Magister Scientiae (Physiotherapy) - MSc(Physio) / Peripheral neuropathy (PN) is a common neurological complication occurring in the asymptomatic and symptomatic stages of human immune deficiency virus (HIV) infection. The pain and other symptoms caused by PN can impair functional ability and limit physical activity that could affect quality of life (QoL). Additionally, studies done on quality of life of people living with HIV/AIDS have shown that, HIV-related neurological syndromes, including PN, significantly reduce QoL. The aim of this study was to determine the prevalence of peripheral neuropathy amongst and the quality of life of adults living with HIV/AIDS attending the out-patient clinic at Rutongo Hospital in Rulindo District in Rwanda. / South Africa

This diploma thesis deals with the topic of nutritional support in patients with neurological diseases (stroke and Critical-Illness-Polyneuropathy). The aim of this thesis is to find out, how implemented unified system of nutritional support affects the well-being of patients at neuro-rehabilitation clinic Asklepios Schlossberg Klinik in Bad König. There were observed 55 patients (30 men and 25 women) for 8 weeks. The theoretical part of this thesis describes basic components of nutrition, energy expenditure and needs, selected neurological diseases, dysphagia, malnutrition. The emphasis is put on nutrition in intensive neurological care. The practical part of the thesis analyses data obtained by the observation. There are observed changes of body weight, BMI and laboratory values of total protein, albumin and glycaemia in serum. These data are divided by sex, age, type of disease and initial BMI values. The observed patients had mainly overweight and obesity, which have lost a part of their excess weight due to catabolism. At the beginning of the observation 13 patient had normal BMI value, this number of patients rose to 24 after eight weeks. At the end of the observation the reduction of BMI value was on the average 2.45 units. Based on the results, it was found that although patients due to...

Ces travaux de recherche s’intéressent à la conception de nouvelles méthodologies analytiques destinées à mesurer le bénéfice d’une transplantation hépatique ou bien encore à l’évaluation de nouvelles voies thérapeutiques à l’essai pour des patients atteints de la polyneuropathie amyloïde familiale à transthyrétine (TTR). Cette maladie rare se caractérise par une déstabilisation structurale du tétramère de TTR qui aboutit à l’agrégation de fibrille dans les tissus du système nerveux autonome, au niveau des nerfs périphériques et autour de certains organes dont le cœur. Dans le cadre d’une collaboration entre hospitalo-universitaires, chimistes analystes, électrochimistes, physico-chimistes et technologues, nous nous sommes attachés à développer des séparations en électrophorèse capillaire couplée avec une détection optique de peptides natif et muté qui sont directement associés à une variente de cette maladie rare. La difficulté première de cette recherche concerne le choix même de ces biomarqueurs qui s’est finalement révélé pertinent grâce de la réalisation de cartes peptidiques à partir du sérum. Ensuite deux voies ont été explorées : une séparation électrocinétique avec une détection spectrométrique d’absorbance dans l’ultra-violet et l’autre nécessitant le marquage préalable de peptides par des molécules fluorophores ou fluorogènes pour ensuite faire une séparation en électrophorèse couplée LIF (laser induced fluorescence). Dans les deux cas le critère principal de séparation, la résolution, autorise une quantification et surtout les validations analytiques associées montrent une réelle robustesse des méthodologies développées. L’autre signe encourageant pour la transposition des ces méthodes à l’analyse de prélèvements issus de patients, concerne la limite de quantification qui est inférieure à celle couramment mesuré dans le sérum. La spectrométrie de masse, moyen d’investigation physico-chimique puissant à permis de suivre et de comprendre d’un point vue plus fondamental le produit des réactions de chimie organique de dérivation des peptides par trois marqueurs fluorescents : le TAMRA-SE, le NDA et le FQ. La possibilité de proposer un outil d’analyse miniaturisé et simple d’utilisation pour le monde hospitalier a également été étudiée. Un poste d’analyse sur puce microfluidique permettant l’analyse quantitative et qualitative a été installé pour permettre la réalisation de premiers essais expérimentaux de séparations électrocinétiques sur puce microfluidique. Ces travaux jettent les bases d’une nouvelle voie analytique pour séparer et quantifier les différents biomarqueurs caractéristiques de la polyneuropathie amyloïde familliale à TTR. / The purpose of our work was the development of new analytical methodologies to measure the benefit of liver transplantation and also the evaluation of new therapeutic approaches under testing on patients with Transtyretin (TTR) familial amyloid polyneuropathy. This rare disease is characterized by a structural destabilization of TTR tetramer leading to it’s aggregation into amyloïd fibrils that accumulate in the tissues of the autonomous nervous system, peripheral nerves and around certain organs, including the heart. As part of a collaboration between university, hospital, analytical chemists, electrochemist, physical chemists and technologists, we are committed to develop separations in capillary electrophoresis coupled with optical detection of native and mutated peptides that are directly associated with a variant of this rare disease. The first challenge of this research is the choice of these biomarkers that ultimately proved relevant with the realization of peptide maps from the serum. Then two approaches have been explored: electrokinetic separation with absorbance spectrometric detection in the ultraviolet and the other requiring the prior labeling peptides with fluorescent molecules and then to a separation on electrophoresis coupled with LIF (Laser induced fluorescence). In both cases the main criterion of separation, resolution, allows quantification and especially analytical validations show actual strength associated methodologies developed. Another encouraging sign for the transposition of these methods to the analysis of samples from patients regarding the quantification limit is lower than commonly measured in serum. Mass spectrometry, using physico-chemical investigation powerful allowed to follow and understand a more fundamental viewpoint the product of organic chemistry reactions bypass peptides by three fluorescent dyes: TAMRA-SE, the NDA and FQ. The ability to provide a miniaturized analysis and easy to use tool for the hospital environment was also studied. A post analysis on microfluidic chip for quantitative and qualitative analysis was installed to allow the realization of the first experimental tests of electrokinetic separations on microfluidic chip. These studies lay the foundation for a new analytical way to separate and quantify the different characteristics biomarkers family TTR amyloid polyneuropathy.

Esta tese assumiu a premissa de que a neuropatia periférica é um sinal de piora da diabetes, além de levantar a questão de que estudos prévios sobre a biomecânica da marcha de diabéticos não têm distinguido os graus de progressão da diabetes nos grupos estudados. Neste contexto, não é possível identificar as diferenças nos padrões de geração da marcha entre estágios precoces e avançados da diabetes. Esta identificação poderia facilitar a intervenção terapêutica precoce nestes pacientes, o que poderá impedir a formação de úlceras e amputações recorrentes subseqüentes. Assim, apresentamos ao longo desta tese, três estudos para investigar a natureza das supostas alterações na marcha (estudo 1) e no descer escadas (estudo 2) de diabéticos, assim como para propor uma forma de classificar a progressão da diabetes levando em consideração as incertezas de fronteiras entre os subgrupos de neuropatas, por meio de um sistema especialista fuzzy (estudo 3). Os estudos 1 e 2 foram feitos com os mesmos três grupos: indivíduos diabéticos (GD) e diabéticos neuropatas (GDN) diagnosticados clinicamente e indivíduos saudáveis (GC). Para a avaliação cinemática e cinética do membro inferior foram utilizadas câmeras infravermelhas e uma plataforma de força durante o andar no plano e descendo uma escada. O cálculo dos momentos articulares de membro inferior foi feito por meio do método da dinâmica inversa. Os principais resultados do estudo 1 mostraram que independente da presença da neuropatia, os pacientes diabéticos exibiram uma maior flexão das três principais articulações do membro inferior e um importante uso da articulação do quadril como uma estratégia cinética de progressão do corpo à frente, em substituição ao tornozelo, que mostrou ser a articulação mais prejudicada. Os principais resultados do estudo 2 indicaram as mesmas mudanças significativas no padrão cinemático do tornozelo durante a fase de propulsão, mesmo na ausência da neuropatia. No entanto, não houve diferença nos padrões cinéticos entre os estágios iniciais e avançados da doença, mas mostraram a mesma tendência observada no estudo 1 de alteração do padrão cinético de quadril para se adaptar às perdas distais nos neuropatas. No estudo 3, desenvolvemos um modelo para classificação da severidade da neuropatia diabética. O modelo fuzzy apresentou um nível de concordância adequado com a classificação feita por especialistas, e também mostrou uma alta precisão na avaliação de pacientes reais que foram submetidos à avaliação do modelo. O modelo foi capaz de simplificar e separar os pacientes em quatro diferentes graus de severidade, o que pode melhorar a eficácia de medidas preventivas, bem como para oferecer uma melhor ajuda para os profissionais de saúde no tratamento destas doenças e suas complicações. Como conclusão geral temos que os grupos diabéticos estudados exibiram comportamentos biomecânicos durante o andar no plano e descendo degraus que são muitas vezes parecidos entre si (GD e GDN), poucas vezes diferentes entre si, mas na maioria das vezes bem distintos do grupo não diabético (GC), indicando que a questão da progressão não se esclareceu completamente ao separamos de maneira crisp os grupos em diabético e diabético neuropata. As perdas sensitivo-motoras-autonômicas impostas pela diabetes não podem ser subestimadas, uma vez que parecem ter início ainda quando a neuropatia não foi diagnosticada. Uma correta classificação do paciente pode antecipar a detecção dos níveis menos severos da doença, evitando esperar que os pacientes apresentem perdas irreversívies para inicar uma intervenção clínica eficaz e preventiva para preservar a locomoção independente destes pacientes / This study assumed the premise that the peripheral neuropathy is a sign of worsening of diabetes, as well as raising the issue that previous studies on the biomechanics of gait in diabetics do not have distinguished the degree of progression of diabetes in both groups. Therefore, it is not possible to identify differences in patterns of gait generation between early and advanced stages of diabetes. This identification would facilitate early therapeutic intervention in these patients, which could prevent the formation of recurrent ulcers and subsequent amputations. We present throughout this thesis, three studies to investigate the nature of the alleged changes in gait (study 1) and stair descent (study 2) of diabetics, and to propose a way to classify the progression of diabetes, taking into account the uncertainties of boundaries between the subgroups of neuropathy through a fuzzy expert system (study 3). Studies 1 and 2 were performed with the same three groups: diabetics (GD) and diabetic neuropathic (GDN) diagnosed clinically and healthy subjects (CG). For the kinematic and kinetic evaluation of the lower limb, we used infrared cameras and a force plate during walking on a level walkway (10 m) and descent a staircase. The calculation of net joint moments of the lower limb was performed using the method of inverse dynamic. The main results of Study 1 showed that, regardless of the presence of neuropathy, diabetic patients exhibited a greater flexion of the three major joints of the lower limb and an important use of the hip joint as a kinetic strategy of progression the body forward, replacing the ankle, which proved to be the most affected joint. The main results of Study 2 showed the same significant changes in the pattern of the ankle kinematics during propulsion phase, even in the absence of neuropathy. However, there was no difference between the kinetic patterns in early and advanced stages of the disease, but showed the same trend observed in the Study 1: a change in the kinetic pattern of the hip to adapt de locomotion to distal loss in neuropathic subjects. In Study 3, the model developed for classification of severity of diabetic neuropathy showed an adequate level of agreement with the classification of experts, and also showed a high accuracy in the evaluation of real patients who underwent to the evaluation of the model. The fuzzy model was able to simplify and separate the patients into four different degrees of severity, which can improve the effectiveness of preventive strategies as well as to offer a better assistance to health professionals in the management of this disease. It is concluded that the studied diabetic groups exhibited biomechanical behavior during walking and descend stairs that are often similar to each other (GD and GDN), a few times different from each other, but most often very different from the non-diabetic group (GC), indicating that the issue of progression was not fully understood separating the groups in a crisp way as diabetic and diabetic neuropathic subjects. The sensory, motor and autonomic losses imposed by the diabetes can not be underestimated, since they seem to appear when the neuropathy is not diagnosed yet. A correct classification of the patient can anticipate the detection of less severe levels of the disease and avoid that the patients show an irreversible loss to start an effective intervention and preventive strategies to keep the independent locomotion of these patients

Amyloidoses comprise a group of gain-of-toxic function protein misfolding diseases, in which normally soluble proteins in their functional state undergo conformational changes into highly organized and generally intractable thread-like aggregates, termed amyloid fibrils. These structures accumulate predominantly in the extracellular space but growing evidence suggests that amyloids may start to form intracellularly. At least 26 different human proteins, intact or in fragmented form, are known to form amyloid, which is linked with many debilitating neurodegenerative diseases such as Alzheimer’s disease (AD), Creutzfeldt-Jakob disease, and transthyretin (TTR)-related amyloidosis (ATTR). In this work, we focus on ATTR, which is one of the most frequent systemic amyloid diseases. A functional link was established between hereditary ATTR, a severe and fatal disorder and the enhanced propensity of the human plasma protein transthyretin (TTR) to form aggregates, caused by single point mutations in the TTR gene. The disease is heterogeneous and clinical symptoms vary from cardiomyopathy to progressing sensorimotor polyneuropathy depending on TTR variant involved and the amyloid deposition site. Despite the fact that TTR-derived amyloid accumulates in different organs such as heart, kidney, eyes, and predominantly in the peripheral nerves of ATTR patients, the exact mechanism of the disease development is not understood. In contrast to the case of AD, it has been difficult to generate an animal model for ATTR in transgenic mice that would be useful in understanding TTR aggregation processes and the mechanisms of the associated toxicity as these mice did not develop any neuropathic phenotype besides amyloid deposits. Therefore, we created a disease-model in Drosophila due to its huge repertoire of genetic techniques and easy genotype – phenotype translation, as well as its success in modeling human neurodegeneration. We have generated transgenic flies that over-express the clinical amyloidogenic variant TTRL55P, the engineered variant TTR-A (TTRV14N ⁄ V16E), and the wild-type protein. All TTR variants were found in the secreted form in the hemolymph where misfolding occurred and depending on the pool of toxic species, the fate of the fly was decided. Within a few weeks, both mutants (but not the wild-type TTR) demonstrated a time-dependent aggregation of misfolded molecules in vivo. This was associated with neurodegeneration, change in wing posture, attenuation of locomotor activity including compromised flying ability, and shortened life span. In contrast, expression of the wild-type TTR had no discernible effect on either longevity or fly behavior. In this work, we also addressed the correlation between TTR transgene dosage and thus, protein levels, with the severity of the phenotypes observed in TTR-A flies which developed a “dragged wing” phenotype. Remarkably, we established that degenerative changes such as damage to the retina strictly correlated with increased levels of mutated TTR but inversely with behavioral alterations and the dragged wing phenotype. We characterized formation of aggregates in the form of 20 nm spherules and amyloid filaments intracellularly in the thoracic adipose tissue and brain glia (both tissues that do not express the transgene). Moreover, we detected a fraction of neurotoxic TTR-A in the hemolymph of young but not old flies. We proposed that these animals counteract formation and persistence of toxic TTR-A species by removal from the circulation into intracellular compartments of glial and fat body cells and this is part of a mechanism that neutralizes the toxic effects of TTR. We validated the fly model for ATTR by applying a genetic screen during study of modifier genes. We found Serum amyloid P component (a product of the APCS gene) as a potent modifier of TTR amyloid-induced toxicity that was effective in preventing the apoptotic response in cell culture assay and capable of reducing the dragged wings when co-expressed in TTR-A flies. Finally, we optimized this fly model in order to screen for therapeutic compounds effective against ATTR. Feeding assays showed the effectiveness of several compounds among known native-state kinetic stabilizers of TTR against its aggregation. We described several early endpoints in this model, which can be used as a rapid and cost-effective method for optimizing concentrations and pre-screening of drug candidates. As the proof of principle, by feeding flies with increasing doses of diflunisal analogue (an FDA-approved Non-Steroidal Anti-Inflammatory Drug) a dose-dependent reduction of the dragged wings was observed.

Background. Familial Amyloidosis with Polyneuropathy (FAP) is an autosomal dominantly inherited systemic amyloid disease. The disease is caused by mutations in the transthyretin (TTR) gene, where close to 100 different amyloidogenic mutations have been identified. FAP is found worldwide, but endemic areas with a high frequency of patients are found in Portugal, Japan and northern Sweden. Cases from these endemic areas all share the same TTR c.148G>A, p.V50M ("V30M") mutation, but the phenotype of the disease varies between the areas, and also within the endemic areas. The mean onset of the disease is two decades earlier in Portugal and Japan compared to Sweden, but late as well as early age at onset cases occur within all the populations. Interestingly, the different populations all display a maternal anticipation, where an earlier onset is observed for those individuals who inherit the trait from their mother. Since substantial variation in the phenotype is observed for different populations, epigenetic/genetic and/or environmental factors must exert a significant impact on the penetrance of the disease. Amyloid formation is caused by conformational changes of proteins, which facilitates their assembly into fibrils, amyloid. Oxidative stress can mediate conformational changes of proteins and since the mitochondria regulate oxidative processes within the cell, mitochondrial function may affect amyloid formation. The mitochondrial DNA is a non-nuclear DNA, which is entirely maternally inherited, and therefore could be related to the observed maternal anticipation of the disease. In addition, differences within the surrounding regions of the TTR gene may have an impact on the transcription of the gene and thereby on the expression of the different alleles. Material and methods. DNA from early and late onset V30M cases and from non-carriers (the latter utilised as controls) from Swedish, French, Japanese and Portuguese populations were analysed. In addition, DNA from healthy Swedish V30M carriers was analysed. Conventional analytical methods were employed, such as PCR, sequencing and genotyping. Conventional statistical methods used were t-test, Chi-squared test and maximum likelihood. Results. The study of V30M carrier frequency in two counties (Lycksele and Skellefteå) within the Swedish endemic area revealed a carrier frequency of 2.14% and 2.54%, respectively. The mitochondrial haplogroup analysis showed that in populations with generally late onset (French and Swedish), the haplogroup distribution of late onset cases resembled that of the controls derived from the same area, whereas haplogroup distribution for early onset patients was significantly different. The most pronounced difference was for the rare haplogroup K, of which early onset cases had a higher frequency than the controls. Analysis of the Portuguese population, with predominantly early onset, showed that haplogroup distribution for early onset cases were similar to the Portuguese control group, which had a different distribution than the Swedish control group. By analysis of pedigrees from Swedish and Portuguese patients it could be shown that mitochondrial genetic variation entirely could explain maternal anticipation in the Portuguese patients, whereas for Swedish patients, an additional parent of origin effect is present. Our analysis of the TTR gene disclosed a polymorphism (rs62093482) in the 3'UTR region of the Swedish patients. This polymorphism was found in all V30M carriers, irrespective of symptoms. In addition, homozygous TTR V30M carriers were homozygous also for the polymorphism. Since Swedish patients share a common founder this polymorphism thus is localised on the V30M allele. This polymorphism was found in only 4% of the Swedish controls. French controls showed the same frequency, but none of the French V30M patients displayed the polymorphism. In the Japanese population the polymorphism was not present at all. Interestingly, this polymorphism generates a potential binding site for microRNA and thereby possibly could down-regulate the expression of the mutated TTR allele. Conclusions. The carrier frequency in the endemic area is remarkably high, above 2% in the Lycksele and Skellefteå areas. The prevailing haplogroup distributions in the different endemic areas are consistent between the general population and the patient group with the predominant phenotype of that area. Mitochondrial genetic differences may explain maternal anticipation in Portuguese patients, and have an influence in Swedish patients. A polymorphism in the 3'UTR regulatory region of the mutated TTR allele is found in all Swedish patients. This polymorphism may down-regulate TTR V30M expression and thereby contribute to the late onset of the disease noted in the Swedish population.

Background Transthyretin amyloid (ATTR) amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin (TTR) monomers. Two main forms exist – wild-type and hereditary ATTR amyloidosis, the latter associated with TTR gene mutations. Wild-type ATTR amyloidosis has a late onset and primarily cardiac manifestations, whereas hereditary ATTR amyloidosis is a rare autosomal dominant condition with a considerable phenotypic diversity. Both disorders are present all over the world, but endemic areas of the hereditary form are found in Sweden, Portugal, Brazil and Japan. Gastrointestinal (GI) complications are common in hereditary ATTR amyloidosis and play an important role in the patients’ morbidity and mortality. Malfunction of the autonomic and enteric nervous systems has been proposed to contribute to the GI disturbances, but the underlying mechanisms have not been fully elucidated. The aims of this thesis were to assess the prevalence of GI disturbances for different subtypes of ATTR amyloidosis, to further explore the mechanisms behind these disturbances, and to evaluate the outcome of the patients’ GI function after liver transplantation, which currently is the standard treatment for hereditary ATTR amyloidosis. Methods The Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with ATTR amyloidosis. THAOS enrollment data were used to assess the prevalence of GI symptoms and to evaluate their impact on nutritional status (mBMI) and health-related quality of life (EQ-5D Index Score). Data from routine investigations of heart-rate variability and cardio-vascular response to tilt tests were utilized to evaluate the impact of autonomic neuropathy on the scintigraphically measured gastric emptying half-times in Swedish patients with hereditary ATTR amyloidosis. Gastric wall autopsy specimens from Japanese patients with hereditary ATTR amyloidosis and Japanese non-amyloidosis controls were analyzed with immunohistochemistry and computerized image analysis to assess the densities of interstitial cells of Cajal (ICC) and nervous tissue. Data from gastric emptying scintigraphies and validated questionnaires were used to evaluate the outcome of Swedish patients’ GI function after liver transplantation for hereditary ATTR amyloidosis. Results Sixty-three percent of the patients with TTR mutations and 15 % of those with wild-type ATTR amyloidosis reported GI symptoms at enrollment into THAOS. Subsequent analyses focused on patients with TTR mutations and, among them, unintentional weight loss was the most frequent symptom (32 %) followed by early satiety (26 %). Early-onset patients (<50 years of age) reported GI symptoms more frequently than late-onset cases (70 % vs. 50 %, p <0.01), and GI symptoms were more common in patients with the V30M mutation than in those with non-V30M mutations (69 % vs. 56 %, p <0.01). Both upper and lower GI symptoms were significant negative predictors of nutritional status and health-related quality of life (p <0.01 for both). Weak but significant correlations were found between gastric emptying half-times and the function of both the sympathetic (rs = -0.4, p <0.01) and parasympathetic (rs = -0.3, p <0.01) nervous systems. The densities of c-Kit-immunoreactive ICC were significantly lower in the circular (median density 0.0 vs. 2.6, p <0.01) and longitudinal (median density 0.0 vs. 1.8, p <0.01) muscle layers of the gastric wall in patients compared to controls. Yet, no significant differences in protein gene product 9.5-immunoreactive nervous cells were found between patients and controls either in the circular (median density 3.0 vs. 6.8, p = 0.17) or longitudinal (median density 1.4 vs. 2.5, p = 0.10) muscle layers. Lastly, the patients’ GI symptoms scores had increased slightly from before liver transplantation to the follow-ups performed in median two and nine years after transplantation (median score 7 vs. 10 vs. 13, p <0.01). However, their gastric emptying half-times (median half-time 137 vs. 132 vs. 125 min, p = 0.52) and nutritional statuses (median mBMI 975 vs. 991 vs. 973, p = 0.75) were maintained at follow-ups in median two and five years after transplantation. Conclusion GI disturbances are common in hereditary ATTR amyloidosis and have a negative impact on the patients’ nutritional status and health-related quality of life. Fortunately, a liver transplantation appears to halt the progressive GI involvement of the disease, although the patients’ GI symptoms tend to increase after transplantation. An autonomic neuropathy and a depletion of gastrointestinal ICC seem to contribute to the GI disturbances, but additional factors must be involved.

Introdução: Polineuropatia periférica (PNP) é descrita em diabéticos, porém estudos têm mostrado alterações neuropáticas em pacientes com pré-diabetes (Pre-DM), Síndrome Metabólica (SM), obesos e submetidos à cirurgia bariátrica (post-BS). Objetivo: Avaliar a prevalência de PNP entre pacientes com Diabetes Mellitus (DM), obesos graus II e III e pré-diabetes (OB-PRE-DM), obesidade graus II e III e síndrome metabólica (OB-SM), obesidade sem PREDM e SM (Ob No MS) e pacientes Post-BS e avaliar a sensibilidade e a especificidade da escala Neuropathy Disability Score (NDS) em comparação com Michigan Neuropathy Screening Instrument (MNSI). Método: Foi realizado um estudo transversal onde as prevalências de PNP foram avaliadas através do MNSI e do NDS. O desempenho do NDS foi comparado ao MNSI através de curvas Receiving Operating Characteristics Curves (ROC). Resultados: Considerando os escores MNSI ≥ 2,5 e ≥ 4 sintomas, MNSI ≥ 2,5 e ≥ 7 sintomas e NDS ≥ 3 em combinação com Neuropathy Symptom Score (NSS) score ≥ 3, houve a prevalência maior de PNP em DM e Pre-DM vs Ob-SM e Ob No MS e em todos vs Post-BS quando os grupos foram comparados entre si. As curvas ROC mostraram que o melhor desempenho do NDS foi ≥ 0,5. Conclusão: A prevalência de PNP descrita com o MNSI é maior em relação a com NDS. O baixo valor obtido para o melhor desempenho do NDS sugere que exploremos escores <3 para avaliar alterações neuropáticas com este escore. / Introduction: Peripheral polineuropathy (PNP) is seen in diabetics, however, studies have shown neuropathic alterations in patients with pre-diabetes (Pre-DM), Metabolic Syndrome (MS), obese and submitted to bariatric surgery (post-BS). Objective: To evaluate the prevalence of PNP among patients with Diabetes Mellitus (DM), obese grades II and III and pre-diabetes (OB-PRE-DM), obesity grades II and III and metabolic syndrome (OB-SM), obesity without PREDM and Ob No MS and Post-BS patients and to assess the sensitivity and specificity of Neuropathy Disability Score (NDS) compared to the Michigan Neuropathy Screening Instrument (MNSI). Method: A cross-sectional study was carried out in which PNP prevalence were evaluated through the MNSI and the Neuropathy NDS. The performance of the NDS was compared to the MNSI through Receiving Operating Characteristics Curves (ROC curves). Results: Considering MNSI scores ≥ 2.5 and ≥ 4 symptoms, MNSI ≥ 2.5 and ≥ 7 symptoms and NDS ≥ 3 in combination with NSS score ≥ 3, there was a higher prevalence of PNP in DM and Pre-DM vs Ob-SM and Ob No MS and in all vs. Post-BS when groups were compared to each other. The curves ROC showed that the best performance of NDS was ≥ 0.5. Conclusion: The prevalence of PNP described with MNSI is higher in relation to described with NDS. The low value obtained for the best performance of NDS suggest that we explore <3 scores to evaluate neuropathic alterations with this score.

Introdução: Polineuropatia periférica (PNP) é descrita em diabéticos, porém estudos têm mostrado alterações neuropáticas em pacientes com pré-diabetes (Pre-DM), Síndrome Metabólica (SM), obesos e submetidos à cirurgia bariátrica (post-BS). Objetivo: Avaliar a prevalência de PNP entre pacientes com Diabetes Mellitus (DM), obesos graus II e III e pré-diabetes (OB-PRE-DM), obesidade graus II e III e síndrome metabólica (OB-SM), obesidade sem PREDM e SM (Ob No MS) e pacientes Post-BS e avaliar a sensibilidade e a especificidade da escala Neuropathy Disability Score (NDS) em comparação com Michigan Neuropathy Screening Instrument (MNSI). Método: Foi realizado um estudo transversal onde as prevalências de PNP foram avaliadas através do MNSI e do NDS. O desempenho do NDS foi comparado ao MNSI através de curvas Receiving Operating Characteristics Curves (ROC). Resultados: Considerando os escores MNSI ≥ 2,5 e ≥ 4 sintomas, MNSI ≥ 2,5 e ≥ 7 sintomas e NDS ≥ 3 em combinação com Neuropathy Symptom Score (NSS) score ≥ 3, houve a prevalência maior de PNP em DM e Pre-DM vs Ob-SM e Ob No MS e em todos vs Post-BS quando os grupos foram comparados entre si. As curvas ROC mostraram que o melhor desempenho do NDS foi ≥ 0,5. Conclusão: A prevalência de PNP descrita com o MNSI é maior em relação a com NDS. O baixo valor obtido para o melhor desempenho do NDS sugere que exploremos escores <3 para avaliar alterações neuropáticas com este escore. / Introduction: Peripheral polineuropathy (PNP) is seen in diabetics, however, studies have shown neuropathic alterations in patients with pre-diabetes (Pre-DM), Metabolic Syndrome (MS), obese and submitted to bariatric surgery (post-BS). Objective: To evaluate the prevalence of PNP among patients with Diabetes Mellitus (DM), obese grades II and III and pre-diabetes (OB-PRE-DM), obesity grades II and III and metabolic syndrome (OB-SM), obesity without PREDM and Ob No MS and Post-BS patients and to assess the sensitivity and specificity of Neuropathy Disability Score (NDS) compared to the Michigan Neuropathy Screening Instrument (MNSI). Method: A cross-sectional study was carried out in which PNP prevalence were evaluated through the MNSI and the Neuropathy NDS. The performance of the NDS was compared to the MNSI through Receiving Operating Characteristics Curves (ROC curves). Results: Considering MNSI scores ≥ 2.5 and ≥ 4 symptoms, MNSI ≥ 2.5 and ≥ 7 symptoms and NDS ≥ 3 in combination with NSS score ≥ 3, there was a higher prevalence of PNP in DM and Pre-DM vs Ob-SM and Ob No MS and in all vs. Post-BS when groups were compared to each other. The curves ROC showed that the best performance of NDS was ≥ 0.5. Conclusion: The prevalence of PNP described with MNSI is higher in relation to described with NDS. The low value obtained for the best performance of NDS suggest that we explore <3 scores to evaluate neuropathic alterations with this score.

Esta tese assumiu a premissa de que a neuropatia periférica é um sinal de piora da diabetes, além de levantar a questão de que estudos prévios sobre a biomecânica da marcha de diabéticos não têm distinguido os graus de progressão da diabetes nos grupos estudados. Neste contexto, não é possível identificar as diferenças nos padrões de geração da marcha entre estágios precoces e avançados da diabetes. Esta identificação poderia facilitar a intervenção terapêutica precoce nestes pacientes, o que poderá impedir a formação de úlceras e amputações recorrentes subseqüentes. Assim, apresentamos ao longo desta tese, três estudos para investigar a natureza das supostas alterações na marcha (estudo 1) e no descer escadas (estudo 2) de diabéticos, assim como para propor uma forma de classificar a progressão da diabetes levando em consideração as incertezas de fronteiras entre os subgrupos de neuropatas, por meio de um sistema especialista fuzzy (estudo 3). Os estudos 1 e 2 foram feitos com os mesmos três grupos: indivíduos diabéticos (GD) e diabéticos neuropatas (GDN) diagnosticados clinicamente e indivíduos saudáveis (GC). Para a avaliação cinemática e cinética do membro inferior foram utilizadas câmeras infravermelhas e uma plataforma de força durante o andar no plano e descendo uma escada. O cálculo dos momentos articulares de membro inferior foi feito por meio do método da dinâmica inversa. Os principais resultados do estudo 1 mostraram que independente da presença da neuropatia, os pacientes diabéticos exibiram uma maior flexão das três principais articulações do membro inferior e um importante uso da articulação do quadril como uma estratégia cinética de progressão do corpo à frente, em substituição ao tornozelo, que mostrou ser a articulação mais prejudicada. Os principais resultados do estudo 2 indicaram as mesmas mudanças significativas no padrão cinemático do tornozelo durante a fase de propulsão, mesmo na ausência da neuropatia. No entanto, não houve diferença nos padrões cinéticos entre os estágios iniciais e avançados da doença, mas mostraram a mesma tendência observada no estudo 1 de alteração do padrão cinético de quadril para se adaptar às perdas distais nos neuropatas. No estudo 3, desenvolvemos um modelo para classificação da severidade da neuropatia diabética. O modelo fuzzy apresentou um nível de concordância adequado com a classificação feita por especialistas, e também mostrou uma alta precisão na avaliação de pacientes reais que foram submetidos à avaliação do modelo. O modelo foi capaz de simplificar e separar os pacientes em quatro diferentes graus de severidade, o que pode melhorar a eficácia de medidas preventivas, bem como para oferecer uma melhor ajuda para os profissionais de saúde no tratamento destas doenças e suas complicações. Como conclusão geral temos que os grupos diabéticos estudados exibiram comportamentos biomecânicos durante o andar no plano e descendo degraus que são muitas vezes parecidos entre si (GD e GDN), poucas vezes diferentes entre si, mas na maioria das vezes bem distintos do grupo não diabético (GC), indicando que a questão da progressão não se esclareceu completamente ao separamos de maneira crisp os grupos em diabético e diabético neuropata. As perdas sensitivo-motoras-autonômicas impostas pela diabetes não podem ser subestimadas, uma vez que parecem ter início ainda quando a neuropatia não foi diagnosticada. Uma correta classificação do paciente pode antecipar a detecção dos níveis menos severos da doença, evitando esperar que os pacientes apresentem perdas irreversívies para inicar uma intervenção clínica eficaz e preventiva para preservar a locomoção independente destes pacientes / This study assumed the premise that the peripheral neuropathy is a sign of worsening of diabetes, as well as raising the issue that previous studies on the biomechanics of gait in diabetics do not have distinguished the degree of progression of diabetes in both groups. Therefore, it is not possible to identify differences in patterns of gait generation between early and advanced stages of diabetes. This identification would facilitate early therapeutic intervention in these patients, which could prevent the formation of recurrent ulcers and subsequent amputations. We present throughout this thesis, three studies to investigate the nature of the alleged changes in gait (study 1) and stair descent (study 2) of diabetics, and to propose a way to classify the progression of diabetes, taking into account the uncertainties of boundaries between the subgroups of neuropathy through a fuzzy expert system (study 3). Studies 1 and 2 were performed with the same three groups: diabetics (GD) and diabetic neuropathic (GDN) diagnosed clinically and healthy subjects (CG). For the kinematic and kinetic evaluation of the lower limb, we used infrared cameras and a force plate during walking on a level walkway (10 m) and descent a staircase. The calculation of net joint moments of the lower limb was performed using the method of inverse dynamic. The main results of Study 1 showed that, regardless of the presence of neuropathy, diabetic patients exhibited a greater flexion of the three major joints of the lower limb and an important use of the hip joint as a kinetic strategy of progression the body forward, replacing the ankle, which proved to be the most affected joint. The main results of Study 2 showed the same significant changes in the pattern of the ankle kinematics during propulsion phase, even in the absence of neuropathy. However, there was no difference between the kinetic patterns in early and advanced stages of the disease, but showed the same trend observed in the Study 1: a change in the kinetic pattern of the hip to adapt de locomotion to distal loss in neuropathic subjects. In Study 3, the model developed for classification of severity of diabetic neuropathy showed an adequate level of agreement with the classification of experts, and also showed a high accuracy in the evaluation of real patients who underwent to the evaluation of the model. The fuzzy model was able to simplify and separate the patients into four different degrees of severity, which can improve the effectiveness of preventive strategies as well as to offer a better assistance to health professionals in the management of this disease. It is concluded that the studied diabetic groups exhibited biomechanical behavior during walking and descend stairs that are often similar to each other (GD and GDN), a few times different from each other, but most often very different from the non-diabetic group (GC), indicating that the issue of progression was not fully understood separating the groups in a crisp way as diabetic and diabetic neuropathic subjects. The sensory, motor and autonomic losses imposed by the diabetes can not be underestimated, since they seem to appear when the neuropathy is not diagnosed yet. A correct classification of the patient can anticipate the detection of less severe levels of the disease and avoid that the patients show an irreversible loss to start an effective intervention and preventive strategies to keep the independent locomotion of these patients