DEVELOPMENTAL

NEUROLOGY

Radha Giridharan, M.D.

Pediatric Neurology
SUNY Downstate Medical
Center
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Developmental Neurology

• An understanding of the
development of the Nervous System
is essential to the understanding of
Pediatric Neurology

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Developmental Neurology

• The Nervous System begins on the

dorsal aspect of the embryo as a
plate of tissue differentiating in the
middle of the ectoderm called the
Neural Plate at approximately 18
days of gestation. The lateral
margins of the neural plate
invaginate and close dorsally to form
the Neural Tube.
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Developmental Neurology
• MAJOR EVENTS IN HUMAN BRAIN
DEVELOPMENT AND PEAK TIMES OF
OCCURRENCE
MAJOR DEVELOPMENTAL PEAK TIME OF OCCURRENCE
EVENT
Primary neurulation 3-4 weeks of gestation

Prosencephalic development 2-3 months of gestation

Neuronal proliferation 3-4 months of gestation

Neuronal migration 3-5 months of gestation

Organization 5 months of gestation –

years postnatal
Myelination Birth – years postnatal
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Developmental Neurology

• Primary Neurulation refers to the

formation of the Neural Tube which
results in the formation of the Brain
and Spinal Cord. Interaction of the
neural tube with the surrounding
mesoderm gives rise to the dura, the
skull and vertebrae.

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Developmental Neurology

• Disorders of Primary Neurulation

Neural Tube Defects (NTD)
Order of decreasing severity

2. Craniorachischisis totalis
3. Anencephaly
4. Myeloschisis
5. Encephalocele
6. Myelomeningocele – Spina Bifida
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Developmental Neurology

• Anencephaly
– This results from failure of Anterior
Neural tube closure. It is associated
with defect in the skull. The exposed
neural tissue is represented by a
hemorrhagic, fibrotic, degenerated mass
of neurons and glia with little definable
structure.

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Developmental Neurology

• Anencephaly
– Onset – Around 24 days of gestation.
75% are still born. Remainder die in
newborn period.

– Incidence – 0.2/1000 live births. Is

readily identified prenatally by cranial
ultrasound in second trimester of
pregnancy.
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Developmental Neurology
• Encephalocele
– This is a restricted disorder of Neurulation
involving anterior neural tube closure. 70-80%
of encephaloceles are located in the occipital
region, less common site is the frontal region,
where it may protrude into the nasal cavity.
Frontal encephalocele is more common in
Southeast Asia. In the typical occipital
encephalocele, the protruding brain tissue is
derived from the occipital lobe and cerebellum.
As many as 50% of cases are associated with
hydrocephalus.

– Timing – Estimated to be around 26 days of

gestation. 13
ENCEPHALOCELE

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Developmental Neurology

• Meckel’s Syndrome
– Occipital encephalocele, Microcephaly,
Microphthalmia, Cleft lip and palate,
Polydactyly, Polycystic kidneys,
Ambiguous genitalia and other
deformities.

– Management – Neurosurgical
intervention is indicated in most
patients. 16
Developmental Neurology
Meningomyelocele (Spina Bifida)
– It is the most common major birth defect
among live born infants in the U.S. Incidence
is decreasing.
0.2-0.4/1000 live births.

• Anatomic Abnormality
– It is due to defect in the closure of the
posterior neural tube. 80% of lesions occur in
the Lumbar region

• Timing – around 26 days of gestation

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Developmental Neurology

Meningomyelocele

• Clinical Aspects – Motor dysfunction

and Hydrocephalus
– Motor weakness of the lower extremities
depends on the level of the lesion.
Motor level will determine their ability to
walk. Scoliosis is frequently associated
with high lesions. They also frequently
have sensory and sphincter 19
LUMBAR MYELOMENINGOCELE

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Developmental Neurology

Meningomyelocele
• Hydrocephalus – Site of lesion is
helpful in predicting the presence
and development of hydrocephalus.
With thoraco-lumbar, lumbar and
lumbosacral lesions, the incidence is
90%. With occipital, cervical,
thoracic or sacral lesions, the
incidence is 60%.
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Developmental Neurology

• Arnold Chiari Malformation

– Is central to the causation of clinical
deficits related to brainstem dysfunction,
a serious complication in a minority of
patients and Hydrocephalus, a serious
complication in a majority of patients with
MENINGOMYELOCELE.

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Developmental Neurology

• Major features – include

– Inferior displacement of the medulla
and the 4th ventricle into the upper
cervical canal.
– Elongation and thinning of the upper
medulla and lower pons and
persistence of embryonic flexure.
– Inferior displacement of the lower
cerebellum through the foramen
magnum. 23
ARNOLD-CHIARI MALFORMATION –
TYPE 2

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Developmental Neurology
Meningomyelocele

• Management
– Delivery whenever possible should be by
Cesarean section to minimize motor deficit.
Neurosurgical closure of the back within 24-48
hours.
Prevent infection.
– Hydrocephalus – V-P shunt. Prevent shunt
infection.
– Orthopedic management. Urologic
management.
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– Education – Most children are of Normal
Developmental Neurology
Meningomyelocele
• Prevention
1. Genetic factors
2. Environmental factors

• Genetic factors
1) Multifactorial inheritance
2) Chromosomal abnormalities (Trisomy 13 &
18)
3) Meckel Syndrome
4) Preponderance in Females
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5) Increased incidence in siblings
Developmental Neurology

Meningomyelocele

• Environmental Influences
1. Vitamin deficiency – Folic Acid
2. Medications – Antiepileptic medications

i.e. Valproic acid and Carbamazepine

3. Maternal Hyperthermia
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Developmental Neurology

Meningomyelocele

• Prenatal Diagnosis
1. Maternal serum Alpha Feto Protein.
2. Amniotic Fluid Alpha Feto Protein and
Acetylcholinesterase.
3. Antenatal Fetal Ultrasonography.

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Developmental Neurology

• Major Developmental Events

1. Primary Neurulation
2. Prosencephalic Development
3. Neuronal Proliferation
4. Neuronal Migration
5. Organization
6. Myelination

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Developmental Neurology

• Prosencephalic Development
1. Prosencephalic Formation
2. Prosencephalic Cleavage
– Holoprosencephaly
3. Midline Prosencephalic Development
– Septo Optic Dysplasia
– Septo Optic Hypothalamic Dysplasia

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Developmental Neurology

• Holoprosencephaly
– Timing – Occurs between 5th and 6th
week of gestation

– Anatomic Abnormality – Single sphered

cerebral structure with a single
ventricle. Absent olfactory bulbs and
hypoplastic optic nerves with marked
abnormality of the cortical
cytoarchitecture with heterotopias. 31
Developmental Neurology
Holoprosencephaly
• Clinical Aspects
– Facial abnormality – marked hypotelorism with
nasal abnormality and median cleft lip and
palate.
Seizures and severe developmental delay.

• Genetics
– Chromosomal abnormalities are frequently
seen such as Trisomy 13, Trisomy 18 and in
chromosome 2,3,7…., but majority have 32
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Developmental Neurology

• Neuronal Proliferation
– Peak time period – 3-4 months.
Ventricular zone and subventricular
zone are the sites of proliferation.

– Disorders
1. Microcephaly
2. Macrocephaly

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Developmental Neurology

• Microcephaly - Causes

1. Primary Microcephaly
2. Secondary Microcephaly

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Developmental Neurology

• Primary Microcephaly
– Microcephaly vera (genetic)
– Chromosomal disorders
– Defective neurulation
• Anencephaly
• Encephalocele
– Defective prosencephalization
• Agenesis of corpus callosum
• Holoprosencephaly (arhinencephaly)
– Defective cellular migration 38
Developmental Neurology
• Secondary Microcephaly
– Intrauterine disorders
• Infection
• Toxins
• Vascular
– Perinatal brain injuries
• Hypoxic-ischemic encephalopathy
• Intracranial hemorrhage
• Meningitis and encephalitis
• Stroke
– Postnatal systemic diseases
• Chronic cardiopulmonary disease
• Chronic renal disease
• Malnutrition
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Developmental Neurology

Macrocephaly
• Causes
1. Hydrocephalus
2. Megalencephaly
3. Thickened Skull

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Developmental Neurology

Causes of Hydrocephalus
1. Communicating
2. Obstructive
3. Hydranencephaly

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HYDROCEPHALUS - SUNSETTING

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SUNSETTING SIGN

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Developmental Neurology

• Hydrocephalus – Communicating
1. Achondroplasia
2. Basilar Impression
3. Benign enlargement of subarachnoid
spaces
4. Choroid plexus papilloma
5. Meningeal Malignancy
6. Meningitis
7. Posthemorrhagic
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Developmental Neurology
• Hydrocephalus – Obstructive
1. Aqueductal stenosis
– Infectious
– X-linked
2. Chiari malformation
3. Dandy-Walker malformation
4. Klippel-Feil syndrome
5. Mass lesions
– Abscess
– Hematoma
– Tumors and Neurocutaneous syndromes
– Vein of Galen malformation
– Walker-Warburg syndrome 45
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Developmental Neurology

• Hydrocephalus – Hydranencephaly
1. Holoprosencephaly
2. Massive hydrocephalus
3. Porencephaly

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Developmental Neurology
• Causes of Megalencephaly
– Anatomic
1. Genetic megalencephaly
2. Megalencephaly with achondroplasia
3. Megalencephaly with gigantism
4. Megalencephaly with a neurologic
abnormality
5. Neurocutaneous disorders
• Epidermal nevus syndrome
• Hypomelanosis of Ito
• Incontinentia pigmenti
• Neurofibromatosis
• Tuberous sclerosis 48
Developmental Neurology
• Causes of Megalencephaly
– Metabolic
1. Alexander disease
2. Canavan disease
3. Galactosemia: Transferase deficiency
4. Gangliosidosis
5. Globoid leucodystrophy
6. Glutaric aciduria type I
7. Leucoencephalopathy with swelling and
cysts
8. Maple syrup urine disease
9. Metachromatic leucodystrophy
10.Mucopolysaccharidoses 49
Developmental Neurology
• Neuronal Migration
– Peak time period – 3-5 months. Migration to
cerebral cortex and cerebellum

• Disorders of Neuronal Migration

– Order of decreasing severity
• Schizencephaly
• Lissencephaly-pachygyria
• Polymicrogyria
• Heterotopias
• Focal cerebrocortical dysgenesis
– Agenesis of Corpus Callosum may accompany
these disorders. 50
LISSENCEPHALY

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Developmental Neurology
• Organization
– Peak time period
• 5 months gestation to years postnatal.

– Major Events
• Subplate neurons – establishment and
differentiation
• Lamination – alignment, orientation and
layering of cortical plate neurons
• Synaptogenesis
• Cell death and selective elimination of
neuronal processes and of synapses
• Glial proliferation and differentiation
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Developmental Neurology
• Disorders of Organization
– Primary Disturbance
• Mental retardation, with or without seizures
• Down syndrome
• Fragile X syndrome
• Angelman syndrome
• Infantile Autism
• Duchenne muscular dystrophy
• Other rare disorders
– Potential Disturbance
• Ventilator-dependent premature infant
• Other perinatal and postnatal insults
• Experiential effects
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