Enrico Bertini, MDBambino Gesu’Children’s Research Hospital Rome, Italy

Barcelona, May 21 2005V Jornada Medico InformativaAtrofia Muscular Espinal (AME)

Mesa redonda: Futuro de la investigacion y tratamiento de AME

Four types of SMA but functionally 3 types of SMArepresenting 3 different disability phenotypes

Age at onset Maximum function achieved

different severity progression disability

different natural history standard care outcome measures (trials)

TYPE I•age of onset < 6 months •children never acquire the ability to sit unsupported•die of respiratory problems by the age of 2 years TYPE II•age of onset between 6 and 18 months •children are able to sit unsupported but not to walk

TYPE III•age of onset > 18 months•patients are able to walk independently

SMA

Crawford & Pardo Neurobiol Dis, 1996;3:97–110

Russman, et al., Neurology. 1996 Oct;47(4):973-6. Zerres et al., J Neurol Sci 146(1 997) 67-7

Still sitting Age at death

Clinical Trials

Type of SMA (different disability phenotypes)

Natural history (information for inclusion criteria)

Outcome measures (primary and secondary)

Standard of Care (best management of patients, and control of confounding factors)

Four classes of factors influence strength and function

1) Amount of SMN reduction

2) Other genetic factors

3) Growth, age, motor unit remodelling

4) Systemic consequences of muscle weakness (immobility, reduced muscle mass, gastrointestinal illness, respiratory cachexia, obesity)Crawford TO Neurmusc Disord 2004 14: 456-460

SMA type I -Standard careStandard care

Pulmonary management Manual or Mechanical Percussion, Postural Drainage, Intrapulmonary Percussive Ventilation, The Vest Airway Clearance System, , assisted coughs and In-exsufflator cough machine or Cough Assist device Periodic BiPAP, and use of nasal nocturnal ventilation.

• The natural history and life expectancy changes in SMA type I whether you use non-invasive ventilation or not.

SMA type I/SMA type II/SMA type III -Standard careStandard care

• Nutrition, feeding supplementation option • Gastrointestinal, gastrostomy

• Growth measures• Dexa (lean body and fat mass) • Skinfold thickness• Weight, length, head, chest and arm circumference• Lab screening of blood count, metabolic screen and nutritional markers • Positioning and posturing management

• Physiotherapy• KAFOS (when applicable) • ORLAU Parawalker

SMA type II /SMA type III -Standard careStandard care

Periodic controls • Every 6 months (?) for monitoring scoliosis (once scolisis appears, control every 3 months)

Respiratory care in SMA type II (Manzur et al., Neuromuscul Disord (2003) 3: 184–9; Wallgren-Pettersson et al., Neuromuscular Disorders 14 (2004) 56–69)

• Every year for FVC ifFVC <40% predicted.

• Poor cough, low VC PCF • SDB and NH overnight pulse oximetry recording

• Ventilatory support

SMA type I- Outcome measuresOutcome measuresA. Life expectancy

B. Functional motor testing CHOP test of strength in SMA, a newly created test of

elicited motor responses (Finkel et al., 2004) Test of infant motor performance (TIMP) (Finkel et al., 2004)

C. Electrophysiological studies: MUNE versus CMAP (Bromberg & Swoboda, 2002)D. Respiratory muscle function Tension time index (TTI) and its derivative (ttmus): measures of respiratory pump muscle

fatigue Maximal inspiratory pressure (MIP): measure of a brief burst of inspiratory strength.  Phase angle (F), the labored breathing index (LBI), and phase relation during the total

breath (phrtb): measures of thoracoabdominal synchrony, or the efficiency of respiratory system mechanics and the rapid shallow breathing index (RSBI) as a measure of the respiratory pattern.

SMA type II/SMA Type III -Outcome measuresOutcome measuresPrimary functional outcome measures (children after age 2,5 years)

Timed tests: 1) walking 10 meters; 2) climbing/descending stairs; 3) rising from the floor. The Hammersmith functional motor scale The Gross Motor Function Measure (GMFM) ? Mesure de Fonction Motrice (M F M)

Primary strength outcome measures (children older than 5 years)Quantitative muscle testing

The Richmond Quantitative Measurement System Hand-held CITEC Myometer

Secondary outcome measures Pulmonary function tests (FVC) Maximum inspiratory pressure (cm of water), Maximum expiratory pressure (cm of water), Cough pressure (peak cough flow, liter per minute), First respiratory volume in the first second (litres)

SMA type I/SMA type II/SMA type III- QOL

Quality of life (QL)PedsQL Neuromuscular Module for Parents (Iannaccone ST et al., 2003)

Caregiver burden questionaires

The experience with the Hammersmith functional motor scoreWe need to reconstruct a natural history using outcome measures

Main et Eur J Paediatr Neurol (2003) 7:155-59.

SCORE 2 POINTS 1 POINT SCORE 0Chair sitting,no hand support 1 hand 2 hand

supportLong sitting, no hands 1 hand 2 hand

supportHands to head,able flexes head unableTwo hands to head,able flexes head unable½ roll from supine, both ways one way unableRolls prone to supine(R) push on hand unableRolls prone to supine(S) push on hand unableRolls supine to prone(R) push on hand unableRolls supine to prone(S) push on hand unableLifts head from prone unableLifts head from supine through side flexion unableSitting from lying unalbeLying form sitting unableProp on forearms-head up hold position when placed

unableProp on extendend arms-head up hold position when placed

unable4 point kneeling-head up hold position when placed

unableCrawls unableStands holding-one hand minimal trunk support orthosis

neededStands independently> 3’’ <3’’ stands

momentarilyTakes > 4 steps, unaided 2-4 steps unable

METHODS

Inclusion criteria: Children with genetic diagnosis of SMASMA II or non-ambulant SMA IIIAge: from 2 ½ to 12 years.

Exclusion criteria :Previous spinal fusion surgery Pharmacological treatments (Salbutamol, creatine, gabapentin) within 60 days Other major medical conditions

HFMS scale was assessed at baseline (T0) and after 3 months (T1) and others after 6 months by two examiners, which had training session with a senior physiotherapist

Score at 3months against Score at baseline

y = 0.9999x + 0.2671r = 0.9945

0

5

10

15

20

25

30

35

40

0 5 10 15 20 25 30 35 40

Count of variation T0/T1 64Average of variation T0/T1 -0.27SD of variation T0/T1 1.01

Multicenter trial (10 centers in Italy)Enrolled 88 patients with SMAII or SMAIII who lost walking

ceiling

effects

floor

6m HAMA score by Baseline score

y = 1.0777x - 1.0897R2 = 0.9788

0

10

20

30

40

0 10 20 30 40

Count of variation T0/T1 24Average of variation T0/T1 -0.13SD of variation T0/T1 1.60

Multicenter trial (10 centers in Italy)Enrolled 88 patients with SMAII or SMAIII who lost walking

Future developments for international Consensus

• ENMC Standard of Care Forum • ENMC SMA functional scales Forum

• International Coordination Committee on SMA (ICC)• Standard Care sub-committee• Outcome measures sub-committee• SMA Clinical Trial Design sub-committee• Patient Registry sub-committee

ENMC Workshop Feb 2005Enrico Bertini (Rome, Italy)Arthur Burghes A (Colombus, USA)Kate Bushby K( Newcastle upon Tyne, UK), Richard Finkel R (USA)Natahlie Goemans (Leuven, Belgium) Susan Iannaccone S ( USA)Maria Jdrzejowska (Varsaw, Poland)Jeannet Pierre Yves (Lausanne, Switzerland)Marion Main (London, UK)Anita Macaulay (Starford upon Avon , UK)Domenico Marchetti (Rome, Italy)Judith Melki ( Evry, France)Eugenio Mercuri (Rome, Italy) Francesco Muntoni (London, UK)Thomas Voit (Essen, Germany) Anita Simmonds (London, UK)Alessandra Solari (Milano, Italy)Volker Straub (Newcastle upon Tyne, UK) Kathryn Swoboda (USA)Danilo Tiziano (Rome, Italy) Edoardo Tizzano, Barcelona, Spain)Haluk Topaloglu H (Ankara, Turkey)Louis Viollet (Paris, France)Dick Willems, (Amsterdam, The Netherlands)Brunhilde Wirth (Cologne, Germany) Klaus Zerres K (Aachen, Germany)

Richard Hughes (London)Christina Brahe (Rome)Brigitte Estournet-Mathiaud (Paris) Andoni J.Urtizberea (Paris, France)Luciano Merlini (Bologna, Italy)Victor Dubowitz (London, UK)ICC on SMA Karen Rabb (USA)Shree Pandya (USA)Leslie Nelson (USA)Jill Jarecki (USA)Cynthia Joyce (USA)Sandy Pacholick (USA)Linda S. Hynan (USA)Brenda Wong (USA)Thomas Crawford (USA)Jiri Vajsar (Canada)Anne Connolly (USA)Mary Schroth (USA)Ching Wang (USA)Leslie Morrison (USA)Uwe Mellies (Germany)Kaufmann, Petra (USA)Linda Hynan (USA)John Kissel (USA)Michael McDermott (USA)Tan Nguyen (USA)