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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


– T1 W – iso or hyperintense

• Demyelinating Leukodystrophy/other myelin


– 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


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


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


• Axial FLAIR

• Cysts in frontal and temporal region

• Hyperintensity in noncystic WM


• 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