A Síndrome de Guillain-Barré é uma polirradiculoneuropatia aguda imuno-mediada, clinicamente apresentando-se com envolvimento sensitivo e motor e curso progressivo, em muitos casos determinando grande incapacidade e morbimortalidade nos pacientes que a desenvolvem. Este projeto de pesquisa teve como objetivo o seguimento de uma coorte de 22 indivíduos portadores da Síndrome de Guillain-Barré admitidos no Hospital de Clínicas de Porto Alegre durante o período de Janeiro de 2008 a Dezembro de 2009 para a correlação dos achados clínicos com os níveis liquóricos de interleucina-6 (IL-6) e do fator neurotrófico ciliar do nervo (CNTF). Na admissão, foi coletado o líquido cefalorraquidiano dos pacientes para dosagem de IL-6 e CNTF e, após seis meses, os pacientes foram estratificados em dois grupos, de acordo com a escala de Hughes: bom e mau prognóstico. Não foi identificada associação entre esses níveis e os achados clínicos. Mesmo assim, acreditamos que o estudo dessas substâncias pode ajudar a esclarecer a fisiopatologia da Síndrome de Guillain-Barré. / The Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy, which is usually immune-mediated. It is characterized by clinical features associated with a progressive motor and sensory involvement, leading often to major disability and morbidity in affected individuals. In this work, we investigate the correlation between clinical findings and cerebrospinal fluid levels of interleukine-6 (IL-6) and of ciliary neurotrophic factor (CNTF) in a cohort of patients with GBS during the period January 2008 - December 2009 at the Hospital de Clínicas in Porto Alegre. Interleukine-6 is an immune modulator produced in the immune system with the function of B-cells’ stimulation and antibody secretion. The CNTF is produced in the CNS and plays an important role in the survival of some types of neurons. In this regard, the clinical and prognostic correlation with cerebrospinal fluid may help to elucidate the physiopathology of the Guillain-Barré syndrome.

A Síndrome de Guillain-Barré é uma polirradiculoneuropatia aguda imuno-mediada, clinicamente apresentando-se com envolvimento sensitivo e motor e curso progressivo, em muitos casos determinando grande incapacidade e morbimortalidade nos pacientes que a desenvolvem. Este projeto de pesquisa teve como objetivo o seguimento de uma coorte de 22 indivíduos portadores da Síndrome de Guillain-Barré admitidos no Hospital de Clínicas de Porto Alegre durante o período de Janeiro de 2008 a Dezembro de 2009 para a correlação dos achados clínicos com os níveis liquóricos de interleucina-6 (IL-6) e do fator neurotrófico ciliar do nervo (CNTF). Na admissão, foi coletado o líquido cefalorraquidiano dos pacientes para dosagem de IL-6 e CNTF e, após seis meses, os pacientes foram estratificados em dois grupos, de acordo com a escala de Hughes: bom e mau prognóstico. Não foi identificada associação entre esses níveis e os achados clínicos. Mesmo assim, acreditamos que o estudo dessas substâncias pode ajudar a esclarecer a fisiopatologia da Síndrome de Guillain-Barré. / The Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy, which is usually immune-mediated. It is characterized by clinical features associated with a progressive motor and sensory involvement, leading often to major disability and morbidity in affected individuals. In this work, we investigate the correlation between clinical findings and cerebrospinal fluid levels of interleukine-6 (IL-6) and of ciliary neurotrophic factor (CNTF) in a cohort of patients with GBS during the period January 2008 - December 2009 at the Hospital de Clínicas in Porto Alegre. Interleukine-6 is an immune modulator produced in the immune system with the function of B-cells’ stimulation and antibody secretion. The CNTF is produced in the CNS and plays an important role in the survival of some types of neurons. In this regard, the clinical and prognostic correlation with cerebrospinal fluid may help to elucidate the physiopathology of the Guillain-Barré syndrome.

A Síndrome de Guillain-Barré é uma polirradiculoneuropatia aguda imuno-mediada, clinicamente apresentando-se com envolvimento sensitivo e motor e curso progressivo, em muitos casos determinando grande incapacidade e morbimortalidade nos pacientes que a desenvolvem. Este projeto de pesquisa teve como objetivo o seguimento de uma coorte de 22 indivíduos portadores da Síndrome de Guillain-Barré admitidos no Hospital de Clínicas de Porto Alegre durante o período de Janeiro de 2008 a Dezembro de 2009 para a correlação dos achados clínicos com os níveis liquóricos de interleucina-6 (IL-6) e do fator neurotrófico ciliar do nervo (CNTF). Na admissão, foi coletado o líquido cefalorraquidiano dos pacientes para dosagem de IL-6 e CNTF e, após seis meses, os pacientes foram estratificados em dois grupos, de acordo com a escala de Hughes: bom e mau prognóstico. Não foi identificada associação entre esses níveis e os achados clínicos. Mesmo assim, acreditamos que o estudo dessas substâncias pode ajudar a esclarecer a fisiopatologia da Síndrome de Guillain-Barré. / The Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy, which is usually immune-mediated. It is characterized by clinical features associated with a progressive motor and sensory involvement, leading often to major disability and morbidity in affected individuals. In this work, we investigate the correlation between clinical findings and cerebrospinal fluid levels of interleukine-6 (IL-6) and of ciliary neurotrophic factor (CNTF) in a cohort of patients with GBS during the period January 2008 - December 2009 at the Hospital de Clínicas in Porto Alegre. Interleukine-6 is an immune modulator produced in the immune system with the function of B-cells’ stimulation and antibody secretion. The CNTF is produced in the CNS and plays an important role in the survival of some types of neurons. In this regard, the clinical and prognostic correlation with cerebrospinal fluid may help to elucidate the physiopathology of the Guillain-Barré syndrome.

In den letzten Jahren gewann das Konzept der Paranodopathien als eigene Krankheitsentität der inflammatorischen Polyneuropathien zunehmend an Bedeutung. Die Forschung konzentrierte sich dabei überwiegend auf die chronisch inflammatorische Polyradikuloneuropathie (CIDP). In dieser Arbeit werden (para-)nodale Antikörper gegen Neurofascin-155, panNeurofascin, Contactin-1 und Caspr-1 in einer großen Kohorte von Patienten mit Guillain-Barré-Syndrom (GBS) und CIDP nachgewiesen. Patienten mit Anti-panNeurofascin-Antikörpern zeigten besonders schwere Verlaufsformen. Patienten mit anderen (para-)nodalen Antikörpern zeigten je nach IgG-Subklasse der Antikörper spezifische klinische Merkmale und ein unterschiedliches Ansprechen auf die Therapie. Die Arbeit zeigt, dass die Bestimmung (para-)nodaler Antikörper bei Patienten mit GBS und CIDP im klinischen Alltag zur Einordung der Prognose und Therapieplanung sinnvoll sein kann. / In the last years the concept of paranodopathy as an own disease entity has gained more relevance. So far, most studies focused on chronic inflammatory polyneuropathy (CIDP). In this study, autoantibodies against neurofascin-155, pan-neurofascin, contactin-1, and capsr-1 in a cohort of Guillain-Barré-syndrome (GBS) and CIDP were detected. All patients with anti-pan-neurofascin-antibodies suffered from a very severe course of disease. Patients with other (para-)nodal autoantibodies showed common clinical features and therapeutic response depending on the autoantibody and their IgG-subclasses. This study shows that (para-)nodal autoantibodies should be determined in GBS and CIDP to estimate clinical course and therapeutic response.

A Síndrome de Guillain-Barré (SGB) é uma neuropatia periférica inflamatória aguda que tem sido definida pelo achado ou história de tetraparesia flácida arreflexa ascendente. Apresentações atípicas podem ser mais frequentes do que tem sido referido na literatura, particularmente na faixa etária infantil. Objetivo: Avaliar dados epidemiológicos e a prevalência de assimetria no exame neurológico em crianças com SGB. Métodos: Foram revisados 40 prontuários de crianças de 0 a 15 anos de idade com o diagnóstico de SGB, atendidas entre janeiro de 2000 e agosto de 2016. Avaliouse a presença de assimetrias no exame neurológico na admissão hospitalar, os desfechos clínicos e as características demográficas e clinico-laboratoriais. Resultados: Dois pacientes apresentaram assimetria no exame neurológico na admissão hospitalar e três pacientes admitidos com tetraparesia simétrica apresentaram um quadro motor assimétrico antes da internação. Uma criança evoluiu para assimetria após ter sido admitida com quadro simétrico. Outros oito casos tinham fraqueza segmentar. A presença de assimetria motora ou fraqueza segmentar se correlacionou com a progressão estática dos sintomas (p=0,004) e observou-se uma tendência desses pacientes serem mais jovens, mas essa diferença não foi significativa (p=0,08). Onze pacientes apresentavam reflexos miotáticos preservados e um paciente exibia hiperreflexia na admissão hospitalar. A maioria dos pacientes foi admitida sem conseguir deambular e, na alta, a maioria deambulava com ou sem apoio. Cinco crianças necessitaram de suporte ventilatório e nenhuma foi a óbito. Conclusão: Uma proporção significativa dos pacientes apresentava quadro motor assimétrico ou segmentar e reflexos miotáticos preservados. Os resultados obtidos delineiam aspectos clínicos atípicos na SGB em crianças e podem ajudar na definição diagnóstica e instituição de tratamento precoce. / Guillain-Barré syndrome (GBS) is an acute, inflammatory, peripheral neuropathy that has been being defined as an ascending flaccid tetraparesis. Atypical presentations can be frequent, particularly in children, leading to greater challenges in the diagnosis. Objectives: To analyze the epidemiological data and the prevalence of motor asymmetries in the neurological examination of children with GBS. Methods: A total of 40 medical records were analyzed, of children aged 0 to 15 years old diagnosed with GBS, admitted from January 2000 to August 2016. We evaluated the presence of motor asymmetries at the hospital admission, the clinical outcomes and the demographic and clinic-laboratorial characteristics. Results: Two patients had motor asymmetries at hospital admission and three patients admitted with symmetric tetraparesis had an initial motor asymmetry before admission. One patient progressed to asymmetric tetraparesis after being initially admitted with symmetric weakness. Eight other cases had segmental weakness at admission. Motor asymmetry and segmental weakness correlated with a static progression of symptoms (p=0.004) and these patients tended to be younger, but this difference was not significant (p=0.08). Eleven patients had preserved deep tendon reflexes and one exhibited hyperreflexia at the hospital admission. Most patients were admitted on wheel-chair or bedridden, and at discharge the majority could walk with or without help. Five children required mechanical ventilation and no patient died. Conclusion: A significant proportion of patients had asymmetric or segmental weakness and preserved deep tendon reflexes. Those results show that the so-called atypical clinical findings in children with GBS are not uncommon, and needs to be kept in mind to allow an earlier diagnosis and treatment.

A Síndrome de Guillain-Barré (SGB) é uma neuropatia periférica inflamatória aguda que tem sido definida pelo achado ou história de tetraparesia flácida arreflexa ascendente. Apresentações atípicas podem ser mais frequentes do que tem sido referido na literatura, particularmente na faixa etária infantil. Objetivo: Avaliar dados epidemiológicos e a prevalência de assimetria no exame neurológico em crianças com SGB. Métodos: Foram revisados 40 prontuários de crianças de 0 a 15 anos de idade com o diagnóstico de SGB, atendidas entre janeiro de 2000 e agosto de 2016. Avaliouse a presença de assimetrias no exame neurológico na admissão hospitalar, os desfechos clínicos e as características demográficas e clinico-laboratoriais. Resultados: Dois pacientes apresentaram assimetria no exame neurológico na admissão hospitalar e três pacientes admitidos com tetraparesia simétrica apresentaram um quadro motor assimétrico antes da internação. Uma criança evoluiu para assimetria após ter sido admitida com quadro simétrico. Outros oito casos tinham fraqueza segmentar. A presença de assimetria motora ou fraqueza segmentar se correlacionou com a progressão estática dos sintomas (p=0,004) e observou-se uma tendência desses pacientes serem mais jovens, mas essa diferença não foi significativa (p=0,08). Onze pacientes apresentavam reflexos miotáticos preservados e um paciente exibia hiperreflexia na admissão hospitalar. A maioria dos pacientes foi admitida sem conseguir deambular e, na alta, a maioria deambulava com ou sem apoio. Cinco crianças necessitaram de suporte ventilatório e nenhuma foi a óbito. Conclusão: Uma proporção significativa dos pacientes apresentava quadro motor assimétrico ou segmentar e reflexos miotáticos preservados. Os resultados obtidos delineiam aspectos clínicos atípicos na SGB em crianças e podem ajudar na definição diagnóstica e instituição de tratamento precoce. / Guillain-Barré syndrome (GBS) is an acute, inflammatory, peripheral neuropathy that has been being defined as an ascending flaccid tetraparesis. Atypical presentations can be frequent, particularly in children, leading to greater challenges in the diagnosis. Objectives: To analyze the epidemiological data and the prevalence of motor asymmetries in the neurological examination of children with GBS. Methods: A total of 40 medical records were analyzed, of children aged 0 to 15 years old diagnosed with GBS, admitted from January 2000 to August 2016. We evaluated the presence of motor asymmetries at the hospital admission, the clinical outcomes and the demographic and clinic-laboratorial characteristics. Results: Two patients had motor asymmetries at hospital admission and three patients admitted with symmetric tetraparesis had an initial motor asymmetry before admission. One patient progressed to asymmetric tetraparesis after being initially admitted with symmetric weakness. Eight other cases had segmental weakness at admission. Motor asymmetry and segmental weakness correlated with a static progression of symptoms (p=0.004) and these patients tended to be younger, but this difference was not significant (p=0.08). Eleven patients had preserved deep tendon reflexes and one exhibited hyperreflexia at the hospital admission. Most patients were admitted on wheel-chair or bedridden, and at discharge the majority could walk with or without help. Five children required mechanical ventilation and no patient died. Conclusion: A significant proportion of patients had asymmetric or segmental weakness and preserved deep tendon reflexes. Those results show that the so-called atypical clinical findings in children with GBS are not uncommon, and needs to be kept in mind to allow an earlier diagnosis and treatment.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

The needs of patients who are nursed on the ICU are becoming more widely recognised and services are beginning to reflect this. However there is little research into how patients who have suffered from a severe and progressive muscular paralysis called Guillain-Barré Syndrome (GBS) experience the disease and subsequent hospitalisation. The purpose of this study was to explore how these patients experience the different aspects of the illness, including an extended period of paralysis and treatment on an ICU. This is intended to expand upon the limited research in this area and identify how the findings can inform clinical practice and future studies. Method: A systematic literature search identified research in relation to the experiences of individuals who had GBS which was utilised to form the basis of the understanding for this study. Very little systematic research has looked at individuals‟ experiences of Guillain-Barré Syndrome whilst ill and their subsequent recovery. A mixed methods study was carried out with the aim of adding to this research. Interpretative Phenomenological Analysis was selected as the method of analysis for Study 1, which involved interviews with seven participants who had experienced GBS severe enough to need treatment on an ICU. This then enabled quantitative questionnaires to be disseminated which asked about individuals‟ levels of anxiety, depression and Post Traumatic Stress symptomatology both retrospectively and following recovery in Study 2. Results: Study1 found that participants experienced GBS as either a slow and frustrating, or as a rapid and scary onset. The main themes that were developed included: the paralysis being viewed as multiple losses, frustration, difficulties associated with communication loss, vulnerability and frightening hallucinations. Study 2 utilised non-parametric analyses of the data and found that participants experienced high levels of anxiety and depression at the onset of GBS and that some continued to experience anxiety, depression and post traumatic symptoms after recovery from GBS. Generally the profile suggests predominantly anxiety problems during the acute onset phase and then predominantly depression at the time of follow-up. Aspects of post traumatic stress were positively correlated with duration of mechanical ventilation which in turn was related to duration of paralysis. This challenged the hypothesis that GBS patients habituate to the experience of paralysis. Conclusion: For some individuals, GBS was experienced as a frightening event, but one that they could draw positive things from. However, for others, GBS was experienced as a traumatic event and some of these people continued to exhibit signs of psychological distress even after recovery. It remains important for staff to feel able to speak about distressing situations with their patients and to signpost them to other psychological services if appropriate.

Verschiedene mögliche Pathomechanismen einer Campylobacter jejuni-spezifischen Immunantwort bei der Entstehung akuter Immunneuropathien wurden untersucht. Neben anderen wurden für die Untersuchungen auch C. jejuni-Stämme eingesetzt, welche von Guillain-Barré- (GBS) und Miller-Fisher-syndrome (MFS) Patienten isoliert worden waren. Es wurden Ultraschall-Gesamt-Homogenate der C. jejuni Stämme sowie von Salmonella typhimurium als Kontrollbakterium hergestellt. Anschließend wurden verschiedene Proteinfraktionen isoliert und die Lipopolysaccharide (LPS) der Bakterien isoliert. Durch Immunisierung von Ratten mit diesen C. jejuni-Präparationen konnten keine Krankheitszeichen der experimentellen autoimmunen Neuritis (EAN) ausgelöst werden. Trotz Produktion hoher Titer C. jejuni-spezifischer Antikörper verlief in diesen Tieren eine anschließend durch P2-spezifische T-Lymphozyten induzierte adoptiv transferierte EAN (AT-EAN) nicht schwerer als in mit komplettem Freund´schen Adjuvans (CFA) kontrollimmunisierten Ratten. Nach Immunisierung mit C. jejuni-Protein wurden C. jejuni-spezifische T-Zellen von Lewis-Ratten gewonnen, die mit allen getesteten C. jejuni-Stämmen als Antigen reagieren, jedoch zeigten C. jejuni-spezifische Ratten-T-Zellen in vitro keine Kreuzreaktivität mit PNS-Antigenen und induzierten in vivo keine Neuritis. Im Modell der EAN läßt sich durch Füttern des Antigens eine natürliche orale Toleranz induzieren, welche die Tiere gegen eine aktiv induzierte EAN resistent macht. Die immunologische Auswirkung der enteralen Gabe von C. jejuni-LPS auf die natürliche Immuntoleranz wurde untersucht. Dabei konnte bei diskrepanten Ergebnissen keine pathogene Bedeutung von enteralen C. jejuni-Antigenen in der Ratte festgestellt werden. Zur Generation und Untersuchung C. jejuni-spezifischer monoklonaler Antikörper wurden Balb/c-Mäuse mit C. jejuni-LPS-Präparationen in CFA immunisiert und die Milzzellen dieser Tiere mit Maus-Myelomzellen fusioniert. Es konnte eine Vielzahl von monoklonalen Antikörpern etabliert werden. Selektive Spezifitäten der monoklonalen Antikörper für C. jejuni-LPS oder -protein wurden detektiert, die meisten der monoklonalen Antikörper als IgM, einige als IgG charakterisiert. Die Antikörper reagieren mit allen getesteten C. jejuni-Stämmen sowohl im ELISA als auch im Western Blot kreuz. Eine Reaktivität der Antikörper mit verschiedenen Gangliosiden konnte nicht nachgewiesen werden. Zur Untersuchung eines elektrophysiologisch fassbaren blockierenden Effektes von C. jejuni-spezifischen Antikörpern wurden Makro-patch-clamp-Untersuchungen am Mäusezwerchfell mit dialysierten Seren von C. jejuni-immunisierten Ratten durchgeführt. Einige der C. jejuni-Antiseren blockierten die präsynaptische Quantenfreisetzung partiell. Dieser Effekt war C. jejuni-spezifisch und durch Salmonella-Antiserum oder Kontrollseren CFA-immunisierter Tiere nicht induzierbar. Ein von uns generierter monoklonaler IgG-Antikörper gegen C. jejuni-LPS wurde ebenfalls in Makro-patch-clamp-Untersuchungen getestet und blockierte die Quantenfreisetzung. Weiterhin wurden humane T-Zellen gegen C. jejuni HB 93-13 generiert. Es konnte erstmals gezeigt werden, daß diese Zellen mit anderen C. jejuni-Stämmen, jedoch nicht mit Salmonellen, kreuzreagieren und ausschließlich Proteine jedoch nicht LPS erkennen. Die generierten Zellen sind alle HLA-DR restringiert und der Phänotyp wurde als CD 4+/CD 8-, /-TZR+ identifiziert. Einige der C. jejuni-spezifischen T-Zell-Linien zeigten eine starke oder partielle Kreuzreaktivität mit humanem rekombinantem P2-Protein des PNS und mit einzelnen P2-Peptiden. Dieser Befund belegt erstmals, dass durch Konfrontation mit C. jejuni eine zelluläre Immunantwort angestoßen werden kann, die in autoimmuner Weise mit Myelinprotein des PNS kreuzreagiert. / The present study evaluates the putative pathogenic role of a Campylobacter jejuni directed immune response in the pathogenesis of acute neuropathies. Among other C. jejuni strains, strains isolated from Guillain-Barré- (GBS) and Miller-Fisher syndrome (MFS) patients were used for this investigation. By sonication, total homogenate of different C. jejuni strains and Salmonella typhimurium, which served as a control, were prepared. Additionally, different protein fractions and bacterial lipopolysaccharides (LPS) were isolated. Immunization of rats with C. jejuni preparations did not lead to clinical manifestation of active experimental autoimmune neuritis (EAN). Furthermore, the severity of adoptive transfer-EAN (AT-EAN), induced by adoptively transferred P2-specific T cells was not altered in rats that had been previously immunized with C. jejuni for production of high anti-C. jejuni antibody titers. C. jejuni-specific T cell lines were generated from Lewis rats immunized with C. jejuni proteins. These T cells proliferated in an antigen-specific manner in the presence of extracts from different C. jejuni strains. C. jejuni-specific rat T cells did not show any cross-reactive proliferation to peripheral nervous system (PNS) antigens. Furthermore, it was not possibe to induce neuritis by adoptive transfer of C. jejuni-specific T cells in vivo. Oral application of myelin antigens induces oral tolerance which renders rats resistant to actively induced EAN. This observation lead to analyse the immunological consequences of oral administration of C. jejuni LPS with respect to the induction of tolerance. C. jejuni/myelin-fed rats developed accelerated clinical sings of EAN compared to control animals. Thus, oral administration of C. jejuni HB 93-13 LPS inhibited the induction of myelin-specific oral tolerance. In order to investigate the humoral immune response, monoclonal C. jejuni-specific antibodies were isolated by immunization of Balb/c mice with C. jejuni LPS preparations emulsified in complete Freund´s adjuvant (CFA). Splenocytes from primed animals were fused with myeloma cells. A number of monoclonal antibodies were characterized. These monoclonal antibodies were either specific for C. jejuni LPS or C. jejuni proteins. These immunoglobulins were characterized to be predominantly IgM, but also IgG antibodies could be found. ELISA and western blot analysis verified cross-reactivity of antibodies with different C. jejuni strains. However, the antibodies were not able to recognize gangliosides. Electrophysiological investigations were used to determine a possible blocking effect of C. jejuni-specific antibodies at the neuromusculare endplate. Alteration of neuromuscular transmission at the diaphragm of mice after appling dialysed sera of C. jejuni immunized rat, were investigated using patch-clamp. Several C. jejuni antisera were able to partially block the pre-synaptic quantal release. This effect was C. jejuni-specific and was not inducible by Salmonella typhimurium antisera or control sera, obtained from CFA immunized animals. Additionally, one of the generated monoclonal C. jejuni LPS specific IgG antibodies was able to block the quantal release. Finally, we were able to generate human T cells reacting specifically with C. jejuni HB 93-13. For the first time it could be shown, that these cells respond to homogenates of other C. jejuni strains but not to Salmonella typhimurium homogenate. Specifically C. jejuni proteins but not C. jejuni LPS were recognized by the human T cell lines. The generated T cells were all HLA-DR restricted and identified to be CD4+/CD8-, /-TCR+. A few of the C. jejuni-specific T cell lines demonstrated a strong cross-reactivity to a PNS-component, the recombinant human P2-protein and single P2-peptides. This observation shows that C. jejuni induces a variety of antigen-specific and non-specific immune responses which are able to facilitate or even trigger autoimmunity against the PNS as occuring in GBS or the MFS.