metabolic disorders primarily affecting white matter
TRANSCRIPT
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Metabolic Disorders primarily affecting white matter
Bhagwan Moorjani
American Society of Neuroimaging37th 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
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Clinical Evaluation
• Is it developmental delay or regression
– Global
– Motor
– Speech and language
• Is there a 2nd 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 12‐14 months
– T2 matures at 24‐26 months
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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 – iso or hyperintense
• Demyelinating Leukodystrophy/other myelin
– T2 W – hyperintensity
– T1 W ‐ hypointense
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White Matter DisordersWhat structures are involved
• Subcortical U fibers
• Diffuse subcortical involvement
• Thalami involvement
• Brainstem – particularly corticospinal tract
• Lack of myelination
• Nonspecific white matter pattern
White Matter DisorderMRI predominance
• Diffuse
• Periventricular
• Subcortical
• Cerebellar
• Brainstem
• Cortex
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
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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
LeukodystrophiesDifferential 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
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Alexander DiseaseT1W-C+:Enhancement of the periventricular rim,caudate heads and putamen bilaterally
Rabbit ear – characteristic of AlexanderNodular appearance of frontal PV rim
Alexander Disease
FLAIR – less severe diseaseHigh signal in the anterior and posterior rims and WM with frontal predominance
Alexander Disease T1W-C+ - enhancement of bifrontal PV WM, PV rim and caudate head.Less intense patchy enhancement in putamen and thalamus
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Alexander Disease
T2W – advanced diseaseSymmetric, hyperintense cerebral WM and deep gray structuresSwollen caudate head and fornicesHyperintensity in external and extreme capsule – claustra stands out
Alexander Disease
FLAIR – large foci of cystic destruction in frontal WM and caudate headThese 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
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Uggetti C et al. AJNR Am J Neuroradiol 2009;30:1971-1976
©2009 by American Society of Neuroradiology
Aicardi Goutieres
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.
Uggetti C et al. AJNR Am J Neuroradiol 2009;30:1971-1976
©2009 by American Society of Neuroradiology
Aicardi Goutieres
Laminin alpha 2 deficiency
Exp Ther Med. 2013 November; 6(5): 1233–1236.
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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
C,D ‐ normal
CSFT2 – brightFLAIR ‐ dark
VU University Center, Amsterdam
Vanishing white matter disease
FLAIR• symmetric, bilateral• Isointense to CSF central WM
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Sonninen P et al. AJNR Am J Neuroradiol 1999;20:433-443
©1999 by American Society of Neuroradiology
Salla Disease
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
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Canavan DiseaseT2W – 6 month oldDiffuse increase signal cerebral WM including thalamus and right globus pallidusSparing of internal capsule, CC and putamen
Canavan DiseaseT2W: infantMarked hyperintense signal and swelling throughout WMStriatum as island of tissue
Canavan mrs
• Elevated naa
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Canavan DiseaseDifferential Diagnosis
• Maple Syrup Urine Disease
– Elevated branch chain AA
• Pelizaeus‐Merzbacher Disease
– Spares GP and thalami
• Alexander Disease
– Enhances
– Predominantly frontal WM
MSUD• 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 2
• Infant
• Axial T2 W
• Edema in pons and cerebellum
• Pearl: significant edema ‐> metabolic brain disease
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MSUD
Axial DWI
• Diffusion restriction in posterior limb of internal capsule and thalamus
• Suggest acute process
Deep White MatterSpares 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
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Krabbe DiseaseCT Scan
Faint hyperdensity in the lateral thalami, from presumed Ca++ depositsCT 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 WMsparing subcortical U fibers
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Krabbe Disease
T2W – advanced disease – atrophy, hypointensity in BG and Thalami
Parieto‐OccipitalPredominance
• Krabbe Disease
• X‐linked ALD
• Early onset peroxisomal disorders
• Neonatal hypoglycemia
ALD
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ALD
• Always abnormal in neurologically symptomatic males
• Often provides first lead
• Predominately posterior white matter – 80%
• Splenium of corpus callosum usually involved
Deep White MatterSpares 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• 2nd 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 tigroidappearance
– No enhancement of WM
– May have enhancement of cranial nerves and cauda equina
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MLD
FLAIR – bilateral, symmetric periventricular and deep WMchanges 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 WMDue to preservation of myelin in perivenular regions
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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
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Megalencephalic leukodystrophywith subcortical cyst (MLC)
• Axial T2 W
• Symmetric hyperintensities WM
• Swelling, Enlarged gyri
Megalencephalic leukodystrophywith subcortical cyst (MLC)
• Axial FLAIR
• Cysts in frontal and temporal region
• Hyperintensity in noncystic WM
Megalencephalic leukodystrophywith subcortical cyst (MLC)
• Sagittal T1 W
• Cyst in frontoparietalregion
• Cyst in anterior temporal region
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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
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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
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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
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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
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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 oldabsence of normal hypointense WM signal
This is normal for a 6-8 month old child
18q‐ deletion
• 3.5 year old
• Axial T2W
• Minimal hypointensesignal in internal capsule and splenium
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Trichothiodystrophy
• 12 year old
• Axial T2W
• Absence of myelination
Jacobseb 11q deletion
• Axial CT brain
• 12 month old
• Accentuation of gray‐white 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
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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
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SSPE
• Nonspecific leukoencephalopathy
• MRS:
– decreased NAA/Cr
– Increased Cho/Cr; Ins/Cr and Lac‐Lip
SSPEProton Density:Inhomogeneous hyperintensity bilaterally, asymmetric involving WMAnd cortex
Biopsy - 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
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Non ketotic hyperglycenemia
• Hypoplatic corpus callosum
• 2 month old infant
Urea cycle DisorderOrnithine 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
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Urea CycleOTCD
• Coronal FLAIR
• Chronic stage
• Cortical and subcortical posterior insular and temporoparietalincreased 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
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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
http://brain.oxfordjournals.org/content/133/10/2971.full.pdf
Hypomyelination with congenital cataract