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MULTIPLE SCLEROSIS

MULTIPLE Is a chronic, progressive, degenerative disorder


of the central nervous system characterized by

SCLEROSIS disseminated demyelination of nerve fibers of


the brain and spinal cord.
MULTIPLE SCLEROSIS AFFECT:

0.1%
>
The illness is approximately three times as common in women as in men

Worldwide incidence
The ratio is
increasing
now
400, 000
people in
US have First manifests between ages: 20-40 years
MS Estimated to affect about 2.5 million people
worldwide

Higher
incidence in
Northern
European
descent and in
temperate
climate, but the
latitude gradient
is decreasing
ETIOLOGY:
The cause of MS is unknown although
polygenetic susceptibility and environmental
factors both play a role.

Altered immune response directed against


self that results in inflammation,
demyelination, neurodegeneration, and
dysfunctional neuronal repair.
ETIOLOGY:
Related to:
Genetic factor
Infectious agents
Immunologic reaction
Stress
Sex hormone
Genetic factor

MS is not considered
a hereditary disease;
A number of genetic
variations have been shown to
increase the risk
Specific genes that have been
linked with MS include
differences in the human
leukocyte antigen (HLA)
systema group of genes
on chromosome 6 that serves
as the major histocompatibility
complex (MHC).
ETIOLOGY:
Related to:
Genetic factor
Infectious agents
Immunologic reaction
Stress
Sex hormone
ETIOLOGY:
Infectious agents
Viral or bacterial infections may be an important environmental
cause of MS. Although no clear association has been identified

Evidence for a virus as a cause include: the presence of oligoclonal


bands in the brain and cerebrospinal fluid of most people with MS,
increased immunoglobulin G (IgG) synthesis in the CNS and
increased antibody titers to viruses.

Many possible agents have been implicated, including


mycoplasma, Chlamydia pneumoniae, spirochetes, rabies
virus, herpes simplex virus, coronavirus, human T-cell
leukemia virus type I (HTLV-I), MS-associated retrovirus,
measles.
ETIOLOGY:
Related to:
Genetic factor
Infectious agents
Immunologic responses
Stress
Sex hormone
ETIOLOGY:
Immunologic responses
Characterized by an intricate
and extensive cascade of
events. Much of our
understanding of processes
that initiate altered immune
response, myelin destruction,
chronic axonal damage.
ETIOLOGY:
Related to:
Genetic factor
Infectious agents
Immunologic reaction
Stress
Sex hormone
pathophysioloGY:
The three main characteristics of MS are the formation of lesions in the central
nervous system, inflammation, and the destruction of myelin sheaths of neurons

Blood-brain barrier breakdown The BBB prevent entrance of T


(BBB) cells into the nervous system.
The bloodbrain 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 bloodbrain barrier
regains its integrity, usually
after infection or virus has
cleared, the T cells are trapped
inside the brain.
Autoimmunology The immune system attacks the nervous
system, forming plaques or lesions.
Commonly involves white matter.
MS involves the loss of oligodendrocytes,
the cells responsible for creating and
maintaining a fatty layerknown as
the myelin sheathwhich helps the
neurons carry electrical signals (action
potentials).

Destroys
oligodendrocytes-
causing demyelination.
Inflammation 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 proteins
in brief:
The initiating event for the first attack of MS is known

Systemic T-lymphocytes become auto-reactive migrating to,


and penetrating, the blood/brain barrier through the interplay
of chemokines, adhesion molecules and metalloproteinase

Once inside the blood/brain barrier, the T-lymphocytes interact


with antigen-presenting cells, macrophages and B-lymphocytes,
resulting in inflammation and tissue damage
TYPES OF MS:
There are four types of MS according to their relapsing or
progressive pattern

They include:

RRMS Relapsing/ Remitting MS

PPMS Primary Progressive MS

SPMS Secondary Progressive MS

PRMS Progressive Relapsing MS


TYPES OF MULTIPLE SCLEROSIS

RRMS Relapsing/ Remitting MS


Discrete attacks which may or may not leave
permanent deficits followed by periods of remission.
Generally evolve over days to weeks.
Between attacks, patients are neurologically stable.
Immunomodulator therapies include Glatimer acetate,
INFb. Drugs are prescribed to reduce the frequency of
relapses

PPMS Primary Progressive MS


Gradual progression of the disease from its onset
with no relapses or remissions.
These patients do not experience attacks but only a
steady functional decline from disease onset.
Compared to RRMS, the disease begins later in life
(mean age, 40 years), and disability develops faster.
SPMS Secondary Progressive MS
Always begin as RRMS, after suddenly begins to
decline without periods of remission and relapses.
Progressive accumulation of neurological disability
Drugs are prescribed to reduce intrathecal
inflammatory responces and biomarker of
inflammation

PRMS
PRMS Progressive Relapsing MS
Disability

Steady decline since onset with super-imposed


attacks.
Deterioration in patients condition from disease
Time onset
clinical manifestations:
Spasticity:
Is characterized by a velocity-dependent
increase in resistance to passive or active
movement of muscles. Spasticity is generally
associated with weakness, extensor plantar
responses, spontaneous muscle spasms,
ecc.

Bladder Symptoms:
About 75% of patients with MS have
symptoms of bladder dysfunction.
Symptoms of urgency, frequency, and urge
incontinence are generally due to detrusor
spasticity.

Fatigue:
Fatigue occurs in about 75% of patients
with MS and is typically worse during
afternoon hours and with increased
ambient temperature.
Depression and inappropriate
expressions of emotion:
Bipolar affective disease, anxiety disorder, and
depression are more common in patients with
MS than in age- and sex-matched groups.
Patients with MS are at increased risk for suicide
compared with the age-matched general
population.

Tremor and Ataxia:


Thremor and ataxia are the most debilitating
consequences of MS. These disorders are poorly
responsive to pharmacotherapy

Dystonic Spasms:
Consist of paroxysmal toniic posturing that
affects one side of the face. In most patients,
dystonic spasms are painful.
diagnostic tests:
There is no specific test for MS and the diagnosis
is still primarily clinical

The techniques fall into two broad categories:

Those which detect clinically occult (silent) lesions.

Those which detect an abnormally of immunological


function in relation to the central nervous system.
Detection of occult lesions: evoked potentials:

Visual-evoked potential (VEP)


Detect the presence of an occult
lesion

Observation that demyelination


produces a slowing of conduction
in demyelinated nerve fibres
Monitor brain wave respond to
what you see and hear.

The results must be interpreted in the light of the rest of the clinical and
investigative picture.
Magnetic resonance imaging:

The most innovation in the investigation of MS in recent


years has been the application of nuclear magnetic
resonance (NMR) methods.

From the diagnostic point of view, magnetic resonance


imaging (MRI) is invaluable.

reveals multiple lesions with one large white matter


lesion.
The best method available for excluding potentially curable
lesions such as benign tumours compressing the spinal cord or
the optic nerve, which may simulate the progressive
manifestations of MS.
Immunological abnormalities: cerebrospinal fluid:

Diagnostic lumbar puncture


provides information about the
existence of inflammation through
a raised cell count and protein level.

The most important development has been the introduction of


isoelectric focusing in cerebrospinal fluid (CSF) protein
electroforesis.

Oligoclonal IgG is found in 95% of patients


with clinically definite disease
GOALS OF THERAPY:
Affect the neurodegenerative and inflammatory
components
Early intervention; initiate therapy as soon
as possible for the best chance of
controlling damage
Reduction of disease activity measured by
relapses, MRI findings, and disability
Provision of therapy that is well tolerated
and safe
IMMUNOTHERAPY

DRUGS ARE ACTIVE FROM THE


OUTSIDE THE BRAIN

THEY DO NOT CROSS THE BLOOD-


BRAIN BARRIER AND ACT ON CELLS
CROSSING IT OR PRODUCING
REGULATORY PROTEIN (CYTOKINES)
IMMUNOTHERAPY:
Current therapy for MS can be divided into several categories:

(1) treatment of acute attacks


CORTICOSTEROIDS (immunosuppression)

(2) treatment with disease modifying agents that reduce the


biological activity of MS
INTERFERON-BETA (Non specific immunomodulation)
GLATIRAMER ACETATE (Selective immunomodulation)
NATALIZUMAB (Selective adhesion molecule)
MITOXANTRONE (Immunosuppression)

(3) symptomatic therapy


CORTICOSTEROIDS:

Have been used to treat MS


exacerbations since the 1950s

Play an important role in the treatment of acute


exacerbations and also may be part of the long-term
immunomodulatory strategy

Reduces the intensity and duration of the neurologic


disability during relapses
Mechanisms of action:
Reduced blood-brain barrier permeability and resulting tissue
edema
Decreased intrathecal immunoglobulin G syntesis and
complement activation
Reduced proinflammatory cytokine production
Reduced expression of adhesion molecules on vascular
endothelium

Adverse effects:
Insomnia
Mood disturbances (typically euphoria and irritability)
Tremor
Edema
Hypertension
INTERFERON-BETA:

Several clinical trials for IFNb have shown significant


reductions in clinical and radiologic measures of disease
activity and severity

No clear evidence of the


persistence of the efficacy over
the long-term
Mechanisms of action:
The mechanism of action of IFN-beta in MS is multifactorial and
incompletely understood

Direct effect on plasma cells


modulating IgG synthesis
Increase nerve growth factor
production, leading to a
potential increase in neuronal
survival and repair
Increase of IL-10 levels
Inhibition of IL-1b and TNFa
reduction of T-cell migration
into the brain by inhibition of
the activity of T cell matrix
metalloproteinases
Inhibits infiltration of the CNS by
acting on T cells to diminish the
surface density of VLA-4

INF-b mediates cleavege of VCAM expressed on the surface of BBB


endothelial cells to generate soluble VCAM .

Soluble VCAM can be bind VLA-4 on the surface of leukocytes and


abrogate the leukocyte-endothelial interactions limit the ability
of T cells to gain entry to the CNS parenchyma and to mediate
pathogenic effets in lesions
GLATIRAMER ACETATE:
Is a random polymer of 4 amino acids found in myelin
basic protein (glutamic acid, lysine, alanine, and
tyrosine).

US Food and Drug Administration (FDA)-approved


formulation include Copaxone and Glatopa
Mechanisms of action:

Competes in some way with myelin basic protein (MBP)


at the antigen-presenting cell (APC) level for binding to
the major histocompatibility complex (MHC), competes
with MBP/MHC for binding to the T-cell receptor (TCR).

Acts to downregulate TH1


activity and to increase TH2
differentiation, thus promoting
the production of anti-
inflammatory cytokines such as
interleukin-4 (IL-4), interleukin-5
(IL-5), interleukin-10 (IL10).
In the periphery GA initially stimulates a population of TH1-like T
cells. During treatment, the properties of the GA-stimulated T cells
change, and they become more TH2-like.
The activated GA-specific T cells enter the CNS, where they
encounter CNS antigens like MBP bound to MHC class II and
presented on the surface of microglia cells.
The GA reactive T cells are stimulated to secrete down modulatory
cytokines like IL-4, which exert a suppressive effect on other T cells.
NATALIZUMAB:

A new disease-modifying therapy for relapsing remitting


multiple sclerosis (RRMS)

Is the first targeted therapy which blocks an essential


mechanism for lymphocyte entry to the CNS and thus
prevents acute demyelinating relapses.
Mechanisms of action:

Acts by preventing the specific inflammatory events leading to the


development of MS lesions.

Binds to 41-integrin (also known


as very late antigen-4) and blocks
its interaction with VCAM-1. As a
result, leukocyte migration into
brain tissue is inhibited, reducing
inflammation and preventing the
formation of lesions.

May also inhibit ongoing CNS inflammation, mediated by leukocytes


already present in the CNS, by interrupting the interactions between 4-
integrin-expressing leukocytes and extracellular matrix proteins such as
fibronectin and osteopontin
MITOXANTRONE:
Was originally synthesized in 1979

Mitoxantrone induces toxic changes because intercalates with


DNA and inhibits topoisomerase II and lead to apoptosis in the
cells, causing them to die. As a chemotherapeutic agent,
mitoxantrone is cytotoxic to tumor cells.

In vitro inhibits B-cell, T-cell, and macrophage proliferation

Because it is a very small molecule, it is able to cross the bloodbrain barrier


and interact with cells in the CNS.
Proinflammatory T cells are
activated in the periphery by
antigens (Ag) presented on major
histocompatibility complex class II
(MHCII) by antigen-presenting cells.

Periphery CNS

The activated T cells penetrate


through the bloodbrain barrier,
a step mediated by adhesion
molecules, proteases, and
chemokines.
Inside the CNS, the T cells are reactivated by CNS Ag
presented on MHCII by predominantly microglia cells.

The reactivated T cells secrete proinflammatory cytokines and


induce CNS inflammation
Macrophages and T cells attack the myelin sheath by cytotoxic
mediators B cells differentiate to plasma cells that secrete
demyelinating antibodies.

Mitoxantrone exerts inhibitory effects on autoreactive T


cells, B cells, and antigen-presenting cells.
FINGOLIMOD:
Is an oral drug with a novel mechanism of action
Is a structural analogue of sphingosine that does not impair T- and B-cell
activation, proliferation and effective function, but interferes with traffic
between lymphoid organs and blood

After phosphorilation, fingolomod acts as high affinity agonist at the G-


protein coupled sphingosine 1-phosphate receptor-1 (S1P1) on
linphocytes
S1P1-mudulated lymphocytes are selectively prevented to exit the
lymphnodes to reach the CNS

Exact mechanism is yet unknown but it is effective in slowing down


reactiveness toward myelin
symptomatic therapy
Spasticity Baclofen 5 mg PO 13 t.i.d. and increase as needed
Diazepam 25 mg PO at bedtime
Pain NSAIDs
Gabapentin effective vs. MS pain syndromes at 300 mg/d PO, may increase to
1,800 mg/d within 1 week, max dose 3,600 mg/d

Bladder Propantheline 7.5 mg PO q34h to start, increase to 15 mg t.i.d. to q.i.d. plus


dysfunction 1530 mg at bedtime
Oxybutynin chloride 5 mg PO t.i.d.q.i.d.
Prophylactic antibiotics for urinary infections
Self-catheterizations for inadequate bladder emptying
Constipation: Stool softeners, bulk-producing agents, laxative suppositories

Incoordination or Incoordination or tremors:


tremors:
Depression and Antidepressant agents such as SSRIs.
emotional lability Psychotherapy and support
Paranoia or mania Haloperidol lithium or atypical antipsychotic

Hemifacial and Carbamazepine 100200 mg PO once or twice a day to start; increase to total
dysesthesias daily dosage of 6001,600 mg t.i.d.q.i.d.
Must monitor serum levels