Leukoencephalopathies
Aetiology
• Acquired
o Inflammatory
o Toxic
o Infectious
• Inherited – Leukodystrophies
Leukodystrophies
Incidence
• 2/100,000
• Most manifest in childhood
Common clinical features
• Cognitive dysfunction
• Gait abnormalities
• Psychiatric problems – depression, change in personality
Signs
• Hyperreflexia
• Ataxia
• Spasticity
Specific clinical features
• Autonomic dysfunction
• Peripheral nervous system involvement
|
|
Inheritance/ Gene |
Pathology |
Metabolic
pathway |
Incidence |
Onset |
Clinical |
MRI |
Dx |
Mx |
|
Adrenoleukodystrophy (ALD) |
XL ABCD1 |
Demyelin.
|
Perox. |
1/20000-50000 |
5-12 |
Behavioural
difficulties Seizures Adrenal
insufficiency Mild
form in female carriers |
Confluent Parieto-occipital (~15%
frontal) |
VLCFA
increased |
Lorenzo’s
oil BMT |
|
Adrenomyeloneuropathy (AMN) |
As
above |
Demyelin. |
Perox |
|
20-35 |
Adult
onset form of ALD |
|
|
|
|
Globoid
Cell Leukodystrophy (Krabbe Disease) |
AR GALC
gene |
Demyelin. |
Lysosomal |
1/70000-100000 |
Infant Juvenile Adult |
Visual
impair. Cognitive
decline Spasticity |
Confluent Parieto-occipital Early
cerebellar – halo’s Enlarges
optic nerves |
Decreased
Galactocerebrosidase activity (leukocytes) |
BMT |
|
Metachromatic
Leukodystophy |
AR ARSA
gene (Arylsulfatase A) 150 mutations of varying severity Or PSAP
(rarely) |
Demyelin. |
Lysosomal |
1/40000 |
Infant Juvenile Adult |
Cognitive
and psychiatric decline Spastic
paraparesis Peripheral
neuropathy |
Periventricular (starts
parieto-occipital) Striped
‘tiger’ pattern to white matter change |
Decreased
ARSA activity (not very specific) Urine
sulfatide Peripheral
nerve biopsy |
BMT |
|
Alexander
Disease |
De
Novo GFAP |
Demyelin.
Or Hypomyelin. Gray and
white matter |
|
|
Infant Juvenile Adult |
Seizures,
spasticity Bulbar
dysfunction Ataxia Palatal
myoclonus (40%) |
Frontal
predominant Periventricular Enlarged
caudate Contrast
enhancement May
be brainstem predominant |
Genetic
|
Nil |
|
Canavan
Disease |
AR ASPA |
Spongiform |
|
Rare Mainly
Ashkenazi |
Infant ?Adult |
Spasticity,
hyperreflexia, optic atrophy and blindness |
Complete
absence of myelin |
Elevated
N-acetyl-L-aspartate (NAA) in urine or serum (organic acid screen) |
Nil |
|
Megaloencephalic Leukodystrophy with Subcortical cysts (MLC) |
AR MLC1
(75%) HEPACAM |
Spongiform |
|
Rare Indian/ Turkish |
Infancy-25yrs |
Macrocephaly Slow
progression Gait
abnormality, ataxia, spasticity, seizures, mild cognitive change |
Diffuse CSF-like
subcortical cysts later seen in ant. Temp and fronto-parietal
lobes |
MRI |
Nil |
|
Vanishing
White Matter Disease |
AR eIF2B
gene (transcription
factor) |
Demyelin. Cystic. |
|
?More
common |
Infant Adult
(15%) |
Episodic,
stress induced deterioration Cognitive
decline, seizures |
Diffuse
Starts
periventricular Later
cystic degeneration |
Genetic |
Stress
avoidance |
|
Pelizaeus-Merzbacher Disease |
XL
(mainly) PLP1 |
Hypomyelin. |
|
5-7%
of leukodys. |
Infants |
Rapid
deterioration |
Hypomyelination – near complete. |
|
|
|
CADASIL |
AD Notch3 |
Vascular |
|
|
20’s |
Stroke Migraine
headache Psychiatric
change Cognitive
decline |
Multiple
lacunar infarcts in subcortical, periventricular white matter and basal
ganglia. External
capsule and ant. Temp lesions more specific. |
MRI Genetic |
|
|
Fabry
disease |
XL Alpha-galactosidase |
Vascular |
Lysosomal |
|
|
Multisystem
vasculopathy Stroke |
Calcification
in basal ganglia/thalami – high pulvinars signal on MRI. Patchy
infarcts in basal ganglia and white matter. |
Decreased
Alpha-galactosidase level (leukocytes) |
Enzyme
replacement |
|
Autosomal
Dominant Leukodystrophy (ADLD) |
AD LMNB1 |
Demyelin. |
|
|
Adult |
Prominent
autonomic features Mild
cognitive change |
Hyperintensities in fronto-parietal (usu. Not periventricular)
cerebellar peduncles |
Genetic |
|
|
Adult
Onset Leukoencephalopathy (ALAS)/ Leukodystrophy with axonal spheroids |
Often
sporadic ?CSF1R |
Axonal |
|
|
Adult
(avg. 42) |
Cognitive
decline, personality change, Autonomic |
Fronto-parietal
white matter change (periventricular) |
Genetic |
|
|
Adult
onset Leukoencephalopathy with predominant
pathologic evidence of Primary demyelination/ Orthochromatic leukodystrophy (OLD) |
No
clear genetic cause found |
Demyelin. |
|
|
Adult |
Psychiatric
and cognitive Spasticity,
gait disturbance |
Frontal
predominant white matter hyperintensity May
spare optic radiations Cerebellar
and brainstem |
?Pathology |
|
|
Mucopolysaccharidoses |
9
types –MPS 1-9 Inability
to metabolise glycosamino-glycans |
|
|
|
Infants |
|
Dilated
perivascular spaces in posterior cerebral white matter and corpus callosum Patchy
or confluent white matter change Thickened
meninges |
|
|
|
|
|
|
|
|
|
|
|
|
|
Metabolic pathway mutation
MRI features