Nessun titolo diapositiva

1
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 GesuChildrens
Research Hospital Rome, Italy
2

• 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)

3
SMA

• TYPE I
• age of onset lt 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 gt 18 months
• patients are able to walk independently

4
Crawford Pardo Neurobiol Dis, 1996397110
Russman, et al., Neurology. 1996 Oct47(4)973-6.
Zerres et al., J Neurol Sci 146(1 997) 67-7
Still sitting Age at death
5
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)

6
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
7
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.

8
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

9
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 1849
• Wallgren-Pettersson et al., Neuromuscular
  Disorders 14 (2004) 5669)
• Every year for FVC if FVC lt40 predicted.
• Poor cough, low VC PCF
• SDB and NH overnight pulse oximetry recording
• Ventilatory support

10
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.

11
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)

12
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
13
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) 7155-59.
14
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
independentlygt 3 lt3
stands momentarily Takes gt 4 steps, unaided
2-4 steps unable
15
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
16
(No Transcript)
17
Multicenter trial (10 centers in Italy) Enrolled
88 patients with SMAII or SMAIII who lost walking
ceiling effects floor
Count of variation T0/T1 64 Average of
variation T0/T1 -0.27 SD of variation
T0/T1 1.01
18
Multicenter trial (10 centers in Italy) Enrolled
88 patients with SMAII or SMAIII who lost walking
Count of variation T0/T1 24 Average of
variation T0/T1 -0.13 SD of variation
T0/T1 1.60
19
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

20
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)
21
(No Transcript)