MRI in evaluation of white matter diseases like multiple sclerosis, leukodystrophies, demyelination, dysmyelination, ADEM, leukoencephalopathies, van der knaap disease, ALD, MLD, Krabbes disease, Leighs disease, Vanishing white matter disease, Canavan disease, Alexander disease

1. MRI EVALUATION OF
WHITE MATTER DISEASES
DR. SINDU P. GOWDAR
MODERATOR: DR. JEEVIKA.M.U

2. NORMAL MYELINATION
After normal myelination in utero, myelination of the neonatal brain is far from complete.
The first myelination is seen as early as the 16th week of gestation, but only really takes off from the
24th week1.
It does not reach maturity until 2 years or so. It correlates very closely to developmental milestones 3.
The progression of myelination is predictable and abides by a few simple general rules; myelination progresses
from:
1. central to peripheral
2. caudal to rostral
3. dorsal to ventral
4. sensory then motor

3. Myelination pattern on MR imaging
Myelination of the brain during infancy progresses in an orderly and predictable fashion.
At birth only certain structures are myelinated
 dorsal brainstem
 ventrolateral thalamus
 lentiform nuclei
 central corticospinal tracts
 posterior portion of posterior limb of internal capsule
Subsequently different parts become myelinated, the first change is increase in T1 signal, and later decrease in T2
 2 - 3 months : anterior limb of internal capsule becomes T1 bright
 3 months : cerebellar white matter tracts becomes T1 bright
 3 - 6 months : splenium of corpus callosum becomes T2 dark
 6 months : genu of corpus callosum becomes T1 bright
 8 months : subcortical white matter becomes T1 bright
 8 months : genu of corpus callosum becomes T2 dark
 11 months : anterior limb of internal capsule becomes T2 dark
 1 year 2 months : occipital white matter becomes T2 dark
 1 year 4 months : frontal white matter becomes T2 dark
 1 1/2 years : majority of white matter becomes T2 dark (except terminal myelination zones adjacent to frontal
horns and periatrial regions)
 2 years : almost all of white matter becomes T2 dark

6. AXIAL T1 MR 6 MONTHS
AXIAL T1 MR 9 MONTHS

7. AXIAL T1 MR 12 MONTHS
AXIAL T1 MR 18 MONTHS

8. • A wide number of diseases may affect brain white matter. This presentation will
attempt to address this wide topic by dividing brain white matter lesions into three
categories:
• 1. Demyelinating Diseases
• 2. Non-demyelinating Diseases of Adults
• 3. Dysmyelinating Disorders of Childhood

9. Demyelinating Diseases
Due to loss of myelin in previously normal white matter regions.
Multiple sclerosis (MS) is a relatively common acquired chronic relapsing demyelinating disease involving the central
nervous system. It is by definition disseminated not only in space (i.e. multiple lesions), but also in time (i.e. lesions are of
different age).
A number of clinical variants are recognised, each with specific imaging findings and clinical presentation. They include:
• classic multiple scleroris (Charcot type)
• tumefactive multiple sclerosis
• acute malignant Marburg type
• Schilder type (diffuse cerebral sclerosis)
• Balo concentric sclerosis (BCS)
Epidemiology
Presentation is usually between adolescence and the sixth decade, with a peak at approximately 35 years of age 12. There is a
strong, well recognised female predilection with a F:M ratio of 2-3:1.
Multiple sclerosis has a fascinating geographic distribution: it is rarely found in equatorial regions, with incidence gradually
increasing with distance from the equator

10. Clinical presentation is both highly variable acutely, as a result of varying plaque location as well as over time, with a
number of patterns of longitudinal disease being described 11-12:
1.relapsing–remitting
1. most common (70% of cases)
2. patients exhibit periodic symptoms with complete recovery (early on)
2.secondary progressive
1. approximately 85% of patients with relapsing-remitting MS eventually enter a secondarily progressive phase
3.primary progressive
1. uncommon (10% of cases)
2. patients do not have remissions, with neurological deterioration being relentless
4.progressive with relapses
5.benign multiple sclerosis
1. 15-50% of cases
2. defined as patients who remain functionally active for over 15 years
As is evident from this list, there is overlap, and in some cases patients can drift from one pattern to another.
Symptoms may be sensory or motor or mixed, including cranial nerve involvement, e.g.trigeminal neuralgia or optic
neuritis.

11. Pathology
The exact aetiology is poorly known although it is believed to have both genetic and acquired contributory components.
MS is believed to result from a cellular mediated autoimmune response against ones own myelin components, with loss of
oligodendrocytes, with little or no axonal degeneration.
Demyelination occurs in discrete foci, termed plaques which range in size from a few millimetres to a few centimeters and
are typically perivenular.
Each lesion goes through three pathological stages:
•early acute stage (active plaques)
• active myelin break down
• plaques appear pink and swollen
•subacute stage
• plaques become paler in colour ("chalky")
• abundant macrophages
•chronic stage (inactive plaques/gliosis)
• little or no myelin breakdown
• gliosis with associated volume loss
• appear grey/translucent
Patients serum IgG levels tend to be elevated and CSF analysis commonly shows oligoclonal bands
Associations
•a strong association with HLA-DR2 class II has been identified.

12. Radiographic features
Plaques can occur anywhere in the central nervous system. They are typically ovoid in
shape and perivenular in distribution.
CT
CT features are usually non-specific, and significant change may be seen on MRI with
an essentially normal CT scan. Features that may be present include:
•plaques can be homogeneously hypo attenuating
•brain atrophy may be evident in with long standing chronic MS
•some plaques may show contrast enhancement in the active phase

13. MRI
•T1
• lesions are typically iso- to hypointense (chronic)
• callososeptal interface may have multiple small hypointense lesions (Venus necklace) or the corpus callosum may
merely appear thinned 11
•T2: lesions are typically hyperintense.
•FLAIR
• lesions are typically hyperintense
• when arranged perpendicular to lateral ventricles, extending radially outward (best seen on parasagittal images)
they are termed Dawson fingers
• FLAIR is more sensitive than T2 in detection of juxtracortical and periventricular plaques while T2 is more
sensitive in infratentorial lesions.
•T1 C+ (Gd)
• active lesions show enhancement
• enhancement is often incomplete around the periphery (open ring sign)
•DWI/ADC: active plaques may demonstrate restricted diffusion 10-11
•MR spectroscopy: may show reduced NAA peaks within plaques
•double inversion recovery DIR: a new sequence that suppress both CSF and white matter signal and better delineation of
the plaques.

14. Location of the plaques can be
• infratentorial,
• deep white matter,
• periventricular,
• juxtacortical or
• mixed white matter-grey matter lesions.
Even on a single scan, some features are helpful in predicting relapsing-
remitting vs progressive disease.
Features favouring progressive disease include:
• large numerous plaques
• hypo intense T1 lesions

15. McDonald's criteria are MRI criteria used in the diagnosis of multiple sclerosis improves sensitivity from 46-
74%.
The diagnosis of multiple sclerosis requires establishing disease disseminated in both space and time.
• Dissemination in space
Dissemination in space requires ≥1 T2 bright lesions in two or more of the following locations 1:
• periventricular
• juxtacortical
• infratentorial
• spinal cord
 if a patient has a brainstem/spinal cord syndrome, the symptomatic lesion(s) are excluded from the
criteria, not contributing to the lesion count
• Dissemination in time
Dissemination in time can be established in one of two ways:
• a new lesion when compared to a previous scan (irrespective of timing)
 T2 bright lesion and/or gadolinium enhancing
• presence of asymptomatic enhancing lesion and a non-enhancing T2 bright lesion on any one scan.

16. Primary progressive multiple sclerosis (PPMS)
In addition to the above criteria, the diagnosis of primary progressive multiple sclerosis has also been
revised.
The diagnosis now requires:
• ≥1 year of disease progression (this can be determined either prospectively or retrospectively)
•plus two of the following three criteria
• brain dissemination in space ( ≥1 T2 bright lesions in ≥1 of juxtacortical, periventricular,
infratentorial areas)
• spinal cord dissemination in space (≥2 T2 bright lesions)
• positive CSF (oligoclonal bands and/or elevated IgG index)

17. 10. Advanced MR Imaging:
• A number of advanced MR imaging techniques, including diffusion imaging, MR spectroscopy
and magnetization transfer imaging have been used to better understand MS. For the most part,
these techniques have been used to diagnose MS but to better understand physiological changes
involved in disease progression.
• Diffusion tensor imaging (DTI) is an example of a technique that can help to better understand
whether normal-appearing white matter in MS patients is, in fact, normal.
• Studies using DTI have shown that normal-appearing white matter adjacent to plaques is very
abnormal in terms of diminished anisotropy values (correlating with loss of integrity of white
matter pathways). Even white matter distant from MS plaques can be seen to be similarly
altered.

18. 31-year-old man with a 10- year history of relapsing-remitting neurologic symptoms

19. Callosal Involvement with multiple sclerosis in 48-year-old woman with clinically definite
multiple sclerosis for 20 years.

20. Multiple sclerosis involving upper spinal cord in 35-year-old woman with acute onset of
quadriparesis.

21. Typical cerebral lesions of multiple
sclerosis in 64-year-old woman with
sudden onset of diplopia and ataxia
Multiple sclerosis lesion in brainstem
of 38-year-old man with bilateral
weakness and sensory symptoms in
lower extremities

22. Multiple sclerosis in 42-year-old woman with clinically definite
multiple sclerosis but no acute symptoms.

23. MULTIPLE SCLEROSIS

24. The differential diagnosis is dependent on the location and appearance of demyelination.
For classic (Charcot type) MS the differential can be divided into intracranial and spinal involvement.
For intracranial disease the differential includes almost all other demyelinating disease as well as:
•CNS fungal infection (e.g. Cryptococcus neoformans ) patients tend to be immunocompromised
•mucopolysaccharidosis (e.g. Hurler disease): congenital and occurs in a younger age group
•Susac syndrome
•CNS manifestations of primary antiphospholipid syndrome.
For spinal involvement the following should be considered:
•transverse myelitis
•infection
•spinal cord tumours, e.g. astrocytomas

25. Acute disseminated encephalomyelitis (ADEM)
• Can occur either on a post-infectious or post-vaccinial basis.
• The history of either of these precipitating factors is important in making the diagnosis.
• The disease can be seen in both adults and children. Compared to children, onset in adults is more often
seen as a more widespread CNS syndrome with impaired consciousness.
• Mean age of onset in childhood is approximately 7 years.
• In approximately 80%, one of the following events in the preceding 3 weeks can be found:
• upper respiratory illness or nonspecific fever (60%);
• specific viral or bacterial illness (20%); and
• immunization (10%).
• The most common infections to precede this disorder are measles, rubella and chickenpox. Neurological
illness typically progresses over the course of a week.

26. Imaging Findings:
• Typically bilateral, asymmetric lesions in central white matter varying in size from
many mm to several cm.
• Solitary, confluent or multiple lesions involving only one hemisphere can be seen in
a minority of cases.
• Thalamic or basal ganglia lesions in 25%
• Contrast enhancement seen in about 25% of cases
• Lesions are seen on MR imaging of the spinal cord in only about 1/3 of cases of
myelopathy
• On follow-up MR imaging weeks to months later, 36% have normal studies, 60%
have persistent but usually smaller lesions and 5% have new lesions.

27. MRI is far more sensitive than CT:
•T2: demonstrates regions of high signal, with surrounding oedema typically situated in subcortical
locations; the thalami and brainstem can also be involved
•T1 C+ (Gd): punctate, ring or arc enhancement (open ring sign) is often demonstrated along the leading
edge of inflammation; absence of enhancement does not exclude the diagnosis
•DWI: there can be peripheral restricted diffusion; the center of the lesion, although high on T2 and low
on T1 does not have increased restriction on DWI (c.f.cerebral abscess); nor does it demonstrate absent
signal on DWI as one would expect from a cyst, this is due to increase in extra cellular water in the region
of demyelination.
Magnetization transfer may help distinguish ADEM from MS, in that normal appearing brain (on T2
weighted images) has normal magnetization transfer ratio (MTR) and normal diffusivity, whereas in MS
both measurements are significantly decreased 3.

28. Potential location of lesions in patients with acquired demyelination.

29. MRI of patient a week before a febrile illness.

30. ADEM

32. Differential diagnosis of ADEM
• Multiple sclerosis (plus variants)
• Cerebral lymphoma
• Infectious encephalitis
• Viral: EBV, CMV, HSV1+2, JCV, HIV, HHV-6, FSME, HTLV,
• enteroviruses, measles
• Bacterial: Tropheryma whipplei, Mycoplasma, Listeria,
• Brucella spp.
• Fungal (e.g., Histoplasma spp.)
• Other autoimmune diseases
• Vasculitis (e.g., Behcet’s disease, panarteritis nodosa)
• Sarcoidosis
• Porphyrias
• Leukodystrophies
• Mitochondrial disorders (e.g., MELAS)
• Myelinolysis after electrolyte imbalances (e.g., central pontine myelinolysis)

33. II. Non-demyelinating White Matter Diseases of Adults
1. Posterior Reversible Encephalopathy Syndrome (PRES)-
This syndrome was formerly known as hypertensive encephalopathy, but it has recently been recognized
that it can be caused by a number of entities other than simply systemic hypertension. The syndrome is an
emergency condition because patients can proceed to cerebral infarction and death if not appropriately
treated.
Treatment consists of reversal of hypertension (if present) or removal of causative agents in other cases.
The syndrome typically occurs in the following settings:
- acute rise in systemic blood pressure, which may be only moderate in degree
- pre-eclampsia or eclampsia
- following treatment with a variety of immunosuppressive agents, including cyclosporine A, cisplatin and
tacrolimus.
The pathophysiological mechanism is thought to be development of vasogenic edema due to loss of
autoregulation within cerebral blood vessels.

34. Aetiology
•severe hypertension
• post partum
• eclampsia/preeclampsia
• acute glomerulonephritis
•haemolytic uraemic syndrome (HUS)
•thrombocytopaenic thromboic purpura (TTP)
•systemic lupus erythematosus (SLE)
•drug toxicity
• cisplatin
• interferon
• erythropoietin
• tacrolimus
• cyclosporin
• azathioprine
•bone marrow or stem cell transplantation
•sepsis

35. On unenhanced CT, regions of hypodensity predominating within the posterior half of the brain and
generally involving white matter up to the gray-white junction are seen.
On MR:
• T1- hypointense and T2 hyperintense lesions.
• No contrast enhancement.
• Cortical regions can occasionally be involved.
• The predilection for involvement of the posterior white matter is thought to be due to decreased
innervation of arteries of these regions by autonomic fibers compared to the remainder of the cerebral
circulation.
• On diffusion-weighted images, lesions often appear isointense, rather than having the hypointense
signal expected in vasogenic edema.
• This finding is most likely due to the net effect of a combination of elevated apparent diffusion
coefficient values on diffusion weighted images (due to vasogenic edema) and increased signal intensity
due to T2 prolongation effects (so-called “T2 shine-through effect”).

36. PRES
A 50-year-old woman 6 months post liver transplant experienced a generalized seizure and unresponsiveness. Blood
pressure at the time of the toxic event fluctuated markedly with a range between 106 and 200 mm Hg systolic and 54 and
80 mm Hg diastolic.

37. A 36-year-old man with severe type 1 diabetes and recurrent septic arthritis of the shoulder requiring frequent
debridement presented with several days of headache, nausea, and visual changes along with hypertension. Blood
pressure at toxicity was 184/111 mm Hg.

38. PROGRESSIVE MULTIFOCAL LEUKOENCEPHELOPATHY (PML)
• It is probably the best known virally induced demyelinating disease.
• It is caused by reactivation of a latent Papova virus (the JC virus) infection.
• Though generally seen in immunocompromised patients, it is found to have a strong association with
AIDS.
• The patient clinically presents with hemiparesis, homonymous hemianopia and altered mentation.
• MR is more sensitive than CT and is the imaging modality of choice in PML.
• MR reveals increased signal intensity in the subcortical or periventricular white matter of parieto
occipital region.
• Multifocal distribution pattern is seen which may be unilateral or more often bilateral and
asymmetric.
• There is absence of mass effect and enhancement due to the paucity of perivenous inflammation.
• The subcortical lesions result in a scalloped appearance due to the involvement of subcortical U
fibres.
• PML is commonly seen to involve the posterior fossa also.

39. PML

40. A 12-year-old boy with seizures and headache.

41. Marked progression of PML documented by serial MR studies

42. HIV ENCEPHALOPATHY
• Human retroviruses like HIV are known to cause white matter changes which may be difficult to assess
subjectively especially in the early stages of the disease.
• HIV encephalopathy is a progressive subcortical dementia that is a form of subacute encephalitis.
• The most common neurological manifestation would be subacute encephalopathy presenting as dementia and
global cognitive impairment.
• Though CT and MRI are relatively insensitive in detecting microglial nodules early in the course of the
disease, they are very sensitive in the detection of secondary parenchymal changes.
• The hallmarks of the disease are cortical atrophy and diffuse white matter changes.

43. • The white matter demyelination is diffuse symmetric periventricular isointense on T1 and with no mass
effect or contrast enhancement.
• Cortical atrophy which indirectly suggests the involvement of cortex is the most frequent finding.
• Lesions in white matter may extend to the basal ganglia and cortex with disease progression.
• Clinical and radiological studies have shown a major contribution of basal ganglia dysfunction in the
pathogenesis of HIV dementia.
• Lesions may also be located in the brain stem, cerebellum and spinal cord.
• White matter changes in HIV is quite nonspecific and mimics PML and CMV encephalitis.

44. HIV ENCEPHALOPATHY

45. A 34-year-old male with loss of orientation to time.

47. HERPES SIMPLEX ENCEHPALITIS (HSE) :
• HSV type 1 viral infection is the most common cause of fatal sporadic encephalitis.
• It is thought to result from reactivation of latent infection in the Gasserian ganglion thus explaining the
predilection of the disease for the temporal lobes.
• Clinical symptoms include nonspecific alteration in mental status, fever and focal neurological deficits.
EEG shows activity localized to the temporal lobe.
• Polymerase chain reaction (PCR) is a rapid way of diagnosis from the CSF but the definite diagnosis is
by brain biopsy.
• Prompt regression of symptoms seen with acyclovir therapy and hence early MRI diagnosis is essential
as antiviral therapy significantly reduces the mortality.

48. MRI
Affected areas however have a similar appearance, in terms of signal characteristics:
• T1
• may show general oedema in affected region
• if complicated by sub acute haemorrhage there may be areas of hyper intense signal
• T1 C+ (Gd)
• enhancement is usually absent early on
• later enhancement is variable in pattern 5
• gyral enhancement
• leptomeningeal enhancement
• ring enhancement
• diffuse enhancement
• T2
• hyperintensity of affected white matter and cortex
• more established haemorrhagic components may be hypo intense.
• DWI / ADC
• more sensitive than T2 weighted images
• restricted diffusion is common due to cytotoxic oedema
• GE / SWI - may demonstrate blooming if haemorrhagic (rare in neonates, common in older patients)

49. This 33 year-old female patient presented with agitation, confusion, mutism, and fever.

50. Vascular-
A. CADASIL- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and
Leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia, linked to a gene on
chromosome 19, which presents with multiple lacunar and subcortical white matter infarctions. There
is disproportionate cortical hypometabolism. Presenile dementia and migraines develop in the third-
to-fourth decades of life.
B. Vasculitis- can caused by a wide spectrum of entities, including drug abuse, collagen vascular diseases
(e.g. systemic lupus erythematosus), granulomatous processes (e.g. sarcoidosis), and infectious causes
(e.g. syphilis).

51. The patient, a 16-year-old girl, presented with headache, optic neuritis, and fatigue.

52. MRI
• widespread confluent white matter
hyperintensities 2.
• More circumscribed hyperintense lesions are also
seen in the basal ganglia, thalamus and pons 3.
• Although the subcortical white matter can be
diffusely involved, the frontal (93%) and temporal
(86%) lobes and subinsular white matter (93%) are
classical 2.
• There is relative sparing of the occipital and
orbitofrontal subcortical white matter 2,subcortical
U-fibers and cortex
CADASIL:

53. Post-therapeutic-
This condition can follow some types of chemotherapy causing necrotizing
leukoencephalopathy (e.g., methotrexate), immunosuppressive agents (e.g.
cyclosporin A) and radiation therapy.
Radiation injury can occur at any point during the post-treatment period. In the acute
period (first few months), this is manifested clinically by hypersomnolence, and
usually has no CT or MR findings.
Early injury (occurring within the first year) is usually marked by encephalopathy,
often with focal white matter lesions on CT and MR imaging.

54. Hemorrhagic radiation injury, asymptomatic.
MR images through temporal lobes in patient who had received helium ion irradiation for nasopharyngeal
carcinoma 3 years earlier.

55. DYSMYELINATING DISORDERS/
LEUKODYSTROPHIES

56. LYSOSOMAL STORAGE DISORDERS:
Lysosomes are membrane-bound cell organelles that contain a variety of hydrolytic enzymes and
aid in the digestion of phagocytosed particles.
When the activity of a specific lysosomal enzyme is deficient, a lysosomal storage disorder may result.
These disorders are classified according to what materials show abnormal accumulation in the
lysosomes (eg, sphingolipidosis, glycoproteinosis, mucopolysaccharidosis, mucolipidosis).
The underlying disorder may be diagnosed clinically with assay for the enzyme deficiency or abnormal
accumulation of material.

57. Metachromatic Leukodystrophy
Metachromatic leukodystrophy is an autosomal recessive disorder caused by a deficiency
of the lysosomal enzyme arylsulfatase A.
This enzyme is necessary for the normal metabolism of sulfatides, which are important
constituents of the myelin sheath. In metachromatic leukodystrophy, sulfatides
accumulate in various tissues, including the brain, peripheral nerves, kidneys, liver, and
gallbladder. The accumulation of sulfatides within glial cells and neurons causes the
characteristic metachromatic reaction.
Metachromatic leukodystrophy is diagnosed biochemically on the basis of an abnormally
low level of arylsulfatase A in peripheral blood leukocytes and in urine.

58. Three different types of metachromatic leukodystrophy are recognized according to
patient’s age at onset:
1. late infantile,
2. juvenile, and
3. adult.
The most common type is late infantile metachromatic leukodystrophy, which usually
manifests in children between 12 and 18 months of age and is characterized by motor
signs of peripheral neuropathy followed by deterioration in intellect, speech, and
coordination.
Within 2 years of onset, gait disturbance, quadriplegia, blindness, and decerebrate
posturing may be seen. Death occurs 6 months to 4 years after onset of symptoms.

59. • At T2-weighted MR imaging, metachromatic leukodystrophy manifests as symmetric confluent
areas of high signal intensity in the periventricular white matter with sparing of the subcortical
U fibers (Fig 1a).
• No enhancement is evident at computed tomography (CT) or MR imaging (Fig 1b).
• The tigroid and “leopard skin” patterns of demyelination, which suggest sparing of the
perivascular white matter, can be seen in the periventricular white matter and centrum
semiovale (Fig 2).
• The corpus callosum, internal capsule, and corticospinal tracts are also frequently involved.
• The cerebellar white matter may appear hyperintense at T2-weighted MR imaging.
• In the later stage of metachromatic leukodystrophy, corticosubcortical atrophy often occurs,
particularly when the subcortical white matter is involved.

60. Metachromatic leukodystrophy.

61. Metachromatic leukodystrophy

62. Metachromatic leukodystrophy with involvement of the corticospinal tract.

63. Krabbe Disease
Krabbe disease, or globoid cell leukodystrophy, is an autosomal recessive disorder
caused by a deficiency of galactocerebroside -galactosidase, an enzyme that degrades
cerebroside, a normal constituent of myelin.
As soon as myelination commences and myelin turnover becomes necessary,
cerebrosides accumulate in the lysosomes of macrophages within the white matter,
forming the globoid cells characteristic of the disease.
The genetic basis for the enzyme defect in Krabbe disease has been traced to a faulty
gene on chromosome 14.
The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood
leukocytes.

64. The clinical manifestation of Krabbe disease varies with patient age at onset.
Infantile, late infantile, juvenile, and adult forms are recognized.
The infantile form is the most common and manifests as hyperirritability, increased muscle
tone, fever, and developmental arrest and regression.
Disease progression is characterized by cognitive decline, myoclonus and opisthotonus, and
nystagmus.
Typically, Krabbe disease is rapidly progressive and fatal.

65. • CT performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci
in the thalami, caudate nuclei, corona radiata, posterior limbs of the internal capsule, and brainstem.
• The centrum semiovale, periventricular white matter, and deep gray matter demonstrate high signal
intensity at T2-weighted MR imaging.
• The subcortical U fibers are spared until late in the disease course.
• Abnormal areas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the
disease course.
• Severe progressive atrophy occurs as the disease advances.
• Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with
the underlying abnormal white matter despite the absence of an inflammatory reaction in the
pathologic specimen.
• Optic nerve hypertrophy may also occur in Krabbe disease.

66. Krabbe disease in a 2-year-old boy.

67. KRABBES DISEASE

68. Mucopolysaccharidosis
Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the
degradation of glycosaminoglycans.
Brain imaging is usually performed when hydrocephalus or spinal cord compression is suspected.
• CT and MR imaging usually reveal delayed myelination, atrophy, varying degrees of hydrocephalus, and
white matter changes.
• These changes manifest as diffuse low-attenuation areas within the cerebral hemispheric white matter at
CT and as focal and diffuse areas of low signal intensity on T1-weighted MR images and high signal
intensity on T2-weighted images (Fig 6).
• The sharply defined foci are commonly present in the corpus callosum, basal ganglia, and cerebral white
matter.
• They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent
mucopolysaccharide-filled perivascular spaces (16).
• As the disease progresses, the lesions become larger and more diffuse, reflecting the development of
infarcts and demyelination.

69. Mucopolysaccharidosis in a 4-year-old boy with Hurler disease.

70. A patient with MPS II at 21 years of age,

71. Peroxisomal Disorders
Peroxisomes are small, intracellular organelles that are involved in the oxidation of very long chain and
monounsaturated fatty acids.
Peroxisomal enzymes are also involved in gluconeogenesis, lysine metabolism, and glutaric acid
metabolism.
Peroxisomal disorders are inborn errors in cellular metabolism caused by a deficiency of one or more
of these enzymes.
ALD is a leukodystrophy caused by a single peroxisomal enzyme deficiency, whereas Zellweger
syndrome and neonatal ALD are caused by multiple enzyme defects.

72. X-linked Adrenoleukodystrophy
• X-linked ALD is a rare peroxisomal disorder that affects the white matter of the central nervous system, adrenal
cortex, and testes (17).
• The genetic defect responsible for X-linked ALD is located in Xq28, the terminal segment of the long arm of the X
chromosome.
• X-linked ALD is caused by a deficiency of a single enzyme, acyl-CoA synthesase. This deficiency prevents the
breakdown of very long chain fatty acids, which then accumulate in tissue and plasma (17).
• In the early stages of classic ALD, symmetric white matter demyelination occurs in the peritrigonal regions and
extends across the corpus callosum splenium (Figs 7, 8).

73. • Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white
matter is affected.
• The subcortical white matter is relatively spared in the early stage but often becomes involved in the later
stages.
• The affected cerebral white matter typically has three different zones.
 The central or inner zone appears moderately hypointense at T1-weighted MR imaging and
markedly hyperintense at T2-weighted imaging. This zone corresponds to irreversible gliosis and
scarring.
 The intermediate zone represents active inflammation and breakdown in the blood-brain barrier. At
T2-weighted MR imaging, this zone may appear isointense or slightly hypointense and readily
enhances after intravenous administration of contrast material (Fig 7c).
 The peripheral or outer zone represents the leading edge of active demyelination; it appears
moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (19–21).
• Symmetric abnormal areas of hyperintensity along the descending pyramidal tract are common at T2-
weighted MR imaging (Fig 9a, 9b) (21).
• Atypical cases with unilateral or predominantly frontal lobe involvement may occur (Fig 10) (22).

74. ALD in a 5-year-
old boy

75. ALD with preferential involvement of the descending pyramidal tract.

76. Atypical ALD

77. Zellweger Syndrome
Zellweger syndrome, or cerebrohepatorenal syndrome, is an autosomal recessive disorder caused
by multiple enzyme defects and characterized by liver dysfunction with jaundice, marked mental
retardation, weakness, hypotonia, and craniofacial dysmorphism (23).
It may lead to death in early childhood. The severity of disease varies and is determined by the
degree of peroxisomal activity.
Ultrasonography of the kidneys reveals small cortical cysts.
MR imaging reveals diffuse demyelination with abnormal gyration that is most severe in the
perisylvian and perirolandic regions (Fig 11). The pattern of gyral abnormality is similar to that
seen in polymicrogyria or pachygyria.

78. Zellweger syndrome in a 5-month-old girl

79. Diseases Caused by Mitochondrial Dysfunction
• Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular
disorders caused by a proved or proposed defect in the oxidative metabolic
pathways of energy production, probably owing to a structural or functional
mitochondrial defect (24–27).
• Some reasonably well-defined disorders include MELAS syndrome, Kearn-Sayre
syndrome, Leigh disease, and MERRF syndrome (Table 1).

80. MELAS Syndrome
(mitochondrial encephalopathy with lactic acidosis and stroke-like
episodes)
• Patients with MELAS syndrome usually appear healthy at birth with normal early development, then
exhibit delayed growth, episodic vomiting, seizures, and recurrent cerebral injuries resembling stroke.
• These stroke like events, probably the result of a proliferation of dysfunctional mitochondria in the
smooth muscle cells of small arteries, may give rise to either permanent or reversible deficits.
• The disease course is progressive with periodic acute exacerbation (27–29).
• Serum and cerebrospinal fluid lactate levels are usually elevated.

81. General features include multiple infarcts involving multiple vascular territories which may be either symmetrical
or asymmetrical. Parieto-occipital and parieto-temporal involvement is most common. Basal ganglia calcification
is seen. These features are more prominent feature in older patients. Atrophy also present.
MRI
chronic infarcts
• involving multiple vascular territories
• may be either symmetrical or asymmetrical
• parieto-occipital and parieto-temporal (most common)
acute infarcts
• swollen gyri with increased T2 signal
• may enhance
• subcortical white matter involved
• increased signal on DWI (T2 shine through) with little if any change on ADC: thought to
represent vasogenic rather than cytotoxic oedema 3
MR spectroscopy : may demonstrate elevated lactate 3

82. MELAS syndrome in a 10-year-old boy with migrating infarction.

83. Sequential MR images of a female patient with MELAS at ages 8 and 13 years.

84. Leighs Disease
• Leigh disease, or subacute necrotizing encephalomyelopathy, is an inherited, progressive,
neurodegenerative disease of infancy or early childhood with variable course and prognosis (30).
• Affected infants and children typically present with hypotonia, psychomotor deterioration, ataxia,
ophthalmoplegia, ptosis, dystonia, and swallowing difficulties.
• Characteristic pathologic abnormalities include micro-cystic cavitation, vascular proliferation,
neuronal loss, and demyelination of the midbrain, basal ganglia, and cerebellar dentate nuclei and,
occasionally, of the cerebral white matter (31).
 Typical MR imaging findings include symmetric putaminal involvement, which may be associated
with abnormalities of the caudate nuclei, globus pallidi, thalami, and brainstem and, less frequently, of
the cerebral cortex (Fig 13).
 The cerebral white matter is rarely affected.
 Enhancement may be seen at MR imaging and may correspond to the onset of acute necrosis (31).

85. LEIGHS DISEASE

86. LEIGHS DISEASE

87. Canavan Disease
Canavan disease, or spongiform leukodystrophy, is an autosomal recessive disorder
caused by a deficiency of N-acetylaspartylase, which results in an accumulation of N-
acetylaspartic acid in the urine, plasma, and brain.
It usually manifests in early infancy as hypotonia followed by spasticity, cortical
blindness, and macrocephaly (2).
Canavan disease is a rapidly progressive illness with a mean survival time of 3 years.
Definite diagnosis usually requires brain biopsy or autopsy.

88. • Canavan disease is characterized at pathologic analysis by extensive vacuolization that initially
involves the subcortical white matter, then spreads to the deep white matter (Fig 14c).
• Electron microscopy demonstrates increased water content within the glial tissue, described as
having the texture of a wet sponge, as well as dysmyelination (32,33).
• T1-weighted MR imaging demonstrates symmetric areas of homogeneous, diffuse low signal
intensity throughout the white matter, whereas T2-weighted imaging shows nearly homogeneous
high signal intensity throughout the white matter.
• The subcortical U fibers are preferentially affected early in the course of the disease.
• In rapidly progressive cases, the internal and external capsules are involved, and the cerebellar
white matter is usually affected as well.
• As the disease progresses, atrophy becomes conspicuous.

89. Canavan disease in a 6-month-old boy with macrocephaly

90. CANAVAN DISEASE

91. Pelizaeus-Merzbacher Disease
• PMD has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid
protein.
• This myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival.
• PMD has traditionally been divided into classic and connatal forms (34,35).
• Classic PMD begins during late infancy with X-linked recessive inheritance.
• Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy. The connatal
form has either X-linked or autosomal recessive inheritance.
• Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye
movements, nystagmus, extrapyramidal hyperkinesias, spasticity, and slow psychomotor
development.

92. T2-weighted MR imaging reveals a nearly total lack of normal myelination with
diffuse high signal intensity that extends peripherally to involve the subcortical U
fibers, along with early involvement of the internal capsule (Fig 15).
Sometimes, the white matter demonstrates high signal intensity with small scattered
foci of more normal signal intensity, a finding that may reflect the tigroid pattern of
myelination (36).
At pathologic analysis, the involved white matter demonstrates patchy distribution of
dysmyelination with preserved myelin islands.
These findings are frequently seen along the perivascular area, thus giving rise to the
characteristic tigroid appearance (35,36).

93. PMD in a 7-month-old boy

94. Alexander Disease
• Alexander disease, or fibrinoid leukodystrophy, is characterized at pathologic analysis by massive
deposition of Rosenthal fibers (dense, eosinophilic, rodlike cytoplasmic inclusions found in astrocytes)
in the subependymal, subpial, and perivascular regions (Fig 16b) (37).
• Three clinical subgroups are recognized.
• The infantile subgroup is characterized by early onset of macrocephaly, psychomotor retardation, and
seizure. Death occurs within 2–3 years. The diagnosis is made on the basis of a combination of
macrocephaly, early onset of clinical findings, and imaging findings, but definite diagnosis usually
requires brain biopsy or autopsy.
• In the juvenile subgroup, onset of symptoms occurs between 7 and 14 years of age. Progressive bulbar
symptoms with spasticity are common.
• In the adult subgroup, onset of symptoms occurs between the 2nd and 7th decades. The symptoms and
disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup.

95. • Alexander disease has a predilection for the frontal lobe white matter early in its course. CT
demonstrates low attenuation in the deep frontal lobe white matter.
• Enhancement is often seen near the tips of the frontal horns early in the disease course (39). The
characteristic frontal lobe areas of hyperintensity are seen at T2-weighted MR imaging.
• These hyperintense areas progress posteriorly to the parietal white matter and internal and external
capsules (Fig 16a).
• The subcortical white matter is affected early in the disease course.
• In the late stages of the disease, cysts may develop in affected regions of the brain.

96. Alexander disease in a 5-year-old boy with macrocephaly

97. Early MR imaging studies in a patient with presumed juvenile Alexander disease, obtained at the age of 4
years.

98. VANISHING WHITE MATTER DISEASE
Childhood ataxia with central hypomyelination (CACH)
• Vanishing white matter disease is an autosomal recessive disease, due to mutations in all five gene
subunits encoding the eukaryotic translation initiation factor eIF2B.
• This factor is a regulator of the final step of proteins production, in which mRNA is translated into
proteins under circumstances of mild stress.
• Clinically, after an initial normal or mildly delayed psychomotor development, patients show a
neurological picture whose course is chronic and progressive with additional episodes of rapid
deterioration following minor infection and minor head trauma that may lead to lethargy or coma.
• Cerebellar ataxia and spasticity are the main neurological signs.
• Optic atrophy and seizures may occur.
• Mental impairment is relatively mild, and usually less severe than motor dysfunction.
• Pathological abnormalities primarily involve the axons.
• It has been suggested that an abnormal stress reaction may cause deposition of denaturated proteins
within oligodendrocytes leading to hypomyelination, loss of myelin, and subsequent cystic degeneration

99. • MRI of vanishing white matter disease (VWMD) also has a characteristic pattern.
• It shows features of confluent cystic degeneration, white matter signal appears CSF-like with
progressive loss of white matter over time on proton density and FLAIR images.
• Regions of relative sparing include the U-fibers, corpus callosum, internal capsule, and the
anterior commissure.
• The cerebellar white matter and brainstem show variable degrees of involvement but do not
undergo cystic degeneration.
• MRS shows complete absence of all metabolites within cystic white matter.
• Few authors opine that MRI of the brain is usually diagnostic in VWM. It shows an abnormal
signal of all or almost all cerebral white matter with relatively spared U-fibers in some cases and
cystic degeneration of the affected white matter that is replaced by fluid.

100. VANISHING WHITE MATTER DISEASE

101. MEGALENCEPHALIC LEUKOENCEPHALOPATHY
• Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a rare disease first
described by van der Knaap et al, in 1995.
• Megalencephalic leukoencephalopathy with subcortical cysts is a relatively new entity of
neurodegenerative disorder characterized by infantile onset macrocephaly, cerebral
leukoencephalopathy and mild neurological symptoms and an extremely slow course of
functional deterioration.
• It is a rare disease with autosomal recessive inheritance.
• In typical cases, the MR findings are often diagnostic of MLC.

102. • MR shows 'swollen white matter' and diffuse supratentorial symmetrical white matter
changes in the cerebral hemispheres with relative sparing of central white matter
structures like the corpus callosum, internal capsule, and brain stem.
• Subcortical cysts are almost always present in the anterior temporal region and are also
frequently noted in frontoparietal region.
• Grey matter is usually spared.
• Gradually the white matter swelling decreases and cerebral atrophy may set in.
• The subcortical cysts may increase in size and number

103. MEGALOENCEPHALIC LEUKOENCEPHALOPATHY

104. Predominance of the white matter abnormalities
Alexander: frontal WM ALD: parieto occipital WM KSS: sparing of PV WM MLD: PV & deep WM, leopard skin
Cortical neuronal disorder:
illdefined, broad PV rim
Hypo/ VMD: diffuse
cerebral WM
Cerebrotendinous
Xanthomatosis:
cerebellar> cerebral
Adult onset ALD: middle
cerebellar peduncles

105. Conclusions
There are many different white matter diseases, each of which has distinctive features.
MR imaging is highly sensitive in determining the presence and assessing the severity
of underlying white matter abnormalities.
Although the findings are often non-specific, systematic analysis of the finer details of
disease involvement may permit a narrower differential diagnosis, which the clinician
can then further refine with knowledge of patient history, clinical testing, and
metabolic analysis.
MR imaging has also been extensively used to monitor the natural progression of
various white matter disorders and the response to therapy.

106. THANK YOU