Epidermal Nerve Fiber Research Articles

Measuring peripheral nerve involvement in Friedreich's ataxia.

ObjectiveExperimental therapies under development for Friedreich’s Ataxia (FRDA) require validated biomarkers. In‐vivo reflectance confocal microscopy (RCM) of skin is a noninvasive way to quantify Meissner’s corpuscle (MC) density and has emerged as a sensitive measure of sensory polyneuropathies. We conducted a prospective, cross‐sectional study evaluating RCM of MCs and conventional peripheral nerve measures as candidate peripheral nerve markers in FRDA.MethodsSixteen individuals with FRDA and 16 age‐ and gender‐matched controls underwent RCM of MC density and morphology, skin biopsies for epidermal nerve fiber density (ENFD), nerve conduction studies (NCS), and quantitative sensory testing (QST) including touch, vibration, and cooling thresholds.ResultsMC densities were measurable in all participants with FRDA, and were lower at digit V (hand), thenar eminence, and arch (foot) compared to controls. By contrast, sensory NCS showed floor effects and were obtainable in only 13% of FRDA participants. QST thresholds for touch, vibration, and cooling were higher at the hand and foot in FRDA than controls. Reductions in ENFDs were present in more severely affected individuals with FRDA (Friedreich’s Ataxia Rating Scale (FARS) >60) compared to matched controls, although skin biopsies were not well tolerated in children. MC densities, ENFDs, and touch and vibration thresholds were associated with clinical disease severity (FARS and modified FARS) and duration since symptom onset.InterpretationMC density, ENFD, and QST thresholds provide structural and physiologic markers of sensory involvement in FRDA. Longitudinal evaluation is needed to determine whether these measures can identify changes associated with disease progression or treatment.

Epidermal expression of human TRPM8, but not of TRPA1 ion channels, is associated with sensory responses to local skin cooling.

Human cold perception and nociception play an important role in persisting pain. However, species differences in the target temperature of thermosensitive ion channels expressed in peripheral nerve endings have fueled discussions about the mechanism of cold nociception in humans. Most frequently implicated thermosensors are members of the transient receptor potential (TRP) ion channel family TRPM8 and TRPA1. Regularly observed, distinct cold pain phenotype groups suggested the existence of interindividually differing molecular bases. In 28 subjects displaying either high or medium sensitivity to local cooling of the skin, the density at epidermal nerve fibers of TRPM8, but not that of TRPA1 expression, correlated significantly with the cold pain threshold. Moreover, reproducible grouping of the subjects, based on high or medium sensitivity to cooling, was reflected in an analogous grouping based on high or low TRPM8 expression at epidermal nerve fibers. The distribution of TRPM8 expression in epidermal nerve fibers provided an explanation for the previously observed (bi)modal distribution of human cold pain thresholds which was reproduced in this study. In the light of current controversies on the role of human TRPA1 ion channels in cold pain perception, the present observations demonstrating a lack of association of TRPA1 channel expression with cold sensitivity-related measures reinforce doubts about involvement of this channel in cold pain in humans. Since TRP inhibitors targeting TRPM8 and TRPA1 are currently entering clinical phases of drug development, the existence of known species differences, in particular in the function of TRPA1, emphasizes the increasing importance of new methods to directly approach the roles of TRPs in humans.

A Bayesian hierarchical point process model for epidermal nerve fiber patterns

We introduce the Thomas process in a Bayesian hierarchical setting as a model for point pattern data with a nested structure. This model is applied to a nerve fiber data set which consists of several point patterns of nerve entry points from 47 subjects divided into 3 groups, where the grouping is based on the diagnosed severity of a certain nerve disorder. The modeling assumption is that each point pattern is a realization of a Thomas process, with parameter values specific to the subject. These parameter values are in turn assumed to come from distributions that depend on which group the subject belongs to. To fit the model, we construct an MCMC algorithm, which is evaluated in a simulation study. The results of the simulation study indicate that the group level mean of each parameter is well estimated, but that the estimation of the between subject variance is more challenging. When fitting the model to the nerve fiber data, we find that the structure within clusters appears to be the same in all groups, but that the number of clusters decreases with the progression of the nerve disorder.

A clinical case-control comparison of epidermal innervation density in Rett syndrome.

IntroductionRett syndrome (RTT), a rare neurodevelopmental disorder occurring primarily in females (1:10–15,000 female live births), is most often caused by loss‐of‐function mutations in the X‐linked methyl‐CpG‐binding protein 2 gene (MECP2). Clinical observations and preclinical findings indicate apparent abnormal sensory and nociceptive function. There have been no direct investigations of epidermal sensory innervation in patients with RTT.MethodsWe compared 3 mm epidermal punch biopsy specimens from adolescent female RTT patients (N = 4, aged 12–19 years) against an archived approximate age‐, sex‐, body‐site matched comparison sample of healthy adolescent females (N = 8, ages 11–17).ResultsConfocal imaging revealed, on average, statistically significant increased epidermal nerve fiber (ENF) peptidergic (co‐stained calcitonin gene‐related protein [CGRP]) innervation density compared with healthy female control individuals.ConclusionsGiven the clinical phenotype of disrupted sensory function along with diagnostic criteria specific to cold hands/feet and insensitivity to pain, our preliminary observations of ENF peptidergic fiber density differences warrants further investigation of the peripheral neurobiology in RTT.

Ratio of Distal to Proximal Epidermal Nerve Fiber Density as Predictor of Small Fiber Neuropathy (P1.4-038)

Ratio of Distal to Proximal Epidermal Nerve Fiber Density as Predictor of Small Fiber Neuropathy (P1.4-038)

Association of small fiber neuropathy and post treatment Lyme disease syndrome.

ObjectivesTo examine whether post-treatment Lyme disease syndrome (PTLDS) defined by fatigue, cognitive complaints and widespread pain following the treatment of Lyme disease is associated with small fiber neuropathy (SFN) manifesting as autonomic and sensory dysfunction.MethodsThis single center, retrospective study evaluated subjects with PTLDS. Skin biopsies for assessment of epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD) and functional autonomic testing (deep breathing, Valsalva maneuver and tilt test) were performed to assess SFN, severity of dysautonomia and cerebral blood flow abnormalities. Heart rate, end tidal CO2, blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery using transcranial Doppler were monitored.Results10 participants, 5/5 women/men, age 51.3 ± 14.7 years, BMI 27.6 ± 7.3 were analyzed. All participants were positive for Lyme infection by CDC criteria. At least one skin biopsy was abnormal in all ten participants. Abnormal ENFD was found in 9 participants, abnormal SGNFD in 5 participants, and both abnormal ENFD and SGNFD were detected in 4 participants. Parasympathetic failure was found in 7 participants and mild or moderate sympathetic adrenergic failure in all participants. Abnormal total CBFv score was found in all ten participants. Low orthostatic CBFv was found in 7 participants, three additional participants had abnormally reduced supine CBFv.ConclusionsSFN appears to be associated with PTLDS and may be responsible for certain sensory symptoms. In addition, dysautonomia related to SFN and abnormal CBFv also seem to be linked to PTLDS. Reduced orthostatic CBFv can be associated with cerebral hypoperfusion and may lead to cognitive dysfunction. Autonomic failure detected in PTLDS is mild to moderate. SFN evaluation may be useful in PTLDS.

Randomized Controlled Trial of Physical Exercise in Diabetic Veterans With Length-Dependent Distal Symmetric Polyneuropathy.

Rationale: Physical exercise is an essential adjunct to the management of patients with type 2 diabetes mellitus. Therapeutic interventions that improve blood flow to peripheral nerves, such as exercise, may slow the progression of neuropathy in the diabetic patient.Aims: This randomized clinical trial was conducted to determine whether a structured program of aerobic, isokinetic strength, or the combination of aerobic–isokinetic strength exercise intervention alters peripheral nerve function in glycemic-controlled diabetic patients with advanced length-dependent distal symmetric polyneuropathy.Methods: Forty-five patients with type 2 diabetes mellitus exhibiting tight glycemic control (HbA1c intergroup range 7.2–8.0%) were randomized by block design across four experimental groups: sedentary controls (n = 12), aerobic exercise (n = 11), isokinetic strength (n = 11), or the combination of aerobic–isokinetic strength training (n = 11). Patients randomized to training groups exercised 3× per week for 12 weeks, whereas patients randomized to the sedentary control group received standard of care. To minimize attention and educational bias, all patients attended a 12-session health promotion educational series. At baseline, immediately following intervention, and again at 12-week post-intervention, detailed nerve conduction studies were conducted as a primary outcome measure. At these same intervals, all patients completed as secondary measures quantitative sensory testing, symptom-limited treadmill stress tests, and a Short-Form 36-Veterans Questionnaire (SF-36V).Results: Of the 45 patients randomized into this study, 37 (82%) had absent sural nerve responses, 19 (42%) had absent median sensory nerve responses, and 17 (38%) had absent ulnar sensory nerve responses. By comparison, responses from tibial nerves were absent in only three (7%) subjects while responses from peroneal nerves were absent in five (11%) subjects. Eleven (92%) of 12 patients that had volunteered to be biopsied exhibited abnormal levels of epidermal nerve fiber densities. Exercise, regardless of type, did not alter sensory or motor nerve electrodiagnostic findings among those patients exhibiting measurable responses (ANOVA). There was, however, a modest (p = 0.01) beneficial effect of exercise on sensory nerve function (Fisher’s Exact Test). Importantly, the beneficial effect of exercise on sensory nerve function was enhanced (p = 0.03) during the post-intervention interval. In addition, three of six patients that had undergone exercise intervention exhibited a marked 1.9 ± 0.3-fold improvement in epidermal nerve fiber density. By comparison, none of three sedentary patients whom agreed to be biopsied a second time showed improvement in epidermal nerve fiber density. Compared to baseline values within groups, and compared with sedentary values across groups, neither aerobic, isokinetic strength, or the combination of aerobic–isokinetic strength exercise intervention altered peak oxygen uptake. Patients that underwent aerobic or the combined aerobic–isokinetic strength exercise intervention, however, demonstrated an increase in treadmill test duration that was sustained over the 12-week post-intervention period.Conclusion: A 12-week course of physical exercise, regardless of type, does not alter sensory or motor nerve electrodiagnostic findings. In a subset of patients, a short-term structured program of aerobic exercise may selectively improve sensory nerve fiber function. Large-scale exercise lifestyle intervention trials are warranted to further evaluate the impact of aerobic exercise on sensory nerve fiber function in diabetic neuropathic patients.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT00955201.

Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1.

ObjectiveTo evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1).MethodsIn this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18–70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events.ResultsBetween August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (−1.5 units, 95% CI −2.8 to −0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (−0.77, 95% CI −1.67 to 0.13, p = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001). There were no serious adverse effects related to l-serine.ConclusionHigh-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.Clinicaltrials.gov identifierNCT01733407.Classification of evidenceThis study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.

Antipruritic Effects of Janus Kinase Inhibitor Tofacitinib in a Mouse Model of Psoriasis.

The Janus kinase 1/3 inhibitor tofacitinib has demonstrated an antipruritic effect in two phase III studies in psoriasis. However, the mechanisms behind this antipruritic effect are still unknown. We presently investigated whether tofacitinib affects spontaneous itch as well as expression of itch-related cytokines and epidermal nerve fiber density (ENFD) in the imiquimod-induced mouse model of psoriasis. Psoriasis-like skin lesions were produced by daily topical application of imiquimod to the back skin. Imiquimod treatment resulted in spontaneous scratching, which was significantly inhibited by tofacitinib treatment. Imiquimod treatment significantly increased mRNA expression of Il22, Il23, and Il31, reduced peptidergic ENFD, and increased nonpeptidergic ENFD compared to naive mice. Tofacitinib significantly decreased the expression of those cytokines and increased peptidergic ENFD without a significant effect on nonpeptidergic ENFD. Tofacitinib may inhibit psoriatic itch through inhibition of cytokine expression as well as modulation of epidermal innervation.

A Postmortem Study of a Patient with Low Titer Nicotinic Acetylcholine Receptor Ganglionic Antibody: Implications for Clinical Neurologic Disease

Small fiber polyneuropathy is a well-recognized syndrome mitigated by somatic sensory afferent and autonomic efferent nerve fibers that respectively mediate pain, heat and cold temperature afferent and autonomic efferent function in the skin. A patient with low serum titers of neuronal acetylcholine receptor ganglionic antibodies and autonomic failure had symptomatic small fiber polyneuropathy late in life in the setting of autoimmune dementia and encephalopathy and prostate cancer. Large and small fiber polyneuropathy and dysautonomia were detected in routine electrodiagnostic and autonomic laboratory studies, and epidermal nerve fiber analysis of the calf and thigh. Clinical improvement for one year concomitant with intravenous immune globulin therapy preceded a clinical decline in neurocognitive function and death. Postmortem examination showed typical features of Alzheimer disease with neuropathic neuropathological changes in the peripheral nervous system, and viable autonomic ganglia consistent with a channelopathy mechanism involving postsynaptic neuronal nAChRs.

The incidental finding of elevated anti GQ1B antibodies in a patient with selective small fiber neuropathy

Small fiber neuropathy occurs in several autoimmune diseases and autoantibodies against neuronal proteins may play a role in SFN pathophysiology.1−2 Antigangliosides antibodies anti-GQ1b have not previously associated to SFN. We describe a 45-year-old woman complaining of a two-year history of tingling and/or burning pain sensation in the arms and legs, with nocturnal exacerbation. The anamnesis revealed a ten-year history of an autoimmune disorder including HLA-B27 negative psoriatic arthritis, complement C3 deficiency membrano-proliferative glomerulonephritis and sicca syndrome. Neurological examination did not disclose ophthalmoplegia, signs of central nervous dysfunctions or peripheral large nerve fiber abnormalities. Laboratory screening disclosed IgM antiganglioside antibodies anti-GQ1b (high titer) and anti-GD1b (low titer). Skin biopsies from distal leg and thigh revealed decreased epidermal nerve fiber density, whereas autonomic innervation of dermal annexes was preserved. Motor and sensory nerve conduction studies were normal excluding a large nerve fiber involvement. SFN likely explained the sensory dysfunctions complained of by the patient. A trial with adalizumab resulted in long-term pain relief. This is the first report of SFN associated with antigangliosides antibodies anti-GQ1b. Further studies will clarify a possible pathogenetic role of these antibodies in SFN. Moreover, their recognition of in SFN may be an indicator of patients who would potentially benefit from immunotherapy.

Disinhibition of Touch-Evoked Itch in a Mouse Model of Psoriasis

Disinhibition of Touch-Evoked Itch in a Mouse Model of Psoriasis

Gender Differences in Skin Biopsy Findings in Small Fiber Neuropathy: A Retrospective Chart Review.

To determine whether there are gender differences in the clinical presentation or skin biopsy measures of nerve fiber density in patients with small fiber neuropathy (SFN). Retrospective chart review of subjects with suspected SFN. Of 218 cases (137 women and 81 men) with suspected SFN, 96 (44%), including 63% of the men and 33% of the women (P < 0.05), had low epidermal nerve fiber density (ENFD) or sweat gland nerve fiber density (SGNFD). There were no differences in the clinical presentation between men and women. In those with abnormal findings, low ENFD alone was more frequent in women than men (51.1% vs. 7.8%, P < 0.05), whereas abnormal SGNFD alone was more frequent in men than women (68.6% vs. 11.1%, P < 0.05). Both SGNFD and ENFD were low in 23.5% of men and 33.3% of women. Skin biopsy findings were independent of clinical presentation or etiology. The clinical presentation of SFN is similar in men and women. In skin biopsy studies, low ENFD is more common in women and low SGNFD in men.

SIV-Induced Immune Activation and Metabolic Alterations in the Dorsal Root Ganglia During Acute Infection.

Human immunodeficiency virus-associated sensory neuropathy (HIV-SN) remains a frequent neurologic complication of HIV infection. Little is known about alterations in the peripheral nervous system during the early stages of HIV, a time when neuroprotective interventions may be most beneficial. We performed Nanostring gene expression analysis on lumbar dorsal root ganglia (DRG) from 6 simian immunodeficiency virus (SIV)-infected pigtailed macaques killed at 7 days post-inoculation and 8 uninfected controls. We found significant upregulation of many genes involved in immune signaling and activation in the DRG. Among genes related to glutamate metabolism, there was significant upregulation of glutamine synthetase (GS), while glutaminase (GLS) was downregulated. Several genes involved in the oxidative stress response also showed significant differential regulation in the DRG of 7d SIV-infected animals, with superoxide dismutase-2 (SOD2) showing the greatest median fold change compared to controls. Novel findings in the DRG were compared to corresponding brain data and further investigated at the protein level by Western blotting and immunohistochemistry. Together with our previous finding of significant epidermal nerve fiber loss at 14 days post-SIV infection, results of this study demonstrate that immune activation and altered cellular metabolism at in the DRG precede and likely contribute to early sensory nerve injury in HIV-SN.

Nociceptin/orphanin FQ opioid peptide‐receptor expression in pachyonychia congenita

Nociceptin/orphanin FQ opioid peptide (NOP)-receptor (NOP-R) is a member of the opioid receptor family. NOP-R activation has demonstrated analgesic effects in preclinical pain models without the addiction risks associated with other opiate targets. Pachyonychia congenita (PC) is a palmoplantar keratoderma characterized by neuropathic pain in affected skin. A cohort of KRT6A gene mutation PC patients with no other explanation for their neuropathic pain offered a unique opportunity to assess potential of NOP-R as a therapeutic target. Plantar biopsies from 10 PC patients and 10 age/gender matched controls were performed at the ball (PC-affected) and the arch (PC-unaffected) of the foot. NOP-R expression was assessed by immunohistochemistry. Localization of NOP-R in subsets of epidermal nerve fibers was investigated using the pan-neuronal marker PGP9.5, markers for unmyelinated peptidergic fibers (calcitonin gene-related peptide [CGRP] and substance P [SP]), as well as for myelinated Aδ and Aβ fibers (neurofilament H [NFH]). Robust NOP-R expression was detected in epidermal keratinocytes and in a subset of PGP9.5+ fibers in both epidermis and dermis, confirmed by western blot and absorption experiments with NOP-R peptide. NOP-R expression in keratinocytes was significantly reduced in PC-affected plantar skin compared with PC-unaffected skin. In addition, NOP-R expression occurred in dermal NFH+ myelinated fibers in all groups, although few CGRP+ fibers co-expressed NOP-R. Furthermore, most SP+ fibers also co-expressed NOP-R. These findings indicate that NOP-R is expressed on epidermal keratinocytes, as well as on epidermal and dermal nerve fibers and has potential as a promising target to treat neuropathic pain in PC.

Structural, functional, and symptom relations in painful distal symmetric polyneuropathies: a systematic review.

The diagnosis of distal symmetric polyneuropathies (DSPs) relies on the presenting symptomatology and neurological sensory examination, supported by objectively quantified structural and functional changes in sensory nerves. Although these separate components have important diagnostic utility, the associations between the structural vs the symptomatic and functional findings in painful DSP are still unclear. It is assumed that delineation of the correlations, or lack of such, between structure, clinical presentation, and function will contribute to a better understanding and treatment of DSP. This systematic review assessed small fiber morphology in patients with different types of painful DSP, and compared it with symptoms, signs, and nerve fiber function. Overall, 111 papers met the inclusion criteria for the systematic review. The results indicate that epidermal nerve fiber loss, in isolation, is not a useful indicator of painful symptoms or their severity in DSP. Intraepidermal nerve fiber density correlated reasonably well with neuropathy scores on tools assessing signs and symptoms (such as the Michigan Neuropathy Screening Instrument and the Total Neuropathy Score), but less so with symptom measures only. Among various psychophysical sensory measures, warmth detection and heat pain thresholds correlated best with intraepidermal nerve fiber density, particularly when assessed at the same anatomical site. The observed sources of heterogeneity, and the lack of associations between structural and functional measures in several studies are discussed. A framework is proposed for uniform assessment of nerve fiber parameters for investigating clinically relevant mechanisms of neuropathic pain in DSP.

Mutation in Nav1.7 causes high olfactory sensitivity

Mutations in the sodium-channel Nav 1.7, encoded by the gene SCN9A, are known to cause pain disorders. In particular, gain-of-function missense mutations in Nav 1.7 have been shown to be causal in primary erythromelalgia. We present a patient with erythromelalgia, pain attacks and hyperosmia with a mutation within the sodium-channel gene SCN9A. A 50-year-old woman presented with burning pain in both feet and abdominal pain attacks developed over the course of 10years. Furthermore, this patient experienced a hypersensitivity for odours. Clinical investigation as well as serum/cerebrospinal fluid laboratory findings and electrophysiological testing were unremarkable. Olfactory testing showed high olfactory acuity for all screened modalities and good intranasal sensitivity. Furthermore, quantitative sensory testing within the trigeminal area revealed very low thresholds for thermal, tactile and pain detection. In addition, quantitative sensory testing at the lower legs showed hyperalgesia and, as the disease progresses, thermal sensory function loss. Skin biopsies of the proximal and distal lower limbs revealed reduced epidermal nerve fibre density indicating small fibre neuropathy. Genetic analysis of the SCN9A gene demonstrated a heterozygous mutation in Exon 20 - c.3734A>G (p.N1245S). Treatment with clinically available sodium-channel inhibitors did not result in significant pain relief. Local application of the sodium-channel blocker ambroxol however, reduced pain intensity. Continuous odour exposure stabilised mood and induced a short-term pain relief. This clinical note illustrates the course of middle-age onset erythromelalgia and points to clinical findings related to a likely pathogenic missense mutation affecting the sodium-channel Nav 1.7. SIGNIFICANCE: This case report illustrates the course of middle-age onset erythromelalgia with presumed gain-of-function in olfactory and pain sensation associated with a Nav1.7 channel mutation.

Fibromyalgia syndrome and small fiber, early or mild sensory polyneuropathy.

ABSTRACT Introduction: Pain mechanisms in fibromyalgia syndrome (FMS) are not clearly understood. Growing evidence appears to suggest a role for small fiber polyneuropathy (SFPN) in some FMS patients, as measured by epidermal nerve fiber density (ENFD). We aimed to better characterize and distinguish the subset of patients with both fibromyalgia and small fiber, early or mild sensory polyneuropathy (FM‐SFSPN). Methods: 155 FMS patients with neuropathic symptoms completed a Short Form McGill Questionnaire and visual analog scale in addition to having skin biopsies, nerve conduction studies (NCS), and serologic testing. Results: Sural and medial plantar (MP) response amplitudes correlated with ENFD, with markers of metabolic syndrome being more prevalent in this subset of patients. Pain intensity and quality did not distinguish patients. Discussion: The FM‐SFSPN subset of patients may be identified through sural and MP sensory NCS and/or skin biopsy but cannot be identified by pain features and intensity. Muscle Nerve 58: 625–630, 2018

Somatotopic heat pain thresholds and intraepidermal nerve fibers in health

For sequential and somatotopic assessment of small fiber neuropathy, heat pain (HP) tests of hypoalgesia might be used instead of decreased counts of epidermal nerve fibers (ENFs), but then healthy subject reference values of HP thresholds are needed. Using the Computer Assisted Sensation Evaluator IVc system, HP thresholds of hypoalgesia were estimated for 10 unilateral sites and counts of ENFs for 4 of them in healthy subjects. In healthy subjects, small but statistically significant differences of both HP thresholds of hypoalgesia and counts of ENFs were observed among tested sites. Significant correlations between HP thresholds and counts of ENFs were not found. For the studied somatotopic sites, we provide ≥95th and ≥99th percentile reference limits for HP 0.5 and 5 of 1-10 HP thresholds of hypoalgesia and decreased counts of ENFs at ≤5th and ≤1st percentile levels. Muscle Nerve 58: 509-516, 2018.

LepVax, a defined subunit vaccine that provides effective pre-exposure and post-exposure prophylaxis of M. leprae infection

Sustained elimination of leprosy as a global health concern likely requires a vaccine. The current standard, BCG, confers only partial protection and precipitates paucibacillary (PB) disease in some instances. When injected into mice with the T helper 1 (Th1)-biasing adjuvant formulation Glucopyranosyl Lipid Adjuvant in stable emulsion (GLA-SE), a cocktail of three prioritized antigens (ML2055, ML2380 and ML2028) reduced M. leprae infection levels. Recognition and protective efficacy of a single chimeric fusion protein incorporating these antigens, LEP-F1, was confirmed in similar experiments. The impact of post-exposure immunization was then assessed in nine-banded armadillos that demonstrate a functional recapitulation of leprosy. Armadillos were infected with M. leprae 1 month before the initiation of post-exposure prophylaxis. While BCG precipitated motor nerve conduction abnormalities more rapidly and severely than observed for control infected armadillos, motor nerve injury in armadillos treated three times, at monthly intervals with LepVax was appreciably delayed. Biopsy of cutaneous nerves indicated that epidermal nerve fiber density was not significantly altered in M. leprae-infected animals although Remak Schwann cells of the cutaneous nerves in the distal leg were denser in the infected armadillos. Importantly, LepVax immunization did not exacerbate cutaneous nerve involvement due to M. leprae infection, indicating its safe use. There was no intraneural inflammation but a reduction of intra axonal edema suggested that LepVax treatment might restore some early sensory axonal function. These data indicate that post-exposure prophylaxis with LepVax not only appears safe but, unlike BCG, alleviates and delays the neurologic disruptions caused by M. leprae infection.