Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of lower motor neurons, with resulting progressive muscle weakness. The clinical phenotype and disease severity can be varied and occupy a wide spectrum. Although many advances have been made regarding our understanding of SMA, no cure is yet available. The care of patients who have SMA can often be complex, with many medical issues to consider. When possible, a multidisciplinary team approach is effective. The current understanding of SMA, and the clinical management and rehabilitative care of patients who have SMA, are discussed in this article.
Spinal muscular atrophy (SMA) is a term used to describe a varied group of inherited disorders characterized by weakness and muscle wasting secondary to degeneration of motor neurons in the spinal cord and brainstem. In the late 19th century, an early-onset form of SMA presenting in infancy was first described independently by Werdnig and Hoffmann . Oppenheim subsequently described a more benign form presenting in early childhood. Wohlfart and colleagues and Kugelberg and Welander later described a more slowly progressing hereditary form of SMA with survival into adulthood. The wide spectrum of disease severity in childhood SMA was noted by Byers and Banker , who divided patients into three categories, depending on age of onset and different life expectancies. Since then, other rare SMA syndromes with childhood and adult onset have been recognized, with varied clinical phenotypes and inheritance pattern. This article focuses on autosomal recessive, predominantly proximal SMA, which is the second most common neuromuscular disease of childhood (after Duchenne muscular dystrophy) estimated to occur in approximately 1:6,000 to 1:10,000 live births .
Classification, patterns of severity, and survival
SMA is generally divided into clinical subtypes using age of onset, achieved developmental milestones, ability to achieve independent sitting, standing, walking, and survival as classification criteria. The International Consortium on SMA attempted to standardize the classification of SMA to provide a rational basis for linkage studies and therapeutic trials ( Table 1 ) . SMA type I (SMA I) (Werdnig-Hoffmann, severe form) was defined by the consortium as follows: onset from birth to 6 months, no achievement of sitting without support, and death usually before the age of 2. In SMA type II (SMA II) (intermediate form), onset is before 18 months, sitting is achieved but standing and ambulation are never obtained, and death occurs after the age of 2 years. In SMA type III (SMA III) (Kugelberg-Welander, mild form), onset is after the age of 18 months, patients develop the ability to stand and walk, and death is in adulthood. However, considerable variability in severity and occasionally some overlap exist within each of the three groups . Clinically, an adult-onset type of SMA with mild disease phenotype, presenting usually in the second or third decade, has been recognized. These patients are able to ambulate with minor motor impairments. Although the adult-onset type of SMA is not classified formally by the criteria set forth by the consortium, among clinicians, SMA type IV (SMA IV), denoting this adult-onset group of patients who have mild disease features, has been used widely. A modified classification scheme has been proposed by Zerres and Rudnik-Schoneborn , as shown in Table 2 .
| Type | Onset | Achieved milestones | Survival |
|---|---|---|---|
| I | ≤6 mo | Never sits without support | Usually less than 2 y |
| II | ≤18 mo | Sits independently but never stands or walks without aids | Usually more than 2 y; often to adulthood |
| III | >18 mo | Stands or walks without support | Adulthood |
| Type | Definition | Mean age of onset | Range of onset | Survival probability at age 20 |
|---|---|---|---|---|
| I | Never sat alone | 1.9 mo | 0–10 mo | 0 |
| II | Sits alone, never walked | 8.6 mo | 0–18 mo | 77% |
| IIIa | Walks without support; age of onset <3 y | 17.9 mo | 3–30 mo | Normal |
| IIIb | Walks without support; age of onset 3–30 y | 10.4 y | 3–24 y | Normal |
| IV | Age of onset >30 y | 44.8 y | 33–54 y | N/A |
Life expectancy is closely related to SMA type. Pooled data regarding age of onset and survival from the United Kingdom and Finalnd are shown in Table 3 . Survival past 2 years is rare for those presenting before 6 months. In a large series, 197 patients classified as type I had the following survival probabilities: 32% at the age of 2, 18% at the age of 4, 8% at the age of 10, and 0% at the age of 20 . For 104 cases classified as SMA II, 98% survived to the age of 10 and 77% to the age of 20. In a prospective study including SMA II patients younger than 6 years old, no deaths occurred during a 5-year period in those cases whose onset of symptoms occurred at the age of 6 months or later . A 10-year prospective study reported by Carter and colleagues documented seven deaths among 32 SMA II patients (mean age at death, 21 years). Patients who have SMA II have been documented to live to as late as the fifth decade with and without mechanical ventilation . Although no survival data exist for patients who have SMA III, cases without mechanical ventilation have been followed into the eighth decade .
| Age of onset (mo) | Number of patients | Mean age at death (mo) | Maximum survival (mo) |
|---|---|---|---|
| Birth | 29 | 4.5 | 12 |
| <1 | 19 | 6.1 | 18 |
| >1–2 | 24 | 6.4 | 12 |
| >2–3 | 18 | 13.6 | 25 a |
| >3–6 | 10 | 15.2 | 30 |
a Excluding two patients who never sat unaided and survived to 10 and >18 years, and a third patient who survived 8 years with tracheostomy and mechanical ventilation.
Genetics of autosomal recessive, predominantly proximal spinal muscular atrophy
The carrier frequency for SMA in the general population is estimated at about 1 in 40 to 50 individuals . Autosomal recessive inheritance has long been documented in proximal SMA with childhood onset. In 1990, all three forms of SMA were mapped to chromosomal region 5q13, indicating that allelic variants of the same disease locus account for the clinical heterogeneity . During the past 2 decades, tremendous advances have been made in our understanding of the genetic basis for SMA . A detailed analysis of the 5q13 region revealed that this chromosomal region in humans contained a large inverted duplication, with at least 2 genes present in telomeric and centromeric copies.
Further studies have identified the SMA causative gene as the survival motor neuron (SMN) 1 gene (SMN1, telomeric copy), along with a disease modifying gene (SMN2, centromeric copy) . Briefly, the two SMN genes are nearly identical except for a difference of only five nucleotides in their 3′ regions, without any alteration of the amino acid sequence of the protein. However, the critical difference between the SMN1 and SMN2 genes is a C-T transition located within the exon-splicing region of the SMN2 that affects the splicing of exon 7. This change results in frequent exon 7 skipping during the splicing of SMN2 transcripts . It is thought that the resulting truncated SMN protein, without its exon 7 contribution, is a less stable form of SMN protein, and therefore, rapidly degraded. In about 95% of SMA patients, both copies of SMN1 exon 7 are absent because of mutations. In the remaining SMA-affected patients, other small or subtle mutations have been identified .
Genetic studies have now established that SMA is caused by mutations in the telomeric SMN1 gene, with all patients having at least one copy of the centromeric SMN2 gene. At least one copy of the SMN2 must be present in the setting of homozygous SMN1 mutations; otherwise, embryonic lethality occurs. The copy number of SMN2 varies in the population, and this variation appears to have some important modifying effects on SMA disease severity . It appears that a higher number of SMN2 copies in the setting of SMN1 mutations results in a less severe clinical SMA phenotype. However, substantial variations in SMA phenotype and disease severity can exist with a given SMN2 copy number, so it is not recommended that disease severity be predicted based on SMN2 copy numbers. Although we now know that SMN protein is expressed widely in many tissues throughout the body, its function is still not completely understood at this time .
Genetics of autosomal recessive, predominantly proximal spinal muscular atrophy
The carrier frequency for SMA in the general population is estimated at about 1 in 40 to 50 individuals . Autosomal recessive inheritance has long been documented in proximal SMA with childhood onset. In 1990, all three forms of SMA were mapped to chromosomal region 5q13, indicating that allelic variants of the same disease locus account for the clinical heterogeneity . During the past 2 decades, tremendous advances have been made in our understanding of the genetic basis for SMA . A detailed analysis of the 5q13 region revealed that this chromosomal region in humans contained a large inverted duplication, with at least 2 genes present in telomeric and centromeric copies.
Further studies have identified the SMA causative gene as the survival motor neuron (SMN) 1 gene (SMN1, telomeric copy), along with a disease modifying gene (SMN2, centromeric copy) . Briefly, the two SMN genes are nearly identical except for a difference of only five nucleotides in their 3′ regions, without any alteration of the amino acid sequence of the protein. However, the critical difference between the SMN1 and SMN2 genes is a C-T transition located within the exon-splicing region of the SMN2 that affects the splicing of exon 7. This change results in frequent exon 7 skipping during the splicing of SMN2 transcripts . It is thought that the resulting truncated SMN protein, without its exon 7 contribution, is a less stable form of SMN protein, and therefore, rapidly degraded. In about 95% of SMA patients, both copies of SMN1 exon 7 are absent because of mutations. In the remaining SMA-affected patients, other small or subtle mutations have been identified .
Genetic studies have now established that SMA is caused by mutations in the telomeric SMN1 gene, with all patients having at least one copy of the centromeric SMN2 gene. At least one copy of the SMN2 must be present in the setting of homozygous SMN1 mutations; otherwise, embryonic lethality occurs. The copy number of SMN2 varies in the population, and this variation appears to have some important modifying effects on SMA disease severity . It appears that a higher number of SMN2 copies in the setting of SMN1 mutations results in a less severe clinical SMA phenotype. However, substantial variations in SMA phenotype and disease severity can exist with a given SMN2 copy number, so it is not recommended that disease severity be predicted based on SMN2 copy numbers. Although we now know that SMN protein is expressed widely in many tissues throughout the body, its function is still not completely understood at this time .
Physical examination findings
Spinal muscular atrophy I
In many instances, mothers of SMA I cases report experiencing reduced fetal movements. Most cases present within the first 2 months. Weak suck, dysphagia, labored breathing during feeding, aspiration of food or secretions, and a weak cry are also frequently noted. Examination shows generalized hypotonia and symmetric weakness involving the lower extremities earlier and to a greater extent than the upper extremities. Proximal muscles are weaker than distal muscles. In the supine position, the lower extremities may be abducted and externally rotated in a “frog-leg” position. Volitional movements of fingers and hands persist well past the time when the shoulders and elbows cannot be flexed against gravity. The thorax is flattened anteroposteriorly, and may be described as bell shaped. The diaphragm is usually more preserved relative to the intercostal and abdominal musculature, which results in a diaphragmatic breathing pattern during respiration, with abdominal protrusion, paradoxical thoracic depression, and intercostal retraction. Neck flexor and extensor weakness are noted with head lag during examination. With advanced disease, the mouth may remain open as a result of masticatory muscle weakness. Facial weakness has been noted in as many as 50% of SMA I patients . Tongue fasciculations have been reported in 56% to 61% of patients . Deep tendon reflexes have been absent in all four extremities in about 74% of cases . Appendicular muscle fasciculations and distal tremor may be present. Extraocular and myocardial muscles are spared. Contractures are generally not severe, although hip, knee, and elbow flexion contractures may be observed. Wrist contractures with ulnar drift of the fingers may be noted. Varus or valgus deformities of the ankles may also be present. Hip subluxation or frank hip dislocation is occasionally observed. Severe arthrogryposis is not typically observed but can be present.
Spinal muscular atrophy II
The onset of SMA II is usually more insidious than that of SMA I. The findings of generalized hypotonia, symmetric weakness, and delayed motor milestones are hallmarks of SMA II. Weakness involves proximal muscles more than distal muscles, and lower extremity more than upper extremity. A fine tremor of the fingers and hands occurs in some patients. Wasting tends to be more conspicuous in SMA II than in SMA I. The deep tendon reflexes are depressed and usually absent in the lower extremities. Appendicular or thoracic wall muscle fasciculations may be observed. Tongue fasciculations have been observed in 30% to 70% of SMA II patients . Progressive kyphoscoliosis and neuromuscular restrictive lung disease is almost invariably seen in the late first decade. Contractures of the hip flexors, tensor fasciae latae, hamstrings, triceps surae, elbow flexors, and finger flexors are common. Hip subluxation and dislocations have been noted commonly in SMA II patients . Sensory examination is normal. Extraocular, sphincter, and myocardial muscles are spared.
Spinal muscular atrophy III
In SMA III, weakness usually initially occurs between the ages of 18 months and the late teens. Motor milestones may be delayed in infancy. Proximal weakness is observed, with the pelvic girdle being more affected than the shoulder girdle. Lumbar lordosis and anterior pelvic tilt are exaggerated, owing to hip extensor weakness. The patient also usually has a waddling gait pattern with pelvic drop and lateral trunk lean over the stance phase side, secondary to hip abductor weakness. If ankle plantar flexion strength is sufficient, the patient may show primarily forefoot or toe contact during gait without heel strike, which is a compensatory measure to maintain a stabilizing extension moment at the knee. The patient may exhibit a Gower’s sign when arising from the floor; stair climbing is also difficult because of hip flexor weakness. Fasciculations in the limb and thoracic wall muscles are common. Fasciculations of the tongue are noted in about one half of the patients and are more common later in the disease course . Deep tendon reflexes are diminished and often become absent over time. Significant scoliosis and contractures are rare in SMA III.
Laboratory findings in spinal muscular atrophy
Serum laboratory studies
Creatine kinase levels have been found to be normal to elevated two to four times in SMA I and II . SMA III patients can also have normal to slightly elevated creatine kinase values . A serum creatine kinase level greater than 10 times the upper limit of normal is generally an exclusionary criterion for SMA and workup for other disorders such as inflammatory or dystrophic myopathies should be pursued. Functional status and disease progression did not correlate with creatine kinase level in a series of SMA III cases . Adolase may also be normal to slightly elevated in SMA.
Electrodiagnosis
Needle electromyography
The predictive value of needle electromyography in the diagnosis of SMA has been established . The findings have largely been consistent with motor axonal loss, denervation, and reinnervation. In the infant, spontaneous activity may be more easily determined with the study of muscles that are not as readily recruited (vastus lateralis, gastrocnemius, triceps, and first dorsal interosseous). Recruitment and motor unit characteristics can be assessed in muscles that are readily activated (anterior tibialis, iliopsoas, biceps, and flexor digitorum sublimes) . The paraspinal muscles are usually not studied because of poor relaxation. The tongue muscle can be examined with needle electromyography; however, for practical reasons, it is rarely performed or needed in the evaluation of the hypotonic infant.
Although some investigators have described high-density fibrillation potentials in infants with poorer prognosis, most studies have not demonstrated abundant fibrillation potentials in the infantile form of SMA . In SMA III, the incidence of fibrillation potentials ranged from 20% to 40% in one series , to 64% in another . The incidence of fibrillation potentials in SMA II appears higher than in SMA III. Spontaneous activity has been observed more frequently in the lower than in the upper limbs, and in proximal more than distal muscles . Fasciculations are more common in SMA I than in SMA II or III . The degree of spontaneous activity has not been found to be independently associated with a worse prognosis .
Voluntary motor unit action potentials (MUAPs) frequently fire with an increased frequency, although recruitment frequency may be difficult to determine consistently in infants. Compared with age-matched norms, MUAPs show longer duration and higher amplitude, particularly in older subjects; however, a bimodal distribution may be seen, with some concomitant, low-amplitude, short-duration potentials . Large-amplitude, long-duration MUAPs may be absent in many infants with SMA I but are more commonly observed in SMA II and III . Other signs of reinnervation, such as polyphasic MUAPs, may be observed in more chronic and mild SMA. A reduced recruitment pattern with maximal effort is perhaps the most consistent finding in all SMA types.
Nerve conduction studies
Motor nerve conduction velocities and compound muscle action potential (CMAP) amplitude have been shown to be reduced in many patients who have infantile SMA. The degree of motor conduction slowing tends to be mild and the conduction velocity tends to be greater than 70% of the lower limit of normal . Significant reductions in CMAP amplitudes have been frequently reported in SMA I to III . A tendency toward greater reductions in CMAP amplitude among patients with earlier age of onset and shorter survival has been reported . Sensory nerve conduction studies are essentially normal. Significant abnormalities in sensory studies exclude a diagnosis of SMA, whereas minor abnormalities in sensory conduction velocities have been noted infrequently .
Pathologic evaluation in spinal muscular atrophy
Histologic changes on muscle biopsy are characterized by sheets of round atrophic fibers (2–8 μM in diameter) intermingled with groups of normal or hypertrophic fibers. Fiber-type grouping is not usually observed in infants but may be observed in older children with SMA. Significant fiber necrosis is usually absent, although occasional muscle fiber changes, such as basophilia, fiber slitting, and internal nuclei, may be observed. Overall, the extent of histologic changes seen within muscle biopsy specimens does not predict the severity or the disease course for children with SMA . Histologic evaluation of the spinal cord from postmortem specimens shows loss of anterior horn cells at all cord levels . Residual anterior horn cells may show swelling, chromatolysis, thickened neurofibrils, and increased lipofuscin granules. The ventral roots are atrophic with myelin loss, whereas the dorsal roots are spared.
Clinical issues in spinal muscular atrophy
Diagnostic evaluations
If the diagnosis of SMA is strongly suspected, a SMN gene deletion test can be done to confirm the diagnosis. At this time, a genetic test for SMA is commercially available. The test is based on the homozygous absence of SMN1 exon 7, with or without a concomitant exon 8 deletion. The sensitivity and specificity of the gene deletion test are excellent and approach 95% and 100%, respectively. The test results are usually available in several weeks. The copy number of the SMN2 gene is also typically reported. If the SMN gene test is negative, then the diagnosis of SMA should be seriously questioned, and work up for other potential neuromuscular diagnoses pursued. However, if further workup and electromyography results continue to point to a motor neuron disease in an individual with the clinical features of SMA, then additional testing for more subtle SMN mutations can be undertaken. SMN1 gene copy number testing and sequencing of the SMN1 gene are available through some research laboratories ( www.genetests.org ).
Family education and genetic counseling
After the diagnosis is established, a meeting with the patient and family is important to explain the disease process, phenotype classification, and prognosis. A geneticist consultation may be necessary for more detailed questions regarding sibling or carrier testing, recurrence risk, and reproductive planning issues. The issues regarding testing of unaffected siblings for presymptomatic diagnosis and prenatal screening for SMA may be discussed with the help of a geneticist. The patients and families should also receive information regarding various support networks or advocacy groups. In addition, information regarding ongoing SMA clinical trials can be obtained through the Web site, www.clinicaltrials.gov .
Clinical management of impairment and disability in spinal muscular atrophy
Strength profiles and exercise
Many studies have performed strength evaluations in SMA patients . Manual muscle test across 34 muscle groups showed that proximal weakness was greater than distal weakness in SMA II and III . Strength measurements across a large age span showed increasing proximal muscle weakness with increasing age, whereas distal muscles showed minimal decline in strength with age . SMA III patients did not show a significant rate of decline in strength when age and disease duration were considered. Extensor muscle groups appear to be weaker than flexor groups at the elbow, wrist, hip, and knee, whereas neck flexors are weaker than neck extensors . In SMA patients 5 years or older, markedly reduced muscle strength approximating 20% of that predicted from age- and gender-matched normative data were found .
The potential benefits of exercise in neuromuscular disorders such as SMA have been described previously . These benefits include increased endurance, greater aerobic capacity, reduction in O 2 cost of locomotion, improved daily functional abilities, improved flexibility, and psychosocial benefits. Limited data exist regarding the effects of strength training in SMA specifically. Strength profile studies have shown no effect of side dominance in SMA . At this time, little clinical evidence suggests that overuse weakness occurs in SMA. One study of resistive exercises included three subjects with SMA II . Strength and endurance were improved in these subjects and exercise was well tolerated. In addition, recent studies in a mouse model of SMA have provided evidence of potential neuroprotective and survival benefits of exercise . A moderate resistance exercise program has been advocated for the postpubertal patient who has a slowly progressive neuromuscular condition such as SMA . Based on the functional status of the patient, a regular exercise program including swimming, aquatherapy, and adaptive sports should be encouraged.
Bulbar dysfunction and swallowing problems
Bulbar dysfunction is more commonly observed in SMA I, but can also occur in SMA II and III patients, especially during the later stages of the disease. Such bulbar involvement leads to problems in buccal and pharyngeal propulsion activities during eating, and it can also contribute to impaired airway protection . The prevalence of self-reported symptoms of swallowing difficulty in 85 SMA II and III patients was 36.5% in one study . Fluoroscopic swallowing evaluations in four SMA I patients revealed involvement of the anterior and posterior phases . Impairment of facial musculature in SMA results in weakened mastication. In addition, SMA patients have been found to have abnormal craniofacial growth patterns. The malocclusion of teeth has been attributed to various factors, including weakness of masticatory muscles, tendency for mouth breathing, and poor head positioning . Management of malocclusion in SMA patients may be important for optimal nutrition and respiratory function.
Body composition and nutrition
Patients who have SMA I and II are often of small stature and have greatly diminished muscle bulk . MRI of limbs has demonstrated severe muscular atrophy in SMA I and II . In addition, increased subcutaneous fat is observed in these patients. Muscles of SMA III patients, in comparison, showed less atrophy but significant fatty infiltration. In these more chronic cases, the use of skin fold measurements may not accurately reflect percent of lean and fat mass.
Diffuse weakness, bulbar dysfunction, or respiratory distress may affect feeding in SMA patients. Therapeutic modifications may include use of a premature baby nipple with a large opening, use of proper head and jaw position along with a semireclined trunk position, and use of frequent small feedings to minimize fatigue . The use of larger bolus feeds may distend the stomach and encroach on the diaphragm. Improved nourishment and nutritional status in individuals with SMA has shown to lead to a feeling of well-being and a better quality of life . Poor nutritional status, labored feeding, or symptoms of dysphagia are indications for the initiation of supplemental enteral feedings by way of nasogastric tube or gastrostomy. Supplemental enteral feedings may be performed by bolus, gravity drip, or continuously during the night by way of a pump. Another common issue facing SMA patients, especially infants, is constipation. Constipation is thought to be caused by a combination of weak abdominal muscles and immobility. Chronic constipation and impaction can further decrease the already impaired lung function, and can decrease oral intake in these patients. Appropriate dietary management and hydration, supplemented with laxatives, are effective in the maintenance of optimal bowel care for these patients.
Cardiac function
Although the myocardium is not primarily involved in SMA, mild nonspecific electrocardiogram changes have been described . Baseline irregularities in tracings, at times caused by skeletal muscle fibrillations, may be observed . Electrocardiogram findings consistent with atrial and ventricular enlargement may be observed in SMA II ; however, echocardiograms have not shown concomitant atrial or ventricular dilation .
Pulmonary function testing and respiratory management
The restrictive lung disease is the most common and serious complication facing patients who have SMA. In general, the severity of restrictive lung disease is proportional to the weakness and functional class of SMA. It is most severe in infants with SMA I but it may not affect patients who have SMA III . Samahu and colleagues showed that absolute forced vital capacity (FVC) was significantly related to height index and functional level in 5- to 18-year-olds who had SMA. Ambulatory patients showed normal or near-normal values, whereas nonsitters showed the lowest values, with absolute FVC of less than 1 to 1.56 L. A need for ventilatory support through intermittent positive pressure breathing was directly related to FVC and functional status. Two thirds of those who could only sit supported used intermittent positive pressure breathing, compared with only 5% of those who walked independently . Carter and colleagues showed significant reductions in FVC over time with increasing disease durations in SMA II, but not in SMA III subjects. In addition, SMA II patients showed more severe declines in maximal expiratory pressure versus maximal inspiratory pressure, suggesting relative diaphragmatic sparing . Progressive restrictive lung disease in SMA III was shown to be mild and rarely necessitated the institution of ventilatory support .
Although no specific spirometry parameters for beginning ventilatory support have been established, it has been found that the institution of mechanical ventilation in SMA II was generally not required until FVC was about 20% of the predicted value . This parameter is not absolute and ventilatory support has been initiated at FVC values of mid-30% . Other pulmonary function measurements including maximal inspiratory pressure, maximal expiratory pressure, and peak cough flow are also useful. When these values decline, they can indicate poor airway clearance function, increased risk for infection, and hastened respiratory failure. In most specialty neuromuscular disease clinics, spirometry evaluation is typically performed at least annually for those SMA patients who have impaired lung function (and every 6 months or more frequently for those at higher risk). Children older than 5 years can usually cooperate and follow directions reliably enough to perform spirometry.
Over the last decade, advances in noninvasive ventilation technology, an increased variety of ventilation interface devices, and miniaturization of ventilators leading to better portability have all contributed to improved pulmonary management of patients who have SMA. Treatment of severe respiratory insufficiency in SMA may use noninvasive intermittent positive pressure ventilation (NIPPV) by way of oral or nasal interfaces, nasally applied bi-level positive airway pressure (BiPAP), or positive pressure mechanical ventilation by way of a tracheostomy . In any method, the most important goal is to obtain a good seal around the interface. The noninvasive ventilation method is particularly convenient for nighttime use. In general, nocturnal NIPPV appears to be effective for sleep-disordered breathing and night-time hypoventilation encountered in patients who have various neuromuscular diseases. In most cases, the BiPAP mode of ventilation, rather than the continuous positive airway pressure, is appropriate for most restrictive lung volume processes secondary to progressive neuromuscular diseases. However, continuous positive airway pressure may have a role, particularly in young infants with SMA I who are unable to synchronize effectively with BiPAP. In all cases, frequent monitoring for adequate mask fit and appropriate ventilator pressure level settings is necessary.
Continuous invasive ventilatory support by way of a tracheostomy should be considered when contraindications or patient aversion to noninvasive ventilation are present, or when noninvasive ventilation is not feasible because of severe bulbar weakness or dysfunction. In these cases, discussions allowing careful consideration of the patient/family’s desires, the child’s prognosis, and the child’s quality of life can often lead to a satisfactory resolution. For those SMA patients requiring full-time ventilatory support, portable ventilators can now be easily attached to power wheelchairs, markedly improving the quality of life for these patients in the community.
Secretion management and airway clearance are also important aspects of respiratory care in SMA patients. Manual cough-assist techniques performed by the caregiver/family, or mechanical insufflator-exsufflators (cough-assist machines), can help improve airway clearance and secretion management. In addition, the use of these methods in conjunction with noninvasive ventilation pre- and postoperatively have helped significantly improve the pulmonary care of patients who have SMA and are undergoing surgery. Intrapulmonary percussive devices and ventilators are also available to help mobilize secretions and improve pulmonary hygiene.
Sleep-disordered breathing and nocturnal alveolar hypoventilation are manifestations of worsening restrictive lung disease and respiratory failure in SMA. Sleep-disordered breathing is now recognized as a significant cause of morbidity in SMA . Common signs and symptoms suggesting sleep-disordered breathing are nightmares, morning headache, and daytime drowsiness. A polysomnography with continuous CO 2 monitoring is helpful in determining sleep-related hypoventilation. However, a nocturnal pulse oximetry in the home environment can serve as an acceptable screening tool for sleep-related oxyhemoglobin desaturation and alveolar hypoventilation when polysomnography is unavailable. Other general measures for patients who have restrictive lung disease include yearly influenza and pneumococcal vaccination. For more detail, a recent update regarding the respiratory care of patients and a consensus statement for standard of care in SMA are available .
Spine deformity
Scoliosis has been estimated to occur in 78% to nearly 100% of SMA II patients . Scoliosis almost always begins in the first decade of life as a result of severe truncal weakness. The curves are collapsing in nature and are thoracolumbar (62%), thoracic (12%), or lumbar (10%), or are double curves involving thoracic with lumbar or thoracic with thoracolumbar (16%) . The average deformity observed over 10 studies was 90°, with a reported range of from 20° to 164° . Severe kyphosis may be a common associated deformity and virtually all patients who have severe scoliosis have significant pelvic obliquity . In contrast, SMA III patients who are ambulatory have less scoliosis, with a reported prevalence of 8% to 63% . Spinal bracing is generally used in SMA patients who are unable to walk, or to improve sitting balance. However, bracing has been repeatedly shown to be ineffective in preventing eventual progression of the scoliosis . In addition, a concern with bracing is that it may compress the rib cage and further impair the pulmonary function by lowering the vital capacity .
Spinal fusion surgery is the only effective treatment for scoliosis in SMA . For children over the age of 10 years with curves exceeding 60°, instrumentation with posterior fusion is the definitive choice . Most consider improved cosmesis, balance, and comfort in the sitting position to be the primary goals of surgery. Segmental sublaminar wiring with Harrington rods or, more recently, Luque instrumentation, has resulted in an average correction of approximately 50%, with maintenance of the correction years after surgery . Anterior surgical approaches in SMA patients can result in significant respiratory difficulty postoperatively and diminished pulmonary function over the long term. Nocturnal pulse oximetry can provide valuable information about potential postoperative ventilation need. In those patients at risk, preoperative mask-fitting and initiation of NIPPV can improve postoperative respiratory recovery . Postoperative management after scoliosis surgery includes early involvement of physical and occupational therapies, mobilization out of bed when clinically stable, pain control, ventilatory support as needed, and appropriate pulmonary toilet. As in other neuromuscular diseases, spinal arthrodesis does not significantly improve the restrictive lung disease component of SMA by increasing the FVC.
Decline in some functional activities can occur after spinal arthrodesis. The most common include decreased gross motor skills, transfer ability, self-feeding, hygiene, dressing, independent toileting, and ambulation . Spinal fixation may impair compensatory lumbar lordosis and lateral trunk sway, which are used by ambulatory patients to compensate for proximal weakness. Therefore, surgery is best deferred until ambulatory function loss is imminent or already lost. Patients and care providers should be adequately informed about possible short-term and long-term functional consequences of spinal arthrodesis.
Hip dislocations and contractures
Nonambulatory SMA patients have a high incidence of coxa valga of the proximal femur and hip subluxation. Frank hip dislocation associated with pelvic obliquity is commonly noted. Significant pain associated with hip subluxation or dislocation is rare . Operative treatment of hip subluxation or dislocation in SMA appears to be poor, with a high recurrence rate . The current consensus is for nonoperative conservative management. Contractures are problematic in SMA II and SMA III patients who have lost ambulatory function. Reductions in range of motion by greater than 20° were found among 22% to 50% of SMA II subjects . Hip, knee, and wrist contractures are the most common. Patients who have SMA perceive their elbow flexion contractures to hinder one or more daily functions and the contractures have been reported to be associated with greater discomfort . Occupational and physical therapy referral, and a daily home stretching program with caregivers, should continue to prevent formation of significant joint contractures. Serial casting for contractures can be used, but a clear and practical goal of improved range of motion should be kept in mind.
Osteopenia and fractures
Osteopenia is a common finding among SMA patients. Fractures at birth may occur in SMA . Falls may also lead to fractures in SMA after seemingly trivial trauma . In one series, fractures occurred in 15% of SMA II cases and 12% of SMA III subjects . Bone mineral density is significantly reduced in SMA, and the nature of bone mineralization at the epiphysis as compared with the diaphysis may be different. A recent study of bone density in SMA patients by dual energy x-ray absorptiometry (DEXA) scan suggests that osteopenia may be secondary to factors other than immobility . Studies now suggest a possible SMN protein role in bone remodeling . Rigid cast immobilization of fractures should be avoided to prevent a cycle of worsening osteopenia and further fractures. Calcium and vitamin D supplementation is reasonable, based on DEXA results.
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