Radiological imaging of pediatric leukoencephalopathy.

Dr/ ABD ALLAH NAZEER. MD.

The leukodystrophies are dysmyelinating disorders which typically, although not invariably, affect children. They include:lysosomal storage diseases

metachromatic leukodystrophygloboid cell leukodystrophy (Krabbe disease)Fabry diseaseNiemann-Pick diseaseMucopolysaccharidoses

peroxisomal disordersadrenoleukodystrophies

x-linkedneonatalpseudo-neonatal

Zellweger syndrome

mitochondrial dysfunctionLeigh diseaseMELASMERRFKearns-Sayre syndrome

amino acid metabolism disordersCanavan disease

unknown mechanism / othersAlexander diseasePelizaeus-Merzbacher diseaseCongenital muscular dystrophies (Fukuyama type)glutaric aciduria

type I glutaric aciduriatype II glutaric aciduria

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 disease. Canavan disease.

Pathophysiology of WM disorders: general concepts

Faulty gene

Structurally abnormal protein

Enzyme defect

Metabolic block

Pathophysiology of WM: general concepts Accumulation of abnormal products:

Interfere with normal neuronal functionInsufficient normal biochemical product �Essential to metabolism of neurons/myelinInjure other organs (lung, heart, liver, kidney) Secondary effect on CNS � Toxic to neurons/myelin.

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.

Normal terminal myelination zones18 -mo -male with normalNormal variant can persist into adulthood

How do we approach pediatric WM disorders:

Ask some questions! 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 Is it primarily SUBCORTICAL or DEEP

white matter?

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 disordersUS & CT- limited role 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 volumesin normal & abnormal regions.

First discuss SUBCORTICAL white matter disorders:

With macrocephaly: 1. If yes, consider: Alexander & Canavan disease 2. + subcortical cysts, think of: van der Knapp disease3. + ataxia & decreased myelination: think of: Vanishing white matter disease.

Canavan disease, also known as spongiform degeneration of white matter (not to be confused with Creutzfeldt-Jakob Disease), is a leukodystrophy clinically characterized by megalocephaly, severe mental deficits and blindness. PathologyIt is an autosomal recessive disorder due to deficiency of N-acetylaspartoacylase (key enzyme in myelin synthesis), with resultant accumulation of NAA in the brain, plasma, CSF and urine. Although its effects are wide spread, it has a predilection for subcortical U-fibers and Alzheimer type II astrocytes in the gray matter.Canavan disease is particularly common between Ashkenazi Jewish community. Clinical onset is in infancy with death before 5 years of age, and often before 18 months.Radiographic featuresCTThe edematous sponginess of the white matter causes a characteristically low radiographic attenuation on CT so that it stands out in relief from the relatively unaffected gray matter.MRIThere is often a large brain (megalencephaly)There is typically a diffuse bilateral involvement of subcortical U-fibers:T1: low signal in white matterT2: high signal in white matterMR spectroscopy: markedly elevated NAA and NAA: creatine ratio

this can be remembered using the mnemonic CaNAAvanThere is no enhancement of affected regions on either CT or MR.

CT Hypodense Subcortical WM Globus pallidi Thalami External capsule Claustra.� � �

Canavan disease in a 6-month-old boy with macrocephaly. (a) T2-weighted MR image shows extensive high-signal-intensity areas throughout the white matter, resulting in gyral expansion and cortical thinning. Striking demyelination of the subcortical U fibers is also noted. (b) T1-weighted MR image shows demyelinated white matter with low signal intensity.

Bilateral diffuse T2 hyper intensity involving cerebral cortical white matter, involvement of thalami and dentate nuclei.Sub cortical U fibers are typically involved.Mild diffuse cerebral cortical atrophy.MR Spectroscopy shows a sharp and long peak of NAA at 2.02 ppm suggestive of marked elevation of NAA.

Imaging diagnosis : Canvan's disease.

Alexander disease (AD), also known as fibrinoid leukodystrophy, is a rare fatal leukodystrophy, which usually becomes clinically evident in the infantile period, although neonatal, juvenile and even adult variants are recognized. As with many other diseases with variable age of presentation, the earlier it manifests the more fulminant the clinical course.There are three clinical forms:1-infantile/childhood onset2-juvenile onset3-adult onset (AOAD)Childhood onset ADChildhood onset Alexander disease is sporadic and typically presents with macrocephaly, rapid neurological deterioration, seizures and spasticity, and retarded psychomotor development.In some cases the gene for glial fibrillary acidic protein (GFAP): mapped to chromosome 17q21: has been implicated. Histologically the disease is characterized by the accumulation of large numbers of Rosenthal fibres and eosinophilic granular bodies (large accumulations aglomerations of astrocytic processes) in the degenerated (demyelinated) white matter which is a product of GFAP. This is on its own a non-specific finding, as they are also seen in slow growing or benign astrocytomas (e.g. pilocytic astrocytomas).Clinical presentationIt generally presents in infants and adolescents. Macrocephaly is typically present and other clinical features include progressive quadreparesis and intellectual failure.

PathologyMost of the cases are sporadic, however familial disease has also been reported. A heterozygous mutation in the coding region of GFAP, an astrocyte specific intermediate filament protein, are associated with most cases of infantile sporadic onset.Histologic examination reveals Rosenthal fibres in the brain, ependyma and pia. Intracellular deposition of these fibres may cause abnormal functioning of the oligodendrocytes.Radiographic featuresThe disease begins in frontal region and extends posteriorly. Subcortical U-fibers are somewhat initially spared but affected relatively early in the course of disease. End stage disease is characterized by contrast enhancing cystic leukomalacia.MRIT2: increased signal in

bifrontal white matter which tends to be symmetrical caudate head > globus pallidus > thalamus > brain stemperiventricular rim

T1 C+ (Gd): enhancement may seen in the same areasObstructive hydrocephalus secondary to periaqueductal involvement and swelling of basal ganglia may be seen.

Alexander disease

Alexander disease.

 Type II (late-onset) 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 Knaap disease with diffuses white matter involvement. Sub cortical white matter involved early shows cystic areas iso intense to CSF representing white matter paucity in fronto parietal and temporal regions. Basal ganglia and internal capsules spared. Cerebral cortical atrophy. Relatively spared cerebellum.

Van Der Knaap disease with diffuses cerebral white matter involvement. Early involvement of sub cortical white matter. Sub cortical white matter cysts iso intense to CSF representing white matter paucity in temporal regions. Basal ganglia and internal capsules spared. Cerebral cortical atrophy.

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

Infant with leukoencephalopathy with vanishing white matter exhibiting developmental regression. Widespread T2 hyperintensities were present in the white matter and FLAIR imaging revealed cystic white matter

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

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

Galactosemia with delayed subcortical White matter myelination at the T2WI.

Proton MR Spectroscopy and imaging of a galactosemic patient before and after dietary treatment.

FDG-PET findings in patients with Galactosemia.

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 Syndrome

Deep White Matter Leukodystrophies. 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: Presentation: 3 -6 months, hypertonia, irritable, fever, developmental delay, poor feeding, optic atrophy, opsomyoclonus & feeding, optic atrophy, opsomyoclonus & hyperacusis. Dx: enzyme assay WBC/skin fibroblasts. Death in first few years.

Krabbe Disease with hyper density at the thalamic and capsular regions.

Krabbe disease MR imaging: Nonspecific abnormal deep WM deep, 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.

Young boy with Krabbe disease who exhibited cognitive and motor regression. CT revealed a hyperintense area (arrow) in the posterior limb of the internal capsule. On T1- and T2-weighted imaging, abnormal signals were evident in the posterior limb of the internal capsule (arrow), the white matter surrounding the posterior horn of the lateral ventricle, and the splenium of the corpus callosum. The U-fibers were preserved.

Krabbe disease.

Krabbe Disease with abnormal signal at the thalami and capsular regions.

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 retardation early childhood (between 1 -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, seizuresAfter 3 After 3 -10 years severe dementia & bed ridden.

GM1 &GM 2 (Tay -Sachs & Sachs & Sandhoff disease) gangliosidoses

Imaging 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.

8-year-old boy with GM1 gangliosidosis. A, Spin-echo T1-weighted image (TR/TE/NEX, 655 ms/15 ms/2) shows abnormal hyperintensity of the globus pallidum bilaterally (arrows). B, B0 diffusion-weighted image (TR/TE/NEX, 3072 ms/70 ms/1) confirms profound hypointensity of both pallida (arrows), consistent with paramagnetic effects. C, Axial fast spin-echo T2-weighted image (TR/TE/NEX, 4161 ms/100 ms/2) shows pallidal hypointensity (arrows) associated with hyperintensity of the posterior putamen bilaterally (arrowheads).

Serial MRIs in a patient with GM1 gangliosidosis at 13 (A and B) and 25 years of age (C and D). (A) Axial T2-weighted images show bilateral symmetric hypointense lesions in the globus pallidi (white arrows) with hyperintensities observed in the putamen (black arrow), which is described in type III GM1 gangliosidosis. Furthermore, asymmetric lesions are observed in the subcortical WM with cortical atrophy. (B) Corresponding axial gradient echo images (G.R.E) reveal bilaterally symmetrical iron deposition in the globus pallidi (black arrows). (C) Axial T2-weighted images again show hypointense pallida (white arrows) with mild progression, compared to previous scan, putaminal hyperintensities, atrophy of the caudate nuclei, and diffuse cortical atrophy with ventriculomegaly. (D) Evidence of exaggerated SWI hypointensities point to progression of iron deposition in bilateral globus pallidi with similar deposits in the SN, red nucleus, and subthalamic nuclei. The arrow shows the proposed “wish bone” sign, which takes its name from the pattern of iron accumulation seen here, wherein the medial (GPi) and lateral parts (GPe) of globus pallidi make the forked ends and the extension downward the pallidi to the anterior SN and red nucleus form the stem of the wish bone.

Unusual Presentation of GM2 Gangliosidosis Mimicking a Brain Stem Tumor in a 3-Year-Old Girl

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 type is most commonAdrenomyeloneuropathy – presents in adults with predominant brainstem & spinal cord disease.Rare neonatal form: AR, multiple enzyme deficiencies Boys 5 – 12 years old Learning difficulties (ADHD), impaired vision, gait or hearing, abnormal pigmentation skin (adrenal insufficiency), 10% seizures, adrenal crisis, coma Progression is rapidDDx: None with appropriate historyAcyl CoA oxidase deficiency, similar imaging, but history differs; 2 year old girls & boys delayed cognitive & motor development. 

X-linked ALDImaging: Several characteristic patterns All have confluent symmetric deep WM with leading edge enhancement (inflammatory reaction) Posterior- 80% Anterior- 15% Unilateral hemispheric – rarelyRestricted to internal capsules Pons & medullaCT – 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.

Adrenoleukodystrophy with bilateral symmetrical peritrigonal white matter involvement.

X-linked adrenoleukodystrophy.

Nine-year-old male patient with childhood cerebral adrenoleukodystrophy (ALD). Top: FLAIR, post-contrast axial T1-weighted (T1-POST), and normalized cerebral blood volume (nCBV) map. Bottom: Co-registered images with regions of interest (ROIs). Five different zones of involvement are distinguished in the white matter (Zones A–E; see main text).

Decreased brain magnetic resonance perfusion in cerebral adrenoleukodystrophy precedes lesion progression. Top: T2, T1 post-contrast weighted and T1-post contrast images co-registered with normalized cerebral blood volume images of a 9-year-old child with progressive cerebral adrenoleukodystrophy shows decreased magnetic resonance perfusion beyond the contrast enhancing region (empty arrows; Zone D). Follow-up T1-post contrast weighted imaging after 12 months shows lesion extension and advancement of contrast material (solid arrows) into prior hypoperfused region. Bottom: T2, T1 post-contrast weighted and T1-post contrast images co-registered with normalized cerebral blood volume images of a 12-year-old child with cerebral adrenoleukodystrophy (CCALD) shows normal normalized cerebral blood volume beyond the contrast enhancing region (empty arrows; Zone D) 9 months after the engraftment of hematopoietic stem cell transplantation (HSCT). No lesion progression was observed up to 14 months post-transplant. Contrast material (solid arrows) has not advanced.

Maple syrup urine disease (MSUD)Rare, heterogenous group of disorders with abnormal oxidative decarboxylation of branched chain fatty acids branched chain fatty acids5 clinical phenotypes – correlate with correlate with degree of enzyme activityClassic 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, basal ganglia & thalamiCT & MRI– very characteristic profound cerebral edemaDeep 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

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

Metachromatic leukodystrophy (MLD) is the most common hereditary (autosomal recessive) leukodystrophy and is one of the lysosomal storage disorders. It has characteristic imaging features including peri-atrial and to a lesser extent frontal horns leukodystrophy as well as periventricular perivenular sparing results in "tigroid pattern" on fluid sensitive MRI sequences. EpidemiologyIt has an estimated prevalence of ~1:100,000 and typically manifests between 12 to 18 months of age. The disease can sometimes be according to the time of onset:late infantile: most common ~65% (range 50-80%)juvenile (onset between 3-10 years)adult (after age 16)Clinical presentationlate infantile form: gait abnormality, muscle rigidity, loss of vision, impaired swallowing, convulsions, dementiajuvenile form: imparied school performance; similar features as in late infantile form but slower progressionadult form: psychiatric disorders and dementia; often protracted course over 10 years

Radiographic featuresMRICharacterized by bilateral symmetrical confluent areas of periventricular deep white matter signal change, in particular around the atria and frontal horns with sparing of subcortical U fibers leading to a "butterfly pattern". Progression can lead to cortical and subcortical atrophy.Signal characteristicsT1: affected areas are low signalT1 C+ (Gd)

no enhancement is characteristichowever some cases may show a linear punctate enhancement pattern within lesionsmultiple cranial nerve enhancement has been reported

T2: affected areas are high signal and may show a "tigroid pattern" on axial plane or "leopard pattern" on sagittal plane: sparing along the venulesMR spectroscopy: (of affected white matter)

reduced N-acetyl-aspartateincreased myo-inositolincreased lactate

One-year-old boy with metachromatic leukodystrophy exhibiting developmental retardation and spastic palsy. T2-weighted imaging revealed bilaterally symmetrical hyperintensities in the white matter. The subcortical white matter was preserved. Bands of normal intensity (tiger stripes) were present within the white matter exhibiting abnormal signals.

METACHROMATIC LEUKODYSTROPHY.

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

Oculocerebrorenal syndrome (Lowe disease).X linked, autosomal recessive Phosphatidylinositol -4,5 –biphosphate-5 phosphatase enzyme anomaly Involves brain, lens, kidneysClinical findings: Congenital cataracts Glaucoma Mental retardationRenal 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 MRICystic areas within abnormal WM Sparing subcortical U fibers. MRS: Some cases elevation of myo-inositol peak due to gliosis or enzyme accumulation.

Congenital muscular dystrophiesHeterogeneous inherited group of disorder resulting from mutation of lamina -alpha -2 gene on chromosome 6 Presentation: Hypotonia & weakness from birth, possibly arthrogyroposis, diminished deep tendon reflexes, diminished deep tendon reflexes, normal intelligenceModerate elevation of serum creatine kinase Major types (according to van der Knapp): Fukuyama congenital muscular dystrophy Associated cortical dysplasia Walker -Warburg syndrome Associated cortical dysplasia �Muscle eye brain syndrome Merosin deficient congenital muscular (classic form) MDC1C – brain mostly normal MDC1D – brain not normal

Fukuyama congenital muscular dystrophyJapaneseAutosomal recessive Onset: infantile marked hypotonia, many ocular anomaliesImaging (findings are not specific): �Diffuse cortical dysplasia Cerebellar cortical dysplasia & subcortical cysts. �WM abnormal signal Pons hypoplasia�

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 cortex3.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

Thank You.