Neurodevelopment and Developmental Delay

Question 1

Developmental delay

def

Answer 1

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

Question 2

Developmental delay

Etiologies list

Answer 2

1. CNS malformations
2. exposure to endogenous or exogenous maternal toxins
3. maternal/fetal infection
4. perinatal trauma or birth asphyxia
5. prematurity or maternal/fetal malnutrition
6. neurocutaneous syndromes
7. genetic disorders
8. inborn errors of metabolism
9. exposure to endogenous or exogenous infant toxins after birth, i.e., hepatic or
   renal failure, lead acquired postnatal CNS infection
10. 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.
11. neuromuscular disorders with CNS involvement
12. idiopathic

Question 3

Peculiarities of immature brain include…

Answer 3

1. presence of developing structures which are not found in adult brain: e.g., germinal matrix.
2. injury early in development may interfere with subsequent development and lead to malformation.
3. reactions to injury may differ because of immaturity of glial and inflammatory cells.
4. cell susceptibility to certain injurious stimuli may differ from adult patterns.
5. plasticity of developing nervous system may be able to compensate for damage.
6. immaturity of brain function may hinder recognition of significant damage until much later in life.

Question 4

Antenatal brain development

Stages/gestational age/examples of disorders

6 Stages

Answer 4

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

Question 5

Malformations

def

Answer 5

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.

Question 6

Which brain structures develop at the same time and should prompt physician to investigate for multiple defects

Answer 6

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.

Question 7

Dorsal induction and primary neurulation
(3-4wks GA)

normal embryologic event

Answer 7

formation of neural tube from ectoderm

Question 8

Dorsal induction and primary neurulation
(3-4wks GA)

neural tube closure defects

list/chars

Answer 8

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

Question 9

Dorsal induction and primary neurulation
(3-4wks GA)

defects of axial mesodermal development

Answer 9

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

Question 10

Dorsal induction and primary neurulation
(3-4wks GA)

pathogenesis

Answer 10

Genetic factors: various genes, syndromes, populations

environmental influences: teratogens (e.g., thalidomide, carbamazepine), vitamin deficiency (folate), maternal hyperthermia, diabetes mellitus

Question 11

Ventral induction and formation of brain and face primordial (5-6wks GA)

Normal events

Answer 11

formation of primary brain divisions including cerebral hemispheres, olfactory and optic nerves

Question 12

Ventral induction and formation of brain and face primordial (5-6wks GA)

defects

Answer 12

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

Question 13

Neuronal proliferation and migration (maximum during months 2-5 GA)

Normal events

Answer 13

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.

Question 14

Neuronal proliferation and migration (maximum during months 2-5 GA)

Disorders of growth

Answer 14

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.)

Question 15

Neuronal proliferation and migration (maximum during months 2-5 GA)

Disorders of migration

Severe/diffuse forms

Answer 15

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

Question 16

Neuronal proliferation and migration (maximum during months 2-5 GA)

Disorders of migration

Diffuse or local forms

Answer 16

• heterotopias: masses of neurons left behind in white matter. Gene mutations in FLN A
• cortical dysplasias: areas of disturbed
  migration and neuronal-glial differentiation

Question 17

Neuronal proliferation and migration (maximum during months 2-5 GA)

Clinical manifestation severity/causes

Answer 17

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)

Question 18

Developmental reflexes

Onset/disappearance

rooting

Answer 18

O: birth

D: 3 months

Question 19

Developmental reflexes

Onset/disappearance

Moro

Answer 19

O: birth

D: 5-6 months

Question 20

Developmental reflexes

Onset/disappearance

Palmar grasp

Answer 20

O: birth

D: 6 months

Question 21

Developmental reflexes

Onset/disappearance

Plantar grasp

Answer 21

O: birth

D: 9-10 months

Question 22

Developmental reflexes

Onset/disappearance

Gallant (truncal incurvation)

Answer 22

O: birth

D: 1-2 months

Question 23

Developmental reflexes

Onset/disappearance

Tonic neck

Answer 23

O: birth

D: 6 months

Question 24

Developmental reflexes

Onset/disappearance

landau

Answer 24

O: 3-5 months

D: 2 years

Question 25

Developmental reflexes Onset/disappearance parachute

Answer 25

O: 6-9 months D: persists

Question 26

Mental retardation def

Answer 26

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.

Question 27

Cerebral palsy def

Answer 27

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

Question 28

Cerebral palsy Pathogenesis/age

Answer 28

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

Question 29

Cerebral palsy etiologies

Answer 29

``` 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 ```

Question 30

Cerebral palsy Clinical patterns

Answer 30

``` spastic hemiplegic quadriplegic (legs>arms) diplegic/paraplegic extrapyramidal mixed ```

Question 31

Developmental delay Forms it can take

Answer 31

``` Mental retardation cerebral palsy disorders of speech and language Disorders of social behavior (ie autism, ADD) Learning disorders ```

Question 32

Intrauterine or perinatal brain injury def

Answer 32

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

Question 33

Intrauterine or perinatal brain injury Porencephaly/hydranencephaly

Answer 33

porencephaly: cavity in wall of cerebrum communicating with ventricle and brain surface hydranencephaly: extreme expansion of ventricles with parenchyma reduced to a thin membrane

Question 34

Intrauterine or perinatal brain injury Injuries occurring later in gestation

Answer 34

Injuries occurring during later gestation, after major developmental events have occurred, usually result in atrophy, loss of structures, or aberrant maturation.

Question 35

Neonatal hemorrhage Common complication of…

Answer 35

Prematurity occurs in very low birth weight infants (<1550g; under 32 weeks gestation) during first weeks of postnatal life

Question 36

Neonatal hemorrhage Loc/grades

Answer 36

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

Question 37

Neonatal hemorrhage Deficits due to..

Answer 37

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

Question 38

Neonatal hypoxic-ischemic encephalopathy Predisposing factors

Answer 38

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

Question 39

Neonatal hypoxic-ischemic encephalopathy Patterns of injury Damage to gray matter

Answer 39

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

Question 40

Neonatal hypoxic-ischemic encephalopathy Patterns of injury Damage to white matter

Answer 40

periventricular leukomalacia (PVL): focal necrosis in deep cerebral white matter diffuse white matter damage

Question 41

Patterns of deficits resulting from intrauterine or perinatal brain injury

Answer 41

* acute encephalopathy (“floppy infant”) at birth * permanent focal deficits * static encephalopathy (cerebral palsy): * mental retardation and developmental delay * epilepsy * hydrocephalus

Question 42

Down syndrome Clinical features

Answer 42

* 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

Question 43

Fragile X syndrome Cause/clinical features

Answer 43

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.

Question 44

Tuberous Sclerosis MOI

Answer 44

Autosomal dominant disorder caused by TSC gene mutation on chromosome 9 (TSC1: hamartin) or 16 (TSC2: tuberin)

Question 45

Tuberous sclerosis Clinical features

Answer 45

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

Question 46

Inherited disorders of metabolism Gen groups

Answer 46

``` 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 ```

Question 47

Inherited disorders of metabolism Gen sx that they can cause

Answer 47

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

Question 48

Fetal alcohol syndrome Clinical features

Answer 48

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.

Question 49

Neuroteratogens list

Answer 49

``` Alcohol Cocaine Retin A Anticonvulsants Ionizing radiation ```

Question 50

Neuroteratogens Cocaine chars

Answer 50

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.

Question 51

Environmental insults

Answer 51

social deprivation and child abuse can contribute to CNS damage.

Question 52

Developmental milestones 24 mo Motor/sensory/language/social/cognitive

Answer 52

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

Question 53

Developmental milestones 12 mo Motor/sensory/language/social/cognitive

Answer 53

Motor: Stands and walks Flexor plantar Throws objects Sensory skills: - Language skills: Single words Social skills: Tries to feed self cognitive: Manipulation of objects

Question 54

Developmental milestones 10 mo Motor/sensory/language/social/cognitive

Answer 54

Motor: Creeps & pulls to stand Maturing reflexes Pincer grasp Sensory skills: - Language skills: Mama, dada Social skills: Sociable games cognitive: Exploration Separation from mother

Question 55

Developmental milestones 6 mo Motor/sensory/language/social/cognitive

Answer 55

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

Question 56

Developmental milestones 2 mo Motor/sensory/language/social/cognitive

Answer 56

Motor: Head control Increased range of motion Reflex grasp Sensory skills: Fixes & follows Language skills: Vocalizes Social skills: smiles cognitive: -

Question 57

Developmental milestones Neonate Motor/sensory/language/social/cognitive

Answer 57

Motor: Random movements Automatisms Reflex grasp Sensory skills: Light response Language skills: - Social skills: - cognitive: -

Question 58

Assessing neurodevelopment Different areas to assess

Answer 58

1. growth (head circumference and shape, overall body growth) 2. level of alertness 3. development of reflexes 4. development of normal neurological functions, including: acquisition of motor and sensory skills acquisition of cognitive skills acquisition of language skills acquisition of social skills

Question 59

Synaptic organization and myelination (6mo-yrs postnatal) normal events

Answer 59

events include elaboration and selective elimination of neurons, axons and dendrites, and synapses; myelination

Question 60

Synaptic organization and myelination (6mo-yrs postnatal) example of disorders

Answer 60

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.)