Children with Fetal Alcohol Syndrome Neuropsychological and (PowerPoint)

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					         Fetal Alcohol Syndrome
Fetal alcohol syndrome is
among the most commonly
known causes of mental
retardation and is a major public
health problem. What is it, how
does it affect people, what can
we do about it? These are the
issues that will be discussed in
this lecture.
     Historical view of alcohol as a
   Foolish, drunken, or harebrain
    women most often bring forth
    children like unto themselves
              Aristotle in Problemata

   Behold, thou shalt conceive and
    bear a son: And now, drink no
    wine or strong drink.
            Judges 13:7

                                        Rosett, 1984
         Safety of Alcohol and Reproduction
                 in the 20th Century
 “...the idea of germ poisoning by alcohol in humans may be
 safely dismissed..”
                        Jellinek, E.M., & Jolliffe, JSA, 1, 1940

The offspring of alcoholics have been found defective not
 because of alcoholism of the parents but because the
 parents themselves came from a defective stock.
                  Journal American Medical Association, 132:419, 1946
Ethanol drip was used in obstetrics for treating premature
labor. - Involved I.V. ethanol infusion for 6–10 hours,
reaching BAC as high as 160 mg/dl
                  Fuchs, F., et al., Am. J. Obstet. Gynecol., 99:627 (1967)
          Fetal Alcohol Syndrome
   Specific pattern of facial
   Pre- and/or postnatal
    growth deficiency
   Evidence of central
    nervous system

                                 Photo courtesy of Teresa Kellerman
FAS – Only the tip of the iceberg

                    Fetal alcohol syndrome
                    Fetal alcohol effects
                    Appear normal but clinical

                               Adapted from Streissguth
    Fetal Alcohol Spectrum Disorders
•   Fetal Alcohol Spectrum Disorder (FASD) is
    NOT a diagnostic term. Rather, it is an
    umbrella term used to describe a broad range
    of effects associated with alcohol use during
    pregnancy. The spectrum can include
    physical effects (ARBD) as well as effects on
    the brain that may result in problems with
    learning, emotions and behavior (ARND).
Improved Diagnostic Schemes
         Facies in Fetal Alcohol Syndrome
Discriminating Features                   Associated Features

                                                Epicanthal folds
Short palpebral fissure
                                                 Low nasal bridge

   Indistinct philtrum                           Minor ear anomalies

     Thin upper lip                            Micrognathia

                          In the young child            Streissguth, 1994
Representative Genetic Syndromes Displaying
        Some of the Features of FAS

 Williams syndrome/DeLange Syndrome/VCFS
Growing up with FAS

              Courtesy of Ann Streissguth
  Prevalence of FAS (rates per 1000)

Alaska   0.2 non AI/AN    Seattle          2.8-3.1
         3 AI/AN          Cleveland        4.6
Aberdeen 2.7 AI/AN        Roubaix          1.3-4.8
BDMP      0.7             Seattle FASD     9.1
Atlanta  0.1                school study    3.1
          0.3 FAS pFAS    South Africa
IOM       0 .5 to 2.0     Western Cape   4.1
          2 - 8.5 AI/AN                  7.4
                            FAS and PFAS 8.9
   FAS in Select Populations Can Occur at
         Higher Rates – Foster Care
 Screen for FAS Facial Phenotype using FAS Photographic Analysis Software.
    Short palpebral fissure length
    Smooth philtrum (Rank 4 or 5)
    Thin upper lip (Rank 4 or 5)
                                                          Palpebral fissure length
Results                                                               (PFL)

 FAS Prevalence                           1 per 100
 Participation Rate                                98 %
 Screened to date                                  2000

       Astley et al., Application of the fetal alcohol syndrome facial photographic screening tool in a foster care
       population. J. Pediatr 2002;141:712.          
       Guides available on          Images Copyright Susan Astley, University of Washington
Example of severe brain damage
 resulting from prenatal alcohol

                        photo: Clarren, 1986
             Change in brain size
                                     Cerebrum       Cerebellum
Cerebrum                       100


                                90                           ***
                                     p < 0.010

                                75       FAS           p < 0.001

Corpus Callosum   Cerebellum

                                      Mattson et al., 1994
Corpus callosum abnormalities

      Mattson, et al., 1994; Mattson & Riley, 1995; Riley et al., 1995
Brain Mapping

                Sowell et al., 2001
Prenatal Alcohol Exposure and White Matter
  in the Corpus Callosum of Young Adults
                                                 CORPUS CALLOSUM

Diffusion Tension Image.           Genu                                              Splenium
Midsagittal slice, demonstrating
the regions of interest of the
genu (CCg) and the splenium
(CCs) of corpus callosum.

       Comparison of ADC and
       FA in corpus callosum of                                                         CON
       adults with FAS and                0.8

       Controls demonstrating             0.4

       decreased integrity of             0.0
       white matter in alcohol-                    ADC         FA   ADC         FA

       exposed individuals                               CCg              CCs

                                                ADC=Apparent Diffusion Coefficient
    (From Ma, et al, 2005, ACER)
                                                 FA= Fractional Anisotropy
General Intellectual Performance
                   115                                      NC
  Standard score

                   100                                      PEA
                          *          *         *
                    85        **           *


                         FSIQ        VIQ       PIQ

                                   IQ scale
                                                         Mattson, S.N., 1997.
Neuropsychological Performance

                       Mattson, et al., 1998
Executive functioning deficits
                                              Move only one piece at a time using
                                              one hand and never place a big piece
                                              on top of a little piece
           3        1
                        2                     6

                            Rule Violations

                                              4       FAS
Starting position

  1                                           2
Ending position
                                                            Mattson, et al., 1999
           Secondary Disabilities
Individuals with FASD have a range of secondary
disabilities – disabilities that the individual is not born with, and
which could be ameliorated with appropriate interventions.

                                                    Streissguth, et al., 1996
Animal models and prenatal alcohol
                 Many studies simply could
                 not be done on humans
                 Confounding factors can
                 rarely be controlled in human
                 Alcohol is rarely the only
                 drug used
                 Many abnormalities occur at
                 low rates
                 Epidemiological studies are
                 extremely time consuming
                 and expensive
    Animal models – Example of the
        comparability of effects
   Growth retardation           Hyperactivity,
   Facial characteristics        attentional problems
   Heart, skeletal defects      Inhibitory deficits
   Microcephaly                 Impaired learning
   Reductions in basal          Perseveration errors
    ganglia and cerebellar       Feeding difficulties
    volumes                      Gait anomalies
   Callosal anomalies           Hearing anomalies

                                  Driscoll, et al., 1990; Samson, 1986;
Facial features of FAS in the mouse

                   Adapted from Sulik & Johnston, 1982
Alcohol and the Cerebellum

                                  Purkinje Cell

                Pictures courtesy of James West
                          Eyeblink conditioning deficits are
                         correlated with cerebellar damage
                                 Eyeblink Conditioning                                                 Correlation between Cerebellar Cell
                                                                                                       Number and Eyeblink Conditioning
                       2.5       Sham                                                            4                                                 r = .80
                                                                                                           Sham Control
Conditioned Response

                                                                         Slope of CR amplitude
                                 Nonintubated Control                                                      Ethanol
                        2                                                                        3         Unintubated Control

                                                                             over training

                       1.5                                                                       2

                        1                                                                        1

                       0.5                                                                       0

                        0                                                                        -1
                             1   2   3     4   5   6    7   8   9   10                                20   40        60   80     100   120   140    160      180
                                                                                                      Number of Deep Cerebellar Nuclear Cells (X
                                         Training Session

                                                                                                           Adapted from Green et al. 2002
    Possible mechanisms for
        alcohol’s effects
 Impaired progression through cell cycle
 Impaired glia development - migration,
  neurotropic factor production, myelination
 Impaired cell adhesion
 Alterations in cell membranes
 Altered production of or responsiveness to factor
  that regulate growth, cell division, or cell survival
 Altered regulation of intracellular calcium
 Increased production of free radicals
Ethanol inhibits cell adhesion in
 L1-transfected mouse L cells.
Control                  L1-transfected
0 mM       0 mM                 5 mM              25 mM

          Courtesy of Michael Charness from Ramanathan et al., 1996
Blockade of ethanol’s effects on L1 cell
adhesion molecules reduces ethanol’s
         teratogenic effects

                            Chen et al. 2001
              Risk Factors
 Dose of alcohol
 Pattern of exposure - binge vs. chronic
 Developmental timing of exposure
 Genetic variation
 Maternal characteristics
 Synergistic reactions with other drugs
 Interaction with nutritional variables
        Treatment and Prevention
   Very little research done on these topics
   Many children with FAS treated for their individual
    symptoms (e.g. stimulants for ADHD)
   Animal data indicates that early intervention with
    environmental variables might have a beneficial
   Warning labels may not be reaching the women
    most likely to have a child with FAS
   Intensive, case-management approaches appear to
    work well.
   Brief interventions also appear to work
Remediation of prenatal alcohol
           Female Rat Performance on Parallel Bars

            Number of slips
                              5       IC          *       5       RC               SC
                              3                           3                        AE

                              1                           1

                                  2       3   4   5   6       2    3   4   5   6
                                              Intrarod Distance (cm)
                                                                       Klintsova AY., 1998
Choline supplementation after prenatal alcohol
          mitigates learning deficits

                           8                                             SALINE
                                           *                    *
                                                                         NO INJECTION

                           6    **




                               ETOH            PAIR FED             LAB CHOW

                                                          Adapted from Thomas et al, 2000
        Prevention – The Birth to 3 Program
   Parent-child assistance program
       Intensive home visitation model for the highest risk mothers
       Paraprofessional Advocates
       Paired with client for 3 years following the birth of the target
       Link clients with community services
       Extensively trained and closely supervised
       Maximum caseload of 15
   Outcomes
       Fewer alcohol/drug affected children
       Reduced foster care placement
       Reduced dependence on welfare
                                      Grant, T.M., 1999; Ernst, C. C., et al. 1999
                 Prevention: Project Care
Brief Intervention (BI) for Alcohol Use During Pregnancy in a WIC
   Compared a brief (10-15 min) intervention (BI) to assessment only (AO)
   Women in BI 5 Xs more likely to stop drinking compared to women in AO
   Newborn outcomes of birth weight, birth length, and mortality better in BI
    compared to AO group in heavier drinking women (> 2 drinks/occasion)
                                       Estimated marginal means (gms)

                        Birth Weight


                                                                        3300                                 BI

                                                                                MAX<=2             MAX>2          O’Connor & Whaley, in press
                                                                               Maximum Drinks Per Drinking
Intervention: Project Bruin Buddies
Parent Assisted Child Friendship Training
   Compared a Child Friendship Training (CFT) group to a Deferred
    Treatment Control (DTC) group
   Parents and children attended 12 - 90 minute sessions over 12 weeks
   Children in the CFT group showed improved social skills and fewer
    problem behaviors than children in the DTC group
   Social skills gains were maintained over a 3-month follow up

                                               O’Connor, Frankel, Paley et al., in press
   Fetal Alcohol Spectrum Disorders are developmental
    disorders that affects children born to women who abuse
    alcohol during pregnancy.
   Although FASD are entirely preventable, and in spite of our
    increasing knowledge about the effects of prenatal alcohol
    exposure, children continue to be born exposed to high
    amounts of alcohol.
   It’s consequences affect the individual, the family, and
   Its costs are tremendous, both personally and financially.
   Effective treatment and prevention strategies have been
    developed and new ones must be found and made

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