The LDIflare method is of additional value compared to the golden standard however rather in a screening program than in a diagnostic process of small-fiber neuropathy because of too low sensitivity. A limitation of this method is that it cannot differentiate between painful and non-painful small-fiber neuropathy. By using the non-invasive and objective LDIflare method as screening tool unnecessary invasive skin biopsies could be spared.
Summary of evidence
Gibbons et al. (2010) have represented sensitivities and specificities of many different techniques for diagnosing neuropathy. The best overall sensitivity and specificity of axon reflex % change measured by Laser Doppler flowcytometry is 71% and 43%, respectively. The LDIflare method studied by Vas et al. (2013) exceeds the best overall sensitivity and specificity of the techniques studied by Gibbons et al. (2010). The sensitivity and specificity of the LDIflare method is 75% respectively 85%. In addition, the LDIflare method using age-specific cut off values allows sensitivity and specificity to increase to 77% and 90%, respectively. Sensitivity and specificity of the LDIflare method studied by Vas et al. (2013) are higher compared to other studies possible by technical differences in the application of the LDIflare method and by using newer techniques obtaining higher temperatures and therefore larger flares.
Despite the low sensitivity and specificity of the LDIflare method found in most studies, Vas et al. believed that the LDIflare method has high sensitivity, specificity and reproducibility. This is because optimizing the technical implementation of the LDIflare method and using newer techniques will obtain better diagnostic values.
The sensitivity and specificity of the golden standard is ranging from 45% to 80% and 95% to 97% respectively for skin biopsy and 61% to 89% and 29% to 75% respectively for QST (25). The LDIflare method has no better sensitivity and specificity compared to the golden standard, except for the specificity of the QST method. That is because the QST method is a subjective test that patients could manipulate leading to false positives.
The LDIflare method might be better to serve as a screening tool than a diagnostic tool because of too low sensitivity in general. Measuring axon reflex flare areas by LDIflare is useful as an objective and non-invasive screening method for detecting SFN in an inelaborate and time-efficient manner. In case of a positive test result SFN could be confirmed by additional diagnostic tests, like skin biopsy.
In addition, due to high specificity of the LDIflare method there are few false positive test results and therefore unnecessary invasive diagnostic tests could be spared in many cases.
Previous studies (Polydefkis et al., 2002 and Oaklander, 2001) suggested a correlation between reduced intraepidermal small-fiber density and clinical pain intensity. For that reason it is assumed that severe loss of intraepidermal small-fiber density generates a high clinical pain intensity.
However, pain does not predominate in most cases of neuropathy.
In contrast, recent studies did not find a correlation between the density of intraepidermal small-fibers and clinical pain intensity determined by both the LDIflare method and golden standard. In the study of Kalliomaki et al. (2011) functional and structural parameters were quantified in individuals with nerve injury. Functional and structural parameters included perception of warmth, cold and heat pain, axon reflex flare area and epidermal small-fiber density. However, there were no significant differences in the functional and structural parameters between neuropathy patients with and without pain. Thus, the LDIflare method is useful as screening tool, however this method cannot differentiate between painful and nonpainful small-fiber neuropathy.
Pros and cons of the LDIflare method
The pros of the LDIflare method are that this method is not invasive, painless, objective, inelaborate and time-efficient.
The cons of the LDIflare method are that this method has a wide spectrum of normal values in normal subjects and that this method is not sufficient alone to describe the dysfunction of SFN.
Limitations
In the reviewed studies, only Diabetes Mellitus patients were investigated because Diabetes Mellitus is the most common cause of SFN. However, there are also other common causes of SFN which also should be studied. For instance deficiencies of vitamin B and folic acid, toxic effects like alcohol abuse, heavy metals and some chemotherapy medicines, infections like hepatitis C, Lyme and HIV, auto-immune diseases like sarcoidosis, Sjogren syndrome, vasculitis and paraneoplastic neuropathy, and hereditary conditions like Nav1.7-mutations and Fabry disease.
In addition, only C-fibers were examined for diagnosing SFN. SFN also comprises dysfunction of thin A??-fibers and therefore A??-fibers also should be examined. Examination of A??-fibers will increase the actuality and thus the reproducibility.
Another limitation is that articles were selected on ‘published in the last 5 years’ missing important articles before the end of 2009. It was beyond the purpose of this review to include as many articles which might relevant for answering the research question.
There are several LDIflare techniques that are practically applied which might (i.e. using a higher temperature) have consequences for the detection of small-fiber dysfunction. The technique and method itself should therefore be standardized. Moreover, different techniques could detect different types of small-fibers (i.e. C-nociceptive fibers for axonal reflexes versus sympathetic non-cholinergic fibers).
Overall conclusion
Overall, although the LDIflare method has not been investigated in comparison with the golden standard, from this review we conclude that LDIflare has a relative low sensitivity and specificity, except for the specificity of the QST method. However the advantage of the LDIflare method is that the test is non-invasive and objective compared to the golden standard. In addition, the LDIflare method can be performed in an inelaborate and time-efficient manner. For these reasons the LDIflare method is rather a screening tool than a diagnostic tool in which invasive diagnostics could be spared. Further research is needed to increase the sensitivity of the LDIflare method. Higher sensitivity could eventually be achieved by optimizing the technical implementation of the LDIflare method and using newer techniques obtaining higher temperatures and thus larger flares.
For future research, it is important to have normative values of LDIflare variables to be able to compare it with patients who might have small-fiber dysfunction. In addition, neuropathy patients with other causes than diabetes mellitus should also be included. Small-fiber neuropathy also comprises dysfunction of A??-fibers and therefore A??-fibers also should be examined to increase the reproducibility.
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