Progressive neuropathy in patients with lepromatous leprosy after multidrug therapy

BACKGROUND The lepromatous pole is a stigmatising prototype for patients with leprosy. Generally, these patients have little or no symptoms of peripheral nerve involvement at the time of their diagnosis. However, signs of advanced peripheral neuropathy would be visible during the initial neurological evaluation and could worsen during and after multidrug therapy (MDT). Disabilities caused by peripheral nerve injuries greatly affect these patients' lives, and the pathophysiological mechanisms underlying nerve damage remain unclear. OBJECTIVES To evaluate the outcome of peripheral neuropathy in patients with lepromatous leprosy (LL) and persistent neuropathic symptoms years after completing MDT. METHODS We evaluated the medical records of 14 patients with LL who underwent nerve biopsies due to worsening neuropathy at least four years after MDT. FINDINGS Neuropathic pain developed in 64.3% of the patients, and a neurological examination showed that most patients had alterations in the medium- and large-caliber fibers at the beginning of treatment. Neurological symptoms and signs deteriorated despite complete MDT and prednisone or thalidomide use for years. Nerve conduction studies showed that sensory nerves were the most affected. MAIN CONCLUSIONS Patients with LL can develop progressive peripheral neuropathy, which continues to develop even when they are on long-term anti-inflammatory and immunosuppressive therapy.

Evidence and practices of the use of next generation sequencing in patients with undiagnosed autosomal dominant cerebellar ataxias: a review / Evidências e práticas do uso do sequenciamento de nova geração em pacientes com ataxias cerebelares autossômicas dominantes não diagnosticadas: uma revisão

ABSTRACT Autosomal dominant cerebellar ataxias (ADCA) are heterogeneous diseases with a highly variable phenotype and genotype. They can be divided into episodic ataxia and spinocerebellar ataxia (SCA); the latter is considered the prototype of the ADCA. Most of the ADCA are caused by polyglutamine expansions, mainly SCA 1, 2, 3, 6, 7, 17 and Dentatorubral-pallidoluysian atrophy (DRPLA). However, 30% of patients remain undiagnosed after testing for these most common SCA. Recently, several studies have demonstrated that the new generation of sequencing methods are useful for the diagnose of these patients. This review focus on searching evidence on the literature, its usefulness in clinical practice and future perspectives.

RESUMO As ataxias cerebelares autossômicas dominantes (ACAD) são doenças heterogêneas com fenótipo e genótipo altamente variáveis. Podem ser divididas em ataxia episódica e ataxia espinocerebelar (SCA), sendo este último considerado o protótipo do ACAD. A maior parte das ACAD são causadas por expansões de poliglutaminas, principalmente SCA 1, 2, 3, 6, 7, 17 e atrofia dentatorubro-palidoluisiana (DRPLA). No entanto, 30% dos pacientes permanecem sem diagnóstico após o teste para essas SCA mais comuns. Recentemente, vários estudos têm demonstrado que a nova geração de métodos de sequenciamento são ferramentas úteis para o diagnóstico desses pacientes. Esta é uma revisão sistemática da literatura, com foco em sua utilidade na prática clínica e em perspectivas futuras.

Pedicle morphology in scoliosis: classification agreement for pre-operative evaluation / Morfologia do pedículo na escoliose: concordância na classificação para avaliação pré-operatória / Morfología del pedículo en la escoliosis: concordancia de clasificación para evaluación prequirúrgica

ABSTRACT Objectives Although Watanabe morphological classification is well known, there is no consensus of its use among spine surgeons. We propose an analysis of the Watanabe classification by three observers, one senior and two recently graduated orthopedic spine surgeons, and its applicability in pre-operative evaluation. Methods An intraobserver and interobserver analysis of the classifications of 937 thoracic pedicles among 55 scoliosis patients treated surgically in two institutions. The average age at time of surgery was 16.3 years (10- 50 years). The etiologies of the scoliosis were: idiopathic (n= 47), congenital (n=4), syndromic (n= 3) and neuromuscular (n=1). The mean Cobb angle was 67 degrees (41- 120º). The evaluation of the thoracic pedicle was performed using pre-operative CT images. Results A total of 937 pedicles were classified by three observers with percentages of 47.5% type A, 28.6% type B, 17.1% type C and 6.9% type D for the total pedicles, convex and concave. Intraobserver agreement was fair to almost perfect (kappa 0.34 to 0.92) and interobserver agreement was fair to moderate (kappa 0.33 to 0.59) with statistical significance of p<0.001. Conclusion Watanabe classification remains a good method for predicting intraoperative difficulties, and has better agreement as the surgeon becomes more experienced. Level of evidence II; Prognostic Studies.

RESUMO Objetivo A classificação morfológica dos pedículos descrita por Watanabe, apesar de bem conhecida, não é consenso entre os cirurgiões de coluna. Propomos uma análise da classificação por três observadores, um sênior e dois cirurgiões de coluna recém-graduados, e sua aplicabilidade na avaliação pré-operatória. Métodos Foi realizada uma análise intraobservador e interobservador das classificações de Watanabe de 937 pedículos em 55 pacientes com escoliose, tratados cirurgicamente em duas instituições. A média de idade no momento da cirurgia foi de 16,3 anos (10 a 50 anos). As etiologias da escoliose foram: idiopática (n = 47), congênita (n = 4), sindrômica (n = 3) e neuromuscular (n = 1). O ângulo médio de Cobb foi de 67 graus (41º a 120º). A avaliação dos pedículos torácicos foi realizada com imagens pré-operatórias de tomografia computadorizada. Resultados Três observadores classificaram 937 pedículos côncavos e convexos, evidenciando 47,5% do tipo A; 28,6% do tipo B; 17,1% do tipo C e 6.9% do tipo D. A concordância intraobservador foi de razoável a quase perfeita (kappa 0,34 a 0,92) e concordância interobservador foi de razoável a moderada (kappa 0,33 a 0,59), com significância estatística de p < 0,001. Conclusões A classificação de Watanabe pode ser considerada um bom método para prever dificuldades intraoperatórias e apresenta melhor concordância à medida que o cirurgião se torna mais experiente. Nível de Evidência II; Estudos Prognósticos.

RESUMEN Objetivo La clasificación morfológica de los pedículos descrita por Watanabe, a pesar de ser bien conocida, no es consenso entre los cirujanos de columna. Proponemos un análisis de la clasificación por 3 observadores, un sénior y dos cirujanos de columna recién graduados, y su aplicabilidad en la evaluación prequirúrgica. Método Fue realizado un análisis intraobservador e interobservador de las clasificaciones de Watanabe de 937 pedículos en 55 pacientes con escoliosis, tratados quirúrgicamente en dos instituciones. El promedio de edad en el momento de la cirugía fue de 16,3 años (10-50 años). Las etiologías de la escoliosis fueron: idiopática (n=47), congénita (n=4), sindrómica (n=3) y neuromuscular (n=1). El ángulo promedio de Cobb fue de 67 grados (41º a 120º). La evaluación de los pedículos torácicos fue realizada con imágenes prequirúrgicas de tomografía computada. Resultados Tres observadores clasificaron 937 pedículos cóncavos y convexos, evidenciando 47,5% tipo A, 28,6% tipo B, 17,1% tipo C y 6,9% tipo D. La concordancia intraobservador fue de razonable a casi perfecta (kappa 0,34 a 0,92)y la concordancia interobservador fue de razonable a moderada (kappa 0,33 a 0,59) con una significancia estadística de p<0,001. Conclusiones La clasificación de Watanabe puede ser considerada un buen método para prever dificultades intraquirúrgicas y presenta mejor concordancia a medida que el cirujano se vuelve más experimentado. Nivel de Evidencia II; Estudios Pronósticos.

Intra- and interobserver analysis of pedicle screw placement in scoliosis correction / Análise intra e interobservador de posicionamento de parafusos pediculares em correção de escoliose / Análisis intra e interobservador de posicionamiento de tornillos pediculares en corrección de escoliosis

ABSTRACT Objective To establish the statistical interobserver and intraobserver concordance of thoracic pedicle screw placement in scoliosis surgery, with a 4-week interval between the two analyses. Methods Of 55 patients that evaluated the intra- and interobserver concordances of the screw positions (according to the Abul-Kasim classification) using the Kappa coefficient. Results The intraobserver concordance ranged from a Kappa coefficient of 0.516 to 0.889 ("moderate" to "almost perfect") between the two analyses performed four weeks apart. Interobserver concordance ranged from 0.379 to 0.633 ("reasonable" to "strong"). Conclusion The intraobserver concordance was always greater than the interobserver concordance. No concordance coefficient was classified as "insignificant" or "weak". Level of Evidence III; Retrospective study.

RESUMO Objetivo Estabelecer a concordância estatística interobservadores e intraobservadores do posicionamento de parafusos pediculares torácicos em cirurgia de escoliose, com intervalo de quatro semanas entre as duas análises. Métodos Com 55 pacientes, que avalia as concordâncias intra e interobservador da posição dos parafusos (segundo a classificação de Abul-Kasim), utilizando o coeficiente de Kappa. Resultados A concordância intraobservador variou entre 0,516 e 0,889 ("moderada" a "quase perfeita") de coeficiente Kappa, entre análises com intervalo de quatro semanas. A concordância interobservador variou entre 0,379 e 0,633 ("razoável" a "forte"). Conclusões A concordância intraobservador foi sempre maior que a interobservador. Nenhum coeficiente de concordância foi classificado como "insuficiente" ou "fraco". Nível de Evidência III; Estudo retrospectivo.

RESUMEN Objetivo Establecer la concordancia estadística interobservadores e intraobservadores del posicionamiento de tornillos pediculares torácicos en cirugía de escoliosis, con intervalo de cuatro semanas entre los dos análisis. Métodos Estudio de cohorte retrospectivo (nivel con 55 pacientes, que evalúa las concordancias intra e interobservador de la posición de los tornillos (según la clasificación de Abul-Kasim), usando el coeficiente de Kappa. Resultados La concordancia intraobservador varió entre 0,516 y 0,889 ("moderada" a "casi perfecta"), de coeficiente Kappa, entre análisis con intervalo por 4 semanas. La concordancia interobservador varió entre 0,379 y 0,633 ("razonable" a "fuerte"). Conclusiones La concordancia intraobservador fue siempre mayor que la interobservador. Ningún coeficiente de concordancia fue clasificado como "insuficiente" o "débil". Nivel de Evidencia III; Estudio retrospectivo.

Fibrosis: a distinguishing feature in the pathology of neural leprosy

BACKGROUND Fibrosis in the peripheral nerve is the end stage of leprous neuropathy and the cause of the resulting permanent neural function impairments. Preventive measures to avoid this irreversible pathological state are a relief strategy for leprosy sufferers. OBJECTIVES The present study describes the frequency of fibrosis along with its characterisation and pathogenic development. METHODS Six-hundred-and-thirteen nerve samples were sorted from 278 neural leprosy (NL) and 335 non-leprosy neuropathy patients (ON). The total number of samples was histologically examined by routine staining methods (haematoxylin-eosin, Wade staining and Gomori's trichrome) and fibrosis was evaluated via semi-quantitative estimation. FINDINGS Fibrosis was most frequent in the NL group (33% against 0.4% in ON) while fibrosis in association with endoneurial microfasciculation was found in 38 (41.3%) of the NL samples in the examination of semithin sections. Pericytic activation in the perivascular environment was confirmed to be the source of the fibroblasts and perineurial cells delimiting microfascicles. End-stage fibrosis in leprosy displays an arrangement of microfascicles devoid of neural components (i.e., Schwann cells and axons) lined by an intermediate phenotype of fibroblastic-perineurial cells filled with bundles of collagen fibres. MAIN CONCLUSIONS The present study underscores that fibrosis is frequently the severe end stage of neural leprosy NL pathogeny after analysing the notably distinct development of fibrosis within the neural environment.

Histopathological examination of nerve samples from pure neural leprosy patients: obtaining maximum information to improve diagnostic efficiency

Nerve biopsy examination is an important auxiliary procedure for diagnosing pure neural leprosy (PNL). When acid-fast bacilli (AFB) are not detected in the nerve sample, the value of other nonspecific histological alterations should be considered along with pertinent clinical, electroneuromyographical and laboratory data (the detection of Mycobacterium leprae DNA with polymerase chain reaction and the detection of serum anti-phenolic glycolipid 1 antibodies) to support a possible or probable PNL diagnosis. Three hundred forty nerve samples [144 from PNL patients and 196 from patients with non-leprosy peripheral neuropathies (NLN)] were examined. Both AFB-negative and AFB-positive PNL samples had more frequent histopathological alterations (epithelioid granulomas, mononuclear infiltrates, fibrosis, perineurial and subperineurial oedema and decreased numbers of myelinated fibres) than the NLN group. Multivariate analysis revealed that independently, mononuclear infiltrate and perineurial fibrosis were more common in the PNL group and were able to correctly classify AFB-negative PNL samples. These results indicate that even in the absence of AFB, these histopathological nerve alterations may justify a PNL diagnosis when observed in conjunction with pertinent clinical, epidemiological and laboratory data.

Pure neural leprosy: steroids prevent neuropathy progression

Multidrug therapy (MDT), with rifampicin, dapsone, and clofazimine, treats leprosy infection but is insufficient in arresting or preventing the nerve damage that causes impairments and disabilities. This case-series study evaluates the benefits of the combined use of steroids and MDT in preventing nerve damage in patients with pure neural leprosy (PNL). In addition to MDT, 24 patients (88 percent male aged 20-79 years, median=41) received a daily morning dose of 60 mg prednisone (PDN) that was gradually reduced by 10 mg during each of the following 5 months. PNL was clinically diagnosed and confirmed by nerve histopathology or PCR. A low prevalence (8.3 percent) of reaction was observed after release from treatment. However, most of the clinical parameters showed significant improvement; and a reduction of nerve conduction block was observed in 42 percent of the patients. The administration of full-dose PDN improved the clinical and electrophysiological condition of the PNL patients, contributing to the prevention of further neurological damage.

A poliquimioterapia (PQT), com rifampicina, dapsona, e clofazimina, trata a infecção na hanseníase, mas é insuficiente para interromper ou prevenir o comprometimento neurológico que causa as incapacidades e desabilidades, nesta enfermidade. Este estudo de série de casos avalia o benefício do uso combinado de prednisona e PQT na prevenção do dano neurológico em pacientes com a forma neural pura da hanseníase (FNP). Além do PQT, 24 pacientes (88 por cento homens, com idade variando entre 20-79, mediana=41) receberam uma dose diária de 60 mg prednisona que foi reduzida gradualmente na dose de 10 mg durante cada um dos 5 meses subseqüentes. FNP foi diagnosticada clinicamente e confirmada através do estudo histopatológico ou PCR. Baixa prevalência de reação (8,3 por cento) foi observada apenas após o final do tratamento. A maioria dos parâmetros clínicos mostrou melhora significativa e redução do bloqueio de condução foi observada em 42 por cento dos pacientes. A administração de doses altas de prednisona melhora a evolução clínica e eletrofisiológica de pacientes com a FNP de hanseníase, contribuindo na prevenção de novos comprometimentos neurológicos.

Contribuição ao diagnóstico e manejo dos estados reacionais: Uma abordagem prática / Contribution to diagnosis and management of reactional states: a practical approach

O reconhecimento clínico precoce dos episódios reacionais traz grandes benefícios para os pacientes com hanseníase, devido à possibilidade de intervenção terapêutica imediata e adequada, evitando o desenvolvimento de incapacidades que tanto estigmatizam e complicam a doença. Existem três formas de episódios reacionais: os tipos 1 e 2, e a neurite. Esta última pode aparecer isoladamente ou acompanhar as formas anteriores. Em alguns casos só são observadas as manifestações cutâneas e/ou neurológicas das reações, enquanto em outros, alterações sistêmicas podem acrescentar-se ao quadro. O tratamento utilizando a associação de medicamentos antiinflamatórios e imunossupressores parece ser o mais adequado para evitar as recorrências e os efeitos colaterais.

The early clinical recognition of reactional states brings great benefits to leprosy patients due to the possibility of appropriate and immediate therapeutic intervention, thus avoiding the development of disabilities that so much stigmatize and complicate the disease. There are three types of reactional episodes: types 1, 2 and neuritis. The latter may occur alone or together with the former forms. In some cases only neurological and/or skin manifestations are observed in the reactions; in others, patients present systemic alterations. The treatment with an association of immunosuppressors and anti-inflammatory drugs seems to be the most effective to avoid recurrences and side effects.

Importância do reconhecimento clínico da hanseníase / Importance of clinical recognition of hanseniase

Neste artigo é realizada uma discussão sobre a hanseníase, relevante doença infecciosa no mundo, com importância marcante nas áreas tropicais. Procurou-se enfatizar os aspectos clínicos e imunopatogênicos, como forma de se proporcionar um melhor panorama do estado atual do problema