Demyelinating Diseases - Subacute Sclerosing Panencephalitis (SSPE) →
Neurology measles virus
Dr. Poblete & Dr. Javier
January 23, 2008
Disorders of Myelination
I. 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
Examples
- 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
II. Demyelination
- Destruction of normal myelin
- Normal production of myelin
a. Primary → Idiopathic Inflammatory Demyelinating
Disorders of the CNS
b. Secondary

Myelin is produced by oligodendrocytes
Take note: Demyelination is different from Dysmyelination
Normal myelin is destroyed Abnormal myelin is produced
Pathologic Criteria of a Demyelinating Disease
1. Destruction of the myelin sheaths of nerve fibers with relative
sparing of the other elements of nervous tissue e.g. of axons,
nerve cells & supporting structures, as reflected by a relative
lack of wallerian or secondary degeneration of fiber tracts
2. Infiltration of inflammatory cells in a perivascular & paravenous
distribution
3. Distribution of lesions that is primarily in white matter
Primary Demyelination
I. Multiple Sclerosis (Disseminated Sclerosis) → most
important; Disseminated Sclerosis as termed by the British;
Sclerose en plaques as termed by the French due to their sharp
delineation
a. Chronic relapsing encephalomyelopathic form → involving
brain and spinal cord; most important among MS
b. Acute Multiple Sclerosis (very rare)
c. Diffuse Cerebral Sclerosis
- Schilder’s diffuse sclerosis
- Balo’s Concentric sclerosis
II. Neuromyelitis Optica (Devic’s Diseases) → involves optic
nerve and cord
III. Acute Disseminated Encephalomyelitis (ADEM)
a. Postinfectious encephalomyelitis → measles and chicken
pox (eczematous diseases)
- Typical course of illness: improving from the disease,
then after 3-4 weeks, with sudden brain involvement
b. Postvaccinal encephalomyelitis → anti-rabies and small
pox vaccination
- Destruction of myelin in brain and cord
IV. Acute and Subacute Necrotizing Hemorrhagic Encephalitis
a. Acute encephalopathic form (Hurst hemorrhagic
leukoencephalitis
b. Subacute necrotic myelopathy
Secondary Demyelination
Causes:
- Viral Infections
- Progressive Multifocal Leukoencephalopathy (PML) →
JC Papilloma virus
- Affects immunocompromised individuals e.g. AIDS
- In the Philippines, usually happens if you have measles
very early in life → 6-8 years later will develop SSPE
- Human T-cell lymphotrophic or leukemia virus type I :
(HTLV associated myelopathy) → HAM or Tropical
Spastic Paraparesis (TSP)
- Some cases of anoxic encephalopathy
- Myelin sheaths of the radiating nerve fibers in the deep
layers of the cerebral cortex & central white matter are
destroyed, while most of the axis cylinders are spared
- 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
- Usually with pernicious anemia, atrophic gastritis, tropical
paraparesis
- 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
Note: In secondary demyelination, cause is known, while in primary
demyelination such as MS, cause is unknown
Multiple Sclerosis
- Chronic inflammatory autoimmune disease of unknown etiology
that involves demyelination of the CNS with resultant neurologic
dysfunction

Must be Central Nervous System not peripheral nervous system
→ the only PNS included is optic nerve since it is considered an
extension of the cerebrum
- The manifestations are extremely variable in type and severity
Incidence and Epidemiology
- 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 increasing 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
- 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
1
 - In MS, an antigen of the oligoclonal IgG has not been Motor Pathway
identified - Axons are the in the white matter of the cerebral hemisphere,
- The cytokines produced by activated T cells and midbrain, brainstem and spinal cord (posterior, lateral and
macrophages may play a role in tissue damage anterior columns)
- T cells reactive against Myelin Basic Protein (MBP) and - White matter is affected and not the grey matter (ventral horn
Proteolytic Lipid Peptide(PLP) mediate the CNS cell, dorsal horn)
inflammation - PNS also not affected

Development of antibodies or activated T lymphocytes to
White matter of the brain and spinal cord affected → so upper
the antigen in myelin (some sort of allergic reaction) motor neuron pathway (pyramidal tract) is affected; weakness of

Both humoral and cellular immunity is involved → hence it MS is upper motor neuron pathway, therefore manifestations
is believed that MS is an autoimmune disease would include:

Theory of autoimmunity → molecular mimicry - Hypereflexia
- (+) Babinski
Virus
You would not expect lower motor neuron lesions signs such as
- Genetic factors influence susceptibility to development of atrophy, fasciculations
demyelination and clinical disease; this susceptibility is
linked to the immune response generated in the animal Somasthenic System
against viral determinants - Posterior column of the spinal cord is most heavily affected
- The 2 virus candidates most commonly implicated in the because it is heavily myelinated → therefore position sense
pathogenesis of MS are Epstein-Barr (EPV) virus and and vibration sense are greatly affected
Human Herpes Virus 6 (HHV 6) - Temperature and pain not as affected since they are finely
- After early infection the viruses persist in latent form, and myelinated or unmyelinated
clinical relapses are caused by periods of viral re-activation
Pathology
Summary - Multifocal white matter lesions (inflammation and
- Cause remains elusive but autoimmune mechanisms demyelination) in the CNS
possibly triggered by environmental factors in genetically - Affects association, commisural and projection fiber tracts
susceptible individuals are probably important with → motor, sensory, autonomic, and cerebellar
- No clear understanding of etiology, severity of disability or functions
variation in the natural history of MS
Most Common Symptoms of MS
Pathogenesis Pyramidal weakness 45%
- Autoimmune mechanism (molecular mimicry) Visual loss (optic neuritis) 40%
- Evidence suggests an autoimmune process directed Sensory loss 35%
against the protein component of myelin Brainstem dysfunction 30%
1. Autoreactive T lymphocytes are activated on exposure Cerebellar ataxia and tremor 25%
to a viral infection Sphincter disturbance 20%
2. Sensitization of T lymphocyte against MBP (T
In brainstem is where the neural tract that connects nuclei III, IV and
lymphocytes recognize an identical structure in both the VI reside called Medial Longitudinal Fasciculus (MLF) → responsible
virus and myelin sheath) for conjugate eye movement; therefore lesion here would manifest as
3. Activation of B lymphocytes to produce MBP antibodies diplopia or nystagmus
or membrane attack complexes by complement
Sphincter disturbance → bowel and bladder (bladder is more
activation → Destruction of myelin common)
4. Activated T lymphocytes enter the CNS, triggering an
immunologic cascade with recruitment of inflammatory Optic Neuritis
cells and local release of lymphokines and cytokines - Inflammation of optic nerve
(TNF-α, interleukin, INF-γ) with resultant injury to Symptoms
oligodendrocytes and myelin - Blurred vision

Viral infection in the past → similar epitope in the The important findings
- Pain in and around the eye
myelin → when infected again, T cells attack the myelin Signs
instead of the virus - Reduced visual acuity
- Reduced contrast sensitivity
Pathological Findings - Reduced color vision
- Multifocal areas of loss of myelin with preservation of axons - Visual field (central scotoma)
around small veins and venules with accompanying
If optic neuritis is the only manifestation, some asymptomatic
lymphocytes and mononuclear cells lesions can be seen in the MRI
- Loss of oligodendrocytes
- Astrogliosis
- Predilection for the white matter of the CNS (especially the
one surrounding the ventricle)
- Site of the lesion is usually periventricular where
subependymal veins line the ventricles
- Other favored structures:
- Optic nerves & chiasm( & rarely the optic tract)
- Spinal cord where pial veins lie next to or within the
white matter
- 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

Myelin is found in white matter → therefore white matter Transverse Myelitis
lesions are found in MS → scarring of white matter → - Acute or subacute development of symptoms and signs of
formation of paques (usually dound near the ventricular neurologic dysfunction in motor, sensory or autonomic nerves
system and nerve tracts of the spinal cord

White matter of spinal cord is called column or funiculus

What is affected is the white matter and not the grey matter
(dorsal or ventral horn)

Thoracic involvement → paraparesis, paraplegia; if higher than
thorax → quadriplegia

2
Bilateral Internuclear Opthalmoplegia (INO)
- Problem in Medial Lonitudinal Fasciculus
Clinical Features (MLF Syndrome)
- Paralysis of adduction (medial rectus muscle)
- Nystagmus of abducting eye (lateral rectus muscle)

In the Philippines, INO is rarely seen as an isolated lesion,
usually it is associated with multiple sclerosis
Lhermitte Sign
- 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 (very non-specific, affects any
other disease that affects posterior column)

Multiple Sclerosis
- Transient disorders may be precipitated by exposure to heat,
exercise or other stimuli:
- Dysthesia
- Weakness
- Diplopia
- Visual blurring (Uhtoff phenomenon)

Therefore patients with multiple sclerosis should avoid sauna
bath

Heat is very bad for MS patients, keep in cool environment

Heat exacerbates MS because even if the nerves are destroyed,
it may still be functional with a lower threshold for stimulation

Clinical Features Suggestive of MS

- Onset between ages of 15-50 (but peak is 20-40)
- Relapsing / remitting course
Eye Movements - Optic neuritis
RE
LE
- Lhermitte’s sign
- Transverse myelitis
Right lateral
- Internuclear ophthalmoplegia
rectus
- Acute urinary retention (especially in young men)
Nucleus III
Medial
- Paroxysmal symptoms
Longitudinal
fasciculus
Nucleus IV
- Diurnal fatigue pattern
Nucleus VI
- Worsening symptoms with heat or exercise
Hypotherical
subcortical
center for
conjugate Clinical Features NOT Suggestive of MS
lateral gaze
- Onset before the age of 10 or after 55
Vestibular
Nucleus - Continued progression from onset without relapses
- Early dementia
Frontal lobe
Corticonuclear - Seizures
tracts
- Aphasia These are grey matter manifestations
- Agnosia
Left occipital lobe
- Apraxia
- Homonymous or bitemporal hemianopsia

In MLF is where the crossing fibers innervating the medial rectus - Encephalopathy
muscle reside for adduction - Extrapyramidal symptoms → substantia nigra

MLF connects nuclei III, IV and VI → lesion is in the connection not - Uveitis
the nuclei itself → which is why is it called internuclear opthalmoplegia - Peripheral Neuropathy
Swinging Light Pupil Test Clinical Criteria for DEFINITE Multiple Sclerosis
- Relative afferent pupillary defect (RAPD) - Two separate central nervous symptoms
- Marcus Gunn Pupil - Two separate attacks → onset of symptoms is separated
- Presence of a unilateral or asymmetric optic nerve disease by at least 1 month
- Strong light directed at right eye produces pupillary constriction - Symptoms must involve the white matter
in both eyes (left) - Objective deficits are present on the neurologic
- When light is directed at left eye (right), both pupils dilate, examination
indicating a left RAPD - Age 10-50 (usually 20-40)

Afferent limb is optic nerve and efferent limb is occulomotor - No other medical problem can be found to explain the
nerve patients condition

Defect is in the optic nerve and not the occulomotor nerve
Note: The key to the clinical criteria for the diagnosis of MS:
- 2 separate symptoms at 2 separate times
The pupils in dim light are - Or lesion disseminated in time
equal
Course of Multiple Sclerosis
Relapsing-remitting
Light directed into the left
eye results in partial and
sluggish constriction in each Secondary progressive
eye
Light directed into the right
eye results in a brisk and Priimary progressive
normal reaction in each eye

The light quickly directed Progressive relapsing

into the left eye results in a (rarest)
dilatation of both pupils

85% Relapsing-Remitting

In this diagram, defect is in the left optic nerve
15% Progressive course from onset

Pupil that is slightly bigger when light directed at it is the defective
Primary progressive must use neuroimaging, difficult to
eye diagnose, usually in older males, signs and symptoms usually
referable to the spinal cord

3
 Differential Diagnosis of Multiple Sclerosis 1. Pleocytosis → during acute onset or exacerbation (L or M
Disorder Distinguishing clinical/laboratory predominant cell)
Features - Polymorphonuclear may predominate in hyperacute
Acute disseminated Follows infections or vaccination in cases
encephalomyelitis children; fever, headaches, and
Note: Pleocytosis may be the only measure of activity of
meningism common the disease
Lyme Disease Antibodies to Borrelia antigens in 2. Oligoclonal bands
serum and CSF by ELISA and - Synthesized in CNS → this IgG is only synthesized in
Western blot the CNS
HIV-associated HIV serology - Migrate in agarose electrophoresis in abnormal discrete
myelopathy population
HTLV-1 myelopathy HTLV-1 serology in serum/CSF
Currently the most widely used CSF test for
Neurosyphilis Serum/CSF serology confirmation of MS
Progressive multifocal Immunosuppressed patients; biopsy of
Nonspecific test → (+) also in Syphilis, SSPE, Lyme
leukoencelopathy lesions demonstrates virus by electron Disease
microscopy - Evoked Potentials (delayed response)
Systemic lupus Non-CNS manifestations of lupus; - Visual Evoked Responses
Erythematosus antinuclear antibodies, anti-dsDNA - Brainstem Auditory Responses
and anti-Sm antibodies - Somatosensory Responses
Polyarteritis nodosa Systemic signs; angiography shows
Any delay means areas of demyelination
microaneuryms; biopsy of involved
areas shows vasculitis Immunotherapy of Multiple Sclerosis
- Corticosteroids
Sjogren syndrome Dry eyes and mouth; anti-Ro and anti-
- Immunomodulators → lessen frequency and severity of
La antibodies; lower lip biopsy helpful
replapses
Behcet disease Oral/genital ulcers, antibodies to oral
- Interferon
mucosa
- Copolymer I
Sarcoidosis Non-CNS signs; increased protein in - Immunosuppressive drugs
CSF; biopsy shows granuloma - Azathioprine
Paraneoplastic Older age group; anti-Yo antibodies; - Cyclophosphamide
syndromes identify neoplasm - Natalizumab → an intergrin antagonist
Subacute combined Peripheral neuropathy, vitamin B12 - Intravenous immunoglobulin
degeneration of cord levels - In fulminant cases
Subacute myelo-optic Mainly in Japanese; adverse reaction - More for the acute
neuritis (SMON) to chlorhydroxyquinoline
Important ones are corticosteroids and immunomodulators, in
Adrenomyeloneuropathy Adrenal dysfunction; neuropathy; more advance course, the immunosuppressive drugs
plasma very-long-chain fatty acids
increased Treatment for Multiple Sclerosis
Spinocerebellar Familial; pes cavus; scoliosis; absent - No treatment is known for acute demyelinating optic neuritis
syndromes reflexes; normal CSF IgG and no that can improve the ultimate visual prognosis compared to the
bands natural history of the disorder
Hereditary spastic Normal CSF studies - Short course of IV methylprednisolone followed by 2 weeks of
paraparesis/primary oral prednisone often increases the speed of recovery of vision
lateral sclerosis by 2-3 weeks but the ultimate visual function at 1 year will be
Miscellaneous Strokes, tumors, arteriovenous the same as it would have been if no treatment were given
malformations, arachnoid cysts, - Treatment of acute exacerbations → IV methylprednisolone
Arnold-Chiari malformations, and - 250-500 mg q 12h x 3-7 days IV
cervical spondylosis all may lead to - Oral prednisone 60-80 mg/day x 7 days
diagnostic dilemmas on occasion. - Taper x 1 month
These conditions may coexist; - > 85% improvement → Relapsing-Remitting MS
differentiation based on history, - < 50% improvement → chronic progressive MS
clinical followup and MRI features. - Immuno-modulators
- Used for prophylaxis for future relapses
Laboratory Studies - Beta-interferon-1a (Avonex) (Rebif)
- No specific reliable diagnostic test for MS exist - Recombinant DNA technology
- MRI → MS plaque, most important - Identical to naturally occurring interferon
- CSF Examination → Oligoclonal bands (>90% of definite - 31% decrease in exacerbations
MS) - Fewer enhancing active lesions than placebo
- Evoked Potentials (delayed response) (suggesting < new episodes of exacerbations)
- Visual Evoked Responses → most sensitive - Abs vs IFN-1a in 2 years (20%)
- Brainstem Auditory Responses - 55% incidence of systemic, flu-like symptoms
- Somatosensory Responses → next most sensitive - Given once a month (6 M units IM)

Abnormalities here would soon say that there is a silent - Beta-interferon-1b (Betasteron)
lesion - 34% decrease in exacerbations
- Given every other day (8M units SC)
MS Laboratory Procedures - 40 % develop Abs vs IFN-1b (Abs vs 1b usually
- MRI → should be done neutralize 1a, and vice versa)
- T2 → see the plaques; multiple periventricular + clinical - Flu-like symptoms (76%), tend to abate with time
sign → MS - Mechanism of action - unknown
- CSF examination - Glatiramen acetate (Copaxone)
- WBC → normal or modest lymphocytic pleocytosis - Synthetic polypeptides designed to mimic MBP
- Total Protein → normal - 4 amino acids: glutamic acid, lysine, arginine, alanine,
- IgG increased (>12% of total protein) tyrosine
- Protein electrophoresis → oligoclonal bands - 29% reduction in exacerbations
- Elevated IgG index: - Given daily (20mg SC)
CSF IgG/ Serum IgG - No significant side effects
CSF alb./Serum alb. - (+) Abs → no clinical significance

>1.7 → probable multiple sclerosis - Mechanism of action – unknown

4
 - Intravenous immunoglobulin (IVIG) Acute Disseminated Encephalomyelitis (ADEM)
- 0.4 gm/kg/day, for 5 days A. Post infectious encephalomyelitis
- Disability scores improved, relapse cut in half B. Post Vaccinal encephalomyelitis
- Well-tolerated, few side-effects Pathology
- Small sample size (148 patients), expensive - Numerous perivenular demyelinative and inflammatory
- Mitoxantrone (Novantrone) lesions in the brain and spinal cord

Proven benefit in treatment of Relapsing-Remitting MS - Multifocal meningeal infiltration → distinguishing factor

Aimed to reduce proinflammatory or increase anti- from acute MS
inflammatory cytokines C. Acute Necrotizing Hemorrhagic Encephalomyelitis

Natural history of MS may be favorably altered by - Most fulminant ADEM
immunomodulatory drugs - May show large confluent edematous lesions in the
- Plasma Exchange: 7 exchange q.i.d. over 14 days cerebral hemisphere with punctate hemorrhages in the gray
- Common Side effects: anemia, hypotension, heparin and white matter
associated thrombocytopenia - Lesions involve cerebrum and spinal cord
- Contraindication: Hemodynamically unstable patient - Monophasic → once you have it, it does not come back; if
you had it and signs and symptoms come back → then it is
Working Capacity and Survival in 800 patients with MS not ADEM but more likely MS
Duration 1-5 yr 6-10 yr 11-15 yr 16-20 yr 21 yr Clinical Manifestations
(%) (%) (%) (%) (%) - More common in children
Working 71 50 31 30 28 - Preceding viral infection (commonly measles and
Disabled 29 40 63 57 52 varicella) or vaccination (old antirabies vaccine and
Dead - 1 6 13 20 small pox vaccine) or occasionally tetanus antitoxin

“It is impossible to predict the long range prognosis of a patient with inoculation
MS” A. Encephalitis
- Few days after with sudden fever, headache,
Predictors of More Favorable Prognosis confusion, somnolence, sometimes convulsion and
- Female sex stiffneck
- Onset before age 40 - In more severe cases stupor, coma, nuchal rigidity
- Presentation with visual or somatosensory rather than B. Cerebellitis
pyramidal or cerebellar dysfunction - More following varicella
- Acute ataxia
Factors of Worse Prognosis - More benign
- Male gender C. Acute Transverse Myelitis
- Late onset - Paraparesis or quadriparesis with depressed DTR’s
- Progressive form from onset - Sensory complains
- Motor symptoms from onset - Bowel and bladder problems
- Poor recovery from first attack - Midline back pain may be prominent

Diffuse Cerebral Sclerosis of Schilder Transcribed by: Fred Monteverde

Pathology Notes from: Denise Zaballero
- Large, sharply outlined, asymmetrical, foci of myelin Cecile Ong
destruction in the cerebral hemispheres
- Discrete lesions in brainstem, spinal cord and optic nerves Fred Monteverde
may be present Emy Onishi
Mitzel Mata
Clinical Manifestations Cecile Ong
- Dementia Regina Luz
- Homonymous hemianopia Mae Olivarez
- Cortical blindness Section C 2009
- Deafness
- Hemiplegia or quadriplegia
- Pseudobulbar palsy
- Protacted remitting course

CSF Findings
- Same as MS, but no oligoclonal bands
- (+) MBP

Prognosis
- 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

Clinical Manifestations
- Similar to Schilder’s Sclerosis
- More common in children

Devic’s Disease
- Variant of MS
- Optic neuritis
- Transverse myelitis