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

Abstract

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.

Keywords

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

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Fig. 4.1
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References

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  9. Claus D, Hilz MJ, Hummer I, Neundorfer B. Methods of measurement of thermal thresholds. Acta Neurol Scand. 1987;76:288–96.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  21. Birklein F, Sommer C. Pain: quantitative sensory testing – a tool for daily practice? Nat Rev Neurol. 2013;9:490–2.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  23. Lacomis D. Small-fiber neuropathy. Muscle Nerve. 2002;26:173–88.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CrossRef  Google Scholar 

  41. Blackmore D, Siddiqi ZA. Pinprick testing in small fiber neuropathy: accuracy and pitfalls. J Clin Neuromuscul Dis. 2016;17:181–6.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  44. Kramer HH, Rolke R, Bickel A, Birklein F. Thermal thresholds predict painfulness of diabetic neuropathies. Diabetes Care. 2004;27:2386–91.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  46. Üçeyler N, Ganendiran S, Kramer D, Sommer C. Characterization of pain in Fabry disease. Clin J Pain. 2014;30:915–20.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  52. Tang Z, Chen Z, Tang B, Jiang H. Primary erythromelalgia: a review. Orphanet J Rare Dis. 2015;10:127.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  68. Heldestad V, Nordh E. Quantified sensory abnormalities in early genetically verified transthyretin amyloid polyneuropathy. Muscle Nerve. 2007;35:189–95.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

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Sommer, C. (2019). Psychophysics: Quantitative Sensory Testing in the Diagnostic Work-Up of Small Fiber Neuropathy. In: Hsieh, ST., Anand, P., Gibbons, C., Sommer, C. (eds) Small Fiber Neuropathy and Related Syndromes: Pain and Neurodegeneration. Springer, Singapore. https://doi.org/10.1007/978-981-13-3546-4_4

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