IENF density were found between skin blisters and biopsies [21].
Specific role of the dermatopathologist After skin biopsy, thicker sections of 50 m can be used for “free-floating” immunohistochemistry because the antibody will penetrate deeper into the tissue. For diagnostic purposes, the most commonly used neuronal protein marker is the Protein Gene Product 9.5 (PGP9.5) antibody (Ultraclone, Isle of Wight UK). PGP9.5 is a notably labile ubiquitin carboxyl terminal hydrolase enzyme that is normally expressed in dermal and epidermal nerve fibres [4]. Because of the instability of PGP9.5, PFA fixation does not withstand any delay. Dark-field indirect immunofluorescence is the most common immunostaining method and allows a manual count of epidermal fibres, although confocal microscopy and immunoperoxidase methods have also been described [6, 19]. The standard protocol includes careful measuring of the length of the epidermis in the section, counting of the intraepidermal fibres at 40× magnification, evaluation of the morphology of the intraepidermal fibres and the presence and thickness of the superficialis dermal plexus (figures 1A-B). The evaluation of each sample requires the use of 3 sections perpendicular to the skin EJD, vol. 24, n◦ 2, March-April 2014
A
B
C
D
Figure 1. Immunostaining of PGP 9.5 on skin biopsies from inferior members in a healthy subject (A, B) and in a patient with a small-fiber neuropathy (C, D). A) tight biopsy magnification ×200: Intraepidermal nerve fibers arrive from the linear subpapillary dermal nerve bundless. B) Leg biopsy magnification ×400: IENF cross the basement membrane and are slightly tortuous, sometimes ramified, and have small varicosities. C) magnification ×20: the sub-papillary dermal plexus is thin and discontinuous. The IENF are scattered. D) magnification ×40: Some fibre swellings are present and some segments of IENF remain isolated in the epidermis.
surface. The total number of intraepidermal fibres is divided by the total epidermal length in the 3 sections, to provide the number of fibres per linear mm of epidermis. Published guidelines state that only the intraepidermal fibres crossing the dermo-epidermal junction need to be counted. Secondary fibre branches and isolated intraepidermal fibre fragments do not need to be counted [6, 22]. A microscopic factor that may perturb the quantification of IENF density (figure 1C), particularly in inexperienced observers, is the difficulty in locating the dermo-epidermal junction. Normally, most intraepidermal fibres climb to the upper layers of the epidermis and may or may not be ramified. Only a few intraepidermal fibres have a different horizontal projection parallel to the basal membrane [23]. Focal intraepidermal fibre swelling (figure 1D) is sometimes observed and may be related to pre-degenerative changes; however, this characteristic, as with fibre regeneration, is not part of the counting criteria [24]. This manual IENF density counting method is a reproducible intra- and inter-observer test. IENF density is a reliable tool to assess the diagnosis of small fibre sensory neuropathy but it is unable to provide any information about the severity or the aetiology of the disease [4]. The normal IENF mean density is related to the region of the body, is maximal at axial sites and follows a decreasing proximal-to-distal gradient in the limbs [19, 25]. IENF is also dependent on age, particularly in the limbs, gender and the immunohistochemical technique used for counting; for example, confocal microscopy studies report a higher IENF density [26]. Therefore, normalised IENF density data are required for skin biopsy interpretation and it should be consistent within each laboratory for it to be reliable. Published in 2010, the most important normative study correlated IENF density for the distal leg to age and sex [7]. A cut-off at the 5th percentile was chosen to establish a decrease in EJD, vol. 24, n◦ 2, March-April 2014
IENF density (table 3). In our practice, the main limitation of this method remains the finding of a distal IENF density at the 5th percentile density in patients with clinical distal small fibre sensory neuropathy.
Pathophysiology Peripheral nerve fibres can be classified as large fibres (e.g., A␣ for motor strength, and A for mechanosensitivity), medium fibres (e.g., A␥ for muscle spindles) and small fibres (e.g., A␦ and C) [9]. Small nerve fibres can be sympathetic or parasympathetic and they can be thermoreceptors, nociceptors or pruriceptors [8]. SFNs consist of a reduction in epidermal and visceral innervation [6, 7, 27], which frequently follows axon swelling. Axon swelling is attributed to the accumulation of cellular debris from the degeneration of the nerve cytoskeleton and transport system [24]. Consequently, patients suffer from abnormal and unpleasant sensations and a reduction in sensitivity. Patients also can suffer from autonomic symptoms, including increased or decreased sweating, facial flushing or skin discoloration, dry eyes and mouth, changes in skin temperature, erectile dysfunction, orthostatic hypotension or gastrointestinal dysmotility [8, 9]. Most SFNs occur in a length-dependent fashion and result in the loss of function in a stocking distribution in the lower extremities [11]. The disease can advance and a glove-like loss in the upper extremities occurs, as other areas become involved. In some cases, SFN is not length-dependent, such as in Gougerot-Sjögren disease, celiac disease and paraneoplastic syndrome. The pathogenesis of injury to small nerve fibres is poorly understood; however, variants in the SCN9A gene (single
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Table 3. IENF density normative values at the distal leg [from ref.7]. Females
Age (years)
20–29 30–39 40–49 50–59 60–69 70–79 ≥80
Males
0.05 Quantile IENF density values per age span
Median IENF density values per age span
0.05 Quantile IENF density values per age span
Median IENF density values per age span
8.4 7.1 5.7 4.3 3.2 2.2 1.6
13.5 12.4 11.2 9.8 8.7 7.6 6.7
6.1 5.2 4.4 3.5 2.8 2.1 1.7
10.9 10.3 9.6 8.9 8.3 7.7 7.2
amino acid substitutions) were found in some patients with idiopathic SFN. These gene variations produce gain-offunction changes in a sodium channel, Na(v)1.7, which is preferentially expressed in small diameter peripheral axons. Functional testing showed that these variants altered fastinactivation, slow-inactivation or resurgent current and they rendered dorsal root ganglion neurons hyperexcitable [28]. One study showed a negative correlation between IENF density and the number of Langerhans cells, suggesting that an increased number of Langerhans cells in the epidermis may play a role in the generation or maintenance of SFN, but it was performed in a small group of diabetic patients [29]. The role of ischemia, oxidative stress and cytokines (i.e., TNF␣) in SFNs has also been proposed [30].
Dermatological and venerological causes of SFN Gougerot-Sjögren syndrome and systemic lupus erythematosus Approximately 40% of patients with primary GougerotSjögren syndrome present with SFN [31, 32]. Currently, skin biopsy to measure the IENF density is the main technique used for patients with this disease and it is often part of a standardized check-up. The role of vasculitisinduced ischemia, cytokines, such as TNFa, and nerve growth factors (NT-3) has been suggested [31]. Several authors hypothesise that NT-3 and NGF are important because these growth factors are known to activate B- and Tcells in primary Gougerot-Sjögren syndrome [31]. Primary Gougerot-Sjögren syndrome is characterised by an involvement of the skin, including the epidermis [33]. Deposits of immunoglobulin G (IgG) located in the intercellular space of the epidermis have been shown in 68% of patients with primary GSS [34]. However, the role of these deposits and memory B-cell aggregates [35] in epidermal nerve fibres remains unclear. SFN are more rare in patients with systemic lupus erythematosus and are not usually included in check-ups. Nonetheless, the presence of SFN has been evidenced in some patients with systemic lupus erythematosus and neuropathic disorders [36].
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Sarcoidosis SFN is present in approximately 10% of patients with sarcoidosis [37]; however, no length-dependent pattern is observed in this case. While much is known about the pathophysiology of large-fibre neuropathy in sarcoidosis, such as the presence of granulomas around nerves, the exact pathology of axon loss in SFN is unknown [37]. The pathophysiology remains elusive because no cell infiltrate has been described around intraepidermal nerve fibres. Sarcoidosis is associated with the presence of the DQB1 allele and sarcoidosis patients with the HLA-DQB1*0602 allele are more likely to have abnormal temperature-threshold testing, consistent with SFN and a more severe sarcoidosis [38]. Hence, the activity of a soluble factor in the skin is likely.
Fabry disease Males and females with Fabry disease suffer from burning or shooting pain or a painful “pins and needles” sensation in the hands and/or feet, intolerance to heat and the inability to sweat. This is one of the main diagnostic criteria for this disease and it is present in heterozygous women. The pathophysiology of pain in Fabry disease is not fully understood; however, SFN as a result of glycolipid accumulation in the dorsal root ganglia has been proposed [39] and confirmed [40] as a mechanism. Indeed, small fibre conduction is impaired in men with Fabry disease and worsens with advanced disease severity [41]. Indeed, 100% of male patients and 57% of female patients have a decrease of IENF density [40]. Despite extensive data regarding the time course and consequences of SFN in Fabry disease, the underlying pathophysiological mechanism remains speculative. It is uncertain whether the neuropathy arises from the storage of lipids in ganglia leading to a so-called dyingback neuropathy or from direct damage to small nerve fibre axons. The susceptibility of A␦ fibres suggests that the ganglia or axons of small myelinated nerve fibres are more vulnerable to lipid accumulation than small unmyelinated fibres [40]. Enzyme replacement therapy has been shown to reduce neuropathic pain [42]. The IENF density did not change after 12–18 months of treatment, whereas small nerve fibre function improved upon treatment [39, 40]. Therefore, the structural damage to the small nerve fibres may be irreversible but the function of the remaining fibres EJD, vol. 24, n◦ 2, March-April 2014
may improve after enzyme replacement. Another hypothesis is that structural nerve fibre is reversible only after a longer treatment [40, 42].
HIV infection Sensory neuropathies affect 30% of individuals with AIDS. They are usually SFN and treatment is often ineffective. IENF density is inversely correlated with neuropathic pain. Decreased IENF density at the distal leg is associated with lower CD4 counts and higher plasma HIV RNA levels [43]. Moreover, a lower leg IENF density, a higher cooling threshold and a higher heat pain threshold for minimal pain are associated with a greater risk of sensory neuropathy in HIV patients [44]. Hence, measurements of small sensory fibres (leg epidermal nerve fibre density, cooling and heat pain thresholds) seem to be associated with the transition to symptomatic HIV-associated distal sensory neuropathy 6 to 12 months later and could be a prognostic factor.
the reduction of IENF density could be a consequence of scratching. Nummular eczema is a chronic inflammatory condition characterized by pruritus and histologically characterized by spongiosis. The etiology is unknown and the lesions frequently arise spontaneously. Neuropeptides contribute to mediating and to maintaining eczematous conditions. Previous research indicates that the number of immunoreactive nerve fibres is increased in pruritic skin lesions. A recent study showed that there was significantly reduced PGP9.5 staining in the epidermis of patients with nummular eczema compared with their respective healthy controls [49].
Burning mouth syndrome
Erythermalgia, including hereditary erythermalgia, is usually considered as a neuropathy belonging to the channelopathies [45] but that does not exclude that it could be a SFN . Erythermalgia is characterised by the flushing of acral areas, such as the feet and hands. A decrease of IENF density has been noted [46] but without comparison to proximal biopsies. Interestingly, there is a common genetic trait and a common pathophysiological mechanism between primary erythermalgia and the risk of SFN [47]. Voltage-gated sodium channels play a pivotal role in pain transmission, and they are widely expressed in nociceptive neurons. These channels also participate in the generation of action potentials. Alteration in ionic conduction of these channels causes abnormal electrical firing and thus renders neurons hyperexcitable. Until recently, gain-of-function mutations in Na(v)1.7 were known to cause two neuropathic pain syndromes, including inherited erythromelalgia and paroxysmal extreme pain syndrome. These syndromes are inherited as a dominant trait. Recently, SFN and chronic non-paroxysmal pain have been described in patients harbouring gain-of-function mutations in the Na(v)1.7 channel [28].
The pathophysiology of primary burning mouth syndrome (BMS) or primary stomatodynia is hardly debated [50]. In addition to spontaneous burning pain, patients may complain of taste alterations. Recent neurophysiological, psychophysical, neuropathological and functional imaging studies have determined that several neuropathic mechanisms, mostly subclinical, act at different levels of the neuraxis and contribute to the pathophysiology of primary BMS [51-53]. The loss of small diameter nerve fibres in the tongue epithelium explains the thermal hypoesthesia and the increase in taste detection thresholds found in quantitative sensory testing [54]. However, it seems that the clinical diagnosis of primary BMS encompasses at least three distinct, subclinical neuropathic pain states which may overlap in individual patients. The first subgroup (50-65%) is characterised by peripheral small diameter fibre neuropathy of the intraoral mucosa. The second subgroup (20-25%) consists of patients with subclinical lingual, mandibular or trigeminal system pathology, which can be dissected with careful neurophysiologic examination but is clinically indistinguishable from the other two subgroups. The third subgroup (20-40%) fits the concept of central pain that may be related to hypofunction of the dopaminergic neurons in the basal ganglia [52]. Hence, BMS could be a small-fibre neuropathy that is related to an oestrogen deficiency [51] or mouth aging, in the majority of cases. Nonetheless, recent contradictory results suggest that the decrease in IENF density may be related to the age of the patients. In this study [55], BMS was not associated with abnormal thermal and pain thresholds, which fails support a true small nerve neuropathy in this condition. However, age was a factor in thermal thresholds and pain in the anterior tongue, with an unexpected increased sensitivity to cold pain and decreased sensitivity to heat-induced pain.
Prurigo nodularis and nummular eczema
Sensitive skin
Prurigo nodularis is a highly pruritic condition with hyperkeratotic nodules predominating in the legs. To date, this condition has been classified as a disease that results as a consequence of atopic dermatitis or systemic or psychiatric disease. An increased number of dermal nerve fibres in this condition is well-described. Recently, reduced IENF density has been shown in lesional and non-lesional skin [48]. Although there is no neuropathic pain, a neuropathic itch has been reported; therefore, prurigo nodularis could be considered to be a SFN. Another hypothesis is that
Sensitive skin (or reactive or hyper-reactive skin) is defined as skin that responds with erythema and/or subjective symptoms (i.e., pricking, burning, pain, pruritus) to stimuli, including wind, heat, cold, water, cosmetics and stress [56, 57]. Due to the variety of sensory symptoms reported, it seems likely that neurosensory dysfunction of nerves in the skin underlies the altered sensations, although this idea awaits experimental exploration. To date, it is unknown if skin nerve fibre density is altered in sensitive skin or if the physical induction of sensitive skin by wind or cold
Dermatological disorders that could be SFN Erythermalgia
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underlies allodynia in nerve fibres [58]. In summary, sensitive skin could be a SFN, but there are presently no data (i.e., IENF density, QST) to confirm this hypothesis.
Treatment In all cases, an etiological treatment for SFN is needed. Symptomatic treatments including gabapentin, pregabalin, tricyclic antidepressants, serotonin-norepinephrine re-uptake inhibitors and analgesics are used [9, 11, 59].
Conclusions Situated between the skin and the nervous system, SFNs are relevant to dermatologists and skin researchers for many reasons: 1. Clinical symptoms are often initially attributed to the skin by patients. 2. The main method of confirming the diagnosis of SFN is through the IENF density in skin biopsies. 3. Several diseases with skin involvement can be associated with a SFN. 4. Some misunderstood dermatological syndromes could be SFNs. 5. Dermatologists have to know SFNs for all these reasons. Disclosure. Financial support: none. Conflict of interest: none.
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Review article Laurent MISERY1,2,3 Céline BODERE1,4 Steeve GENESTET2,5 Fabien ZAGNOLI1,2,6 Pascale MARCORELLES1,2,7 1
University of Western Brittany, Laboratory of Neurosciences of Brest, Brest, France 2 Breton Competence Centre of Rare Neuro-Muscular Diseases and Neuropathies with Cutaneous-Mucosal Symptoms, Brest, France 3 Department of dermatology, 4 Department of odontology, 5 Department of clinical neurophysiology, 6 Department of neurology, Armed Forces Instruction Hospital Clermont-Tonnerre, Brest, France 7 Department of pathology, University Hospital of Brest, 29609 Brest, France
Reprints: L. Misery
Small-fibre neuropathies and skin: news and perspectives for dermatologists Small-fibre neuropathies (SFNs) can be defined as diseases of small nerve fibres. Because their symptoms are mainly located in the skin in the initial stages, dermatologists may frequently be confronted with these diseases. Moreover, skin biopsies and the subsequent measurement of intraepidermal nerve fibre density have become a widely accepted technique to investigate the structural integrity of small nerve fibres. The pathogenesis of injury to small nerve fibres is poorly understood. It probably depends on the cause. SCN9A-gene variants have been reported. Diabetes mellitus is one of the main causes of SFNs. Some causes of SFNs are very well-known to dermatologists: Gougerot-Sjögren syndrome, lupus, sarcoidosis and Fabry disease. We also discuss erythermalgia, prurigo nodularis, nummular eczema, burning mouth syndrome and sensitive skin as SFNs. Key words: small-fibre neuropathy, PGP9.5, nerve, Gougerot-Sjögren syndrome, sarcoidosis, Fabry disease, erythermalgia, pruritus, burning mouth syndrome, sensitive skin
Article accepted on 8/24/2013
M
any dermatologists have met patients suffering from pruritus, pain, stinging, tingling, chaffing, burning, prickling or other abnormal skin sensations that predominate on the hands and feet. Often these sensations are atypical and nerve conduction studies do not show abnormalities; therefore, a diagnosis of ‘idiopathic’ or ‘psychogenic’ paraesthesia is common. However, SFN may be a more appropriate diagnosis. Small-fibre neuropathies have been recently described [1] and are one of the main causes of neuropathic itch [2].
that typically affects the limbs in a distal-to-proximal gradient) [9]. More recently, a diminution of intraepidermal nerve fibre (IENF) density became a major diagnostic criterion [10]. New diagnostic criteria can be proposed (table 1).
Causes SFNs are frequently idiopathic [11]. The main medical conditions associated with SFNs are summarized in table 2.
doi:10.1684/ejd.2013.2189
Definition Small nerve fibres are numerous in the skin and mucosa and they include myelinated A␦ fibres and unmyelinated C fibres. In addition, the presence of nerve fibres in the epidermis can be identified with the use of immunostaining for neurofilaments [3] with PGP9.5 [4] and electron microscopy [5]. Small-fibre neuropathies (SFNs) are defined as diseases of small nerve fibres but conclusive diagnostic criteria are not yet available [6-8]. However, the following diagnostic criteria are generally accepted: normal sural nerve conduction (NCS), clinical symptoms and signs considered suggestive of SFN and/or altered quantitative sensory testing (QST) [6, 7]. Clinical symptoms include autonomic symptoms (i.e., dry eyes, dry mouth, dizziness, constipation, bladder incontinence, sexual dysfunction, sweating troubles, red or white skin discoloration) and sensory symptoms (i.e., pain, pruritus, burning, tingling, or numbness EJD, vol. 24, n◦ 2, March-April 2014
Table 1. Diagnostic criteria of small-fibre neuropathies, according to Devigili [10]. At least two of the following examinations: - clinical signs of small fibre impairment (pinprick and thermal sensory loss and/or allodynia and/or hyperalgesia), the distribution of which is consistent with peripheral neuropathy (length or non-length dependent neuropathy) - abnormal warm and/or cooling threshold in the foot, assessed by QST - reduced IENF density in the distal leg. Ruled out in the presence of: - any sign of large fibre impairment (light touch and/or vibratory and/or proprioceptive sensory loss and/or absent deep tendon reflexes) - any sign of motor fibre impairment (muscle waste and/or weakness); - any abnormality on sensorimotor NCS.
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To cite this article: Misery L, Bodere C, Genestet S, Zagnoli F, Marcorelles P. Small-fibre neuropathies and skin: news and perspectives for dermatologists. Eur J Dermatol 2014; 24(2): 147-153 doi:10.1684/ejd.2013.2189
Table 2. Diseases associated with small-fibre neuropathies. Glucose dysmetabolism (diabetes and pre-diabetes) Systemic lupus erythematous Gougerot-Sjögren disease Sarcoidosis Paraproteinemia, amyloidosis Dysthyroidism Alcoholism Vitamin B12 deficiency HIV or hepatitis C infection Celiac disease Restless legs syndrome Neurotoxic drug exposure (metronidazole, linezolide, bortezomid. . .) Complex regional pain syndrome type I Hereditary diseases (Fabry disease, autosomal recessive hereditary neuropathy, familial amyloidosis, Friedreich’s ataxia, hereditary sensory and autonomic neuropathy, Ross syndrome, Tangier disease) Paraneoplastic syndromes
Diagnosis Patient history and physical examination are considered important for diagnosing SFN. If a patient presents with a compelling history for a SFN and an appropriate clinical examination, further testing to confirm the diagnosis may be unnecessary [11]. This scenario is particularly likely in the context of an associated disease, such as diabetes. However, in many cases, the diagnosis may be less clear, and ancillary testing may provide additional guidance. Scoring examinations have been developed and may aid in the diagnosis of SFN [12]. The Neuropathic Pain Symptom Inventory (NPSI) and the Douleur Neuropathique-4 (DN4) differentiate various aspects of neuropathic pain [13, 14]. Quantitative sensory testing (QST) is an extension of the physical examination and can provide thresholds of detection for thermal sensation, thermal pain and vibratory sensation [15]. QST is frequently used in the diagnosis of SFNs; however, further study is required to determine the utility of new variations of QST in the diagnosis of SFN [11]. There are a variety of methods to quantify sudomotor function that could be used to help in the diagnosis of SFN. The most frequently utilised and well-known is the quantitative sudomotor axon reflex test (QSART), which is a measure of postganglionic sympathetic cholinergic function [16].
Specific role of dermatologists in the diagnosis Impairment of water-induced skin wrinkling (WISW) was found to correlate with low IENF density in patients with foot and hand dysaesthesia [17]. The Neuropad® is marketed as an inexpensive and easy test of sudomotor function,
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to screen for early peripheral neuropathy in patients with diabetes mellitus. In SFN, the sensitivity of the Neuropad® was 29% and its specificity 93%. The sensitivity of WISW was 66% and its specificity 70%. Regarding abnormality in at least one test to define the combination as abnormal yielded a sensitivity of 71% and specificity 67%. When both tests had to be abnormal to judge the combination abnormal, sensitivity was 23% and specificity 97%. Hence, the Neuropad® has a high specificity, so an abnormal result can be used to confirm SFN. WISW has a moderate sensitivity and specificity. Combining these two tests can be helpful: when both tests are abnormal the diagnosis of SFN is highly likely [18]. Skin biopsies have become a widely accepted technique to investigate the structural integrity of small nerve fibres [11]. In addition, there is international consensus to use a skin biopsy examination for the diagnosis of SFNs. Guidelines have been established for the measurement of IENF density in the diagnosis of SFN; however, this approach cannot measure the severity [6, 7]. The diagnostic value of skin biopsy has been evaluated at approximately 90% [9] and measurement of the IENF density could replace all other possibilities for diagnostic testing. However, normal IENF density does not exclude SFN and reduced IENF density does not prove it [10]. Performed under local anaesthesia, skin biopsies using a 3 mm punch diameter are taken from the distal leg (10 cm above the lateral malleolus) in the territory of the sural nerve and from the proximal lateral thigh to control for length-dependent pathology [7, 19]. The biopsies must be immediately fixed in 4% paraformaldehyde (PFA) for 12-24 hours, submerged in 10% sucrose for another 12-24 hours, cryopreserved at -80 ◦ C and subsequently sectioned into sections with a thickness of 30 m [20]. In order to avoid skin biopsies, a suction skin blister method has been proposed and no systematic differences in IENF density were found between skin blisters and biopsies [21].
Specific role of the dermatopathologist After skin biopsy, thicker sections of 50 m can be used for “free-floating” immunohistochemistry because the antibody will penetrate deeper into the tissue. For diagnostic purposes, the most commonly used neuronal protein marker is the Protein Gene Product 9.5 (PGP9.5) antibody (Ultraclone, Isle of Wight UK). PGP9.5 is a notably labile ubiquitin carboxyl terminal hydrolase enzyme that is normally expressed in dermal and epidermal nerve fibres [4]. Because of the instability of PGP9.5, PFA fixation does not withstand any delay. Dark-field indirect immunofluorescence is the most common immunostaining method and allows a manual count of epidermal fibres, although confocal microscopy and immunoperoxidase methods have also been described [6, 19]. The standard protocol includes careful measuring of the length of the epidermis in the section, counting of the intraepidermal fibres at 40× magnification, evaluation of the morphology of the intraepidermal fibres and the presence and thickness of the superficialis dermal plexus (figures 1A-B). The evaluation of each sample requires the use of 3 sections perpendicular to the skin EJD, vol. 24, n◦ 2, March-April 2014
A
B
C
D
Figure 1. Immunostaining of PGP 9.5 on skin biopsies from inferior members in a healthy subject (A, B) and in a patient with a small-fiber neuropathy (C, D). A) tight biopsy magnification ×200: Intraepidermal nerve fibers arrive from the linear subpapillary dermal nerve bundless. B) Leg biopsy magnification ×400: IENF cross the basement membrane and are slightly tortuous, sometimes ramified, and have small varicosities. C) magnification ×20: the sub-papillary dermal plexus is thin and discontinuous. The IENF are scattered. D) magnification ×40: Some fibre swellings are present and some segments of IENF remain isolated in the epidermis.
surface. The total number of intraepidermal fibres is divided by the total epidermal length in the 3 sections, to provide the number of fibres per linear mm of epidermis. Published guidelines state that only the intraepidermal fibres crossing the dermo-epidermal junction need to be counted. Secondary fibre branches and isolated intraepidermal fibre fragments do not need to be counted [6, 22]. A microscopic factor that may perturb the quantification of IENF density (figure 1C), particularly in inexperienced observers, is the difficulty in locating the dermo-epidermal junction. Normally, most intraepidermal fibres climb to the upper layers of the epidermis and may or may not be ramified. Only a few intraepidermal fibres have a different horizontal projection parallel to the basal membrane [23]. Focal intraepidermal fibre swelling (figure 1D) is sometimes observed and may be related to pre-degenerative changes; however, this characteristic, as with fibre regeneration, is not part of the counting criteria [24]. This manual IENF density counting method is a reproducible intra- and inter-observer test. IENF density is a reliable tool to assess the diagnosis of small fibre sensory neuropathy but it is unable to provide any information about the severity or the aetiology of the disease [4]. The normal IENF mean density is related to the region of the body, is maximal at axial sites and follows a decreasing proximal-to-distal gradient in the limbs [19, 25]. IENF is also dependent on age, particularly in the limbs, gender and the immunohistochemical technique used for counting; for example, confocal microscopy studies report a higher IENF density [26]. Therefore, normalised IENF density data are required for skin biopsy interpretation and it should be consistent within each laboratory for it to be reliable. Published in 2010, the most important normative study correlated IENF density for the distal leg to age and sex [7]. A cut-off at the 5th percentile was chosen to establish a decrease in EJD, vol. 24, n◦ 2, March-April 2014
IENF density (table 3). In our practice, the main limitation of this method remains the finding of a distal IENF density at the 5th percentile density in patients with clinical distal small fibre sensory neuropathy.
Pathophysiology Peripheral nerve fibres can be classified as large fibres (e.g., A␣ for motor strength, and A for mechanosensitivity), medium fibres (e.g., A␥ for muscle spindles) and small fibres (e.g., A␦ and C) [9]. Small nerve fibres can be sympathetic or parasympathetic and they can be thermoreceptors, nociceptors or pruriceptors [8]. SFNs consist of a reduction in epidermal and visceral innervation [6, 7, 27], which frequently follows axon swelling. Axon swelling is attributed to the accumulation of cellular debris from the degeneration of the nerve cytoskeleton and transport system [24]. Consequently, patients suffer from abnormal and unpleasant sensations and a reduction in sensitivity. Patients also can suffer from autonomic symptoms, including increased or decreased sweating, facial flushing or skin discoloration, dry eyes and mouth, changes in skin temperature, erectile dysfunction, orthostatic hypotension or gastrointestinal dysmotility [8, 9]. Most SFNs occur in a length-dependent fashion and result in the loss of function in a stocking distribution in the lower extremities [11]. The disease can advance and a glove-like loss in the upper extremities occurs, as other areas become involved. In some cases, SFN is not length-dependent, such as in Gougerot-Sjögren disease, celiac disease and paraneoplastic syndrome. The pathogenesis of injury to small nerve fibres is poorly understood; however, variants in the SCN9A gene (single
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Table 3. IENF density normative values at the distal leg [from ref.7]. Females
Age (years)
20–29 30–39 40–49 50–59 60–69 70–79 ≥80
Males
0.05 Quantile IENF density values per age span
Median IENF density values per age span
0.05 Quantile IENF density values per age span
Median IENF density values per age span
8.4 7.1 5.7 4.3 3.2 2.2 1.6
13.5 12.4 11.2 9.8 8.7 7.6 6.7
6.1 5.2 4.4 3.5 2.8 2.1 1.7
10.9 10.3 9.6 8.9 8.3 7.7 7.2
amino acid substitutions) were found in some patients with idiopathic SFN. These gene variations produce gain-offunction changes in a sodium channel, Na(v)1.7, which is preferentially expressed in small diameter peripheral axons. Functional testing showed that these variants altered fastinactivation, slow-inactivation or resurgent current and they rendered dorsal root ganglion neurons hyperexcitable [28]. One study showed a negative correlation between IENF density and the number of Langerhans cells, suggesting that an increased number of Langerhans cells in the epidermis may play a role in the generation or maintenance of SFN, but it was performed in a small group of diabetic patients [29]. The role of ischemia, oxidative stress and cytokines (i.e., TNF␣) in SFNs has also been proposed [30].
Dermatological and venerological causes of SFN Gougerot-Sjögren syndrome and systemic lupus erythematosus Approximately 40% of patients with primary GougerotSjögren syndrome present with SFN [31, 32]. Currently, skin biopsy to measure the IENF density is the main technique used for patients with this disease and it is often part of a standardized check-up. The role of vasculitisinduced ischemia, cytokines, such as TNFa, and nerve growth factors (NT-3) has been suggested [31]. Several authors hypothesise that NT-3 and NGF are important because these growth factors are known to activate B- and Tcells in primary Gougerot-Sjögren syndrome [31]. Primary Gougerot-Sjögren syndrome is characterised by an involvement of the skin, including the epidermis [33]. Deposits of immunoglobulin G (IgG) located in the intercellular space of the epidermis have been shown in 68% of patients with primary GSS [34]. However, the role of these deposits and memory B-cell aggregates [35] in epidermal nerve fibres remains unclear. SFN are more rare in patients with systemic lupus erythematosus and are not usually included in check-ups. Nonetheless, the presence of SFN has been evidenced in some patients with systemic lupus erythematosus and neuropathic disorders [36].
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Sarcoidosis SFN is present in approximately 10% of patients with sarcoidosis [37]; however, no length-dependent pattern is observed in this case. While much is known about the pathophysiology of large-fibre neuropathy in sarcoidosis, such as the presence of granulomas around nerves, the exact pathology of axon loss in SFN is unknown [37]. The pathophysiology remains elusive because no cell infiltrate has been described around intraepidermal nerve fibres. Sarcoidosis is associated with the presence of the DQB1 allele and sarcoidosis patients with the HLA-DQB1*0602 allele are more likely to have abnormal temperature-threshold testing, consistent with SFN and a more severe sarcoidosis [38]. Hence, the activity of a soluble factor in the skin is likely.
Fabry disease Males and females with Fabry disease suffer from burning or shooting pain or a painful “pins and needles” sensation in the hands and/or feet, intolerance to heat and the inability to sweat. This is one of the main diagnostic criteria for this disease and it is present in heterozygous women. The pathophysiology of pain in Fabry disease is not fully understood; however, SFN as a result of glycolipid accumulation in the dorsal root ganglia has been proposed [39] and confirmed [40] as a mechanism. Indeed, small fibre conduction is impaired in men with Fabry disease and worsens with advanced disease severity [41]. Indeed, 100% of male patients and 57% of female patients have a decrease of IENF density [40]. Despite extensive data regarding the time course and consequences of SFN in Fabry disease, the underlying pathophysiological mechanism remains speculative. It is uncertain whether the neuropathy arises from the storage of lipids in ganglia leading to a so-called dyingback neuropathy or from direct damage to small nerve fibre axons. The susceptibility of A␦ fibres suggests that the ganglia or axons of small myelinated nerve fibres are more vulnerable to lipid accumulation than small unmyelinated fibres [40]. Enzyme replacement therapy has been shown to reduce neuropathic pain [42]. The IENF density did not change after 12–18 months of treatment, whereas small nerve fibre function improved upon treatment [39, 40]. Therefore, the structural damage to the small nerve fibres may be irreversible but the function of the remaining fibres EJD, vol. 24, n◦ 2, March-April 2014
may improve after enzyme replacement. Another hypothesis is that structural nerve fibre is reversible only after a longer treatment [40, 42].
HIV infection Sensory neuropathies affect 30% of individuals with AIDS. They are usually SFN and treatment is often ineffective. IENF density is inversely correlated with neuropathic pain. Decreased IENF density at the distal leg is associated with lower CD4 counts and higher plasma HIV RNA levels [43]. Moreover, a lower leg IENF density, a higher cooling threshold and a higher heat pain threshold for minimal pain are associated with a greater risk of sensory neuropathy in HIV patients [44]. Hence, measurements of small sensory fibres (leg epidermal nerve fibre density, cooling and heat pain thresholds) seem to be associated with the transition to symptomatic HIV-associated distal sensory neuropathy 6 to 12 months later and could be a prognostic factor.
the reduction of IENF density could be a consequence of scratching. Nummular eczema is a chronic inflammatory condition characterized by pruritus and histologically characterized by spongiosis. The etiology is unknown and the lesions frequently arise spontaneously. Neuropeptides contribute to mediating and to maintaining eczematous conditions. Previous research indicates that the number of immunoreactive nerve fibres is increased in pruritic skin lesions. A recent study showed that there was significantly reduced PGP9.5 staining in the epidermis of patients with nummular eczema compared with their respective healthy controls [49].
Burning mouth syndrome
Erythermalgia, including hereditary erythermalgia, is usually considered as a neuropathy belonging to the channelopathies [45] but that does not exclude that it could be a SFN . Erythermalgia is characterised by the flushing of acral areas, such as the feet and hands. A decrease of IENF density has been noted [46] but without comparison to proximal biopsies. Interestingly, there is a common genetic trait and a common pathophysiological mechanism between primary erythermalgia and the risk of SFN [47]. Voltage-gated sodium channels play a pivotal role in pain transmission, and they are widely expressed in nociceptive neurons. These channels also participate in the generation of action potentials. Alteration in ionic conduction of these channels causes abnormal electrical firing and thus renders neurons hyperexcitable. Until recently, gain-of-function mutations in Na(v)1.7 were known to cause two neuropathic pain syndromes, including inherited erythromelalgia and paroxysmal extreme pain syndrome. These syndromes are inherited as a dominant trait. Recently, SFN and chronic non-paroxysmal pain have been described in patients harbouring gain-of-function mutations in the Na(v)1.7 channel [28].
The pathophysiology of primary burning mouth syndrome (BMS) or primary stomatodynia is hardly debated [50]. In addition to spontaneous burning pain, patients may complain of taste alterations. Recent neurophysiological, psychophysical, neuropathological and functional imaging studies have determined that several neuropathic mechanisms, mostly subclinical, act at different levels of the neuraxis and contribute to the pathophysiology of primary BMS [51-53]. The loss of small diameter nerve fibres in the tongue epithelium explains the thermal hypoesthesia and the increase in taste detection thresholds found in quantitative sensory testing [54]. However, it seems that the clinical diagnosis of primary BMS encompasses at least three distinct, subclinical neuropathic pain states which may overlap in individual patients. The first subgroup (50-65%) is characterised by peripheral small diameter fibre neuropathy of the intraoral mucosa. The second subgroup (20-25%) consists of patients with subclinical lingual, mandibular or trigeminal system pathology, which can be dissected with careful neurophysiologic examination but is clinically indistinguishable from the other two subgroups. The third subgroup (20-40%) fits the concept of central pain that may be related to hypofunction of the dopaminergic neurons in the basal ganglia [52]. Hence, BMS could be a small-fibre neuropathy that is related to an oestrogen deficiency [51] or mouth aging, in the majority of cases. Nonetheless, recent contradictory results suggest that the decrease in IENF density may be related to the age of the patients. In this study [55], BMS was not associated with abnormal thermal and pain thresholds, which fails support a true small nerve neuropathy in this condition. However, age was a factor in thermal thresholds and pain in the anterior tongue, with an unexpected increased sensitivity to cold pain and decreased sensitivity to heat-induced pain.
Prurigo nodularis and nummular eczema
Sensitive skin
Prurigo nodularis is a highly pruritic condition with hyperkeratotic nodules predominating in the legs. To date, this condition has been classified as a disease that results as a consequence of atopic dermatitis or systemic or psychiatric disease. An increased number of dermal nerve fibres in this condition is well-described. Recently, reduced IENF density has been shown in lesional and non-lesional skin [48]. Although there is no neuropathic pain, a neuropathic itch has been reported; therefore, prurigo nodularis could be considered to be a SFN. Another hypothesis is that
Sensitive skin (or reactive or hyper-reactive skin) is defined as skin that responds with erythema and/or subjective symptoms (i.e., pricking, burning, pain, pruritus) to stimuli, including wind, heat, cold, water, cosmetics and stress [56, 57]. Due to the variety of sensory symptoms reported, it seems likely that neurosensory dysfunction of nerves in the skin underlies the altered sensations, although this idea awaits experimental exploration. To date, it is unknown if skin nerve fibre density is altered in sensitive skin or if the physical induction of sensitive skin by wind or cold
Dermatological disorders that could be SFN Erythermalgia
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underlies allodynia in nerve fibres [58]. In summary, sensitive skin could be a SFN, but there are presently no data (i.e., IENF density, QST) to confirm this hypothesis.
Treatment In all cases, an etiological treatment for SFN is needed. Symptomatic treatments including gabapentin, pregabalin, tricyclic antidepressants, serotonin-norepinephrine re-uptake inhibitors and analgesics are used [9, 11, 59].
Conclusions Situated between the skin and the nervous system, SFNs are relevant to dermatologists and skin researchers for many reasons: 1. Clinical symptoms are often initially attributed to the skin by patients. 2. The main method of confirming the diagnosis of SFN is through the IENF density in skin biopsies. 3. Several diseases with skin involvement can be associated with a SFN. 4. Some misunderstood dermatological syndromes could be SFNs. 5. Dermatologists have to know SFNs for all these reasons. Disclosure. Financial support: none. Conflict of interest: none.
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