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.