Progressive Multiple Sclerosis

(PMS)

Semester#6
B.Pharm
Keivan
Introduction
 Multiple Sclerosis (MS) is believed to be
caused by an autoimmune attack on the
myelin and axons of the central nervous
system.
 MS is the most common cause of
nontraumatic disability in individuals of
young and middle age.
Introduction
 Saint Lidwina lived in Holland
 At the age of 16, she developed neurological
symptoms after suffering a fall while ice skating.
 Soon after, she developed walking difficulties and
headaches.
 By the age of 19, she was paralyzed from the waist
down and had vision disturbances.
 For the rest of her life, she experienced periods of
exacerbations and remissions.
 At the age of 53 MS won the battle .
Multiple Sclerosis day:

 A) May 26th 2010.

 B) May 26th 2010.
 C) May 26th 2010.
 D) May 26th 2010.
Prevalence
 Approximately 400,000 individuals have
been diagnosed with MS in the United
States and as many as two and a half
million worldwide, with an estimated
10,000 new cases diagnosed in the
United States annually.
Prevalence:
 The distribution of this disease is not
totally random. On average, women are
three times as likely than men to
develop MS.
 People living in high altitude are much
more prone to develop MS.
 MS prevalence is high in Scotland.
Pathophysiology:
Pathophysiology:
 As has been previously discussed, inflammation is a primary
cause of pathology in MS.
 Inflammatory cells may breach the blood-brain barrier (BBB)
causing demyelination by macrophages and
 producing inflammatory substances, such as nitrous oxide, that
further damage nerve conduction.
 This damage may leave behind lesions or markers that could be
identified with various imaging techniques.
 Demyelinated plaques are associated with inflammation, loss of
myelin, axons, and
 gliosis, which is the production of astrocytes that occurs in
response to damage to neurons.
Pathophysiology:
 the cell death and tissue damage seen in MS is generally
accepted to be caused by activation of the immune system and
subsequent inflammation .
 The pathogenesis of MS consists of inflammatory and
neurodegenerative phases.
 Acute MS lesions are generally characterized by active
demyelination and inflammatory cell infiltrates, including T cells,
B cells, macrophages, and activated microglia.
 Axonal transection is present in acute inflammatory lesions, but
most axonal loss is seen in secondary progressive MS.
 with relatively early loss of oligodendrocytes (OLGs) by
apoptosis and loss of myelin-associated glycoprotein
 demyelination is associated with cell necrosis.
Genes involvement:
 MS is not contagious or hereditary,
 But susceptibility to MS is increased if a
family member has MS.
 Risk factors:

 Another factor linked to MS is cigarette

smoking.
 Women who smoke are 1.6 times more
likely to develop MS than women who
are non-smokers.
 Worsens during
afternoon.
Signs and symptoms:
Usually due to Heat
intolerance

Primary Secondary Tertiary

Visual complains Muscle contraction Emotional problems
Gait abnormalities Infections (depression)
Weakness Poor appetite Personal problems
Pain decubiti Social problems
Spasticity
Fatigue
Cognitive changes
Speech difficulty
Sexual dysfunction
tremor
Expanded Disability Status
Scale (EDSS)
 EDSS is the most widely used clinical
rating scale in MS.

 Demerits:
 Insensitive to clinical changes such as:
changes in cognition, fatigue.
Expanded Disability Status
Scale (EDSS)
Diagnosis:
 Because there is no definitive diagnostic test for MS, clinicians
must rely on a thorough history and physical examination
coupled with a battery of laboratory and imaging investigations
These may include:

 Analysis of the cerebrospinal fluid (CSF) for oligoclonal bands

that represent antibodies commonly found in patients with
clinically definite MS (CDMS),

 and examination of the blood for anti-myelin antibodies and/or

for evidence suggesting other conditions.

 However, perhaps the most important contributing

investigations for MS are conventional MRI and advanced
applications of this technique.
 Laboratory
studies:
 Imaging studies:
MRI,
CT scan,
Laboratory
studies:
 CSF evaluation:
 CNS synthesis of IgG is increased.

But serum IgG levels are normal.

 Oligoclonal banding (OCBs) of IgG is present.

 Increased CSF protein concentration.

 Myelin basic proteins (MBP) being

detected.
 Mild CSF leuckocytosis.
Laboratory
studies:

 Blood studies:
 Presence of antimyelin antibodies in
serum .
Laboratory
studies:
 Evoked potentials:

 Slowed conduction of brain stem, visual

and somatosensory.
Poser and
McDonald
Criteria
Relapsing-Remitting Multiple
Sclerosis) (RRMS)
 On average, 80 percent of people with
MS begin with the relapsing-remitting
form of MS (RRMS).
 Temporary symptom flare-ups or
"exacerbations"
 Between relapses, remission for a year
or more. (symptom free period)
Initial signs and symptoms
RRMS:
 sensory disturbances (such as
numbness or tingling).
 optic neuritis (inflammation of the optic
nerve causing visual changes or loss;
usually occurring in one eye), these
changes are usually temporary.
 diplopia (double vision)
Secondary-Progressive MS
(SPMS)
 If untreated, 90%of individuals with RRMS
may eventually enter a second phase of
RRMS, known as secondary-progressive
MS (SPMS), within 25 years.

 The patient experiences a progressive

worsening of symptoms. SPMS may occur
with or without superimposed relapses.
Primary-Progressive MS
(PPMS)
 While 80% of individuals with MS are diagnosed with
RRMS, most of the other 20% fall under the heading
of primary-progressive MS (PPMS).

 This form of MS presents a gradual but steady

accumulation of neurological problems from the
onset, without the presence of relapses and
remissions.

 Unlike RRMS, PPMS is equally divided between the

genders
Other less common types
 Benign (little or no change after 20
years),
 progressive-relapsing MS (PRMS)
(progressive course from the onset with
acute relapses).
 Malignant MS (rapidly progressive
disease course).
Treatment:
 Several clinical trials have been conducted to
study each of these drugs separately for their
effects on MS. Although differences exist in
study design and specific findings, trials
generally showed these common results:
 Reduced the number of relapses
 Reduced the severity of relapses
 Reduced the development of new areas of
inflammation as seen on MRI
Treatment:
 Many effective medications are
available for the treatment of multiple
sclerosis (MS). These types of drugs
may be prescribed for three different
categories of MS treatment:
 disease-modifying immunotherapy,
 exacerbation management,
 symptom management
Treatment of Acute
exacerbations:

 High dose corticosteroids from 3 to 10 days.

 Preferably IV methylprednisolone
1000mg/day.
 Methylprednisolone shortens the duration of
exacerbation.
 ACTH use has been supplanted by
methylprednisolone due to quicker clinical
improvement observed by
methylprednisolone.
Disease modifying therapy:
ABC-R therapy with Avonex,
Betaseron, Copaxone and Rebif
 Treatment: Baseline complete blood
counts
-Platelet determination
Anovex and Rebif-Liver function tests should be
are
ordered before the start of
produced by recombinant
Brand Generic Dose
chinese hamster ovary treatment Side effects
cells and then every 3
Synthesized technique.
in E. coli. months for first one year.
-Inhibits the secretion
Interferon 30 µg(6 million IU) Flu-like symptoms,
of interferon-gamma,
taken via weekly redness at the site
Avonex® beta-1a
-suppresses the T-cell
IM
proliferation
of injection.
- may decrease BBB Depression.
permeability
Interferon
Synthetic 250 µg(8 million IU) Flu-like symptoms,
Betaseron® polypeptide: S/C every other
beta-1b redness at the site
1- L-alanine day of injection.
(first agent) 2- L-glutamic acid Depression.
3- L-lysine
4- L-tyrosine 20 µg S/C daily
Glatiramer Mild pain and
acetate pruritis at the site
Copaxone®
(copolymer-1) of injection.
Chest tightness

Interferon 44 µg S/C three Flu-like symptoms,

times weekly redness at the site
Rebif® beta-1a
of injection.
Depression.
Treatment:
 Other available treatment options:
 Tysabri® (natalizumab), which is
approved for relapsing forms of MS.
 300mg IVI over 1 H
every 4 weeks
Treatment:
 After its original approval, Tysabri was
temporarily suspended after two individuals
(taking Tysabri in combination with Avonex)
developed Progressive Multifocal
Leukoencephalopathy (PML),
 PML is an often-fatal viral infection of the
brain.
 Since then it has been re-approved and
patients are closely monitored.
 Symptomatic Treatment:
Gait Tremor Bladder Sensory Sexual Fatigue
difficulties symptoms symptoms dysfunction

baclofen propranolol oxybutinine carbamazepine sildenafil amantadine

tizanidine isoniazid imipramine gabapentine tadalafil methylphenid

ate

clonazepam Self amitriptyline

catheterization
Treatment:
 Other treatments include:
 intravenous immunoglobulin (IVIg)
therapy,
 methotrexate, azathioprine (Imuran®),
and cyclophosphamide (Cytoxan®).
Complementary and alternative
medicine (CAM) use
 There are insufficient clinical trials
supporting the CAM use in
patients with MS.
Conclusion:
 Ms is a chronic inflammatory, autoimmune disease of
CNS that appears to affect young genetically
susceptible individuals.
 A definite treatment yet to be established.
 Its causes are not yet fully understood and
researchers continue to search for answers.
 Meanwhile it is understood that MS can be triggered
by viral infections.
 MS is not contagious.
 Although the disease may not be cured or prevented
at this time, treatments are available to reduce
severity and delay progression.
 Depression should be dealt with care.
Reference:
 Pharmacotherapy,
by Joseph T. Dipiro
Barbara G. Wells