Background The recently postulated “disease spreading hypothesis” has gained much attention, especially for Parkinson’s disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND. Methods We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls. Results In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression. Conclusion NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated “disease spreading hypothesis.” The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.

Many people with the incurable and often times fatal motor neuron diseases have pain, but there is lack of knowledge about people’s experiences of living with pain. Further, the correlation between pain and their quality of life is not well understood, and previous studies have not used individual quality of life, namely that people with their own words express what quality of life is.   The aim of these studies was to explore the experiences of pain and the association between pain and quality of life in people with MND. Methods: Study I was explorative about the individual experience of pain, while study II was correlational between pain, pain severity, disease severity and IQOL. Study I was qualitative, whereas study II used both qualitative and quantitative analysis. Results and conclusions: People with motor neuron diseases experienced pain to have multiple characteristics and impact. However, the results emphasise that the individual experienced some pain characteristics as difficult and that pain could worsen functions that were already affected by the disease. The experience was also that it could be challenging to manage pain. However, the symptom of pain could pass unnoticed in contacts with healthcare professionals (study I). The three most important areas for individual quality of life in both participants with and without pain were: Social relations, followed by Activities for amusement and relaxations, and Being in the outdoor environment. Individual quality of life was noticed to be good regardless of pain. Pain and pain severity were not found to be associated with satisfaction of individual quality of life in patients with motor neuron diseases, neither was disease severity. The results support previous findings, that strong associations between symptoms of MND and IQoL are not obvious. However, this does not infer that pain in people with MNDs should be neglected and undertreated. On the contrary, it seems to be important for healthcare to pay more attention to pain in people with motor neuron diseases and that pain continuously is measured, individually treated and followed. Regardless of whether persons with MND have pain or not, the results point to the importance of healthcare professionals providing support to not only the patient but also the patient’s family and friends, as well as assisting in various forms of relaxing activities and possibility of being in the outdoor environment.

Background The recently postulated “disease spreading hypothesis” has gained much attention, especially for Parkinson’s disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND. Methods We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls. Results In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression. Conclusion NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated “disease spreading hypothesis.” The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.

The diploma thesis is focused on the issue of acquired dysarthric and swallowing disorders in amyotrophic lateral sclerosis and on multidisciplinary care provided to patients with this disease. Theoretical part of the thesis is divided into three chapters. The introductory chapter presents a summary of current knowledge about amyotrophic lateral sclerosis (ALS). The following two chapters are dedicated to dysarthria and dysphagia and their specifics in ALS. The practical part of the diploma thesis is represented by the fourth chapter which incorporates a research survey focused on multidisciplinary care provided to patients with ALS. The primary aim of the research is to evaluate the multidisciplinary care provided to two selected patients with ALS with a focus on speech and swallowing disorders. The secondary objectives of the research relate to the evaluation of the extent of acquired dysarthric and swallowing disorders of these patients, providing a comprehensive overview of the course and content of the provided care and gathering information to create information brochure for patients with ALS and caregivers. The research approach to achieve the determined objectives of the research survey is creation of case studies using qualitative methods of data collection, which is a structured interview...

Peu d’études françaises ont abordé le rôle des expositions chimiques autres que les pesticides dans les maladies neurodégénératives. Des interrogations persistent notamment sur le rôle de l’exposition environnementale ou professionnelle aux métaux dans la maladie de Parkinson (MP) et sur l’existence d’un excès de maladies du motoneurone (MMN) parmi les militaires qui peuvent être exposés au plomb ou à d’autres produits. Nous avons abordé ces questions en France à travers des études nationales au sein du Système National des Données de Santé (SNDS). Nous avons observé une augmentation de l’incidence de la MP (2010-2014) dans les cantons caractérisés par des proportions élevées de travailleurs dans les secteurs de l’agriculture, la métallurgie et l’industrie textile ; l’exposition professionnelle aux pesticides, métaux et solvants respectivement pourraient contribuer à ces associations. Par ailleurs, nous avons observé une incidence de la MMN (2010-2016) plus élevée de 16% chez les hommes de 50 ans et plus affiliés à la Caisse nationale militaire de sécurité sociale par rapport aux hommes de la population générale. Le tabagisme et des facteurs professionnels pourraient expliquer cette association. Enfin, nous avons utilisé des données de biosurveillance à partir de mousses prélevées dans les régions rurales pour étudier le rôle des retombées atmosphériques en métaux (cuire, fer, mercure, manganèse, plomb, zinc) dans la MP. Son incidence (2010-2015) était 4% plus élevée dans les régions où la concentration en métaux dans les mousses était la plus élevée. Une association positive et statistiquement significative est retrouvée pour le cuivre et le mercure. En utilisant différents indicateurs pour approcher l’exposition aux métaux, ce travail souligne la complexité de l’étude du rôle étiologique de nuisances dont les déterminants d’exposition sont à la fois environnementaux et professionnels. / Few French studies have examined the role of chemical exposures other than pesticides in neurodegenerative diseases. There are still uncertainties regarding the role of environmental or occupational exposure to metals in Parkinson’s disease (PD) and the excess risk of motor neuron disease (MND) among military personnel who can be exposed to lead and other products. We have examined these questions in France through nationwide incidence studies within national health insurance databases (Système National des Données de Santé, SNDS). We observed an increased PD incidence (2010-2014) in areas characterized by high proportions of workers in agriculture, metallurgy and textile sectors; occupational exposure to pesticides, metals, or solvents respectively may contribute to these associations. Furthermore, we observed a 16% increased incidence of MND (2010-2016) among men aged 50 years and older covered by the national military social security fund (Caisse nationale militaire de sécurité sociale) compared to men from the general population. This excess risk is possibly explained by smoking and occupational factors. Finally, we used biomonitoring data from mosses obtained in rural regions to investigate the role of atmospheric deposition of metals (copper, iron, mercury, manganese, lead, zinc) in PD. Its incidence (2010-2015) was 4% higher in areas where overall metal concentrations in mosses were the highest. There was a statistically significant positive association for copper and mercury. Using different indicators to assess exposure to metals, our work highlights the complexity of studies on the etiologic role of chemicals whose exposure determinants are both environmental and occupational.

Der Palmomentalreflex (PMR) wird im Allgemeinen als Primitivreflex und kortikales Enthemmungszeichen (frontal release sign) gedeutet. Erstmals wurde er bei der Amyotrophen Lateralsklerose (ALS) beschrieben und mit einer Schädigung der kortikobulbären Trakte assoziiert. Auch ein Zusammenhang mit kognitiven Veränderungen wird diskutiert. Diese spielen bei der ALS neben motorischen Defiziten mittlerweile eine ebenso wichtige Rolle. Ziel der vorliegenden prospektiven monozentrischen Querschnittsstudie war es, den Einfluss motorischer und neurokognitiver Dysfunktionen auf das Auftreten eines PMR in der ALS zu untersuchen. Hierfür wurden 97 Patienten mit ALS und ALS-Varianten eingeschlossen und in Abhängigkeit des PMR untereinander verglichen. Der PMR wurde in einem standardisierten Verfahren klinisch getestet. Das neurokognitive Profil wurde mithilfe des Edinburgh Cognitive and Behavioral ALS Screen (ECAS) erhoben. Die Krankheitsschwere und motorische Affektion wurden anhand der revidierten ALS Functional Rating Scale (ALSFRS-R) und einer standardisierten klinischen Untersuchung ermittelt. In 52 % aller Patienten konnte ein pathologischer PMR nachgewiesen werden. Diese Patienten zeigten im Vergleich zu Patienten ohne PMR signifikant häufiger klinische Zeichen einer motorischen Dysfunktion in der bulbären Region. Eine systematische Untersuchung mithilfe einer adaptierten Form des Sydney Facial Grading System konnte zudem signifikante Beeinträchtigungen der bulbär-innervierten mimischen Muskulatur bei Patienten mit pathologischem PMR aufdecken. Allerdings konnte die vorliegende Arbeit entgegen bisherigen Annahmen keine Korrelation mit einer isolierten Schädigung des oberen Motoneurons in der bulbären Region bestätigen. In der ALSFRS-R schnitten Patienten mit PMR schlechter in bulbären, aber auch in spinal-respiratorischen Funktionen ab. Das kognitive Leistungsprofil des ECAS zeigte für Patienten mit PMR signifikant niedrigere Durchschnittswerte im ALS-spezifischen Teil, in der Subdomäne der exekutiven Funktionen und der ECAS Gesamtwertung. Auch unter Berücksichtigung der alters- und bildungsadaptierten Cut-Off-Werten war deren Anteil mit kognitiven Defiziten in jenen Teilergebnissen höher. Ferner erbrachte die Verhaltens- und Psychose-Befragung bei Patienten mit PMR Hinweise auf eine Häufung von Verhaltensauffälligkeiten. Eine multivariate Regressionsanalyse legte einen signifikanten Einfluss von bulbär-motorischen Schädigungszeichen, niedrigeren Werten spinal-respiratorischer Funktionen der ALSFRS-R und Beeinträchtigungen exekutiver Funktionen für das Auftreten eines PMR dar. Dabei war der motoneuronale Schaden in der Bulbärhirnregion der stärkste Prädiktor. In der Studie konnte damit gezeigt werden, dass ein motoneuronaler Schaden in der nach den El-Escorial-Kriterien definierten bulbären Region einen deutlich stärkeren Einfluss im Vergleich zu exekutiven Funktionsstörungen auf das Auftreten eines PMR hat. Bei dem Krankheitsbild der ALS scheint er daher primär ein klinisches Zeichen eines motorischen Schadens in der bulbären Region und nur in geringerem Maße exekutiver Dysfunktion zu sein. In unklaren diagnostischen Situationen könnte der PMR daher als zusätzlicher klinischer Marker herangezogen werden, um eine motoneuronale Schädigung in der bulbären Region oder eine exekutive Funktionsstörung aufzudecken.:I. Abkürzungsverzeichnis I II. Abbildungsverzeichnis II III. Tabellenverzeichnis IV 1 Einleitung 1 1.1 Der Palmomentalreflex 1 1.1.1 Allgemeine Definition 1 1.1.2 Epidemiologie des PMR 1 1.1.3 Neuroanatomische Grundlagen des PMR 3 1.1.4 Klinische Bedeutung 5 1.2 Amyotrophe Lateralsklerose (ALS) 6 1.2.1 Definition 6 1.2.2 Einteilung und klinische Phänotypen 7 1.2.2.1 Spinaler Beginn 7 1.2.2.2 Bulbärer Beginn 8 1.2.2.3 Varianten der ALS 9 1.2.2.3.1 Progressive Muskelatrophie (PMA) 9 1.2.2.3.2 Primäre Lateralsklerose (PLS) 10 1.2.2.3.3 Flail-Arm-Syndrom und Flail-Leg-Syndrom 10 1.2.2.3.4 Progressive Bulbärparalyse und Pseudobulbärparese 11 1.2.2.3.5 Axiale und respiratorische ALS 12 1.2.2.3.6 Hemiplegische und pseudopolyneuritische ALS 12 1.2.3 Krankheitsprogress und Erkrankungsschwere der ALS 13 1.2.4 ALS und kognitiv-behaviorale Veränderungen 13 1.2.5 Kognitions- und Verhaltenserfassung bei der ALS 15 1.2.5.1 Diagnostische Kriterien nach Strong et al. 15 1.2.5.2 Der Edinburgh Cognitive and Behavioral ALS Screen (ECAS) 15 1.3 Fragestellungen 17 2 Material und Methoden 18 2.1 Studiendesign und Patientenkollektiv 18 2.1.1 Ein- und Ausschlusskriterien 18 2.1.2 Patientengruppen nach revidierten El-Escorial-Kriterien 18 2.2 Klinisch-neurologische Untersuchung 20 2.2.1 Untersuchung der zervikal- und lumbosakral-innervierten Muskulatur 20 2.2.1.1 Evaluation der Kraftgrade 20 2.2.1.2 Evaluation des Reflexstatus 22 2.2.2 Untersuchung der bulbär-innervierten Muskulatur 23 2.3 Untersuchung des PMR 25 2.3.1 Auslösbarkeit des PMR 26 2.3.1.1 Uni- oder bilaterale Reflexantwort 26 2.3.1.2 Habituation 26 2.3.1.3 Reflexzonenerweiterung 26 2.4 Bewertung des PMR 27 2.5 Die revidierte ALS Functional Rating Scale (ALSFRS-R) 28 2.6 Der Edinburgh Cognitive and Behavioral ALS Screen (ECAS) 30 2.7 Statistische Auswertung 32 3 Ergebnisse 33 3.1 Demographische Daten 33 3.1.1 Gesamtkohorte 33 3.1.2 Kohorten 33 3.2 ALS Phänotypen 34 3.3 Erstmanifestationsort der Erkrankung 36 3.4 Bulbäre Region 37 3.4.1 Differenzierte Motoneuronaffektion in der bulbären Region 38 3.5 Zervikale Region 40 3.5.1 Differenzierte Motoneuronaffektion in der zervikalen Region 41 3.6 Lumbosakrale Region 43 3.6.1 Differenzierte Motoneuronaffektion in der lumbosakralen Region 44 3.7 Der PMR und eine Affektion des 1. bzw. 2. Motoneurons 46 3.8 Funktionsprüfung der mimischen Muskulatur 48 3.9 Ergebnisse des Edinburgh Cognitive and Behavioral ALS Screen (ECAS) 50 3.9.1 Ergebnisse der durchschnittlichen kognitiven Leistungen des Gesamtkollektivs 50 3.9.2 Prävalenz und Profil der kognitiven Dysfunktion des Gesamtkollektivs nach alters- und bildungskorrigierten Cut-Off-Werten 50 3.9.3 Spezifität und Sensitivität der Subscores bezüglich der ECAS Gesamtpunktzahl 51 3.9.4 Spezifität und Sensitivität der Einzeldomänen des ALS-spezifischen Teils 52 3.9.5 Spezifität und Sensitivität der Einzeldomänen des nicht-ALS-spezifischen Teils 52 3.9.6 ECAS - ALS-spezifische Funktionen in Abhängigkeit des PMR 53 3.9.7 ECAS - nicht-ALS-spezifische Funktionen in Abhängigkeit des PMR 54 3.9.8 ECAS Teil- und Gesamtergebnisse in Abhängigkeit des PMR 55 3.9.9 Prävalenz und Profil der kognitiven Dysfunktion nach alters- und bildungskorrigierten Cut-Off-Werten in Abhängigkeit des PMR 56 3.9.10 Ergebnisse der ECAS Verhaltens- und Psychose-Befragung 59 3.10 Ergebnisse der revidierten ALS Functional Rating Scale (ALSFRS-R) 61 3.10.1 Durchschnittswert in der ALSFRS-R des Gesamtkollektivs 61 3.10.2 Durchschnittswert in der ALSFRS-R in Abhängigkeit des PMR 61 3.11 Einflussfaktoren auf das Auftreten des PMR 63 3.11.1 Univariate logistische Regressionsanalyse mit der Zielvariable PMR 63 3.11.2 Bivariate Korrelationen, Prüfung auf Multikollinearität und Modellformulierung 65 3.11.3 Einfluss bulbär-motorischer Schädigungszeichen, exekutiver Dysfunktionen und der ALSFRS-RS auf das Auftreten des PMR 66 4 Diskussion 68 4.1 Patienten und Methoden 68 4.2 Motoneuronale Schädigung und der PMR 70 4.3 Die ALSFRS-R und der PMR 73 4.4 Kognitiv-behavoriale Veränderungen im ECAS und der PMR 73 4.5 Einfluss bulbär-motorischer Schädigungszeichen und kognitiver Dysfunktionen auf den PMR 76 4.6 Schlussfolgerung und Ausblick 76 4.7 Limitationen der Studie 77 5 Zusammenfassung 79 6 Abstract 81 7 Literaturverzeichnis 82 8 Aus der Arbeit hervorgegangene Publikationen 95 9 Danksagung 96 10 Anlage 1: Erklärungen zur Eröffnung des Promotionsverfahrens 97 11 Anlage 2: Bestätigung über Einhaltung der aktuellen gesetzlichen Vorgaben 98 / The palmomental reflex (PMR) is commonly interpreted as a primitive reflex and a sign of cortical disinhibition (frontal release sign). It has originally been described in amyotrophic lateral sclerosis (ALS) and attributed to lesions of corticobulbar tracts. A relation to cognitive changes is also discussed, which play an essential role in ALS besides motor deficits. The aim of this prospective cross-sectional monocenter study was to investigate the impact of motor and neurocognitive impairment on the appearance of PMR in ALS patients. 97 patients with ALS and ALS variants were enrolled and compared among each other regarding PMR. PMR was clinically examined in a standardized procedure. To assess the cognitive profile the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) was performed. Disease severity and affection of motor system were evaluated by the revised ALS functional rating scale (ALSFRS-R) and standardized clinical examination. In 52 % of all patients pathological PMR was present. These patients showed significantly more frequent motor dysfunction in bulbar region than patients without PMR. By applying an adapted version of the Sydney Grading System a systematic examination revealed significant impairment of bulbar-innervated facial muscles in patients with pathological PMR. However, contrary to previous assumptions, this study could not confirm a correlation with isolated upper motor neuron involvement in the bulbar region. In ALSFRS-R, patients with PMR performed worse for bulbar functions as well as for spinal and respiratory functions. The neurocognitive profile of the ECAS revealed significantly lower average values in the ALS-specific sub score, its subdomain of executive functions and ECAS total score for patients with PMR. In consideration of age- and education-adapted cut off values published by Loose et al., the proportion with cognitive deficits in above mentioned scores was also higher in patients with PMR. Furthermore, a behavioral and psychosis assessment detected indications of behavioral impairment in patients with PMR. In a multivariate regression analysis, motor dysfunction in the bulbar region, lower scores for spinal and respiratory functions in ALSFRS-R and impaired executive functions had an impact on the appearance of PMR, while motor dysfunction in the bulbar region being the strongest predictor. This study hereby presented that motor dysfunction in the bulbar region based on El-Escorial criteria has a much stronger impact on PMR than executive dysfunctions. Therefore, PMR is suggested to be primarily a sign of bulbar involvement and, to a lesser degree, of executive dysfunction in ALS. As an additional clinical marker, PMR may help to define bulbar involvement or executive dysfunction in unclear situations.:I. Abkürzungsverzeichnis I II. Abbildungsverzeichnis II III. Tabellenverzeichnis IV 1 Einleitung 1 1.1 Der Palmomentalreflex 1 1.1.1 Allgemeine Definition 1 1.1.2 Epidemiologie des PMR 1 1.1.3 Neuroanatomische Grundlagen des PMR 3 1.1.4 Klinische Bedeutung 5 1.2 Amyotrophe Lateralsklerose (ALS) 6 1.2.1 Definition 6 1.2.2 Einteilung und klinische Phänotypen 7 1.2.2.1 Spinaler Beginn 7 1.2.2.2 Bulbärer Beginn 8 1.2.2.3 Varianten der ALS 9 1.2.2.3.1 Progressive Muskelatrophie (PMA) 9 1.2.2.3.2 Primäre Lateralsklerose (PLS) 10 1.2.2.3.3 Flail-Arm-Syndrom und Flail-Leg-Syndrom 10 1.2.2.3.4 Progressive Bulbärparalyse und Pseudobulbärparese 11 1.2.2.3.5 Axiale und respiratorische ALS 12 1.2.2.3.6 Hemiplegische und pseudopolyneuritische ALS 12 1.2.3 Krankheitsprogress und Erkrankungsschwere der ALS 13 1.2.4 ALS und kognitiv-behaviorale Veränderungen 13 1.2.5 Kognitions- und Verhaltenserfassung bei der ALS 15 1.2.5.1 Diagnostische Kriterien nach Strong et al. 15 1.2.5.2 Der Edinburgh Cognitive and Behavioral ALS Screen (ECAS) 15 1.3 Fragestellungen 17 2 Material und Methoden 18 2.1 Studiendesign und Patientenkollektiv 18 2.1.1 Ein- und Ausschlusskriterien 18 2.1.2 Patientengruppen nach revidierten El-Escorial-Kriterien 18 2.2 Klinisch-neurologische Untersuchung 20 2.2.1 Untersuchung der zervikal- und lumbosakral-innervierten Muskulatur 20 2.2.1.1 Evaluation der Kraftgrade 20 2.2.1.2 Evaluation des Reflexstatus 22 2.2.2 Untersuchung der bulbär-innervierten Muskulatur 23 2.3 Untersuchung des PMR 25 2.3.1 Auslösbarkeit des PMR 26 2.3.1.1 Uni- oder bilaterale Reflexantwort 26 2.3.1.2 Habituation 26 2.3.1.3 Reflexzonenerweiterung 26 2.4 Bewertung des PMR 27 2.5 Die revidierte ALS Functional Rating Scale (ALSFRS-R) 28 2.6 Der Edinburgh Cognitive and Behavioral ALS Screen (ECAS) 30 2.7 Statistische Auswertung 32 3 Ergebnisse 33 3.1 Demographische Daten 33 3.1.1 Gesamtkohorte 33 3.1.2 Kohorten 33 3.2 ALS Phänotypen 34 3.3 Erstmanifestationsort der Erkrankung 36 3.4 Bulbäre Region 37 3.4.1 Differenzierte Motoneuronaffektion in der bulbären Region 38 3.5 Zervikale Region 40 3.5.1 Differenzierte Motoneuronaffektion in der zervikalen Region 41 3.6 Lumbosakrale Region 43 3.6.1 Differenzierte Motoneuronaffektion in der lumbosakralen Region 44 3.7 Der PMR und eine Affektion des 1. bzw. 2. Motoneurons 46 3.8 Funktionsprüfung der mimischen Muskulatur 48 3.9 Ergebnisse des Edinburgh Cognitive and Behavioral ALS Screen (ECAS) 50 3.9.1 Ergebnisse der durchschnittlichen kognitiven Leistungen des Gesamtkollektivs 50 3.9.2 Prävalenz und Profil der kognitiven Dysfunktion des Gesamtkollektivs nach alters- und bildungskorrigierten Cut-Off-Werten 50 3.9.3 Spezifität und Sensitivität der Subscores bezüglich der ECAS Gesamtpunktzahl 51 3.9.4 Spezifität und Sensitivität der Einzeldomänen des ALS-spezifischen Teils 52 3.9.5 Spezifität und Sensitivität der Einzeldomänen des nicht-ALS-spezifischen Teils 52 3.9.6 ECAS - ALS-spezifische Funktionen in Abhängigkeit des PMR 53 3.9.7 ECAS - nicht-ALS-spezifische Funktionen in Abhängigkeit des PMR 54 3.9.8 ECAS Teil- und Gesamtergebnisse in Abhängigkeit des PMR 55 3.9.9 Prävalenz und Profil der kognitiven Dysfunktion nach alters- und bildungskorrigierten Cut-Off-Werten in Abhängigkeit des PMR 56 3.9.10 Ergebnisse der ECAS Verhaltens- und Psychose-Befragung 59 3.10 Ergebnisse der revidierten ALS Functional Rating Scale (ALSFRS-R) 61 3.10.1 Durchschnittswert in der ALSFRS-R des Gesamtkollektivs 61 3.10.2 Durchschnittswert in der ALSFRS-R in Abhängigkeit des PMR 61 3.11 Einflussfaktoren auf das Auftreten des PMR 63 3.11.1 Univariate logistische Regressionsanalyse mit der Zielvariable PMR 63 3.11.2 Bivariate Korrelationen, Prüfung auf Multikollinearität und Modellformulierung 65 3.11.3 Einfluss bulbär-motorischer Schädigungszeichen, exekutiver Dysfunktionen und der ALSFRS-RS auf das Auftreten des PMR 66 4 Diskussion 68 4.1 Patienten und Methoden 68 4.2 Motoneuronale Schädigung und der PMR 70 4.3 Die ALSFRS-R und der PMR 73 4.4 Kognitiv-behavoriale Veränderungen im ECAS und der PMR 73 4.5 Einfluss bulbär-motorischer Schädigungszeichen und kognitiver Dysfunktionen auf den PMR 76 4.6 Schlussfolgerung und Ausblick 76 4.7 Limitationen der Studie 77 5 Zusammenfassung 79 6 Abstract 81 7 Literaturverzeichnis 82 8 Aus der Arbeit hervorgegangene Publikationen 95 9 Danksagung 96 10 Anlage 1: Erklärungen zur Eröffnung des Promotionsverfahrens 97 11 Anlage 2: Bestätigung über Einhaltung der aktuellen gesetzlichen Vorgaben 98

Doenças do neurônio motor (DNM) representam um grupo de doenças que cursam com fraqueza muscular progressiva e inexorável, e o manejo clínico é baseado no controle dos sintomas. Estes doentes sofrem de acometimentos motores e não motores intensos e de evolução progressiva. Entretanto, além dos sintomas motores, de humor e de déficits cognitivos, uma caracterização mais profunda de sintomas não- motores nesses doentes raramente foi relatada. Este estudo transversal objetivou descrever os sintomas não motores na DMN e seu impacto na qualidade de vida e no estado funcional, com foco na dor e alterações sensoriais. Oitenta doentes (31 mulheres, 55,7 ± 12,9 anos) com DNM foram submetidos a exame clínico extenso, avaliação de dor (questionário de dor McGill, Inventário breve de dor, questionário douleur neuropathique-4), avaliação psicofísica [teste quantitativo da sensibilidade (TQS) e modulação condicionada da dor (MCD)], avaliações de humor e catastrofismo, e foram comparados com controles saudáveis (CS) pareados por sexo e idade. Dor crônica (presente a maior parte dos dias por mais de três meses) foi presente em 46% dos doentes (escala numérica da dor = 5,18 ± 2,0). A dor de origem musculo- esquelética ocorreu em 40,5% e foi localizada principalmente na região da cabeça/pescoço (51%) e da região lombar (35%). A dor neuropática não presente nesta amostra. Comparado aos CS, os doentes com DNM apresentaram menor limiar de detecção de frio (p < 0,002) e valores de MCD significativamente menores (4,9 ± 0,2% vs. 22,1 ± 0,2%, p = 0,012). Os resultados do TQS/MCD não diferiram entre os doentes com DNM com e sem dor. A intensidade da dor foi correlacionada estatisticamente com ansiedade, depressão e catastrofismo, e os escores de espasticidade foram correlacionados inversamente com a MCD (rho = -0,30, p = 0,026). A dor é um sintoma frequentemente relatado por doentes com DNM. Alterações somatossensoriais e de MCD existem em DNM e podem estar relacionadas com a natureza neurodegenerativa da doença. Estudos adicionais devem investigar formas de melhor quantificar estas alterações e explorar estratégias de tratamento mais apropriadas para o seu controle / Motor neuron disorders (MNDs) represent a group of diseases that curse with inexorable muscle weakness and medical management is based on symptom control. These patients suffer from intense motor and non-motor progressive symptoms. However, apart from motor symptoms, mood and cognitive impairments, deeper characterization of non-motor symptoms in these patients have been rarely reported. This cross-sectional study aimed to describe non-motor symptoms in MND and their impact on quality of life and functional status, with a focus on clinical pain and sensory changes. Eighty patients (31 females, 55.7±12.9 years old) with MND underwent a extensive clinical examination, pain (McGill pain questionnaire, brief pain inventory, douleur neuropathique-4), psychophysics [quantitative sensory testing (QST) and conditioned pain modulation (CPM)], mood and catastrophizing assessments, and were compared to sex- and age-matched healthy controls (HC). Chronic pain (present on most days for more than three months) was present in 46% of patients (numerical visual scale=5.18±2.0). Pain of musculoskeletal origin occurred in 40.5% and was mainly located in the head/neck (51%) and lower back (35%). Neuropathic pain was not present in this sample. Compared to HC, MND patients had a lower cold detection threshold (p < 0.002), and significantly lower CPM scores (4.9±0.2% vs. 22.1±0.2%, p=0.012). QST/CPM results did not differ between MND patients with and without pain. Pain intensity was statistically correlated with anxiety, depression, and catastrophism, and spasticity scores were inversely correlated with CPM (rho=-0.30, p=0.026). Pain is frequently reported by patients with MNDs. Somatosensory and CPM changes exist in MNDs and may be related to the neurodegenerative nature of the disease. Further studies should investigate ways to better quantify these changes and explore the treatment strategies most appropriated for their control

Doenças do neurônio motor (DNM) representam um grupo de doenças que cursam com fraqueza muscular progressiva e inexorável, e o manejo clínico é baseado no controle dos sintomas. Estes doentes sofrem de acometimentos motores e não motores intensos e de evolução progressiva. Entretanto, além dos sintomas motores, de humor e de déficits cognitivos, uma caracterização mais profunda de sintomas não- motores nesses doentes raramente foi relatada. Este estudo transversal objetivou descrever os sintomas não motores na DMN e seu impacto na qualidade de vida e no estado funcional, com foco na dor e alterações sensoriais. Oitenta doentes (31 mulheres, 55,7 ± 12,9 anos) com DNM foram submetidos a exame clínico extenso, avaliação de dor (questionário de dor McGill, Inventário breve de dor, questionário douleur neuropathique-4), avaliação psicofísica [teste quantitativo da sensibilidade (TQS) e modulação condicionada da dor (MCD)], avaliações de humor e catastrofismo, e foram comparados com controles saudáveis (CS) pareados por sexo e idade. Dor crônica (presente a maior parte dos dias por mais de três meses) foi presente em 46% dos doentes (escala numérica da dor = 5,18 ± 2,0). A dor de origem musculo- esquelética ocorreu em 40,5% e foi localizada principalmente na região da cabeça/pescoço (51%) e da região lombar (35%). A dor neuropática não presente nesta amostra. Comparado aos CS, os doentes com DNM apresentaram menor limiar de detecção de frio (p < 0,002) e valores de MCD significativamente menores (4,9 ± 0,2% vs. 22,1 ± 0,2%, p = 0,012). Os resultados do TQS/MCD não diferiram entre os doentes com DNM com e sem dor. A intensidade da dor foi correlacionada estatisticamente com ansiedade, depressão e catastrofismo, e os escores de espasticidade foram correlacionados inversamente com a MCD (rho = -0,30, p = 0,026). A dor é um sintoma frequentemente relatado por doentes com DNM. Alterações somatossensoriais e de MCD existem em DNM e podem estar relacionadas com a natureza neurodegenerativa da doença. Estudos adicionais devem investigar formas de melhor quantificar estas alterações e explorar estratégias de tratamento mais apropriadas para o seu controle / Motor neuron disorders (MNDs) represent a group of diseases that curse with inexorable muscle weakness and medical management is based on symptom control. These patients suffer from intense motor and non-motor progressive symptoms. However, apart from motor symptoms, mood and cognitive impairments, deeper characterization of non-motor symptoms in these patients have been rarely reported. This cross-sectional study aimed to describe non-motor symptoms in MND and their impact on quality of life and functional status, with a focus on clinical pain and sensory changes. Eighty patients (31 females, 55.7±12.9 years old) with MND underwent a extensive clinical examination, pain (McGill pain questionnaire, brief pain inventory, douleur neuropathique-4), psychophysics [quantitative sensory testing (QST) and conditioned pain modulation (CPM)], mood and catastrophizing assessments, and were compared to sex- and age-matched healthy controls (HC). Chronic pain (present on most days for more than three months) was present in 46% of patients (numerical visual scale=5.18±2.0). Pain of musculoskeletal origin occurred in 40.5% and was mainly located in the head/neck (51%) and lower back (35%). Neuropathic pain was not present in this sample. Compared to HC, MND patients had a lower cold detection threshold (p < 0.002), and significantly lower CPM scores (4.9±0.2% vs. 22.1±0.2%, p=0.012). QST/CPM results did not differ between MND patients with and without pain. Pain intensity was statistically correlated with anxiety, depression, and catastrophism, and spasticity scores were inversely correlated with CPM (rho=-0.30, p=0.026). Pain is frequently reported by patients with MNDs. Somatosensory and CPM changes exist in MNDs and may be related to the neurodegenerative nature of the disease. Further studies should investigate ways to better quantify these changes and explore the treatment strategies most appropriated for their control

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 5 uppsatser. Även tryckt utgåva.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects the somatic motor system through the degeneration of upper and lower motors neurons. Evidence suggests that the cerebrospinal fluid (CSF), which is in direct contact with the nervous system, has soluble substance that could cause injuries in motor neurons. Animal models that express mutant ALS associated genes have been created to study the various etiopathological mechanisms which manifest themselves similarly to that occur in ALS patients. However, these models best represent the etiology of the disease in familiar cases and there is not yet an animal model that represents the characteristics of the disease in sporadic form, despite the similarity between familiar and sporadic cases. Thus, the aim of this study was to evaluate the motor and histological changes after intracerebroventricular injection (i.c.v.) of CSF from ALS sporadic patients in rats. 43 seven-month-old Wistar rats were used, coming from the sectoral animal facility of the Department of Physiology at the Federal University of Sergipe. The study was divided into two experiments: (I) with a single administration i.c.v. of the CSF and (II) with repeated administration i.c.v. of the CSF. In the experiment I, the animals were divided into 3 groups: control (CTR, artificial CSF solution), non-ALS (N-ALS, CSF of patients without neurological disease) and ALS (ALS, LCR of patients with sporadic ALS) who received a single injection i.c.v. (7.5μL) and one week after were subjected to motor tests: strength test, catalepsy test, open field test and walking test once a week for 30 days. In the Experiment II, animals were divided into 3 groups: control (CTR) Non-ALS (N-ALS) and ALS and they received daily injection for 6 days, i.c.v. (5.0μL). Throughout the treatment the animals underwent the motor tests already mentioned. After the tests, in both experiments, rats were anesthetized, perfused, their spinal cords were removed and subjected to histological analysis by hematoxylin-eosin for general morphological observation. In the first experiment ,in ALS group, motor alteration was observed in the strength test, open field and in the walking test, accompanied by a reduction of motor neurons and glial cells in the thoracic and lumbar regions of the spinal cord. In the second experiment, Also in the ALS group, it was observed driving change in catalepsy, open field and in the walking test, accompanied by an increase of glial cells in the lumbar region of the spinal cord. Data presented in this study show that the CSF management of ALS patients can cause pathogenic mechanisms similar to those seen in humans and other animal models of ALS. / A Esclerose Lateral Amiotrófica (ELA) é uma doença neurodegenerativa progressiva, que afeta o sistema motor somático através da degeneração dos neurônios motores superiores e inferiores. Evidências apontam que o líquido cefalorraquidiano (LCR), que está em íntimo contato com o sistema nervoso, apresenta substâncias solúveis que podem provocar lesões em neurônios motores. Modelos animais que expressam genes mutantes associados à ELA foram desenvolvidos, para o estudo dos mais diversos mecanismos etiopatológicos que se manifestam de forma similar aos que ocorrem em pacientes com a doença. Entretanto, esses modelos representam melhor a etiologia da doença em casos familiares e, apesar da semelhança entre casos familiares e esporádicos, ainda não se tem um modelo animal que represente características da doença nesta última. Diante disso, o objetivo do presente trabalho foi avaliar as alterações motoras e histológicas após injeção intracerebroventricular (i.c.v.) de LCR de pacientes com ELA esporádica em ratos Wistar. Foram ultilizados 43 ratos Wistar, com idade aproximada de sete meses, provenientes do Biotério Setorial do Departamento de Fisiologia da Universidade Federal de Sergipe. O trabalho foi dividido em 2 experimentos: (I) com uma única administração i.c.v. de LCR e (II) com administrações repetidas i.c.v. de LCR. No experimento I os animais foram divididos em 3 grupos, controle (CTR, solução de LCR artificial), não-ELA (NELA, LCR de pacientes sem doenças neurológicas) e ELA (ELA, LCR de paciente com ELA esporádica) que receberam uma única injeção i.c.v. de 7,5 μL e após uma semana foram submetidos aos testes motores: teste de força, catalepsia, campo aberto e teste de marcha uma vez por semana durante 30 dias. No experimento II, os animais foram divididos em 3 grupos, controle (CTR), Não-ELA (N-ELA) e ELA que receberam uma injeção diária, durante 6 dias, i.c.v. de 5 μL. Ao longo do tratamento, os animais foram submetidos aos testes motores acima mencionados. Após os testes, em ambos experimentos, os ratos foram anestesiados, perfundidos, suas medulas removidas e submetidas à análise histológica pela coloração de hematoxilina-eosina para observação morfológica geral. No experimento I, no grupo ELA, foi observado alteração motora no teste de força, campo aberto e no teste de marcha, acompanhado por uma redução de neurônios motores e células gliais na região torácica e lombar da medula espinal. No experimento II, também no grupo ELA, foi observado alteração motora na catalepsia, campo aberto e no teste de marcha, acompanhado de um aumento de células gliais na região lombar da medula espinal. Os dados apresentados neste estudo mostram que a administração de LCR de pacientes com ELA pode provocar mecanismos patogênicos semelhantes aos observados em humanos e outros modelos animais de ELA.