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“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.