11/14/2013 1 The Quest for the Perfect ASD Medical Intervention Ricki Robinson, MD, MPH Co-Director Descanso Medical Center for Development and Learning La Canada CA Clinical Professor of Pediatrics Keck School of Medicine at USC www.DrRickiRobinson.com Copyright 2013 • Review causes of ASD that require Treatment • Discuss Multifactorial Treatment planning in ASD • Consider Medical Conditions associated LECTURE OVERVIEW • Consider Medical Conditions associated with ASD • Present Illustrative Case Examples • Introduce Pediatric Approach to Clinical Problem Solving Copyright 2013 Cause Cause Cause Cause Cause Common Pathway ASD Pathway Core Symptoms + + + (heterogeneity) Copyright 2013 ASD Medical Concerns Comorbidities Double Syndromes Idiopathic Copyright 2013
Transcript
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The Quest for the PerfectASD Medical Intervention
Ricki Robinson, MD, MPHCo-Director
Descanso Medical Center for Development and LearningLa Canada CA
Clinical Professor of PediatricsKeck School of Medicine at USC
www.DrRickiRobinson.comCopyright 2013
• Review causes of ASD that require Treatment
• Discuss Multifactorial Treatment planning in ASD
• Consider Medical Conditions associated
LECTURE OVERVIEW
• Consider Medical Conditions associated with ASD
• Present Illustrative Case Examples
• Introduce Pediatric Approach to Clinical Problem Solving
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Cause Cause Cause Cause Cause
Common Pathway
ASD
Pathway
Core Symptoms
+ + +(heterogeneity)
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ASD
Medical ConcernsComorbidities
Double Syndromes
Idiopathic
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• ASD specific
• DIR/FT model specific
• Double syndrome specific• Double syndrome specific
What are Mitochondria?Structures within cellsPlay central role in metabolismCells’ energy producersContain own DNA which directs mitochondria how to produce energyBrain and Muscles put great demands on body’s energy systems
Dysfunctional Mitochondria can result in problems in:ThinkingMovement
Recently associated with ASD: Poling, J. (2008) ‘Dad in autism vaccine case speaks out.’ WebMD Health News Mar 6; webmd.com/brain/autism/news
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Mitochondrial Disorder Symptoms
Low muscle tone
Major difficulties with feeding
Developmental delay
Seizures
All may overlap with ASD
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Diagnosis of Mitochondrial DisordersDifficult to diagnose
Blood lactate/Pyruvate
Muscle Biopsyp y
EEG
EMG
Molecular testing for Mitochondrial DNA
May require consultation with genetic/metabolic specialist
Consider periodic genetic re‐testing for all individuals with ASD as methodologies individuals with ASD as methodologies improve (if warranted by history/physical)
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• Seizures
• GI
• Immune problems
• Sleep
• Psychiatric
• Any other related health issues
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• Psychopharm Management
• Catatonia
• PANDAS
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www.DrRickiRobinson.com
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• Are medical concerns causative or secondary to ASD?
• Examples• F d iti iti ( l t i )• Food sensitivities (gluten, casein)
• Genetic disorders (e.g. Fragile X)
• Infantile Bipolar disorder
• Seizures
• Mitochondrial disorders
• MET gene mutationCopyright 2013
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• Observations• Many individuals with ASD exhibit GI, immune, seizure symptoms
• GI symptoms frequently reported:• Chronic diarrhea
C ti ti• Constipation• Abdominal discomfort
• GERD• Food intolerance
• GI symptoms significantly increased in ASD vs. controls (typically developing and non‐ASD developmental disorders)
ValicentiValicenti--McDermott M., et al. McDermott M., et al. J Dev Behav PediatrJ Dev Behav Pediatr 2006:27 (suppl 2): 2006:27 (suppl 2): S128S128--S136S136Copyright 2013
• Hypothesis: similar gene(s) influence both neurological and GI function in ASD
• MET Gene• Location on 7th chromosome (known ASD candidate)• MET signaling key component
MET Gene Association: ASD
• In brain growth of cortex and cerebellum• Immune function• GI repair
• MET protein significantly decreased in post‐mortem temporal cortex of individuals with ASD compared to match control
Campbell DB, et al. Ann Neurol. 2007;62(3):243-250Copyright 2013
AGRE families(multiplex)
214 families / 918 individuals
Phenotype / Genotype
Campbell, D.B., Buie, T.M., et al. Pediatrics 2009;123;1018-1024.
MET rs1858830C
allele determined
118 Families with at least one child with presence of ASD +
GI symptoms
96 Families with ASD and no GI
symptoms
+ -
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•• C Allele disrupts transcription of the MET gene. This equals C Allele disrupts transcription of the MET gene. This equals reduced gene signaling reduced gene signaling which could therefore which could therefore contribute to a syndrome that includes ASD with contribute to a syndrome that includes ASD with coco‐‐occurring GI conditionsoccurring GI conditions
•• ReducedReduced MET signaling in the brain results in:MET signaling in the brain results in:•• Abnormal interneuron migration in frontal and parietal Abnormal interneuron migration in frontal and parietal
MET Gene Signaling in ASD
•• Abnormal interneuron migration in frontal and parietal Abnormal interneuron migration in frontal and parietal regions of regions of cortexcortex and and hippocampushippocampus
•• Decreased proliferation of granule cells and size of Decreased proliferation of granule cells and size of cerebellumcerebellum
•• Decreased augmentation of Decreased augmentation of NMDANMDA neuronsneurons
• Partial list of common issues often overlooked:• General (sleep disorders, feeding issues)• Infection (otitis media, sinusitis, streptococcus)• Allergies (environmental, food)• Immunologic (PANDAS)• Gastrointestinal (GERD, constipation)• Urologic (infection, atonic bladder)• Endocrine (puberty related, hormone deficiency)• Neurological (seizures, migraines)• Dental (carries)• Medication Related (side effect)• Pain (from any source)
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• High index of suspicion with increasing ASD symptoms
• Consider untreated URI may be acute or chronic e.g.• Otitis media• Sinusitis• Untreated Group A Streptococcal tonsillitisUntreated Group A Streptococcal tonsillitis
• UTI
• Aggressively diagnose & treat
• Problem: under‐served population
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• Allergies occur in approx 20% pediatric population
• Allergic rhinitis, asthma, atopic skin disease
• Food & environmental antigens
• Needs to be diagnosed & treated vigorously
• Pediatric allergist referral if needed
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• More common than expected?
• Studies documenting rates of GI symptoms in ASD reveal higher rate than:
• Children with typical development• Children with typical development
• Children with other developmental disabilities
Valicenti‐McDermott et al Peds 27 (2 Suppl): S128‐36
www.medicalnewstoday.com/articles/268522.php
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• Chronic Diarrhea or Constipation
• Feeding, eating disorders
• Change in sleep patterns
• Food allergies or apparent reactions with eating particular foods
•• + Interstitial mucosal biopsy+ Interstitial mucosal biopsy•• Treatment = no gluten Treatment = no gluten –– lifelonglifelong•• New study New study –– no increased celiac disease in ASDno increased celiac disease in ASD
•• Possible SensitivityPossible Sensitivity•• +Serology+Serology•• ‐‐ Intestinal biopsy for any degree of inflammation Intestinal biopsy for any degree of inflammation
• May still consider ELIMINATION TRIAL:• Know what symptom(s) are being treated
• Eliminate one food at a time
• Double blind follow up if possible
• Reintroduction to test onset of symptoms with possible offender
• Consider reintroduction of small amounts eventually
• Casein elimination requires protein/Ca/vit D replacement
• Multiple food elimination – work with MD or nutritionist
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• A child who feels good can interact, think and make developmental progress
• Consider early and often the possibility of GI issues with increasing ASD behaviors
• Not making the correct diagnosis can lead to serious consequences
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• 16.5 year old male• Non‐verbal, NDD Type IV• Types slow if independent; quick with support at elbow and shoulder• 3‐4 week history of spitting numerous times per hour (all environments)• Parents, therapists, teachers very upset. Attributed to his hostility,
threatening punishment as a response.• Lately, in addition to spitting
• He started hitting & scratching his chest • If someone was in the way, they were often hit (interpreted as aggression)
S
• Mother fearful of being hurt• No new changes at school or home to explain behavioral change (except for
heightened anxiety of adults as symptoms persisted)• Symptoms seemed to be unrelated to eating or sleeping• No one was aware whether any dysregulated sleep occurred• Review of Systems otherwise unremarkable• When Mike was asked about pain:
• My body is hurting all over, especially my heart he replied.• “Is it worse when you lie down?”
• Yes
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• Appeared very dysregulated• More anxious than usual – fidgeting and darting around the room• Before Mike would spit could observe:
• accumulating saliva in his mouth• followed by spitting• hitting & scratching his chest• ballistic arm movements
• Unable to examine abdomen
O
• Spitting behavior:• most likely from excess saliva • following reflux of stomach acid (heart pain)• motor system not responding well• probable GERD
• Source of pain not clear to Mike• linked to what he knew about location of his heart
• Aggression not intentional – response to pain
A
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Demystification with MikeTalked directly to him Explained what was happeningTold him not a heart issueHe relaxed Suggested he could swallow his saliva instead of spitting (practiced)Let him know I would prescribe a medication that would help
within 1‐2 weeks
P
Demystification with Family and TeamHad meeting later in the week to discuss how to be prepared for
behavioral episodes
Medical treatment trial: PrevacidBetter in a few daysAll symptoms resolved 2 weeks later
Interoceptive Sense is important to understandingand responding appropriately to body needs
Behavior = body needs in ASDCopyright 2013
• More common in ASD
• General population 0.5%
• ASD population 4‐40%
• Most likely occur in ASD
f • Before age 5
• After puberty
• Seizures
• Impact child’s language, motor planning, sleep, learning, interactions
• May result in regression
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Types of Seizures
• Generalized
• Grand mal
• Petit mal (absence)( )
• Partial
• Simple (no loss of consciousness)
• Complex (altered state of consciousness affecting ability to perform)
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Detecting Subtle Seizures• Children often described as unfocused,
spacey, dreamy, autistic‐stare
• In play look for “starts and stops”p ay oo o sta ts a d stops
• Characteristic EEG findings for major seizure disorders
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• EEG findings in children with ASD who do not have seizures (subclinical epileptiform discharges‐SEDs)
• “Sharp waves” and “slowing patterns” intermixed with typical electrical activity
• Generally found in temporal lobe region of brain• Generally found in temporal lobe region of brain
• Abnormalities more obvious in sleep
• 50‐60% in overnight EEG
• 14% in 2‐hour
Chez et al (2006) Epilepsy and Behavior 8:267-271
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• SEDs may:
• impact child’s functioning
• interfere with learning and relating
• go unnoticed in your child’s daily life
• Studies in adults experiencing SEDs
• Difficulty driving
• Cognitive loss relative to area where SED occurs
• Can’t be a pilot in Europe
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• What does SED look like?• Subtle seizure pattern• May not notice until looking back after
treatment improvement
• Look at behavior overall• Brief staring spells • Major receptive language delay
• Motor planning challenges• Difficulty sleeping
• Regression• SEDS a possibility
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• Frequency of SEDs
• Chez et al found 60.7% of 889 children with ASD and no history of seizures
• 1.4% of typical
• My approach
• All children with ASD deserve an overnight EEG evaluation
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• Cause of SEDs
• Possible immune reaction
• Pardo et al found factors related to a neuroimmune reaction in CSF of children with ASD (? Chicken or egg)(? C c e o egg)
• Children treated with anticonvulsant (Depakote) plus steroid anti‐inflammatory medication can normalize EEG resulting in improved receptive language abilities
Chez et al. (1998) Annals of Neurology 44:539 (Abstract)Pardo, et al. (2005) International Review of Psychiatry 176(6):485-95
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• Treatment of seizures
• If seizure disorder, standard protocol with anticonvulsants
• If SEDs, options:
W it d t h• Wait and watch
• Treat anticonvulsants (Depakote)
• Little treatment response, may add steroids
• Required monitoring for serious side effects
• Initial target for improvement: receptive language
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Problematic Sleep PatternsBreathing Pattern % Preschool Age
ChildrenSnoring / Difficulty breathing 5‐12
Waking during the night 16‐25
ff l ff lDifficulty getting off to sleep ~ 9
Seeming tired in the morning ~ 1
(Rosen et al, Ped 2004; 114(6): 1640-48)Copyright 2013
Breathing Pattern % Preschool age children
Snoring/difficulty breathing 5‐12
Waking during the night 16‐25g g g
Difficulty getting off to sleep ~ 9
Seeming tired in the morning ~ 1
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• Population‐based study Parent‐reported neurobehavioral issues with SDB (pre‐schoolers)
•Neurobehavioral issues
•Hyperactive / inattentive behavior
•Daytime tiredness / sleepiness
•Emotional / social problems
• Significantly associated with snoring
• Significant improvement with snoring cessation
(Urschitz et al, Ped 2004; 114 (4): 1041-48)Copyright 2013
• School‐aged children problematic sleep patterns impact adversely on:
•Behavior• School functioning•Health related quality of life
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829 inner‐city children 8‐11 years old
SDB = Primary Snoring to Obstructive Sleep Apnea(OSA/objective measurement)
SDB:
OSA (40/829) 5%
Primary Snoring (122/829) 15%
Neither (667/829) 80%
SDB Significant Increase Behaviors:Externalizing
Hyperactive
Emotional lability
Oppositional
Aggressive
Internalizing
Somatic complaints
Social behaviors (Rosen et al, Ped 2004; 114(6): 1640-48)Copyright 2013
• Sleep apnea has been shown to kill neurons• Intermittent hypoxia kills rodent cells in the
hypocampus (key memory center)
• Interferes with process of long‐term potentiation (strengthening of neuro‐connections crucial for learning and memory)g y)
• Surgical Rx (adenotonsillectomy) for OSA resulted in significant improvements in ADHD symptoms compared to methylphenidate treatment
(Huang et al, Sleep Med 2007; 8:18-30)
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• Historically major sleep problems in ASD patients
• Need to document sleep issues in large ASD populations to determine rate compared to typical pediatric population
• Expect at least as many SDB as typical in ASD
l i di l l d (E l d) fi d f • 2013 longitudinal sleep study (England) confirmed for children with ASD (compared to typical)
• Sleep duration decreased from 30 months of age until adolescence due to:
• Later bedtime
• Earlier waking
• Frequent waking during night
Arch Dis Child published online 9/23/2013 doi: 10.1136/archdischild-2013-304083Copyright 2013
• Difficulty falling asleep
• Difficulty staying asleep
• Difficulty arising in the a.m.
• Waking up at night (“ready to go”)
• Moving all over the bed
• If consistent & persistent sleep behavior over long period
• Possible sleep disorder
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• Need to know your child’s pattern of sleep
• Develop consistent routines
• Sleep survey and suggestions to help in Autism SolutionsAutism Solutions
• Role of Melatonin
• Consider sleep disorder if warranted
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• Sleep disorders differential diagnosis
• REM Behavior Disorder (RBD)
• Periodic Limb Movement sleep (PLMS)
• Obstructive Sleep Apnea (OSA)
• Bruxism
• Epilepsy (seizures)
(Thirumalai, Robinson, Ricki et al. Jrnl Child Neurology. March 2002; 17:3: 173-178)
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Patient Age Gender Diagnosis
GK 3 F RBD
AS 4 M RBD, OSA
JS 9 F RBD, Seizures
JS 3 M RBD
DS 3 M OSA
ZV 4 M PLMS, Seizures
BD 8 M Bruxism
MN 4 M OSA,, PLMS
RR 5 M PLMS, Bruxism
KP 4 M PLMS
RBD – Rem Behavior DisorderOSA – Obstructive Sleep ApneaPLMS – Periodic Limb Movements of Sleep
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(Thirumalai, Robinson, Ricki et al. Jrnl Child Neurology. March 2002; 17:3: 173-178)
Disorder # Treatment
REM Behavior Disorder (RBD 4/10 Clonazepam, Valproic acid
Periodic Limb Movement (PLMS)
4/10 Clonazepam, Galapentin
Obstructive Sleep Apnea 3/10 T & AObstructive Sleep Apnea (OSA)
3/10 T & A
Bruxism 2/10 Bite Splints
Epilepsy 2/10 Valproic Acid, Prednisone
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(Thirumalai, Robinson, Ricki et al. Jrnl Child Neurology. March 2002; 17:3: 173-178)
What could have been missed?
C ti hi !!Continue searching!!
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18 year old female
Diagnosed with ASD at age 3
Evaluated by SIG age 5 RR referralDIR/FT model approach – NDD type III
Multidisciplinary program
Supported communicationSupported communication
Additional diagnoses (over time)Seizure disorder
Attentional issues
Anxiety
Pubertal mood swings
All controlled by treatment
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• Laboratory• Abnormal EEG• Normal genetic testing (karyotype, fragile X)
• Seen by over 10 medical consultants
• Clinical progress• Dyspraxia without motor deterioration• Unexplained urinary retention
Copyright 2013 Copyright 2013 Video 2 – G Fall 2010
I think a good friend needs to be a good listener above all. This is something I am still learning to do and I need help with sometimes. For the first time in my life I feel that recently I have made real friends, not circumstantial ones from my family or from school. When I started typing a few years ago it opened the door of communication for me, but it took a while for me to climb the language ladder enough to have a meaningful climb the language ladder enough to have a meaningful conversation. Since I have reached that point in the last year, I have been leaning a lot about the dynamics of friendship that I previously hadn’t experienced. So far, I think that just being there for a friend during a tough time and listening – not just listening but offering understanding – is the best thing you can do for someone. I hope I can do at least that much for my friends.
Copyright 2013 Copyright 2013 Video 3 – G Mag
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What do you observe?
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• My reaction:
• Clinical course did not “fit” what we know about the double syndromes, yet ?????
• Decision to repeat genetic testing using • Decision to repeat genetic testing using contemporary methods:
•MECP2 mutation identified
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• Clinical syndrome based on distinct set of clinical features in a girl
• Normal birth and development
• Followed by period of developmental stagnation
• Regression in language and hand use
• Development of repetitive hand stereotypies
• Difficulty with walking
• Related to mutation MECP2 gene
• MECP2 located on X chromosome
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RETT Syndrome Case StudyMotor Regression ?
Gait abnormalities Mild dyspraxia
Hypotonia +/-
Difficulty feeding No
Loss of purposeful use of hands Nop p
Compulsive hand movements (wringing, washing)
No
Autistic-like behaviors Yes
Seizures Yes
Abnormal sleep patterns Yes
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• Identifying increased number of individuals who do notmeet typical criteria of Rett Syndrome but who have other neurodevelopmental disorders as ASD, intellectual disability or other neurologic problems
Si hi i l i l l hi d • Since this is relatively new, natural history and prognosis for these individuals not known
• Monitor for GI dysfunction, autonomic dysfunction and further seizures
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• Consultation at Rett Syndrome centers
• Family joined Rett and MECP2 complex support groups
• Enrolled in the MECP2 Complex natural history study
• Potential treatment?
• Daily injections of insulin‐like growth factor(IGF‐1) extended the life span of infant RettSyndrome mice and improved their motor function
• Clinical Trial with medication used for MS
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• If parent reports sudden change• repetitive/OCD/tic behavior• activity• aggression
Behavior change = cry for help!Behavior change cry for help!
• DIR Model approach• Take history• Environmental changes (emotional, situation,
physical‐external/internal)• PE / Floortime observation
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• Common entities happen commonly!
• Infection
• Allergy
Mi i• Migraine
• Constipation
• Sleep changes
• Adverse response to meds
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• Follow up considerations• Seizures (especially if regression)• Co‐morbid psychiatric disorders• Autoimmune issues
• Lab Tests• GABHS• GABHS• ASOT• Anti DNAse• UA/UC• Abdominal XRay• Sleep EEG if needed• Others warranted by Hx/PE
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• Treatment
• Appropriate to Dx
• Medicine trial often used e.g.:
• Anti‐inflammatory (migraine)
• Neuropsychopharmacology
• If resolution
• Close follow up required
• Documentation/timeline very useful (e.g. seasonal affective disorder)
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• No improvement despite best efforts –BACK TO THE DRAWING BOARD!
• Potential Reasons:
• Development is uneven leaving big gaps – e.g. “comprehension wall”
M di l i di d d• Medical concern is not diagnosed or treated
• Challenging individual difference not understoodor untreated (e.g. V/S)
• Emotional issues not supported (e.g. anger, sadness, fears)
• Family issues unresolved and/or not addressed
• OthersCopyright 2013
10 year old male with ASD, NDD Type III
Sudden onset increasing aggression with self injury
Poor sleep
S
p
Rocks in his bed at night
Eventually kicks hole in wall behind his bed
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Further history obtained
Previous episodes of vocal tics (sounds and spitting)
‐ age 8 and 9
Episodes were secondary to “strep” infections
S
Episodes were secondary to strep infections
Positive response to extended antibiotic treatment
New episode – no environmental changes
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In the exam room:• No tics or spitting observed
• Anxious
• Highly over‐reactive
O
• Kinetic movements
• Fidgety
• Ballistic arm gestures
• Mother extremely anxious and worried
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• Possible recurrent secondary effects of recurrent strep
• Possible PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders)
A
Laboratory confirms PANDAS
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Tension at Home
Over-reactive
PANDAS
Tics, Spitting
Motor challenge
Poor comprehension
PhysicalSymptoms
A
+ Fidgety
+ Ballistic+ Over Kinetic
+Aggression
Add fuel to the
fire
MentalSymptoms
EmotionalSymptoms
Symptoms
ANXIETY
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• Demystify
• Treat the primary problem with appropriate follow up
P
• Educate
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• Age 17 – ALL of his symptoms return
• Team unable to maintain his regulation to keep him secure in any setting
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Now What?
Symptoms may return but
etiology may be different . . .
requiring
new problem solving
Must remain vigilant!!
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p gand
new solutions
Requires the entire treatment team to provide solutions
Child
FCD
BehavioralMental Health
SLP
CreativeArts
DIRModel
Community
Optometry ParentsCaregiverFamily
OT
Education
Medical
PT
Other
FCD =Foundational Capacities for Development DIR Model =
Social Emotional DevelopmentIndividual DifferencesRelationships
Optometry
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Child
FCD
BehavioralMental Health
SLP
CreativeArts
DIRModel
Development Emotional regulation
Language:‐ receptive /
expressive ‐ comprehension‐ motor ability
‐ gestures‐ oral
language
TalentSkillEmotional expression
Behaviors derailing development
ParentsCaregiverFamily OT
EducationMedical
PT
‐Sensory responsiveness‐Sensory processing
‐Motorplanning
Grossmovement & coordination
Health & well‐beingVisual spatial
Factors relating to academic success – ability to learn and advance (e.g. read, write, math, comprehend)
OptometryVisual Integration
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Child
FCD
DevelopmentalPediatrician
Pediatrician/Family Doctor
GI
NeurologistDIR
Model
Community
ParentsCaregiver
Family Sleep
Psychiatry
Dental
Immunology
Other
FCD =Foundational Capacities for Development
DIR =Social Emotional DevelopmentIndividual DifferencesRelationshipsCopyright 2012
Dietician
Potential case manager
Keeping a child healthy is a necessary step to assuring developmental growth
Complex medical problems often require a
Finding a health care provider who can work together
with your child and your family in partnershipover the long term is the most ideal situation
p p qmulti‐disciplinary medical teamto address all of the child’s needs
Don’t forget that medical conditions for all of us changes over time and need to be
addressed in creative ways
Getting help is a major step in making this happen for every child
