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PERVASIVE DEVELOPMENTAL DISORDERS A PEDIATRIC NEUROLOGICAL PERSPECTIVE

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Title: PERVASIVE DEVELOPMENTAL DISORDERS A PEDIATRIC NEUROLOGICAL PERSPECTIVE


1

PERVASIVE DEVELOPMENTAL DISORDERS
A PEDIATRIC NEUROLOGICAL PERSPECTIVE
  • DIAGNOSTIC CLASSIFICATIONS
  • NEUROLOGICAL CONSIDERATIONS
  • THER APEUTIC INTERVENTIONS (ESPECIALLY
    PHARMACOTHERAPIES)

2
PERVASIVE DEVELOPMENTAL DISORDERS
  • AUTISM
  • ASPERGERS
  • PDD, NOS
  • CHILDHOOD DISINTEGRATIVE DISORDER
  • RETTS

3
PDD/AUTISM SPECTRUM
  • DEFICITS IN SOCIAL INTERACTION (DISORDERS OF
    EMPATHY)
  • DEFICITS IN VERBAL AND NONVERBAL COMMUNICATION
  • RESTRICTED, STEREOTYPED PATTERNS OF BEHAVIOR AND
    INTERESTS

4
Three Core Dimensions of Autism Spectrum Disorders
Social Phobia
SOCIAL IMPAIRMENT
Aspergers
Autism
OCD
COMMUNICATION IMPAIRMENT
RESTRICTED INTERESTS AND COMPULSIVITY
5
AUTISM SPECTRUM DISORDERS Complex,
Heterogeneous Disorders of Learning and Memory
  • Studies using fMRI have demonstrated Structural
    Differences in Multiple Brain Areas Involved
    with Working Memory, Declarative Memory, Habit
    Learning, Motor conditioning, Social Awareness,
    Linguistic Prosody, and Theory of Mind
  • These areas include Dorsolateral Prefrontal
    Cortex, Temporal Lobe, Hippocampus, Basal
    Ganglia, Cerebellum
  • But-FMRI studies require adequate performance of
    tasks being measured, for example, autistic
    individuals dont attend to the same facial
    features as do nonautistic individuals.

6
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7
BRAIN STRUCTURE AND FUNCTION
8
BRAIN STRUCTURE AND FUNCTIONS
9
MEDICAL/NEUROLOGICAL EVALUATION
  • MEDICAL AND NEUROLGICAL EXAMINATION
  • head circumference atypical physical
    features skin markings motor and sensory
    testing hearing, vision assessments cognitive
    and language functioning (with appropriate
    consultations,team evaluations)
  • IMAGING STUDIES/EEG AS INDICATED
  • GENETIC TESTING (chromosomes/microarray, FragileX
    DNA as indicated)

10
POTENTIAL TARGETS OF PHARMACOTHERAPY
  • Motor hyperactivity, Inattention
  • Repetitive behavior, tics
  • Aggression, self-injury, property destruction
  • Impaired social relatedness

11
ATTENTION DEFICIT, HYPERACTIVITY
  • IS ATTENTION DEFICIT IN PDD THE SAME AS IN
    ADHD?
  • STIMULANT EFFECTS
  • ON MOTOR STEREOTYPIES
  • ON COMPULSIVE BEHAVIORS
  • ON HYPERACTIVITY

12
Psychostimulants
  • Early studies with amphetamines disappointing
  • More recent small controlled studies of
  • methylphenidate improvement in
    hyperactivity and irritability in some
    individuals
  • Adverse effects insomnia, anorexia,
    irritability, aggression common
  • Ongoing controlled study of methyphenidate by
    multicenter network
  • Mixed data on Strattera, Aricept, Wellbutrin

13
Alpha2 Adrenergic Agonists
  • Clonidine Some benefits for hyperactivity,
    irritability, oppositional behavior, but adverse
    effects (hypotension, sedation, depression) in
    some individuals
  • Guanfacine-Usually less sedating than clonidine
    longer half-life than clonidine less
    hypotension. 1/3 show improvement in
    hyperactivity, inattention, insomnia and tics

14
RITUALIZED, COMPULSIVE BEHAVIORS
  • MOTOR STEREOTYPIES, RESTRICTIVE AREAS OF
    KNOWLEDGE
  • SIMILARITIES TO OCD
  • SEROTONIN IN OCD
  • SEROTONIN IN PDD
  • SSRIS IN PDD/AUTISM SPECTRUM DISORDERS

15
Serotonin Reuptake Inhibitors
  • Clomipramine (Anafranil)
  • Fluvoxamine (Luvox)
  • Fluoxetine (Prozac)
  • Sertraline (Zoloft)
  • Paroxetine (Paxil)
  • Citalopram (Celexa)
  • Escitalopram (Lexapro)

16
ANXIETY AND OVERAROUSAL
  • INSISTENCE ON SAMENESS
  • CATASTROPHIC RESPONSE TO CHANGE
  • HYPERVENTILATION, BREATHOLDING, AUTONOMIC SIGNS
  • TREATMENT WITH PROPANOLOL, CLONIDINE,
    BUSPIRONE, BENZODIAZEPINES (SPARINGLY), SSRIS,
    NEUROLEPTICS

17
AGGRESSIVE OUTBURSTS
  • BEHAVIOR MODIFICATION TECHNIQUES
  • TRADITIONAL NEUROLEPTICS
  • ATYPICAL NEUROLEPTICS
  • BETA-BLOCKERS AND ALPHA-ADRENERGIC AGONISTS
  • BUSPIRONE

18
Typical Neuroleptics
  • Haloperidol (Haldol) many studies in autism
  • Improvement in withdrawal, stereotypies,
    hyperactivity, lability of affect, negativism,
    angry affect.
  • Problem Acute and chronic dyskinesias

19
Atypical Neuroleptics
  • (Clozapine Clozaril)
  • Risperidone (Risperdal)
  • Olanzapine (Zyprexa)
  • Quetiapine (Seroquel)
  • Ziprasidone (Geodon)
  • Aripiprazole (Abilify)

20
Atypical Neuroleptics in Autism
  • Theoretical advantages Dual action-block
    Dopamine and increase Serotonin lower risk of
    tardive dykinesia
  • Most studies have been with Risperidone at
    least 50 of subjects have shown improvements in
    tantrums, aggression, self-injurious behavior.
    Side effects weight gain, fatigue, etc.
  • Fewer studies with other Atypicals, but Zyprexa,
    Seroquel, Geodon, and Abilify have shown similar
    benefits in pilot studies.

21
SELF-ABUSIVE BEHAVIOR
  • SIB WIDESPREAD IN MR, AUTISM
  • OPIATE HYPOTHESIS
  • SIB STIMULATES PRODUCTION OF ENDORPHINS
  • RELATIVE ANALGESIA IN PDD DUE TO HIGH
    ENDORPHINS
  • TREATMENT WITH OPIATE ANTAGONISTS (NALTREXONE,
    NALOXONE)

22
SELF-ABUSIVE BEHAVIOR
  • COMPULSIVE HYPOTHESIS
  • SIB REPRESENTS ANOTHER FORM OF COMPULSIVE
    BEHAVIOR
  • TREATMENT WITH SSRIS AND ATYPICAL
    NEUROLEPTICS

23
SLEEP DISTURBANCES
  • DELAYED SLEEP ONSET
  • PROLONGED NOCTURNAL WAKING
  • EARLY RISING
  • PHARMACOLOGICAL INTERVENTIONS
  • ANTIHISTAMINES, BENZODIAZEPINES, MELATONIN,
    CLONIDINE, TRAZODONE

24
CYCLICAL BEHAVIORS
  • PERIODS OF AGITATION, AGGRESSIVENESS, LITTLE
    NEED FOR SLEEP, ALTERNATING WITH PERIODS OF
    RELATIVE DOCILITY
  • HIGHER RATES OF BIPOLAR DISORDER IN RELATIVES OF
    PDD PATIENTS
  • TREATMENT WITH MOOD STABILIZERS LITHIUM,
    CARBAMAZEPINE, VALPROATE
  • TREATMENT WITH ATYPICAL NEUROLEPTICS

25
SOCIAL COGNITION/SOCIAL AWARENESS
  • UNDERSTANDING SOCIAL/EMOTIONAL MEANING OF OTHERS
    VERBALIZATIONS, FACIAL EXPRESSIONS, BODY
    LANGUAGE,
  • FORECASTING HOW THE OTHER PERSON MIGHT RESPOND TO
    CERTAIN SITUATIONS THEORY OF MIND (BEING ABLE TO
    PUT YOURSELF IN SOMEONE ELSES SHOES)
  • UNDERSTANDING LIKELY CONSEQUENCES OF ONES
    BEHAVIOR IN A SOCIAL SETTING

26
Neural Structures/Neurotransmitters Involved in
Social Cognition
  • Amygdala Links perceptual representations to
    cognition and behavior on basis of emotional and
    social value of the stimuli rapid processing of
    potentially threatening stimuli
  • Right somatosensory cortices involved in theory
    of mind tasks, judgment of others emotional
    states-empathy

27
Neural Structures/Neurotransmitters Involved in
Social Cognition
  • Prefrontal cortex and cingulate gyrus response
    selection, decision-making, volitional control of
    behavior, motivation,
  • Neurotransmitters oxytocin and vasopressin
    (hypothalamic), serotonin, endogenous opiates.
  • Proposed medications SSRIs, Glutamatergic
    Agents (e.g. Amantadine), Aricept,
    anticonvulsants (Lamictal, Keppra, Depakote),
    ?Oxytocin

28
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29
OxytocinA Neuropeptide for Social Recognition?
  • OT knockout mice have a selective deficit in
    social recognition
  • OT rescues the social recognition deficit via OTR
    mediated effects in medial amygdala
  • OT-KO data are consistent with comparative
    studies suggesting that OT is critical for
    processing social information and social
    information is special Ferguson
    et al. Nature Genetics, 2000

  • Ferguson et al
    J. Neuroscience, 2001

30
PRAIRIE VOLE Highly Social Biparental Pair
Bonds Separation Distress-High
31
MONTANE VOLE Asocial Minimally Parental Promiscuou
s Separation Distress-Low
32
Oxytocin/Vasopressin in Voles
  • Insertion of V1a receptor gene and prairie
    promotor in the montane voles results in
    increased social interest
  • Vasopressin facilitates behaviors associated with
    monogamy in male vole
  • AVP in males and OT in females appear necessary
    and sufficient for mating induced pair bond
    formation


  • Work of Thomas Insel,
    M.D., Director, NIMH
  • Proc.Natl.Acad.Sci,USA Vol89,pp5981-5985,
    July,1992

33
Oxytocins Potential for Treatment in Autism
(Hollander, et al, 2006)
  • Intravenous infusion of oxytocin in high
    functioning adults reduced repetitive behaviors.
  • Intravenous and intranasal oxytocin resulted in
    improved ability to assign affective significance
    to speech (e.g.social cognition)
  • Both short trials, preliminary data, etc. but
    promising new approach

34
SUMMARY
  • A Multimodal Approach is Imperative in the
    Treatment of Autism
  • Medications may frequently be of benefit to some
    individuals for targeted maladaptive behaviors
    and to enhance learning and social cognition
  • Well-designed studies are needed to fill in the
    many gaps in our current knowledge
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