Epidermal nerve fibers

Engelstad, Ja Nean K.; Taylor, Stuart R.; Witt, Lawrence V.; Hoebing, Belinda J.; Herrmann, David N.; Klein, Christopher J.; Johnson, David M.; Davies, Julian; Carter, Rickey E.; Dyck, Peter J.

doi:10.1212/wnl.0b013e3182759608

Cited by 24 publications

(37 citation statements)

References 39 publications

(36 reference statements)

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“…One IENF is comparable for magnitude to the inter-rater variation (0.4 ± 1.5 IENF/mm) as calculated on the same sections (Goransson et al, 2004). Therefore, as previously suggested (Engelstad et al, 2012), values of IENFD very close to the cut-off (just normal or just abnormal) must be considered with caution before providing a diagnostic judgment.…”

Section: Discussionsupporting

confidence: 63%

Epidermal innervation morphometry by immunofluorescence and bright‐field microscopy

Nolano

Biasiotta

Lombardi

et al. 2015

J Peripheral Nervous Sys

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We investigated the agreement between simple indirect immunofluorescence (IF) and bright-field immunohistochemistry (BFI) on free-floating sections for intraepidermal nerve fiber density (IENFD) quantification. Fifty-five healthy subjects and 63 patients with probable small fiber neuropathy (SFN) underwent two adjacent skin biopsies at the distal leg processed by IF and BFI technique. Agreement between IENFD pairs obtained by each method was assessed by Bland-Altman testing. The area under the curve of the receiving operating characteristics (ROC) curves was used to compare the discrimination ability. The diagnostic judgment was based on sex and age-adjusted normative values. IF and BFI showed good correlation (r = 0.81), with a ratio of about 2:1 and a mean difference of 5.5 ± 3.0 IENF per millimeter between paired measures, as demonstrated by linear regression and Bland-Altman test analyses. The square root transformation confirmed a Poisson distribution of the data and a fixed bias between IF and BFI measurements. The ROC curves analysis demonstrated a striking overlap between IF and BFI (0.83 and 0.82; p = 0.72). The diagnosis of SFN disagreed in only 6.7% of cases when the judgment was based on a difference of >1 IENF from 5% cut-off value. IF and BFI showed comparable diagnostic efficiency when referred to appropriate normative reference values.

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Section: Discussionsupporting

confidence: 63%

Epidermal innervation morphometry by immunofluorescence and bright‐field microscopy

Nolano

Biasiotta

Lombardi

et al. 2015

J Peripheral Nervous Sys

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“…40,42,46–49 Minimally invasive skin biopsies can assess intraepidermal fiber density, but they have shown considerable variability, even among controls, and their invasive nature remains a burden for patients and researchers. 123,124 Corneal confocal microscopy has shown early promising results for non-invasive detection and stratification of the severity of DPN. 125,126 However, the sensitivity and specificity of the technique for feet at risk of ulceration is moderate.…”

Section: Current Limitations In Assessing Intervention Efficacy In Dpnmentioning

confidence: 99%

Declining Skeletal Muscle Function in Diabetic Peripheral Neuropathy

Parasoglou

Rao

Slade

2017

Clinical Therapeutics

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Purpose In this review, we highlight the current concepts in the effects of diabetic peripheral neuropathy (DPN) in skeletal muscle. We discuss the lack of effective pharmacological treatments and the role of physical exercise intervention in limb protection and symptom reversal. We also highlight the importance of Magnetic Resonance Imaging (MRI) techniques in providing a mechanistic understanding of the disease and helping develop targeted treatments. Methods This review provides a comprehensive reporting on the effects of DPN in the skeletal muscle of diabetic patients. It also provides an update on the most recent trials of exercise intervention targeting DPN pathology. Lastly, we report on emerging MRI techniques that have shown promise in providing a mechanistic understanding of DPN and can help improve the design and implementation of clinical trials in the future. Findings Impairments in lower limb muscles reduce functional capacity and contribute to altered gait, increased fall risk, and impaired balance in patients with DPN. This is an important concern for DPN patients as their falls are very likely to be injurious, and lead to bone fractures, poorly healing wounds, and chronic infections that may require amputation. Preliminary studies have shown that moderate intensity exercise programs are well tolerated by patients with DPN. They can improve their cardiorespiratory function and can partially reverse some of the DPN symptoms. MRI has the potential to bring new mechanistic insights into the effects of DPN as well as to objectively measure small changes in DPN pathology as a result of intervention. Implications Non-invasive exercise intervention is particularly valuable in DPN due to its safety, low cost, and potential to augment pharmacological interventions. As we gain a better mechanistic understanding of the disease, more targeted and effective interventions can be designed.

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“…15 and 18; idiopathic SFN) had IENFD bilaterally about 30% higher than the cutoff, thus not confirming the diagnosis of SFN pathologically, whereas the others (no. 4,9,10) showed values at the cutoff, making the diagnosis possible pathologically. In HVs, mean and median values of IENFD were 6.38 IENF/mm and 6.3 IENF/mm 6 2.81 SD at the right side, and 6.0 IENF/mm and 6.2 IENF/mm 6 2.3 SD at the left side, a nonsignificant difference.…”

mentioning

confidence: 99%

“…If IENFD was affected by the turnover of keratinocytes, a follow-up biopsy at their half-life of renewal should have captured any related change. In the absence of any factor that can vary IENFD, such as neuropathy progression, biopsy in a different sensory nerve territory, technical issues in biopsy processing section, and number of sections quantified, 9 any significant change would be attributed to intrinsic skin variables. Since we used the bright-field method and not indirect immunofluorescence, 10 we did not reassess intra-and interobserver agreement on IENFD quantification, knowing its excellent results have already been published.…”

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confidence: 99%

Side and time variability of intraepidermal nerve fiber density

et al. 2015

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Objective: To assess the right-to-left and short-term variability of intraepidermal nerve fiber density (IENFD) at the distal site of the leg.Methods: Patients with possible or probable small fiber neuropathy (SFN) and healthy volunteers (HVs) underwent skin biopsies at the right and left distal leg. A subgroup of participants underwent follow-up biopsies 20 days later. Biopsies were immunostained by polyclonal anti-protein gene product 9.5 antibodies, and IENFD was quantified in nonconsecutive sections following published guidelines by operators blinded to the participants' condition (diagnosis, side, and time of biopsy). Findings were referred to sex-and age-adjusted normative values.Results: Forty patients and 17 HVs underwent bilateral skin biopsies; 15 patients and 8 HVs underwent follow-up skin biopsies. Sural nerve and dorsal sural nerve conduction studies were normal in all participants. Interside IENFD did not differ both in patients (median 2.45 IENF/ mm 6 1.45 SD right; 2.2 IENF/mm 6 1.32 SD left) and HVs (median 6.3 IENF/mm 6 2.81 right; 6.2 IENF/mm 6 2.3 SD left). The right-to-left correlation coefficients were excellent (Pearson 0.95 in SFN and 0.97 in HVs). The analysis of IENFD at 20-day follow-up biopsy showed no difference between sides in both groups and yielded excellent correlation coefficients. Conclusions:The diagnosis of SFN can be reliably ascertained by unilateral skin biopsy at the distal site of the leg, and IENFD is not expected to vary within 3 weeks. Neurology ® 2015;84:2368-2371 GLOSSARY HV 5 healthy volunteer; IENF 5 intraepidermal nerve fiber; IENFD 5 intraepidermal nerve fiber density; SFN 5 small fiber neuropathy.Intraepidermal nerve fiber density (IENFD) at the distal site of the leg is a widely used tool to confirm the diagnosis of small fiber neuropathy (SFN).1 The availability of age-and sex-adjusted reference values has improved the reliability of the method based on bright-field immunohistochemistry.2 Skin biopsy, like electrodiagnostic studies, is usually performed unilaterally, and no recommendation currently exists to perform it on the right or left side for diagnosing SFN. However, while the right-to-left concordance of sural nerve conduction velocity and amplitude has been investigated in patients with neuropathy and healthy volunteers (HVs), 3 it is unknown whether this variable can affect the diagnostic performance of skin biopsy. One further variable is the consistency of IENFD over a short period of time. Skin is a self-renewal tissue, and the epidermis has an active turnover estimated at about 40 days. 4 The loss of IENF, which is the hallmark of SFN, can modify the architecture of the epidermis and possibly of keratinocyte functioning, which are part of the complex peripheral network involved in thermal sensation and nociception.5 It is unknown whether epidermis turnover can influence IENFD in neuropathy and HVs. Our study aimed at addressing the right-to-left and time variability of IENFD over a period of 20 days, namely, the estimated half-life for t...

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Epidermal nerve fibers

Cited by 24 publications

References 39 publications

Epidermal innervation morphometry by immunofluorescence and bright‐field microscopy

Epidermal innervation morphometry by immunofluorescence and bright‐field microscopy

Declining Skeletal Muscle Function in Diabetic Peripheral Neuropathy

Side and time variability of intraepidermal nerve fiber density

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