Outcome Targets : What to measure?

1. Outcome Targets :What to measure? SAROJINI BUDDEN MD, FRCP C Director Rett Syndrome Clinic Associate Professor Pediatrics Oregon Health & Sciences University Medical Director Pediatric Development Program Legacy Emanuel Children’s Hospital Portland, Oregon

2. MECP-2 mutations Occur in 80-85 % classic Rett syndrome Occur in approximately 30-35 % atypical cases Rett syndrome is a CLINICAL DIAGNOSIS Rett syndrome is not synonymous with MECP-2 mutations MECP-2 mutations being identified in a wide range of phenotypes from fatal encephalopathy to mild learning disabilities and in normal carriers due to random inactivation of X chromosome

3. Genotype-Phenotype StudiesUse with Caution!!! Rett syndrome is not synonymous with MECP-2 Mutations Should mothers of siblings with positive studies who have similar mutations be included as having RS???

4. Use of Severity Scale What scales does one use if a child shows classic stagnation of development and over many years acquires ambulation and or use of expressive language? Our current severity scale does not account for late improvement

5. Outcome measures2 cases with MutationsVideos • Classic Rett with emerging ambulation at 12 years continues to walk verbal no language • Early onset delayed walking at 5 years. Onset of seizures, followed with hand ringing at 8 yrs Onset of language at 15 years continues to use language .

6. Documenting Regression of motor function Consider age and document identifiable factors affecting motor skills See list below Use simple measures of gross and fine motor function (listed) Such a study is easily designed and simple to collaborate with other centers

7. Factors influencing poor motor outcome • Extreme hypotonia • Marked rigidity • Leg length discrepency • Dystonic patterns • Rapidly Progressive Scoliosis • Sympathetic Dystrophy/Foot Deformities • Osteoporosis with or without fractures

8. Gross Motor Functional ClassificationBest used in 3-12 years of age • Level 1: Clumsy child; no assistive devices • Level 2: walks independently but limited in outdoor activities • Level 3: walks with assistive mobility devices • Level 4: Self-mobility severely limited even with assistive devices • Level5; No self mobility even with assistive devices Palisano R et al DMCN 1997; 39;214-223

9. MACSManual Ability Classification System • I Handles objects easily and successfully • II Handles most objects but with somewhat reduced quality and/or speed of achievement • III Handles objects with difficulty; needs help to prepare and modify activities • IV Handles limited selection of easily managed objects in adapted situations • V Does not handle objects and has severely limited ability to perform even simple actions www.macs.nu/

10. Suggested simple studies designed to measure effectiveness of medical treatmentsSuggest that the clinical trials group look at these and prioritize

11. What should we measure?? • Sleep: Salivary Melatonin, actigraphic studies • Agitation: Sensory integration therapy (OT) Medications: Naltrexone, Tranzene, Respiradol, Tegretol. • Hyperactivity: Straterra, Concerta. • Respiratory dysfunction. Use of Disipramine?? • Seizures: Early use and effectiveness of VNS • Depression: Prozac, Zoloft, Depakote.

12. What should we Measure? • Drooling: Effectiveness of non invasive methods Swabbing mouth with food extract, Use of 1% Atropine Ophthalmic drops PO • Nutrition/growth Keeping BMI normal and maintaining optimal caloric and nutritional intake • Reflux-Esophageal dysmotility Identification (Manometric studies) and treatment (medical and surgical ) • Constipation: Common and a chronic issue

13. What should we measure? • Rigidity: Use of local BOTOX, Oral Baclofen, L-Dopa • Dystonia: Use of night time Valium, oral Baclofen, Artane • Reflex Sympathetic Dystrophy: Use of Neurontin (Gabapentine) • Osteoporosis: Maintaining muscle strength, adequate Vit D, Calcium, and Vitamin C intake • Fractures: Treatment of fractures with Pamidronate or Alaendronate (Fosamax)

14. Osteoporosis • Risk of fractures is quite high • Osteopenia is identified in young children who do not have any of the precipitating factors • Urine studies and blood work has not been diagnostically useful • Bone studies have shown that rate of bone formation is very low compared to norms

15. Growth measurements • Microcephaly • Short Stature/wt (BMI) • Small organs appropriate for height • Poor muscle mass ( Impedence studies) • Discrepency in skeletal growth • Osteporosis as a result of poor bone formation

16. Agitation • In younger girls panic –like attacks • In older girls intermittent or constant screaming or moaning • This needs identification and treatment • At times there is a known cause but needs treatment

17. Causes of Agitation and Distress • Reflux • Constipation • Infections • Dental problems • Gall Stones • Surgical abdomen (often acute onset) • Dystonic spasms • Fractures

18. Causes of Agitation and Distress(cont) • Reflexive Sympathetic Dystrophy • Seizures • Headache • Long standing sleep deprivation • Premenstrual distress • Urinary retention • Change in school • Change in care givers • Abuse

19. Documentation of Depression • This is being recognized more frequently in those young women who are isolated from family and friends and their earlier school based activities. • There is clearly an organic and environmental basis to this.

20. Lessons learned and to be learnt • Early medical and therapeutic intervention is useful and should be provided • The potential for functional development is unknown in young children with Rett Syndrome • There is no one parameter that can be measured as best criteria of outcome • Functional development needs to be measured at different ages • Outcomes based on genotype /phenotype need to be used with discretion