MULTIPLE SCLEROSIS DR.waleed batayha consult.neurologist … · 2019-10-17 · Genetics 1-the...
Transcript of MULTIPLE SCLEROSIS DR.waleed batayha consult.neurologist … · 2019-10-17 · Genetics 1-the...
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MULTIPLE SCLEROSIS
Dr Sadik AL Ghazawi
Associated Professor
Neurologist
MRCP,FRCP UK
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What is Multiple Sclerosis (MS)?
1-CHRONIC Autoimmune demyelination
disease of
CNS:
a- brain
b-optic nerve
c- and spinal cord
2-Affects 2.3 million people in the world
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What is the epidemiology of MS?
• Geographic distribution
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What are the possible risk factors?
1-Infections : viral ,bacterial, fungal.
2-Age: 15yr.-45yr.
3-Gender :female: male 3:1
4-Genetic Factors
5-DR15 haplotype
6-Autoimmune diseases
7-Race
8-Climate
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What are the possible triggers of MS?
1-Epstein-Barr Virus
2-Smoking
3-Vitamin-D deficiency
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What is the genetic factor?
• The risk of getting MS is approximately:
– 1/750 for the general population (0.1%)
– 1/40 for person with a close relative with MS (3%)
– 1/4 for an identical twin (25%)
• 20% of people with MS have a blood relative with MS
The risk is higher in any family in which there are
several family members with the disease (aka
multiplex families)
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Genetics
1-the probability of developing the disease is higher in relatives of an affected
person, with a greater risk among those more closely related.
EXAMPLE identical twins both are affected about 30% of the time, while around 5% for non-
identical twins and
3-if both parents are affected the risk in their children is 10 times that of the
general population. 4- MS is also more common in some ethnic groups than others
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What RISKS OF MS?
1-Genetic
Predisposition
2-
Environmental
Trigger
Autoimmunity
Loss of myelin
& nerve fiber
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What happens in MS?
...cross the blood-brain barrier…
…launch attack on myelin & nerve fibers...
“Activated” T cells...
…to obstruct nerve signals.
myelinated nerve fibermyelinated nerve fiber
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How are myelin autoreactive T-cells
activated?
1-Myelin-reactive T-cells
Myelin basic protein (MBP)
2-T-cell activation
Autoantigens
Molecular mimicry
3-Immune cell recruitment
CD8+ cells
B cells
Granulocytes
Monocytes
Mast cells
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What happens once across the BBB?
1-Reactivation of CD4+ cells
Proinflammatory cytokines
2-Microglial and astrocyte activation
Myelin phagocytosis
3-Humoral response
4-B cell co-stimulation of CTLs
5-Demyelination
Type II hypersensitivity
CTL apoptosis
Reactive species
https://michellepetersen76.files.wordpress.com/2
015/05/discovery-of-a-treatment-to-block-the-
progression-of-multiple-sclerosis-
neuroinnovations.jpg
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What causes neuronal degeneration?
MS lesions
1-Active lesions
2-Inactive, chronic lesions
Demyelination
Immune mechanisms cause:
1-Oligodendrocyte damage------
2-Injury and loss of axon
3-Gliosis
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Lublin et al, 2014
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The relapsing-remitting subtype.
1---80-85 present.
2---female predominant.
3-- characterized by unpredictable rapid onset relapses
followed by period of months or years of partial or
complete recovery.
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➢4--Attack is a symptoms or objectively observed signs suggestive demyelinationprocess with duration of at least 24 hours, in the absence of fever or infection.
➢5-For paroxysmal symptoms (such as paroxysmal dysarthria, tonic spasms, or paroxysmal sensory symptoms) to be considered an attack, must be recurrent over at least 24 hours.
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6--Once MS has been established ,we must evaluate for evidence of
dissemination in space( DIS) (multiple areas) , and for dissemination in
time( DIT)(ongoing disease activity over time).
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7-- Deficits that occur during attacks may either
A-Resolve or leave problems in about 40% of attacks.
B-being more common the longer a person has had the disease.
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8-When deficits always resolve between attacks, this is
sometimes referred to as benign
MS, although people will still build up some degree of disability in
the long term.
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Secondary Progressive MS
• 1-Majority of RRMS many years following onset
• 2-Progressive impairment (spastic gait disturbance) between or
in absence of attacks
– with ongoing relapses
– Substantial ongoing on new MRI inflammatory lesions
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➢1-25% to 40% of patients with relapsing remitting MS go on to a secondary progressive course after an average of about 20 years.
➢2-diagnosed when, after an initial relapsing-remitting course, a patient demonstrates disease progression independent of relapses for at least 6 months.
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➢3-deterioration with respect to gait, balance,spasticity, and bladder
function ,Many patients experience cognitive decline.
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Primary Progressive MS
• Presents with progressive myelopathic gait, cerebellar ataxia or cognitive impairment without clear history of any clinical attacks
• Clinical progression must be for at least 1year and accompanied by a combination of brain&spinal abnormalities and/or CSF abnormalities consistent with MS
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The primary progressive subtype=-
1- occurs in approximately 10–20% of individuals,
with no remission after the initial symptoms.
2- It is characterized by progression of disability
from onset, with no, or only occasional and minor,
remissions and improvements.
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3-10% to 15%.
4-insidious onset of symptoms followed by gradual deterioration over time.
5-Clinical disease in these patients typically presents as a progressive myelopathy, and less frequently as a brainstem or cerebellar syndrome.
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6-Older.
7-no clear gender predominance
8-MRI lesions :➢ fewer in number
➢less likely to enhance with gadolinium compared to relapsing-remitting MS.
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9-The usual age of onset for the primary progressive
subtype is later than of the
relapsing-remitting subtype.
10-- It is similar to the age that secondary progressive
usually begins in relapsing-remitting MS, around 40 years
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Clinically Isolated Syndrome (CIS)
1-A first neurologic event suggestive
of demyelination
2-Individuals with CIS are at high risk
for developing clinically definite MS if
the neurologic event is accompanied
by multiple, clinically silent
(asymptomatic) lesions on MRI typical
of MS
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CLINICALLY ISOLATED SYNDROM (CIS)
1-the condition begins in 85% of cases as clinically isolated syndrome (CIS) .
2--45% having motor or sensory problems.
3--20% having optic neuritis, and
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4-10% having symptoms related brain stem dysfunction,
5-while the remaining 25% have more than one of the previous
difficulties
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Radiologically Isolated Syndrome (RIS)
– No typical symptoms of CNS demyelination
– No formally accepted diagnostic criteria
– MRI : Typical MS lesions
– CSF abnormalities
– Clinical MS Attack:
– 35% over 5 years
– MRI progression:
• 59-83% in 2 years
Okuda DT et al, Neurology2011:76()8, 686-692
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What are the symptoms of MS?
Early symptoms
Daily effects
Age range
Characteristics of symptoms
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Cycle of MS Symptoms:
Related and Interdependent
Sleep
Fatigue
Depression
Bladder
& Bowel
problems
Sexuality
issues
Spasticity
Constipation
Cognitive
function
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Features Consistent With MS
• Relapses and remissions
• Age Onset between ages 15 and 50
• Optic neuritis
• Lhermitte's sign
• Internuclear ophthalmoplegia
• Fatigue
• Uhthoff's phenomenon
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How is MS diagnosed?
MS is a clinical diagnosis
1-Medical history
2-SIGNS And symptoms
3-Laboratory tests
Requires dissemination in time and space:
1-Space: Evidence of scarring (plaques) in at
least two separate areas of the CNS (space)
2-Time: Evidence that the plaques occurred
at different points in time
There must be no other explanation
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Diagnosis of MS
1-No single test for diagnosing MS
2-Usually diagnosed when all other possibilities ruled
out
3-Many tests
A-Medical history
B-Nervous system functioning
C-MRI McDonald criteria
D-Evoked potential tests, spinal tap
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INITIAL SYMPTOMS
1- ascending numbness starting in the feet;- bilateral hand
numbness;- hemiparesthesia;- dysesthesia in one of the above
distributions;- generalized heat intolerance
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Sensory systems:
2--Lhermitte's sign-dysesthetic pain-paresthesia-numbness-dorsal column
signs (i.e.,. severe decrease or loss of vibratory sense and
proprioception,
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Ongoing Symptoms and Signs
Motor system:-
3-weakness (variable severity mono- and paraparesis, hemiparesis,
quadriparesis)-
4-increased spasticity resulting in spastic gait
5-pathologic signs (Babinski's, , Hoffmann,etc.) -dysarthria
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Cerebellar signs
1-incoordination (dysdiadochokinesia, problems with heel-to-shin test)-slowing
of rapid repeating movements-cerebellar ataxia (ataxic gait)
2-scanning speech-
3-loss of balance
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Expanded Disability Status Scale
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What tests may be used to help
confirm the diagnosis?
1-Magnetic resonance
imaging (MRI)
2-Visual evoked potentials
(VEP)
3-Lumbar puncture
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McDonald Diagnostic CriteriaMRI-High Specificity & Sensitivity for MS
Typical MS demyelinating lesions meeting at least 3 of the
following 4 criteria:
1-At least 1 Gd lesion or at least 9 T2 lesions
2-At least one infratentorial lesion
3-At least one juxtacortical lesion
4-At least 3 periventricular lesions
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McDonald Diagnostic Criteria
MRI-Dissemination in Time
If the first MRI is performed 3 months after the clinical event, 1 of the 2 below must be found:
> 1 Gd lesion not at site of original attack; or
MRI 3 months later showing a new T2 or Gdlesion
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If the first MRI is performed < 3 months after the clinical event,
then a second MRI done 3 months after the attack provides evidence for DIT
if 1 of the 2 below must be found:
New Gd lesion on the second MRI
Later MRI showing new T2 or Gd lesion
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Case : MRI Brain
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Case 2: MRI Spine
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Case 1: Fundoscopy
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© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What role does lumbar puncture play in
diagnosis?
➢ Spinal fluid can reveal signs of MS
❑ Unique oligoclonal bands in spinal fluid by isoelectric
focusing (in 90%-95% of patients with MS)
❑ Elevation of IgG index (in 50%-75%)
❑ Mild pleocytosis (in ≈50%)
➢ Negative CSF result alone doesn’t rule out MS
❑ But when clinical and radiologic suspicion is low, a normal
CSF result reassures patients they probably don’t have MS
➢ For RRMS diagnosis
❑ Criteria don’t require confirmation by CSF testing
➢ For PPMS diagnosis
❑ Test CSF if MRI features don’t meet criteria for dissemination
in space
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Case : CSF Oligoclonal bands
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© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
What are the differential diagnoses?
➢ Other demyelinating diseases
❑ Acute disseminated encephalomyelitis
❑ Neuromyelitis optica (Devic disease)
❑ Idiopathic transverse myelitis
➢ Systemic inflammatory disease
❑ Systemic lupus erythematosus
❑ The Sjögren syndrome
❑ Sarcoidosis
❑ The Behçet syndrome
➢ Metabolic disorders
❑ Adult-onset leukodystrophy
❑ Vitamin B12 deficiency
❑ Copper deficiency
❑ Zinc toxicity
❑ Vitamin E deficiency
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© Copyright Annals of Internal Medicine, 2014
Ann Int Med. 160 (4): ITC4-1.
➢ Infections
❑ HIV, Lyme disease, syphilis
❑ Human T-lymphotropic virus
➢ Vascular disorders
❑ Sporadic and genetic stroke syndromes
❑ CNS vasculitis
❑ The Susac syndrome
❑ Dural arteriovenous fistula
➢ Migraine
➢ Neoplasia (i.e., primary CNS neoplasm (glioma or lymphoma)
or metastatic disease)
➢ Paraneoplastic syndromes
➢ Somatoform disorders
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An Overview of Treatment Strategies
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How is MS treated?
1-There is no cure for MS
2-Treatments FOR:
A-MS attacks or acute relapse.
B-Immune Modify agents
to prevent progression and reduce activity
Of the disease.
3-Treatment of symptoms
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HOW SHOULD CLINICIANS CHOOSE THERAPY FOR PATIENTS WHO ARE HAVING AN ACUTE RELAPSE?
• Relapse: new or worsening neurologic symptoms
lasting ≥24h without clear underlying triggers of
pseudo-relapse
➢ Standard treatment: high-dose corticosteroids
❑ IV infusion methylprednisolone, 1g/d for 3-5 days .
➢ OTHER treatment if relapse doesn’t respond to steroids
❑ Plasma exchange
❑ 5 days of IM or SC adrenocorticotrophic hormone .
❑ Pulse-dose IV cyclophosphamide
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Disease-Modifying Drugs for RRMS
1-All reduce attack frequency and severity, reduce lesions on MRI, and probably slow disease progression.
2-These medications are not designed to:
A-Cure the disease
B-Make people feel better
C-Alleviate symptoms
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How is the disease course treated?
Thirteen disease-modifying therapies are FDA-approved for relapsing
forms of MS:
glatiramer acetate (Copaxone®; Glatopa™ - generic equivalent)
[inj.]
interferon beta-1a (Avonex®, Plegridy™, Rebif®) [inj.]
interferon beta-1b (Betaseron® and Extavia®) [inj.]
dimethyl fumarate (Tecfidera™) [oral]
fingolimod (Gilenya™) [oral]-MELLIOR ORAL
teriflunomide (Aubagio®) [oral]
alemtuzumab (Lemtrada™) [Inj.]
natalizumab (Tysabri®) [inf]
mitoxantrone (Novantrone®) [inj.]
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Treatment AMildly effective, mildly toxic
Disease active
Escalation Strategy
Disease suppressed Disease still active
Treatment BMore effective, more toxic
Disease suppressed Disease still active
Treatment CMost effective, most toxic
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Incr
eas
ing
eff
icac
y
Increasing burden of treatment(worse safety, more difficult administration)
Interferon-beta
NatalizumabJC+
Mitoxantrone
FingolimodDimethyl fumarate
Autologous stem cell transplantation
Glatiramer
First, second and third line therapies
Laquinimod
Alemtuzumab
NatalizumabJC neg
Rituximab / ocrelizumab
Teriflunomide
Third line
Second line
First line
Daclizumab
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Incr
eas
ing
eff
icac
y
Increasing burden of treatment(worse safety, more difficult administration)
Interferon-beta
NatalizumabJC+
Mitoxantrone
FingolimodDimethyl fumarate
Autologous stem cell transplantation
Glatiramer
High and low risk treatments
Daclizumab
Laquinimod
Alemtuzumab
NatalizumabJC neg
Rituxmab / ocrelizumab
Teriflunomide
“Dangerous”
“Aggressive”
“Safe”
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IFNβ-1b SC qod
GA
SC qd
IFNβ-1a IM qwk
Mitox
IV q 90
d wks
IFNβ-1a SC tiw
Natalizuma
b
IV q 4 wks Fingolimo
d
0.5 mg gd
Teriflun
PO qd
Laquin
PO
Daclizuma
b
SC
BG-12
PO bid
Alemtu
z
IV
The Changing Landscape of MS Disease Modifying Treatment
Of Approved and Emerging Therapies
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Slide 64 of 26
FDA-approved disease modifying agents
• Interferon beta
– Interferon beta-1b (Betaseron®) 250 mcg qod
– Interferon beta-1a (Rebif®) 44 mcg SC TIW
– Interferon beta-1a (Avonex®) 30 mcg IM weekly.
– Commn side effects: inj.site reactions,flu like symptoms,abdominal pain,depression,abn.liver function
• Glatiramer acetate (Copaxone®)
– 20 mg\ml SC \day or 40mg\ml 3 times\week.
– Side effects: vasodilatation,rash,sob,chest pain,anexiety.
• Mitoxantrone (Novantrone®)
– 12 mg/m2 q3mo: lifetime max, 144 mg/m2
– Side effects: nausea,hair thinning,bladder infection.low wbc,and
platletes
• Natalizumab (Tysabri®)
– 300 mg IV monthly infusion
Side effects: UTI,RTI,DIAREA,PML,ENCEPHALITIS
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Slide 65 of 26
• Continue disease modifying drugus
• Parenteral (IV) drugs
– Monoclonal antibodies: rituximab/ocrelizumab, alemtuzumab,
daclizumab
• Oral Drugs
– Fingolimod, teriflunomide,Dymethyl fumarate, laquinimod
• Symptomatic therapies
– Fampridine (4-AP), nerispirdine
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Glatiramare acetate(copaxon)
Glatiramer acetate, the active ingredient of COPAXONE, consists of the acetate salts of synthetic polypeptides
containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine
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COPAXON
• COPAXONE 20 mg per mL: administer once per day
or
• COPAXONE 40 mg per mL: administer three times per week
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FINGOLIMOD
Sphingosine-1-Phosphate (S1P) Receptor Agonist
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Fingolimod
Treatment with fingolimod 0.5 mg:
Significant benefits on relapse-related outcomes within first 3 months
and on volume loss over 6 months effects of fingolimod treatment
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Injectable therapiesOral therapies
Consider side
effects
BG 12
Fingolimod0,5mg\
day
DIMETHYL
FUMARATE
Terflunomide
Natalizumab 300MG
I.V inj.\month
Glatiram
er
Interferon
β
Relapsing inflammatory MS clinical course
First lineFirst
line?
Severe relapsing
inflammatory
MS/JCV negative
Inadequate
response/inj
intolerance
Inadequate
response/oral
intolerance
Parallel switch
Inadequate
response/JCV
negative
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What is the prognosis?
One hallmark of MS is its unpredictability.
Approximately 1/3 will have a very mild course
Approximately 1/3 will have a moderate course
Approximately 1/3 will become more disabled
• Certain characteristics predict a better outcome:
Female
Onset before age 35
Sensory symptoms
Monofocal rather than multifocal episodes
Complete recovery following a relapse
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Who is on the MS “Treatment Team”?
• Neurologist
Urologist
Nurse
Physiatrist
Physical therapist
Occupational therapist
Speech/language pathologist
Psychiatrist
Psychotherapist
Neuropsychologist
Social worker/Care manager
Pharmacist
Primary care physician
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So what do we know about MS?
MS is a chronic, unpredictable disease
The cause is still unknown
MS affects each person differently; symptoms vary
widely
MS is not fatal, contagious, directly inherited, or always
disabling
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74
Early diagnosis and treatment are important Significant,
on
Available treatments reduce the number of relapses and may slow
progression
Treatment includes: attack management, symptom management,
disease modification, rehab,
emotional support
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THANK YOU