title: Asymptomatic small fiber neuropathy in diabetes mellitus: investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials.
abstract: This study aimed at evaluating the performance of a battery of morphological and functional tests for the assessment of small nerve fiber loss in asymptomatic diabetic neuropathy (DNP). Patients diagnosed for ≥10 years with type 1 (n = 10) or type 2 (n = 13) diabetes mellitus (DM) without conventional symptoms or signs of DNP were recruited and compared with healthy controls (n = 18) and patients with overt DNP (n = 5). Intraepidermal nerve fiber density (IENFd) was measured with PGP9.5 immunostaining on punch skin biopsies performed at the distal leg. Functional tests consisted of quantitative sensory testing (QST) for light-touch, cool, warm and heat pain detection thresholds and brain-evoked potentials with electrical (SEPs) and CO(2) laser stimulation [laser-evoked potentials (LEPs)] of hand dorsum and distal leg using small (0.8 mm(2)) and large (20 mm(2)) beam sizes. Results confirmed a state of asymptomatic DNP in DM, but only at the distal leg. Defining a critical small fiber loss as a reduction of IENFd ≤-2 z scores of healthy controls, this state prevailed in type 2 (30%) over type 1 DM (10%) patients despite similar disease duration and current glycemic control. LEPs with the small laser beam performed best in terms of sensitivity (91%), specificity (83%) and area-under-the ROC curve (0.924). Although this performance was not statically different from that of warm and cold detection threshold, LEPs offer an advantage over QST given that they bypass the subjective report and are therefore unbiased by perceptual factors.
authors.affiliation: Faculty of Medicine, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium. michael.rage@uclouvain.be
authors.forename: Michael
authors.initials: M
authors.lastname: Ragé
authors.forename: Nathalie
authors.initials: N
authors.lastname: Van Acker
authors.forename: Michiel W M
authors.initials: MW
authors.lastname: Knaapen
authors.forename: Maarten
authors.initials: M
authors.lastname: Timmers
authors.forename: Johannes
authors.initials: J
authors.lastname: Streffer
authors.forename: Michel P
authors.initials: MP
authors.lastname: Hermans
authors.forename: Christian
authors.initials: C
authors.lastname: Sindic
authors.forename: Theo
authors.initials: T
authors.lastname: Meert
authors.forename: Léon
authors.initials: L
authors.lastname: Plaghki
mesh_terms: D000328:Adult; D001706:Biopsy; D003920:Diabetes Mellitus / Q000473:pathology / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000175:diagnosis* / Q000473:pathology / Q000503:physiopathology; D042241:Early Diagnosis; D004558:Electric Stimulation; D005073:Evoked Potentials, Somatosensory / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007834:Lasers; D008297:Male; D008875:Middle Aged; D009412:Nerve Fibers / Q000473:pathology; D012680:Sensitivity and Specificity; D012684:Sensory Thresholds / Q000502:physiology; D012867:Skin / Q000294:innervation