Background
Objectives
Table | Recommended speciality focus |
---|---|
Table 2: General principles for the management of patients with MPS VI | all |
Table 3: Recommended routine monitoring and assessments in patients with MPS VI | all |
Table 4: Guidance statement for galsulfase | geneticist, metabolic physician, paediatrician, nurse, physiotherapist |
Table 5: Guidance statements for HSCT | anaesthetist, bone marrow transplant expert/hematopoietic stem cell transplant expert, geneticist, paediatrician, nurse |
Table 6: Guidance statements for continuous positive airway pressure (CPAP), non-invasive positive pressure ventilation (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 statements for decompression of the median nerve, tenosynovectomy and pulley release | anaesthetist, geneticist, hand surgeon, orthopaedic surgeon, neurosurgeon, paediatrician |
Table 12: Guidance statement for cardiac valve replacement and left ventricular apical aneurysms | anaesthetist, cardiologist, geneticist, paediatrician |
Table 13: 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
Setting the clinical questions to be answered by the guidance
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Interventions that address the underlying enzyme deficiency
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◦ ERT
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◦ HSCT
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Interventions used to manage the symptoms of MPS
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◦ Respiratory and sleep disorders
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◦ Anaesthetics
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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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Measures to address independence
Results
Guidance statements
General principles (Table 2)
Statement | Percentage consensus |
---|---|
All guidance statements are evidence Grade D (level 5 expert clinical opinion) | |
Diagnosis of MPS VI 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 a 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 VI, monitor the impact of treatment and assess the need for treatment interventions to manage the symptoms of MPS VI. 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 VI, and to manage the disease manifestations and maintain long-term quality of life (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 VI | 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 VI, 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 (based on 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), joint stiffness, 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 [23] | 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 [24] | 100% |
Spine: standing or sitting plain radiography of the cervical and thoracolumbar spine to examine for spinal deformities is recommended in patients with MPS VI at diagnosis and every 2–3 years thereafter, or sooner if clinically indicated [24] Evidence Grade: C (level 3/4 studies) | 85% |
Magnetic resonance imaging (MRI) of the whole spine (in neutral position) should be performed annually in children with MPS VI 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 VI, 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 VI 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 individuals with MPS VI 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 [25] | 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 as part (ideally every 6 months) 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) | 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 | 95% |
Urinary glycosaminoglycan (uGAG) levels | |
Urinary GAG levels should be tested prior to starting galsulfase and every 6 months thereafter to determine the pharmacodynamic effects of ERT [13] Evidence Grade: C (level 3/4 studies) | 97% |
Measurement of total uGAG levels may be performed using standard dye-based quantitative methods, preferably in the same laboratory and assessed against age-related reference values | 93% |
Where available tandem mass spectrometry may be used to assess levels of specific GAGs (such as dermatan sulphate) b [27‐32] Evidence Grade: C (level 3/4 studies) | 97% |
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) [33] | 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% |
92% | |
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 [36] | 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 motiond | 78% |
Upper limb function | |
Symptoms of carpal tunnel syndrome (CTS) are often atypical in patients with MPS VI, therefore recommend clinical examination, assessment of range of finger movement and strength, electrophysiology nerve conduction assessment and detailed medical history to be performed at diagnosis and annually thereafter | 89% |
Standardized clinical examination, assessment of active and passive range of movement and nerve conduction studies (NCS) are recommended to assess hand and upper limb function in individuals with MPS VI | 89% |
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 apnoea, patients should be asked to report presence of snoring and morning headaches at every clinic visite | 100% |
94% | |
Ear-nose-throat (ENT) | |
ENT examination, including tympanometryf, should be conducted every 3–6 months during childhood and every 6–12 months thereafter | 91% |
ENT examination in patients with MPS VI should include visualization 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 VI 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 VI with suspected obstruction or malaciag | 92% |
Age-adjusted audiometric assessment as a baseline objective hearing evaluation should be conducted in the first clinic visit and repeated annually to assess conductive and sensory-neural hearing loss [39] | 100% |
If speech problems are determined during ENT examination, an assessment by a speech pathologist should be conducted | 100% |
Balance tests should be conducted if the patient has a history of balance problems | 95% |
Ophthalmological function | |
Age-appropriate evaluations by an ophthalmologist is recommended every 6 months if possible, or at least annually | 90% |
Ophthalmic assessment may include visual acuity, refraction, slit-lamp examination of cornea, funduscopic evaluation including optic nerve, and measurement of intraocular pressure | 100% |
Intraocular pressure monitoring and pachymetry may be considered prior to corneal transplant | 100% |
Evaluation of oral health by dentist | |
Recommend close monitoring of dental development (at least annually) 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]) and age-appropriate ADL questionnaires (e.g. MPS Health Assessment Questionnaire [MPS HAQ]), and assessment of wheelchair/walking aid use | 97% |
These assessments may have to be adapted both for language, culture, and individual physical limitations as they have not been validated in the 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 upper and lower 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 |
---|---|
Initiation of long-term ERT with galsulfase at a dose of 1 mg/kg/week by intravenous infusion is recommended in patients with MPS VI as soon as possible after a confirmed diagnosis Evidence Grade: B (level 2/3/4 studies) | 89% |
Statement | Percentage consensus |
---|---|
With consideration of the associated risks of morbidity and mortality associated with this procedure, HSCT may be an option for patients with MPS VI who have a matched related donor (or unrelated donor), or cord blood grafta Evidence Grade: C (consistent with level 4 studies and extrapolations from level 3 studies) | 86% |
Due to the risk of mortality, it is critical that HSCT is only performed in an institution with a multidisciplinary team experienced in the care of patients with MPS VI Evidence Grade: D (level 3/4 studies with inconsistent risk/benefit results) | 91% |
Interventions to support respiratory and sleep disorders
Statement | Percentage consensus |
---|---|
CPAP therapy is recommended for patients with MPS VI who display the presence of obstructive sleep apnoea (OSA) which persists after tonsillectomy and/or adenoidectomy Evidence Grade: B (extrapolations from level 1 studies) | 100% |
NIPPV therapy is recommended for patients with MPS VI who display nocturnal hypoventilation and are unresponsive to CPAP, or display daytime hypoventilation with increased PaCO2 and/or serum HCO3 levels Evidence Grade: B (extrapolations from level 1 studies) | 94% |
Oxygen supplementation is recommended for patients with MPS VI who display sleep apnoea with nocturnal hypoxemia and who do not tolerate CPAP or NIPPV masks Evidence Grade: B (extrapolations from level 1/3/4 studies) | 83% |
Patients with MPS VI should be monitored for development of hypercapnia after starting oxygen therapy with measurement of PaCO2 and/or serum HCO3 Evidence Grade: D (level 5, expert clinical opinion) | 97% |
Anaesthetics and surgical interventions
Statement | Percentage consensus |
---|---|
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 (level 3/4 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 (level 4 study and extrapolation from level 3 study) | 100% |
ENT respiratory, cardiac, and radiological assessment should be performed prior to any procedure requiring anaesthesia Evidence Grade: C (level 3 study and extrapolation from level 3 study) | 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 (level 3/4 studies) | 87% |
Pre-operative and intra-operative measures to avoid hypotension should be adopted during all surgical procedures in patients with MPS VI to maintain spinal cord perfusion and therefore protect spinal cord function Evidence Grade: D (expert clinical opinion) | 98% |
Intra-operative neurophysiological monitoring (including somatosensory evoked potentials [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 should be used with extreme caution in patients with MPS VI, due to the anatomical challenges of very short stature, as well as spinal abnormalities causing insertion problems and unpredictability of spread of local anaesthesia. However, these techniques may be considered to avoid general anaesthesia in a high-risk situation or during pregnancy Evidence Grade: D (expert clinical opinion) | 88% |
Statement | Percentage consensus |
---|---|
Hip replacement can be considered in adult patients with MPS VI 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% |
Hip reconstruction is not routinely indicated, but may be considered in paediatric patients with MPS VI who exhibit hip pain, reduced walking and endurance related to hip disease, as well as abnormal radiographic findings Evidence Grade: D (limited published evidence) | 92% |
Growth modulation surgery is recommended in patients with MPS VI who have signs of genu valgum and should be performed as early as possible during the period of growth Evidence Grade: D (limited published evidence) | 87% |
Statement | Percentage consensus |
---|---|
Decompression of the spinal cord is recommended in patients with MPS VI who have evidence of spinal cord compression based on clinical and radiographica findings Evidence Grade: D (limited published evidence) | 97% |
Spinal stabilisation of the craniocervical junction with either cervical fusion or occipital-cervical fusion is recommended in patients with MPS VI who have evidence of significant instability Evidence Grade: D (expert clinical opinion) | 100% |
Correction of thoracolumbar kyphoscoliosis is recommended in patients with MPS VI who present with progressive radiographic changes, intractable pain and clinical deterioration as defined by gait, lung function and changes in the degree of kyphosis Evidence Grade: D (limited published evidence) | 97% |
Statement | Percentage consensus |
---|---|
Corneal transplantation can be considered for patients with MPS VI who have significant visual loss attributed to corneal opacification Evidence Grade: B (extrapolations from level 1/3/4 studies) | 100% |
Statement | Percentage consensus |
---|---|
Decompression of the median nerve and tenosynovectomy of all flexor tendons in the carpal tunnel is recommended in patients with MPS VI who display flexion contractures and distal interphalangeal (DIP) joints and/or proximal interphalangeal (PIP) joints (clawing), as well as clinical symptoms of hand pain and/or numbness in the thumb to middle finger, and in patients with positive nerve conduction studies Evidence Grade: C (level 4 studies) | 89% |
A1 and A3 pulley release is recommended in patients with MPS VI who display obvious trigger finger Evidence Grade: C (level 4 studies) | 94% |
Statement | Percentage consensus |
---|---|
Cardiac (aortic, mitral) valve replacement should be considered in patients with MPS VI who display symptomatic and severe valve stenosis or regurgitation Evidence Grade: C (level 4 studies) | 100% |
Left ventricular apical aneurysms occur rarely in patients with MPS VI, but should be resected whenever possible Evidence Grade: D (limited published evidence) | 85% |
Statement | Percentage consensus |
---|---|
Tonsillectomy and/or adenoidectomy is recommended in patients with MPS VI who display upper airway obstruction, recurrent otitis media, snoring and/or OSA, as early as possible following diagnosis without waiting for disease progression Evidence Grade: C (level 2/3/4 studies) | 91% |
Tracheostomy is recommended in patients with MPS VI who exhibit severe upper airway obstruction that cannot be treated by an alternative approach, and in patients with severe sleep apnoea that is not treatable by CPAP or tonsillectomy and/or adenoidectomy Evidence Grade: D (limited published evidence) | 95% |
Insertion of ventilation tubes is recommended for patients with MPS VI 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) | 96% |