1. 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)

2. 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

3. 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

4. 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

5. 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

6. Axial FLAIR Hx: 25 yr woman with relapsing- remitting MS
Periventricular
hyperintense
WM lesions
NEJM 343:938-52, 2000

7. 9 months later Axial FLAIR  number &  size of WM lesions
NEJM 343:938-52, 2000

8. With gadolinium Many lesions demonstrate ring or peripheral
enhancement
NEJM 343:938-52, 2000

9. T1-weighted MRI Multiple regions of diminished signal, “black
holes”, in peri-
ventricular
WM and corpus
callosum.
Chronic lesions
of MS.
NEJM 343:938-52, 2000

10. MS - Demyelinated Plaques
Well-demarcated, gray, gelatinous
S. Schochet

11. MS Plaque, often periventricular
Lateral
Ventricle
Ellison & Love

12. MS Plaque Dawson’s fingers? Extensions along blood vessels
Rarely see layers of
demyelinated & more
normally myelinated
white matter (not here)
Robbins, 6th ed.

13. Shadow Plaques - partial myelination
adjacent to complete demyelination
GRIPE

14. MS Plaque with H&E Stain
Univ. Utah

15. MS Plaque
Luxol Fast
Blue Stain
Univ. Utah

16. MS Plaque - Luxol Fast Blue Stain
Univ. Utah

17. MS Plaque with Bodian Stain - Axons
Univ. Utah

18. MS Demyelinated Plaques
Loss of myelin (Luxol Fast Blue Stain)
Perivascular
lymphocytes
Robbins, 6th ed., 2000

19. MS Demyelinated Plaques
Preservation of axons
Robbins, 6th ed., 2000

20. MS - Perivascular Lymphocytes
Univ. Utah

21. MS-lymphocytes & reactive astrocytes
Univ. Utah

22. MS-lymphocytes & reactive astrocytes
Univ. Utah
Enlarged, atypical nuclei, not hyperchromatic

23. MS Plaque - Subacute
- Macrophages
Univ. Utah

24. MS Plaque - Subacute - Macrophages
Gitter cells - myelin breakdown products
Univ. Utah

25. Creutzfeldt cell with minute chromatin fragments Often found in
acute plaques
of MS or in
astrocytomas.
Short-lived due
to cell degen-
eration.
NEJM 339:542-9,1998

26. 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, yr, acute onset and
often rapidly progressive

27. Devic’s
Disease
Optic Nerve
Ellison & Love

28. 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

29. 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

30. 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

31. 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

32. Acute (Marburg-type) MS

33. Schilder’s Disease (diffuse sclerosis)
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

34. Balo’s Concentric Sclerosis
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)

35. Concentric Sclerosis (Balo’s Disease)

36. 2. Acquired Metabolic Demyelination
Central pontine myelinolysis (CPM)
Multifocal necrotizing
leukoencephalopathy (MNL)
Marchiafava-Bignami disease
Osmotic demyelination syndromes ?

37. Central Pontine Myelinolysis
What is the typical clinical scenario?
Rapid  serum Na+
in hyponatremic patient,
(chronic liver dz, alcoholics)
Very similar to MS plaque

38. Central Pontine Myelinolysis
S. Schochet

39. Leukoencephalopathy (MNL)
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

40. Multifocal Necrotizing Leukoencephalopathy
Ellison and Love, Fig , 1998
- ill-defined chalky white foci
- distributed in pons and white matter

41. MNL - spongy vacuolation - swollen axons (may Ca++)
- macrophages foci often microscopic

42. 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)

43. Marchiafava - Bignami Disease
Ellison & Love

44. 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)

45. Targets of Toxins in Cerebral WM
Filley & Kleinschmidt-DeMasters, NEJM, 2001

46. Toxic Leukoencephalopathies
Clinical:
WM tracts for higher cerebral function affected
Inattention
Forgetfulness
Changes in personality
Dementia
Coma
Death
Absence of aphasia, language preserved

47. 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

48. 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

49. T2-MRI in man with right frontal GBM after radiation & chemotherapy
with carmustine
shows
symmetric
hyperintensity
of the cerebral
white matter
(2 arrows)
Filley & Kleinschmidt-DeMastsers, NEJM, p.428, 2001

50. Methotrexate Toxicity
6 yr
old girl
treated
intrathecally
for leukemia with
CNS relapses

51. Methotrexate Toxicity
Swollen axons, many are mineralized

52. Toluene Myelin degradation Spray paints, varnishes,
thinners, dyes, glues,
histology reagents, &
aviation fuels
Abused as an inhalant
(glue-sniffing)
T2 MRI in man with dementia
and long-term toluene abuse
Symmetric hyperintensity of
WM & ventricular enlargement
Myelin degradation

53. 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

54. MDMA (“Ecstasy”) 3,4 - methylenedioxymethamphetamine
% U.S. high school seniors
Serotoninergic axonal injury
Oxidative stress damages myelin

55. Please send suggestions to
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