# Presentation: 469187

## The Science of FAS or FASD: Not Just Another Pretty Face 

- Edward Riley
- Center for Behavioral Teratology and Department of Psychology
- San Diego State University
- San Diego, CA

- Presented: Building FASD State Systems
-  Crystal City, VA     May 2003

## Sarah Mattson SDSU
Jennifer Thomas SDSU
Kenneth Lyons Jones UCSD
National Institute on Alcohol Abuse and Alcoholism
Ken Warren
Faye Calhoun
Sam Zakari

- Jennifer Thomas SDSU
- Kenneth Lyons Jones UCSD
- National Institute on Alcohol Abuse and Alcoholism
- Ken Warren
- Faye Calhoun
- Sam Zakari

- Acknowledgements

## Growth retardation

- CNS anomalies
- Distinct facies

## Facies in Fetal Alcohol Syndrome

- Discriminating Features

- In the young child

- Streissguth, 1994

## The Faces of FASD: FAS

- Pictures unavailable due to
- copyright and permission issues

## FAS – Only the tip of the iceberg (FASD)

- Fetal alcohol effects/ARND
- Clinical suspect but appear normal
- Normal, but never reach their potential

**Notes:**
Background
This slide illustrates an extremely important point.  Fetal alcohol syndrome only represents one point on what appears to be a continuum of effects from prenatal alcohol exposure.  Towards one end may be fetal death and FAS.  As one moves to the other end of the continuum, one may find isolated effects resulting from prenatal alcohol: maybe only some of the facial characteristics or maybe only behavioral problems.  The point is that FAS represents only a small sampling of the effects of prenatal alcohol.  Many more children are included when we consider those with FAE who might or might not have obvious signs of alcohol exposure, and those that do not manifest any physical features of FAS, but have behavioral problems.  FAS is only the tip of the iceberg.
Interestingly only 10 – 40% of children of chronic alcohol abusers can be diagnosed as having FAS.  However, there is very good data suggesting that these non-FAS children are affected, most notably behavioral and cognitive deficits.  Even in children with normal IQs who have been exposed to alcohol prenatally, there is evidence that they do not live up to their true potential.  

## The Other Faces of FASD

- Pictures unavailable due to
- copyright and permission issues

## Five-day-old with FAS

## Brain damage resulting from prenatal alcohol

- photo: Clarren, 1986

**Notes:**
Background
The brain on the left was obtained from a 5-day-old child with FAS while the brain on the right is a control brain.  The effects are obvious.  The brain on the left suffers from microencephaly (small brain) and migration anomalies (neural and glia cells did not migrate to their proper location in the brain, but instead many of them simply migrated to the top of the cortex).  Although it cannot be seen here, there is also agenesis of the corpus callosum and the ventricles are dilated.  The corpus callosum is the major fiber tract connecting the two hemispheres of the brain (more on this later). Major findings of other autopsies of children with FAS have found microcephaly, hydrocephaly, cerebral dysgenesis, neuroglial heterotopias, corpus callosum anomalies, ventricle anomalies, and cerebellar anomalies.  It must be pointed out, however, that these autopsies have typically been conducted only on the most severe cases, since these children often have enough problems that they do not survive.  The interested reader on the pathological changes that occur in FAS is referred to the following articles.
References
Clarren, S. K. (1986). Neuropathology in fetal alcohol syndrome. In J. R. West (Ed.), Alcohol and Brain Development (pp. 158-166). New York: Oxford University Press. 
Roebuck, T.M., Mattson, S.N., and Riley, E.P. (1998). A review of the neuroanatomical findings in children with fetal alcohol syndrome or prenatal exposure to alcohol. Alcoholism: Clinical and Experimental Research, 22 (2),339-344. 

## Conclusion from autopsy studies

- 	“The extreme variability in the nature and degree of brain malformations in children with FAS suggests that no specific pattern of neurological, behavioral, or intellectual deficit should be found.”
- 						Clarren, S.K. _Alcohol and Brain Dev_. (1986)

- 	But didn’t make sense given the common patterns of behavioral anomalies; Similar cognitive, attentional, motor, developmental problems.

**Notes:**
There were also numerous studies conducted both in animals and in humans at the end of the 19th and beginning of the 20th centuries.  All of these showed the detrimental effects of prenatal alcohol.  However, for a variety reasons, including prohibition, the effects of prenatal alcohol exposure did not attract much attention.  While people recognized that the offspring of alcoholics had problems they felt that these were the result of poor genetic stock rather than to any direct effects of the alcohol. For example the Journal of the American Medical Association in 1946 stated “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). The modern era of the recognition of the detrimental effects of prenatal alcohol exposure began when Ken Jones, David Smith and associates published two papers in 1973, describing a common set of features in 11 children whose mothers were known to be alcoholics or heavy drinkers during their pregnancies.  Subsequently, it was discovered that a common pattern of anomalies had been described previously in the French medical literature in 1967 by a French physician, Philip Lemoine.

## Image Analysis

- T1-Weighted

- Skull stripped tissue segmented

- Surface rendering

##  Take Home Message 1

- Prenatal exposure to alcohol, at least high doses of alcohol, can cause permanent changes in the brain.

## Diagnostic Groups

- Fetal Alcohol Syndrome (FAS)
- Children with all of the required diagnostic criteria and a confirmed history of heavy prenatal alcohol exposure

- Prenatal Exposure to Alcohol (PEA)
- Children with a known history of significant alcohol exposure, but without the physical features necessary for a diagnosis of FAS
- Non-exposed Control (CON)
- Children who have no history of exposure to alcohol or other known teratogens

## What do FAS Brains Look Like? 

**Notes:**
Emphasize that most MRI scans are described by neuroradiologists as “normal scans” or “unremarkable”

## Brain Size

**Notes:**
The first thing to look at is overall brain size. These data indicate that both children with FAS and PEA have reductions in cerebral and cerebellar volumes, although only the FAS group is statistically significant. Here the data are presented as a percentage of control, so for example, the FAS group shows about a 13% reduction in cerebral volume, which is consistent with the microcephaly which is seen in most of these kids. Their cerebellar volumes are even smaller, and are about 83% of controls. 

## Change in brain size

**Cerebrum**

**Cerebellum**

**Corpus Callosum**

**Notes:**
Background
The image on the left is a normal midsaggital MRI scan of the human brain with the cerebrum and cerebellum pointed out. The data on the right show the reduction in size of the these two areas in children with FAS and PEA.  PEA stands for Prenatal Exposure to Alcohol, and includes children with known histories of heavy prenatal alcohol exposure, but who lack the features necessary for a diagnosis of FAS.  As can be seen, the extent of reduction in the volume of both the cerebrum and cerebellum is significant.  While the PEA group shows a reduction in volume, with these sample sizes, this is not a significant difference.  Other brain imaging studies indicate disproportionate size reductions in the basal ganglia, cerebellum, and corpus callosum. The data are presented as percent of normal matched controls. 
References
Mattson, S. N., Jernigan, T. L., & Riley, E. P. (1994a). MRI and prenatal alcohol exposure. Alcohol Health & Research World, 18(1), 49-52. 
Archibald, S.L., Fennema-Notestine, C., Gamst, A., Riley, E.P., Mattson, S.N., and Jernigan, T.L. (submitted, 2000). Brain dysmorphology in individuals with severe prenatal alcohol exposure. 

## The cerebellum, little brain

- Pictures unavailable due to
- copyright and permission issues

## Cerebellum Size

## Cerebellum

- Reduced cerebellar volume

- Reduction in the size of the vermis
- Primarily in the anterior regions (I-V)
- Similar to animal studies
- May be related to balance and attentional problems

## The Corpus Callosum

- Connects the left and right halves of the brain
- Allows them to work together and put information together

- Pictures unavailable due to
- copyright and permission issues

## Corpus callosum abnormalities

**Notes:**
Background
One anomaly that has been seen in FAS is agenesis of the corpus callosum.  While not common, it occurs in FAS cases (~6%) more frequently than in the general population (0.1%) or in the developmentally disabled population (2-3%).  In fact it has been suggested that FAS may be the most common cause of agenesis of the corpus callosum.  
The top left picture, is a control brain. The other images are from children with FAS. In the top middle the corpus callosum is present, but it is very thin at the posterior section of the brain.  In the upper right the corpus callosum is essentially missing.  The bottom two pictures are from a 9 year old girl with FAS.  She has agenesis of the corpus callosum and the large dark area in the back of her brain above the cerebellum is a condition known as colpocephaly.  It is essentially empty space.  
Most children with FAS do have a corpus callosum, although it may be reduced in size.  The reduction in size occurs primarily in the front and rear portions (genu and splenium).  One interesting item is that this same pattern of reduction in the genu and splenium has been found in ADHD children.  The behavioral problems seen in FAS frequently are similar to those seen in ADHD.  
References
Mattson, S. N., Jernigan, T. L., & Riley, E. P. (1994a). MRI and prenatal alcohol exposure. Alcohol Health & Research World, 18(1), 49-52.
Mattson, S. N., & Riley, E. P. (1995). Prenatal exposure to alcohol:  What the images reveal. Alcohol Health & Research World, 19(4), 273-277.
Riley, E. P., Mattson, S. N., Sowell, E. R., Jernigan, T. L., Sobel, D. F., & Jones, K. L. (1995). Abnormalities of the corpus callosum in children prenatally exposed to alcohol. Alcoholism: Clinical and Experimental Research, 19(5), 1198-1202. 

## Reductions in Corpus Callosum Area

**Notes:**
In a third study done by Sowell et al., the displacement of the corpus callosum in 3-d space was investigated. Remember the posterior region of the CC was especially reduced in size in our alcohol-exposed children. And this is exactly the region that is also displaced in space. If you look at the top panel, the red line represents the average control and the blue line represents the average alcohol-exposed subject. What we see is a significant displacement from normal in the posterior region, illustrated by the red color in the lower half of that figure. 
The bottom panel illustrates that the FAS and PEA brains are similar, showing the same region of displacement from controls. 

## Corpus Callosum

- Agenesis of the corpus callosum
- FAS is perhaps the most common cause of this condition
- present in ~5% of individuals with FAS (compared to 0.1% in general and 2-3% in developmentally disabled populations)

- Reduction in size
- specific to genu and splenium - similar to ADHD children
- may be related to difficulty in dealing with complex stimuli and situations (e.g. innocent delinquency)
- Displaced
- lies more anterior and inferior

## Subcortical Structures

**Caud *******

**Lent**

**Accumb *******

**70**

**75**

**80**

**85**

**90**

**95**

**100**

**PEA**

**FAS**

*******

*****

******

**+**

*****

**Notes:**
The subcortical brain regions, including the basal ganglia, have been of great interest to me for quite some time. This slide illustrates that, in addition to overall brain size, children with FAS and PEA also show reductions in some of the subcortical sections. Here we see significant reductions in the caudate in both children with FAS and PEA and in fact,  these caudate reductions remain when overall brain size is taken into consideration.
Red = caudate
Yellow&gold= lenticular nuclei (globus pallidus and putamen)
magenta = accumbens

## Basal ganglia

- Reduced in volume

- Primarily due to a reduction in the size of the caudate
- Concordant with animal data
- May be related to deficits in spatial memory, perseverative tendencies, attentional problems

## Brain Shape

- Area in red indicate where the brain is too small
- or too thin, relative to normal brain shape

**Notes:**
The “distance from the center” or DFC measure has been developed primarily to quantify group differences in local growth or brain shape.  It is a measure of radial expansion measured from the center of the brain, roughly at the midline decussation of the anterior commisure (i.e., x = 0, y = 0, z = 0), to each of the 65,536 brain surface points.  Note that the distance measure at each point for each individual is reflective of anatomical location in addition to radial expansion, thus only relative differences in DFC are meaningful in terms of brain shape. 
This figure shows the difference in “Distance from Center” or DFC between FAS and normals in millimeters, along with the outline of the average brain surface for each group in NATIVE unscaled space. This slide highlights that while they are microcephalic overall, there are prominent regions of brain size, or surface extent reduction localized to inferior parietal lobes bilaterally and to the orbital frontal lobe, primarily in the left hemisphere.  These are regions where the brain is too small above and beyond the overall microcephaly.  Note also that the smallest decreases appear to be in the frontal cortex (the region that is too big in the scaled data sets).  
Perhaps sparing of frontal lobe size, but certainly not of frontal lobe function.  Caudate might be more responsible for frontal behavioral deficits. 
These pictures are all in “Native” space.
Both are native.  you can kind of tell because the color scale is all in the negative range indicating that the controls are bigger than ALC everywhere, but mostly in the inferior parietal lobes.  Remember in scaled space, there are some regions where you would have positive numbers (i.e., in the frontal lobes) because the size of the brain would be normalized overall showing relative increases and decreases in DFC.

## Brain Mapping

- Sowell et al., 2001

**Notes:**
(Left) Areas of increased gray matter density (shown in blue) in children with heavy prenatal alcohol exposure mapped on a surface rendering of a representative brain. 
(Right) Areas of decreased white matter density (shown in red) in children with heavy prenatal alcohol exposure mapped on a surface rendering of a representative brain. Figures courtesy of Dr. Elizabeth Sowell.
This is work done by Elizabeth Sowell, Paul Thompson, and Art Toga at UCLA using structural MRI data obtained from our San Diego sample of children with FAS/PEA.
Brain Mapping. Brain mapping is a technique that allows for localization of brain abnormality more easily than previous techniques because the whole brain can be studied at once. This method makes use of a structural MRI, but provides greater visualization of all structures. The images of individuals with FAS and PEA were subjected to this brain mapping technique and compared to non-exposed controls . Results were consistent with those of Archibald et al. ; both studies suggested disproportionate reductions in the white matter of the brain (where the axons are located) with relative sparing of the gray matter of the brain (where the cell bodies are located). Furthermore, it appears that the parietal lobe is especially susceptible to alcohol’s effects. Once overall brain size was accounted for, both the volume  and the density of white matter in this region were significantly reduced. In addition, there was also a significant increase in gray matter density in this area . 

## Summary of MRI Findings

- Studies indicate size reductions in the cerebral vault, cerebellum, basal ganglia, corpus callosum, as well as overall brain size

- Greater amounts of gray matter and lesser amounts of white matter in some areas, and less symmetry
- Distortions in shape of brain
- These brain changes can be related to changes in behavior

## Prenatal exposure to alcohol, at least in high doses, can cause permanent changes in the brain

- These changes in brain may cause or contribute to many of the behavioral problems seen in individuals exposed to alcohol.

- These changes in brain are not due to poor postnatal environments, being in foster care, or a host of other possibilities.
- Knowing what brain areas are involved might enable us to develop better treatment strategies.

## Take Home Message 2

- Prenatal exposure to alcohol can result in a variety of behavioral dysfunctions, even in the absence of obvious physical effects.

## General Intellectual Performance

**IQ scale**

- Mattson, S.N., 1997.

- FAS is the leading
- known cause of
- mental retardation
- in the western world

**Notes:**
Background
There have been over a dozen retrospective studies of children with FAS (total N = 269). Overall, these studies, such as the Seattle studies or studies out of Germany, reported an overall mean IQ of 72.26 (range of means = 47.4-98.2). The data presented here were collected in San Diego, CA as part of a project at the Center for Behavioral Teratology.
The mean IQ performances of children with FAS were compared to alcohol-exposed children with few if any features of FAS.  All children in this study were exposed prenatally to high amounts of alcohol, however only the FAS group displayed the craniofacial anomalies and growth deficits associated with the diagnosis.  The other group was designated as having prenatal exposure to alcohol (PEA) and had documented exposure to high levels of alcohol but were not dysmorphic, microcephalic, or growth-retarded.  In comparison to normal controls, both groups of alcohol-exposed children displayed significant deficits in overall IQ measures as well as deficits on most of the subtest scores.  While the PEA subjects usually obtained marginally higher IQ scores than those with FAS, few significant differences were found between the two alcohol-exposed groups.  These results indicate that high levels of prenatal alcohol exposure are related to an increased risk for deficits in intellectual functioning and that these deficits can occur in children without all of the physical features required for a diagnosis of FAS.  Our PEA subjects may be somewhat similar to individuals identified by other groups as having FAE, however individuals with PEA display few if any of the facial features of FAS, and are not growth retarded or microcephalic.  References
Streissguth AP, Aase JM, Clarren SK, Randels SP, LaDue RA, Smith DF (1991). Fetal alcohol syndrome in adolescents and adults. Journal of the American Medical Association 265:1961-1967. Mattson, S.N., Riley, E.P., Gramling, L., Delis, D.C., and Jones, K.L. (1997). Heavy prenatal alcohol exposure with or without physical features of fetal alcohol syndrome leads to IQ deficits. Journal of Pediatrics, 131 (5), 718-721. Mattson, S.N. and Riley, E.P. (1998). A review of the neurobehavioral deficits in children with fetal alcohol syndrome or prenatal exposure to alcohol. Alcoholism: Clinical and Experimental Research, 22 (2), 279-294. 

## Boston Naming Test

- Picture unavailable due to
- copyright and permission issues

## Peabody Picture Vocabulary Test

- Pictures unavailable due to
- copyright and permission issues

## Language Test Performance

**PPVT-R**

**BNT**

- 30

- 70

**Standard score**

- 0

- 10

- 20

- 40

- 50

- 60

**Raw score**

- 

**Language Measure**

- 115

- 130

- 40

- 55

- 85

- 100

- 

## Grooved Pegboard Test

- Picture unavailable due to
- copyright and permission issues

## Fine-Motor Skill:Grooved Pegboard Test

- Dominant

- Nondominant

- 150

**Hand**

- NC

## Assessment of Balance

- Picture unavailable due to
- copyright and permission issues

## Body Sway Tracings

**Condition 1**

**Condition 2**

**Condition 3**

**Condition 4**

**Condition 5**

**Condition 6**

## Neuropsychological Performance

**Notes:**
The next study was to evaluate the alcohol-exposed children with a more detailed neuropsychological test battery. Prior to 1990, there were 14 studies of children with FAS which evaluated IQ levels. In contrast, there were only 2 studies that evaluated other cognitive abilities; one was from Germany and the other was from Sweden and both included only  very basic visual-perceptual tasks.
The study we did included a broad range of neuropsychological tests, such as:
The Wide Range Achievement Test- which assesses academic skills
The Peabody Picture Vocabulary Test and the Boston Naming test-both assessment of basic language functioning
The California Verbal Learning Test-a list learning test
The Visual-Motor Integration Test which measures basic visual-perceptual skills
Grooved Pegboard test-a test of fine-motor speed and coordination
The Children’s Category Test-a measure of nonverbal learning.
Along the x-axis are the tests included in the battery; for comparison purposes, all scores were converted to standard scores with a mean of 100 and an SD of 15.
What we found, as in the IQ study, was that children with FAS or PEA showed deficits in comparison to controls and that they were very similar to each other. There does seem to be some indication that the nonverbal measures (on the right of the slide) are not as impaired as the verbal and academic measures, which are on the left and center of the slide.

## “We wondered how a child could get A’s in school and not have the sense to understand that when she is rude to friends they might get mad at her.”
			-Hilary O’Loughlin
			 (Iceberg, 1995)

- 			-Hilary O’Loughlin
- 			 (Iceberg, 1995)

- Pictures unavailable due to
- copyright and permission issues

## The frontal lobes, making

** ****logical decisions**

- Pictures unavailable due to
- copyright and permission issues

## Frontal-Subcortical Circuits

## Executive Functioning

- Evidence of deficits relating to executive functioning
- Cognitive Flexibility
- Selective Inhibition
- Planning Ability
- Fluency
- Concept Formation and Reasoning

## Executive functioning deficits

**Notes:**
Background
In addition to the abilities already discussed, a few studies have documented other specific neuropsychological deficits in individuals with FAS.  Children with prenatal alcohol exposure, with and without FAS, have demonstrated various deficits on measures of executive functioning. These measures have revealed problems in areas such as planning (tower task-shown above), cognitive flexibility (trails test), inhibition (stroop test), and concept formation and reasoning (word context tests). Generally, performance on these measures is characterized by increased errors and more difficulty adhering to rules. Therefore, children are less successful overall.  For example, on the tower measure shown above (Tower of California-similar to Tower of London), children with FAS and PEA passed fewer items overall and made more rule violations than controls. The only two rules were to never place a larger piece on top of a smaller one and to move only one piece at a time.  As can be seen the alcohol exposed children had many more rule violations.
In addition, deficits have been found on the WCST (Wisconsin Card Sort Test), a nonverbal measure of problem solving. The WCST test requires both problem solving and cognitive flexibility and has been proposed to be sensitive to frontal system dysfunction. Children with prenatal exposure to alcohol made more errors and had more difficulty with the conceptual nature of the task than controls. New data indicate that they have trouble identifying and defining concepts.
Finally, tests of planning ability are also thought to be sensitive to frontal systems dysfunction although few such studies have been done in individuals with FAS.  On the Progressive Planning Test which is similar to the Tower of London test children with FAS/FAE had difficulty with planning ahead and tended to perseverate on incorrect strategies.  So far the results could be summarized as:
1) Heavy prenatal alcohol exposure is associated with a wide range of neurobehavioral deficits including visuospatial functioning, verbal and nonverbal learning, and executive functioning
2) Heavy prenatal alcohol exposure causes microcephaly and disproportionate reductions in the  corpus callosum, basal ganglia, and cerebellum 
3) Children with and without physical features of the fetal alcohol syndrome display qualitatively similar deficits
ReferencesCarmichael O.H., Feldman JJ, Streissguth AP, Gonzalez RD: Neuropsychological deficits and life adjustment in adolescents and adults with fetal alcohol syndrome. Alcoholism:  Clinical and Experimental Research 16:380, 1992 Kodituwakku PW, Handmaker NS, Cutler SK, Weathersby EK, Handmaker SD: Specific impairments in self-regulation in children exposed to alcohol prenatally. Alcoholism: Clinical and Experimental Research 19:1558-1564, 1995 Mattson, S. N., Goodman, A. M., Caine, C., Delis, D. C., & Riley, E. P. (1999). Executive functioning in children with heavy prenatal alcohol exposure. Alcoholism, Clinical and Experimental Research, 23(11), 1808-1815. 

## The Corpus Callosum, Cooperation Between the Hemispheres

-  and
-  “Innocent Delinquency”

- Relationship between brain areas
-  and behavioral changes

- Picture unavailable due to
- copyright and permission issues

## Left brain/Right brain

- The Corpus Callosum

## Look at the chart and say

-  the color not the word

## Slide 48

## Global-Local Test

## Why is FAS Important to Mental Health Providers?

- Over 90% of individuals with FAS/FAE have received mental health treatment

- 60% of individuals with FAS/FAE over the age of 11 have experienced school disruption
- FAS is the leading known cause of mental retardation
- Attention problems are a hallmark feature and FAS is often misdiagnosed as ADHD

## Secondary Disabilities

- Disabilities that an individual is not born with, but may be acquired as a result of the CNS deficits associated with FAS

- Presumed to be ameliorated or preventable through better understanding and appropriate interventions for children and adults with FAS and their families

## Secondary Disabilities

- Mental health problems >90%

- Conduct problems in school >60%
- Trouble with the law or incarceration 45-60%
- Alcohol or drug dependence 30-45%
- Dependent living >80%

## Protective Factors

- Diagnosis before age 6

- Nurturing, stable home, good quality of home
- Never experiencing violence
- Being diagnosed FAS rather than FAE

## Prenatal exposure to alcohol can result in a variety of behavioral dysfunctions, even in the absence of obvious physical effects.

- Heavy prenatal alcohol exposure is associated with a wide range of neurobehavioral deficits including visuospatial functioning, verbal and nonverbal learning, attentional, and executive functioning

- Children with and without physical features of the fetal alcohol syndrome display qualitatively similar deficits
- A specific pattern of relative strengths and weaknesses may exist

## Summary

- FAS is a devastating developmental disorder that affects individuals born to women who abuse alcohol during pregnancy.

- Although it is entirely preventable children continue to be born exposed to high amounts of alcohol.
- It’s consequences affect the individual, the family, and society and its costs are tremendous, both personally and financially.
- Effective treatment and prevention strategies must be developed and made available