“Demyelinating” diseases

Mark L Cohen, M.D.Department of Pathology

University Hospitals Case Medical CenterJanuary 6th, 2009

Learning Objectives

• Describe an algorithmic approach to the differential diagnosis of a patient with white matter disease.

• Provide examples of diseases representing the three major categories of leukoencephalopathies (genetic, acquired non-inflammatory & inflammatory) and discuss diagnostic features of each.

• Discuss the pathophysiology of Charcot’s triad, Uhthoff’s phenomenon, and L’hermitte’s symptom.

Normal myelinated axon

• Lipid-rich myelin sheath produced by oligodendrocytes• Axon insulation• Sodium channels clustered at nodes of Ranvier• Increased conduction speed and metabolic efficiency

Demyelination

• Decreased conduction velocity or block• Destablization of axonal cytoskeleton• Remodelling of internodal membrane• Progressive axonal loss

Oligodendroglial pathology

• Inborn errors– Leukodystrophies

• Acute injury– Inflammatory (multiple sclerosis and related

disorders)– Toxic and metabolic disturbances

• Chronic injury– Multiple system atrophy, progressive supranuclear

palsy

• Viral infection– Progressive multifocal leukoencephalopathy

• Neoplastic transformation– Oligodendrogliomas

Leukoencephalopathies: White matter damage with relative axonal preservation

• Inherited– Lipid, Protein, Mitochondrial,

Vascular• Acquired, non-inflammatory

– Toxic, Metabolic, Vascular, Traumatic

• Acquired, inflammatory– Infectious, Immunologic

MRI in Leukoencephalopathies

• Diffuse (Leukodystrophies)

• Discrete (Multiple sclerosis)

• Diverse (everything else)

Genetic disorders of white matter

• Lipid disorders (e.g. Adrenoleukodystrophy)• Cytoskeletal disorders (e.g. Alexander

disease)• Myelin protein disorders

(e.g Pelizaeus-Merzbacher disease)• Organic acid disorders (e.g Canavan disease)• Disorders of energy metabolism (e.g.

MELAS)

• Other (e.g. CADASIL)

Normal vs. Leukodystrophy (ALD)

Disease Cellular defect

Pathologic features

Metachromatic

Leukodystrophy

Lysosomal Metachromatic sulfatides within

macrophages

Krabbe Disease Lysosomal Globoid (multinucleated)

microglia

Adreno-

leukodystrophy

Peroxisomal Perivascular inflammation

Alexander disease

Cytoskeletal Rosenthal fibers

Subcortical U-fibers

Krabbe Disease Alexander Disease

Now you see ‘em Now you don’t

Globoid cell leukodystrophy (Krabbe)

Adrenoleukodystrophy

Alexander disease

Pelizaeus-Merzbacher Disease

Non-inflammatory Leukoencephalopathies

• Toxic (e.g. antineoplastic agents)• Metabolic (e.g. B12 deficiency)• Vascular (e.g hypertension)• Traumatic (e.g diffuse axonal injury)

Toxic leukoencephalopathies

• Structural alteration of white matter in which myelin suffers most

• Particularly involves tracts devoted to higher cerebral functioning

• Language usually preserved• Focal neurologic signs usually less

prominent than mental status changes

Radiation leukoencephalopathy

• Months to years after therapy (usually doses of 20 Gy or more)

• Vascular damage with hyalinization

• Coagulative necrosis of white matter

Central pontine myelinolysis Marchifava-Bignami disease

Inflammatory Leukoencephalopathies

• Infectious – HIV encephalitis– Progressive multifocal

leukoencephalopathy

• Immunologic – Multiple sclerosis & related disorders

HIV encephalitis

P24 immunostaining

Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy

JC virus immunostaining

Carswell, 1838

Babinski, 1885

1868

Nystagmus, intention tremor, scanning speech

Barber Chair phenomenon

Worsening of vision with exercise in optic neuritis

1890 1920

Site Symptoms Signs

Cerebrum Cognitive impairmentAttention deficit, dementia (late)

Optic Nerve Unilateral painful visual loss

Scotoma, afferent pupillary defect

CerebellumTremor

Clumsiness

Intention tremor

Ataxia, dysarthria

Brainstem Diplopia, vertigo, emotional lability

Nystagmus, INO, ophthalmoplegias

Spinal cordSpasms; bowel, bladder, erectile

dysfunctionSpasticity

• Reduced capacitance of thinly or unmyelinated axon segments underlies Uhthoff symptom

• Increased mechanical sensitivity of partially demyelinated axons underlies L’hermitte’s symptom

Clinical DDx of MS

• Systemic diseases with relapsing CNS involvement (vasculitis, collagen vascular disease, B12 deficiency)

• Progressive CNS system degenerations (hereditary ataxias, neuroaxonal dystrophies)

• Focal lesions with relapsing or progressive course (especially CNS tumors)

• Disseminated monophasic disorders (e.g. acute disseminated encephalomyelitis)

• Non-organic symptoms that mimic MS

MS Pathogenesis

•Molecular mimicry causes inappropriate migration of autoreactive myelin T cells across the blood-brain barrier, initiating an inflammatory reaction against proteins of the oligodendrocyte-myelin unit•T cells activated by IL-23 secrete IL-17, disrupting the blood-brain barrier•Th17 cells and activated microglia damage glia, axons, and neurons

Glia limitans perivascularis

2 steps to neuroinflammation

1 2

Glia limitans perivascularis

Post-capillary venule

Active demyelinating plaque

CD68 IHC

Gross pathology

Gross pathology

Inactive plaque

MS: Active & inactive plaques

Evolution of an MS plaque

Axonal pathology in MS

• Plaque associated axonal swellings (Charcot, 1880)

• More axons lost than generally believed (Marburg, 1906)

• Axonal sprouts arising from terminal spheroids (Jakob, 1915)

• Axonal transections in MS (Trapp et.al., NEJM, 1998)

• Nitric oxide donors produce reversible conduction block

• Prolonged NO causes NMDA receptor mediated toxicity

• Loss of oligodendroglial IGF1 support contributes to neuronal & axonal loss

Primary demyelination vs. primary neuroaxonal degeneration

Primary demyelination demonstrates:

• Lack of anatomic restriction

• Extension to pial surface

• Complete absence of myelin (occasionally with partial loss at interface secondary to remyelination)

MS: Recent advances

• Remyelination occurs in ~20% of people with MS, and is probably an important factor in re-establishing conduction

• Premyelinating oligodendrocytes are present in MS plaques

• In chronic MS plaques, persisting axons appear unreceptive to remyelination

Learning Objectives

• Describe an algorithmic approach to the differential diagnosis of a patient with white matter disease.

• Provide examples of diseases representing the three major categories of leukoencephalopathies (genetic, acquired non-inflammatory & inflammatory) and discuss diagnostic features of each.

• Discuss the pathophysiology of Charcot’s triad, Uhthoff’s phenomenon, and L’hermitte’s symptom.

References

• Compston A, Coles A. Multiple sclerosis. Lancet. 2008 Oct 25;372(9648):1502-17.

• Owens T, Bechmann I, Engelhardt B. Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol. 2008 Dec;67(12):1113-21.