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- 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
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Bilateral Internuclear Opthalmoplegia (INO) Lhermitte Sign
- Problem in Medial Lonitudinal Fasciculus - Sensation of electricity down the back after passive or active
Clinical Features (MLF Syndrome) flexion of neck
- Paralysis of adduction (medial rectus muscle) - Indicates a lesion in the posterior column in the cervical spinal
- Nystagmus of abducting eye (lateral rectus muscle) cord
In the Philippines, INO is rarely seen as an isolated lesion, - May be seen in other diseases (very non-specific, affects any
usually it is associated with multiple sclerosis 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
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
CSF Findings
- Same as MS, but no oligoclonal bands
- (+) MBP
Prognosis
- Death in few months or years
- Some survive a decade or longer
Clinical Manifestations
- Similar to Schilder’s Sclerosis
- More common in children
Devic’s Disease
- Variant of MS
- Optic neuritis
- Transverse myelitis