Myelination in Pediatric Neurology
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Transcript of Myelination in Pediatric Neurology
Myelination in Pediatric NeurologyRobert Carson MD PhD
Pediatric Neurology Resident Lecture SeriesDOT 815509.13.2013
GoalsReview development of MyelinDiscuss Normal Myelin ImagingOutline an approach to
Leukodystrophies
What we will not discuss todayADEMMSPrimary inflammatory disorders
of CNSMyelin basic science (2 weeks)My groundbreaking research in
exquisite detail :^(
Abnormal connectivity may contribute to neurocognitive deficits in:◦Autism◦TSC◦Angelman’s◦Periventricular leukomalacia
White matter in neurodevelopment.
(Nave, K. 2010)
(spike-timing dependent plasticity)
Timing of myelination mirrors human development
Cortical thickness reaches a developmental nadir while myelin continues to increase
Normal myelination/general MRI patternsNeed 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 myelinationRostral to caudalPosterior to anteriorCentral to peripheral
T1 T1
T2 FLAIR
T1 FLAIR
T2-FSE T2-FSE
T1 FLAIR
T2-FSE T2-FSE
T1 FLAIR
T2-FSE T2-FSE
FLAIR FLAIR
T2-FSE T2-FSE
FLAIR FLAIR
T2-FSE T2-FSE
Normal Variant
FLAIR Signal evolution
9m 15m
2y 3y
Terminal Zones of myelination
Components of myelin:Sheath: protein-lipid-protein-lipid-
proteinGlycolipids: glalctocerebroside,
sulfatide, cholesterol◦Outer layer of membrane
Long chain fatty acids (middle)Phospholipids:
◦Hydrophobic, on inner membraneOthers: MAG, MOG, PLP, MBP, CNPase
LeukodystrophiesGenetic, 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 presentationInsiduous, in a previously healthy
child. Slowly progressing, may have
periods of stagnationVague/progressive motor and
mental symptoms.Widely variable phenotypes
associated with single genetic disease
Presents from infancy to adulthood.
Age of onset
ExamPhysical 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 testStepwise approach:
1. Hypomyelination? Differentiate delayed vs. permanent with
serial MRI studies2. 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, parieto-occiptial, periventricular, subcortical, diffuse, posterior fossa)
Abnormal MRIs are not pathognomonic
Tigroid appearance◦ MLD◦ Globiod cell
Sparing of U-fibers◦ X-ALD◦ MLD
“Nearly pathognomonic”Alexander
disease
Contrast enhancement if an inflammatory component
FLAIR good for cysts
Additional imagingMRS
◦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
ElectrophysiologyNCS
◦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
diseaseEvoked 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 systemsOptho
◦ Cataracts Cerebrotendinous xanthomatosis Some forms of hypomyelination
◦ Cherry red spot: differentiate infantile/macrocephalic leukodystrophies from GM2 gangliosidosis Such as Tay-Sachs and Sandhoff
Endocrine◦ Addison’s disease +/- neuro invovlement in X-ALD◦ Ovarian failure
GI◦ Feeding and swallow issues are common.◦ Gallbladder papilloma in MLD
TreatmentPrognosis is dismalSupportive care
◦Swallow eval/g-tube◦Abx when indicated◦Antispasmodics and pain control. ◦ACTH monitoring/stress dose steroids
Treatment ContinuedLorenzo’s 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 therapyExperimental
◦ Therapeutic window is narrow Asymptomatic____ Too far gone
Leukodystrophies, in Summary:Incurable with progressive motor
and mental disabilityLeukodystrophy 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
ReferencesWelker 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.