Transcript WhiteMatterDisease

White Matter Lesions
Marie Beckner, MD
1. Idiopathic demyelinating disease (MS)
2. Acquired metabolic demyelination
3. Toxic leukoencephalopathies
Not described in this module:
Dysmyelinating diseases, “leukodystrophies”
Infectious demyelination (PML)
Post-infectious demyelination (cross rx to Ag)
Primary Demyelination
Damage to oligodendroglia & their
myelin sheaths
Axons are relatively preserved
Secondary Demyelination
Damaged axon  loss of myelin
Axonal transectionWallerian
degeneration in distal portion
1. MULTIPLE SCLEROSIS
First described in 1870’s
Chronic, idiopathic, inflammatory
demyelinating disease of CNS
Selective destrx of oligodendrocytes
& myelin with preserved axons
Foci (plaques) widely dispersed in CNS
?Environmental influence acting upon
genetically susceptible individuals
Multiple Sclerosis
1 million worldwide, increasing rate
Higher prevalence in colder climates
CNS lesions disseminated in space & time
Symptoms: Paresthesias, gait difficulty,
weakness/incoordination of 1 or both
lower extremities, visual changes
MS - Magnetic Resonance Imaging
MRI: T1, T2, FLAIR (fluid-attenuated
inversion recovery)
New lesions
Gadolinium enhancement (recent
disruption of blood brain barrier)
Monitoring may help to identify agents
that may be active against early
inflammatory stage of MS
Hx: 25 yr woman
with relapsingremitting MS
Axial FLAIR
Periventricular
hyperintense
WM lesions
NEJM 343:938-52, 2000
9 months later
Axial FLAIR
 number &
 size of
WM lesions
NEJM 343:938-52, 2000
With gadolinium
Many lesions
demonstrate
ring or
peripheral
enhancement
NEJM 343:938-52, 2000
T1-weighted MRI
Multiple regions
of diminished
signal, “black
holes”, in periventricular
WM and corpus
callosum.
Chronic lesions
of MS.
NEJM 343:938-52, 2000
MS - Demyelinated Plaques
Well-demarcated, gray, gelatinous
S. Schochet
MS Plaque, often periventricular
Lateral
Ventricle
Ellison & Love
MS Plaque
Dawson’s fingers?
Extensions along
blood vessels
Robbins, 6th ed.
Rarely see layers of
demyelinated & more
normally myelinated
white matter (not here)
Shadow Plaques - partial myelination
adjacent to complete demyelination
GRIPE
MS Plaque with H&E Stain
Univ. Utah
MS Plaque
Luxol Fast
Blue Stain
Univ. Utah
MS Plaque - Luxol Fast Blue Stain
Univ. Utah
MS Plaque with Bodian Stain - Axons
Univ. Utah
MS Demyelinated Plaques
Loss of myelin (Luxol Fast Blue Stain)
Perivascular
lymphocytes
Robbins, 6th ed., 2000
MS Demyelinated Plaques
Preservation of axons
Robbins, 6th ed., 2000
MS - Perivascular Lymphocytes
Univ. Utah
MS-lymphocytes & reactive astrocytes
Univ. Utah
MS-lymphocytes & reactive astrocytes
Univ. Utah
Enlarged, atypical nuclei, not hyperchromatic
MS Plaque - Subacute - Macrophages
Univ. Utah
MS Plaque - Subacute - Macrophages
Gitter cells - myelin breakdown products
Univ. Utah
Creutzfeldt cell
with minute
chromatin
fragments
Often found in
acute plaques
of MS or in
astrocytomas.
Short-lived due
to cell degeneration.
NEJM 339:542-9,1998
Multiple Sclerosis
Other locations for plaques?
Optic nerves, brain stem, cerebellum,
spinal cord white matter, etc.
What is Devic’s Disease?
Demyelinating lesions of optic nerve(s)
& spinal cord (neuromyelitis optica)
Clinically, 30-40 yr, acute onset and
often rapidly progressive
Devic’s
Disease
Optic Nerve
Ellison & Love
Multiple Sclerosis - Tests
CSF: IgG oligoclonal bands or  IgG
and lymphocytes (<50 cells)
MRI: Abnormal in 95% patients
Gadolinium enhanced lesions
5-10X > than clinical relapses
Basis for future clinical trials as
an outcome measure
Abnormal evoked potential studies: central
conduction velocities
MS Clinical Categories
Relapsing-remitting - episodes of acute worsening
w/ recovery & a stable course between relapses
Secondary progressive - gradual neurologic
deterioration w/ or w/o superimposed acute
relapses in a patient who previously had
relapsing-remitting MS
Primary progressive - gradual, nearly continuous
neurologic deterioration from the onset of sympt.
Progressive relapsing - gradual neurologic
deterioration from the onset of symptoms but with
subsequent superimposed relapse
MS Variants - Clinical Progression
Charcot type - most common (variable)
relapsing-remitting
- signs & symptoms w/n days recovery(wks)
many develop secondary progression with persistent
- signs of CNS dysfunction after relapse
- disease may progress between relapses
10% benign MS - do well > 20 years
10% primary progressive MS - older patients,
chronic progressive myelopathy
Rare -Progressive relapsing MS
Rare MS Variants
Acute MS (Marburg variant)
Fulminant, rapid downhill course
(fatal w/n months or 1 year)
Younger patients
Prominent tissue destruction in
addition to demyelination
CT & MRI lesions may be suspicious
due to mass effect & edema and
are then biopsied
Acute (Marburg-type) MS
Rare MS Variants cont...
Schilder’s Disease (diffuse sclerosis)
Bihemispheric widespread demyelination
Scattered typical MS plaques
Axonal injury, cavitation, & Wallerian
degeneration with sparing of U fibers
Leukodystrophy must be excluded
Diff. Dx. Of “mental deterioration” in
adolescents
Rare MS Variants cont...
Balo’s Concentric Sclerosis
Young patients
Acute onset with strokelike symptoms
Absence of remissions & exacerbations
Affected tissue looks layered (onionskin)
demyelinated white matter and more
myelinated white matter (maybe due
to remyelination)
Concentric Sclerosis (Balo’s Disease)
2. Acquired Metabolic Demyelination
Central pontine myelinolysis (CPM)
Multifocal necrotizing
leukoencephalopathy (MNL)
Marchiafava-Bignami disease
Osmotic demyelination syndromes ?
Central Pontine Myelinolysis
What is the typical clinical scenario?
Rapid  serum Na+
in hyponatremic patient,
(chronic liver dz, alcoholics)
Very similar to MS plaque
Central Pontine Myelinolysis
S. Schochet
Multifocal Necrotizing
Leukoencephalopathy (MNL)
Foci of necrosis with Ca++, WM > GM
Formerly “focal pontine leukoencephalopathy”
Predominantly immunosuppressed patients (AIDS,
leukemia, irradiation, amphotericin B,
methotrexate, other cytotoxic drugs)
Clinically - complex neurologic abnormalities in
patients with long critical illnesses
Multifocal Necrotizing Leukoencephalopathy
Ellison and Love, Fig. 22.33, 1998
- ill-defined chalky white foci
- distributed in pons and white matter
MNL
- spongy vacuolation
- macrophages
- swollen axons (may Ca++)
- foci often microscopic
Marchiafava - Bignami Disease
Rare complication of alcoholism
Destruction of myelinated fibers
Degeneration of corpus callosum &
anterior commissure
Loss of callosal fiberscortical laminar
sclerosis
Morel’s laminar sclerosis (frontal &
temporal cortex, usually layer III)
Marchiafava - Bignami Disease
Ellison & Love
3. Toxic Leukoencephalopathy
Variability:
Diverse mechanisms
Target of injury (myelin, astrocytes,
blood vessels, etc.)
Etiologies:
Cranial irradiation
Therapeutic drugs (antineoplastics)
Drugs of abuse (cocaine, heroin, ecstasy or
MDMA, toluene, etc.)
Environmental solvents (organic solvents)
Targets of Toxins in Cerebral WM
Filley & Kleinschmidt-DeMasters, NEJM, 2001
Toxic Leukoencephalopathies
Clinical:
WM tracts for higher cerebral function affected
Inattention
Forgetfulness
Changes in personality
Dementia
Coma
Death
Absence of aphasia, language preserved
Cranial Irradiation
More common for whole brain > local field
Neurobehavioral dysfunction in 28%
3 stages:
acute reaction - patchy, reversible WM edema
delayed reaction - widespread edema &
demyelination
severe delayed reaction - loss of myelin and
axons due to vascular necrosis and
thrombosis
Chemotherapy Drugs
Especially those given intrathecally
Especially when given with irradiation
Methotrexate - discrete or confluent necrosis
- can cause MNL
- vascular lesions in some
Carmustine
Others (cisplatin, cytarabrine, fluorouracil,
levamisole, fludarabine, thiopeta)
Sometimes IL-2, interferon-alpha
T2-MRI in man with
right frontal GBM
after radiation &
chemotherapy
with carmustine
shows
symmetric
hyperintensity
of the cerebral
white matter
(2 arrows)
Methotrexate Toxicity
6 yr
old girl
treated
intrathecally
for leukemia with
CNS relapses
Methotrexate Toxicity
Swollen axons, many are mineralized
Toluene
Spray paints, varnishes,
thinners, dyes, glues,
histology reagents, &
aviation fuels
Abused as an inhalant
(glue-sniffing)
Myelin degradation
T2 MRI in man with dementia
and long-term toluene abuse
Symmetric hyperintensity of
WM & ventricular enlargement
Ethanol Leukotoxicity
Alcoholics have  hyperintense WM foci - MRI
Frontal WM preferentially affected
Dz already discussed?
Marchiafava - Bignami
Fetal alcohol syndrome - delayed myelination &
agenesis of the corpus callosum
Atrophy of corpus callosum with necrosis
MDMA (“Ecstasy”)
3,4 - methylenedioxymethamphetamine
1999 - 8% U.S. high school seniors
Serotoninergic axonal injury
Oxidative stress damages myelin
End of this module
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