DISORDERS OF MYELINATION

1. DYSMYELINATION
(LEUKODYSTROPHY)
• Production of an abnormal and unstable myelin
sheath, often associated with hypomyelination
• Hereditary disorder of myelin metabolism
• Tends to present in childhood, although adult forms
are being increasingly recognized
• Always involves central myelin and in several
diseases, peripheral myelin is involved as well
DISORDERS OF MYELINATION
• DYSMYELINATION
(LEUKODYSTROPHY)
• Metachromatic leukodystrophy – deficiency of
enzyme: ARYL SULFATASE
• Krabbe’s globoid cell leukodystrophy – deficiency of
enzyme: GALACTOSYL CERAMIDASE
• Adrenoleukodystrophy – defect in the metabolism of
very long chain fatty acids
• Pelizeus Merzbacher – defective PLP gene
• Canavan’s disease (Spongy degeneration of cerebral
white matter) – ASPARTO ACYLASE deficiency
DISORDERS OF MYELINATION

I. DEMYELINATION
- destruction of normal myelin

a. Primary - Idiopathic Inflammatory

Demyelinating Disorders of the CNS

b. Secondary
 PRIMARY
(Idiopathic Inflammatory Demyelinating Disorders of the CNS)

I. Multiple Sclerosis (Disseminated

Sclerosis)
– Chronic relapsing encephalomyelopathic
form
– Acute Multiple Sclerosis
– Diffuse Cerebral Sclerosis
• Schilder’s diffuse sclerosis
• Balo’s Concentric sclerosis
II. Neuromyelitis Optica (Devic’s Disease)
 PRIMARY
(Idiopathic Inflammatory Demyelinating Disorders of the CNS)

I. Acute Disseminated Encephalomyelitis

(ADEM)
– Postinfectious encephalomyelitis
– Post vaccinal encephalomyelitis

II. Acute and Subacute necrotizing hemorrhagic

encephalitis
a. Acute encephalopathic form (Hurst hemorrhagic
leukoencephalitis
b. Subacute necrotic myelopathy
 SECONDARY DEMYELINATION

A. Viral infections:
• Progressive Multifocal Leukoencephalopathy
(PML) – JC Papilloma virus
• Subacute Sclerosing Panencephalitis (SSPE) –
measles virus
• Human T-cell lymphotrophic or leukemia virus
type I : (HTLV associated myelopathy) – HAM
or Tropical Spastic Paraparesis (TSP)
 SECONDARY DEMYELINATION

A. Some cases of anoxic encephalopathy

• Some small ischemic foci due to vascular occlusion
• Subacute Combined Degeneration of the Spinal Cord
(B12 deficiency) – demyelination of posterior and
lateral funiculi of the spinal cord
• Central Pontine Myelinolysis – demyelination of the
ventral pons secondary to rapid correction of
hyponatremia
• Marchiafava-Bignami disease – demyelination of
corpus callosum in male heavy alcohol drinkers
• Demyelinative lesions associated with connective
tissue diseases
 MULTIPLE SCLEROSIS
Multiple Sclerosis (MS)
• Chronic inflammatory autoimmune
disease of unknown etiology that involves
demyelination of the CNS with resultant
neurologic dysfunction.
• The manifestations are extremely variable
in type and severity
 Incidence & Epidemiology of MS
• 70% symptoms at ages 21-40 (Child bearing age)
• More common in women (F /M = 1.4 – 3.1 )
• 10% disease onset during pregnancy

• Increases in frequency with latitude in both the northern and

southern hemisphere (temperate countries)
• High prevalence in northern Europe, northern USA, southern
Canada, southern Australia and New Zealand
• Southern USA-prevalence of 10/10.000
• Northern USA-prevalence of 50/10.000
• Low prevalence in Asia and Latin and South America

• Racial differences
– White population at greatest risk
– Asian and black populations have low risk
Incidence & Epidemiology of MS
• Environmental changes in risk of MS
– Children born in USA of immigrants from Asia
showed relatively higher incidence rates of
MS
– Asians migrating to USA after age 15 had the
risk of the country of origin

– The above data suggest that an infectious

agent of long latency is acquired at the time of
puberty
 Genetic Susceptibility
“MS has NO clear genetic predisposition”
• Susceptibility to MS is inherited
– Siblings of MS have a risk of 2.6 %
– Parents of MS have a risk of 1.8 %
– Children of MS have a risk of 1.5 %
– 15% of patients with MS have affected relatives

• Twin studies , concordance rate of

– 25% in monozygotic twins
– 2.4% for same sex dizygotic twins

• Multiple genes probably confer susceptibility

• In Whites, class II haplotype DR15, DQ6, Dw2 is

associated with increase risk of MS
 Immunology
• Reduction in activity of suppressor CD8+T cells

• Decrease number of CD4+CD45RA+suppressor inducer T cells in

the peripheral blood

• Reduction in activity of autologus mixed lymphocyte reaction

(AMLR) – an indication of autoreactive cell suppresion

• Activation of Antibody-secreting B cells

• In MS, an antigen of the oligoclonal IgG has not been identified

• The cytokines produced by activated T cells and macrophages may

play a role in tissue damage

• T cells reactive against Myelin Basic Protein (MBP) and Proteo Lipid
Peptide(PLP) mediate the CNS inflammation
 Virus
• Genetic factors influence susceptibility to development of
demyelination and clinical disease; this susceptibility is
linked to the immune response generated in the animal
against viral determinants

• The 2 virus candidates most commonly implicated in the

pathogenesis of MS are Epstein-Barr (EPV) virus and
Human Herpes Virus 6 (HHV 6)

• After early infection the viruses persist in latent form, and

clinical relapses are caused by periods of viral re-
activation
 Multiple Sclerosis
• Cause remains ELUSIVE but
– AUTOIMMUNE MECHANISMS
Possibly triggered by
• ENVIROMENTAL FACTORS
• In GENETICALLY SUSCEPTIBLE individuals
are probably important

NO clear understanding of ETIOLOGY

SEVERITY OF DISABILITY or
VARIATION IN THE NATURAL HISTORY
of MS
 MULTIPLE SCLEROSIS
PATHOGENESIS
Autoimmune mechanism (molecular mimicry)
• Evidence suggests an autoimmune process
directed against the protein component of
myelin

1. Autoreactive T lymphocytes are activated on

exposure to a viral infection

3. Sensitization of T lymphocyte against MBP

(T lymphocytes recognize an identical structure in
both the virus and myelin sheath)
 MULTIPLE SCLEROSIS
ETIOLOGY AND PATHOGENESIS

3a. Activation of B lymphocytes to produce MBP

antibodies or membrane attack complexes by
complement activation

Destruction of myelin

3b. Activated T lymphocytes enter the CNS, triggering

an immunologic cascade with recruitment of
inflammatory cells and local release of lymphokines
and cytokines (TNF-α, interleukin, INF-γ) with
resultant injury to oligodendrocytes and myelin
 MULTIPLE SCLEROSIS
PATHOLOGY

• Multifocal areas of loss of myelin with preservation of

axons around small veins and venules with
accompanying lymphocytes and mononuclear cells
• Loss of oligodendrocytes
• Astrogliosis
• Predilection for the white matter of the CNS (especially
the one surrounding the ventricle)
• New active plaques tend to be pink with faint borders
grossly, old inactive plaques are gray, firm, are sharply
demarcated and have a gliotic background devoid of
oligodendrocytes
Motor pathway

Spinal effector Mechanism

Somesthetic
System
Cerebral
Plaque

Spinal Cord
MS
 PATHOLOGY
• Multifocal white matter lesions
(inflammation and demyelination)
in the CNS
• Association, commisural and projection
fiber tracts with - motor
- sensory
- autonomic
- cerebellar functions
Most Common Symptoms of MS
1. Pyramidal weakness 45%
2. Visual loss 40%
3. Sensory Loss 35%
4. Brainstem dysfunction 30%
5. Cerebellar ataxia and tremor 25%
6. Sphincter disturbance 20%
 Optic Neuritis

Symptoms
1. Blurred vision
2. Pain in and around the eye

Signs
5. Reduced visual acuity
6. Reduced contrast sensitivity
7. Reduced color vision
8. Visual field (central scotoma)
OPTIC NEURITIS

Visual Pathways
 Transverse Myelitis
Acute or subacute development of symptoms
and signs of neurologic dysfunction in motor,
sensory or autonomic nerves and nerve tracts of
the SPINAL CORD
Bilateral INO

Clinical features of INO

(MLF syndrome)

- Paralysis of adduction
- Nystagmus of abducting
eye
 Eye
LE RE
Movements

Right lateral
rectus
Nucleus III
Medial
Longitudinal
fasciculus Nucleus IV

Nucleus VI

Hypotherical
subcortical
center for
conjugate
lateral gaze

Vestibular
Nucleus

Frontal lobe Corticonuclear

tracts

Left occipital lobe

 Swinging Light Pupil Test
• Relative afferent
pupillary defect
(RAPD)
• Marcus Gunn Pupil
• Presence of a
unilateral or
asymmetric optic
nerve disease
Swinging Light Pupil Test

Strong light directed

at right eye
produces pupillary
constriction in both
eyes (left)

When light is
directed at left eye
(right), both pupils
dilate, indicating a
left RAPD
A. The pupils in dim light are equal

D. Light directed into the left eye

results in partial and sluggish
constriction in each eye

F. Light directed into the right eye

results in a brisk and normal
reaction in each eye

H. The light quickly directed into the

left eye results in a dilatation of
both pupils
 Lhermitte

• Sensation of electricity down the back

after passive or active flexion of neck
• Indicates a lesion in the posterior column
in the cervical spinal cord
• May be seen in other diseases
 Multiple Sclerosis
• Transient disorders may be precipitated by
exposure to heat, exercise or other stimuli:
– dysthesia
– weakness
– diplopia
– visual blurring (Uhtoff phenomenon)
Clinical Features Suggestive of MS

1. Onset between ages of 15-50

2. Relapsing / remitting course
3. Optic neuritis
4. Lhermitte’s sign
5. Transverse myelitis
6. Internuclear ophthalmoplegia
7. Acute urinary retention (especially in young men)
8. Paroxysmal symptoms
9. Diurnal fatigue pattern
10. Worsening symptoms with heat or exercise
Clinical Features NOT Suggestive of MS
1. Onset before the age of 10 or after 55
2. Continued progression from onset without relapses
3. Early dementia
4. Seizures
5. Aphasia
6. Agnosia
7. Apraxia
8. Homonymous or bitemporal hemianopsia
9. Encephalopathy
10. Extrapyramidal symptoms
11. Uveitis
12. Peripheral Neuropathy
 Clinical Criteria for Definite
Multiple Sclerosis
• Two separate central nervous symptoms
• Two separate attacks – onset of symptoms is
separated by at least 1 month
• Symptoms must involve the white matter
• Objective deficits are present on the neurologic
examination
• Age 10-50 (usually 20-40)
• No other medical problem can be found to
explain the patients condition
NOTE: the key to the clinical criteria for the diagnosis of MS is ;
2 separate symptoms at 2 separate times
or lesion disseminated in time
Course Multiple Sclerosis

A
• Relapsing-remitting

B
• Secondary
progressive

C
• Primary progressive

D
• Progressive
relapsing
85% Relapsing-Remitting
15% Progressive course from onset
 Differential Diagnosis
of Multiple Sclerosis
Disorder Distinguishing clinical/Laboratory features

Acute disseminated Follows infections or vaccination in children; fever,

encephalomyelitis headaches, and meningism common
Lyme disease Antibodies to Borrelia antigens in serum and CSF by
ELISA and Western blot
HIV-associated myelopathy HIV serology
HTLV-I myelopathy HTLV-1 serology in serum/CSF
Neurosyphilis Serum/CSF serology
Progressive multifocal Immunosuppressed patients; biopsy of lesions
leukoencephalopathy demonstrates virus by electron microscopy
Systemic lupus erythematosus Non-CNS manifestations of lupus; antinuclear antibodies,
anti-dsDNA and anti-Sm antibodies
Polyarteritis nodosa Systemic signs; angiography shows microaneuryms;
biopsy of involved areas shows vasculitis
Sjogren syndrome Dry eyes and mouth; anti-Ro and anti-La antibodies;
lower lip biopsy helpful
 Differential Diagnosis
of Multiple Sclerosis
Disorder
Behset disease
Sarcoidosis
Paraneoplastic syndromes
Subacute combined
degeneration of cord
Subacute myelo-optic neuritis
(SMON)
Adrenomyeloneuropathy
Spinocerebellar syndromes
Hereditary spastic
paraparesis/primary lateral
sclerosis
Miscellaneous
Distinguishing clinical/Laboratory features
Oral/genital ulcers, antibodies to oral mucosa
Non-CNS signs; increased protein in CSF; biopsy shows
granuloma
Older age group; anti-Yo antibodies; identify neoplasm
Peripheral neuropathy, vitamin B12 levels
Mainly in Japanese; adverse reaction to
chlorhydroxyquinoline
Adrenal dysfunction; neuropathy; plasma very-long-chain
fatty acids increased
Familial; pes cavus; scoliosis; absent reflexes; normal
CSF IgG and no bands
Normal CSF studies
Strokes, tumors, arteriovenous malformations, arachnoid
cysts, Arnold-Chiari malformations, and cervical
spondylosis all may lead to diagnostic dilemmas on
occasion. These conditions may coexist; differentiation
based on history, clinical followup and MRI features.
 Laboratory Studies
“NO specific reliable diagnostic test for MS exists”
• MRI (MS plaque)

• CSF Examination
• Oligoclonal bands (> 90% of definite MS)

• Evoked Potentials
– Visual Evoked Responses
– Brainstem Auditory Responses
– Somatosensory Responses
(delayed response)
Multiple Sclerosis Plaque in the
Brain
T1 Contrast
Multiple Sclerosis Plaque in the Spinal Cord

T1 Contrast
 MS Laboratory Procedures
A. CSF examination
• WBC – normal or modest lymphocytic
pleocytosis
• Total Protein – normal
• IgG increased (>12% of total protein)
• Protein electrophoresis – oligoclonal bands
• Elevated IgG index: CSF IgG/ Serum IgG
CSF alb./Serum alb.
- >1.7 – probable multiple sclerosis
 MS Laboratory Procedures
A. CSF examination
2. Pleocytosis – during acute onset or
exacerbation (L or M predominant cell)
- polymorphonuclear may predominate
in hyperacute cases

NOTE: Pleocytosis may be the only measure of activity of

the disease
 MS Laboratory Procedures
• CSF examination (continuation)
2. Oligoclonal bands
- synthesized in CNS
- migrate in agarose electrophoresis in
abnormal discrete population
Currently the most widely used CSF test for
confirmation of MS
Nonspecific test – (+) also in Syphilis, SSPE,
Lyme Disease
MS Laboratory Procedures
• Evoked Potentials (delayed response)
– Visual Evoked Responses
– Brainstem Auditory Responses
– Somatosensory Responses
Somesthetic
System
Auditory
Pathway
 Immunotherapy of
Multiple Sclerosis
1. Corticosteroids
2. Immunomodulators
• Interferon
• Copolymer I
3. Immunosuppressive drugs
• Azathioprine
• Cyclophosphamide
4. Natalizumab – an intergrin antagonist
5. Intravenous immunoglobulin
• in fulminant cases
 Multiple Sclerosis
Treatment
1. NO TREATMENT
is known for acute demyelinating optic neuritis that can
improve the ultimate visual prognosis compared to the natural
history of the disorder

2. Short course of IV
METHYLPREDNISOLONE
followed by 2 weeks of ORAL PREDNISONE often
increases the speed of recovery of vision by 2-3
weeks but the ultimate visual function at 1 year will
be the same as it would have been if no treatment
were given
 Multiple Sclerosis
Treatment
• Treatment of acute exacerbations
– IV methylprednisolone
• 250-500 mg q 12h x 3-7 days IV
• Oral prednisone 60-80 mg/day x 7 days
• Taper x 1 month

– > 85% improvement – R-R MS

– < 50% improvement – chronic progressive
MS
 Multiple Sclerosis
Treatment
• Immuno-modulators
– Beta-interferon-1a (Avonex) (Rebif)
– Beta-interferon-1b (Betasteron)
– Glatiramen acetate (Copaxone)
– Intravenous immunoglobulin (IVIG)
– Mitoxantrone (Novantrone)

Proven benefit in Tx of Relapsing-Remitting MS

Aimed to reduce proinflammatory or increase anti-inflammatory cytokines
Natural history of MS may be favorably altered by immunomodulatory drugs
 Multiple Sclerosis
Treatment
• Beta-interferon-1a
– Recombinant DNA technology
– Identical to naturally occurring interferon
– 31% decrease in exacerbations
– Fewer enhancing active lesions than placebo
(suggesting < new episodes of exacerbations)
– Abs vs IFN-1a in 2 years (20%)
– 55% incidence of systemic, flu-like symptoms
– Given once a month (6 M units IM)
 Multiple Sclerosis
Treatment
• Beta-interferon-1b
– 34% decrease in exacerbations
– Given every other day (8M units SC)
– 40 % develop Abs vs IFN-1b (Abs vs 1b
usually neutralize 1a, and vice versa)
– Flu-like symptoms (76%), tend to abate with
time
– Mechanism of action - unknown
 Multiple Sclerosis
Treatment
• Glatiramen acetate (Copaxone)
– Synthetic polypeptides designed to mimic MBP
– 4 amino acids: glutamic acid, lysine, arginine, alanine,
tyrosine
– 29% reduction in exacerbations
– Given daily (20mg SC)
– No significant side effects
– (+) Abs – no clinical significance
– Mechanism of action - unknown
 Multiple Sclerosis
Treatment
• Intravenous immunoglobulin
– 0.4 gm/kg/day, for 5 days
– Disability scores improved, relapse cut in half
– Well-tolerated, few side-effects
– Small sample size (148 patients), expensive
 Multiple Sclerosis
Treatment
Plasma Exchange:
7 exchange q.i.d. over 14 days

Common Side effects: anemia, hypotension,

heparin associated thrombocytopenia
Contraindication: Hemodynamically unstable
patient
 Working Capacity and Survival in 800
patients with MS
Duration 1-5 yr 6-10 yr 11-15 yr 16-20 21 yr
(%) (%) (%) yr (%) (%)
Working 71 50 31 30 28
Disabled 29 40 63 57 52
Dead - 1 6 13 20
From Bauer HJ. Neurology 1978;28:8-20
Merrits,11th ed, 2005

“It is IMPOSSIBLE to predict the long range

prognosis of a patient with MS”
 Predictors of more favorable
Prognosis
1. Female sex
2. Onset before age 40
3. Presentation with visual or
somatosensory rather than pyramidal or
cerebellar dysfunction
 Predictors of worse prognosis
1. Male gender
2. Late onset
3. Progressive form from onset
4. Motor symptoms from onset
5. Poor recovery from first attack
 Diffuse Cerebral Sclerosis of
Schilder
• Pathology
– Large, sharply outlined, asymmetrical, foci of
myelin destruction in the cerebral
hemispheres
– Discrete lesions in brainstem, spinal cord and
optic nerves may be present
 Diffuse Cerebral Sclerosis of
Schilder
• Clinical Manifestations
- dementia
- homonymous hemianopia
cortical blindness
deafness
- hemiplegia or quadriplegia
pseudobulbar palsy
protacted remitting course
Diffuse Cerebral Sclerosis of
Schilder
• CSF findings
- same as MS, but
no oligoclonal
bands
- (+) MBP

• MRI
 Diffuse Cerebral Sclerosis of
Schilder

• Death in few months or years

• Some survive a decade or longer
 Concentric Sclerosis of Balo
• Pathology
- alternating bands of destruction and
preservation of myelin in a series of
concentric rings
 Concentric Sclerosis of Balo
• Clinical Manifestations
- similar to Schilder’s Sclerosis
Devic’s Disease
Variant of MS
• Optic neuritis
• Transverse myelitis
 Acute Disseminated
Encephalomylitis (ADEM)
• Post infectious encephalomyelitis
• Post Vaccinal encephalomyelitis

Pathology:
- numerous perivenular demyelinative and
inflammatory lesions in the brain and spinal
cord
- multifocal meningeal infiltration
(distinguishing factor from acute MS)
Acute Disseminated Encephalomyelitis
 Acute Disseminated
Encephalomyelitis (ADEM)
C. Acute Necrotizing Hemorrhagic
Encephalomyelitis
- most fulminant ADEM
- may show large confluent edematous
lesions in the cerebral hemisphere with
punctate hemorrhages in the gray and
white matter
 Acute Disseminated
Encephalomyelitis (ADEM)
• Clinical Manifestations
- more common in children
- preceding viral infection (commonly measles
and varicella) or vaccination (old antirabies
vaccine and small pox vaccine) or occasionally
tetanus antitoxin inoculation
A. Encephalitis
- few days after with sudden fever, headache,
confusion, somnolence, sometimes convulsion
and stiffneck
 Acute Disseminated
Encephalomyelitis (ADEM)
• Clinical Manifestations
A. Encephalitis
- few days after with sudden fever,
headache, confusion, somnolence,
sometimes convulsion and stiffneck
- in more severe cases stupor, coma,
nuchal rigidity
 Acute Disseminated
Encephalomyelitis (ADEM)
• Clinical Manifestations
B. Cerebellitis
- more following varicella
- acute ataxia
- more benign
 Acute Disseminated
Encephalomyelitis (ADEM)
• Clinical Manifestations
C. Acute Transverse Myelitis
- paraparesis or quadriparesis with
depressed DTR’s
- sensory complains
- bowel and bladder problems
- midline back pain may be prominent
Thank you !!!