Download Neural Development

Neurology Pathophysiology: Neurodevelopment (Simvaswany)
DEVELOPMENTAL DELAY:

Definition: a disturbance in the acquisition of cognitive, motor, language or social skills which has SIGNFICANT and
CONTINUING impact on the developmental progress of a child
Not the same as mental retardation or intellectual disability

Etiologies:
Prenatal:
o Congenital CNS malformations
o Genetic disorders
o Antenatal endogenous/exogenous maternal toxins
o Antenatal maternal/fetal infection
o Prematurity or maternal/fetal malnutrition
o Neurocutaneous diseases
Perinatal: perinatal trauma or birth asphyxia
Postnatal:
o Inborn errors of metabolism
o Postnatal endogenous/exogenous toxins
o Endocrine disorders
o Postnatal CNS infections
o CNS trauma (ie. child abuse)
o Other (neoplasms, neuromuscular etc.)

Manifestations of Developing Brain Issues:
Basics: the developing brain is subject to the same injuries/diseases as adult brains, but the expression is
modified by IMMATURITY of tissues and other factors
Unique Features of Immature Brain:
o Presence of developing structures that are not found in the adult brain (ie. germinal matrix)
o Injury in early development can interfere with subsequent development (leads to malformation)
o Reaction to injury may differ due to immaturity of glial and inflammatory cells
o Cell susceptibility to certain injurious stimuli may differ from adult patterns
o Plasticity of developing nervous system may be able to compensate for damage
o Immaturity of brain function may prevent recognition of significant damage until later in life
STAGES OF BRAIN DEVELOPMENT AND ASSOCIATED MALFORMATIONS:

Stages of Brain Development:
Stage
Gestational Age
Examples of Disorders
Neural Tube Closure (Dorsal Induction)
3-4 weeks
Spina bifida (dysraphic states)
Ventral Induction
5-6 weeks
Holoprosencephaly
Neuronal Proliferation
2-4 months
Micro/macroencephaly
Neuronal Migration
3-5 months
Abberant gyration (lissencephaly)
Synaptic Organization and Differentiation
6 months - years post natal
Mental retardation
Myelination
7 months – years post natal
Leukodystrophy

Malformations: primary structural defects that result from errors of MORPHOGENESIS (often interferes w/ function)

Defects of Dorsal Induction and Primary Neurulation (3-4 Weeks):
Normal Embryologic Event: formation of the neural tube from the ectoderm
Disorder= NEURAL TUBE DEFECTS (Dysraphic Disorders):
o Neural Tube Closure Defects: failure of closure of neural tube results in faulty modeling of skeleton
around malformed neural tube

Anencephaly: failure of closure of ANTERIOR NEUROPORE, with subsequent brain
degeneration (lethal; do not resuscitate these children)

Myelomeningocele: herniation of MENINGES and SPINAL CORD through vertebral defect
o Defects of Axial Mesodermal Development: defective development of mesodermal elements, without
persistent open neural tube

Encephalocele: protrusions of the brain and membranes covering it through the skull
 75% are in the OCCIPITAL region

Meningocele: herniation of cerebral or spinal MENINGES through a bony defect
 Spinal forms occur 1-5/1000 live births

o
o
o
Associated with Arnold Chiari malformation (congenital herniation of cerebellar
tonsils through foramen magnum)
Clinical Manifestations: depend on location and severity of defect

Severe: anencephaly, encephalocele, spinal meningomyelocele

Mild: spinal meningocele, spina fibida occulta
Pathogenesis:

Genetic Factors:
 Various implicated genes
 Specific genetic syndromes (ie. Meckel-Gruber)
 Susceptible populations (Wales, Ireland, SE Asia)

Environmental Influences:
 Specific teratogens (valproate, carbamazepine, thalidomide)
 Vitamin deficiency (folate)
 Maternal hyperthermia
 Maternal diabetes
Prenatal Screening:

Alpha Fetoprotein: elevated in amniotic fluid in OPEN DEFECTS

Defects in Ventral Induction and Formation of the Brain and Face Primordia (5-6 Weeks):
Normal Embryonic Events: formation of the primary divisions, including CEREBRAL HEMISPHERES, OLFACTORY
and OPTIC NERVES
o Development induced by PRECHORDAL PLATE interacting with ROSTRAL NEURAL TUBE
Disorder= HOLOPROSENCEPHALY:
o Basics: failure of development of paired olfactory, telencephalic and optic vesicles, resulting in
INCOMPLETE formation of the FOREBRAIN
o Associated Craniofacial Abnormalities: often MIDLINE defects

Cyclopia (seen in severe form)

Ocular hypotelorism (eyes close together)

Cleft lift or palate

Nasal abnormalities

Single central incisor
o Pathogenesis:

Trisomy 13 (Patau Syndrome)

Trisomy 18 (Edward’s Syndrome)

Genetic/familial forms

Maternal diabetes

Maternal infections (toxoplasmosis, rubella, syphilis)

Alcohol

Defects in Neuronal Proliferation and Migration (2-5 Months/8-16 Weeks):
Normal Embryonic Events:
o Neuronal Proliferation (2-4 Months):

Proliferation at ventricular surface (ependymal zone)

Proliferation in local masses in subventricular areas (formation of germinal matrix)
o Neuronal Migration (3-5 Months):
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Radial migration to final destination along radial glial cells (radial route)
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Tangential migration along surfaces
o Specific Structures Formed:
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Cerebral Cortex: 3-5 months

Cerebellum: 5 months to 1 year post natal

Gyri and Sulci: begins at 20 weeks and is complete by birth (has adult pattern)
Disorders of Proliferation:
o Microcephaly: low brain weight with small head size (head circumference 2 SD from the mean in
comparison to weight and height)

Can be secondary to tissue destruction (intrauterine infection or injury)

Associated with karyotype abnormalities (genetic conditions)

Postnatal conditions (stroke, meningitis, malnutrition)
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May be part of CRANIOSYNTOSIS SYNDROMES
o
-

Macrocephaly: relatively uncommon; patients usually have normal development

Failure of programmed cell death
 Familial megalencephaly
 Hemimegalencephaly

Various syndromes (NF1, tuberous sclerosis)
Disorders of Migration:
o Severe/Diffuse Forms:

Lissencephaly (Agyria)/Pachygyria: 3-4 months
 Failure of gyration due to severe migrational failure
o Diffuse or Focal Forms:

Polymicrogyria: 4-5 months
 Excessive number of gyris on the surface of the brain

Heterotopias: 4-5 months
 Masses of neurons left behind in the white matter
 May result in infantile spasms
 Due to gene mutations in FLN A

Cortical Dysplasias: unclear what the timeframe is
 Areas of disturbed migration and neuronal-glial differentiation
 Higher risk for seizures
o Clinical Manifestations: vary with severity of defect

Mental retardation and developmental delay

Epilepsy

Microcephaly
o Causes:

Primary Malformations: genetic syndromes, unknown causes

Secondary Malformations: destructive (encephaloclastic) events occurring during migration
 Ex: polymicrogyria along edges of large defects in the cerebral wall (porencepaly)
Disorders of Synaptic Organization and Myelination (6 Months – Years Postnatal):
Normal Embryologic Events:
o Formation of axonal and dendritic arborizations
o Formation of synapses
o Selective (programmed) cell death and synaptic remodeling
o Myelination (requires proliferation and maturation of oligodendrocyte precursors- myelination glia)

Occurs CAUDAL  ROSTRAL

Occurs in PHYLOGENETICALLY OLDER STRUCTURES  NEWER STRUCTURES

Occurs PRIMARY  SECONDARY  ASSOCIATION
Disorders of Synaptic Organization and Myelination:
o Chromosomal Defects:

Down’s Syndrome (Trisomy 21): mental retardation associated with abnormalities in
dendritic and axonal development
o Autism:

Abnormalities in the development of minicolumns (failure of normal pruning)

Results in language delay, stereotypical behaviors and lack of social communication

May or may not be cognitively impaired
o Single Gene Disorders:

Leukodystrophies: inherited diseases resulting from mutations in genes important in myelin
FORMATION or DEGRADATION
 Example: metachromatic leukodystrophy (deficiency of arylsulfatase A)
o Late Fetal/Perinatal/Neonatal Insults: discussed later*
o Environmental Exposure in Early Life:
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Nutrition
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Toxic agents
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Other diseases
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Richness of learning experiences
CLINICAL BRAIN DEVELOPMENT AFTER BIRTH:
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Basics: brain development reflected in the progressive acquisition and maturation of neurologic function

Assessment of Neurodevelopment: must be assessed in many areas
Growth
o Head circumference and shape
o Overall body growth
Level of alertness
Development of reflexes
Development of normal neurological functions
o Motor and sensory skills
o Cognitive skills
o Language skills
o Social skills

Physical Exam at Birth:
Motor Skills:
o Random movements and automatisms (blinking, sucking, rooting, swallowing, yawning, eye deviation
on head turning)
o Almost complete lack of head control
o Head turned to one side
o Pelvis high, knees up under abdomen
o Raises head when half pulled up
o Uniformly rounded back when sitting
Sensory Skills: responds to stimuli
Language Skills: cries
Social Skills: can be comforted
Cognitive Skills: sleep/wake periods
Autonomic Functions: temperature, BP, respiration

Developmental Milestones: defined times by which development of certain neurological functions are expected to
have occurred (defined statistically over age ranges)
Important Milestones to Know:
o Social Smile: 2 months
o Stranger Anxiety: 6 months (recognizes family and strangers)
o Sits Unsupported: 6 months
o Babbles: 6 months
o Pincer Grasp: 10 months (picks up an object with finger and thumb)
o Stands and Walks: 1 year

Developmental Reflexes:
Reflex
Onset
Disappearance
Rooting
Birth
3 months
Moro
Birth
5-6 months
Palmar Grasp
Birth
6 months
Plantar Grasp
Birth
9-10 months
Tonic Neck
Birth
6 months
Landau: if infant placed face down, will lift their
3-5 months
2 years
head and extend legs (prevents smothering)
Parachute
6-9 months
Persists
Important: some of these primitive reflexes can appear later in life as manifestations of brain damage

Clinical Assessment of Neural Development:
History: most important*
Observation:
o Physical and interactive skills
o Child at play (blocks, drawing, ball)
Physical Examination:
o Directed neurological exam
o Physical manipulations (ventral suspension, positioning child)
o Measurements
Formal Testing:
o Denver Developmental Test
FORMS OF DEVELOPMENTAL DELAY:

Mental Retardation:
Definition: subaverage general intellectual functioning
o Concurrent deficits in adaptive behavior
o IQ more than 2 SD below the mean for their age
o Onset before the age of 18 months

Cerebral Palsy:
Definition: disordered motor function that is evident early in infancy
o Characterized by changes in muscle tone, involuntary movements and ataxia

Signs in infant are scissoring of the legs and fisted hands
o Result of brain dysfunction
o NOT episodic or progressive, however, full extent of motor disability not evident until 3-4 years old
Incidence: 1.2-2.5/1000 births
Etiologies:
o Neonatal hypoxic ischemic encephalopathy
o Stroke
o Intrauterine maldevelopment (congenital malformations)
o Low birth weight
o Twin birth/death in utero of a co-twin
o Hyperbilirubinemia
o Toxins
o Intrauterine and neonatal infections
Clinical Patterns:
o Spastic:
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Hemiplegic (one side of the body)
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Quadriplegic (all extremities involved; legs > arms; MOST SEVERE)
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Diplegic (only lower extremities involved)
 Note: diplegic patients are often born PREMATURELY
o Extrapyramidal:
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Choreoathetotic
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Dystonic
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Atonic/hypotonic (rare)

Ataxic
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Mixed

Disorders of Speech and Language: developmental speech delay

Disorders of Social Behavior: autism, ADHD

Learning Disorders
CONDITIONS MANIFESTED AS DEVELOPMENTAL DELAY:

Intrauterine or Perinatal Brain Injury:
Definition: destructive (encephaloclastic) processes occurring during gestation
o If occurring during EARLY gestation:

May lead to loss of structure (aplasia or cavitation)

May lead to underdevelopment of structure (hypoplasia)

May lead to maldevelopment of adjacent and related structures
o If occurring during LATE gestation (after developmental events have occurred)

May result in atrophy, loss of structures or aberrant maturation
Terms:
o Porencephaly: cavity in wall of cerebrum communicating with ventricle and brain surface

May lead to polymicrogyria
o Hydranencephaly: extreme expansion of ventricles with parenchyma reduced to a thin membrane
Examples:
o Neonatal Intracranial Hemorrhage of the Premature (Germinal Matrix Hemorrhage):

Occurrence: common complication of prematurity during first weeks of postnatal life
 Very low birth weight infants (<1550g and <32 weeks old)

Location: most arise in subependymal germinal matrix and rupture into lateral ventricles
 Due to small veins in ganglionic eminence (germinal matrix)
 Germinal matrix normally involutes after 32-34 weeks gestation



Grading:
 Grade 1: confined to germinal matrix
 Grade 2: confined to lateral ventricle
 Grade 3: dilates ventricle
 Grade 4: secondary rupture into parenchyma

Sequela: ranges from DEATH to ASYMPTOMATIC*
 Infants with grade 3 and 4 IVH have a high chance of developing cerebral palsy
o If they don’t develop CP, still have poor cognitive outcomes
 Infants with low grade bleeds have a higher incidence of poor academic outcome
 Hydrocephalus often develops acutely (ventricular obstruction)
o May become chronic due to organization of hematoma with impairment
of CSF reabsorption
o Neonatal Hypoxic-Ischemia Encephalopathy:

Predisposing Factors:
 Maternal conditions (asphyxia, hypotension, diabetes, eclampsia)
 Difficult labor and delivery
 Neonatal events (umbilical cord compression, neonatal/postnatal RDS, congenital
heart disease, pulmonary hypoplasia, congenital diaphragmatic hernia)

Patterns of Damage: reflect difference in vulnerability between immature and mature brain
 Damage to Gray Matter:
o Selective neuronal necrosis in vulnerable areas

Subiculum

Pons

Thalamus

Cerebellar Purkinje cells
o Infarcts (border zones like the parasagittal area)
o Porencephaly
o Ulegyria (selective loss of cortex in depths of sulci)
o Multicystic encephalomalacia (severe brain destruction with cavitations)
o Status marmoratus (neuronal loss and glial scars followed by abnormal
meylination in the BG and thalamus)
 Damage to White Matter:
o Periventricular leukomalacia (focal necrosis in deep cerebral WM)
o Diffuse white matter damage
Patterns of Deficits from Intrauterine/Perinatal Brain Injury:
o Acute encephalopathy (“floppy infant”) at birth
o Permanent focal deficits
o Static encephalopathy (cerebral palsy)
o Mental retardation and developmental delay
o Epilepsy
o Hydrocephalus (acute and chronic)
Chromosomal Abnormalities:
Down’s Syndrome (Trisomy 21):
o Incidence: 1/600 live births (increasing frequency with increasing maternal age)
o Clinical Features: mental retardation, hypotonia at birth, microcephaly, increased risk AD
Fragile X Syndrome:
o Incidence: 1/2000-3000 births
o Defect: CGG triplet repeat expansion (>200) in the FMR1 gene (normal is <50)
o Clinical Features:

Mental retardation (most common cause of MR in males)*

Gross motor and language delay

Shyness

Above average height and head circumference

Macroorchidism (post-pubertal)
Neurocutaneous Disorders:
Tuberous Sclerosis:
o Inheritance: autosomal dominant
o Mutation: in TSC gene on cs 9 (TSC1- hamartin) or 16 (TSC2- tuberin)
o
o

Incidence: 1/29,000 births
Clinical Features:

Mental retardation

Behavior disorders

Seizures (infantiles spasms)

Occurrence of non-neoplastic and neoplastic tumors
 Intracerebral tumors (hamartomas)
 Cardiac rhabdomyomas
 Renal (angiomyolipomas), retinal and tumors

Occurrence of other cutaneous and organ lesions (reflects abnormal organ development and
cell differentiation)
 Facial angiofibromas
 Ashleaf spots (depigmented skin macules)
 Shagreen patches
Inherited Disorders of Metabolism:
Basics: heterogeneous group of diseases in which the mutation results in a disturbance of a metabolic pathway
important in nervous system development or function
Classification:
o Organic acidopathies
o Urea cycle disorders
o Amino acid disorders
o Glycogen storage diseases

Example- Pompe’s Disease (Glycogen Storage Disease Type II):
 Deficiency of acid maltase
 Weak cry, impaired swallowing, cardiac involvement
 Early death unless enzyme replacement
o Fatty acid oxidation defects
o Peroxisomal disorders
o Lipid storage disorders
o Lysosomal storage disorders
Consider when infant has the following signs:
o Excessive irritability, somnolence or coma
o Depressed or absent brainstem reflexes
o Abnormal muscle tone (hyper or hypotonia)
o Abnormal muscle movements (clonus, tremor, posturing)
o Exaggerated or depressed reflexes (DTRs, developmental reflexes)
o Seizures or myoclonus
o Prominent unexplained vomiting
o Unusual odors
REGRESSION:

Maternal Toxins:
Fetal Alcohol Syndrome: most common preventable chemical cause of mental retardation
o Risk: 6% risk of FAS in children of alcoholic mothers (increases to 70% in subsequent offspring)
o Clinical Features:

Prenatal and post natal growth deficiency
 Lower weight, shorter height, smaller head circumference at 3 years

Microcephaly

Mental retardation

Restless and irritable as infants

Cognitive and behavior problems in school

Craniofacial anomalies
 Short palpebral fissures
 Frontonasal alterations
 Midface hypoplasia (flattened midface)
 Thin upper lip
 Maxiallry/mandibular hypoplasia
-

Other Neuroteratogens:
o Cocaine (IUGR and microcephaly, intracranial hemorrhage, antenatal/perinatal infaracts)

Irritable babies with high pitched cry

Poor feeders

Poorly developed verbal, language and motor skills
o Retin A
o Anticonvulsants
o Ionizing radiation
Environmental Toxins:
Social deprivation
Exposure to drugs/toxins
Child abuse