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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 62-70

Rehabilitation in spinal muscular atrophy


1 Department of Orthopaedics, School of Medicine, Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia
2 Department of Biochemistry, Perdana University Graduate School of Medicine, Perdana University, Serdang, Selangor, Malaysia
3 Department of Anatomy, School of Medicine, Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia
4 Department of Surgery, School of Medicine, Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia

Date of Web Publication22-May-2019

Correspondence Address:
Prof. Agus Iwan Foead
Block D1, MAEPS Building, MARDI Complex, Jalan MAEPS Perdana, 43400 Serdang, Selangor
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jisprm.jisprm_4_19

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  Abstract 


Spinal muscular atrophy (SMA) is an autosomal recessive disorder with symptoms of progressive skeletal muscular atrophy which requires multidisciplinary medical care. The advent of nusinersen treatment has created a paradigm shift in rehabilitation treatment for SMA. However, the principles of rehabilitation remain the same for the respiratory, musculoskeletal, gastrointestinal, and speech and nutrition care which are all required. Patient education based on multiple sources of easily available evidence-based information has improved quality of life and has changed treatment goals. Functional assessment is critical before rehabilitation is commenced. In general, SMA patients are classified as “nonsitter,” “sitter,” and “walker.” This review provides an update on rehabilitation provided in contemporary SMA centers.

Keywords: Breathing, musculoskeletal, nutrition, patient education, rehabilitation, speech therapy, spinal muscular atrophy


How to cite this article:
Foead AI, Yeo WW, Vishnumukkala T, Larvin M. Rehabilitation in spinal muscular atrophy. J Int Soc Phys Rehabil Med 2019;2:62-70

How to cite this URL:
Foead AI, Yeo WW, Vishnumukkala T, Larvin M. Rehabilitation in spinal muscular atrophy. J Int Soc Phys Rehabil Med [serial online] 2019 [cited 2021 Apr 13];2:62-70. Available from: https://www.jisprm.org/text.asp?2019/2/1/62/257840




  Introduction Top


Spinal muscular atrophy (SMA) is one of the neurodegenerative spectra of diseases that mandates multidisciplinary approaches for effective care to be provided.[1] SMA includes a spectrum of neuromuscular disorders characterized by degeneration of alpha motor neurons within the spinal cord, which leads to progressive muscle atrophy, weakness, and paralysis.[2] Mutation or deletion of the survival motor neuron 1 (SMN1) gene results in insufficient production of the SMN protein to maintain motor neuron survival in the spinal cord. Reduced SMN protein levels lead to loss of motor neurons, and thus signaling from the central nervous system (CNS) to muscles, leading to progressive muscle weakness and atrophy. Nusinersen (Spinraza®) targets a closely related gene, SMN2, and raises SMN protein levels. Before the introduction of nusinersen therapy, early death was reported, although some SMA patients survived into adulthood. In 2004, a committee of SMA experts held an International Conference to create a consensus statement on the standard of care for SMA aiming to introduce practice guidelines for clinical care.[1],[2] Aside from pharmacological intervention, rehabilitation still plays an important role in strengthening muscles, reducing spasticity, and increase the range of motion (ROM). Exercises also help to maintain circulatory flow. Some patients may require specific therapy for speech, chewing, and swallowing.

In general, the goals of medical rehabilitation include improvement or restoration of function, and also prevention and/or compensation of functional loss, or the maintenance of current functional levels, whatever the underlying medical condition. In SMA, these goals require patient education, exercises and postural management, pain management, application of orthotics and wheelchairs, and may include the use of an ambulatory ventilator. The achievement of the goals of care also depends strongly on the patient and family's wishes.


  Functional Assessment in Spinal Muscular Atrophy Top


Before a rehabilitation program is embarked on, the natural progression of SMA must be assessed and documented. Documentation of current functional levels is also required as a baseline, and also helps to address funding requirements if medical insurance is involved. Many assessment methods are available, but commonly they are classified into three broad functional groups; that is, “nonsitter,” “sitter,” and “walker.” For nonambulatory patients (nonsitter and sitter), the Egen Klassifikation (EK) scale[3] or Hammersmith Functional Motor Scale (HFMS)[4] can be used to assess functional performance. The EK scale developed by Steffensen et al. in 2002 was first intended to assess Duchenne muscular dystrophy patients, however, it can also be used to assess functional status and predict the prognosis of SMA patients. The first HFMS was developed in 2003 as both a clinical and research tool to assess the physical abilities of Type 2 and Type 3 SMA patients. The Revised Hammersmith Scale (RHS)[5] was developed in 2017 to address discontinuity in the recorded performance of HFMS expanded. Use of the RHS in combination with WHO motor milestones may enable more sensitive description of SMA phenotype and trajectories, which subsequently facilitate more accurate subtype analysis.

The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders is a valid and reliable measure of motor skills in patients with Type 1 SMA and neuromuscular disorders in infants. The scale was developed to capture both increases and decreases in motor function without a ceiling or floor effect in the Type 1 SMA cohort patients.[6] However, the available scales were still considered insensitive at the extremes of the clinical spectrum of SMA. An international panel with specific neuromuscular expertise recently developed a revised upper limb module as a more robust clinical assessment. It was specifically designed for upper limb motor function in SMA patients.[7]

In general, SMA walkers have relatively preserved pulmonary function until late into their course of their disease. Functional assessment would include general physical examination as well as pulmonary function test, of which would be discussed in further details below. The “6-Min Walk Test” (6MWT) can be safely and easily performed in ambulatory patients with SMA to evaluate functional exercise capacity and correlates well with established outcome measures.[8] The “Timed Up and Go” (TUG) measures the time it takes a patient to stand up from an armchair, walk a distance of 3 m, turn, walk back to the chair, and sit down. Unlike the 6MWT, TUG incorporates rising and sitting in a chair adding another objective assessment of balance, gait speed, and functional mobility.[9] These specific assessments for SMA can also be compared to generic outcome measure to allow comparison of rehabilitation outcomes across diseases. The most commonly used are the “Functional Independence Measure,”[10] “Functional Assessment Measure,”[11] and modified Barthel Index.[12] These measures were previously developed for brain injury, multiple sclerosis, stroke, and traumatic spinal cord injury, but has been used to measure other cases of rehabilitation in general.


  Spinal Muscular Atrophy Breathing Rehabilitation Top


Respiratory complications are the chief cause of morbidity and mortality in SMA patients.[13] Contributing factors include respiratory muscular weakness and fatigue, as well as thoracic cage deformity due to the complication of kyphoscoliosis. Normal breathing is an active work of involuntary process which involves diaphragm and external intercostal muscles. During inhalation, the diaphragm and external intercostal muscles contract, while expansion of the thorax causes negative intrapulmonary pressure, pulling air into the lungs. In the respiratory zone, as the cross-sectional area of the lung progressively increases toward alveoli and the flow velocity of air gradually slows, the mode of ventilation across the alveolar membrane becomes diffused. Exhalation occurs passively after gas exchange mainly due to the elastic recoil properties of the lung and rib cage. The recoil of these structures increases intrapulmonary pressure, reverses airflow, and expels CO2 and other gases from the lungs. The work of breathing depends on both the elastic properties of the lungs and the strength of respiratory muscles. In normal condition, the work requires <5% of total resting O2 consumption and is quite small. However, in restrictive lungs caused by SMA, the work of breathing increases. Respiratory failure can result from factors that either directly or indirectly increase work of breathing, including (i) respiratory muscle weakness and fatigue, (ii) alteration in respiratory system mechanics, and (iii) impairment of the central control of respiration.[14]

Respiratory weakness results in inadequate lung expansion, with subsequent microatelectasis, leading to ventilation/perfusion mismatch and hypoxemia. Compensatory tachypnea, with small tidal volumes, exacerbates the atelectasis and further reduces the compliance of the respiratory system, increasing the mechanical load on already weakened respiratory muscles. Muscular weakness and fatigue leads to restrictive lung disease with hypoventilation, hypercarbia and eventually respiratory failure.



Pulmonary function outcome measurement

Pulmonary function outcome measures in SMA aimed to focus on survival, measurements of exhaled lung volumes, and respiratory muscle strength. For Type 1 SMA, progressive respiratory failure is the primary cause of death. Progressive respiratory muscle weakness is a slower process for Type 2 SMA, and changes in respiratory muscle strength could be measurable in adolescence or adulthood in Type 3 SMA. For Type 1 SMA, to estimate survival, i.e., whether the prognosis is death or the patient is a candidate for permanent ventilation, it is defined as those who require 16 h or more of ventilation support use per nasal mask, tracheostomy tube or endotracheal tube for 14 consecutive days not associated with an acute illness or surgical procedure.[15],[16] Forced vital capacity (FVC) achieved the best reliability as pulmonary function test in Type 2 and Type 3 SMA.[15],[17] FVC is the maximal volume of air exhaled with maximally forced effort from a maximal inspiration and measured as a function of time. It is an indirect measure of respiratory muscle strength and is impacted by weakness of the diaphragm and external intercostal muscles. Limitations of FVC test include patient cooperation and understanding of the test procedure. It is also challenging in nonambulatory patients with contracture and scoliosis.

Research into the best measures of respiratory muscle strength of patients with neuromuscular diseases, and on how these measures could offer prognostic information and predict the onset of nocturnal hypoxemia and respiratory are ongoing.[14] Noninvasive measures of respiratory muscle strength include maximal inspiratory pressure, maximal expiratory pressure, spontaneous nasal inspiratory pressure maneuvers and peak cough flow (PCF).[15],[18] Infants with Type 1 SMA have intercostal muscle weakness and breathe primarily with their diaphragm, resulting in expansion of the abdomen and collapse of the chest wall during inspiration. During exhalation, the chest wall and the abdomen recoil to baseline. This paradoxical movement during inspiration gives the appearance of “belly breathing” and resulting in thoracoabdominal asynchrony.[19] Plethysmography can be performed by obtaining inductance measures of cross-sectional area of the chest and abdominal wall movements. From these measurements, the phase angle, phase relation during total breath, and labored breathing index can be calculated.[19],[20] Placing a nasoesophageal and/or nasogastric pressure transducing catheter may not be practical in infants with type 1 SMA because of fatigue and agitation with catheter placement. Another choice to assess respiratory muscle fatigue is noninvasive tension time index (TTmus). The TTmus is calculated from the mean inspiratory pressure, inspiratory time, and duration of the total respiratory cycle.[21]

Ventilatory support

Respiratory development in ventilatory support has altered the management of patients with severe SMA. Outcome information and assessment of benefit and risk of ventilator support should ethically be informed to the patients and/or caretakers.[22] Noninvasive ventilation support (NVS) is preferable to invasive one in term of palliating symptoms and allowing the child to be cared for at home. According to a review by Bach,[23] NVS has been proven to prolong survival and preserve the quality of life. Conventionally, patients are typically prescribed supplemental O2 and bronchodilators although there is no evidence that either is beneficial. β-sympathomimetic bronchodilators have side effects of causing anxiety, tachycardia, nausea, and vomiting. Supplemental O2 can depress ventilatory drive, exacerbate hypercapnia, and increase CO2 levels by 50–100 mmHg or more.[23],[24] Prolonged hypercapnia will eventually result in cor pulmonale and symptoms of CO2 narcosis. The hypercapnia associated with O2 therapy can result in ventilator arrest. On the other hand, if NVS is administered instead of O2, symptoms can dissipate, blood gases normalize, excess bicarbonate is excreted, and ventilatory drive returns to normal.[23] Contrary to acute respiratory distress syndrome, patients with SMA have healthy lungs but impaired respiratory muscle function, so volumes more than 7 mL/kg delivered through ventilatory assistance will risk of developing barotrauma. Some authors recommend 5 mL/kg to be delivered even at the cost of greater hypercapnia. Most SMA patients do not require tracheostomy.[23] Bach observed that the misleading concept of management, fear of liability, and financial incentives incurred lead the choice of ventilator protocol away from unnecessary tracheostomies and invasive management.[23],[24],[25] The only indication for tracheostomy is the inability to expulse aspirated saliva or other airway debris to the extent that ambient air oxyhemoglobin saturation (O2 sat) decreases below 95%, or because of upper motor neuron hypertonicity closing the upper airway too much for mechanical insufflation-exsufflation (MIE) device to be effective.[25] These conditions can be observed in amyotrophic lateral sclerosis.[26] With the availability of oximetry and capnography to measure end-tidal CO2, arterial blood gas sampling is rarely needed for patients with neuromuscular diseases.[27]

Assisted cough

When SMA patients are unable to achieve an adequate peak expiratory flow, they might also have impaired cough resulting from inspiratory and expiratory muscle weakness. This can be evidenced from reduction in their PCF.[13],[28] Ineffective cough, i.e., inability to clear the airway by coughing, is associated with PCF <160 L/min.[28] When PCF is <270 L/min, ineffective coughing can increase the risk of respiratory infection, impair the removal of secretions and proper airway clearance, which will lead to respiratory failure.[29]

Air staking, active lung volume recruitment, is performed by receiving consecutively delivered volumes of air through a manual resuscitator. Air stacking can increase vital capacity and PCF and diminish atelectasis.[30] It results in deep lung volumes which also permit patients to raise voice volume and speak longer phrases. Any patient who can air stack is also able to use NVS. Respironics Incorporated (Murrysville, Pennsylvania, USA) evolved the in-exsufflator into the CoughAssist® which can be manually or automatically cycled. Manual cycling facilitates caretaker–patient coordination of inspiration and expiration with insufflation and exsufflation. One treatment consists of 5 cycles of MIE followed by short period of unassisted breathing or ventilator to avoid hyperventilation. Treatment continues until no further secretions are expulsed and secretion-related O2 desaturations are reversed.[23]

Decannulation

Intubated patient due to acute respiratory failure or progressive muscle weakness should achieve ventilator wean parameter from critical care management in order to be extubated. Unweanable patients can be safely extubated without undergoing tracheostomy following Bach criteria [Table 1].[23],[31] Once extubated, the patient is put under continuous NVS on assist/control with volumes preset from 800 to 1500 mL and rate of 10–14/min in ambient air. When intubated patients fail ventilator weaning parameters and spontaneous breathing trials or fail extubations to O2 and bilevel-PAP, the patients or their caregivers are informed that tracheostomy is their only option for survival.[23],[24]
Table 1: Bach extubation criteria for unweanable patient from ventilator

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  Musculoskeletal Rehabilitation in Spinal Muscular Atrophy Top


Muscle weakness in SMA will eventually result in joint contracture, spinal deformity, increased pain, osteopenia, and fractures. It is important to include in clinical evaluation: ROM of upper and lower extremities, their strength and function, and sitting or mobile ability of patients. Jaw function and contracture must be evaluated because it is concerned with speech and swallowing ability of the patients. Radiographs of the spine and other joints as well as dual-energy X-ray absorptiometry scan are also helpful to rule out fracture and osteopenia.

The requirement of motor unit assessment in neuromuscular disease as a biomarker for assessing disease categorization, its progression and prognosis grading cannot be overemphasized. A number of different methods have been advocated, but none has achieved widespread applicability. Physiologically with advancing age, inactivity will lead to loss of motor units, which is more pronounced in distal muscles. In spinal cord injury or amyotrophic lateral sclerosis or postpolio syndrome, the mean rate of motor unit loss is swift, however, in late-onset cases of SMA, the rate of loss does not appear to progress.[32] In 2010, Rutkove et al. have suggested that electrical impedance myography can accurately categorize patients with SMA Type 2 and Type 3.[33]

Contracture management involves splinting to preserve ROM and prevent joint or muscle pain. Combination of dynamic splinting and neuromuscular electrical stimulation to prevent wrist and elbow contractures has been studied in patients with cerebral palsy,[34] but none in patients with SMA.

Fatigue in SMA is worth highlighting since it is a common complication which significantly interferes with rehabilitation strategies and affects the quality of life. Physiological fatigue is different from perceived fatigue in SMA and both are independent from each other.[35] Physiological fatigue or in other words, activity-induced fatigue and weakness are caused by repetitive activity or exertion. This phenomenon is due to activity-dependent conduction blocks arising in demyelinated axons.[36] Perceived fatigue is linked to cognitive, homeostatic, or physiologic factors such as chronic respiratory insufficiency, CO2 retention, and chronic malnutrition.[35],[37]

Exercises

Previously, before the era of nusinersen treatment, there was no effective physical therapy which could cure or delay progression of this progressive neuromuscular disorder. However, in 2005 interesting evidence came to light from Grondard et al. who demonstrated that physical exercises in trained neonatal mice expected to develop an SMA Type II phenotype increased the amounts of exon 7-containing transcripts in the spinal cord. It is postulated that exercise is likely to exert neuroprotective effects as well as to activate molecular and cellular cascades that support CNS function and plasticity.[38] A furthermore recent study by Chali et al. in 2016 revealed that long-term exercise in Type 3 SMA-like mice benefits by enhancing motor neuron survival as well as inducing resistance to muscle damage, energetic metabolism, muscle fatigue, and motor behavior.[39]

Preliminary evidence in SMA animal models suggest that exercise could be a form of supportive therapeutic developments for human SMA patients. This is exemplified by the work by Lewelt et al.[40] who in 2015 observed trends in improved strength and motor function during progressive resistance strength training exercise program in children with SMA Types II and III, without any study-related adverse events occurred. Meanwhile, in another study, 12 weeks of cycle ergometer training in patients with SMA Type III was associated with an improvement in maximal oxygen uptake (VO2 max) without causing muscle damage, yet still induced fatigue.[41]

Reciprocally, Bora et al.[42] found that there is no association between the physical functions and the molecular response of SMA Type II patients to arm cycling exercise. Despite the improvements in the patients' physical condition, no link was reported in exercise-induced benefits with SMN2 copy numbers, SMN protein levels, insulin-like growth factor 1 (IGF1), and binding protein 3 (IGFBP3) levels. Taken together, skeletal muscle training such cycling on an ergometer, running on a treadmill, and lifting weights may contribute toward functional performance and muscle strength by utilizing the available muscle tissue, which may further prevent the muscle deterioration in SMA patients.[43]

Although there has no much research on hydrotherapy on SMA, the study on the effect of hydrotherapy on chronic stroke patients suggested that hydrotherapy has significant improvement on walking ability and balance compared to land-based exercise. Hydrotherapy offers more significant benefit than land-based exercise in term cardiorespiratory, resistance training, and management of spasticity and pain.[44]

Orthosis

Orthotic care is also an important aspect of treatment SMA in order to deal with the clinical problems caused by muscle weakness, i.e., scoliosis or other spinal deformities, shortening of the muscles or joints contractures, and hips subluxation or dislocation. The choice of orthosis varies on a case-by-case basis. In “walker” patients, treatment focuses on offering them more support so that they can gain ability to move around independently. Spinal braces and hip abduction splints are sometimes useful to stabilize the spine and to enable patients to stand, sit or walk, and perform daily activities. In “nonsitter” and “sitter” patients, splints may be useful to prevent joint contractures. These types of splints could be the “forearm cock-up splint,” knee–ankle–foot orthoses, or ankle–foot orthoses. However, the most common disadvantage includes the development of pressure ulcers, particularly if the orthosis is not properly fitted.

Scoliosis is commonly seen in those “sitter” patients with severe early onset of weakness; however, scoliosis can also arise in infants with severe SMA before upright posture is maintained.[45] To a lesser extent, most likely after loss of independent ambulation, walker patients are also at risk for progressive scoliosis.[45],[46],[47] The curve is usually thoracolumbar, C-shaped, and often associated with marked kyphosis and pelvic obliquity. The severity of scoliosis was directly proportional to muscle weakness in the lower limb.[47] The scoliosis eventually will impair respiratory function, reduces functional ability, and personal esthesis.[47] External spine bracing has been accepted as the best temporary therapy before skeletal maturity and closure of physes. Although no proper study has been done, external bracing has the potential for worsening pulmonary function.[48] Nakamura et al. in their published series proposed that external bracing tends to work best in neuromuscular patients with broad “C” curve deformities characteristic of SMA, particularly Cobb angle <45°.[49] The braces should be replaced periodically to accommodate the child's growth and to avoid compression of the chest wall. Patients with severe curves (over 85°), progression of curves, or deterioration of pulmonary function should be referred for surgical treatment,[47] however, surgical treatment should never be performed on a routine basis or for preventive reasons. Growing rods in early-onset neuromuscular scoliosis caused by SMA showed significant improvement in major Cobb angles and pelvic obliquity but high infection rates in those with cerebral palsy.[50] For sitter, or wheelchair-bound patients with scoliosis, customized, adaptive seating support system with 2–3 points of lateral contact is more effective and favorable to prevent further progression than using a spinal brace, as the latter causes significant chest and/or abdominal discomfort, leads to lack of compliance and risks pressure injury since most patients are thin and undernourished.

Functional electrical stimulation

Functional electrical stimulation (FES) has been widely studied in patients with spinal cord injury; however, it has never been reported in SMA. Insult or damage to the central command pathway results in disuse atrophy. Low contractile forces and inability of the muscle to sustain contractions are of concern in physical therapy. Laboratory experiment in rats showed electrical stimulation could be beneficial therapeutic modality to prevent hypotrophy of the skeletal muscles.[51] Muscular atrophy in SMA also risks developing increased intramuscular fat and reduced skeletal muscle oxidative capacity. Erickson et al. postulated that endurance neuromuscular electrical stimulation could improve skeletal muscle oxidative capacity in disused skeletal muscle atrophy.[52] FES has been showed to be able to train the paralyzed muscle to increase strength (muscle force) and endurance (fatigue resistance).[53]


  Speech Therapy and Nutrition Issue in Patients With Spinal Muscular Atrophy Top


Other aspects of rehabilitation that are important to consider include the areas of communication and swallowing across the life span. This requires the participation of speech and language practitioners (SLPs)[54] and nutritionists. SLPs usually assess and treat patients with cerebral palsy, craniofacial anomaly, language impairment, stuttering, and vocal cord paralysis. However, SLPs can counsel and assist the patient with SMA and support network plan for future communication and swallowing adaptations.

Patients with SMA may present with feeding and swallowing problems due to bulbar dysfunction.[55] Clinically, the key symptoms include prolonged mealtimes, fatigue with oral feeding, choking or coughing during or after swallowing, and recurrent pneumonia. Causes of feeding difficulty may be divided into preoral, oral, and swallowing phases. In the preoral phase, patients may present with limited mouth opening due to reduced range of mandibular motion and difficulty in getting food into the mouth for self-feeding. In the oral phase, they exhibit weak bite force and increased fatigue of masticatory muscles. Patients in swallowing phase may have poor head control, inefficient pharyngeal phase of swallowing, and poor coordination of the swallow with airway closure. Evaluation of feeding and swallowing includes: feeding assessment, mealtime observation, oral structures examination with positioning and head control on feeding. Fiberoptic endoscopic evaluation of swallowing with or without videofluoroscopic swallow studies may be helpful to evaluate therapeutic strategies. Treatment should aim at reducing risk of aspiration and optimizing efficiency of feeding and promote enjoyable mealtimes. Nutritionists may advocate changing food consistency, while occupational therapists and/or physiotherapists might work with orthosis to enable sitting position and enhance self-feeding ability.

Malnutrition and poor diet may contribute to breathing muscle weakness and deterioration of the immune system.[56] Several factors that make up a well-balanced diet including calorific content, fat, protein, carbohydrates, vitamins, and minerals, taking into account the health maintenance needs of patients. Other benefits of a healthy diet include improvements in the quality of life, muscle function, and bone health.[57] Current guidelines also emphasize supervision of nutrition by a trained dietician at every follow-up visit at SMA clinics.[1]

Among the barriers to provide sufficient nutrition in SMA are difficulties in lifting food to the mouth, swallowing difficulties, and choking on food. Thirty-six percent of SMA patients experience swallowing problems.[58],[59] Simple compensatory strategies for swallowing disorders can be helpful, such as chin tuck, effortful swallow, double swallow, head tilt, and oromotor exercises. Malnutrition or choking risks could be indications for nasogastric tubes or percutaneous gastrostomy or enterostomy tubes. Abdominal discomfort, constipation, and reflux may require dietary manipulation or pharmacotherapy. A low daily intake of fiber and fluids may worsen constipation. Some children with SMA Type 1 who depend on their abdominal muscles to breathe may experience a drop in PO2 or breathing difficulties when attempting bowel movements. Thus, it is recommended to administer high-fiber diets such as whole-grain cereals and breads and fruit and vegetables such as apples, carrots, celery, and oranges. These can be soft-cooked and mixed into smoothies, battered (potatoes), or shakes. The needs of the amount of daily fiber are calculated by adding 5 to the age of a person (e.g., 4-year-old patient will need 9 g of fiber every day).[58] If constipation persists, laxatives such as polyethylene glycol (Miralax®), lactulose, and milk of magnesia may be recommended, depending on the patient's muscle strength.[60]

Calcium and vitamin D are vital in maintaining bone health. Joyce et al. reported that there were very few studies examining at Vitamin D deficiency in individuals with SMA.[61] Insufficient intake of Vitamin D is about 75% in individual with SMA Type 1,[62] while low level of vitamin D is detected in the blood of 36.7% individuals with SMA Type 2 or 3.[63] There was significant difference in bone density when individuals were provided with increased dietary supplementation. In “walker” patients, returning back to walking after a fracture may be difficult. Both factors of bone strength and avoiding fractures are very important to maintain ability to walk and weight bear for as long as possible.[57],[62]


  Changing Paradigm of Treatment With Nusinersen (Spinraza®) Top


In SMA, there is a deletion or loss-of-function mutation in the SMN1 gene on chromosome 5q13. However, humans possess a homolog SMN2 gene copy that differs from SMN1 due to a C-to-T exchange in exon 7. The SMN-2 gene can undergo an alternative splicing process, resulting in an mRNA with an absence of exon 7, thereby leading to a small amount of full-length SMN protein being produced. Research into replacing SMN1 or decreasing SMN2 exon skipping to provide increased amount of SMN protein yielded the antisense oligonucleotide nusinersen (Spinraza®). It was developed by Ionis Pharmaceuticals (formerly Isis Pharmaceuticals) upon procuring the license from the University of Massachusetts Medical School in 2010. In 2015, Biogen acquired an exclusive license to develop the drug.[64] The main pharmacological action of 2'-O-methoxyethyl phosphorothioate-modified nusinersen consists of an alteration of the SMN2 pre-RMA splicing process by inhibiting splicing factors. This in turn will facilitate integration of exon 7 into the mRNA and thus increases full-length SMA protein level.[65]

Previous clinical studies indicated intrathecal application with a fixed-dose scheme, 12 mg across all age groups, nusinersen has shown significant improvements in the achievement of motor milestones and functions, survival or independency of permanent ventilation. Laboratory studies also recorded electrophysiological increases in compound muscle action potentials. Nusinersen is given intrathecally with an initial 4 loading doses, the first 3 doses at 14-day intervals and the fourth dose 30 days after the third dose; thereafter, one dose of 12 mg is given as a maintenance dose every 4 months. No severe side effects were recorded so far, however the recorded incidence of nephrotoxicity (fatal glomerulonephritis), blood clotting disorders and acute severe thrombocytopenia are similar to other antisense oligonucleotides drugs. Other side effects include lower respiratory tract infection, constipation, headache, vomiting, back pain, and postlumbar puncture syndrome. Baseline laboratory tests such as platelet count, prothrombin time, activated partial thromboplastin time, and quantitative spot urine protein testing are advocated before treatment.[66] The US Food and Drug Administration in December 2016, followed by the European Medicines Agency in July 2017, approved usage of nusinersen for all 5q-associated SMA types. Expert commentary emphasized that nusinersen collectively show improvement in motor function across SMA of all types, including SMA Type 3 which is commonly seen in adolescent or young adult.[67] Since the advent of nusinersen, SMA is considered no longer debilitating disease. Many of the rehabilitation principles remain the same as stated earlier, but the timing must change. Rate dependency to ventilator, requirement of spine braces, or other orthosis will decrease. However, exercises rehabilitation should begin as early as the nusinersen treatment begins. Exercise rehabilitation will include pain management, restoration of joint flexibility and ROM, strength and endurance, and proprioception and coordination. Furthermore other rehabilitation programs still apply to those who are not treated with the medication for any reason, or to those who develop complications. However, there is a continuing cost-effectiveness debate among the health insurers, pharmaceutical companies, and policy-makers because nusinersen costs US$ 125,000/injection.[65]


  Patient Education in Spinal Muscular Atrophy Top


Patients themselves, if they came to age, or their family or caretakers need to understand the fact sheet of spectrum of disease. The purpose is to enable them to anticipate the shortcoming of the body system, and also encourage them to adhere to treatment plans. They should be able to remind themselves to maintain good posture to prevent deformity. When treated, the side effects of nusinersen should be warned of so that early intervention could be carried out promptly.

Patients will need to be taught energy conservation techniques and activity pacing to combat fatigability. Sometimes, environmental modification are needed, including adaptive devices such as motorized wheelchair.[68]

Socially, some patients will be able to marry. Although high-risk and not recommended, successful pregnancy has been reported in an SMA patient with severe kyphoscoliosis.[69] Marriage counseling can be provided by team of obstetricians, social workers, and rehabilitation physicians. Genetic counseling or prenatal testing is recommended if both partners are carriers of SMA. Chorionic villus sampling at 10–14 weeks or amniocentesis at 16–20 weeks can determine if the SMA gene mutation has been inherited.[70]


  Conclusion Top


With the recent advent of nusinersen in clinical treatment, significant improvements in the achievement of motor milestones have changed the approach of rehabilitation programs. The increased survival of SMA has allowed a re-evaluation of this disorder as a treatable condition. Rehabilitation still has a major role in the care of SMA patients, the principles remain the same, but the timing to apply rehabilitation program must change to suit individual needs. Patient education based on the best available evidence-based information can change the quality of life and goal of treatment [Figure 1]. Multidisciplinary approaches and the cooperation from caregivers, families, the patients, pharmaceutical suppliers, and policy-makers are vital to the success of the management.
Figure 1: Perdana University Spinal Muscular Atrophy Resource Center, Perdana University, Malaysia

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Acknowledgments

This project was inspired by Perdana University Spinal Muscular Atrophy Resource Centre, which was founded by Prof. Dr. Zabidi Azhar bin Mohd Hussin with collaboration of Adnuri SMA Research Centre (M) Sdn Bhd, and also Dr. Siti Safura Jaapar, who is the founder and president of Spinal Muscular Atrophy Malaysia, she also has spinal muscular atrophy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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