Immune checkpoint inhibitors can cause immune side effects, with myasthenia gravis (MG) being relatively rare. With this review, we present 66-year-old man with melanoma treated with pembrolizumab who developed MG. With immuno-oncology (IO) single agent usage, 42 cases reported new-onset MG and 9 cases reported exacerbation of pre-existing MG. Among the patients who had new-onset MG after administration of programmed cell death protein 1 (PD-1) inhibitors, 14 patients (38.8%) developed severe respiratory failure and required intubation and 10 patients (27.02%) died. Among the patients with exacerbation of pre-existing MG after receiving PD-1 inhibitors, 1 patient (11.1%) required intubation, and no death was reported. Combination IO therapy-induced MG was reported in seven cases, with at least two cases complicated by respiratory failure and one death. Our observations suggest a possible difference in the severity of the disease and outcome among different IO therapy options.

Background: Dilated Cardiomyopathy (DCM) is the most common functional type of cardiomyopathy in children with significant morbidity and the leading indication for cardiac transplant over 5 years of age. Identification of baseline risk factors for failing medical management by etiologic grouping remain to be elucidated in a large populationbased study. The competing risk for heart death between all-cause mortality and heart transplantation is often overestimated in the literature and may obscure additional novel risk factors associated with poor clinical outcomes. Methods: The National Heart Lung and Blood Institute Pediatric Cardiomyopathy Registry collected longitudinal data from 1731 children with DCM in North America from 1990 to 2007. Composite endpoint (CEP) was the earlier occurrence of death or heart transplant. Univariate and multivariate predictors were identified from demographic and echocardiographic data (expressed as z-scores) collected within 30 days of diagnosis. A competing risk analysis was performed calculating cumulative incidence and identifying novel prognostic factors. All analyses were performed by etiologic group. Results: Multivariate Cox regression identified the highest mortality risk among children with idiopathic disease (N=1192, CEP: 41%) when diagnosed over age 6 years, and with congestive heart failure (CHF) and decreased left ventricular fractional shortening (FS). Risk factors for those with myocarditis (N=272, CEP: 26%) were older age, CHF, and increased left ventricular (LV) end-diastolic dimension (EDD); while for neuromuscular disease (N=139, CEP: 40%), it was a decreased FS and increased EDD. Only univariate predictors were identified for children with familial isolated cardiomyopathy (N=79, CEP: 44%) including: CHF, increased EDD, end-systolic dimension, or LV mass, and decreased FS or ejection fraction), while for children with inborn errors of metabolism (N=43, CEP: 33%) risk factors included: a positive family history of cardiomyopathy or genetic syndromes. The group of children with malformation syndromes (N=6, CEP: 50%) was not large enough to model. Comparison of cause-specific event rates between Kaplan-Meier and cumulative incidence demonstrated an overestimation with the former method. Competing risk multivariate regression showed similar models to those for CEP, with the following exceptions: for neuromuscular disease, an increased EDD had a larger hazard ratio for transplant than for death; for idiopathic disease, an increased EDD was associated with transplant, but not with death, and growth retardation (height-for-age zscore) was associated with death but not transplant. Conclusions: Within etiologic grouping, demographics and echocardiographic values at diagnosis have varying predictive value. Generally, the presence of symptomatic disease in the form of CHF, echocardiographic evidence of more severe DCM, and increased age were indicative of worse outcomes. These results help to validate those from conflicting studies; however, they suggest that etiology modifies the importance of particular factors. Analysis of competing risk provides an alternate interpretation of studies with composite endpoints and assists in the transfer of clinically relevant information. For children with idiopathic and neuromuscular disease, the degree of dilation had a differential effect that has gone unrecognized. The novel finding of reduced stature and its effect on mortality suggests a potential for treatment and mitigation of poor outcomes in idiopathic DCM. Both increased dilation and reduced stature could be used to improve the triage process and refer children to cardiac transplantation who otherwise might die prematurely and unnecessarily. Subsequent studies on the utility of these factors and their effect on improving survival are warranted.

Made available in DSpace on 2015-07-22T20:50:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-01-01 / Objetivo: avaliar os efeitos do treinamento muscular inspiratório (TMI), e da associação do TMI ao anabolizante oxandrolona (Ox), na função pulmonar de indivíduos com doenças neuromusculares (DNM). Métodos: Foram avaliados 14 indivíduos (9 homens e 5 mulheres; idade: 36±17 anos) com as seguintes doenças: distrofia muscular cintura membros (n=9), distrofia muscular de Becker (n=1), distrofia muscular facio-escápulo-umeral (n=1) e atrofia muscular espinhal tipo III (n=3). Os indivíduos realizaram as seguintes avaliações respiratórias: pressões respiratórias estáticas máximas (PImáx e PEmáx), ventilação voluntária máxima (VVM), teste de resistência muscular respiratória (RMR) e espirometria. O estudo consistiu de quatro etapas: avaliação inicial, avaliação após 30 dias de TMI (40% da PImáx inicial), avaliação após 30 dias de destreinamento e avaliação após 30 dias de TMI (40% da PImax)+ Ox (0,1mg/Kg/dia). Resultados: O TMI aumentou a PImáx e a PEmáx (p<0,05). O tempo de destreinamento foi suficiente para a perda desses efeitos (p<0,05). A associação de TMI+Ox potencializou o aumento da PImáx e da PEmáx (p<0,05) e melhorou a RMR (p<0,05). Entretanto, ocorreu queda de algumas variáveis analisadas na espirometria (p<0,05), quando associamos a Ox ao TMI (CVF, VEF1 e FEF25-75%). Conclusões: A associação da oxandrolona potencializou os efeitos do TMI, entretanto, apesar de ter ocorrido queda em algumas variáveis analisadas na espirometria, não observamos alteração no diagnóstico funcional ventilatório, em todos os pacientes estudados. / Purpose: to evaluate the effects of inspiratory muscle training (IMT) associated to anabolic steroid oxandrolone in pulmonary function of patients with neuromuscular diseases. Methods: Fourteen subjects (9 male, 5 female, mean age 36±17 years) with the following diseases: limb-girdle muscular dystrophy (n=9), Becker muscular dystrophy (n=1), facioescapulohumeral muscular dystrophy (n=1) and spinal muscular atrophy (n=3), performed the following assessments: maximal static inspiratory and expiratory pressures (respectively, MIP and MEP), maximal voluntary ventilation in 12 seconds (MVV), respiratory muscle resistance (RMR) and spirometry. The research included four evaluations: baseline, after 30 days of IMT at 40% of baseline MIP, after 30 days of washout and after 30 days of IMT (at 40% of MIP) associated with oxandrolone (0.1 mg/kg/day). Results: MIP and MEP increased after IMT (p<0,05), and after washout they returned to baseline levels. MIP, MEP and RMR were higher after oxandrolone was associated to IMT (p<0,05), but a reduction in dynamic pulmonary volumes (FVC, FEV1 and FEF25-75%) was found in this condition (p<0,05). Conclusion: The association of oxandrolone increased the effect of the IMT, however, although to have occurred fall in some variables analyzed in the spirometry, we do not observe alteration in the ventilatory functional diagnosis, in all the studied patients. / TEDE

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease of motor neurons characterized by muscle paralysis and death within 3-5 years of onset. However, due to unknown mechanisms, the extraocular muscles (EOMs) remain remarkably unaffected. The EOMs are highly specialized muscles that differ from other muscles in many respects, including innervation and satellite cells (SCs). Understanding whether these factors play a role in the relative sparing of EOMs in ALS could provide useful clues on how to slow down the progression of ALS in other muscles. The EOMs and limb muscles from terminal ALS patients and age-matched controls as well as the commonly used SOD1G93A ALS mouse model were studied with immunofluorescence. Antibodies against neurofilament and synaptophysin were used to identify nerves and neuromuscular junctions (NMJs); against Pax7, NCAM, MyoD, myogenin, Ki-67, dystrophin and laminin, to identify SCs and their progeny in EOMs and limb muscles. The proportion and fiber size of myofibers containing myosin heavy chain (MyHC) slow tonic and MyHC slow twitch were also determined in human EOMs. The abundance of SCs differed extensively along the length of control human EOMs, being twice as abundant in the anterior portion. Pax7-positive cells were also detected in non-traditional SC positions. EOMs from terminal ALS patients showed similar numbers of resting and activated SCs as the controls. In limb muscles of ALS patients, the number of resting and activated SCs ranged from low (similar to normal aged, sedentary individuals) to high numbers, especially in muscles with long duration of disease and varied between the upper and lower limbs. The EOMs maintained a high degree of innervation compared to hindlimb muscles of symptomatic SOD1G93A mice. MyHC slow tonic fibers were less abundant in ALS patients than in controls. The change seemed more pronounced in bulbar onset patients, and in this group of subjects only, there was a strong association between decline in MyHC slow tonic fibers and age of death. Notably, the decline in MyHC slow tonic fibers was unrelated to disease duration. Our data suggested that SCs play a minor role in the progression of ALS in general and in the sparing of the EOMs in particular. The generally preserved innervation in the EOMs of G93A mice may reflect distinct intrinsic properties relevant for sparing of the oculomotor system.  Even though the EOMs are relatively spared in ALS, MyHC slow tonic myofibers were selectively affected and this may reflect differences in innervation, as these fibers are multiply innervated. / Amyotrofisk lateralskleros (ALS) är en obotlig neurodegenerativ sjukdom som främst påverkar kroppens viljestyrda motoriska nervceller. ALS leder till förlamning, muskelförtvining och slutligen döden genom andningssvikt, vanligen inom tre till fem år efter sjukdomsdebuten. Av okända anledningar så bibehålls ögonmusklernas funktion mycket bättre vid ALS i jämförelse med andra muskler och är hos merparten av patienter i stort sett opåverkade. Ögonmusklerna är mycket specialiserade muskler som skiljer sig från andra muskler i kroppen på flera sätt, bland annat genom deras unika nervförsörjning och genom de satellitceller – muskelspecifika stamceller, som finns i dem. En ökad förståelse för hur dessa faktorer inverkar på ögonmusklernas motståndskraft vid ALS skulle kunna ge värdefulla ledtrådar till hur man skulle kunna sakta ned sjukdomens fortskridande i andra muskler vid ALS. Ögonmuskler och extremitetsmuskler från avlidna ALS-patienter och åldersmatchade friska kontroller, tillsammans med transgena möss med den sjukdomsalstrande mutationen SOD1G93A, studerades genom immunfluorescens och efterföljande mikroskopering. Antikroppar mot molekylerna Pax7, NCAM, MyoD, myogenin, Ki-67, laminin och dystrofin användes för att identifiera satellitceller och deras dotterceller i ögonmuskler och extremitetsmuskler. Antikroppar mot neurofilament och synaptofysin användes för att identifiera nerver och neuromuskulära synapser hos transgena SOD1-möss. Antikroppar mot toniska (tonic) och ryckande (twitch) muskelmyosinkedjor användes för att bestämma proportionen av och storleken på dessa typer av muskelfibrer i ögonmuskler från avlidna ALS-patienter och friska kontroller. Mängden satellitceller varierade mellan de främre och de mer bakre delarna i friska, humana ögonmuskler och var dubbelt så många i den främre delen av muskeln jämfört med den mellersta och bakre delen av muskeln. Celler som uttryckte satellitcellsmarkören Pax7 hittades även i icke-traditionella satellitcellspositioner i ögonmusklerna. Mängden satellitceller i ögonmusklerna från ALS-patienter var samma som hos friska kontroller. I extremitetsmusklerna hos ALS-patienter varierade mängden satellitceller mellan låga nivåer (liknande de hos friska åldrade, inaktiva individer) till höga nivåer, särskilt i muskler där sjukdomen fortskridit under lång tid. Dessutom varierade mängden satellitceller mellan övre och nedre extremiteter. Hos symptomatiska SOD1G93A-möss hade ögonmusklerna en mycket välbevarad innervation jämfört med bakbensmusklerna, där många neuromuskulära synapser saknade kontakt mellan nerven och motorändplattan. Proportionen muskelfibrer med toniska muskelmyosinkedjor var lägre hos ALS-patienter jämfört med friska kontroller. Denna minskning var tydligare hos patienter där sjukdomssymtomen hade debuterat i tugg- och ansiktsmuskulaturen – så kallad bulbär ALS. Dessutom fanns det i den här gruppen, men ingen annan studerad grupp, en stark korrelation mellan nedgången i toniska fibrer och patientens ålder. Värt att notera är att minskningen av toniska muskelfibrer saknade korrelation med hur länge patienten hade varit sjuk i ALS. Den generellt välbevarade innervationen i ögonmusklerna hos SOD1G93A-möss kan spegla distinkta inneboende egenskaper hos ögonmusklerna som är av vikt för bevarandet av ögonrörligheten vid ALS. Gällande satellitceller så antyder våra data att satellitceller och deras regenerativa kapacitet spelar en försumbar roll vid ALS i allmänhet och vid ögonmusklernas bevarande i synnerhet. Slutligen, även om ögonmuskler generellt är välbevarade vid ALS så är toniska muskelfibrer märkbart påverkade och detta kan spegla skillnader mellan olika nervcellsgruppers känslighet vid ALS.

Striking disparities exist in higher education and employment rates between young adults with disabilities and their non-disabled peers. This qualitative study examined the lived experiences of nine young adults ages 24-35 with neuromuscular disease and how their use of personal assistance services (PAS) impacted their pursuit of higher education and employment. Participants overall had positive college experiences and reported the easiest time coordinating PAS was during college. Families of participants expected college attendance, but the lack of experience with PAS prior to college impacted higher education; the need for PAS influenced choice of college. Participants used consumer-driven and agency based models, experienced great stress coordinating PAS, experienced low quality and high turnover of staff, were restricted in their ability to be spontaneous, and at times limited their needs to avoid asking for assistance. A significant amount of informal caregiving from family and friends was used to support higher education and employment. Participants speculated that societal stereotypes and low expectations of people with disabilities contribute to low rates of employment and higher education, and reported negative interactions with vocational rehabilitation counselors. Eligibility criteria for federal and state PAS programs limited income and created work disincentives, were complex to understand and navigate, and discouraged both advancement in their careers and the willingness to pursue advanced degrees. Young adults with neuromuscular disease are willing, wanting, and capable to participate in higher education and gainful employment and could not do so without access to reliable quality PAS. Efforts to prepare families and youth to fund and coordinate PAS, eliminate work disincentives, and coordinate transition planning between multiple support agencies could help break the cycle of poverty in the disability community and encourage employment.

Background: Progressive respiratory muscle weakness and ineffective cough contributes to pulmonary morbidity and mortality in children with neuromuscular disease. Inspiratory muscle training aims to preserve or improve respiratory muscle strength, reduce respiratory complications and improve health-related quality of life. Objectives: To describe South African physiotherapists' knowledge and respiratory management strategies and determine the safety, viability, acceptability and efficacy of inspiratory muscle training for children 5-18 years with neuromuscular disease. Methods: Four studies were conducted: i) a quantitative descriptive survey; ii) a systematic review using Cochrane methodology; iii) a prospective, pre-experimental observational study and iv) a prospective, cross-over randomised controlled trial using a standardised 12-week inspiratory muscle training intervention. Results: i) South African physiotherapists (n=64) reported being aware of international clinical practice recommendations, however they favoured manual airway clearance techniques. The use of inspiratory muscle training in chronic management was well supported by South African physiotherapists. ii) Results of the systematic review (seven included studies; n=168) suggested that inspiratory muscle training may be effective in improving inspiratory muscle strength. There was insufficient evidence for an effect on patient morbidity or health-related quality of life. iii) The pre-experimental, pilot study (n=8) suggested that a six-week inspiratory muscle training programme was safe, viable, acceptable and associated with a significant increase in inspiratory muscle strength. iv) The cross-over randomised controlled trial (n=23) did not show evidence of a difference in the primary outcome measures (number of hospitalisations and respiratory tract infections) between intervention and control periods. There were no adverse events related to inspiratory muscle training. Inspiratory muscle strength (Pimax) and peak expiratory cough flow increased by 14.57 (±15.67)cmH2O and 32.27 (±36.60)L/min respectively during the intervention period compared to a change of 3.04 (±11.93)cmH2O (p=0.01) and -16.59 (±48.29)L/min (p=0.0005) during the control period. There was no evidence of change in spirometry, functional ability or total health-related quality of life scores following the intervention. Overall participant satisfaction with inspiratory muscle training was high and adherence was good. Conclusions: Inspiratory muscle training in children with neuromuscular disease is well tolerated, appears to be safe and is associated with significant improvements in inspiratory muscle strength and cough efficacy.

The biphasic cuirass ventilation (BCV) device is an alternative respiratory support device for patients with chronic respiratory failure. Considered by some a “forgotten” mode of supportive ventilation, the device is portable, lightweight, and easy to operate. Biphasic cuirass ventilation can also be used to rapidly resuscitate patients in acute respiratory distress and requires minimal technical skill to operate. Biphasic cuirass ventilation can be employed by the patient’s caregiver in the home setting, making it a viable alternative to other forms of mechanical ventilation (e.g., BiPAP) for patients enrolled in home hospice or palliative care. The article reviews current knowledge and aims to enhance awareness and encourage further study about cuirass ventilation, particularly with regard to its use in treating patients in the palliative care setting and in the home.

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.

Bibliographic record ONDRÁČKOVÁ, Radka. Application of physiotherapy in treating myasthenia gravis. Prague: Charles University, 2nd Faculty of Medicine, Department of Rehabilitation and Sports Medicine, 2015, p. 90, Supervisor of the work: Doc. PaedDr. Libuše Smolíková, Ph.D. Abstract Myasthenia gravis is an autoimmune disease affecting the neuromuscular transmission. It manifests in muscular weakness and tiredness, which characteristically fluctuate and change throughout the time. The most typically affected muscles are extraocular, mimic, oropharyngeal and the muscles of lower and upper extremities. The danger of respiratory difficulties is aggravated by worsening physical condition, which comes as a consequence of muscular weakness and with the onset of the myasthenic crisis. The work is focused on the use of respiratory physiotherapy and aerobic physical activity in patients with myasthenia gravis. The aim is to verify the effect of respiratory physiotherapy and aerobic physical activity to improve lung function and condition, and the disease stabilization. Keywords Myasthenia gravis, neuromuscular disease, physiotherapy, respiratory physiotherapy, aerobic training

Amyotrophic lateral sclerosis (ALS) is a lethal, progressive neurodegenerative disorder that selectively affects both upper and lower motor neurons, leading to muscle weakness, paralysis and death. Despite recent advances in the identification of genes associated with ALS, the quest for a sensitive biomarker for rapid and accurate diagnosis, prognosis, and treatment response monitoring has not been fulfilled. In this thesis, I report a method of quantifying the integrity of motor neurons in vivo using imaging to record uptake and retrograde transport of intramuscularly injected tetanus toxin fragment C (TTC) into spinal motor neurons. This method tracks and profiles progression of disease (transgenic SOD1G93A and PFN1 ALS mice) and detects subclinical perturbations in net transport, as analyzed in C9orf72 transgenic mice. It also defines a progressive reduction in net transport with aging. To address whether our technique enables drug development, I evaluated therapeutic benefits of (1) gene editing and (2) mutant gene silencing (with RNAi targeting SOD1) in SOD1G93A transgenic mice by characterizing their net axonal transport profiles. I constructed a computational model to evaluate key molecular processes affected in net axonal transport in ALS mouse model. The model allows prediction of key parameters affected in a C9ORF72 BAC transgenic mouse line. Prior immunization with tetanus toxoid does not preclude use of this assay, and it can be used repetitively in the same subject. This assay of net axonal transport offers broad clinical application as a diagnostic tool for motor neuron diseases and as a biomarker for rapid detection of benefit from therapies for transport dysfunction in a range of motor neuron diseases.