Demyelinating Disorders Pathology Study Guide

Demyelinating Disorders Pathology Video

Demyelinating Disorders

Demyelinating disorders are pathologic conditions due to the degeneration of myelin.

Axons are insulated by myelin, which increases conduction efficiency and speed.

Oligodendrocytes myelinate the central nervous system.

Schwann cells myelinate the peripheral nervous system.

Myelin and oligodendrocytes are typically destroyed in demyelinating illnesses, but axons are typically retained.

Examples of demyelinating disorders include:

Leukodystrophies
Multiple sclerosis
Subacute sclerosing panencephalitis
Progressive multifocal leukodystrophy (PML)
Central pontine myelinolysis

Leukodystrophies

Leukodystrophies are due to mutations that are inherited in the myelin-producing or myelin-maintaining enzymes.

The most prevalent form of leukodystrophy, metachromatic leukodystrophy, is caused by an autosomal recessive arylsulfatase deficiency.

Metachromatic leukodystrophy

In metachromatic leukodystrophy, arylsulfatase deficiency results in myelin build up in oligodendrocyte lysosomes because it cannot be broken down (lysosomal storage disease).

Krabbe disease

Galactocerebroside p-galactosidase deficiency causes Krabbe disease in an autosomal recessive pattern.

Macrophages accumulate galactocerebroside in Krabbe disease.

Adrenaleukodystrophy

Adrenoleukodystrophy is caused by an X-linked mutation.

Adrenoleukodystrophy causes the addition of coenzyme A to long-chain fatty acids to be hindered.

In adrenoleukodystrophy, fatty acid buildup harms the brain’s white matter and glands.

Leukodystrophies. Globoid cell leukodystrophy PAS - Multinucleated macrophages ("globoid cells") and loss of myelinated fibers in a case of Krabbe's leukodystrophy Jensflorian - Not altered. CC BY-SA 3.0
Leukodystrophies. Autorecessive Inheritance Pattern en:User:Cburnett - Own work in Inkscape Autosomal recessive gene. Not altered. CC BY-SA 3.0
Leukodystrophies. Adrenoleukodystrophy, and MRI showing T2 weighted axial scan at the level of the caudate heads demonstrates marked loss of posterior white matter, with reduced volume and increased signal intensity. The anterior white matter is spared. Features are consistent with X-linked adrenoleukodystrophy. sources:Radiopediacase Frank Gaillard . Not altered. CC BY-SA 3.0
MRI of the brain performed at the age of 28, demonstrating evidence of a hypomyelinating leukodystrophy. Compared to grey matter structures, there is diffuse hyperintensity of the white matter on T2 weighted images (a, b, c), with hyperintense signal on T1 weighted images (d), consistent with hypomyelination. As previously reported, there is characteristic relative preservation of myelination within the following structures: optic radiations (long thin white arrow; a, b), anterolateral nucleus of the thalamus (thick white arrow; a, b), globus pallidus (short thin white arrow; a, b), posterior corpus callosum (white arrow head; b), corticospinal tracts (white arrow; c), and the dentate nucleus (white arrow; e). Sagittal T1 weighted imaging (f) demonstrates thinning of the corpus callosum and mild cerebellar atrophy.Endocrine Aspects of 4H Leukodystrophy: A Case Report and Review of the Literature. Billington E, Bernard G, Gibson W, Corenblum B - Case reports in endocrinology (2015). Not Altered. CC.

Multiple Sclerosis (MS)

Multiple sclerosis (MS) is the most common chronic central nervous system (CNS) disease of young adults (20 – 30 years of age), and is more frequently found in women.

Multiple sclerosis (MS) results from autoimmune myelin and oligodendrocyte destruction.

Multiple sclerosis (MS) is associated with HLA-DR2.

Multiple sclerosis (MS) is observed more frequently in areas further from the equator.

Multiple sclerosis (MS) is associated with recurrent neurologic impairments with times of remission are present (multiple lesions in time and space).

Clinical symptoms of multiple sclerosis (MS) include:

Blurry vision (optic nerve(s))
Vertigo and scanning speech that resemble alcohol intoxication (brainstem)
Internuclear ophthalmoplegia (medial longitudinal fasciculus)
Hemiparesis is a loss of sensation to one side (cerebral white matter, usually periventricular)
Weakness or lack of feeling in the lower extremity (spinal cord)
Malfunction of the bowels, bladder, and sexual (autonomic nervous system)

Both magnetic resonance imaging (MRI) and lumbar puncture (LP) are used to diagnose multiple sclerosis (MS).

Magnetic resonance imaging (MRI) identifies plaques (areas of white matter demyelination) associated with multiple sclerosis (MS).

Lumbar puncture findings of multiple sclerosis (MS) show:

Increased oligoclonal bands
Increased lymphocytes
Myelin basic protein

Treatment of multiple sclerosis (MS) depends on the severity or timing of the attack:

High-dose steroids are used in the treatment of acute attacks
Interferon beta therapy for a long period of time reduces the disease’s progression.

Gross inspection of brains with multiple sclerosis (MS) reveal white matter plaques that appear gray.

Multiple Sclerosis
Multiple Sclerosis. Demyelination in MS. On Klüver-Barrera myelin staining, decoloration in the area of the lesion can be appreciated Marvin 101 - Not altered. CC BY-SA 3.0
Multiple Sclerosis. Main symptoms of multiple sclerosis Mikael Häggström. Not altered. Public Domain
Multiple Sclerosis. Photomicrograph of a demyelinating MS-Lesion. Immunohistochemical staining for CD68 highlights numerous macrophages (brown) . Original Magnification 10x Marvin 101 - Not altered. CC BY-SA 3.0
DARC expression in human subcortical white matter of control and multiple sclerosis cases. Immunohistochemical analysis of brain vessels within the human cortex from multiple sclerosis (MS) cases with active inflammatory demyelinating lesion (first column, MS lesions), within meninges (second column, MS Meninges), within normal appearing white matter (third column, MS NAWM) and from a control case within subcortical white matter (fourth column, Control WM) are shown. MOG: MOG immunohistochemistry for myelin differentiating demyelinating lesions from normal myelinated areas in cerebral cortex and subcortical cortical white matter in multiple sclerosis and controls (A). DARC: DARC-positive blood vessels were detected in all areas in multiple sclerosis cases and in controls (B). CD68: CD68 immunohistochemistry detects inflamed blood vessels (first panel) as well as activated microglia throughout the white matter (C). HE: Histology shown by haematoxylin and eosin staining of the corresponding area (D). Scale bar = 50 μm. Bottom: Collagen IV immunohistochemistry in multiple sclerosis normal appearing white matter identifying all blood vessels (E), whereas DARC staining could only be detected in a subset of blood vessels (F, arrows). DARC immunoreactivity was detected in larger (large arrow, higher magnification in inset) as well as in smaller blood vessels (small arrow). Insets show area around the blood vessel highlighted by the large arrow. Arrowhead points to a blood vessel, which is DARC-negative. Scale bar = 500 μm. (G) Quantification showing more DARC-positive blood vessels in multiple sclerosis normal appearing white matter compared with control white matter (P-value = 0.0282).DARC shuttles inflammatory chemokines across the blood-brain barrier during autoimmune central nervous system inflammation. Minten C, Alt C, Gentner M, Frei E, Deutsch U, Lyck R, Schaeren-Wiemers N, Rot A, Engelhardt B - Brain : a journal of neurology (2014). Not Altered. CC.

Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis is a progressive, fatal encephalitis that worsens over time.

Subacute sclerosing panencephalitis is due to the measles virus’s lingering, slowly spreading infection of the brain.

Measles infection starts in utero.

Neurologic symptoms associated with measles infection manifest in childhood.

Subacute sclerosing panencephalitis is characterized by viral inclusions in oligodendrocytes and gray matter neurons (white matter).

Subacute Sclerosing Panencephalitis. Subacute sclerosing panencephalitis. Figure 1. MRI scans of the brain at the time of presentation in the neurology clinic (A and B) and 3 months later (C and D). Panels A and C are T1-weighted images; B and D are T2-weighted images. The initial MRI scan (A and B) reveals a focal abnormality in the subcortical white matter of the left frontal lobe, consisting of a hypointense signal on the T1-weighted image (arrow in A) and a hyperintense signal on the T2-weighted image (arrow in B). In the followup scan, the focal abnormality in the left frontal lobe is less obvious than previously (arrow in D), but advanced and diffuse cortical atrophy is present, signified by the ventriculomegaly and markedly enlarged sulci (arrowheads in C). Bonthius D, Stanek N, Grose C/ CDC - Bonthius D, Stanek N, Grose. Not altered. Public Domain

Progressive Multifocal Leukoencephalopathy (PML)

Progressive multifocal leukodystrophy (PML) is caused by John Cunningham (JC) virus infection of oligodendrocytes (white matter).

John Cunningham (JC) virus is also known as human polyoma virus 2.

The latent JC virus is reactivated by immune suppression, such as:

HIV infection
AIDS
Leukemia
Immunosuppression status post (s/p) organ transplant

In progressive multifocal leukodystrophy (PML), rapid progression of neurologic symptoms (such as dementia, paralysis, and vision loss) eventually cause death.

Progressive Multifocal Leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML). Not altered. CC BY 3.0

Central Pontine Myelinolysis

Central pontine myelinolysis is focal demyelination of the pons (anterior brain stem) due to rapid intravenous hyponatremia correction.

Risk factors for central pontine myelinolysis include:

Liver disease
Alcoholism

Locked in syndrome is the result of central pontine myelinolysis.

Locked in syndrome is characterized by acute bilateral paralysis.

Central Pontine Myelinolysis. Axial fat saturated T2-Weighted MRI showing hyperintense signal in the central pons. The patient was an alcoholic admitted with a serum Na 101 who was treated with hypertonic saline. He had severe quadriparesis, and dysarthria. - Not altered. CC BY-SA 3.0
MRI of the brain revealed symmetric, high-intensity signal in the pons with sparing of the peripheral portion, suggesting central pontine myelinolysis (A, axial view and B, sagittal view).Plasma exchange successfully treats central pontine myelinolysis after acute hypernatremia from intravenous sodium bicarbonate therapy. Chang KY, Lee IH, Kim GJ, Cho K, Park HS, Kim HW - BMC nephrology (2014). Not Altered. CC.