Background
Objectives
Table | Recommended speciality focus |
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Table 2: General principles for the management of patients with MPS IVA | all |
Table 3: Recommended routine monitoring and assessments in patients with MPS IVA | all |
Table 4: Guidance statement for elosulfase alfa | geneticist, metabolic physician, paediatrician, nurse, physiotherapist |
Table 5: Guidance statement for HSCT | anaesthetist, bone marrow transplant expert/hematopoietic stem cell transplant expert, geneticist, paediatrician, nurse |
Table 6: Guidance statements for CPAP, NIPPV, oxygen supplementation and hypercapnia monitoring | anaesthetist, ear-nose-throat specialist, geneticist, paediatrician, respiratory physician/pulmonologist, nurse |
Table 7: Guidance statements for anaesthesia | all |
Table 8: Guidance statements for hip reconstruction, hip replacement and growth modulation surgeries | anaesthetist, geneticist, orthopaedic surgeon, neurosurgeon, paediatrician, physiotherapist |
Table 9: Guidance statements for decompression of the spinal cord, spinal stabilisation and thoracolumbar kyphoscoliosis | anaesthetist, geneticist, orthopaedic surgeon, neurosurgeon, paediatrician, physiotherapist |
Table 10: Guidance statement for corneal transplantation | anaesthetist, geneticist, ophthalmologist, paediatrician |
Table 11: Guidance statement for cardiac valve replacement | anaesthetist, cardiologist, geneticist, paediatrician |
Table 12: Guidance statements for tonsillectomy and/or adenoidectomy, tracheostomy and insertion of ventilation tubes | anaesthetist, geneticist, ear-nose-throat specialist, paediatrician, respiratory physician/pulmonologist |
Methods and process
Convening of the steering committee
Setting the clinical questions to be addressed by the guidance
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Interventions that address the underlying enzyme deficiency including:
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ERT
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HSCT
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Interventions used to manage the symptoms of MPS IVA/VI including:
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Respiratory and sleep disorders
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Anaesthesia
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Limb and spinal surgeries
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Ophthalmic surgeries
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Cardio-thoracic surgeries
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ENT surgeries
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Patient Advocacy Groups insights
Systematic literature review methodology
Development and validation of guidance statements
Measures to ensure independence
Results
Patient Advocacy Groups insights
Modified-Delphi results
Appraisal of Guidelines for Research and Evaluation (AGREE) II assessment
Guidance statements
General principles (Table 2)
Statement | Percentage consensus |
---|---|
All guidance statements are evidence Grade D (level 5 expert clinical opinion) | |
Diagnosis of MPS IVA during infancy is critical to optimise patient outcomes | 98% |
The first consultation should be conducted by a physician with experience of treating MPS as soon as possible after diagnosis. This should include a full discussion of disease pathology, progression, treatment options and management. Ongoing information should be provided to optimise patient outcomes | 97% |
Patients and caregivers should receive ongoing psychosocial support from a social worker and/or psychologist, and should be directed towards an MPS society or relevant patient organisation in their country | 94% |
A comprehensive medical history and multi-system evaluation should be conducted within days of diagnosis to set a baseline for ongoing assessments and evaluate the physical and neurological manifestations of disease, functional ability and disease burden | 88% |
Ongoing and regular multi-system monitoring, and assessments are recommended to track the natural history of MPS IVA, monitor the impact of treatment and assess the need for treatment interventions to manage the symptoms of MPS IVA. These should be conducted at every clinic visit, annually or in some cases as clinically indicated (for example pre- and post-operatively) | 100% |
Timely interventions are recommended where clinically indicated by monitoring, to help avoid irreversible damage caused by the natural history of MPS IVA, and to manage the disease manifestations and maintain long-term QoL | 99% |
A multidisciplinary team (MDT) of metabolic specialists, surgeons and allied healthcare professionals (including, but not limited to: nurses, physiotherapists, occupational therapists, psychologists and audiologists) is required to manage the diverse range of disease manifestations of MPS IVA | 99% |
Co-ordination of the entire MDT care team is required prior to any procedure to determine the need for surgery, to discuss the benefits and risks of combining surgeries to minimise the need for multiple anaesthetics and to decide the optimal order of procedures. The decision to combine surgeries should take into consideration the surgical and intubation time, and complexity of procedures | 93% |
The risks and benefits of any intervention and the competing risks of other medical problems should be assessed and discussed with patients, families and caregivers such that they can make an informed decision on the appropriateness of the therapy/surgery | 100% |
Surgical procedures should be performed by (or under the guidance of) specialist surgeons and anaesthetists with experience of MPS, in medical centres with intensive care units | 99% |
Management of pain should be a fundamental part of the care of patients with MPS IVA, with the aim of improving QoL and maintaining mobility. Refer to general guidelines for pain management | 100% |
Recommended routine monitoring and assessments (Table 3)
Statement | Percentage consensus |
---|---|
All guidance statements are evidence Grade D (level 5 expert clinical opinion), unless otherwise stated | |
Physical examination | |
A physical examination should be performed during every visit to assess general health, growth, vital signs, abdominal organ size, presence of hernia, neurologic function (including gait), ligamentous laxity, and functions of the eyes, ears, heart and lungs | 90% |
Routine physical examination can also identify signs of potential respiratory problems, such as an enlarged tongue or sniffing position | 90% |
Radiology | |
While X-rays are essential to identify the natural history of disease and response to treatment, efforts should be made to minimise radiation exposure, and images should be requested only when clinically useful | 85% |
Hips: an anteroposterior (AP) pelvis radiograph should be performed at diagnosis and as clinically indicated (based on physical examination or reports of pain) to quantify hip dysplasia or identify early signs of hip migration | 88% |
Lower limbs: in patients with clinical evidence of valgus deformity of the lower limbs, standing AP radiographs of lower extremities should be performed prior to guided growth surgery | 100% |
Spine: standing or sitting plain radiography of the cervical and thoracolumbar spine to examine for spinal deformities is recommended in patients with MPS IVA at diagnosis and every 2–3 years thereafter, or sooner if clinically indicated | 85% |
Magnetic resonance imaging (MRI) of the whole spine (in neutral position) should be performed annually in children with MPS IVA to assess for spinal cord injury. The frequency may be reduced for adult patients with stable imaging who do not display symptomsa | 84% |
Flexion/extension MRI of cervical spine may be needed to identify changes in spinal canal and spinal cord | 86% |
MRI of the brain is recommended at diagnosis in patients with MPS IVA, and should be repeated as needed in individuals with clinical suspicion of hydrocephalus | 80% |
MRI of the brain and spinal cord in patients with MPS IVA may require sedation or general anaesthesia, depending on patient age and cooperation. General anaesthesia carries substantial risk for patients with MPS | 95% |
Flexion/extension computerised tomography (CT) of the craniocervical junction may be considered in patients with MPS IVA if MRI is not available or if sedation is not possible | 92% |
The presence of specific radiological signs may indicate the need for surgical intervention to correct skeletal deformities; however, there is insufficient evidence to support preventative surgery based on radiological findings | 88% |
Endurance | |
Choice of assessment depends on the patient’s physical and developmental ability | 97% |
Baseline assessment is the most important and ideally two values should be obtained as a minimum. Consistent protocols should be used when performing repeat measurements to minimise variability | 95% |
87% | |
In patients with limited ambulation who are unable to perform the 6MWT, endurance should be assessed via alternative methods such as an adapted timed 25-ft walk test (T25FW) | 76% |
Endurance testing is also recommended prior to initiation of ERT and annually thereafter as a measure of treatment efficacy and to provide early evidence of possible neurologic or skeletal issues | 87% |
Growth | |
Assessment of growth should be performed at each clinic visit (ideally every 6 months) as part of a regular physical examination and should include: standing height (sitting height if the patient is unable to stand), length (supine position), weight, head circumference (≤3 years), Tanner pubertal stage (until maturity) [47] | 95% |
Height and weight should also be measured before initiation of ERT and at every clinic visit thereafter (ideally every 6 months) to evaluate the impact of treatment [47] | 95% |
Urinary keratan sulphate (KS)/urinary glycosaminoglycan (uGAG) levels | |
Where available, tandem mass spectrometry may be used to assess levels of urinary keratan sulphate prior to starting elosulfase alfa and every 6 months thereafter to determine the pharmacodynamic effects of ERT [48] | 94% |
Total uGAG levels are often elevated in neonates and infants with MPS IVA and may overlap with normal values in adults and some teenagers. However, if a specific keratan sulphate assay is not available, measurement of uGAG levels using standard dye-binding methods may be useful. Preferably, measurements should be performed in the same laboratory and assessed against age-related reference values | 85% |
Cardiac function | |
Initial cardiac evaluation should be performed at the time of diagnosis and include assessment of vital signs with measurement of oxygen saturation, right arm and leg blood pressure measurements, careful auscultation, full transthoracic two-dimensional and Doppler echocardiogram, and 12-lead electrocardiogram (ECG) | 100% |
Longer ECG monitoring (prolonged Holter/event monitoring) may be considered in older patients, especially if they have symptoms of black outs, unexpected falls or dizziness | 96% |
Follow-up in expert centres should be annually initially, but may be extended to every 2–3 years if there is no evidence of cardiac abnormality | 92% |
Additional cardiac assessment, including a standard ECGb, should be performed prior to any surgical procedure requiring general anaesthesia | 92% |
Neurological exam | |
A detailed neurological examination should be performed at every clinic visit (minimally every 6 months) and, where possible, these should correlate with imaging studies of the spine to detect early spinal stenosis or instability compromising the cervical cord. For patients without clinical or radiographic concern, annual neurological examination may be sufficient [56] | 87% |
Standard MRI of the cervical spine should be performed to assess for presence of spinal cord compression. In the absence of significant spinal cord compression, proceed with flexion/extension MRI to confirm the presence of worsening spinal cord compression with motionc | 78% |
Respiratory function and sleep disorder | |
Evaluation of respiratory function by spirometry, including forced vital capacity (FVC) and maximum voluntary ventilation (MVV), should be performed to assess changes in lung volume and obstruction in children over 5 years of age | 97% |
Respiratory function should be assessed annually until children stop growing, and every 2–3 years thereafter, provided that respiratory symptoms remain unchanged. Additional testing should be performed if respiratory symptoms change or if intercurrent illnesses occur | 91% |
Normative values are not available, therefore change in absolute volume from patient’s own baseline will be the best indicator of deterioration or improvement | 97% |
Measurement of respiratory rate and arterial oxygen saturation before and after annual endurance testing is recommended | 86% |
Evaluation of gas exchange and respiratory function is also recommended before any planned air travel, to ensure safety during the flight | 86% |
To identify symptoms of sleep apnoead, patients should be asked to report presence of snoring and morning headaches at every clinic visit | 100% |
An overnight sleep study (polysomnography) is recommended at diagnosis (if possible, and no later than 2 years of age), and every 3 years thereafter or when signs and symptoms of obstructive sleep apnoea (OSA) are noted | 94% |
Ear-nose-throat (ENT) | |
ENT examination, including tympanometrye, should be conducted every 3–6 months during childhood and every 6–12 months thereafter | 91% |
ENT examination in patients with MPS IVA should include visualisation of the upper respiratory tract to determine diagnosis, management and assist in pre-operative planning. Endoscopic examinations should be recorded and kept, to monitor disease progression | 92% |
Fibreoptic examination in patients with MPS IVA should be performed at diagnosis and at least annually thereafter, or as clinically indicated. For those individuals who require general anaesthesia, ENT examination should be performed during the pre-operative evaluation for other surgical procedures | 83% |
Upper airway CT, focused on airway anatomy preferably with reconstruction, may be useful to identify the area of the abnormality and possible cause of obstruction in patients with MPS IVA with suspected obstruction or malaciaf | 92% |
100% | |
If speech problems are determined during ENT examination, an assessment by a speech pathologist should be conducted [59] | 100% |
Balance tests should be conducted if the patient has a history of balance problem | 95% |
Ophthalmological function | |
Age-appropriate evaluations by an ophthalmologist is recommended every 6 months if possible, or at least annually [60] | 90% |
Ophthalmic assessment may include visual acuity, refraction, slit-lamp examination of cornea, funduscopic evaluation including optic nerve, and measurement of intraocular pressure | 100% |
Scotopic and photopic electroretinogram may be performed in patients with clinical suspicion of retinopathy or when considering corneal transplantation [60] | 100% |
Intraocular pressure monitoring and pachymetry may be considered prior to corneal transplant [60] | 100% |
Evaluation of oral health by dentist | |
Close monitoring of dental development (at least annually) is recommended to prevent caries and attrition, as is monitoring of occlusion and chewing functions | 100% |
The need for subacute bacterial endocarditis (SBE) prophylaxis prior to dental procedures should be assessed by a cardiologist | 100% |
Disease burden | |
Annual assessment of patient-reported outcomes is recommended for: pain severity, QoL (as assessed by reproducible and age-appropriate questionnaires [e.g. EQ-5D-5 L]), fatigue), and activities of daily living (ADL; as assessed by functional tests [6MWT/T25FW]), age-appropriate ADL questionnaires (e.g. MPS Health Assessment Questionnaire [MPS HAQ]), and assessment of wheelchair/walking aid use [61] | 97% |
These assessments may have to be adapted both for language, culture, and individual physical limitations, as they have not been validated in specific disorders | 97% |
Physical therapy | |
Regular assessments by a physical therapist (lower limb), occupational therapist (upper limb) and rehabilitation medicine specialist should be conducted to assess limb function and provide support as needed | 93% |
The physical therapist could also assist in suggesting walking aids and other adaptations that may improve QoL | 98% |
Disease-modifying interventions
Statement | Percentage consensus |
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Initiation of long-term ERT with elosulfase alfa at a dose of 2.0 mg/kg/week through intravenous infusion is recommended in all patients with MPS IVA as soon as possible after a confirmed diagnosis Evidence Grade: B (level 2 or 3 studies) | 79% |
Statement | Percentage consensus |
---|---|
Due to the lack of evidence, HSCT cannot be recommended for patients with MPS IVA and at this time is considered an investigational procedure Evidence Grade: D (level 3/4 studies with inconsistent risk/benefit results) | 91% |
Interventions to support respiratory and sleep disorders
Statement | Percentage consensus |
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CPAP therapy is recommended for patients with MPS IVA who display the presence of obstructive sleep apnoea (OSA) that persists after tonsillectomy and/or adenoidectomy Evidence Grade: D (limited published evidence) | 97% |
NIPPV therapy is recommended for patients with MPS IVA who display nocturnal hypoventilation and are unresponsive to CPAP, or display daytime hypoventilation with increased PaCO2 and/or serum HCO3 levels Evidence Grade: D (level 5 expert clinical opinion) | 91% |
Oxygen supplementation during sleep is recommended for patients with MPS IVA who exhibit sleep apnoea with nocturnal hypoxemia, and who do not tolerate CPAP or NIPPV masks Evidence Grade: D (level 5 expert clinical opinion) | 77% |
Patients with MPS IVA should be monitored for development of hypercapnia after starting oxygen therapy using measurement of PaCO2 and/or serum HCO3 Evidence Grade: D (level 5 expert clinical opinion) | 97% |
Anaesthesia and surgical interventions
Statement | Percentage consensus |
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Pre-, intra- and post-operative care (until extubation is complete) for all procedures requiring general anaesthesia, conscious or deep sedation, should be supervised by an anaesthetist with experience in treating patients with MPS and/or complex airway management. In addition, the anaesthetist should have access to Intensive Care support and be surrounded by an experienced team capable of performing emergency tracheotomy if required Evidence Grade: C (consistent level 4 studies) | 98% |
A full assessment of the risks and benefits should take place with the patient and family prior to any procedure. All pre-operative information should be made available to allow decision making Evidence Grade: C (consistent level 4 studies) | 100% |
ENT respiratory, cardiac, and radiological assessment should be performed prior to any procedure requiring anaesthesia Evidence Grade: C (consistent level 4 studies) | 93% |
It is critical to maintain a neutral neck position during all surgeries, and during intubation and extubation to avoid paralysisa. Strongly recommend the use of techniques that allow maintenance of the neutral neck position, including use of laryngeal mask airway (LMA) for shorter procedures, or intubation with a video laryngoscope or fibreoptic intubation Evidence Grade: C (consistent level 4 studies) | 87% |
Pre-operative and intra-operative measures to avoid hypotension should be adopted during all surgical procedures in patients with MPS IVA to maintain spinal cord perfusion and therefore protect spinal cord function Evidence Grade: D (limited published evidence) | 98% |
Intra-operative neurophysiological monitoring (including somatosensory evoked potential [SSEP], electromyography [EMG] and motor evoked potentials [MEP]) is strongly recommended during all spinal surgeries and other potentially lengthy or complicated procedures, including those that require manipulation of the head and neck Evidence Grade: D (limited published evidence) | 94% |
For other surgeries and procedures, neurophysiologic monitoring should be considered based on pre-existing risk for spinal cord compression and instability, need for spine manipulation, possibility of hemodynamic changes and blood loss, or extended length of time Evidence Grade: D (limited published evidence) | 94% |
Intrathecal and epidural techniques are high-risk in patients with MPS IVA and should be avoided wherever possible Evidence Grade: D (limited published evidence) | 83% |
Statement | Percentage consensus |
---|---|
Hip reconstruction can be considered in paediatric patients with MPS IVA who exhibit hip pain, reduced walking and endurance related to hip disease, as well as abnormal radiographic findings Evidence Grade: D (limited published evidence) | 86% |
Hip replacement can be considered in adult patients with MPS IVA who exhibit hip pain, reduced walking and endurance related to hip disease, as well as abnormal radiographic findings Evidence Grade: D (limited published evidence) | 100% |
Growth modulation surgery is recommended for all patients with MPS IVA who have evidence of genu valgum and should be performed as early as possible during the period of growth Evidence Grade: D (limited published evidence) | 77% |
Statement | Percentage consensus |
---|---|
Decompression of the spinal cord is recommended in patients with MPS IVA who have evidence of spinal cord compression based on clinical and radiographic findingsa Evidence Grade: C (level 3/4 studies) | 97% |
Spinal stabilisation of the craniocervical junction with either cervical fusion or occipital-cervical fusion is recommended in patients with MPS IVA who have evidence of significant instability Evidence Grade: D (limited published evidence) | 97% |
Correction of thoracolumbar kyphoscoliosis is recommended in patients with MPS IVA who present with progressive radiographic deformity, intractable pain and neurological deterioration Evidence Grade: C (level 3/4 studies) | 100% |
Statement | Percentage consensus |
---|---|
While significant corneal clouding is rare in patients with MPS IVA, corneal transplantation can be considered for patients with significant visual loss attributed to corneal opacification | 95% |
Evidence Grade: D (limited published evidence) |
Statement | Percentage consensus |
---|---|
Cardiac (aortic, mitral) valve replacement should be considered in patients with MPS IVA who display symptomatic and severe valve stenosis or regurgitationa Evidence Grade: C (level 4 studies) | 95% |
Statement | Percentage consensus |
---|---|
Tonsillectomy and/or adenoidectomy is recommended for patients with MPS IVA who display recurrent otitis media, snoring and/or OSA as early as possible following diagnosis without waiting for disease progression Evidence Grade: C (level 2, 3 and 4 studies) | 94% |
Insertion of ventilation tubes is recommended for patients with MPS IVA with otitis media with effusion and/or recurrent otitis media to maintain hearing and/or prevent recurrent acute otitis media Evidence Grade: D (limited published evidence) | 100% |
Tracheostomy is recommended in patients with MPS IVA who do not respond to any of the treatment modalities mentioned above Evidence Grade: D (limited published evidence) | 77% |