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The natural progression of spinal muscular atrophy (SMA) can be assessed by age- and ability-appropriate motor function scales* and electrophysiological measurement of motor-unit health1-3

A number of motor function scales have been developed that have proven useful in a range of settings, including3-5:

  • Assessment of the natural history of spinal muscular atrophy in clinical studies
  • Establishment of a baseline in order to observe potential functional motor benefits of investigational therapeutic agents in clinical trials
  • Documentation of function for insurance purposes, if required6


*
This is not a comprehensive list of motor function scales.

MEASURE: MOTOR MILESTONES
INFANTS (2-24 months of age)

The Hammersmith Infant Neurological Examination (HINE)  is designed to be a simple and scorable method for evaluating infants from 2 months to 2 years of age. The HINE includes 3 sections containing 26 items that assess different aspects of neurologic function7,8:

  • Section 1: Neurologic examination assessing cranial nerve function, posture, movements, tone, reflexes, and reactions
  • Section 2: Developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking)
  • Section 3: Behavioral assessment (state of consciousness, emotional state, social orientation)

HINE Section 2 (motor milestones) includes 8 items scored on a 5-point scale with 0 as the absence of activity, and a maximum score of 4 points9

  • Some items have a maximum score of 2 or 3 points (see table below)

HINE Section 2 scoring chart illustrating the motor developmental milestones9

HINE Section 2 motor milestones achieved in a study of 249 infants without SMA7

Age at achievement

% reaching milestone

Motor milestone

Age at achievement

12 months

% reaching milestone

90%

Motor milestone

Able to maintain head control
Turn in sitting position (pivot)
Form a pincer grasp
Play with feet
Roll from prone to supine (and back)
Crawl on hands and knees

79%

Able to stand unaided

51%

Walk

Age at achievement

18 months

% reaching milestone

90%

Motor milestone

Stand/walk unaided

Motor milestone achievements are rare in infantile-onset (Type I) SMA

In a retrospective study of individuals (n=33) with infantile-onset (Type I) SMA who were 1 to 8 months of age at the onset of symptoms, none of the more severely affected infants achieved a major milestone such as rolling over, independent sitting, crawling, standing, or walking.

Motor milestones are rarely acquired in infantile-onset SMA. Infants with the most severe symptoms of SMA (early onset) may show a score of 0 on all 8 items of the HINE Section 2.9

MEASURE: MOTOR FUNCTION
INFANTS AND CHILDREN WITH SMA
 ( ≈4 months to >4 years of age)

The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) may be used to evaluate the motor skills of infants with SMA10,11:

  • CHOP INTEND was developed by evaluating infants (n=26) with Type I SMA, mean age 11.5 months (1.4-37.9 months), and has been shown to be valid for the assessment of children ranging in age from 3.8 months to over 4 years
  • Includes 16 items used to assess motor skills. Each item is graded on a scale of 0-412:
    0=No response
    4=Complete response
  • Total score ranges from 0-64
symptoms-spinal-muscular-atrophy symptoms-spinal-muscular-atrophy

Infants with SMA may score significantly lower on CHOP INTEND than unaffected infants

Kolb et al conducted a prospective, longitudinal natural history study of infants with genetically confirmed SMA that compared their CHOP INTEND scores with those of healthy infants. Age of onset of SMA symptoms ranged from <1 month to 4 to 5 months.5

Patient type

CHOP INTEND score

(average)

Age at enrollment

(average)

Age of SMA onset

Patient type

Healthy infants

(n=14)

CHOP INTEND score (average)

50.1 points
(SD=10.2, range = 32-62, P < 0.01)

Age at enrollment (average)

3.3 months

Patient type

Infants with SMA (n=16)


2 SMN2 copies

CHOP INTEND score (average)

20.2 points
(SD=7.4, range = 10-33)

Age at enrollment (average)

3.7 months

Age of SMA onset

<1 month (6/16)
1-2 months (5/16)
2-3 months (3/16)
4-5 months (1/16)

A CHOP INTEND score >40 is rarely observed for symptomatic individuals with infantile-onset

(Type I) SMA who have 2 SMN2 gene copies.13

MEASURE: MOTOR FUNCTION
LATER-ONSET (Type II and Type III) SMA

The Hammersmith Functional Motor Scale—Expanded (HFMSE) is a measure that has been used in several clinical trials to evaluate the motor function of individuals with later-onset (Type II and Type III) spinal muscular atrophy.

The HFMSE includes 13 clinically relevant items from the Gross Motor Function Measure (GMFM) related to lying/rolling, crawling, crawling/kneeling, standing, and walking/running/jumping4,14,15:

  • Exam has 33 items that are scored on a scale of 0-2
  • Total score ranges from 0 to 66, with lower scores indicating poorer motor function
  • Patient fatigue is an important consideration; the HFMSE can be conducted in 12 minutes (mean time)
Hammersmith Functional Motor Scale
Child depicted in graphic above is >2 years of age.

Individuals with later-onset (Type II and Type III) SMA may demonstrate progressive decline in HFMSE scores.4

In one natural history study of SMA, individuals with later-onset SMA declined by 0.56 points (mean) in HFMSE score over 12 months.4 However, in another study of individuals (n=79) with later-onset SMA, motor function appeared to decline in a nonlinear fashion. The mean change in HFMSE scores at 36 months was -1.71 (P=0.01). During the study16:

  • 2 patients with 2 copies of the SMN2 gene lost the ability to sit
  • 1 patient with 3 copies of the SMN2 gene lost the ability to sit
  • 5 patients with 3 copies of the SMN2 gene lost the ability to walk

The Upper Limb Module (ULM) was developed to assess aspects of function related to everyday life in nonambulatory individuals with SMA. These skills might only be partly captured by the HFMSE in weaker patients.17

The ULM has been validated in the assessment of individuals with SMA (aged 30 months-27 years), including nonambulatory young and weaker children.18

The module includes 9 tasks that can be performed in a brief amount of time (5-10 minutes) using common equipment (eg, drawing a continuous line with a pencil, picking up a coin and placing in a cup, pressing a button to turn on a lamp, lifting a beverage can to drink, removing the lid from a plastic container, lifting a weight and moving it from circle to circle on pre-printed paper). The maximum score possible is 18.18

labeled items

ULM scores may remain relatively stable over a 12-month period.17

A study was conducted with nonambulatory individuals (n=74) with later-onset SMA (Type II and Type III); age range was 3.5 to 29 years (mean 10.22, SD 6.15).17 The mean change in ULM at 12 months was 0.04 points (SD 1.17) from baseline (mean 10.23, SD 4.81). Most of the ≥2-point changes in ULM occurred in children who were <5 years of age.17

  • 79.7% of the patients had ±1 point change
  • 2.7% of the patients had >2-point gain in ULM (age <5 years)
  • 2.7% of the patients had <2-point loss in ULM (age <5 years)

Changes greater than ±1-2 points in the ULM may be considered clinically relevant.17

Revised Upper Limb Module (RULM): The ULM was revised to address a ceiling effect and make the test useful in a wider population of individuals with SMA. The RULM consists of a total of 20 items for a maximum score of 37. Activities are graded from 0 to 2.19

The 6-Minute Walk Test (6MWT) is an objective evaluation of exercise capacity that may be used to assess function in ambulatory individuals with later-onset spinal muscular atrophy20

  • Participants are instructed to walk as fast as possible along a 25-meter course on a flat linoleum surface, turn around a marker cone, and return in the opposite direction20
  • The loop is repeated as often as possible for 6 minutes20
  • The test course has a start line, with horizontal lines placed every 1 meter. Running or jogging is not permitted20
6MWT-illustration
  • In a study of ambulatory individuals (n=18) with later-onset SMA (4-48 years of age) the mean distance walked in 6 minutes was 289 meters (948 feet)20
  • 6MWT distance is significantly associated with HFMSE score (r=0.83, P<0.0001)20

Progressive decline in 6MWT may occur in later-onset SMA.21

One study of ambulatory individuals with later-onset (Type III) SMA demonstrated a reduction
of 1.5 meters (5 feet, mean) per year from their baseline on the 6MWT.21

In spinal muscular atrophy, electrophysiologic measurements may be used to assess the health of motor neurons22  

  • Compound muscle action potential (CMAP) response is a measure of the electrophysiologic output from a specific muscle or muscle group following stimulation of the innervating nerve23
  • Motor unit number estimation (MUNE) is a method that estimates the number of motor units involved in the contraction of a specific muscle24

Motor units include motor neurons and the muscle fibers they innervate.25

CMAP may decrease rapidly in some individuals with spinal muscular atrophy22

Trend lines represent CMAP declines in individuals with spinal muscular atrophy. The shaded area indicates estimated normal values.

Adapted from Swoboda et al.22

In a clinical study, the average CMAP peak amplitude for infants with SMA was 1.4 mV (SD = 2.2, n = 25) compared with 5.5 mV in healthy infants (SD = 2.0, n = 27; P < 0.01).5 

Natural history studies among patients with Type I SMA demonstrate that CMAP amplitude is abnormally low and does not improve after symptom onset26

Green dots indicate children who were identified presymptomatically via genetic testing because a sibling was previously diagnosed with SMA.

Adapted from Swoboda et al.22    

Early diagnosis may be an important consideration in the management of spinal muscular atrophy26

The pattern of motor neuron loss seen in SMA suggests that an intervention for infantile-onset (Type I) SMA should be administered as early as possible, including in the presymptomatic period before significant loss of motor neurons.26

REFERENCES 

1. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014;83(9):810-817. 2. Montes J, Gordon AM, Pandya S, De Vivo DC, Kaufmann P. Clinical outcome measures in spinal muscular atrophy. J Child Neurol. 2009;24(8):968-978. 3. Darras BT, Royden Jones H Jr, Ryan MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. 2nd ed. London, UK: Elsevier; 2015. 4. Mercuri E, Finkel R, Montes J, et al. Patterns of disease progression in type 2 and 3 SMA: implications for clinical trials. Neuromuscul Disord. 2016;26(2):123-131. 5. Kolb SJ, Coffey CS, Yankey JW, et al; the NeuroNEXT Clinical Trial Network and on behalf of the NN101 SMA Biomarker Investigators. Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann Clin Transl Neurol. 2016;3(2):132-145. 6. Data on file. Biogen Inc, Cambridge, MA.   7. Haataja L, Mercuri E, Regev R. Optimality score for the neurologic examination of the infant at 12 and 18 months of age. J Pediatr. 1999;135(2 pt 1):153-161. 8. Romeo DM, Ricci D, Brogna C, Mercuri E. Use of the Hammersmith Infant Neurological Examination in infants with cerebral palsy: a critical review of the literature. Dev Med Child Neurol. 2016;58(3):240-245. 9. De Sanctis R, Coratti G, Pasternak A, et al. Developmental milestones in type I spinal muscular atrophy. Neuromuscul Disord. 2016;26(11):754-759. 10. Glanzman AM, Mazzone E, Main M, et al. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord. 2010;20(3):155-161. 11. Glanzman AM, McDermott MP, Montes J. Validation of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther. 2011;23(4):322-326. 12. Spinal Muscular Atrophy Clinical Research Center. CHOP INTEND for SMA Type I score sheet. http://columbiasma.org/links.html. Updated March 14, 2013. Accessed April 26, 2016. 13. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016; 388(10063):3017-3026. 14. Glanzman AM, O’Hagen JM, McDermott MP, et al; the Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy (PNCR), and the Muscle Study Group (MSG). Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III. J Child Neurol. 2011;26(12):1499-1507. 15. The Pediatric Neuromuscular Clinical Research Network for SMA. Expanded Hammersmith Functional Motor Scale for SMA (HFMSE). http://columbiasma.org/links.html. March 7, 2009. Accessed April 25, 2016. 16. Kaufmann P, McDermott MP, Darras BT, et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. 2012;79(18):1889-1897. 17. Sivo S, Mazzone E, De Sanctis, et al. Upper limb module in non-ambulant patients with spinal muscular atrophy: 12 month changes. Neuromuscul Disord. 2015;25(3):212-215. 18. Mazzone E, Bianco F, Martinelli D, et al. Assessing upper limb function in nonambulant SMA patients: development of a new module. Neuromuscul Disord. 2011;21(6):406-412. 19. Mazzone ES, Mayhew A, Montes J, et al. Revised Upper Limb Module for spinal muscular atrophy: development of a new module. Muscle Nerve. 2016. doi:10.1002/mus.25430. 20. Montes J, McDermott MP, Martens WB, et al. Six-minute walk test demonstrates motor fatigue in spinal muscular atrophy. Neurology. 2010;74(10):833-838. 21. Mazzone E, Bianco F, Main M, et al. Six minute walk test in type III spinal muscular atrophy: a 12 month longitudinal study. Neuromuscul Disord. 2013;23(8):624-628. 22. Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol. 2005;57(5):704-712. 23. Arnold WD, Sheth KA, Wier CG, et al. Electrophysiological motor unit number estimation (MUNE) measuring compound muscle action potential (CMAP) in mouse hindlimb muscles. J Vis Exp. 2015;103:1-8. 24. Bromberg MB, Swoboda KJ. Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve. 2002;25(3):445-447. 25. Monti RJ, Roy RR, Edgerton VR. Role of motor unit structure in defining function. Muscle Nerve. 2001;1;24(7):848-866. 26. Finkel RS. Electrophysiological and motor function scale association in a pre-symptomatic infant with spinal muscular atrophy type I. Neuromuscul Disord. 2013;23(2):112-115.

How might the basic function and progression of an individual with SMA determine daily activities and lifestyle?

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