There are approximately 6000 to 8000 rare diseases, each with a prevalence of less than 1 / 10 000, but in aggregate affecting 6 to 8% of the population. It is important to evaluate disease development and progression to know the natural course of any disease. This information can be utilized in diagnostics and in assessing effects of therapeutic interventions as they become available. This thesis describes the natural clinical history and evolution of imaging findings of two rare diseases over approximately two decades. Papers I, II and III present clinical, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) findings in LMNB1-related autosomal dominant leukodystrophy (ADLD). MRI was found to be very sensitive in finding pathology in patients with LMNB1-related ADLD, even before the onset of clinical symptoms. However, even patients with widespread MRI changes can have a relatively mild symptomatology and present only slight disturbances in metabolic examinations such as MRS and FDG-PET. This is compatible with relatively intact axons, even as myelin impairment is widespread. Paper IV presents clinical and MRI findings in the brain and musculature in SIL1-positive Marinesco-Sjögren syndrome (MSS), and describes a new, mild phenotype of the disease with no intellectual disabilities and only slight motor disabilities. With a 19-year-long radiological follow-up, a slow progressive atrophic process in the cerebellum and brainstem could be demonstrated. MRI of the musculature shows early involvement of the quadriceps and gastrocnemii but not the tibialis anterior, progressing to widespread atrophy in the back and upper and lower limbs at the age of 20 years. In the mildest phenotype, the most severely affected muscles were the m gluteus maximus, m sartorius, m peroneus longus, and the lateral head of the m gastrocnemius.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Candidate: Bc. Barbora Zedníková Supervisor: Doc. MUDr. Josef Herink, DrSc. Title of diploma thesis: The role of the gut microbiome in immune-mediated CNS disorders Human body hosts a large number of microorganisms - i.e. Archea, Eukarya, Bacteria and viruses. These microorganisms form microbiome, the total number of the microorganisms is ten times higher than the number of all human cells. Largest part of the microbiome is located in the intestine. The current development of molecular genetics revealed the close relationship between intestinal microbiome and health. Recent studies the most recent studies have pointed to a connection with the pathogenesis of various diseases. This dissertation is focused on the connection between intestinal microbiome and autoimmune diseases of the central nervous system. Research shows that the key factor are the ongoing changes in the composition of microbiome. These changes lead to increased immune stimulation and thereby to inflammatory proliferation.

La polyradiculonévrite inflammatoire démyélinisante chronique (PIDC) est une pathologie neurologique auto-immune du système nerveux périphérique dont la physiopathologie est actuellement mal connue, pour laquelle les options thérapeutiques sont peu nombreuses et dont il n’existe pas de modèle animal fiable. Le premier objectif de ce travail était de valider et de caractériser un modèle animal de PIDC par immunisation de rat Lewis avec le peptide P0(180-199) palmitoylé. Les animaux ont développé une pathologie chronique ou à rechute qui a pu être caractérisée aux plans clinique, histologique, électrophysiologique et immunologique. Les résultats sont en faveur d’un modèle fiable et reproductible mimant bien la PIDC humaine. Le deuxième objectif de ce travail était de tester, sur notre modèle, le fingolimod, modulateur des récepteurs à la sphingosine 1-phosphate, comme potentiel traitement de la pathologie. Le fingolimod a permis, dans notre modèle, de diminuer la sévérité et la chronicité de la maladie, d’améliorer les paramètres électrophysiologiques, de diminuer l’infiltration par les cellules inflammatoires et les anomalies immunologiques. / Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune pathology of the peripheral nervous system whose pathophysiology is currently poorly understood, for which there are few therapeutic options and no reliable animal model. The first aim of this work was to validate and characterize an animal model of CIDP by immunization of rat Lewis with the palmitoylated peptide P0(180-199). The animals developed a chronic or relapsing pathology that could be characterized clinically, histologically, electrophysiologically and immunologically. The results are in favor of a reliable and reproducible model that mimics the human CIDP. The second aim of this work was to test, on our model, the fingolimod, sphingosine 1-phosphate receptor modulator, as potential treatment of the pathology. In our model, fingolimod has reduced the severity and the chronicity of the disease, improved electrophysiological parameters, reduced infiltration by inflammatory cells and recue immunological abnormalities.

INTRODUÇÃO: Neuromielite óptica (NMO) e suas formas limitadas são doenças desmielinizantes autoimunes do sistema nervoso central que acometem preferencialmente a medula espinhal e o nervo óptico. Várias formas clínicas do espectro da NMO (NMO-SD) tem sido descritas e incluem desde um evento único de mielite transversa longitudinalmente extensa (MTLE) à NMO recorrente. O comprometimento neurológico destes pacientes pode levar a diversas disfunções autonômicas, incluindo disfunção miccional. OBJETIVOS: Determinar a prevalência e as características dos sintomas do trato urinário inferior (STUI) e dos achados urodinâmicos em pacientes portadores de NMO-SD, e analisar suas associações com o grau de comprometimento neurológico e qualidade de vida (QV). MÉTODOS: Avaliamos 30 pacientes (23 mulheres e 7 homens) com diagnóstico estabelecido de NMO-SD, que foram convidados a participar do estudo a despeito de apresentarem ou não STUI. A avaliação neurológica foi realizada por meio da Escala Expandida do Estado de Incapacidade (EDSS), ressonância magnética de crânio e coluna vertebral, e dosagem de NMOIgG. Os STUI foram avaliados pelo Questionário de Avaliação da Bexiga Hiperativa (OAB-V8) e pelo Escore Internacional de Sintomas Prostáticos (IPSS). A qualidade de vida de forma geral foi avaliada pelo questionário de Satisfação com a Vida (LiSat-9). Todos os pacientes foram submetidos ao estudo videourodinâmico. RESULTADOS: A idade média dos pacientes foi de 41,1 ± 13,5 anos (intervalo de 13 a 70) e o tempo médio de duração da doença neurológica foi de 33,8 ± 30,8 meses (intervalo de 3 a 135). A avaliação neurológica mostrou pacientes com EDSS médio de 5,3 ± 1,8 (intervalo de 1 a 8,5). O escore médio do OAB-V8 foi de 17,5 ± 14,0 (intervalo de 0 a 40) e de 14,3 ± 10,6 (intervalo de 0 a 35) para o I-PSS. A média da QV geral medida pelo Lisat-9 foi de 38,9 ± 6,8 (intervalo de 26 a 49). Os STUI mais comuns foram urgência em 15 (50%) pacientes, noctúria em 15 (50%), jato urinário fraco em 15 (50%), intermitência em 14 (46,6%), esvaziamento incompleto em 13 (43,3%), hesitação em 13 (43,3%), aumento da frequência urinária em 13 (43,3%) e urge-incontinência em 5 (16%). Os achados urodinâmicos mais comuns foram hiperatividade detrusora (HD) com dissinergia detrusor-esfincteriana (DDE) em 11 (36,6%) pacientes, DDE sem HD em 7 (23,3%), HD sem DDE em 6 (20%), e incontinência urinária de esforço em 1 (3,3%). Cinco (16,6%) pacientes apresentaram estudo videourodinâmico sem anormalidades. Sintomas urinários medidos pelo IPSS e pelo OAB-V8 correlacionaram-se com maior comprometimento neurológico (r=0,42; p=0,018 e r=0,48; p=0,006 respectivamente). Pacientes portadores de DDE foram aqueles que mostraram maior comprometimento neurológico (p=0,027). Da mesma forma, pacientes dissinérgicos apresentaram maiores escores ao I-PSS (p=0,029) e ao OAB-V8 (p=0,008). Pacientes com maior comprometimento neurológico foram aqueles que apresentaram pior QV (r=-0,410; p=0,022). CONCLUSÃO: Encontramos alta prevalência de STUI e disfunção miccional em portadores de NMO, sendo DDE e a HD as anormalidades urodinâmicas mais frequentes. Dissinergia detrusor-esfincteriana e STUI se correlacionam com a gravidade da doença neurológica. A severidade da doença neurológica correlaciona-se com a qualidade de vida geral / INTRODUCTION: Neuromyelitis optica (NMO) and its limited forms are demyelinating autoimmune diseases of the central nervous system that preferentially affects the spinal cord and optic nerve. Several clinical forms of NMO spectrum disorders (NMO-SD) have been described and range from a limited event of longitudinally extensive transverse myelitis (LETM) to relapsing NMO. The neurological damage in these patients may lead to a range of autonomic dysfunctions, including voiding dysfunction. OBJECTIVES: To determine the prevalence and characteristics of the lower urinary tract symptoms (LUTS) and the urodynamic findings in patients with NMO-SD and analyze their correlations with the level of neurological damage and quality of life (QoL). METHODS: We evaluated 30 patients (23 women and 7 men) with an established diagnosis of NMO-SD based on stringent criteria. All patients were invited to participate irrespective of the presence of LUTS. Neurological impairment was assessed with the Expanded Disability Status Scale (EDSS), magnetic resonance imaging of the brain and spinal cord and NMO-IgG status. LUTS were evaluated with the Overactive Bladder V8 (OAB-V8) questionnaire and by the International Prostate Symptom Score (I-PSS). Quality of Life was evaluated using the Life Satisfaction questionnaire (LiSat-9). All patients underwent videourodynamics, transabdominal urinary tract sonography, urine culture and serum creatinine levels. RESULTS: The mean age of the patients was 41.1 ± 13.5 years (range 13 to 70) and the mean time of neurological disease duration was 33.8 ± 30.8 months (range 3 to 135). Neurological evaluation showed a mean EDSS score of 5.3 ± 1.8 (range 1 to 8.5). The mean OAB-V8 score was 17.5 ± 14.0 (range 0 to 40) and the mean I-PSS score was 14.3 ± 10.6 (range of 0 to 35). Mean general QoL measured by the Lisat-9 was 38.9 ± 6.8 (range 26 to 49). The most common urinary symptoms were urgency in 15 (50%) patients, nocturia in 15 (50%), weak urinary stream in 15 (50%), intermittence in 14 (46.6%), incomplete emptying in 13 (43.3%), hesitation in 13 (43.3%), increased urinary frequency in 13 (43.3%) and urge-incontinence in 5 (16,6%). The most frequent urodynamic findings were detrusor overactivity (DO) with sphincter dyssinergia (DSD) in 11 (36.6%) patients, DSD alone in 7 (23.3%), DO without DSD in 6 (20%) and stress urinary incontinence (SUI) in 1 (3.3%). Five (16.6%) patients had normal findings. Voiding dysfunction assessed by I-PSS and OAB-V8 increased with the degree of neurological impairment (r=0.42; p=0.018 and r=0.48; p=0.006 respectively). Patients with DSD had significantly higher symptoms based in the I-PSS (p=0.029) as well as the OAB- V8 scores (p=0.008) and greater neurological impairment (p=0.027). Patients with more severe neurological impairment were associated with worse Qol (r=-0.410; p=0.022). CONCLUSION: We have shown a high prevalence of LUTS and voiding dysfunction, with DSD and DO as the main urodynamic findings. Detrusor-sphincter dyssinergia and LUTS correlates with more severe neurological impairment. The severity of neurological impairment correlates with QoL

Introdução: Polineuropatias são doenças do sistema nervoso periférico com etiologias variadas. Dentre elas são freqüentes as inflamatórias e as hereditárias, com prevalência de 0,67-7,7/100000 e 7,9-82,3/100000 para polineuropatia inflamatória desmielinizante crônica (PIDC) e Doença de Charcot-Marie-Tooth (CMT), respectivamente. Existem poucas evidências de sobreposição entre estas duas doenças e também algumas dificuldades diagnósticas em situações específicas. Objetivos: Estudar a freqüência de mutações (duplicações e deleções) do gene PMP22 em uma coorte de pacientes inicialmente diagnosticados como PIDC ou suspeitos de apresentarem as duas condições, os sinais e sintomas sugestivos da sobreposição e os fatores implicados em erro de classificação da neuropatia. Métodos: 111 pacientes com diagnóstico de PIDC foram estudados. DNA foi isolado a partir de leucócitos de sangue periférico segundo protocolo padrão. Duplicações e deleções do gene PMP22 foram avaliadas através de marcadores polimórficos do DNA localizados dentro do cromossomo 17p11.2-12, o qual contém o gene PMP22. Achados clínicos e laboratoriais também foram estudados e comparados entre os grupos. Resultados: Dentre os 111 pacientes estudados, mutações no PMP22 foram encontradas em 10 (9%), sendo duplicações em 9 pacientes e deleção em 1 paciente. Concomitância entre PIDC e CMT foi verificada em 4 pacientes (3,6%), todos com duplicação do PMP22. Os outros 6 pacientes foram diagnosticados como CMT puro (5) ou Neuropatia Hereditária Susceptível à Compressão (1), visto que não apresentaram melhora com o uso de tratamento imunomodulador e/ou imunossupressor (5 casos) ou foi estabelecido diagnóstico alternativo associado (1). Os outros 101 pacientes não tiveram duplicação nem deleção deste gene e, portanto, tinham PIDC apenas. Idade média dos pacientes com PIDC/CMT foi de 23,8±18,0 anos e 43,6±19,3 anos para pacientes sem mutações (p=0,04). Houve diferença estatísticamente significativa na resposta ao tratamento entre os grupos PIDC/CMT X CMT (p=0,008) e PIDC X CMT (p=0,00). Ausência de história familiar e presença de doenças e hábitos ligados ao desenvolvimento de neuropatias periféricas, como diabetes mellitus e ingesta de bebidas alcoólicas, por exemplo, bem como achados atípicos na eletroneuromiografia e na biópsia de nervo podem ter contribuído para a confusão diagnóstica nos casos de CMT puro. Conclusões: Alguns pacientes podem desenvolver PIDC em associação com CMT e se beneficiam do tratamento. A neuropatia hereditária poderia predispor à neuropatia inflamatória, uma vez que estes pacientes tendem a apresentar essa condição em idades mais precoces. Cautela deve ser dispensada àqueles pacientes com suspeita diagnóstica de PIDC que não têm os achados clássicos ou não melhoram com o tratamento, uma vez que podem apresentar outras etiologias para a neuropatia, dentre elas uma neuropatia hereditária, como a CMT. / Introduction: Polyneuropathies are peripheral nervous system disorders with a wide range of etiologies. Among them, inflammatory and hereditary are frequent with prevalence of 0.67-7.7/100000 and 7.9-82.3/100000, for chronic inflammatory demyelinating polyneuropathy (CIDP) and Charcot-Marie-Tooth disease (CMT), respectively. There are a few evidence of ovelapping between these two conditions and also some diagnostic difficulties in specific situations. Objectives: To study the frequency of mutations in PMP22 gene (duplications and delections) among a cohort of patients initially diagnosed as CIDP or suspected to have both conditions, the signs and symptoms related to this ovelapping and factors implicated in misdiagnose. Methods: 111 patients with an initially CIDP suspected diagnosis were studied. DNA was isolated from peripheral blood leucocytes following a standard salting-out protocol. Duplications and delections in the PMP22 gene were analysed by polymorphic DNA markers located within the chromosome 17p11.2-12, wich contains the PMP22 gene. Clinical and laboratory findings were also studied and compared within groups. Results: Among 111 patients studied, 10 (9%) were found to harbor mutations in PMP22 gene, specifically duplications in nine and delection in one. We therefore diagnosed CIDP plus CMT in four patients (3.6%), all of them with a duplicated PMP22 gene. The other six patients were diagnosed as pure CMT (5) or Hereditary Neuropathy with liability to Pressure Palsy (1), as they did not improved with the use of immunomodulatory and/or immunosupressive treatment (five cases) or were found to have alternative associated diagnosis (one patient). The other 101 patients did not show duplication nor delection in this gene, so they had CIDP. Mean age of patients with CIDP/CMT were 23.8±18.0 years and 43.6±19.3 years for patients without mutations (p=0.04). There were statistically significant difference in treatmet response between groups CIDP/CMT X CMT (p=0.008) and CIDP X CMT (p=0.00). The lack of family history and presence of other diseases and habits linked to the development of peripheral neuropathies, as diabetes mellitus and alcohol intake, for instance, as well as atypical findings in electrodiagnostic studies and nerve biopsy may have contributed to misdiagnose in the pure CMT cases. Conclusions: Some patients may develop CIDP in association with CMT and have benefit from treatment. The hereditary neuropathy may predispose to the inflammatory neuropathy as these patients tend to show this condition at younger ages. Caution should be dispensed to those patients with a suspected diagnose of CIDP who do not have the classical disease findings or do not improve with treatment, as they can have alternative etiologies for the neuropathy, among them a hereditary neuropathy as CMT disease.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2005. / Härtill 4 uppsatser.

INTRODUÇÃO: Neuromielite óptica (NMO) e suas formas limitadas são doenças desmielinizantes autoimunes do sistema nervoso central que acometem preferencialmente a medula espinhal e o nervo óptico. Várias formas clínicas do espectro da NMO (NMO-SD) tem sido descritas e incluem desde um evento único de mielite transversa longitudinalmente extensa (MTLE) à NMO recorrente. O comprometimento neurológico destes pacientes pode levar a diversas disfunções autonômicas, incluindo disfunção miccional. OBJETIVOS: Determinar a prevalência e as características dos sintomas do trato urinário inferior (STUI) e dos achados urodinâmicos em pacientes portadores de NMO-SD, e analisar suas associações com o grau de comprometimento neurológico e qualidade de vida (QV). MÉTODOS: Avaliamos 30 pacientes (23 mulheres e 7 homens) com diagnóstico estabelecido de NMO-SD, que foram convidados a participar do estudo a despeito de apresentarem ou não STUI. A avaliação neurológica foi realizada por meio da Escala Expandida do Estado de Incapacidade (EDSS), ressonância magnética de crânio e coluna vertebral, e dosagem de NMOIgG. Os STUI foram avaliados pelo Questionário de Avaliação da Bexiga Hiperativa (OAB-V8) e pelo Escore Internacional de Sintomas Prostáticos (IPSS). A qualidade de vida de forma geral foi avaliada pelo questionário de Satisfação com a Vida (LiSat-9). Todos os pacientes foram submetidos ao estudo videourodinâmico. RESULTADOS: A idade média dos pacientes foi de 41,1 ± 13,5 anos (intervalo de 13 a 70) e o tempo médio de duração da doença neurológica foi de 33,8 ± 30,8 meses (intervalo de 3 a 135). A avaliação neurológica mostrou pacientes com EDSS médio de 5,3 ± 1,8 (intervalo de 1 a 8,5). O escore médio do OAB-V8 foi de 17,5 ± 14,0 (intervalo de 0 a 40) e de 14,3 ± 10,6 (intervalo de 0 a 35) para o I-PSS. A média da QV geral medida pelo Lisat-9 foi de 38,9 ± 6,8 (intervalo de 26 a 49). Os STUI mais comuns foram urgência em 15 (50%) pacientes, noctúria em 15 (50%), jato urinário fraco em 15 (50%), intermitência em 14 (46,6%), esvaziamento incompleto em 13 (43,3%), hesitação em 13 (43,3%), aumento da frequência urinária em 13 (43,3%) e urge-incontinência em 5 (16%). Os achados urodinâmicos mais comuns foram hiperatividade detrusora (HD) com dissinergia detrusor-esfincteriana (DDE) em 11 (36,6%) pacientes, DDE sem HD em 7 (23,3%), HD sem DDE em 6 (20%), e incontinência urinária de esforço em 1 (3,3%). Cinco (16,6%) pacientes apresentaram estudo videourodinâmico sem anormalidades. Sintomas urinários medidos pelo IPSS e pelo OAB-V8 correlacionaram-se com maior comprometimento neurológico (r=0,42; p=0,018 e r=0,48; p=0,006 respectivamente). Pacientes portadores de DDE foram aqueles que mostraram maior comprometimento neurológico (p=0,027). Da mesma forma, pacientes dissinérgicos apresentaram maiores escores ao I-PSS (p=0,029) e ao OAB-V8 (p=0,008). Pacientes com maior comprometimento neurológico foram aqueles que apresentaram pior QV (r=-0,410; p=0,022). CONCLUSÃO: Encontramos alta prevalência de STUI e disfunção miccional em portadores de NMO, sendo DDE e a HD as anormalidades urodinâmicas mais frequentes. Dissinergia detrusor-esfincteriana e STUI se correlacionam com a gravidade da doença neurológica. A severidade da doença neurológica correlaciona-se com a qualidade de vida geral / INTRODUCTION: Neuromyelitis optica (NMO) and its limited forms are demyelinating autoimmune diseases of the central nervous system that preferentially affects the spinal cord and optic nerve. Several clinical forms of NMO spectrum disorders (NMO-SD) have been described and range from a limited event of longitudinally extensive transverse myelitis (LETM) to relapsing NMO. The neurological damage in these patients may lead to a range of autonomic dysfunctions, including voiding dysfunction. OBJECTIVES: To determine the prevalence and characteristics of the lower urinary tract symptoms (LUTS) and the urodynamic findings in patients with NMO-SD and analyze their correlations with the level of neurological damage and quality of life (QoL). METHODS: We evaluated 30 patients (23 women and 7 men) with an established diagnosis of NMO-SD based on stringent criteria. All patients were invited to participate irrespective of the presence of LUTS. Neurological impairment was assessed with the Expanded Disability Status Scale (EDSS), magnetic resonance imaging of the brain and spinal cord and NMO-IgG status. LUTS were evaluated with the Overactive Bladder V8 (OAB-V8) questionnaire and by the International Prostate Symptom Score (I-PSS). Quality of Life was evaluated using the Life Satisfaction questionnaire (LiSat-9). All patients underwent videourodynamics, transabdominal urinary tract sonography, urine culture and serum creatinine levels. RESULTS: The mean age of the patients was 41.1 ± 13.5 years (range 13 to 70) and the mean time of neurological disease duration was 33.8 ± 30.8 months (range 3 to 135). Neurological evaluation showed a mean EDSS score of 5.3 ± 1.8 (range 1 to 8.5). The mean OAB-V8 score was 17.5 ± 14.0 (range 0 to 40) and the mean I-PSS score was 14.3 ± 10.6 (range of 0 to 35). Mean general QoL measured by the Lisat-9 was 38.9 ± 6.8 (range 26 to 49). The most common urinary symptoms were urgency in 15 (50%) patients, nocturia in 15 (50%), weak urinary stream in 15 (50%), intermittence in 14 (46.6%), incomplete emptying in 13 (43.3%), hesitation in 13 (43.3%), increased urinary frequency in 13 (43.3%) and urge-incontinence in 5 (16,6%). The most frequent urodynamic findings were detrusor overactivity (DO) with sphincter dyssinergia (DSD) in 11 (36.6%) patients, DSD alone in 7 (23.3%), DO without DSD in 6 (20%) and stress urinary incontinence (SUI) in 1 (3.3%). Five (16.6%) patients had normal findings. Voiding dysfunction assessed by I-PSS and OAB-V8 increased with the degree of neurological impairment (r=0.42; p=0.018 and r=0.48; p=0.006 respectively). Patients with DSD had significantly higher symptoms based in the I-PSS (p=0.029) as well as the OAB- V8 scores (p=0.008) and greater neurological impairment (p=0.027). Patients with more severe neurological impairment were associated with worse Qol (r=-0.410; p=0.022). CONCLUSION: We have shown a high prevalence of LUTS and voiding dysfunction, with DSD and DO as the main urodynamic findings. Detrusor-sphincter dyssinergia and LUTS correlates with more severe neurological impairment. The severity of neurological impairment correlates with QoL

Introdução: Polineuropatias são doenças do sistema nervoso periférico com etiologias variadas. Dentre elas são freqüentes as inflamatórias e as hereditárias, com prevalência de 0,67-7,7/100000 e 7,9-82,3/100000 para polineuropatia inflamatória desmielinizante crônica (PIDC) e Doença de Charcot-Marie-Tooth (CMT), respectivamente. Existem poucas evidências de sobreposição entre estas duas doenças e também algumas dificuldades diagnósticas em situações específicas. Objetivos: Estudar a freqüência de mutações (duplicações e deleções) do gene PMP22 em uma coorte de pacientes inicialmente diagnosticados como PIDC ou suspeitos de apresentarem as duas condições, os sinais e sintomas sugestivos da sobreposição e os fatores implicados em erro de classificação da neuropatia. Métodos: 111 pacientes com diagnóstico de PIDC foram estudados. DNA foi isolado a partir de leucócitos de sangue periférico segundo protocolo padrão. Duplicações e deleções do gene PMP22 foram avaliadas através de marcadores polimórficos do DNA localizados dentro do cromossomo 17p11.2-12, o qual contém o gene PMP22. Achados clínicos e laboratoriais também foram estudados e comparados entre os grupos. Resultados: Dentre os 111 pacientes estudados, mutações no PMP22 foram encontradas em 10 (9%), sendo duplicações em 9 pacientes e deleção em 1 paciente. Concomitância entre PIDC e CMT foi verificada em 4 pacientes (3,6%), todos com duplicação do PMP22. Os outros 6 pacientes foram diagnosticados como CMT puro (5) ou Neuropatia Hereditária Susceptível à Compressão (1), visto que não apresentaram melhora com o uso de tratamento imunomodulador e/ou imunossupressor (5 casos) ou foi estabelecido diagnóstico alternativo associado (1). Os outros 101 pacientes não tiveram duplicação nem deleção deste gene e, portanto, tinham PIDC apenas. Idade média dos pacientes com PIDC/CMT foi de 23,8±18,0 anos e 43,6±19,3 anos para pacientes sem mutações (p=0,04). Houve diferença estatísticamente significativa na resposta ao tratamento entre os grupos PIDC/CMT X CMT (p=0,008) e PIDC X CMT (p=0,00). Ausência de história familiar e presença de doenças e hábitos ligados ao desenvolvimento de neuropatias periféricas, como diabetes mellitus e ingesta de bebidas alcoólicas, por exemplo, bem como achados atípicos na eletroneuromiografia e na biópsia de nervo podem ter contribuído para a confusão diagnóstica nos casos de CMT puro. Conclusões: Alguns pacientes podem desenvolver PIDC em associação com CMT e se beneficiam do tratamento. A neuropatia hereditária poderia predispor à neuropatia inflamatória, uma vez que estes pacientes tendem a apresentar essa condição em idades mais precoces. Cautela deve ser dispensada àqueles pacientes com suspeita diagnóstica de PIDC que não têm os achados clássicos ou não melhoram com o tratamento, uma vez que podem apresentar outras etiologias para a neuropatia, dentre elas uma neuropatia hereditária, como a CMT. / Introduction: Polyneuropathies are peripheral nervous system disorders with a wide range of etiologies. Among them, inflammatory and hereditary are frequent with prevalence of 0.67-7.7/100000 and 7.9-82.3/100000, for chronic inflammatory demyelinating polyneuropathy (CIDP) and Charcot-Marie-Tooth disease (CMT), respectively. There are a few evidence of ovelapping between these two conditions and also some diagnostic difficulties in specific situations. Objectives: To study the frequency of mutations in PMP22 gene (duplications and delections) among a cohort of patients initially diagnosed as CIDP or suspected to have both conditions, the signs and symptoms related to this ovelapping and factors implicated in misdiagnose. Methods: 111 patients with an initially CIDP suspected diagnosis were studied. DNA was isolated from peripheral blood leucocytes following a standard salting-out protocol. Duplications and delections in the PMP22 gene were analysed by polymorphic DNA markers located within the chromosome 17p11.2-12, wich contains the PMP22 gene. Clinical and laboratory findings were also studied and compared within groups. Results: Among 111 patients studied, 10 (9%) were found to harbor mutations in PMP22 gene, specifically duplications in nine and delection in one. We therefore diagnosed CIDP plus CMT in four patients (3.6%), all of them with a duplicated PMP22 gene. The other six patients were diagnosed as pure CMT (5) or Hereditary Neuropathy with liability to Pressure Palsy (1), as they did not improved with the use of immunomodulatory and/or immunosupressive treatment (five cases) or were found to have alternative associated diagnosis (one patient). The other 101 patients did not show duplication nor delection in this gene, so they had CIDP. Mean age of patients with CIDP/CMT were 23.8±18.0 years and 43.6±19.3 years for patients without mutations (p=0.04). There were statistically significant difference in treatmet response between groups CIDP/CMT X CMT (p=0.008) and CIDP X CMT (p=0.00). The lack of family history and presence of other diseases and habits linked to the development of peripheral neuropathies, as diabetes mellitus and alcohol intake, for instance, as well as atypical findings in electrodiagnostic studies and nerve biopsy may have contributed to misdiagnose in the pure CMT cases. Conclusions: Some patients may develop CIDP in association with CMT and have benefit from treatment. The hereditary neuropathy may predispose to the inflammatory neuropathy as these patients tend to show this condition at younger ages. Caution should be dispensed to those patients with a suspected diagnose of CIDP who do not have the classical disease findings or do not improve with treatment, as they can have alternative etiologies for the neuropathy, among them a hereditary neuropathy as CMT disease.

Background: Anti-NMDA receptor encephalitis (NMDAR-E) is an autoimmune encephalitis (AE) mainly affecting young females. It typically presents with isolated psychiatric symptoms (e.g. depressed mood) at first and neurological abnormalities (e.g. seizures, movement disorders) only develop later. Thus, there is a high risk of overlooking NMDAR-E in patients with preexisting psychiatric illness due to symptom overlap in the prodromal period of the disease when treatment is most effective. Although rare, concomitant or sequential development of a demyelinating disorder is increasingly recognized as an associated disease entity (overlap syndrome), with immediate diagnostic and therapeutic implications. Case presentation: We report a patient with a borderline personality disorder (BPD), which developed NMDAR-E and an overlapping demyelinating disorder with anti-Myelin oligodendrocyte glycoprotein (MOG) -IgG positivity. The initial clinical presentation with predominantly affective symptoms (e.g. mood lability, anxiety, depressed mood) lead us to suspect an exacerbation of the BPD at first. However, acute changes in premorbid behavior, newly developed psychotic symptoms and memory deficits lead us to the correct diagnosis of an AE, which was further complicated by the development of a demyelinating disorder. As a result of impaired illness awareness and psychosis, diagnostic and treatment was difficult to carry out. The symptoms completely remitted after treatment with methylprednisolone 1 g daily for 5 days and 5 cycles of plasma exchange. Conclusions: Continuous awareness for neuropsychiatric clinical warning signs in patients with a pre-diagnosed psychiatric disorder is important for a timely diagnosis. Therefore, we believe that the diagnostic and therapeutic algorithm provided here, for the first time specifically addressing patients with preexisting psychiatric illness and integrating overlap syndromes, can be a useful tool. Moreover, in order to timely perform diagnostics and treatment, judicial approval should be obtained rapidly.

Made available in DSpace on 2015-06-26T13:08:44Z (GMT). No. of bitstreams: 2 stella_aparecida_iff_mest_2013.pdf: 2260165 bytes, checksum: eb12d331363220960351de6e8f16c16d (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2013 / Fundação Oswaldo Cruz. Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira. Departamento de Ensino. Programa de Pós-Graduação em Saúde da Criança e da Mulher. Rio de Janeiro, RJ, Brasil. / As lesões tumefativas desmielinizantes (LTD) do SNC apresentam extrema dificuldade diagnóstica em virtude da similaridade clínica e radiológica com outras entidades nosológicas, incluindo doenças neoplásicas, inflamatórias e infecciosas. Frequentemente, o caráter indefinido das lesões aponta para a necessidade de biópsia cerebral com alto risco de morbidade. Portanto, o reconhecimento das características neurorradiológicas da LTD é fundamental para evitar a utilização de procedimentos invasivos. Na prática clínica, os exemplos das formas tumefativas não tumorais são os seguintes: esclerose múltipla (EM), neuromielite óptica (NMO), doença de Schilder e encefalomielite agudadisseminada (ADEM).Objetivo e Métodos: Analisar, através de revisão sistemática da literatura, quais ferramentas diagnósticas clínicas, radiológicas e laboratoriais são utilizadas pelos autores na investigação da etiologia das LTDs do SNC na infância.Resultados: As doenças desmielinizantes encontradas foram as seguintes: EM em 36% dos casos; LTD, sem classificação específica, em 27%; ADEM 17%;doença de Schilder 13 % e NMO 7%. De todos os casos estudados, em 45% houve recorrência de eventos desmielinizantes. Não há protocolo definido em relação aos tipos de exame solicitados nem a sequência apropriada ou oportunidade de indicá-los. Os exames mais realizados pelos autores foram os seguintes: RM de crânio, exame histopatológico, pesquisa de bandas oligoclonais e índice de IgG no líquor, RM de coluna e pesquisa de anticorpo antiaquaporina 4. Conclusão: A análise da literatura mostra que os dados mais relevantes para se definir o diagnóstico das LTDs são obtidos através da história e evolução clínica dos pacientes, e exames de neuroimagem; é fundamental que pacientes portadores de LTD sejam acompanhados a médio/longo prazo na tentativa de aumentar as possibilidades diagnósticas; não existe protocolo universal de abordagem das LTDs; há necessidade incondicional de implementação de fluxo de procedimentos capazes de orientar o diagnóstico das LTDs na infância e adolescência. / Introduction: The tumefactive demyelinating lesions (TDL) of the CNS have extremely difficult diagnosis due to the clinical and radiological similarity with other nosological entities, including neoplastic, inflammatory and infectious diseases. Commonly, the undefined character of the lesions points to the need of brain biopsy with high risk of morbidity. Thus, the recognition of neuroradiological characteristics of the TDL is critical to avoid the use of invasive procedures. In the clinical practice, the examples of the non tumorous forms of tumefactive lesions are the following: multiple sclerosis (MS), optic neuromyelitis (ONM), Schilder`s disease and acute disseminated encephalomyelitis (ADEM). Objective and Methods: Analysis, through the systematic review of the literature, which clinic, radiological and laboratorial diagnostic tools are used by the authors in the investigation of the etiology of the TDL`s of the CNS in the childhood. Results: The following demyelinating diseases have been found: MS in 36% of the cases; TDL without a specific classification in 27%; ADEM 17%;Schilder`s disease 13 % and ONM 7%. Considering all the cases studied, in 45% had recurrence of demyelinating events. There is no defined protocol with respect to the types with medical exams requested neither the appropriate sequence or the opportunity of indicate them. The medical exams more conducted by the authors were the following: MRI of skull,histopathological exam, research of oligoclonal bands and IgGindex in the liquor, MRI of spine and research of anti-aquaporin-4 antibody. Conclusion: The analysis of the literature shows that the most relevant data to define the diagnosis of the TDLs are obtained through the history and clinical evolution of the patients and neuroimaging tests.It is critical that the patients with TDL be accompanied over the medium/long term in an attempt of increase the diagnostic possibilities; there is not an universal protocol of approach of the TDL; there is unconditional necessity of implementation of flow of procedures able to guide the diagnosis of the TDLs in the childhood and adolescence.