1. FASD Barnsley Oct 11 Dr Raja Mukherjee
Consultant Psychiatrist / Honorary Senior Lecturer
Lead Clinician FASD Behavioural Clinic
Surrey and Borders Partnership NHS trust/ St George's university of London

2. 1.Fetal Alcohol Syndrome : Confirmed alcohol exposure :
Facial pattern of Short palpebral fissures < / = 10 percentile, Thin upper lip vermillion, Smooth philtrum
Evidence of pre / postnatal growth retardation
Evidence of Neurocognitive deficits
2Fetal Alcohol Syndrome: No confirmed alcohol exposure
As above but no alcohol exposure found
3Partial Fetal Alcohol syndrome: Confirmed Alcohol Exposure
Not all of the above features are present but neurocognitive and some facial features needed
4Alcohol Related Birth Defect (ARBD)
Confirmed maternal alcohol consumption as well as some but not all of the facial features are present however the behavioural features or structural abnormalities are more pronounced.
5Alcohol Related Neurodevelopmental Disorder (ARND)
Confirmed maternal alcohol consumption with the absence of growth retardation or facial features and with the neurocognitive features being prominent.
6 Fetal Alcohol Spectrum Disorders
Umbrella term. Not a diagnostic term
Other Terms to be discussed later
Diagnostic Terms
Summary of diagnostic categies and methods. (Stratton 1996 Hoyme 2005).

3. Alcohol as a Teratogen

4. How genetics works
Genes
Amino - Acids
Proteins
Organs

5. Amino – Acids coded incorrectly Incorrect Proteins
Abnormal genetics
Genes Faulty
Amino – Acids coded incorrectly
Incorrect Proteins
Organs
Malformed

6. How a Teratogen has effect
Genes
Amino - Acids
Teratogen e.g. Alcohol
Abnormal Proteins

7. Epigenetics
The study of heritable changes in gene function not controlled by changes in the DNA sequence. Epigenetic phenomena play a significant role in development and evolution, and include histone modifications and DNA methylation

8. Example of epigenetic in action in genetically identical mice using the 'agouti viable yellow', or Avy
Avy gene has little or no methylation, then it is active in all cells, and the mouse is yellow
Avy is highly methylated, it switches off throughout the entire body. This means the mouse is a sooty-brown colour
In between these two extremes, Avy can be methylated to varying degrees

9. Incidence and risk

10. Examples of recent prevalence studies using the same methodology
Prevalence Rates /1000 population
FAS
PFAS
FASD
S Africa
Western cape 2002
59.2
78.6
Italy 2006
6.2
28.0
35.2
Croatia 2010
6.4
34.3
40.8

11. Rates Figure as high as 3.5 % has been quoted in research (may 2006)
We don’t know what is the UK figure
Percentage drinking during pregnancy
61% DOH
57% IFS

12. Rates International prevalence This figure is changing
1/1000 FAS
9.1 / 1000 FASD (O’Leary 2003)
1-2 / 100 FASD ( University of Washington 2004)
This figure is changing
Figure as high as 3.5 % has been quoted in research (may 2006)
We don’t know what is the UK figure
Percentage drinking during pregnancy
61% DOH
57% IFS

13. Note of caution this is assumption and not known
Risk by drinking group
Level of Alcohol Consumption
Number of Women in group
(Millions)
Is this true level What should we expect?
Note of caution this is assumption and not known
Nil
3.1
Low occasional
14.2
Few not as many as figures quoted
Above recommend levels
2.6
Possible more but probably not at levels quoted
Binge
1.9
Unknown but regular binge drinking high risk and probably higher than figures quoted
Moderate – heavy
2.5
Probably higher than figures quoted
Heavy
0.6
Higher than figures quoted
Totals
24.9
FASD Risk 1/ 100 or FAS 1./1000

14. Relationships
Full FAS
ARND
No identifiable
Problem

15. Mukherjee et al JRSM 2006 Gray and Mukherjee JMHLD 2007
How it presents
Mukherjee et al JRSM 2006
Gray and Mukherjee JMHLD 2007

16. Reasons for referral Growth problems Behavioural issues
Learning issues
Physical problems

17. What do people know Mukherjee, Wray, Hollins, Curfs

18. Themes Lack of knowledge Need for consistent guidance/ Cynicism
Need for education
Lack of support services

19. Professional Attitudes
Do you feel you have been generally provided with enough information to acquire knowledge for yourself? (N = 427) N
Valid %
Yes
176
41.2%
No/ Don’t know
251
58.8%

20. Professional Attitudes
Do you feel you have been generally provided with enough information to advise pregnant mothers safely? (N = 417) N
Valid %
Yes
115
27.6%
No/ Don’t know
302
72.4%

21. Diagnosis

22. Facial features

23. Comparison: Child with FAS and mouse fetus with fetal alcohol exposure
Mouse fetuses
Small head
Short palpebral fissures
Small nose
Small midface
Long philtrum;
Thin upper lip *
alcohol-exposed
normal

24. Critical periods and facial features
Normal
Alc–Day 7
Alc–Day 8
Fetus
Neonate
Modified from Sulik et al.
Slides Courtesy of Professor E Riley University of San Diego

26. Methods of Diagnosis of facial abnormalities: note all of these require careful history taking and evidence of growth retardation to make the diagnosis (Chudley 2005)
Gestalt: Facial pattern recognition requires experience and clear history. Issues of accuracy and inconsistency often found
D Score method: computational method for facial pattern based on careful measurements of abnormalities: requires a high degree of training and skill restricting practice to a few.
4 Digit scoring method and Facial photographic recognition software: applies areas of history and facial recognition to four 4-point likhert scales to establish diagnosis. Requires minimal training and can be used easily by all in clinical settings.

27. Comparison between diagnostic Tools
CDC
IOM revised
Canadian
4 Digit
Face
10th percentile
PFL and rank 4/5 on lip philtrum
10th percentile PFL and rank 4/5 on lip philtrum
3rd percentile PFL and rank 4/5 on lip philtrum
Growth
Pre / post natal growth below 10th percentile
Neurological
1 out of several brain parameters including OFC <10 %, CNS deficits
1 out of l brain parameters including OFC <10 %, CNS deficits
Or abnormal structure
3+ soft hard neurological signs
1 out of several brain parameters including OFC <3 %, CNS deficits
Alcohol
Confirmed or unknown
Confirmed to be excessive or unknown

28. Screening tool Designed and used by Raja Mukherjee

29. Tools to help identify drinking behaviours
First Things First
Ethical considerations
History and rapport
Screening tools
MAST
Audit-C
TACE
TWEAK
Biomarkers
Meconium FFA
Hair Sample / Urine analysis
Blood Test

30. 4 Digit Diagnostic Code Astley and Clarren 96,00,02 4 broad categories
Growth
Facial features
Brain
Alcohol exposure
Based on defined criteria giving score each areas and then diagnosis
26 Categories
Static encephalopathy
A,B,C,E,F, (G,H) relate to FASD diagnoses
Caution (requires modification of Alcohol scoring)

31. 4- Digit Score and Photographic Software
She hates me for This!!!
Forgave me after getting some flowers!

32. 4- Digit Score and Photographic Software
Known marker for pixel length
Allows Calculation of perameters

33. 4- Digit Score and Photographic Software
Known marker for pixel length
Allows Calculation of perameters
More objective way of discrimination

34. 4- Digit Score and Photographic Software
Lip Philtrum Guide from 4 Digit Score Schedule : Astley and Clarren University of Seattle

35. 4- Digit Score and Photographic Software
Known marker for pixel length
Allows Calculation of perameters
More objective way of discrimination
Still some subjectivity
Gives a range of Scores
Combined with other parameters leads to overall score
My Wife’s Score : 1212 : P
No Physical or CNS abnormalities

36. FAS Child 12

37. ARND Child 15

38. FAS or not? Case 1

39. FAS or not? Case 2
? Who was exposed to more alcohol case 1 or 2

40. Cause or Effect?

41. Top Down: Phemomenology
Top down or bottom up ?
Top Down: Phemomenology
Symptoms / Function
Bottom Up: Aetiology

42. Cluster of Symptoms Inattention Poor social understanding
Poor Planning
Receptive language deficits
obsessionality
Hyperactivity
Cognitive flexibility problems
Expressive language deficits
Poor imagination
Tics
Impulsivity
Working Memory deficits

43. Cluster of Symptoms: ADHD
Inattention
Hyperactivity
Impulsivity
Poor Planning
Tics
Cognitive flexibility problems
Receptive language deficits
Expressive language deficits
Poor social understanding
Poor imagination
obsessionality
Working Memory deficits

44. Cluster of Symptoms: ASD
Poor Planning
Inattention
Cognitive flexibility problems
Hyperactivity
Impulsivity
obsessionality
Tics
Receptive language deficits
Expressive language deficits
Poor social understanding
Working Memory deficits
Poor imagination

45. Cluster of Symptoms: ASD / ADHD
Poor Planning
Cognitive flexibility problems
Inattention
Hyperactivity
Impulsivity
obsessionality
Tics
Receptive language deficits
Expressive language deficits
Poor social understanding
Working Memory deficits
Poor imagination

46. Cluster of Symptoms: FASD
Working Memory deficits
Poor Planning
obsessionality
Receptive language deficits
Inattention
Poor social understanding
Hyperactivity
Cognitive flexibility problems
Poor imagination
Impulsivity
Expressive language deficits
Tics

47. Characteristic vs. Discriminating symptoms 3 Disorders with overlapping symptoms
C = Characteristic: D= Discriminating

49. What is so important about an S?
Fetal alcohol spectrum Disorder
Unitary diagnosis
Separate from others
Fetal Alcohol Spectrum disorders : note the S!!
An umbrella term
Donates the range of conditions that can be encompassed by the effects of alcohol in utero
Becomes a teratogenic aetiological factor causing phenomenological outcomes
Not mutually exclusive from current diagnostic criteria

50. Aetiology Vs Phenomenology
Poor social understanding
Receptive language deficits
Expressive language deficits
Poor imagination
FASD
Fragile X
Noonans
Downs

51. Common Ground Downs obsessionality Pre Frontal Cortex Inattention
Damage
Inattention
Hyperactivity
Poor social understanding
Impulsivity
obsessionality
Tics
Poor Planning
Cognitive flexibility problems
Poor imagination
Noonans
Fragile X
FASD

52. Relationships ADHD ASD Mental health problems No identifiable Problem
Full FAS
ARND

53. DC- LD A Developmental disorders B Psychiatric illness
Developed Faculty of Learning Disability Psychiatry 2001
Multiaxial
1Severity of LD
2Cause of LD
3Psychiatric Disorders
A Developmental disorders
B Psychiatric illness
C Personality Disorders
D Problem Behaviours
E Other Disorders

54. Multi axial way of thinking!
Level of Functioning
Aetiology e.g. FASD
Symptoms e .g. Autism
Depression

55. F84.0 = 76.2%
No ASD = 19.0

56. Type of Social Impairment :From DISCO scoring
Bishop et al: FASD group more likely
to initiate social contact
Possible correlation with IQ level p=0.005 56 56 56

57. What does it all mean to me?
Management approaches based on pulling all what has been learnt together
What does it all mean to me?

58. Impulsivity / Distractibility

59. No Clear statistical link with the
Small numbers between
Diagnosis
Age IQ
Sex

60. Ranking of most difficult behaviours with score of 1.5 Mean on DBC
DBC Parameter
Mean Score
Easily Distracted
1.95
Over excited
1.86
Impulsive
1.81
Problems with feelings
1.77
Poor sense of danger
1.76
Easily Led
1.75
Poor attention span
1.71
Temper Tantrums
1.70
Impatient
1.65
Irritable
1.61
Tells Lies
1.52
Does not mix with own peer group
1.50
Attention seeking

61. Single item analysis of ADHD diagnostic criteria: inattentive symptoms
Percentage of Group meeting Criteria (n) Total in group (21)
Not pay attention
81 (17)
Fail to stick at task
76.2 (16)
Not listen when spoken to
Fail to Finish an instruction
95.2 (20)
Difficulties planning
90.5 (19)
Avoid areas find difficult
Loose things needed for task
85.7 (18)
Easily distracted
100 (21)
Forgetful

62. Lobe Analysis * Volume Lobe Frontal Temporal Parietal Occipital
30000
60000
90000
120000
150000
Volume
Lobe
Controls
FAS p
= .0003
= .018
= .030
= .0002 *
Slides Courtesy of Professor E Riley University of San Diego 62 62

63. Change in cerebellum size75 80 85 90 95
100
NDFASD
FAS
< p
0.001
Mattson et al., 1994
Cerebrum
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),
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.
Cerebellum
Corpus Callosum *
Slides Courtesy of Professor E Riley University of San Diego 63 63

64. Summary of other research in this area
People with FASD is worse in the visual modality than the auditory. Coles 2002
Executive function in deficit in people with FASD Rasmussen 2005
Not simply related to IQ
Not related to dysmorphology
Relationship between frontal brain size and maternal alcohol consumption Wass et al 2001, Persutte 2000
Executive functioning not reflective of IQ Connor 2000

65. Executive control of Schemas
Hungry
Activating
Impulse
Orange
Action
Peel Orange
Schema
Peel orange
schema
Supervisory Attention System = EC
Norman and Shallice 86

66. Executive control of Schemas
Not Hungry
Activating
Impulse
Orange
Action
Peel Orange
Schema
Peel orange
schema
Norman and Shallice 86

67. Executive control of Schemas
Not Hungry
Activating
Impulse
Orange
Action
Peel Orange
Schema
Peel orange
schema
Norman and Shallice 86

68. Decision making

69. Ranking of most difficult behaviours with score of 1.5 Mean on DBC
DBC Parameter
Mean Score
Easily Distracted
1.95
Over excited
1.86
Impulsive
1.81
Problems with feelings
1.77
Poor sense of danger
1.76
Easily Led
1.75
Poor attention span
1.71
Temper Tantrums
1.70
Impatient
1.65
Irritable
1.61
Tells Lies
1.52
Does not mix with own peer group
1.50
Attention seeking

70. Active Memory Model Central Executive Long term memory store
Visual spatial
Active memory
Stored visual spatial information
Semantic active
memory
Stored semantic information
Phonological
Active memory
Stored phonological information

71. Model of relationship between Working memory, Consolidation system and long term memory
Memory Store
Working Memory
Consolidation system

72. Hippocampal Circuit Entorhinal Cortex -> Dentate Gyrus ->
Subiculum ->
Fimbria ->
Fornix

73. Examples of other research in this area
Immediate memory worse than long term memory Mattson 2002
Working memory and effects on attention affected by alcohol Burden 2005
GABAa receptors affected by alcohol more likely to be linked to deficits with memory Gibbs 2005
Linked to Executive deficits already shown

74. The frontal lobes, making logical decisions
Frontal Cortex
Striatum
(caudate & putamen)
Globus Pallidus
(part of lenticular nucleus)
Thalamus
Caudate *
Accumbens * 70 75 80 85 90 95
100
NDFASD
FAS
*** *
Concordant with animal data
Slides Courtesy of Professor E Riley University of San Diego

75. White versus gray matter
What is Myelin?
Clinically delayed myelination it has been observed
Riikonen et al., 1999
alcohol-induced delayed myelination are due to the delayed expression of myelin basic protein (MBP) and transferrin
Ozer et al., 2000
Slides Courtesy of Professor E Riley University of San Diego

76. Summary of other research in this area
Prenatal alcohol linked to slower processing speed Burden 2005b
Trade off between speed and accuracy Sampson 1997
Problems passing information between hemispheres Roebuck 2002

77. A possible model of Executive function integration
Motor Response
Stepping on Brake initiated,
Stepping on accelerator inhibited
Posterior
Association Areas
Time 2
Child
Crossing
Anterior Cingulate
Initiating and
focusing attention
Dorsolateral
Pre frontal
Cortex
Selecting
And
Monitoring
Directory
schemas
Motivating
Reward
behaviour
Medial
Inhibiting
Unwanted
behaviour
Lateral
Time 1
Green light
Knowledge
and
action
Schemas
Orbito Frontal Cortex

78. How the brain organises informationC D E

79. How the brain organises informationC D E
Executive Control monitors locates and plans activities

80. How the brain organises informationD A B C E
Executive Control monitors locates and plans activities

81. How the brain organises information
Pedestrian
crossing
How to cross a
road C
Cars can kill
Executive Control monitors locates and plans activities

82. Source Monitoring

83. Individual learns where something is and stores information how items linkedB

84. When asked to recall information the source of the learning is muddledB

85. How the brain organises information : External Support
Pedestrian
crossing C
Cars can kill
How to cross a
road
Executive Control monitors locates and plans activities

86. Ways of overcoming memory deficts
Structure and routine
Repetition
Not expecting people to learn quickly and changing your not their experiences
Concrete tasks avoiding ambiguity

87. Mental Health

88. Rates of Autism in other conditions

89. Type of Social Impairment :From DISCO scoring
Bishop et al: FASD group more likely
to initiate social contact
Possible correlation with IQ level p=0.005 89 89 89

90. Vineland adaptive behaviour schedule: adaptive age scores (n=19) (2 not returned)
Domain
Minimum
Maximum
Average
Age
6.10
16.00
9.93 (95%CI)
Receptive language
1.1
5.6
3.12 ( )
Expressive language
2.2
13.0
5.23 ( )
Written Language
4.5
14.0
8.73(7.37 – 10.09)
Personal Daily living Skills
2.3
8.6
5.62 ( )
Domestic Daily living skills 11
5.61( )
Community skills
3.6
10.6
6.27 (5.30 – 7.24)
Interpersonal skills
0.11
10.0
4.2 ( )
Play/ leisure socialisation
1.0
8.0
4.56 (3.56 – 5.56)
Coping
1.6
9.6
3.99 ( )

91. Secondary Disabilities
Disability %
Psychiatric problem 90
Disrupted School experience 60
Trouble with the law
Confinement 50
Inappropriate sexual behaviour
Alcohol /Drug problems 30
Streissguth et al 1996, 2000

92. Frequency as a % of Psychiatric Diagnoses seen in cohorts of people with FASD
Famy 1997 (n=23)
Barr 2006 (n=136?)
Total 92
Alcohol / Drug Dependence 60
53.5
Major Depression 44
47.9
Psychotic Disorder 40
1.4
Bipolar 1 20
2.8
Anxiety disorder
33.8
Eating Disorder 16
4.2 PD 48

93. Where can I go for help?

94. Referral pathways Clinical Genetics (diagnosis only)
FASD Specialist (very few around)
Paediatrician
Child psychiatry
Child Psychology
Adult Psychiatry
LD Psychiatry
Often need to
Specify
suspected
diagnosis

95. FASD Clinic Information leaflets and referral process available
SPECIALST
FETAL ALCOHOL SPECTRUM DISORDER CLINIC
Information leaflets and referral
process available

96. Second European Conference on FASD Fetal Alcohol Spectrum Disorder: Clinical and Biochemical Diagnosis, Screening and Follow-up Barcelona October 2012
Venue: Barcelona Biomedical Research Park, PRBB
Av. Dr. Aiguader 88, Barcelona, SPAIN

97. Questions SAVE THE DATE – 13th & 14th October 2011
Launch of UK Professionals Forum on FASD
(Foetal Alcohol Spectrum Disorders)
Practical guide for those who want to know what to do