white matter lesions
DESCRIPTION
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) - PowerPoint PPT PresentationTRANSCRIPT
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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
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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
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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
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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
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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
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Axial FLAIR
Periventricular hyperintense WM lesions
Hx: 25 yr woman with relapsing- remitting MS
NEJM 343:938-52, 2000
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9 months later
Axial FLAIR
number & size ofWM lesions
NEJM 343:938-52, 2000
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With gadolinium
Many lesions demonstrate ring or peripheral enhancement
NEJM 343:938-52, 2000
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T1-weighted MRIMultiple regionsof diminishedsignal, “blackholes”, in peri-ventricularWM and corpuscallosum. Chronic lesionsof MS.
NEJM 343:938-52, 2000
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MS - Demyelinated PlaquesWell-demarcated, gray, gelatinous
S. Schochet
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MS Plaque, often periventricular
Lateral Ventricle
Ellison & Love
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MS Plaque
Dawson’s fingers?
Extensions alongblood vessels
Rarely see layers ofdemyelinated & morenormally myelinatedwhite matter (not here)
Robbins, 6th ed.
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Shadow Plaques - partial myelination adjacent to complete demyelination
GRIPE
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MS Plaque with H&E Stain
Univ. Utah
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MS Plaque
Luxol FastBlue Stain
Univ. Utah
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MS Plaque - Luxol Fast Blue Stain
Univ. Utah
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MS Plaque with Bodian Stain - Axons
Univ. Utah
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MS Demyelinated PlaquesLoss of myelin (Luxol Fast Blue Stain)
Perivascularlymphocytes
Robbins, 6th ed., 2000
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MS Demyelinated Plaques
Preservation of axons
Robbins, 6th ed., 2000
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MS - Perivascular Lymphocytes
Univ. Utah
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MS-lymphocytes & reactive astrocytes
Univ. Utah
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MS-lymphocytes & reactive astrocytes
Enlarged, atypical nuclei, not hyperchromatic
Univ. Utah
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MS Plaque - Subacute - Macrophages
Univ. Utah
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MS Plaque - Subacute - Macrophages
Gitter cells - myelin breakdown products
Univ. Utah
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Creutzfeldt cell with minute chromatinfragments
Often found inacute plaques of MS or inastrocytomas.Short-lived dueto cell degen-eration.
NEJM 339:542-9,1998
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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
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Ellison & Love
Devic’sDisease
Optic Nerve
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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
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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
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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
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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
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Acute (Marburg-type) MS
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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)
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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)
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Concentric Sclerosis (Balo’s Disease)
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2. Acquired Metabolic Demyelination
Central pontine myelinolysis (CPM)
Multifocal necrotizing leukoencephalopathy (MNL)
Marchiafava-Bignami disease
Osmotic demyelination syndromes ?
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Central Pontine Myelinolysis
Rapid serum Na+in hyponatremic patient,(chronic liver dz, alcoholics)Very similar to MS plaque
What is the typical clinical scenario?
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Central Pontine Myelinolysis
S. Schochet
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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
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Multifocal Necrotizing Leukoencephalopathy
- ill-defined chalky white foci- distributed in pons and white matter
Ellison and Love, Fig. 22.33, 1998
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MNL
- spongy vacuolation - swollen axons (may Ca++)- macrophages - foci often microscopic
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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)
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Marchiafava - Bignami Disease
Ellison & Love
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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)
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Targets of Toxins in Cerebral WM
Filley & Kleinschmidt-DeMasters, NEJM, 2001
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Toxic Leukoencephalopathies
Clinical: WM tracts for higher cerebral function affected Inattention
Forgetfulness Changes in personality
Dementia Coma Death Absence of aphasia, language preserved
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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
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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
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T2-MRI in man withright frontal GBMafter radiation &chemotherapywith carmustineshowssymmetrichyperintensityof the cerebralwhite matter (2 arrows)
Filley & Kleinschmidt-DeMastsers, NEJM, p.428, 2001
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Methotrexate Toxicity
6 yrold girl treatedintrathecallyfor leukemia withCNS relapses
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Methotrexate Toxicity
Swollen axons, many are mineralized
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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
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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?
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MDMA (“Ecstasy”)
3,4 - methylenedioxymethamphetamine
1999 - 8% U.S. high school seniors
Serotoninergic axonal injury
Oxidative stress damages myelin