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Physician Educa-on in Developmental Disabili-es Webinar

Series Characteris-cs of Neurodevelopmental Disorders;

The Five Essen-al Concepts

Seth M. Keller, MD

July 31, 2012

What are the facts?  Sixteen =mes as many people have intellectual disabili=es as have HIV

 Intellectual disability is fiHy =mes more prevalent than blindness

 Intellectual disability is twenty-‐five =mes more prevalent than deafness

 7.7% of the popula=on have neurodevelopmental disorders / intellectual disabili=es (ND/ID)

 22 million Americans with ND/ID

With respect to the dispari=es in healthcare;

 The medical and dental professions bear some responsibility for the dispari=es in:

-‐ Pa=ent Care

-‐ Teaching

-‐ Research

Results in dispari=es in access and quality of care

Curriculum Assessment of Needs (CAN) Project

 How many hours of clinical training in the care of pa=ents with ND/ID do our medical and dental graduates say they actually have upon gradua=on?

 Medical Students 81% report 0 hours   Dental Students 51% report 0 hours*

*JADA, March 2004 -‐ Wolff A.J.; Waldman H.B.; Milano M.; Perlman S.P.

Concepts needed for the op=mal prac=ce of Developmental Medicine;

The 5 Essen=al Concepts

1. Childhood onset Brain Dysfunc=on can lead to chronic disabili=es

2. Neurodevelopmental Disorder 3. Complica=ons 4. Consequences 5. Syndrome Specific Complica=ons

Why are the Five Essen=al Concepts so important?

 There is a widespread lack of a meaningful, scien=fically sound vocabulary or language, rooted in the basic principles of physiology and medicine.

 Healthcare providers need a biomedically-‐based conceptual framework, which provides a theore=cal basis for the clinical diagnosis and treatment of pa=ents with neurodevelopmental disorders.

The First Essen=al Concept  The major func=ons of the brain require that specific interrelated brain structures work together, in a coordinated fashion. When these rela=onships are improperly developed or disrupted, neurodevelopmental (brain) dysfunc6on will occur. All issues, clinical or otherwise, per=nent to the disability experienced by the individual with neurodevelopmental illness, can be traced directly to this brain dysfunc=on.

The Second Essen=al Concept  With the establishment of an accurate diagnosis, the underlying neurodevelopmental disorder responsible for the neurodevelopmental dysfunc=on can be iden=fied.

Neurodevelopmental Disorders  Neurodevelopmental disorders can be either gene=c or acquired.

  Gene=c causes:   Metabolic (PKU)   Chromosomal (Trisomy 21, Fragile X)   Structural (Spina Bifida, Sturge Weber)

 Acquired causes:   Prenatal (Fetal Alcohol Syndrome)   Perinatal (Hypoxic Injury)   Postnatal (Lead Toxicity)

Phenylketonuria Cri-‐du-‐Chat syndrome Homocysteinuria Fragile X syndrome Galactosemia Myotonic dystrophy Lesch-‐Nyhan syndrome Juvenile Huntington’s disease Metachromatic leukodystrophy Tuberous sclerosis San Fillippo syndrome Neurofibromatosis Down syndrome Lissencephaly Trisomy 13 Schizencephaly Trisomy 18 Septo-‐optic dysplasia Klinefelter’s syndrome Sturge Weber syndrome Turner’s syndrome Dandy-‐Walker malformation Arnold-‐Chiari malformation Velo-‐cardio-‐facial syndrome Ring 22 syndrome Agenesis of corpus callosum Angelman syndrome Cornelia de Lange syndrome Prader Willi syndrome Lowe’s syndrome William’s syndrome Lysinuric protein intolerance Smith Magenis syndrome MELAS Rubnstein Taybi syndrome Wilson’s disease

Congenital rubella syndrome Congenital hypothyroidism Toxoplasmosis Toxemia of pregnancy Cytomegalovirus Post-‐natal head injury Herpes Post-‐natal hypoxia HIV Brain tumor Syphilis Post-‐immunization Bacterial meningitis Nutritional disorders Fetal alcohol syndrome Sensory deprivation Cocaine baby syndrome Multiple sclerosis Maternal PKU syndrome Hypoglycemia Placental insufficiency syndrome Childhood suicide attempt Peri-‐natal traumatic brain injury syndrome Surgical complication Kernicterus Severe drug allergy Lead toxicity Pre-‐natal folate deficiency Measles encephalitis Shaken baby syndrome

The Third Essen=al Concept  Each neurodevelopmental disorder is associated with one or more primary complica6ons. These complica=ons include:

  Cogni-ve impairment (e.g. intellectual disability)   Neuromotor dysfunc-on   Seizure   Psychiatric disorders / abnormal impulsive behavior   Sensory Impairment

Complica=ons Cogni-ve Impairment Neuromotor Dysfunc-on*

  Intelligence   Aeen=on   Percep=on   Language   Visual-‐Spacial   Execu=ve Func=on

  Hypertonus (Spas=city)   Extremity Weakness; low tone

  Movement Disorders

*Cerebral Palsy

Complica=ons

Seizures Psychiatric/Behavior

  Primary Generalized   Focal   Seizure Syndrome; Lennox-‐Gaustaut

  Au=sm   Anxiety/Depression   Psycho=c   SIB/Aggressive

  Visual   Hearing   Tac=le   Olfactory

Sensory

The Fourth Essen=al Concept  Depending on which of these five primary complica=ons is present and its severity (some pa=ents manifest all four); the pa=ent suffering from a neurodevelopmental disorder may also demonstrate a number of secondary condi=ons or health

consequences that result from the primary complica=ons.

Cognitive Impairment

Intellectual Disability

Dementia

Special education Reduced $ potential

Access to health care

Poor self esteem

Depression

Reduced chance marriage

No children

Depression/Anxiety

Poor hygiene

Gait dysfunction Trauma

Infections

Neuromotor Dysfunction

Immobility Osteoporosis

Chronic Lung Disease

Scoliosis Aspiration Pneumonia

Fracture

Ca of Esophagus

GERD


Spasticity

Tremors

Gait dysfunction Falls Trauma

Pain Difficult behavior

Hygiene Infections

Difficulty eating

Difficulty writing

Medicine

Trauma

Seizures

AED complications

Cognitive Fatigue/sedation Dec. ADL’s

Physiologic Organ dysfunction

Psychological Depression/Anxiety

Respiratory failure

Fractures

Osteoporosis Fractures

SIB

Abnormal Behaviors

Anxiety/Depression

Autism

SIB

?????

?????

Psychopharm.

Aggressive

?????

Social withdrawal

Limited Communication

Consequences of Abnormal Impulsive Behavior

The FiHh Essen=al Concept  In addi=on to the complica=ons and consequences, pa=ents with neurodevelopmental disorders, depending on the precise e=ology, may also demonstrate syndrome-‐specific condi6ons, which may be mul=-‐system in nature, and e=ologically unrelated to the neurodevelopmental (brain) dysfunc=on.

The Six Most Common Diagnoses

  Cerebral Palsy   Autism   Down Syndrome   Fragile X Syndrome   Fetal Alcohol Syndrome (or Spectrum)   Intellectual Disability of Unknown Origin

Cerebral Palsy   CP is a disorder of tone, posture or movement due to a lesion in the developing brain; Neuromotor Dysfunc=on

  2-‐4/1000; 7-‐10,000 new babies each yr   It is sta=c, but it symptoms may change with matura=on

  During past 3 decades considerable advances made in obstetric & neonatal care, but unfortunately there has been virtually no change in incident of CP

Cerebral Palsy: E=ologic   Prenatal (70%) Infec=on, anoxia, toxic, vascular, Rh disease, gene=c, congenital malforma=on of brain

 Natal (5-‐10%) Anoxia, trauma=c delivery, metabolic

  Post natal Trauma, infec=on, toxic

Cerebral Palsy: Physiologic

 Athetoid  Ataxic   Rigid-‐Spas=c  Atonic  Mixed

Cerebral Palsy: Complica=ons   Spas=city  Weakness

  Increase reflexes  Clonus   Seizures  Ar=cula=on & Swallowing difficulty

 Visual compromise  Deforma=on

 Hip disloca=on  Kyphoscoliosis  Cons=pa=on  Urinary tract infec=on  Cogni=ve Impairment

Au=sm Spectrum Disorders  Au=sm is a complex, developmental disability that is evident within the first 3 years of life.

  It is a behaviorally defined syndrome that is recognized by difficul=es in communica=on, social interac=on and perceptual organiza=on.

  Symptoms vary in degree of severity, from mild to severe impairments.

Au=sm Many other disorders have “au=s=c features” and must be excluded:

  Sensory deficits   IDD   Child abuse/neglect   Childhood psychoses  Neurodegenera=ve diseases   Primary communica=on disorders

What Causes Au=sm?   It is thought that autism may be associated with a genetic event but no single gene or group of genes account for all autism cases.

 Thus, there may be several “autism” genes, potentially representing different ‘profiles’ of autism.

 Environmental and dietary factors may also contribute

Incidence   Prior to 1990: 4-‐5/10,000 (1/2000 – 1/2500)   1990’s: 21-‐31/10,000 (1/476 – 1/323)  A review of 23 epidemiologic studies between 1966 and 1988: 18.7/10,000

  Incidence changes to 91/10,000 when Asperger’s syndrome is included

  2009: 1/91 to 1/110; M:F ra=o of 4 to 1   556% increase in incidence

Why is the prevalence of ASD increasing?

  Changes in diagnos=c criteria-‐-‐broader view of spectrum

  Increasing awareness of ASD   Recogni=on that ASD can be associated with other disorders

  Real increase in the number of individuals with ASD due to factors such as diet, allergies, environmental toxins, vaccines, etc. (Research does not support causal associa=ons with these factors)

Summary of Wing, L. & Potter, D., Mental Retardation and Developmental Disabilities Research Reviews (2002)

by Gail Williams, M.D., Assoc. Professor of Pediatrics, UofL, Weisskopf Center for the Evaluation of Children,

In KATC Newsletter, Issue 8, Winter 2003

CONDITIONS ASSOCIATED WITH AUTISM Condi6on Features   Epilepsy Prevalence ranges from 11 to 39 percent

Increased risk in girls and persons with intellectual disability

  Gastrointes=nal Primarily diarrhea and cons=pa=on. Associated with day=me behavioral problems

  Sleep Disorders Insomnia very common, associated with day=me behavioral problems.

Includes circadian rhythm disturbance and periodic limb movements of sleep

  Intellectual disability Prevalence of 41 percent; 30% normal/near normal IQ

  Motor impairments Includes hypotonia, apraxia (motor planning), clumsiness, toe walking, gross motor delay

  Psychiatric condi=ons High prevalence of anxiety, aeen=on-‐deficit/hyperac=vity disorder, depression

  Sensory processing Differences in the percep=ons of sights, sounds, textures, disorder smells, and pain

Down Syndrome  Most common and well known gene=c disorder  Occurs in about 1/1000 live births in all ethnic groups  Nearly all cases occur just once within a given family  Only about 2-‐5% of cases run in families  Accounts for about 10% of all mentally disabled children

  Improved life expectancy mid 50’s but ½ for African American

Incidence   In the U.S., approximately 4,000 children are born with Down Syndrome each year

 One in every 800 live births  Risk increases with maternal age

  Age 20 (1/1600)   Age 35 (1/350)

  Increased risk for second child

Down Syndrome: Cytogene=c Causes

 Trisomy: 92%   Non-‐disjunc=on results from unequal chromosome division, usually in the mother's egg produc=on

 Transloca=on: 3-‐4%   the extra chromosome 21 is permanently aeached to another chromosome causing a transloca=on

 Mosaicism: 2-‐4%   two popula=ons of cells, the trisomy 21 cells, and a second cell line, usually normal

Clinical Features

  Brachycephaly   Up-‐slan=ng palpebral fissures   Epicanthal folds   Brushfield spots   Flat nasal bridge   Folded or dysplas=c ears   Open mouth   Protruding tongue   Short neck   Excessive skin at the nape of

neck

  Short broad hands   Short fiHh finger   Incurved fiHh finger   Transverse palmer crease   Space between first and second

toe

  Hyper flexibility of joints

Head and Neck Extremi=es

Special Health Problems Associated With Down Syndrome

  Heart defects occur in 30-‐50%

  Atlantoaxial Instability

  Intes=nal malforma=ons requiring surgery occur in 10-‐12%

  Visual and hearing impairments occur in > 50%

  Periodontal disease in 90%

  Thyroid problems, adult onset leukemia, epilepsy, diabetes,

and Alzheimer's occur more frequently

Intellectual Disability  Almost all DS babies have ID  Majority have mildly to moderate ID  Starts in the first year of life  Average age of sixng(11 mon), and walking (26 mon) is twice the typical age

 First words at 18 months   IQ declines through the first 10 years of age, reaching a plateau in adolescence that con=nues into adulthood

Fragile X Syndrome Leading heritable form of IDD •  One in ~260 females and one in ~800 males •  are carriers •  One-‐third of all X-‐linked IDD

•  One in ~4,000 in general popula=on

Leading (known) single gene associated with au=sm •  3-‐6% of all children with au=sm

•  Approximately 30% of young children with fragile X syndrome have au=sm

• Is caused by a large CGG-‐repeat expansion in a non-‐coding por=on of the FMR1 gene

Fragile site

Fragile X Syndrome Physical features

•  long face/frontal bossing •  high arched paleee •  large/prominent ears

•  macroorchidism

•  recurrent O==s Media; Conduc=ve hearing loss

•  aor=c dilata=on with mitral valve prolapse

•  patellar disloca=ons/joint laxity •  premature menopause

Expression of the FMR1 gene Normal Premutation Full mutation

(CGG) n < 55 55 ≥ n ≤ 200 (CGG) n ≥ 200 (CGG)

Normal Emotional problems Fragile X syndrome Premature ovarian failure FXTAS

gene

mRNA

FMRP

Clinical phenotype

transcription

translation

Fetal Alcohol Spectrum Disorders

FAS -‐-‐the most severe diagnosis on the spectrum of alcohol related disorders

FASD -‐-‐Fetal Alcohol Spectrum Disorder   ARBD (alcohol related birth defects)   ARND (alcohol related neuro-‐developmental disorder)

  FAE (fetal alcohol effects)   FAS (fetal alcohol syndrome)

FAS Facts

•  The leading cause of acquired and preventable IDD •  Dose-‐response effect-‐-‐-‐the more alcohol the higher the likelihood of FAS •  No known safe level of alcohol use during pregnancy

Criteria for FAS Diagnosis  A diagnosis requires the presence of all three of the following:   Documenta=on of three facial abnormali=es

  smooth philtrum   thin vermillion border   small palpebral fissures

  Documenta=on of growth deficits   Documenta=on of CNS abnormali=es

Changes Over Time

CNS Abnormali=es

•  Memory problems •  Aeachment disorder •  Impaired motor skills •  Learning disabili=es •  Problems with reasoning and judgment •  Inability to discern consequences of ac=ons •  Intellectual impairment

Neurodevelopmental Disorders

ID of Unknown Origin   S=ll very common, but with selec=ve workup and history may be able to determine cause in majority of cases

 Understand ra=onale to find underlying cause; An=cipatory Guidance

  Syndromic vs non-‐Syndromic; Phenotype   Family History

 Medical chart review  May guide family’s reproduc=ve health


ND Disorder

Cognitive Impairment

Seizures

Abnormal Behaviors

Genetics Nutrition

Trauma Toxins

Complications

Complications

Complications

Complications

Complications

Complications

Complications

Complications Syndrome Specific Conditions

Sensory Impairment

Remember what the Five Essen=al Concepts tell us . . . 1.  There’s a problem with the brain (brain dysfunc=on) 2.  There’s an underlying neurodevelopmental disorder involved

3.  The disorder will manifest classic symptom complexes / complica=ons

4.  There will be secondary health consequences associated with those complica=ons

5.  There will also be syndrome-‐specific condi=ons, unrelated to brain dysfunc=on

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