Aim
To examine the long‐term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy.
Method
Using neuropsychological ...tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years.
Results
From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white‐matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white‐matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities.
Interpretation
As treatment enables patients with classic infantile Pompe disease to reach adulthood, white‐matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow‐up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next‐generation therapeutic strategies for classic infantile Pompe disease.
What this paper adds
In our long‐term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white‐matter abnormalities.
Cognitive development varied from stable and normal to declines towards intellectual disabilities.
Resumen
Pacientes con la enfermedad de Pompe infantil clásico aproximándose a la adultez: un estudio de cohorte acerca de las consecuencias para el cerebro
Objetivo
Examinar las consecuencias a largo plazo del depósito de glucógeno en el sistema nervioso central (SNC) por la enfermedad de Pompe infantil clásico usando terapia de reemplazo enzimático.
Método
Usando test neuropsicológicos y resonancia nuclear magnética (RMN) de cerebro, nosotros valoramos prospectivamente una cohorte de 11 pacientes con Pompe infantil clásico de hasta 17 años de edad.
Resultados
Desde aproximadamente los dos años de edad en adelante, la RMN de cerebro mostró compromiso de la sustancia blanca periventricular y centro semioval. Después de los 8 años de edad, se agregaron anormalidades en la sustancia blanca a nivel del cuerpo calloso, cápsula interna y externa y áreas subcorticales. Desde los 11 años de edad se encontraron anormalidades de la sustancia blanca en tronco cerebral. A pesar de que parece haber un patrón característico de compromiso en el tiempo, hubo considerables variaciones entre pacientes reflejadas por variaciones en el desarrollo neuropsicológico. El desarrollo cognitivo varió desde estable y normal hasta declinaciones que condujeron a la discapacidad intelectual
Interpretacion
Así como el tratamiento posibilita a los pacientes con la enfermedad de Pompe infantil clásico alcanzar la adultez, las anormalidades de la sustancia blanca se tornan progresivamente evidentes, afectando el desarrollo neuropsicológico. Por lo tanto, aconsejamos que los programas de seguimiento sean extendidos para evidenciar compromiso del SNC en cohortes de pacientes más numerosas e internacionales, para incorporar nuestros hallazgos al asesoramiento de los padres antes de comenzar el tratamiento, y para incluir al cerebro como un objetivo adicional en el desarrollo de nuevas generaciones de próximas estrategias terapéuticas para la enfermedad de Pompe infantil clásico.
Resumo
Pacientes com a doença de Pompe infantil clássica conforme se aproximam da vida adulta: um estudo de coorte sobre as consequências para o cérebro
Objetivo
Examinar as consequências de longo prazo do armazenamento de glicogênio no sistema nervosa central (SNC) para a doença de Pompe infantil clássica usando terapia de reposição enzimática
Método
Usando testes neuropsicológicos e imagens por ressonância magnética (IRM), avaliamos prospectivamente uma coorte de 11 pacientes com Pompe infantil clássica com até 17 anos de idade.
Resultados
De aproximadamente 2 anos de idade em diante, a IRM do cérebro mostrou envolvimento da substância branca periventricular e do centrum semioval. Após os 8 anos de idade, anormalidades adicionais da substância branca ocorreram no corpo caloso, cápsula interna e externa, e áreas subcorticais. A partir dos 11 anos, anormalidades da substância branca também foram encontradas no tronco cerebral. Embora pareça ser um padrão característico de envolvimento com o passar do tempo, houve variações consideráveis entre pacientes, refletidas por variações no desenvolvimento neuropsicológico. O desenvolvimento cognitivo variou de estável e normal para declínios levando a incapacidade intelectual.
Interpretação
Conforme o tratamento permite que pacientes com doença de Pompe infantil clássica atinjam a vida adulta, anormalidades da substância branca se tornam crescentemente evidentes, afetando o desenvolvimento neuropsicológico. Portanto, aconselhamos que programas de acompanhamento sejam expandidos para captar o envolvimento do SNC em coortes de pacientes maiores e internacionais, para incorporar nossos achados no aconselhamento dos pais antes do início do tratamento, e para incluir o cérebro como um alvo adicional do desenvolvimento da próxima geração de estratégias terapêuticas para a doença de Pompe infantil clássica.
What this paper adds
In our long‐term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white‐matter abnormalities.
Cognitive development varied from stable and normal to declines towards intellectual disabilities.
This article is commented on by Schoser on page 536 of this issue.
This article's has been translated into Spanish and Portuguese.
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Objectives
To provide insight into the health and social care costs during the disease trajectory in persons with dementia and the impact of institutionalization and death on healthcare costs ...compared with matched persons without dementia.
Methods
Electronic health record data from family physicians were linked with national administrative databases to estimate costs of primary care, medication, secondary care, mental care, home care and institutional care for people with dementia and matched persons from the year before the recorded dementia diagnosis until death or a maximum of 4 years after the diagnosis.
Results
Total mean health and social care costs among persons with dementia increased substantially during the disease trajectory, mainly due to institutional care costs. For people who remained living in the community, mean health and social care costs are higher for people with dementia than for those without dementia, while for those who are admitted to a long‐term care facility, mean health and social care costs are higher for people without dementia than for those with dementia.
Conclusions
The steep rise in health and social care costs across the dementia care trajectory is mainly due to increasing costs for institutional care. For those remaining in the community, home care costs and hospital care costs were the main cost drivers. Future research should adopt a societal perspective to investigate the influence of including social costs.
Key points
Health and social care costs among persons with dementia increase substantially during the disease trajectory.
This steep rise in costs during the disease trajectory is mainly due to institutional care costs.
For people who remained living in the community, mean health and social care costs are higher for people with dementia than for those without dementia.
For people who are admitted to a long‐term care facility, mean health and social care costs are higher for people without dementia than for those with dementia.
Health care systems that succeed in preventing long term care and hospital admissions of frail older people may substantially save on their public spending. The key might be found in high-quality ...care in the community. Quality Indicators (QIs) of a sufficient methodological level are a prerequisite to monitor, compare, and improve care quality. This systematic review identified existing QIs for community care for older people and assessed their methodological quality.
Relevant studies were identified by searches in electronic reference databases and selected by two reviewers independently. Eligible publications described the development or application of QIs to assess the quality of community care for older people. Information about the QIs, the study sample, and specific setting was extracted. The methodological quality of the QI sets was assessed with the Appraisal of Indicators through Research and Evaluation (AIRE) instrument. A score of 50% or higher on a domain was considered to indicate high methodological quality.
Searches resulted in 25 included articles, describing 17 QI sets with 567 QIs. Most indicators referred to care processes (80%) and measured clinical issues (63%), mainly about follow-up, monitoring, examinations and treatment. About two-third of the QIs focussed on specific disease groups. The methodological quality of the indicator sets varied considerably. The highest overall level was achieved on the domain 'Additional evidence, formulation and usage' (51%), followed by 'Scientific evidence' (39%) and 'Stakeholder involvement' (28%).
A substantial number of QIs is available to assess the quality of community care for older people. However, generic QIs, measuring care outcomes and non-clinical aspects are relatively scarce and most QI sets do not meet standards of high methodological quality. This study can support policy makers and clinicians to navigate through a large number of QIs and select QIs for their purposes. PROSPERO Registration: 2014:CRD42014007199.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To evaluate the cost‐effectiveness of the Geriatric Care Model (GCM), an integrated care model for frail older adults based on the Chronic Care Model, with that of usual care.
Design
...Economic evaluation alongside a 24‐month stepped‐wedge cluster‐randomized controlled trial.
Setting
Primary care (35 practices) in two regions in the Netherlands.
Participants
Community‐dwelling older adults who were frail according to their primary care physicians and the Program on Research for Integrating Services for the Maintenance of Autonomy case‐finding tool questionnaire (N = 1,147).
Intervention
The GCM consisted of the following components: a regularly scheduled in‐home comprehensive geriatric assessment by a practice nurse followed by a customized care plan, management and training of practice nurses by a geriatric expert team, and coordination of care through community network meetings and multidisciplinary team consultations of individuals with complex care needs.
Measurements
Outcomes were measured every 6 months and included costs from a societal perspective, health‐related quality of life (Medical Outcomes Study 12‐item Short‐Form Survey (SF‐12) physical (PCS) and mental component summary (MCS) scales), functional limitations (Katz activities of daily living and instrumental activities of daily living), and quality‐adjusted life years based on the EQ‐5D.
Results
Multilevel regression models adjusted for time and baseline confounders showed no significant differences in costs ($356, 95% confidence interval = −$488–1,134) and outcomes between intervention and usual care phases. Cost‐effectiveness acceptability curves showed that, for the SF‐12 PCS and MCS, the probability of the intervention being cost‐effective was 0.76 if decision‐makers are willing to pay $30,000 per point improvement on the SF‐12 scales (range 0–100). For all other outcomes the probability of the intervention being cost‐effective was low.
Conclusion
Because the GCM was not cost‐effective compared to usual care after 24 months of follow‐up, widespread implementation in its current form is not recommended.
The aim of this longitudinal cohort study, is to provide more insight into the pattern of brain abnormalities, and possible consequences for cognitive functioning, in patients with classic infantile ...Pompe disease. We included 19 classic infantile Pompe patients (median age last assessment 8.9 years, range 1.5–22.5 years; 5/19 CRIM negative), treated with ERT. Using MR imaging of the brain (T1, T2, and FLAIR acquisitions), we classified progression of brain abnormalities on a 12‐point rating scale at multiple time points throughout follow‐up. Additionally we noted specific white matter patterns and examined atrophy. Cognitive development was studied using Wechsler IQ assessments obtained by certified neuropsychologists. The association between age and cognitive functioning, and MRI ratings and cognitive functioning was assessed by linear regression models. All but one patient developed brain abnormalities. The abnormalities progressed in a similar pattern throughout the brain, with early involvement of periventricular white matter, later followed by subcortical white matter, gray matter structures, and juxtacortical U‐fibers. We found a significant decline (p < 0.01), with increasing age for full scale IQ, performance IQ and processing speed, but not for verbal IQ (p = 0.17). Each point increment in the 12‐point MRI rating scale was associated with a significant decline (3.1–6.0 points) in all the IQ index scores (p < 0.05). The majority of long‐term surviving patients in our cohort develop incremental brain MRI abnormalities and decline in cognitive functioning. This highlights the need for new therapies that can cross the blood–brain barrier in order to treat this CNS phenotype.
The aim of this study was to compare the long‐term outcome of classic infantile Pompe patients treated with 20 mg/kg alglucosidase alfa every other week (eow) to those treated with 40 mg/kg/week, and ...to study the additional effect of immunomodulation. Six patients received 20 mg/kg eow and twelve 40 mg/kg/week. Five patients were cross‐reactive immunologic material (CRIM)‐negative, two in the 20 mg, three in the 40 mg group. We compared (ventilator‐free) survival, motor outcome, infusion associated reactions (IARs), and antibody formation. From 2012 on patients >2 months in the 40 mg group also received immunomodulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) in an enzyme replacement therapy (ERT)‐naïve setting. Survival was 66% in the 20 mg group and 92% in the 40 mg group. Ventilator‐free survival was 50% and 92%. Both CRIM‐negative patients in the 20 mg group died, whereas all three are alive in the 40 mg group. In the 20 mg group, 67% learned to walk compared with 92% in the 40 mg group. At the age of 3 years, 33% and 92% were able to walk. Peak antibody titers ranged from 1:1250 to 1:31 250 in the 20 mg group and from 1:250 to 1:800 000 in the 40 mg group. Five patients of the 40 mg group of whom two CRIM‐negative also received immunomodulation. B‐cell recovery was observed between 5.7 and 7.9 months after the last dose of rituximab. After B‐cell recovery titers of patients with and without immunomodulation were similar (ranges 1:6 250‐1:800 000 and 1:250‐1:781 250). This study shows that classic infantile patients treated with 40 mg/kg/week from the start to end have a better (ventilator‐free) survival and motor outcome. Immunomodulation did not prevent antibody formation in our study.
Pompe disease is a lysosomal storage disease treated with life-long enzyme replacement therapy (ERT). Home-based ERT has been provided in the Netherlands since 2008 because it diminishes the burden ...of treatment, increases patient flexibility and autonomy, and is thus a more patient-centred approach to ERT.
All Dutch Pompe patients receiving alglucosidase alfa infusions at home were approached to participate in a questionnaire to validate the safety of home-based ERT. Prospective data on symptoms occurring during or within 48 h after infusion and retrospective data on infusion associated reactions (IARs) in the last three months were collected four times during one year.
In total, 116 out of 120 eligible patients (17 classic infantile, 2 atypical infantile, 15 childhood onset and 82 adult) filled out 423 questionnaires (response rate: 88.1%). Symptoms during or after infusion were reported 27 times in 17 patients. Fatigue was the most commonly reported health complaint (in 9.5% of patients). Four health complaints were judged to be IARs and reported to the Erasmus MC University Medical Center. None of the IARs reported in this study warranted emergency clinical care.
Our data demonstrate that home-based ERT in Pompe disease can be safely implemented as few, mostly mild, symptoms were reported during or after infusion. Insights from this study can be used as a base for implementing home-based ERT in other countries and to further optimize patient care, as unreported mild symptoms do not pose a health risk but may still be relevant to the patient.
As little information is available on children with non-classic presentations of Pompe disease, we wished to gain knowledge of specific clinical characteristics and genotypes. We included all ...patients younger than 18 years, who had been evaluated at the Pompe Center in Rotterdam, the Netherlands, between 1975 and 2012, excluding those with the classic-infantile form. None were treated with enzyme replacement therapy at the time of evaluation. We collected information on first symptoms, diagnosis, use of a wheelchair and/or respirator, and enzyme and mutation analysis and assessed muscle strength, pulmonary function, and cardiac parameters.
Thirty-one patients participated. Median age at symptom onset was 2.6 years (range 0.5-13y) and at diagnosis 4.0 years. Most first problems were delayed motor development and problems related to limb-girdle weakness. Fatigue, persistent diarrhea and problems in raising the head in supine position were other first complaints. Ten patients were asymptomatic at time of diagnosis. Five of them developed symptoms before inclusion in this study. Over 50 % of all patients had low or absent reflexes, a myopathic face, and scoliosis; 29 % were underweight. Muscle strength of the neck flexors, hip extensors, hip flexors, and shoulder abductors were most frequently reduced. Pulmonary function was decreased in over 48 % of the patients; 2 patients had cardiac hypertrophy. Patients with mutations other than the c.-32-13T > G were overall more severely affected, while 18 out of the 21 patients (86 %) with the c.-32-13T > G/'null' genotype were male.
Our study shows that Pompe disease can present with severe mobility and respiratory problems during childhood. Pompe disease should be considered in the differential diagnosis of children with less familiar signs such as disproportional weakness of the neck flexors, unexplained fatigue, persistent diarrhea and unexplained high CK/ASAT/ALAT. Disease presentation appears to be different from adult patients. The majority of affected children with GAA genotype c.-32-13T > G/'null' appeared to be male.
Enzyme replacement therapy (ERT; alglucosidase alfa) has improved the prospects for patients with classic infantile Pompe disease considerably. However, over time we noticed that many of these ...children exhibit distal muscle weakness at an early age, which is in contrast to the primarily proximal and axial muscle weakness in patients with late-onset Pompe disease. This was reason to study the prevalence and severity of distal muscle weakness, and the sequence of muscle involvement over time in patients that had learned to walk under ERT.
In this prospective, single-center cohort study, we studied 16 classic infantile patients. We used video recordings that were made during regular standardized assessments to investigate distal muscle function (active dorsiflexion of the feet during walking; ability to use a pincer grasp/actively extend the fingers) and proximal muscle function (standing up from a supine position; raising the arms above the head).
Median age at start of ERT was 3.2 months (0.1-5.8 months), median age at study end was 5.6 years (2.9-18.2 years). Six patients (6/16, 38%) initially had no evident signs of distal muscle weakness and developed a gait with active dorsiflexion of the feet. The other 10 patients never exhibited active dorsiflexion of the feet during walking. At study-end two patients showed no loss of distal muscle function. A subset of five patients (5/16, 31%) developed also weakness of the hands, particularly of the extensors of the 3rd and 4th digit.
We found that the majority (14/16, 88%) of patients who had learned to walk exhibited distal muscle weakness of the lower extremities, while a subset (5/16, 31%) also developed weakness of the hands. The distal muscle weakness was often more serious than, and preceded the development of, the proximal muscle weakness.
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