Functional outcome measurement in SMA

Allan Glanzman PT,DPT,PCS Neuromuscular Clinic

The Children’s Hospital of Philadelphia

How is development unique in SMA • Cross sectional vs. longitudinal understanding of SMA development

• Natural history characterized • skill gain • Plateau or decline • Stabilization and slow decline measureable over years • Variability

• Similarities to the cross section • Following a loss of skills

• Type III following loss of ambulation-similarities and differences with type II • Type II and loss of rolling/sitting

• Comorbidity –contracture, scoliosis, dislocation, fracture, weight • Impact of medical intervention

• How is this different in the context of a treatment • Scoliosis surgery • G-tube and nutritional management

• Over weight and motor impact • Under weight

Outcome measurement

Developmental • Norm reference

• Based on cross sectional sample of typical development

• Developmental sequence • Sensitivity

• Dependent on Item coverage based on typical progression • Variability of the population over the age range

• Mean and std. dev. at each age

Norm referenced measures

• Limitations – Floor effect – Item set selection methodology based on normal development

• Bayley gross motor – Thrusts legs, thrusts arms, controls head upright (intermittent->3sec.) – Prone crawling movement, turns head

• Peabody – Head control prone, thrusting arms/kicking, rolling to side

• TIMP/TIMPSI – Many appropriate items – designed for premature infants up to 4 months – Tolerance issues

Outcome measures Disease specific • Follows the unique dev. sequence

• SMA -prone progression vs. sitting & standing

• Floor and ceiling • Accommodates disease specific expectation • Allows for sensitivity at the extremes or beyond typical dev.

• Sensitivity dependent • Age • Severity • Stage in the disease

• Comorbidity • Fusion/scoliosis

• Contracture

• Pulmonary tolerance • Prone, sitting

Type I - CHOP INTEND

• Constructed to avoid poor prone tolerance • Ordered with least tolerated items last

– Avoid position change to improve tolerance

Type I - CHOP INTEND

• Correlates with age – r= −0.51; P = .007 (n = 27)

• Differentiates based on BiPAP – Mean 15 vs 31 p>.0001 (n=27)

Finkel;2014

Point Decline Per Year • Type IB -1.83 pts/year

– 95% CI -3.35 to -0.32, p=0.02

• Type IC -0.83 pts/year – 95% CI -2.18 to 0.52, p=0.22

• All type I -1.27 pts/year – 95% CI -2.33 to -0.21, p=0.02

Longitudinal Data •Within 3 months of symptom onset (“recent”) •More than 3 months after symptom onset (“chronic”)

Hammersmith motor milestones

• Used in premi and newborn assessment

• Each milestone formatted as a 4 or 5 point stream – Head control – Sitting – Grasp – Kicking – Rolling – Crawling – Standing – Walking

Haataja;1999

World health organization

• 6 motor milestones • Typical development • Spans first 18 months • Development

– Longitudinally assessed – Parent and evaluator

Wijnhoven;2006

Development of motor milestones

• Onset of motor milestones of walking and sitting

• 90% of SMA II sitting by 1yr – 27% learn beyond 9 months

• 92% of SMA IIIa walking by 2yr – 16% learn beyond 18 months

Rudnik-Schoneborn; Eur Neurol 2001

Hammersmith Functional Motor Scale For SMA

• Initially developed as a clinical scale for type II • Expanded with a module to accommodate type III

– Items from the GMFM – Items added, easier than sitting and harder than walking

• Kicking in supine • Kneeling and pulling to stand • Jumping and Steps

– Core of sitting, rolling, prone progression, and standing

Sitting &reaching 1-4

Lifting legs & Rolling 5-9 & 21&22

Transitioning to and from sitting 10&14

Stepping 20

Standing 19

Standing supported 18

Crawling 15&16

Prone progression 11-13

Steps 30-33

Jumping & squatting 28&2

Kneeling & pulling to/from stand 23-27

Hammersmith motor

milestones

Expanded Hammersmith Functional Motor Scale

HFMSE

Error bars indicate 1 SEM. Mean changes are plotted for spinal muscular atrophy (SMA) 2 and SMA 3 combined, SMA 2 only, and SMA 3 only. Kaufmann;2012

Fig. 4. Average 12-month change of the Hammersmith scale according to age classes and ambulation. Mercuri;2016

Upper limb module

• Important functional domain for type II

• Type II function not fully evaluated by gross motor

• Upper extremity function differentiate between the weaker type II

Mazzone;2011

HFMSE and the ULS

• The HFMSE and ULS – 80% +/-1 on both over 12mo.

• Longitudinal agreement

– Cross sectional correlation

12-month HFMSE changes in non-ambulant SMA patients, subdivided according to 12-month ULM changes. Note that the 79.7% of the patients had 12 month changes in the ULM ± 1 from baseline and that the great majority had also ±1 changes on the HFMSE.

Sivo;2015

Upper limb module Correlation of ULM and HFMSE scores

Sivo;2015

r=0.66

Mazzone;2011

Six min walk

• Ambulatory function • Measure of fatigue • Well accepted from regulatory

perspective

Montes;2010 Young;2014

SMA-Functional Composite

• 126 SMA type II & III • International collaboration • Leverage the strengths of

– Upper limb – HFMSE – 6-min-walk

SMA-FC

• Combines ULM, HFMSE, 6-min-walk • 82% of variability of components • Nearly equally weighted. SMA-FC=(0.54 × ULM Z-score) + (0.62 × HFMSE Z-score) + (0.57 × 6MWT Z-score).

Questions for the future

• In the face of a changing natural history – What will the functional variability be among the population – Will our measures be adequate or need to be adapted – Will norm referenced measures better reflect the natural history

Comments?