Disease burden of myotonic dystrophy type 1

Objective: The objective of this cross-sectional, observational study was to investigate the disease burden of myotonic dystrophy type 1 (DM1), a disabling muscle disorder. Methods: Adults with DM1 were recruited as part of the PhenoDM1 study from Newcastle University (Newcastle upon Tyne, UK). Disease burden data were recorded through the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. Results were examined by sex and clinical variables [e.g. the six-minute walk test (6MWT), the Mini Mental State Examination, and estimated progenitor and modal allele CTG repeat length]. Results: Our sample consisted of 60 patients with DM1 (mean age: 45 years; 45% female). Muscle weakness and fatigue constituted the two most common disease manifestations, reported by 93% and 90% of patients, respectively, followed by muscle locking (73%). Most patients (> 55%) reported feeling anxious/worried, depressed, frustrated, and/or having low confidence/self-esteem, 23% and 33% indicated substantial impairment of daily and leisure activities, respectively, and 47% did not work as a consequence of the disease. Estimated progenitor CTG length corrected by age correlated surprisingly well with INQoL scores. Differences by sex were generally minor. Conclusion: We show that DM1 is associated with a substantial disease burden resulting in impairment across many different domains of patients’ lives, emphasizing the need for a holistic approach to medical management. Our results also show that the INQoL records relevant information about patients with DM1, but that further investigation of the psychometric properties of the scale is needed for meaningful interpretation of instrument scores

Change over time in ability to perform activities of daily living in myotonic dystrophy type 1

Objective: The objective of this longitudinal, observational study was to investigate change over time in ability to perform activities of daily living in myotonic dystrophy type 1 (DM1). Methods: Adults with genetically confirmed DM1 were recruited as part of the PhenoDM1 study in the UK. Data on activities of daily living were recorded through the DM1-ActivC at baseline and a follow-up visit after 12 (± 3) months. A subset of patients had advanced genetic testing to determine the size of the progenitor allele. Results: Our sample comprised 150 patients with DM1 (mean age: 45 years; 52% female). Mean follow-up was 383 days. Mean DM1-ActivC total score at baseline was 71.24 (95% confidence interval 67.77–74.71) and at the follow-up visit 69.04 (65.54–72.54). Approximately 43% of patients had a lower score at the follow-up visit (indicating a decreased ability to perform activities of daily living), 24% a higher score (indicating an increased ability), and 33% the same score at baseline and follow-up. The mean annual change in the DM1-ActivC total score, estimated at − 2.06 (− 3.54 to − 0.59), was significantly related to patients’ baseline score, but not sex, disease duration, timed test results, or cytosine-thymine-guanine repeat length. Conclusions: Change over time in ability to perform activities of daily living as recorded through the DM1-ActivC varies substantially between patients with DM1. Our data contribute to the understanding of the natural evolution of the disease, and should be helpful to inform the design of future trials based on the DM1-ActivC

Areas of improvement in the medical care of SMA : evidence from a nationwide patient registry in Germany

Background Management and treatment of spinal muscular atrophy (SMA) has changed in recent years due to the introduction of novel transformative and potentially curative therapies resulting in the emergence of new disease phenotypes. Yet, little is known about the uptake and impact of these therapies in real-world clinical practice. The objective of this study was to describe current motor function, need of assistive devices, and therapeutic and sup‑ portive interventions provided by the healthcare system, as well as the socioeconomic situation of children and adults with diferent SMA phenotypes in Germany. We conducted a cross-sectional, observational study of German patients with genetically confrmed SMA identifed and recruited via a nationwide SMA patient registry (www.sma-register. de) within the TREAT-NMD network. Study data was recorded directly from patient-caregiver pairs through a study questionnaire administered online via a dedicated study website. Results The fnal study cohort consisted of 107 patients with SMA. Of these, 24 were children and 83 adults. In total, about 78% of all participants were taking medication for SMA (predominantly nusinersen and risdiplam). All children with SMA1 were able to sit and 27% of children with SMA2 were able to stand or walk. Impaired upper limb function, scoliosis and bulbar dysfunction were observed more frequently in patients with reduced lower limb performance. Physiotherapy, occupational therapy, and speech therapy, as well as the use of cough assists were less common than indicated by care guidelines. Family planning and educational and employment status appear to be related to motor skill impairment. Conclusions We show that the natural history of disease has changed in Germany following improvements in SMA care and the introduction of novel therapies. Yet, a non-trivial proportion of patients remain untreated. We also identi‑ fed considerable limitations in rehabilitation and respiratory care, as well as low labour-market participation among adults with SMA, calling for action to improve the current situation

Activities of daily living in myotonic dystrophy type 1

Objectives: The objective of this cross‐sectional, observational study was to investigate performance of activities of daily living in patients with myotonic dystrophy type 1 (DM1). Materials and Methods: Adults with genetically confirmed DM1 were recruited from Newcastle University (Newcastle upon Tyne, UK) and University College London Hospitals NHS Foundation Trust (London, UK). Data on activities of daily living were recorded through the DM1‐ActivC (scale scores range between 0 and 100, where a higher/lower score indicates a higher/lower ability). Results: Our sample comprised 192 patients with DM1 (mean age: 46 years; 51% female). Patients reported most difficulties with running, carrying and putting down heavy objects, and standing on one leg, and least difficulties with eating soup, washing upper body, and taking a shower. Irrespective of the disease duration (mean: 20 years), most patients were able to perform basic and instrumental activities of daily living (eg personal hygiene and grooming, showering, eating, cleaning and shopping), with the exception of functional mobility/transfer tasks (eg walking uphill and running). The mean DM1‐ActivC total score was estimated at 71 (95% CI: 68‐74). Estimated progenitor cytosine‐thymine‐guanine repeat length and age explained 27% of the variance in DM1‐ActivC total scores (P < .001). Conclusions: We show that DM1 impairs performance of activities of daily living, in particular those requiring a high degree of muscle strength, stability and coordination. Yet, across the evolution of the disease, the majority of patients will still be able to independently perform most basic and instrumental activities of daily living

The health economics of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease characterized by progressive muscle degeneration resulting in loss of independent ambulation, serious multisystem complications, and a mean life expectancy at birth of about 25 years. Several therapies are on the horizon for DMD and it has thus become urgent to better understand the health economic context of the disease to enable assessments of cost-effectiveness and inform decisions regarding reimbursement of new health technologies. However, to date, little is known of the burden of DMD, including cost of illness and impact on health-related quality of life (HRQoL). The aim of this thesis was to estimate and describe the health economics of DMD, develop a tool measuring disease progression, and construct a model framework for economic evaluation of new treatments. Paper I to IV were based on data collected in a cross-sectional, observational study. Patients with DMD from Germany, Italy, the UK, and the US were identified and recruited through the Translational Research in Europe – Assessment and Treatment of Neuromuscular Diseases (TREAT-NMD) network and invited with a caregiver to complete a study questionnaire online. Paper V was a modelling study synthesizing data from the preceding papers. In paper I to III, we estimated direct and indirect costs of DMD and measured patient and caregiver HRQoL and burden using several generic and disease-specific instruments. In paper IV, we developed the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT), a new rating-scale measuring functional ability in DMD. Item selection for the DMDSAT was led by neuromuscular specialists and the psychometric properties of the instrument were examined using Rasch analysis. In paper V, we synthesized our health economic evidence and developed a decision-analytic model framework for the assessment of the cost-effectiveness of treatments for DMD based on the DMDSAT. For comparison, we also developed two models based on stages of disease as defined in the international DMD clinical care guidelines and patients’ ventilation status, respectively. In paper I, we show that DMD is associated with a substantial cost burden to society and affected households. Across countries, the mean per-patient annual direct cost of illness was found to be 7 to 16 times higher than the mean per-capita health expenditure. Indirect and informal care costs of DMD were substantial, each component constituting between 18% and 43% of total costs. In paper II, we show that HRQoL (as valued by the general population) in DMD is substantially impaired in relation to general population reference values, strongly negatively associated with disease progression, and in good agreement with the caregivers’ subjective rating of patients’ current health and mental status. Still, most children and young adults with DMD were perceived as happy and in good health by their caregivers, indicating that some domains of HRQoL remain intact through the progression of the disease. In paper III, we show that caring for a person with DMD can be associated with a substantial burden and impaired HRQoL. Our findings suggest that caregivers to patients with DMD should be screened for depression and emphasize the need for a holistic approach to family mental health in the context of chronic childhood disease. In paper IV, the administered version of the new rating-scale, the DMDSAT, comprised a total of eight questions covering four domains (arm function, mobility, transfers, and ventilation status). Results from the psychometric analysis show that the DMDSAT is an instrument fit for purpose to measure functional ability in ambulant and non-ambulant patients with DMD. In paper V, we found that model structure and perspective of analysis have a substantial impact on assessments of cost-effectiveness of treatments for DMD. Our results show that the DMDSAT represents a sensitive and clinically relevant option for modelling DMD across the entire trajectory of disease in economic evaluations compared with frameworks based on conventional staging of disease progression. In summary, this thesis provides a description of the previously unknown health economic context of DMD, including a portfolio of cost and utility data, a new tool designed to measure DMD disease severity, and a fully populated decision-analytic model framework for cost-effectiveness analysis. These data and tools should be helpful to inform health technology assessments and health economic programmes of new treatments for DMD

Rasch Analysis of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales Administered to Patients With Duchenne Muscular Dystrophy.

OBJECTIVES: The objective of this study was to examine the psychometric properties of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0 GCS) in Duchenne muscular dystrophy (DMD), a rare, severely debilitating, and ultimately fatal neuromuscular disease. METHODS: Patients with DMD were recruited from 20 centers across 9 countries as part of the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (NCT00468832). The psychometric properties of the PedsQL 4.0 GCS were examined using Rasch analysis. RESULTS: In total, 329 patients with DMD (mean age 9 years, range 3-18 years, 75% ambulatory) completed the PedsQL 4.0 GCS. The most difficult instrument items, expressing the greatest loss in health-related quality of life, were those associated with emotional well-being (eg, being teased by other children, feeling sad, and not making friends), as opposed to somatic disability (eg, lifting heavy objects, participating in sports, and running). The mean item and person fit residuals were estimated at 0.301 (SD: 1.385) and -0.255 (1.504), respectively. In total, 87% (20 of 23) of items displayed disordered thresholds, and many exhibited nontrivial dependency. The overall item-trait interaction χ2 value was 178 (115 degrees of freedom, P<.001). Our analysis also revealed significant issues with differential item functioning, and by investigating residual principal component loadings, the PedsQL 4.0 GCS total score was found to be multidimensional. CONCLUSIONS: The PedsQL 4.0 GCS records information clinically relevant to patients with DMD, but the total scale score may not be fit for purpose as a measure health-related quality of life in this disease population

Predicerar skriftliga bildbeskrivningar demens? : -En retrospektiv studie

Skrivning är en biomekaniskt invecklad process som kräver en viss nivå av såväl motorisksom kognitiv förmåga. Forskning om Alzheimers sjukdom tyder på att nedsättningar i flerakognitiva domäner förekommer innan den kliniska diagnosen ställs. Det finns även forskningsom tyder på att ett innehållsrikt skriftspråk i unga år minskar risken för demensutveckling påäldre dagar. För att studera om mått från texter kunde predicera demens på ett tidigt stadiumanalyserades 141 skriftliga bildbeskrivningar insamlade inom ramen för rutinmässigaminnesutredningar vid Karolinska universitetssjukhuset, Huddinge. Deltagarna delades in itre grupper utifrån diagnos (minnesutredning, lindrig kognitiv svikt och demens).Utgångspunkt för studien var de fyra textmåtten: idétäthet, verbtäthet, läsbarhetsindex (LIX)och T-enheter. Då texterna i de flesta fall var skrivna av personer med kognitiv nedsättninghar måtten varit tvungna att modifieras och särskilda instruktioner för bedömning av texternahar utformats. Resultaten tyder på att skriftliga bildbeskrivningar utförda av individer meddemens innehåller färre totalt antal ord än de skrivna av individer diagnostiserade medlindrig kognitiv svikt eller mindre svårigheter än så. De innehåller även färre propositioner,verb, långa ord, T-enheter, ord per T-enhet, har en kortare meningslängd samt har i snitt ettlägre LIX-värde. En logistisk regressionsanalys visade att demens (kontra minnesutredningarmed subjektiva besvär) predicerades signifikant (p < 0.01) av antalet verb samt av LIXvärdet.Totalt 85 % av fallen klassificerades korrekt.Writing is a biomechanically complex process which demands a certain level of motor aswell as cognitive ability. Research concerning Alzheimer’s disease shows that impairmentsin multiple cognitive domains are notable before a clinical diagnosis can be made. There isalso research which indicates that written language ability in early life predicts the risk ofdementia in old age. The purpose of this study was to analyze whether measures derivedfrom narrative writing could predict dementia cross-sectionally. The material was 141 writtenpicture descriptions collected during routine investigations of cognitive disorders at theMemory Clinic, Karolinska University Hospital, Stockholm. The participants were classifiedinto three groups based on their diagnosis (subjective memory complaints, mild cognitiveimpairment and dementia). This study was based essentially on the four text measures: ideadensity, verb density, index of readability (LIX) and T-unit. As most of the texts were writtenby participants with some degree of cognitive decline the measures had to be modified tosome extent and detailed scoring protocols were worked out. The results indicate that writtenpicture descriptions made by individuals with dementia contained fewer words than thosewritten by individuals diagnosed with mild cognitive impairment or subjective cognitivecomplaints. They also contained fewer propositions, verbs, long words, T-units, words per Tunit,had a shorter mean sentence length and had a lower average LIX-value. A logisticregression analysis showed that cases of dementia, as opposed to subjective cognitivecomplaints, were significally predicted (p < 0.01) by the number of verbs and also by theLIX-value. Overall, 85 % of the cases were correctly classified

Mortality cost of Duchenne muscular dystrophy

BackgroundDespite advances in management and care, Duchenne muscular dystrophy (DMD) remains universally fatal. The objective of this study was to estimate the mortality cost of DMD.MethodsWe estimated the mean total national annual mortality cost associated with DMD by simulating the mean number of patients who would have been alive in 2012 in the absence of DMD using data on the mean DMD incidence, mean number of live male births, mean life expectancy at birth in DMD and the male general population, and a societal willingness-to-pay (WTP) for a life-year. We attributed each patient who would have been alive in 2012 a lost life-year. Finally, to estimate the mean mortality cost of DMD, we multiplied the estimated mean number of life-years lost with a societal WTP for a life-year of €75,000.ResultsThe mean total number of patients who would have been alive in 2012 in the absence of DMD was estimated at 4470 (95% bootstrapped CI: 4449-4492) in Germany, 3313 (3297-3329) in Italy, 3564 (3547-3581) in the UK, and 16,105 (16,029-16,186) in the USA. The corresponding mean mortality cost (in millions) was estimated at €335 (€334-€337) for Germany, €248 (€247-€250) for Italy, €267 (€266-€269) for the UK, and €1,208 (€1,202-€1,214) for the USA.ConclusionsWe show that DMD is associated with a considerable mortality cost and a substantial total economic burden to society. Our findings serve as important intelligence input to health economic policy decisions, allocation of funds for research, and cost-effective care delivery systems