1. Myelination in Pediatric Neurology
Robert Carson MD PhD
Pediatric Neurology Resident Lecture Series
DOT 8155

2. Goals Review development of Myelin Discuss Normal Myelin Imaging
Outline an approach to Leukodystrophies

3. What we will not discuss today
ADEM MS
Primary inflammatory disorders of CNS
Myelin basic science (2 weeks)
My groundbreaking research in exquisite detail :^(

4. White matter in neurodevelopment.
Abnormal connectivity may contribute to neurocognitive deficits in:
Autism
TSC
Angelman’s
Periventricular
leukomalacia
(spike-timing
dependent plasticity)
(Nave, K )

5. Timing of myelination mirrors human development

6. Cortical thickness reaches a developmental nadir while myelin continues to increase

7. 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

8. General Patterns of myelination
Rostral to caudal
Posterior to anterior
Central to peripheral

10. T T1
T FLAIR

11. T FLAIR
T2-FSE T2-FSE

12. T FLAIR
T2-FSE T2-FSE

13. T FLAIR
T2-FSE T2-FSE

14. FLAIR FLAIR
T2-FSE T2-FSE

15. Normal Variant
FLAIR FLAIR
T2-FSE T2-FSE

16. FLAIR Signal evolution

17. 9m m
2y y

18. Terminal Zones of myelination

19. 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

20. 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

23. 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 adulthood.

24. Age of onset

25. Exam Physical abnormalities uncommon Neurologic (progressive):
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)

26. Diagnosis: MRI most important test
Stepwise approach:
Hypomyelination?
Differentiate delayed vs. permanent with serial MRI studies
Confluent, bilateral, symmetric wm lesions c/w genetic disease vs. multifocal or asymmetric with acquired disease
If confluent lesions are present, what is the localization? (frontal, parieto-occiptial, periventricular, subcortical, diffuse, posterior fossa)

28. Abnormal MRIs are not pathognomonic
Tigroid appearance
MLD
Globiod cell
Sparing of U-fibers
X-ALD

29. “Nearly pathognomonic”
Alexander disease

30. Contrast enhancement if an inflammatory component

31. FLAIR good for cysts

32. Additional imaging MRS CT: better than MRI for calcifications
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

33. Globoid cell leukodystrophy
Swelling of optic nerves
Contrast enhancement of spinal roots
+/- peripheral nerve thickening

34. Electrophysiology NCS Evoked potentials
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

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

36. Other organ systems Optho Endocrine GI 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

37. Treatment Prognosis is dismal Supportive care Swallow eval/g-tube
Abx when indicated
Antispasmodics and pain control.
ACTH monitoring/stress dose steroids

38. Treatment Continued Lorenzo’s oil in X-ALD Bone Marrow transplantation
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

39. 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.

40. Summary continued, Diagnosis through:
Physical examination
MRI imaging
With help from targeted laboratory testing
Important for family counseling and optimization of care
Palliative
experimental

41. References
Welker and Patton. Assessment of normal myelination with magnetic resonance imaging. Semin Neurol ;32:15-28.
Kohlshutter and Eichler. Childhood leukodystrophies: a clinical perspective. Expert Rev. Neurother. 2011;11: