Table 2.

Management approaches commonly used for adults with SMA

Clinical Issue	Assessments and monitoring	Management and sources of evidence	Level of evidencea	Context for clinical implementation	References
Rehabilitation
Muscle weakness limiting mobility, function and activities of daily living	Optimal methods for evaluation and monitoring for adults are lacking	Assistive devices Consensus statements and surveys describing use of orthoses and assistive devices	Level V	Limited evidence for selection of optimal assistive devices	[3, 27, 60, 66]
		Qualitative studies incorporating patient experience	Unclear – patient reported benefits		[67–70]
		Case reports of development and trial of upper limb assistive exoskeletons	Level V		[63, 64]
		Pilot study of a brain computer interface	Level V		[62]
		Case report of ocular movement detector system to aid communication in severe SMA	Level V		[65]
		Exercise Single randomised controlled trial in ambulatory SMA of 14 patients – no change in 6MWT, fatigue or function, improvement in V02max.	Level III	Further evidence is needed to develop exercise guidelines	[71]
		Open label study in 6 SMA III patients – training improves oxidative capacity, induces fatigue	Level IV		[72]
Respiratory Care
Impaired cough and ability to clear airway sections	Evaluate cough effectiveness	Reviews and consensus statements outlining methods for airway clearance; case series of NIV, manually assisted coughing, MI-E	Level IV	Evidence supporting optimal methods for evaluation and management are lacking	[1, 59, 73]
Respiratory muscle weakness	Monitor gas exchange for evidence of hypoventilation	Respiratory support for chronic ventilatory insufficiency: Non- invasive ventilation Consensus statements, surveys, observational study and case reports describing use of non-invasive ventilation	Level V		[1, 17, 59, 60, 74–76]
		Invasive ventilation Case studies and surveys describing use of invasive ventilation in a small number of adults	Level IV	Invasive ventilation when NIV is insufficient is an individual decision incorporating views of person and quality of life	[77] [60]
Recurrent respiratory infections		Immunizations Consensus statements	Level V		[1, 59]
Gastrointestinal and Nutritional Care
Feeding and swallowing difficulties associated with lower body weight and increased risk of aspiration pneumonia	Speech therapist and dietitian evaluation of feeding, swallowing and nutrition	Reviews and consensus statements describe modifying food consistency, optimizing oral intake, enhance feeding with positioning, seating and equipment Gastrostomy to provide nutritional supplementation when oral intake inadequate	Level V	No evidence to support specific diets. No consensus on when to commence enteral supplementation: an individual decision incorporating views of person and quality of life	[3]
		Surveys and case reports describing frequency and management of feeding difficulties in adult SMA	Level IV		[78, 79] [52]
Gastrointestinal dysmotility (reflux, constipation and delayed gastric emptying)		Consensus statements suggests gastroesophageal reflux medications, prokinetic agents, aperients, nissen fundoplication	Level V		[3]
Disease modifying medication
Agent	Study design	Results	Level of evidencea	Context for clinical implementation	References
Valproate	Prospective randomized placebo controlled cross-over trial of 33 ambulatory adults with SMA	No change in max voluntary isometric contraction, pulmonary, electrophysiological, or functional outcomes	Level I	Valproate is well tolerated, no improvement in strength or function in adults with SMA	[80]
	Open label, 6 adults with SMA II and III Retrospective open label, 7 adults with SMA III and IV, mean duration 8 months	No change in motor function, variable changes in pulmonary outcomes Increased quantitative muscle strength and subjective function	Level V Level V		[81] [82]
Gabapentin	Randomized controlled vs no treatment in 120 adults with SMA II and III over 12 months	Improvement in leg muscle strength at 12 months; no change in functional tests or FVC.	Level IV	Inconsistent evidence of efficacy	[83]
	Randomized double blind placebo controlled trial in 84 adults with SMA II and III	No differences between placebo and drug in strength, FVC, functional rating scale, impact profile	Level I		[84]
Hydroxyurea	Randomized, double-blind, placebo controlled trial – 55 SMA II and SMA III patients (aged 5–41)	No improvements in motor or respiratory function, increased development of neutropenia in the hydroxyurea group	Level I	No evidence of efficacy	[85]
Salbutamol	Randomized, double-blind, placebo-controlled trial – 45 SMA III (aged 21–53 years), 12 months duration Open label, 10 patients (aged 28–61 years), 12–72 months of salbutamol treatment	Safe and well tolerated. Significant and progressive increase in blood SMN2 full length protein in peripheral blood in salbutamol treated patients. Patients reported benefits of decreased fatigue, improved functioning, infrequent side effects	Level II Level IV	Underpowered to demonstrate clinical efficacy Unclear – patient reported benefits	[86] [87]
Nusinersen	Prospective open label observational study, 19 SMA III (aged 18–59 years), 10 months duration Retrospective open label case series, 4 adults SMA III (aged 19–52 years), follow up 4–20 months Descriptive studies of repeated intrathecal nusinersen administration in adolescent and adult patients – 78 patients in total (aged 11–61 years)	Statistically significant change in 6MWT (mean improvement 8.25 m), RULM and peak cough flow with negligible effect size. Well tolerated, adverse events of back pain in 7 and post lumbar puncture headache in 4 patients. Stable RULM, subjective improvement in endurance, hand strength, bulbar functioning Adverse events: headache, back pain CT guidance an option for administration using transforaminal or interlaminar approaches +/− laminotomy. Lumbar punctures were mostly well tolerated; adverse events included post lumbar headache and subarachnoid haemorrhage in 1 patient.	Level III Level IV Level IV	Mild treatment effect in adults with chronic SMA Available outcome measures not adequate to capture meaningful subjective improvements Feasibility and safety of intrathecal treatment with nusinersen demonstrated in adolescent adult patients with SMA II and III. Treatment can be medically and logistically challenging due to the clinical features of SMA.	[88] [89] [90–95]

^a Level of evidence according to the Oxford Centre for Evidence-based Medicine: Level I - Properly powered and conducted randomised clinical trial; systematic review with meta-analysis, Level II - Well-designed controlled trial without randomization; prospective comparative cohort trial, Level III - Case-control studies, retrospective cohort study, Level IV - case series with or without intervention; cross-sectional study, Level V - Opinion of respected authorities; case reports

Abbreviations: MI-E Mechanical insufflation-exsufflation, FVC Forced vital capacity, VO₂Max Maximal oxygen uptake;