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  • 1
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    Natural history of respiratory muscle strength in spinal muscular atrophy: a prospective national cohort study
    Springer Science and Business Media LLC ; 2022
    In:  Orphanet Journal of Rare Diseases Vol. 17, No. 1 ( 2022-02-21)
    Details
    In: Orphanet Journal of Rare Diseases, Springer Science and Business Media LLC, Vol. 17, No. 1 ( 2022-02-21)
    Abstract: Respiratory complications are the most important cause of morbidity and mortality in spinal muscular atrophy (SMA). Respiratory muscle weakness results in impaired cough, recurrent respiratory tract infections and eventually can cause respiratory failure. We assessed longitudinal patterns of respiratory muscle strength in a national cohort of treatment-naïve children and adults with SMA, hypothesizing a continued decline throughout life. Methods We measured maximal expiratory and inspiratory pressure (PE max and PI max ), Sniff Nasal inspiratory pressure (SNIP), peak expiratory flow (PEF), and peak cough flow (PCF) in treatment-naïve patients with SMA. We used mixed-models to analyze natural history patterns. Results We included 2172 measurements of respiratory muscle function from 80 treatment-naïve patients with SMA types 1c-3b. All outcomes were lower in the more severe phenotypes. Significant differences in PEF were present between SMA types from early ages onwards. PEF decline was linear (1–2%/year). PEF reached values below 80% during early childhood in types 1c-2, and during adolescence in type 3a. PE max and PI max were severely lowered in most patients throughout life, with PE max values abnormally low (i.e. 〈  80 cmH 2 O) in virtually all patients. The PE max /PI max ratio was 〈  1 throughout life in all SMA types, indicating that expiratory muscles were most affected. All but SMA type 3b patients had a lowered PCF. Patients with types 2b and 3a had PCF levels between 160 and 270 L/min, those with type 2a around 160 L/min and patients with type 1c well below 160 L/min. Finally, SNIP was low in nearly all patients, most pronounced in more severely affected patients. Conclusions There are clear differences in respiratory muscle strength and its progressive decline between SMA types. We observed lower outcomes in more severe SMA types. Particularly PEF may be a suitable outcome measure for the follow-up of respiratory strength in patients with SMA. PEF declines in a rather linear pattern in all SMA types, with clear differences at baseline. These natural history data may serve as a reference for longer-term treatment efficacy assessments.
    Type of Medium: Online Resource
    ISSN: 1750-1172
    URL: Article
    DOI: 10.1186/s13023-022-02227-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
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    Population-based assessment of nusinersen efficacy in children with spinal muscular atrophy: a 3-year follow-up study
    Oxford University Press (OUP) ; 2022
    In:  Brain Communications Vol. 4, No. 6 ( 2022-11-02)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 4, No. 6 ( 2022-11-02)
    Abstract: Nusinersen (Spinraza®) improves survival of infants with hereditary proximal spinal muscular atrophy and motor function in children up to 12 years. Population-based assessments of treatment efficacy are limited and confined to select cohorts of patients. We performed a nationwide, population-based, single-centre cohort study in children with spinal muscular atrophy younger than 9.5 years at start of treatment in line with reimbursement criteria in the Netherlands. We assessed age-relevant motor function scores, the need for tube feeding, hours of ventilatory support and documented adverse events. We used linear mixed modelling to assess treatment effects. We compared motor function during treatment with natural history data and to individual trajectories of muscle strength and motor function before the start of treatment. We included 71 out of 72 Dutch children who were treated (median age 54 months; range 0–117) and followed them for a median of 38 months (range 5–52). We observed improvement of motor function in 72% and stabilization in another 18% of the symptomatic children, which differed from the natural disease course in a matched cohort of which we had previously collected natural history data. Longitudinal analysis showed that motor function improved up to a median of 24 months (range 12–30) of treatment after which it stabilized. Shorter disease duration at start of treatment resulted in better treatment efficacy (P & lt; 0.01). Sixteen children (23%) achieved new motor milestones. Bulbar and respiratory function did not improve significantly during treatment. In 15 patients from whom treatment-naïve data were available, the pre-treatment trajectory of motor function decline changed to stabilization or improvement after the start of treatment. We documented 82 adverse events after 934 injections (9%) in 45 patients. None of the adverse events led to treatment discontinuation. Intrathecal nusinersen treatment is safe and improves or stabilizes motor function in 90% of young children with spinal muscular atrophy types 1c–3a. We did not observe improvement of respiratory and bulbar functions.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcac269
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 3020013-1
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  • 3
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    Lung function decline preceding chronic respiratory failure in spinal muscular atrophy: a national prospective cohort study
    Springer Science and Business Media LLC ; 2023
    In:  Orphanet Journal of Rare Diseases Vol. 18, No. 1 ( 2023-02-23)
    Details
    In: Orphanet Journal of Rare Diseases, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2023-02-23)
    Abstract: Progressive lung function decline, resulting in respiratory failure, is an important complication of spinal muscular atrophy (SMA). The ability to predict the need for mechanical ventilation is important. We assessed longitudinal patterns of lung function prior to chronic respiratory failure in a national cohort of treatment-naïve children and adults with SMA, hypothesizing an accelerated decline prior to chronic respiratory failure. Methods We included treatment-naïve SMA patients participating in a prospective national cohort study if they required mechanical ventilation because of chronic respiratory failure and if lung function test results were available from the years prior to initiation of ventilation. We analyzed Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 s (FEV 1 ), Peak Expiratory Flow (PEF) and Maximum Expiratory Pressure (PE max ). We studied the longitudinal course using linear mixed-effects models. We compared patients who electively started mechanical ventilation compared to patients who could not be weaned after acute respiratory failure. Results We analyzed 385 lung function tests from 38 patients with SMA types 1c–3a. At initiation of ventilation median age was 18.8 years (IQR: 13.2–30.1) and median standardized FVC, FEV 1 and PEF were 28.8% (95% CI: 23.5; 34.2), 28.8% (95% CI: 24.0; 33.7) and 30.0% (95% CI: 23.4; 36.7), with an average annual decline of 1.75% (95% CI: 0.86; 2.66), 1.72% (95% CI: 1.04; 2.40) and 1.65% (95% CI: 0.71; 2.59), respectively. Our data did not support the hypothesis of an accelerated decline prior to initiation of mechanical ventilation. Median PE max was 35.3 cmH 2 O (95% CI: 29.4; 41.2) at initiation of mechanical ventilation and relatively stable in the years preceding ventilation. Median FVC, FEV 1, PEF and PE max were lower in patients who electively started mechanical ventilation ( p   〈  0.001). Conclusions Patterns of lung function decline cannot predict impending respiratory failure: SMA is characterized by a gradual decline of lung function. We found no evidence for an accelerated deterioration. In addition, PE max remains low and stable in the years preceding initiation of ventilation. Patients who electively started mechanical ventilation had more restrictive lung function at initiation of ventilation, compared to patients who could not be weaned after surgery or a respiratory tract infection.
    Type of Medium: Online Resource
    ISSN: 1750-1172
    URL: Article
    DOI: 10.1186/s13023-023-02634-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 4
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    Natural history of lung function in spinal muscular atrophy
    Springer Science and Business Media LLC ; 2020
    In:  Orphanet Journal of Rare Diseases Vol. 15, No. 1 ( 2020-12)
    Details
    In: Orphanet Journal of Rare Diseases, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2020-12)
    Abstract: Respiratory muscle weakness is an important feature of spinal muscular atrophy (SMA). Progressive lung function decline is the most important cause of mortality and morbidity in patients. The natural history of lung function in SMA has, however, not been studied in much detail. Results We analysed 2098 measurements of lung function from 170 treatment-naïve patients with SMA types 1c–4, aged 4–74 years. All patients are participating in an ongoing population-based prevalence cohort study. We measured Forced Expiratory Volume in 1 s (FEV 1 ), Forced Vital Capacity (FVC), and Vital Capacity (VC). Longitudinal patterns of lung function were analysed using linear mixed-effects and non-linear models. Additionally, we also assessed postural effects on results of FEV 1 and FVC tests. In early-onset SMA types (1c–3a), we observed a progressive decline of lung function at younger ages with relative stabilisation during adulthood. Estimated baseline values were significantly lower in more severely affected patients: %FEV 1 ranged from 42% in SMA type 1c to 100% in type 3b, %FVC 50 to 109%, and %VC 44 to 96%. Average annual decline rates also differed significantly between SMA types, ranging from − 0.1% to − 1.4% for FEV 1 , − 0.2% to − 1.4% for FVC, and + 0.2% to − 1.7% for VC. In contrast to SMA types 1c–3a, we found normal values for all outcomes in later-onset SMA types 3b and 4 throughout life, although with some exceptions and based on limited available data. Finally, we found no important differences in FVC or FEV 1 values measured in either sitting or supine position. Conclusions Our data illustrate the longitudinal course of lung function in patients with SMA, which is characterised by a progressive decline in childhood and stabilisation in early adulthood. The data do not support an additional benefit of measuring FEV 1 or FVC in both sitting and supine position. These data may serve as a reference to assess longer-term outcomes in clinical trials.
    Type of Medium: Online Resource
    ISSN: 1750-1172
    URL: Article
    DOI: 10.1186/s13023-020-01367-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 5
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    Randomized double-blind placebo-controlled crossover trial with pyridostigmine in spinal muscular atrophy types 2–4
    Oxford University Press (OUP) ; 2022
    In:  Brain Communications Vol. 5, No. 1 ( 2022-12-29)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 5, No. 1 ( 2022-12-29)
    Abstract: Hereditary proximal spinal muscular atrophy causes weakness and increased fatigability of repetitive motor functions. The neuromuscular junction is anatomically and functionally abnormal in patients with spinal muscular atrophy. Pharmacological improvement of neuromuscular transmission may therefore represent a promising additional treatment strategy. We conducted a Phase II, monocentre, placebo-controlled, double-blind, cross-over trial with the acetylcholinesterase inhibitor pyridostigmine in treatment-naïve patients with spinal muscular atrophy types 2–4. We investigated the safety and efficacy of pyridostigmine on fatigability and motor function. Each participant received pyridostigmine and a placebo for 8 weeks, in random order. Primary outcomes were the repeated nine-hole peg test for fatigability and motor function measure. Secondary outcomes were patient-reported effects, endurance shuttle test combined scores and adverse events. We included 35 patients. For the repeated nine-hole peg test, the mean difference was 0.17 s/trial (95% confidence interval: −1.17–1.49; P = 0.8), favouring placebo, and for the motor function measure, 0.74% (95% confidence interval: 0.00–1.49; P = 0.05), favouring pyridostigmine. Around 74% of patients reported medium-to-large beneficial effects of pyridostigmine on fatigability, compared with 29.7% in the placebo arm. This was paralleled by a reduced dropout risk of 70% on the endurance shuttle test combined scores (hazard ratio: 0.30; 95% confidence interval: 0.15–0.58) under pyridostigmine. Adverse events, mostly mild and self-limiting, occurred more frequently under pyridostigmine. No serious adverse events related to the study medication were observed. Patients with spinal muscular atrophy tolerated pyridostigmine well. There were no significant differences in primary outcomes, but the self-reported reduction of fatigability and improved endurance shuttle test combined score performance suggest that pyridostigmine may be useful as an additional therapy to survival motor neuron-augmenting drugs. Trial registration number: EudraCT: 2011–004369-34, NCT02941328
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcac324
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 6
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    Association of motor milestones, SMN2 copy and outcome in spinal muscular atrophy types 0–4
    BMJ ; 2017
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 88, No. 4 ( 2017-04), p. 365-367
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 88, No. 4 ( 2017-04), p. 365-367
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2016-314292
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2017
    detail.hit.zdb_id: 1480429-3
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  • 7
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    Fatigability in spinal muscular atrophy: validity and reliability of endurance shuttle tests
    Springer Science and Business Media LLC ; 2020
    In:  Orphanet Journal of Rare Diseases Vol. 15, No. 1 ( 2020-12)
    Details
    In: Orphanet Journal of Rare Diseases, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2020-12)
    Abstract: To determine construct validity and test-retest reliability of Endurance Shuttle Tests as outcome measures for fatigability of remaining motor functions in children and adults with Spinal Muscular Atrophy (SMA) across the severity spectrum. Results We assessed the Endurance Shuttle - Nine Hole Peg Test (ESNHPT), − Box and Block Test (ESBBT) and – Walk Test (ESWT) in 61 patients with SMA types 2–4, 25 healthy controls (HC) and 15 disease controls (DC). Convergent validity, discriminative validity and test-retest reliability were investigated. Additionally, we compiled the Endurance Shuttle Combined Score (ESTCS) by selecting the most relevant endurance test of each individual. 54, 70 and 73% of patients with SMA demonstrated increased fatigability on the ESNHPT, ESBBT and the ESWT. Endurance response in SMA was characterized by a decrease in muscle strength, an increase in muscle fatigue and an increase in motor adaptions, thereby confirming convergent validity. Patients with SMA showed increased drop-out rates and a shorter endurance time compared to HC and DC demonstrating good discriminative validity. Test-retest reliability was moderate to excellent (ICC’s ranging from .78 to .91) with a trend towards better performance on retest. The ESTCS increased sample size and drop-out rate up to 100 and 85%. Conclusions Fatigability is an important additional dimension of physical impairments across the severity spectrum in children and adults with SMA. The EST’s are reliable and valid to document fatigability of walking, proximal- and distal arm function in SMA and thus are promising outcome measures for use in clinical trials.
    Type of Medium: Online Resource
    ISSN: 1750-1172
    URL: Article
    DOI: 10.1186/s13023-020-1348-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 8
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    Natural course of scoliosis and lifetime risk of scoliosis surgery in spinal muscular atrophy
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Neurology Vol. 93, No. 2 ( 2019-07-09), p. e149-e158
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 93, No. 2 ( 2019-07-09), p. e149-e158
    Abstract: To investigate the natural course of scoliosis and to estimate lifetime probability of scoliosis surgery in spinal muscular atrophy (SMA). Methods We analyzed cross-sectional data from 283 patients from our population-based cohort study. Additional longitudinal data on scoliosis progression and spinal surgery were collected from 36 consecutive patients who received scoliosis surgery at our center. Results The lifetime probability of receiving scoliosis surgery was ≈80% in SMA types 1c and 2. Patients with type 2 who only learned to sit (type 2a) were significantly younger at time of surgery than those who learned to sit and stand (type 2b). The lifetime risk of surgery was lower in type 3a (40%) and strongly associated with age at loss of ambulation: 71% in patients losing ambulation before 10 years of age vs 22% losing ambulation after the age of 10 years ( p = 0.005). In type 3a, preserving the ability to walk 1 year longer corresponded to a 15% decrease in lifetime risk of scoliosis surgery (hazard ratio 0.852, p = 0.017). Scoliosis development was characterized by initial slow progression, followed by acceleration in the 1.5- to 2-year period before surgery. Conclusion The lifetime probability of scoliosis surgery is high in SMA types 1c and 2 and depends on age at loss of ambulation in type 3. Motor milestones such as standing that are not part of the standard classification system are of additional predictive value. Our data may act as a reference to assess long-term effects of new SMA-specific therapies.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000007742
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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  • 9
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    Galectin‐9 and CXCL10 as Biomarkers for Disease Activity in Juvenile Dermatomyositis: A Longitudinal Cohort Study and Multicohort Validation
    Wiley ; 2019
    In:  Arthritis & Rheumatology Vol. 71, No. 8 ( 2019-08), p. 1377-1390
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 71, No. 8 ( 2019-08), p. 1377-1390
    Abstract: Objective evaluation of disease activity is challenging in patients with juvenile dermatomyositis ( DM ) due to a lack of reliable biomarkers, but it is crucial to avoid both under‐ and overtreatment of patients. Recently, we identified 2 proteins, galectin‐9 and CXCL 10, whose levels are highly correlated with the extent of juvenile DM disease activity. This study was undertaken to validate galectin‐9 and CXCL 10 as biomarkers for disease activity in juvenile DM , and to assess their disease specificity and potency in predicting the occurrence of flares. Methods Levels of galectin‐9 and CXCL 10 were measured by multiplex immunoassay in serum samples from 125 unique patients with juvenile DM in 3 international cross‐sectional cohorts and a local longitudinal cohort. The disease specificity of both proteins was examined in 50 adult patients with DM or nonspecific myositis (NSM) and 61 patients with other systemic autoimmune diseases. Results Both cross‐sectionally and longitudinally, galectin‐9 and CXCL 10 outperformed the currently used laboratory marker, creatine kinase ( CK ), in distinguishing between juvenile DM patients with active disease and those in remission (area under the receiver operating characteristic curve [ AUC ] 0.86–0.90 for galectin‐9 and CXCL 10; AUC 0.66–0.68 for CK ). The sensitivity and specificity for active disease in juvenile DM was 0.84 and 0.92, respectively, for galectin‐9 and 0.87 and 1.00, respectively, for CXCL 10. In 10 patients with juvenile DM who experienced a flare and were prospectively followed up, continuously elevated or rising biomarker levels suggested an imminent flare up to several months before the onset of symptoms, even in the absence of elevated CK levels. Galectin‐9 and CXCL 10 distinguished between active disease and remission in adult patients with DM or NSM ( P = 0.0126 for galectin‐9 and P 〈 0.0001 for CXCL10) and were suited for measurement in minimally invasive dried blood spots (healthy controls versus juvenile DM, P = 0.0040 for galectin‐9 and P 〈 0.0001 for CXCL10). Conclusion In this study, galectin‐9 and CXCL 10 were validated as sensitive and reliable biomarkers for disease activity in juvenile DM . Implementation of these biomarkers into clinical practice as tools to monitor disease activity and guide treatment might facilitate personalized treatment strategies.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v71.8
    DOI: 10.1002/art.40881
    RVK:
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    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2754614-7
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  • 10
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    Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2–4 (SPACE trial)
    BMJ ; 2018
    In:  BMJ Open Vol. 8, No. 7 ( 2018-07), p. e019932-
    Details
    In: BMJ Open, BMJ, Vol. 8, No. 7 ( 2018-07), p. e019932-
    Abstract: Hereditary proximal spinal muscular atrophy (SMA) is caused by homozygous loss of function of the survival motor neuron 1 gene. The main characteristic of SMA is degeneration of alpha motor neurons in the anterior horn of the spinal cord, but recent studies in animal models and patients have shown additional anatomical abnormalities and dysfunction of the neuromuscular junction (NMJ). NMJ dysfunction could contribute to symptoms of weakness and fatigability in patients with SMA. We hypothesise that pyridostigmine, an acetylcholinesterase inhibitor that improves neuromuscular transmission, could improve NMJ function and thereby muscle strength and fatigability in patients with SMA. Methods and analysis We designed a monocentre, placebo-controlled, double-blind cross-over trial with pyridostigmine and placebo to investigate the effect and efficacy of pyridostigmine on muscle strength and fatigability in patients with genetically confirmed SMA. We aim to include 45 patients with SMA types 2–4, aged 12 years and older in the Netherlands. Participants receive 8 weeks of treatment with pyridostigmine and 8 weeks of treatment with placebo in a random order separated by a washout period of 1 week. Treatment allocation is double blinded. Treatment dose will gradually be increased from 2 mg/kg/day to the maximum dose of 6 mg/kg/day in four daily doses, in the first week of each treatment period. The primary outcome measures are a change in the Motor Function Measure and repeated nine-hole peg test before and after treatment. Secondary outcome measures are changes in recently developed endurance tests, that is, the endurance shuttle nine-hole peg test, the endurance shuttle box and block test and the endurance shuttle walk test, muscle strength, level of daily functioning, quality of and activity in life, perceived fatigue and fatigability, presence of decrement on repetitive nerve stimulation and adverse events. Ethics and dissemination The protocol is approved by the local medical ethical review committee at the University Medical Center Utrecht and by the national Central Committee on Research Involving Human Subjects. Findings will be shared with the academic and medical community, funding and patient organisations in order to contribute to optimisation of medical care and quality of life for patients with SMA. Trial registration number NCT02941328 .
    Type of Medium: Online Resource
    ISSN: 2044-6055 , 2044-6055
    URL: Article
    URL: Article
    DOI: 10.1136/bmjopen-2017-019932
    DOI: 10.1136/bmjopen-2017-019932.supp1
    Language: English
    Publisher: BMJ
    Publication Date: 2018
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