Clinical Neurophysiology xxx (2013) xxx–xxx

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Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph

Sensory correlates of pain in peripheral neuropathies Sophie Ng Wing Tin a,c, Daniel Ciampi de Andrade b,d, Colette Goujon a,e, Violaine Planté-Bordeneuve f, Alain Créange a,f, Jean-Pascal Lefaucheur a,b,⇑ a

Faculté de Médecine, Université Paris Est Créteil, EA 4391, Créteil, France Service de Physiologie – Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique – Hôpitaux de Paris, Créteil, France c Service de Physiologie – Explorations Fonctionnelles, et Médecine du Sport, Hôpital Avicenne, Assistance Publique – Hôpitaux de Paris, Bobigny, France d Pain Center, Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil e Service de Neurochirurgie, Hôpital Henri Mondor, Assistance Publique – Hôpitaux de Paris, Créteil, France f Service de Neurologie, Hôpital Henri Mondor, Assistance Publique – Hôpitaux de Paris, Créteil, France b

a r t i c l e

i n f o

Article history: Accepted 30 September 2013 Available online xxxx Keywords: Nerve excitability Neuropathic pain Pain Questionnaire Peripheral pain Quantitative sensory testing Small fiber neuropathy

h i g h l i g h t s  In 74 patients, quantitative sensory testing was performed to characterize the changes induced by

peripheral neuropathy, especially associated with pain.  The presence or absence of pain was not associated with differences in sensory thresholds, regarding

either detection or pain thresholds for mechanical and thermal sensations.  However, the intensity of pain, when present, increased with thermal and pain threshold alteration,

showing complex relationship between pain and small fiber dysfunction.

a b s t r a c t Objective: To characterize sensory threshold alterations in peripheral neuropathies and the relationship between these alterations and the presence of pain. Methods: Seventy-four patients with length-dependent sensory axonal neuropathy were enrolled, including 38 patients with painful neuropathy (complaining of chronic, spontaneous neuropathic pain in the feet) and 36 patients with painless neuropathy. They were compared to 28 age-matched normal controls. A standardized quantitative sensory testing protocol was performed in all individuals to assess large and small fiber function at the foot. Large fibers were assessed by measuring mechanical (pressure and vibration) detection thresholds and small fibers by measuring pain and thermal detection thresholds. Results: Between patients with neuropathy and controls, significant differences were found for mechanical and thermal detection thresholds but not for pain thresholds. Patients with painful neuropathy and those with painless neuropathy did not differ regarding mechanical or thermal thresholds, but only by a higher incidence of thermal or dynamic mechanical allodynia in case of painful neuropathy. Pain intensity correlated with the alteration of thermal detection and mechanical pain thresholds. Conclusions: Quantitative sensory testing can support the diagnosis of sensory neuropathy when considering detection threshold measurement. Thermal threshold deterioration was not associated with the occurrence of pain but with its intensity. Significance: There is a complex relationship between the loss or functional deficit of large and especially small sensory nerve fibers and the development of pain in peripheral neuropathy. Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Quantitative sensory testing (QST) is a neurophysiological and psychophysical approach of clinical sensory examination that is ⇑ Corresponding author at: Service Physiologie, Explorations Fonctionnelles, Hôpital Henri Mondor, 51 Avenue de Lattre de Tassigny, 94010 Créteil cedex, France. Tel.: +33 1 4981 2694; fax: +33 1 4981 4660. E-mail address: [email protected] (J.-P. Lefaucheur).

increasingly studied for diagnosis, monitoring, or research (Chong and Cros, 2004; Hansson et al., 2007; Zaslansky and Yarnitsky, 1998). QST assesses sensory nerve function noninvasively. Different tests and methods can be applied to evaluate mechanical and thermal sensations. The light-touch and vibration testing modalities assess large myelinated A-alpha and A-beta sensory fibers, whereas the thermal testing modalities assess small myelinated Adelta and unmyelinated C sensory nerve fibers. Pain threshold mea-

1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.09.038

Please cite this article in press as: Ng Wing Tin S et al. Sensory correlates of pain in peripheral neuropathies Clin Neurophysiol (2013), http://dx.doi.org/ 10.1016/j.clinph.2013.09.038

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surement to nociceptive stimuli applies more generally to C fibers. In clinical setting, QST can be used to characterize various sensory disturbances, such as hypoaesthesia, allodynia, or hyperalgesia. QST has benefitted from various technological and methodological improvements in the past years. The development of automated devices with new software and algorithms has increased the scope of these tests and improved the reliability and clinical interest of this approach. In 1992, the American Diabetes Association has approved QST as a valid diagnostic tool in epidemiologic studies and drug trials in diabetic neuropathy (American Diabetes Association, 1992a,b). However, the standardization of the testing procedure is essential to obtain accurate and reproducible results. In 2006, the German Research Network on Neuropathic Pain (Deutscher Forschungsverbund Neuropathischer Schmerz, DFNS) proposed a comprehensive QST protocol assessing all aspects of somatosensation (Rolke et al., 2006a,b). Tests based on nociceptive and non-nociceptive thermal and mechanical stimuli were included. Sensory loss and sensory gain, for small and large fiber function, were assessed. Reference data were published (Magerl et al., 2010; Rolke et al., 2006a). This protocol has been used to differentiate secondary restless legs syndrome associated with small fiber neuropathy from primary restless legs syndrome (Bachmann et al., 2010) and to establish sensory profiles in patients with neuropathic pain of different origins (Maier et al., 2010). In this study, we investigated a series of patients with painful or painless symmetric, length-dependent sensory axonal polyneuropathy using this standardized QST protocol. The presence or absence of pain among patients with peripheral neuropathy, particularly in diabetics, has been previously associated with a number of variables including: (i) clinical features (Spallone et al., 2011); (ii) genetic polymorphism (Cheng et al., 2010); (iii) circulating plasma levels (Doupis et al., 2009; Oyibo et al., 2002; Tsigos et al., 1993), but not cerebrospinal fluid levels (Tsigos et al., 1995) of various biological markers; (iv) thalamic vascularity (Selvarajah et al., 2011); (v) skin or nerve local hemodynamic factors and microvascular reactivity (Doupis et al., 2009; Eaton et al., 2003; Krishnan et al., 2009; Quattrini et al., 2007a); (vi) autonomic dysfunction (Gandhi et al., 2010); (vii) data from corneal confocal microscopy (Quattrini et al., 2007b); (viii) nerve conduction parameters (Seok Bae et al., 2007); (ix) laser evoked potentials (Truini et al., 2010); and (x) pathological findings on nerve (Britland et al., 1990a,b; Llewelyn et al., 1991) and skin (Quattrini et al., 2007b) biopsies. Regarding QST, a comparative study of thermal or mechanical thresholds between patients with painful and painless neuropathies, whatever the type of neuropathy, was only reported in 13 articles to our knowledge (Bouhassira et al., 1999; Krämer et al., 2004; Krishnan et al., 2009; Llewelyn et al., 1991; Malik et al., 2001; Martin et al., 2003; Martinez et al., 2010; Sorensen et al., 2006a; Sorensen et al., 2006b; Spallone et al., 2011; Tsigos et al., 1992; Veves et al., 1994; Vrethem et al., 2002). Table 1 summarizes the conflicting QST results reported in these studies, in which 1–10 variables have been evaluated. The present work is clearly more comprehensive, with 18 variables studied, including seven variables studied for the first time in this context. In addition, it was based on a larger series of patients (n = 74) with neuropathy of various etiologies, exceeded only by three studies of 84–191 patients (Veves et al., 1994; Sorensen et al., 2006a; Spallone et al., 2011), all with diabetic neuropathy and only based on 1–3 QST tests.

2. Patients and methods 2.1. Patients This study was conducted in 12 months in the department of neurophysiology of Henri Mondor hospital, Créteil. To be eligible

for the study, patients need to have a chronic sensory or sensory-motor length-dependent axonal polyneuropathy, but with clearly predominant sensory involvement on both clinical and neurophysiological grounds. One hundred consecutive patients with these features were screened in the context of their usual neurophysiological follow-up. Seventy-nine of these patients gave their consent for the QST study and were prospectively included in this study. After inclusion, patients were divided into two groups, according to the presence or absence of chronic neuropathic pain in the feet. Regarding painless neuropathy, the absence of pain should be obtained without analgesic medication. Regarding painful neuropathy, foot pain should be present for at least 3 months with intensity score superior to 4/10 on visual analogue scale (VAS) in the average of 7 daily assessments during a representative week. In addition, pain should be defined as neuropathic with a score superior or equal to 4 for the DN4 questionnaire (Bouhassira et al., 2005). Five patients who reported foot pain with a DN4 score inferior to 4 were excluded from the study, because of uncertainty about the origin of their pain and its relationship with the neuropathy. Thus, the analyses were performed on 74 patients with painless (n = 36) or painful (n = 38) neuropathy. The study was performed in accordance with the Declaration of Helsinki and approved by our local Institution Review Board (CPP IdF IX, Créteil, France). 2.2. Clinical characteristics In patients with painless neuropathy (n = 36), neuropathy was related to diabetes (n = 13), monoclonal gammopathy or autoimmune disorder (n = 13), familial amyloidosis (n = 5), chemotherapy (n = 1), hepatitis C virus infection (n = 1), alcohol (n = 1), kidney failure (n = 1), or Charcot-Marie-Tooth disease of axonal type (CMT2A) (n = 1). In patients with painful neuropathy (n = 38), neuropathy was related to diabetes (n = 6), monoclonal gammopathy or autoimmune disorder (n = 12), familial amyloidosis (n = 4), chemotherapy (n = 2), hepatitis C virus infection (n = 1), alcohol (n = 1), or idiopathic small nerve fiber neuropathy (n = 12), according to previously described criteria (Holland, 2001; Hoitsma et al., 2004; Faber et al., 2012). Twenty-five patients with painful neuropathy received drug treatment for neuropathic pain, including antidepressants (n = 9), antiepileptics (n = 21), and opioids (n = 3) that were not administered the day of neurophysiological investigation. 2.3. Quantitative sensory testing (QST) QST was carried out in the right foot or the foot that was the most symptomatic of neuropathy. However, if there was a history of trauma or lumbar radiculalgia on one side, the other side was chosen. All tests were performed on the plantar and dorsal surfaces of each studied foot. Our standardized QST protocol was similar to that developed by the DFNS (Rolke et al., 2006a,b). Briefly, the protocol consisted of a comprehensive battery of tests, measuring 10 parameters to assess thermal sensitivity and eight parameters to assess mechanical sensitivity. Regarding thermal sensitivity, we measured detection thresholds for cold (CDT) and warm (WDT) stimuli, thermal sensory limen (TSL) and paradoxical heat sensations (PHS) in a series of alternating warm and cold stimuli, pain thresholds for cold (CPT) and hot (HPT) stimuli, and allodynia and hyperalgesia for cold (C-All, C-Hyp) and warm/hot (W-All, H-Hyp) stimuli. All these tests were performed using a 16 cm2 Peltier probe connected to a Thermal Sensory Analyzer TSA 2001 (Medoc, Ramat Yishai, Israël) (Yarnitsky and Sprecher, 1994). All detection and pain thresholds (in °C) were determined as the average value from three trials

Please cite this article in press as: Ng Wing Tin S et al. Sensory correlates of pain in peripheral neuropathies Clin Neurophysiol (2013), http://dx.doi.org/ 10.1016/j.clinph.2013.09.038

Cold detection threshold Llewelyn et al. (1991) Tsigos et al. (1992) Veves et al. (1994) Bouhassira et al. (1999) Malik et al. (2001) Vrethem et al. (2002) Martin et al. (2003) Krämer et al. (2004) Sorensen et al. (2006a) Sorensen et al. (2006b) Krishnan et al. (2009) Martinez et al., 2010 Spallone et al., 2011 Present study

Diabetic neuropathy: painful (9)/painless (10) Diabetic neuropathy: painful (19)/painless (14) Diabetic neuropathy: painful (52)/painless (32) HIV neuropathy: painful (15)/painless (25) Diabetic neuropathy: painful (6)/painless (9) Various neuropathies: painful (37)/painless (18) HIV neuropathy: painful (18)/painless (13) Diabetic neuropathy: painful (15)/painless (15) Diabetic neuropathy: painful (122)/painless (69) Diabetic neuropathy: painful (25)/painless (13) Diabetic neuropathy: painful (10)/painless (12) Guillain–Barré syndrome: painful (13)/painless (17) Diabetic neuropathy: painful (78)/painless (57) Various neuropathies: painful (38)/painless (36)

Higher

No diff

Warm detection threshold

Cold pain threshold

Heat pain threshold

Cold hyperalgesia

Heat hyperalgesia

Lower

Lower

No diff

Lower

No diff

No diff

No diff

No diff

No diff

No diff

No diff

Lower No diff

No diff

No diff

Higher

(*)

No diff

No diff

Dynamic mechanical allodynia

Mechanical detection threshold

Mechanical pain threshold

Static mechanical hyperalgesia

No diff

Lower(*)

Higher(*)

Higher

No diff

No diff

Higher

No diff

No diff(*)

No diff

Higher

No diff No diff Higher (*)

Lower

No diff

Higher

No diff No diff

No diff

No diff

Higher

No diff

no diff

Higher Lower

Vibration detection threshold

Lower

(*)

Lower

No diff

No diff

Higher

Lower No diff

Lower No diff

No diff

(*)

No diff

(*)

No diff

No diff

No diff

No diff

No diff

S. Ng Wing Tin et al. / Clinical Neurophysiology xxx (2013) xxx–xxx

Results are presented as significant changes (higher or lower values) observed in patients with painful neuropathy compared to patients with painless neuropathy. No diff: absence of significant difference between the two groups. Variable correlated with the intensity of pain. Seven variables were evaluated for the first time in the present study and are not reported in the table (thermal sensory limen, paradoxical heat sensations, cold allodynia, warm allodynia, wind-up ratio, static mechanical allodynia, pressure pain threshold).

(*)

3

Please cite this article in press as: Ng Wing Tin S et al. Sensory correlates of pain in peripheral neuropathies Clin Neurophysiol (2013), http://dx.doi.org/ 10.1016/j.clinph.2013.09.038

Table 1 Review of literature data regarding comparative studies of thermal and mechanical thresholds between patients with painful and painless neuropathies.

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S. Ng Wing Tin et al. / Clinical Neurophysiology xxx (2013) xxx–xxx

Table 2 Quantitative sensory testing results regarding thermal sensations. Controls

Painless neuropathy

Painful neuropathy

KW test

Dunn post-test

Cold detection threshold-dorsal (°C)

28.83 ± 2.37 (29.8)

20.06 ± 10.73 (25.1)

21.93 ± 10.2 (26.4)

Sensory correlates of pain in peripheral neuropathies.

To characterize sensory threshold alterations in peripheral neuropathies and the relationship between these alterations and the presence of pain...
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