Table 3.
Overview of the current methodologies for testing small fibres in DSPN [adapted from Sharma S et al. (9)].
| Functional tests for SFN | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Test | Type | Technique | Equipment Needed | Time to acquire results | Normative Data | Operating Characteristics for DSPN | Limitations | ||
| Quantitative sensory testing (QST) (41) | Non-invasive, quantitative | Computerised measurement of thermal thresholds and heat pain thresholds | Computerised assessment device, temperature controlled laboratory and a trained technician | Takes about half an hour but could take longer, depending on subject concentration | Commercial normative data present from the bigger manufacturers. | None available | Psychophysical test- results are dependent on subject compliance and attention. Complex testing protocols present. Varying reproducibility depending on experience of the unit undertaking testing. | ||
| Laser Doppler imager Flare (LDIflare) (42) | Non-invasive, quantitative ( Figure 2 ) | Measurement of the axon-reflex mediated flare response as a marker of small fibre function | Laser Doppler imager, temperature controlled room, operator with experience | Image acquisition took ~1 hour with the older method. Newer method takes approximately 25 minutes. Results available immediately | One site normative values determined at a single centre. Larger data set of normative valves desired (43) | For the newer technique: Sensitivity of 70-75%, specificity of 66-85%, positive predictive value of 74%, and negative predictive value of 86% | Dependent on the microcirculation. Patients need to have no significant macrovascular distal circulatory impairment. Has correlation with Confocal microscopy (44). | ||
| Current perception threshold (CPT) (45) | Non-invasive, quantitative | Low current intensity stimulation of the small nerve fibres at frequency of 250 Hz for A-delta fibres and the 5 Hz for C-fibres. |
Neurometer device temperature controlled room and a trained technician | Takes about half an hour but could take longer, depending on subject concentration | None available. Most studies have included age matched controls for comparison. | None available | Requires active patient co-operation. Like QST, therefore reproducibility has been a challenge and other methodological challenges persist (such as what frequency to use. Not widely available. | ||
| Contact Heat Evoked Potentials (CHEPs) (46) | Non-invasive, quantitative | Measure cerebral responses to thermal stimuli mediated by A-delta fibres | Needs thermal threshold testing first. Then small discs are placed on the head to record signals received to the brain from application of 10 to 20 short (a fraction of a second) heat or cold stimuli at a particular point of interest (face, arm or leg) |
Takes about half an hour but could take longer, depending on subject concentration | Multicentre normative data on 226 adult subjects are available | The AUC for DSPN detection in a small sample has been estimated at 0.778. | Requires active patient co-operation. Like QST and CPT, therefore reproducibility has been a challenge. Not widely available. Also unclear if both A-delta and C-fibres are assessed. | ||
| Microneuro-graphy (47) | Minimally invasive, semi quantitative | Measurement of Single fibre recordings from peripheral axons | Skilled operator and extensive equipment list. Preserve of a large neurophysiology lab rather than clinic based procedure. | May take up to 3 hours to get a satisfactory recording. | None available | None available. Considered by EFNS to possess grade A evidence for assessing function of the A-delta fibre pathways in patients with neuropathic pain | Still primarily a research tool. May have a role in assessment of neuropathic pain rather than early neuropathy. Expensive and needs skill to elicit responses. Patient cooperation is also extensively required. | ||
| Laser Evoked Potentials (LEPs) (48) | Non-invasive, quantitative | Radiant heat generate by laser selectively excites free nerve endings in the superficial skin layers activating nearby A-delta and C -fibre nociceptors | CO2-laser stimulator, technician with experience and a temperature controlled room ideally. | May take up to 1 hour to complete the procedure and ensure no artefacts presents in readings gained | Single centre normative values available on 100 subjects. No decade specific data reported. | None available. Studies have used age matched control data. | Limited availability. May be useful in demonstrating reduced function but unable to detect enhanced transmission as found in hyperalgesia. Small changes in pain sensitivity are not easily detectable with LEP | ||
| Quantitative sudomotor axon reflex test (QSART) (49) | Sudomotor Non-invasive, quantitative | Information on skin autonomic function and evaluation of postganglionic sudomotor function using acetylcholine iontophoresis | Purpose built lab, iontophoresis and sudomotor quantification equipment. | 45-60 minutes to complete. | Normative data available from specific centres for QSART. A commercially available device QSWEAT is also available | No specific data available for DSPN but has been widely used, especially in the Rochester Diabetic Neuropathy study | Requires precautions for electrical safety and small risk of minor local injury to the skin | ||
| Thermo-regulatory sweat test (TST) (50) | Sudomotor Non-invasive, semi-quantitative |
When core temperature rises beyond a hypothalamic thermoregulatory set point (>38°C), sweating occurs |
Needs a laboratory and a digital camera | 90-120 minutes to perform correctly. Maximal sweating is achieved within 30–65 minutes. |
Unclear | Helpful data on the TST available in DSPN mainly from the autonomic lab at the Mayo Clinic, Rochester USA. | Patients may not be able to tolerate 60 minutes of warming up | ||
| Sympathetic Skin Response (51) | Sudomotor Non-invasive, quantitative | Information on skin autonomic function and evaluation of postganglionic sudomotor function using electrodermal activity | Purpose built lab, SSR equipment includes electrodes. | 45-60 minutes to complete. | Normative data available from specific centres but usually has been derived from a small normative group | Minimal data only available in DSPN. Some helpful data in diabetic autonomic neuropathy and bladder dysfunction. | Limited availability, needs expertise and experience to test correctly. Popular in Japan. | ||
| Sudoscan® (32) | Sudomotor Non-invasive, quantitative | Testing is based on stimulation of sweat glands by a low-voltage current (<4volts) representing a electrochemical reaction between electrodes and chloride ions, | Just the Sudoscan® device | Takes less than 5 minutes | Comes with inbuilt normative data. Limited experience at the moment | Increasing literature now available of its use in DSPN. Similar AUC as IENFD (0.761) in one study. For Cardiac autonomic neuropathy sensitivity was 65%, specificity 80%. | Still limited availability. Needs more detailed validation work for different ethnicities. | ||
| Neuropad® (52) | Simple qualitative indicator of sudomotor dysfunction | Simple sticker which changes colour in the presence of sweating. | Cheap and easy to avail. | Takes less than 10 minutes | Qualitative, does not need normative data. | Lots of available literature and has been validated against IENFD. In one study, Neuropad had a sensitivity 85% and specificity of 45% for detection of clinical DSPN. | Difficult to interpret when there is partial change in colour though. One centre has published data on semi-quantification using digital imaging of the Neuropad®. | ||
| Structural tests for SFN | |||||||||
| Skin Biopsy (53) | Invasive (minimally), quantitative | Measurement of intra-epidermal nerve fibre density | Sterile equipment for biopsy, access to trained personnel and laboratory | Procedure takes 5-10 minutes but takes a few days to get the results back. | Worldwide normative Data present | Published sensitivity doe DSPN is between 60% and 95% and specificity between 90% and 95% | Challenging to use in prospective studies of very large cohorts, infection risk at site of biopsy | ||
| Sural nerve biopsy (54) | Invasive, quantitative | Ultrastructure and morphometric analysis of sural nerve biopsy specimens | Experienced operator who can perform biopsy and access to pathologist and at times, electron or confocal microscope | Procedure may take up to 45 minutes. Results usually take a few days. | None available | None available | Infection, pain and hypoesthesia at biopsy site | ||
| Corneal Confocal Microscopy (55, 56) | Non-invasive, quantitative | Measurement of nerve parameters of the corneal sub-basal layer | Corneal scanning confocal microscope, trained technician | Image acquisition takes 5-10 minutes. Results available immediately if automated counting used | Worldwide normative Data present | Reported sensitivity of 85% and specificity of 84% |
Surrogate marker of DSPN rather than a direct indicator. Previously reliant on manual counting but newer automated methods emerging. Unclear which of the three- CNFB, CNFL or CBNFD best representative/predictive of DSPN | ||