Rett syndrome therapy for WEbinar COMBINED MMrev · 2017-05-31 · Bruxism while awake 3. Altered sleep pattern 4. Abnormal muscle tone 5. Peripheral vasomotor disturbance 6. Scoliosis/kyphosis

5/31/2017

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Early Intervention Training Program at the University of Illinois at Urbana‐Champaign presents

Rett Syndrome: A Different Kind of

Developmental Disorder

Your Facilitators for Today

Peter Heydemann, MD

Head, Department of Pediatric NeurologyRush University Medical Center

Colleen Burhfiend, MD

Department of Pediatric Neurology

Rush University Medical Center

Today’s Moderator

Maria Matticks, RN, BSNProfessional Development ConsultantEarly Intervention Training Program at University of Illinois

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Who is participating in our webinar today?

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Rett Syndrome

Rush Rett Syndrome Clinic

Peter Heydemann, MD (ped neuro)Colleen Buhrfiend, MD (ped neuro)

Randolph McConnie, MD (GI Ped + adult)Sheila Raikar, MD (Ped GI)

Maria Brown, DO (Fam Prac, basic GYN)Laura Deon, MD (physiatry)

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Have any of you ever worked with someone with Rett Syndrome?

Yes or No

What is Rett Syndrome?

Genetic developmental disorder

Occurs (almost) only in girls

specific distinguishing characteristics

• hand wringing

What is Rett Syndrome?

Incidence 1/10,000 girls

Despite regression, it is not a degenerative disorder

Developmental Disorders Etiology

● Congenital● Genetic● Teratogenic● Toxic● Maldevelopment● Destructive (e.g. hypoxic, infectious)

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Diagnosing Developmental Syndromes

Birth history

Facies

Diagnostic Behaviors

Body habitus

Head Size

Birth Marks

Audiology Evaluation

Retinal exam

Brain Imaging

Genetic Testing

(microarray, FraX, gene

panels, exome)

What Dr. Rett published in Vienna 1966

● Developmental delay

● History of regression

● Hand wringing

● Small stature

● Periodic breathing

● (wrongly noted hyperammonemia)

● Developmental delay

● History of regression

● Hand wringing

● Small stature

● Periodic breathing

● (wrongly noted hyperammonemia)

Wien Med Wochenschrift, Oct 1966

Rett Criteria Revised 2010 (Neul, Rett Syndrome: Revised Diagnostic Criteria and Nomenclature, Ann Neurol; orignal

criteria by Hagberg 1983)

Typical (Classic ) Rett:Regression, stabilization, and recovery, plus:

All 4 Main & both exclusion criteria

Supportive criteria not required

Rett Criteria Revised 2010 (Neul, Rett Syndrome: Revised Diagnostic Criteria and Nomenclature, Ann Neurol; orignal

criteria by Hagberg 1983)

Typical (Classic ) Rett: Aypical (variant) Rett:

Regression, stabilization, and recovery, plus:

All 4 Main & both exclusion criteria

Supportive criteria not required

Regression, stabilization, and recovery

2 of 4 Main criteria

5 of 11 supportive criteria

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Rett Criteria (continued)

Main Criteria:

1. Loss of purposeful hand skills2. Loss of spoken language3. Dyspraxic gait or non‐ambulatory4. Stereotypic hand movements(wringing, hand mouthing, fingering)

Exclusion Criteria:

1. Brain Injury2. Grossly abnormal

development in first 6 months of life

Rett Criteria (continued)

1. Periodic breathing in wakefulness

2. Bruxism while awake3. Altered sleep pattern4. Abnormal muscle tone5. Peripheral vasomotor

disturbance

6. Scoliosis/kyphosis7. Growth Failure8. Small cool/cold hands and/or feet9. Inappropriate laughing or screaming10. Delayed or diminished pain response11. Intense eye communication or “eye

pointing”

Supportive Criteria:

MECP2 Gene ‐‐ Zoghbi 1999

X‐linked, site Xq28

sporadic mutation (rarely familial)

Gene function: DNA methylation

(methylation turns genes off)

http://wikivisually.com/wiki/Rett_syndrome

← Xq28

after wiki.ggc.edu

Neuropathology: Differences in the Rett Brain

Small brain with normal gross exam

smaller neuron cell bodies

fewer dendrites

fewer dendritic spines & synapses

Small brain with normal gross exam

smaller neuron cell bodies

fewer dendrites

fewer dendritic spines & synapses

from Armstrong, “Neuropathology of Rett Syndrome,” J Child Neurol 2005;20:747–753).

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Multisystem Disorder: Rett is a brain disorder plus more:

GI tract Growth Peripheral vascular symptoms Scoliosis Cardiac conduction Puberty Longevity

Rett Brain Symptoms

Apraxia (language, gross motor, fine motor, oromotor)

Cognition

Behavior Seizures

Myoclonus

Cerebral palsy (hypotonic,

hypertonic, ataxic, dystonic)

4 Stages of Rett Syndrome

Early onset phase

Rapid destructive phase usually 12‐30 months, up to 48 months;

• involves hand skill & expressive language more than ambulation and receptive language

Plateau

Late deterioration,

variable timing, if at

all.

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Stereotypies

21 yr old: hand wringing and right wrist contracture

Stereotypies

21 yr old: hand wringing and right wrist contracture 30 yr old with callus from wringing and mouthing

Rett Behavior and Anxiety

Infant personality is often placid

Large range of affects and emotionsHappyirritableangrytantrumaggressive

Infant personality is often placid

Large range of affects and emotionsHappyirritableangrytantrumaggressive

Rett Behavior and Anxiety

Treatmentapproach:

• without adequate expressive language it is hard to assess mood and behavior

Assess medical causes:

• constipation, gastric reflux, bloating, dystonia, migraine, menses, musculoskeletal and dental

Assess:

• environment, wants and needs with diary

trial and error:

• massage, foods, positioning, etc.

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Incidence

• ~60%, mostly by age 10

• 75% by 15 yrs

“Spells”

• Not all seizure‐like events are seizures

EEG

• Abnormal and “epileptiform”, but does not mean the girl is having seizures

Video‐EEG Monitoring is often needed for treatment decisions (in order to “capture a spell”)

There is no ‘best’ anticonvulsant

Breath holding and

hyperventilation

Spacing out and “freezing” episodes

Laughter or Screaming

Tremors Falling forward Pupil dilation

Gastric RefluxAutonomic dysfunction

Stiffening or motor

dysfunction

Awake symptoms, not sleep symptoms (separate sleep apnea can occur)Awake symptoms, not sleep symptoms (separate sleep apnea can occur)

Range of symptoms from near continuous HV or breath‐holding to noneRange of symptoms from near continuous HV or breath‐holding to none

Commonly worse with anxietyCommonly worse with anxiety

Aerophagia may be associated which results in bloatingAerophagia may be associated which results in bloating

Prolonged breathholding can result in cyanosis, but episodes spontaneously resolve Prolonged breathholding can result in cyanosis, but episodes spontaneously resolve

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Incidence

• ~80% have sleep problems

• 30% problems going to sleep

• 40% frequent awakenings

• 8% difficulty waking up

Treatment

• Behavior rx,

• Polysomnogram

• Medications

• Etc.

(after Glaze, D, Baylor College of Medicine from Rett Natural History Study)

Growth and Nutrition

Short stature is typical

Low body fat is common

Dysphagia is common

• Slow intake

• Aspiration

• G‐tubes are needed in ~40%

Rett Growth Charts

from Tarquino, Motil etal, Neurology 79:1658, 2012

HEIGHT

WEIGHT BMI

HEAD CIRC

Incidence

• 8% of 4 yr olds

• ~80% of girls by age 16

Associated with:

• non‐ambulation

• low tone

Frequent gene mutations:

• R294X

• R306C

Treatment:

• positioning

• upright supports

• molded seat cushion

• TLSO

• spinal fusion, avg 12 yr

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EKG: Long QT Interval

SymptomSymptom

• QTc >450 msec

IncidenceIncidence

• Estimated 18% of Rett girls

• Rare sudden death in Rett, ?related to long QT

TreatmentTreatment

• follow QT interval yearly

• minimize and scrutinize use of drugs that prolong QT

• Drugs, rarely pacemaker ECG of a heart in normal sinus rhythm.

from Wikipedia

Cool, pale or cyanotic hands and/or feet

Breathing dysregulation

Body temperature

Gut: dysmotility /GERD

21 yr girl with Rett, purple cold feet (hands are warmer with mild pallor)

Sarizotan for Breath Holding in Rett

• Age 6 and up

• Multicenter study

Natural History of Rett and Related

Disorders


Biobanking of RettSyndrome and

Related Disorders


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Apraxia/dyspraxia of motor movements

‐‐Language abilities

‐‐Fine motor movements

‐‐Gross motor skills

Praxis able to think of a motor task and execute it

Apraxia Inability to perform complex coordinated motor movements despite having normal strength and sensation

Ideomotorcan not perform a task to command, imitate gestures, They know what to do but are not able to execute it

Ideationlost/difficulty conceptualizing how to use an object(do not know objects purpose), plan and then performing

Dyspraxia Decreased ability to perform motor actions

Apraxia Often due to lesions in the dominant parietal or frontal lobes, although can be in non‐dominant hemisphere as well.

CNS insult: stroke, tumor, bleed, TBI

Genetic causes—Rett syndrome

Unknown

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• Diffuse volumetric reduction in brain matter thru out brain

• Greater reduction found in the left inferior parietal lobe

• tactile processing, pain, hand proprioception

Brain MRI Selective cerebral

volume reduction in Rett Syndrome: a multiple approach

MRI study

Carter JC, Lanham DC, Pham D, Bibat G, Naidu S, Kaufmann WE.

AJNR Am J Neuroradiol. 2008 Mar;29(3):436‐41.



MRI study



• Diffuse volumetric reduction in brain matter thru out brain

• Greater reduction found in the left inferior parietal lobe

• tactile processing, pain, hand proprioception

• Bilateral dorsal posterior parietal regions

• limb, ocular movements, connections to the premotor cortex

• Anterior Frontal cortex –greater the volume loss, the greater severity (gait)



MRI study





MRI study



Alan Percy –Advance in Neuroscience

Relative brain volumes in twins

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Rett Neurons

Apraxia/dyspraxia of speech

In stage 3 apraxia/dyspraxia

4‐16% of girls with RS speak words

“Not being able to talk is not the same as not having anything to say.”

Rosemary Crossley PhD ‐ Speech/communication

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Prelinguistic forms of communication

Eye contact (most common)

Vocalization (second most common)

Sounds

Laugh

scream

Smile/laugh

Cry

Tensing

Facial expression(happy, sad, fearful)

Lean towards an object

Reach for an object/bat/grab an object

Touch

Walk

Studies show…

Coss et al. (2003)

Coss et al. (2003)

• 87 subjects

• 66% eye pointing

Lavas et al. (2006)

Lavas et al. (2006)

• 125 subjects

• 90 % eye pointing

Bidden et al. (2010)

Bidden et al. (2010)

• 120 subjects

• 95% eye pointing

Communication Strong desire to communicate Strong desire to communicate

Receptive language superior to expressive languageReceptive language superior to expressive language

True intellectual/cognitive abilities are not well known because it is difficult to test due to:


• apraxia of hand movement

• poor eye‐hand coordination

• praxia of speech

Do know that they know much more than what they show!

Communication Strong desire to communicate Strong desire to communicate

Receptive language superior to expressive languageReceptive language superior to expressive language



• apraxia of hand movement

• poor eye‐hand coordination

• praxia of speech

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Draw attention to themselves

To show their wants/needs

Reject

To show their feeling towards activity/situation/person

Make choices

Communication…Knowing…

Opportunity to CHOOSE:

Show two real objects

Show them pictures of objects

Yes –No board

Use of augmentative and alternative communication approaches/devices

Sophisticated

Symbolic speech

Communication…PECS

Communication Book

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Screen‐touch‐eye gaze

Eye gaze tracker

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Dyspraxia Have a specific intention action

In order to perform an action:

understand the task(ideation)

organize, plan, and recollect past experiences

carry it out

Girls will look at an object for a long time prior to reaching…

Girls will look at an object for a long time prior to reaching…

Automatic, spontaneous movements are easier

‐scratching nose, rubbing eyes

‐automatic‐voluntary dissociation

Emotions Task associated with emotion easier to perform

Excited about cake may be able to grab cake

May not be able to repeat activity

Some may see this as stubborn child

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• 30% were unable to grasp any of the objects

• 17% ‐hold an object when been placed in hand

• 12% ‐grasp and continue to hold a large object using cylindrical or spherical grasping

• 40.3% ‐ had finer grasping skills could pick up a piece of food

• Some were able to transfer

Downs, J et al, 2010:

Hand function in 144

children/women with RS

Developmental Medicine and child neurology


Hand function in 144

children/women with RS

Developmental Medicine and child neurology

Motor planning theoryPractice skills

Intrinsic feedback(perform and reach goal)

Extrinsic feed back(encouragement, compliment)

Rest periods

Perform under new conditions (place, different object)

Stereotypies Joined hand movementsJoined hand movements

• wringing, hand clasping, mouthing, clapping

Single hand movementsSingle hand movements

• tapping, mouthing, finger rubbing

Most commonmidline wringingMost commonmidline wringing


Stereotypies Joined hand movementsJoined hand movements

• wringing, hand clasping, mouthing, clapping

Single hand movementsSingle hand movements

• tapping, mouthing, finger rubbing

Most commonmidline wringingMost commonmidline wringing

Leave them alone unlessLeave them alone unless

• Restricting hand use

• Causing self injurious behaviors: biting, chewing, rubbing‐> skin break done

TREAT: SOFT MATERIALS THAT RESTRICT MOTION AROUND ELBOW TREAT: SOFT MATERIALS THAT RESTRICT MOTION AROUND ELBOW


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Elbow immobilizers Consider the following in therapy…

Develop a relationship

Working with hands ‐ start by rubbing, passively rotating, she will take note of her hands

Be certain she is seated properly with support and give her space to move

Do not like small rooms or crowded spaces

Use toys/objects that are of interest to her

Consider the following in therapy…

Develop a relationship

Working with hands ‐ start by rubbing, passively rotating, she will take note of her hands

Be certain she is seated properly with support and give her space to move

Do not like small rooms or crowded spaces

Use toys/objects that are of interest to her

Give her time to perform the activity

Repeat, demonstrate, verbalize, and assist when needed

Music

Like soft whisper

Family members, pets, videos for anxiety

Start with easy goals and then increase depending on skill level

Gait

~80% ambulate, about 30 % loose this ability later in life

Some girls never sit, stand or walk

If non‐ambulatory most girls can walk with assistance

Encourage walking in those that can

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Apraxia/dyspraxia

Ataxia/balance

Spatial disorientation

Hypotonia

Hypertonia/spasticity

Rigidity

Dystonia

Foot deformities

Scoliosis

Gait

Wide based

Ataxic

Wandering

Initiate gait by stepping backwards first

Hypertonicity in Achilles tendon Child tilts to side or tilt pelvis backwards

throwing off balance

Rocking

Benefits of ambulationHelps prevent osteoporosis/osteopenia

Helps prevent scoliosis‐

• spinal abnormalities found in 80‐85% adults

• 25% mobile, 61% non‐mobile

Strengthens lower extremities

Improves cardiovascular function

Improves focus, concentration, mood –best to perform academic skills after therapy

Non‐ambulatory

Standing frame daily

Standing reduces the risk for osteoporosis

Prevents hip dislocations assisting in normal growth and development of hips

Improving balance and postural control

Use most active systems

2 hours a day

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Gait trainers Standers

TONE abnormalities:

Tone: normal tone, hypotonia, hypertonia, rigidity, dystonia

Infants: normal or hypotonic

Over time many develop hypertonicity and/or rigidity

ankles, extremities, trunk

Dystonia: pulling of muscles into an unwanted position when performing a specific activity, can cause spasms or pain

Therapy for increased tone

Hip joints: adductors or flexors muscles can be tight

• place prone lying position, hippotherapy

Ankle hypertonicity‐often positioned in plantar flexion with supination

• preventive splinting with AFO’s

• daily standing, use platform with a wedge

• Range of motion exercises

Medications: Baclofen, Botox

Surgery

Solid and hinged AFO’s

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Non‐pharmacological treatment

Improve muscle tone and range of motion

Improve and preserve mobility

Improve apraxic movements

Improve cardiovascular fitness

Improve ataxia and balance through daily exercises and activities including walking, stander, gait trainer

Gradually increase postural awareness through exercises

Improve body awareness by deep proprioceptive input and active motion

Prevent and/or improve scoliosis

Improve and work on protective reflexes

Considerations during physical therapy

Fear of movement: First bond with patient

Careful, slow manual manipulation: prone to fractures due to low bone mineralization, high pain tolerance and slow reaction time

Music is a motivator and can ease anxiety during therapy

Prefer soft whisper

Use interesting toys or gadgets with ample opportunity for tactile experiences

• 30% were unable to grasp any of the objects

• 17% ‐hold an object when been placed in hand

• 12% ‐grasp and continue to hold a large object using cylindrical or spherical grasping

• 40.3% ‐ had finer grasping skills could pick up a piece of food

• Some were able to transfer


Hand function in 144 children/women with

RS Developmental

Medicine and child neurology


Hand function in 144 children/women with

RS Developmental

Medicine and child neurology

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• Evaluated motor deficit in heterozygous Mecp2 female mice and showed that training on rotarod improved their performance to that of wild type mice.

• Noted an increase in BDNF

Environmental enrichment

ameliorates a motor coordination deficit in a mouse MODEL of Rett syndrome Mecp2 gene dosage effects

and BDNF expression

Kondo et al, European journal of neuroscience

Environmental enrichment

ameliorates a motor coordination deficit in a mouse MODEL of Rett syndrome Mecp2 gene dosage effects

and BDNF expression

Kondo et al, European journal of neuroscience

• Evaluated 5 girls, by way of prompting and reinforcement showed that they had improved their ability to self feed.

Teaching self‐feeding skills to patients with Rett

Syndrome

Developmental Medicine and Child Neurology,

1993

Teaching self‐feeding skills to patients with Rett

Syndrome

Developmental Medicine and Child Neurology,

1993

• 11 year old underwent hydrotherapy for 8 weeks and found to have improvement in stereotypic movement, functional hand movement, gait, balance and anxiety.

Hydrotherapy for Rett Syndrome

Journal of Rehabilitation Medicine 2003

Hydrotherapy for Rett Syndrome

Journal of Rehabilitation Medicine 2003

• 4 girls

• 8‐11 years

• Treadmill speeds 0.5km‐1.5 km/h depending on ability

• Low rails, hands strapped by Velcro and therapists there to help

• Time increased to 30 minutes over 3 week period

• Total intervention 2 months

• The average heart rate during activity: 145 121

• Improvement in knee walking, going up and down stairs, and walking speed for a distance of 25 m

Improving functional skills and physical fitness in children with Rett syndrome

M. Lotan,1 E. Isakov2 & J. Merrick3 Journal

of intellectual disability research,

2004

Improving functional skills and physical fitness in children with Rett syndrome

M. Lotan,1 E. Isakov2 & J. Merrick3 Journal

of intellectual disability research,

2004

Well designed studies are needed to evaluate therapeutic effects on motor outcomes

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References‐links https://www.researchgate.net/publication/23934818_Gross_Motor_Profile_in_Rett_Sy

ndrome_as_Determined_by_Video_Analysis

https://www.researchgate.net/publication/250921473_Perspectives_on_hand_function_in_girls_and_women_with_Rett_syndrome

https://www.researchgate.net/publication/10878900_Hydrotherapy_for_Rett_Syndrome

https://www.researchgate.net/publication/5298678_Environmental_enrichment_ameliorates_a_motor_coordination_deficit_in_a_mouse_model_of_Rett_syndrome_Mecp2_gene_dosage_effects_and_BDN

http://www.sld.cu/galerias/pdf/sitios/rehabilitacion‐equino/jidr‐2004‐rett‐lotan.pdf

References continued https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837828/

https://www.hindawi.com/archive/2014/345270/

Advances in Neuroscience

Volume 2014 (2014), Article ID 345270, 20 pages

http://dx.doi.org/10.1155/2014/345270

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Documents

Rett syndrome therapy for WEbinar COMBINED MMrev · 2017-05-31 · Bruxism while awake 3. Altered sleep pattern 4. Abnormal muscle tone 5. Peripheral vasomotor disturbance 6. Scoliosis/kyphosis