Evaluation of proxy tests for SFSN: evidence for mixed small and large fiber dysfunction.

BACKGROUND: Though intra-epidermal nerve fiber density (IENFD) is considered the gold standard for diagnosis of small fiber sensory neuropathy (SFSN), we aimed to determine if novel threshold values derived from standard tests of small or large fiber function could serve as diagnostic alternatives. METHODS: Seventy-four consecutive patients with painful polyneuropathy and normal nerve conduction studies (NCS) were defined as SFSN cases or controls by distal IENFD <5.4 and ≥5.4 fibers/mm, respectively. Diagnostic performance of small fiber [cooling (CDT) and heat perception (HP) thresholds, axon reflex-mediated neurogenic vasodilatation] and large fiber function tests [vibration perception thresholds (VPT) and sural nerve conduction parameters] were determined by receiver operating-characteristic (ROC) curve analyses. RESULTS: The 26(35%) SFSN cases had mean IENFD 3.3±1.7 fibers/mm and the 48(65%) controls 9.9±2.9 fibers/mm. Male gender (p = 0.02) and older age (p = 0.02) were associated with SFSN cases compared to controls. VPT were higher and CDT lower in SFSN cases, but the largest magnitude of differences was observed for sural nerve amplitude. It had the greatest area under the ROC curve (0.75) compared to all other tests (p<0.001 for all comparisons) and the optimal threshold value of ≤12 µV defined SFSN cases with 80% sensitivity and 72% specificity. CONCLUSION: In patients presenting with polyneuropathy manifestations and normal NCS, though small fiber function tests were intuitively considered the best alternative measures to predict reduced IENFD, their diagnostic performance was poor. Instead, novel threshold values within the normal range for large fiber tests should be considered as an alternative strategy to select subjects for skin biopsy in diagnostic protocols for SFSN

Reliability and validity of a point-of-care sural nerve conduction device for identification of diabetic neuropathy.

BACKGROUND: Confirmation of diabetic sensorimotor polyneuropathy (DSP) relies on standard nerve conduction studies (NCS) performed in specialized clinics. We explored the utility of a point-of-care device (POCD) for DSP detection by nontechnical personnel and a validation of diagnostic thresholds with those observed in a normative database. RESEARCH DESIGN AND METHODS: 44 subjects with type 1 and type 2 diabetes underwent standard NCS (reference method). Two nontechnical examiners measured sural nerve amplitude potential (SNAP) and conduction velocity (SNCV) using the POCD. Reliability was determined by intraclass correlation coefficients (ICC [2], [1]). Validity was determined by Bland-Altman analysis and receiver operating characteristic curves. RESULTS: The 44 subjects (50% female) with mean age 56 ± 18 years had mean SNAP and SNCV of 8.0 ± 8.6 µV and 41.5 ± 8.2 m/s using standard NCS and 8.0 ± 8.2 µV and 49.9 ± 11.1 m/s using the POCD. Intrarater reproducibility ICC values were 0.97 for SNAP and 0.94 for SNCV while interrater reproducibility values were 0.83 and 0.79, respectively. Mean bias of the POCD was -0.1 ± 3.6 µV for SNAP and +8.4 ± 6.4 m/s for SNCV. A SNAP of ≤6 µV had 88% sensitivity and 94% specificity for identifying age-and height-standardized reference NCS values, while a SNCV of ≤48 m/s had 94% sensitivity and 82% specificity [corrected].. Abnormality in one or more of these thresholds was associated with 95% sensitivity and 71% specificity for identification of DSP according to electrophysiological criteria. CONCLUSIONS: The POCD demonstrated excellent reliability and acceptable accuracy. Threshold values for DSP identification validated those of published POCD normative values. We emphasize the presence of measurement bias--particularly for SNCV--that requires adjustment of threshold values to reflect those of standard NCS

Identification and prediction of diabetic sensorimotor polyneuropathy using individual and simple combinations of nerve conduction study parameters.

OBJECTIVE: Evaluation of diabetic sensorimotor polyneuropathy (DSP) is hindered by the need for complex nerve conduction study (NCS) protocols and lack of predictive biomarkers. We aimed to determine the performance of single and simple combinations of NCS parameters for identification and future prediction of DSP. MATERIALS AND METHODS: 406 participants (61 with type 1 diabetes and 345 with type 2 diabetes) with a broad spectrum of neuropathy, from none to severe, underwent NCS to determine presence or absence of DSP for cross-sectional (concurrent validity) analysis. The 109 participants without baseline DSP were re-evaluated for its future onset (predictive validity). Performance of NCS parameters was compared by area under the receiver operating characteristic curve (AROC). RESULTS: At baseline there were 246 (60%) Prevalent Cases. After 3.9 years mean follow-up, 25 (23%) of the 109 Prevalent Controls that were followed became Incident DSP Cases. Threshold values for peroneal conduction velocity and sural amplitude potential best identified Prevalent Cases (AROC 0.90 and 0.83, sensitivity 80 and 83%, specificity 89 and 72%, respectively). Baseline tibial F-wave latency, peroneal conduction velocity and the sum of three lower limb nerve conduction velocities (sural, peroneal, and tibial) best predicted 4-year incidence (AROC 0.79, 0.79, and 0.85; sensitivity 79, 70, and 81%; specificity 63, 74 and 77%, respectively). DISCUSSION: Individual NCS parameters or their simple combinations are valid measures for identification and future prediction of DSP. Further research into the predictive roles of tibial F-wave latencies, peroneal conduction velocity, and sum of conduction velocities as markers of incipient nerve injury is needed to risk-stratify individuals for clinical and research protocols

Shows the linear regression model for IENFD as a function of the sural sensory nerve action potential amplitude. (R² = 0.22, p<0.001).

<p>Shows the linear regression model for IENFD as a function of the sural sensory nerve action potential amplitude. (R² = 0.22, p<0.001).</p

Comparison of the Area Under the Receiver Operating Characteristic Curve and Optimal Thresholds for Sural Nerve Amplitude and the Other Nerve Fiber Function Tests.

*<p>Two-tailed p values were calculated using a z-score obtained from testing the hypothesis that the areas under two different ROC curves are the same, according to the method of Pencina et al.</p>†<p>P value not applicable for sural nerve amplitude as it used as the reference to which the other tests are compared.</p>**<p>Optimal values were obtained by calculating the shortest distance between each variable’s ROC curve and the upper left hand corner of the ROC graph, according to the distance formula for two points in the plane, .</p

Shows the ROC curves for large fiber function tests of sural nerve amplitude and conduction velocity and vibration perception thresholds at index finger and first toe.

<p>The curve for sural nerve amplitude lies closest to the upper y-axis and has the largest AUC at 0.75.</p

Shows the ROC curves for small fiber function tests of cooling detection thresholds and heat perception thresholds in upper and lower extremities and the laser Doppler flow studies in the foot.

<p>Shows the ROC curves for small fiber function tests of cooling detection thresholds and heat perception thresholds in upper and lower extremities and the laser Doppler flow studies in the foot.</p

Characteristics of the 72 Patients with Clinical Polyneuropathy and Normal Large Fiber Tests According to Presence and Nature of Small Fiber Neuropathy.

*<p>P values for dichotomous variables were calculated with the χ2 test and t-test was used for continuous variables.</p><p>For VPT, the normal values are highly age-dependent, but values ≤5 are normal in the finger and ≤15 Volts are normal in the toe. For VPT, data are available in 42 patients with normal IENFD and on 24 patients with SFSN.</p><p>Cut-offs for quantitative sensory thresholds are age-dependent although, generally a normal CDT would be ≥25°C. The normal values for heat pain are ≤50°C.</p