Demyelination and Dysmyelination

Brian W. Little, MD, PhD 2017

This presentation is solely for the use of the students in
Pathology at the Xavier University School of Medicine.
It is not to be copied, reproduced or distributed in any
way.
The sources of images are noted in the Notes section of
the presentation, when available.
Objectives
• Define demyelination and dysmyelination
• Describe the definition, epidemiology, gross and microscopic
pathology and possible/proposed etiologies of Multiple
Sclerosis
• Identify five diseases that might be included in the differential
diagnosis of suspected Multiple Sclerosis; suggest ways in
which they can be differentiated
• Describe Central Pontine Myelinolysis, and explain the
correlation of the anatomy and pathologic findings
• Describe the pathology of Guillain-Barre Syndrome
• Describe the general pathology of the major dysmyelinating
syndromes
 MYELIN
• Electrical insulator – rapid propagation of
impulses
• Plasma membrane of the oligodendrocytes in
CNS and Shwann cells in PNS
• Internode and nodes of Ranvier
• DEMYELINATION - the loss of
previously present, normal myelin,
either through direct attack on the
myelin sheath, or indirect damage to
the oligodendroglial cell

• DYSMYELINATION - the production of

normal or abnormal amounts of
structurally abnormal myelin
DEMYELINATING DISEASES

• Multiple sclerosis
• Perivenous encephalomyelitis
• Central pontine myelinolysis
• Progressive multifocal leukoencephalopathy [
PMLE ]
• Immune mediated neuron destruction
• Anti-NMDA
• Others
DYSMYELINATING DISEASES
• LEUKODYSTROPHY
• adrenoleukodystrophy
• adrenomyeloneuropathy
• metachromatic leukodystropohy
• globoid cell leukodystrophy [Krabbe]
• sudanophilic leukodystrophy
Multiple Sclerosis - definition

• an acquired disease of the central nervous

system in which there are multiple, discrete
areas of myelin destruction associated with
reactive gliosis and perivascular infiltrates of
lymphocytes

• A disease with episodes separated in TIME

and SPACE
Multiple Sclerosis - Clinical Presentation

• onset - 20 to 40 yrs - peak year 33

• Rare before 15
• Rare after 50
• must involve two or more separate
areas of brain or spinal cord
[“multiple”] at two or more times
• multiple diagnostic modalities may be
used to identify areas of involvement
Subtypes of Multiple Sclerosis

• Relapsing/Remitting
• About 80% of cases initially
• Primary Progressive
• About 15% of cases initially
• Secondary Progressive
• R/R progressing to PP
• Benign – few episodes
Clinical Features of Multiple Sclerosis
• Involve any part of cortex and cerebellum
• Multiple signs and symptoms depending on location
• Brain stem involvement :
• Cranial nerve signs.
• Ataxia, nystagmus, internuclear ophthalmoplegia.
• Spinal cord involvement :
• Motor and sensory impairment of trunk and limbs,
and spasticity.
• Prognosis – Some patients have fulminant course
dying within week most have a slow chronic
relapsing debilitating course
 Multiple Sclerosis - Clinical
Course
• “special” forms
• Marburg - acute progressive
• Devic - neuromyelitis optica
• Schilder - diffuse sclerosis
• therapy - immune mediation
• corticosteroid, ACTH, immune suppression, beta-
interferon, copolymer 1
• Numerous monoclonal antibodies
Multiple Sclerosis -
Epidemiology
• >1/1000 persons in US [prevalence]
• 400,000 active cases in US today
• >10,000 new cases each year in US
• excess of females [2:1]
• mild familial association
• twin studies – monozygotic – 25%, dizygotic – 3%
• excess of HLA-A3, B7, DR2
Multiple Sclerosis - Epidemiology
• more prevalent in temperate
climates higher latitudes
• this is an oversimplification
• only truly holds for
Australia/New Zealand
• lower incidence in orientals,
blacks, American indians,
aborigines
• the “Viking” hypothesis
Multiple Sclerosis - Precipitating Factors

• diet • pregnancy
• heavy metals • exertion
• trauma • fatigue
• surgery • heat
• stress • infections
Multiple Sclerosis -
Epidemiology
• Migration studies
• very difficult to control
• the approximate prevalence for those moving to a
new area after age 15 is equal to the prevalence in
the area from which the people migrated
• Faroe Island Study
• suggestion that disease was absent prior to arrival
of British Troops in Second World War
• suggestion that the disease is associated with
Canine Distemper Virus - never proven
Multiple Sclerosis - Etiology
• the etiology of multiple sclerosis is unknown
• virus/infective
• multiple virus antigens, antibodies and nucleic
acid fragments have been associated with MS
• HHV6, HTLV, CMV, Newcastle disease, Marek
disease, EBV, distemper, others
• ? double hit - infancy and adult
 Multiple Sclerosis - Etiology
• immunologic
• it is presumed that cell mediated immune
mechanisms contribute to the demyelination,
but neither the inducing agent, nor the exact
mechanism have been defined
• lack of vitamin D - production by sunlight
 Multiple Sclerosis - Etiology
• genetic components
• certain HLA alleles are more common
– A3, B7, DR2, DW2 in US populations
– (-) A1, B12 in Northern Europe
• twin studies
– dizygotic - 40 x general population [3%]
– monozygotic -300 x general population [25%]
Laboratory finding - Multiple Sclerosis

• Gamma globulin is elevated in CSF with discrete

oligoclonal bands.
• Antibody arise in response to myelin injury and
do not play a primary role in demyelination.
• Myelin basic protein is elevated in CSF in periods
of active demyelination.
• Gamma globulin and MBP used as a marker of
disease acivity
• Both are NOT specific from MS
• MRI studies are the most helpful
 MS - Oligoclonal Bands

• multiple immunoglobulins
in CSF
• produced in CNS, not
leaking from serum
• antigens not known
• may be making a
resurgence in diagnostic
criteria
Multiple sclerosis - MRI
 Multiple Sclerosis - Gross Pathology

• Plaque
• preferentially
periventricular, optic
chiasm, subpial
• may be symmetrical
• may occur anywhere
in the brain
– not limited to white
matter
Multiple Sclerosis

The white matter has a large "plaque" of

demyelination. The plaque has a grey-tan
appearance.
 Multiple Sclerosis - Gross Pathology

• Plaque
• sharp border,
irregular shape
• gray, similar to
gray matter
• firm, “sclerotic”
due to gliosis
Multiple Sclerosis - Microscopic Pathology

• myelin loss, detected by myelin stains

• early lesions are perivenous
• mononuclear cells - macrophages with lipid
• loss of oligodendroglial cells
• reactive astrocytes - may be “bizarre”
• lymphocytic infiltrate – perivenous
• mostly T-cell
• the axons are largely preserved
Multiple Sclerosis

Active plaque: myelin breakdown with abundant

macrophages containing lipid-rich, PAS- positive
debris. Lymphocytes and monocytes are present
in a perivascular cuff.
The Active Lesion of Multiple Sclerosis in Human Tissue (Panels A, B, C, D, F, G, H, and I) and Mouse Tissue (Panel
E).

Frohman EM et al. N Engl J Med 2006;354:942-955.

 The Chronic Lesion of Multiple Sclerosis in Humans.

Frohman EM et al. N Engl J Med 2006;354:942-955.

 Treatment Options for Multiple Sclerosis.

Frohman EM et al. N Engl J Med 2006;354:942-955.

“Variants” of MS – all RARE
• Neuromyelitis Optica:
• Devic’s syndrome
• Optic neuritis combined with attacks of myelitis
• Aquaporin-4 Antibody disease, or Myelin Glycoprotein
Antibody
• Acute MS
• Marburg’s variant
• Fulminant demyelinating process
• Shilder disease
• Severe childhood MS
• Balo Concentric Sclerosis
• Unusual pattern of demyelination
Multiple Sclerosis - Differential
Diagnosis
• disseminated encephalomyelitis
• HTLV-1 associated paraparesis
• CNS AIDS
• neurobrucellosis
• neuroborreliosis [Lyme disease]
• neurosarcoidosis
• CNS vasculitis
• CNS systemic lupus erythematosis
Perivenous Encephalomyelitis
• Acute Disseminated Encephalomyelitis
• Acute Necrotizing Hemorrhagic
Leukoencephalitis
• Experimental Allergic Encephalomyelitis in
Animals
Acute Disseminated Encephalomyelitis

• Postinfectious/Postvaccinial
• measles
• smallpox vaccination [vaccinia]
• less common in those under 2 yr
• onset 1-2 weeks after exposure
• headache, meningismus
• 5/6 recover, but with CNS deficits
Acute Disseminated
Encephalomyelitis
• Post immunization or infection
• Widely scattered small foci of perivenular
inflammation and demyelination
• Lesions can have hemorrhagic conversion
• Progression is rapid over hours
• May or may not result in permanent disability
 Acute Disseminated Encephalomyelitis
• grossly edematous brain with perivenous
acute hemorrhages
• myelin destruction with relative axon
preservation
• with measles, the virus does not appear in the
CNS
• T-cells sensitive to myelin basic protein
Acute Necrotizing Hemorrhagic
Leukoencephalitis

• follows viral respiratory infection

• headache, fever, coma, death
• acute white matter hemorrhage with
edema
• perivenous demyelination and necrosis
Experimental Allergic Encephalomyelitis
[EAE]

• subacute demyelinating disease in animals

• produced by injecting myelin or purified myelin
components into CSF
• myelin basic protein, proteolipid protein
• produces inflammatory demyelination
• repeated stimulus gives “relapsing” course
• experimental model mimicking MS
Progressive Multifocal
Leukoencephalopathy [PMLE]
• Confined largely to immunosuppressed individuals
• HIV/AIDS
• Inherited immune deficiencies
• Iatrogenic immune deficiencies [e.g. cancer chemotherapy, high
dose corticosteroid therapy]
• Progressive, relentless
• Multiple areas of white matter with demyelination
• Minimal inflammation [part of immune deficiency?]
• Caused by “JC” virus
• Polyoma virus
• Most individuals have virus; held in check by intact immune
system
Progressive Multifocal
Leukoencephalopathy [PMLE]
Central Pontine Myelinolysis
• Associated with rapid correction of
hyponatremia; liver transplant
• Confusion, weakness, eye palsies, dysarthria,
dysphagia
• Central pons proper [lower]
• Relatively symmetrical
• Lateral geniculate, external capsule, thalamus,
basal ganglia, subcortical white
• Active demyelination w/o inflammation
Guillain Barre Syndrome
• acute inflammatory polyneuropathy
• monophasic illness with predominant motor
involvement
• mild disease to life threatening illness
• 2/3 have infection in preceeding 3 weeks - 25%
associated with Campylobecter Jejuni
• < 10% of adults infected with Zikavirus
Guillain Barre Syndrome

• motor weakness, distal to proximal

• face involved
• loss of deep tendon reflexes
• EMG/NCV - denervation, demyelination
• may have autonomic involvement
• progresses for 2-4 weeks, then resolves slowly
Guillain Barre Syndrome

• CSF protein elevated, few cells

• “albuminocytologic dissociation”
• nerves show demyelination and
chronic [lymphocyte, macrophage]
infiltration
• axons are relatively preserved
Peripheral Neuropathies
• Immune Mediated
• Myelin associated protein
• Myelin associated glycoprotien
• Sporadic
• Adult, usually
• Childhood – Neuromyelitis optica [Devic
syndrome]
• Affect multiple nerves – “diffuse neuropathy”
• IG-A or IG-M
Inherited Diseases of the
Nervous System
• Those involving Neurons vs. those involving myelin and white
matter
• The genetic inheritance pattern
• The biochemical defect
• The organelle involved – eg, peroxisome, lysosome,
mitochondrion
• The clinical pattern of disease
• Age of onset
• Symptoms – weakness, fatigue, seizure, neuropathy, etc.

• Most are quite rare, but may be more common in specific

population groups
Leukodystrophies
• An intrinsic defect that interferes with the
generation and/or maintenance of myelin.
• Hereditary (majority):
• X-linked.
• Autosomal recessive.
• Age: infancy and childhood.
• Some are associated with specific lysosomal
enzyme defect  myelin loss
• or peroxisomal enzyme defect
Generalities – not always true

• Affected children are normal at birth but

begin to miss developmental milestones
• Deterioration in motor skill
• Spasticity
• Ataxia
• GI or renal symptoms

Earlier the age at onset of symptoms the

more severe the clinical course
Some well described leukodystrophies
• metachromatic leukodystrophy,
• Krabbé disease,
• adrenoleukodystrophy,
• Pelizaeus-Merzbacher disease,
• Canavan disease,
• Childhood Ataxia with Central Nervous System
Hypomyelination or CACH (also known as Vanishing White
Matter Disease),
• Alexander disease,
• Refsum disease, and
• cerebrotendinous xanthomatosis
Some well described leukodystrophies
• metachromatic leukodystrophy, arylsulfatase A, AR
• Krabbé disease, galactocerebrosidease, AR
• adrenoleukodystrophy, Peroxisome ALDP, X-linked
• Pelizaeus-Merzbacher disease, Proteolipid Protein, X-linked
• Canavan disease, Aspartoacyclase, AR
• Childhood Ataxia with Central Nervous System
Hypomyelination or CACH (also known as Vanishing White
Matter Disease), eukaryotic initiation factor 2B, AR
• Alexander disease, GFAP, Sporadic
• Refsum disease, Peroxisome phytanic acid breakdown, AR
• cerebrotendinous xanthomatosis, sterol 27-hydroxylase
The Leukodystrophies (in alphabetical order)
• 18q Syndrome with deficiency of myelin basic protein
• Acute Disseminated Encephalomyeolitis (ADEM)
• Acute Disseminated Leukoencephalitis
• Acute Hemorrhagic Leukoencephalopathy
• Adrenoleukodystrophy X-Linked (ALD)
• Adrenomyeloneuropathy (AMN)
• Aicardi-Goutieres Syndrome
• Alexander Disease
• Adult-onset Autosomal Dominant Leukodystrophy (ADLD)
• Autosomal Dominant Diffuse Leukoencephalopathy with neuroaxonal spheroids (HDLS)
• Autosomal Dominant Late-Onset Leukoencephalopathy
• Childhood Ataxia with diffuse CNS Hypomyelination (CACH or Vanishing White Matter Disease)
• Canavan Disease
• Cerebral Autosomal Dominant Arteropathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
• Cerebrotendinous Xanthomatosis (CTX)
• Craniometaphysical Dysplasia with Leukoencephalopathy
• Cystic Leukoencephalopathy with RNASET2
• Extensive Cerebral White Matter abnormality without clinical symptoms
• Familial Adult-Onset Leukodystrophy manifesting as cerebellar ataxia and dementia
• Familial Leukodystrophy with adult onset dementia and abnormal glycolipid storage
• Globoid Cell Leukodystrophy (Krabbe Disease)
• Hereditary Adult Onset Leukodystrophy simulating chronic progressive multiple sclerosis
• Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (HABC)
• Hypomyelination, Hypogonadotropic, Hypogonadism and Hypodontia (4H Syndrome)
• Lipomembranous Osteodysplasia with Leukodystrophy (Nasu Disease)
• Metachromatic Leukodystrophy (MLD)
• Megalencephalic Leukodystrophy with subcortical Cysts (MLC)
• Neuroaxonal Leukoencephalopathy with axonal spheroids (Hereditary diffuse leukoencephalopathy with spheroids – HDLS)
• Neonatal Adrenoleukodystrophy (NALD)
• Oculodetatoldigital Dysplasia with cerebral white matter abnormalities
• Orthochromatic Lleukodystrophy with pigmented glia
• Ovarioleukodystrophy Syndrome
• Pelizaeus Merzbacher Disease (X-linked spastic paraplegia)
• Refsum Disease
• Sjogren-Larssen Syndrome
• Sudanophilic Leukodystrophy
• Van der Knaap Syndrome (Vacuolating Leukodystrophy with Subcortical Cysts or MLC)
• Vanishing White Matter Disease (VWM) or Childhood ataxia with diffuse central nervous system hypomyelination, (CACH)
• X-linked Adrenoleukodystrophy (X-ALD)
• Zellweger Spectrum: Zellweger Syndrome, Neonatal Adrenoleukodystrophy, and Infantile Refsum Disease

http://ulf.org/types-of-leukodystrophy
Adrenoleukodystrophy

• Incidence – about 1:22,000 males

• variable onset and course - infant to adult
• x chromosome, q28, sex-linked recessive
• disorder of peroxisomes
• accumulation of very long chain fatty acids
• dysmyelination, bizarre astrocytes
• EM - linear cytoplasmic inclusions
Metachromatic
Leukodystrophy
• Incidence about 1:100,000
• sulfatide lipidosis
• onset as child or adult, autosomal recessive
• deposits in brain, nerve, liver, kidney, GB, WBC
• arylsulfatase A deficiency
• Cresyl violet, toluidine blue, thionine stain BROWN
in frozen sections [the sulfatide]
Metachromatic Leukodystrophy
Subacute Combined degeneration
• Late manifestation of vitamin B12 deficiency
• ? Defective methylation of Myelin Basic Protein
• Degeneration of lateral and posterior columns, thoracic
predominates
• Not identifiable to specific nuclei
• Untreated – paraplegia, sensory loss
• Associated lesions
• Peripheral neuropathy
• Optic atrophy
• Megaloblastic anemia [pernicious anemia]
Neurologic disease of Ethanol
• Intertwined with trauma
• Many linked to nutritional deficiency
• Wernicke disease – acute
• Korsakoff syndrome – chronic
• Midline cerebellar degeneration
• Marchiafava-Bignami disease
• Peripheral neuropathy
• others
Thiamine B1 Deficiency
• Acute – Wernicke
• Ophthalmoplegia, confusion, ataxia
• Hypothalamic area, DMN thalamus, PN, corpora
quadrigemina, 4th ventricle, olives
• May be subtle grossly
• Neurons preserved early
• Cerebellum
• Superior vermis
• Chronic – Korsakoff Psychosis
• Aphasia, apraxia, agnosia
• You do not have to be alcoholic !!!!!!!!!
Midline Cerebellar Vermis Atrophy
Marchiafava-Bignami Disease
Fetal Alcohol Syndrome
• Characteristic facies
• Short palpebral fissure
• Flattened nose and maxilla
• Wide mouth
• Microcephaly
• Hydrocephalus
• Heterotopias of gray matter
• Agenesis of corpus callosum
• Schizencephaly
• Cerebellar malformations
Radiation
Leukoencephalopathy
• The CNS is moderately sensitive to radiation –
above 5500 rad
• Myelin loss and degeneration
• Prominent vascular changes – hyaline
• Minimal lymphocytic infiltration
• Toxicity may be enhanced by therapeutic agents
• Acute, subacute, chronic
Metabolic Encephalopathy

• Hepatic – hyperammonemic
• Confusion, asterixis
• Alzheimer Type II cells – Caudate and Putamen
• Fewer in deep cerebral cortex
Alzheimer Type 2 astrocytes
Carbon Monoxide Poisoning
• Odorless gas heavier than air
• Tight binding to hemoglobin, displacing oxygen
• Acute – focal discoloration of Globus Pallidus
• Chronic – chronic hypoxia
Chronic Manganese Poisoning
• Behavioral disturbance, psychosis
• Hallucinations
• Parkinsonism
• Accumulation in corpus striatum and globus pallidus
• Detectable by MRI
• No specific pathology
• Neruonal loss and gliosis
Organic Mercury Poisoning
• Minimata Disease
• Inorganic mercury discharged
• Local bacteria methylated
• Ingested by fish, and into local diet
• Oral paresthesias, ataxia, tunnel vision
• Neuronal loss
• Visual cortex, auditory cortex
• Cerebellar granular cell layer loss
• Severe damage to fetus
Hepatolenticular Degeneration
• Wilson disease
• Liver failure, cirrhosis
• Wide range of CNS symptoms
• Kayser-Fleischer rings
• Copper transport ATPase (ATP7B) mutation - 13q14.3
• Disease of caudate & Putamen
• Opalski cell – shrunken, eosinophilic neuron