Current guidelines in diagnosis and management of Multiple Sclerosis

1. Dr Sandhya Manorenj
Department of Neurology
ESIC Medical College,
Superspeciality hospital
Hyderabad
20/12/17

2. Munschauer et al. Clin Ther. 1997;19:868.
It’s a disease of
young adults – 20
– 40yr age group -
Affects more
women than men
Several factors are
believed to be
triggers for MS,
but the exact
cause is unknown
MS is a disease with
3 main
components:
inflammation,
demyelination, and
axonal loss
MS is an
immune-
mediated
disorder
Affects about 1
million people
worldwide
MS
Chronic progressive de-
myelinating disease
MULTIPLE SCLEROSIS (MS)
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3. Relapsing-Remitting MS Primary Progressive MS
Secondary Progressive MS Progressive-Relapsing MS
<5%
<12%
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70 – 80 % (inc CIS)
4 COMMON CLINICAL PATTERNS

4. TYPES OF MS
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5. oRough estimated prevalence of 5–10 per 100,000 individuals1
oMore prevalent in female subjects
oAverage age at onset is approximately 25–30 years (mean:27
years)
oClinical features of MS in India are similar to those seen
elsewhere
5
EPIDEMIOLOGY OF MS (INDIA)
Dr. BS Singhal: Multiple sclerosis – Indian perspective:2015 Neurology
India Sandhya Manorenj

6. McDonald criteria, established in 2001, were revised in 2005 and 2010 to clarify the meaning
of attack, dissemination, and positive MRI
Clinical Attacks Additional Data Needed
≥2 attacks
Objective evidence of ≥2 lesions or objective
clinical evidence of 1 lesion with reasonable
historical evidence
 None. Clinical evidence is sufficient.
≥2 attacks
Objective clinical evidence of 1 lesion
For dissemination in space (DIS), demonstrated by
 ≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS*; or await a further clinical attack implicating
a different CNS site
1 attack
Objective clinical evidence of ≥2 lesions
For dissemination in time (DIT), demonstrated by
 Simultaneous presence of asymptomatic Gd+ and nonenhancing lesions; or a new T2 and/or Gd+ lesion on
follow-up MRI, irrespective of timing with reference to a baseline scan; or await a second clinical attack
1 attack
Objective clinical evidence of 1 lesion (CIS)
 For DIS: ≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS*; or await a further clinical attack
implicating a different CNS site
 For DIT: Simultaneous presence of asymptomatic Gd+ and nonenhancing lesions; or a new T2 and/or
Gd+ lesion on follow-up MRI, irrespective of timing with reference to a baseline scan; or await a second
clinical attack
Insidious neurological progression suggestive of MS
(PPMS)
One-year progression (retrospectively or prospectively determined), and 2 of the following:
A. Evidence for DIS in the brain based on ≥1 T2 lesions in the MS-typical regions of the CNS*
B. Evidence for DIS in the spinal cord based on ≥2 T2 lesions in the cord
C. Positive CSF†
*Periventricular, juxtacortical, infratentorial, or spinal cord; †isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index.
MS=multiple sclerosis; MRI=magnetic resonance imaging; CNS=central nervous system; Gd+=gadolinium-enhancing; CIS=clinically isolated syndrome;
PPMS=primary progressive MS; CSF=cerebral spinal fluid; IgG=immunoglobulin G.
Polman CH et al. Ann Neurol. 2011;69:292-302.
Diagnosing MS
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7. MAGNIMS 2016 (DIS)
Changes
1. One Periventricular to 3 Periventricular Lesions
2. Optic nerve inclusion
3. Cortical lesion Inclusion
4. Symptomatic lesions are included in lesion count
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8.  New McDonald`s 2017 Criteria ( Proposed )(This data is based on oral
presentation of Jeffery Cohen in ECTRIMS 2017)
1)Recommendation to use the presence of OCBs in cerebrospinal fluid (CSF) to make
the diagnosis of MS in a patient with typical clinically isolated syndrome (CIS) who has
clinical or MRI evidence of dissemination in space
2)Both symptomatic and asymptomatic MRI lesions can be considered in determining
dissemination in space and time
3)Cortical lesions can be used to demonstrate dissemination in space
4)Specific criteria for diagnosing primary progressive MS have not changed
5)criteria recommend determining a provisional disease course as specified by Lublin
et al at the time of diagnosis, and periodically re-evaluating it based on accumulated
evidence
Recent Advances in Diagnosis
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9. What is acute relapse in MS?
Also called as attacks or acute
exacerbations.
Defined as episodes of focal
neurological disturbance lasting longer
than 24 hrs with a preceding period of
clinical stability of at least 30 days and
without an alternate explanation such
as infection or fever.
Redefining Acute Relapses in Multiple Sclerosis: Implications for Phase 3 Clinical Trials and Treatment
Algorithms
Innov Clin Neurosci. 2017 Mar-Apr; 14(3-4): 38–40. Sandhya Manorenj

10. What is Pseudo relapse?
 The temporary worsening of existing MS
symptoms in the setting of heat exposure or
infection.
 It can be differentiated by true relapse by the
presence of new lesion that enhances with the
administration of gadolinium on MRI brain/
spinal cord in true relapse.
 So suspected attacks should be evaluated

11. Types of relapse in MS
 Mild relapse in MS : Only sensory symptoms.
 Highly active relapsing form: ≥ 2 relapses in a year and ≥ 1
Gad+ lesion on T1-weighted MRI
 High disease activity:≥ 1 relapse in a year on therapy or ≥ T2
lession on cranial MRI or ≥ 1 Gad lesion.
 Rapidly evolving severe RRMS: ≥ 2 disabiling relapses in a
year and ≥ 1 Gad+ lesion on T1-weighted MRI or sigificant
increase in T2 burden from previous MRI.

12. Clinically isolated syndrome(CIS)
 Defined as the first clinical episode ,an event or
precedent history that is suggestive of demyelination
or of multiple sclerosis, lasts at least 24hrs and occurs
in the absence of fever, infection or encephalopathy.
 Single attack in time, it is not necessary isolated in
space, one quarter present with multifocal
abnormalities.
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13. Radiologically isolated
sydrome(RIS)
 RIS defined as incidental brain or spinal cord MRI
findings that are highly suggestive of MS ,based on
location and morphology within CNS in an
asymptomatic patient lacking any history ,symptoms
or signs of multiple sclerosis.
 Follow up needed.
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14. How to assess disability ?
Adapted from Kurtzke. Neurology. 1983;33:1444.
0 1 1.5
2.5
3.5
4.5
5.5
6.5
7.5
8.5
9.5
10
2
3
4
5
6
7
8
9
500
200
Normal
Neurological
exam
Minimal
disability
Increased limitation
in walking ability
Need for walking assistance
Restricted to wheelchair
Bedridden patient Death
EDSS Is a Validated Measurement of Physical Disability in MS
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15. Early Treatment to Minimise Further Damage
Gd+ = gadolinium enhancing.
Adapted from: Trapp BD et al. Neuroscientist. 1999;5:48-57. Sandhya Manorenj
Relapses
Brain Volume T1 Black Hole Lesion Load
Cognitive Dysfunction
Accumulated MRI
Lesion Burden
Acute (New and Gd+)
MRI Activity
Time
IncreasingDisability/Deterioration
Subclinical EARLY MS Relapsing-Remitting Secondary Progressive
Natural course of MS
Later treatment
Early treatment

16. Management of multiple sclerosis
Treatment of acute relapse
Disease modifying treatment
Symptomatic treatment
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17. Treatment of acute relapse
IV methylprednisolone
• (first line therapy)
Plasma exchange
• (second line therapy)
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18. IV Methylpredisolone-
recommendations
 1000mg daily for 5 days without an oral taper.
 2 hrs onset of effect peaks by 12 hours lasts for hrs.
 Relative few side effects: mental status changes &
psychiatric side effects
 Repository corticotropin injection gel (80-100 units IM
or SC) as an alternative who cannot tolerate high dose
glucorticoids.
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19. Plasma exchanges-Indication
Who do not respond to
glucocorticoids.
5-7 exchanges recommeded on every 2
days
30-50ml/kgw Sandhya Manorenj

20. Disease modifying therapy(DMT)
 Patients with RRMS who have current
disease activity manifested clinically or MRI
lesions should be offered DMT.
 CIS cases
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21. DMT
Injectable therapy
Infusion therapy
Oral therapy
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22. Injectable therapy
 Interferons
 Glatiramer (20 mg sc daily)
 Daclizumab
IFN beta 1a 30mcg IM once weekly
IFN beta 1b SC 22 or 44 mcg 3 times/week
IFN beta 1b 0.25mg SC daily
Peglated IFN beta 1a 125mcg every 2 weeks
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23. Infusion therapy
Natalizumab
Alemtuzumab
Ocrelizumab
Mitoxantrone
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24. Oral therapy
Dimethyl fumarate
Teriflunomide
Fingolimod
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25. Other treatments
 Azathioprine
 Cyclophosphamide
 Rituximab
 Cladribine
 Glucocorticoids in combinations
 IVIG
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26. 

28. Symptomatic management in MS
 Cognitive impairment-DMT
 Depression- Duloxetine,escitalopram
 Fatigue:Amantidine,Modafinil,Dextroamphetamine,methylphei
date
 Gait impairment:Dalfampridine (K channel blocker) 10 mg bd,
increases seizure so Contraindicated (CI)if seizure history
 Heat intolerance-Dalfampridine
 Paroxysmal symptoms- Carbamazepine(CBZ)
 Lhermitte sign-gaapentin,pregaba,CBZ
 Sandhya Manorenj

29. Symptomatic management
 Spasticity-
Tizantidine,baclofen,dantrolone,clonezepam(phase
spasticity)
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30. Treatment of PPMS
 Ocrelizumab:only drug to receive FDA for use in adult
PPMS(march 2017) grade2B
 Anti-CD20 monoclonal ab designed to optomize cell
depletion
 ORATORIO trial
 300mg infusion given 14 days apart(total-600mg) for
atleast 120 weeks
 CI in hepatitis B infection
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31. MS in children-Management
 Methylprednisolone 20-30mg/kg given for 5 days
 Failure to steroids-IVIG 400mg/kg for 5days.
 DMT-Injectable therapy first line then natalizumab,
fingolimod,dimethyl fumarate
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32. Monitoring response to therapy
 Clinical follow up –acute attacks,
 Cognitive assessment
 EDSS every 3 months
 MRI every 12 months
 Modified Rio score
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34. Sandhya manorenj

35. Pivotal Studies
Avonex Betaferon Rebif Copaxone Tysabri TECFIDERA
CIS CHAMPS BENEFIT
ETOMS
REFLEX
PRECISE
RRMS MSCRG
IFNB MS
Study
Group
Neurology
1993/1995
PRISMS
Johnson
Trial
Neurology
1995
AFFIRM
SENTIN
EL
DEFINE &
CONFIRM
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36. Sandhya Manorenj