ORIGINAL

ARTICLE

Pruritus: An underrecognized symptom of small-fiber neuropathies Emilie Brenaut, MD,a,d Pascale Marcorelles, MD, PhD,c,d,e Steeve Genestet, MD,b,e Dominique Menard, MD,e,f and Laurent Misery, MD, PhDa,d,e Brest and Rennes, France Background: Small-fiber neuropathies (SFN) are diseases of small nerve fibers that are characterized by autonomic and sensory symptoms. Objective: We sought to evaluate sensory symptoms, especially pruritus, in patients with SFN. Methods: A questionnaire was given to patients with SFN. Results: In all, 41 patients responded to the questionnaire (71.9% response rate). The most frequent sensory symptoms were burning (77.5%), pain (72.5%), heat sensations (70.2%), and numbness (67.5%). Pruritus was present in 68.3% of patients. It appeared most often in the evening, and was localized to the limbs in a distal-to-proximal gradient, although the back was the most frequent location (64%). Exacerbating factors were fatigue, xerosis, sweating, hot temperature, and stress. Cold water was an alleviating factor. Limitations: Recall bias associated with filling out the questionnaire, relatively small sample size, and the uncontrolled, retrospective nature of the study were limitations. Conclusion: Pruritus occurs frequently in patients with SFN and could be recognized as a possible presenting symptom, especially if there are other sensory or autonomic symptoms. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2014.10.034.) Key words: pruritus; questionnaire; sensory symptoms; small-fiber neuropathy.

mall-fiber neuropathies (SFN) are disorders of thinly myelinated A-d and unmyelinated C fibers. SFN have recently been described.1 In a recent study, the incidence of SFN was 11.7 cases/ 100,000 people/y, and the overall minimum prevalence was 52.95 cases/100,000.2 Hence, they are not rare disorders. SFN are usually idiopathic but may be associated with various diseases, such as metabolic diseases (eg, diabetes and prediabetes), infectious diseases (eg, HIV, hepatitis C infection), inflammatory diseases (eg, Sj€ ogren syndrome), autoimmune diseases, paraneoplastic syndromes, or genetic diseases (eg, Fabry disease).3,4 The pathogenesis is

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poorly understood and probably depends on the cause. SFN lead to a significant reduction in the overall quality of life.5 The clinical manifestations include autonomic symptoms such as dry eyes, dry mouth, dizziness, constipation, bladder incontinence, sexual dysfunction, excessive sweating, and red or white skin discoloration. Patients also have sensory symptoms that are often their main symptom, including pain, pruritus (itch), burning, tingling, or numbness, and typically affect the limbs in a distal to proximal gradient.6 Because their symptoms are mainly located in the skin in the initial stages, dermatologists may frequently be confronted

From the Departments of Dermatology,a Clinical Neurophysiology,b and Pathology,c University Hospital, Brest; Laboratory of Neurosciences of Brest, University of Western Brittanyd; Breton Competence Center of Rare Neuromuscular Diseases and Neuropathies with Cutaneous-Mucosal Symptoms, Breste; and Department of Neurology, University Hospital, Rennes.f Funding sources: None. Conflicts of interest: None declared.

Accepted for publication October 24, 2014. Reprint requests: Emilie Brenaut, MD, Department of Dermatology, University Hospital, 2 avenue Foch, 29609 Brest, France. E-mail: [email protected]. Published online December 4, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.10.034

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The study used an exploratory approach with a with this disease. The following diagnostic criteria questionnaire in French adapted from previous are generally accepted7: normal sural nerve conducquestionnaires8,10 that had been used in a previous tion, clinical symptoms and signs considered suggestive of SFN, and/or altered quantitative study to investigate pruritus characteristics in sensory testing. A diminution of intraepidermal different dermatoses.9 The questionnaire first asks nerve fiber (IENF) density has become the major patients about the duration of their symptoms diagnostic criterion. Treatment of SFN is based and then asks whether they have any sensory on etiology; symptomatic symptoms. Patients evalutreatments (eg, gabapentin, ated the following sympCAPSULE SUMMARY pregabalin, tricyclic antidetoms from 0 (nonexistent) pressants) can be used as to 3 (severe): pain, stinging, Little is known about sensory symptoms well. The aim of this study tickling, crawling, stabbing, in small-fiber neuropathies. was to evaluate the frepinching, burning, biting, Pruritus was present in 68.3% of our quency and severity of stroking, electric discharge, patients. It was intense, appeared most sensory symptoms in panumbness, heat sensations, often in the evening, and was localized tients with SFN with a special and cold sensations. Next, to the limbs in a distal-to-proximal focus on pruritus and its patients reported whether gradient. characteristics. A questionthey had pruritus. If they naire adapted from previous answered ‘‘yes,’’ the patient Pruritus should be recognized as a questionnaires was sent filled out the second part of possible presenting symptom of smallto each patient with SFN.8-10 the questionnaire about the fiber neuropathies. characteristics of their pruritus that included questions METHODS about the chronology, localization, intensity, Patients were recruited at the Department of disruption of daily activities, and characteristics of Pathology, University Hospital, Brest, France, in scratching. Written informed consent was obtained which all biopsy specimens for the area are sent from all patients. when the diagnosis of SFN is suspected. After a positive biopsy specimen, we checked in patients’ reports if they filled eligibility and exclusion criteria. The questionnaire was sent to all patients RESULTS with SFN who had been given a diagnosis in the The questionnaire was sent to 57 patients, 41 of last year. whom responded (71.9% response rate). The deEligibility was based on the following criteria: (1) mographic and baseline clinical characteristics of the age 18 years and older; and (2) diagnosis of SFN patients are summarized in Table I. according to criteria of Devigili et al7: (a) clinical Concerning the duration of their symptoms, 10.3% of patients declared that sensory symptoms signs of small-fiber impairment (pinprick and therhad been present for just a few months; for most mal sensory loss and/or allodynia and/or hyperpatients (89.7%), sensory symptoms had been prealgesia), the distribution of which is consistent with sent for 1 year or more. peripheral neuropathy (length- or non-lengthEach sensory symptom was evaluated by the dependent neuropathy); (b) abnormal warm and/ patient from 0 (nonexistent) to 3 (severe). The or cooling threshold in the foot, as assessed by frequency of these symptoms is presented in Fig 1. quantitative sensory testing; and (c) reduced IENF Of 41 patients with SFN, 28 (68.3%) had mild or density in the distal leg. severe pruritus. The characteristics of pruritus were Eligible patients were ruled out based on the studied in these patients. presence of the following: (1) any sign of large Itch appeared daily for 13 patients (46.4%), almost fiber impairment (light touch and/or vibratory daily for 10 (35.7%), on a weekly basis for 1 (3.6%), and/or proprioceptive sensory loss and/or absent on a monthly basis for 2 (7.1%), and infrequently for tendon reflexes); (2) any sign of motor fiber 1 (3.6%). impairment (muscle waste and/or weakness); and The occurrence of pruritus at different times of the (3) any abnormality on sensorimotor sural nerve day is presented in Fig 2. Pruritus tended to appear conduction. more frequently in the evening than in the morning, The exclusion criteria were as follows: (1) other afternoon, or night. putative causes of pruritus; or (2) inability to comThe areas of the body most commonly afflicted plete the questionnaire because of cognitive or were the back (63%); foot (59%); shin (56%); forearm physical impairment. d

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Table I. Demographic and baseline clinical characteristics of patients with small-fiber neuropathies included in the study No (%)

Age, y Mean Median Range Sex Men Women Causes of SFN* €gren disease Gougerot-Sjo Idiopathic Diabetes Vitamin-B12 deficiency HIV infection Hypothyroidism Rheumatoid arthritis Gammopathy

61.5 63 31-85 15 (36.6) 26 (63.4) 16 14 6 3 2 2 1 1

(39.0) (34.1) (14.6) (7.3) (4.9) (4.9) (2.4) (2.4)

SFN, Small-fiber neuropathies. *There are more causes than patients because some patients have several diseases causing SFN.

and head (52%); neck, hand, thigh, arm (44%); chest (40%); and abdomen (30%). The intensity of pruritus was assessed by a visual analog scale. At its worst, pruritus was intense (7.36/ 10), and at its best, pruritus was mild but still present (2.24/10). On average, the intensity of pruritus was rated as 4.79/10. The effects of normal daily activities on pruritus are shown in Table II. The following activities had a variable effect or no effect: sleep, rest, activity, physical effort, hot water, and cold ambient temperature. The following activities increased the intensity of pruritus: fatigue, skin dryness, sweating, hot ambient temperature, and stress. Cold water was an alleviating factor for 44% of patients. For the question, ‘‘Do you scratch?’’ 14% of patients answered ‘‘very often,’’ 57% answered ‘‘often,’’ and 29% answered ‘‘rarely’’; no patients reported never scratching. Scratching was considered highly pleasurable for 15%, moderately pleasurable for 33%, neutral for 15%, moderately unpleasant for 19%, and highly unpleasant for 18%.

DISCUSSION In the literature, little information is given on the sensory symptoms of patients with SFN; the sensory symptoms are only described as pain, pruritus, burning, tingling, or numbness that typically affect the limbs in a distal-to-proximal gradient.3,11 The pain is often burning, prickling, or shooting. Paresthesia, sheet intolerance, and restless leg syndrome are also described.12 In our study, the sensory

symptoms more frequently reported (evaluated as mild or severe in percent of patients) were (in decreasing order): burning (77.5%), pain (72.5%), heat sensations (70.2%), pruritus (68.3%), numbness (67.5%), crawling (65.0%), stinging (60.0%), electric discharge (59.0%), and cold sensations (57.9%). In our study, pruritus was one of the most frequent symptoms in patients with SFN. However, the incidence of pruritus in this patient population is rarely reported in the literature, suggesting that pruritus is underrecognized in patients with SFN. In chronic pruritus, 8% of cases can be associated with a neuropathic origin,13 and SFN is described as a cause of neuropathic pruritus.6,14 Chronic pruritus is called ‘‘neuropathic’’ when nerve fiber damage is responsible for the symptom.15,16 The nerve fiber damage causes overlapping symptoms of pruritus and pain.13 A reduction of the intraepidermal density of small fibers was measured in all our patients and is usually observed in patients with SFN, as it is a diagnostic criterion. Pruritus is known to usually originate in the area around the dermoepidermal junction6 where nerve endings are damaged. Consequently, it is not surprising that pruritus was found to be a predominant symptom of SFN. Pruritus was predominant in the evening, an observation that has been described in other dermatoses.9 In SFN, symptoms may be mild initially, with some patients reporting vague discomfort, but more often, the intensity is severe. At its worst, it was evaluated at an intensity of 7.36/10 on a visual analog scale and 4.79/10 on average, which is similar to other dermatoses such as psoriasis17,18 or urticaria.19 Sensory symptoms of SFN are usually described to be predominant in the hands and feet in a stockingglove distribution. However, other localizations are described; in some cases, SFN follow a non-lengthdependent distribution in which symptoms may be manifested predominantly in the arms, face, or trunk.11 These sensory symptoms are sometimes described as patchy or asymmetric. Pruritus is described as generalized as often as it is described as localized.13 In our study, the back was the most frequent location (64%), but head and neck were frequently involved. The presence of pruritus in these unexpected areas has also been observed in other cases of neuropathic pruritus6 (eg, brachioradial pruritus20) and is most likely secondary to a central sensitization to itch. Worsening factors of pruritus were fatigue, stress, skin dryness, sweating, and hot temperature; these findings are similar to the findings in previous studies on dermatoses.9,21 Cold water was found to be an alleviating factor, as frequently

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Fig 1. Frequency of sensory symptoms in patients with small-fiber neuropathies, evaluated from 0 (nonexistent) to 3 (severe).

Table II. Effects of daily activities on pruritus

Fig 2. Frequency of pruritus depending on the time of day.

reported by patients with chronic pruritus. Compared with other skin diseases that are similar to pruritus, there is no difference in triggering or alleviating factors, and similar advice applies to alleviate symptoms: apply topical emollients, avoid hot temperature, etc. Limitations of this study are the relatively small sample size and the retrospective study, but they are explained by the low prevalence of SFN. This study was based on a questionnaire filled out by patients, not physicians, but this is the main way to have information on sensory symptoms that are subjective, especially on pruritus. Patients were recruited from the department of pathology, based on a positive biopsy specimen.

Sleep Rest Activity Stress Fatigue Physical effort Skin dryness Hot water Cold water Sweating Cold ambient temperature Hot ambient temperature Specific fabrics

Increases

Does not affect

Relieves

18% 18% 15% 46% 55% 36% 56% 26% 11% 50% 20% 48% 40%

50% 68% 73% 54% 41% 48% 37% 59% 48% 42% 60% 48% 52%

32% 14% 12% 0% 4% 16% 7% 15% 41% 8% 20% 4% 8%

Nowadays, a diminution of IENF density is the major diagnostic criterion of SFN. After stepped skin biopsy specimens, numeration of protein gene product 9.5 fibers is done by trained teams. Patients came from different practices (dermatology, neurology, and rheumatology) and all patients with SFN confirmed by biopsy specimen were recruited. SFN have been recently identified and have been receiving increasing attention in the last 15 years, especially with the introduction of IENF density measurements. The number of patients given a diagnosis of this type of neuropathy is increasing rapidly because of better recognition of the disease.

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However, the clinical features of SFN are not precisely known and they are most likely still underdiagnosed. Patient history and physical examination are considered the most important for diagnosing SFN. Diagnosis can be confirmed with quantitative sensory testing (abnormal warm and/or cooling threshold in the foot) or reduced IENF density in the distal leg with skin biopsy specimens.22,23 It is important to increase clinicians’ knowledge about sensory symptoms in order for them to make the correct diagnosis. Our study shows that pruritus is a very frequent symptom in patients with SFN and could be recognized by dermatologists as a possible presenting symptom, especially if there are other sensory symptoms, or autonomic symptoms. REFERENCES 1. Holland NR, Crawford TO, Hauer P, Cornblath DR, Griffin JW, McArthur JC. Small-fiber sensory neuropathies: clinical course and neuropathology of idiopathic cases. Ann Neurol. 1998;44: 47-59. 2. Peters MJH, Bakkers M, Merkies ISJ, Hoeijmakers JGJ, van Raak EPM, Faber CG. Incidence and prevalence of small-fiber neuropathy: a survey in the Netherlands. Neurology. 2013;81: 1356-1360. 3. Misery L, Bodere C, Genestet S, Zagnoli F, Marcorelles P. Small-fibre neuropathies and skin: news and perspectives for dermatologists. Eur J Dermatol. 2014;24:147-153. 4. Hovaguimian A, Gibbons CH. Diagnosis and treatment of pain in small-fiber neuropathy. Curr Pain Headache Rep. 2011;15: 193-200. 5. Bakkers M, Faber CG, Hoeijmakers JGJ, Lauria G, Merkies ISJ. Small fibers, large impact: quality of life in small-fiber neuropathy. Muscle Nerve. 2014;49:329-336. 6. Misery L, Brenaut E, Le Garrec R, et al. Neuropathic pruritus. Nat Rev Neurol. 2014;10:408-416. 7. Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008;131:1912-1925. 8. Darsow U, Scharein E, Simon D, Walter G, Bromm B, Ring J. New aspects of itch pathophysiology: component analysis of atopic itch using the ‘‘Eppendorf Itch Questionnaire.’’ Int Arch Allergy Immunol. 2001;124:326-331.

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9. Brenaut E, Garlantezec R, Talour K, Misery L. Itch characteristics in five dermatoses: non-atopic eczema, atopic dermatitis, urticaria, psoriasis and scabies. Acta Derm Venereol. 2013;93: 573-574. 10. Yosipovitch G, Goon ATJ, Wee J, Chan YH, Zucker I, Goh CL. Itch characteristics in Chinese patients with atopic dermatitis using a new questionnaire for the assessment of pruritus. Int J Dermatol. 2002;41:212-216. 11. Tavee J, Zhou L. Small fiber neuropathy: a burning problem. Cleve Clin J Med. 2009;76:297-305. 12. Hoitsma E, Reulen JPH, de Baets M, Drent M, Spaans F, Faber CG. Small fiber neuropathy: a common and important clinical disorder. J Neurol Sci. 2004;227:119-130. 13. Stumpf A, St€ander S. Neuropathic itch: diagnosis and management. Dermatol Ther. 2013;26:104-109. 14. Oaklander AL. Common neuropathic itch syndromes. Acta Derm Venereol. 2012;92:118-125. 15. Bernhard JD. Neurogenic pruritus and strange skin sensations. In: Bernhard JD, editor. Itch, mechanisms and management of pruritus. New York: McGraw-Hill; 1994. pp. 185-201. 16. Marziniak M, Pogatzki-Zahn M, Evers S. Other neurological causes of itch. In: Misery L, Stander S, editors. Pruritus. London: Springer; 2010. pp. 163-166. 17. Amatya B, Nordlind K. Focus groups in Swedish psoriatic patients with pruritus. J Dermatol. 2008;35:1-5. 18. Yosipovitch G, Goon A, Wee J, Chan YH, Goh CL. The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis. Br J Dermatol. 2000;143:969-973. 19. Yosipovitch G, Ansari N, Goon A, Chan YH, Goh CL. Clinical characteristics of pruritus in chronic idiopathic urticaria. Br J Dermatol. 2002;147:32-36. 20. Kwatra SG, Stander S, Bernhard JD, Weisshaar E, Yosipovitch G. Brachioradial pruritus: a trigger for generalization of itch. J Am Acad Dermatol. 2013;68:870-873. 21. Chrostowska-Plak D, Salomon J, Reich A, Szepietowski JC. Clinical aspects of itch in adult atopic dermatitis patients. Acta Derm Venereol. 2009;89:379-383. 22. Lauria G, Bakkers M, Schmitz C, et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst. 2010;15:202-207. 23. Lauria G, Hsieh ST, Johansson O, et al, European Federation of Neurological Societies; Peripheral Nerve Society. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2010;17:903-912, e44-e49.

Pruritus: an underrecognized symptom of small-fiber neuropathies.

Small-fiber neuropathies (SFN) are diseases of small nerve fibers that are characterized by autonomic and sensory symptoms...
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