Psychophysics: Quantitative Sensory Testing in the Diagnostic Work-Up of Small Fiber Neuropathy

  • Claudia SommerEmail author


Quantitative sensory testing (QST), in particular using thermodes to apply defined warm and cold stimuli, is a well-established method to detect functional changes of Aδ- and C-fibers. Protocols have been established, and normative values have been determined in large cohorts. QST can be understood as an extension of clinical examination used to detect, confirm, and quantify subtle sensory abnormalities. Usually, thresholds for warm and cold detection, for pain induced by heat and cold, and for the detection of changes in temperature are assessed. The equipment, to date, is costly and bulky, but smaller and more affordable devices are being developed. To obtain intra- and interobserver comparability, it is important to observe a standardized method with fixed instructions given to the patient. As a psychophysical test, QST requires patient cooperation, and there may be errors due to lack of attention or malingering. Also, the range of normal is large, so that false-negative findings may result. Given these caveats, QST has been used by many groups and has been found a simple and moderately sensitive instrument to detect small fiber dysfunction both in small fiber neuropathy and in other conditions associated with damage to the small fibers. In particular, this noninvasive method can be used for intraindividual follow-up in prospective studies.


Thermal detection thresholds Mechanical detection thresholds Pain thresholds Windup Diabetes mellitus Fabry disease Channelopathy Sarcoidosis 


  1. 1.
    Backonja MM, Walk D, Edwards RR, Sehgal N, Moeller-Bertram T, Wasan A, et al. Quantitative sensory testing in measurement of neuropathic pain phenomena and other sensory abnormalities. Clin J Pain. 2009;25:641–7.CrossRefGoogle Scholar
  2. 2.
    Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain. 2006;123:231–43.CrossRefGoogle Scholar
  3. 3.
    Dyck PJ, Zimmerman IR, O’Brien PC, Ness A, Caskey PE, Karnes J, et al. Introduction of automated systems to evaluate touch-pressure, vibration, and thermal cutaneous sensation in man. Ann Neurol. 1978;4:502–10.CrossRefGoogle Scholar
  4. 4.
    Backonja MM, Attal N, Baron R, Bouhassira D, Drangholt M, Dyck PJ, et al. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain. 2013;154:1807–19.CrossRefGoogle Scholar
  5. 5.
    Rolke R, Baron R, Maier C, Tölle TR, Treede RD, Beyer A, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain. 2006;123:231–43.CrossRefGoogle Scholar
  6. 6.
    Maier C, Baron R, Tolle TR, Binder A, Birbaumer N, Birklein F, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain. 2010;150:439–50.CrossRefGoogle Scholar
  7. 7.
    Baron R, Maier C, Attal N, Binder A, Bouhassira D, Cruccu G, et al. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain. 2017;158:261–72.CrossRefGoogle Scholar
  8. 8.
    Demant DT, Lund K, Vollert J, Maier C, Segerdahl M, Finnerup NB, et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study. Pain. 2014;155:2263–73.CrossRefGoogle Scholar
  9. 9.
    Claus D, Hilz MJ, Hummer I, Neundorfer B. Methods of measurement of thermal thresholds. Acta Neurol Scand. 1987;76:288–96.CrossRefGoogle Scholar
  10. 10.
    Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S, Birklein F, et al. Quantitative sensory testing: a comprehensive protocol for clinical trials. Eur J Pain. 2006;10:77–88.CrossRefGoogle Scholar
  11. 11.
    Rolke R, Andrews Campbell K, Magerl W, Treede RD. Deep pain thresholds in the distal limbs of healthy human subjects. Eur J Pain. 2005;9:39–48.CrossRefGoogle Scholar
  12. 12.
    Magerl W, Krumova EK, Baron R, Tolle T, Treede RD, Maier C. Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data. Pain. 2010;151:598–605.CrossRefGoogle Scholar
  13. 13.
    Pfau DB, Krumova EK, Treede RD, Baron R, Toelle T, Birklein F, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): reference data for the trunk and application in patients with chronic postherpetic neuralgia. Pain. 2014;155:1002–15.CrossRefGoogle Scholar
  14. 14.
    Blankenburg M, Boekens H, Hechler T, Maier C, Krumova E, Scherens A, et al. Reference values for quantitative sensory testing in children and adolescents: developmental and gender differences of somatosensory perception. Pain. 2010;149:76–88.CrossRefGoogle Scholar
  15. 15.
    Vollert J, Mainka T, Baron R, Enax-Krumova EK, Hullemann P, Maier C, et al. Quality assurance for Quantitative Sensory Testing laboratories: development and validation of an automated evaluation tool for the analysis of declared healthy samples. Pain. 2015;156:2423–30.CrossRefGoogle Scholar
  16. 16.
    Heldestad V, Wiklund U, Hornsten R, Obayashi K, Suhr OB, Nordh E. Comparison of quantitative sensory testing and heart rate variability in Swedish Val30Met ATTR. Amyloid. 2011;18:183–90.CrossRefGoogle Scholar
  17. 17.
    Vollert J, Attal N, Baron R, Freynhagen R, Haanpaa M, Hansson P, et al. Quantitative sensory testing using DFNS protocol in Europe: an evaluation of heterogeneity across multiple centers in patients with peripheral neuropathic pain and healthy subjects. Pain. 2016;157:750–8.CrossRefGoogle Scholar
  18. 18.
    Blankenburg M, Meyer D, Hirschfeld G, Kraemer N, Hechler T, Aksu F, et al. Developmental and sex differences in somatosensory perception – a systematic comparison of 7- versus 14-year-olds using quantitative sensory testing. Pain. 2011;152:2625–31.CrossRefGoogle Scholar
  19. 19.
    Haanpää M, Attal N, Backonja M, Baron R, Bennett M, Bouhassira D, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain. 2011;152:14–27.CrossRefGoogle Scholar
  20. 20.
    Cruccu G, Sommer C, Anand P, Attal N, Baron R, Garcia-Larrea L, et al. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol. 2010;17:1010–8.CrossRefGoogle Scholar
  21. 21.
    Birklein F, Sommer C. Pain: quantitative sensory testing – a tool for daily practice? Nat Rev Neurol. 2013;9:490–2.CrossRefGoogle Scholar
  22. 22.
    Stewart JD, Low PA, Fealey RD. Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes. Muscle Nerve. 1992;15:661–5.CrossRefGoogle Scholar
  23. 23.
    Lacomis D. Small-fiber neuropathy. Muscle Nerve. 2002;26:173–88.CrossRefGoogle Scholar
  24. 24.
    Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008;131:1912–25.CrossRefGoogle Scholar
  25. 25.
    Üçeyler N, Kafke W, Riediger N, He L, Necula G, Toyka KV, et al. Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology. 2010;74:1806–13.CrossRefGoogle Scholar
  26. 26.
    Üçeyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain. 2013;136:1857–67.CrossRefGoogle Scholar
  27. 27.
    Serra J, Collado A, Sola R, Antonelli F, Torres X, Salgueiro M, et al. Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol. 2014;75:196–208.CrossRefGoogle Scholar
  28. 28.
    Vallbo AB, Olausson H, Wessberg J. Unmyelinated afferents constitute a second system coding tactile stimuli of the human hairy skin. J Neurophysiol. 1999;81:2753–63.CrossRefGoogle Scholar
  29. 29.
    Cole J, Bushnell MC, McGlone F, Elam M, Lamarre Y, Vallbo A, et al. Unmyelinated tactile afferents underpin detection of low-force monofilaments. Muscle Nerve. 2006;34:105–7.CrossRefGoogle Scholar
  30. 30.
    Lauria G, Sghirlanzoni A, Lombardi R, Pareyson D. Epidermal nerve fiber density in sensory ganglionopathies: clinical and neurophysiologic correlations. Muscle Nerve. 2001;24:1034–9.CrossRefGoogle Scholar
  31. 31.
    Scherens A, Maier C, Haussleiter IS, Schwenkreis P, Vlckova-Moravcova E, Baron R, et al. Painful or painless lower limb dysesthesias are highly predictive of peripheral neuropathy: comparison of different diagnostic modalities. Eur J Pain. 2009;13:711–8.CrossRefGoogle Scholar
  32. 32.
    Scott K, Simmons Z, Kothari MJ. A comparison of quantitative sensory testing with skin biopsy in small fiber neuropathy. J Clin Neuromuscul Dis. 2003;4:129–32.CrossRefGoogle Scholar
  33. 33.
    Magda P, Latov N, Renard MV, Sander HW. Quantitative sensory testing: high sensitivity in small fiber neuropathy with normal NCS/EMG. J Peripher Nerv Syst. 2002;7:225–8.CrossRefGoogle Scholar
  34. 34.
    Shukla G, Bhatia M, Behari M. Quantitative thermal sensory testing – value of testing for both cold and warm sensation detection in evaluation of small fiber neuropathy. Clin Neurol Neurosurg. 2005;107:486–90.CrossRefGoogle Scholar
  35. 35.
    Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G, et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst. 2010;15:202–7.CrossRefGoogle Scholar
  36. 36.
    Vlckova-Moravcova E, Bednarik J, Dusek L, Toyka KV, Sommer C. Diagnostic validity of epidermal nerve fiber densities in painful sensory neuropathies. Muscle Nerve. 2008;37:50–60.CrossRefGoogle Scholar
  37. 37.
    Rage M, Van Acker N, Knaapen MW, Timmers M, Streffer J, Hermans MP, et al. Asymptomatic small fiber neuropathy in diabetes mellitus: investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials. J Neurol. 2011;258:1852–64.CrossRefGoogle Scholar
  38. 38.
    Vollert J, Maier C, Attal N, Bennett D, Bouhassira D, Enax-Krumova E, et al. Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations. Pain. 2017;158(8):1446–55.CrossRefGoogle Scholar
  39. 39.
    Üçeyler N, Vollert J, Broll B, Riediger N, Langjahr M, Saffer N, et al. Sensory profiles and skin innervation of patients with painful and painless neuropathies. Pain. 2018;159(9):1867–76.PubMedGoogle Scholar
  40. 40.
    Schestatsky P, Stefani LC, Sanches PR, Silva Junior DP, Torres IL, Dall-Agnol L, et al. Validation of a Brazilian quantitative sensory testing (QST) device for the diagnosis of small fiber neuropathies. Arq Neuropsiquiatr. 2011;69:943–8.CrossRefGoogle Scholar
  41. 41.
    Blackmore D, Siddiqi ZA. Pinprick testing in small fiber neuropathy: accuracy and pitfalls. J Clin Neuromuscul Dis. 2016;17:181–6.CrossRefGoogle Scholar
  42. 42.
    Sveen KA, Karime B, Jorum E, Mellgren SI, Fagerland MW, Monnier VM, et al. Small- and large-fiber neuropathy after 40 years of type 1 diabetes: associations with glycemic control and advanced protein glycation: the Oslo Study. Diabetes Care. 2013;36:3712–7.CrossRefGoogle Scholar
  43. 43.
    Vlckova-Moravcova E, Bednarik J, Belobradkova J, Sommer C. Small-fibre involvement in diabetic patients with neuropathic foot pain. Diabet Med. 2008;25:692–9.CrossRefGoogle Scholar
  44. 44.
    Kramer HH, Rolke R, Bickel A, Birklein F. Thermal thresholds predict painfulness of diabetic neuropathies. Diabetes Care. 2004;27:2386–91.CrossRefGoogle Scholar
  45. 45.
    Themistocleous AC, Ramirez JD, Shillo PR, Lees JG, Selvarajah D, Orengo C, et al. The Pain in Neuropathy Study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy. Pain. 2016;157:1132–45.CrossRefGoogle Scholar
  46. 46.
    Üçeyler N, Ganendiran S, Kramer D, Sommer C. Characterization of pain in Fabry disease. Clin J Pain. 2014;30:915–20.CrossRefGoogle Scholar
  47. 47.
    Burlina AP, Sims KB, Politei JM, Bennett GJ, Baron R, Sommer C, et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol. 2011;11:61.CrossRefGoogle Scholar
  48. 48.
    Schiffmann R, Pastores GM, Lien YH, Castaneda V, Chang P, Martin R, et al. Agalsidase alfa in pediatric patients with Fabry disease: a 6.5-year open-label follow-up study. Orphanet J Rare Dis. 2014;9:169.CrossRefGoogle Scholar
  49. 49.
    Biegstraaten M, Arngrimsson R, Barbey F, Boks L, Cecchi F, Deegan PB, et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet J Rare Dis. 2015;10:36.CrossRefGoogle Scholar
  50. 50.
    Dütsch M, Marthol H, Stemper B, Brys M, Haendl T, Hilz MJ. Small fiber dysfunction predominates in Fabry neuropathy. J Clin Neurophysiol. 2002;19:575–86.CrossRefGoogle Scholar
  51. 51.
    Üçeyler N, He L, Schonfeld D, Kahn AK, Reiners K, Hilz MJ, et al. Small fibers in Fabry disease: baseline and follow-up data under enzyme replacement therapy. J Peripher Nerv Syst. 2011;16:304–14.CrossRefGoogle Scholar
  52. 52.
    Tang Z, Chen Z, Tang B, Jiang H. Primary erythromelalgia: a review. Orphanet J Rare Dis. 2015;10:127.CrossRefGoogle Scholar
  53. 53.
    McDonnell A, Schulman B, Ali Z, Dib-Hajj SD, Brock F, Cobain S, et al. Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype and somatosensory profile. Brain. 2016;139:1052–65.CrossRefGoogle Scholar
  54. 54.
    Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, et al. Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71:26–39.CrossRefGoogle Scholar
  55. 55.
    Faber CG, Lauria G, Merkies IS, Cheng X, Han C, Ahn HS, et al. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A. 2012;109:19444–9.CrossRefGoogle Scholar
  56. 56.
    Han C, Yang Y, de Greef BT, Hoeijmakers JG, Gerrits MM, Verhamme C, et al. The domain II S4-S5 linker in Nav1.9: a missense mutation enhances activation, impairs fast inactivation, and produces human painful neuropathy. NeuroMolecular Med. 2015;17:158–69.CrossRefGoogle Scholar
  57. 57.
    Harrer JU, Uceyler N, Doppler K, Fischer TZ, Dib-Hajj SD, Waxman SG, et al. Neuropathic pain in two-generation twins carrying the sodium channel Nav1.7 functional variant R1150W. Pain. 2014;155:2199–203.CrossRefGoogle Scholar
  58. 58.
    Hoitsma E, Marziniak M, Faber CG, Reulen JP, Sommer C, De Baets M, et al. Small fibre neuropathy in sarcoidosis. Lancet. 2002;359:2085–6.CrossRefGoogle Scholar
  59. 59.
    Saito H, Yamaguchi T, Adachi Y, Yamashita T, Wakai Y, Saito K, et al. Neurological symptoms of sarcoidosis-induced small fiber neuropathy effectively relieved with high-dose steroid pulse therapy. Intern Med. 2015;54:1281–6.CrossRefGoogle Scholar
  60. 60.
    van Velzen M, Heij L, Niesters M, Cerami A, Dunne A, Dahan A, et al. ARA 290 for treatment of small fiber neuropathy in sarcoidosis. Expert Opin Investig Drugs. 2014;23:541–50.CrossRefGoogle Scholar
  61. 61.
    Nolano M, Provitera V, Estraneo A, Selim MM, Caporaso G, Stancanelli A, et al. Sensory deficit in Parkinson’s disease: evidence of a cutaneous denervation. Brain. 2008;131:1903–11.CrossRefGoogle Scholar
  62. 62.
    Martinez V, Fletcher D, Martin F, Orlikowski D, Sharshar T, Chauvin M, et al. Small fibre impairment predicts neuropathic pain in Guillain-Barre syndrome. Pain. 2010;151:53–60.CrossRefGoogle Scholar
  63. 63.
    Reimer M, Rempe T, Diedrichs C, Baron R, Gierthmuhlen J. Sensitization of the nociceptive system in complex regional pain syndrome. PLoS One. 2016;11:e0154553.CrossRefGoogle Scholar
  64. 64.
    Gierthmühlen J, Maier C, Baron R, Tolle T, Treede RD, Birbaumer N, et al. Sensory signs in complex regional pain syndrome and peripheral nerve injury. Pain. 2012;153:765–74.CrossRefGoogle Scholar
  65. 65.
    Üçeyler N, Eberle T, Rolke R, Birklein F, Sommer C. Differential expression patterns of cytokines in complex regional pain syndrome. Pain. 2007;132:195–205.CrossRefGoogle Scholar
  66. 66.
    Oaklander AL, Fields HL. Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy? Ann Neurol. 2009;65:629–38.CrossRefGoogle Scholar
  67. 67.
    Kim DH, Zeldenrust SR, Low PA, Dyck PJ. Quantitative sensation and autonomic test abnormalities in transthyretin amyloidosis polyneuropathy. Muscle Nerve. 2009;40:363–70.CrossRefGoogle Scholar
  68. 68.
    Heldestad V, Nordh E. Quantified sensory abnormalities in early genetically verified transthyretin amyloid polyneuropathy. Muscle Nerve. 2007;35:189–95.CrossRefGoogle Scholar
  69. 69.
    Adams D, Suhr OB, Hund E, Obici L, Tournev I, Campistol JM, et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol. 2016;29(Suppl 1):S14–26.CrossRefGoogle Scholar
  70. 70.
    Weis J, Katona I, Muller-Newen G, Sommer C, Necula G, Hendrich C, et al. Small-fiber neuropathy in patients with ALS. Neurology. 2011;76:2024–9.CrossRefGoogle Scholar
  71. 71.
    Isak B, Pugdahl K, Karlsson P, Tankisi H, Finnerup NB, Furtula J, et al. Quantitative sensory testing and structural assessment of sensory nerve fibres in amyotrophic lateral sclerosis. J Neurol Sci. 2017;373:329–34.CrossRefGoogle Scholar
  72. 72.
    Truini A, Biasiotta A, Onesti E, Di Stefano G, Ceccanti M, La Cesa S, et al. Small-fibre neuropathy related to bulbar and spinal-onset in patients with ALS. J Neurol. 2015;262:1014–8.CrossRefGoogle Scholar
  73. 73.
    Gröne E, Üçeyler N, Abahji T, Fleckenstein J, Irnich D, Mussack T, et al. Reduced intraepidermal nerve fiber density in patients with chronic ischemic pain in peripheral arterial disease. Pain. 2014;155:1784–92.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Universitätsklinikum WürzburgWürzburgGermany

Personalised recommendations