Thurs Oct 9

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Thurs Oct 9 Adverse Influences on Brain
Development and Behavior
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• Variables Governing Susceptibility
• Gestational Age at Exposure
• Genotype
• Characteristics of Agent
• Mechanism of Action
• Amount
• Route

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• Research Designs and Issues Important in
  Associating Prenatal Events with Postnatal
  Outcomes
• 1. Criteria For Inclusion of Participants
• Prospective Identification
• Reliable Pre - Peri- natal History
• Known Socioeconomic Status
• - Parental Occupational Level
• - Parental Educational Level

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• 2. Criteria For Exclusion of Participants
• Mental Retardation in either Parent
• Prenatal Exposure to other Harmful Agents
• Chromosomal/Genetic Abnormality
• Brain Damage Sustained in Childhood
• - illness
• - injury

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3. Need for Comprehensive Assessment of Physical
Features A thorough morphological exam is done
to detect dysmorphology abnormalities of
structure
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• 4. Need for Comprehensive Assessment of Function
  (to capture effects on any brain area)
• Medical status
• General Mental Ability
• Sensory Ability
• Sensory/Perceptual/Motor Integration
• Motor Coordination
• Planning/Organization/Attention
• Language Based Abilities
• Reasoning Ability

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Teratology - study of abnormal development Teratog
en - an environmental agent that causes abnormal
development Neurobehavioral Teratology study of
abnormal brain or behavioral development
resulting from an environmental exposure
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• Known Human Neurobehavioral Teratogens
• Rubella
• Cytomegalovirus
• X-Irradiation
• Retinoic Acids
• Anticonvulsant Drugs (Phenytoin Valproic
  Acid Phenobarbital Carbamazepine)
• Drugs of Abuse (Alcohol Heroin Methadone
  Methamphetamine Cocaine)

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• Known Neurobehavioral Teratogens (continued)
• Methylmercury
• Lead
• PCBs

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• Causes of Behavioral Dysfunction
• Reduced Number of Neurons
• Migration Defects
• Abnormalities of Cytoarchitecture
• Neurochemical Disturbances

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• The individual agents/drugs selected allow
  certain principles to be illustrated
• Some things are evident at birth some are not.
• Generally, neurobehavioral teratogens impair the
  function of more children than the number
  affected with malformations our techniques are
  not yet good enough to detect structural brain
  abnormalities at birth.
• Some agents do not cause structural
  malformations, but do compromise behavior.
• Agents that are harmful during pregnancy may also
  be harmful during childhood brain development.

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Adverse Outcome Due to Prenatal Rubella (From
Alford, Pass, and Stagno, 1983) 30 of infants
are symptomatic at birth Heart
Defects Microcephaly Deafness Growth
Retardation Retinopathy Cataracts
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Rubella continued Of those symptomatic at birth,
80 show neurobehavioral problems in
childhood Hearing loss Language
disorders Visual abnorm. Motor
disorders Hormonal abnorm. Cognitive
dysfunction Dental Defects Emotional disorders
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Rubella continued Of the 70 of infants who are
not symptomatic at birth, 70 show Hearing
loss Language disorders Visual abnorm. Motor
disorders Hormonal abnorm. Cognitive
dysfunction Dental defects Emotional disorders
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Teratogenic Effects of Radiation

• Mental retardation
• Highest risk during major neuronal migration, on
  8-15 weeks. Incidence increases with dose. At 1
  Gy fetal dose 75 experience severe retardation
• At 16-25 weeks, fetus shows no increase in mental
  retardation at doses lt 0.5 Gy
• IQ - Risk factor associated with diminution of IQ
  is 21-33 points at 1 Gy to fetus on 8-15 weeks.
• Microcephaly
• observed in 30 children of 1000 exposed in
  Hiroshima and Nagasaki pregnant women
• the effect lt0.3 Gy is not significantly
  different of control

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• Accutane pill used to treat cystic acne
• a synthetic Vitamin A (a retinoic acid)
• isotretinoin

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• Accutane interferes with the development of
• Central Nervous System
• Craniofacial structures
• The Heart
• The Thymus and Parathyroid Glands
• Other organ systems

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• Embryonic Exposure to Accutane (Isotretinoin)
• Spontaneous Abortion (40)
• Major Malformations (35)
• Prematurity 16

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• CNS Abnormalities
• Cerebellar Hypoplasia (small cerebellum)
• Absence or Reduced Size of the Cerebellar
  Vermis (a part of the cerebellum)
• Ventriculomegaly (4th) enlargement of the 4th
  ventricle
• Cranial Nerve Abnormalities (optic oculomotor)

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• Additional CNS Abnormalities (visible on
  autopsy Lammer and Armstrong, 1991)
• Pons
• Medulla
• Thalamus
• Hippocampus
• Heterotopias in Frontal Cortex
• reduced myelination

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Figure 1. Mental ability of children exposed to
isotretinoin during embryonic development.
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• Prenatal Exposure to Anticonvulsant Medications
• Major malformations
• Craniofacial Abnormalities
• Digit Hypoplasia
• Reduced learning ability

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• Diagnosis of Fetal Alcohol Syndrome
• Minimal criteria
• Abnormalities in three areas
• Prenatal and/or postnatal growth retardation
• Central nervous system involvement
• Characteristic facial dysmorphology

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When criteria for effect are just disturbances in
CNS function, affected is much higher.
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CNS Dysfunction Infants feeding problems
sleep problems irritable difficult to soothe
abnormal muscle tone Permanent reduced
intelligence behavioral abnormalities (reduced
inhibitory control social difficulties
increased activity) Alcohol is the 1
preventable cause of mental retardation.