H1: Brain development 4
1.1 Introduction 4
1.1.1 Two important phases in the development of the CNS 4
1.1.2 Developmental stages of the CNS 4
1.2 Embryogenesis 4
1.2.1 Primary neurulation (3-4 weeks PMA) 4
1.2.1.1 Three germ layers 5
1.2.1.2 Link to pathology: neural tube defects 5
1.2.1.3 Link to pathology: neurocutaneous disorders 6
1.2.2 Vesicle formation 6
1.2.2.1 What is vesicle formation? 6
1.2.2.2 Link to pathology: holoprosencephaly 7
1.2.3 Ventricle formation 8
1.2.3.1 What is ventricle formation? 8
1.2.3.2 Link to pathology: aqueduct stenosis 9
1.3 Histogenesis 9
1.3.1 Neuronal proliferation (1-4m PMA) 9
1.3.1.1 What is neuronal proliferation? 9
1.3.1.2 Link to pathology: disorders of proliferation 9
1.3.2 Neuronal migration (3-5m PMA) and organisation (5m PMA-postnatal) 10
1.3.2.1 What is neuronal migration and organisation? 10
1.3.2.2 Link to pathology: disorders of migration and organisation 10
1.3.3 Synaptic pruning 11
1.3.4 Myelinisation (25w PMA - postnatal) 11
1.4 Corpus callosum 11
1.5 Brain growth and development after birth 12
1.6 Nature - nurture 12
1.7 What in case of preterm birth? 13
1.7.1 What is prematurity? 13
1.7.2 Impact of preterm birth? 13
1.8 The underlying brain damage in cerebral palsy 14
1.8.1 Lesion type 14
1.8.2 Reorganisation of motor and somatosensory white matter tracts 15
H2: Cognitive development 16
2.1 Typical cognitive development 16
2.1.1 Basic principles of developmental theories 16
2.1.2 Piaget’s developmental milestone theory 16
2.1.2.1 Adaptation 16
2.1.2.2 Phases of cognitive development 16
1. Sensorimotor stage (0-2 years) 16
2. Preoperational period (2-7 years) 17
3. Concrete operational period (7-11 years) 18
4. Formal operational period (> 12 years) 18
1
, 2.1.2.3 Critical considerations 19
2.2 Assessment of cognition 19
2.2.1 Bayley Scales of Infant Development III (BSID-III) 20
2.2.2 Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) 20
2.2.3 Wechsler Intelligence Scale for Children (WISC-V) 20
2.2.4 Coloured Progressive Matrices 21
2.2.5 Vineland Adaptive Behavior Scale (VABS) 21
2.2.6 Uzgiris Hunt Ordinal Scales 22
2.3 Definitions of average and impaired cognitive development 22
2.4 Executive functioning 23
2.5 Screening and monitoring 25
H3: Socio-emotional development 26
3.1 Typical socio-emotional development 26
3.1.1 4-18m: ages & stages questionnaires - socio-emotional (A&SQ:SE-2) 26
3.1.2 18-72m: child development tool for observation and planning (TOP) - The Portage
project 26
3.1.2.1 Relationships 27
3.1.2.2 Emotional response 28
3.1.2.3 Interactions with others 29
3.1.2.4 Social play development 30
3.1.2.5 Creative self-expression 30
3.2 Screening 31
H4: Visual development 33
4.1 Prenatal eye development 33
4.2 Eye anatomy 34
4.3 Visual physiology 34
4.3.1 Primary/retinocortical visual system 34
4.3.2 Subcortical/retinotectal visual system 36
4.4 Visual functions and its assessment 36
4.4.1 Oculomotor functions (eye movements) 36
4.4.2 Geniculostriate functions in visual cortex 37
4.4.2.1 Visual acuity 37
4.4.2.2 Contrast sensitivity 37
4.4.2.3 Visual field 38
4.4.2.4 Stereopsis 38
4.4.2.5 Depth perception 38
4.4.3 Colour vision 39
4.4.4 Face recognition 39
4.5 Maturation of the visual system 39
4.6 Vulnerability and plasticity of the visual system 40
H5: Early intervention and detection 41
5.1 Early detection of cerebral palsy 41
5.1.1 Why early detection? 41
5.1.2 How to do early detection of cerebral palsy 41
2
, 5.1.3 Red flags 42
5.1.4 General movements 42
5.1.5 Hammersmith Infant Neurological Examination (HINE) 43
5.2 Early detection of unilateral cerebral palsy 44
5.2.1 False negatives and positives 45
5.2.2 Importance and challenges of determining 45
5.2.2.1 Determining severity 45
5.2.2.2 Determining motor type and topography 45
5.2.3 Keep in mind 46
5.3 Communication to parents 46
5.4 Early intervention 46
5.4.1 Environmental enrichment 46
5.4.2 Early CIMT 46
5.4.3 Early bimanual therapy 47
5.4.4 Goals - Activity - Motor - Enrichment (GAME) 48
5.4.5 Coping with and Caring for Infants with Special Needs (COPCA) 48
5.4.6 Key components of early intervention 48
3
, Typical and atypical sequences of human
development: course and assessment
H1: Brain development
1.1 Introduction
1.1.1 Two important phases in the development of the CNS
● Embryogenesis
○ Embryo = seed
○ Genesis = development
● Histogenesis
○ After week 11: now foetal development
○ Proliferation and migration of neural cells
● On average:
○ 40 weeks of pregnancy
○ Preterm before 37 weeks and postterm after 42 weeks
○ Three trimesters
○ From week 24 there is a 50% chance of survival
1.1.2 Developmental stages of the CNS
Stage Timing
Primary neurulation 3 - 4 weeks PMA
Neuronal proliferation 1 - 4 months PMA
Neuronal migration 3 - 5 months PMA
Organisation 5m PMA - postnatal
Myelinisation 25w PMA - postnatal
● PMA = postmenstrual age
● Neuronal proliferation starts during the embryogenesis and ends in the histogenesis
● The brain is not fully matured during birth
1.2 Embryogenesis
1.2.1 Primary neurulation (3-4 weeks PMA)
● Primary neurulation is the process by which the neural tube is
shaped from the neural plate
● Neural tube = the precursor of the brain and spinal cord
● Primary neurulation comprises two distinct processes
○ Neural plate shaping
■ Neural plate forms from the ectoderm
■ The plate becomes more narrow and longer
○ Neural plate bending, which culminates in fusion
■ The neural folds begin to elevate -> forming
the neural groove
4
, ■ The neural folds meet and fuse, closing the neural tube
■ The neural canal forms, which will later develop into the central nervous
system (CNS)
1.2.1.1 Three germ layers
● Ectodermal germ layer:
○ CNS and PNS
○ Sensory epithelia of the eyes, nose and ears
○ Epidermis: skin, hair & nails
○ Pituitary, mammillary glands, enamel of the teeth
● Mesodermal germ layer
○ Connective tissue, cartilage, and bone
○ Striated and smooth muscles
○ The heart walls, blood and lymph vessels and cells
○ The kidneys
○ The gonads (ovaries and testes) and genital ducts
○ The serous membranes lining the body cavities
○ The spleen
○ The suprarenal (adrenal) cortices
● Endodermal germ layer
○ Epithelium of digestive and respiratory system
○ Organs associated with digestive system (e.g. liver, pancreas)
1.2.1.2 Link to pathology: neural tube defects
● Closed spinal dysraphism
○ Intact overlying skin
○ Nothing wrong with the spinal cord
○ 50% has minor abnormalities of the overlying skin, cutaneous stigmata:
■ Lumps, depigmented region, capillary haemangiomas, hair tufts …
○ Defect posterior vertebral arches
○ Association with “tethered cord syndroom”
5
, ● Myelomeningocele = form of open spinal dysraphism: skin is not closed, spinal cord and/or
membranes are exposed
○ Coele at the back, which can contain meninges and nervous tissue
○ Damage to nervous tissue because of contact with amniotic fluid
○ Secondary problems - central brain damage
■ Chiari II: low position of the cerebellar tonsils
■ Hydrocephaly: blockage of normal flow of cerebrospinal fluid and
accumulation of fluid in the ventricles
1.2.1.3 Link to pathology: neurocutaneous disorders
● Neurofibromatosis: cafe-au-lait macules, freckling, lisch nodules, …
● Tuberous Sclerosis: skin, kidney, heart and brain abnormalities
● Sturge-Weber syndrome:
○ Features:
■ Port-wine stain (vascular malformation on the skin, usually on the face)
■ Leptomeningeal angiomas (abnormal blood vessels in the brain), which can
lead to:
● Seizures
● Oedema (brain swelling)
● Cognitive impairment
■ Ocular abnormalities, like glaucoma
○ Treatment: untreatable, but symptoms (e.g., seizures) can be managed with
medication and surgery if needed
1.2.2 Vesicle formation
1.2.2.1 What is vesicle formation?
6
, ● 3 vesicle stage, week 4 PMA: prosencephalon - mesencephalon - rhombencephalon
● 5 vesicle stage, week 5 PMA
○ Prosencephalon: will develop in the first phase of the hemispheres
■ Telencephalic vesicles
■ Diencephalon
○ Mesencephalon
○ Rhombencephalon:
■ Metencephalon
■ Myelencephalon
● 5 vesicle stage, week 6 PMA
○ Prosencephalon: depression between tel- & diencephalon
○ Mesencephalon
○ Rhombencephalon: pontine flexure
Primary vesicles Secondary vesicles Adult structures
Brain Prosencephalon Telencephalon Rhinencephalon, Amygdala,
Hippocampus, Cerebrum(Cortex), Basal
Ganglia, Lateral ventricles
Diencephalon Epithalamus, Thalamus, Hypothalamus,
Subthalamus, Pituitary, Pineal, Third
ventricle
Mesencephalon / (Pre)Tectum, Cerebral peduncle,
Cerebral Aqueduct (one structure)
Rhombencephalon Metencephalon Pons, Cerebellum
Myelencephalon Medulla Oblongata
Spinal cord
1.2.2.2 Link to pathology: holoprosencephaly
● The prosencephalon fails to properly divide into two hemispheres, leading to abnormal brain
and facial structures
● Different types and severity of HPE
○ Alobar holoprosencephaly (HPE) = most severe form of HPE
■ MRI:
● Enlarged midline monoventricle with fusion of the frontal lobes and
the midline gray matter structures
● The corpus callosum and the third ventricle are absent
7
, ■ Facial features:
● Single eye-like structure (cyclopia)
● Overriding nose-like structure (proboscis)
○ Semilobar HPE
■ MRI
● Fusion of the frontal lobes, but presence of some septation
posteriorly with presence of a falx and interhemispheric fissure
● More significant fusion of anterior brain structures (cortex, basal
ganglia, thalamus) persists in this variant
■ Facial features
● Closely spaced eyes
● Depressed nasal ridge with cleft lip
○ Axial plane depicting lobar HPE = least severe of the major types of HPE
■ MRI:
● The cerebral hemispheres are separated
● Varying degree of fusion of the midline gray structures
■ Facial features:
● Relatively normal facial appearance
● Subtle dysmorphisms: f.e. narrow forehead, relatively large ears,
relatively depressed nasal bridge, broad and well-defined philtrum
● Prognosis
○ Severe cases lead to death shortly after birth due to brain dysfunction and
respiratory failure
○ Milder cases may survive but often have severe neurodevelopmental impairments
1.2.3 Ventricle formation
1.2.3.1 What is ventricle formation?
Origin Ventricle
Prosencephalon Lateral and 3rd ventricle
Mesencephalon Aqueduct of Sylvius
Rhombencephalon 4th ventricle
8
,1.2.3.2 Link to pathology: aqueduct stenosis
● Cause & effect
○ Cerebral aqueduct (narrow passage between 3rd and 4th ventricles) becomes
blocked or narrowed
○ CSF cannot flow properly -> ventricular dilation and increased intracranial pressure
○ Lateral and 3rd ventricles enlarge due to CSF buildup, while the fourth ventricle
remains normal or collapsed
● Clinical consequences
○ Increased intracranial pressure -> head enlargement in infants, headaches, vomiting,
and vision problems in older individuals
○ Brain tissue damage -> cognitive and motor impairments
○ Hydrocephalus -> if untreated -> severe brain injury or death
● There are treatment options
1.3 Histogenesis
-> the brain volume will increase a lot
1.3.1 Neuronal proliferation (1-4m PMA)
1.3.1.1 What is neuronal proliferation?
● Starts: 5-6 weeks PMA -> starts already in the embryogenesis
● Ends: normally around 24 weeks PMA
● Neural stem cells divide rapidly to produce a large number of neurons
● During this formation: ventricular, intermediate and marginal zone are formed
○ Process might be disturbed in case of germinal matrix hemorrhage
○ Subsequent development might be disturbed: less cells, cells stop migrating …
○ Germinal matrix = highly vascularised premature birth: higher risk to get a problem
in this place (hemorrhage)
1.3.1.2 Link to pathology: disorders of proliferation
● Microcephaly (reduced proliferation)
○ Abnormally small brain due to decreased proliferation of neural progenitor cells
○ Clinical features:
■ Small head size
■ Developmental delays and intellectual disabilities
● Megalencephaly (excessive proliferation)
○ Brain overgrowth due to excessive proliferation of neural progenitors
○ Clinical features:
■ Enlarged head size
■ Risk of epilepsy and developmental delays
9
, ● Hemimegalencephaly
○ Overgrowth of one cerebral hemisphere while the other remains normal or
underdeveloped -> asymmetry in brain size (one side is abnormally large)
○ Caused by mutations in genes
○ Clinical consequences
■ Severe epilepsy (drug-resistant) due to cortical malformations
■ Developmental delays -> intellectual disability and motor impairment
■ Hemiparesis: weakness on 1 side of the body (opposite to the enlarged
hemisphere)
■ Cognitive and behavioral issues: vary based on the extent of overgrowth
○ Treatment is possible
1.3.2 Neuronal migration (3-5m PMA) and organisation (5m PMA-postnatal)
1.3.2.1 What is neuronal migration and organisation?
● Neuronal migration
○ 3-5 months PMA
○ Is the method by which neurons travel from their origin birthplace (ventricular zone
or germinal matrix ) to their final position in the brain
○ Inside out direction: migrate through intermediate zone and make different layers
■ Earliest neurons that start to migrate, will form the first layers at the outside
of developing brain
■ Second neurons will migrate through layers that are already formed, to form
a second layer
■ Eventually, 6 cortical layers will be developed
● Neuronal organisation -> start: month 5 PMA
○ Lamination (6 layers)
○ Neurons -> two options after migration:
■ Neurite outgrowth + synaptogenesis
■ Cell death (apoptosis)
○ Selective elimination of neuronal processes or synapses (apoptosis and pruning,
mostly after birth)
1.3.2.2 Link to pathology: disorders of migration and organisation
● Lissencephaly
○ Cortical maldevelopments caused by deficient neuronal migration and organisation
○ Result: absent or reduced gyration -> the brain surface is smooth
○ Different grades of type 1 lissencephaly
10
1.1 Introduction 4
1.1.1 Two important phases in the development of the CNS 4
1.1.2 Developmental stages of the CNS 4
1.2 Embryogenesis 4
1.2.1 Primary neurulation (3-4 weeks PMA) 4
1.2.1.1 Three germ layers 5
1.2.1.2 Link to pathology: neural tube defects 5
1.2.1.3 Link to pathology: neurocutaneous disorders 6
1.2.2 Vesicle formation 6
1.2.2.1 What is vesicle formation? 6
1.2.2.2 Link to pathology: holoprosencephaly 7
1.2.3 Ventricle formation 8
1.2.3.1 What is ventricle formation? 8
1.2.3.2 Link to pathology: aqueduct stenosis 9
1.3 Histogenesis 9
1.3.1 Neuronal proliferation (1-4m PMA) 9
1.3.1.1 What is neuronal proliferation? 9
1.3.1.2 Link to pathology: disorders of proliferation 9
1.3.2 Neuronal migration (3-5m PMA) and organisation (5m PMA-postnatal) 10
1.3.2.1 What is neuronal migration and organisation? 10
1.3.2.2 Link to pathology: disorders of migration and organisation 10
1.3.3 Synaptic pruning 11
1.3.4 Myelinisation (25w PMA - postnatal) 11
1.4 Corpus callosum 11
1.5 Brain growth and development after birth 12
1.6 Nature - nurture 12
1.7 What in case of preterm birth? 13
1.7.1 What is prematurity? 13
1.7.2 Impact of preterm birth? 13
1.8 The underlying brain damage in cerebral palsy 14
1.8.1 Lesion type 14
1.8.2 Reorganisation of motor and somatosensory white matter tracts 15
H2: Cognitive development 16
2.1 Typical cognitive development 16
2.1.1 Basic principles of developmental theories 16
2.1.2 Piaget’s developmental milestone theory 16
2.1.2.1 Adaptation 16
2.1.2.2 Phases of cognitive development 16
1. Sensorimotor stage (0-2 years) 16
2. Preoperational period (2-7 years) 17
3. Concrete operational period (7-11 years) 18
4. Formal operational period (> 12 years) 18
1
, 2.1.2.3 Critical considerations 19
2.2 Assessment of cognition 19
2.2.1 Bayley Scales of Infant Development III (BSID-III) 20
2.2.2 Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) 20
2.2.3 Wechsler Intelligence Scale for Children (WISC-V) 20
2.2.4 Coloured Progressive Matrices 21
2.2.5 Vineland Adaptive Behavior Scale (VABS) 21
2.2.6 Uzgiris Hunt Ordinal Scales 22
2.3 Definitions of average and impaired cognitive development 22
2.4 Executive functioning 23
2.5 Screening and monitoring 25
H3: Socio-emotional development 26
3.1 Typical socio-emotional development 26
3.1.1 4-18m: ages & stages questionnaires - socio-emotional (A&SQ:SE-2) 26
3.1.2 18-72m: child development tool for observation and planning (TOP) - The Portage
project 26
3.1.2.1 Relationships 27
3.1.2.2 Emotional response 28
3.1.2.3 Interactions with others 29
3.1.2.4 Social play development 30
3.1.2.5 Creative self-expression 30
3.2 Screening 31
H4: Visual development 33
4.1 Prenatal eye development 33
4.2 Eye anatomy 34
4.3 Visual physiology 34
4.3.1 Primary/retinocortical visual system 34
4.3.2 Subcortical/retinotectal visual system 36
4.4 Visual functions and its assessment 36
4.4.1 Oculomotor functions (eye movements) 36
4.4.2 Geniculostriate functions in visual cortex 37
4.4.2.1 Visual acuity 37
4.4.2.2 Contrast sensitivity 37
4.4.2.3 Visual field 38
4.4.2.4 Stereopsis 38
4.4.2.5 Depth perception 38
4.4.3 Colour vision 39
4.4.4 Face recognition 39
4.5 Maturation of the visual system 39
4.6 Vulnerability and plasticity of the visual system 40
H5: Early intervention and detection 41
5.1 Early detection of cerebral palsy 41
5.1.1 Why early detection? 41
5.1.2 How to do early detection of cerebral palsy 41
2
, 5.1.3 Red flags 42
5.1.4 General movements 42
5.1.5 Hammersmith Infant Neurological Examination (HINE) 43
5.2 Early detection of unilateral cerebral palsy 44
5.2.1 False negatives and positives 45
5.2.2 Importance and challenges of determining 45
5.2.2.1 Determining severity 45
5.2.2.2 Determining motor type and topography 45
5.2.3 Keep in mind 46
5.3 Communication to parents 46
5.4 Early intervention 46
5.4.1 Environmental enrichment 46
5.4.2 Early CIMT 46
5.4.3 Early bimanual therapy 47
5.4.4 Goals - Activity - Motor - Enrichment (GAME) 48
5.4.5 Coping with and Caring for Infants with Special Needs (COPCA) 48
5.4.6 Key components of early intervention 48
3
, Typical and atypical sequences of human
development: course and assessment
H1: Brain development
1.1 Introduction
1.1.1 Two important phases in the development of the CNS
● Embryogenesis
○ Embryo = seed
○ Genesis = development
● Histogenesis
○ After week 11: now foetal development
○ Proliferation and migration of neural cells
● On average:
○ 40 weeks of pregnancy
○ Preterm before 37 weeks and postterm after 42 weeks
○ Three trimesters
○ From week 24 there is a 50% chance of survival
1.1.2 Developmental stages of the CNS
Stage Timing
Primary neurulation 3 - 4 weeks PMA
Neuronal proliferation 1 - 4 months PMA
Neuronal migration 3 - 5 months PMA
Organisation 5m PMA - postnatal
Myelinisation 25w PMA - postnatal
● PMA = postmenstrual age
● Neuronal proliferation starts during the embryogenesis and ends in the histogenesis
● The brain is not fully matured during birth
1.2 Embryogenesis
1.2.1 Primary neurulation (3-4 weeks PMA)
● Primary neurulation is the process by which the neural tube is
shaped from the neural plate
● Neural tube = the precursor of the brain and spinal cord
● Primary neurulation comprises two distinct processes
○ Neural plate shaping
■ Neural plate forms from the ectoderm
■ The plate becomes more narrow and longer
○ Neural plate bending, which culminates in fusion
■ The neural folds begin to elevate -> forming
the neural groove
4
, ■ The neural folds meet and fuse, closing the neural tube
■ The neural canal forms, which will later develop into the central nervous
system (CNS)
1.2.1.1 Three germ layers
● Ectodermal germ layer:
○ CNS and PNS
○ Sensory epithelia of the eyes, nose and ears
○ Epidermis: skin, hair & nails
○ Pituitary, mammillary glands, enamel of the teeth
● Mesodermal germ layer
○ Connective tissue, cartilage, and bone
○ Striated and smooth muscles
○ The heart walls, blood and lymph vessels and cells
○ The kidneys
○ The gonads (ovaries and testes) and genital ducts
○ The serous membranes lining the body cavities
○ The spleen
○ The suprarenal (adrenal) cortices
● Endodermal germ layer
○ Epithelium of digestive and respiratory system
○ Organs associated with digestive system (e.g. liver, pancreas)
1.2.1.2 Link to pathology: neural tube defects
● Closed spinal dysraphism
○ Intact overlying skin
○ Nothing wrong with the spinal cord
○ 50% has minor abnormalities of the overlying skin, cutaneous stigmata:
■ Lumps, depigmented region, capillary haemangiomas, hair tufts …
○ Defect posterior vertebral arches
○ Association with “tethered cord syndroom”
5
, ● Myelomeningocele = form of open spinal dysraphism: skin is not closed, spinal cord and/or
membranes are exposed
○ Coele at the back, which can contain meninges and nervous tissue
○ Damage to nervous tissue because of contact with amniotic fluid
○ Secondary problems - central brain damage
■ Chiari II: low position of the cerebellar tonsils
■ Hydrocephaly: blockage of normal flow of cerebrospinal fluid and
accumulation of fluid in the ventricles
1.2.1.3 Link to pathology: neurocutaneous disorders
● Neurofibromatosis: cafe-au-lait macules, freckling, lisch nodules, …
● Tuberous Sclerosis: skin, kidney, heart and brain abnormalities
● Sturge-Weber syndrome:
○ Features:
■ Port-wine stain (vascular malformation on the skin, usually on the face)
■ Leptomeningeal angiomas (abnormal blood vessels in the brain), which can
lead to:
● Seizures
● Oedema (brain swelling)
● Cognitive impairment
■ Ocular abnormalities, like glaucoma
○ Treatment: untreatable, but symptoms (e.g., seizures) can be managed with
medication and surgery if needed
1.2.2 Vesicle formation
1.2.2.1 What is vesicle formation?
6
, ● 3 vesicle stage, week 4 PMA: prosencephalon - mesencephalon - rhombencephalon
● 5 vesicle stage, week 5 PMA
○ Prosencephalon: will develop in the first phase of the hemispheres
■ Telencephalic vesicles
■ Diencephalon
○ Mesencephalon
○ Rhombencephalon:
■ Metencephalon
■ Myelencephalon
● 5 vesicle stage, week 6 PMA
○ Prosencephalon: depression between tel- & diencephalon
○ Mesencephalon
○ Rhombencephalon: pontine flexure
Primary vesicles Secondary vesicles Adult structures
Brain Prosencephalon Telencephalon Rhinencephalon, Amygdala,
Hippocampus, Cerebrum(Cortex), Basal
Ganglia, Lateral ventricles
Diencephalon Epithalamus, Thalamus, Hypothalamus,
Subthalamus, Pituitary, Pineal, Third
ventricle
Mesencephalon / (Pre)Tectum, Cerebral peduncle,
Cerebral Aqueduct (one structure)
Rhombencephalon Metencephalon Pons, Cerebellum
Myelencephalon Medulla Oblongata
Spinal cord
1.2.2.2 Link to pathology: holoprosencephaly
● The prosencephalon fails to properly divide into two hemispheres, leading to abnormal brain
and facial structures
● Different types and severity of HPE
○ Alobar holoprosencephaly (HPE) = most severe form of HPE
■ MRI:
● Enlarged midline monoventricle with fusion of the frontal lobes and
the midline gray matter structures
● The corpus callosum and the third ventricle are absent
7
, ■ Facial features:
● Single eye-like structure (cyclopia)
● Overriding nose-like structure (proboscis)
○ Semilobar HPE
■ MRI
● Fusion of the frontal lobes, but presence of some septation
posteriorly with presence of a falx and interhemispheric fissure
● More significant fusion of anterior brain structures (cortex, basal
ganglia, thalamus) persists in this variant
■ Facial features
● Closely spaced eyes
● Depressed nasal ridge with cleft lip
○ Axial plane depicting lobar HPE = least severe of the major types of HPE
■ MRI:
● The cerebral hemispheres are separated
● Varying degree of fusion of the midline gray structures
■ Facial features:
● Relatively normal facial appearance
● Subtle dysmorphisms: f.e. narrow forehead, relatively large ears,
relatively depressed nasal bridge, broad and well-defined philtrum
● Prognosis
○ Severe cases lead to death shortly after birth due to brain dysfunction and
respiratory failure
○ Milder cases may survive but often have severe neurodevelopmental impairments
1.2.3 Ventricle formation
1.2.3.1 What is ventricle formation?
Origin Ventricle
Prosencephalon Lateral and 3rd ventricle
Mesencephalon Aqueduct of Sylvius
Rhombencephalon 4th ventricle
8
,1.2.3.2 Link to pathology: aqueduct stenosis
● Cause & effect
○ Cerebral aqueduct (narrow passage between 3rd and 4th ventricles) becomes
blocked or narrowed
○ CSF cannot flow properly -> ventricular dilation and increased intracranial pressure
○ Lateral and 3rd ventricles enlarge due to CSF buildup, while the fourth ventricle
remains normal or collapsed
● Clinical consequences
○ Increased intracranial pressure -> head enlargement in infants, headaches, vomiting,
and vision problems in older individuals
○ Brain tissue damage -> cognitive and motor impairments
○ Hydrocephalus -> if untreated -> severe brain injury or death
● There are treatment options
1.3 Histogenesis
-> the brain volume will increase a lot
1.3.1 Neuronal proliferation (1-4m PMA)
1.3.1.1 What is neuronal proliferation?
● Starts: 5-6 weeks PMA -> starts already in the embryogenesis
● Ends: normally around 24 weeks PMA
● Neural stem cells divide rapidly to produce a large number of neurons
● During this formation: ventricular, intermediate and marginal zone are formed
○ Process might be disturbed in case of germinal matrix hemorrhage
○ Subsequent development might be disturbed: less cells, cells stop migrating …
○ Germinal matrix = highly vascularised premature birth: higher risk to get a problem
in this place (hemorrhage)
1.3.1.2 Link to pathology: disorders of proliferation
● Microcephaly (reduced proliferation)
○ Abnormally small brain due to decreased proliferation of neural progenitor cells
○ Clinical features:
■ Small head size
■ Developmental delays and intellectual disabilities
● Megalencephaly (excessive proliferation)
○ Brain overgrowth due to excessive proliferation of neural progenitors
○ Clinical features:
■ Enlarged head size
■ Risk of epilepsy and developmental delays
9
, ● Hemimegalencephaly
○ Overgrowth of one cerebral hemisphere while the other remains normal or
underdeveloped -> asymmetry in brain size (one side is abnormally large)
○ Caused by mutations in genes
○ Clinical consequences
■ Severe epilepsy (drug-resistant) due to cortical malformations
■ Developmental delays -> intellectual disability and motor impairment
■ Hemiparesis: weakness on 1 side of the body (opposite to the enlarged
hemisphere)
■ Cognitive and behavioral issues: vary based on the extent of overgrowth
○ Treatment is possible
1.3.2 Neuronal migration (3-5m PMA) and organisation (5m PMA-postnatal)
1.3.2.1 What is neuronal migration and organisation?
● Neuronal migration
○ 3-5 months PMA
○ Is the method by which neurons travel from their origin birthplace (ventricular zone
or germinal matrix ) to their final position in the brain
○ Inside out direction: migrate through intermediate zone and make different layers
■ Earliest neurons that start to migrate, will form the first layers at the outside
of developing brain
■ Second neurons will migrate through layers that are already formed, to form
a second layer
■ Eventually, 6 cortical layers will be developed
● Neuronal organisation -> start: month 5 PMA
○ Lamination (6 layers)
○ Neurons -> two options after migration:
■ Neurite outgrowth + synaptogenesis
■ Cell death (apoptosis)
○ Selective elimination of neuronal processes or synapses (apoptosis and pruning,
mostly after birth)
1.3.2.2 Link to pathology: disorders of migration and organisation
● Lissencephaly
○ Cortical maldevelopments caused by deficient neuronal migration and organisation
○ Result: absent or reduced gyration -> the brain surface is smooth
○ Different grades of type 1 lissencephaly
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