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

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