3. Basic principles of myelination on MRI
1. Un-myelinated White matter
• Hypointense on T1 W
• Hyperintense on T2 W
2. Myelinated White matter
Hyperintense on T1 W
Hypointense on T2W
Normal brain Myelination is a dynamic process that
begins during 5th fetal month & continuous through
out life
.
PROGRESS FAST UPTO 2 YRS. Some association fibres
remains unmyelinated until the age of 20-30 years
4. Dys-myelination refers to the abnormal
development or destruction of the myelin
sheath, a fatty layer that surrounds and
insulates nerve fibers in the brain and spinal
cord.
DEFINATION
5. Cognitivedefecits an early presentation-hereditary
diffuse leukoencephalopathy with axonal spheroids
(HDLS) .
Prominent features
behavioural changes, mood changes and loss of
realistic assessments of daily life experiences
Bulbar symptoms at onset –Alexander disease
Extrapyramidal signs and symptoms - dystonia
and/or dyskinesias , are less frequent
but might be a predominant manifestation in certain
disorders, including progressive leukoencephalopathy
with ovarian failure, various HLDs and AxD.
Seizures – MLD , krabbes ,Alexander disease
7. Step 1 Identify Symmetric White
Matter Involvement
Symmetric white matter involvement at MRI is a typical finding in patients with
leukodystrophies.
(a) Axial T2-weighted
MR image in a 23-year-old woman
shows symmetric white matter
involvement.
(b) Axial FLAIR MR image shows an
asymmetric pattern in a 46-year-old
woman shows asymmetric white
matter involvement
8. Step 2: Look for a White Matter
Involvement Pattern
9. X- linked Adrenoleukodystrophy
Inherited disorder of peroxisomal metabolism.
Altered peroxisome metabolism in ALD results from absent or deficient acyl CoA synthetase
leading to impaired β-oxidation of very-long-chain fatty acids (VLCFAs)
ABCD1 gene mutation
10. Imaging
MRI : White matter abnormalities are usually first seen in occipital regions, with
early involvement of the splenium of the corpus callosum and posterior limbs
of the internal capsule.
The changes then progress to involve more anterior regions.
In cerebral ALD, contrast enhancement at the periphery of the signal
abnormalities is said to be characteristic
11.
12.
13.
14.
15. Axial T2-weighted MR image shows parieto-occipital symmetric white
matter hyperintensity.
(b) Contrast-enhanced axial T1-weighted MR image in the shows
enhancement foci in the white
(c) Sagittal T2-weighted MR image shows thoracic cord atrophy.
16. The Loes Scoring System.
The Loes scoring system is universally applied to quantify the extent
of cerebral involvement.
Regions of the brain (such as parietooccipital white matter, anterior
temporal white matter, visual pathway, corpus callosum, auditory
pathway, basal ganglia, projection fibers, and cerebellum) are
subdivided and scored based on the extent of disease .
With a score of 0 if normal, 0.5 if unilateral involvement is present,
and 1 if the lesion or atrophy is bilateral.
Global atrophy is also assessed.
A normal MRI scan has a score of 0, and the maximum severity score
is 34.
17. Abbreviation: MRI, magnetic resonance imaging.
Each region is given a score of 0 for normal, 0.5 for unilateral involvement, and 1
for bilateral involvement or atrophy. The maximum score is 34.
Parieto-occipital white matter
(maximum 4)
Basal ganglia (maximum 1)
Anterior temporal white matter
(maximum 4)
•Frontal white matter (maximum 4)
•Periventricular
•Central
•Subcortical
•Local atrophy
•Visual pathway (maximum 4)Optic
radiation
•Meyer’s loop
•Lateral geniculate body
•Optic tract
•Corpus callosum (maximum 5)
•Splenium
•Genu
•Body
•Splenium atrophy
•Genu atrophy
•Auditory pathway (maximum 4)Medial
geniculate body
•Brachium of inferior colliculus
•Lateral lemniscus
•Pons
•Global atrophy (maximum 4)Mild
•Moderate
•Severe
•Brainstem
•Cerebellum (maximum 2)White matter
•Atrophy
•Projection fibers (maximum 2)Internal
capsule
•Brain stem
MRI severity scale scoring (Loes et al 5 )
18.
19. Metachromatic Leukodystrophy
AR lysosomal storage disorder
An enzyme deficiency of arylsulfatase A, which is encoded on the ARSA gene on
chromosome 22 q/or pathogenic mutations in PSAP (which encodes
prosaposin)
Sulfatides accumulate in the central and peripheral nervous systems, kidneys,
testes, and visceral organs (gall bladder).
MLD is an adulthood leukodystrophy that is frequently misdiagnosed as early-
onset dementia and/or a schizophrenic disorder, as the neurological symptoms
can occur late in the disease course.
20. A high index of suspicion for metachromatic leukodystrophy must exist for patients
presenting with a peripheral neuropathy or gall bladder abnormality in the absence of
other neurologic features.
The MRI may not reveal pathology early in the disease course; therefore, a normal MRI is
not sufficient to exclude metachromatic leukodystrophy.
23. A low arylsulfatase A level (less than 10% of normal values) is detected in
white blood cells or cultured fibroblasts, confirmed by the detection of
elevated sulfatides in the urine and ARSA sequencing for mutations.
Phase 1/II trial of intrathecal aryl sulfatase A .
Juvenile MLD – autologous HSCT .
Genetherapy under trial .
24.
25. Leukoencephalopathy with Axonal Spheroids and Pigmented Glia.—
• Autosomal dominant
• Colony-stimulating factor 1 receptor (CSF1R) gene mutation.
• The gene defect affects the tyrosine kinase domain of macrophage
colony-stimulating factor 1 receptor.
• Unlike other leukodystrophies, this disease manifests exclusively in
adults(20-50).
• P/W Behavioral changes, dementia, motor impairment.
26. (a) Luxol fast blue stain for myelin shows myelin loss and tissue vacuolation
with axonal spheroids [arrows in (a) and (b)], that are immunopositive for
amyloid precursor protein (b). Affected white matter has many lipid-laden
macrophages immunohistochemistry-positive for HLA-DR (c)
27.
28. (a) Case 1 (MRI performed 1.2 years after start
of symptoms); localized white matter lesions
(arrow) in both frontal and parietal
hemispheres involving the corpus callosum
(arrow dashed). (b) Case 2 (MRI performed 1.9
years after start of symptoms); confluent white
matter lesions in both frontal and parietal
hemispheres with cortical atrophy in the
affected areas. (c) Case 3 (MRI performed 3.5
years after start of symptoms); localized
periventricular lesions (arrow) with
corresponding frontoparietal atrophy and
involvement of the corpus callosum (arrow
dashed). (d) Case 4 (MRI performed 2.5 years
after start of symptoms); bilateral frontoparietal
white matter changes (arrow) extending into
the corpus callosum (arrow dashed).
29. Axial T2-weighted MRI with increased signal intensity in the frontoparietal white matter sparing arcuate U fibres (A)
and in the corticospinal tracts (B, arrows). Sagittal proton density imaging with atrophy and increased signal
intensity in the posterior body of the corpus callosum (C, arrow). Restricted diffusion on diffusion weighted
imaging (D, arrows) that is dark on apparent diffusion coefficient mapping in the areas of T2 signal abnormality (E,
arrows). Haematoxylin–eosin staining (F) demonstrates unpigmented macrophages and large neuroaxonal
spheroids (arrows).
30. leukoencephalopathy with axonal spheroids and pigmented glia in a 43-year-old
woman. (a) Axial FLAIR MR image shows symmetric white matter involvement with
diffuse hyperintensity and cysts (arrow). (b) Axial diffusion-weighted MR image shows
areas of restricted diffusion, which was confirmed on the apparent diffusion coefficient
map (not shown). (c) Nonenhanced CT image shows bilateral deep and periventricular
cerebral calcification
31. CT images in 40 year old male (A-C) show multiple symmetric small-sized
discrete calcifications in the bilateral frontal and parietal subcortical and
periventricular white matter.
32. Small bilateral calcifications in the frontal
white matter adjacent to the anterior
horns of the lateral ventricles on an axial
CT image (arrows). B, Sagittal view
represents the symmetric and
characteristic stepping stone appearance
(arrows). C, Case 4. Small bilateral
calcifications in the parietal subcortical
white matter on an axial CT image
(arrows), but there are no calcifications in
the frontal area. D, Sagittal CT image
displays subtle calcifications in the
anterior pericallosal region bilaterally
(arrows)
33.
34. Globoid Cell Leukodystrophy (Krabbe Disease)
Globoid cell leukodystrophy, or Krabbe disease, is an autosomal recessive lysosomal
storage disorder caused by mutations in GALC on chromosome 14q31.
GALC encodes the enzyme galactosylceramidase, which is essential in the degradation of
lipids (galactosylceramide and psychosine) during myelin turnover.
Adult form (10% of cases)
Presents with pyramidal tract dysfunction and spastic paraparesis.
Can also develop cognitive decline, seizures & cortical blindness.
20% of patients abnormal NCS (slowing of conduction velocity)
35. Krabbe disease in a 48-year-oldman. (a) Axial FLAIR image shows
bilateralparieto-occipital white matter involvement,extending to the splenium of
the corpus callosum.(b) Coronal T2-weighted MR image also shows a posterior
white matter involvement pattern extending to the corticospinal tracts
bilaterally(arrows).
36.
37.
38.
39.
40. Sjögren-Larsson Syndrome
Sjögren-Larsson syndrome is a rare autosomal recessive
disorder
Sjögren-Larsson syndrome is caused by inactivating
mutations in the aldehyde dehydrogenase 3 family
member A2 gene (ALDH3A2), which encodes for fatty
aldehyde dehydrogenase (FALDH) and results in abnormal
metabolism of long-chain aliphatic aldehydes and
alcohols.
41. Magnetic resonance imaging of the brain in a 4year old child with Sjogren Larsson
syndrome demonstrating hyperintense signal changes in the periventricular and deep white
matter on FLAIR axial view (A and B) and hypointense signal changes on T1weighted axial
image
42. Late-phase SjögrenLarsson syndrome in a 27-yearold man. (a) Axial
FLAIR MR image shows a periventricular white matter involvement
pattern. (b) Proton spectroscopic image of the frontal white matter,
obtained with a short echo time, shows abnormal peaks at 1.3 ppm
(arrow), indicating lipid deposition. Cho = choline, Cr = creatine, mI
= myoinositol, NAA = N-acetyl aspartate
43.
44. L-2-hydroxyglutaric aciduria
• autosomal recessive inheritance [L2HGDH] gene
• Cerebellar ataxia and intellectual decline.
• Hearing loss is another possible symptom of the disease.
• Increased L2-hydroxyglutaric acid in urine is diagnostic.
MRI
• shows predominant subcortical white matter involvement, initially focal and evolving to become
confluent.
• Periventricular white matter is spared.
• Increased signal intensity on T2-weighted or FLAIR MR images may be observed in the globus pallidus,
and less importantly, in the caudate nucleus and putamen, with symmetric distribution. These same
signal intensity abnormalities also may be observed in the dentate nucleus .
45. L-2-hydroxyglutaric aciduria in a 29-year-old woman. (a) Axial FLAIR image shows a subcortical
pattern of white matter involvement. (b) Coronal T2-weighted MR image shows the same pattern and
bilateral hyperintensities in the dentate nuclei (arrow), which are commonly observed in patients with
this disease.
46. Axial T2-weighted MRIs show (A) bilateral symmetrical
white matter (WM) hyperintensity (red arrows) in the
centripetal pattern involving subcortical and deep WM,
with sparing of periventricular WM (white arrows). (B)
Hyperintense basal ganglia (white arrows) with more
hyperintensity along the outer rim of the putamen (outer
rim sign, red arrow). (C) Hyperintense dentate nucleus
(white arrows). (D) The fluid-attenuated inversion recovery
image shows rarefaction (white arrows).
47. CORONAL FLAIR
SHOWS SUBCORTICAL T2/ FLAIR
HYPERINTENSITY
MRI shows hyperintensity of the basal ganglia with a higher
signal intensity of the outer rim of the caudate nucleus (white
arrow) and putamen (black arrow); the entire globus
pallidus(open arrow) shows high signal intensity. (b) Axial T2-
weighted shows a homogeneously affected caudate nucleus
(black arrow), putamen (white arrow), and globus pallidus (open
arrow) in an advanced stage of disease.
48.
49. Alexander disease
Etiology & inheritance:
AD is sporadic leukoencephalopathy of unknown etiology.
GFAP gene
Mutations in the GFAP gene lead to the production of a structurally altered glial
fibrillary acidic protein. The altered protein is thought to impair the formation of
normal intermediate filaments.
No definitive diagnostic biochemical test for AD & the diagnosis is made by
biopsy
50.
51.
52.
53. (a) Sagittal T1-weighted magnetic resonance image
showing “tadpole” atrophy of brainstem; i.e., atrophy of
medulla oblongata and cervical cord (arrowhead) with
preserved basis pontis (arrow). (b) Axial T2 sequence
showing marked atrophy of medulla oblongata (arrows)
54. .
T2-weighted MR image shows symmetric demyelination in the
frontal lobe white matter.The internal and external capsules and
parietal white matter are also involved.
Alexander disease in a 5-year-old boy with macrocephaly
55.
56. Adult onset autosomal dominant
leukodystrophy (ADLD)
ADLD is caused by duplications of the LMNB1 gene on chromosome 5q23, which
result in overexpression of lamin B1 protein.
Overexpression of this protein leads to disruption of myelin homeostasis and slowly
progressive, non-inflammatory demyelination, predominantly in deep white matter
structures and cerebral peduncle, mistaken for chronic progressive MS.
57. Typically, patients present in 4th or 5th decade with autonomic abnormalities,
followed by pyramidal symptoms, ataxia and cognitive deterioration
MRI :
Diffuse white matter T2 hyperintensities involving the frontal lobe, parietal
lobe and middle cerebellar peduncle.
Atrophy of the brainstem and corpus callosum
58. FLAIR show symmetric hyperintense signals involving the deep white matter of
both hemispheres with relative sparing of the periventricular regions (A, arrows)
and hyperintensity of cerebellar peduncles and pontine nuclei (B, arrows). T1-
weighted images show diffuse spinal cord atrophy (C).
59. A, Frontoparietal changes are less severe in the periventricular region..C, Changes
in the middle cerebellar peduncles and in the pontine nuclei.
60. FIGURE 4. T1-weighted spin-echo image (T1W) (A), T2W (B), and cross-
sectional (C) MR image T1W on sagittal surface and cross-sectional MRI
showed diffuse shriking, with accompanying abnormal signal in white matter
of thoracic one to four level spinal cord on T2WI.
61.
62. Cerebrotendinous Xanthomatosis
Autosomal recessive disorder caused by mutations in the CYP27A1 gene, which
encodes sterol 27-hydroxylase.
The deficiency of this enzyme results in the accumulation of cholesterol and
cholestanol leading to premature arteriosclerosis,neurotoxicity and the formation of
xanthomas in tendons, CNS, skin, and other organs.
63. Adolescence with cataracts
In adulthood - spastic paraparesis, pyramidal tract signs, cerebellar ataxia, bulbar symptoms
and peripheral neuropathy
Childhood history of diarrhoea or failure to thrive.
64. MRI : Non- specific supratentorial atrophy and deep periventricular white matter
changes
Sparing of U fibres and corpus callosum are spared.
classic picture - high signal intensity within the cerebellar white matter and low signal
intensity in the dentate nucleus on T2
65. MRI brain of 20-year-old female, (a) T2 sagittal
section showing mild cerebellar atrophy. (b and
c) T2 and FLAIR axial section showing
bilaterally symmetrical hyperintensities
involving the dentate nuclei and the deep
cerebellar white matter (arrow), which appears
iso to hypointense on T1 (arrow in d).
66. a) Achilles tendon xanthoma. Magnetic resonance
imaging brain showing (b) symmetrical cerebellar
atrophy and T2 hyperintensity of dendate nuclei, (c)
fluid-attenuated inversion recovery hyperintensities in
globus pallidus and white matter, (d) fluid-attenuated
inversion recovery hyperintensity in substantia nigra
67.
68.
69. Canavan disease
Etiology & inheritance:
Synonym :Spongyform leukodystrophy,
van Bogaert-Bertrand disease.
Caused by deficiency of N acetylaspartylase that results in the
accumulation of N-acetyl aspartic acid in urine, plasma & brain.
Inheritance is autosomal recessive.
70. Figure 1: (a) MRI of brain, T2
axial image, showing marked
symmetrical hyperintensity of
cerebral white matter with
involvement of the subcortical
arcuate fibres; (b) T2-weighted
axial section at the level of
cerebellum showing
hyperintensities in dentate
nuclei; (c) Axial section showing
extensive symmetrical diffusion
restriction in the subcortical
white matter; (d) Single voxel
MRS from left parietal white
matter showing NAA peak with
normal creatine and choline
peaks
CANAVAN
74. Adult polyglucosan body disease
APBD typically presents in the fifth to the sixth decade of life with a
combination of upper and lower motor neuron impairment
resembling amyotrophic lateral sclerosis,along with cerebellar ataxia
or Parkinson disease-like symptoms with extrapyramidal movement
disorders.
In some patients, polyneuropathic symptoms with hyporeflexia,
distal symmetric sensory loss, muscle atrophy and fasciculations can
be prominent, with slowed nerve conduction velocity and
denervation potentials on electrophysiological testing.
Cognitive deficits, reflecting white matter involvement, tend to be
very mild.
75. The affected gene in APBD, GBE1, encodes a glycogen- branching enzyme (GBE1),
dysfunction of which leads to accumulation of polyglucosan bodies in the central
and peripheral nerves.
Triheptanoin diet( 7 carbon triglyceride ) therapy under trial
76. MRI
Diffuse periventricular white matter changes predominantly the occipital and
temporal lobes and the mesencephalon and cerebellum.
Most prominent in the periventricular region, posterior limb of the internal capsule
and external capsule .
Later stages - thinning of the corpus callosum diffuse cerebral, cerebellar and spinal
cord atrophy
77. Brain MRI (FLAIR) shows Symmetric hyperintense white
matter lesions in the (A) periventricular area, (B) optic
radiations, (C) mesencephalic white matter, (D) superior
cerebellar peduncles, and (E) medulla. No contrast
enhancement was noted (not shown).
78. Cervical spine MRI(A) T2 fluid-attenuated inversion
recovery and (B) T2-weighted images show marked
atrophy of the medulla and cervical spinal cord. (C) T2-
weighted images show hyperintensities in the
corticospinal tracts and (D) increased signal in the dorsal
columns (arrowhead).
79. Differential diagnoses for adulthood
leukodystrophies
Inherited vasculopathies with white matter involvement –CADASIL ,CARASIL
Inherited CNS diseases with grey and white matter involvement- fragile x ataxia
syndrome ,DRPLA
Inborn errors of metabolism
Other disorders with white matter involvement like Wilson,s Disease
Acquired inflammatory, toxic, and traumatic white-matter predominant central
nervous system disorders
80.
81. Assessment and Diagnosis
Initial assessment should focus on the exclusion of common acquired causes and
severe small vessel disease(round 1).
If these initial tests are negative and the patient is suspected to have a genetic
disorder, then the first line of testing should include white cell enzyme activities, a
VLCFA profile(in men), plasma cholestanol and bile alcohols and plasma amino acids,
to exclude the classical leukodystrophies which can present in adulthood
82.
83. 1)Hydrocortisone supplementation for Addison syndrome in
adrenoleukodystrophy
2) cholecystectomy for gall bladder dysfunction, polyps and to
prevent cancer in metachromatic leukodystrophy
3) avoid head trauma and ensure prompt treatment of fever
and infection to avoid triggering deterioration
Mangement
84.
85. Evolving Therapeutic Approach
Multimodal therapy approaches have the
highest potential not only of halting but
also repairing the complex and
multifactorial pathology of
leukodystrophies.
The CRISPR (clustered regularly
interspaced palindromic
repeats)-Cas (CRISPR-associated protein)
approach
is a promising method for precise gene
editing,
