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Presentation1, radiological imaging of pediatric leukodystrophy.
This document discusses various pediatric leukodystrophies and white matter disorders that can be evaluated on radiological imaging. It provides descriptions of diseases such as Canavan disease, Alexander disease, Van der Knapp disease, Krabbe disease, GM1 and GM2 gangliosidoses, galactosemia, and Kearns-Sayre syndrome. It discusses the characteristic imaging findings and patterns of involvement for each disease to help with diagnosis. Approaches for evaluating pediatric white matter disorders based on features like macrocephaly, subcortical or deep white matter involvement, and thalamic abnormalities are also outlined.
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Presentation1, radiological imaging of pediatric leukodystrophy.
- 1. Radiological imaging ofpediatric leukoencephalopathy. Dr/ ABD ALLAH NAZEER. MD.
- 2. The leukodystrophies aredysmyelinating disorders which typically, although not invariably, affect children. They include: lysosomal storage diseases metachromatic leukodystrophy globoid cell leukodystrophy (Krabbe disease) Fabry disease Niemann-Pick disease Mucopolysaccharidoses peroxisomal disorders adrenoleukodystrophies x-linked neonatal pseudo-neonatal Zellweger syndrome
- 3. mitochondrial dysfunction Leigh disease MELAS MERRF Kearns-Sayresyndrome amino acid metabolism disorders Canavan disease unknown mechanism / others Alexander disease Pelizaeus-Merzbacher disease Congenital muscular dystrophies (Fukuyama type) glutaric aciduria type I glutaric aciduria type II glutaric aciduria
- 4. Lysosomal disorders: Metachromatic leukodystrophy. Krabbe’s disease. Mucopolysaccharidoses. Gangliosidoses. Peroxisomaldisorders: Zellweger syndrome. Neonatal ALD. XR adrenoleukodystrophy. Mitochondrial dysfunction: Leigh disease. MELAS. Kearns-Sayre syndrome. Unknown metabolic defect: Pelizaeus –Merzbacher. Alexander disease. Canavan disease.
- 5. Pathophysiology of WM disorders:general concepts Faulty gene Structurally abnormal protein Enzyme defect Metabolic block
- 6. Pathophysiology of WM:general concepts Accumulation of abnormal products: Interfere with normal neuronal function Insufficient normal biochemical product ƒEssential to metabolism of neurons/myelin Injure other organs (lung, heart, liver, kidney) Secondary effect on CNS ƒToxic to neurons/myelin.
- 7. Normal developmental anatomy andpitfalls 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.
- 11. Normal terminal myelination zones 18-mo -male with normal Normal variant can persist into adulthood
- 12. How do weapproach pediatric WM disorders: Ask some questions! Are there any useful symptoms? Head size: Macrocephaly WM symptoms: Spasticity, hyperreflexia, ataxia ƒOther 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?
- 13. Approach to pediatricWM 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?
- 14. Imaging technique WMdisorders US & CT- limited role limited role US – screen macrocephaly in developmentally normal children. CT – abnormal areas usually hypodense. MRI – Imaging modality of choice ƒRoutine brain + Gadolinium MRS – Just do it! It may help you. TE 30msec & 270msec. Multivoxel nice to compare sample volumes in normal & abnormal regions.
- 15. First discuss SUBCORTICAL whitematter 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.
- 17. Canavan disease, alsoknown 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. Pathology It 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 features CT The 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. MRI There is often a large brain (megalencephaly) There is typically a diffuse bilateral involvement of subcortical U-fibers: T1: low signal in white matter T2: high signal in white matter MR spectroscopy: markedly elevated NAA and NAA: creatine ratio this can be remembered using the mnemonic CaNAAvan There is no enhancement of affected regions on either CT or MR.
- 18. CT Hypodense SubcorticalWM ƒGlobus pallidi ƒThalami External capsule ƒClaustra.
- 19. Canavan disease ina 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.
- 20. Bilateral diffuse T2hyper 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.
- 24. 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 onset 2-juvenile onset 3-adult onset (AOAD) Childhood onset AD Childhood 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 presentation It generally presents in infants and adolescents. Macrocephaly is typically present and other clinical features include progressive quadreparesis and intellectual failure.
- 25. Pathology Most of thecases 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 features The 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. MRI T2: increased signal in bifrontal white matter which tends to be symmetrical caudate head > globus pallidus > thalamus > brain stem periventricular rim T1 C+ (Gd): enhancement may seen in the same areas Obstructive hydrocephalus secondary to periaqueductal involvement and swelling of basal ganglia may be seen.
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- 30. Type II (late-onset)Alexander disease.
- 31. Van der Knappdz 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.
- 33. Van Der Knaapdisease 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.
- 34. Van Der Knaapdisease 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.
- 35. Vanishing white matterdisease 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 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
- 37. Infant with leukoencephalopathywith vanishing white matter exhibiting developmental regression. Widespread T2 hyperintensities were present in the white matter and FLAIR imaging revealed cystic white matter
- 38. Approach to SUBCORTICALwhite 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
- 39. Galactosemia with delayedsubcortical White matter myelination at the T2WI.
- 40. Proton MR Spectroscopyand imaging of a galactosemic patient before and after dietary treatment.
- 41. FDG-PET findings inpatients with Galactosemia.
- 42. Kearns Sayre Mitochondrial disorder Dxrequires 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
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- 45. Deep White MatterLeukodystrophies. THALAMIC involvement?: Krabbe disease. GM 1. GM 2. ƒ Tay-Sach disease. ƒSandhoff disease.
- 46. Krabbe disease Globoid cellleukodystrophy Lysosomal enzyme deficiency ƒgalacto 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.
- 48. Krabbe Disease withhyper density at the thalamic and capsular regions.
- 49. Krabbe disease MR imaging: Nonspecificabnormal 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.
- 50. Young boy withKrabbe 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.
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- 55. Krabbe Disease withabnormal signal at the thalami and capsular regions.
- 57. GM 1 gangliosidosis RareLysosomal 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.
- 58. 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 After 3 -10 years severe dementia & bed ridden.
- 59. 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.
- 61. 8-year-old boy withGM1 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).
- 62. Serial MRIs ina 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.
- 64. Unusual Presentation ofGM2 Gangliosidosis Mimicking a Brain Stem Tumor in a 3-Year-Old Girl
- 65. Approach to DEEPwhite 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.
- 66. Adrenoleukodystrophy Rare peroxisomal disorder Chromosome28 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 common Adrenomyeloneuropathy – 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 rapid DDx: None with appropriate history Acyl CoA oxidase deficiency, similar imaging, but history differs; 2 year old girls & boys delayed cognitive & motor development.
- 67. X-linked ALD Imaging: Severalcharacteristic 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.
- 70. Adrenoleukodystrophy with bilateralsymmetrical peritrigonal white matter involvement.
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- 72. Nine-year-old male patientwith 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).
- 73. Decreased brain magneticresonance 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.
- 74. Maple syrup urinedisease (MSUD) Rare, heterogenous group of disorders with abnormal oxidative decarboxylation of branched chain fatty acids branched chain fatty acids 5 clinical phenotypes – correlate with 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.
- 75. Maple syrup urinedisease (MSUD) Imaging classic MSUD: Sonography – echogenic periventricular WM, basal, 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
- 78. Approach to DEEPwhite matter disorders Is there is brainstem (corticospinal tract) brainstem (corticospinal tract) involvement?: 1. If NO, consider: Metachromatic leukodystrophy Phenylketonuria Mucopolysaccharidoses Lowe disease Merosin deficient muscular dystrophy Radiation or chemotherapy damage
- 79. 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. Epidemiology It 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 presentation late infantile form: gait abnormality, muscle rigidity, loss of vision, impaired swallowing, convulsions, dementia juvenile form: imparied school performance; similar features as in late infantile form but slower progression adult form: psychiatric disorders and dementia; often protracted course over 10 years
- 80. Radiographic features MRI Characterized bybilateral 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 characteristics T1: affected areas are low signal T1 C+ (Gd) no enhancement is characteristic however some cases may show a linear punctate enhancement pattern within lesions multiple 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 venules MR spectroscopy: (of affected white matter) reduced N-acetyl-aspartate increased myo-inositol increased lactate
- 84. One-year-old boy withmetachromatic 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.
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- 86. Mucopolysaccharidosis Group of rarelysosomal 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
- 90. Oculocerebrorenal syndrome (Lowe disease). Xlinked, autosomal recessive Phosphatidylinositol -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.
- 91. Oculocerebrorenal syndrome (Lowe disease). Imagingfindings 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.
- 94. Congenital muscular dystrophies Heterogeneousinherited 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 intelligence Moderate elevation of serum creatine kinase Major types (according to van der Knapp): Fukuyama congenital muscular dystrophy Associated cortical dysplasia Walker -Warburg syndrome ƒAssociated cortical dysplasia Muscle eye brain syndrome Merosin deficient congenital muscular (classic form) MDC1C – brain mostly normal MDC1D – brain not normal
- 95. Fukuyama congenital musculardystrophy Japanese Autosomal recessive Onset: infantile marked hypotonia, many ocular anomalies Imaging (findings are not specific): ƒ Diffuse cortical dysplasia Cerebellar cortical dysplasia & subcortical cysts. ƒ WM abnormal signal ƒPons hypoplasia
- 97. Merosin deficient musculardystrophy 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
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