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 • Angelman’s • Periventricular leukomalacia (spike-timing dependent plasticity) (Nave, K. 2010)
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 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
Normal Variant FLAIR FLAIR T2-FSE T2-FSE
9m 15m 2y 3y
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 adulthood.
Exam • Physical abnormalities uncommon • Big head: Alexander, Canavan, megalencephalicleukodystrophy 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: • 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)
Abnormal MRIs are not pathognomonic • Tigroid appearance • MLD • Globiod cell • Sparing of U-fibers • X-ALD • MLD
“Nearly pathognomonic” • Alexander disease
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 • Cerebrotendinousxanthomatosis • Some forms of hypomyelination • Cherry red spot: differentiate infantile/macrocephalicleukodystrophies from GM2 gangliosidosis • Such as Tay-Sachs and Sandhoff • Endocrine • Addison’s disease +/- neuroinvovlement 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 • Lorenzo’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 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.