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Corneal Subbasal Nerve Plexus Changes in Severe Diabetic Charcot Foot Deformity: A Pilot Study in Search for a DNOAP Biomarker.

ABSTRACT: Introduction:Diabetic neuroosteoarthropathy (DNOAP) early symptoms are unspecific, mimicking general infectious symptoms and rendering a diagnosis challenging. Consequently, unfavourable outcomes occur frequently, with recurrent foot ulceration, infectious complications, and eventually amputation. Corneal confocal microscopy (CCM) of the subbasal nerve plexus (SNP) is used to detect early peripheral neuropathy in diabetic patients without diabetic retinopathy. This pilot study was designed to determine if specific SNP changes manifest in severe DNOAP in comparison to a healthy control group. Methods:This pilot study utilized a matched-pair analysis to investigate SNP changes by in vivo CCM for 26 patients (mean patient age 63.7 years, range 27 to 78) with severe DNOAP defined by condition after the need for reconstructive foot surgery (n = 13) and a healthy control group (n = 13). Corneal nerve fibre length (CNFL), nerve fibre density (CNFD), nerve branch density (CNBD), average weighted corneal nerve fibre thickness (CNFTh), nerve connecting points (CNCP), and average weighted corneal nerve fibre tortuosity (CNFTo) were assessed as well as the general clinical status, diabetic status, and ophthalmologic basic criteria. Results:In vivo CCM revealed significantly reduced SNP parameters in the DNOAP group for CNFL (p = 0.010), CNFD (p = 0.037), CNBD (p = 0.049), and CNCP (p = 0.012) when compared to the healthy control group. Six patients (46%) of the DNOAP group suffered from diabetic retinopathy and none of the control group. Conclusions:This pilot study revealed a rarefication of SNP in all measured parameters in patients with severe DNOAP. We see a potential value of CCM providing a SNP-based biomarker for early stages of DNOAP prior to the development of any foot deformities that needs to be evaluated in further studies. This trial is registered with German Clinical Trials Register (DKRS) DRKS00007537.

SUBMITTER: Herlyn A

PROVIDER: S-EPMC6247393 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Corneal Subbasal Nerve Plexus Changes in Severe Diabetic Charcot Foot Deformity: A Pilot Study in Search for a DNOAP Biomarker.

Herlyn Anica A Prakasam Ruby Kala RK Peschel Sabine S Allgeier Stephan S Köhler Bernd B Winter Karsten K Guthoff Rudolf F RF Mittlmeier Thomas T Stachs Oliver O

Journal of diabetes research 20181104

<h4>Introduction</h4>Diabetic neuroosteoarthropathy (DNOAP) early symptoms are unspecific, mimicking general infectious symptoms and rendering a diagnosis challenging. Consequently, unfavourable outcomes occur frequently, with recurrent foot ulceration, infectious complications, and eventually amputation. Corneal confocal microscopy (CCM) of the subbasal nerve plexus (SNP) is used to detect early peripheral neuropathy in diabetic patients without diabetic retinopathy. This pilot study was design ...[more]

PMID: 30525053

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Project description:BackgroundCharcot neuropathic osteoarthropathy associated foot deformity can result in joint instability, ulceration, and even amputation. The purpose of the present study was to follow patients with and without active Charcot osteoarthropathy for as long as two years to examine the magnitude and timing of foot alignment changes.MethodsWe studied fifteen subjects with Charcot osteoarthropathy and nineteen subjects with diabetes mellitus and peripheral neuropathy without Charcot osteoarthropathy for one year; eight of the subjects with osteoarthropathy and five of the subjects with diabetes and peripheral neuropathy were followed for two years. Bilateral weight-bearing radiographs of the foot were made at baseline for all subjects, with repeat radiographs being made at six months for the osteoarthropathy group and at one and two years for both groups. Radiographic measurements included the Meary angle, cuboid height, calcaneal pitch, and hindfoot-forefoot angle.ResultsThe Meary angle, cuboid height, and calcaneal pitch worsened in feet with Charcot osteoarthropathy over one year as compared with the contralateral, uninvolved feet and feet in patients with diabetes and peripheral neuropathy. Cuboid height continued to worsen over the two-year follow-up in the feet with Charcot osteoarthropathy. These feet also had a greater change in the hindfoot-forefoot angle at one year as compared with the feet in patients with diabetes and peripheral neuropathy and at two years as compared with the contralateral, uninvolved feet.ConclusionsIn patients with Charcot neuropathic osteoarthropathy, radiographic alignment measurements demonstrate the presence of foot deformity at the time of the initial clinical presentation and evidence of progressive changes over the first and second years. The six-month data suggest worsening of medial column alignment prior to lateral column worsening. This radiographic evidence of worsening foot alignment over time supports the need for aggressive intervention (conservative bracing or surgical fixation) to attempt to prevent limb-threatening complications.

Project description:Charcot-Marie-Tooth disease type 1A, caused by a duplication of the gene peripheral myelin protein 22?kDa, is the most frequent subtype of hereditary peripheral neuropathy with an estimated prevalence of 1:5000. Patients suffer from sensory deficits, muscle weakness and foot deformities. There is no treatment approved for this disease. Outcome measures in clinical trials were based mainly on clinical features but did not evaluate the actual nerve damage. In our case-control study, we aimed to provide objective and reproducible outcome measures for future clinical trials. We collected skin samples from 48 patients with Charcot-Marie-Tooth type 1A, 7 patients with chronic inflammatory demyelinating polyneuropathy, 16 patients with small fibre neuropathy and 45 healthy controls. To analyse skin innervation, 40-µm cryosections of glabrous skin taken from the lateral index finger were double-labelled by immunofluorescence. The disease severity of patients with Charcot-Marie-Tooth type 1A was assessed by the Charcot-Marie-Tooth neuropathy version 2 score, which ranged from 3 (mild) to 27 (severe) and correlated with age (P?<?0.01, R?=?0.4). Intraepidermal nerve fibre density was reduced in patients with Charcot-Marie-Tooth type 1A compared with the healthy control group (P?<?0.01) and negatively correlated with disease severity (P?<?0.05, R = -0.293). Meissner corpuscle (MC) density correlated negatively with age in patients with Charcot-Marie-Tooth type 1A (P?<?0.01, R = -0.45) but not in healthy controls (P?=?0.07, R?=?0.28). The density of Merkel cells was reduced in patients with Charcot-Marie-Tooth type 1A compared with healthy controls (P?<?0.05). Furthermore, in patients with Charcot-Marie-Tooth type 1A, the fraction of denervated Merkel cells was highly increased and correlated with age (P?<?0.05, R?=?0.37). Analysis of nodes of Ranvier revealed shortened paranodes and a reduced fraction of long nodes in patients compared with healthy controls (both P?<?0.001). Langerhans cell density was increased in chronic inflammatory demyelinating polyneuropathy, but not different in Charcot-Marie-Tooth type 1A compared with healthy controls. Our data suggest that intraepidermal nerve fibre density might be used as an outcome measure in Charcot-Marie-Tooth type 1A disease, as it correlates with disease severity. The densities of Meissner corpuscles and Merkel cells might be an additional tool for the evaluation of the disease progression. Analysis of follow-up biopsies will clarify the effects of Charcot-Marie-Tooth type 1A disease progression on cutaneous innervation.

Dataset Information

Corneal Subbasal Nerve Plexus Changes in Severe Diabetic Charcot Foot Deformity: A Pilot Study in Search for a DNOAP Biomarker.

Publications

Corneal Subbasal Nerve Plexus Changes in Severe Diabetic Charcot Foot Deformity: A Pilot Study in Search for a DNOAP Biomarker.

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