Mirror peripheral neuropathy and unilateral chronic neuropathic pain: insights from asymmetric neurological patterns in leprosy.

ABSTRACT: Leprosy-related multiple mononeuropathy offers a pattern of impairment where neuropathy with and without neuropathic pain (NeP) are present in the same individual, thus allowing to investigate peripheral sensory and innervation in both conditions. This cross-sectional study collected data on clinical and neurological examination, pain assessment questionnaires, quantitative sensory test, and intraepidermal nerve fiber density of patients with leprosy and divided the cohort into 2 groups: with NeP (P+) and without NeP (P-). Furthermore, we assessed mirror body areas in the same NeP individuals with bilateral neuropathy also presenting unilateral NeP. Pain-free patients having unilateral neuropathy were controls. A total of 37 P+ and 22 P- patients were evaluated. Limb areas with NeP had signs of C-fiber dysfunction and hyperesthesia on quantitative sensory testing compared with limb areas having neuropathy without NeP. Skin denervation was found in all patients with leprosy. Comparisons of limbs with and without neuropathy and with and without NeP revealed that higher heat pain thresholds (HPTs) were associated with neuropathic pain areas, whereas less altered HPT was correlated with higher fiber density. Furthermore, a relationship was found between time of leprosy treatment termination and more intense neuropathy, expressed by HPT increasing 0.03°C each month. As expected, interindividual comparisons failed to show differences in intraepidermal nerve fiber density and subepidermal plexus areas between P+ and P- patients ( P = 0.2980, P = 0.9044; respectively). Higher HPT and lower mechanical detection threshold were related to NeP. This study pointed out the relevance of intraindividual comparisons including mirror areas when assessing local changes in peripheral NeP.

Semmes-Weinstein monofilament: A tool to quantify skin sensation in macular lesions for leprosy diagnosis.

INTRODUCTION: Hypochromatic macules with altered sensitivity are the first manifestations of skin leprosy. Validation of this sensory loss assists in the confirmation of the clinical diagnosis. AIMS: The aim of the study was to quantify the loss of sensation in leprosy lesions using the Semmes-Weinstein monofilament to strengthen the clinical diagnosis mainly of macular forms. METHODS: Seventy-four hypochromatic macules in the macular leprosy subgroup, 27 typical borderline leprosy subgroup lesions and 49 macules of other macular dermatoses (non-leprosy group) were evaluated using the 0.05 g force Semmes-Weinstein monofilament to quantify the alteration of sensitivity within and outside of the lesions. The esthesiometric change index was established as the total number of points with altered sensation divided by the total number of tested points within the lesions to calculate the internal esthesiometric change index and outside the lesions to calculate the peripheral esthesiometric change index; these indexes were calculated for all groups. The difference (Δ) between the esthesiometric change indices of the lesional area and the adjacent skin was calculated for the leprosy and nonleprosy groups. RESULTS: The percentage of points with touch sensitivity alterations within the macular and typical borderline leprosy lesions was higher in leprosy than in the non-leprosy group. The borderline and macular leprosy presented higher esthesiometric change index within injured areas than outside injured areas or in the nonleprosy group (P < 0.005). When internal esthesiometric change index values in the macular and borderline leprosy groups were higher than 0.53 and 0.5, respectively, the receiver operating characteristic curve showed 98% sensitivity and approximately 99% specificity for both groups (P < 0.0001). Regarding the difference between indices, borderline and macular leprosy had values that were higher and closer to one than in the nonleprosy group (P < 0.0001), with 100% sensitivity and 96.5% specificity for leprosy diagnosis when ΔLG was higher than 0.34. A limitation was the inability to perform a double-blind study. CONCLUSION: Semmes-Weinstein esthesiometry is a simple, useful and low-cost tool to quantify the focal alteration of cutaneous sensitivity to improve clinical leprosy diagnosis, especially for macular lesions.

Oct-6 transcriptional factor a possible biomarker for leprosy diagnosis.

Leprosy is an infectious disease caused by Mycobacterium leprae that affects the skin and nerves. The nerve damage in leprosy may be related to alterations in transcriptional factors, such as Krox-20, Oct-6, Sox-10. Thirty skin biopsies in leprosy patients and 15 non-leprosy skin biopsies were evaluated using RT-qPCR to assess Krox-20, Oct-6, and Sox-10 and these data was related with S-100 immunohistochemistry. Changes in gene expression were observed in the skin and dermal nerves of leprosy patients in Oct-6 and Sox-10. When comparing Oct-6 with S-100 IHC as diagnostic tests for leprosy, Oct-6 showed a sensitivity of 73.3%, and specificity of 100%, while S-100 IHC showed a sensitivity of 96.6% and specificity of 100%. Our data suggest Oct-6 could be an auxiliary biomarker specific to detecting changes in dermal nerves in leprosy and thus useful to health workers and pathologists with no expertise to observe nerve injuries in leprosy.

The selection of dermatomes for sham (placebo) acupuncture points is relevant for the outcome of acupuncture studies: a systematic review of sham (placebo)-controlled randomized acupuncture trials.

BACKGROUND: Many randomized controlled trials (RCTs) of acupuncture reveal no significant differences between acupuncture and so-called placebo acupuncture. There is a strong tendency to replace the term "placebo" by the term "sham," because any needling stimulates a certain physiological response. However, neither concept accounts for the great diversity of results in RCTs comparing verum acupuncture and sham (placebo) acupuncture. Some trials have shown little or no difference, while other studies have found statistically significant differences. OBJECTIVE: Verum acupuncture and sham (placebo) acupuncture may achieve similar results to the extent that they share active constituents. We identified these common active constituents as dermatomes: the segmental structure of the human body. In our study, we tested the hypothesis that the more verum and sham (placebo) acupuncture share the same dermatomes, the closer the clinical outcomes will be, and vice versa. METHODS: All major databases were searched for RCTs that tested acupuncture versus sham (placebo) acupuncture. The dermatome charts of Hansen and Schliack were used to verify verum and sham (placebo) needling locations. Reported clinical outcomes were assessed in relation to the percentage of overlap between the dermatomes stimulated by acupuncture and sham (placebo) acupuncture. RESULTS: Our literature search yielded a total of 1738 references. Thirty-four studies met the inclusion criteria. The effects of sham (placebo) acupuncture varied according to the dermatomes stimulated: high overlap with those stimulated by verum acupuncture resulted in almost identical efficacy, while low overlap resulted in significant differences in efficacy. Clinical outcomes were similar when verum acupuncture and sham (placebo) acupuncture shared the same dermatomes (p < 0.01). DISCUSSION: The findings of this review confirm our hypothesis. Acupuncture studies that employed verum and sham locations on overlapping dermatomes helped to create a mediocre to negative picture of acupuncture's efficacy. The segmental structure of the body with its interconnected reflex system offers an additional neurophysiological explanation for the effectiveness of acupuncture applied to structures segmentally innervated by the spinal and visceral nervous system. Further comparative acupuncture studies should be based on knowledge of segmental anatomy. In testing verum acupuncture versus sham acupuncture, the chosen sham acupuncture needling locations should be situated on non-overlapping dermatomes.

Skin innervation: important roles during normal and pathological cutaneous repair.

The skin is a highly sensitive organ. It is densely innervated with different types of sensory nerve endings, which discriminate between pain, temperature and touch. Autonomic nerve fibres which completely derive from sympathetic (cholinergic) neurons are also present. During all the phases of skin wound healing (inflammatory, proliferative and remodelling phases), neuromediators are involved. Several clinical observations indicate that damage to the peripheral nervous system influences wound healing, resulting in chronic wounds within the affected area. Patients with cutaneous sensory defects due to lepromatous leprosy, spinal cord injury and diabetic neuropathy develop ulcers that fail to heal. In addition, numerous experimental observations suggest that neurogenic stimuli profoundly affect wound repair after injury and that delayed wound healing is observed in animal models after surgical resection of cutaneous nerves. All these observations clearly suggest that innervation and neuromediators play a major role in wound healing. Interactions between neuromediators and different skin cells are certainly crucial in the healing process and ultimately the restoration of pain, temperature, and touch perceptions is a major challenge to solve in order to improve patients' quality of life.

Understanding itch: an update on mediators and mechanisms of pruritus.

Pruritus is the most common symptom secondary to skin diseases. Advances in the fields of neurobiology, immunology and physiology have made it possible for us to understand and unravel the deeper pathophysiological basis of pruritus. This review aims to update our current understanding of the mechanisms and mediators of pruritus. Special attention is paid to endogenous itch mediators particularly newly identified ones like endovanilloids, opioids, neurotrophins, cannabinoids, proteases and cytokines. Various theories explaining the peripheral encoding of itch are reviewed. Multiple neural pathways including the central itch pathways as well as supraspinal processing of itch and brain areas involved in pruritus are highlighted. Apart from peripheral itch mediators, spinal neural receptors are also involved in control of itch and should form part of the development of a novel antipruritic strategy. Further studies are required to fill the lacunae in our current understanding of the pathophysiology of pruritus.

Sporotrichoid pattern of nerve abscesses in borderline tuberculoid leprosy: A Case Report (sporotrichoid like abscesses in leprosy).

Linear distribution of multiple subcutaneous nodules or ulcers along the course of lymphatics, classically seen in lymphocutaneous sporotrichosis, has been observed in a number of other infections like localized cutaneous leishmaniasis, cutaneous tuberculous and non tuberculous mycobacterial infections, Pasteurella tularensis, Scopulariopsis blochi, Nocardia brasiliensis, yaws and syphilis. A case of borderline tuberculoid leprosy with multiple cutaneous nodules corresponding to resolving nerve abscesses in a sporotrichoid pattern is being reported.

Hanseníase neural, aspectos diagnósticos da forma neural pura e mecanismos imunopatogênicos da lesão do nervo na doença. Participação de quimiocinas CCL2 e CXCL10 e metaloproteinases 2 e 9 / Neural leprosy, pure neural leprosy diagnosis and imunopatogenic mechanisms of nerve damage during the disease. Participation of chemokines CCL2 and CXCL10) and metalloproteinases 2 and 9

O diagnóstico da hanseníase neural pura baseia-se em dados clínicos e laboratoriais do paciente, incluindo a histopatologia de espécimes de biópsia de nervo e detecção de DNA de Mycobacterium leprae (M. leprae) pelo PCR. Como o exame histopatológico e a técnica PCR podem não ser suficientes para confirmar o diagnóstico, a imunomarcação de lipoarabinomanana (LAM) e/ou Glicolipídio fenólico 1 (PGL1) - componentes de parede celular de M. leprae foi utilizada na primeira etapa deste estudo, na tentativa de detectar qualquer presença vestigial do M. leprae em amostras de nervo sem bacilos. Além disso, sabe-se que a lesão do nervo na hanseníase pode diretamente ser induzida pelo M. leprae nos estágios iniciais da infecção, no entanto, os mecanismos imunomediados adicionam severidade ao comprometimento da função neural em períodos sintomáticos da doença. Este estudo investigou também a expressão imuno-histoquímica de marcadores envolvidos nos mecanismos de patogenicidade do dano ao nervo na hanseníase. Os imunomarcadores selecionados foram: quimiocinas CXCL10, CCL2, CD3, CD4, CD8, CD45RA, CD45RO, CD68, HLA-DR, e metaloproteinases 2 e 9. O estudo foi desenvolvido em espécimes de biópsias congeladas de nervo coletados de pacientes com HNP (n=23 / 6 BAAR+ e 17 BAAR - PCR +) e pacientes diagnosticados com outras neuropatias (n=5) utilizados como controle. Todas as amostras foram criosseccionadas e submetidas à imunoperoxidase. Os resultados iniciais demonstraram que as 6 amostras de nervos BAAR+ são LAM+/PGL1+. Já entre as 17 amostras de nervos BAAR-, 8 são LAM+ e/ou PGL1+. Nas 17 amostras de nervos BAAR-PCR+, apenas 7 tiveram resultados LAM+ e/ou PGL1+. A detecção de imunorreatividade para LAM e PGL1 nas amostras de nervo do grupo HNP contribuiu para a maior eficiência diagnóstica na ausência recursos a diagnósticos moleculares...

The diagnosis of pure neural leprosy (PNL) is based on clinical and laboratory data, including the histopathology of nerve biopsy specimens and detection of M. leprae DNA by polymerase chain reaction (PCR). Given that histopathological examination and PCR methods may not be sufficient to confirm diagnosis, immunolabeling of lipoarabinomanan (LAM) and/or phenolic glycolipid 1 (PGL1) M. leprae wall components were utilized in the first step of this investigation in an attempt to detect any vestigial presence of M. leprae in AFB- nerve samples. Furthermore, it´s well known that nerve damage in leprosy can be directly induced by Mycobacterium leprae in the early stages of infection; however, immunomediated mechanisms add gravity to the impairment of neural function in symptomatic periods of the disease. Therefore, this study also investigated the immunohistochemical expression of immunomarkers involved in the pathogenic mechanisms of leprosy nerve damage. These markers selected were CXCL10, CCL2 chemokines and CD3, CD4, CD8, CD45RA, CD45RO, CD68, HLA-DR, metalloproteinases 2 and 9 in nerve biopsy specimens collected from leprosy (23) and nonleprosy patients (5) suffering peripheral neuropathy. Twenty-three PNL nerve samples (6 AFB+ and 17 AFB-PCR+) were cryosectioned and submitted to LAM and PGL1 immunohistochemical staining by immunoperoxidase; 5 nonleprosy nerve samples were used as controls. The 6 AFB-positive samples showed LAM/PGL1 immunoreactivity. Among the 17 AFB- samples, only 8 revealed LAM and/or PGL1 immunoreactivity. In 17 AFB-PCR+ patients, just 7 had LAM and/or PGL1-positive nerve results. In the PNL cases, the detection of immunolabeled LAM and PGL1 in the nerve samples would have contributed to enhanced diagnostic efficiency in the absence of molecular diagnostic facilities...

Nerve involvement in granuloma annulare.

BACKGROUND: Nerve involvement developed in a patient with granuloma annulare, as evidenced by a perineural infiltrate of histiocytes in the dermis. The histopathologic pattern was suggestive of leprosy. No mycobacteria were observed, and neurologic testing was normal. OBJECTIVE: To determine whether inflammation of the nerves or perineural tissue is common in granuloma annulare, we studied the cutaneous nerves in skin biopsy specimens from 14 patients with granuloma annulare. METHODS: Sections were stained with hematoxylin-eosin to highlight inflammatory cells and with S-100 to identify cutaneous nerves. RESULTS: No inflammation around nerves was found in 12 specimens, abutting granulomatous inflammation was found in 1 specimen, and enveloping granulomatous inflammation was found in 1 specimen. No nerves were infiltrated by inflammatory cells. CONCLUSION: Perineural granulomatous inflammation resembling the perineural infiltrate of leprosy appears to be an uncommon characteristic of granuloma annulare. Clinical correlation and acid-fast stains can assist in establishing the correct diagnosis.

[A man with a white macula]. / Een man met witte vlekken.

A man from the Dominican Republic presented with a white macula on the arm with sensibility loss. Skin biopsy showed a dermatitis with infiltration of dermal nerves. The diagnosis was indeterminate leprosy.

Complex regional pain syndrome secondary to leprosy.

INTRODUCTION: Leprosy is a chronic infectious disease caused by Mycobacterium leprae affecting the skin and the nerves. Complex regional pain syndrome (CRPS/Sudeck's dystrophy) is a painful and disabling condition--a triad of autonomic, sensory, and motor symptoms disproportionate to the inciting event (inflammatory, infective, or traumatic nerve damage). CASE: A 20-year-old male presented with continuous pain, aggravated by cold and emotions, loss of fine touch and temperature sensation, redness, swelling, along lateral aspect of left hand and forearm with weakness in the grip of 6 months' duration. There was a 5-year history of sensory loss only over left index finger that he ignored. Examination revealed abnormal sensory and autonomic functions along left radial and median nerve distribution that were confirmed by nerve conduction studies suggestive of mononeuritis multiplex. Radial cutaneous nerve biopsy was suggestive of leprosy. Magnetic resonance imaging and ultrasonography showed no compressive etiology; however, MRI showed involvement of brachial plexus. Antileprosy, anti-inflammatory drugs, and steroids were given in view of neuritis because of lepra reaction with supportive measures of physiotherapy, transcutaneous electrical nerve stimulation, to no avail. A surgical median nerve decompression also failed to relieve the pain. Temporary stellate ganglion block improved the pain scale. Thus, excluding all other causes, the final diagnosis was CRPS secondary to leprosy. There is only one reported case of CRPS with leprosy. CONCLUSION: Leprous neuropathy caused the nerve damage that lead to CRPS type 2. Very rarely leprosy can lead to CRPS. CRPS is a diagnosis of exclusion.

Leprosy patients: neurotrophic factors and axonal markers in skin lesions.

Neurotrophins are growth factors with crucial roles in neural pathophysiology. These mediators functionally modulate nociceptive fibers, and changes in neurotrophins expression have been correlated with early loss of nociception in leprosy. This study investigated the expression of NGF, BDNF, and NT3 in dermal nerves of leprosy patients. Characterization of Remak bundles was achieved by p75(NTR), and axonal markers NF-L and PGP 9.5 immunostaining. Clinical parameters of neural impairment have been evaluated by Semmes-Wenstein monofilaments. Our findings demonstrated decrease of NGF in borderline leprosy, when compared to control specimens. Similar results were observed in PGP 9.5 expression (borderline: p<0.001 and lepromatous: p<0.05) and NF-L (lepromatous: p<0.05), suggesting advanced Remak bundles degeneration in multibacillary leprosy. It has also been observed positive correlation between p75(NTR) and PGP 9.5, indicating association between Schwann cells and axons in Remak bundles. Present data indicate that neurotrophins imbalance may participate in the establishment of peripheral nerve damage.

Leprosy patients: neurotrophic factors and axonal markers in skin lesions / Pacientes com hanseníase: fatores neurotróficos e marcadores axonais em lesões de pele

Neurotrophins are growth factors with crucial roles in neural pathophysiology. These mediators functionally modulate nociceptive fibers, and changes in neurotrophins expression have been correlated with early loss of nociception in leprosy. This study investigated the expression of NGF, BDNF, and NT3 in dermal nerves of leprosy patients. Characterization of Remak bundles was achieved by p75NTR, and axonal markers NF-L and PGP 9.5 immunostaining. Clinical parameters of neural impairment have been evaluated by Semmes-Wenstein monofilaments. Our findings demonstrated decrease of NGF in borderline leprosy, when compared to control specimens. Similar results were observed in PGP 9.5 expression (borderline: p<0.001 and lepromatous: p<0.05) and NF-L (lepromatous: p<0.05), suggesting advanced Remak bundles degeneration in multibacillary leprosy. It has also been observed positive correlation between p75NTR and PGP 9.5, indicating association between Schwann cells and axons in Remak bundles. Present data indicate that neurotrophins imbalance may participate in the establishment of peripheral nerve damage.

Neurotrofinas são fatores de crescimento com papel fundamental na fisiopatologia neural. Esses mediadores modulam funcionalmente fibras nociceptivas. Mudanças em sua expressão têm sido relacionadas à perda precoce da nocicepção na hanseníase. Este estudo investigou a expressão de NGF, BDNF e NT3 em nervos dérmicos de pacientes hansenianos. A caracterização de fibras nervosas não mielinizadas foi feita por p75NTR e marcadores axonais NF-L e PGP 9.5. Os parâmetros clínicos de dano neural foram avaliados por monofilamentos Semmes-Wenstein. Nossos achados demonstram diminuição de NGF nos pacientes dimorfos em comparação aos controles. Resultados similares foram observados para PGP 9.5 (dimorfos: p<0,001; virchowianos: p<0,05) e NF-L (virchowianos: p<0.05), sugerindo degeneração avançada das terminações nervosas na hanseníase multibacilar. Foi observada correlação positiva entre p75NTR e PGP 9.5, indicando associação entre células de Schwann e axônios em fibras nervosas não mielinizadas. Os resultados indicam que o desequilíbrio na expressão das neurotrofinas pode participar do dano neural periférico.

Thermal record of the test tubes method used for small fibers assessment / Registro térmico do método dos tubos de ensaio aplicado na avaliação de fibras finas

In Brazil, the test that uses test tubes filled with cold water (25ºC) and tubes filled with water heated to a temperature of 45ºC is recommended by the Ministry of Health as a way of evaluate thermal sensitivity on the injured skin of leprosy patients. The purpose of this work was to quantify the thermal stimulation applied to the skin, as well as the temperature variation of the heated water and of the tube's outer surface during stimulation sessions. The experiment had the participation of 14 healthy volunteers (31.2±11.4 years-old), ten of which were male (33.1±13.5 years-old) and four were female (26.5±4.7 years-old). Three consecutive stimulation sessions were carried out, each of them with four stimuli. The maximum skin temperature at the end of the stimuli was measured at 35.8±0.6ºC. Such temperature values may be useful in the assessment of the loss of small fibers, which are responsible for the sensation of warmth.

No Brasil, o teste que utiliza tubos de ensaio preenchidos com água aquecida (45ºC) e resfriada (25ºC) é preconizado pelo Ministério da Saúde como forma de avaliar a sensibilidade térmica nas lesões de pele de pacientes com hanseníase. O objetivo deste trabalho foi quantificar o estímulo térmico na pele e a variação das temperaturas da água aquecida e da superfície externa do tubo, durante as sessões de estimulação. O experimento contou com 14 voluntários saudáveis (31,2±11,4 anos), sendo dez do gênero masculino (33,1±13,5 anos) e quatro do gênero feminino (26,5±4,7 anos). Realizaram-se três sessões seguidas de estimulação com quatro estímulos em cada sessão. A temperatura registrada na pele, ao final dos estímulos, apresentou diferenças entre as sessões, atingindo o máximo de 35,8±0,6ºC. Estes valores de temperatura podem ser úteis na avaliação da perda de fibras finas responsáveis pela sensação de aquecimento.

Dorsal cutaneous branch of the ulnar nerve: a light and electron microscopy histometric study.

This study describes the normal morphology and morphometry of the dorsal cutaneous branch of the ulnar nerve (DCBU) in humans. Fourteen nerves of eight donors were prepared by conventional techniques for paraffin and epoxy resin embedding. Semiautomatic morphometric analysis was performed by means of specific computer software. Histograms of the myelinated and unmyelinated fiber population and the G-ratio distribution of fibers were plotted. Myelinated fiber density per nerve varied from 5,910 to 10,166 fibers/mm(2) , with an average of 8,170 ± 393 fibers/mm(2) . The distribution was bimodal with peaks at 4.0 and 9.5 µm. Unmyelinated fiber density per nerve varied from 50,985 to 127,108, with an average of 78,474 ± 6,610 fibers/mm(2) , with a unimodal distribution displaying a peak at 0.8 µm. This study thus adds information about the fascicles and myelinated and unmyelinated fibers of DCBU nerves in normal people, which may be useful in further studies concerning ulnar nerve neuropathies, mainly leprosy neuropathy.

Thermal record of the test tubes method used for small fibers assessment.

In Brazil, the test that uses test tubes filled with cold water (25ºC) and tubes filled with water heated to a temperature of 45ºC is recommended by the Ministry of Health as a way of evaluate thermal sensitivity on the injured skin of leprosy patients. The purpose of this work was to quantify the thermal stimulation applied to the skin, as well as the temperature variation of the heated water and of the tube's outer surface during stimulation sessions. The experiment had the participation of 14 healthy volunteers (31.2 ± 11.4 years-old), ten of which were male (33.1 ± 13.5 years-old) and four were female (26.5 ± 4.7 years-old). Three consecutive stimulation sessions were carried out, each of them with four stimuli. The maximum skin temperature at the end of the stimuli was measured at 35.8 ± 0.6ºC. Such temperature values may be useful in the assessment of the loss of small fibers, which are responsible for the sensation of warmth.