Diagnostic performance of a multivariate model of normal epidermal nerve fiber (enf) density for skin-biopsy diagnosis of small-fiber polyneuropathy (sfpn)

Chronic pain may affect 30–50% of the world’s population and an important cause is small fiber neuropathy (SFN). Recent research suggests that autoimmune diseases may be one of the most common causes of small nerve fiber damage. There is low awareness of SFN among patients and clinicians and it is difficult to diagnose as routine electrophysiological methods only detect large fiber abnormalities, and specialized small fiber tests, like skin biopsy and quantitative sensory testing, are not routinely available. Corneal confocal microscopy (CCM) is a rapid, non-invasive, reproducible method for quantifying small nerve fiber degeneration and regeneration, and could be an important tool for diagnosing SFN. This review considers the advantages and disadvantages of CCM and highlights the evolution of this technique from a research tool to a diagnostic test for small fiber damage, which can be a valuable contribution to the study and management of autoimmune disease.

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The value of skin biopsy with recording of intraepidermal nerve fiber density and quantitative sensory testing in the assessment of small fiber involvement in patients with different causes of polyneuropathy

Journal of Neurology ◽

10.1007/s00415-009-5181-8 ◽

2009 ◽

Vol 256 (6) ◽

pp. 1034-1034 ◽

Cited By ~ 1

Author(s):

Maria Nebuchennykh ◽

Sissel Løseth ◽

Sigurd Lindal ◽

Svein Ivar Mellgren

Keyword(s):

Skin Biopsy ◽

Nerve Fiber ◽

Quantitative Sensory Testing ◽

Sensory Testing ◽

Fiber Density ◽

Small Fiber ◽

Intraepidermal Nerve Fiber Density ◽

Nerve Fiber Density ◽

Intraepidermal Nerve Fiber

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Alpha-synuclein oligomers and small nerve fiber pathology in skin are potential biomarkers of Parkinson’s disease

npj Parkinson s Disease ◽

10.1038/s41531-021-00262-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Elena Vacchi ◽

Camilla Senese ◽

Giacomo Chiaro ◽

Giulio Disanto ◽

Sandra Pinton ◽

...

Keyword(s):

Skin Biopsy ◽

Nerve Fiber ◽

Temporal Dynamics ◽

Alpha Synuclein ◽

Small Fiber Neuropathy ◽

Proximity Ligation Assay ◽

Anatomical Site ◽

Small Fiber ◽

Intraepidermal Nerve Fiber Density ◽

Small Nerve

AbstractThe proximity ligation assay (PLA) is a specific and sensitive technique for the detection of αSyn oligomers (αSyn-PLA), early and toxic species implicated in the pathogenesis of PD. We aimed to evaluate by skin biopsy the diagnostic and prognostic capacity of αSyn-PLA and small nerve fiber reduction in PD in a longitudinal study. αSyn-PLA was performed in the ankle and cervical skin biopsies of PD (n = 30), atypical parkinsonisms (AP, n = 23) including multiple system atrophy (MSA, n = 12) and tauopathies (AP-Tau, n = 11), and healthy controls (HC, n = 22). Skin biopsy was also analyzed for phosphorylated αSyn (P-αSyn) and 5G4 (αSyn-5G4), a conformation-specific antibody to aggregated αSyn. Intraepidermal nerve fiber density (IENFD) was assessed as a measure of small fiber neuropathy. αSyn-PLA signal was more expressed in PD and MSA compared to controls and AP-Tau. αSyn-PLA showed the highest diagnostic accuracy (PD vs. HC sensitivity 80%, specificity 77%; PD vs. AP-Tau sensitivity 80%, specificity 82%), however, P-αSyn and 5G4, possible markers of later phases, performed better when considering the ankle site alone. A small fiber neuropathy was detected in PD and MSA. A progression of denervation not of pathological αSyn was detected at follow-up and a lower IENFD at baseline was associated with a greater cognitive and motor decline in PD. A skin biopsy-derived compound marker, resulting from a linear discrimination analysis model of αSyn-PLA, P-αSyn, αSyn-5G4, and IENFD, stratified patients with accuracy (77.8%), including the discrimination between PD and MSA (84.6%). In conclusion, the choice of pathological αSyn marker and anatomical site influences the diagnostic performance of skin biopsy and can help in understanding the temporal dynamics of αSyn spreading in the peripheral nervous system during the disease. Skin denervation, not pathological αSyn is a potential progression marker for PD.

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Skin Biopsy in Complex Regional Pain Syndrome: Case Series and Literature Review

January 2018 - Pain Physician ◽

10.36076/ppj.2012/15/255 ◽

2012 ◽

Vol 3;15 (3;5) ◽

pp. 255-266 ◽

Cited By ~ 1

Author(s):

Robert J. Schwartzman

Keyword(s):

Skin Biopsy ◽

Complex Regional Pain Syndrome ◽

Nerve Fiber ◽

Quantitative Sensory Testing ◽

Pain Syndrome ◽

Sensory Testing ◽

Fiber Density ◽

Epidermal Nerve Fiber Density ◽

Nerve Fiber Density ◽

Epidermal Nerve Fiber

Background: Accumulating experimental and clinical evidence supports the hypothesis that complex regional pain syndrome type I (CRPS-I) may be a small fiber neuropathy. Objectives: To evaluate the use of commercially available standard biopsy methods to detect intradermal axon pathology in CRPS-I, and to ascertain if these structural changes can explain quantitative sensory testing (QST) findings in CRPS-I. Study Design: Retrospective review of charts and laboratory data. Setting: Outpatient clinic Methods: Skin biopsies from 43 patients with CRPS-I were stained with PGP 9.5, and epidermal nerve fiber density, sweat gland nerve fiber density and morphological abnormalities were evaluated. Thirty-five patients had quantitative sensory testing. Results: Alterations in skin innervation were seen in approximately 20% of CRPS-I patients with commercial processing. There were no patient characteristics, including duration of disease, that predicted a decreased epidermal nerve fiber density (ENFD). There was no consistent relationship between QST changes and ENFD measured by standard commercial skin biopsy evaluation procedures. Limitations: Commercial processing of tissue does not utilize stereologic quantitative analysis of nerve fiber density. Biopsy material is utilized from a proximal and distal source only, and differences in denervation of a partial nerve territory may be missed. The functional attributes of small fibers cannot be assessed. Conclusions: The negative results indicate that CRPS-I may be associated with changes in the ultramicroscopic small fiber structure that cannot be visualized with commercially available techniques. Alternatively, functional rather than structural alterations of small fibers or pathological changes at a more proximal site such as the spinal cord or brain may be responsible for the syndrome. Key words: Complex Regional Pain Syndrome, CRPS-1, CRPS, skin biopsy, epidermal nerve fiber density, sweat gland nerve fiber density, quantitative sensory testing.

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Contribution of Skin Biopsy in Peripheral Neuropathies

Brain Sciences ◽

10.3390/brainsci10120989 ◽

2020 ◽

Vol 10 (12) ◽

pp. 989

Author(s):

Maria Nolano ◽

Stefano Tozza ◽

Giuseppe Caporaso ◽

Vincenzo Provitera

Keyword(s):

Skin Biopsy ◽

Nerve Fiber ◽

Sural Nerve ◽

Nerve Biopsy ◽

Nerve Fibers ◽

Sural Nerve Biopsy ◽

Invasive Technique ◽

Myelinated Fibers ◽

Small Fiber ◽

Over Time

In the last three decades the study of cutaneous innervation through 3 mm-punch-biopsy has provided an important contribution to the knowledge of small fiber somatic and autonomic neuropathies but also of large fiber neuropathies. Skin biopsy is a minimally invasive technique with the advantage, compared to sural nerve biopsy, of being suitable to be applied to any site in our body, of being repeatable over time, of allowing the identification of each population of nerve fiber through its target. In patients with symptoms and signs of small fiber neuropathy the assessment of IntraEpidermal Nerve Fiber density is the gold standard to confirm the diagnosis while the quantification of sudomotor, pilomotor, and vasomotor nerve fibers allows to evaluate and characterize the autonomic involvement. All these parameters can be re-evaluated over time to monitor the disease process and to evaluate the effectiveness of the treatments. Myelinated fibers and their receptors can also be evaluated to detect a “dying back” neuropathy early when nerve conduction study is still normal. Furthermore, the morphometry of dermal myelinated fibers has provided new insight into pathophysiological mechanisms of different types of inherited and acquired large fibers neuropathies. In genetic neuropathies skin biopsy has become a surrogate for sural nerve biopsy, no longer necessary in the diagnostic process, to study genotype–phenotype correlations.

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Intraepidermal nerve fiber density reduction as a marker of preclinical asymptomatic small-fiber sensory neuropathy in hypothyroid patients

Acta Endocrinologica ◽

10.1530/eje-10-0285 ◽

2010 ◽

Vol 163 (2) ◽

pp. 279-284 ◽

Cited By ~ 17

Author(s):

Flavia Magri ◽

Michelangelo Buonocore ◽

Antonio Oliviero ◽

Mario Rotondi ◽

Anna Gatti ◽

...

Keyword(s):

Skin Biopsy ◽

Nerve Fiber ◽

Sensory Neuropathy ◽

Fiber Density ◽

Density Reduction ◽

Small Fiber ◽

Proximal Site ◽

Hypothyroid Patients ◽

Nerve Fiber Density ◽

Intraepidermal Nerve Fiber

AimTo evaluate, by using skin biopsy technique, the intraepidermal nerve fiber (IENF) density in a group of untreated patients with hypothyroidism, either overt (OH) or subclinical (SH), who did not complain of neurologic symptoms.MethodsWe evaluated 18 neurologically asymptomatic patients newly diagnosed with OH or SH. Fifteen healthy, age-matched, controls were also studied. A nerve conduction study was performed. Skin biopsy was carried out from the skin of upper thigh and distal leg. Nerve fiber density was measured using an immunofluorescence technique. The density of innervation was calculated by counting only fibers crossing the basement membrane.ResultsElectroneurographic parameters were similar in patients and controls. When compared with healthy controls, patients with OH or SH showed a significantly lower IENF density. As assessed by the proximal/distal fiber density ratio, the hypothyroid neuropathy was length dependent. When individually considered, an abnormally reduced IENF was observed in 60% of patients with OH at the distal leg and in 20% at the proximal site. In patients with SH, an abnormal IENF density was found at the distal leg in 25% of cases and at the proximal thigh in 12.5% of cases.ConclusionsOur study provides the first direct demonstration of reduced IENF density in patients with OH or SH. In all patients, the IENF density reduction was length dependent. These findings suggest that a considerable number of untreated hypothyroid patients may have preclinical asymptomatic small-fiber sensory neuropathy.

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