White Matter Lesions Marie Beckner, MD 1. Idiopathic demyelinating disease (MS) Not described in this module: Dysmyelinating diseases, “leukodystrophies”
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White Matter LesionsMarie Beckner, MD
1. Idiopathic demyelinating disease (MS)
Not described in this module:Dysmyelinating diseases, “leukodystrophies”Infectious demyelination (PML)Post-infectious demyelination (cross rx to Ag)
2. Acquired metabolic demyelination
3. Toxic leukoencephalopathies
Primary Demyelination
Damage to oligodendroglia & their myelin sheaths Axons are relatively preserved
Secondary Demyelination
Damaged axon loss of myelin Axonal transectionWallerian degeneration in distal portion
1. MULTIPLE SCLEROSIS
First described in 1870’s
Chronic, idiopathic, inflammatorydemyelinating 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
Higher prevalence in colder climates
1 million worldwide, increasing rate
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
Axial FLAIR
Periventricular hyperintense WM lesions
Hx: 25 yr woman with relapsing- remitting MS
NEJM 343:938-52, 2000
9 months later
Axial FLAIR
number & size ofWM lesions
NEJM 343:938-52, 2000
With gadolinium
Many lesions demonstrate ring or peripheral enhancement
NEJM 343:938-52, 2000
T1-weighted MRIMultiple regionsof diminishedsignal, “blackholes”, in peri-ventricularWM and corpuscallosum. Chronic lesionsof MS.
NEJM 343:938-52, 2000
MS - Demyelinated PlaquesWell-demarcated, gray, gelatinous
S. Schochet
MS Plaque, often periventricular
Lateral Ventricle
Ellison & Love
MS Plaque
Dawson’s fingers?
Extensions alongblood vessels
Rarely see layers ofdemyelinated & morenormally myelinatedwhite matter (not here)
Robbins, 6th ed.
Shadow Plaques - partial myelination adjacent to complete demyelination
GRIPE
MS Plaque with H&E Stain
Univ. Utah
MS Plaque
Luxol FastBlue Stain
Univ. Utah
MS Plaque - Luxol Fast Blue Stain
Univ. Utah
MS Plaque with Bodian Stain - Axons
Univ. Utah
MS Demyelinated PlaquesLoss of myelin (Luxol Fast Blue Stain)
Perivascularlymphocytes
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
Enlarged, atypical nuclei, not hyperchromatic
Univ. Utah
MS Plaque - Subacute - Macrophages
Univ. Utah
MS Plaque - Subacute - Macrophages
Gitter cells - myelin breakdown products
Univ. Utah
Creutzfeldt cell with minute chromatinfragments
Often found inacute plaques of MS or inastrocytomas.Short-lived dueto cell degen-eration.
NEJM 339:542-9,1998
Multiple SclerosisOther 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
Ellison & Love
Devic’sDisease
Optic Nerve
Multiple Sclerosis - TestsCSF: IgG oligoclonal bands or IgG
and lymphocytes (<50 cells)
Abnormal evoked potential studies: central conduction velocities
MRI: Abnormal in 95% patientsGadolinium enhanced lesions 5-10X > than clinical relapses Basis for future clinical trials as an outcome measure
MS Clinical CategoriesRelapsing-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 years10% primary progressive MS - older patients, chronic progressive myelopathyRare -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...
Bihemispheric widespread demyelinationScattered typical MS plaquesAxonal injury, cavitation, & Wallerian degeneration with sparing of U fibersLeukodystrophy must be excludedDiff. Dx. Of “mental deterioration” in adolescents
Schilder’s Disease (diffuse sclerosis)
Rare MS Variants cont...
Balo’s Concentric Sclerosis
Young patientsAcute onset with strokelike symptomsAbsence of remissions & exacerbationsAffected 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
Rapid serum Na+in hyponatremic patient,(chronic liver dz, alcoholics)Very similar to MS plaque
What is the typical clinical scenario?
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
- ill-defined chalky white foci- distributed in pons and white matter
Ellison and Love, Fig. 22.33, 1998
MNL
- spongy vacuolation - swollen axons (may Ca++)- macrophages - foci often microscopic
Marchiafava - Bignami Disease
Rare complication of alcoholism
Destruction of myelinated fibersDegeneration of corpus callosum & anterior commissure
Loss of callosal fiberscortical laminar sclerosisMorel’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 intrathecallyEspecially when given with irradiationMethotrexate - discrete or confluent necrosis - can cause MNL - vascular lesions in someCarmustineOthers (cisplatin, cytarabrine, fluorouracil, levamisole, fludarabine, thiopeta)Sometimes IL-2, interferon-alpha
T2-MRI in man withright frontal GBMafter radiation &chemotherapywith carmustineshowssymmetrichyperintensityof the cerebralwhite matter (2 arrows)
Filley & Kleinschmidt-DeMastsers, NEJM, p.428, 2001
Methotrexate Toxicity
6 yrold girl treatedintrathecallyfor leukemia withCNS relapses
Methotrexate Toxicity
Swollen axons, many are mineralized
TolueneSpray paints, varnishes,thinners, dyes, glues, histology reagents, &aviation fuels
Abused as an inhalant(glue-sniffing)
Myelin degradationT2 MRI in man with dementiaand long-term toluene abuseSymmetric hyperintensity ofWM & ventricular enlargement
Ethanol Leukotoxicity
Alcoholics have hyperintense WM foci - MRI
Frontal WM preferentially affected
Fetal alcohol syndrome - delayed myelination & agenesis of the corpus callosum
Marchiafava - Bignami
Atrophy of corpus callosum with necrosis
Dz already discussed?
MDMA (“Ecstasy”)
3,4 - methylenedioxymethamphetamine
1999 - 8% U.S. high school seniors
Serotoninergic axonal injury
Oxidative stress damages myelin
End of this module
Please send suggestions tobecknerme@msx.upmc.edu
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