Barcelona, May 21 2005
V Jornada Medico Informativa
Atrofia Muscular Espinal (AME)
Mesa redonda: Futuro de la
investigacion y tratamiento de
AME
Enrico Bertini, MD
Bambino Gesu’Children’s Research Hospital Rome, Italy
Four types of SMA but functionally 3 types of SMA
representing 3 different disability phenotypes
Age at onset
Maximum function achieved
different severity
 progression
 disability
different
 natural history
 standard care
 outcome measures (trials)
SMA
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
Crawford & Pardo Neurobiol Dis, 1996;3:97–110
Russman, et al., Neurology. 1996 Oct;47(4):973-6.
Still sitting
Zerres et al., J Neurol Sci 146(1 997) 67-7
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 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 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 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
• Poor cough, low VC
• SDB and NH
• Ventilatory support
if FVC <40% predicted.
PCF
overnight pulse oximetry recording
SMA type I- Outcome measures
A. 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 measures
Primary 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
We need to reconstruct a natural history using outcome measures
The experience with the Hammersmith functional motor score
.
Main et Eur J Paediatr Neurol (2003) 7:155-59
SCORE 2 POINTS
1 POINT
SCORE 0
Chair sitting,no hand support
1 hand
2 hand support
Long sitting, no hands
1 hand
2 hand support
Hands to head,able
flexes head
unable
Two hands to head,able
flexes head
unable
½ roll from supine, both ways
one way
unable
Rolls prone to supine(R)
push on hand
unable
Rolls prone to supine(S)
push on hand
unable
Rolls supine to prone(R)
push on hand
unable
Rolls supine to prone(S)
push on hand
unable
Lifts head from prone
unable
Lifts head from supine
through side flexion
unable
Sitting from lying
unalbe
Lying form sitting
unable
Prop on forearms-head up
hold position when placed
unable
Prop on extendend arms-head up hold position when placed
unable
4 point kneeling-head up
hold position when placed
unable
Crawls
unable
Stands holding-one hand
minimal trunk support
orthosis needed
Stands independently> 3’’
<3’’
stands momentarily
Takes > 4 steps, unaided
2-4 steps
unable
METHODS
Inclusion criteria:
Children with genetic diagnosis of SMA
SMA II or non-ambulant SMA III
Age: 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
Multicenter trial (10 centers in Italy)
Enrolled 88 patients with SMAII or SMAIII who lost walking
Score at 3months against Score at baseline
40
35
30
25
20
15
y = 0.9999x + 0.2671
r = 0.9945
10
5
0
0
5
10
15
20
25
30
35
40
ceiling
Count of variation
Average of variation
SD of variation
T0/T1 64
T0/T1 -0.27
T0/T1 1.01
effects
floor
Multicenter trial (10 centers in Italy)
Enrolled 88 patients with SMAII or SMAIII who lost walking
6m HAMA score by Baseline score
40
y = 1.0777x - 1.0897
2
R = 0.9788
30
20
10
0
0
10
Count of variation
Average of variation
SD of variation
20
T0/T1 24
T0/T1 -0.13
T0/T1 1.60
30
40
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 2005
Enrico 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)