Essay: Is Laser Doppler Imaging of additional value compared to the golden standard in the diagnosis of small-fiber neuropathy?

 
1. ABSTRACT
INTRODUCTION
Small-fiber neuropathy (SFN), a disease known for its dysfunction of thin myelinated A??-fibers and unmyelinated C-fibers, is clinically characterized by sensory and autonomic symptoms.
To date, the diagnosis of SFN is set by an abnormal intraepidermal nerve fiber density (IENFD) by skin biopsies and/or an abnormal quantitative sensory testing (QST) in combination with the clinical characteristics of the patient. However sensitivity and specificity are questioned (1, 2). Diagnostic tools with higher sensitivity are needed to set the diagnosis of SFN. Analysis of axon reflex flare measured by the Laser Doppler Imaging Flare Technique (LDIflare) is a simple method to evaluate the peripheral C-fiber function. The LDIflare method may be a recent, non-invasive and non-subjective technique for diagnosing SFN in an inelaborate and time-efficient manner (1, 3). In addition, the LDIflare method may be useful in order to make a distinction between painful and non-painful SFN.
This literature review will answer the question whether Laser Doppler Imaging is of additional value compared to skin biopsy and QST in the diagnosis of small-fiber neuropathy .
METHODS
The literature search was performed using database PubMed to find articles about diagnosing small-fiber neuropathy. In this search MeSH terms and free terms were combined to obtain optimal results possibly useful for answering the research question. This literature search was performed according the top 5 search terms of the diagnosis critical appraisal of a topic (CAT).
Subsequently, other criteria based on the research question were used to include and exclude articles.
RESULTS
The PubMed search yielded 52 results. After selecting for ‘published in the last 5 years’ 17 articles remained. A selection of these 17 articles was performed on the basis of title and abstract according the inclusion and exclusion criteria. In the end, 7 articles were included in this review to answer the research question. Critical assessment of these 7 articles was performed with the diagnostic CAT criteria.
CONCLUSION
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.
2. INTRODUCTION
2.1 Background
Small-fiber neuropathy (SFN), a disease known for its dysfunction of thin myelinated A??-fibers and unmyelinated C-fibers, is clinically characterized by sensory and autonomic symptoms (4). Sensory symptoms include pain, paraesthesias, allodynia, thermal sensory loss, pinprick loss, sheet or sock intolerance and restless legs symptoms (4). A??-fibers and C-fibers also are found in organs and therefore could lead to autonomic symptoms like Sicca syndrome, accommodation problems, hyperhydrosis or hypohydrosis, micturation dysfunction, sexual dysfunction, bowel dysfunction, hot flushes, orthostatic hypotension and cardiac palpitations (4). Diabetes Mellitus is the most common cause of SFN (5). Remaining causes could be classified into the following categories: metabolic, toxic (i.e. after chemotherapy), infectious, immune-mediated and hereditary (5). Some cases, however, are idiopathic.
An important hypothesis is that small-fiber neuropathy precedes large-fiber neuropathy, clinically characterized by vibration, proprioception and protective sensation dysfunction (6, 7). For that reason it is important to detect small-fiber neuropathy in an early stage as can be dealt earlier with the disease.
The prevalence and incidence of SFN are unknown (4). However, the prevalence and incidence of Diabetes Mellitus, as most common cause of SFN, was 834.100 respectively 52.700 in 2011 in the Netherlands (8). Because of the high prevalence and incidence of Diabetes Mellitus, good diagnostic performance of SFN is of interest.
To date, the diagnosis of SFN is set by an abnormal intraepidermal nerve fiber density (IENFD) by skin biopsies and/or an abnormal quantitative sensory testing (QST) in combination with the clinical characteristics of the patient (4). Skin biopsy is a reliable, minimally invasive, safe, mostly painless and inexpensive technique to determine IENFD (4). However sensitivity and specificity are questioned (1, 2). In addition, skin biopsy provides no information about the function of small nerve fibers (9). QST is performed by temperature threshold measurements (4) and also has unclear sensitivity and specificity regarding the pain symptoms (1, 2). In addition, QST is a subjective test that patients could manipulate. Therefore patients should be attentive and co-operative to obtain reliable results (4).
2.2 Objective
Diagnostic tools with higher sensitivity are needed to set the diagnosis of SFN in an early stage. Analysis of axon reflex is a simple method to evaluate the peripheral C-fiber function. Electrical, mechanical and chemical stimuli can activate unmyelinated C-fibers in the skin resulting in a visible flare response due to vasodilatation (1). The flare is dependent on the density and C-fiber function in the skin and the response could be measured by the Laser Doppler Imaging Flare Technique (LDIflare) (1). The assessment of the LDIflare technique is illustrated in figure 1 (10). The LDIflare method may be a recent, non-invasive and non-subjective technique for diagnosing SFN in an inelaborate and time-efficient manner (1, 3). In addition, the LDIflare method may be useful in order to make a distinction between painful and non-painful SFN.
Several studies showed that the axon reflex flare size is reduced in patients with SFN (4, 11, 12). In addition, results of recent studies showed that LDI is sufficient sensitive to detect small-fiber dysfunction (1, 13).
This literature review will answer the question whether Laser Doppler Imaging is of additional value compared to skin biopsy with quantification of intraepidermal nerve fiber density and quantitative sensory testing in the diagnosis of small-fiber neuropathy?
3. METHODS
3.1 Search strategy
The literature search was performed using database PubMed to find articles about diagnosing small-fiber neuropathy. In this search MeSH terms and free terms were combined to obtain optimal results possibly useful for answering the research question. This literature search was performed according the top 5 search terms of the diagnosis critical appraisal of a topic (CAT): disease, test, methodology, patient characteristics and golden standard. The used MeSH terms and free terms are represented in Table 1 (Appendix 2). Most recent articles were especially of interest so we used the inclusion criterium of ‘published in the last 5 years’.
3.2 Criteria for selecting studies based on title and abstract
Subsequently, other criteria based on the research question were used to include and exclude articles. The following inclusion and exclusion criteria (Table 2) were used in order to make a selection of most useful articles for answering the research question.
Table 2: Inclusion and exclusion criteria
Inclusion criteria Exclusion criteria
Disease Small-fiber neuropathy –
Clinical characteristics Diabetes Mellitus 1/2 –
Study population Adults Pediatric population, rats
Diagnostic technique LDIflare diagnostic –
Diagnostic method Skin fibers Other than skin fibers
Study design Cross-sectional studies Review
Language English, Dutch Other than English, Dutch
4. RESULTS
4.1 Results of search strategy
The PubMed search yielded 52 results as shown in Table 3 (Appendix 3). After selecting for ‘published in the last 5 years’ 17 articles remained (Appendix 4). A selection of these 17 articles was performed on the basis of title and abstract (Appendix 5). Articles in this review are included according inclusion criteria described in the methods. Reasons for not including articles are using a small research population (14), using a modified LDIflare method (14), not understanding Japanese (15), not comparing the LDIflare method with the golden standard (16), using the LDIflare method for a different purpose (17), excluding of neuropathy patients (18, 19), studies performed on rats (20, 21), studies performed in pedriatic populations (22) and studying other unmyelinated C-fibers in regions other than the skin (21) (Appendix 5).
In the end, 7 articles were included in this review to answer the research question.
4.2 Critical assessment of included studies
After selection 7 articles (1, 6, 9, 10, 23-25) remain to write this review.
Critical assessment of these 7 articles was performed with the diagnostic CAT criteria. The Dutch Cochrane diagnostic criteria will complement the diagnostic CAT criteria. Both the diagnostic CAT criteria and the Dutch Cochrane diagnostic criteria are shown in Appendix 6.
4.3 Results of critical review
4.3.1 Comparison with golden standard
In summary, in none of the articles the LDIflare method is compared to the golden standard, skin biopsy with quantification of intraepidermal nerve fiber density and/or quantitative sensory testing in combination with the clinical characteristics of the patient. However, Vas et al. (2013) compared the sensitivities and specificities of the LDIflare method with the golden standard. The characteristics, symptoms and stage of SFN were well described in most articles.
4.3.2 Bias
4.3.2.1 Work-up bias
Work-up bias was avoided in the study of Lysy et al. (2014), Gibbons et al. (2013), Namer et al (2013) and Gibbons et al. (2010) because both the LDIflare method and reference tests were performed. In the other studies (1, 9, 23), determining work-up bias was not possible because only LDIflare was applied.
4.3.2.2 Expectation bias
Expectation bias was avoided in the study of Vas et al. (2013), Kokotis et al. (2013), Gibbons et al. (2013) and Gibbons et al. (2010) by blinding trained examiners to other test results, for example test results of nerve conduction studies. In the other articles, expectation bias was not to determine because nothing was mentioned about it in the article (6, 9, 10).
4.3.3 Reproducibility
Studies have a cross-sectional manner and patients were only examined once. Therefore, the reproducibility and repeatability of the method is unclear. Although this is unknown, all articles presented a sufficient description that was used or they referred to other articles that used the same method.
4.3.4 Validity
In general, no confidence intervals of validity outcomes were represented. Only the 95% confidence intervals of the outcome value LDIflare were represented. Therefore the validity of the LDIflare method is hard to determine. In contrast, Kokotis et al. (2013) described both the 95% confidence intervals of the outcome value LDIflare and the 95% confidence intervals of the sensitivity and specificity. The width of the 95% confidence interval of the sensitivity is approximately 38% while the width of the 95% confidence interval of the specificity is approximately 15%. The 95% confidence interval of the sensitivity is too large, which indicates less accuracy and validity
4.3.5 Sensitivity and specificity
In general, sensitivity and specificity of the LDIflare method are lower than the sensitivity and specificity of the golden standard. In contrast, Vas et al. (2013) found higher sensitivity and specificity of the LDIflare method, namely a sensitivity of 75% and a specificity of 85% by means of ROC analysis. In addition, the LDIflare technique using age-specific cut off values has even higher sensitivity and specificity, 77% and 90% respectively. Kokotis et al. (2013) found a sensitivity and specificity of the flare area measured by LDI of 43.5% and 95.3%, respectively. Nabavi et al. (2012) found an AUC of 0.72 when employing the England criteria (9). The optimal threshold value of 1.90 cm2 has limited sensitivity and specificity of 70% and 66%, respectively. When employing the sural nerve criteria for subclinical diabetic sensorimotor neuropathy, the AUC was 0.75 and the sensitivity was 79% for LDIflare. Gibbons et al. (2010) found a best overall sensitivity of 71% and specificity of 43% for axon reflex % change measured by Laser Doppler flowcytometry.
4.3.6 Diagnostic process
In all studies, there is no appropriate cut-off point used because these cut-off points were not decisive for diagnosing SFN. However, in the study of Vas et al. (2013), Namer et al. (2013) and Nabavi et al. (2012) cut-off points were decisive whether the outcome LDIflare was abnormal. In all studies, there was no question of a diagnostic process and therefore the moment of performing the LDIflare method cannot be compared with the moment in practice, when patients experience sensory and autonomic symptoms.
4.4 Overview
In the overview below results of the critical appraisal of a topic are represented (Table 4). There are points awarded to the plus and minus signs in which ++ = 2 points, + = 1 point, +/- = 0 points, – = -1 point and — = -2 points. The sign X is awarded if the criterion could not be determined. This should be taken into account in the assessment of the article. From the results it appears that few articles are of sufficient quality to answer the research question. The article of Vas et al. (2013) is the most useful to write this review. Additional, the article of Kokotis et al. (2013) and Gibbons et al. (2013) also will be useful to answer the research question. The remaining articles will still be included due to the fact that these articles meet certain criteria (6, 9, 10, 25).
Table 4. Overview of the critical assessment of articles according the CAT criteria
Reference Criteria
1
2
3
4
5
6
7
8
9
Points
Lysy et al.
(2014) — ++ ++ x + +/- — x +/- 1
Vas et al.
(2013) +/- + x ++ ++ – +/- x + 5
Kokotis et al.
(2013) – +/- x ++ ++ + +/- x +/- 4
Gibbons et al.
(2013) – ++ ++ ++ ++ — — x x 3
Namer et al.
(2013) – +/- ++ x + – +/- x x 1
Nabavi et al.
(2012) — ++ x x + – +/- x +/- 0
Gibbons et al.
(2010) – + ++ ++ + — — x +/- 1
5. DISCUSSION
5.1 Findings
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.
5.2 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 (25). 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 (23). 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 (23).
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 (23). 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 (26) 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 (1). 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 (1). In case of a positive test result SFN could be confirmed by additional diagnostic tests, like skin biopsy (10).
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 (27).
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 (10, 27). 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 (27). Thus, the LDIflare method is useful as screening tool, however this method cannot differentiate between painful and nonpainful small-fiber neuropathy (10).
5.3 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.
5.4 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 (4).
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).
5.5 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.
6. REFERENCES
1. Kokotis P, Schmelz M, Papagianni AE, Zambelis T, Karandreas N. Objective assessment of C-fiber function by electrically induced axon reflex flare in patients with axonal and demyelinating polyneuropathy. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 2013 Aug;30(4):422-7. PubMed PMID: 23912584.
2. Shy ME, Frohman EM, So YT, Arezzo JC, Cornblath DR, Giuliani MJ, et al. Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003 Mar 25;60(6):898-904. PubMed PMID: 12654951.
3. Krishnan ST, Rayman G. The LDIflare: a novel test of C-fiber function demonstrates early neuropathy in type 2 diabetes. Diabetes care. 2004 Dec;27(12):2930-5. PubMed PMID: 15562209.
4. Hoeijmakers JG, Faber CG, Lauria G, Merkies IS, Waxman SG. Small-fibre neuropathies–advances in diagnosis, pathophysiology and management. Nature reviews Neurology. 2012 Jul;8(7):369-79. PubMed PMID: 22641108.
5. Hoeijmakers JG, Bakkers M, Blom EW, Drenth JPH, Merkies IS, Faber CG. Dunnevezelneuropathie. NED TIJDSCHR GENEESKD. 2012;156.
6. Lysy Z, Lovblom LE, Halpern EM, Ngo M, Ng E, Orszag A, et al. Measurement of cooling detection thresholds for identification of diabetic sensorimotor polyneuropathy in type 1 diabetes. PloS one. 2014;9(9):e106995. PubMed PMID: 25216179. Pubmed Central PMCID: 4162569.
7. Breiner A, Lovblom LE, Perkins BA, Bril V. Does the prevailing hypothesis that small-fiber dysfunction precedes large-fiber dysfunction apply to type 1 diabetic patients? Diabetes care. 2014 May;37(5):1418-24. PubMed PMID: 24574353.
8. (RIVM) BC, (RIVM) PM, (RIVM) UE, (RIVM) SM. Hoe vaak komt diabetes mellitus voor en hoeveel mensen sterven eraan? 2014. Available from: http://www.nationaalkompas.nl/gezondheid-en-ziekte/ziekten-en-aandoeningen/endocriene-voedings-en-stofwisselingsziekten-en-immuniteitsstoornissen/diabetes-mellitus/omvang/.
9. Nabavi Nouri M, Ahmed A, Bril V, Orszag A, Ng E, Nwe P, et al. Diabetic neuropathy and axon reflex-mediated neurogenic vasodilatation in type 1 diabetes. PloS one. 2012;7(4):e34807. PubMed PMID: 22529938. Pubmed Central PMCID: 3328500.
10. Namer B, Pfeffer S, Handwerker HO, Schmelz M, Bickel A. Axon reflex flare and quantitative sudomotor axon reflex contribute in the diagnosis of small-fiber neuropathy. Muscle & nerve. 2013 Mar;47(3):357-63. PubMed PMID: 23180613.
11. Bickel A, Kramer HH, Hilz MJ, Birklein F, Neundorfer B, Schmelz M. Assessment of the neurogenic flare reaction in small-fiber neuropathies. Neurology. 2002 Sep 24;59(6):917-9. PubMed PMID: 12297579.
12. Bickel A, Heyer G, Senger C, Maihofner C, Heuss D, Hilz MJ, et al. C-fiber axon reflex flare size correlates with epidermal nerve fiber density in human skin biopsies. Journal of the peripheral nervous system : JPNS. 2009 Dec;14(4):294-9. PubMed PMID: 20021571.
13. Kr??mer HH, Schmelz M, Birklein F, Bickel A. Electrically stimulated axon reflexes are diminished in diabetic small-fiber neuropathies. Diabetes. 2004;53:769-74.
14. Vas PR, Rayman G. Validation of the modified LDIFlare technique: a simple and quick method to assess C-fiber function. Muscle & nerve. 2013 Mar;47(3):351-6. PubMed PMID: 23169592.
15. Obayashi K. [Construction and clinical evaluation of novel methods for detecting autoinomic dysfunction]. Rinsho byori The Japanese journal of clinical pathology. 2012 May;60(5):435-42. PubMed PMID: 22774572.
16. Schley M, Bayram A, Rukwied R, Dusch M, Konrad C, Benrath J, et al. Skin innervation at different depths correlates with small fibre function but not with pain in neuropathic pain patients. European journal of pain. 2012 Nov;16(10):1414-25. PubMed PMID: 22556099.
17. Alhadad A, Wollmer P, Svensson A, Eriksson KF. Erythromelalgia: Incidence and clinical experience in a single centre in Sweden. VASA Zeitschrift fur Gefasskrankheiten. 2012 Jan;41(1):43-8. PubMed PMID: 22247059.
18. Vas PR, Green AQ, Rayman G. Small fibre dysfunction, microvascular complications and glycaemic control in type 1 diabetes: a case-control study. Diabetologia. 2012 Mar;55(3):795-800. PubMed PMID: 22193513.
19. Green AQ, Krishnan S, Finucane FM, Rayman G. Altered C-fiber function as an indicator of early peripheral neuropathy in individuals with impaired glucose tolerance. Diabetes care. 2010 Jan;33(1):174-6. PubMed PMID: 20040675. Pubmed Central PMCID: 2797968.
20. Pelletier J, Fromy B, Morel G, Roquelaure Y, Saumet JL, Sigaudo-Roussel D. Chronic sciatic nerve injury impairs the local cutaneous neurovascular interaction in rats. Pain. 2012 Jan;153(1):149-57. PubMed PMID: 22054597.
21. Hanada T, Uchida S, Hotta H, Aikawa Y. Number, size, conduction, and vasoconstrictor ability of unmyelinated fibers of the ovarian nerve in adult and aged rats. Autonomic neuroscience : basic & clinical. 2011 Oct 28;164(1-2):6-12. PubMed PMID: 21636330.
22. Cook-Norris RH, Tollefson MM, Cruz-Inigo AE, Sandroni P, Davis MD, Davis DM. Pediatric erythromelalgia: a retrospective review of 32 cases evaluated at Mayo Clinic over a 37-year period. Journal of the American Academy of Dermatology. 2012 Mar;66(3):416-23. PubMed PMID: 21798623.
23. Vas PR, Rayman G. The rate of decline in small fibre function assessed using axon reflex-mediated neurogenic vasodilatation and the importance of age related centile values to improve the detection of clinical neuropathy. PloS one. 2013;8(7):e69920. PubMed PMID: 23936119. Pubmed Central PMCID: 3723820.
24. Gibbons CH, Freeman R, Tecilazich F, Dinh T, Lyons TE, Gnardellis C, et al. The evolving natural history of neurophysiologic function in patients with well-controlled diabetes. Journal of the peripheral nervous system : JPNS. 2013 Jun;18(2):153-61. PubMed PMID: 23781962. Pubmed Central PMCID: 3694741.
25. Gibbons CH, Freeman R, Veves A. Diabetic neuropathy: a cross-sectional study of the relationships among tests of neurophysiology. Diabetes care. 2010 Dec;33(12):2629-34. PubMed PMID: 20805259. Pubmed Central PMCID: 2992203.
26. Lauria G, Devigili G. Skin biopsy as a diagnostic tool in peripheral neuropathy. Nature clinical practice Neurology. 2007 Oct;3(10):546-57. PubMed PMID: 17914343.
27. Kalliomaki M, Kieseritzky JV, Schmidt R, Hagglof B, Karlsten R, Sjogren N, et al. Structural and functional differences between neuropathy with and without pain? Experimental neurology. 2011 Oct;231(2):199-206. PubMed PMID: 21683699.
7. APPENDIX 1
Figure 1. Illustration of the LDIflare method (10)
APPENDIX 2
Table 1. MeSH terms and free terms
Top 5 diagnosis CAT MeSH terms Free terms
1. Disease Polyneuropathies (diagnosis, etiology, therapy), Nerve Fibers, Unmyelinated Small-fiber neuropathy (SFN), small fibre neuropathy (SFN)
2. Test Laser-Doppler Flowcytometry Laser doppler imaging, laser doppler, axon reflex flare reaction, axon reflex flare
3. Methodology – –
4. Patient characteristics – –
5. Golden standard Physical Examination, biopsy Clinical examination, biopsy, intraepidermal nerve fiber density (IENFD), quantitative sensory testing (QST), temperature threshold testing, autonomic testing
APPENDIX 3
Table 3. PubMed search
APPENDIX 4
1: Lysy Z, Lovblom LE, Halpern EM, Ngo M, Ng E, Orszag A, Breiner A, Bril V,
Perkins BA. Measurement of cooling detection thresholds for identification of
diabetic sensorimotor polyneuropathy in type 1 diabetes. PLoS One. 2014 Sep
12;9(9):e106995. doi: 10.1371/journal.pone.0106995. eCollection 2014. PubMed
PMID: 25216179; PubMed Central PMCID: PMC4162569.
2: Vas PR, Rayman G. The rate of decline in small fibre function assessed using
axon reflex-mediated neurogenic vasodilatation and the importance of age related
centile values to improve the detection of clinical neuropathy. PLoS One. 2013
Jul 25;8(7):e69920. doi: 10.1371/journal.pone.0069920. Print 2013. PubMed PMID:
23936119; PubMed Central PMCID: PMC3723820.
3: Kokotis P, Schmelz M, Papagianni AE, Zambelis T, Karandreas N. Objective
assessment of C-fiber function by electrically induced axon reflex flare in
patients with axonal and demyelinating polyneuropathy. J Clin Neurophysiol. 2013
Aug;30(4):422-7. doi: 10.1097/WNP.0b013e31829ddb97. PubMed PMID: 23912584.
4: Gibbons CH, Freeman R, Tecilazich F, Dinh T, Lyons TE, Gnardellis C, Veves A.
The evolving natural history of neurophysiologic function in patients with
well-controlled diabetes. J Peripher Nerv Syst. 2013 Jun;18(2):153-61. doi:
10.1111/jns5.12021. PubMed PMID: 23781962; PubMed Central PMCID: PMC3694741.
5: Namer B, Pfeffer S, Handwerker HO, Schmelz M, Bickel A. Axon reflex flare and
quantitative sudomotor axon reflex contribute in the diagnosis of small-fiber
neuropathy. Muscle Nerve. 2013 Mar;47(3):357-63. doi: 10.1002/mus.23543. Epub
2012 Nov 24. PubMed PMID: 23180613.
6: Vas PR, Rayman G. Validation of the modified LDIFlare technique: a simple and
quick method to assess C-fiber function. Muscle Nerve. 2013 Mar;47(3):351-6. doi:
10.1002/mus.23532. Epub 2012 Nov 21. PubMed PMID: 23169592.
7: Alport AR, Sander HW. Clinical approach to peripheral neuropathy: anatomic
localization and diagnostic testing. Continuum (Minneap Minn). 2012
Feb;18(1):13-38. doi: 10.1212/01.CON.0000411546.13207.b1. Review. PubMed PMID:
22810068.
8: Obayashi K. [Construction and clinical evaluation of novel methods for
detecting autoinomic dysfunction]. Rinsho Byori. 2012 May;60(5):435-42. Review.
Japanese. PubMed PMID: 22774572.
9: Schley M, Bayram A, Rukwied R, Dusch M, Konrad C, Benrath J, Geber C, Birklein
F, H??ggl??f B, Sj??gren N, Gee L, Albrecht PJ, Rice FL, Schmelz M. Skin innervation
at different depths correlates with small fibre function but not with pain in
neuropathic pain patients. Eur J Pain. 2012 Nov;16(10):1414-25. doi:
10.1002/j.1532-2149.2012.00157.x. Epub 2012 May 3. PubMed PMID: 22556099.
10: Nabavi Nouri M, Ahmed A, Bril V, Orszag A, Ng E, Nwe P, Perkins BA. Diabetic
neuropathy and axon reflex-mediated neurogenic vasodilatation in type 1 diabetes.
PLoS One. 2012;7(4):e34807. doi: 10.1371/journal.pone.0034807. Epub 2012 Apr 17.
PubMed PMID: 22529938; PubMed Central PMCID: PMC3328500.
11: Alhadad A, Wollmer P, Svensson A, Eriksson KF. Erythromelalgia: Incidence and
clinical experience in a single centre in Sweden. Vasa. 2012 Jan;41(1):43-8. doi:
10.1024/0301-1526/a000162. PubMed PMID: 22247059.
12: Vas PR, Green AQ, Rayman G. Small fibre dysfunction, microvascular
complications and glycaemic control in type 1 diabetes: a case-control study.
Diabetologia. 2012 Mar;55(3):795-800. doi: 10.1007/s00125-011-2417-9. Epub 2011
Dec 23. PubMed PMID: 22193513.
13: Pelletier J, Fromy B, Morel G, Roquelaure Y, Saumet JL, Sigaudo-Roussel D.
Chronic sciatic nerve injury impairs the local cutaneous neurovascular
interaction in rats. Pain. 2012 Jan;153(1):149-57. doi:
10.1016/j.pain.2011.10.001. Epub 2011 Nov 3. PubMed PMID: 22054597.
14: Cook-Norris RH, Tollefson MM, Cruz-Inigo AE, Sandroni P, Davis MD, Davis DM.
Pediatric erythromelalgia: a retrospective review of 32 cases evaluated at Mayo
Clinic over a 37-year period. J Am Acad Dermatol. 2012 Mar;66(3):416-23. doi:
10.1016/j.jaad.2011.01.010. Epub 2011 Jul 27. PubMed PMID: 21798623.
15: Hanada T, Uchida S, Hotta H, Aikawa Y. Number, size, conduction, and
vasoconstrictor ability of unmyelinated fibers of the ovarian nerve in adult and
aged rats. Auton Neurosci. 2011 Oct 28;164(1-2):6-12. doi:
10.1016/j.autneu.2011.05.001. Epub 2011 Jun 1. PubMed PMID: 21636330.
16: Gibbons CH, Freeman R, Veves A. Diabetic neuropathy: a cross-sectional study
of the relationships among tests of neurophysiology. Diabetes Care. 2010
Dec;33(12):2629-34. doi: 10.2337/dc10-0763. Epub 2010 Aug 30. PubMed PMID:
20805259; PubMed Central PMCID: PMC2992203.
17: Green AQ, Krishnan S, Finucane FM, Rayman G. Altered C-fiber function as an
indicator of early peripheral neuropathy in individuals with impaired glucose
tolerance. Diabetes Care. 2010 Jan;33(1):174-6. doi: 10.2337/dc09-0101. PubMed
PMID: 20040675; PubMed Central PMCID: PMC2797968.
APPENDIX 5
Included articles
1: the article of Lysy et al. is about quantitative sensory testing (QST), the golden standard for diagnosis of SFN. Therefore this article is useful to answer the research question of LDIflare is of additional value compared to QST.
2: the article of Vas et al. is about the LDIflare technique which measure the rate of decline in small-fiber function dependent on age. They believe that the LDIflare technique has high sensitivity, specificity and reproducibility to investigate the etiology of small-fiber neuropathy.
This article may contribute to my answer to my research question.
3: the article of Kokotis et al. represents the value of LDIflare as screening method for SFN. Therefore this article is useful.
4:the article of Gibbons et al. is about detecting changes in neurophysiological function in patients with well controlled diabetes mellitus, which is the most common cause of SFN. Their results suggest that the LDIflare can detect the largest change in well controlled diabetes mellitus patients and could therefore be of additional value. This article is useful to answer this research question.
5: the study of Namer et al. establish that LDIflare contribute to set the diagnosis of SFN and is therefore useful in this review.
10: the article of Nabavi Nouri et al. is about axon reflex-mediated neurogenic vasodilatation and may be a diagnostic test to detect early, pre-clinical small-fiber neuropathy. This article also include sensitivity values of the LDIflare technique, so this article can contribute to my research answer.
16: Gibbons et al. studied the relationships among diagnostic tests, including axon-reflex-mediated blood flow measured by Laser Doppler Flowmetry, and is therefore very useful for answering the research question.
Excluded articles
6: the article of Vas et al. compared a modified LDIflare technique with the original LDIflare. This study cannot contribute to the research question: is LDIflare of additional value in the diagnosis of SFN and is therefore not useful. In addition, this study included a very small population.
7: the article of Alport et al. is not useful because this is a review.
8: the article of Obayashi et al. is not useful because it is written in Japanese, which I cannot read. For this reason this article is not useful.
9: the article of Schley et al. studied the correlation of nerve fiber density in different layers of the skin with neuronal function and level of neuropathic pain by different diagnostic tools, including LDI. However, this article is not useful because this study does not compare the different techniques.
11: the article of Alhadad et al. is only about the investigation of the incidence of erythromelalgia by for example LDIflare technique. Therefore this article is not useful to answer my question.
12: Vas et al. studied the influence of microvascular disease on unmyelinated C fiber function in diabetes mellitus 1 patients measured by LDIflare. Controls and diabetes mellitus 1 patients with neuropathy were excluded so for that reason the additional value of LDIflare for diagnosing SFN cannot be studied. Therefore this article not useful.
13: the study of Pelletier et al. was performed in rats and is therefore not useful to answer this research question.
14: the study of Cook-Norris et al. was performed in a pediatric population and is therefore not useful.
15: the study of Hanada et al. is about the unmyelinated fibers in the ovarian nerve and not in the skin. It also was performed in rats. For these reasons this article is not useful.
17: The article of Green et al. is about detecting early peripheral neuropathy in impaired glucose tolerance patients by LDIflare. However clinical neuropathy is excluded and for that reason this study cannot contribute to answer the research question and is therefore not useful.
APPENDIX 6
Diagnostic CAT criteria
Dutch Cochrane diagnostic criteria