Monitoring function in Rett
syndrome for Clinical Trials
Helen Leonard
Anne Marie Williams Jenny Downs
Clinical Severity Score
from Percy et al. (2000)
1:
2:
Age at onset of regression 8:
9:
Head growth
3:
4:
Motor function
Crawling and creeping
10: Hand use
5:
Ambulation
12: Onset of stereotypies
6:
Nonverbal communication 13: Somatic growth
7:
Language
Respiratory dysfunction
Epilepsy and seizures
11: Feeding
14: Autonomic dysfunction
15: Scoliosis
Clinical Features Score
from Kerr et al. (2001)
A: Head circumference during
first year
B: Early developmental progress
0-6 months
C: Present head circumference
D: Weight
E: Height
F: Muscle tone
G: Spine posture
H: Joint contractures (not used)
I: Gross motor function
J: Hand stereotypies (wringing
squeezing,patting, mouthing)
K:
L:
M:
N:
O:
P:
Q:
Other involuntary movements
Voluntary hand use
Oro-motor function
Intellectual disability
Speech
Epilepsy
Disturbed awake breathing rhythm
(hyperventilation, panting, breath
holding)
R: Peripheral circulation of
extremities
S: Mood disturbance
T: Sleep disturbance
Clinical Severity Score
from Pineda et al. (2001)
1:
Age at loss of social
interaction
2:
Head growth
3:
4:
5:
6:
Respiratory function
7:
Epilepsy
Sitting alone
Ambulation
8:
Hand use
9:
Air swallowing / bloating
Language
10: Onset of stereotypies
What do we need for a
clinical trial
• Measurement of symptoms that are clinically
relevant
• Sensitive to interventional change
• Use appropriate measurement of signs and
symptoms
Normal development
of hand function
• Infants - visually attend to objects and their own hands
before they can reach and grasp
• Neonatal period - Reflex palmer grasp, hand to mouth
• 6 months - raking to pick up an object and development of
reach
• 7-9 months - scissors grasp, transfers, bangs 2 objects
together, patting etc
• 9 months – inferior pincer grasp
• 10-12 months – superior pincer grasp, pokes object with
finger, more precise release
• 12-15 months – building tower with 2 cubes etc....
Normal development
of hand function
• Infants - visually attend to objects and their own hands
before they can reach and grasp
• Neonatal period - Reflex palmer grasp, hand to mouth
• 6 months - raking to pick up an object and development of
reach
• 7-9 months - scissors grasp, transfers, bangs 2 objects
together, patting etc
• 9 months – inferior pincer grasp
• 10-12 months – superior pincer grasp, pokes object with
finger, more precise release
• 12-15 months – building tower with 2 cubes etc....
What do we see in Rett
syndrome?
• Loss of hand function skills during early
childhood – usually to a very low level
• Usually good head control and potential for
looking at objects
• Development of apraxia – disorder of skill
not related to tone, weakness, co-ordination,
tremor
• But may also have altered muscle tone,
tremor, stiffness, hand stereotypies develop
and there is an intellectual deficit
Hand function in Rett syndrome
• Poor hand function is one of the core
diagnostic criteria – single most
informative early sign of RTT
• Einspieler 2005 – video pre-regression
suggests variations in early hand skills
• Cass 2003 – ~80% could grasp and ~60%
could hold an object
– 25-43% can finger feed
• Umansky 2003 – marked restriction of
hand function, internal > external object
function and simple (eg holding cup) >
Hand function assessment in
Rett syndrome
• Mount 2002 and Cass 2003 – broad 8 point
Likert scale without defined categories
• Mount 2002 – RSBQ – “does not use hands for
purposeful grasping” – 3 point scale
• Ellaway 2001 – Rett Syndrome Symptom
Checklist – yes/ no responses to a series of
tasks uses the Hand Apraxia scale and the
tasks are supposed to be summative
• Fitzgerald 1990 – Rett Syndrome MotorBehavioural Assessment – “does not reach for
objects or people” and “hand clumsiness” – 5
point scale
Hand function assessment in
RTT (cont)
• RTT global severity scales
• Kerr
– None (54%), reduced or poor (32%), normal(14%)
• Pineda
– never acquired (11%)
– acquired and lost (44%)
– lost purposefulness < 24 months but conserved grasping
(16%)
– lost purposefulness 2-6 years with conserved manipulation
(17%)
– acquired and conserved (11%)
• Percy
–
–
–
–
never acquired (11%)
holding objects acquired and lost (33%)
holding objects acquired and partially conserved (44%)
acquired and conserved (11%)
Hand use by mutation
Summary of RTT hand
assessments
• Limited characterisation of variability and
unlikely to be able to capture improvements
resulting from an intervention
• The meaning of the categories are not always
clear and some items/category labels are
subjective
• Limited psychometric information
• Variability in hand function seen on our
videos and described as case studies in the
literature (Umansky 2001) – therefore a more
sensitive assessment based on observations
and not judgements is required
Other specific hand function
assessments
• Erhardt Developmental Prehension Assessment
– 3 sections: primary involuntary hand/arm patterns, primary voluntary
movements, pre-writing skills
– Primary voluntary movements: posture, reach, grasp and manipulation
– Score gives a functional age
• Peabody Developmental Fine Motor Scale
– Comprises 112 items, 4 skill categories including grasping, hand use, eyehand co-ordination and manual dexterity
• Quality of Upper Extremity Skills Test
– 4 domains – dissociated movements (64 items), grasp (24 items), weight
bearing (50 items) and protective extension (36 items)
– Each item comprises several subitems and there are a total of 174 items
which are coded on a dichotomous scale of can or can’t do
• Manual Ability Classification System
• 5 levels, developed for children with cerebral palsy
• Classifies according to how the child handles objects with a background of
spasticity and less relevant to severe intellectual disability
2004 and 2007 video study
• Families asked to film their daughter picking up
and holding a selection of large objects (toy, small
ball, cup, utensil) and a small object (sultana,
smartie, often demonstrated with a dried apricot,
small pieces of sandwich etc)
• Described reach, accuracy, initiation of movement,
pre-shaping of the hand, transfer, raking or pincer
grasp to pick up small objects
• Viewing other activities that gave us additional
opportunities for observation
Development of a video-based evaluation tool in Rett syndrome. Journal of Autism and Developmental
Disorders Fyfe et al. 2007;37(9):1636-46.
Hand function at work
Hand assessment so far
• N = 116, 103 showed hand function, 13
missing hand function footage. Best efforts
were coded
• Development of levels based on observation,
sultana girls were roughly the mid point,
worked backwards and forwards looking at
frequencies
• So far – 8 levels of function
– Describe picking up objects and transferring
– Doesn’t describe pointing, pressing a switch,
Level 1
• No evidence of active hand function
• N = 25 (18 with mutation)
Level 2
• (1) hold a large object but not grasp or
pick up the object OR (2) pick a large
object up momentarily but drop
immediately
• Represents a single skill
• N=13 (9 with a mutation)
– 11 could hold and 2 could pick up
– 6/13 (46.2%) looked at the object
– 4/13 (30.1%) had some form of reach
Level 3
• Pick up and hold a large object and
sometimes a small object
• Increased variability, combination of
movements and greater potential for
function
• N=8 (5 with mutation)
– 4/8 (50%) looked at the object
– 3/8 (37.5%) could reach
– 1/8 (12.5%) picked up a small object
Level 4
• Reach, grasp, hold and pick up one of the
large objects
• Could not grasp, hold and pickup a small
object
• N=12 (6 with a mutation)
– Two could also pick up and hold a small object
but need help to grasp the small object
– 11/12 (91.7%) looked at the object
– 8/12 (66.7%) reached accurately
– 3/12 (25.0%) initiated movement satisfactorily
– no close approximation when pre-shaping the
hand
Level 5
• Reach, grasp, pick up and hold a small
object using a raking grasp
• N=10 (7 with a mutation)
– All girls looked at the object
– 8/10 (80.0%) reached accurately
– 8/10 (80.0%) initiated movement
satisfactorily
– 2/10 (20.0%) could transfer
– 0/10 (0.0%)had close pre-shaping of the
hand
Level 6
• Reach, grasp, pick up and hold a small object using
the thumb– a scissors, inferior pincer or pincer
grasp
• N = 20 (19 with mutation)
– All girls looked at the object
– All girls reached accurately
– 15/20 (75.0%) initiated movement satisfactorily
– 0 could transfer
– 3/20 (15.0%) had close pre-shaping of the hand
Level 7
• Could achieve level 6 and also
demonstrated ability to transfer an
object
• N=8 (6 with mutation)
– All looked at the object
– All reached accurately
– 7/8 (87.5%) initiated movement
satisfactorily
– None had close approximation of hand
orientation and size recognition when
preshaping hand
Level 8
• Those who could achieve level 7 and
who also demonstrated close preshaping skills of hand orientation and
size recognition
• N = 6 (3/6 with mutation)
• All looked at the object, reached
accurately and initiated movement
satisfactorily
Distribution of hand
function level
30
25
20
15
No mutation iden
Mutation positive
10
5
8
7
6
5
4
3
2
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What next?
• Validation of scale
– Construct – Relationship between hand
function and finger feeding, age, genotype,
WeeFIM scores
– Concurrent - relationship between hand
function and Pineda scale item (existing scale
with the biggest spread of abilities)
– Content and face – probably reasonable from
today’s presentation
– Reliability – test retest and intertester R
Special thanks go to...
•
National Institutes of Health
•
Janelle Lillis and family
•
NHMRC
•
Bill Callaghan and the Rett
•
Australian Paediatric Surveillance
Syndrome Association of
Unit
Australia
•
Anne Marie Williams
•
Jenny Downs, Carol Philippe,
•
The families and clinicians
Philippa Carter, Ami
who support the research
Bebbington,Sue Fyfe and the team
so well
Current funding NIH 1 R01 HD043100-01A1 & NHMRC #303189