3. Multiple Sclerosis (MS)
A chronic neurological disorder that affects the
central nervous system,
in which myelin is destroyed in the brain and spinal
cord and
causes scarring at multiple sites in the CNS.
4. • first described by French neurologist Jean-
Martin Charcot in 1868.
• Yet, after more than 140 years of research ,
much remains a mystery.
• There is no known cause, and as yet, no
cure.
6. • The exact cause remains unknown, but researchers
believe that a combination of several factors may be
involved-
Immunologic Reaction - MS is generally believed to
be an autoimmune disease
Viral or other Infectious Agents - Some factor –
probably infectious – must be encountered before the
age of 15 in order for MS to develop later in life.
7. Environmental Factors - MS occurs in geographic
locations that are farther from the equator probably
because of vitamin –D deficiency.
Genetic Factor - Family history is associated with risk of
MS. It is strongly associated with MHC on ch 6, HLA DR
B1-1501.
9. • When brain is inflammed –lymphocytes cross BBB.
• If there is antigen cross reactivity –lymphocytes get
activated and secrete cytokines- which cause
inflammation and axon degeneration.
10. Extravasation
astrocytes BRAIN
TISSUE
M Y E L I
oligodendrocyte
B cell
Rolling Adhesion
a4 Integrin
VCAM
B L O O D F L O W
LUMEN OF
VENULE
B A S A L L A M I N A
Circulation
Activated T cell Proteases
Antigen presenting cell
(Astrocyte or Microglial cell)
Activated
microglia/macro
phages
T CELL
REACTIVA
TION
Activated
Macrophage
Autoantibodies
Complement
IL-1, IL-12,
chemokines
Cytokines and
chemokines
Proteases
TNF-a
O2
•-
NO•
AXONAL
DAMAGE
MS DISEASE PATHOLOGY
13. >
Predominant age: 20-40
MULTIPLE SCLEROSIS AFFECT:
0.1%Worldwide incidence
PREVALENCE
IS HIGH IN
TEMPERATE
ZONE(NORTH
AMERICA AND
EUROPE,AUST
RALIA)
The ratio is
increasing
now
people in
US have
MS
400, 000
1–3% risk of MS among 1st-degree relatives
worse
prognosis
15. The most common initial symptoms
•changes in sensation (33%)
•Optic neuritis (20%)
•Weakness(exercise induced) (13%)
•double vision- internuclear opthalmoplegia (7%)
•unsteadiness while walking (5%)
•and balance problems (3%)
Lhermitte's sign (25-40%) is an electrical sensation that
runs down the back and into the limbs and is produced by
bending the neck forwards. The sign suggests a lesion of
the dorsal columns of the cervical cord or of the caudal
medulla.
Uhthoff's phenomenon is the worsening of neurologic
symptoms in multiple sclerosis when the body gets
overheated from hot weather, exercise, fever,
16. Partially demyelinated axons have property to –
1. Discharge spontaneously, causes sensory
symptoms like tingling, parasthesia.
2. Stimulated by mechanical stimulation like neck
flexion causes electric shock like sensation
(Lhermitte's symptom).
3. Stimulated by temp. change –visual blurring
after hot shower or after exercise (Uhthoff's
symptom).
4. Can stimulate adjacent normal neuron causes
trigeminal neuralgia, hemifacial spasm.
18. PRMS Progressive Relapsing MS
SPMS Secondary Progressive MS
PPMS Primary Progressive MS
RRMS Relapsing/ Remitting MS
CLASSIFICATION OF MULTIPLE SCLEROSIS
Gradual progression of the disease from its onset
with no relapses or remissions in 50% of the cases.
More common in older patients above 40.
Unpredictable attacks which may or may not leave
permanent deficits followed by periods of remission
accounts for 85% of total cases.
Initial RRMS that suddenly begins to decline without
periods of remission and relapses.
Steady decline since onset with super-imposed
attacks.
20. There is no definitive diagnostic test .
We need certain investigation to support the
clinical diagnosis –
1. MRI
2. CSF EXAMINATION
3. EVOKED POTENTIAL
21. • MRI has revolutionized the diagnosis and
management of MS.
• Lesion mainly involve ----
a) Periventricular
b) ant. Portion of corpus callosum
c) juxtra cortical
d) infratentorial (brainstem ,cerebellum ,spinal cord)
MRI
22.
23.
24.
25.
26.
27. DAWSON'S FINGERS APPEARING ON AN MRI SCAN
The condition is thought
to be the result of
inflammation around
long axis of medular
veins.
29. EP testing assesses function in afferent (visual,
auditory, and somatosensory) or efferent (motor)
CNS pathways.
These tests provide the most information when the
pathways studied are clinically uninvolved.
Abnormalities occur in 80–90% of MS patients.
EVOKED POTENTIALS
30. 1. If history of two clinical attacks are present.
2. If history of only one attack is present.
3. If disease is continously progressive.
MCDONALD’S DIAGNOSTIC
CRITERIA
31.
32. Associated with one objective lesion, then you need
positive CSF oligoclonal banding and MRI lesion to
diagnose MS.
If CSF is negative for OCB then one gd –enhancing
lesion and another gd-enhansing lesion after 3 month
on different location is needed for the diagnosis.
DIAGNOSTIC CRITERIA IF SINGLE ATTACK IS
PRESENT
33.
34. Most difficult to suspect MS in this kind of patient because
of no history of relapse and recur.
For diagnosis –
a) 1 year progression with
b) two of the following –
>9 T2 lesion or >4 T2 lesion with abnormal visual evoked
potentials.
>2 spinal cord lesion.
Oligoclonal banding in CSF.
DIAGNOSTIC CRITERIA FOR PRIMARY
PROGRESSIVE MS
35. The possibility of an alternative diagnosis should always
be considered , particularly when –
a) Symptoms are localized exclusively to the posterior
fossa, or spinal cord.
b) The patient is aged <15 or >60 years;
c) The clinical course is progressive from onset;
d) The patient has never experienced visual, sensory, or
bladder symptoms ;
e) Laboratory findings (e.g., MRI, CSF, or EPs) are atypical.
DIFFERENTIAL DIAGNOSIS
36. 1) ADEM(acute disseminated encephalomyelitis)
2) APLAS , Behcet’s disease, Sjogren, SLE,
Sarcoidosis
3) Syphilis
4) Vit. B 12 def.
5) Congenital leucodystrophies
6) HIV , neoplasms
DISORDERS THAT CAN MIMIC MS
(CAN INVOLVE MULTIPLE
LOCATION IN BRAIN)
37. • Early age of onset.
• Female sex.
• Optic neuritis as presenting episode.
• Sensory symptoms as presenting episode.
• Acute onset.
• Little residual disabilty.
• Long inter exacerbation period.
• Small lesion load.
FAVORABLE INDICATORS:
38. Patients with first attack with a normal brain MRI, the
likelihood of developing MS is <20%.
With three or more typical T2-weighted lesions, the
risk of developing MS after 20 years is 80%.
PROGNOSIS
39. Therapy for MS can be divided into several
categories:
1) Treatment of acute attacks.
2) Treatment with disease-modifying agents that
reduce the biological activity of MS.
3) Symptomatic therapy.
TREATMENT
40. I/V Methylprednisolone 1 gm/d for 3 to 5
days.
Fulminant attacks -- unresponsive to
glucocorticoids.
Treatment is Plasma exchange.
ACUTE ATTACKS
41. Treatment options for MS have changed dramatically since
1993, when the first disease-modifying drug, Betaseron®,
became commercially available.
These drugs are not a cure .
However, they can alter the course by decreasing the
number and severity of relapses by slowing the
progression .
TREATMENT WITH DISEASE-
MODIFYING AGENTS
42. 10 such agents are approved by the US (FDA) till april 2014,
1) IFN--1a (Avonex)
2) IFN--1a (Rebif)
3) IFN--1b (Betaseron)
4) glatiramer acetate (Copaxone)
5) natalizumab (Tysabri)
6) fingolimod (Gilenya)
7) mitoxantrone (Novantrone)
8) dimethyl fumurate (Tecfidera )
9) teriflunomide( Aubagio )
10) interferon beta-1b kit(Lyophilized EXTAVIA)
DISEASE-MODIFYING THERAPIES
44. Therapy with a disease-modifying drug should be
initiated as early in the disease course as possible.
Treatment should be continued indefinitely except in
the case of clear lack of benefit, intolerable side
effects.
TREATMENT GUIDELINES:
45. Avonex, Betaseron, Extavia, and Rebif are all
interferon beta products.
The interferon drugs seal off blood brain barrier
and inhibit T cells from being activated.
46. Beta Interferon
Avonex – 30 ug, I/M weekly
Rebif –44 ug S/C three times per week
Betaseron – 250 ug S/C every other day
47. Common Side Effects…
Typical Flu-like symptoms
headache, nausea, and fever
muscle aches
Chills
Irritation at the injection site
Alcohol and exposure to sunlight may irritate side
effects
48. The glatiramer molecule resembles myelin basic protein.
T cells produced in response to glatiramer can suppress
the immune attack on myelin.
S/E -
• lipoatrophy at injection site
• dilation of blood vessels, chest pain,
Previously it was given 20 mg daily S/C. But in 2014 FDA
approve 3 times /week of 40mg/ml dose.
GLATIRAMER
ACETATE(COPAXONE)
49. Natalizumab (Tysabri) is a monoclonal antibody directed
against the integrin, a cellular adhesion molecule expressed
on the surface of lymphocytes.
It is most effective. Only problem with it is its fatal side effect –
progressive multifocal leucoencephalopathy(PML)
Because of PML, natalizumab is currently recommended only
for patients who have failed other therapies or who have
particularly aggressive disease presentations.
Natalizumab (300ug) is administered by IV infusion each
month.
NATALIZUMAB (TYSABRI)
50. 2010 - The first oral drug Fingolimod.
2012 – Teriflonamide
2013 - Dimethyl fumerate
FDA APPROVED ORAL DRUG
51. Fingolimod is a sphingosine1-phosphate receptor
modulator that sequesters lymphocytes
orally 0.5 mg od
The first dose of Fingolimod is given in a monitored setting,
because of first-dose side effects- bradycardia and heart
block.
GILENYA (FINGOLIMOD)
52. Teriflunomide is a pyrimidine synthesis inhibitor that inhibits
the function of specific immune cells.
Teriflunomide (7 mg or 14 mg) OD
AUBAGIO (TERIFLUNOMIDE)
53. Dimethyl fumurate, an immunosuppressant, is thought to
have anti-inflammatory and cytoprotective properties.
The starting dose of Tecfidera is 120 mg twice daily for
seven days, then 240 mg twice daily thereafter.
Dimethyl fumerate, is expected by many investors to
become the top-selling product for the treatment of multiple
sclerosis.
TECFIDERA (DIMETHYL
FUMURATE),
54. 12mg/m2 of Novantrone by short IV infusion once every
three months for 24 months.
Approval by the U.S. (FDA) for Patients with
a) Secondary progressive MS
b) Progressive-relapsing MS
c) Worsening relapsing-remitting MS
mitoxantrone should not be used as a first-line agent.
Use mitoxantrone when other approved therapies have
failed because it is responsible for heart faliure and low
EF, acute leukemia.
MITOXANTRONE
55. 2011 — The US (FDA) says it won't approve oral
cladribine for multiple sclerosis (MS) without more safety
information.
Cladribine was recently approved in Russia and Australia
but received a negative opinion from European regulators.
CLADRIBINE
56. Monoclonal cd 52 antibody
Company could not submitted evidence from adequate and
well-controlled studies that demonstrate the benefits of
Lemtrada outweigh its serious adverse effects.
FDA DECLINES APPROVAL FOR
ALEMTUZUMAB (LEMTRADA)
58. Jan 2014-
Some preliminary data has indicted that Vitamin A may help
alleviate symptoms of multiple sclerosis, and more research is
on the way.
Antioxidant Shows Promise in Fight Against MS.
A vaccine used to prevent tuberculosis in other parts of the
world may help prevent multiple sclerosis.
Vitamin D appears to block damage-causing immune cells from
migrating to the central nervous system.
Study Suggests Obesity Increases Risk of MS in Girls.
FDA Approves Unique Stem Cell Therapy Trial
in MS Patients in 2013