Demyelinating diseases

INTRODUCTION
• Demyelinating diseases comprise of diseases of central and
peripheral nervous system in which disruption of myelin is
a dominant feature.
• Diseases affecting central nervous system (CNS) myelin
can be classified on the basis of whether a primary
biochemical abnormality of myelin exists (dysmyelinating)
or whether some other process damages the myelin or
oligodendroglial cells (demyelinating).
• Demyelinating diseases include autoimmune, infectious,
toxic, metabolic, and vascular processes; dysmyelinating
diseases in which a primary abnormality of the formation of
myelin exists include several hereditary disorders
2DEMYELINATING DISEASES13-03-2016

PARTS OF A NEURON
13-03-2016 DEMYELINATING DISEASES 4
• Cell Body
– Contains the nucleus
• Dendrites
– Receptive regions; transmit impulse to cell
body
– Short, often highly branched
– May be modified to form receptors
• Axons
– Transmit impulses away from cell body
– Axon hillock; trigger zone
• Where action potentials first develop
– Presynaptic terminals (terminal boutons)
• Contain neurotransmitter substance (NT)
• Release of NT stimulates impulse in next
neuron
– Bundles of axons form nerves

MYELIN AND WHITE MATTER
• The gray and white matter of the central nervous system (CNS)
differ not only in gross morphology but also in water content and
macromolecular components, notably membrane lipids.
• Although the gray matter primarily contains neurons and their
processes, the white matter is composed predominantly of
myelinated bundles of axons
• The oligodendroglial cell membrane is the source of the myelin
sheath, which is a tightly wrapped, multilayered membrane
composed of a repeating structure characterized by lipid-
cytoplasm-lipid-water and which ensheathes axons.

A co-culture of oligodendrocytes and neurons,
in which oligodendrocyte is labelled in green
and neuron-specific tubulin in red. An
oligodendrocyte is shown extending processes
to neurites. Where it engages it will start to
ensheath them.
Transmission electron micrograph of a
myelinated axon, myelin sheath,
which is a tightly wrapped,
multilayered membrane

• Cholesterol, galactocerebroside, sphingomyelin, and
phospholipids are the lipids found in fully formed white matter
and account for the stability and strength
• Proteins are also embedded within the myelin.
• Any process, including metabolic injury or ischemia, that
changes the chemical composition of myelin will result in a
less stable structure that is more susceptible to injury .
• Because myelination of the CNS is essentially a postnatal
process, the neonatal brain contains considerably more water
(89% for gray matter and 82% for white matter) than the
mature adult brain (82% for gray matter and 72% for white
matter)

• Neuroglial cells, namely oligodendrocytes, astrocytes, and
microglia, are primarily responsible for the maintenance or “well-
being” of the white matter- by providing structural and nutritional
support of neurons, regulating the extracellular environment, and
acting as scavenger cells
Normal Progression of Myelination
• Proximal pathways before distal (e.g., brainstem before
supratentorial brain)
• Sensory (visual and auditory) before motor
• Central white matter before peripheral
• Posterior before anterior

Drawings of the brain depict the progression of myelination. (a) Myelination
progresses in a caudocranial direction from the brain stem, through the posterior
limb of the internal capsule, and to the hemispheric white matter, proceeding
from the central sulcus toward the poles. (b) Myelination advances from deep to
superficial and from posterior to anterior.

Myelinated Regions at Birth (or Shortly After Birth)
• Dorsal brainstem
• Inferior, superior cerebellar peduncles
• Perirolandic region
• Corticospinal tract
• Central portion of centrum semiovale
• Posterior limb of internal capsule to cerebral peduncle
• Ventrolateral thalamus
• Optic nerve, chiasm, tract

Myelination and MR Findings
• The most commonly used marker for evaluating
normal brain maturation on conventional MR is the
progression of myelination.
• Myelination starts in the second trimester of gestation
and continues into adulthood, beginning with the
peripheral nervous system and then the spinal cord, the
brainstem, and finally the supratentorial brain.
• Myelination of the brain evolves in a predictable
sequential fashion over the first 2 postnatal years.
• Studies have suggested that the sequence of
myelination has functional significance and is
correlated with psychomotor development.

• As white matter becomes myelinated, it appears
hyperintense on T1-weighted and hypointense on
T2-weighted images relative to gray matter
• It is known that the signal changes on T1-
weighted MR increases with increase in certain
lipids that occur during the formation of myelin
from oligodendrocytes .
• The signal changes on T2-weighted MR have
been presumed to be histologically as thickening
and tightening of the spiral of myelin around the
axon and loss of water .

• During the first 6 months of life, T1-weighted images are most
useful for evaluating the progression of myelination.
• After 6 months of age, most cerebral white matter appears
high in signal intensity on the T1-weighted images, beyond
this time the T2-weighted images are generally relied on to
further evaluate myelin progression .
• By 24 months of age, the process of myelination is essentially
complete except for the terminal zones of myelination found in
the occipital-parietal periventricular white matter.
• These regions appear as subtle, ill-defined areas of
hyperintensity

Axial T1-weighted images of
a 2-week-old infant born at
34 weeks of gestation.
Hyperintensity is
seen around the fourth
ventricle due to myelmnation
present in the surrounding
structures: medulla (m in a),
vermis (v in a), inferior
cerebellar peduncle (arrow in
a), and dorsal aspect ofthe
pons (arrow in b). Increased
signal intensity is noted in
the posterior limb of the
internal capsule as well
(arrow in c). The
unmyelinated
supratentonial white matter
is hypointense with respect
to the gray matter, better
seen in d.

Matching T1-weighted, T2-weighted, images
from three patients ages 5 weeks (A,B), 8
months (D,E), and 3
years (G,H).

16
CONDUCTION OF NERVE FIBRES BEFORE & AFTER
DEMYELINATION
DEMYELINATING DISEASES13-03-2016

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

INTRODUCTION
• Multiple sclerosis is a demyelinating disease of the central
nervous system caused by an autoimmune reaction that is the
result of a complex interaction of genetic and environmental
factors.
• Most commonly affects women of childbearing age who are of
north European descent.

DEFINITION
• Multiple sclerosis is a chronic progressive, degenerative
disorder of the CNS characterized by disseminated
demyelination of the nerve fibres of the brain and spinal cord.
• Multiple sclerosis (MS) is characterized by a triad of
inflammation, demyelination, and gliosis (scarring); the course
can be relapsing-remitting or progressive.

EPIDEMIOLOGY

ETIOLOGY
Unknown cause related to
– Infection
– Physical injury
– Emotional stress
– Excessive fatigue
– Pregnancy

MORPHOLOGIC
FEATURES. The
pathologic hallmark is the
presence of many scattered
discrete areas of
demyelination termed
plaques.
• Grossly, plaques appear as
grey-pink, swollen, sharply
defined, usually bilaterally
symmetric areas in the
white matter.

1. ln active enlarging
plaques, the histologic
features are accumulation of
lymphocytes and
macrophages around venules
and at the plaque margin
where demyelination is
occurring. In addition, there
is loss of oligodendrocytes
and presence of reactive
astrocytosis with numerous
lipidladen macrophages
(microglia) in the plaque.
The axons in the plaque are
generally intact.
25
2. In old inactive plaques,
there is no perivascular
inflammatory cell infiltrate
and nearly total absence of
oligodendrocytes.
Demyelination in the plaque
area is complete as there is
only limited regeneration of
myelin. Gliosis is well-
developed but astrocytes are
less prominent. Some
axonal loss may be present.
Microscopically, the features vary according to the age of the
plaque:

• The BBB prevent entrance of T cells into the nervous
system.
The blood–brain barrier is normally not permeable to
these types of cells, unless triggered by infection or a
virus, which decreases the integrity of the tight junctions.
When the blood–brain barrier regains its integrity, usually
after infection or virus has cleared, the T cells are trapped
inside the brain.
Blood-brain
barrier
breakdown
• The immune system attacks the nervous system, forming
plaques or lesions.
Commonly involves white matter.
Destroys oligodendrocytes- causing demyelination
Remyelination occurs in early phase but not completely.
Repeated attacks lead to fewer remyelination.
Autoimmunology
• T-cells attacks on myelin triggers inflammatory processes,
stimulating other immune cells and soluble factors like
cytokines and antibodies.
Leaks form in the BBB cause swelling, activation of
macrophages, and more activation of cytokines and other
destructive protein
Inflammation

AUTOIMMUNE ACTION

Extravasation
astrocytes BRAIN
TISSUE
M Y E L I N
oligodendrocyte
B cell
Rolling Adhesion
a4 Integrin
VCAM
B L O O D F L O W
LUMEN OF
VENULE
B A S A L L A M I N A
Circulation
Activated T cell Proteases
Antigen presenting cell
(Astrocyte or Microglial cell)
Activated
microglia/macro
phages
T CELL
REACTIVATIO
N
Activated
Macrophage
Autoantibodies
Complement
IL-1, IL-12,
chemokines
Cytokines and
chemokines
Proteases
TNF-a
O2
•-
NO•
AXONAL
DAMAGE
MS Disease Pathology

There are eight types of multiple sclerosis. They are:
• Relapsing-remitting
• Primary progressive
• Secondary progressive
• Relapsing progressive
• Benign
• Spinal form
• Neuromyelitis optica
• Marburg variant

COMMON SYMPTOMS
• Bladder and Bowel dysfunction
• Fatigue ( Central in nature)
• Pain
• Visual disturbances: Optic neuritis, diplopia,
nystagmus
• Cerebellum and basal ganglia: ataxia,
intention tremor
• Doral column: Sensory abnormalities
(paresthesias), impairment of deep sensation,
proprioception
• Corticospinal tract: Weakness and spasticity
• Frontal lobe dysfunction: Cognitive, memory,
learning, and impaired emotional responses,
depression
• Speech abnormalities: Dysarthria
• Brainstem abnormalities: Myokymia,
deafness, tinnitus, vertigo, vomiting
Top 3 most prevalent
symptoms
1. Bladder and Bowel
dysfunction
2. Fatigue ( Central in
nature)
3. Pain
Top 3 problems affecting
ADLs
reported by patients:
1. Fatigue
2. Balance difficulties
3. Weakness

13-03-2016 DEMYELINATING DISEASES
The most common initial symptoms
•changes in sensation (33%)
•Optic neuritis (20%)
•Weakness(exercise induced) (13%)
•double vision- internuclear opthalmoplegia (7%)
•unsteadiness while walking (5%)
•and balance problems (3%)
Lhermitte's sign (25-40%) is an electrical sensation that
runs down the back and into the limbs and is produced by
bending the neck forwards. The sign suggests a lesion of
the dorsal columns of the cervical cord or of the caudal
medulla.
Uhthoff's phenomenon is the worsening of neurologic
symptoms in multiple sclerosis when the body gets
overheated from hot weather, exercise, fever,

COMMON SIGNS
Lhermitte’s sign: Classic but not pathognomonic.
• Passive neck flexion causing an electric shock-like sensation radiating to
the spine, shoulders as well as other areas. This sign is most likely a result
of the increased sensitivity of the myelin to stretch or traction
• Upper motor neuron signs: Increased muscle stretch reflex (MSR) and
plantar responses, spasticity
• Weakness
• Decreased sensation
Note: Not all new symptoms result from new MS lesion. Temporary
aggravation of symptoms in old and previously silent lesions may be
caused by fever, heat, stress, fatigue, or other medical problems, especially
pulmonary or urinary tract infection, dehydration or medication side-
effects. Aggravating factors and other medical problems must either be
identified and treated, or ruled out.

SYSTEMIC
MANIFESTATIONS

(a) Clinical Findings
• “Lesions scattered in time and space”; a lesion must occur in
different locations in the CNS at different points of time.
• Neurologic deficits in 2 or more areas, reflecting white matter
involvement, at 2 points in time for >24 hours separately by 1 month
• Age: 10–59 years, commonly 20–40 years
• Two separate attacks with the onset of symptoms at least 1 and up
to 6 months apart or progression of the neurologic disease for
greater than 6 months
• Two separate lesions in which the symptoms cannot be explained
by a single lesion
• Objective deficits seen on exam
• Feature of typical signs and symptoms supported by diagnostic
data

(b) Diagnostic Data:
– There is no pathognomonic test for MS. All labs are nonspecific
and are to be interpreted within the clinical picture.
Cerebral Spinal Fluid (CSF) Examination
• Increased in Protein (myelin basic, 25%), Oligoclonal IgG
bands (greatest sensitivity), IgG and WBCs
VEP (Visual Evoked Potentials) (high sensitivity along with
MRI)
• P100 latency is abnormal (slowing secondary to plaques)
in 75%
BAER (Brainstem Auditory Evoked Response)
• Investigates the pontine area displaying an absence or
delay of wave formation secondary to the demyelinating
process
SEP (Sensory Evoked Potentials)
• Prolongation of absolute peak or interpeak latency

EMG/NCS
• Sensory Nerve Action Potentials (SNAPs), Compound Motor Action
Potentials (CMAPs), Conduction Velocity (CV) worsens as the myelin thins
• EMG may show Abnormal activity: Fibs, Positive Sharp Waves (PSW),
Facial myokymia and a decrease Motor Unit Action Potentials (MUAP)
• Single Fiber Electromyography (SFEMG): jitter (Grana, 1994)
• Blink Reflex: May be abnormal
MRI (Greatest sensitivity for the diagnosis of MS)
• Multifocal areas of increased intensity (plaques) on T2 weighted images are
abnormal in 85% of the cases
• These ovoid-appearing plaques are located in the periventricular white
matter (corpus callosum)
• Enhancement with gadolinium may precede the onset of deficits and
identify active
disease
• May visualize subclinical lesions
CT Scan
• Not effective in visualizing lesion of brainstem, cerebellum, and optic
nerve.
• Cerebral atrophy is most common sign.

MRI of the
brain and
spinal cord
in patient
with MS

MRI of the brain in multiple sclerosis. a Asymmetrically scattered foci of abnormal
signal, affecting only the white matter, are seen in the periventricular regions and at the
anterior and posterior ends of the lateral ventricles. There is mild internal
hydrocephalus. b There are typical signal abnormalities in the corpus callosum,
extending into the white matter of the hemispheres.

During an acute exacerbation treatment should include a comprehensive rehabilitation
program. Relative rest, hydration, bladder and bowel management, PT and OT speech
(swallowing protection) and dietary (nutrition) are essential in the care of the patient.
Medications
Immunomodulator agents: Disease-modifying
Corticosteroids (Methylprednisolone)
• Used in short bursts for acute attacks secondary to its anti-inflammatory and
anti-edema effects. Acute attacks = “exacerbation” which is new or worsening MS
symptoms lasting > 24 hours and not related to metabolic factors (Urinary Tract
Infection [UTI], etc.)
• Dose: ~1000mg/day Intravenous IV for 4–7days with a 2 week taper, switch to
PO
• Risks: Gastrointestinal (GI) disturbance, fluid retention, mood swings,
electrolyte imbalance, insomnia, acne, hyperglycemia, hypertension (HTN)
• Most responsive symptoms: Optic neuritis, brainstem, motor, acute pain, bowel
and bladder
Glatiramer acetate C=Copaxone
• Dose: Subcutaneous Injection qd
• Side effects: Self-limited transient flushing, injection site reactions, post injection
self-limiting

• Least responsive: Cerebellar, sensory
• Long-term use leads to increase increased risk of HTN,
osteoporosis, diabetes, and cataracts
• Hastens recovery, but does not prevent further attacks or alter
disease progression
Three Agents to Alter the Course of the Disease (“A, B, C’s”)
Interferon-A (Avonex®) A=Avonex
• Dose: 6 million units IM Q week
• Side effects: flu-like symptoms, myalgia, fever, chills, asthenia
• 18% reduction in relapse rate
Interferon-B (Betaseron®) B=Betaseron
• Dose: 8 million units Subcutaneous QOD.
• Side effects: Flu-like symptoms, increase liver function tests (LFTs),
decreased WBC, myalgia, injection site reaction, injection site necrosis
(5%)

chest tightness
Serum neutralizing antibodies may form with Avonex® and Betaseron® (25%)
decreasing efficacy
Immunosuppression agents are reserved for patients with unresponsive disabling
MS.
These are commonly used as second-line medications. The side effects need to be
weighed when prescribing these medications and patients should be closely
monitored.
Cyclosporin
Cyclophosphamide (Cytotoxin®)—modest improvement
Azathioprine—mixed results
Plasmapheresis
Methotrexate
Side effects: mucosal ulceration, Bowel Movement (BM) abnormalities, GI.
Current Medications Under Review
Mitoxantrone—IV months, antineoplastic, for advanced MS—pending FDA review
for this indication.
Intravenous Immunoglobulin (IVIG)—being studied.

PROGNOSIS

ACUTE DISSEMINATED
ENCEPHALOMYELITIS

INTRODUCTION
• Acute disseminated encephalomyelitis is an immune-mediated
inflammatory demyelinating condition that predominantly
affects the white matter of the brain and spinal cord.
• ADEM is a demyelinating syndrome most commonly affecting
young adults and children and occurs in association with
vaccination (post-vaccination) or systemic infection
(parainfectious encephalomyelitis)
• The hallmark of ADEM is the presence of widely scattered
small foci of perivenular inflammation and demyelination in
contrast to larger confluent demyelinating lesions typical of
MS.

PATHOLOGIC FEATURES
• ADEM is characterised by
perivascular inflammation,
oedema, and demyelination
within the CNS. The pathology
of encephalomyelitis following
infections and vaccines is
indistinguishable from each
other. ADEM results from an
aberrant immune attack on the
brain and/or spinal cord,
triggered by temporally related
infections or vaccinations.
58
MRI brain T2W image in a 28
years man showing postinfectious
ADEM
showing hyperintense bilateral
lesions in thalami and in the left
parieto-occipital area.

CLINICAL FEATURES
• The hallmark clinical feature is the development of a focal or
multifocal neurological disorder following exposure to virus or
receipt of vaccine.
• The onset of the CNS disorder is usually rapid, with peak
dysfunction within several days.
• Initial features include encephalopathy ranging from lethargy
to coma, seizures, and focal and multifocal signs reflecting
cerebral(hemiparesis), brainstem (cranial nerve palsies), and
spinal cord(paraparesis) involvement. Other reported findings
include movement disorders and ataxia.

TREATMENT
• Initial treatment is with high-dose glucocorticoids as for
exacerbations of NMO depending on the response, treatment
may need to be continued for 4–8 weeks.
• Patients who fail to respond within a few days may benefit
from a course of plasma exchange or intravenous
immunoglobulin.

TRANSVERSE
MYELITIS
• Transverse myelitis is a heterogenous group of inflammatory
disorders characterised by acute or subacute motor, sensory
and autonomic spinal cord dysfunction.
• Myelitis: non-specific term for inflammation of spinal cord
• Transverse: involvement across one level of the spinal cord.
• TM occurs with optic neuritis in neuromyelitis optica ( Devic’s
disease).

ETIOLOGY
• Acquired alteration in the innate or acquired immune system
• Cellular injury and dysfunction
• Infectious trigger: infectious agent triggers breakdown of immune
tolerance for self-antigens
• TM and ADEM: Superantigen-mediated activation of T
lymphocytes
• Suspected that multiple immune system components contribute to
observed dysfunction including T and B lymphocytes, macrophages,
and NK cells
• Mechanism of injury also probably involves multiple pathways
including T lymphocyte killing of neural cells, cytokine injury,
activation of toxic microglial pathways, immune-complex
deposition, and apoptosis

DISEASES ASSOCIATED
WITH TM

PATHOLOGY

CLINICAL FEATURES

DIAGNOSTIC CRITERIA

BY,
JAYASRI K
S

Demyelinating diseases

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