Outcome Targets :Outcome Targets :What to measure?What to measure?

SAROJINI BUDDEN MD, FRCP CSAROJINI BUDDEN MD, FRCP CDirector Rett Syndrome ClinicDirector Rett Syndrome ClinicAssociate Professor PediatricsAssociate Professor Pediatrics

Oregon Health & Sciences UniversityOregon Health & Sciences UniversityMedical Director Pediatric Development Medical Director Pediatric Development

Program Legacy Emanuel Children’s Program Legacy Emanuel Children’s Hospital Hospital

Portland, OregonPortland, Oregon

MECP-2 mutationsMECP-2 mutationsOccur in 80-85 % classic Rett syndrome Occur in 80-85 % classic Rett syndrome Occur in approximately 30-35 % atypical casesOccur in approximately 30-35 % atypical cases

Rett syndrome is a Rett syndrome is a CLINICAL DIAGNOSISCLINICAL DIAGNOSISRett syndrome is Rett syndrome is not synonymous with MECP-2 not synonymous with MECP-2 mutationsmutations

MECP-2 mutations being identified in a wide range MECP-2 mutations being identified in a wide range ofof

phenotypes from fatal encephalopathy to mild phenotypes from fatal encephalopathy to mild learning learning

disabilities and in normal carriers due to randomdisabilities and in normal carriers due to randominactivation of X chromosomeinactivation of X chromosome

Genotype-Phenotype Genotype-Phenotype StudiesStudies

Use with Caution!!!Use with Caution!!!

Rett syndrome is Rett syndrome is not synonymous with not synonymous with MECP-2 MECP-2

MutationsMutations

Should mothers of siblings with Should mothers of siblings with positive studies who have similar positive studies who have similar mutations be included as having RS???mutations be included as having RS???

Use of Severity ScaleUse of Severity Scale

What scales does one use if a child shows What scales does one use if a child shows classic stagnation of development and over classic stagnation of development and over many years acquires ambulation and or use of many years acquires ambulation and or use of expressive language?expressive language?

Our current severity scale does not account for Our current severity scale does not account for late improvement late improvement

Outcome measuresOutcome measures2 cases with Mutations2 cases with Mutations

VideosVideos

Classic Rett with emerging ambulation at 12 Classic Rett with emerging ambulation at 12 years continues to walk verbal no languageyears continues to walk verbal no language

Early onset delayed walking at 5 years. OnsetEarly onset delayed walking at 5 years. Onset of seizures, followed with hand ringing at 8 of seizures, followed with hand ringing at 8

yrs yrs Onset of language at 15 years continues to useOnset of language at 15 years continues to use language . language .

Documenting Regression of Documenting Regression of motor functionmotor function

Consider age and document identifiable Consider age and document identifiable factors affecting motor skills factors affecting motor skills

See list below See list below Use simple measures of gross and fine motor Use simple measures of gross and fine motor

function (listed) Such a study is easily function (listed) Such a study is easily designed and simple to collaborate with designed and simple to collaborate with

other centersother centers

Factors influencing poor Factors influencing poor motor outcomemotor outcome

Extreme hypotoniaExtreme hypotonia Marked rigidityMarked rigidity Leg length discrepencyLeg length discrepency Dystonic patternsDystonic patterns Rapidly Progressive Scoliosis Rapidly Progressive Scoliosis Sympathetic Dystrophy/Foot Sympathetic Dystrophy/Foot

DeformitiesDeformities Osteoporosis with or without Osteoporosis with or without

fracturesfractures

Gross Motor Functional Gross Motor Functional ClassificationClassification

Best used in 3-12 years of ageBest used in 3-12 years of age Level 1: Clumsy child; no assistive devicesLevel 1: Clumsy child; no assistive devices Level 2: walks independently but limited in Level 2: walks independently but limited in

outdoor activitiesoutdoor activities Level 3: walks with assistive mobility Level 3: walks with assistive mobility

devicesdevices Level 4: Self-mobility severely limited even Level 4: Self-mobility severely limited even

with assistive deviceswith assistive devices Level5; No self mobility even with assistive Level5; No self mobility even with assistive

devicesdevices Palisano R et al DMCN 1997; 39;214-223

MACSMACSManual Ability Manual Ability

Classification SystemClassification System I Handles objects easily and successfullyI Handles objects easily and successfully II Handles most objects but with somewhat II Handles most objects but with somewhat

reduced reduced

quality and/or speed of achievementquality and/or speed of achievement III Handles objects with difficulty; needs help toIII Handles objects with difficulty; needs help to

prepare and modify activities prepare and modify activities IV Handles limited selection of easily managedIV Handles limited selection of easily managed

objects in adapted situationsobjects in adapted situations V Does not handle objects and has severely limited V Does not handle objects and has severely limited

abilityability

to perform even simple actionsto perform even simple actions www.macs.nu/

Suggested simple studies Suggested simple studies designed to measure designed to measure

effectiveness of medical effectiveness of medical treatmentstreatments

Suggest that the clinical Suggest that the clinical trials group look at these trials group look at these

and prioritizeand prioritize

What should we What should we measure??measure??

Sleep:Sleep: Salivary Melatonin, actigraphic Salivary Melatonin, actigraphic studies studies

Agitation:Agitation: Sensory integration therapy (OT) Sensory integration therapy (OT) Medications: Naltrexone, Tranzene, Medications: Naltrexone, Tranzene,

Respiradol, Tegretol.Respiradol, Tegretol. Hyperactivity: Hyperactivity: Straterra, Concerta.Straterra, Concerta. Respiratory dysfunctionRespiratory dysfunction. Use of . Use of

Disipramine??Disipramine?? Seizures:Seizures: Early use and effectiveness of VNS Early use and effectiveness of VNS Depression: Depression: Prozac, Zoloft, Depakote.Prozac, Zoloft, Depakote.

What should we What should we Measure?Measure?

Drooling:Drooling: Effectiveness of non invasive Effectiveness of non invasive methodsmethods

Swabbing mouth with food extract, Swabbing mouth with food extract,

Use of 1% Atropine Ophthalmic drops PO Use of 1% Atropine Ophthalmic drops PO Nutrition/growthNutrition/growth Keeping BMI normal and Keeping BMI normal and

maintaining optimal caloric and nutritional maintaining optimal caloric and nutritional intakeintake

Reflux-Esophageal dysmotility Reflux-Esophageal dysmotility Identification (Manometric studies) and Identification (Manometric studies) and treatment (medical and surgical ) treatment (medical and surgical )

Constipation: Constipation: Common and a chronic issueCommon and a chronic issue

What should we What should we measure?measure?

Rigidity:Rigidity: Use of local BOTOX, Oral Baclofen, Use of local BOTOX, Oral Baclofen, L-Dopa L-Dopa Dystonia:Dystonia: Use of night time Valium, oral Use of night time Valium, oral

Baclofen, ArtaneBaclofen, Artane Reflex Sympathetic Dystrophy:Reflex Sympathetic Dystrophy: Use of Use of

Neurontin (Gabapentine)Neurontin (Gabapentine) Osteoporosis: Osteoporosis: Maintaining muscle strength, Maintaining muscle strength,

adequate Vit D, Calcium, and Vitamin C adequate Vit D, Calcium, and Vitamin C intakeintake

Fractures:Fractures: Treatment of fractures with Treatment of fractures with Pamidronate or Alaendronate (Fosamax)Pamidronate or Alaendronate (Fosamax)

OsteoporosisOsteoporosis

Risk of fractures is quite highRisk of fractures is quite high Osteopenia is identified in young Osteopenia is identified in young

children who do not have any of the children who do not have any of the precipitating factorsprecipitating factors

Urine studies and blood work has not Urine studies and blood work has not been diagnostically usefulbeen diagnostically useful

Bone studies have shown that rate of Bone studies have shown that rate of bone formation is very low compared bone formation is very low compared to normsto norms

Growth measurementsGrowth measurements

MicrocephalyMicrocephaly Short Stature/wt (BMI)Short Stature/wt (BMI) Small organs appropriate for heightSmall organs appropriate for height Poor muscle mass ( Impedence Poor muscle mass ( Impedence

studies)studies) Discrepency in skeletal growth Discrepency in skeletal growth Osteporosis as a result of poor bone Osteporosis as a result of poor bone

formationformation

AgitationAgitation

In younger girls panic –like attacksIn younger girls panic –like attacks In older girls intermittent or In older girls intermittent or

constant screaming or moaningconstant screaming or moaning This needs identification and This needs identification and

treatmenttreatment At times there is a known cause but At times there is a known cause but

needs treatment needs treatment

Causes of Agitation and Causes of Agitation and DistressDistress

RefluxReflux ConstipationConstipation InfectionsInfections Dental problemsDental problems Gall StonesGall Stones Surgical abdomen (often acute onset)Surgical abdomen (often acute onset) Dystonic spasmsDystonic spasms FracturesFractures

Causes of Agitation and Causes of Agitation and DistressDistress(cont)(cont)

Reflexive Sympathetic DystrophyReflexive Sympathetic Dystrophy SeizuresSeizures HeadacheHeadache Long standing sleep deprivationLong standing sleep deprivation Premenstrual distressPremenstrual distress Urinary retentionUrinary retention Change in school Change in school Change in care giversChange in care givers AbuseAbuse

Documentation of Documentation of DepressionDepression

This is being recognized more This is being recognized more frequently in those young frequently in those young women who are isolated from women who are isolated from family and friends and their family and friends and their earlier school based activities.earlier school based activities.

There is clearly an organic and There is clearly an organic and environmental basis to this.environmental basis to this.

Lessons learned and to Lessons learned and to be learntbe learnt

Early medical and therapeutic intervention Early medical and therapeutic intervention is useful and should be providedis useful and should be provided

The potential for functional development is The potential for functional development is unknown in young children with Rett unknown in young children with Rett SyndromeSyndrome

There is no one parameter that can be There is no one parameter that can be measuredmeasured

as best criteria of outcomeas best criteria of outcome Functional development needs to be Functional development needs to be

measured at different agesmeasured at different ages Outcomes based on genotype /phenotype Outcomes based on genotype /phenotype

need to be used with discretion need to be used with discretion