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The Cochrane Database of Systematic... Jan 2014Mucopolysaccharidosis II, also known as Hunter syndrome, is a rare, X-linked disease caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase, which... (Review)
Review
BACKGROUND
Mucopolysaccharidosis II, also known as Hunter syndrome, is a rare, X-linked disease caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase, which catalyses a step in the catabolism of glycosaminoglycans. The glycosaminoglycans accumulate within tissues affecting multiple organs and physiologic systems. The clinical manifestations include neurologic involvement, severe airways obstruction, skeletal deformities and cardiomyopathy. The disease has a variable age of onset and variable rate of progression. In those with severe disease, death usually occurs in the second decade of life, whereas those patients with less severe disease may survive into adulthood. Enzyme replacement therapy with intravenous infusions of idursulfase has emerged as a new treatment for mucopolysaccharidosis type II.
OBJECTIVES
To evaluate the effectiveness and safety of enzyme replacement therapy with idursulfase compared to other interventions, placebo or no intervention, for treating mucopolysaccharidosis type II.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register (date of last search 22 July 2013).We also searched EMBASE, PubMed and the Literature Latino-Americana e do Caribe em Ciências da Saúde (LILACS) (date of last search 09 July 2013).
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials of enzyme replacement therapy with idursulfase compared to no intervention, placebo or other options (e.g. behavioral strategies, transplantation).
DATA COLLECTION AND ANALYSIS
Two authors independently screened the trials identified, appraised quality of papers and extracted data.
MAIN RESULTS
One study (96 patients) met the inclusion criteria, although the primary outcome of this review - z score for height and weight, was not assessed in the study. This trial was considered to be of overall good quality. Following 53 weeks of treatment, patients in the weekly idursulfase 0.5 mg/kg group demonstrated a significant improvement rate compared with placebo for the primary outcome: distance walked in six minutes on the basis of the sum of ranks of change from baseline, mean difference 37.00 (95% confidence interval 6.52 to 67.48). The every-other-week idursulfase 0.5 mg/kg group also showed an improvement, which was not significant compared with placebo, mean difference 23.00 (95% confidence interval -4.49 to 50.49). After 53 weeks, there was no statistical significance difference in per cent predicted forced vital capacity between the three groups and absolute forced vital capacity was significantly increased from baseline in the weekly dosing group compared to placebo, mean difference 0.16 (95% confidence interval CI 0.05 to 0.27). No difference was observed between the every-other-week idursulfase 0.5 mg/kg group and placebo.In addition, liver and spleen volumes and urine glycosaminoglycan excretion were significantly reduced from baseline by both idursulfase dosing regimens. Idursulfase was generally well tolerated, but infusion reactions did occur. Idursulfase antibodies were detected in 31.7% of patients at the end of the study and they were related to a smaller reduction in urine glycosaminoglycan levels.
AUTHORS' CONCLUSIONS
The current evidence is limited. While the randomised clinical trial identified was considered to be of good quality, it failed to describe important outcomes. It has been demonstrated that enzyme replacement therapy with idursulfase is effective in relation to functional capacity (distance walked in six minutes and forced vital capacity), liver and spleen volumes and urine glycosaminoglycan excretion in patients with mucopolysaccharidosis type II compared with placebo. There is no available evidence in the included study and in the literature on outcomes such as improvement in growth, sleep apnoea, cardiac function, quality of life and mortality. More studies are needed to obtain more information on the long-term effectiveness and safety of enzyme replacement therapy.
Topics: Drug Administration Schedule; Enzyme Replacement Therapy; Humans; Iduronate Sulfatase; Mucopolysaccharidosis II; Randomized Controlled Trials as Topic; Rare Diseases
PubMed: 24399699
DOI: 10.1002/14651858.CD008185.pub3 -
The Cochrane Database of Systematic... Nov 2011Mucopolysaccharidosis II, also known as Hunter syndrome, is a rare, X-linked disease caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase, which... (Review)
Review
BACKGROUND
Mucopolysaccharidosis II, also known as Hunter syndrome, is a rare, X-linked disease caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase, which catalyses a step in the catabolism of glycosaminoglycans. The glycosaminoglycans accumulate within tissues affecting multiple organs and physiologic systems. The clinical manifestations include neurologic involvement, severe airways obstruction, skeletal deformities and cardiomyopathy. The disease has a variable age of onset and variable rate of progression. In those with severe disease, death usually occurs in the second decade of life, whereas those patients with less severe disease may survive into adulthood. Enzyme replacement therapy with intravenous infusions of idursulfase has emerged as a new treatment for mucopolysaccharidosis type II.
OBJECTIVES
To evaluate the effectiveness and safety of enzyme replacement therapy with idursulfase compared to other interventions, placebo or no intervention, for treating mucopolysaccharidosis type II.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register (date of last search 01 September 2011).We also searched EMBASE, PubMed and the Literature Latino-Americana e do Caribe em Ciências da Saúde (LILACS) (date of last search October 2009).
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials of enzyme replacement therapy with idursulfase compared to no intervention, placebo or other options (e.g. behavioral strategies, transplantation).
DATA COLLECTION AND ANALYSIS
Two authors independently screened the trials identified, appraised quality of papers and extracted data.
MAIN RESULTS
One study (96 patients) met the inclusion criteria, although the primary outcome of this review - z score for height and weight, was not assessed in the study. Following 53 weeks of treatment, patients in the weekly idursulfase 0.5 mg/kg group demonstrated a significant improvement rate compared with placebo for the primary outcome: distance walked in six minutes on the basis of the sum of ranks of change from baseline, mean difference 37.00 (95% confidence interval 6.52 to 67.48). The every-other-week idursulfase 0.5 mg/kg group also showed an improvement, which was not significant compared with placebo, mean difference 23.00 (95% confidence interval -4.49 to 50.49). After 53 weeks, there was no statistical significance difference in per cent predicted forced vital capacity between the three groups and absolute forced vital capacity was significantly increased from baseline in the weekly dosing group compared to placebo, mean difference 0.16 (95% confidence interval CI 0.05 to 0.27). No difference was observed between the every-other-week idursulfase 0.5 mg/kg group and placebo.In addition, liver and spleen volumes and urine glycosaminoglycan excretion were significantly reduced from baseline by both idursulfase dosing regimens. Idursulfase was generally well tolerated, but infusion reactions did occur. Idursulfase antibodies were detected in 31.7% of patients at the end of the study and they were related to a smaller reduction in urine glycosaminoglycan levels.
AUTHORS' CONCLUSIONS
The current evidence is limited. While the randomised clinical trial identified was considered to be of good quality, it failed to describe important outcomes. It has been demonstrated that enzyme replacement therapy with idursulfase is effective in relation to functional capacity (distance walked in six minutes and forced vital capacity), liver and spleen volumes and urine glycosaminoglycan excretion in patients with mucopolysaccharidosis type II compared with placebo. There is no available evidence in the included study and in the literature on outcomes such as improvement in growth, sleep apnoea, cardiac function, quality of life and mortality. More studies are needed to obtain more information on the long-term effectiveness and safety of enzyme replacement therapy.
Topics: Enzyme Replacement Therapy; Humans; Iduronate Sulfatase; Mucopolysaccharidosis II; Randomized Controlled Trials as Topic; Rare Diseases
PubMed: 22071845
DOI: 10.1002/14651858.CD008185.pub2 -
Orphanet Journal of Rare Diseases Apr 2018Sanfilippo syndrome (mucopolysaccharidosis [MPS] III subtypes A, B, C, and D) is a rare autosomal recessive inherited metabolic disorder that causes progressive...
BACKGROUND
Sanfilippo syndrome (mucopolysaccharidosis [MPS] III subtypes A, B, C, and D) is a rare autosomal recessive inherited metabolic disorder that causes progressive neurocognitive degeneration. This systematic literature review was undertaken to compile and assess published epidemiological data, including various frequency measures and geographical variation on Sanfilippo syndrome.
METHODS
The following databases were systematically searched for terms related to Sanfilippo syndrome epidemiology: Medline, Embase, Cochrane Database of Systematic Reviews, Academic Search Complete, Cumulative Index to Nursing and Allied Health Literature, and the Centre for Reviews and Dissemination. Qualitative synthesis of research findings was performed.
RESULTS
Of 2794 publications found in the initial search, 116 were deemed eligible after title and abstract screening. Following full-text review, 46 papers were included in the qualitative synthesis. Results of this systematic literature review indicate that lifetime risk at birth ranges from 0.17-2.35 per 100,000 live births for all 4 subtypes of MPS III together, and from 0.00-1.62 per 100,000 live births for the most frequent subtype, MPS IIIA.
CONCLUSION
All 4 subtypes of MPS III are exceptionally rare, but they each have devastating effects on children. Higher-quality epidemiological data are needed to appropriately target resources for disease research and management.
Topics: Global Health; Humans; Mucopolysaccharidosis III; Rare Diseases
PubMed: 29631636
DOI: 10.1186/s13023-018-0796-4 -
The Cochrane Database of Systematic... Nov 2013Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler syndrome, Hurler-Scheie syndrome and Scheie syndrome, with the scale of severity being... (Review)
Review
BACKGROUND
Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler syndrome, Hurler-Scheie syndrome and Scheie syndrome, with the scale of severity being such that Hurler syndrome is the most severe and Scheie syndrome the least severe. It is a rare, autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. Deficiency of this enzyme results in the accumulation of glycosaminoglycans within the tissues. The clinical manifestations are facial dysmorphism, hepatosplenomegaly, upper airway obstruction, skeletal deformity and cardiomyopathy. If Hurler syndrome is left untreated, death ensues by adolescence. There are more attenuated variants termed Hurler-Scheie or Scheie syndrome, with those affected potentially not presenting until adulthood. Enzyme replacement therapy has been used for a number of years in the treatment of Hurler syndrome, although the current gold standard would be a haemopoietic stem cell transplant in those diagnosed by 2.5 years of age.
OBJECTIVES
To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, MEDLINE via OVID and EMBASE.Date of most recent search: 08 February 2013.
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials of laronidase enzyme replacement therapy compared to placebo.
DATA COLLECTION AND ANALYSIS
Two authors independently screened the identified trials. The authors then appraised and extracted data.
MAIN RESULTS
One study of 45 patients met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational trial looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in patients with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this trial. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned analysis of covariance). The levels of urinary glycoaminoglycans were also significantly reduced. In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all patients in the treatment group with no apparent clinical effect and titres were reducing by the end of the study. Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation.
AUTHORS' CONCLUSIONS
The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included trial was comprehensive and of good quality, although there were few participants. The trial included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters (reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute-walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those patients diagnosed under 2.5 years of age.
Topics: Adolescent; Adult; Antibodies; Child; Enzyme Replacement Therapy; Female; Humans; Iduronidase; Male; Mucopolysaccharidosis I; Randomized Controlled Trials as Topic; Rare Diseases; Severity of Illness Index; Young Adult
PubMed: 24257962
DOI: 10.1002/14651858.CD009354.pub3 -
The Cochrane Database of Systematic... Sep 2013Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler syndrome, Hurler-Scheie syndrome and Scheie syndrome, with the scale of severity being... (Review)
Review
BACKGROUND
Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler syndrome, Hurler-Scheie syndrome and Scheie syndrome, with the scale of severity being such that Hurler syndrome is the most severe and Scheie syndrome the least severe. It is a rare, autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. Deficiency of this enzyme results in the accumulation of glycosaminoglycans within the tissues. The clinical manifestations are facial dysmorphism, hepatosplenomegaly, upper airway obstruction, skeletal deformity and cardiomyopathy. If Hurler syndrome is left untreated, death ensues by adolescence. There are more attenuated variants termed Hurler-Scheie or Scheie syndrome, with those affected potentially not presenting until adulthood. Enzyme replacement therapy has been used for a number of years in the treatment of Hurler syndrome, although the current gold standard would be a haemopoietic stem cell transplant in those diagnosed by 2.5 years of age.
OBJECTIVES
To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, MEDLINE via OVID and EMBASE.Date of most recent search: 08 February 2013.
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials of laronidase enzyme replacement therapy compared to placebo.
DATA COLLECTION AND ANALYSIS
Two authors independently screened the identified trials. The authors then appraised and extracted data.
MAIN RESULTS
One study of 45 patients met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational trial looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in patients with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this trial. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.66, when using a prospectively planned analysis of covariance). The levels of urinary glycoaminoglycans were also significantly reduced. In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all patients in the treatment group with no apparent clinical effect and titres were reducing by the end of the study. Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation.
AUTHORS' CONCLUSIONS
The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included trial was comprehensive and of good quality, although there were few participants. The trial included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters(reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those patients diagnosed under 2.5 years of age.
Topics: Enzyme Replacement Therapy; Humans; Iduronidase; Mucopolysaccharidosis I; Randomized Controlled Trials as Topic; Rare Diseases
PubMed: 24085657
DOI: 10.1002/14651858.CD009354.pub2 -
ANZ Journal of Surgery Apr 2022The skeletal manifestations of lysosomal storage diseases (LSDs) are largely refractory to available therapeutic modalities. Consequently, there is an increasing need to... (Review)
Review
BACKGROUND
The skeletal manifestations of lysosomal storage diseases (LSDs) are largely refractory to available therapeutic modalities. Consequently, there is an increasing need to manage their spinal deformities. The aim was to perform a systematic review to answer the questions, "What are the reported indications for surgery for spinal deformity in patients with LSDs?" and "what are the published surgical management strategies?".
METHODS
Articles that made reference to at least one LSD, a spinal abnormality and surgical management were included. Extracted study data included: study type, sample size, methodology and year of publication. The following clinical information was collected: demographics, spinal abnormalities, and surgical indications, details and outcomes.
RESULTS
Thirty-seven articles were included, with 23 describing surgical management of craniocervical manifestations seen in mucopolysaccharidosis. Radiological evidence of myelopathy at the craniocervical junction and/or progressive clinical neurological compromise were accepted as surgical indications. Prophylactic surgery was proposed by some authors. The recommended surgical technique and whether to stabilise and/or decompress varied between articles and LSD types. Twenty-one articles discussed thoracolumbar pathology, including thoracolumbar kyphosis and scoliosis. Radiological severity, progression of deformity, and presence of neurological deterioration were discussed as surgical indications. Most papers recommended circumferential arthrodesis via combined anterior and posterior approaches.
CONCLUSION
The surgical management of spinal disorders in LSDs remains controversial. Centres managing these patients should be encouraged to have a standardised system of reporting outcomes, to facilitate recommendations for management of the spinal manifestations.
Topics: Humans; Kyphosis; Lysosomal Storage Diseases; Spinal Fusion; Thoracic Vertebrae; Treatment Outcome
PubMed: 34984775
DOI: 10.1111/ans.17430 -
Orphanet Journal of Rare Diseases Jul 2015An orphan disease is defined in the EU as a disorder affecting less than 1 in 2 000 individuals. The concept of ultra-orphan has been proposed for diseases with a... (Review)
Review
An orphan disease is defined in the EU as a disorder affecting less than 1 in 2 000 individuals. The concept of ultra-orphan has been proposed for diseases with a prevalence of less than 1:50 000. Drugs for ultra-orphan diseases are amongst the most expensive medicines on a cost-per-patient basis. The extremely high prices have prompted initiatives to evaluate cost-effectiveness and cost-utility in EU-member states. The objective of this review was to evaluate the quality of cost-effectiveness and cost-utility studies on ultra-orphan drugs. We searched 2 databases and the reference lists of relevant systematic reviews. Studies reporting on full economic evaluations, or at least aiming at such evaluation, were eligible for inclusion. Quality was assessed with the use of the Consensus on Health Economic Criteria (CHEC)-list. Two-hundred-fifty-one studies were identified. Of these, 16 fitted our inclusion criteria. A study on enzyme replacement and substrate reduction therapies for lysosomal storage disorders did not perform a full economic evaluation due to the high drug costs and the lack of a measurable effect on either clinical or health-related quality of life outcomes. Likewise, a cost-effectiveness analysis of laronidase for mucopolysaccharidosis type 1 was considered unfeasible due to lack of clinical effectiveness data, while in the same study a crude model was used to estimate cost-utility of enzyme replacement therapy (ERT) for Fabry disease. Three additional studies, one on ERT for Fabry disease, one on ERT for Gaucher disease and one on eculizumab for paroxysmal nocturnal haemoglobinuria, used an approach that was too simplistic to lead to a realistic estimate of the incremental cost-effectiveness (ICER) or cost-utility ratio (ICUR). In all other studies (N = 11) more sophisticated pharmacoeconomic models were used to estimate cost-effectiveness and cost-utility of the specific drug, mostly ERT or drugs indicated for pulmonary arterial hypertension (PAH). Seven studies used a Markov-state-transition model. Other models used were patient-level simulation models (N = 3) and decision trees (N = 1). Only 4 studies adopted a societal perspective. All but 2 studies discounted costs and effects appropriately. Drugs for metabolic diseases appeared to be significantly less cost-effective than drugs indicated for PAH, with ICERs ranging from €43 532 (Gaucher disease) to €3 282 252 (Fabry disease). Quality of studies using a Markov-state-transition or patient-level simulation model is in general good with 14-19 points on the CHEC-list. We therefore conclude that economic evaluations of ultra-orphan drugs are feasible if pharmacoeconomic modelling is used. Considering the need for modelling of several disease states and the small patient groups, a Markov-state-transition model seems to be most suitable type of model. However, it should be realised that ultra-orphan drugs will usually not meet the conventional criteria for cost-effectiveness. Nevertheless, ultra-orphan drugs are often reimbursed. Further discussion on the use of economic evaluations and their consequences in case of ultra-orphan drugs is therefore warranted.
Topics: Drug Costs; Europe; Orphan Drug Production
PubMed: 26223689
DOI: 10.1186/s13023-015-0305-y -
Current Medical Research and Opinion Apr 2024To systematically review the literature and summarize the health-related quality-of-life (HRQoL) of patients undergoing treatment for mucopolysaccharidoses (MPS), a...
OBJECTIVE
To systematically review the literature and summarize the health-related quality-of-life (HRQoL) of patients undergoing treatment for mucopolysaccharidoses (MPS), a rare, hereditary lysosomal storage disorder.
METHODS
A systematic review was performed in accordance with PRISMA guidelines to identify research studies that describe the humanistic burden of MPS. A comprehensive literature search was conducted in EMBASE, MEDLINE, and eligible conferences were screened to include applicable abstracts.
RESULTS
Of 870 identified articles, 15 studies reported the HRQoL burden of patients with MPS undergoing or with a history of ERT and/or HSCT. These studies include patients of MPS I ( = 2), MPS II ( = 4), MPS IV ( = 6), MPS VI ( = 1), and subtype not mentioned ( = 2). Although the quality-of-life of MPS patients is influenced by time of diagnosis, pain, cognitive involvement, severity of disease, mobility, dependence, and time of treatment initiation, the HRQoL scores of MPS patients across all the scales were below the median reference population scores across all dimensions. This is seen in comparison to healthy participants but also in comparison to patients with other chronic illnesses. The multi-organ involvement, neurological impairment, pain, and morbidity associated with the condition not only affects activity of daily living but also affects social functioning, emotional status, employment status among adults, and school functioning among children.
CONCLUSIONS
This systematic literature review revealed the substantial humanistic burden of individuals affected by MPS as well as caregivers. Significant variation in HRQoL scores was observed, however studies indicate that the quality-of-life of MPS patients is influenced primarily by severity of disease (MPS type and phenotype), and then by time of diagnosis, pain, cognitive involvement, mobility, dependence, and time of treatment initiation. Further studies are needed to assess the global humanistic burden of MPS, particularly in MPS III, VI, VII, and IX subtypes, in adults, and for a longer follow-up period. Considering the vast array of HRQoL assessment tools available and used in this study, researchers should also consider using scales with condition-specific measures to ensure appropriate estimates of effectiveness.
Topics: Child; Adult; Humans; Mucopolysaccharidoses; Quality of Life; Chronic Disease; Caregivers; Pain
PubMed: 38328952
DOI: 10.1080/03007995.2024.2316213 -
The Cochrane Database of Systematic... Oct 2015Obstructive sleep-disordered breathing (oSDB) is a condition that encompasses breathing problems when asleep, due to an obstruction of the upper airways, ranging in... (Review)
Review
BACKGROUND
Obstructive sleep-disordered breathing (oSDB) is a condition that encompasses breathing problems when asleep, due to an obstruction of the upper airways, ranging in severity from simple snoring to obstructive sleep apnoea syndrome (OSAS). It affects both children and adults. In children, hypertrophy of the tonsils and adenoid tissue is thought to be the commonest cause of oSDB. As such, tonsillectomy - with or without adenoidectomy - is considered an appropriate first-line treatment for most cases of paediatric oSDB.
OBJECTIVES
To assess the benefits and harms of tonsillectomy with or without adenoidectomy compared with non-surgical management of children with oSDB.
SEARCH METHODS
We searched the Cochrane Register of Studies Online, PubMed, EMBASE, CINAHL, Web of Science, Clinicaltrials.gov, ICTRP and additional sources for published and unpublished trials. The date of the search was 5 March 2015.
SELECTION CRITERIA
Randomised controlled trials comparing the effectiveness and safety of (adeno)tonsillectomy with non-surgical management in children with oSDB aged 2 to 16 years.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures expected by The Cochrane Collaboration.
MAIN RESULTS
Three trials (562 children) met our inclusion criteria. Two were at moderate to high risk of bias and one at low risk of bias. We did not pool the results because of substantial clinical heterogeneity. They evaluated three different groups of children: those diagnosed with mild to moderate OSAS by polysomnography (PSG) (453 children aged five to nine years; low risk of bias; CHAT trial), those with a clinical diagnosis of oSDB but with negative PSG recordings (29 children aged two to 14 years; moderate to high risk of bias; Goldstein) and children with Down syndrome or mucopolysaccharidosis (MPS) diagnosed with mild to moderate OSAS by PSG (80 children aged six to 12 years; moderate to high risk of bias; Sudarsan). Moreover, the trials included two different comparisons: adenotonsillectomy versus no surgery (CHAT trial and Goldstein) or versus continuous positive airway pressure (CPAP) (Sudarsan). Disease-specific quality of life and/or symptom score (using a validated instrument): first primary outcomeIn the largest trial with lowest risk of bias (CHAT trial), at seven months, mean scores for those instruments measuring disease-specific quality of life and/or symptoms were lower (that is, better quality of life or fewer symptoms) in children receiving adenotonsillectomy than in those managed by watchful waiting:- OSA-18 questionnaire (scale 18 to 126): 31.8 versus 49.5 (mean difference (MD) -17.7, 95% confidence interval (CI) -21.2 to -14.2);- PSQ-SRBD questionnaire (scale 0 to 1): 0.2 versus 0.5 (MD -0.3, 95% CI -0.31 to -0.26);- Modified Epworth Sleepiness Scale (scale 0 to 24): 5.1 versus 7.1 (MD -2.0, 95% CI -2.9 to -1.1).No data on this primary outcome were reported in the Goldstein trial.In the Sudarsan trial, the mean OSA-18 score at 12 months did not significantly differ between the adenotonsillectomy and CPAP groups. The mean modified Epworth Sleepiness Scale scores did not differ at six months, but were lower in the surgery group at 12 months: 5.5 versus 7.9 (MD -2.4, 95% CI -3.1 to -1.7). Adverse events: second primary outcomeIn the CHAT trial, 15 children experienced a serious adverse event: 6/194 (3%) in the adenotonsillectomy group and 9/203 (4%) in the control group (RD -1%, 95% CI -5% to 2%).No major complications were reported in the Goldstein trial.In the Sudarsan trial, 2/37 (5%) developed a secondary haemorrhage after adenotonsillectomy, while 1/36 (3%) developed a rash on the nasal dorsum secondary to the CPAP mask (RD -3%, 95% CI -6% to 12%). Secondary outcomesIn the CHAT trial, at seven months, mean scores for generic caregiver-rated quality of life were higher in children receiving adenotonsillectomy than in those managed by watchful waiting. No data on this outcome were reported by Sudarsan and Goldstein.In the CHAT trial, at seven months, more children in the surgery group had normalisation of respiratory events during sleep as measured by PSG than those allocated to watchful waiting: 153/194 (79%) versus 93/203 (46%) (RD 33%, 95% CI 24% to 42%). In the Goldstein trial, at six months, PSG recordings were similar between groups and in the Sudarsan trial resolution of OSAS (Apnoea/Hypopnoea Index score below 1) did not significantly differ between the adenotonsillectomy and CPAP groups.In the CHAT trial, at seven months, neurocognitive performance and attention and executive function had not improved with surgery: scores were similar in both groups. In the CHAT trial, at seven months, mean scores for caregiver-reported ratings of behaviour were lower (that is, better behaviour) in children receiving adenotonsillectomy than in those managed by watchful waiting, however, teacher-reported ratings of behaviour did not significantly differ.No data on these outcomes were reported by Goldstein and Sudarsan.
AUTHORS' CONCLUSIONS
In otherwise healthy children, without a syndrome, of older age (five to nine years), and diagnosed with mild to moderate OSAS by PSG, there is moderate quality evidence that adenotonsillectomy provides benefit in terms of quality of life, symptoms and behaviour as rated by caregivers and high quality evidence that this procedure is beneficial in terms of PSG parameters. At the same time, high quality evidence indicates no benefit in terms of objective measures of attention and neurocognitive performance compared with watchful waiting. Furthermore, PSG recordings of almost half of the children managed non-surgically had normalised by seven months, indicating that physicians and parents should carefully weigh the benefits and risks of adenotonsillectomy against watchful waiting in these children. This is a condition that may recover spontaneously over time.For non-syndromic children classified as having oSDB on purely clinical grounds but with negative PSG recordings, the evidence on the effects of adenotonsillectomy is of very low quality and is inconclusive.Low-quality evidence suggests that adenotonsillectomy and CPAP may be equally effective in children with Down syndrome or MPS diagnosed with mild to moderate OSAS by PSG.We are unable to present data on the benefits of adenotonsillectomy in children with oSDB aged under five, despite this being a population in whom this procedure is often performed for this purpose.
Topics: Adenoidectomy; Adolescent; Child; Child, Preschool; Humans; Randomized Controlled Trials as Topic; Sleep Apnea, Obstructive; Tonsillectomy
PubMed: 26465274
DOI: 10.1002/14651858.CD011165.pub2 -
Orphanet Journal of Rare Diseases Apr 2017Morquio A syndrome is an ultra-rare, inherited lysosomal storage disorder associated with progressive, multi-systemic clinical impairments, causing gradual loss of... (Review)
Review
Morquio A syndrome is an ultra-rare, inherited lysosomal storage disorder associated with progressive, multi-systemic clinical impairments, causing gradual loss of functional capacity and endurance, impaired quality of life, and early mortality. Studies in Morquio A patients have used the 6-min walk test (6MWT) to assess functionality and endurance and to evaluate disease progression or efficacy of treatment. The objective of the present study was to review minimal clinically important differences (MCIDs) for the 6MWT reported for disease states that widely use the 6MWT to evaluate clinical benefit and to discuss the results in view of the challenges in estimating MCID for ultra-rare diseases, using the case of elosulfase alfa in Morquio A patients. A systematic literature search was performed using Embase and Medline to identify studies specifically estimating the MCID using either anchor-based or distribution-based methods. A total of 19 publications on 17 studies were identified; none of these included patients with Morquio A syndrome or the wider disease category of lysosomal storage disorders. Therefore, the MCIDs determined by studies in patients with respiratory, cardiovascular, or musculoskeletal disease were compared to changes in the 6MWT seen in Morquio A patients in the pivotal phase 3 clinical trial of elosulfase alfa enzyme replacement therapy. The literature review showed a mean MCID for the 6MWT of 7% change (range 3-15%) in studies using anchor-based methods and a 9% change (range 4-16%) using distribution-based methods. Results of the elosulfase alfa clinical trial and its extension showed a placebo-adjusted 14.9% improvement in the 6MWT from baseline at week 24, which was greater than the mean MCID based on the results of the systematic literature review. After 2 years, 6MWT distance increased by a mean of 20.7% from baseline in a modified per-protocol population, versus a reduction of 6.9% in comparable untreated patients from the MorCAP natural history study over the same period. Although further research is required to establish the MCID of the 6MWT in Morquio A patients, the presented data provide further evidence for the positive effect of elosulfase alfa in this patient population.
Topics: Adult; Enzyme Replacement Therapy; Humans; Male; Minimal Clinically Important Difference; Mucopolysaccharidosis IV; Walk Test
PubMed: 28441951
DOI: 10.1186/s13023-017-0633-1