Table 3.

Quantitative Sensory Testing (QST).

Author(s) & study aim	Study population & design	Study outcomes & implications
Abraham et al. 71 -Explore utility of SFN testing in patients with a clinical presentation suggesting SFN	N = 123 M = 55 ± 16 yrs/age n = 32 +DM Retrospective study	• Using the portable TSA-II NeuroSensory Analyzer (Medoc, Ramat Yishai, Isarel), participants with clinically suggestive SFN plus DM had significantly elevated vs. normal cooling thresholds (37%, 19%, respectively) & heat thresholds (67%, 22%, respectively) • Participants with clinically suggestive SFN plus DM had significantly reduced (37%) vs. normal (16%) LDIFlare (measure of SFN) values • Using Cohen’s kappa coefficient, agreement between the different small-fiber testing modalities were significant; agreement was moderate between LDIFlare & cold testing thresholds (k = 0.52), fair between cooling & heat testing thresholds (k = 0.22), & poor between LDIFlare & heat testing thresholds (k = 0.11) for the entire sample
Alam et al. 72 - Compare diagnostic capability of CCM against skin biopsy & QST in patients with DSPN	N = 88 n = 30 T1D, -DSPN M = 38.8 ± 12.5 n = 31 T1D, +DSPN M = 53.3 ± 11.9 n = 27 HCs M = 41.0 ± 14.9 Cross-sectional	• ROC curve analyses used to define Wilcoxon estimate of AUROC & optimal cutoff values with associated sensitivity & specificity for CST & WST (TSA-II NeuroSensory Analyzer) • UROC for CST was 0.76 with an optimal cutoff of 25°C; sensitivity of 57% & specificity of 89% for diagnosing DSPN • AUROC for WST was 0.74 with an optimal cutoff of 38°C; sensitivity of 86% & specificity of 64% for diagnosing DSPN • AUROCs revealed moderate accuracy of CST & WST parameters
Azmi, et al. 73 -Assess whether baseline and follow-up measures of neuropathy, particularly small-fiber neuropathy, relate to changes in glucose tolerance over 3 yrs	N = 47 n = 30 IGT M = 60 ± 2.1 n = 17 Controls M = 62.3 ± 1.8 Longitudinal (3-yr FU)	• FU: CT & WT (TSA-II NeuroSensory Analyzer) values did not significantly change for participants who reverted to NGT, remained with IGT, or developed T2D at 3-yr FU • Findings suggest CT & WT are not responsive to changes in glucose tolerance status or T2D development
Courtin, at al. 74 -Investigate the potential of evaluating not only the threshold but also the slope of the psychometric functions for cold & warm detection	N = 30 n = 15 T2D M = 55 ± 4 age/yrs n = 15 HCs M = 53 ± 4 age/yrs Cross-sectional	• Using a Laser Stimulator Device (SIFEC, Ferrières, Belgium), ROC analysis revealed warm detection thresholds did not well discriminate between T2D participant & control groups at the wrist (AUC: 0.65) or foot (AUC: 0.67) • ROC analysis showed the spread of psychometric function for warm detection was also uninformative (AUC wrist: 0.59; AUC foot: 0.50) • Using a Thermal Cutaneous Stimulator (QST.Lab, Strasbourg, France), ROC analysis indicated both CDT (AUC wrist: 0.83; AUC foot: 0.80) & spread of psychometric function for cold detection (AUC wrist: 0.82; AUC foot: 0.84) displayed very good discriminative properties • Including both slope & threshold in ROC analysis, cold detection discrimination performance between T2D participants & HCs was further increased (AUC wrist: 0.89; AUC foot: 0.94) • Combining slope & threshold parameters of cold detection performance may yield better discriminative ability than relying solely on thresholds
Dhage, et al. 75 -Assess the longitudinal utility of different measures of neuropathy in patients with diabetes	N = 38 n = 19 +DM M = 52.5 ± 14.7 yrs/age (baseline) n = 19 HCs M = 47.4 ± 14.2 yrs/age (baseline) Longitudinal cohort study (M = 6.5 yrs FU)	• At baseline, QST (TSA-II NeuroSensory Analyser) measures of CPT, WPT, CIP, & WIP did not significantly vary between DM participants & controls • Compared to baseline, significant decreases in CPT were observed in DM participants at FU • CPT may serve as a biomarker of nerve damage in patients with DM
Fabry et al. 76 -Determine diagnostic value of skin biopsy, QST, Q-Sweat, LEP, ESC & AVCT for SFN diagnosis	N = 245 M = 50.4±15.0 yrs/age n = 24, +DM n = 6, IGT n = 102 +SFN n = 90 -SFN Retrospective study	• Using the Thermotest (Somedic, Sollentuna, Sweden) device as the measure of QST, no significant difference was found between +SFN & -SFN groups • QST or Thermotest had a sensitivity of 72%, specificty of 39% & positive predictive value of 57% for SFN diagnosis • QST found to be most sensitive test for SFN diagnosis relative to IENFD, QSART (Q-Sweat, WR Medical Electronics, Minneapolis, USA), ESC (Sudoscan, Impeto Medical, Paris, France), LEP, & AVCT • Combining QST, IENFD, ESC & LEP yielded a sensitivity of 92%, specifity of 88%, & positive predictive value of 90% for diagnosing SFN
Farooqi et al. 77 - Validate the performance of CDT to detect DSP in T2D	N = 220, +DM M = 63 ±11 yrs/age n = 52 Pre-clinical DSP n = 139 +DSP n = 29 Controls Cross-sectional	• Using the TSA-II NeuroSensory Analyzer to detect clinical DSP with CDT, AUCCDT was 0.79, significantly higher than AUCHRV & AUCLDIFLARE values; CDT (optimal threshold of ≤22.8°C) had a sensitivity of 64% & specificity of 83% in identifying clinical DSP with a positive predictive value of 87% • Using the TSA-II NeuroSensory Analyzer to detect pre-clinical DSP with CDT, AUCCDT was 0.80, significantly higher than AUCHRV & AUCLDIFLARE values; CDT (optimal threshold of ≤27.5°C) had a sensitivity of 83% & specificity of 72% in identifying pre-clinical DSP with a positive predictive value of 95% • CDT revealed good diagnostic performance for detection of clinical & pre-clinical DSP in T2D
Ferdousi, et al. 78 -Compare the utility of quantifying corneal nerve loss at the inferior whorl & central cornea to QST & NCS in the diagnosis & assessment of DPN severity	N = 143 n = 93 +DM n = 51 –DPN M = 57.68 ± 1.6 yrs/age n = 47 Mild DPN M = 60.16 ± 1.7 yrs/age n = 45 Moderate to severe DPN M = 64.1 ± 1.48 yrs/age n = 30 Controls M = 54.51 ± 2.3 yrs/age Cross-sectional	• ROC curve & Youden Index used to define the optimum cutoff point for WPT & CPT (TSA-II NeuroSensory Analyzer); WPT AUC 0.67, sensitivity 50%, & specificity 76%; CPT AUC 0.64, sensitivity 80%, & specificity 47% • CPT was significantly lower in patients with mild (19.52±1.47, p=0.02) and moderate to severe (18.99±1.55, p=0.01) neuropathy compared with controls (25.38±2.06) • WPT was significantly higher in patients with no (41.65±0.6, p=0.01), mild (43.47±0.6, p<0.0001) and moderate to severe (43.62±0.7, p<0.0001) neuropathy compared with controls (38.87±0.9) • While CPT & WPT, overall, had suboptimal performance values, progressive abnormalities in CPT & WPT were observed with increasing severity of DPN
Løseth et al. 79 - Evaluate progression of DPN & differences in the spectrum & evolution of large- and small-fiber involvement in patients with T1D & T2D over 5 yrs	N = 59 n = 35 T1D M = 47.4 ± 12.0 yrs/age at 5 yr FU n = 24 T2D M = 57.8 ± 9.0 yrs/age at 5 yr FU Longitudinal	• Using Thermotest Type 1 (Somedic AB, Sösdala, Sweden) device for QST measurement, baseline values of CPT were elevated at baseline for participants with T1D (4.4 ± 4.4) & T2D (4.8 ± 3.8) • At 5-yr FU, CPT values increased significantly for participants with T2D (6.7 ± 5.3) but not for those with T1D (5.4 ± 5.3) • Yet, CPT z-scores, calculated to adjust for physiologic effects of age, height, & gender, did not reveal significant increases in CPT values for participants with T2D from baseline to 5-yr FU • Further research is indicated to identify if elevated CPT values are a biomarker for DN progression
Pfau et al. 80 -Assess the reliability/validity of “Q-Sense” (portable device) by comparing it with TSA II	N = 204 n = 83 +DM n = 71 +DNP n = 121 HCs M = 32.9 ± 13.7 age/yrs Cross-sectional	• Agreement between Q-Sense & TSA II NeuroSensoryAnalyzer (both portable devices) was excellent for CDT (ICC = 0.89) & WDT (ICC = 0.90), moderate for HPT (ICC = 0.53), & poor for CPT (ICC = 0.31) • Sensitivity of Q-Sense to detect cold hypoesthesia was reduced in males >60 years • ROC curves for both devices were calculated, using skin biopsy results (“normal” vs. “pathologic”) as reference measure, & resulting AUROCs were compared; statistical comparisons of AUROCs (related to TSA II & Q-Sense measurements, respectively) were non-significant for CDT, WDT, & TSL, revealing the non-inferiority of the Q-Sense, relative to TSA II, for thermal detection • Q-Sense is not advised to use for CPT thresholds & HPT thresholds should be used with caution. Q-Sense suitable for thermal detection thresholds (cutoff lowered to 18° C)
Pritchard et al. 81 -Determine if deficits in CNFL assessed using CCM can predict future onset of DPN	N = 90 T1D, –DPN (baseline) 4-yr FU n = 16 +DPN M = 51 ± 14 yrs/age (baseline)	• DPN developed in 16 participants (18%) after 4 yrs • Participants who developed DPN at 4-yr FU had significantly lower baseline values of CST & CPT (TSA-II NeuroSensory Analyzer) & significantly higher baseline values of WST & WPT (TSA-II NeuroSensory Analyzer) relative to those that did not develop DPN • For CST, AUROC was 0.77; sensitivity was 88% & specificity was 55% with a CST cutoff of 29.2°C
	n = 64 –DPN M = 42 ± 16 yrs/age (baseline) Longitudinal	• For CPT, AUROC was 0.68; sensitivity was 50% & specificity was 86% with a CPT cutoff of 0.2°C • For WST, AUROC was 0.71; sensitivity was 56% & specificity was 82% with a WST cutoff of 39.1°C • For WPT, AUROC was 0.68; sensitivity was 56% & specificity was 80% with a WPT cutoff of 49.5°C
Ponirakis et al. 82 -Establish the reproducibility & diagnostic validity of NerveCheck for detecting DPN	N = 186 n = 130 +DM Med = 55.7 yrs/age IQR: 42.9–66.1 n = 74 +DM n = 28 +DPN n = 46 –DPN n = 56 controls Med = 43.6 yrs/age IQR: 35.7–53.1 Longitudinal	• Controls & DM participants tested 2 times (test-retest intervals: 1-8 weeks) with identification of intraclass agreement for NerveCheck (Phi Med Europe SL, Barcelona, Spain) CPT (0.86) & WPT (0.71) • Using ROC curve analysis, diagnostic accuracy for detecting DPN, against the TSA-II NeuroSensory. Analyzer, revealed AUCs for CPT (0.79) & WPT (0.72) • CPT sensitivity was 89% & specificity was 67%; WPT sensitivity was 75% & specificity was 66% • Findings indicate NerveCheck has good reproducibility & moderate diagnostic accuracy for detecting DPN
Ponirakis et al. 83 -Examine diagnostic performance of NerveCheck	N = 144 n = 74 +DM n = 33 +DPN M = 64.1±1.79 yrs/age n = 41 –DPN M = 44.3 ± 2.19 yrs/age n = 70 Controls M = 41.8 ± 1.63 yrs/age Cross-sectional	• ROC curve analysis used to compare diagnostic accuracy of CPT & WPT against IENFD; AUC of CPT was 0.70 & WPT was 0.69; CPT sensitivity was 53% & specificity was 82%; WPT sensitivity was 56% & specificity was 81% • Diagnostic accuracy of NerveCheck is poor to good with reference to IENFD

Abbreviations: ACVT, autonomic cardiovascular tests; AUC, area under the curve; AUROC, area under receiver operator characteristic; CCM, corneal confocal microscopy; CDT, cold detection threshold; CIP, cold induced pain; CPT, cold pain threshold or cold perception threshold; CST, cold sensation threshold; CT, cold threshold; DM, diabetes mellitus; DNP, diabetic neuropathy; DPN, diabetic peripheral neuropathy; DSP, diabetic sensorimotor polyneuropathy; DSPN, diabetic symmetrical peripheral neuropathy; ESC, electrochemical skin conductance; FU, follow-up; HC, healthy control; HPT, heat pain threshold; HRV, heart rate variability; ICC, intraclass correlation coefficient; IENFD, intraepidermal nerve fiber density; IGT, impaired glucose tolerance; IQR, interquartile range; LDIFLARE, laser doppler imager flare; LEP, laser evoked potentials; M, mean; Med, median; NCS, nerve conduction study; NGT, normal glucose tolerance; QST, quantitative sensory testing; ROC, receiver operator characteristic; SFN, small fiber neuropathy; SNAP, sensory nerve action potential; SNCV, sural nerve conduction velocity; T1D, type 1 diabetes; T2D, type 2 diabetes; TSA, Thermal Sensory Analyzer; TSL, thermal sensory limen; VPT, vibration perception threshold; WDT, warm detection threshold; WIP, warm induced pain; WPT, warm pain or perception threshold; WST, warm sensation threshold; WT, warm threshold; yrs, years.