Dramatic secukinumab-mediated improvements in refractory leprosy-related neuritis via the modulation of T helper 1 (Th1) and T helper 17 (Th17) immune pathways

Abstract A 39-year-old woman was diagnosed with relapsed multibacillary leprosy and refractory neuritis. Here, we describe an evident loss of therapeutic effectiveness after the third pulse of corticosteroids, which may be attributed to tachyphylaxis and the posterior modulation of interferon- γ (IFN-γ), tumor necrosis factor- α (TNF-α,) interleukin-17A (IL-17A), and IL-12/23p40 after the induction phase of secukinumab. In this case, plasma cytokine analysis showed that secukinumab induced a reduction in IL-17 concomitant with impressive clinical improvements in the patient's neural function. Interestingly, secukinumab induced reductions in cytokines related to Th1 responses and earlier stages of the Th17 response, including IL-23/12.

Surgical treatment of type I neuritis in a teenage boy with borderline tuberculoid leprosy

Exacerbation of the immune response against Mycobacterium leprae can lead to neuritis, which is commonly treated via immunosuppression with corticosteroids. Early neurolysis may be performed concurrently, especially in young patients with a risk of functional sequelae. We report the case of a young patient experienced intense pain in the left elbow one year after the treatment of tuberculoid-tuberculoid leprosy. The pain was associated with paresthesias in the ulnar edge and left ulnar claw. After evaluation, the diagnosis was changed to borderline tuberculoid leprosy accompanied with neuritis of the left ulnar nerve. Early neurolysis resulted in rapid reduction of the pain and recovery of motor function.

Neuropatía hanseniana en una adulta joven / Hansenian neuropathy in a young adult

Se presenta el caso de una paciente de 27 años de edad, sin previos antecedentes, que en el período de puerperio comenzó a presentar deterioro neurológico progresivo, dificultad para la marcha, graves trastornos sensitivos, del tipo de las parestesias y artralgias, pérdida de la sensibilidad propioceptiva, al tacto, al dolor, a la temperatura y en zonas dístales de miembros inferiores, además de manchas violáceas en tórax, abdomen y rodillas. En la muestra para biopsia se encontró un patrón inflamatorio compatible con lepra lepromatosa.

The case of a 27 year-old patient without previous history is reported, who in the puerperium began to present with progressive neurological deterioration, difficult walking, serious sensitive conditions such as paresthesia and arthralgia, loss of the proprioceptive sensibility to the tact, pain, temperature and in distal areas of inferior extremities besides violaceuos plaques in thorax, abdomen and knees. In the biopsy sample an inflammatory pattern consistent with lepromatous leprosy was found.

Fatores preditivos de incapacidades em pacientes com hanseníase / Factores predictivos de incapacidades en pacientes con hanseníasis / Predictive factors of disability in patients with leprosy

OBJETIVO:Analisar os fatores preditivos na evolução do grau de incapacidade em pacientes com hanseníase. MÉTODOS:Foram analisados dados de coorte retrospectiva, que acompanhou 595 pacientes com incapacidades, registrados em uma unidade de saúde de Belo Horizonte (MG), de 1993 a 2003. Informações sociodemográficas e clínicas dos pacientes foram coletadas dos respectivos prontuários. Comparou-se o grau de incapacidade na admissão e no final do tratamento por meio do teste de homogeneidade marginal. Para identificar os fatores associados à evolução do grau de incapacidade foram utilizadas as análises univariada (teste qui-quadrado de tendência linear) e multivariada pelo algoritmo Chi-square Automatic Interaction Detector. RESULTADOS:Dos casos com registro de grau de incapacidade na admissão e na alta, observou-se que 43,2 por cento que tinham grau 1 na primeira avaliação evoluíram para grau 0. Dos que apresentavam grau 2, 21,3 por cento passaram a ter grau 0 e 20 por cento passaram a grau 1. Na análise univariada as variáveis que se mostraram estatisticamente associadas à evolução no grau de incapacidade foram: neurite, tempo até a ocorrência de neurite, número de nervos acometidos, tipo de tratamento fisioterápico e maior dose de prednisona. Na análise multivariada, o principal fator que se associou à evolução do grau de incapacidade foi o grau de incapacidade na admissão. CONCLUSÕES:Os resultados mostraram a importância do diagnóstico precoce de neuropatia, assim como da eficiente associação das intervenções medicamentosas e não-medicamentosas por meio das técnicas de prevenção de incapacidade e dosagens adequadas de corticoterapia.

OBJECTIVE:To analyze predictive factors in the progression of the disability grade in patients with leprosy. METHODS: A retrospective cohort study followed up 595 patients with disability registered at a healthcare unit in the city of Belo Horizonte (Southeastern Brazil) from 1993 to 2003. Patients' sociodemographic and clinical information was collected from the respective medical records. Comparisons were made between the disability grade upon admission and at the end of treatment using a marginal homogeneity test. To determine factors associated with progression in the disability grade, univariate analysis (linear trend chi-square test) was employed, as well as multivariate analysis by means of the algorithm Chi-square Automatic Interaction Detector. RESULTS:Among the cases in which the disability grade was recorded upon admission and upon discharge, 43.2 percent of the patients who had grade 1 in the first assessment progressed to grade 0. Among those who began with grade 2, 21.3 percent progressed to grade 0 and 20 percent progressed to grade 1. In the univariate analysis, the variables that proved to be statistically associated with progression in the disability grade were: neuritis, time elapsed until the occurrence of neuritis, number of damaged nerves, type of physiotherapy treatment and higher dose of prednisone. In the multivariate analysis, the main factor associated with the progression of disability was the disability grade upon admission. CONCLUSIONS: The results showed the importance of an early diagnosis of neuropathy as well as the efficient association of pharmacological and non-pharmacological treatment, through disability prevention techniques and adequate doses of steroid.

OBJETIVO: Analizar los factores predictivos en la evolución del grado de incapacidad en pacientes con hanseníasis. MÉTODOS: Fueron analizados datos de cohorte retrospectiva, que acompañó 595 pacientes con incapacidades, registrados en una unidad de salud de Belo Horizonte (Sureste de Brasil), de 1993 a 2003. Informaciones sociodemográficas y clínicas de los pacientes fueron colectadas de los respectivos prontuarios. Se comparó el grado de incapacidad en la admisión y en el final del tratamiento por medio de la prueba de homogeneidad marginal. Para identificar los factores asociados a la evolución del grado de incapacidad fueron utilizados los análisis univariado (prueba chi-cuadrado de tendencia linear) y multivariado por el algoritmo Chi-square Automatic Interaction Detector. RESULTADOS: De los casos con registro de grado de incapacidad en la admisión y en el alta, se observó que 43,2 por ciento que tenían grado 1 en la primera evaluación evolucionaron para el grado 0. De los que presentaban grado 2, 21,3 por ciento pasaron a tener grado 0 y 20 por ciento pasaron a grado 1. En el análisis univariado las variables que se mostraron estadísticamente asociados a la evolución en el grado de incapacidad fueron: neuritis, tiempo hasta la ocurrencia de la neuritis, número de nervios afectados, tipo de tratamiento fisioterapéutico y mayor dosis de prednisona. En el análisis multivariado, el principal factor que se asoció a la evolución del grado de incapacidad fue el grado de incapacidad en la admisión. CONCLUSIONES: Los resultados mostraron la importancia del diagnóstico precoz de neuropatía, así como de la eficiente asociación de las intervenciones medicamentosas y no medicamentosas por medio de las técnicas de prevención de incapacidad y dosis adecuadas de corticoterapia.

Ocorrência de neurite em pacientes com hanseníase: análise de sobrevida e fatores preditivos / Occurrence of neuritis among leprosy patients: survival analysis and predictive factors

A neurite na hanseníase é responsável pelas deformidades e incapacidades. O objetivo desta coorte histórica foi investigar os fatores de risco associados ao tempo até a ocorrência da neurite. Foram acompanhados 595 pacientes, no período de 1993 a 2003. Empregou-se a técnica de tabela de vida e o método de Kaplan-Meier para a curva de sobrevida. Para testar diferenças entre os grupos quanto ao tempo até a ocorrência de neurite, foi usado o log-rank e para estimar as razões de risco, o modelo de regressão de Cox. Pouco mais da metade (54 por cento) da amostra teve neurite, sendo o principal intervalo de tempo de zero a 11,9 meses. O grau de incapacidade na admissão e o índice baciloscópico associaram-se fortemente à ocorrência de neurite, confirmando a necessidade do diagnóstico precoce da hanseníase, bem como do acompanhamento neurológico regular e intervenções adequadas.

Neuritis in leprosy cases is responsible for deformities and disability. The objective of this historical cohort study was to investigate the risk factors associated with the time taken for neuritis to occur. This study followed up 595 patients from 1993 to 2003. The life table technique and the Kaplan-Meier method for survival curves were used. The log-rank test was used to test differences between groups regarding the time take for neuritis to occur, and the Cox regression model was used to estimate the hazard ratios. Just over half (54 percent) of the sample had neuritis, which had mostly taken 0 to 11.9 months to appear. The degree of disability at admission and the bacillary index were strongly associated with the occurrence of neuritis, thus confirming the need for early diagnosis of leprosy, as well as regular neurological follow-up and appropriate interventions.

Quality of reporting and of methodology of studies on interventions for trophic ulcers in leprosy: a systematic review.

BACKGROUND: In the process of conducting a systematic review on interventions for skin lesions due to neuritis in leprosy, we assessed several primary papers with respect to the quality of reporting and methods used in the studies. Awareness of what constitutes weak points in previously conducted studies may be used to improve the planning, conducting and reporting of future clinical trials. AIMS: To assess the quality of reporting and of methodology in studies of interventions for skin lesions due to neuritis in leprosy. METHODS: Items of importance for preventing selection bias, detection bias, attrition bias and performance bias were among items assessed. The items for assessing methodological quality were used as a basis for making the checklist to assess the quality of reporting. RESULTS: Out of the 854 references that we inspected eight studies were included on the basis of the inclusion criteria. The interventions tested were dressings, topical agents and footwear and in all studies healing of ulcers was the main outcome measure. Reporting of both, methods and results suffered from underreporting and disorganization. The most under-reported items were concealment of allocation, blinding of patients and outcome assessors, intention to treat and validation of outcomes. CONCLUSION: There is an apparent need to improve the methodological quality as well as the quality of reporting of trials in leprosy ulcer treatment. The most important threat in existing studies is the threat of selection bias. For the reporting of future studies, journals could promote and encourage the use of the CONSORT statement checklist by expecting and requiring that authors adhere to it in their reporting.

Neurological manifestations of Behcet's disease

To determine the prevalence, clinical manifestations, and laboratory features of Neuro-Behcets disease. This prospective study was carried out in the Behcets Research Clinic in Shiraz [south-west Iran] and included the patients referred from 1990-1999. The patients' clinical records, images, CSF analyses, and electrodiagnostic studies were reviewed. Eighteen [15 males and 3 females] out of 690 Behcet s patients [2.6%, 95% CI = 1.4-3.8%] were found to have neurological involvement. The mean +/- standard deviation age of these patients was 34.7 +/- 8.6 years. All fulfilled the criteria of the International Study Group of Behcet s Disease. Central nervous system involvement was more common than peripheral nervous system manifestations. Headache, weakness, tingling, and numbness were the most common symptoms. Hyperreflexia, upward plantar reflex, and somatosensory findings were the most frequent signs. Hemispheral and brainstem stroke-like syndromes and cerebral venous thrombosis were the major neurologic presentations. There were also cases of myelitic, pure meningoencephalitic, amyotrophic lateral sclerosis-like, multiple sclerosis-like, and Guillain Barre syndromes. Neuro-Behcets disease must be considered in the differential diagnosis of stroke in young adults, chronic meningitis, intracranial hypertension, multiple sclerosis, myelopathies, and peripheral neuropathies

Diagnosis of acute flaccid paralysis: injection injury or polio?

In many countries, the treatment of choice for all fevers is one or more injections. These injections are associated with a risk of nerve damage. If cases of poliomyelitis are not to be missed, the diagnosis of injection trauma or traumatic neuritis (TN) must be exact. The guides for distinguishing between TN and polio are not clear. It is probable that some cases of polio are misdiagnosed as TN. As three-quarters of children with paralytic polio receive injections just before the onset of paralysis, their paralysis may be mistaken for TN. Clearer guidelines are proposed, together with suggestions for better documentation of muscles injected and paralysed. All cases of reported TN should be monitored and new diagnostic guidelines published. To protect their children, mothers must be educated to understand that injections for fever can cause harm. This must be an important part of the eradication programme for poliomyelitis.

The diagnosis of leprosy among patients with symptoms of peripheral neuropathy without cutaneous lesions: a follow-up study

Forty-four patients with neuritic leprosy were individually followed for periods ranging from 4 months to almost 4 years for the purpose of ascertaining the presence and/ or absence of leprosy. The neural symptoms presented were sensory impairment (41), parasthesia (28), nerve enlargement (22), nerve tenderness (20), paresia (20), amyotrophy (8). Leprosy was diagnosed in ten out of the total number of patients studied. Leprosy was confirmed by the appearance of reactional neuritis (4), reversal reaction (2), biopsy of the hypoesthesic area (3) and the appearance of non-reactional cutaneous lesion. We reported an experience in the diagnosis of neuritic leprosy and its most frequent clinical presentation with which clinicians have to be acquainted. We can also state that the clinical follow-up was an effective strategy for the diagnosis of the disease when diagnostic facilities are not available or have not confirmed the diagnosis

Consideraçöes sobre os distúrbio neurológicos da endocardite infecciosa: apresentaçäo e discussäo acerca de 10 pacientes / Considerations on neurologic disturbances in infectious endocarditis: presentation and discussion of ten patients

Säo apresentados os protocolos de 10 enfermos com endocardite infecciosa (e.i), alguns deles com confirmaçäo clínico-patológica que tornam claras e fidedignas as informaçöes clínicas da história e do exame físico, à luz das respectivas correlaçöes. Ficam demonstradas, nos 10 casos desta doença aqui apresentados, a gravidade da e.i. e a sua complexidade em muitas ocasiöes. As lesöes neurológicas säo achados frequentes nesta patologia (30 a 50 por cento), podendo abrir a cena clínica dos enfermos, aparecer na evoluçäo e/ou mesmo nos períodos de tratamento, de convalescença ou, ainda, tardiamente, meses ou anos após a cura clínica. Quando presentes, os distúrbios neurológicos, dependendo da fase de surgimento e da sua natureza podem complicar ou facilitar o diagnóstico da e.i., mas em todas as circunstâncias o prognóstico é sempre mais sério em sua presença, constituindo-se näo raramente na causa mortis. Qualquer queixa ou achado de alteraçäo neurológica na e.i. obriga-nos à ampla investigaçäo que, no mínimo, deve incluir a realidade de tomografias computadorizadas cerebrais e o estudo angiográfico cerebral completo, à procura de lesöes potencialmente fatais, como aneurisma/s micótico/s cerebral/ais e abscesso/s cerebral/ais, ou ainda na busca de lesöes outras, isoladas ou associadas, como nos pacientes apresentados no presente estudo

RM en neurosífilis: presentación atípica como neuritis trigeminal, comunicación de un caso / MR in neurosyphilis: trigeminal neuritis

Presentamos los hallazgos por RM de un caso de neuritis trigeminal bilateral como manifestación atípica de neurosífilis en un paciente varón, de 34 años, HIV + para demostrar la utilidad de la RM como método para la valoración postratamiento, arribando a las siguientes conclusiones: 1) la neuritis trigeminal constituye una presentación excepcional de la neurosífilis. No hemos encontrado reportes al respecto en la literatura imagenológica; 2) la RM con cortes de alta resolución y con gadolinio no sólo demuestran con claridad los cambios inflamatorios en los trigéminos sino que, además, podría detectar lesiones silentes o subclínicas (nuestro paciente mostraba realce bilateral y tenía manifestaciones clínicas sólo del lado derecho) y 3) la RM sin y con gadolinio es un método adecuado para valorar la respuesta al tratamiento en casos de neuritis trigeminal

Características antigénicas de los virus aislados del líquido cefalorraquídeo de pacientes con neuropatía epidémica / Antigenic characteristics of the viruses isolated from the cerebrospinal fluid of patients with epidemic neuropathy

Durante la epidemia de neuropatía ocurrida en Cuba en los años 1992/1994 se aislaron del líquido cefalorraquídeo de pacientes agentes virales relacionados antigénicamente con los virus Coxsackie. Para establecer una función de estos virus en la etiopatogenia de la enfermedad se seleccionaron las cepas 47/93 IPK identificada como Coxsackie A9 y la cepa 44/93 IPK de efecto citopático ligero (ECP-L) y se realizó un estudio de sus características antigénicas mediante Western Blot. Se comprobó la relación antigénica entre ambas cepas y se demostró la ausencia de proteínas estructurales en su forma nativa en los agentes de ECP-L. A partir de estos resultados se plantea la posibilidad de que la persistencia sea un mecanismo por el cual estos virus participen en la etiopatogenia de la neuropatía epidémica en Cuba

Etiología nutro-viral de la neuropatía epidémica / Nutritional and viral etiology of epidemic neuropathy

Se amplificaron secuencias virales del LCR empleando líquido cefalorraquídeo de pacientes con el empleo de oligonucleótidos homólogos con la región 5ïde los Enterovirus, los resultados arrojaron una gran variabilidad en las secuencias amplificadas, sugiriendo la presencia de cuasiespecies enterovirales con propiedades biológicas alteradas en los individuos estresados, que pueden desempeñar una función fundamental en el daño neurológico

Nuevas evidencias de la relación antigénica entre los virus de la neuropatía epidémica y el sistema nervioso humano. Estudio de la respuesta inmune celular en pacientes con neuropatía epidémica y controles. Revisión del tema / New evidences of the antigenic relationship existing between the viruses of epidemic neuropathy and the human nervous system. Study of the immune cellular response in patients with epidemic neuropathy and in controls. Review of the topic

Este estudio tiene por objetivo demostrar electrofisiológicamente la existencia de trastornos del sistema nervioso autonómico (SNA) y profundizar en la probable topografía de las lesiones. Se estudió la respuesta simpática cutánea (RSC) en 37 pacientes con neuropatía epidémica cubana (NEC) y en 29 sujetos sanos, en respuesta a estímulos eléctricos y con registro simultáneo en las 4 extremidades. Tanto las latencias como las amplitudes de las RSC registradas en miembros inferiores (MI) de los pacientes fueron significativamente diferentes a las de los controles (p<0,05). En los miembros superiores (MS) no se apreció esta diferencia entre ambos grupos. Estos resultados constituyen una evidencia objetiva y reproducible de la lesión del SNA en la NEC. La mayor intensidad de la afectación de las amplitudes de las RSC de MI, con relativa indemnidad de las de MS, sugiere un predominio de la lesión axonal en la rama eferente periférica hacia las extremidades inferiores, congruente con la mayor afectación de los nervios periféricos en esta localización

Neuropatía epidémica. Hipótesis etiopatogénica / Epidemic neuropathy. Etiopathogenic hypothesis

Durante la epidemia de neuropatía ocurrida en Cuba en los años 1992/1994 se aislaron del líquido cefalorraquídeo de pacientes agentes virales relacionados antigénicamente con los virus Coxsackie. Para establecer una función de estos virus en la etiopatogenia de la enfermedad se seleccionaron las cepas 47/93 IPK identificada como Coxsackie A9 y la cepa 44/93 IPK de efecto citopático ligero (ECP-L) y se realizó un estudio de sus características antigénicas mediante Western Blot. Se comprobó la relación antigénica entre ambas cepas y se demostró la ausencia de proteínas estructurales en su forma nativa en los agentes de ECP-L. A partir de estos resultados se plantea la posibilidad de que la persistencia sea un mecanismo por el cual estos virus participen en la etiopatogenia de la neuropatía epidémica en Cuba

Mecanismo de participación de los Enterovirus en la neuropatía epidémica. Hipótesis fisiopatológica / Mechanism of participation of the enterovirus in the epidemic neuropathy. Physiopathological hypotheses

Durante la neuropatía epidémica ocurrida en Cuba en los años 1992 y 1993, se obtuvieron del líquido cefalorraquídeo de pacientes aislamientos virales relacionados antigénicamente con los virus Coxsackie. Conjuntamente con las investigaciones virológicas se efectuaron otras de tipo epidemiológicas, toxicológicas, nutricionales, inmunológicas e histopatológicas. A pesar que la enfermedad estuvo unida a factores tóxicos-nutricionales, no ha sido posible identificar la causa de la epidemia. Teniendo en consideración los resultados obtenidos en las distintas investigaciones, hemos formulado una hipótesis integral, multifactorial, para explicar el mecanismo fisiopatológico de la participación de los virus aislados como mediadores de un proceso de autoinmunidad en la patogenia de la enfermedad

Accidente paralítico posvacunal (rabia) (APPV): informe de un caso / Neuroparalytic accident following immunization with antirabies vaccine: a report case

Introducción: los accidentes neuroparalíticos secundarios a la vacunación contra la rabia, se observan a menudo en los países en vías de desarrollo. Objetivo: presentar un caso poco común de polineuropatía debido a la administración de la vacuna antirrábica de cerebro de embrión de ratón (CER). Reporte del caso: una mujer de 48 años de edad fue mordida por un perro desconocido y recibió 14 dosis de vacuna antirrábica (CER). Trece días después desarrolló polineuropatía e insuficiencia ventilatoria. Se le asistió con ventilación mecánicas y pocas semanas después se le practicó una traqueostomía. El día 156 de estancia en la UCI falleció por mediastinitis (secundaria a fístula traqueo-esofágica). En octubre de 1995 la Secretaría de Salud de México anunció que se suspendío la producción de la vacuna antirrábica preparada con cerebro de embrión de ratón, y que la misma dejaría de utilizarse. Por lo tanto, éste podría ser el último caso de complicaciones neurológicas debido a este tipo de vacuna en México

Disabilities in multibacillary leprosy patients: before, during and after multidrug therapy.

One hundred fifty-one patients (125 males and 26 females) of multibacillary leprosy (LL 88, BL 40, BB 23), registered during 1986-1992 for multidrug therapy (MDT), were analysed with reference to their disabilities before, during and after MDT. At induction 48 (31.7%) had no disability (Gr 0), 59 (39.0%) had only peripheral anaesthesia (Gr 1) and 44 (29.1%) had Gr 2 and 3 deformities with or without anaesthesia. The parallel analysis of the three groups, with nearly equal duration of symptoms, revealed that new deformities developed in only a few cases during and after MDT, least in the Gr 0 group. The crude fresh deformity incidence was 59.2 per 1,000 person years of observation. The rate of recovery from anaesthesia was higher (64%) in Gr 1 group than that (44%) in group with Gr 2, 3 deformities. No significant difference was observed between the incidence of Gr 2 deformities developed before, during and after MDT (incidence of claw-hands 9.2% before and 7.9% during and after MDT, trophic ulcers 13.9% before and 17.8% during and after MDT). Out of 19 cases which developed motor weakness during MDT and follow-up, 10 (52.6%) were instances of quite nerve paralysis. Occupational factors influenced the development of deformities but not the sex and bacterial load. Generally, the lower the Grade of disability at induction of patient for MDT, the lower the chances of new disability development and higher the chances of recovery from sensory impairments.

Nerve in reversal reaction.

1. Much of the nerve destruction in leprosy takes place during the reactive phase, both during ENL reaction and RR. 2. The high risk patients expected to develop RR are borderline patients with generalized lesions (more than 10 skin lesions) and those presenting with three or more thickened nerve trunks. 3. In RR there is a sudden enhancement of already existing DTH to M. leprae and its antigens resulting in the release of excessive quantities of TNF alpha, INF gamma, and IL-2. The triggering mechanisms of this phenomenon is poorly understood. 4. The already existing granulomas suddenly increase considerably in size due to oedema and rapid influx of lymphocytes, Langhan's and foreign body giant cells. Fragments of M. leprae are also present in the granuloma of some patients. 5. In RR, the acute granulomatous inflammation can produce destruction of nerves even to the extent of causing caseous necrosis of the nerve tissue and irreversible paralysis. The swelling of the nerves due to sudden increase in inflammatory cells and oedema within an unyielding perineurium produce ischaemia and transient paralysis. 6. With prompt administration of anti-inflammatory drugs, paralysis recovers quickly, if it is of ischaemic origin; but will not recover if the Schwann cells and other nerve tissues are destroyed as a result of the immune granuloma. 7. A course of corticosteroids for six months along with anti-leprosy therapy is suggested in high risk patients as a preventive measure. 8. Further the serious problem of continuing nerve damage after clinical cure should be urgently tackled.