Neurodevelopmental Pediatrics: Genetic and Environmental Influences

Preface
Acknowledgment
Contents
Contributors
Part I: Overview of CNS Development and Disorders
1: Overview of CNS Organization and Development
Introduction: Brain Development
Types of Neurons
Neurochemical Signaling Molecules and Their Receptors in Brain Development
Neurotrophic Factors
Neurotransmitters
Neuropeptides and Peptide Hormones
Steroid and Thyroid Hormones
Chemokines and Cytokines
Synapses and Neural circuits
Synapses
Neural Circuits
Glial Cells and Brain Development
The Tripartite Synapse and Gliotransmitters
Development of the Neuroendocrine System: The Hypothalamic-Pituitary System
The Hypothalamus
The Pituitary Gland
The Neuroendocrine System and Neurodevelopmental Disorders
Development of the Neuroimmune System
The Neuroimmune System and NDD
Signaling Molecules as Epigenetic Transducers: Converting Environmental Signals to Gene Expression and Protein Synthesis
Critical (Sensitive) Periods in Development
Puberty as a Critical Period in Brain Development
Critical Periods and Neurodevelopmental Disorders
Summary
References
2: Neural Induction and Regionalization
Introduction to the Neural Tube and Early Regionalization of the Central Nervous System
Neural Induction
Model Systems: Drosophila, C. Elegans, Xenopus, Chick, and Mouse
Setting Up Anterior/Posterior and Dorsal/Ventral Axes
Nodes and Organizers
Inducers, Morphogens, Gradients, and Signaling Pathways
Retinoids
Vertical Versus Planar Neural Induction
Lateral Inhibition and Notch Signaling
Asymmetric Versus Symmetric Cell Divisions
Radial Versus Tangential Migration
Induced Pluripotent Stem Cells (iPSC)
Three-Dimensional (3D) Central Nervous System Organoids
Disorders of Neural Induction, Early Regionalization, and Patterning
Holoprosencephaly
Anencephaly and Other Neural Tube Defects
Lissencephaly, a Neuronal Migration Disorder
Hydrocephalus
References
3: Neural Stem Cells, Differentiation, and Migration
Introduction
Building the Central Nervous System
Embryonic Neural Stem Cells, Migration, and Differentiation
Neural Stem Cell Heterogeneity
Neurogenic Niches
The Subependymal Zone
The Subgranular Zone
The Periventricular Zone
Regulating the Neurogenic Niche: Sex, Age, and Injury
Neural Stem Cells in Regenerative Medicine
Exogenous Stem Cell-Based Approaches
Endogenous Stem Cell-Based Approaches
Obstacles, Challenges, and Considerations
Summary and Conclusions
References
4: Neurotrophins and Cell Death
Developmental Cell Death and Brain Development
Neurotrophins
Neurotrophins and their Receptors
Downstream Signaling
Pro-Neurotrophins
Pro-Neurotrophin Receptors and Downstream Signaling
NGF, proNGF, and Neuronal Refinement
Neurotrophins and Development
NGF
BDNF
BDNF, Activity-Dependent Expression, and Dendritic and Axonal Arborization
BDNF and Synapse Development
BDNF and Synaptic Plasticity
NT-4
NT-3
Parallels in the Adult Brain
Neurogenesis
BDNF and Neurodevelopmental Disorders
Autism Spectrum Disorder
Epilepsy
Fetal Alcohol Spectrum Disorder
Summary
References
5: Synaptogenesis
Overview of the Structure of Synapses in the Central Nervous System
The Presynaptic Compartment
The Postsynaptic Compartment
Astrocytes: A Third Compartment at the Synapse
Synaptogenesis
Initial Contact
Synapse Assembly
Neuronal and Glial Secreted Molecules in Synaptogenesis
Synapse Remodeling and Elimination
Role of Glia in Synapse Elimination
Altered Excitatory/Inhibitory Balance in Neurodevelopmental Disorders
Conclusion
References
6: Axonal Guidance
Introduction
The Growth Cone
Role of the Substrate: Adhesive Guidance and Labeled Pathways
Intermediate Targets Simplify the Journey
Robo/Slit Signaling Prevents Commissural Axons from Recrossing the Midline
Semaphorin/Plexin/Neuropilin Signaling
Class 3 Semaphorins Help to Expel Commissural Axons from the Floor Plate
Ephrin/Eph Signaling
EphrinBs and EphAs Constrain Non-Crossing Axons in the Spinal Cord
Mapping of Retinal Axon Projections by EphrinA Signaling
Netrins
Netrins Attract Commissural Axons to the Midline
Response-Switching Regulatory Mechanisms
Regulatory Mechanisms Not Involving Changes in Receptor Expression in the Growth Cone
Intracellular Signaling in the Growth Cone
Axon Guidance in Human Disease
Axonal Regeneration
Summary
References
7: Myelination
Introduction
Myelin: Structure and Function
Function
Structure
Myelinogenesis
Oligodendrocytes: Development and Function
Oligodendrocyte Function
Development of the Oligodendrocyte Lineage
Oligodendrocytes in the Adult CNS
Genes Implicated in Oligodendrocyte Development
Olig Genes
Plp1
Mbp
Cnp
PDGFRa
Mouse Models
Olig1-Null Mice
Jimpy
Rumpshaker
Shiverer
Disorders of Myelination
Leukodystrophies
Autoimmune Disorders
Remyelination and Rehabilitation Medicine
Remyelination
Remyelination Failure
Regeneration/Therapeutic Approaches to Restore Myelin
Transplantation of Exogenous OPCs
Promotion of Endogenous Remyelination
Conclusion
References
8: Epigenetics
Introduction
Epigenetic Mechanisms
Chromatin and Histones
Chromatin Remodeling
Histone Variants
Histone Posttranslational Modifications
DNA Modifications
DNA Methylation
DNA Hydroxymethylation
RNA Modifications
Noncoding RNAs
Small Noncoding RNAs
Long Noncoding RNAs
Conclusions
Epigenetics of Neurodevelopment
Preconception, Fertilization, and Early Embryogenesis
Neural Tube Formation and Neurogenesis
Structuring of the Brain Architecture
Epigenetic Regulation of Synapses
Balance Between Proliferation and Neuronal Cell Death
Gliogenesis and Myelination
Epigenetic Dysregulation and Neurological Disorders
Epigenetic Embedding of EarlyLife Influences
Tools and Techniques to Study Epigenetics
Model Organisms and Human Populations
DNA Modification Studies
Epigenetic Clocks
Cell Type Specificity
Chromatin Studies
RNA Studies
Multiomics
Conclusion
References
9: The Impact of an Adverse Intrauterine Environment on Neurodevelopment
Section 1: An Adverse Intrauterine Environment
Chorioamnionitis (CHORIO)
Progression of Chorioamnionitis
Chorioamnionitis and Preterm Labor
Chorioamnionitis and Term Birth
Placental Insufficiency and Intrauterine Growth Restriction
Section 2: Fetal Inflammatory Response Syndrome and Systemic Inflammatory Response Syndrome
Progression of FIRS
Funisitis Develops Concomitantly with FIRS
Systemic Inflammatory Response Syndrome
Section 3: Sustained Peripheral Immune Hyperreactivity
Evidence for SPIHR
Peripheral Inflammation Infiltrates the CNS
CNS Immune Response – Neuroinflammation
Sustained CNS Inflammation
Section 4: Neonatal Brain Injury
Section 5: Long-Term Outcomes
Cerebral Palsy
Posthemorrhagic Hydrocephalus Secondary to Intraventricular Hemorrhage
Cognitive Impairment/Executive Dysfunction
Chapter Summary
References
10: Stress as a Determinant of Neurodevelopmental Outcomes
Outcomes
Altered HPA Axis Function
Altered Attention (ADHD Symptomology)
Affective Disorder (Internalizing/Externalizing Behaviour (Depression/Anxiety))
Cognitive Impairment
Mechanisms
Brain Structure
Serotonin
Inflammation
Placental 11β-Hydroxysteroid Dehydrogenase 2 (11β-HSD2)
Genetic and Epigenetic Mechanisms
Paternal Influence
Conclusion
End-of-Chapter Summary
References
11: Sex Differences in Neurodevelopment and Its Disorders
Introduction to Sex Differences in Neurodevelopmental Disorders
Sex Determination and Sexual Differentiation
Genetic and Epigenetic Disorders of Sex Determination
The Neurobiology of X-Linked Intellectual Disabilities and Infectious Diseases
Sexual Differentiation of the Brain
Genetic and Epigenetic Factors in Brain Sexual Differentiation
Genes, Hormones, and Microglia Interact in the Sexual Differentiation of the Brain
Sexual Differentiation of Glial Cells: Astrocytes and Microglia
Sex Differences in the Brain
Neuroanatomy
Neural Circuits
Neurochemistry
Summary: Sex Differences in Brain Structure, Function, and Neurochemical Pathways
The Role of Glial Cells in the Sexual Differentiation of the Brain
The Role of Glial Cells in Sex Differences in NDD
Gut Microflora, the Immune System, Glial Cells, and Sex Differences in NDD
Sexual Differentiation of the Hypothalamic-Pituitary (Neuroendocrine) System
Neurohypophyseal Hormones and Sex Differences in NDD
Adenohypophyseal Hormones, Sex Differences, and NDD
HPG System
HPA System
The HPT System
GH and Prolactin
Summary and a Caveat
Puberty: The Organization of the Adult Brain and the Integration of Sex Differences in the Neuroendocrine, Neuroimmune, and Energy Homeostasis Systems
Puberty-Related Neural and Neuroendocrine Reorganization
Sex Differences in Microglia at Puberty
Sex Differences in Gene Expression at Puberty: Epigenetic Effects of Gonadal Hormones
Summary
Puberty-Related Neurodevelopmental Disorders
Disorders of Puberty Timing
Sex Differences in the Activation of Reward Pathways at Puberty: Eating Disorders and Addictions
Sex Differences in Neuropsychiatric Disorders, Anxiety, and Depression at Puberty
Disorders/Differences of Sexual Development
Summary: Theories About the Causes of Sex Differences in Neurodevelopmental Disorders: Genetic, Hormonal, Immune, and Environmental (epigenetic) Mechanisms
References
Part II: Autism Spectrum Disorders
12: The History of Autism Spectrum Disorder
Introduction
Early Definitions of Autism
Child and Adolescent Psychiatry as an Emerging Field
Applying Psychoanalytic Theories to Understand Childhood Schizophrenia
Categorizing and Classifying to Understand Childhood Schizophrenia
Autism Emerging as a Distinct Disorder
Differentiating Between Autism as an Intrinsic Condition Vs. Autism as Experientially Derived
Applying an Empirical Behaviourist Approach to Understand Autism
Exploring Autism as a Language Disorder
Exploring Autism as a Social Cognition Disorder
Early Understandings of Autism as a Neurobiologic Condition
Looking Back: Possible Early Accounts of Autism in our Histories
Other Social and Cultural Factors Shaping Views of Autism
Conclusion
Considering Historical Figures: Spotlight on Bruno Bettelheim
Considering Historical Figures: Spotlight on Hans Aspergers
Considering Historical Figures: Spotlight on Bernard Rimland
References
13: Epidemiology
Introduction
International Policy Context
Epidemiological Estimates
Case Definition
Case Finding
Case Identification and Evaluation
Cultural Considerations in Case Definition and Evaluation
Risk Factors Vs. Social Determinants
Sex
Demographics
Socioeconomic Status
Race/Ethnicity and Nativity
Time Trends
Conclusion
References
14: An Approach to the Diagnosis of Autism Spectrum
Introduction
History Taking
Collateral Information
Observation and Interaction
Standardized Testing
Physical Examination
Allied Health Assessments
Diagnostic Feedback
Family Preferences
Cultural Considerations
References
15: Autism Spectrum Disorder: Cognition
Introduction
Theories of Autism Spectrum Disorder
Attention
Perception
Intelligence, Academics, and General Cognition
Memory
Executive Functioning
Social Cognition
Language
Limitations and Future Directions
References
16: The Neuroradiology of Autism: Framing Neuroimaging Investigations of the Autistic Brain Based on the US NIMH Research Domain Criteria
Introduction
Neuroimaging Findings Based on RDoC Domains
Negative Valence Systems
Positive Valence Systems
Cognitive Systems
Attention, Cognitive Control, and Working Memory
Perception
Language
Summary of Cognitive Systems
Social Processes Systems
Arousal and Regulatory Systems
Sensorimotor Systems
Caveats in Current Understanding and Future Perspectives
Developmental and Environmental Influences
Heterogeneity
Understudied Populations
Imaging Methodology
Measuring Idiosyncrasy
Searching for Biomarkers
Conclusion
References
17: Neuropathology of Autism
Introduction
Whole Brain Alterations
Alterations Consistently Found by Region
Cortical Alterations
Cerebellar Alterations
Amygdala Alterations
Brainstem Alterations
Immunologic-Driven Alterations
Animal Models of ASD and Related Neuropathological Alteration
A Short Briefing on Genetics
Fragile X Mental Retardation Gene (FMR1)
Tuberous Sclerosis complex1/2 Genes (TSC1/2)
Methyl-CpG-Binding Protein 2 (MECP2)
SH3 and Multiple Ankyrin Repeat Domains 3 Gene (SHANK3)
Neurexins (NRXN)
Neuroligins (NLGN)
Chromodomain Helicase DNA-Binding Protein 8 (CHD8)
Synaptic GTPase-Activating Protein 1 (SynGAP1)
AT-Rich Interactive Domain Containing Protein 1B (ARID1B)
Glutamate Receptor Ionotropic, NMDA 2B (GRIN2B)
T-Brain-1 (TBR1)
Final Considerations
References
18: Genetics and Epigenetics of ASD
Introduction
Genetic Etiology
Genetic Heritability of ASD
Genomic Architecture of ASD
From ASD Candidate Gene to Candidate Pathways
Regulation of Gene Expression Mechanisms
Epigenetics and Chromatin Remodeling
Transcription Factors
Alternative Splicing
MicroRNA Gene Expression
Synaptic and Signaling Pathways
Synaptic Development and Altered Neural Circuit
GABA- and Glutamate-Mediated Neurotransmission
Environmental Factors
Maternal Gestational Environment
Parental Age
Gut Microbiota
Sex-Specific Traits and Gene–Environment Interactions
Conclusion
End-of-Chapter Summary
References
19: Preclinical Models of Autism Spectrum Disorder
Introduction
Modelling ASD in Animals
Genetic Models
Environmental Models
Animals Used to Model ASD
Methods for Assessing Animal Models
Behavioural Assessments
Molecular-Anatomical Methods
Functional-Anatomical Methods
Findings from Preclinical Studies
Neurobiology and Neuroanatomy
Treatment Discovery
Conclusions
References
20: Biomedical Interventions for Autism Spectrum Disorder
Introduction
Where We Have Evidence for Effective Medications (Table 20.1)
Irritability
Attention-Deficit Hyperactivity Disorder (ADHD) Symptoms
Repetitive Behaviors
Anxiety and Depression
Seizures
Sleep
Complementary and Alternative Medicine
Research Directions
References
21: Interventions in ASD: Psychosocial Interventions and Supports for ASD
Introduction
Behavioural (ABA-Based) Intervention
ABA-Based Intervention in the Preschool and Early School Years
Parent Involvement in ABA-Based Programs
Naturalistic Treatment Approaches for Young Children
Naturalistic Developmental Behavioural Intervention (NDBI)
Developmental and Social-Pragmatic Intervention Models
Intervention Approaches for Toddlers
‘Packaged’ Parent-Implemented Interventions for Toddlers
Group-Based Social Skills Interventions
Educational and Other School-Based Supports
Academic and Learning Supports
Other School-Based Interventions
Post-Secondary Education
Mental Health Supports
Behavioural Interventions for Disruptive Behaviour Challenges
Conclusions
References
Part III: Fetal Alcohol Spectrum Disorder
22: Clinical Perspectives on the Diagnostic Assessment of Individuals with FASD
Introduction
Confirmation of Prenatal Alcohol Use
Symptoms of FASD across the Lifespan
Common Symptoms in Infancy
Common Symptoms in Preschoolers
Common Symptoms in School Age
Common Symptoms in Adolescents
Adults with FASD
Diagnostic Process and Multidisciplinary Assessments
Medical Assessment
Assessment of FASD Dysmorphology
Multidisciplinary Neurobehavioral Assessment
Case Example of FASD Diagnostic Assessment by Age
Case Example: April
Referral History
Social Background
Prenatal Alcohol/Drug Exposure History
Maternal/Neonatal History
Medical and Family History
Developmental History
Physical Assessment
Neurodevelopmental Assessments
Psychological Assessment
Occupational Therapy Assessment
Speech Language Assessment
Final Diagnoses
Clinical Suggested Recommendations
Adolescent Follow-Up
Final Comments/Summary
References
23: Epidemiology of Alcohol Consumption among Pregnant and Childbearing Age Women and Fetal Alcohol Spectrum Disorder
Prevalence of Alcohol Use among Childbearing-Aged Women
Alcohol Use during Pregnancy
What Is Fetal Alcohol Spectrum Disorder?
Prevalences of Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Spectrum Disorder (FASD) in the General Population
FASD Prevalence in Sub-Populations
Conclusion
References
24: Fetal Alcohol Spectrum Disorder: Diagnosis
Introduction
Epidemiology and Cost of FASD
Importance of Early Diagnosis
Background and Terminology for the Diagnosis of Fetal Alcohol Spectrum Disorder
Terminology Associated with Diagnosis
Diagnosis
The Diagnostic Process
Confirmation of Prenatal Alcohol Exposure
Prenatal Alcohol Exposure and the Developing Fetus
Confirming Maternal Alcohol Exposure
Biomarkers
The Physical Examination and Differential Diagnosis
Facial Features
The Neurobehavioural Assessment
Diagnostic Criteria from the Canadian Guidelines
FASD and Mental Health
Imaging as a Diagnostic Tool
Treatment and Follow-Up
Specific Populations
FASD Diagnosis in Infants
FASD Diagnosis in Adults
Conclusion
References
25: Magnetic Resonance Imaging in Fetal Alcohol Spectrum Disorder (FASD)
Introduction
Quantitative MRI findings in FASD
Brain structure in FASD
Brain Function in FASD
Brain Development in FASD
Newer Techniques
Links to Cognition and Behaviour
Future Directions
Conclusions
References
26: Neuropathological Changes in Humans with History of Prenatal Alcohol Exposure or Diagnosis of Fetal Alcohol Spectrum Disorder
Introduction
Review of PNAE/FASD Neuropathology
Discussion
Alcohol Dose and Multiple Substance Abuse
Microencephaly
Neural Tube Defects
Vascular Damage
Corpus Callosum Anomalies
Hydrocephalus
In Utero and Neonatal Infections
Shortcomings of Autopsy Studies
Conclusions
References
27: Genetics and Epigenetics of FASD
Genetic Component to FASD
Genetic Pathways Implicated in FASD
Epigenetic Modifications that Occur as a Result of Alcohol Exposure in Humans and Animals
Long-Term Effects of Prenatal Alcohol Exposure
References
28: Genetic, Epigenetic, and Environmental Influences on Fetal Alcohol Spectrum Disorder: Implications for Diagnosis, Research and Clinical Practice
Introduction
FASD as a Common Neurodevelopmental Disorder: Prevalence and Diagnosis
Risk and Protective Factors for FASD: What Is the Evidence?
Maternal and Environmental Factors
Paternal Factors
Genetics of FASD
Genes and Cell Signaling Pathways Involved in FASD
SHH Mutations and Signaling Pathway Impairments in FASD
WNT Mutations and Signaling Pathway Impairments in FASD
FGF Signaling Pathway
BMP Signaling Pathway
Retinoic Acid Deficiency and Signaling Pathway Impairments in FASD
Susceptibility and Resilience Genes and Factors in FASD
Co-Morbidities with Other Developmental Genetic Disorders
Epigenetics of FASD
DNA Methylation
Chromatin Modifications
Non-coding RNA
Considerations for Epigenetic Research on FASD
Transcriptomic and Proteomic Alterations of FASD
Transcriptomic Alterations
Proteomic Alterations
Applications to Clinical Setting and Conclusions
References
29: Fetal Alcohol Spectrum Disorder: Interventions
Introduction
Targeted Interventions
Self-Regulation and Behaviour
Executive Functioning Abilities
Academics
Activities of Daily Living
Integrated Interventions
Boost Parental Capacity
Nurture Parent-Child Relationships
Increase Home Stability
Promote Mental Health and Well-being
Support Healthy Families
Plan for Activities of Daily Living (ADL) during Transitional Years
Adopting an Evidence-Based Intervention Framework
Investing in Relationships
Adopting a Strength-Based Perspective
Creating Opportunities for Expectation and Engagement
Recognizing FASD Is a Lifelong Disability
Leveraging Existing Community Capacities
Conclusions
References
Part IV: Cerebral Palsy
30: Cerebral Palsy: Clinical Vignettes
Introduction
Case #1
Commentary-Case #1
Case #2
Commentary-Case #2
Case #3
Commentary-Case #3
Case #4
Commentary-Case #4
Case #5
Commentary-Case #5
Conclusion
References
31: Cerebral Palsy: Epidemiology
Introduction
Definitions
Prevalence
High-Income Countries
Low- and Middle-Income Countries
Motor Type and Topography
Classification Systems and Severity
Risk Factors for CP
Pre-Conception and Early Pregnancy
Genetics
Maternal Age
Assisted Reproductive Technology
Congenital Anomalies
Multiple Birth
Pregnancy
Congenital Infections
Perinatal
Hypoxic Ischaemic Encephalopathy
Low Gestational Age
Post-Neonatally Acquired CP
An Examination of Microcephaly in CP: Including Genetic and Environmental Influences
Definition of Congenital Microcephaly
The Case Control Study of Cerebral Palsy and Perinatal Death (CCCP)
Percentage and Prevalence of Congenital Microcephaly in Children with CP in the CCCP
Clinical Outcomes of Children with CP and Congenital Microcephaly
Genetic and Environmental Pathways to CP That Include Congenital Microcephaly
Genetic Pathways to CP Including Microcephaly: Known Genetic and Chromosomal Syndromes
Genetic Pathways to CP Including Microcephaly: With Additional Congenital Anomalies
Environmental Pathways to CP Including Microcephaly: Congenital Infections
Prevention
Pathways to CP Including Microcephaly That Remain Unclear
The Special Case of Postnatally Developing Microcephaly in CP
Conclusion
References
32: Diagnosis of Cerebral Palsy
Introduction
Perspectives
Definition
Classic Cerebral Palsy “Syndromes”
Spastic Hemiplegia/Unilateral Spastic Cerebral Palsy
Spastic Diplegia/Bilateral Spastic Cerebral Palsy (Predominantly Affecting Lower Limbs)
Spastic Quadriplegia/Bilateral Spastic Cerebral Palsy (Affecting All Limbs)
Dyskinetic (Extrapyramidal) Cerebral Palsy
Mixed Cerebral Palsy
Hypotonic Cerebral Palsy
Ataxic Cerebral Palsy
Developmental Coordination Disorder (DCD)
Diagnostic Evaluation
Etiologic Evaluation
Individualized Evaluation
Motor Abnormalities and Their Distribution
Functional Classification
Co-Existing Conditions
Early Diagnosis
Clinical Risk Factors
Motor Dysfunction in Infancy
Neuroimaging
Severity, Type, and Topography Indicators
Early Intervention
Conclusion
References
33: Neuroradiology of Cerebral Palsy
Introduction
Available Imaging Techniques
Head Ultrasound (HUS)
Head Computed Tomography (CT)
Brain Magnetic Resonance Imaging (MRI)
Typical Neuroimaging Pattern of Some Perinatal Causes of CP
Neonatal Encephalopathy
Intraventricular Hemorrhage (IVH) and Periventricular Hemorrhagic Infarction (PVHI)
Periventricular White Matter Injury (PWMI) or Periventricular Leukomalacia (PVL)
Stroke
Acute Perinatal Arterial Ischemic Stroke (PAIS)
Presumed Perinatal Arterial Ischemic Stroke (PPAIS)
Cerebral Venous Sinus Thrombosis (CVST)
Central Nervous System Infections
Bacterial Meningitis
Herpes Simplex Virus (HSV)
Kernicterus
Typical Neuroimaging Pattern of Some Prenatal Causes of CP
Congenital Brain Malformations
Intrauterine Infections
Congenital CMV (cCMV)
Congenital Toxoplasmosis
Typical Neuroimaging Pattern of Some Postnatal Causes of CP
Non-Accidental Head Injuries (NAHI)
End-of-Chapter Summary/Bullet Points
References
34: Neuropathology of Cerebral Palsy
Introduction
Aetiology and Pathogenesis
Semantics
Traditional and Modern Neuropathological Examination
Neuropathological Changes in Brain Tissue in Cerebral Palsy
Cerebral Dysgeneses or Malformations Associated with Cerebral Palsy
Tuberous Sclerosis Complex (TSC), Hemimegalencephaly (HME) and Focal Cortical Dysplasia Type II (FCD II): Disorders of the mTOR Signalling Pathway
Holoprosencephaly (HPE)
Septo-optic-pituitary Dysplasia (du Morsier syndrome)
Schizencephaly
Polymicrogyria (PMG)
Lissencephaly Types I and II
Periventricular Nodular Heterotopia, Subcortical Laminar (‘band’) Heterotopia and Scattered Deep White Matter Heterotopia
Cerebral Ischaemia and Infarcts in the Foetal and Perinatal Periods, Including Porencephaly
Ulegyria
Porencephaly
Brainstem Watershed Infarcts
Periventricular Leukomalacia, White Matter Gliosis, and the Roles of Iron and Zinc
Historical Perspective and Descriptive Morphology
Impediment of Oligodendrocytic Lineage in PVL
Astrocytic Role
Iron
Zinc
Grey Matter Lesions in PVL
Basal Ganglia
Cerebellum
Congenital Infections
Inborn Metabolic Encephalopathies
Ventriculomegaly and Hydrocephalus
Microcephaly
References
35: Genetics and Genomics of Cerebral Palsy
Introduction
Twin and Other Family Studies
Candidate Gene Association Studies
Studies of Chromosomal Abnormalities and Genomic Copy Number Variants
Studies of Single Nucleotide Variants and Indels
Epigenetic Studies
The Genetics and Genomics of Cerebral Palsy
References
36: Pre-Clinical Models of Cerebral Palsy
Introduction
Cerebral Palsy Definition and Phenotypes
Considerations of Animal Models
Ideal Animal Model
Pre-Clinical Animal Models
Murid Rodents
Placental Insufficiency
Guinea Pig
Rabbit
Cat
Pig
Sheep
Non-Human Primates
Conclusion
References
37: Therapeutic Approaches for the Treatment of Cerebral Palsy and Developmental Disability
Section I: Prevention
Introduction
Non-Preventable Risk Factors/Pregnancy Planning
Education, Social Programs, and Consistent Healthcare Access
Mechanisms of Fetal Brain Injury
Prevention of Premature Birth
Prevention of Infection
Neuroprotection
Magnesium Sulfate (MgSO4)
Corticosteroids
Other: Vitamin K, Phenobarbital
Conclusions and Future Directions
Section II: Therapeutic Hypothermia
Section III: Rehabilitation in Cerebral Palsy
CP Diagnosis
Therapeutic Interventions
Tone Management
Orthotics and Mobility Devices
Future Directions
Section IV: Transcranial Magnetic Stimulation (TMS)
Section V: Regenerative Approaches to Treating Cerebral Palsy
Introduction
Where to Target Stem Cell Therapies
What We Know About Stem Cell Therapies
Sources of Stem Cells
Types of Multipotent Stem Cells for Cerebral Palsy
Mesenchymal Stromal Cells and Hematopoietic Stem Cells
Neural Precursor Cells
Conclusions
References
Part V: Co-Morbidities in Neurodevelopmental Disorders
38: Sleep Disorders
Introduction to Sleep Problems in Children with NDD
What Is Sleep?
Regulation of Sleep
How Sleep Physiology Differs in Children with NDD Compared to TD Children
What Are Sleep Disorders
Etiology of Sleep Disorders in Children with NDD
How to Evaluate Sleep Disorders and Considerations for Children with NDD
Screening Assessment
Subjective Assessment
Objective Assessment
How to Treat Sleep Disorders in Children with NDD
Psychoeducation
Healthy Sleep Practices
Specific Behavioral Sleep Interventions
Medication
Transdiagnostic Approach to Treatment
References
39: Optimizing Therapy of Seizures in Children and Adolescents with Developmental Disabilities
Introduction: Epilepsy and Developmental Disability
Specific Developmental Disabilities
Cerebral Palsy (CP)
Prevalence and Pathophysiology of Comorbid Epilepsy
Risk Factors for Development of Epilepsy in Cerebral Palsy
Types of Epilepsy in Cerebral Palsy
Natural History of Epilepsy Associated with Cerebral Palsy
Management of Epilepsy in Cerebral Palsy
Autism Spectrum Disorders
Prevalence and Pathophysiology of Comorbid Epilepsy
Risk Factors for Development of Epilepsy in ASD
Types of Epilepsy in ASD
Natural History of Epilepsy Associated with ASD
Management of Epilepsy in ASD
Cortical Malformations
Prevalence and Pathophysiology of Comorbid Epilepsy
Risk Factors for Development of Epilepsy with Cortical Malformations
Types of Epilepsy Associated with Cortical Malformations
Natural History of Epilepsy Associated with Cortical Malformations
Management of Epilepsy Associated with Cortical Malformations
Fetal Alcohol Syndrome
Prevalence and Pathophysiology of Comorbid Epilepsy
Risk Factors for the Development of Epilepsy
Types of Epilepsy in Fetal Alcohol Syndrome
Natural History of Epilepsy Associated with Fetal Alcohol Syndrome
Management of Epilepsy in Fetal Alcohol Syndrome
Investigation of Seizures in Children with Neurodevelopmental Disabilities
Treatment of Seizures in Children with Neurodevelopmental Disabilities
Summary Points
Clinical Vignettes
References
40: Behavioral and Mental Health Disorders (Including Attentional Disorders)
Introduction and Overview
Adverse Childhood Experiences
Behavioral and Mental Health Disorders in Children with Neurodevelopmental Disorders
Autism Spectrum Disorders
Persistent Deficits in Social Communication and Social Interaction Across Multiple Contexts
Speech and Language
Social Interaction
Restricted, Repetitive Patterns of Behavior, Interests, or Activities
Repetitive behaviors
Unusual Sensory Reactions
Tendency to Overreaction
Psychiatric Comorbidities
Anxiety
Tics and Tourette’s
ADHD
Medical Conditions Expressing as Behavior Disorders
Disparities in Diagnosis and Treatment of ASD
Section Bullets
Cerebral Palsy
Conclusion
Fetal Alcohol Spectrum Disorders FAS (D)
Pathology and Pathophysiology
Clinical Characteristics and Diagnosis
Behavioral and Mental Health Concerns
Social Context
Behavioral and Mental Health
Educational Concerns
Transition to Adulthood
Attention Deficit Hyperactivity Disorder (ADHD)
Introduction
The Evolution of Attention Deficit/Hyperactivity Disorder
Overview of Neurodevelopmental Disorders
Diagnostic Criteria for ADHD
ADHD diagnostic criteria
Co-occurring and Comorbid Conditions
Assessment
Trends in Treatment
Summary
Summary Bullets
Chapter Discussion
References
41: Role of Gender and Neurodevelopmental Disabilities
Introduction
Neurodevelopmental Disabilities and Males
Attention-Deficit/Hyperactivity Disorder (ADHD)
Autism Spectrum Disorder (ASD)
Intellectual Disability (Intellectual Developmental Disorder)
Specific Learning Disorder
Communication Disorders
Tourette’s Disorder
Cerebral Palsy
Schizophrenia
Neurodevelopmental Disabilities and Females
Myelomeningocele
Mental Health Disorders
Eating Disorders
Depressive Disorders
Anxiety Disorders
Other Conditions/Disorders
In Utero Milieu: Protection Versus Toxicity
Placental Milieu
Epigenetic Role of O-Linked N-Acetylglucosamine Transferase (OGT)
Conclusions
References
42: A Non-Categorical Approach to Childhood Neurodisability: Concepts, Evidence, and Implications for Clinical Practice, Organization of Services, Teaching, and Research
Introduction
Background Concepts
The Non-categorical Approach: Overview
The Case for a Non-categorical Approach in Childhood Neurodisability
The Non-categorical Approach: State of the Evidence
Implications of These Ideas
Concluding Comments
References
43: Pain and Symptom Management in Neurodevelopmental Disorders: Sensory and Nociceptive Function/Pain and Symptom Management
Background and Significance
Approaches and Challenges to Pain Assessment in IDD
Sensory Measurement
Observational Measurement
Proxy Report
Biomarkers
Neuroimaging
Current Assessment and Treatment Approaches
Assessment
Treatment
Knowledge Transfer
Secondary Caregivers—A Literature Gap, Current Work, and Continued Future Directions
Continuing Issues and Hope for the Future
Summary
References
44: Pharmacology, Psychopharmacology, and Adverse Drug Reactions
Introduction
Psychopharmacology as a Subset of Basic Pharmacology
Pharmacogenomics
Pharmacogenetics (See Appendix 1)
Pharmacokinetics
Bullets
Pharmacodynamics
Bullets
Precision Medicine
Bullets
Classifying Psychiatric Disorders
Bullets
Summary, Synthesis, and Conclusions
Appendix 1. Current Applications of Pharmacogenetics to the Psychiatry Treatment
Limitations
Appendix 2. What New Treatment Ideas Are on the Horizon?
References
45: Developmental Origins, Differential Susceptibility, and Resilience in Neurodevelopmental Disorders
Introduction
The Developmental Origins of Health and Disease
Critical Periods of Sensitivity
Sensitive Periods of Brain Development
Early Life Environmental Factors That Influence Brain Development and Susceptibility to Neurodevelopmental Disorders
Prenatal Environments
Prenatal Nutritional Environment
Maternal Metabolic State and Hypertensive Disorders in Pregnancy
Maternal Mood, Anxiety and Adverse Life Events
Prenatal Depression
Prenatal Worries and Anxiety
Adverse Life Events
Prenatal Stress and Genetic Susceptibility
Mechanism
Sex-Specific Responses
Summary
Postnatal Modifiers of Prenatal Programming
Toxicants, Nutrition, and the Microbiome
Sleep Hygiene
Mind and Body
Rearing Environment
Modeling the Joint Effect of Genetic Susceptibility and Environmental Exposures in Developmental Programming
The Three Types of Gene-by-Environment Interactions Models
Definition of a G×E Model
Components of the G×E Model
Environment
Genetics
How to Test for the Type of Interaction?
Modeling with Examples
Conclusions
References
Part VI: Neurodevelopmental Disorders in the Context of Families
46: Children with Neurodevelopmental Disabilities and the Right to Health
An Introduction to Human Rights and Rights-Based Approaches in Childhood Disabilities
Human Rights Application in Signatory Countries
The Right to Health and Its Intersections with Health Frameworks
The Right to Health and Childhood Disability
Rights-Based Approaches in Childhood Disabilities: What Is the Research Evidence?
Applying Rights-Based Approaches to Health Care and Research
Conclusions
References
47: Patient Navigation: Core Concepts and Relevance to the Field of Pediatric Neurodisability
Introduction
Patient Navigation: Origins and Core Concepts
Patient Navigation and Children with NDD/D
Insights from Quality Improvement
Insights from Empirical Evidence
Navigation and its Alternatives
Moving the Field Ahead: Challenges and Opportunities
Concluding Thoughts
References
48: Evaluating the Economic Impact of Neurodevelopmental Disability Intervention on the Family and Community
Introduction
Considering the Perspective and Time Horizon for an Evaluation
Evaluation Perspective
Time Horizon and Discounting
Measurement of NDD Costs
Direct Costs
Indirect Costs
Measurement of NDD Effectiveness
Economic Evaluation of Interventions for Children with NDD
Cost of Illness (COI)
Types of Economic Evaluations
Cost Minimization (CMA)
Cost-Effectiveness Analysis (CEA)
General Health Profile Measures
ASD, CP, and FASD-Specific Measures
Cost-Utility Analysis (CUA)
Preference-Based HRQoL Measures
Cost-Benefit Analysis (CBA)
Measurement of Family Effects and Caregiver Effects
Challenges for the Economic Evaluation of NDD
Important Considerations when Choosing Outcome Measures
Important Considerations when Incorporating Caregivers and Family Effects
Important Considerations when Estimating Costs
Conclusions
References
Part VII: Resources
49: Using Large-Scale Population-Based Data
Introduction
Large-Scale Population-Based Survey Data
Large-Scale Population-Based Administrative Data
Record Linkage
Research Examples
Criteria to Assess a Secondary Data Source for Data Analysis in Neurodevelopmental Pediatrics
Summary
References
50: Tools for Knowledge Dissemination and Translation to Help Your Journey from Research to Impact
Introduction
Section 1: The Co-Produced Pathway to Impact (CPPI)—You Need to Know How to Get There from Here
Section 2: Research to Impact Canvas—You Need to Know How to Plan to Get There from Here
Section 3: Stakeholder Engagement—You Need to Know Why You Are Trying to Get There from Here and Where “There” Is
Section 4: Dissemination—Necessary But Not Sufficient to Get There from Here
Section 5: International Perspectives—Others Are Also Trying to Get There
Conclusion
References
Index