Demyelinating Diseases

Question 1

What are Demyelinating diseases of the CNS ?.

Answer 1

• acquired conditions
• characterized by preferential damage to myelin
• , with relative preservation of axons

Question 2

The clinical deficits of Demyelinating diseases are due to the effect
of ____________

Answer 2

myelin loss on the transmission of electrical impulses along axons.

Question 3

-The natural history of
demyelinating diseases is determined, in part, by the________-

Answer 3

limited capacity of the CNS to regenerate
normal myelin and by the degree of secondary damage to axons that occurs as the disease
runs its course.

Question 4

Several disease processes can cause loss of myelin.

These include destruction of myelin by
_______________

Answer 4

• immunological reactions, as in multiple sclerosis, and by infections.
• In progressive multifocal leukoencephalopathy, JC virus infection of oligodendrocytes results in loss of myelin (described above).
• In addition, inherited disorders may affect synthesis or turnover of myelin components;
  these are termed leukodystrophies and are discussed with metabolic disorders

Question 5

What are you demyelinating diseases?

Answer 5

• MULTIPLE SCLEROSIS
• NEUROMYELITIS OPTICA
• ACUTE DISSEMINATED ENCEPHALOMYELITIS AND ACUTE NECROTIZING HEMORRHAGIC
  ENCEPHALOMYELITIS
• Central pontine myelinolysis

Question 6

What is Multiple sclerosis (MS)

Answer 6

• autoimmune demyelinating disorder
• characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space.

Question 7

What is the most common demyelinating disorder?

Answer 7

MS

Question 8

What is the prevalence rate of MS?

Answer 8

having a prevalence
of approximately 1 per 1000 personsin most of the United States and Europe.

Question 9

What is the age onset of MS?

Answer 9

The disease may
become clinically apparent at any age, although onset in childhood or after age 50 years is
relatively rare.

Question 10

In terms of gender, which is more affected in MS?

Answer 10

** Women are affected twice as often** as are men.

Question 11

What is the clinical course of MS?

Answer 11

In most individuals with MS, the
clinical course takes the form of relapsing and remitting episodes of variable duration (weeks to
months to years) marked by neurologic defects, followed by gradual, partial recovery of
neurologic function.

The frequency of relapses tends to decrease during the course of time, but
there is a steady neurologic deterioration in most affected individuals.

Question 12

The lesions of MS are caused by an _________ that is directed against the components
of the myelin sheath. [27,] [28]

Answer 12

immune response

Question 13

What is the pathogenesis of MS?

Answer 13

As in other autoimmune disorders, the pathogenesis of this
disease involves both genetic and environmental factors ( Chapter 6 ).

The incidence of MS is
15-fold higher when the disease is present in a first-degree relative and roughly 150-fold higher
with an affected monozygotic twin.

Question 14

Genetic linkage of MS susceptibility to the_____________extended
haplotype of the major histocompatibility complex is also well established.

Answer 14

DR2

Question 15

What are the other genetic association in pathogenesis of MS ?

Answer 15

In recent genome-wide
screen supported this association and identified additional associations with single-nucleotide
polymorphisms in IL-2 and IL-7 receptor genes. [29]

The current thinking is that these cytokine
receptor polymorphisms may influence the balance between pathogenic effector T cells and protective regulatory T cells. These genetic associations point to the importance of the immune system in the susceptibility to MS.

Question 16

What is the pathogenesis of MS?

Answer 16

Given the prominence of chronic inflammatory cells within and around MS plaques as well as
this genetic validation, immune mechanisms that underlie the destruction of myelin are the
focus of much investigation.

The available evidence indicates that the disease is initiated by
CD4+ TH1 and T H17 T cells that react against self myelin antigens and secrete cytokines .
TH1 cells secrete IFNγ, which activates macrophages, and **TH17 cells promote the recruitment
of leukocytes **( Chapter 6 ).

The demyelination is** caused by these activated leukocytes and
their injurious products**.

The infiltrate in plaques and surrounding regions of the brain consistsof T cells (mainly CD4+, some CD8+) and macrophages.

How the autoimmune reaction is
initiated is not understood; a role of viral infection (e.g., EBV) in activating self-reactive T cells
has been proposed but remains controversial.

Question 17

Based on the growing understanding of the pathogenesis of MS, therapies are being developed
that ________________

Answer 17

modulate or inhibit T cell responses and block the recruitment of T cells into the brain

. A potential contribution of humoral immunity has also been suspected for a long time, based on
the early observation of oligoclonal bands of immunoglobulin in CSF. [31]

The demonstration
that B-cell depletion can decrease the incidence of demyelinating lesions lends support to this
idea.

Question 18

What is the morphology of MS?

Answer 18

MS is a white matter disease that is best appreciated in sections of the brain
and spinal cord.

Lesions appear as:

• multiple,
• well-circumscribed,
• somewhat depressed,
• glassy,
• graytan,
• irregularly shaped plaques ( Fig. 28-33 ).

Question 19

What is the appearance of MS In the fresh state?

Answer 19

these are firmer than the surrounding white matter (sclerosis)

Plaques can be found throughout the white matter
and also extend into gray matter, since these have myelinated fibers running through them.
The size of lesions varies considerably, from small foci that are only recognizablemicroscopically to confluent plaques that involve large portions of the centrum semiovale.

The
lesions often have sharply defined borders ( Fig. 28-34 ). Plaques commonly occur adjacent
to the lateral ventricles.

They are also frequent in the optic nerves and chiasm, brainstem,
ascending and descending fiber tracts, cerebellum, and spinal cord.

Question 20

What is the microscopic finding in MS?

Answer 20

Microscopically, in an active plaque there is evidence of ongoing myelin breakdown with
abundantmacrophages containing lipid-rich, PAS-positive debris.

Inflammatory cells, including

• *both lymphocytes and monocytes**, are present, mostly as perivascular cuffs, especially at the
• *outer edge of the lesion** ( Fig. 28-35A ).

Question 21

Where Active lesions are often located?

Answer 21

centered on small veins.
Within a plaque there is relative preservation of axons ( Fig. 28-35B ) and depletion of
oligodendrocytes.

In time, astrocytes undergo reactive changes.

As lesions become
quiescent, the inflammatory cells slowly disappear.

Question 22

Within inactive plaques of MS, which type of cell predominates?

Answer 22

little to no myelin is found, and there is a** reduction in the number of oligodendrocyte nuclei**;

instead,
astrocytic proliferation and gliosis are prominent.

Question 23

What can you find in the inactive plaques of MS?.

Answer 23

Within inactive plaques,** little to no
myelin is found,and there is areduction in the number of oligodendrocyte nucle**i; instead,
astrocytic proliferation and gliosis are prominent.

Axons in old gliotic plaques show severe
depletion of myelin and are also greatly diminished in number

Question 24

Active plaques can also be grouped into four basic patterns:

Answer 24

1. Pattern 1
   
   • those that are sharply
     demarcated and centered on blood vessels, either with (pattern I)
2. Pattern 2
   * or without (pattern II) deposition of immunoglobulin and complement,
3. (patterns III and IV)

and those that are less well demarcated and are not centered on vessels.

Question 25

How to distinguish pattern 3 and 4?

Answer 25

These latter two are distinguished by the
distribution of oligodendrocyte apoptosis (III, widespread; IV, cental only).

It has been
observed that only one pair of patterns (I/II or III/IV) may be present in a given individual,
suggesting that these may reflect distinct mechanisms rather than different stages of lesion

Question 26

In some MS plaques (shadow plaques) the border between normal and affected white
matter is characterized by:

Answer 26

not sharply circumscribed.

In this type of lesion some abnormally thinned-out myelin

• *sheaths can be demonstrated**, especially at the outer edges. This phenomenon is most commonly interpreted as evidence of partial and incomplete remyelination by surviving
• *oligodendrocytes.**

Abnormally myelinated fibers have also been observed at the edges of typical plaques.

Although these histologic findings suggest a limited potential for remyelination
in the CNS, the remaining axons within most MS plaques remain unmyelinated; studies aimed
at promoting remyelination are an important focus of research.

Question 27

Answer 27

MS

The same lesion stained for
axons shows relative preservation.

Question 28

Answer 28

A,

Myelin-stained section shows the sharp edge of a
demyelinated plaque and perivascular lymphocytic cuffs.

Question 29

What are the clinical feature of MS?

Answer 29

Although MS lesions can occur anywhere in the CNS and consequently may induce a wide range of clinical manifestations, certain patterns of neurologic symptoms and signs are
commonly observed.

• Unilateral visual impairment, due to involvement of the optic nerve (optic neuritis, retrobulbar neuritis), is a frequent initial manifestation of MS.
• However, only some affected individuals (10% to 50%, depending on the population studied) with optic neuritis go on to develop MS
• . Involvement of the brainstem produces cranial nerve signs, ataxia, nystagmus, and internuclear ophthalmoplegia from interruption of the fibers of the medial longitudinal fasciculus.
• Spinal cord lesions give rise to motor and sensory impairment of trunk and limbs, spasticity, and difficulties with the voluntary control of bladder function

Question 30

What is the frequent initial manifestation of MS?

Answer 30

Unilateral visual impairment, due to involvement of the optic nerve (optic
neuritis, retrobulbar neuritis), is a frequent initial manifestation of MS.

Question 31

What is the CSF finding of MS?

Answer 31

• mildly elevated protein level, and in one third of cases, there is** moderate pleocytosis**.
• IgG levels in the CSF are increased and oligoclonal IgG bands are usually observed on immunoelectrophoresis;
• these are indicative of the presence of a small number of activated B cell clones, postulated to be self-reactive, in the CNS.

Question 32

Radiologic studies using magnetic resonance imaging, typically based on identifying gadolinium-enhancing
lesions,have taken on aprominent role in assessing disease progression of MS; these studies, when
correlated with autopsy studies as well as clinical findings, have indicated that some plaques
may be clinically silent even in otherwise symptomatic patients.

Question 33

What is neuromyelitis optica or Devic disease?

Answer 33

The development of synchronous (or near synchronous) bilateral optic neuritis and spinal cord
demyelination

Question 34

What is the CSF finding in neuromyelitis optica?

Answer 34

White cells are common in
the CSF, often including neutrophils.

Question 35

What are the morphologic findings in neuromyelitis optica?

Answer 35

Within the damaged areas of white matter, there is typically
necrosis,aninflammatory infiltrateincludingneutrophils,andvascular deposition of
immunoglobulin and complement.

These lesions have been suggested to be mediated by
humoral immune mechanisms. [34]

Many affected individuals show antibodies to aquaporins,
which are in part responsible for maintenance of astrocytic foot process and thus the integrity of
the blood-brain barrier. [

Question 36

What is Acute disseminated encephalomyelitis (ADEM, perivenous encephalomyelitis)

Answer 36

It is a diffuse,
monophasic demyelinating diseasethat followseither a viral infection or, rarely, a viral
immunization.

Symptoms typically develop a week or two after the antecedent infection and
include headache, lethargy, and coma rather than focal findings, as seen in MS.

The clinical
course is rapid, and as many as 20% of those affected die; the remaining patients recover
completely.

Question 37

What is Acute necrotizing hemorrhagic encephalomyelitis (ANHE, acute hemorrhagic leukoencephalitis
of Weston Hurst)

Answer 37

It is a fulminant syndrome of CNS demyelination, typically affecting young adults
and children.

The illness is almost invariably preceded by a recent episode of upper respiratory
infection, most often of unknown cause.

The disease is fatal in many patients, with significant
deficits present in most survivors.

Question 38

What are you macroscopic findings in ADEM?

Answer 38

In ADEM, macroscopic examination of the brain shows only grayish
discoloration around white-matter vessels.

Question 39

What is the microscopic finding in ADEM?

Answer 39

On microscopic examination, myelin loss with
relative preservation of axons can be found throughout the white matter.

In the early stages,

• *polymorphonuclear leukocytes can be found within the lesions;** later, **mononuclear infiltrates
  predominate. **

The breakdown of myelin is associated with the accumulation of lipid-laden
macrophages.

In contrast with MS, all lesions appear similar, consistent with the clinically
monophasic nature of the disorder.

Question 40

Describe the morphological findings of ANHE?

Answer 40

ANHE shows histologic similarities with ADEM, including a perivenular distribution of
demyelinationandwidespread dissemination throughout the CNS (sometimes with extensive
confluence of lesions)

. However, the lesions are much more severe than those of ADEM and
include destruction of small blood vessels, disseminated necrosis of white and gray matter
with acute hemorrhage, fibrin deposition, and abundant neutrophils.

Scattered lymphocytes
are seen in foci of demyelination.

Question 41

The lesions of ADEM are similar to those

Answer 41

induced by immunization of animals with myelin
components or with early rabies vaccines that had been prepared from brains of infected animals.

This has suggested that ADEM may represent an acute autoimmune reaction to myelin
and that ANHE may represent a hyperacute variant, although no inciting antigens have been
identified.

Question 42

What is Central pontine myelinolysis?

Answer 42

It is characterized by loss of myelin (with relative preservation of
axons and neuronal cell bodies)in aroughly symmetric pattern involving the basis pontis and
portions of the pontine tegmentumbutsparing the periventricular and subpial regions. [37]

Lesions may be found more rostrally; it is extremely rare for the process to extend below the
pontomedullary junction.

Extra-pontine lesions occur in the supratentorial compartment, with similar appearance and apparent etiology.

Question 43

CEntral pontine myelinolysis is most commonly associated with?

Answer 43

The condition is most commonly associated with
rapid correction of hyponatremia, although it can be associated with other severe electrolyte or
osmolar imbalance, as well asorthotopic liver transplantation.

Question 44

What is the clinical finding of central pontine myelinolysis?

Answer 44

The clinical presentation of
central pontine myelinolysis is that of a rapidly evolving quadriplegia; radiologic imaging studies
localize the lesion to the basis pontis.

Morphologically there is myelin loss without evidence of
inflammation; neurons and axons are well preserved.

Again, because of the monophasic nature
of the disease all lesions appear to be at the same stage of myelin loss and reaction.