Asymptomatic small fiber neuropathy in diabetes mellitus: investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials

Ragé, Michaël; Acker, Nathalie Van; Knaapen, Michiel; Timmers, Maarten; Streffer, Johannes; Hermans, Michel P.; Sindic, Christian; Meert, Theo; Plaghki, Léon

doi:10.1007/s00415-011-6031-z

Cited by 77 publications

(63 citation statements)

References 43 publications

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“…A recent study showed abnormal LEPs in a subgroup of 29 patients with painful peripheral neuropathy associated to hepatitis C virus, in contrast to normal sensory action potentials and intra-epidermal nerve fibre density 32. A comparative study including punch skin biopsies, QST and LEPs showed that the latter presented the highest specificity (83%) and sensitivity (91%) in detecting asymptomatic diabetic neuropathy in the distal leg in a cohort of 23 patients with a disease duration of >10 years 33. Taking these observations into account, a three-step diagnostic approach is recommended: (1) QST and nerve conduction studies and, if negative, followed by (2) LEPs and finally by (3) punch skin biopsy.…”

Section: Pain-related Laser Evoked Potentials (Leps)mentioning

confidence: 95%

Clinical evoked potentials in neurology: a review of techniques and indications

Lascano

Lalive

Hardmeier

et al. 2017

J Neurol Neurosurg Psychiatry

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Evoked potentials (EPs) are a powerful and cost-effective tool for evaluating the integrity and function of the central nervous system. Although imaging techniques, such as MRI, have recently become increasingly important in the diagnosis of neurological diseases, over the past 30 years, many neurologists have continued to employ EPs in specific clinical applications. This review presents an overview of the recent evolution of 'classical' clinical applications of EPs in terms of early diagnosis and disease monitoring and is an extension of a previous review published in this journal in 2005 by Walsh and collaborators. We also provide an update on emerging EPs based on gustatory, olfactory and pain stimulation that may be used as clinically relevant markers of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and cortical or peripheral impaired pain perception. EPs based on multichannel electroencephalography recordings, known as high-density EPs, help to better differentiate between healthy subjects and patients and, moreover, they provide valuable spatial information regarding the site of the lesion. EPs are reliable disease-progression biomarkers of several neurological diseases, such as multiple sclerosis and other demyelinating disorders. Overall, EPs are excellent neurophysiological tools that will expand standard clinical practice in modern neurology.

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Section: Pain-related Laser Evoked Potentials (Leps)mentioning

confidence: 95%

Clinical evoked potentials in neurology: a review of techniques and indications

Lascano

Lalive

Hardmeier

et al. 2017

J Neurol Neurosurg Psychiatry

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“…However, the abnormalities are not as extensive as in patients with classical disease (Biegstraaten et al 2011(Biegstraaten et al , 2012 and predominantly concern small nerve fibre structure as represented by the IENFD. Similarly, in patients with diabetes mellitus (DM), an abnormal IENFD in the distal leg and impaired cold sensation have been found, even without neuropathic symptoms (Umapathi et al 2007;Loseth et al 2008;Ragé et al 2011). For both DM and nonclassical FD, it may be hypothesized that a reduced IENFD and abnormal QST modalities reflect a presymptomatic state.…”

Section: Discussionmentioning

confidence: 99%

In Patients with an α-Galactosidase A Variant, Small Nerve Fibre Assessment Cannot Confirm a Diagnosis of Fabry Disease

et al. 2015

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Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by an a-galactosidase A enzyme deficiency due to pathogenic variants in the agalactosidase A gene (GLA). An increasing number of individuals with a GLA variant, but without characteristic FD features, are identified. A definite diagnosis of FD has important consequences for treatment and counselling.Objectives: We assessed the diagnostic value of quantitative sensory testing (QST) and intraepidermal nerve fibre density (IENFD) for patients with an uncertain FD diagnosis.Methods: All patients with a GLA variant who initially presented at the Academic Medical Center with an uncertain FD diagnosis were included. A biopsy of an affected organ in a patient or family member showing FD characteristic storage is used as a reference standard for a diagnosis of FD. All patients underwent a comprehensive QST protocol and IENFD assessment which was compared to age and gender-matched healthy controls. Sensitivity and specificity were calculated for a combination of !1 abnormal QST modality and an abnormal IENFD.Results: Twenty-six patients participated (nonclassical FD n ¼ 18, 9 males; no FD n ¼ 5, 3 males; uncertain n ¼ 3, 1 male). Of the patients classified as nonclassical FD, 28% had !1 abnormal QST modalities, and 83% had an abnormal IENFD. From the patients without FD, 20% had !1 abnormal QST modality, and IENFD was abnormal in 25% (1 not available). Sensitivity was 28% and specificity 80%.Conclusions: In our study cohort, QST and IENFD could not reliably distinguish patients with FD from those without FD.

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“…References and inclusion criteria can be obtained from previously published work [6,51]. Written informed consent was obtained from all participants.…”

Section: Methodsmentioning

confidence: 99%

“…The Toronto Clinical Scoring System (TCSS) was used to screen for diabetic neuropathy. None of the control subjects had a history of alcohol or drug abuse, significant illnesses, or clinical findings suggestive of peripheral or central nervous system disorders [51]. …”

Section: Methodsmentioning

confidence: 99%

“…During the studies conducted by Ragé and colleagues [6,51] skin biopsies were processed according to the standard skin biopsy procedure for IENF density assessment and in parallel according to the method described here. Skin punch biopsies (3–4 mm in diameter; Biopsy punch, Kai Europe GmbH, Germany) were performed under local anesthesia at the lateral aspect of the distal leg in a clinical unit.…”

Section: Methodsmentioning

confidence: 99%

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NRP-1 Receptor Expression Mismatch in Skin of Subjects with Experimental and Diabetic Small Fiber Neuropathy

Acker¹,

Ragé²,

Vermeirsch³

et al. 2016

PLoS ONE

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The in vivo cutaneous nerve regeneration model using capsaicin is applied extensively to study the regenerative mechanisms and therapeutic efficacy of disease modifying molecules for small fiber neuropathy (SFN). Since mismatches between functional and morphological nerve fiber recovery are described for this model, we aimed at determining the capability of the capsaicin model to truly mimic the morphological manifestations of SFN in diabetes. As nerve and blood vessel growth and regenerative capacities are defective in diabetes, we focused on studying the key regulator of these processes, the neuropilin-1 (NRP-1)/semaphorin pathway. This led us to the evaluation of NRP-1 receptor expression in epidermis and dermis of subjects presenting experimentally induced small fiber neuropathy, diabetic polyneuropathy and of diabetic subjects without clinical signs of small fiber neuropathy. The NRP-1 receptor was co-stained with CD31 vessel-marker using immunofluorescence and analyzed with Definiens® technology. This study indicates that capsaicin application results in significant loss of epidermal NRP-1 receptor expression, whereas diabetic subjects presenting small fiber neuropathy show full epidermal NRP-1 expression in contrast to the basal expression pattern seen in healthy controls. Capsaicin induced a decrease in dermal non-vascular NRP-1 receptor expression which did not appear in diabetic polyneuropathy. We can conclude that the capsaicin model does not mimic diabetic neuropathy related changes for cutaneous NRP-1 receptor expression. In addition, our data suggest that NRP-1 might play an important role in epidermal nerve fiber loss and/or defective regeneration and that NRP-1 receptor could change the epidermal environment to a nerve fiber repellant bed possibly through Sem3A in diabetes.

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Asymptomatic small fiber neuropathy in diabetes mellitus: investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials

Cited by 77 publications

References 43 publications

Clinical evoked potentials in neurology: a review of techniques and indications

Clinical evoked potentials in neurology: a review of techniques and indications

In Patients with an α-Galactosidase A Variant, Small Nerve Fibre Assessment Cannot Confirm a Diagnosis of Fabry Disease

NRP-1 Receptor Expression Mismatch in Skin of Subjects with Experimental and Diabetic Small Fiber Neuropathy

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