Transcript Peak Times of Occurrence

Developmental
Brain Disorders
Erick Sell
CHEO 2017
Objectives
Major Developmental Events
Peak Times of Occurrence
Dorsal induction
Ventral induction
Cell proliferation
Cell migration
Organization
Myelination
Apoptosis
3-4 wks gestation
5-6 wks gestation
2-4 mos gestation
3-5 mos gestation
6 mos gest. – youth
Birth – adolescence
Throughout
Major Developmental Events
Dorsal
induction
3 weeks GA
4 weeks GA
Ventral induction: 5 weeks GA
Ventral induction: 6 weeks GA
Proliferation and migration: cortical plate maturation (Rakic)
Neuronal migration
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Formation of cerebral cortex, basal ganglia,
thalamus, cerebellum by cell migration away
from the ventricular zones of the lateral, 3rd
and 4th ventricles
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3 – 5 months gestation
Neuronal migration
Organization
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Orientation, layering of cortical neurons
Dendritic, axonal growth and differentiation
Synaptic spine formation
Glial differentiation
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6 months gestation to postnatal life
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Growth of cerebral hemisphere, 25 days → term
Cerebral
cortex
Golgi prep
25 wks GA
→ 32 wks
Apical dendrite maturation/ synaptic spines
25 wks
36 wks
Cerebral cortex
pyramidal cell with
synaptic spines (ss)
on apical (A) and
basal (B) dendrites
ss
ss
The remarkable voyage of the upper
motor neuron axonal growth cone!
Layer 5 motor cortex →
centrum semiovale →
internal capsule →
cerebral peduncle →
basis pontis →
pyramidal decussation →
lateral corticospinal
tract, cervical cord →
anterior horn cell region
-without getting lost!
← start
← finish
Example of apoptosis: fate of Cajal-Retzius (cortical layer 1
after neuronal migration phase is complete
T1
Term
T2
Myelination
Predominantly a post-term process progressing in a predictable manner
Pre-term: Cerebral peduncle (25 wks)
Posterior brain stem and VL thalamus (29 wks)
Term: Posterior limb of internal capsule and corona radiata
Completed by the second year of life
Developmental brain disorders
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May be considered in terms of the
developmental stage(s) at which the normal
processes are disrupted, or
In terms of the type of disease process
present:
Vascular
Toxic
Infectious
Metabolic
Degenerative
Genetic
Timing of pathologic interference
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The same pathological process (e.g.
vascular, infectious) may cause vastly
different brain anomalies, depending upon
the stage of brain development at which it
occurs
Mode of presentation
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From the clinical standpoint, developmental
brain disorders are best considered in terms
of:
1) age of fetus or child at the time of
presentation
2) symptoms and signs present at the time of
presentation
Scenario 1 – fetal malformation
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Routine abdominal U/S exam in 18 wks GA
mother shows large lateral ventricles
(hydrocephalus) and defect in dorsal
lumbosacral spine
Infant delivered by c-section at 37 wks GA:
large head and lumbosacral skin sac
No leg movement except hip flexion; no pain
sensation in legs
Myelomeningocele repair and VP shunt (for
hydrocephalus) on day 1
GA : 23 weeks
spina bifida with
lumbosacral mass
23 wks GA
spina bifida
enlarged lateral
ventricles
sagittal
coronal
Lumbosacral myelomeningocele – dorsal
induction defect
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Multiple etiologic factors: familial
predisposition; maternal folate deficiency;
teratogenic drugs (e.g. valproic acid)
Incidence reduced by maternal folate
supplementation at conception
Most common deficits are varying degrees of
flaccid leg weakness, insensate legs, urinary
incontinence with risk of UTIs, renal damage
Lumbosacral myelomeningocele (2)
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Almost invariably accompanied by small
posterior fossa and herniation of posterior
fossa contents into the upper cervical cord
region (Chiari malformation)
Small posterior fossa leads to hydrocephalus,
either in utero or after birth; if present during
the 2nd trimester, hydrocephalus may cause
partial absence of the corpus callosum and
septum pellucidum + many other anomalies
Myelomeningocele: Chiari 2 malformation and partial
callosal agenesis
Lumbosacral myelomeningocele (3)
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Intellectual capacity often normal, especially
if intrauterine hydrocephalus develops late
(30+ wks GA)
Those with neurological deficits below L4
level can walk independently; those with
deficits above L3 confined to wheelchair
Care requires multidisciplinary team:
neurosurgery, urology, orthopedic surgery,
physiotherapy, physical medicine
Other commonly encountered
malformations detected in utero
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Holoprosencephaly – failure to form two
completely separate cerebral hemispheres:
alobar type – complete failure; semilobar type
– no separation of frontal lobes
Agyria-pachgyria (lissencephaly): smooth
agyric cortex or large, simple gyri
Holoprosencephaly – ventral induction
defect
Semilobar type:
single frontal lobe
with no interhemispheric
fissure; two
distinct temporal
lobes; no septum
pellucidum
Agyria-pachygyria (lissencephaly) – cell
migration defect
Mutations in LIS1 or XLIS genes (chr 17; X chr)
Scenario 2 – neonatal seizures
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Apparently normal term female infant
develops focal seizures at age 3 hrs:
rhythmic twitching of right face/arm/leg ±
tonic stiffening of all 4 limbs
EEG: continuous spike discharges from left
hemisphere
MRI: extensive cortical dysplasia of left
hemisphere – small, irregular, thickened gyri
typical of polymicrogyria
Scenario 2 – interictal EEG
Scenario 2 (2)
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Almost daily seizures, often clustered,
predominantly right-sided, to age 2
No response to variety of AEDs
Markedly delayed motor and language milestones
Modified left hemispherectomy at age 2 → seizurefree
Marked right hemiparesis and field defect but
marked improvement in ambulation and
communication
Pre-operative
Post-operative
Polymicrogyria – late neuronal migration
defect
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Focal cerebral cortical
vascular disruption
(stroke) during late
stage of neuronal
migration (4 months
GA) → infarction of
existing layers of
cortical plate (layers
4-6)
Polymicrogyria – etiology and clinical
features
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Second trimester stroke due to
hyperviscosity, genetic prothrombotic
disorder, maternal drug abuse (cocaine,
phencyclidine (“angel dust”),
phenylpropanolamine (cold medications)
If bilateral may be of genetic origin (rare)
Severe epilepsy is common; depending on
location, may produce hemiparesis, field
defect, hyperactivity etc.
Other causes of neonatal seizures
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Perinatal hypoxic-ischemic brain injury (postnatal day 1)
Neonatal meningitis
Intracranial hemorrhage (especially
premature infants)
Cerebral venous sinus thrombosis
Hypoglycemia (typically first day – e.g. infant
of diabetic mother)
Hypocalcemia (typically at 4-6 days of age)
Scenario 3 – delayed development &
developmental arrest
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3 year-old girl comes to office for assessment
of developmental delay
Normal to age 1; between 12-18 months
stopped using hands completely, stopped
babbling, lost ability to crawl or stand
No further deterioration to age 3 but also no
progress; development of “hand-washing”
posture with constant tapping of fingers on
chest
Scenario 3 (2)
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On examination at 3, small head size (had been
normal at age 1)
Good eye contact; piercing stare
Generalized hypotonia; flexed arms at elbows with
constant hand dyskinesia but no useful hand
function
MRI head normal
DNA analysis: nonsense mutation in 1 of the
MECP2 genes at Xq28 – diagnostic of Rett
syndrome
Rett syndrome:
second most
common genetic
cause of severe
mental handicap
in girls after Down
syndrome
Rett syndrome – reduced
brain volume
Rett syndrome:
Golgi stain showing
reduced dendritic
arborization in
comparison with
control
Rett syndrome, genetic defect
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Gene located at Xq28
95% of cases due to mutations in gene for
methyl-CpG-binding protein 2 (MECP2)
MeCP2, the gene product, is a transcription
repressor and growth promoter
Lack of MeCP2 appears to result in lack of
synaptic bud formation during learning
processes (defect in synaptic plasticity)
Other features of Rett syndrome
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Later in first decade, increased ability to
communicate, using assistive devices
Epilepsy, usually around age 4
Hyperpnea, apnea, teeth-grinding, airswallowing
Progressive scoliosis
Progressive dystonia, sometimes leading to a
parkinsonian state in adult life
osteoporosis
Other common syndromes with
developmental delay/arrest
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Down syndrome – trisomy 21
Fragile X syndrome (mostly boys)
Angelman syndrome (maternal origin 15q
deletion or loss of function)
Prader-Willi syndrome (paternal origin 15q
deletion or loss of function)
Fragile X
syndrome:
severe mental
handicap with
autistic
features; large
head;
prominent ears;
macroorchidism
Angelman
syndrome:
severe mental
handicap; epilepsy;
jerky ataxia;
constant laughter
Deletion or inactivity
of maternallyimprinted genes at
15q11-q13
Prader-Willi
syndrome
Almond-shaped
eyes
Small mouth with
thin upper lip
Fair skin & hair
Obesity, but not
invariable
Mild-moderate
mental handicap
Scenario 4a – impaired motor
development
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1 yr-old girl never used right hand: always
fisted
Drags right leg when crawling
Normal term pregnancy and delivery
Developed head control, rolling, independent
sitting and crawling at normal ages
Scenario 4a – physical exam
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Normal use of left hand, with pincer grasp;
unable to open right hand
Spasticity in right arm/leg
Increased tendon reflexes (4+) on right
Extensor plantar response on right; flexor
response on left
Walks on toes of right foot
Arm-dominant
right spastic
hemiparesis
Intra-uterine stroke
MCA territory
Intra-uterine
stroke with
typical hand
posture at age 1 yr
Intra-uterine stroke
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Fetuses and neonates prone to development
of arterial and venous stroke because of high
hematocrit and  viscosity
Genetic prothrombotic disorders also
associated with intra-uterine stroke: Factor V
Leiden mutation; prothrombin gene mutation;
MTHFR mutation homozygosity; Protein C/S
deficiencies
Early GA strokes → malformations (e.g.
polymicrogyria – Scenario 2)
Cerebral palsy
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Congenital hemiparesis is one of the more
common patterns of cerebral palsy (CP),
defined as a non-progressive motor disability
resulting from damage to, or malformation of
the developing brain in early life
Other forms of CP include spastic diparesis
(primarily lower limbs), spastic quadriparesis
and dyskinetic/dystonic quadriparesis
Etiologies of other forms of CP
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Spastic diparesis (lower limb predominance):
hypoxic-ischemic brain injury in premature
infants
Spastic quadriparesis: hypoxic-ischemic brain
injury in term infants; prenatal infections
Dystonic/dyskinetic quadriparesis (twisted
postures, involuntary movements): severe
anoxic brain injury [e.g. uterine rupture];
neonatal hyperbilirubinemia [kernicterus]
Scenario 4b – impaired motor
development (2)
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24 hr-old term GA girl transferred for
assessment of multifocal clonic seizures,
small head, large liver
HC 29 cm (normal 32-35)
Hepatosplenomegaly; petechial rash
No ocular fixation; retinal lacunes
Generalized spasticity & joint contractures
Hands always fisted; hyper-reflexia; extensor
plantar responses
Scenario 4b – lab data
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CBC: marked thrombocytopenia
Elevated liver enzymes (hepatocellular
damage)
Cranial imaging: diffuse cerebral atrophy and
intracranial calcifications (mostly
periventricular)
High antibody titers to cytomegalic inclusion
virus (CMV, HHV4)
Intra-uterine infections – “TORCHES”
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Toxoplasmosis
Rubella
Cytomegalic inclusion virus (CMV)
Herpes simplex 2
Syphilis
Varicella-zoster
Arm-dominant
spastic
quadriparesis,
severe mental
handicap due
to CMV
CMV retinitis
Toxoplasmosis – microcephaly, quadriparesis
Periventricular leukomalacia (PVL)
Hypoxicischemic
injury to
periventricular
white matter,
typically in
premature
infants or in
utero –
produces
spastic
diparesis
Leg-dominant
spastic
quadriparesis
due to PVL
Learning problems
common, especially
visually-related;
25% epileptic
Anoxic injury in term infants, e.g. prolapsed cord
Selective injury
to posterior
putamen,
lateral thalamic
nuclei (motor)
and motor
cortex, leading
to dystonic/
dyskinetic
quadriparesis
Motor cortex anoxic injury at term
Pseudobulbar palsy, dystonic quadriparesis
Normal IQ
Dystonic hand posture
Scenario 5 – developmental regression
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10 yr-old Acadian boy with ?rapid-onset
hearing loss
Normal student until 3 months ago →
increasing inattention, class disruption, failing
courses, lack of response to questioning
On exam: restless, anxious; no response to
questions or commands unless accompanied
by gesture; normal response to soft sounds
Hyperpigmented skin creases; otherwise
normal neurological examination
Scenario 5
MRI study
Scenario 5 – lab studies
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Marked elevation in serum levels of verylong-chain fatty acids (VLCFA)
ACTH stimulation test: marked reduction in
peak cortisol response, i.e. Addison’s
disease!
WBC DNA assay → mutation in ABCD1 gene
(ATP-binding cassette, subfamily D, number
1) – diagnostic of X-linked
adrenoleukodystrophy
Leukodystrophies
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Hereditary degenerative disorders of white matter –
initial process of myelin formation often disturbed
(dysmyelination) → progressive myelin degradation
→ spastic quadriparesis, dementia and optic atrophy
Most common additional examples include
metachromatic leukodystrophy (MLD – AR) and
Pelizaeus-Merzbacher disease (PMD-XL)
Some leukodystrophies also involve peripheral
myelin (e.g. MLD) → peripheral neuropathy at onset
Adrenoleukodystrophy (ALD)
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Onset of MRI changes and Addisonian
features is insidious (years) but onset of
neurological symptoms is typically abrupt,
toward the end of the first decade
? If neurological symptoms and MRI signs of
WM inflammation are due to a secondary
autoimmune inflammatory process
~1/10 boys with typical MRI changes never
develop CNS symptoms!
ALD variants
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Some males with ABCD1 mutations never
develop MRI changes; others develop
adrenal failure and a progressive spastic
paraparesis in adult life:
adrenomyeloneuropathy (AMN)
Carrier females may also develop AMN
Treatment of ALD
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High serum levels of VLCFAs can be
corrected with dietary supplementation with
Lorenzo’s oil (see Hollywood movie!)
Presymptomatic males with MRI changes
remain stable if treated with a bone-marrow
transplant from a compatible donor
Once CNS symptoms are present, there is no
response to either BM transplant or to
Lorenzo’s oil
Normal catabolic recycling
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Many pediatric neurodegenerative diseases
result from a breakdown in the normal
recycling of cellular constituents, e.g. VLCFA,
membrane glycolipids in neurons and glia
Failure to complete the orderly breakdown of
these compounds → accumulation of partially
degraded material in cell lysosomes or
peroxisomes → death of the cell
Classic examples include Tay-Sachs disease
(GM2 gangliosidosis), MLD/sulfatide lipidosis
(GM2)
Tay-Sachs disease – lipid (GM2
ganglioside) storage in neurons
→
←
Tay-Sachs – stacked lipid in lysosomes
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Tay-Sachs – retinal ganglion cell GM2
lipid storage
*
Tay-Sachs – macular cherry red spot
Rare disorders?
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In case you think the preceding scenarios are all
concerned with rare disorders that you will
probably never encounter in clinical practice,
consider the following:
● prevalence of CP – 2.4/1000 children
● prevalence of mental handicap – 2.5 - 3.0/100
● prevalence of autistic disorders – >1/100