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Jcn332702 968.978

Clinical Outcome Measures in Spinal Muscular Atrophy
Jacqueline Montes, Andrew M. Gordon, Shree Pandya, Darryl C. De Vivo and Petra Kaufmann 2009; 24; 968 originally published online Jun 9, 2009; The online version of this article can be found at: can be found at:
Journal of Child Neurology
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Jacqueline Montes, PT, MA, NCS, Andrew M. Gordon, PhD, Shree Pandya, PT, MS,Darryl C. De Vivo, MD, and Petra Kaufmann, MD, MSc Spinal muscular atrophy is one of the most devastating Acceptance of a few standardized, easily administered, and neurological diseases of childhood. Affected infants and functionally meaningful outcomes, applicable to the phenoty- children suffer from often severe muscle weakness caused pic spectrum of spinal muscular atrophy, is needed. Consen- by degeneration of lower motor neurons in the spinal cord sus is imperative to facilitate collaboration and explore the and brainstem. Identification of the causative genetic muta- ability of these measures to identify the therapeutic effect of tion in most cases has resulted in development of potential disease-modifying agents. Following is an evidence-based treatment strategies. To test these new drugs, clinically fea- review of available clinical outcome measures in spinal sible outcomes are needed. Several different assessments, validated in spinal muscular atrophy or similar disorders,are being used by national and international research groups; spinal muscular atrophy; outcome measures; however, their sensitivity to detect change is unknown.
Spinalmuscularatrophyisageneticallydetermined muscularatrophytype1,beginninginearlyinfancyandthe motor neuron disease that often presents in infancy least severe form, spinal muscular atrophy type 3, later in or childhood. The most severe form of the disease, childhood and adulthood.3 Although the phenotypic hetero- occurring in infancy and first described in the late 19th geneity is in part because of the copy number of survival century by Werdnig and Hoffman, remains the leading motor neuron 2, a disease-modifying homologue gene,4 genetic cause of infant death today.1 More than 50 years there is phenotypic variability within participants carrying later, Kugelberg and Welander described a milder form the same number of survival motor neuron 2 copies.
of the disease that presents later in childhood.
Identification of the causative genetic mutation occur- Spinal muscular atrophy affects motor neurons and the ring in most patients with spinal muscular atrophy has led motor units associated with them, causing muscle atrophy to advances in diagnosis and has facilitated research into and weakness. It is an autosomal recessive disorder geneti- the mechanisms underlying spinal muscular atrophy. Sev- cally characterized by homozygous deletion of the survival eral new drug treatments are now on the horizon and the motor neuron 1 gene located on chromosome 5q13.2 A clin- first clinical trials are ongoing. However, there are no vali- ical classification of spinal muscular atrophy, based on max- dated biomarkers, so researchers must rely on clinical imum motor function achieved, is used to help describe the benefit. Suitable outcome measures must be sensitive, different phenotypes, with the most severe form, spinal reliable, easy to interpret, and not burdensome to patients.
At a time when disease-modifying therapies are approaching the clinical community, it is imperative to Received December 22, 2008. Received revised January 10, 2009.
identify a few standardized, reliable, and functionally Accepted for publication January 11, 2009.
meaningful outcome measures. Selection should be based From the Department of Neurology, Columbia University Medical Center, on ease of administration, burden imposed on the patient, New York, (JM, DCD, PK); Department of Biobehavioral Sciences Teach-ers College, Columbia University, New York (AMG); and School of Medi- and relevance to the largest possible phenotypic spectrum.
cine and Dentistry, University of Rochester, Rochester, New York (SP).
Consensus is important to allow for collaboration. This This review was supported in part by grant support from the SMA review will summarize the available evidence for outcomes Address correspondence to: Jacqueline Montes, PT, MA, NCS, SMAClinical Research Center, Columbia University, 180 Ft Washington Ave- nue, 5th Floor, New York, NY 10032; e-mail:
Montes J, Gordon AM, Pandya S, De Vivo DC, Kaufmann P. Clinical The overall incidence of all types of spinal muscular atro- outcome measures in spinal muscular atrophy. J Child Neurol. 2009;24:968-978.
phy is 1 per 6700 live births in the United States.5 Life Clinical Outcome Measures in Spinal Muscular Atrophy / Montes et al Clinical Outcome Measures for Spinal Muscular Atrophy Type I ICF Classification18 Published Clinical Trials Survival/ventilation >16 hours/day Any age Functional motor assessment Activity limitation Test of Infant Motor Performance <4 months Functional motor assessment Activity limitation Functional motor assessment Activity limitation Note: CHOP, Children’s Hospital of Philadelphia, ICF, International Classification of Functioning, Disability and Health.
expectancy is strongly correlated with age of onset6 with the age-matched controls and found that the older children and most severe cases often not living into adulthood7 and the adolescents with spinal muscular atrophy had significantly least severe cases with survival rates not significantly differ- higher verbal IQ scores than their peers.14 ent from the normal population.8 Spinal muscular atrophyhas been divided into 3 clinical groups defined by maximumfunction achieved.3 In all spinal muscular atrophy types,the disease typically enters a stable course with little if any decline. Especially in the early-onset forms, there can be amore rapid rate of decline early in the course of the disease Recent preclinical research has identified potential thera- with a stabilization over time, which is modified by influ- peutics agents that have shown beneficial effects in animal ences such as growth and complications of weakness.9 models or in vitro.15 Clinical studies must select a few Within each clinical group exists a spectrum of disease meaningful outcome measures to evaluate a treatment severity and functional ability. Type I spinal muscular effect. These measures must be valid, reliable, sensitive atrophy includes infants diagnosed before 6 months of age to change, and assess disability at both the impairment and, by definition, never achieving the ability to sit unsup- and performance level.16 It will be difficult to assess the ported. This group could be further classified into 3 sub- sensitivity of an outcome measure for spinal muscular types.10 Patients with the most severe form are usually atrophy, a mostly stable disease, until there is an effective diagnosed in the neonatal period, suffer a paucity of move- agent that influences the disease course.
ment, and require neonatal ventilatory support. Less National and international clinical research networks severe type I infants have poor head control, difficulty collaborate in multicenter projects to reach more patients handling secretions, feeding problems, and eventually with this relatively rare disease. Ideal measures for require noninvasive respiratory support. Infants who multicenter clinical trials are easily administered, require achieve head control or can sit with support have the best minimal training and equipment, and minimize patient prognosis among patients with spinal muscular atrophy burden.17 Selecting the same outcome measures will per- type I. Recent, more proactive, clinical management is mit meta-analysis and facilitate comparable trials data that likely changing the natural course of type I patients.11 can accelerate research. To facilitate research collabora- Patients with spinal muscular atrophy type II are typi- tions and to allow for future meta-analyses between trials, cally diagnosed between 6 and 18 months and achieve a consensus on outcome measures for spinal muscular unsupported sitting at some point but never walk. Pulmon- atrophy is needed. This review aims to provide an overview ary and orthopedic complications are common in this group and often require respiratory interventions such as nonin-vasive ventilatory support and scoliosis management.12 Patients with spinal muscular atrophy type III have the mildest form of the disease and usually a normal life Available standardized functional motor exams for this age expectancy.8 Diagnosed after the age of 18 months, people group are primarily designed to track motor development with spinal muscular atrophy type III are able to walk in preterm infants. These exams often include both unaided at some point, but some loose the ability to walk.
observed and elicited movements. In spinal muscular atro- Symptom onset after 3 years of age has a greater associa- phy type I, survival has been suggested as a primary out- tion with remaining ambulatory later in life.8,13 come. However, families make a range of choices in the Spinal muscular atrophy is limited to the motor system, extent of aggressive medical care resulting in a variation affecting the motor unit from the anterior horn cell to the of outcomes for spinal muscular atrophy type I, making muscle, leaving cognitive function intact. Anecdotally, survival a less robust outcome.11 Concurrent controls are clinicians believe children with spinal muscular atrophy recommended as available historical data may falsely indi- may be brighter than their peers but there is limited evi- cate a treatment effect because of progress in supportive dence to substantiate this observation. One published study treatment. Available clinical outcomes, suitable for type compared intellectual ability in spinal muscular atrophy to I patients, are described in detail below (Table 1).
Journal of Child Neurology / Vol. 24, No. 8, August 2009 Alberta Infant Motor Scale. The Alberta Infant Motor developmental motor delay. Although spinal muscular Scale is a norm referenced measure of motor development atrophy is sometimes considered a developmental disor- for preterm infants. It is a gross motor scale assessing der,24 these measures may have a ceiling effect and possi- weight bearing, posture, and antigravity movement, vali- bly not capture the unique patterns of weakness.31-35 dated in a large sample of children from 0 to 18 months.19 Designed specifically for neuromuscular disease, the Chil- The scale has both discriminate and predictive validity as dren’s Hospital of Philadelphia Test of Strength in spinal well as excellent interrater and intrarater reliability.20 The muscular atrophy and infant test for neuromuscular dis- Alberta Infant Motor Scale has been used as a primary ease may be more sensitive but more evidence is needed.
outcome measure in infants with metabolic myopathy21,22and preterm infants23 and has been used as a standard for the development of new measures.24 A comprehensivemanual is available and test administration does not The phenotypic spectrum of spinal muscular atrophy types II and III is continuous. There is overlap in the age at dis-ease onset and in functional status as many patients withspinal muscular atrophy type III lose the ability to walk Test of Infant Motor Performance. The Test of Infant independently. The wide age range of people affected, Motor Performance is a functional scale validated in pre- from early childhood through adulthood, is an additional term infants under 4 months of age, which includes both challenge. To facilitate recruitment into trials, outcome observed and elicited movements.25 The Test of Infant measures that assess a continuum of ability are necessary Motor Performance is sensitive to age-related develop- and would avoid a floor and ceiling effect. Functional ment,25 discriminates between those at low and high risk assessments are feasible in patients 2 years and older.
for motor problems,26 and predicts delayed motor devel- Strength measures such as quantitative and manual mus- opment in preterm infants.27 The Test of Infant Motor cle testing are possible in types II and III patients 5 years Performance has excellent intrarater and interrater relia- and older. Quantifiable muscle strength testing does not bility in preterm infants.28 In spinal muscular atrophy, a directly correlate with function36 and is therefore consid- screening version of the Test of Infant Motor Performance ered less clinically meaningful. Clinical outcome mea- also demonstrated excellent interrater and test-retest sures used in spinal muscular atrophy types II and III reliability.29 However, to date, no published clinical trial but not specifically designed for the disease as well as used the Test of Infant Motor Performance or the screen- disease-specific assessments are outlined in detail below ing version of the Test of Infant Motor Performance as a primary outcome measure in spinal muscular atrophy.
Gross Motor Function Measure. The Gross Motor Func- Children’s Hospital of Philadelphia (CHOP) Test of tion Measure, developed as an outcome measure for Strength in spinal muscular atrophy and Infant Test for children with cerebral palsy,45-47 is a comprehensive func- Neuromuscular Disease. Children’s Hospital of Philadel- tional exam that was shown to be a valid and reliable phia Test of Strength in spinal muscular atrophy and measure in patients with spinal muscular atrophy.48-50 Infant Test for Neuromuscular Disease were developed The Gross Motor Function Measure contains 88 items specifically for weak infants with neuromuscular disease in 5 dimensions: (a) lying and rolling, (b) sitting, (c) crawling including spinal muscular atrophy. The tests include and kneeling, (d) standing, and (e) walking, running, and assessments of neck, trunk, proximal and distal limb jumping and takes approximately 45 to 60 minutes to com- strength using both observational and elicited movements.
plete. This hierarchical organization permits patients to Initially, the Children’s Hospital of Philadelphia Test of progress through each dimension according to their ability Strength in spinal muscular atrophy was compared to the Test of Infant Motor Performance in 7 patients with spinal Although some items and postures are not possible in muscular atrophy and then later revised and called the the setting of contractures and scoliosis, the Gross Motor Children’s Hospital of Philadelphia Infant Test For Neuro- Function Measure discriminates between walkers and muscular Disease, which includes the initial assessments nonwalkers and correlates with quantitative muscle plus 4 items from the Test of Infant Motor Performance.
strength in patients with spinal muscular atrophy.48 The Excellent interrater and intrarater reliability were shown Gross Motor Function Measure has high interrater relia- in a small sample of participants with spinal muscular atro- bility49 and is a feasible outcome measure in clinical trials phy.30 Instructional videos in test administration and writ- in spinal muscular atrophy.51,52 A revised version with 22 ten procedural and scoring directions are available.
less items was later developed, removing items that did not The Alberta Infant Motor Scale and Test of Infant fit the construct using a standardized statistical model.53 A Motor Performance both assess function at the perfor- detailed published manual for the Gross Motor Function mance level and have demonstrated sensitivity to Measure is available including video instruction.
Clinical Outcome Measures in Spinal Muscular Atrophy / Montes et al Clinical Outcome Measures for Spinal Muscular Atrophy Type II/III gabapentin,44 L-carnitine, andvalproic acid41 Note: ICF, International Classification of Functioning, Disability and Health.
Hammersmith Functional Motor Scale. The Hammersmith reliability in the nonambulant patients but lower reliability Functional Motor Scale, devised specifically for use in in the ambulatory cohort because of significant ceiling patients with spinal muscular atrophy type II and nonam- bulatory type III patients, is a 20-item functional assess- The Hammersmith Functional Motor Scale has also ment arranged in an order of progressive difficulty.54 been augmented by 13 relevant items from the Gross This disease-specific scale was designed for ease of use Motor Function Measure to eliminate the ceiling effect and minimal patient burden. Good interrater reliability of the original scale with patients having ambulant spinal has been demonstrated.54,55 The Hammersmith Func- muscular atrophy.59 The items chosen from the Gross tional Motor Scale is sensitive to change resulting from Motor Function Measure for the Expanded Hammersmith intercurrent illness or surgery,55 correlates with biomar- Functional Motor Scale were deemed statistically most kers of disease severity,56 and has been used in single cen- sensitive, without a ceiling effect, and most clinically ter, phase I and multicenter center, phase II clinical trials meaningful by expert consensus. The Expanded Hammer- in patients with spinal muscular atrophy type II.38-40 smith Functional Motor Scale shows good test-retest relia- To further enhance the scale’s usability in multicenter bility, is highly correlated with the Gross Motor Function collaborative settings, the scale was modified to include Measure, and discriminates between walkers and non- concrete operational definitions and instructions for scor- walkers.59 It correlates with other clinical and phy- ing.57 Additionally, the items on the scale were reordered siological measures such as forced vital capacity and to minimize position changes and associated fatigue, for- isometric muscle strength assessed using handheld dyna- going the original functional hierarchy of activities. High mometry as well as survival motor neuron 2 copy num- intrarater reliability in live patients and interrater reliabil- ber.60 The scale retained its original properties of ease of ity from videotaped assessments were achieved in nonam- use and minimal patient burden requiring only standard bulatory type II and III patients from 2 to 12 years of age.
equipment and taking less than 15 minutes on average.
They also showed good test-retest reliability withno significant difference in scores within 6 months. In amulticenter, phase II clinical trial, the Modified Hammer- Motor Function Measure. The Motor Function Measure smith Functional Motor Scale showed excellent intrarater was developed for people with neuromuscular disease, Journal of Child Neurology / Vol. 24, No. 8, August 2009 including spinal muscular atrophy, to assess motor func- clinical trial of gabapentin in adult patients with spinal tion. It is made up of 32 items organized in 3 domains; muscular atrophy42 and is currently an outcome in a trial standing position and transfers, axial and proximal motor assessing valproic acid in ambulant, adult patients with function, and distal motor function. Test items include a continuum of functional ability, ranging from simplemotor skills in a supine position to a 10-m run. Also Egen Klassifikation Scale. The Egen Klassifikation Scale included in the Motor Function Measure is a fine motor was developed to assess motor function in patients with later stage Duchenne muscular dystrophy and nonambu- The Motor Function Measure was validated in a large lant spinal muscular atrophy.71 This interview-based sample of neuromuscular patients, aged 6 to 62 years, less questionnaire, designed for older children, teens, and than 12% of which were patients with spinal muscular adults, has 10 questions encompassing performance of atrophy.61 Interrater and intrarater reliability was excel- functional tasks scored on a 4-point ordinal scale. Activi- lent for the total score and subscores of the 3 domains.
ties of daily living assessments such as wheelchair use, High correlations were found with the Functional Inde- ability to transfer, arm function and feeding, turning in pendence Measure as well as specific scales that assess bed, coughing, speaking, and health-related quality of life only lower and upper extremity function. It takes an aver- are included in the Egen Klassifikation Scale but not all age of 36 minutes to complete and has been shown to be items are relevant to spinal muscular atrophy conditions.
sensitive to change in Duchenne muscular dystrophy.62 Scores on the Egen Klassifikation Scale did not correlatewith or change similarly over time with manual muscle Wee Functional Independence Measure. The Wee Func- testing and forced vital capacity in patients with spinal tional Independence Measure is an evaluator adminis- muscular atrophy.72 The Egen Klassifikation Scale has a tered, questionnaire designed to assess disability, based user’s manual with detailed directions for scoring. A on the framework proposed by the World Health Organi- revised version, designed specifically for patients of any zation,16 and validated for children between 6 months and age with spinal muscular atrophy, is currently being 6 years with developmental disabilities63 and Down Syndrome.64 It is organized in 3 main domains: self care,mobility, and cognition, and it is scored on a 7-point scale Quantitative Muscle Testing. Quantitative Muscle Testing ranging from total assistance to complete independence.
is used to assess strength using maximal voluntary iso- In a cross-sectional study of patients recruited from a metric contraction in neuromuscular disease and has been spinal muscular atrophy patient registry, the Wee Func- used as a primary outcome measure in adult motor neuron tional Independence Measure was able to discern between disease trials.73-75 It was found to be more sensitive than type I and type II participants and weak and strong type III manual muscle testing in Amyotrophic Lateral Sclerosis, patients; however, it was unable to distinguish type II from but because it requires special equipment, extensive type III patients as they often overlap in functional and evaluator training, and can be burdensome to patients, it disability level.65 As expected, all patients with spinal mus- may no longer be considered an ideal outcome for multi- cular atrophy performed best in the cognition domain.
However, because the scale is designed for children up Good intrarater and interrater reliability of quantita- to 6 years of age, this assessment has limited applicability tive muscle testing has been demonstrated in children to patients with spinal muscular atrophy type II and III.
with Duchenne muscular dystrophy and spinal muscularatrophy50,77 but did not correlate with functional changes Spinal Muscular Atrophy Functional Rating Scale. The in spinal muscular atrophy.78,79 Because patient coopera- Spinal Muscular Atrophy Functional Rating Scale is an tion is essential, the test is not applicable to young evaluator-administered questionnaire adapted from the children. In an adult spinal muscular atrophy clinical trial, Amyotrophic Lateral Sclerosis Functional Rating Scale.66 where quantitative muscle testing was the primary out- Modeled after already validated scales in other adult come measure, some patients had to be excluded because neurodegenerative diseases,67 the Amyotrophic Lateral of weakness sufficient to preclude registering strength by Sclerosis Functional Rating Scale is used as a primary out- come measure in phases II68,69 and III70 clinical trials in Handheld dynamometry is another method of quanti- fying strength. The examiner fixes a handheld device The Spinal Muscular Atrophy Functional Rating Scale against a limb or body part while the patient performs a measures 4 components of physical functioning: bulbar maximal voluntary isometric contraction. Similar to quan- function, arm function and ability to perform activities titative muscle testing, it is not practical in children under of daily living, leg function, and respiratory function. The 5 years old, and requires evaluator training, but is less scale was used as a secondary outcome measure in a Clinical Outcome Measures in Spinal Muscular Atrophy / Montes et al Clinical Outcome Measures for Ambulant Patients With Spinal Muscular Atrophy Note: ICF, International Classification of Functioning, Disability and Health.
In spinal muscular atrophy, good interrater reliability gait. In clinical trials, tests that quantify functional and test-retest reproducibility has been shown in all mobility are commonly used in similar pediatric (PTC muscle groups except ankle dorsiflexors.36 In a study of 124 Duchenne muscular dystrophy) and adult82 neuro- gabapentin in spinal muscular atrophy, leg megascores from handheld dynamometry improved significantly but The Six-Minute Walk Test is an objective evaluation of this improvement did not correlate with functional assess- functional exercise capacity, which measures the distance ments.44 In a separate observational study, handheld a person can walk quickly in 6 minutes.83 It is a global dynamometry scores correlated with timed function tests measure of multiple body systems including cardiopul- and could discern between walkers and nonwalkers.80 monary, vascular, and neuromuscular systems. It is easily Performance-based measures such as the Gross Motor administered and requires no special equipment or train- Function Measure, Hammersmith Functional Motor Scale, ing. Of functional measures used in cardiopulmonary Expanded Hammersmith Functional Motor Scale, Motor care, the Six-Minute Walk Test is best tolerated, most Function Measure, and Egen Klassifikation Scale assess representative, and meaningful of a person’s ability to functionally meaningful abilities that one would want to perform activities of daily living because the intensity of affect in a treatment trial. Outcome measures designed the test is self-selected.84 Although most commonly used to evaluate impairment such as manual muscle testing and in cardiorespiratory disorders, the Six-Minute Walk Test quantitative muscle testing may detect change that does has been used to assess function in neurological disorders not necessarily correlate with noticeable changes for the such as Parkinson disease,85 stroke,86,87 cerebral palsy,88 patient. For observational studies, or studies that aim to and Kennedy disease.89 Currently, the Six-Minute Walk describe the natural course of spinal muscular atrophy, Test is the primary outcome measure in an international impairment based measures are useful. Treatment trial clinical trial in Duchenne muscular dystrophy and is outcomes must demonstrate clinically meaningful differ- currently being assessed in a spinal muscular atrophy ences to evaluate the benefit of the intervention. The Spinal Muscular Atrophy Functional Rating Scale and Gait observation and descriptive gait assessments are Wee Functional Independence Measure, also function- routinely part of a neuromuscular evaluation and are the based evaluations, and the Egen Klassifikation Scale are areas where improvements or deteriorations are noted easily administered but do not encompass a large age during clinic visits. Timed walking is a quantitative mea- range of patients with spinal muscular atrophy. The Gross sure used to evaluate mobility in similar pediatric and Motor Function Measure, although shown to be reliable adult neurological conditions. In clinical management, in spinal muscular atrophy, is not disease specific and can timed walking tests predict falls in neurological disorders be burdensome to patients. The Expanded Hammersmith other than spinal muscular atrophy,82,90 and fall risk and Functional Motor Scale carries little patient burden and assessments are part of recently defined practice guide- assesses a large spectrum of disease severity without a In clinical trials, objective gait assessments are easy to administer and clinically relevant but to date in spinalmuscular atrophy are limited. As an adjunct to gross motor function measures, quantifying walking ability may be Proximal muscle weakness, common in spinal muscular more sensitive to changes in the ambulatory cohort of atrophy, affects a person’s ability to stand, rise from a patients with spinal muscular atrophy. A pediatric seated position, walk, and negotiate stairs. Limited endur- neuromuscular clinical network in the United Kingdom ance and fatigue may also impair functional mobility and compiled a battery of timed functional tests including time performance in activities of daily living but measures to rise from the floor, ascend and descend stairs, jump, sensitive enough to quantify fatigue have not been hop, and run, but no published data are available. Assess- identified.81 In clinical practice, neurologists and rehabi- ments used in ambulatory patients in spinal muscular litation therapists routinely assess functional mobility and atrophy are described below (Table 3).
Journal of Child Neurology / Vol. 24, No. 8, August 2009 10-m walk test. The 10-m walk test quantifies the time it phrenic nerve108,109 have been shown to correlate with takes to walk 10 m as fast as possible. It has been shown nonvolitional tests and forced vital capacity in neuromus- to be a valid and reliable measure in assessing walking cular disease including spinal muscular atrophy.110 ability in spinal cord injury92,93 and sensitive to change Assessing the ventilatory response to carbon dioxide is a in Duchenne muscular dystrophy.94 In spinal muscular nonvolitional assessment of respiratory function, which atrophy, the 10-m walk test correlated with knee extensor distinguishes between ventilated and nonventilated and flexor strength and discriminated between young and children with neuromuscular disease111 and predicts noc- turnal hypercapnia in Duchenne muscular dystrophy.112These alternatives to forced vital capacity are useful Time to ascend/descend stairs–Time to rise from floor.
clinical tools but to date, their utility and responsiveness in clinical trials have not been explored.
descending stairs and rising from the floor are used in theclinical management of patients with Duchenne musculardystrophy to assess functional leg strength. In addition to the quantitative assessment, these tests allow qualitativeassessment of mobility. Similar to the 10-m walk test, time Evaluating quality of life is important if a change had an to ascend/descend stairs and rise from floor correlated association with a change detected by a clinical or biologi- with leg strength in patients with spinal muscular cal measure. Therefore, assessments of quality of life should be included as a secondary outcome measure inclinical trials.113 Additionally, the effects of the disease on the family’s as well as the individual’s burden shouldbe quantified. In families with chronically ill children, the Pulmonary function tests, such as forced vital capacity, Pediatric Evaluation of Disability Inventory, Parts II and measure respiratory muscle strength and are commonly III has been validated as an objective measure of caregiver used to monitor pulmonary status and determine clinical burden,114,115 and the Impact on Family Scale offers a respiratory interventions in neuromuscular diseases95-97 measure of perceived burden.116,117 Standardized instruc- including spinal muscular atrophy.12 Typically, children tions for administration and scoring are available for the must be at least 5 years old because cooperation is essen- Pediatric Evaluation of Disability Inventory but neither tial in the performance of this effort dependent test.
have been used in spinal muscular atrophy.
Forced vital capacity scores are expressed in percentage To date, no published spinal muscular atrophy clinical predicted determined by height and age. Contractures and trial has included a validated quality of life or caregiver scoliosis, common in spinal muscular atrophy, make accu- burden measure as an outcome. However, a Likert-type rate height measurements difficult and may influence the survey has been used to compare caregiver and clinician test results and deem them less reliable.
perception of quality of life in patients with spinal muscu- Despite its limitations, forced vital capacity is a com- lar atrophy type I.118 In adult neuromuscular disease, mon secondary outcome measure in spinal muscular caregiver burden measures were highly correlated with atrophy clinical trials39,42,44 and good interrater reliability function.119,120 Assessments used to assess quality of life can be achieved.50 Forced vital capacity can discriminate in spinal muscular atrophy are outlined below.
between ambulant and nonambulatory participants,80,98,99but does not change significantly over time100 and may not PedsQL Pediatric Quality of Life Inventory be a sensitive indicator of the need for mechanical ventila-tion in spinal muscular atrophy.101,102 The PedsQL Pediatric Quality of Life Inventory instru- Alternative volitional pulmonary function tests that are ment, a proprietary test, to measure quality of life, is a simple and unlike forced vital capacity, do not require validated measure for use with healthy school and aptitude and coordination, are available. Maximal sniff community populations as well as with pediatric popu- pressure103,104 is a simple maneuver used to assess inspira- lations with acute and chronic health conditions.121,122 tory muscle strength. Calculated by performing repetitive, The validity of the PedsQL Pediatric Quality of Life short, maximal sniffs, maximal sniff pressure is the best pre- Inventory was demonstrated through known group com- dictor respiratory failure in adult motor neuron disease.105 parisons and correlations with other measures of disease Additionally, cough peak cough flow and peak expiratory burden. Age-specific forms for children 5 to 18 years old, flow are clinically meaningful and feasible measures of parent/caregiver forms for children 2 to 18 years old as respiratory muscle strength in adults and children with well as a neuromuscular disease-specific module are available. In spinal muscular atrophy, both the generic Other respiratory function tests such as measuring gas- module49 and neuromuscular module50 have been shown tric cough pressure107 and magnetic stimulation of the Clinical Outcome Measures in Spinal Muscular Atrophy / Montes et al 5. Burd L, Short SK, Martsolf JT, Nelson RA. Prevalence of type I spinal muscular atrophy in North Dakota. Am J Med Genet.
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