Imaging Pediatric Leukodystrophies

Imaging Pediatric Leukodystrophies Jonathan A Phelan MS IV 1 & Lisa H Lowe MD 2 1 Kansas City University of Medicine and Biosciences 2 Department of Radiology, Children s s Mercy Hospital and Clinics and 2 The University of Missouri-Kansas City

Learning objectives 1. Distinguish between normal and abnormal white matter in children 2. Formulate an approach to white matter disorders in children 3. Recognize the findings of common white matter problems in children

Introduction White matter (WM) disorders in children are extensive, complex and challenging to learn

Important Cell Organelles Lysosome (garbage disposal unit) Peroxisome (oxidation & catalation) Mitochondria (power house)

Lysosomal disorders Metachromatic leukodystrophy Krabbe s disease Mucopolysaccharidoses Gangliosidoses Peroxisomal disorders Zellweger syndrome Neonatal ALD XR adrenoleukodystrophy Mitochondrial dysfunction Leigh disease MELAS Kearns-Sayre syndrome Unknown metabolic defect Pelizaeus-Merzbacher Alexander s s disease Canavan disease

Pathophysiology of WM disorders: general concepts Faulty gene Structurally abnormal protein Enzyme defect Metabolic block

Pathophysiology of WM disorders: general concepts Accumulation of abnormal products Interfere with normal neuronal function Insufficient normal biochemical product Essential to metabolism of neurons/myelin Injure other organs (lung, heart, liver, kidney) Secondary effect on CNS Toxic to neurons/myelin

Treatment options WM disorders Supportive, symptomatic Substrate deprivation Bone marrow transplant Enzyme replacement Gene therapy Neural stem cell transplantation

What are the obstacles to learning pediatric WM disorders? Many classifications systems and most are not useful for imaging Organelle based Biochemical based Clinical syndrome Histochemical staining pattern

Other obstacles to learning pediatric WM disorders Various forms Single vs. multiple enzyme defects Various presentations Infant vs. juvenile vs. adult Present - nonspecific Overlap - imaging Advanced cases look alike 60% never get a Dx

How can we overcome these obstacles? Have an approach to imaging of WM leukodystrophies Be familiar with common autoimmune & infectious disorders that may affect WM in children Know the key history & imaging patterns useful to formulate a limited differential diagnosis

Outline Normal development Leukodystrophies Subcortical WM Deep WM Disorders with lack of WM myelination Nonspecific WM disorders

Normal developmental anatomy and pitfalls that simulate disease WM signal changes with age Adult appearance at 18 mo - 2 years Myelination progresses back to front Assess myelination with MRI Terminal myelination zones Periatrial and subcortical WM Lack of myelination can mimic WM disease

Normal milestones myelination Brain region Middle cerebellar peduncle, post limb internal capsule Anterior limb internal capsule, centrum semiovale Splenium corpus callosum Genu corpus callosum T1 Birth 2-33 mo 3-44 mo 4-66 mo T2 Birth 2mo 7-11 mo 4-66 mo 5-88 mo Occipital white matter, peripheral Frontal white matter, peripheral 4-77 mo 7-11mo T1 used < 6 mo, T2 used > 6 months 11-15 15 mo 14-18m 18m

Newborn 5 months Normal progression of myelination 8 months

T2 nb 5mo 8mo T2 12mo 18mo 24mo

Normal terminal myelination zones 18-mo mo-male male with normal brain Normal variant that can persist into adulthood

How do we approach pediatric WM disorders: Ask some questions! 1. Are there any useful symptoms? Head size: Macrocephaly WM symptoms: Spasticity, hyperreflexia, ataxia Other organs: liver, msk, renal, eye, ear 2. Is the disorder primarily WM, gray matter or both? 3. Is it primarily SUBCORTICAL or DEEP white matter?

Subcortical vs. Deep? Note the region of sparing in the subcortical WM region Note the abnormal signal in the WM extends to the subcortical U fiber region

Approach to pediatric WM disorders Other questions: 1. Distribution - anterior, posterior, both? 2. Subcortical or deep WM cysts? 3. Thalamic involvement? 4. Brainstem involvement? 5. Delayed or lack of myelination? 6. Leading edge of enhancement? 7. Cortical dysplasia? 8. Elevated NAA, lactate or other peaks on MRS?

Imaging technique WM disorders US & CT - limited role US screen macrocephaly in developmentally normal children CT abnormal areas usually hypodense MRI Imaging modality of choice Routine brain + Gadolinium MRS Just do it! It may help you. TE 30msec & 270msec Multivoxel nice to compare sample volumes in normal & abnormal regions

Begin with Subcortical White Matter leukodystrophies Caveat: : nearly all have some gray matter involvement Approach according to Barkovich JE. Pediatric Neuroimaging 4th ed.

First discuss SUBCORTICAL white matter disorders With macrocephaly: 1. If yes, consider: Alexander & Canavan disease 2. + subcortical cysts,, think of: van der Knapp disease 3. + ataxia & decreased myelination think of: Vanishing white matter disease Approach according to Barkovich JE. Pediatric Neuroimaging 4th ed. e

Canavan disease Spongiform leukodystrophy Autosomal recessive, Ashkenazi Jews Aspartoacylase deficiency; Chromosome 17 Presentation: hypotonia with head lag in first few weeks of life,, followed by macrocephaly & seizures, then spacticity Rapid progression Death 2 nd year of life

Canavan disease Hx: : 2-month2 month-old old hypotonic female Imaging: CT Hypodense Subcortical WM Globus pallidi Thalami Extreme capsule Claustra Image from Barkovich JE. Pediatric neuroimaging 2005

Canavan disease Imaging: MRI hypointense T1 & hyperintense T2 Diffuse subcortical WM Globus pallidi with normal putamina Internal & external capsules in rapid cases P GP

Canavan disease Restricted diffusion in WM acute disease ADC DWI

Canavan disease MRS Marked elevation NAA peak Specific for Canavan disease NAA Cr

T1 Canavan disease T2 T2 Spongiform leukodystrophy

Alexander disease Fibrinoid leukodystrophy Rosenthal fibers on histology Mutated GFAP (glial fibrillary acidic protein) Presentation macrocephaly 1 st year of life, developmental delay, failure to thrive 3 subgroups: Infantile most common; ; death in 2-32 3 year of life Juvenile 7-14 years ataxia & spasticity Adult present like juvenile Dx: analysis of GFAP gene Prognosis: Death first year of life

Alexander disease Hx: : 2 year old male, macrocephaly & ataxia Imaging: : CT Hypodense subcortical WM Frontal Contrast enhancement Adjacent to frontal horns Caudate heads Image from Barkovich JE. Pediatric neuroimaging 2005

Alexander disease MR imaging criteria according to van der Knapp: Subcortical WM, frontal lobe predominance Contrast enhancment of gray and WM structures (esp adjacent to frontal horn tips and ventricular trigones) Brain stem abnormalities Abnormal basal ganglia, thalami DWI - increased water motion (bright on ADC map, dark on DWI) MRS low NAA +/- elevated myo-inositol van der Knapp MS, et al. Alexander disease: Diagnosis with MR imaging. AJNR 2001;22:541-52 52

Alexander disease Bright, anterior subcortical to periventricular WM, basal ganglia & thalami Image courtesy of Mauricio Castillo, MD

Alexander disease

van der Knapp dz or Megalencephalic leukoencephalopathy with cysts Imaging: Absent myelin in subcortical WM Spared deep WM and basal ganglia Subcortical cysts in posterior frontal and temporal lobes DWI increased diffusion (dark on DWI, bright on ADC map) MRS non-specific; low NAA levels

van der Knapp dz or Megalencephalic leukoencephalopathy with cysts

Vanishing white matter disease Familial childhood ataxia with diffuse CNS hypomyelination Chromosome 3 Presentation: Relapsing-remitting periods of progressive ataxia & spastic diplegia Dx criteria: initial motor and mental (a) development is nl, (b) chronic episodic neuro deterioration, (c) cerebellar ataxia & spasticity (d) MRI shows symmetric WM signal of CSF Lab screening: elevated glycine in the CSF, serum and urine Prognosis: death 2 nd decade

Vanishing white matter disease WM gradually looks the same as CSF T2 FLAIR Image from van der Knapp. Magnetic Resonance of myelination and myelin disorders

Approach to SUBCORTICAL white matter disorders Without macrocephaly?: Galactosemia also involves liver Kearns Sayre especially if globus pallidus is involved

Galactosemia Autosomal recessive Defective conversion of glucose to galactose Galactose-1-phosphate phosphate-uridyl transferase Presentation: newborns or young children with signs of increased intracranial pressure and vomiting Untreated: severe liver disease & mental retardation, seizures, choreoathetosis Rx: dietary restriction of galactose Prognosis: varies

Galactosemia Imaging: CT nonspecific low density WM MRI delayed subcortical WM myelination on T2 (nl on T1); Occasional WM focal lesions and late atrophy MRS - normal FLAIR Image from Barkovich JE. Pediatric neuroimaging

Kearns Sayre Mitochondrial disorder Dx requires external opthalmoplegia, retinitis pigmentosa and onset of neurologic dysfunction < 20 years +/- protein in CSF, heart block & cerebellar ataxia Imaging: abnormal WM early, atrophy, later basal deep gray matter CT - WM hypodense with calcifications MRI -subcortical WM, globus pallidus DWI - restricted diffusion MRS non-specific increased lactate & low NAA

Kearns Sayre Subcortical WM + spared deep WM + Globus pallidus Image from Barkovich JE. Pediatric neuroimaging

Next Deep White Matter Leukodystrophies Caveat: nearly all have some gray matter involvement

Approach to DEEP WM disorders THALAMIC involvement?: Krabbe disease GM 1 GM 2 Tay-Sach disease Sandhoff disease

Krabbe disease Globoid cell leukodystrophy Lysosomal enzyme deficiency galacto-sylceramide beta-galactosidase Multiple mutations (chromosome 14) Presentation: 3-66 mos, hypertonia, irritable, fever, developmental delay, poor feeding, optic atrophy, opsomyoclonus & hyperacusis Dx: enzyme assay WBC/skin fibroblasts Death in first few years

Krabbe disease CT is characteristic: Hyperdense thalami, hypodense deep WM Images from Barkovich JE. Pediatric neuroimaging and van der Knapp MR of Myelination and Myelin disorder

Krabbe disease MR imaging: Nonspecific abnormal deep WM,, post limbs internal capsule, cerebellar WM & nuclei Thalami involved later Cranial nerve & cauda equina enhancement DWI early reduced diffusion, later increased MRS Most abnormal in infants. Elevated myo- inositol, creatine (CR), reduced NAA, +/- lactate; Juvenile - less severe MRS Adult - mild decrease in NAA & mild elevations of Cr & myo-inositol

Krabbe disease MRI: T2 bright deep WM cerebrum & cerebellum, thalamus Image from van der Knapp. MRI of myelin disorders

Krabbe disease Deep cerebral + cerebellar WM bright + spared subcortical WM Image courtesy of Mauricio Castillo, MD; UNC-Chapel Hill, NC

Krabbe disease

GM 1 gangliosidosis Rare lysosomal disorder Deficient activity of beta-galactosidase Chromosome 3 Three forms: Infantile, childhood, adult Infantile - most common Dysmorphic facial features, osseous dysplasias, hepatosplenomegaly, hypotonia, mental retardation early childhood (between 1-51 5 years), seizures, spasticity Death in a few years Childhood & adult forms more slowly progressive dysarthria, ataxia, myoclonus, normal facies, no hepatosplenomegaly

GM 2 gangliosidoses (Tay-Sachs & Sandhoff disease) Autosomal recessive sphingolipidosis Deficient hexosaminidase (2 parts) Isoenzyme A Tay Sachs disease Isoenzyme A & B Sandhoff disease Accumulation of GM2 ganglioside causes damage Clinical & imaging findings are similar for TSD & SD Presentation: Infant with hypotonia, psychomotor retardation Late first year - spasticity, weakness, dystonia, ataxia, then macrocephaly, abnormal movements, seizures After 3-103 years severe dementia & bed ridden

GM1 &GM 2 (Tay-Sachs & Sandhoff disease) gangliosidoses Imaging nearly identical for GM1 & GM2 CT early hyperdense thalami & hypodense WM,, late atrophy MRI T2 bright periventricular WM Tay-Sacchs: Posteromedial thalami T2 bright with reduced diffusion Sandoff: Basal ganglia isointense with WM Late stage atrophy cerebral and cerebellar hemispheres

GM 1 gangliosidosis Imaging appearance: Nonspecific WM & same as GM2 CT- Hypodense WM, late atrophy MRI T2 bright WM Image courtesy of Mauricio Castillo, MD; UNC-Chapel Hill, NC

GM 2 (Tay-Sachs & Sandhoff disease) gangliosidoses Diffuse atrophy Hypoattenuated WM Hyperdense atrophic thalami Image courtesy of M Castillo, MD; UNC-Chapel Hill, NC

Approach to DEEP white matter disorders No THALAMIC involvement: Is there brainstem (corticospinal tract) involvement?: X-linked adrenoleukodystrophy if pons and medulla Maple syrup urine disease if internal capsule, cerebral peduncle and dorsal pons

Adrenoleukodystrophy Rare peroxisomal disorder Chromosome 28 mutation (300+ mutations) Acyl-CoA synthetase, peroxisomal membrane transport protein (prevents long chain fatty acid breakdown) CNS, adrenal, testes 2 main forms: Classic X-linked X type is most common Adrenomyeloneuropathy presents in adults with predominant brainstem & spinal cord disease Rare neonatal form: AR, multiple enzyme deficiencies

Classic X-linked X ALD Boys 5 12 years old Learning difficulties (ADHD), imparied vision, gait or hearing, abnormal pigmentation skin (adrenal insufficiency), 10% seizures, adrenal crisis, coma Progression is rapid DDx: None with appropriate history Acyl CoA oxidase deficiency similar imaging, but history differs; 2 year old girls & boys delayed cognitive & motor development

X-linked ALD Imaging: Several characteristic patterns All have confluent symmetric deep WM with leading edge enhancement (inflammatory reaction) Posterior - 80% Anterior - 15% Unilateral hemispheric rarely Restricted to internal capsules Pons & medulla CT low density, MRI T1 and T2 prolongation relaxation times, increased diffusion MRS (may be abnormal prior to visible changes on MRI) decreased NAA, increased choline, glutamine/glutamate, decreased myo-inositol, +/- lactate

X-linked ALD Hx: 6-year6 year-old boy with SNHL Pons, medulla, posterior deep WM, leading edge enhancement T2 T1 T1+Gd

X-linked ALD Posterior (85%) distribution is most common Note 3 zones: Burned out Inflammatory Demyelinating

X-linked ALD Hx: 12 year old male with ataxia & ADHD Atypical frontal distribution (15%) MRS elevated glutamine/glutamate & lactate

Maple syrup urine disease (MSUD) Rare, heterogenous group of disorders with abnormal oxidative decarboxylation of branched chain fatty acids 5 clinical phenotypes correlate with degree of enzyme activity Classic MSUD present week of life 1 with vomiting, dystonia, seizures,, and die in a few weeks without treatment Other forms MSUD are less severe, present in later childhood with metabolic crisis

Maple syrup urine disease (MSUD) Imaging classic MSUD: Sonography echogenic periventricular WM, basal ganglia & thalami CT & MRI very characteristic profound cerebral edema Deep cerebellar WM, dorsal pons, cerebral peduncles, internal capsule, deep cerebral WM Restricted diffusion, drop in ADC by 20-30% MRS Mild elevation lactate, abnormal methyl proton peak at.9ppm on long echo (TE-270 ms) Imaging milder forms of MSUD: Lack of myelination superimposed on damage to areas listed in classical MSUD

Maple syrup urine disease Hx: 1 week old male vomiting & lethargy MRI: Restricted diffusion in the cerebellar WM, cerebral peduncles & dorsal pons T2 DWI ADC map

Maple syrup urine disease MRS: Lactate peak and branched chain amino acid peak Cho NAA NAA Cr Lactate Branched chain amino acids Image from Barkovich JE. Pediatric neuroimaging, 4 th ed.

Approach to DEEP white matter disorders Is there is brainstem (corticospinal tract) involvement?: 1. If NO,, consider: Metachromatic leukodystrophy Phenylketonuria Mucopolysaccharidoses Lowe disease Merosin deficient muscular dystrophy Radiation or chemotherapy damage

Metachromatic leukodystrophy Autosomal recessive Lysosomal disorder Arylsulfatase (AS) deficiency Sulfatides accumulate in brain, kidneys, liver, GB, peripheral nerves Dx: low AS in urine & peripheral blood 3 types: infant, juvenile, adult Infantile form is most common

Metachromatic leukodystrophy Infantile form: 12-18 months Early motor signs of peripheral neuropathy Later decrease intelligence, speech, coordination Death 6 month - 4 years after DX

Metachromatic leukodystrophy Imaging: Deep WM, symmetric, confluent Bright on T2; no enhancement Spares subcortical WM early Tigroid or leopard skin appearance due to perivascular space distension Other sites of involvement: Corpus callosum, internal capsule, corticospinal tracts, cerebellar WM

Metachromatic leukodystrophy Hx: 2-year2 year-old male with vomiting CT: Nonspecific low density of deep WM

Metachromatic leukodystrophy MRI: Deep WM, sparing subcortical WM & no leading edge of enhancement T2 FLAIR T1+Gd

Metachromatic leukodystrophy Advanced disease with tigroid appearance

Mucopolysaccharidosis Group of rare lysosomal enzyme deficiency disorders All involve metabolism of glycosaminoglycans Imaging: Delayed myelination, atrophy, hydrocephalus, cysts in periventricular WM, corpus callosum, basal ganglia Presentation, prognosis depend on specific disorder Hurler disease is most common

Mucopolysaccharidosis Hx: : 15-month month-old old male with Hurler syndrome MRI: T2 deep WM bright signal, distended perivascular spaces give

Mucopolysaccharidosis Cysts - perivascular spaces & corpus callosum

Mucopolysaccharidoses Inferior beak of spine Cysts - perivascular spaces & corpus callosum

Oculocerebrorenal syndrome (Lowe disease) X linked, autosomal recessive Phosphatidylinositol-4,5 4,5-biphosphate-5 phosphatase enzyme anomaly Involves brain, lens, kidneys Clinical findings: Congenital cataracts Glaucoma Mental retardation Renal tubular dysfunction (Fanconi syndrome) Metabolic bone disease

Oculocerebrorenal syndrome (Lowe disease) Imaging findings can be distinct: Bilateral, symmetrical deep WM low density on CT, with T1 and T2 shortening on MRI Cystic areas within abnormal WM Sparing subcortical U fibers MRS: Some cases elevation of myo- inositol peak due to gliosis or enzyme accumulation

Lowe disease CT: Nonspecific hypodense deep WM MRI: Deep WM bright on T2 early Image courtesy of Mauricio Castillo, MD; UNC-Chapel Hill, NC

Lowe disease Congenital cataracts WM cysts on T1 Orbit images courtesy of Mauricio Castillo, MD; UNC-Chapel Hill, NC Image from Barkovich JE. Pediatric Neuroimaging, 4 th ed.

Congenital muscular dystrophies Heterogeneous inherited group of disorder resulting from mutation of lamina-alpha alpha-2 2 gene on chromosome 6 Presentation: Hypotonia & weakness from birth, possibly arthrogyroposis, diminished deep tendon reflexes, normal intelligence Moderate elevation of serum creatine kinase

Congenital muscular dystrophies Major types (according to van der Knapp): Fukuyama congenital muscular dystrophy Associated cortical dysplasia Walker-Warburg Warburg syndrome Associated cortical dysplasia Muscle eye brain syndrome Merosin deficient congenital muscular dystrophy (classic form) MDC1C brain mostly normal MDC1D brain not normal

Fukuyama congenital muscular dystrophy Japanese Autosomal recessive Onset: infantile marked hypotonia, many ocular anomalies Imaging (findings are not specific): Diffuse cortical dysplasia Cerebellar cortical dysplasia & subcortical cysts WM abnormal signal Pons hypoplasia

Fukuyama congenital muscular dystrophy 5-month-old old Japanese female Cortical dysplasia, WM abnormal T1 T2 T2

Merosin deficient muscular dystrophy 3 types of congenital muscular dystrophy (according to Barkovich): 1. Children with normal brains 2. Children with CNS symptoms, abnormal myelin & normal cortex 3. Children with CNS symptoms, abnormal myelin & cortical involvement Imaging: Delayed or hypomyelinated deep cerebral WM, with mild pontine & cerebellar hypoplasia Dx: : muscle biopsy, MRI & clinical evaluation

Merosin deficient (classical) congenital muscular dystrophy Nonspecific deep WM bright on T2 T2 T2

Congenital muscular dystrophy without merosin deficiency CT: Nonspecific deep WM & generalized atrophy MRI: : Lack of myelination without WM destruction MRS: : Controversial T2 FLAIR FLAIR Image courtesy of Mauricio Castillo, MD; UNC-Chapel Hill, NC

Conclusion White matter disorders in children are complex, but an organized approach can allow formulation of a narrow differential diagnosis