Table 6.

Confirmatory tests for lesion or disease of somatosensory system in patients with suspected neuropathic pain

Name	Objective(s) of test	Description	Remarks on dPNP	References
Basic neurological examination	Mapping of sensory changes	Inspection of feet, evaluation of clinical signs (e.g., sensory loss, allodynia, hyperalgesia), pulse state, skin state, general state of patient, reflexes etc	Recommended in all guidelines. Essential for grading of NP in all patients.	Holiner et al. (2013) German National Disease Management Guideline for Diabetic Neuropathy Pop-Busui et al. (2017) Cruccu et al. (2010)
Quantitative sensory testing (QST)	Quantification of sensory changes in a few defined areas	Mechanical and thermal detection and pain thresholds to assess small (C and Aδ) and large (Aβ) sensory nerve fibers	QST is proven to be reliable and reproducible, and sensitive to change in NP, also in diabetic patients.	Treede (2019) Rolke et al. (2006) Cheliout-Heraut et al. (2005) Weintrob et al. (2007) Hsieh (2010) Backonja et al. (2013) Jensen et al. (1991)
NerveCheck	A portable QST device	Vibration and thermal testing for functional testing of large and small nerve fibers	Validated against neuropathy disability score, nerve conduction studies, intraepidermal and corneal nerve fiber density.	Ponirakis et al. (2016)
Ankle reflexes	Assess muscle spindle afferents and Aα motoneurons	Tendon tap by reflex hammer; assesses only large fiber functions	Loss of ankle reflexes occurs early in dPNP. Part of recommended clinical examination.	Tesfaye et al. (2010) Pop-Busui et al. (2017)
Nerve conduction studies (NCS)	Estimating severity of diabetic neuropathy by testing motor (Aα) and large sensory (Aβ) nerve fibers	Usually NCs of sural nerve; objective and quantitative measure	Changes in amplitude of motor nerve fibers typically follow changes in amplitude of sensory nerve fibers. If NCS is normal, validated measures of small fiber neuropathy are needed.	Tesfaye et al. (2010) Dyck et al. (1993) Dyck et al. (2010) Dyck et al. (2011) Apfel et al. (2001)
Laser-evoked potentials (LEPs)	Testing small fiber function (Aδ and C): thermo-nociceptors	Laser heat pulses on hairy skin; easiest and most reliable technique for objective assessment of nociceptive fibers	Validated for detection of small fiber neuropathy against skin punch biopsy. Diagnostic accuracy in diabetic small fiber neuropathy is established.	Di Stefano et al. 2017) Cruccu et al. 2008)
Cold evoked potentials	Small fiber function: thermoreceptors	Objective test for thermoreception by contact stimulator	Note: validity and role in routine diagnostic are not yet established!	De Keyser et al. (2018) Leone et al. (2019) Farooqi et al. (2016)
Axon reflex flare response	Efferent function of small nociceptive nerve fibers	Stimulation of peptidergic C-fibers by iontophoresis or heat, assessment of vasodilation by laser Doppler imaging	Reduced in subjects with impaired glucose tolerance and type 2 diabetic patients with and without neuropathy.	Caselli et al. (2003) Krishnan and Rayman (2004)
Neuropad	Evaluate cholinergic small sympathetic nerve fiber function	A simple visual indicator test based on sweating and on color change	Test for autonomic neuropathy.	Ponirakis et al. (2014)
Intraepidermal nerve fiber density (IENF)	Gold standard for the structural diagnosis of small­fiber neuropathy (skin punch biopsy)	Acquired by skin punch biopsy or blister technique at ankle	Invasive, rarely used in routine diagnostic, only advised when NCS and QST are normal. IENF density correlates inversely with both cold and heat detection thresholds.	Vlcková-Moravcová et al. (2008) Nebuchennykh et al. (2009) Shun et al. (2004) Andersson et al. (2016) Devigili et al. (2008) Sorensen et al. (2006) Alam et al. (2017)
Corneal confocal microscopy	Structural diagnosis of small fiber neuropathy	Autofluorescence of corneal nerve fibers; corneal anesthesia required	Correlates with IENF loss and the severity of dPNP, was more prominent in patients with pDN.	Quattrini et al. (2007) Mehra et al. (2007) Alam et al. (2017)
Nerve biopsy	Structural diagnosis of large fiber neuropathies	Usually biopsy of the sural nerve	Invasive and highly specialized procedure requiring electron-microscopy. Not recommended for routine use.	Malik et al. 2005) Quattrini et al. (2007)

Confirmatory tests have different scopes (sensory loss, surrogate nerve damage, morphology of peripheral nerve endings). Pain is per definition a subjective experience (IASP) and thus does not have a confirmatory test itself (Davis et al. 2017). This table is not exhaustive