Myelination in Pediatric

Neurology
Robert Carson MD PhD
Pediatric Neurology Resident Lecture Series
DOT 8155
09.13.2013

Goals
Review

development of Myelin
Discuss Normal Myelin Imaging
Outline an approach to
Leukodystrophies

What we will not discuss

today
ADEM
MS
Primary

inflammatory disorders

of CNS
Myelin basic science (2 weeks)
My groundbreaking research in
exquisite detail :^(

White matter in
neurodevelopment.
Abnormal

connectivity may contribute to

neurocognitive deficits in:

Autism
TSC
Angelmans
Periventricular
leukomalacia

(spike-timing
dependent plasticity)

(Nave, K. 201

Timing of myelination mirrors

human development

Cortical thickness reaches a developmental

nadir while myelin continues to increase

Normal myelination/general MRI

patterns
Need

to know what is normal to know what is

not normal.
Neonate:
T1 hypo T2 hyper
Fully myelinated: T1 hyper T2 hypo

T1

signal increases with increasing cholesterol

and galactocerebroside
T2 signal decreases with decreasing amount
of brain water
displaced by myelin
Increased length hydrocarbons and double bonds
T2

changes lag behind T1 changes

General Patterns of
myelination
Rostral

to caudal
Posterior to anterior
Central to peripheral

T1

T2

T1

FLAIR

T1

T2-FSE

FLAIR

T2-FSE

T1

T2-FSE

FLAIR

T2-FSE

T1

T2-FSE

FLAIR

T2-FSE

FLAIR

T2-FSE

FLAIR

T2-FSE

Normal Variant

FLAIR

FLAIR

T2-FSE

T2-FSE

FLAIR Signal evolution

9m

15m

2y

3y

Terminal Zones of
myelination

Components of myelin:
Sheath:

protein-lipid-protein-lipid-

protein
Glycolipids: glalctocerebroside,
sulfatide, cholesterol
Outer layer of membrane
Long

chain fatty acids (middle)

Phospholipids:
Hydrophobic, on inner membrane
Others:

MAG, MOG, PLP, MBP, CNPase

Leukodystrophies
Genetic,

with degeneration of myelin

sheaths in CNS (+/-) PNS
Related to synthesis and maintenance of
myelin membranes.
Vast majority autosomal recessive

Leukoencephalopathies:

defects
causing secondary myelin damage

Diagnosis

requires a clinical strategy

Clinical presentation
Insiduous,

in a previously healthy

child.
Slowly progressing, may have
periods of stagnation
Vague/progressive motor and
mental symptoms.
Widely variable phenotypes
associated with single genetic
disease
Presents from infancy to

Age of onset

Exam
Physical

abnormalities uncommon

Big head: Alexander, Canavan, megalencephalic

leukodystrophy with cysts and vanishing white
matter
Dysmorphic features similar to
mucopolysacharidoses: fucosidosis, MLD
Neurologic

(progressive):

Motor (spasticity)
Changes in cognition and language
Seizures are rare
Peripheral nerve (MLD, globoid cell,
hypomyelination)

Diagnosis: MRI most important

test
Stepwise

approach:

1. Hypomyelination?

Differentiate delayed vs. permanent with

serial MRI studies

2. Confluent, bilateral, symmetric wm

lesions c/w genetic disease vs. multifocal
or asymmetric with acquired disease
3. If confluent lesions are present, what is
the localization? (frontal, parietoocciptial, periventricular, subcortical,
diffuse, posterior fossa)

Abnormal MRIs are not

pathognomonic

Tigroid

appearance
MLD
Globiod cell
Sparing

fibers
X-ALD
MLD

of U-

Nearly pathognomonic
Alexander

disease

Contrast enhancement if an
inflammatory component

FLAIR good for cysts

Additional imaging
MRS

NAA elevated in Canavan

Decreased NAA suggests neuronal
involvement in primary WM disease
Lactate in leukencephalopathy with
brainstem and spinal cord involvement
and elevated lactate
Other mitochondrial disorders
CT:

better than MRI for calcifications

Globoid cell
leukodystrophy
Swelling

of optic

nerves
Contrast
enhancement of
spinal roots
+/- peripheral
nerve thickening

Electrophysiology
NCS

Symmetric involvement of long spinal

tracks and peripheral nerves
May help differentiate leukodystrophies
Normal in X-ALD, usually abnormal with
metachromatic or globoid cell

Correlates with severity of clinical

disease
Evoked

potentials

BAER abnormal first, then SSEP lower

limbs, then MEPs of lower limbs

 Tests

to
consider early
on in
evaluation.
Low yield of
done prior to
exam and
evaluation of
imaging.

Other organ systems

Optho

Cataracts
Cerebrotendinous xanthomatosis
Some forms of hypomyelination

Cherry red spot: differentiate infantile/macrocephalic

leukodystrophies from GM2 gangliosidosis
Such as Tay-Sachs and Sandhoff

Endocrine

Addisons disease +/- neuro invovlement in X-ALD

Ovarian failure
GI

Feeding and swallow issues are common.

Gallbladder papilloma in MLD

Treatment
Prognosis

is dismal
Supportive care

Swallow eval/g-tube
Abx when indicated
Antispasmodics and pain control.
ACTH monitoring/stress dose steroids

Treatment Continued
Lorenzos

oil in X-ALD

Erucic and oleic acid

Lowers VLC FAs
Benefits asymptomatic boys
Bone

Marrow transplantation

Can halt progression in X-ALD, but

2/3 boys develop cerebral disease, and
Successful only in early stages of disease.
Gene

therapy
Experimental
Therapeutic window is narrow
Asymptomatic____ Too far gone

Leukodystrophies, in
Summary:
Incurable

with progressive motor

and mental disability
Leukodystrophy if due to myelin
sheath, leukoencephalopathy if
outside. (similar)
White matter and gray matter
disease may overlap.
Definitive diagnosis is
challenging, though timely
diagnosis is required.

Summary continued,
Diagnosis

through:

Physical examination
MRI imaging
With help from targeted laboratory
testing
Important

for family counseling

and optimization of care
Palliative
experimental

References
Welker

and Patton. Assessment

of normal myelination with
magnetic resonance imaging.
Semin Neurol. 2012;32:15-28.

Kohlshutter

and Eichler.
Childhood leukodystrophies: a
clinical perspective. Expert Rev.
Neurother. 2011;11:1485-1496.