WHAT’S THE MATTER WITH WHITE MATTER? A REVIEW OF PEDIATRIC

WHITE MATTER DISEASES(EEDE-164)

Fang Yu1 M.D., Michael Wang1 M.D., Kiran Sargar2 M.D., Yutaka Sato3 M.D., Achint K. Singh1 M.D.

1: University of Texas Health Science Center San Antonio2: Mallinckrodt Institute of Radiology, Washington University, St. Louis3: University of Iowa Hospitals and Clinics

Disclosures

The authors have no disclosures

Table of contentsIntroduction

Imaging Considerations

What is Myelin?

Normal Myelination

Acquired white matter pathology

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Inborn errors of metabolism

Introduction A host of diseases affect myelin within the cerebral white

matter in the pediatric population. These leukodystrophies are often categorized into demyelinating and dysmyelinating disorders. In demyelinating disorders, the culprit destroys the myelin sheath

and often times the associated axons and oligodendrocytes [1]. Dysmyelinating disorders result from an inability to form normal

myelin [2]. Hypomyelinating diseases may be regarded as a rare third group,

where myelination is delayed/incomplete. For the purposes of our presentation, we will be

categorizing in terms of hereditary versus acquired white matter pathology. Due to differences in prognosis and therapeutic options,

distinguishing these diseases is of great clinical importance.

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Imaging Considerations A special consideration in pediatric subjects is difficulty with

cooperation for lengthy exams. This may be addressed with audio-visual aids for distraction or through the use

of general anesthesia. The following sequences should be included:

Decreased field-of-view and slice thickness (3-mm or less) to accommodate the smaller anatomy compared to adults.

Axial turbo spin echo T1 and/or T1-inversion recovery pre- and post-gadolinium Axial turbo spin echo T2 weighted & FLAIR sequences.

○ Consider sagittal or 3D FLAIR for multiple sclerosis T2* or SWI (susceptibility weighted imaging)

○ The detection of blood products (i.e. ferritin) as well as calcifications can aid in the differential.

Advanced MR sequences, including diffusion tensor imaging, functional MRI, magnetization transfer ratios, and MR spectroscopy may be considered in specific situations. Future directions include the development of myelin-specific sequences.

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What is Myelin? On the microstructural level, myelin consists of

multiple concentric spiraling lipid bilayer sheaths, which contain a variety of proteins such as myelin basic protein (MBP) [3].Between the bilayers are aqueous extracellular

compartments, which measure approximately to 3-4 nm.

Myelin in different regions of the nervous system differ slightly in terms of lipid composition.

It is found predominantly in the white matter, but is also present in grey matter

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What is Myelin? Formed as sheaths by oligodendrocytes wrapping

around axons in the CNS Schwann cells in the PNS

Gaps between the myelin sheaths are Nodes of Ranvier (high concentration of Na-channels).○ Action potentials cannot penetrate the myelin

sheaths, and instead must jump from one gap to the next (Figure 1).

This organization allows increased action potential conduction velocity (100x)

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What is Myelin?

Myelin Myelin Myelin

Node of Ranvier

Node of Ranvier

Action PotentialAction Potential Action Potential

Axon Axon

Axon

a

b

Figure 1: Longitudinal schematic of a myelinated axon with action potentials (a) traversing between the Nodes of Ranvier. Cross-sectional schematic (b) demonstrating concentric lipid bilayer sheaths (yellow) and intervening extracellular aqueous compartments (blue) surrounding the axon.

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Normal myelination In order to detect pathology, it is crucial to be

familiar with normal myelination [3]. The process begins at ~5 months gestation

and is largely complete by the 2nd year.It continues slowly until the 3rd-4th decades of life.

Myelination proceeds from:Inferior superior, posterior anterior, central

periphery○ e.g. the brainstem myelinates before the

cerebellum, and the occipital white matter generally precedes the frontotemporal region.

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Normal myelination T1 & T2-weighted MR sequences can be used

to evaluate white matter (WM) in early life. At birth, WM is largely non-myelinated,

demonstrating T1 prolongation (hypo-intense to grey matter) [4]Exceptions include: medial lemnisci, medial

longitudinal fasciculi, & posterior limbs of the internal capsule.

Myelinated white matter demonstrates T1 shortening (hyper-intense to grey matter), secondary to the cholesterol and glycolipid content in myelin [3].

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Normal myelination On the other hand, myelination results in

decreased water content and subsequent T2 shortening (hypo-intense to grey matter).Note: T2W images at birth resemble adult T1W

images Myelinated white matter becomes

hyperintense on T1 before it becomes T2 hypointense. It is generally recommended to use T1-weighted

sequences during the first 8 months of life, and T2-weighting from 8-18 months.

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Normal myelination By 18 months, the majority of

the intracranial white matter has myelinated, with the exception of:Subcortical U-fibersParieto-occipital association fibers

(“terminal zones of myelination”)○ Important to distinguish from

pathology.

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Figure 2: Axial T2 & FLAIR images (a & b) demonstrate symmetric iso-intense signal in the peritrigonal regions (separated from the ventricles by thin layer of normal myelinated WM representing terminal zones of myelination.

a

b

Normal myelinationAge T1 (hyperintense) T2 (hypointense)

Birth • Internal capsule posterior limb• Dorsal brainstem• Perirolandic gyri

• Dorsal brainstem• Perirolandic gyri

6 months • Internal capsule anterior limb• Ventral brainstem• CC genu & splenium• Parietal, occipital, & cerebellar

WM

• Internal capsule anterior & posterior limbs

• CC splenium• Occipital WM

12 months Most WM except U-fibers (approximates adult’s by 18 months)

• Corpus callosum genu• Deep frontal WM

2 years All WM including U-fibers All WM including U-fibers*

Table 1 – Overview of myelination appearance on MRI. CC = Corpus callosum; WM = White matter* Unmyelinated “Terminal Zones” (parietooccipital association fibers) often persist into adulthood

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Normal myelinationT1 T2

Birth

4 mo.

12 mo.

18 mo.

24 mo.

Figure 3: Schematic animation of myelination on T1 and T2-weighted images at the level of the internal capsule over time, from birth to 24 months of age.

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Normal myelination

Figure 4: Normal myelination on T1 (left) & T2 (right). At birth, myelination is seen in IC posterior limbs (a & b), which progresses to the occipital WM and CC on T1 at 5 months (c). T2 lags behind slightly (d). By 1 year, there is further progression of myelination in the frontal, temporal and occipital region on the T1 (e) & T2 (f).

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Birth5 months

1 year

a bc d

e f

T1-IR T1

T1

T2 T2

T2

White matter pathology:In-born Errors of Metabolism

A host of disease processes can affect the cerebral white matter in pediatric patients These include acquired diseases as well as hereditary disorders

(i.e. In-born Errors in Metabolism [IEMs]). IEMs include a large set of diseases which primarily target

3 organelles [4]: Lysosomes – e.g. Metachromatic leukodystrophy, Krabbe

disease, Fabre disease Peroxisomes – e.g. Zellweger syndrome, adrenoleukodystrophy Mitochondria – e.g. Leigh syndrome, MELAS, MERRF

IEMs can result in demyelination, hypomyelination, or dysmyelination. Hypomyelination tends to have less pronounced findings on T1

and T2 weighted sequences.

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White matter pathology:In-born Errors of Metabolism

Based on imaging, the presence of enhancement, involvement of grey matter, calcifications, patterns of progression, & spectropy findings can help to distinguish the different disorders [5].

However, there is a significant degree of overlap between the various IEMs as well as acquired etiologies. Correlation with clinical & laboratory findings is essential to

arrive at the correct diagnosis. IEMs produce progressive changes on imaging, while acquired

pathology often stabilize/regress.

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IEM: Metachromatic Leukodystrophy

Autosomal recessive disorderDue to decreased arylsulfatase A resulting in

accumulation of lysosomal sphingolipid sulfatide [4]. ○ Apart from CNS, also accumulates in kidneys,

peripheral nerves, and liver [6].

Prevalence of 1:100,000 3 distinct clinical forms:

Infantile (usually 12-18 months) - most common, present with visual and motor impairment, deterioration in intellect, & death within 4 years.

Juvenile (< 16 years) – survival rare beyond 20 years.Adult – may resemble multiple sclerosis clinically.

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IEM: Metachromatic Leukodystrophy

CT – hypodensity in periventricular white matter MRI – symmetric T2 prolongation involving the

periventricular white matter.Begins in parieto-occipital region, spreads centrifugally

to frontal and then temporal periventricular WM○ Islands of normal myelinated WM may be present

around medullary veins, producing “tiger” / “leopard” pattern

Spares subcortical U-fibersNo contrast enhancementDiffusion restriction often presentSpectroscopy shows choline

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IEM: Metachromatic Leukodystrophy

Figure 5: Axial FLAIR images (a, b, c) demonstrate confluent symmetric white matter hyperintensity, with sparing of the subcortical U-fibers. Bilateral normal appearing white matter is noted along a perivenular distribution in the centrum semi-ovale (a), producing a “tigroid” pattern.

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a b c

IEM: Adrenoleukodystrophy

An X-linked peroxisomal disorder resulting from a defect involving the long arm of chromosome 18 [4] [6]. This results in impaired b-oxidation of very long

chain fatty acids, with then accumulate in tissues. Incidence of 1:20,000 – 50,000

Classic form is most common, presenting at 5-12 years of age with behavioral problems, and neurological progressive deterioration. A minority present with adrenal failure without

neurological symptoms.

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IEM: Adrenoleukodystrophy

Non-contrast CT - may demonstrate calcification and hypodensity in the posterior periventricular (peri-trigonal) white matter.

MRI - posterior-predominant WM T2 hyperintensity, often beginning in the CC splenium. The disease spreads posterior anterior & central peripheral. Three distinct zones:

○ The leading edge of demyelination is often T1-hyperintense, without enhancement.

○ Enhancement and diffusion restriction is often seen in intermediate zone

○ The inner/central zone represents irreversible gliosis, & is significantly T2 hyperintense.

Spectroscopy shows NAA, choline/myoinositol

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IEM: Adrenoleukodystrophy

Figure 6: Axial FLAIR (a, b, c) images of the brain demonstrate bilateral hyperintensity in the periventricular white matter about the atria and temporal horns, as well as along the posterior limb of the internal capsule/corticospinal tract. The latter finding is associated with the adrenomyelopathy variant

a b c

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IEM: Canavan Disease An autosomal recessive disorder that results in

abnormal accumulation of NAA (N-acetyl-L-aspartate) in the brain [4] [6].Results in myelin edema and damage.Occurs most frequently in Ashkenazi Jewish

population. On pathology, there is spongiform white matter

degeneration with swollen astrocytes in the deep grey nuclei.

The Infantile form is most common, presenting between 3-6 months with seizures, macrocephaly, hypotenia, & death within 1-2 years.

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IEM: Canavan Disease NECT - There may be macrocephaly with

diffuse cerebral & cerebellar white matter hypoattenuation. The deep grey nuclei may also be hypodense.

MRI – Confluent T2/FLAIR hyperintensity throughout the white matter, which may involve the globus pallidi. No contrast enhancementSpectroscopy demonstrates NAA.

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IEM: Canavan Disease

Figure 7: Axial NECT (a, b, c) demonstrates confluent hypodensity throughout the visualized cerebral white matter.

Figure 8: Axial FLAIR (a & b) & T2 weighted images (c) in a different patient demonstrates confluent hyperintensity throughout the cerebral white matter.

a b

a b c

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IEM: OverviewDisorder Deficit / defect Imaging findings

Pelizaeus-Merzbacher disease (hypomyelination)

• X-linked• Proteolipid Protein-1 deletion leads

to Proteolipid Protein

• Diffuse WM T2 hyperintensity

• Variable T1

Metachromatic Leukodystrophy(Lysosomal)

Arylsulfatase A activity leads to metachromatic sulfatide

• Symmetric deep WM T2 hyperintensity,

• Spares subcortical U-fibers

Adrenoleukoencephalopathy(Perixosomal)

• X-linked• Deficient oxidation of very long

chain fatty acids, resulting in accumulation

• Peritrigonal & CC splenium WM T2 hyperintensity

• intermediate zone enhancement.

MELAS(Mitochondrial)

Impaired mitchondrial function Migrating cortical and subcortical infarcts

Canavan Disease • Autosomal recessive• Accumulation of NAA

• Confluent WM T2 hyperintensity

• Macrocephaly• MRS shows NAA

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AcquiredWhite Matter (WM) Pathology

Non-hereditary pathology of the cerebral white matter is considerably more common in the pediatric population than hereditary diseases.

Etiologies include: Infectious – CMV, HIV/AIDS Idiopathic Inflammatory – Acute Disseminated

Encephalomyelitis, Multiple Sclerosis, Sarcoidosis Iatrogenic/toxic – methotrexate, carbon monoxideHypoxic-ischemic injuries – periventricular

leukomalaciaVasculitis

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Acquired WM Pathology: ADEM

ADEM (Acute Disseminated Encephalomyelitis) is an immune-mediated demyelinating disorder [4]. May mimic multiple sclerosis, but often with a history of

a preceding infection (i.e. viral illnesses) or vaccination. Typically occurs in children under 10 years of age.

Generally regarded as a monophasic illness, although recurrent and multiphasic forms have been recognized. Although over half of patients completely recover within

a few months, mortality can be as high as 10-25%. Cerebral white matter is typically involved, although

deep grey nuclei and spinal cord can be as well.

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Acquired WM Pathology: ADEM

CT - Enhancing lesions may be seen after administration of contrast.

MRI Multiple T2 hyperintense WM lesions are typical,

which range from small ovoid foci to larger “cotton ball” lesions. There is relatively little mass effect.○ Often bilateral and asymmetric, with involvement of

the basal ganglia & cerebellum.Variable contrast enhancement can be seen.Diffusion restriction may be seen in acute lesions.Nonspecific spectroscopy with NAA, lactate

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Acquired WM Pathology: ADEM

Figure 9: Axial FLAIR images (a, b, c) demonstrate diffuse bilateral, asymmetric hyperintense lesions primarily involving the subcortical and deep white matter.

a b c

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Acquired WM Pathology:Multiple Sclerosis

Pediatric multiple sclerosis (MS) is defined as multiple sclerosis occurring before the age of 16 years [7].Most common idiopathic demyelinating disorder in

both children and adults. Diagnosis is based on the revised McDonalds

Criteria, although this approach may be less adequate of children < 11 years old [8].A presentation of multiple relapses with progressive

disease, without preceding history of febrile illness, is supportive of MS over ADEM.

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Acquired WM pathology: Multiple Sclerosis

Distinguishing MS from ADEM can be challenging based on imaging.

Utilizing MRI, features that favor pediatric MS over ADEM include [8] [9]:Absence of diffuse bilateral lesion patternPresence of T1 “black holes”Presence of 2 or more periventricular T2

hyperintense lesionsSparing of the basal ganglia

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Acquired WM pathology: Multiple Sclerosis

a b c

Figure 10: Sagittal FLAIR image (a) demonstrates multiple pericallosal hyperintense lesions. Axial FLAIR (b) and T1-post contrast (c) images demonstrate an enhancing C-shaped lesion within the right frontal deep WM

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Acquired WM pathology: CMV

CMV (Cytomegalovirus) is the most common of the congenital infections, being detected in up to 1% of newborns (~10% of these have signs of infection) [4].

Manifestations vary depending on the gestational age during which the infection occurs. White matter injury is ubiquitous, and is often accompanied

by cortical malformations & migrational abnormalities. Sensorineural hearing loss is frequent, with mild

developmental delays. Pathologically, microscopic viral inclusions may be

seen in the cell nuclei. Grossly, there is necrosis of the germinal matrix, with

vascular inflammation/thrombosis.

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Acquired WM pathology: CMV

CT – Often demonstrates periventricular calcifications, ventriculomegaly, and microcephaly.

MRI – In addition to microcephaly, cortical / migrational abnormalities, and ventriculomegaly, there is focal or confluent T2 WM hyperintensity.Periventricular cysts are common, especially

in the anterior temporal lobe.

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Acquired WM pathology: CMV

a b c

Figure 11: Axial FLAIR (a & c) and T1-post contrast images (b) demonstrate bilateral peritrigonal WM FLAIR hyperintensity/T1-hypointensity. No significant contrast enhancement is seen. Further inferiorly, there are periventricular cysts within the right anterior temporal lobe.

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Acquired WM Pathology: Toxic exposures

Numerous toxic exposures can lead to abnormalities within the white matter:Carbon monoxide – bilateral globus pallidus

lesions and diffuse leukoencephalopathyToulene – white matter & deep grey nuclei

lesions Treatment of pediatric cancers is

associated with WM changes from both radiation and chemotherapy, which are distinct.

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Acquired WM Pathology: Toxic exposures

Chemotherapy results in 2 distinct clinical entities [4]:Posterior Reversible Leukoencephalopathy

(PRES)○ Imaging findings are often “atypical” for PRES, with

sparing of the occipital lobes, & increased incidence diffusion restriction and enhancement

Treatment induced leukoencephalopathy○ Especially common with methotrexate in acute

lymphocytic leukemia○ Bilateral symmetric confluent WM T2 hyperintensity,

which often resolves after therapy

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Acquired WM Pathology: Methotrexate Leukoencephalopathy

Figure 12: Axial T2 weighted images (a & b) demonstrate confluent bilateral T2 hyperintensity within the cerebral white matter.

a b

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Conclusion Pediatric white matter diseases can be

challenging diagnostically. Familiarity with the patterns of normal

myelination at different ages is of great importance.

Recognizing with a few key imaging features, in conjunction with clinical and laboratory findings, can help lead to the appropriate diagnosis.

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References1. Verhey LH, Sled JG. “Advanced magnetic resonance imaging in pediatric multiple sclerosis”. Neuroimaging Clin N Am. 2013 May; 23(2): 337-54.

 

2. Ibrahim M, Parmar HA, Hoefling N, Srinivasan A. “Inborn errors of metabolism: combining clinical and radiologic clues to solve the mystery”. AJR Am J Roentgenol. 2014 Sep; 203 (3), W315-27.

 

3. Guleria S, Kelly TG. “Myelin, myelination, and corresponding magnetic resonance imaging changes”. Radiol Clin North Am. 2014 Mar;52(2):227-39

 

4. Osborn AG. Osborn’s Brain: Imaging, Pathology, and Anatomy. Lippincott Williams & Wilkins. Salt Lake City, UT. 2012. 853-902

 

5. Barkovich AJ. “An approach to MRI of metabolic disorders in children”. J Neuroradiol. 2007 May; 34(2): 75-88.

 

6. Cheon JE, Kim IO, Hwang YS, Kim KJ, Wang KC, Cho BK, Chi JG, Kim CJ, Kim WS, Yeon KM. “Leukodystrophy in children: a pictorial review of MR imaging features”. Radiographics. 2002 May-Jun; 22(3): 461-76.

 

7. Weygandt M, Hummel HM, Schregel K, Ritter K, Allefeld C, Dommes E, Huppke P, Haynes JD, Wuerfel J, Gärtner J. “MRI-based diagnostic biomarkers for early onset pediatric multiple sclerosis”. Neuroimage Clin. 2014 Jul; 7:400-8. 

  

8. Chabas D, Castillo-Trivino T, Mowry EM, Strober JB, Glenn OA, Waubant E. “Vanishing MS T2-bright lesions before puberty: a distinct MRI phenotype?” Neurology. 2008 Sep 30; 71(14): 1090-3.

 

9. Callen DJ, Shroff MM, Branson HM, Li DK, Lotze T, Stephens D, Banwell BL. “Role of MRI in the differentiation of ADEM from MS in children.” Neurology. 2009 Mar 17;72(11):968-73.

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