approach to white matter diseae - Dr pallav jain

1. Approach to WHITE MATTER
DISEASES
PRESENTER- DR.PALLAV JAIN
DM RESIDENT(NEUROLOGY)
GMC,KOTA

2. Introduction
“White matter disease”- loosely defined term that includes
practically any disease process that has pathologic changes
limited to or predominantly within the WM.
Pathologic point of view
• Primary demyelination
• Secondary demyelination
• Dysmyelination
• Hypomyelination

3. Difference between white matter &
gray matter diseases
WHITE MATTER GRAY MATTER
Pyramidal signs Early and prominent Late
Ataxia Early and prominent Late
Dementia Late Early
Psychiatric symptoms Uncommon Present
EPS No Present
Eye involvement Primary optic atrophy
may be present
Retinal disease may be
present
Peripheral neuropathy may be associated No neuropathy
MRI shows subcortical WM
involvement
MRI shows cortical
involvement

4. Primary demyelinating diseases
Characterized by loss of normally formed myelin
with relative preservation of axons
• Multiple sclerosis
• Neuromyelitis optica

5. Secondary demyelination
Demyelination associated with a known etiology
or a systemic disorder
Preferential destruction of WM (destruction of
both axons and myelin)
• Infectious-ADEM,PML,HIV
• Metabolic-CPM,Vitamin B12
• Vascular-Ageing,Hypertension
• Trauma

6. Dysmyelinating/Hypomyelinating
(Leukodystrophies)
•Dysmyelinating diseases
Defective formation or maintenance of myelin
•Hypomyelinating disorders
WM partially myelinates but never myelinates
completely

7. 1. Pathologically loss of
myelin
2. Inflammation
3. Asymmetrical
involvement
4. Cause – idiopathic or
secondary
5. Subcortical U fibres
involved
1. Myelin not formed
or altered
2. No inflammation
3. Symmetrical
involvement
4. Cause – Metabolic or
unknown
5. Subcortical fibres
usually spared
DEMYELINATION DYSMYELINATION

8. Clinical Approach- ADEM vs MS
ADEM typically follows a prodromal
viral illness
MS may or may not
ADEM may present with fever and stiff
neck
unusual in MS
Widespread central nervous system
disturbance, often with impaired
consciousness and/or encephalopathy
MS typically
is monosymptomatic and has a
relapsing-remitting course

9. When to suspect leukodystrophies
Common:
 Slow/regression of mile stones
 B/L symmetrical signs & symptom
 Family H/o Mental retardation or early death
 Early onset of visual failure
 Progressive ataxia`
 Spasticity
 Behavioral changes,cognitive decline
Uncommon
 Seizure, Myoclonus
 Tremor or other involuntary movements

10. Approach to leukodytrophies
1.Are there any useful symptoms?
Head size: Macrocephaly
2.Is the disorder primarily WM, gray matter or both?
WM : spasticity, hyperreflexia, ataxia
Cortical Grey matter : seizure, dementia
Deep grey matter : Movement disorders, dystonia,
chorea
3.Involvement of Other organs:
liver, MSK, renal, eye, ear

11. 4. Is it primarily SUBCORTICAL or DEEP white
matter?

12. 5.Pattern - anterior, posterior, both?
Subcortical or deep WM cysts?
Thalamic /Brainstem
6. Myelination- Lack of or Delayed ?
7. MRS : Elevated NAA, lactate or other peaks

13. Classification
Neonatal 0-3 months
Infancy 1-12 months
Early childhood 1-4 years
Late childhood 5-15 years
Adult >15 years

14. Childhood onset disorder
MLD/ALD
Krabbe’s
Alexander’s leukodystrophy
Canavan’s disease
Pelizaeus-Merzbacher disease
Cerebrotendinous xanthomatosis
Adult Onset
MLD / ALD
Krabbe’s disease (late-onset form)
Alexander’s leukodystrophy
CTX
HDLS
. CADASIL
ADLD
Adult Polyglucosan Body Disease
LBSL
Classification

15. Clinical Approach
Neonatal or infantile
• Early: axial hypotonia
• Nystagmus or seizures.
• Late: spastic quadriparesis
Childhood :
• Delayed / regression of motor mile stones
• Progressive UMN signs
• Ataxia or dysarthia .

16. Adolescent or adult :
• Cognitive regression
• Psychiatric manifestation
• Behavioral abnormalities
• Motor manifestations are more subtle.

17. Head Size
• With macrocephaly:
Alexander & Canavan disease
Type 1 glutaric aciduria, GM2 Gangliosidoses, Zellweger
• With macrocephaly + subcortical cysts
Van der Knapp disease
• With macrocephaly + ataxia & decreased myelination
Vanishing white matter disease

18. ONSET OF ILLNESS
• <1YRKrabbe, Metachromatic leukodystrophy,Cannavan
• 1-2yrMetachromatic leukodystrophy
• 5-10yrAdreneleukodystrophy
RATE OF PROGRESSION
• RAPID Krabbe, Canavan
• SLOWMetachromatic leukodystrophy, Pelizeus Merzbacher

19. Environmental precipitants ( fever/trauma)
Adrenoleukodystrophy
Vanishing white matter disease
Ethinicity
• JEWSCannavan
• BRONZE SKINAdrenoleukodystrophy

20. EXTRAPYRAMIDAL Metachromatic leukodystrophy
NYSTAGMUS Pelizeus Merzbacher, Metachromatic
leukodystrophy
EARLY CEREBELLAR Pelizeus Merzbacher
EARLY HYPOTONIA Cannavan
ABSENT DTR Metachromatic leukodystrophy
,Adrenomyeloneuropathy,Krabbe
Seizures Krabbe disease,neonatal
Adrenoleukodystrophy

21. Radiological approach
• Brain MRI investigation in a patient with a suspected patient
with white matter disease
• Imaging findings interpreted a/w history, examination findings
• May often be diagnostic even before these elements are
known in leukodystrophies

22. Primary demyelinating disease
Cerebral lesions in NMO
• Dorsal medulla(Area
prostrema) contagious with
upper cervical cord lesion
• Periependymal surfaces of
4th ventricle in
brainstem/cerebellum
• Hypothalmus,thalmus,peri
ependymal surface of 3rd
ventricle
• Large,confluent,U/L or B/L
subcortical or deep white
matter lesions
Cerebral lesions in MS
• Periventricular
• Corpus callosum
• Centrum semiovale
• Deep white matter
structures and basal
ganglia

23. MS VS ADEM
ADEM usually has more MRI lesions than
MS
larger bilateral but
asymmetric white matter abnormalities
ADEM lesions tend to have poorly defined
margins,
While MS lesions tend to
have better defined margins
The presence of brain lesions of about the
same age on MRI is most
consistent with ADEM
Presence of brain lesions of different ages
and/or the presence of black holes
(hypointense T1-weighted lesions)
suggests MS
Thalamic lesions are common in ADEM Rare in MS
Periventricular lesions common in ADEM Less common in MS

24. Leukodystrophies
• Sagittal T1, Axial T1, T2-weighted FLAIR sequences should be
obtained.
• T1 weighted imaging may be more sensitive to immature
myelin than T2 weighted imaging
• MR spectroscopy,Diffusion tensor imaging- sensitive
indicators of involvement of certain white matter tracts or
myelination but principally remain research tools.

25. • A single brain MRI(especially<1yr)-Not sufficient
• Distinguish between delayed myelination, hypomyelination
and the early stages of demyelination.
• Serial MRI scans are often required, usually with a minimum
of 6–12 months interval between studies.
• Ideally, at least one scan should be obtained after the age of
two years

26. What to look in MRI
• Presence or absence of hypomyelination
Hypomyelination-unchanged pattern of deficient myelination
on two MRI scans at least six months apart in a child older
than one year.
• Whether the white matter abnormalities are confluent or
isolated and multifocal
Multifocal changes-infection,vasculopathy,structural
chromosomal disorders
Bilateral, symmetric confluent-leukodystrophies
• Predominant localization of the abnormalities
• MRI features unique to disorders-cysts, contrast
enhancement, calcifications

27. Imaging Characteristics

28. Patterns of white matter involvement

29. • Hereditary diffuse
leukoencephalopathy with
spherois
• Alexander disease
• Adrenoleukodystrophy
• Metachromatic
leukodystrophy

30. • Metachromatic leukodystrophy
• Leukoencephalopathy with
brainstem and spinal cord
involvement and
elevated white matter lactate
• Krabbe disease

31. • Adrenoleukodystrophy
• Krabbe’s

32. • Canavan disease
• Megaencephalic
leukoencephalopathy
• Leukoencephalopathy
with brainstem and
spinal cord involvement
and
elevated white matter
lactate
• Vanishing white matter
disease

33. • Krabbe’s
• Alexander disease
• Adrenoleukodystrophy
• Leukoencephalopathy with
brainstem and spinal cord
involvement and
elevated white matter lactate
• CTX

35. Advance MR techniques
• Proton MRS, DTI-changes in metabolite levels and water
diffusion parameters
• Offer an opportunity to assess the degree of axonal loss
and demyelination in the leukodystrophies
Measurements of white matter metabolites
• Help assess disease progression
• Determine optimal candidates for treatment options

36. MRS
• MRS changes precede MRI changes, very sensitive tool for
monitoring disease activity and progression
• N-acetyl aspartate- evaluates axonal integrity
• Choline- active demyelination
• Lactate- increased in secondary LD
• Myo-inositol- glial marker, early indicator of demyelination
and gliosis

37. Alexander Disease Infantile form: myoinositol
elevations in white and gray
matter, decreased Nacetylaspartate
Canavan Disease Highly elevated Nacetylaspartate
Globoid Leukodystrophy
(Krabbe Disease
Choline and myoinositol
elevations,
decreased N-acetylaspartate
Leukoencephalopathy with Brain
Stem and Spinal Cord
Involvement and Elevated Lactate
Decreased N-acetylaspartate
and increased myo-inositol,
choline and lactate
Megalencephalic
Leukodystrophy with Cysts
Decreased ratio of Nacetylaspartate
to Creatine

40. METACHROMATIC LEUKODYSTROPHY
• AR, Most common
• Deficiency of enzyme arylsulfatase
• Three types-late infantile, juvenile and adult
forms
• Age of onset 1 to 2 years

41. Diagnosis
• NCV- marked slowing
• High protein content of CSF
• Sural N Bx: pathognomonic deposits of sulfatides in Schwann
cells and macrophages
• Diagnosis-Deficient arylsulfatase A gene (ARSA gene) activity in
leukocytes or cultured skin fibroblasts.
• ARSA Pseudodeficiency (1%)
• Increase levels of urine sulfatides

45. Adrenoleukodystrophy
• Defect of peroxisomal beta-oxidation pathway
• Raised level of plasma VLCFA
• Mutations in the ABCD1 gene
Three main phenotypes
• Childhood cerebral forms
• Adrenomyeloneuropathy
• Adrenal insufficiency

46. ADRENOLEUKODYSTROPHY

48. Megalencephalic Leukoenphalopathy with subcortical
cysts:Vander knapp disease
• Remarkable for its relatively mild neurological signs and
symptoms in the setting of a very abnormal imaging study
• Delayed milestones, macrocephaly
• Slow neurological deterioration with dysarthria and ataxia
• Seizures in some
• In India, predominantly seen in the Agarwal community.

51. • Caused by deficiency of enzyme aspartoacylase.
• Excessive accumulation of N-acetyl aspartic acid in the brain
• Onset 3-6 months
• Progressive macrocephaly, severe hypotonia, persistent head lag
• Later hyperreflexic, hypertonic,Seizures and optic atrophy
• Most patients die in first decade of life
CANAVANS DISEASE

53. Alexander Disease
• Macrocephaly ,frequently associated with hydrocephalus
• Frontal lobe predeliction.
• Classified into 3 forms- infantile, juvenile and adult.
• Mutations in GFAP
• Anterior to posterior progression with generalized gray and
white matter atrophy.
• Treatment- supportive. AED - to control seizures

55. Vanishing white matter disease
• Chronic and progressive often exacerbated by infection or head trauma
• Mutations- eukaryotic translation initiation factor(eIF2B)
• Confluent cystic degeneration, white matter signal appears
CSF-like with progressive loss of white matter over time on
proton density and FLAIR images.
• Lab screening: elevated glycine in the CSF,serum and urine
• Prognosis: death 2nd decade

56. VANISHING WHITE MATTER DISEASE

57. KRABBE’S DISEASE ( GLOBOID CELL
LEUKODYSTROPHY )
• Autosomal recessive
• Deficient enzyme-galactocerebroside beta galactosidase
• Early onset, rapidly progressive and invariably fatal disease of
infants
• Raised CSF protein,Decreased motor NCV
• HSCT -beneficial if performed before the onset of symptoms

58. Krabbe’s disease ( globoid cell leukodystrophy )

60. Conclusion
• White matter disease are difficult to diagnose and patients
with these disorders typically undergo a large number of
expensive, time-consuming tests over a long time.
• MRI brain is central to the differential diagnosis of white
matter disease & should be interpreted in context of clinical
features
• Newer MRI techniques, genetic testing and advances in gene
therapy and HSCT will help us in treatment of these disorders.

61. REFRENCES
• Lynch DS, Wade C.Practical approach to the diagnosis of adult-
onset leukodystrophies: an updated guide in the genomic era.
J Neurol Neurosurg Psychiatry. 2019
• Scott Atlas.White matter imaging.MRI OF BARIN AND SPINE 5th
edition
• A clinical approach to the diagnosis of patients with
leukodystrophies and genetic leukoencephalopathies. Mol
Genet Metab. 2015 April ; 114(4): 501–515
• Deborah L. Clinical Approach to Leukoencephalopathies.2012
• Osborn brain and spine imaging 3rd edition
• www.uptodate.com

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