What happens when Schwann cells are exposed to Mycobacterium leprae - A systematic review.

Mycobacterium leprae, the pathogen that causes human leprosy, has a unique affinity for infecting and persisting inside Schwann cells, the principal glia of the peripheral nervous system. Several studies have focused on this intricate host-pathogen interaction as an attempt to advance the current knowledge of the mechanisms governing nerve destruction and disease progression. However, during the chronic course of leprosy neuropathy, Schwann cells can respond to and internalize both live and dead M. leprae and bacilli-derived antigens, and this may result in divergent cellular pathobiological responses. This may also distinctly contribute to tissue degeneration, failure to repair, inflammatory reactions, and nerve fibrosis, hallmarks of the disease. Therefore, the present study systematically searched for published studies on M. leprae-Schwann cell interaction in vitro to summarize the findings and provide a focused discussion of Schwann cell dynamics following challenge with leprosy bacilli.

Peripheral neuropathy in leprosy: Clinical manifestations and disability in a Colombian national referral center.

To aim of the paper was to describe the neurological features of the physical examination in patients with Hansen's disease who were treated in Bogotá, Colombia. We carried out a descriptive study of all patients with a Hansen's disease diagnosis treated at a referral center between 2003-2018. There were 327 eligible electronic health records (EHRs) with a final sample of 282 subjects. Leprosy was most common in males (57.45%), median age at the diagnosis was 54 years, and lesions of the lower limbs were more common (75.1%). The median time from disease onset to consult was 12 months. Most of them were classified as having lepromatous leprosy (39.7%). Pain over the median nerve trunk was the most common manifestation of disease (28%), followed by pain over the radial trunk (22%). Sensitive alterations were more common than motor ones. Specifically, the posterior tibial nerve was affected in nearly half of subjects. Dual impairment was more common in the ulnar nerve (13.8%). Some disability was apparent in 23.8% of subjects; predominantly grade 1 disability. Findings regarding age, leprosy type, and the frequency of individual nerve compromise were consistent with reports from other countries. Nerve trunk thickening was infrequent, which might be a consequence of subjectiveness in the examination and sample differences in sex distribution, degree of disability and time since disease onset. The frequency of morbidity and disability found in this sample, though low when compared with other series, fails to meet public health goals, including those limiting disability in younger subjects.

Gene Expression Profile of Mycobacterium leprae Contribution in the Pathology of Leprosy Neuropathy.

Peripheral neuropathy is the main cause of physical disability in leprosy patients. Importantly, the extension and pattern of peripheral damage has been linked to how the host cell will respond against Mycobacterium leprae (M. leprae) infection, in particular, how the pathogen will establish infection in Schwann cells. Interestingly, viable and dead M. leprae have been linked to neuropathology of leprosy by distinct mechanisms. While viable M. leprae promotes transcriptional modifications that allow the bacteria to survive through the use of the host cell's internal machinery and the subvert of host metabolites, components of the dead bacteria are associated with the generation of a harmful nerve microenvironment. Therefore, understanding the pathognomonic characteristics mediated by viable and dead M. leprae are essential for elucidating leprosy disease and its associated reactional episodes. Moreover, the impact of the viable and dead bacteria in Schwann cells is largely unknown and their gene signature profiling has, as yet, been poorly explored. In this study, we analyzed the early differences in the expression profile of genes involved in peripheral neuropathy, dedifferentiation and plasticity, neural regeneration, and inflammation in human Schwann cells challenged with viable and dead M. leprae. We substantiated our findings by analyzing this genetic profiling in human nerve biopsies of leprosy and non-leprosy patients, with accompanied histopathological analysis. We observed that viable and dead bacteria distinctly modulate Schwann cell genes, with emphasis to viable bacilli upregulating transcripts related to glial cell plasticity, dedifferentiation and anti-inflammatory profile, while dead bacteria affected genes involved in neuropathy and pro-inflammatory response. In addition, dead bacteria also upregulated genes associated with nerve support, which expression profile was similar to those obtained from leprosy nerve biopsies. These findings suggest that early exposure to viable and dead bacteria may provoke Schwann cells to behave differentially, with far-reaching implications for the ongoing neuropathy seen in leprosy patients, where a mixture of active and non-active bacteria are found in the nerve microenvironment.

Gene expression profile of Mycobacterium leprae contribution in the pathology of leprosy neuropathy

Peripheral neuropathy is the main cause of physical disability in leprosy patients.Importantly, the extension and pattern of peripheral damage has been linked to how the host cell will respond against Mycobacterium leprae (M. leprae) infection, in particular, how the pathogen will establish infection in Schwann cells. Interestingly, viable and dead M. leprae have been linked to neuropathology of leprosy by distinct mechanisms. While viable M. leprae promotes transcriptional modifications that allow the bacteria to survive through the use of the host cell's internal machinery and the subvert of host metabolites, components of the dead bacteria are associated with the generation of a harmful nerve microenvironment. Therefore, understanding the pathognomonic characteristics mediated by viable and dead M. leprae are essential for elucidating leprosy disease and its associated reactional episodes. Moreover, the impact of the viable and dead bacteria in Schwann cells is largely unknown and their gene signature profiling has, as yet, been poorly explored. In this study, we analyzed the early differences in the expression profile of genes involved in peripheral neuropathy, dedifferentiation and plasticity, neural regeneration, and inflammation in human Schwann cells challenged with viable and dead M. leprae. We substantiated our findings by analyzing this genetic profiling in human nerve biopsies of leprosy and non-leprosy patients, with accompanied histopathological analysis. We observed that viable and dead bacteria distinctly modulate Schwann cell genes, with emphasis to viable bacilli upregulating transcripts related to glial cell plasticity, dedifferentiation and anti-inflammatory profile, while dead bacteria affected genes involved in neuropathy and pro-inflammatory response. In addition, dead bacteria also upregulated genes associated with nerve support, which expression profile was similar to those obtained from leprosy nerve biopsies. These findings suggest that early exposure to viable and dead bacteria may provoke Schwann cells to behave differentially, with far-reaching implications for the ongoing neuropathy seen in leprosy patients, where a mixture of active and non-active bacteria are found in the nerve microenvironment.

Morphometric analysis of nerve fibers in neural leprosy.

BACKGROUND: The present study assesses the contributions of axonal degeneration and demyelination in leprosy nerve damage. New clinical strategies can emerge from an in-depth understanding of the pathogenesis of neural leprosy (NL). METHODS: Morphometric analysis of myelinated nerve fibers was performed on 44 nerve biopsy samples collected from leprosy patients. Measures of density, diameter distribution, g-ratios, and the counting of axonal ovoids on the myelinated fibers were taken and compared to those in the control group. RESULTS: The proportion of small myelinated fibers increased in the leprosy group while large fiber frequency decreased. Indicative of axonal atrophy, the g-ratio was lower in the leprosy group. The frequency of axonal ovoids was identical to that found in the non-leprosy neuropathies. CONCLUSIONS: Axonal atrophy, Wallerian degeneration, and demyelination coexist in NL. Axonal degeneration predominates over demyelination in the chronic course of the disease; however, this may change during leprosy reactive episodes. This study regards demyelination and axon degeneration as concurrent mechanisms of damage to nerve fibers in leprosy. It also calls into question the view that demyelination is the primary and predominant mechanism in the complex pathogeny of NL.

Functional Impairment of Skin Appendages Due to Peripheral Nerve Involvement by Mycobacterium leprae.

In the earliest stage of Mycobacterium leprae infection, bacteria parasitize fine fiber twigs of autonomic peripheral nerves supplying efferent impulses to appendages of the skin. This obligate intracellular pathogen invades Schwann cells, the glial cells of peripheral nerves. Intracellular events inhibit Schwann cell physiology in complex ways, which include demyelination and dedifferentiation. Ultimately, axons embraced by their surrounding dysfunctional glia are damaged by poorly understood mechanisms. Loss of nerve conduction impairs the functions of skin appendages including hair growth, sebaceous gland secretion, sweating, and skin pigmentation. At the clinical level, these changes may be subtle and may precede the more obvious anesthetic skin lesions associated with Hansen's disease. Recognizing the early signs of skin appendage malfunction may aid in diagnosis leading to initiation of antimycobacterial treatment. Effective therapy administered early during infection may prevent irreversible peripheral nerve destruction, the presage for morbid complications of leprosy.

Diseases of the peripheral nerves.

This chapter reviews the diseases of the peripheral nerves from a neuropathologic point of view, with a special focus on specific morphologic changes, and includes a summary of the histopathologic methods available for their diagnosis. As the rate of obesity and the prevalence of type 2 diabetes increase, diabetic neuropathy is the most common cause of peripheral neuropathy. Many systemic disorders with metabolic origin, like amyloidosis, hepatic failure, vitamin deficiencies, uremia, lipid metabolism disorders, and others, can also cause axonal or myelin alterations in the peripheral nervous system. The most notable causes of toxic neuropathies are chemotherapeutic agents, alcohol consumption, and exposure to heavy metals and other environmental or biologic toxins. Inflammatory neuropathies cover infectious neuropathies (Lyme disease, human immunodeficiency virus, leprosy, hepatitis) and neuropathies of autoimmune origin (sarcoidosis, Guillain-Barré syndrome/acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, and diverse forms of vasculitis. The increasing number of known diseases causing gene mutations in hereditary peripheral neuropathies requires precise characterization, which includes histopathology.

Neuropatía hipertrófica secundaria a enfermedad de Hansen. Presentación de un caso / Hypertrophic Neuropathy Secondary to Hansen’s Disease. A Case Report

Se presenta el caso de una paciente de 49 años de edad, soltera, atendida en el Hospital de Cienfuegos, que comenzó con cuadro clínico de debilidad muscular en miembros inferiores y "entumecimiento" (parestesia) de las cuatro extremidades, con mejoría relativa. Un año después sufrió empeoramiento de las manifestaciones de debilidad muscular y parestesia de extremidades, fundamentalmente las superiores, lesiones hipopigmentadas en piel de tórax y abdomen. Se inició protocolo de investigación por sospecha de polineuropatía hipertrófica. Se realizó biopsia de lesiones hipocrómicas y se concluyó como una polineuropatía hipertrófica secundaria a enfermedad de Hansen, tipo lepra tuberculoide. Se decidió la presentación de este caso, pues en estos pacientes la neuropatía suele ser lenta, insidiosa y de larga evolución, pero durante las leprorreaciones puede haber lesión neurológica aguda, momento de mayor gravedad a la hora de la instauración de deformidades y discapacidades, por lo que se debe actuar con rapidez con la finalidad de evitarlas.

We present the case 49-year-old unmarried woman treated at the hospital of Cienfuegos. The patient complained of weakness in the lower limbs and "numbness" (paresthesia) of all four extremities, which improved slightly after treatment. A year later, the muscle weakness and paresthesia worsened, particularly in the upper limbs. She also developed hypopigmented skin lesions on the chest and abdomen. The investigation was initiated due to suspicion of hypertrophic polyneuropathy. A biopsy of the hypochromic lesions was performed, which led to the conclusion that the patient suffered from a hypertrophic polyneuropathy secondary to tuberculoid Hansen’s disease. We decided to present this case since a neuropathy is usually slow, insidious and has a long course in these patients; however, leprosy reactions can lead to acute nerve damage, resulting in disabilities and deformities. Consequently, it is important to act quickly in order to avoid them.

High resolution sonography in the evaluation of the peripheral nervous system in polyneuropathy--a review of the literature.

Clinical, laboratory and electrodiagnostic studies are the mainstay in the diagnosis of polyneuropathy. An accurate etiological diagnosis is of paramount importance to provide the appropriate treatment, prognosis and genetic counselling. High resolution sonography of the peripheral nervous system allows nerves to be readily visualized and to assess their morphology. Ultrasonography has brought pathophysiological insights and substantially added to diagnostic accuracy and treatment decisions amongst mononeuropathies. In this study the literature on its clinical application in polyneuropathy is reviewed. Several polyneuropathies have been studied by means of ultrasound: Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, multifocal motor neuropathy, paraneoplastic polyneuropathy, leprosy and diabetic neuropathy. The most prominent reported pathological changes were nerve enlargement, increased hypo-echogenicity and increased intraneural vascularization. Sonography revealed intriguingly different patterns of nerve enlargement between inflammatory neuropathies and axonal and inherited polyneuropathies. However, many studies concerned case reports or case series and showed methodological shortcomings. Further prospective studies with standardized protocols for nerve sonography and clinical and electrodiagnostic testing are needed to determine the role of nerve sonography in inherited and acquired polyneuropathies.

Avaliação sensitiva de hansenianos pelos monofilamentos Semmes-Weinstein em serviço terciário de fisioterapia / Effectiveness of Semmes-Weinstein monofilaments in leprosy neuropathy in physiotherapy tertiary sevice

OBJETIVOS: Identificar a frequência das alterações da sensibilidade de mãos e pés de hansenianos através dos monofilamentos Semmes-Weinstein no hospital terciário.MÉTODO: Trinta pacientes do setor de fisioterapia do Hospital da Clínicas da FMRP-USP foram avaliados clinico-epidemiologicamente e submetidos ao teste por monofilamentos de agosto a dezembro de 2004.RESULTADOS: A média de idade dos pacientes foi de 48,4 anos, sendo 80% do sexo masculino e 70% oriundos da região de Ribeirão Preto. Classificavam-se como multibacilares 70% dos pacientes e 80% apresentavam-se com Grau I de incapacidade. Quanto ao teste nos membros superiores, o nervo ulnar foi o mais acometido nos paucibacilares (78%) e nos multibacilares (83%). Nos membros inferiores, o ramo plantar medial do nervo tibial posterior encontrou-se acometido em todos os pacientes do grupo multibacilar. A sensação protetora estava ausente nas mãos em 26% no grupo pauci e 46% no multibacilar, e nos pés 44% no paucibacilar e 56% no multibacilar. O diagnóstico foi tardio em 37% dos pacientes, apresentando no mínimo dois nervos com perda da sensação protetora.CONCLUSÃO: Os resultados evidenciaram que o acompanhamento da neuropatia da hanseníase pelos monofilamentos S-W, mostrou-se capaz de identificar alterações da sensibilidade em múltiplos nervos das extremidades, tanto nos pacientes paucibacilares quanto multibacilares, tornando-se evidente a gravidade dos pacientes atendidos nos serviço de atenção terciária à saúde.

OBJECTIVES: To identify the frequency of changes in the sensibility of hands and feet from leprosy patients through the Semmes-Weinstein monofilament in tertiary hospital.METHOD: Thirty patients of the Physiotherapy Service of Hospital das Clínicas FMRP-USP were evaluated from August to December 2004. The patients were clinically and epidemiologically evaluated. Afterwards, monofilaments were tested.RESULTS: The mean age was 48.4 years, 80% male and 70% came from the Ribeirão Preto region. Seventy percent of the patients were classified as multibacilary and 80% presented grade 1 of incapacity. Concerning to Semmes-Weinstein test on the upper limbs, the ulnar was the most impaired nerve on the paucibacillary patients (78%) and on the multibacillary (83%). On the lower limbs, the plantar medial branch from the tibial posterior nerve had been impaired in all patients. The protective sensation was absent on the hands in 26% on the paucibacillary group and 46% on the multibacillary, and on the feet in 44% on the paucibacillary and 56% on the multibacillary. Thirty seven percent of the patients have received late diagnosis, showing at least two nerves without protective sensation.CONCLUSIONS: The results showed the reliable use of Semmes-Weinstein monofilaments during the follow up of leprosy patients. This tool was able to identify sensitive changes in multiple nerves of the extremities, for paucibacilary and multibacilary patients, what clearly shows the severity of incoming patients in health tertiary care service.

Biópsia do nervo sural: técnica, indicações e resultados / Sural nerve biopsy: technique, indications and results

A biópsia de nervo pode ser útil no diagnóstico de neuropatias periféricas quando não forpossível determinar a causa por métodos convencionais como eletromiografia ou testes desensibilidade. Nós revisamos as indicações desse procedimento, descrevemos a técnica ediscutimos os resultados.

A sural nerve biopsy may be useful to enable the clinician to diagnose of peripheral neuropathy,when no clear underlying cause has been determined with conventional assessmentsuch as electrophysiology or quantitative sensory testing. We review the indications of thisprocedure, describe the technique, and discuss the results.

Leprosy type 1 reactions and erythema nodosum leprosum: [review]

Leprosy reactions are a major cause of nerve damage and morbidity in a significant proportion of leprosy patients. Reactions are immunologically mediated and can occur even after successful completion of multi-drug therapy. This review focuses on the epidemiology, pathology and treatment of leprosy type 1 reactions, erythema nodosum leprosum and silent neuropathy.

As reações hansênicas são a principal causa de dano e morbidade neural em grande parte dos pacientes hansênicos. São imunomediadas e podem ocorrer mesmo após o término bem sucedido da poliquimioterapia. Esta revisão enfoca a epidemiologia, a patologia e o tratamento das reações hansênicas do tipo 1, do eritema nodoso hansênico e da neuropatia silenciosa.