multiple sclerosis- recent guidelines 2018

Dr. Rahi Kiran. B
SR Neurology
GMC Kota
Recent Guidelines for
Diagnosis and Treatment of
Multiple Sclerosis

Munschauer et al. Clin Ther. 1997;19:868.
It’sadiseaseof
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 diseasewith
3 main
components:
inf lammation,
demyelination, and
axonal loss
MS is an
immune-
mediated
disorder
Affects about 1
million people
worldwide
MS
Chronic progressivede-
myelinating disease
MULTIPLE SCLEROSIS (MS)

Relapsing-Remitting MS
70 – 80 % (inc CIS)
Primary Progressive MS
<12%
Secondary Progressive MS Progressive-Relapsing MS
<5%
4 COMMON CLINICAL PATTERNS

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)
Ofeatures of MS in India are similar to those seen elsewhere
5
EPIDEMIOLOGY OF MS (INDIA)
Dr. BS Singhal: Multiple sclerosis – Indian perspective:2015 Neurology

McDonald criteria, established in 2001, were revised in 2005 and 2010 to clarify
the meaning of attack, dissemination, and positive MRI
*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.
Diagnosing MS
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†

1)Recommendation to use the presence of OCBs in CSF to make
the diagnosis of MS in a patient with typical CIS who has clinical or
MRI evidence of DIS
2)Both symptomatic and asymptomatic MRI lesions can be
considered in determining DIT and DIS
3)Cortical lesions can be used to demonstrate DIS
4)Specific criteria for diagnosing PPMS have not changed
Recent Advances in Diagnosis
 New McDonald`s 2017 Criteria ( Proposed )
 (based on oral presentation of Jeffery Cohen in ECTRIMS 2017)

MAGNIMS 2016 (DIS)
Changes
1. One Periventricular to 3 Periventricular Lesions
2. Optic nerve inclusion
3. Cortical lesion Inclusion
4. Symptomatic spinal cord or brain stem lesions are included in
lesion count

acute relapse
Also called as attacks or acute exacerbation
“Defined as episodes of FND lasting > 24 hrs with
a preceding period of clinical stability of at least
30 days and without an alternate explanation
such as infection or fever."
 The temporary worsening - heat exposure or infection.
 differentiated from true relapse -new lesion that enhances
with gadolinium on MRI brain/ spinal cord
 So suspected attacks should be evaluated
Pseudo relapse

Types of relapse in MS
 Mild : Only sensory symptoms.
 Highly active relapsing form: ≥ 2 relapses in a year
and ≥ 1 Gad+ lesion on T1-weighted MRI
 Rapidly evolving severe RRMS: ≥2 disabiling relapses
in a year and ≥1 Gad+ lesion or sigificant increase in T2
burden from previous MRI.
 Inactive MS: no relapses or MRI activity in the last 24
months (NEDA)

Clinically isolated syndrome(CIS)
“First clinical episode ,an event or precedent history that is
suggestive of demyelination lasts at least 24hrs and occurs in the
absence of fever, infection or encephalopathy."
prognostic factor for conversion to CDMS and disability-
low impact-female sex, younger age
non-optic neuritis presentations
medium-impact- OCBs
high impact- ≥10brain lesions on brain MRI
If MRI s/o multifocal disease - half to two-third - transform into
CDMS.

Radiologically isolated sydrome(RIS)
“Incidental brain or spinal cord MRI findings that are highly
suggestive of MS in an asymptomatic patient lacking any
history ,symptoms or signs of multiple sclerosis."
 34% of patients with RIS develop a first acute clinical event
consistent with CIS within 5 years;
 risk factors - male sex, younger age (<37 years),

Panel : 2017 McDonald criteria for PPMS
PPMS can be diagnosed in patients with:
1 year of disability progression (retrospectively or
prospectively determined) independent of clinical relapse
Plus two of the following criteria:
1. nine T2 lesions or at least four T2 lesions with positive VEP
2. Two or more T2-hyperintense lesions in the spinal cord.
3. Presence of CSF-specific oligoclonal bands

Pre-symptomatic Symptomatic
At-risk Asymptomatic MS (RIS) Prodromal MS CIS Multiple Sclerosis
MS Endophenotype
Disease state - focal MSpathologyPre-disease state
Diagnostic phasePre-diagnostic phase
Kantarci et al. Ann Neurol. 2016 Feb;79(2):288-94.
453
⬇
128 (28%)
⬇
CIS/MS 113 (88%)
+
PPMS 15 (12%)

Management of MS
Treatment of acute relapse
Disease modifying treatment
Symptomatic treatment

 1000mg daily for 5 days without an oral taper.
 2 hrs onset of effect, peaks by 12 hours
 few side effects: mental status changes & psychiatric
Treatment of acute relapse
IV methylprednisolone (first line therapy)
Plasma exchange (second line therapy)
5-7 exchanges recommeded on every 2 days, 30-50ml/kgw
Who do not respond to glucocorticoids

1. RRMS
2. CIS with MRI findings consistent with MS
3. SPMS but patient continues to have relapses and/or
changes on MRI
Disease modifying therapy(DMT)

Disease modifying therapy(DMT)

NICE Clinical guideline 2014
 Do not diagnose MS on the basis of MRI findings alone
 Do not routinely suspect MS if main symptoms are fatigue,
depression or dizziness unless they have a history or evidence of
FND.
 Encourage people to exercise which may have beneficial effects.
 live vaccinations may be contraindicated in people with MS who are
being treated with DMTs

Amantadine, CBT, aerobic, balance and stretching exercises including
yoga to treat fatigue in people with MS.
Do not use vitamin B12 injections to treat fatigue.
Do not use fampridine to treat lack of mobility in people with MS
because it is not a cost effective treatment
to treat spasticity, Consider baclofen or gabapentin as a first-line drug,
tizanidine or dantrolene as a second-line, BZDs as a third-line
Consider amitriptyline to treat emotional lability

to treat oscillopsia, Consider gabapentin as first-line, memantine as
the second-line drug
Do not offer vitamin D and omega-3 or omega-6 fatty acid solely for
the purpose of treating MS.
relapse rates may reduce during pregnancy and increase 3–6 months
after childbirth before returning to pre-pregnancy rates and pregnancy
does not increase the risk of progression of disease.
Smoking may increase the progression of disability.

AAN recommendations April 23, 2018
Starting DMT :
Clinicians should counsel people with newly diagnosed MS about
specific treatment options with DMT at a dedicated treatment visit. Level B
Clinicians must ascertain preferences in terms of safety, route of
administration, lifestyle, cost, efficacy, AEs and tolerability in the choice of
DMT. Level A
counsel patients that DMTs are prescribed to reduce relapses and new
MRI lesion activity and not for symptom improvement in people with MS.
Level B

After discussing the risks and benefits, DMT should be prescribed to
people with a single clinical demyelinating event and ≥2 brain lesions
characteristic of MS who decide they want this therapy. Level B
Clinicians should offer DMTs to people with relapsing forms of MS with
recent clinical relapses or MRI activity. Level B
recommend serial imaging at least annually for the first five years and
close follow-up rather than initiating DMT in people with CIS or RRMS
who are - not on DMT,
no relapses in the last two years,
no active new MRI lesion. Level C
Starting DMT :

Clinicians should monitor the reproductive plans of women with MS
and counsel regarding reproductive risks and use of birth control during
DMT use in women of childbearing potential who have MS. Level B
If women with MS are planning pregnancy soon, DMT use may need
to be deferred until after pregnancy
Clinicians should counsel men with MS on their reproductive plans
regarding treatment implications before initiating treatment with
teriflunomide or cyclophosphamide. Level B
Starting DMT :

Clinicians may direct people with MS who are candidates for DMTs to
support programs and may recommend azathioprine or cladribine for
people with relapsing forms of MS who do not have access to approved
DMTs. Level C
Because of the high frequency of severe AEs, clinicians should not
prescribe mitoxantrone to people with MS unless the potential
therapeutic benefits greatly outweigh the risks. Level B
Clinicians should monitor for medication adherence, AEs, tolerability,
safety, and effectiveness of the therapy in people with MS on DMTs.
Level B
Starting DMT :

Clinicians should prescribe alemtuzumab, fingolimod, or natalizumab for
people with MS with highly active MS. Level B
Clinicians may initiate natalizumab treatment in people with MS with
positive anti-JCV antibody indexes above 0.9 only when there is a
reasonable chance of benefit compared with the low but serious risk of
PML. Level C
Clinicians should offer ocrelizumab to people with PPMS who are
ambulatory and likely to benefit from this therapy unless there are risks of
treatment that outweigh the benefits Level B
Starting DMT :

discuss switching from one DMT to another who have been using a DMT
long enough for the treatment to take full effect and are adherent to their
therapy when they experience
one or more relapses
two or more unequivocally new MRI-detected lesions
increased disability on examination, over a one-year period of using a DMT. Level B
Clinicians should evaluate the degree of disease activity, adherence, AE
that may affect adherence and MOA of DMTs when switching DMTs with
breakthrough disease activity during DMT use. Level B
discuss a change to noninjectable or less frequently injectable DMTs
who report intolerable discomfort with the injections or in those who report
injection fatigue on injectable DMTs. Level B
Switching DMT :

switch DMT or reducing dosage or frequency when there are
persistent laboratory abnormalities. Level B
If a patient develops malignancy or oppurtunistic infection while using
a DMT, discuss switching to an alternate DMT, especially for people
using azathioprine, methotrexate, mycophenolate, cyclophosphamide,
fingolimod, teriflunomide, alemtuzumab, or dimethyl fumarate. Level B
check for natalizumab antibodies - who have infusion reactions and in
people who experience breakthrough disease activity - should switch
DMTs if they have persistent antibodies. Level B
Switching DMT :

counsel people considering natalizumab discontinuation that there is an
increased risk of MS relapse within six months of discontinuation Level A
and should initiate treatment(fingolimod, rituximab) within eight to 12 weeks
after natalizumab discontinuation Level B
counsel women to stop their DMT before conception for planned
pregnancies and should not initiate DMTs during pregnancy unless the risk
of MS activity during pregnancy outweighs the risk associated with the
specific DMT during pregnancy. Level B
Switching DMT :

Clinicians should advocate that people with MS who are stable on
DMT should continue their current DMT unless the patient and physician
decide a trial off therapy is warranted. Level B
Clinicians should assess the likelihood of future relapse in individuals
with SPMS by assessing patient age, disease duration, relapse history,
and MRI-detected activity (e.g., frequency, severity, time since most
recent relapse or gadolinium-enhanced lesion). Level B
Stopping DMT :

Clinicians may advise discontinuation of DMT in people with SPMS who
do not have ongoing relapses (or gadolinium-enhanced lesions on
MRI activity) and have not been ambulatory (EDSS 7 or greater) for at
least two years. Level C
Clinicians should review the associated risks of continuing DMTs versus
those of stopping DMTs in people with CIS using DMTs who have not been
diagnosed with MS. Level B
Stopping DMT :

EAN/ ECTRIMS recommendations 2017
1. Offer IFN or glatiramer to patients with CIS and an abnormal MRI with
lesions suggestive of MS who do not fulfil criteria for MS. [strong]
2. Offer early treatment with DMDs in patients with active RRMS as
defined by clinical relapses and/or MRI activity and also includes CIS
fulfilling current diagnostic criteria for MS. [strong]
3. Consider treatment with ocrelizumab for patients with PPMS. [weak]

4. Consider treatment with IFN beta-1a or beta-1b, mitoxantrone in
patients with active SPMS taking into account dubious efficacy, as
well as the safety and tolerability profile of these drugs. [weak]
5. Consider combining MRI with clinical measures when evaluating
disease evolution in treated patients. [weak]
6. When monitoring treatment response in patients treated with DMDs,
perform a reference brain MRI usually within 6 months of treatment
onset and compare it with a further brain MRI performed typically 12
months after starting treatment. [consensus statement]

7. When monitoring treatment response, measurement of new or
unequivocally enlarging T2 lesions is the preferred MRI method
supplemented by GAD enhancing lesions for monitoring treatment
response. [consensus statement]
8. When monitoring treatment safety, perform brain MRI yearly in low risk
and 3-6 monthly in high risk PML patients [consensus statement]
9. When deciding on which drug to switch to, in consultation with the
patient, consider the following factors: patient characteristics and
comorbidities, drug safety profile, disease severity/activity

10. Offer a more efficacious drug to patients treated with IFN or
glatiramer who show evidence of disease activity [strong]
11. When treatment with a highly efficacious drug is stopped, either due
to inefficacy or safety concerns, consider starting another highly
efficacious drug. [consensus statement]
12. In treatment decisions, consider the possibility of resumed disease
activity or even rebound when stopping treatment, particularly with
natalizumab. [weak]
13. Advise all women of childbearing potential that DMTs are not
licensed during pregnancy, except glatiramer .
[consensus statement]

13. For women planning a pregnancy, if there is a high risk of disease
reactivation, consider using IFN or glatiramer until pregnancy is
confirmed. In some very specific (active) cases, continuing this
treatment during pregnancy could also be considered. [weak]
14. women with persistent high disease activity, advise to delay
pregnancy. If despite this advice, still decide to become pregnant:
a) treatment with natalizumab throughout pregnancy may be considered
b) treatment with alemtuzumab could be an alternative, provided that a
4-month interval is strictly observed from the latest infusion until
conception. [weak]

Symptomatic management in MS
 Cognitive impairment-DMT
 Depression-Duloxetine,escitalopram
 Fatigue:Amantidine,Modafinil,Dextroamphetamine,methylpheni
 Gait impairment:Dalfampridine (K channel blocker) 10 mg bd,
C/I-if seizure history
 Heat intolerance-Dalfampridine
 Paroxysmal symptoms- Carbamazepine(CBZ)
 Lhermitte sign-gaapentin,pregaba,CBZ
 Spasticity- Tizantidine, baclofen, dantrolone, clonezepam


Treatment of PPMS(march 2017) Grade 2B
 Ocrelizumab: only drug to receive FDA for use in adult
PPMS(march 2017) Grade 2B
 Anti-CD20 mab designed to optomize cell depletion
 ORATORIO trial
 300mg infusion given 14 days apart(total-600mg) for atleast
120 weeks
 C/I in hepatitis B infection

PPMS-Ocrelizumab (march 2017) Grade 2B
Anti-CD20 mab
300mg infusion 14
days apart(total-
600mg) for atleast
120 weeks
C/I in HBV infection

MS in children-Management
 IV MPS 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

Indian context
Pandit L, Murthy J. Treatment of multiplesclerosis. Ann Indian Acad Neurol 2011;14:65-9.

multiple sclerosis- recent guidelines 2018

Corni G. Evolving concepts in the treatment of relapsing multiple sclerosis,.2016 nov 23
http://dx.doi.org/10.1016/

Monitoring response to therapy
 Clinical follow up –acute attacks,
 Cognitive assessment
 EDSS every 3 months
 MRI every 12 months
 Modified Rio score

Pivotal StudiesAvonex 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

New and Emerging
Immunotherapeutic Strategies
Multipotent hematopoietic stem cells (HSC)
BHT-3009, a DNA vaccine
Nanoparticles
Altered peptide ligands (APL)
Cyclic Peptides
Mannan as a Carrier to Modulate Immune Responses

Agents in development
1.Benztropine: anticholinergic
2.Opicinumab: anti-LINGO-1
3.Clemastine: anti-histamine/anti-cholinergi (M3)
4.GSK239512: histamine H3 receptor antagonist
5.IRX4204 & bexarotene: RXR agonist
6.rHIgM22: oligodendrocyte target
7.VX15: anti-SEMA4D
8.MD1003 (High-dose biotin): myelin
biosynthesis
9.Elezanumab (ABT-555): anti-RGMa
Remyelination

Suggestions for Future Research
role of cheaper drugs such as azathioprine
biomarkers that can predict DMT efficacy
benefits of DMTs in nonambulatory SPMS -including
cognition and upper limb function.
comparative studies-highly active DMTs in the treatment
of MS and CIS.
Whether to treat RIS

Suggestions for Future Research
Continued research is urged to identify
biomarkers that can predict DMT efficacy in
different patient subpopulations.
CSF Neurofilament light chain predicts
disease activity in RRMS

Risk of PML- natalizumab, fingolimod, rituximab,
ocrelizumab, and dimethyl fumarate
Relapses are associated with more rapid disability
progression in SPMS but tend to occur in those at
younger ages (younger than 55 years) and
earlier in the disease course

multiple sclerosis- recent guidelines 2018

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