1. Monitoring function in Rett syndrome for Clinical Trials Helen Leonard Anne Marie Williams Jenny Downs

2. Clinical Severity Score from Percy et al. (2000) 1:Age at onset of regression 2:Head growth 3:Motor function 4:Crawling and creeping 5:Ambulation 6:Nonverbal communication 7:Language 8:Respiratory dysfunction 9:Epilepsy and seizures 10:Hand use 11:Feeding 12:Onset of stereotypies 13:Somatic growth 14:Autonomic dysfunction 15:Scoliosis

3. 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:Other involuntary movements L: Voluntary hand use M:Oro-motor function N:Intellectual disability O:Speech P :Epilepsy Q:Disturbed awake breathing rhythm (hyperventilation, panting, breath holding) R:Peripheral circulation of extremities S:Mood disturbance T:Sleep disturbance

4. Clinical Severity Score from Pineda et al. (2001) 1:Age at loss of social interaction 2:Head growth 3:Sitting alone 4:Ambulation 5:Language 6:Respiratory function 7:Epilepsy 8:Hand use 9:Air swallowing / bloating 10:Onset of stereotypies

5. 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

6. 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....

7. 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....

8. 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

9. 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) > complex (eg playing with toy)

10. 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 Motor- Behavioural Assessment – “does not reach for objects or people” and “hand clumsiness” – 5 point scale

11. 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%)

12. Hand use by mutation

13. 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

14. 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, eye- hand 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

15. Other hand function assessments Physical disability scales – eg WeeFIM, Pedi scale, some of the arthritis scales (Functional Status Index and Health Assessment Questionnaire Items usually relate to feeding and use of utensils, opening car doors, dialling on the phone Either doesn’t capture detail of the hand function or may not be relevant to those with a severe intellectual disability

16. Hand Apraxia Scale Burd et al 1990 10 items with a yes no response Methods –Population characteristics not clear –Carer report for responses – needed to do skill 25% of time when asked Reported as summative and continue testing until a negative response for an item Represents a suggestion that holding precedes picking up and holding large objects precedes small objects

17. More thoughts on the Hand Apraxia Scale Scanning of 2004 questionnaire responses show that the yes responses are not summative but are scattered throughout the 10 items What is functional hand use? Why does ability to finger feed precede ability to pick up large objects? Why does picking up a small object come after putting a small object in a container and taking it out again? Why is drinking from a cup a hand skill?

18. 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.

19. Hand function at work

20. 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, dexterity...

21. Level 1 No evidence of active hand function N = 25 (18 with mutation)

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. Level 8 Those who could achieve level 7 and who also demonstrated close pre- shaping skills of hand orientation and size recognition N = 6 (3/6 with mutation) All looked at the object, reached accurately and initiated movement satisfactorily

29. Distribution of hand function level

30. 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

31. Special thanks go to... National Institutes of Health NHMRC Australian Paediatric Surveillance Unit Anne Marie Williams Jenny Downs, Carol Philippe, Philippa Carter, Ami Bebbington,Sue Fyfe and the team Janelle Lillis and family Bill Callaghan and the Rett Syndrome Association of Australia The families and clinicians who support the research so well Current funding NIH 1 R01 HD043100-01A1 & NHMRC #303189