35 MIBG/SPECT Imaging cardiac sympathetic function can be used to determine SFN. 123I-meta-iodobenzylguadine (MIBG) is radioactive and can be visualized with the use of single photon emission computed tomography (SPECT). 123I-MIBG acts as a substrate for norepinephrine and thus marks post-ganglionic sympathetic noradrenergic innervation. The heart-to-mediastinal uptake ratio (H/M ratio) and washout ratio (WR) are used to quantify sympathetic innervation.110,140 Autonomic or cardiac disorders result in either impaired uptake of I-MIGB or accelerated washout after 3-5 hours.140 CAN is visualized in amongst others diabetics and Parkinson’s disease (PD) patients. A high correlation between H/M ratio and IENFD is shown in PD patients140, but not in diabetes141 . Non-small fiber nerve tests 8.1 Peripheral nerve ultrasound Recently, US measurements of the sural nerve revealed structural change of the sural nerve in subjects with SFN.142 The superficial peroneal nerve is also assessed, but shows no change between SFN and healthy controls. Cross-sectional area significantly increases in patients with SFN from 2.7±0.6mm2 in healthy volunteers to 3.2±0.8 mm2 in subjects with SFN. Thickness-to-width ratio does not show difference between healthy volunteers and subjects with SFN.142 The exact pathophysiology of enlargement of a large fiber like the sural nerve, is unknown. Theories include loss or injury of distal small fibers or impaired sodium channel function resulting in impaired axoplasmatic flow. As consequence, axons degenerate and swell.48 Functional Magnetic Resonance Imaging (fMRI) Functional activity in the brain can modulate the perception of pain. Balance between non-nociceptive and nociceptive information, control nociceptive information transmission in higher centers. Multiple studies assessed brain functionality in subjects with SFN and healthy controls. Subjects with SFN show volume reduction in pain-processing regions (anterior cingulate cortex). Moreover, the degree of volume reduction correlates with the degree of IENFD decrease.143 Figure 2 shows an overview of the available diagnostic tools for testing pure SFN and their corresponding measuring area. Most methods only measure post-ganglionic NFD or function. Two methods which do test SFN, but are not based on small nerve fiber testing, are DNA analysis from blood samples and US of the peripheral sural nerve. AUC values Figure 5 shows AUC values for all techniques published in the last 19 years. The AUC value represents the direct relation between sensitivity and specificity. Each bubble represents one article and the diameter represents the sample size (n). This visual representation gives insight on the number of studies investigating different techniques and show the spread of diagnostic accuracy. From these figures, however, it cannot be concluded which technique shows the best performance. The large range of AUC values within one method, might be caused by multiple parameters as outcome measures, with some measures more sensitive compared to the other. 2 37 2
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