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Flashcards in Neurodevelopment and Developmental Delay Deck (60):
1

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

2

Developmental delay

Etiologies list

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

3

Peculiarities of immature brain include…

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.

4

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

5

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.

6

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.

7

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

normal embryologic event

formation of neural tube from ectoderm

8

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

9

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

10

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

11

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

12

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

13

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.

14

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.)

15

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

16

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

17

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)

18

Developmental reflexes

Onset/disappearance

rooting

O: birth

D: 3 months

19

Developmental reflexes

Onset/disappearance

Moro

O: birth

D: 5-6 months

20

Developmental reflexes

Onset/disappearance

Palmar grasp

O: birth

D: 6 months

21

Developmental reflexes

Onset/disappearance

Plantar grasp

O: birth

D: 9-10 months

22

Developmental reflexes

Onset/disappearance

Gallant (truncal incurvation)

O: birth

D: 1-2 months

23

Developmental reflexes

Onset/disappearance

Tonic neck

O: birth

D: 6 months

24

Developmental reflexes

Onset/disappearance

landau

O: 3-5 months

D: 2 years

25

Developmental reflexes

Onset/disappearance

parachute

O: 6-9 months

D: persists

26

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.

27

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

28

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

29

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

30

Cerebral palsy

Clinical patterns





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

31

Developmental delay

Forms it can take





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

32

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

33

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

34

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.

35

Neonatal hemorrhage

Common complication of…

Prematurity

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

36

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

37

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

38

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

39

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

40

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

41

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

42

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

43

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.

44

Tuberous Sclerosis

MOI

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

45

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

46

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

47

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

48

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.

49

Neuroteratogens

list

Alcohol
Cocaine
Retin A
Anticonvulsants
Ionizing radiation

50

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.

51

Environmental insults

social deprivation and child abuse can contribute to CNS damage.

52

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

53

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

54

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

55

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

56

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: -

57

Developmental milestones

Neonate

Motor/sensory/language/social/cognitive

Motor:
Random movements
Automatisms
Reflex grasp

Sensory skills:
Light response

Language skills: -

Social skills: -

cognitive: -

58

Assessing neurodevelopment

Different areas to assess

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

59

Synaptic organization and myelination
(6mo-yrs postnatal)

normal events

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

60

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.)