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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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