Aplicación de un método in house para el estudio de la esclerosis múltiple / Application of an in-house method for the study of multiple sclerosis

Resumen El método de referencia para el estudio bioquímico de la esclerosis múltiple (EM) es el isoelectroenfoque (IEE) y la evaluación de las cadenas livianas libres (CLL) podría brindar una información adicional de relevancia. Por lo tanto, se propone evaluar la presencia de las CLL y la aplicabilidad de los estados de polimerización en el estudio de la EM. Se puso a punto un método compuesto por una separación electroforética en gel de poliacrilamida al 12,5% con posterior electrotransferencia (PAGE-WB) y se realizó la evaluación de 121 pacientes con sospecha de EM en simultáneo al IEE. Los patrones de PAGE-WB relacionados con la EM fueron el aumento de la concentración de monómeros Kappa o dímeros Lambda en líquido cefalorraquídeo (LCR) en comparación con el suero. Este método tuvo una muy alta significación de asociación con el IEE (p<0,0001) con sensibilidad del 95%, especificidad del 90%, VPP 83% y VPN 97%. La síntesis intratecal de CLL quedó evidenciada por el aumento de intensidad del monómero Kappa y/o el dímero Lambda observado en LCR. La técnica de PAGE-WB para CLL demostró ser un método alternativo para detectar la síntesis intratecal en pacientes con sospecha de EM.

Abstract The reference method for the biochemical study of multiple sclerosis (MS) is isoelectric focusing (IEF) and the evaluation of free light chains (FLC) could provide additional information of relevance. Therefore, it is proposed here to evaluate the presence of FLC and the applicability of the polymerisation states in the study of MS. A method consisting of a 12.5% polyacrylamide gel electrophoretic separation with a subsequent electrotransfer (PAGE-WB) was developed and the evaluation of 121 patients with suspected MS was carried out simultaneously with the IEF. MS-related PAGE-WB patterns were the increase in the concentration of Kappa monomers or Lambda dimers in CSF compared to serum. This method had a very high significance of association with the IEF (p<0.0001) with 95% sensitivity, 90% specificity, 83% PPV and 97% NPV. Intrathecal synthesis of FLC was evidenced by the increased intensity of the Kappa monomers and/or Lambda dimers observed in CSF. The PAGE-WB technique for FLC proved to be an alternative method to detect intrathecal synthesis in patients with suspected MS.

Resumo O método de referência para o estudo bioquímico da esclerose múltipla (EM) é a focalização isoelétrica (IEE) e a avaliação de cadeias leves livres (CLL) poderiam fornecer informações adicionais de relevância. Assim, propõe-se avaliar a presença das CLL e a aplicabilidade dos estados de polimerização no estudo de EM. Foi desenvolvido um método que consiste na separação eletroforética em gel de poliacrilamida a 12,5% com posterior eletrotranferência (PAGE-WB) e a avaliação de 121 pacientes com suspeita de EM foi realizada paralelamente à IEE. Os padrões de PAGE-WB relacionados com a EM foram o aumento na concentração de monômeros Kappa ou dímeros Lambda em líquido cefalorraquidiano (LCR) em comparação com o soro. Este método teve uma associação de significância muito alta com o IEE (p<0,0001) com sensibilidade de 95%, especificidade de 90%, VPP 83% e VPN 97%. A síntese intratecal de CLL foi evidenciada pelo aumento de intensidade do monômero Kappa e/ou dímero Lambda observado em LCR. A técnica PAGE-WB para CLL mostrou-se um método alternativo para detectar a síntese intratecal em pacientes com suspeita de EM.

Quantitative and qualitative evaluation of IgG synthesis in 8,947 cerebrospinal fluid samples / Avaliação quantitativa e qualitativa da síntese de IgG em 8.947 amostras de líquido cefalorraquidiano

ABSTRACT Introduction: Increased intrathecal immunoglobulin class G (IgG) synthesis can be found in several neuroinflammatory diseases. Objective: The aim of this study was to analyze quantitative and qualitative methods of intrathecal immunoproduction evaluation. Methods: We retrospectively assessed data from cerebrospinal fluid (CSF) and serum samples sent to Senne Liquor Diagnóstico from 2001 to 2017. Cytological, biochemical, and immunological data were compared between cases with and without oligoclonal bands (OCBs). Comparisons between samples with OCBs (OCB+) and without them (OCB-) were carried out, and the ability to predict the presence of OCBs was assessed with ROC analysis. Results: We included 8,947 samples (2,599 OCB+ samples and 6,348 OCB- samples). CSF lymphocytes and monocytes were significantly associated with the presence of OCB (p < 0.001). All the inflammatory parameters were significantly associated with OCB, and the methods with the highest predictive ability for OCB were IgG index and Reiber diagram [area under the receiver operating characteristic (AUROC) curve = 0.881 and 0.863, respectively]. A small percentage of cases without OCB had high IgG index (9.56%) or Reiber diagram, showing increased IgG production (4.6%). Conclusion: We showed a strong association between OCB and other CSF inflammatory parameters. The presence of cases with increased quantitative CSF IgG synthesis without OCB suggests that both quantitative and qualitative methods should be performed in the evaluation of neuroinflammatory processes.

RESUMEN Introducción: El incremento de la síntesis intratecal de inmunoglobulina G (IgG) puede ser encontrado en diferentes enfermedades neuroinflamatorias. Objetivo: Analizar retrospectivamente diferentes métodos de evaluación de la producción intratecal. Métodos: Se examinaron datos del líquido cefalorraquídeo (LCR) y suero enviados para el Senne Liquor Diagnóstico entre 2001 y 2017. Se compararon datos de citología, bioquímica e inmunología entre muestras con y sin bandas oligoclonales (BOC). Se hicieron comparaciones de los parámetros del LCR entre muestras con (BOC+) y sin BOC (BOC-), y la habilidad para predecir la presencia de BOCs fue evaluada mediante curvas ROC. Resultados: Se incluyeron 8.947 muestras, con 2.599 BOC+ y 6.348 BOC-. Recuentos de linfocitos y monocitos fueron significativamente asociados a la presencia de BOC (p < 0,001). Todos los métodos de evaluación de IgG fueron significativamente asociados a BOC+; aquellos con mayor asociación fueron el índice de IgG y el Reiber (área bajo la curva ROC = 0,881 y 0,863), respectivamente. Entre los casos BOC-, el índice de IgG fue alto en 9,56% y el Reiber demostró incremento de producción en 4,6%. Conclusión: Hubo fuerte asociación entre BOC y otros parámetros neuroinflamatorios del LCR. La existencia de casos BOC- con incremento de producción de IgG mediante métodos cuantitativos sugiere que tanto métodos cualitativos como cuantitativos deben ser usados en la evaluación de procesos neuroinflamatorios.

RESUMO Introdução: O aumento da síntese intratecal de imunoglobulina da classe G (IgG) pode ser encontrado em diferentes doenças neuroinflamatórias. Objetivo: Avaliar retrospectivamente diferentes métodos de avaliação da imunoprodução intratecal. Métodos: Dados de líquido cefalorraquidiano (LCR) e soro enviados para o Senne Liquor Diagnóstico entre 2001 e 2017 foram avaliados. Dados de citologia, bioquímica e imunologia foram comparados entre amostras com e sem bandas oligoclonais (BOCs). Comparações dos parâmetros do LCR entre amostras com (BOC+) e sem BOCs (BOC-) foram realizadas, e a habilidade de predizer a presença de BOCs foi avaliada por meio de curvas ROC. Resultados: Foram incluídas 8.947 amostras, sendo 2.599 BOC+ e 6.348 BOC-. Contagens de linfócitos e monócitos foram significativamente associadas à presença de BOC (p < 0,001). Todos os métodos de avaliação da IgG foram significativamente associados a BOC+; os com maior associação foram o índice de IgG e o Reiber [área sob a curva receiver operating characteristic (AUROC) = 0,881 e 0,863, respectivamente]. Entre os casos BOC-, o índice de IgG foi elevado em 9,56%, e o Reiber mostrou aumento de produção de IgG em 4,6%. Conclusão: Houve forte associação entre BOC e outros parâmetros neuroinflamatórios do LCR. A existência de casos BOC- com aumento da produção de IgG por métodos quantitativos sugere que tanto métodos qualitativos quanto quantitativos devem ser utilizados na avaliação dos processos neuroinflamatórios.

Síndrome clínico aislado: abordaje del primer evento desmielinizante / Clinically isolated syndrome: approach to the first demyelinating event

RESUMEN El síndrome Clínico Aislado (SCA) denota al primer síntoma neurológico sugestivo de esclerosis múltiple (EM), de por lo menos 24 horas de duración; en ausencia de fiebre, procesos infecciosos y encefalopatía. Se caracteriza por su presentación frecuente en adultos jóvenes y afecta al nervio óptico, hemisferios cerebrales, tronco encefálico o médula espinal. La estratificación temprana del SCA es indispensable ya que con herramientas predictoras clínicas, radiológicas y biológicas, se puede establecer el riesgo de conversión a EM. El uso de terapias modificadoras de la enfermedad (TME) en el primer evento desmielinizante, ha demostrado retrasar la conversión de SCA a esclerosis múltiple en un 44 a 50 %. Sin embargo, no todos los pacientes con SCA evolucionarán a EM, por lo que el estudio de diversos marcadores prónosticos permitirá reconocer el escenario ideal donde los pacientes se beneficien del inicio temprano de TME.

SUMMARY Clinically Isolated Syndrome (CIS), denotes the first neurological symptom suggestive of Multiple Sclerosis (MS), at least 24 hours in duration; In the absence of fever, infectious processes and encephalopathy. It is characterized by its frequent presentation in young adults and affects the optic nerve, brainstem or spinal cord. The early stratification of CIS is essential because with clinical, radiological and biological predictors, the risk of conversion to MS can be established. The use of Disease Modifying Therapies (DMT) in CIS has been shown to delay the conversion of CIS to Multiple Sclerosis by 44 to 50 %%. However, not all patients with CIS will evolve to MS, so the study of several prognostic markers will allow to recognize the ideal scenario where patients benefit from the early onset of DMT.

Factores pronósticos de la Esclerosis Múltiple / Prognostic factors in Multiple Sclerosis

Resumen La Esclerosis Múltiple es una enfermedad inflamatoria y degenerativa del Sistema Nervioso Central que afecta a la población adulta joven. La prevalencia de esta entidad es heterogénea en el mundo y baja en el Ecuador. El diagnóstico se basa en los criterios de McDonald 2017. Una vez que el diagnóstico se ha establecido, es necesario determinar si los pacientes tienen factores de mal pronóstico los cuales van a generar un impacto en el tipo de tratamiento a elegir. Al momento, se han estudiado factores pronósticos epidemiológicos, clínicos, biomoleculares y de imagen los cuales nos permiten predecir si la enfermedad tiene un comportamiento agresivo o por el contrario un curso benigno. El número de lesiones en las imágenes de resonancia magnética cerebral, la presencia de lesiones en tronco encefálico y médula espinal son los factores que han demostrado tener un impacto en la progresión de discapacidad. La presencia de bandas oligoclonales en el líquido cefalorraquídeo tiene un rol fundamental en la conversión de un síndrome clínico aislado en esclerosis múltiple clínicamente establecida. Los niveles bajos de vitamina D ha demostrado estar asociado con mal pronóstico pero su aplicabilidad en países como el Ecuador es aún tema de investigación.

Abstract Multiple sclerosis is an inflammatory and degenerative disease of the central nervous system which affects young adults. The prevalence of multiple sclerosis in the world is heterogeneous and is low in Ecuador. The diagnosis is based on the McDonald 2017 criteria. Once the diagnosis has been made, it is necessary that any negative factors which will impact the type of treatment used be identified. At this time, factors such as epidemiological, clinical, biomolecular, and magnetic resonance images, which will allow us to identify if the case is aggressive or benign, are studied. The number of lesions shown in a brain MRI, the presence of lesions in the brain stem and spinal cord are factors which have been demonstrated to have an impact on the progression of disability. The presence of oligoclonal bands in the cerebrospinal fluid has a fundamental role in the conversion of an isolated clinical syndrome to multiple sclerosis. Low levels of vitamin D have been associated with a negative prognosis, however how important vitamin D is in the prognosis of MS in countries such as Ecuador is still an area to be studied.

Clinical Application of 2017 McDonald Diagnostic Criteria for Multiple Sclerosis

BACKGROUND AND PURPOSE: McDonald criteria for multiple sclerosis diagnosis have been revised over the years, diagnostic procedures have been simplified and earlier diagnosis facilitated. The new 2017 revision introduces other important changes, with a further simplification for the diagnosis. Oligoclonal bands reassume a more relevant role in the workup. METHODS: We describe 3 typical cases of patients admitted for clinically isolated syndrome and illustrate how the application of the new criteria can change the diagnostic approach with respect to the previous criteria. RESULTS: In two of the three cases a diagnosis of multiple sclerosis is now possible. CONCLUSIONS: The new 2017 Multiple Sclerosis criteria may have an important impact in clinical practice with an earlier treatment to avoid the risk of disease dissemination. Their application requires a careful assessment to avoid misdiagnosis and mistreatments.

For survival, the emergence of oligoclonal bands after multiple myeloma treatment is less important than achieving complete remission

Abstract Background: The emergence of oligoclonal bands, proteins differing from those originally identified at diagnosis, has been reported in multiple myeloma patients after high-dose chemotherapy followed by autologous stem cell transplantation and after successful conventional chemotherapy. The clinical relevance of oligoclonal bands remains unclear, but their emergence has been associated with better prognosis. The aim of the present study was to determine the prevalence, clinical characteristics and prognostic impact of the presence of oligoclonal bands in multiple myeloma patients. Methods: A retrospective cohort study was conducted. The study included newly diagnosed multiple myeloma patients with at least very good partial response after conventional dose or high-dose chemotherapy followed by autologous stem cell transplantation. The emergence of oligoclonal bands was identified using serum protein electrophoresis as well as serum and urine immunofixation techniques. Results: A total of 101 patients were included with a median follow-up of 42 months. In total, 55% were male, and the median age was 58 years (29-87 years). Fifty-one (50.5%) patients developed oligoclonal bands. They comprised 60% (45/75) of patients treated with autologous stem cell transplantation and 23% (6/26) of those who were not transplanted. Patients with oligoclonal bands showed better progression-free survival than those without the emergence of oligoclonal bands (p-value = 0.0075). Conclusion: The prevalence of oligoclonal bands in this study population was 50.5% with its frequency being greater in cases treated with autologous stem cell transplantation and in those attaining complete remission. Complete remission was more important than the emergence of oligoclonal bands on progression-free survival.

Clinical Profiles and Short-Term Outcomes of Acute Disseminated Encephalomyelitis in Adult Chinese Patients

BACKGROUND AND PURPOSE: Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder that predominantly affects children. Previous studies have mostly involved children in Western developed countries. METHODS: This study retrospectively reviewed the clinical profiles of ADEM in adult Chinese patients. RESULTS: ADEM occurred during summer and autumn in about two-thirds of the 42 included patients. Prior infection was found in five patients and no preimmunization was recorded. The most frequent clinical presentations were alterations in consciousness (79%) and behavior changes (69%), followed by motor deficits (64%) and fever (50%). About one-quarter (26%) of the patients showed positive results for oligoclonal bands, and about half of them exhibited increases in the IgG index and 24-hour IgG synthesis rate. Magnetic resonance imaging showed white- and gray-matter lesions in 83% and 23% of the patients, respectively. Steroids were the main treatment, and full recovery occurred in 62% of the patients, with residual focal neurological deficits recorded in a few patients. After a mean follow-up period of 3.4 years, two patients exhibited recurrence and one patient exhibited a multiphasic course. One patient was diagnosed with multiple sclerosis (MS). CONCLUSIONS: With the exception of the seasonal distribution pattern and prior vaccine rate, the clinical profiles of ADEM in adult Chinese patients are similar to those in pediatric populations. No specific markers are available for distinguishing ADEM from MS at the initial presentation. Careful clinical evaluations, cerebrospinal fluid measurements, and neuroradiological examinations with long-term follow-up will aid the correct diagnosis of ADEM.

Clinical Profiles and Short-Term Outcomes of Acute Disseminated Encephalomyelitis in Adult Chinese Patients

BACKGROUND AND PURPOSE: Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder that predominantly affects children. Previous studies have mostly involved children in Western developed countries. METHODS: This study retrospectively reviewed the clinical profiles of ADEM in adult Chinese patients. RESULTS: ADEM occurred during summer and autumn in about two-thirds of the 42 included patients. Prior infection was found in five patients and no preimmunization was recorded. The most frequent clinical presentations were alterations in consciousness (79%) and behavior changes (69%), followed by motor deficits (64%) and fever (50%). About one-quarter (26%) of the patients showed positive results for oligoclonal bands, and about half of them exhibited increases in the IgG index and 24-hour IgG synthesis rate. Magnetic resonance imaging showed white- and gray-matter lesions in 83% and 23% of the patients, respectively. Steroids were the main treatment, and full recovery occurred in 62% of the patients, with residual focal neurological deficits recorded in a few patients. After a mean follow-up period of 3.4 years, two patients exhibited recurrence and one patient exhibited a multiphasic course. One patient was diagnosed with multiple sclerosis (MS). CONCLUSIONS: With the exception of the seasonal distribution pattern and prior vaccine rate, the clinical profiles of ADEM in adult Chinese patients are similar to those in pediatric populations. No specific markers are available for distinguishing ADEM from MS at the initial presentation. Careful clinical evaluations, cerebrospinal fluid measurements, and neuroradiological examinations with long-term follow-up will aid the correct diagnosis of ADEM.

Estudio de las subpoblaciones linfocitarias y secreción intratecal en pacientes con esclerosis múltiple defnida / Study of lymphocyte subpopulations and intrathecal secretion in patients with defnite multiple sclerosis / Estudo das subpopulações de linfócitos e secreção intratecal em pacientes com esclerose múltipla defnida

La esclerosis múltiple (EM) es una enfermedad infamatoria desmielinizante y autoinmune del sistema nervioso central que afecta al cerebro y a la médula espinal. El objetivo del estudio fue la cuantificación de subpoblaciones linfocitarias en líquido cefalorraquídeo y sangre de pacientes diagnosticados de esclerosis múltiple y en pacientes con enfermedades no degenerativas (controles), para encontrar variables o relaciones entre las mismas que permitan diferenciar el estado inmunológico de los pacientes de cada grupo. Este trabajo se ha llevado a cabo conjuntamente con el Hospital Universitario Virgen Macarena de Sevilla entre los años 2008 y 2010. Es un estudio de tipo descriptivo, transversal y de cohortes. La población seleccionada (n=142) estuvo compuesta por sujetos a los que se les realizó una punción lumbar y una citometría de fujo, tanto de LCR como de sangre. El Grupo 1 (n=70) fue el grupo control, Grupo 2: (n=53): pacientes con esclerosis múltiple remitente recidivante (EMRR), Grupo 3: (n=5), pacientes con esclerosis múltiple de tipo primaria progresiva y Grupo 4 (n=14), pacientes que presentaban un síndrome neurológico aislado. Los resultados mostraron un aumento de células B en LCR en pacientes con EM que sugirieron un aumento de la actividad infamatoria focal en el SNC. En cuanto a NKCD8- se observó una disminución de los niveles totales de NK, así como de los NKCD8 con respecto a los controles y un mayor valor del índice de IgG en los pacientes con EMRR.

Multiple sclerosis is an infammatory demyelinating autoimmune disease that affects the brain and spinal cord. The aim of the study was to quantify lym-phocyte subpopulations in cerebrospinal fuid and blood of patients diagnosed with multiple sclerosis and in patients whit degenerative diseases not (control) in order to fnd some relationships between them that make it possible to differentiate the immune status of patients in each group. This work was jointly carried out with Hospital Universitario Virgen Macarena in Seville during 2008, 2009 and 2010. It is a descriptive, transversal and cohort study. The selected population is composed of 142 subjects who were subjected to lumbar puncture and a blood sample. Group 1 (n=70), control, Group 2 (n=53), patients with relapsing remitting multiple sclerosis, Group 3 (n=5), patients with primary type progressive multiple sclerosis, and Group 4 (n=14) patients with isolated neurological syndrome. The results show an increase in CSF B cells in MS patients suggesting an increase in focal infammatory activity in the CNS. Regarding NKCD8, reduced total levels of NK and NKCD8 regard-ing controls were observed, and it showed an increased IgG index value in patients with RRMS.

A esclerose múltipla é uma doença infamatória desmielinizante autoimune do sistema nervoso central que afeta o cérebro e a medula espinhal. O objetivo do estudo foi quantificar subpopulações linfocitarias em líquido cefalorraquidiano e sangue de pacientes com diagnóstico de esclerose múltipla e em pacientes com doenças não degenerativas (controles) para encontrar variáveis ou relações entre as mesmas que permitam diferenciar o estado imunológico dos pacientes cada grupo. Este trabalho foi realizado em conjunto com o Hospital Uni-versitário Virgen Macarena de Sevilha, entre os anos 2008 e 2010. É um estudo de tipo descritivo, tranversal e de coortes. A população selecionada é (n=142) foi constituída por indivíduos submetidos a punção lombar e citometria de fuxo tanto de LCR como de sangue. O Grupo 1 (n=70), foi o grupo controle, o Grupo 2 (n=53): pacientes com esclerose múltipla recidivante-remitente (EMRR), o Grupo 3 (n=5), pacientes com esclerose múltipla de tipo primária progressiva e o Grupo 4 (n=14) pacientes com síndrome neurológica isolada. Os resultados mostraram um aumento de células B no LCR em pacientes com EM, sugerindo um aumento da atividade infamatória focal no SNC. Quanto a NKCD8, observou-se uma diminuição dos níveis totais de NK bem como dos NKCD8 com relação a controles e maior valor do índice de IgG nos pacientes com EMRR.

Controversias en Neurología: Esclerosis Múltiple / Controversies in Neurology: Multiple Sclerosis

La esclerosis múltiple es la condición desmielinizante que afecta con mayor frecuencia el sistema nervioso central (SNC). Se considera una enfermedad de alto costo y una de las principales causas de discapacidad neurológica en adultos jóvenes. A pesar de los avances logrados en su diagnóstico y tratamiento, algunos aspectos continúan siendo controversiales. En este manuscrito se discuten 15 puntos polémicos, reconocidos en la práctica clínica diaria y la investigación de sujetos con EM. Para analizar el contexto de cada controversia con la mejor evidencia disponible, se realizó una revisión sistemática de la literatura disponible en MEDLINE, Embase, Cochrane y LILACS. Los temas incluyen la interrupción del tratamiento inmunomodulador, la utilidad de las bandas oligoclonales, el cambio a fármacos de segunda línea, las indicaciones de seguimiento con resonancia magnética, la plasmaféresis, el síndrome radiológico aislado, el manejo ambulatorio de las recaídas, la duración óptima de los ciclos de corticoides intravenosos, el beneficios de la tomografía de coherencia óptica, la deficiencia de vitamina D, el manejo de la EM secundariamente progresiva, los nuevos medicamentos orales y la seguridad del uso de interferón durante el embarazo. En el marco de cada controversia, se plantean recomendaciones específicas y conclusiones que pueden ser de utilidad para futuras investigaciones.

Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system, and contributes greatly to health care costs and disability in young adults. Despite advances in diagnostic techniques and treatment, several important issues remain controversial. We addressed fifteen specific controversies that arise at the bedside and affect clinical practice, education and research in MS. We reviewed these issues followed by some opinions as to how use the best available evidence in a way that support clinical decisions. Topics discussed include utility of oligoclonal IgG bands in the diagnosis and prognosis of multiple sclerosis, cost-effectiveness of disease-modifying therapies, change from first- to second-line treatment, indications for follow-up MR imaging, plasma exchange, radiologically isolated syndrome, discontinuation of immunomodulatory therapies, home administration of intravenous methylprednisolone, duration of corticosteroids treatment, role of optical coherence tomography, vitamin D deficiency and supplementation, management of secondary progressive multiple sclerosis, emerging therapies and interferon during pregnancy. A systematic review of the literature was conducted using MEDLINE, Embase, Cochrane and the Literatura Latino-Americana y del Caribe en Ciencias de la Salud (LILACS) databases. Answers to the targeted questions were formulated and specific recommendations were made with the hope to stimulate future research.

Análisis de anticuerpos antifosfolipídicos y cistatina C en pacientes con esclerosis múltiple / Analysis of antiphospholipid antibodies and cystatin C in multiple sclerosis patients / Teste de anticorpos antifosfolípídes e cistatina C em pacientes com esclerose múltipla

La cistatina C es considerada el inhibidor fisiológico más importante de las proteasas de cisteína endógenas. Se cree que el papel de la cistatina C es el de modular la actividad de las proteasas secretadas o liberadas de células dañadas o en proceso de necrosis, siendo por tanto las cistatinas fundamentales para los procesos de regulación y prevención del potencial daño proteolítico local. Los anticuerpos antifosfolípidos se usan para esclarecer el diagnóstico de esclerosis múltiple (EM) ya que existen patologías que pueden cursar con sintomatología o hallazgos paraclínicos semejantes. El objetivo de este trabajo fue analizar la concentración de cistatina C y la presencia o ausencia de anticuerpos antifosfolipídicos en pacientes diagnosticados de esclerosis múltiple remitente recurrente (EMRR) como marcadores de desmielinización. Este trabajo se llevó a cabo conjuntamente por el laboratorio de Riesgo Vascular, el laboratorio de Autoinmunidad y la Unidad de Esclerosis Múltiple del Hospital Universitario Virgen Macarena de Sevilla, España, con una duración de un año. Se seleccionaron dos tipos de poblaciones: grupo 1, n=30 pacientes con EMRR y un segundo grupo, denominado grupo control, n=30. Se determinó cistatina C y anticuerpos antifosfolípidos IgG e IgM, anticuerpos anticardiolipina IgG e IgM y anticuerpos f>2 glicoproteína IgG e IgM. Los pacientes diagnosticados de EMRR presentan títulos negativos de anticuerpos antifosfolípidos IgG e IgM, anticardiolipina IgG e IgM y f>2 glicoproteína IgG e IgM. La concentración de cistatina C es menor en el grupo de pacientes diagnosticados de EM, lo que podría producir un déficit en la modulación de las proteasas de cisteína endógenas. Dicha desmielini-zación agudizaría el progreso de la EM.

Cystatin C is considered the most important physiological inhibitor of endogenous cysteine proteases; the role of cystatin C is believed to be to modulate the activity of proteases secreted or released from damaged cells or in the process of necrosis, therefore cystatins being fundamental regulatory processes and a potential prevention of local proteolytic damage. Antiphospholipid antibodies are used to clarify the diagnosis of diseases like multiple sclerosis (MS) and other pathologies could present similai symptoms or paraclinical findings. The objective of the present work is to analyze the concentration of cystatin C and the presence or absence of antiphospholipid antibodies in patients diagnosed with relapsing remitting multiple sclerosis (RRMS) as markers of demyelization. This work was carried out jointly by the Vascular Risk Laboratory, the Laboratory of Autoimmunity and Multiple Sclerosis Unit, Hospital Universitario Virgen Macarena in Seville in one year. Two types of people were selected: Group 1 (n = 30) RRMS group and a control group, n = 30. Cystatin C and antiphospholipid antibodies IgG and IgM, IgG and IgM anticardiolipin, $2 glycoprotein IgG and IgM were determined. Patients showed negative titers of antiphospholipid antibodies IgG and IgM, IgG and IgM anticardiolipin, $2 glycoprotein IgG and IgM. Cystatin C concentration is lower in the group of patients diagnosed with MS, which could give rise to a decrease in the modulation of endogenous cysteine proteases. This would exacerbate the progress of demyelization in MS.

A cistatina C é considerada o inibidor fisiológico das proteases de cisteína endógenas mais importante. Acredita-se que o papel da cistatina C é o de modular a atividade de proteases secretadas ou liberadas a partir de células danificadas ou em processo de necrose, sendo por isso as cistatinas fundamentais para os processos de regulagao e prevengao do potencial dano proteolítico local. Anticorpos antifosfolípides sao usados para esclarecer o diagnóstico de EM, visto que existem patologias que podem apresentar sintomas ou achados paraclínicos semelhantes. O objetivo deste trabalho foi o de analisar a concentra-gao de cistatina C e a presenga ou ausencia de anticorpos antifosfolípides em pacientes diagnosticados com esclerose múltipla recidivante - remitente (EMRR) como marcadores de desmielinizagao. Este trabalho foi realizado em conjunto pelo laboratório de Risco Vascular, o laboratório de Autoimunidade e a Unidade de Esclerose Múltipla do Hospital Universitario Virgen Macarena, de Sevilha, Espanha, com uma duragao de um ano. Foram selecionados dois tipos de populagdes-. Grupo 1 (n = 30) pacientes com EMRR e um segundo grupo, chamado de grupo controle, n = 30. Determinou-se cistatina C e anticorpos antifosfolípides IgG e IgM, anticorpos anticardiolipina IgG e IgM, e anticorpos $2 glicoproteína IgG e IgM. Pacientes diagnosticados com EMRR apresentam títulos negativos de anticorpos antifosfolípides IgG e IgM, anticardiolipina IgG e IgM e $2 glicoproteína IgG e IgM. A concentragao de cistatina C é menor no grupo de pacientes diagnosticados com EM, o que poderia produzir um déficit na modulagao das proteases de cisteína endógenas. Tal desmielinizagao agravaría o progresso da EM.

Antiparasitic antibodies occur with similar frequency in patients with clinically established multiple sclerosis with or without oligoclonal bands in the cerebrospinal fluid / Anticorpos antiparasitarios ocorrem com frequencia semelhante em pacientes com esclerose multipla quando ha e quando nao ha bandas oligoclonais no liquido cefalorraquidiano

The "hygiene hypothesis" postulates an inverse relationship between the prevalence of parasitic infections and the frequency of multiple sclerosis (MS). Objective: It was to study whether antibodies against parasites could be demonstrated more frequently in blood serum from MS patients with oligoclonal bands (OCB) than from MS patients without OCB. Methods: We studied serum samples from 164 patients who had previously been analyzed to investigate OCB. Parasitic antibodies were studied through unidimensional electrophoresis of proteins on polyacrylamide gel against Taenia antigens, searching for antiparasitic specific low molecular weight antibodies and also for antiparasitic nonspecific high molecular weight antibodies. Results: Two of the 103 patients with no evidence of OCB had antibodies of low molecular weight and 59 of them had antibodies of high molecular weight. Of the 61 patients with evidence of OCB, one showed antibodies of low molecular weight and 16 showed antibodies of high molecular weight. Conclusion: Antiparasitic antibodies are detected with similar frequency in MS patients with OCB and in MS patients without OCB.

A "hipótese da higiene" postula haver relação inversamente proporcional entre a prevalência de infecções por parasitas e a frequência da esclerose múltipla (EM). Objetivo: Foi verificar se em pacientes com EM aparecem anticorpos antiparasitários mais frequentemente no grupo com bandas oligoclonais (BOC) do que no grupo sem BOC. Métodos: Foram estudadas amostras de sangue de 164 pacientes previamente analisadas para investigar BOC. Foi feita eletroforese unidimensional de proteínas em gel de poliacrilamida contra antígenos de Taenia para pesquisa de anticorpos específicos de baixo peso molecular e também de anticorpos inespecíficos de alto peso molecular. Resultados: Dois dos 103 pacientes em que não havia BOC apresentaram anticorpos de baixo peso molecular, e 59 apresentaram anticorpos de alto peso molecular. Dos 61 pacientes em que não havia BOC, um apresentou anticorpos de baixo peso molecular e 16, anticorpos de alto peso molecular. Conclusão: Anticorpos antiparasitários foram detectados com frequência semelhante em doentes com EM independentemente da presença ou não de BOC.

Oligoclonal bands in the cerebrospinal fluid and increased brain atrophy in early stages of relapsing-remitting multiple sclerosis / Bandas oligoclonales en líquido cefalorraquídeo y incremento de la atrofia cerebral en estadios tempranos de pacientes con esclerosis múltiple forma recaída-remisión

OBJECTIVE: To determine if the presence of oligoclonal bands (OB) at early stages of multiple sclerosis was associated with higher brain atrophy, when compared with patients without OB. METHODS: Relapsing-remitting multiple sclerosis (RRMS) patients with less than two years of disease onset and OB detection in cerebrospinal fluid (CSF) were included. SIENAX was used for total brain volume (TBV), gray matter volume (GMV), and white matter volume (WMV). RESULTS: Forty patients were included, 29 had positive IgG-OB. No differences were found between positive and negative patients in gender, expanded disability status scale (EDSS), treatment received, and T2/T1 lesion load. TBV in positive IgG-OB patients was 1.5 mm³ x 10(6) compared with 1.64 mm³ x 10(6) in the negative ones (p=0.02). GMV was 0.51 mm³ x 10(6) in positive IgG-OB compared with 0.62 mm³ x 10(6) in negative ones (p=0.002). No differences in WMV (p=0.09) were seen. CONCLUSIONS: IgG-OB in the CSF was related to neurodegeneration magnetic resonance (MR) markers in early RRMS.

OBJETIVO: Evaluar si la presencia de bandas oligoclonales (BO) en líquido cefalorraquídeo (LCR) de pacientes con esclerosis múltiple recaídaremisión (EMRR) se asociaba con mayor atrofia cerebral al inicio de la enfermedad. MÉTODOS: Pacientes con EMRR con menos que dos años del inicio de la enfermedad y en quiénes se realizó la búsqueda de IgG-BO en LCR fueron incluidos. SIENAX fue usado para la medición del volumen cerebral total (VCT), volumen de substancia gris (VSG) y volumen de sustancia blanca (VSB). RESULTADOS: Cuarenta pacientes fueron incluidos, 29 tenían IgG-BO positivo. No fueron encontradas diferencias entre pacientes positivos y negativos en: género, expanded disability status scale (EDSS), tratamiento recibido y carga lesional en resonancia magnética. El VCT en pacientes IgG-BO positivos fue de 1,5 mm³ x 10(6) versus 1,64 mm³ x 10(6) en BO negativo (p=0,02). El VSG fue 0,51 mm³ x 10(6) BO positivo versus 0,62 mm³ x 10(6) BO negativo (p=0,002). No fueron encontradas diferencias en VSB (p=0,09). CONCLUSIONES: La presencia de IgG-BO en el LCR se asoció con signos de neurodegeneración temprana en este estudio.

Bandas oligoclonales en líquido cefalorraquídeo de pacientes con esclerosis múltiple del Hospital Militar Central, Bogotá DC / Oligoclonal bands in cerebrospinal ñuid of patients with multiple sclerosis at the Hospital Militar Central- Bogotá DC

INTRODUCCIÓN: la esclerosis múltiple es la enfermedad neurológica más común y discapacitante en adultos jóvenes. Hasta el momento no existe ninguna prueba certera para su diagnóstico. El laboratorio clínico ha tomado gran importancia al incluir la valoración de la producción intratecal de anticuerpos en el proceso diagnóstico de esta patología. OBJETIVO: describir el comportamiento de las bandas oligoclonales del líquido cefaloraquídeo en un grupo de pacientes. MATERIALES Y METODOS: se realizó un estudio observacional descriptivo tipo serie de casos para describir el comportamiento del resultado de las bandas oligoclonales (BO) en el líquido cefalorraquídeo, en pacientes con esclerosis múltiple (EM) del Hospital Militar Central (HMC) de Bogotá que estaban en tratamiento. Se calcularon las frecuencias absolutas y medidas de tendencia central de las variables estudiadas. RESULTADOS: entre la población de usuarios del Hospital Militar Central hubo 26 pacientes con esclerosis multiple, con edad media de 43 años (DS = 8,54). El 75,1 % (19 pacientes) mujeres y el 26.9% (7 pacientes) hombres. El 50 % (13 pacientes) presentaron bandas oligoclonales positivas.. CONCLUSIÓN: al utilizar la electroforesis de proteínas de alta resolución como técnica para la determinación de las bandas oligoclonales en el líquido cefalorraquídeo se obtuvieron resultados similares a los reportados en la literatura. Sin embargo, se deben hacer todos los esfuerzos para introducir la detección de bandas oligoclonales por la técnica recomendada internacionalmente: el isoelectroenfoque comparando simultáneamente el suero y el líquido cefalorraquídeo, con lo cual se puede obtener una gran sensibilidad; allí radica su importancia y utilidad como valor predictivo negativo.

INTRODUCTION: multiple sclerosis is the most common disabling neurological disease in youth adults. So far there is no accurate test for diagnosis. The laboratory tests have become very important because include assessment of intrathecal antibody production in the diagnosis of this disease. OBJETIVE: describe the behavior of cerebrospinal fluid oligoclonal bands in a group of patients MATERIAL AND METHODS: a descriptive case series, with the population of MS patients currently receiving specific treatment in the Hospital Militar Central in Bogota. The absolute frequencies and measures of central tendency of the variables studied were calculated. RESULTS: among the population described there are 26 patients with MS, with a mean age of 43 years old (SD +/- 8.542). 75.1% (19) were females and 26.9% (7) male. 50% (13) of patients had positive oligoclonal bands.. CONCLUSION: with a standardized technique for determining oligoclonal bands in cerebrospinal fluid, as the high-resolution agarose gel electrophoresis the authors obtained similar results as reported in the international literature. It should make all efforts to introduce the detection of BO with the internationally recommended technique named "isoelectric focusing", who simultaneously compared serum and cerebrospinal fluid, that can get a great sensitivity and a high negative predictive value.

Clinical Significance of Oligoclonal Bands in Patients with Multiple Myeloma after Autologous Stem Cell Transplantation

BACKGROUND: Oligoclonal bands or isotype switch detectable by serum immunofixation electrophoresis (IFE) has been reported following chemotherapy and stem cell transplantation in patients with multiple myeloma (MM). We studied the significance of oligoclonal bands appearing after chemotherapy and autologous stem cell transplantation (ASCT) in Korean MM patients, and its impact on relapse. And we investigated the serial serum free light chain (FLC) ratio to establish its possible relationship with the relapse of MM. METHODS: We conducted a retrospective analysis of the serial serum IFE and FLC ratio in 16 MM patients treated with chemotherapy and ASCT. RESULTS: Eleven out of 16 patients (68.8%) had oligoclonal bands with or without isotype switch after ASCT and the median interval from transplantation was 2.0 months. And relapse or persistence rate of monoclonal gammopathy was lower in patients with oligoclonal bands (27.3% vs. 60.0%), though without statistical significance (P=0.299). In eight patients who developed oligoclonal bands and did not relapse, the serial serum FLC ratio was normal in range. But one patient who developed oligoclonal bands and showed increase of plasma cells in bone marrow, the serial serum FLC ratio was abnormal in range. CONCLUSIONS: The occurrence of oligoclonal bands after chemotherapy and ASCT in Korean MM patients is not significantly associated with adverse consequence of relapse or persistence of monoclonal gammopathy. Therefore oligoclonal bands may be not bad prognostic criterion. And the measurement of serum FLC ratio may be a useful indicator to predict relapse in MM patients who developed oligoclonal bands.

Diagnostic value of oligoclonal band detected by isoelectric focusing with immunoblotting in inflammatory demyelinating diseases in nervous system / 中华神经科杂志

Objective To explore the diagnostic value of oligoclonal band (OB) detected by isoelectric focusing (IEF) with immunoblotting in inflammatory demyelinating diseases (IDD) in nervous system.Methods Serum and cerebrospinal fluid (CSF) OB was detected by IEF with immunoblotting in 112 patients with IDD ( multiple sclerosis ( MS):n = 48;neuromyelitis optica ( NMO):n = 21:acute disseminated encephalomyelitis ( ADEM):n = 4;secondary IDD from systemic autoimmune diseases:n = 19;peripheral nervous system IDD:n =20) and 24 patients with non-inflammatory neurological disease (NIND).Results CSF-restricted OB was detected in 91.7% (44/48) of MS patients,23.8% (5/21) of NMO patients(x2nmO vs MS= 32.679),1/4 of ADEM patients (Fisher' s excact test),15.8% (3/19) of secondary IDD patients (x2secondary IDD vs MS = 37.425 ),0 of peripheral nervous system IDD patients (x2peripheral nervous system IDD vs MS =37.425) and 0 of NIND patients (x2NIND vs MS =37.425).MS patients had significantly higher percentage of patients with CSF-restricted OB ( all P ＜0.01),compared with NIND and other IDD patients.The sensitivity and specificity of OB detected by IEF with immunoblotting for MS were 91.7% and 89.8%,which were higher than that of OB detected by other methods.Identical serum and CSF OB ( mirror pattern ) was detected in 2 of 4 ADEM patients and 1 of 48 MS patients.Conclusion IEF with immunoblotting to detect OB is a reliable method of diagnosis for MS.

Study of oligoclonal bands restricted to the cerebrospinal fluid in multiple sclerosis patients in the city of São Paulo / Estudo de bandas oligoclonais restritas ao líquido cefalorraquidiano em pacientes com esclerose múltipla na cidade de São Paulo

The frequency of oligoclonal bands (OCB) restricted to the cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) varies widely in different populations. The objective of this study was to determine the frequency of these OCB in a group of MS patients in the city of São Paulo. Techniques used to detect OCB consisted of isoelectric focusing followed by immunoblotting. Oligoclonal bands were found in 49 (54.4 percent) out of 90 patients with clinically definite MS; in (31.2 percent) of the 16 patients with clinically isolated syndrome; in 7 (17.9 percent) of 39 patients with inflammatory disorders of the central nervous system (IDCNS), and in none of the individuals with no neurological condition (control group). The specificity of the method was 100 percent when compared to the control group and 82.1 percent when compared to the IDCNS group. These results suggest that the frequency of CSF OCB is much lower in Brazilian MS patients from São Paulo city than that reported in MS series from Caucasian populations.

A frequência da detecção de bandas oligoclonais (BOC) restritas ao líquido cerebrorraquidiano (LCR) em pacientes com esclerose múltipla (EM) varia amplamente em diferentes populações. O objetivo deste estudo foi determinar a frequência destas BOC em pacientes com EM em amostra de população da cidade de São Paulo. A técnica utilizada para a detecção das BOC foi a focalização isoelétrica, seguida do immunoblotting. BOC foram detectadas: em 49 (54,4 por cento) de 90 pacientes com EM clinicamente definida; em 5 (31,2 por cento) de 16 pacientes com síndrome clínica isolada; em 7 (17,9 por cento) de 30 pacientes com doenças inflamatórias do sistema nervoso central (DISNC); e em nenhum indivíduo sem doença neurológica. A especificidade do método foi 100 por cento quando comparada ao grupo controle e 82,1 por cento quando comparada ao grupo de DISNC. Estes resultados sugerem que a freqüência de BOC no LCR é mais baixa em pacientes da cidade de São Paulo portadores de EM do que aquelas descritas em populações caucasianas.

Clinical Significance of Oligoclonal Bands and IgG Index for Multiple Sclerosis / 中国康复理论与实践

@#Objective To study the positive rates of oligoclonal bands(OCB)and the IgG index in patients with multiple sclerosis(MS)and in other nervous system disorders(OND).Methods Cerebrospinal fluid(CSF)and serum were collected from 54 patients with MS,271 patients with OND including 62 patients with infections of central nervous system and 209 patients with non-infections.The OCB and IgG index of CSF and serum were detected.Results The positive rate of OCB was 35.2% in MS,8.9% in OND(P<0.05),in which 24.2% in infections of central nervous system(P>0.05),4.5% in non-infections of central nervous system.The positive rate of IgG index was 83.3% in MS,78.2% in OND(P>0.05).Conclusion OCB is helpful to diagnose MS if infection diseases have be excluded,while IgG index can be referenced.

Preliminary Studies on the Clinical Features of Multiple Sclerosis in Korea

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) in Asians is characterized by frequent involvement of the spinal cord and optic nerve and low prevalence rates, but even the most fundamental epidemiologic findings and unique clinical features of MS patients in Korea have not been studied extensively. We performed this study to establish the clinical spectrum of MS patients in Korea. METHODS: Sixty-two MS patients (25 men and 37 women) who satisfied the diagnostic criteria for definite MS were reviewed retrospectively using medical records from two university hospitals and one general hospital. The MS patients were classified into the three clinical subtypes according to the involved site (opticospinal, spinal, and conventional MS). RESULTS: The age at MS onset was 35.2+/-13.3 (mean+/-SD) years, and the predominant initial clinical manifestations were myelopathy (54.8%) and optic neuropathy (33.9%). The single most common involved lesion site was the spinal cord (35.5%). Spinal (35.5%) and opticospinal (25.8%) MS were the most common type, and they had a frequent relapsing-remitting course and long lesions extending over two vertebral segments (as assessed using spinal cord MRI). The interval between the first symptom and relapse was 35.6+/-71.1 months, and the number of relapses was 3.8+/-2.6. The spinal form of MS was associated with a higher age at onset and a higher male-to-female ratio than the other types. Positive rates of CSF oligoclonal bands and IgG index and the number of patients with characteristic brain MRI lesions were low. However, the abnormal rate of visual evoked potentials was relatively high (64.4%). CONCLUSION: The clinical features of MS patients in Korea are different from those in Western patients, but similar to those in Far East Asian patients. The value of the various diagnostic tools used for MS should therefore be reevaluated, at least for Korean patients.

Diagnostic value of the oligoclonal bands and IgG index in multiple sclorosis / 临床神经病学杂志

0.05). When MS and NID groups compared with NNID group, the difference was extremely significant(all P