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

Axial FLAIR Hx: 25 yr woman with relapsing- remitting MS 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 peri- ventricular 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 Rarely see layers of demyelinated & more normally myelinated white 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 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 degen- eration. 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

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

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)

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

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

Multifocal Necrotizing Leukoencephalopathy Ellison and Love, Fig. 22.33, 1998 - ill-defined chalky white foci - distributed in pons and white matter

MNL - spongy vacuolation - swollen axons (may Ca++) - macrophages - 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) Filley & Kleinschmidt-DeMastsers, NEJM, p.428, 2001

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

Methotrexate Toxicity Swollen axons, many are mineralized

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

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

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