Rehabilitation Strategies for Patients With Spinal Muscular Atrophy in the Era of Disease-Modifying Therapy
Article information
Abstract
The impact of disease-modifying therapy ranges from cure to no impact with a wide range of intermediates. In cases where the intermediate group reaches a plateau after the acquisition of some muscle strength, it is necessary to set a functional level appropriate for increased motor power and establish a long-term exercise plan to maintain it. As the disease status stabilizes and the life span increases, early nonsurgical interventions are required, such as using a standing frame to prevent joint contracture, applying a spinal brace at the early stage of scoliosis, and maintaining sitting postures that exaggerate lumbar lordosis. In cases where scoliosis and hip displacement occur and progress even after conservative managements are implemented, early referral to surgery should be considered. Oromotor activity and swallowing function are influenced not only by the effects of disease-modifying drugs, but also by post-birth experience and training. Therefore, although the feeding tube cannot be removed, it is necessary to make efforts to simulate the infant feeding development while maintaining partial oral feeding. Since the application period of non-invasive ventilators has increased, it has become more important to prevent long-term complications such as facial abrasion, skin allergy, orthodontic deformities, and maxillary flattening caused by the interface. Dual ventilator mode or interface can also be utilized.
INTRODUCTION
Spinal muscular atrophy (SMA), an autosomal-recessive disorder characterized by motor neuron degeneration and progressive skeletal muscle weakness, is caused by the deletion of the survival motor neuron 1 (SMN1) gene located at chromosome 5q13. The SMN protein is required for motor neuron development and viability. The SMN2 gene is a homologous gene with variable copy numbers, producing only small amounts of SMN protein. Although SMN2 fails to fully compensate for the loss of SMN1, the SMN2 copy number is the major SMA disease predictor and correlates inversely with disease severity. However, since the SMN2 copy number imperfectly predicts the severity, it is expected that other related genetic factors exist [1].
Since the late 2010s, positive clinical study results using disease-modifying drugs have been reported. The Food and Drug Administration has approved three drugs for SMA: (1) nusinersen (Spinraza®) injected at intervals of 4 months after the implementation of a loading dose through the intrathecal injection route [2,3]; (2) risdiplam (Evrysdi®), orally administered, small-molecule splicing modifier [4]; and (3) onasemnogene abeparvovec-xioi (Zolgensma®) where only a single dose is implemented through the intravenously administered, adeno-associated virus vector–based gene-transfer mechanism [5].
With the enterprise of drug treatment for SMA, it is mandatory to consider extended survival and enhanced motor function, which are different from the previously known typical trajectories of this disease. These range from remaining asymptomatic—i.e., cure—to having no impact and with a wide range of intermediates; for example, slower than normal acquisition of some motor function skills, such as sitting or assisted walking, reaching a plateau [6].
With regard to rehabilitation strategies for patients within the intermediate drug impact range, experience and scientific evidence remain scarce, and a consensus has not been established. In this review, preexisting rehabilitation strategies are summarized per domain of rehabilitation treatment, and issues to be considered when establishing rehabilitation strategies in the era of disease-modifying treatment are additionally described.
CLINICAL CLASSIFICATION
Traditionally, the severity of this disease is classified into types 0, 1, 2, 3, and 4, depending on the clinical features. Type 3 is divided into types 3A and 3B, depending on the onset of weakness before or after three years. Based on the head control achievement and signs in the neonatal period, type 1 can be divided into types 1A, 1B, and 1C, as shown in Table 1 [7].
Classification of spinal muscular atrophy
With the advent of drug treatments for SMA, alterations from the typical SMA course are expected, resulting in new phenotypes ranging from delayed onset to stopping the progression, reversing, or even curing the disease. The maximal motor function can be sustained as a child grows or may deteriorate more slowly over time. Changes in motor function may or may not correlate with the bulbar function (the ability to handle oral secretions, feeding, and vocalization), respiratory function, or orthopedic issues [6].
These issues are influenced not only by the effects of drugs, but also by experience, rehabilitation therapy, and preventive management during growth.
Validated outcome measurement tools for the SMA motor function include the revised Hammersmith score [8], revised upper limb module [9], 6-minute walk test [10], Hammersmith functional motor scale-expanded [11], and Children’s Hospital of Philadelphia infant test of neuromuscular disorders [12].
PREVENTION OF SKELETAL DEFORMITY
Prevention of joint contracture
An active assisted range of motion (ROM) exercise technique can be implemented, where the therapist or equipment helps the patient generate muscle power to achieve ROM, or a passive ROM technique without using one’s muscular strength. Since contractures in the major joints of lower extremities, such as the hip, knee, and ankle joints, hinder weight-bearing activity, preventive ROM exercises are necessary even when a contracture has not developed.
Using a standing frame not only allows age-appropriate positioning but also effectively prevents lower extremity joint contractures. The joint contracture directions include ankle plantar flexion and, knee, hip, wrist, and elbow flexion. When standing in a standing frame, lower-extremity bracing support (e.g., knee-ankle-foot orthoses or ankle-foot orthoses) can be provided to optimize joint alignment and mitigate excessive valgus forces at the knee and ankle joints [13]. The hip joint should be placed in slight abduction to optimize the hip congruence. Consistent use of 3–7 times per week is usually feasible if use of a stander is tolerated [13].
Unlike the cases of Duchenne muscular dystrophy [14,15], operative interventions to relieve lower extremity joint contractures have not been described in the existing literature. Future research is required on the role of the operative management of joint contractures in the era of disease-modifying treatments. In particular, when the motor function is stabilized in a plateau state and no weight-bearing activity can be implemented owing to joint contractures, it could be required to consider operative intervention.
Scoliosis
Progressive scoliosis due to deteriorating axial muscle strength impairs respiratory function and functional activities, such as maintaining a sitting position. Wijngaarde et al. [16] reported that 60% of patients with SMA type 1 through 4 had scoliosis, and 34% underwent scoliosis surgery in their Dutch cohort. The surgical probability was much higher for SMA types 1C and 2 at 77% and 84%, respectively. These results suggest that periodic radiographic follow-ups are essential. Merlini et al. [17] observed that when children with SMA begin to sit, their backs become kyphotic and between two and four years of age, a scoliotic curve developed. The same was observed in patients with mild SMA when they stopped walking. Kerr et al. [18] reported in their biomechanical study that spinal stability was improved by inducing a lumbar lordosis in patients with Duchenne muscular dystrophy. They speculated that this stability (e.g., tolerance to lateral loading) was associated with locking of the articular facet joints without the contribution of spinal musculature. Therefore, it could be possible to help prevent the development of scoliosis through the application of a seat device that exaggerates and maintains lumbar lordosis by utilizing a biangular backboard, lumbar pad, and shoulder strap. When scoliosis occurs, a spinal orthosis attempts to delay further progression using spinal support at three points of the controlling mechanism. Spine flexibility or reducibility should be maintained to ensure the effectiveness of braces [19]. To evaluate flexibility, the Cobb angle can be compared between the sitting position, where gravity is applied, and the supine position, where gravity is eliminated. Choi et al. [20] reported that scoliosis in patients with Duchenne muscular dystrophy was fully reducible at the early stage and became structural. These results suggest that spinal brace should be applied to scoliosis associated with neuromuscular disease at an early stage after the development of scoliosis.
When attempting a rigid spinal orthosis, poor patient tolerance is a known difficulty in managing neuromuscular scoliosis using a brace [21]. Noble-Jamieson et al. [22] showed that the reduction in forced vital capacity owing to rigid spinal bracing was proportional to the angle of scoliosis. Therefore, they proposed a strategy that applies the spinal brace at an early stage of curve development.
Several researchers have attempted to overcome poor compliance with braces caused by skin pressure problems on the bony prominences and postprandial discomfort due to abdominal flanges. Accordingly, a few researchers have reported improvements in patient tolerance and sitting position in addition to achieving immediate scoliotic curve correction through changes in spinal brace design or materials [23-25]. However, long-term longitudinal studies on the effectiveness of preventing further progression of scoliotic curves are scarce. When conservative methods such as external bracing and spinal casting are not efficient in preventing curve progression, surgical treatment is required. However, definitive spinal fusion could be detrimental in young children with skeletal immaturity, who have a significant potential for growth and pulmonary development. To allow vertebral growth before the end of skeletal maturity, several growing rod lengthening techniques without fusion have been developed [26].
There is no impact on intrathecal drug delivery of nusinersen, even when a surgical operation is performed using such methods since posterior fusion is not performed. To reduce the burden of repeated surgical procedures for rod lengthening in young patients, less invasive or noninvasive rod lengthening techniques have been developed [27-30]. In particular, lengthening can be performed non-surgically at intervals of 3–6 months on an outpatient basis after implanting magnetically controlled growing rods (MCGR). Results regarding curve correction and spinal growth during MCGR treatment are encouraging [28,31,32]. Advances in these technologies have enabled early surgical referrals.
Hip instability
Ulusaloglu et al. [33] reported that, in the SMA patient group, the prevalence of hip displacement (HD) was 75.6%, with a mean age of onset of 4.6 years. When stratified by severity (types I, II, and III), the prevalence/mean age (years) of onset was 84%/3.1, 80%/5.8, and 36%/9.0, respectively. The prevalence and clinical characteristics of HD in the presence of disease-modifying drugs remain unclear.
As in the case of the cerebral palsy group, monitoring by pediatric orthopedist or physiatrist is needed when the migration percentage (MP) exceeds 30% [34]. When MP<40%, hip abduction postural management, neuromotor treatment, and spasticity management should be implemented; when 40%<MP<50%, preventive surgery such as soft tissue release or varus de-rotation osteotomy, can be implemented. When MP>50%, reconstructive surgery, including pelvic osteotomy, could be necessary [35]. The same surveillance programs for the early detection of HD that allow timely management can be used in the SMA group as well [33].
However, since the SMA group is not associated with adductor spasticity, the impact of postural management and spasticity treatment on HD will be much lower in comparison with the cerebral palsy group. In this context, early bone surgery may be required instead of soft tissue surgery. In the era of disease-modifying drugs, it is apparent that functional or therapeutic ambulatory patients require early orthopedic intervention.
Traditionally, when HD occurred in patients with non-ambulatory SMA and symptoms such as hip pain and functional difficulties (positioning, skin and perineal care) were not observed, no surgical treatment was performed considering the progressive nature, high rate of recurrent dislocation, and limited life span of the disease [36,37]. However, in a medical environment where the lifespan of SMA patients is substantially extended, orthopedic surgical intervention may also be required due to the following reasons: (1) HD may have an impact on the development and progression of scoliosis. (2) When HD exists, it is difficult to facilitate bone health through passive standing. (3) HD induces pelvic obliquity, making the sitting posture inappropriate. Temporary medial hemi-epiphysiodesis of the proximal femur which is much less invasive and can minimize the possibility of acetabular dysplasia, could be considered [38].
No brace application has been suggested to prevent HD or slow its progression. Exercises facilitating the contraction of the hip abductor muscles (e.g., gait training) could contribute to minimizing HD.
Bone health
Even young children with SMA are at risk of severe bone fragility. Researchers have provided evidence of reduced bone formation [39] and increased bone resorption [40,41], resulting in a negative effect on bone mass over time in patients with SMA. Although Kroksmark et al. [39] reported that bone mineral density was higher in children with better motor function, knowledge gaps still exist regarding the bone mineral density and physical activity in addition to the role of the SMN protein in bone remodeling. The high incidence of osteopenia and fractures in SMA patients may not be simply attributed to muscle weakness and a lower level of physical activity [42,43].
Periodic dual-energy X-ray absorptiometry analysis is necessary to monitor bone density. In case with history of fractures, the administration of bisphosphonates should be considered. Wasserman et al. [43] reported that the femur was the most common fracture location (43.9%).
In an era where the lifespan is extended due to disease-modifying drugs, facilitating weight bearing activities such as standing or gait training and preventing joint contractures, which may hinder such activities, are essential.
EXERCISE
Resistance and aerobic training
Exercise enhanced motor neuron survival in the SMA mouse model [44]. In preclinical studies, exercise is related to a change in the alternative splicing pattern of exon 7 in the SMN2 gene, leading to increased amounts of exon 7-containing transcripts in the spinal cord of trained mice [44,45].
However, the benefits have not been demonstrated in human studies. Bora et al. [46] reported that when a 12-week arm cycling exercise protocol was implemented in five patients with SMA type 2, the active cycling distance and duration significantly improved. However, these benefits were not associated with SMN2 copy number, SMN protein level, insulin-like growth factor 1, or binding protein 3 levels.
Lewelt et al. [47] reported that a 12-week supervised, home-based, 3 days/week progressive resistance training exercise program is feasible, safe, and well tolerated in children with SMA. In this study, the exercises were performed without weight for at least one week. Once a participant was able to complete 2 sets of 15 repetitions, resistance was added. A free weight was attached to the distal limbs of the wrist and ankle. Each exercise was progressed by adding a weight in 0.08 kg increments. The weight increased until the participant scored 6/10 (somewhat hard) or 8/10 (hard) on the Children’s OMNI-Resistance Exercise Scale of perceived exertion at the end of the second set [47]. To this date, whether exercise has a protective or restorative effect on motor neurons remains unclear. The purpose of muscle strengthening exercises may be just utilizing the available muscle tissue to prevent further muscle deterioration caused by disuse and lower levels of activity.
Although there have been limited studies on aquatic therapy for the SMA, several authors suggest that it has the potential to enhance activities of daily living and muscle strength in both sitters and non-sitters [48-50].
In a study conducted before the era of disease-modifying therapy, therapeutic electrical stimulation was applied to the deltoid and biceps muscles of patients with SMA types 2/3 for 6 months, and based on a comparison with the control group, no improvement in muscle strength was demonstrated [51].
Functional activity
The impact of disease-modifying therapy ranges from cure to having no impact with wide range of intermediates. In cases where the intermediate group reaches a plateau after the acquisition of muscle strength, it is necessary to set a functional level appropriate for increased motor power and establish a long-term exercise plan to maintain it. For example, in cases where the lower extremity strength of sitter patients increases through disease-modifying therapy, therapeutic gait training can be attempted using a body support walker and ankle foot orthosis, although walking with a conventional walker or crutch is still impossible. Each manufacturer provides diverse body support walker designs and components, such as saddles and trunk support modules.
As observed in the cerebral palsy group, hip abductor weakness is one of the mechanisms of HD. This affects the lateral alignment of the proximal femoral growth plate, leading to coxa valga and hip subluxation [52]. In the SMA group, the abnormal physeal alignment could be causally related to weakness of the hip abductor muscles than to spasticity or muscle imbalance between the hip adductor and abductor muscles [38]. Therefore, gait training that activates the hip abductor muscles can be recommended in addition to passive standing exercise on a standing frame.
For non-sitters, a seat device or spinal orthosis should be manufactured to maintain a sitting posture with enhanced lumbar lordosis [53,54]. Di Pede et al. [54] suggested the following methods for manufacturing the spinal orthosis: a plaster cast is taken in a sitting position with a cervical traction at approximately 1/4–1/5 of the body weight. An abdominal opening is made to permit the movement of diaphragm. An elastic strip applied over this opening aids expiration to improve the abdominal wall response. Catteruccia et al. [53] applied an orthosis called the Garches brace not only to prevent the progression of spinal deformities but also to maintain a sitting position with head support.
SWALLOWING AND NUTRITION
McGrattan et al. [55] reported in their 24 months follow-up study that patients with SMA type 1 who received onasemnogene abeparvovec treatment achieved and maintained their swallowing function; 92% (60/65) of patients had a normal swallow, and 75% (49/65) achieved full oral nutrition. This encouraging result is clearly different from the known trajectory: swallowing function deteriorates at an approximate age of 6 months [56]. However, a report also states that, even after the start of nusinersen, impaired feeding and swallowing remain compromized in infants with SMA type 1 [57]. As infants with SMA type 1 grow, it is necessary to record and evaluate the change of swallowing function using tools such as Neuromuscular Disease Swallowing Status Scale (NdSSS) [58] and/or videofluoroscopic swallowing study. As described in the NdSSS staging, there are cases in which partial oral feeding is performed between full oral feeding and tube feeding, and the food texture of partial oral feeding should be escalated to be in line with ordinary weaning food. A small amount of oral feeding challenges may be attempted even with the findings of aspiration in infants/young children with tracheostomy [59]. A partial oral feeding strategy is also necessary for the transition from tube feeding to full oral feeding [60].
Sucking is dependent on both neural maturation and experience; therefore, even infants with SMA type 1 require nutritive/non-nutritive sucking trials immediately after birth in this era of disease- modifying treatment. Once a baby is 6 months or older, it is very difficult to establish bottle feeding for the first time [61]. Furthermore, the oromotor activity depends on maturation and experience. For example, lateral tongue movements are texture-dependent, and therefore do not emerge unless the child is given a particular texture that requires these skills [62]. If tube-fed children are not exposed to a wide variety of tastes and textures in their first year of life, it may be difficult to achieve oral acceptance at a later age [60]. The second half of the first year is a period of rapid maturation for chewing skills [63].
RESPIRATORY REHABILITATION
Gonski et al. [64] reported that stabilization of respiratory outcomes occurred within 2 years of commencing nusinersen therapy, while some of the SMA type 2/3 cohorts ceased noninvasive ventilation (NIV). Pechmann et al. [65] reported that, when respiratory function improved with nusinersen administration, it was not equivalent to the motor function.
Breathing exercises, such as the active cycle of breathing techniques and autogenic drainage have rarely been implemented in patients with SMA. Even in patients with SMA and relatively preserved respiratory muscle function, the benefits of breathing exercise have not yet been investigated. In the future, it would be necessary to conduct a study to investigate whether inspiratory muscle training has synergistic or additive effects on improving respiratory function induced by disease-modifying drugs [66]. Additionally, modifying traditional breathing exercises would be possible by concurrently implementing active inspiration and passive insufflation using a manual resuscitator or NIV.
Airway clearance techniques should be implemented before the development of respiratory symptoms. These techniques can be classified as cough augmentation, mucus mobilization and postural drainage. Cough augmentation techniques include mechanical insufflation-exsufflation (MI-E), manually assisted cough, lung volume recruitment (breath stacking), and intermittent positive pressure breathing. The manually assisted cough immediately after breath stacking will be effective from the point when the peak cough flow (PCF) drops below 270 L∙min-1 [67]. The patient receives an assisted inspiration from a manual resuscitator and is instructed not to breathe out. This maneuver is then repeated one to three times. The purpose of this technique is to obtain an augmented inspiratory vital capacity (lung insufflation capacity) beyond the spontaneous vital capacity of a patient. By securing the lung insufflation capacity, atelectasis prevention can be promoted and cough flow can be increased. MI-E delivers positive pressure during inspiration to promote maximal lung inflation, followed by an abrupt change to negative pressure in the upper airway, thereby producing an augmented cough. MI-E can generate a higher PCF than manually assisted cough methods, and patients are more likely to benefit from it if the PCF is <160 L∙min-1 [68]. MI-E can be used in infants and young children, although it is challenging even for experienced caregivers to synchronize MI-E with the patient’s own breaths [69].
Mucus mobilization techniques include intrapulmonary percussive ventilation (IPV), chest oscillations using a vibration vest, and assisted autogenic drainage. Because IPV and chest oscillation techniques are passive therapies that do not require patient compliance, they can be implemented in very young children. The postural drainage technique can be implemented in the side-lying or prone position. It is preferable to focus on a few specific postures to enhance compliance. For example, drainage can be performed comfortably in the prone position if the patient lies face down with a pillow placed diagonally across the thorax and abdomen, with the chest lower than the buttocks.
In patients with SMA, hypoventilation due to respiratory muscle weakness does not cause symptoms in the early stage and has a clinical course of isolated nocturnal alveolar hypoventilation without daytime hypoventilation [70]. Several authors have suggested initiating NIV at this point. In a state where acute respiratory exacerbations are caused by triggers such as upper respiratory infections, the initiation of NIV is psychologically more stressful and difficult than applying it before symptoms occur [71]. To determine when to initiate NIV, nocturnal transcutaneous carbon dioxide tension can be directly measured [70]. However, this is limited as it requires hospitalization and the maintenance of sensitive equipment. Therefore, maximal in/expiratory and sniff nasal pressures are commonly measured to predict the possibility of nocturnal hypoventilation and to decide when to hospitalize [72,73]. Sniffing is a natural maneuver that many children over the age of 3–4 years find much easier to perform [74].
When respiratory muscle weakness progresses, additional ventilator support during the daytime becomes necessary. NIV interfaces may cover the nose (nasal mask), the nose and the mouth (oronasal mask), and the face (full face mask). The nasal pillow-type interface is a minimal contact interface that is also available to children, and there may be a significant preference. As the duration of NIV application has increased owing to the prolonged lifespan caused by disease-modifying drugs, it has become more important to prevent long-term complications such as facial abrasion, skin allergy, orthodontic deformities, and maxillary flattening in children. To alleviate the complications caused by the interface, two different interfaces can be applied separately during the daytime and nighttime. In particular, the mouthpiece interface can be used during the day as vocalization or feeding may feel more comfortable. Many ventilator manufacturers provide dual mode setting.
Training is essential for both caregivers and patients as they should be familiar with applying and removing the NIV interface and device. In addition, they should be appropriately trained in emergency situations, such as mucus plugging in the tracheal cannula tube that may occur at home to tracheostomized children [75]. It is necessary to check caregivers’ skills before discharge. Visits by trained nurses and/or technicians are important factors for the successful implementation of home NIV program.
CONCLUSION
Disease-modifying drugs affect motor performance, respiratory function, swallowing and oromotor function, and skeletal development in children with SMA. These issues are influenced not only by the effects of drugs but also by post-birth experience and multidisciplinary management, which necessitates a comprehensive team approach. A consensus on the changes needed in rehabilitation strategies and techniques has not been established in this era of disease-modifying therapies. Nevertheless, it is clear that rehabilitation interventions are increasingly proactive in terms of extended lifespan and stabilized disease status.
Notes
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
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