Neurodevelopment and Developmental Delay Flashcards
Developmental delay
def
a disturbance in the acquisition of cognitive, motor, language or social skills which has a significant and continuing impact on the developmental progress of a child
Developmental delay
Etiologies list
- CNS malformations
- exposure to endogenous or exogenous maternal toxins
- maternal/fetal infection
- perinatal trauma or birth asphyxia
- prematurity or maternal/fetal malnutrition
- neurocutaneous syndromes
- genetic disorders
- inborn errors of metabolism
- exposure to endogenous or exogenous infant toxins after birth, i.e., hepatic or
renal failure, lead acquired postnatal CNS infection - CNS trauma-Child abuse- can take the form of nonaccidental injury leading to subdural, epidural bleeds, subarachnoid hemorrhages, contusions, concussions, lacerations, intraparenchymal bleeds, shearing injuries.
- neuromuscular disorders with CNS involvement
- idiopathic
Peculiarities of immature brain include…
- presence of developing structures which are not found in adult brain: e.g., germinal matrix.
- injury early in development may interfere with subsequent development and lead to malformation.
- reactions to injury may differ because of immaturity of glial and inflammatory cells.
- cell susceptibility to certain injurious stimuli may differ from adult patterns.
- plasticity of developing nervous system may be able to compensate for damage.
- immaturity of brain function may hinder recognition of significant damage until much later in life.
Antenatal brain development
Stages/gestational age/examples of disorders
6 Stages
Stage
Gestational age
Examples of disorders
Dorsal induction
3-4 weeks
Dysraphic states
Ventral induction
5-6 wks
Holoprosencephalies
Neuronal proliferation
2-4 mo
Micro/macoencephaly
Neuronal migration
3-5 mo
Aberrant gyration (lissencephaly)
Synaptic organization
6mo-yrs postnatal
Mental retardation
Myelination
7mo-yrs postnatal
leukodystrophy
Malformations
def
Malformations are primary structural defects that result from errors of morphogenesis and often interfere with subsequent function .
General principle: malformations and developmental abnormalities are datable to specific times during development.
Which brain structures develop at the same time and should prompt physician to investigate for multiple defects
It should be kept in mind that the cerebral cortex, corpus callosum, cerebellum and deep nuclei develop about the same time. Hence one anomaly should prompt the physician to look hard for others.
Dorsal induction and primary neurulation
(3-4wks GA)
normal embryologic event
formation of neural tube from ectoderm
Dorsal induction and primary neurulation
(3-4wks GA)
neural tube closure defects
list/chars
a. neural tube closure defects: probably reflect failure of closure of neural tube resulting in faulty modeling of skeleton around malformed neural tube
b. anencephaly: failure of anterior neuropore closure with subsequent degeneration of brain
c. myelomeningocele: herniation of meninges and spinal cord through vertebral defect
Dorsal induction and primary neurulation
(3-4wks GA)
defects of axial mesodermal development
Probably result from defective developmental of mesodermal elements without persistent open neural tube
encephalocele: 75% occur in occipital region meningocele: herniation of cerebral or spinal meninges through bony defect failure; spinal forms occur in 1-5/1000 live births, often associated with Arnold-Chiari malformation
Dorsal induction and primary neurulation
(3-4wks GA)
pathogenesis
Genetic factors: various genes, syndromes, populations
environmental influences: teratogens (e.g., thalidomide, carbamazepine), vitamin deficiency (folate), maternal hyperthermia, diabetes mellitus
Ventral induction and formation of brain and face primordial (5-6wks GA)
Normal events
formation of primary brain divisions including cerebral hemispheres, olfactory and optic nerves
Ventral induction and formation of brain and face primordial (5-6wks GA)
defects
a. development is induced by prechordal plate interacting with rostral neural tube
b. disorders: holoprosencephaly/ arrhinencephaly series: spectrum of severity representing failure of development of paired olfactory, telencephalic, and optic vesicles resulting in incomplete formation of forebrain
c. brain defects are usually accompanied maldevelopment of skull and by mid-face defects such as cyclopia (severe form), cleft lip or palate, and other midface defects.
d. implicated pathogenetic factors include trisomies 13 and 18, other genetic and familial forms, maternal diabetes, maternal infections (toxoplasmosis, rubella, syphilis), ETOH
Neuronal proliferation and migration (maximum during months 2-5 GA)
Normal events
Events include neuronal proliferation at ventricular surface and in local masses in subventricular zones (germinal matrix) followed by migration to final destination along radial glial cells (radial route) or along surfaces (tangential route)
formation of cerebral cortex: 3-5 mo GA
formation of cerebellum: 5mo GA to 1 yr
postnatal formation of gyri and sulci reflects growth and maturation of cortex and occurs in an orderly pattern, beginning at about 20wk GA; by term, the gyral pattern approximates the adult pattern.
Neuronal proliferation and migration (maximum during months 2-5 GA)
Disorders of growth
microcephaly (low brain weight) with microcephaly (small head): can be secondary to tissue destruction (e.g., intrauterine infection) or primary (genetic, teratogens such as irradiation or alcohol, unknown)
macrocephaly: rare, associated with various syndromes, failure of programmed cell death (includes familial megalencephaly, hemimegalencephaly, some patients with NF1, etc.)
Neuronal proliferation and migration (maximum during months 2-5 GA)
Disorders of migration
Severe/diffuse forms
agyria (“lissencephaly”)/pachygyria: 3-4 months GA, sporadic and familial cases;
characterized by migrational arrest of neurons in white matter, failure of cortical lamination, and failure of gyration, resulting in a smooth- surfaced (“lissencephalic”) brain. Genes implicated include ARX, DCX, LIS1, and RELN
Neuronal proliferation and migration (maximum during months 2-5 GA)
Disorders of migration
Diffuse or local forms
- heterotopias: masses of neurons left behind in white matter. Gene mutations in FLN A
- cortical dysplasias: areas of disturbed
migration and neuronal-glial differentiation
Neuronal proliferation and migration (maximum during months 2-5 GA)
Clinical manifestation severity/causes
c. clinical manifestations vary with severity of defect but include mental retardation and epilepsy.
d. causes include various genetic syndromes; destructive events occurring during migration may result in focal abnormalities, e.g., polymicrogyria along edges of large defects in the cerebral wall (porencephaly)
Developmental reflexes
Onset/disappearance
rooting
O: birth
D: 3 months
Developmental reflexes
Onset/disappearance
Moro
O: birth
D: 5-6 months
Developmental reflexes
Onset/disappearance
Palmar grasp
O: birth
D: 6 months
Developmental reflexes
Onset/disappearance
Plantar grasp
O: birth
D: 9-10 months
Developmental reflexes
Onset/disappearance
Gallant (truncal incurvation)
O: birth
D: 1-2 months
Developmental reflexes
Onset/disappearance
Tonic neck
O: birth
D: 6 months
Developmental reflexes
Onset/disappearance
landau
O: 3-5 months
D: 2 years
Developmental reflexes
Onset/disappearance
parachute
O: 6-9 months
D: persists
Mental retardation
def
Definition: subaverage general intellectual functioning with concurrent deficits in adaptive behavior, IQ more than 2 standard deviations below the mean for age, i.e., <70, with onset before the age of 18 months.
Cerebral palsy
def
Definition: disordered motor function that is evident in early infancy and characterized by changes in muscle tone, involuntary movements, ataxia or a combination of these
Cerebral palsy
Pathogenesis/age
It is the result of brain dysfunction and is not episodic or progressive, but the full extent of the motor disability may not be evident until 3-4 years of age
Cerebral palsy
etiologies
neonatal hypoxic ischemic encephalopathy stroke intrauterine maldevelopment low birth weight twin birth/death in utero of a co-twin hyperbilirubinemia toxins intrauterine and neonatal infections
Cerebral palsy
Clinical patterns
spastic hemiplegic quadriplegic (legs>arms) diplegic/paraplegic extrapyramidal mixed
Developmental delay
Forms it can take
Mental retardation cerebral palsy disorders of speech and language Disorders of social behavior (ie autism, ADD) Learning disorders
Intrauterine or perinatal brain injury
def
Definition: destructive (“encephaloclastic”) processes occurring during early gestation lead to loss of structure (aplasia or even cavitation), underdevelopment of structure (hypoplasia), or subsequent maldevelopment of adjacent and related structures, resembling primary malformations
Intrauterine or perinatal brain injury
Porencephaly/hydranencephaly
porencephaly: cavity in wall of cerebrum communicating with ventricle and brain surface
hydranencephaly: extreme expansion of ventricles with parenchyma reduced to a thin membrane
Intrauterine or perinatal brain injury
Injuries occurring later in gestation
Injuries occurring during later gestation, after major developmental events have occurred, usually result in atrophy, loss of structures, or aberrant maturation.
Neonatal hemorrhage
Common complication of…
Prematurity
occurs in very low birth weight infants (<1550g; under 32 weeks gestation) during first weeks of postnatal life
Neonatal hemorrhage
Loc/grades
most arise in subependymal germinal matrix (GM) and rupture into lateral ventricles
grade 1 confined to GM
grade 2 confined to ventricle
grade 3 dilates ventricle
grade 4 2o rupture into parenchyma
Neonatal hemorrhage
Deficits due to..
sequelae range from death to asymptomatic; hydrocephalus commonly develops acutely, due to ventricular obstruction, or chronically, due to organization of hematoma and impairment of CSF reabsorption
Neonatal hypoxic-ischemic encephalopathy
Predisposing factors
predisposing factors include maternal asphyxia or hypotension, diabetes, eclampsia, prolonged labor, difficult delivery, umbilical cord compression, neonatal/postnatal respiratory distress syndrome (RDS), congenital heart disease, pulmonary hypoplasia
Neonatal hypoxic-ischemic encephalopathy
Patterns of injury
Damage to gray matter
selective neuronal necrosis in vulnerable areas, especially subiculum, pons, thalamus, cerebellar
Purkinje cells infarcts: border zones, eg. Parasagittal area.
porencephaly
ulegyria: selective loss of cortex in depths of sulci
multicystic encephalomalacia: severe brain destruction with multiple cavitations
status marmoratus: neuronal loss and glial scars followed by abnormal myelination in basal ganglia and thalamus
Neonatal hypoxic-ischemic encephalopathy
Patterns of injury
Damage to white matter
periventricular leukomalacia (PVL): focal necrosis in deep cerebral white matter
diffuse white matter damage
Patterns of deficits resulting from intrauterine or perinatal brain injury
- acute encephalopathy (“floppy infant”) at birth
- permanent focal deficits
- static encephalopathy (cerebral palsy):
- mental retardation and developmental delay
- epilepsy
- hydrocephalus
Down syndrome
Clinical features
- mental retardation
- short stature
- mild microcephaly
- craniofacial abnormalities (upslanted palpebral fissures, epicanthal folds, flat facial profile, small low-set ears
- other dysmorphisms (redundant folds of nuchal skin, single transverse palmar crease)
- hypotonia at birth
- congenital heart and gastrointestinal defects
- increased risk for atlantoaxial dislocation
- increased risk of developing Alzheimer disease in later life
Fragile X syndrome
Cause/clinical features
characterized by CGG triplet of bases repeated >200 times, normal <=50
clinical features include mental retardation, gross motor and language delay, shyness, above average height and head circumference. Macroorchidism noted post pubertal stage of life.
Tuberous Sclerosis
MOI
Autosomal dominant disorder caused by TSC gene mutation on chromosome 9 (TSC1: hamartin) or 16 (TSC2: tuberin)
Tuberous sclerosis
Clinical features
mental retardation and behavioral disorders
seizures (including infantile spasms)
occurrence of non-neoplastic and neoplastic tumors
intracerebral tubers (hamartomas) cardiac rhabdomyomas renal, retinal and other tumors
Occurrence of other cutaneous and organ lesions reflecting
abnormal organ development and cell differentiation
facial angiofibromas
ashleaf spots (depigmented skin macules)
Shagreen patches
Inherited disorders of metabolism
Gen groups
organic acidopathies urea cycle disorders aminoacid disorders glycogen storage diseases fatty acid oxidation defects peroxisomal disorders lipid storage disorders mitochondrial diseases lysosomal storage disorders- eg. Mucopolysaccharidosis
Inherited disorders of metabolism
Gen sx that they can cause
most can cause an acute or progressive encephalopathy in the newborn or infant period and thus need to be considered when the following signs occur:
- excessive irritability or somnolence or coma
- depressed or absent brainstem reflexes
- abnormal muscle tone (hypotonia, hypertonia) or movements (clonus, tremor, posturing)
- exaggerated or depressed reflexes (deep tendon reflexes, developmental reflexes)
- seizures or myoclonus
- prominent unexplained vomiting
- unusual odors
Fetal alcohol syndrome
Clinical features
prenatal and postnatal growth deficiency
microcephaly
mental retardation
restless and irritable as infants
craniofacial anomalies, ie. short palpebral fissures, frontonasal alterations, midface hypoplasia (flat midface), thin upper lip, maxillary and sometimes mandibular hypoplasia
cognitive and behavior problems in school
children with FAS have lower weight, shorter height and smaller head circumferences at 3 years old compared to age matched controls.
Neuroteratogens
list
Alcohol Cocaine Retin A Anticonvulsants Ionizing radiation
Neuroteratogens
Cocaine
chars
Infants exposed to cocaine have IUGR and microcephaly. Maternal cocaine use has also been causative in intracranial hemorrhage and antenatal/perinatal infarcts.
Such babies are frequently irritable, tremulous, have a high pitched cry, are poor feeders, and at follow up may have poorly developed verbal, language and motor skills.
Environmental insults
social deprivation and child abuse can contribute to CNS damage.
Developmental milestones
24 mo
Motor/sensory/language/social/cognitive
Motor:
Runs, climbs steps
Hand dominance
Picks up objects
Sensory skills: -
Language skills:
Short sentences
Social skills:
Organized play
May be toilet trained
cognitive:
Recognizes some body parts
Pictures
scribbles
Developmental milestones
12 mo
Motor/sensory/language/social/cognitive
Motor:
Stands and walks
Flexor plantar
Throws objects
Sensory skills: -
Language skills:
Single words
Social skills:
Tries to feed self
cognitive:
Manipulation of objects
Developmental milestones
10 mo
Motor/sensory/language/social/cognitive
Motor:
Creeps & pulls to stand
Maturing reflexes
Pincer grasp
Sensory skills: -
Language skills:
Mama, dada
Social skills:
Sociable games
cognitive:
Exploration
Separation from mother
Developmental milestones
6 mo
Motor/sensory/language/social/cognitive
Motor:
Sits unsupported
Normalizing tone
Reaches & grasps objects
Sensory skills:
Responds to sounds
Language skills:
Babbles
Social vocalization
Social skills:
Recognizes family & strangers
cognitive:
Early interest in surroundings
Developmental milestones
2 mo
Motor/sensory/language/social/cognitive
Motor:
Head control
Increased range of motion
Reflex grasp
Sensory skills:
Fixes & follows
Language skills:
Vocalizes
Social skills:
smiles
cognitive: -
Developmental milestones
Neonate
Motor/sensory/language/social/cognitive
Motor:
Random movements
Automatisms
Reflex grasp
Sensory skills:
Light response
Language skills: -
Social skills: -
cognitive: -
Assessing neurodevelopment
Different areas to assess
- growth (head circumference and shape, overall body growth)
- level of alertness
- development of reflexes
- development of normal neurological functions, including:
acquisition of motor and sensory skills
acquisition of cognitive skills
acquisition of language skills
acquisition of social skills
Synaptic organization and myelination
(6mo-yrs postnatal)
normal events
events include elaboration and selective elimination of neurons, axons and dendrites, and synapses; myelination
Synaptic organization and myelination
(6mo-yrs postnatal)
example of disorders
chromosomal defects: trisomy 21 (Down’s syndrome): mental retardation associated with abnormalities in dendritic and axonal development
Autism – characterized by abnormalities in the minicolumns
single gene disorders: leukodystrophies: inherited diseases resulting from mutations in genes important in myelin formation or degradation
late fetal, perinatal or neonatal insults (see below)
environment during early life (nutrition, toxic agents, other diseases, richness of learning experience, etc.)
