Metabolic Disorders primarily affecting white matter. Disclosure Nothing to disclose Images were obtained form the following sources

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1 Metabolic Disorders primarily affecting white matter Bhagwan Moorjani American Society of Neuroimaging 37 th Annual Meeting Disclosure Nothing to disclose Images were obtained form the following sources Bhagwan Moorjani personal collection Barkovich pediatric neuroimaging books and online Amirsys online library Radiopeedia.org Mary Rutherford Imaging AJNR Radiologic Evaluation Does not take into account the clinical presentation Age is important to know Major symptom is also important to know Pattern recognition White matter vs gray matter vs mixed Need to differentiate between delayed myelination (improving) or hypomyelination (permanent) Confluent or multifocal Progressive or static Atrophy or edema Symmetric or asymmetric 1

2 Clinical Evaluation Is it developmental delay or regression Global Motor Speech and language Is there a 2 nd predominant symptom Epilepsy Ataxia Behavioral changes/cognitive/dementia Head Circumference Macrocephalic Canavan Alexander Tay Sachs (GM2 gangliosidosis) Vanishing White Matter Van der Knaap Disease L 2 hydroxyglutaric aciduria NF1 Hypomelanosis of Ito Microcephalic/Normal ALD MLD Cockayne Disease Pelizaeus Merzbacher disease Zellweger Disease Krabbe White Matter Disorders Knowledge of normal myelination pattern is essential General rules: Caudal to cranial Posterior to anterior MRI provides the best imaging modality T1 matures at months T2 matures at months 2

3 1 month 9 months 36 months From Alberico Definitions Myelination delay progression of myelination pattern after 6 months Static/permanent myelination pattern Pattern is unchanged on 2 MRIs after 6 12 months apart in children over 1 year of age MR Imaging Definition Leukodystrophy T2 W hyperintensity T1 W variable Hypomyelinating leukodystrophy T2 W hyperintensity T1 W isoor hyperintense Demyelinating Leukodystrophy/other myelin T2 W hyperintensity T1 W hypointense 3

4 White Matter Disorders What structures are involved Subcortical U fibers Diffuse subcortical involvement Thalami involvement Brainstem particularly corticospinal tract Lack of myelination Nonspecific white matter pattern Diffuse Periventricular Subcortical Cerebellar Brainstem Cortex White Matter Disorder MRI predominance Subcortical white matter (U fibers) Alexander disease Frontal, small NAA peak, large head Van der Knaap disease Subcortical cyst Canavan Disease Galactosemia Salla Disease Free sialic acid in urine 4 hydroxybutyric aciduria (6p22.3) Cerebellar atrophy succinic semialdehyde dehydrogenase deficiency 4

5 Leukodystrophies Abnormal signal in white matter Symmetric usually Periventricular, deep or subcortical in location Failure to achieve myelination milestones MRS abnormalities reflect neuronal loss and increased cellular turnover Some have contrast enhancement ALD: zone of active inflammation Alexander: ventricular lining, periventricular rim, frontal WM, optic chiasm, fornix, BG, thalamus, dentate nucleus Leukodystrophies Differential Diagnosis Radiation and Chemotherapy injury Viral encephalitis ADEM MS In neonates: HIE Periventricular pattern Alexander Disease Clinical S/S: macrocephaly, seizures Mutation: GFAP, Chromosome 17q21 Imaging Extensive WM changes with frontal predominance Abnormal signal in BG and thalami Enhancement: ventricular lining, periventricular rim, frontal WM, optic chiasm, fornix, BG, thalamus, dentate nucleus Give contrast to all unknown cases of hydrocephalus and abnormal WM 5

6 T1W-C+: Enhancement of the periventricular rim, caudate heads and putamen bilaterally Rabbit ear characteristic of Alexander Nodular appearance of frontal PV rim Alexander Disease Alexander Disease FLAIR less severe disease High signal in the anterior and posterior rims and WM with frontal predominance T1W-C+ - enhancement of bifrontal PV WM, PV rim and caudate head. Less intense patchy enhancement in putamen and thalamus Alexander Disease 6

7 Alexander Disease T2W advanced disease Symmetric, hyperintense cerebral WM and deep gray structures Swollen caudate head and fornices Hyperintensity in external and extreme capsule claustra stands out Alexander Disease FLAIR large foci of cystic destruction in frontal WM and caudate head These are late findings Differential Diagnosis of Frontal predominance WMD Frontal variant X linked ALD Aicardi Goutieres syndrome Brain, skin, immune system, hepatomegaly Laminin alpha 2 deficiency Metachromatic Leukodystrophy 7

8 Aicardi Goutieres Uggetti C et al. AJNR Am J Neuroradiol 2009;30: by American Society of Neuroradiology Coronal fast spin-echo T2-weighted MR image (1.5T, TR = 5022 ms, TE = 100 ms) of case 10 shows a diffuse signal-intensity abnormality of the cerebral lobar white matter. Aicardi Goutieres Uggetti C et al. AJNR Am J Neuroradiol 2009;30: by American Society of Neuroradiology Laminin alpha 2 deficiency Exp Ther Med November; 6(5):

9 VWMD Vanishing White Matter Disease Childhood ataxia with diffuse CNS hypomyelination, childhood ataxia with central hypomyelination (CASH) WM ultimately becomes isointense to CSF, begins in central cerebral WM Vanishing White Matter Disease CSF T2 bright FLAIR dark C,D normal VU University Center, Amsterdam Vanishing white matter disease FLAIR symmetric, bilateral Isointense to CSF central WM 9

10 Salla Disease Sonninen P et al. AJNR Am J Neuroradiol 1999;20: by American Society of Neuroradiology Canavan Disease Clinical S/S: Macrocephaly, hypotonia Imaging: Diffuse T2 hyperintensity preferentially involves subcortical U fibers Spares internal capsule and corpus callosum Involves thalamus, globus pallidus + dentate Spares caudate and putamen MRS shows marked elevation of NAA peak Canavan Disease T2W diffuse cerebral WM hyperintensity. Involvement of subcortical U fibers 10

11 T2W 6 month old Diffuse increase signal cerebral WM including thalamus and right globus pallidus Sparing of internal capsule, CC and putamen Canavan Disease T2W: infant Marked hyperintense signal and swelling throughout WM Striatum as island of tissue Canavan Disease Elevated naa Canavan mrs 11

12 Canavan Disease Differential Diagnosis Maple Syrup Urine Disease Elevated branch chain AA Pelizaeus Merzbacher Disease Spares GP and thalami Alexander Disease Enhances Predominantly frontal WM Autosomal recessive Mennonite populations Cerumen and urine smell like burnt syrup Brain edema Accumulation of branch chain amino acids leucine, valine, and isoleucine Treatment is dialysis in acute phase and low protein diet for life Detected on most states newborn screening programs MSUD MSUD 2 Infant Axial T2 W Edema in pons and cerebellum Pearl: significant edema > metabolic brain disease 12

13 MSUD Axial DWI Diffusion restriction in posterior limb of internal capsule and thalamus Suggest acute process Deep White Matter Spares U fibers Short T1 in thalami Krabbe GM1 and GM2 gangliosidosis Normal thalami Brainstem involvement MSUD Dentatorubral and pallidoluysian atrophy (DRPA) Krabbe Disease aka Globoid cell leukodystrophy Clinical S/S: irritability Juvenile form: protracted course with slow rate of progression CT: hyperdensity in thalamus, BG MRI Imaging: Faint hyperintensities in thalamus and BG (T1W) Ring like appearance around dentate nucleus (T2W) PV WM hyperintensities (T2W) Initially spares U fibers Enlarged optic nerves and cranial nerves (T1W) MRS: increased choline,myoinositol, decreased NAA, lactate accumulation 13

14 Krabbe Disease CT Scan Faint hyperdensity in the lateral thalami, from presumed Ca++ deposits CT more sensitive than MR in early course Krabbe Disease FLAIR focal symmetric hyperintensity capsular portion of corticospinal tracts. Krabbe Disease FLAIR juvenile onset symmetric hyperintensity in parietal WM sparing subcortical U fibers 14

15 Krabbe Disease T2W advanced disease atrophy, hypointensity in BG and Thalami Parieto Occipital Predominance Krabbe Disease X linked ALD Early onset peroxisomal disorders Neonatal hypoglycemia ALD 15

16 ALD Always abnormal in neurologically symptomatic males Often provides first lead Predominately posterior white matter 80% Splenium of corpus callosum usually involved Deep White Matter Spares U fibers No specific brainstem involvement MLD PKU MSUD may involve cerebellum and cerebral peduncle Lowe s disease cysts Sjorgen Larson syndrome Hyperhomocysteinemia MTHFR Cobalamin metabolism Merosin deficient CMD Metachromatic Leukodystrophy 2 nd year of life Decreased arylsulfatase A Central and peripheral demyelination Imaging Confluent butterfly shaped increased T2 signal deep cerebral WM Spares U fibers in early disease Involves U fibers in late disease Sparing of perivenular myelin producing the tigroid appearance No enhancement of WM May have enhancement of cranial nerves and cauda equina 16

17 MLD FLAIR bilateral, symmetric periventricular and deep WM changes sparing U-fibers MLD Axial T2 W Bilateral symmetrical hyperintensities Deep WM frontal and parietal Sparing subcortical U fibers (open arrow) MLD T2W tigroid appearance of WM Due to preservation of myelin in perivenular regions 17

18 MLD 4 month old Single voxel MRS PVWM Increase choline peak Normal peak is NAA Merosin CMD Axial T2W Diffuse hyperintensities Corpus callosum spared Some sparing of the subcortical u fibers Diffuse Cerebral Involvement Megalencephalic leukodystrophy with subcortical cyst (MLC) Mitochondrial disorders Inborn error of metabolism BCAA Homocystinuria Glutaric acidemia End stage of white matter disease 18

19 Megalencephalic leukodystrophy with subcortical cyst (MLC) Axial T2 W Symmetric hyperintensities WM Swelling, Enlarged gyri Megalencephalic leukodystrophy with subcortical cyst (MLC) Axial FLAIR Cysts in frontal and temporal region Hyperintensity in noncystic WM Megalencephalic leukodystrophy with subcortical cyst (MLC) Sagittal T1 W Cyst in frontoparietal region Cyst in anterior temporal region 19

20 Prominent Perivascular Spaces Mucopolysaccharidosis Chromosomal abnormalities Lowe syndrome Disorder of branch chain amino acid (MSUD) Hunter Syndrome Axial T2 FSE Large virchow robin spaces Filled with glycosaminoglycans MPS, Type 1 T1W Toddler Significant dilatation of PVS Peritrigonal and callosal 20

21 Periventricular predominance MLD Krabbe IEM (PKU, glutaric aciduria 2, mannosidosis) PVL HIV encephalopathy Krabbe Axial T2 W Increased signal in PV WM Increased signal CST Cerebellar predominance MSUD Fragile X premutation Alexander disease Peroxisomal disorders Methylmalonic acidemia 21

22 MSUD Increased signal in the cerebellum, brainstem and temporal lobe Methylmalonic acidemia 1.5 month old boy Cerebellar vermis Hypomyelination Disorder Areas to assess: internal capsule, pyramidal tracts, peripheral frontal lobe WM T1 signal reflects presence of myelin Children < 10 months Myelinated WM hyperintense T2 reflects displacement of water Children > 10 months Mature WM hypointense T2 hypointensity of myelin normally lags behind T1 hyperintensity by 4 8 months Myelination on T2WI should be complete by 3 years, usually by 2 years of age 22

23 Hypomyelination Disorders Primary hypomyelination syndromes 2 to chromosome deletions and mutations Pelizaeus Merzbacher disease (PMD) Spastic paraplegia type 2 (SPG2) Hypomyelination with atrophy of basal ganglia and cerebellum (H ABC) 18q syndrome Jacobsen syndrome (11q ) Hypomyelination with congenital cataracts (DRCTNNB1A) Hypomyelination + trichothiodystrophy Dystroglycanopathies D2 hydroxyglutaric aciduria hypomyelination Axial T2W 2 year old Diffuse lack of T2 hypointense myelin Cortex, bilaterally Internal capsule Corpus callosum Pearl: almost all WM should be myelinated (T2 hypointense) Myelination Birth dorsal brainstem ventrolateral thalamus lentiform nuclei central corticospinal tracts posterior portion of posterior of internal capsule 23

24 Pelizaeus Merzbacher Disease Clinical S/S: microcephaly, hypertonia, stridor Deficiency of proteolipid protein (PLP) Hypomyelination disorder Imaging Variable Nonspecific and symmetrical abnormality of WM Lack of myelin Pelizaeus Merzbacher Disease T2W: 13 year old absence of normal hypointense WM signal This is normal for a 6-8 month old child 18q deletion 3.5 year old Axial T2W Minimal hypointense signal in internal capsule and splenium 24

25 Trichothiodystrophy 12 year old Axial T2W Absence of myelination Jacobseb 11q deletion Axial CT brain 12 month old Accentuation of graywhite differentiation Caused by abnormal hypodense WM Jacobsen 11 q deletion 12 month old Axial T2W Extensive hyperintensities in cerebral WM Evidence of myelination in genu and splenium 25

26 Hypomyelination with atrophy of basal ganglia and cerebellum (H ABC) 2 year old Sagittal T2 W Cerebellar atrophy Thin corpus callosum Decrease myelination in cortex and cerebellum Hypomyelination with atrophy of basal ganglia and cerebellum (H ABC) Coronal T2 W 2 year old Atrophy of the caudate heads > enlarged frontal horn Absence of normal myelin in peripheral WM Non specific WM pattern Nonketotic hyperglycinemia Urea cycle disorders Viral Infections (HSV, CMV) Demyelinating disease (MS, ADEM) Collagen Vascular disease 26

27 SSPE Nonspecific leukoencephalopathy MRS: decreased NAA/Cr Increased Cho/Cr; Ins/Cr and Lac Lip Proton Density: Inhomogeneous hyperintensity bilaterally, asymmetric involving WM And cortex Biopsy - SSPE SSPE Non ketotic hyperglycenemia Axial ADC map Restrictive diffusion posterior limb of internal capsule Pearl in neonates restrictive diffusion will only be seen in structures that are myelinated at birth 27

28 Non ketotic hyperglycenemia Hypoplatic corpus callosum 2 month old infant Urea cycle Disorder Ornithine transcarbamylase Neonate CT scan Diffuse low attention Loss of gray white differentiation Cytotoxic edema form hyperammonemia Urea cycle 2 day old Axial T2 W Increase signal between lateral nuclei of GP and putamen 28

29 Urea Cycle OTCD Coronal FLAIR Chronic stage Cortical and subcortical posterior insular and temporoparietal increased signal Most marked at depths of sulci Key Points IEM > abnormal growth/development of myelin sheath > progressive degeneration of white matter Symmetrical subcortical or deep WM +GM Initial PVWM involvement: MLD, Globoid cell, ALD Initial SC WM involvement: MLC, VWMD Diffuse WM and atrophy seen in many conditions MRS Decreased NAA majority of conditions Increased NAA Canavan Key Points No myelination with atrophy Neuronal disease with secondary hypomyelination Dentate involvement Mitochondrial disease Abnormal Pons PMD like disorders 29

30 Summary Neuroimaging has a role in determining the etiology of pediatric metabolic conditions Knowledge of the optimal sequence selection and contrast resolution for the individual patient is important Serial MRI may provide for prognostication and progression of disease Knowledge of normal myelination pattern will decrease the chances of misinterpretation To obtain the most complete data set for pattern recognition, a systematic and comprehensive evaluation of brain structures is mandatory Flow Chart of WM disorders Hypomyelination with congenital cataract 30