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Table 3 Recommended routine monitoring and assessments in patients with MPS IVA

From: Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance

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%
 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%
 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%
 Annual endurance testing using the 6-min walk test (6MWT) is recommended, as per the American Thoracic Society guidelines [1, 45]
 Evidence Grade: C (level 4 study and extrapolation from level 1 study) [8, 46]
 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%
 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]
 Evidence Grade: D (level 3/4 studies support the statement; [8, 49,50,51,52,53,54] however, one level 3 study [55] does not support use of urinary keratan sulphate for monitoring the therapeutic effect of ERT)
 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%
 Age-adjusted audiometric assessment as a baseline objective hearing evaluation should be conducted at first clinic visit and repeated annually to assess conductive and sensory-neural hearing loss Evidence Grade: C (Grade 4 studies) [57, 58] 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%
  1. Post-consensus comments by the SC to be taken into consideration:
  2. aMagnetic resonance imaging (MRI) can also be used to assess for spinal cord compression. The frequency may be reduced for older patients with stable imaging who do not display symptoms
  3. bEchocardiogram (ECHO) should also be performed prior to any surgical procedure requiring general anaesthesia
  4. cThis topic was discussed in detail with the neurosurgical and orthopaedic colleagues in the SC group. It was their expert clinical opinion that flexion/extension MRI is not dangerous to perform within the hands of an experienced team. It is important that the range of motion (ROM), flexion and extension of the patient is evaluated while they are awake immediately before anaesthesia. The ROM during anaesthesia should not exceed the ROM as noted in the awake state, and should only be carried out after it is confirmed that there is no spinal cord compression. See Table 9 for guidance statements on spinal surgeries including spinal cord decompression
  5. dSigns and symptoms for sleep apnoea (a type of sleep disordered breathing (SDB)) can be divided into nocturnal and daytime symptoms. Nocturnal symptoms include loud snoring, observed episodes of breathing cessation during sleep, abrupt awakenings accompanied by gasping or choking, and awakening with a dry mouth or sore throat. Daytime symptoms include excessive daytime sleepiness, morning headaches, difficulty concentrating during the day, personality and mood changes including depression or irritability, and high blood pressure. To identify presence of SDB, patients should be asked to report snoring and other signs and symptoms of SDB at every clinic visit
  6. eTympanometry is used to measure the volume of the ear canal/tympanic membrane movement and indirectly assess for fluid accumulation and opening of pressure equalising tubes
  7. fUpper airway CT may also be useful to identify the area of the abnormality and possible cause of obstruction in patients with MPS IVA with suspected tracheo bronchomalacia