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)

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 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

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 adulthood.

Age of onset

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)

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

“Nearly pathognomonic” Alexander disease

Contrast enhancement if an inflammatory component

FLAIR good for cysts

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

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

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

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

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

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 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

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.