practical issues in multiple sclerosis

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Amr Hassan, M.D. Associate professor of Neurology - Cairo

University 2016

Practical Issues in Multiple

Sclerosis

AGENDA

• Immunopathogenesis

• Diagnosis

• Biomarkers

• Treatment options

• Optimization of treatment

2

3

Immunopathogenesis

Genetics

Environment Autoimmunity

6

Peripheral Immune System

1) Engagement of T cell receptor

by crossreactive microbial

antigen

CD28 2) B7

3) IL-12

TH P

auto-reactive

TH 1

auto-reactive

VLA-4

VCAM

TH 1

auto-reactive

TH 1

auto-reactive

Inflammed

Tissue

Immunopathogenesis of M.S.


8

Peripheral activation

Migration of autoreactive T cells

Central reactivation

Myeline damage

Remyelination Axonal loss


9




Myeline damage


10

Tissue Damage

IL-2

IFN-

TNF-

CD154 CD40

IL-12

tissue

APC

autoantigens

CD28 B7

TH 1

auto-reactive

Peripheral Immune System

1) Engagement of T cell receptor

by crossreactive microbial

antigen

CD28 2) B7

3) IL-12

TH P

auto-reactive



12




Myeline damage



13




Myeline damage


17

More Than a Demyelinating Disease

Helper T-Cell Differentiation

IL-12/STAT4 IFN- Pro-inflammatory TH1

TH2

IL-4

IL-5

IL-10

IL-13

Anti-inflammatory/

Allergy

IL-4/STAT6

IL-23

IL-17 Pro-inflammatory TH17 IL-6 + TGF-β

TGF-β Regulatory Treg

TGF-β

Graphic courtesy of Dr. Scott Zamvil.


21




Myeline damage


22

More Than a Demyelinating Disease

Time (Years)

Dis

ease P

ara

mete

r

INFLAMMATORY ACTIVITYINFLAMMATORY ACTIVITY

NEURODEGENERATIONNEURODEGENERATION

PROGRESSIONPROGRESSION

RelapsesRelapses

cMRIcMRI WMLsWMLsFLAIRFLAIR T1 Gd+T1 Gd+

FLAIRFLAIR

Rx effectRx effect

Poor Rx effectPoor Rx effect

No New No New WMLsWMLs

23

Inflammation and Neurodegeneration in MS

Diseas

e

Stage

Dominant

Component

Main Clinical

Outcome MRI

Early

INFLAMMATION

Edema

Demyelination (axonal loss,

brain atrophy)

Relapses Gd enhancement

Late NEURODEGENERATION

Severe axonal injury

Permanent tissue loss

Disability Black Holes

Gd enhancement

Brain Atrophy

Filippi et al., EJN 2001, 8:291-297

26

Fingolimod

Fingolimod

27

Mechanism of action of DMD (Fingolimod)

28

Mechanism of action of DMD (Fingolimod)

29

Diagnosis

Multiple Sclerosis Diagnosis

30

• Diagnosis relies on clinical judgment.

• MS is extremely variable.

• There is no specific test.

• The diagnosis has dramatic implications.

Multiple Sclerosis Diagnosis

31

Diagnosis of MS

includes

To prove it is M.S To exclude other

diagnoses

How to diagnose MS?

32

Clinical:

• History and

examination.

• Evidence of CNS

involvement.

• Dissemination in

space and time.

Paraclinical:

• Neuroimaging.

• Evoked potentials.

• CSF analysis.

Diagnostic Criteria

• Dawson criteria: 1916

• Schumacher criteria: 1965

• Poser criteria: 1983

• McDonald criteria: 2001



All criteria require dissemination in time and space

Summarized Diagnostic Criteria

1. Dissemination in space: Objective evidence of neurological deficits localized to two separate parts of the CNS

2. Dissemination in Time:

Onset of neurological deficits separated by at least one month

3. Rule out other explanations!

2010

2014

Diagnostic Criteria 2005

• Incorporate use of MRI

• Clinically Isolated Syndrom + MRI

Dissemination in space + MRI

Dissemination on time =

Earlier MS Diagnosis

August

DIS

DIT

November

New Diagnostic Criteria 2010

• Incorporate use of MRI

• Clinically Isolated Syndrom + MRI

Dissemination in space + MRI

Dissemination on time =

Earlier MS Diagnosis

August

DIS

DIT

August

Magnetic resonance imaging

T1 weighted Pre & Post Contrast

38

Magnetic resonance imaging

T2 weighted images showing plaques

41

INVESTIGATIONS

CSF examination

46

IgG index:

• [IgGCSF/albuminCSF]/[IgGserum/albuminserum]

MS patients elevated IgG index (>1.7). (normal is <0.77)

47

Oligoclonal Bands in CSF

Mental map for diagnosis of MS

48

Clinical/Paraclinical/Imaging

Typical for MS Fulfills Criteria

Atypical for MS Red Flags Present

Work Up for Alternative Diagnoses

Clinical/Imaging Follow Up

Alternative Diagnosis Established

Further clinical/imaging typical for MS

MS Diagnosis

Typical for MS not Fulfilling Criteria


PRESENTING SYMPTOMS IN MS Total %

SENSORY LOSS IN LIMBS 30.7

VISUAL LOSS 15.9

MOTOR WEAKNESS 14.2

DIPLOPIA 6.8

GAIT DISTURBANCE 4.8

INCOORDINATION 2.9

SENSORY LOSS-FACE 2.8

LHERMITTE’S 1.8

VERTIGO 1.7

BLADDER SYMPTOMS 1

AUTE TRANSVERSE MYELOPATHY 0.7

PAIN 0.5

OTHERS 2.5

POLYSYMPTOMATIC 13.7

The Red Flags

50

Red flags

51

• Major red flags point fairly definitively to a non-MS

diagnosis

• Intermediate red flags point to poor agreement and

uncertainty among raters about the weighting of the flag

for differential diagnosis in MS

• Minor red flags suggest that a disease other than MS

should be considered and fully explored, but an MS

diagnosis is not excluded.

Outline

The Red Flags

52

• Clinical

• Lab

• Imaging

Outline

The Red Flags

53

• Clinical

• Lab

• Imaging

54

Clinical Red

Flags

Clinical Red Flags (Major)

55

Bone lesions

Lung involvement

Multiple cranial neuropathies or

polyradiculopathy

Peripheral neuropathy

Tendon xanthomas

Cardiac disease

Myopathy

Renal involvement

Extrapyramidal features

Livedo reticularis

Retinopathy

Diabetes insipidus

Increase serum lactate level

Hematological manifestations

Mucosal ulcers

Myorhythmia

Hypothalamic disturbance

Recurrent spontaneous abortion or

thrombotic events

Rash

Arthritis, polyarthalgias, myalgias

Amyotrophy

Headache or meningismus

Persistently monofocal manifestations

Clinical Red Flags (Intermediate)

56

Sicca syndrome

Gastrointestinal symptoms

Loss of hearing

Fulminant course

Increase serum ACE level

Prominent family history

Constitutional symptoms

Progressive ataxia alone

Neuropsychiatric syndrome

Seizure

Uveitis

Pyramidal motor involvement

alone

Gradually progressive course

from onset

Clinical Red Flags (Minor)

57

Brainstem syndrome

Myelopathy alone

Onset before age 20

Abrupt onset

Onset after age 50

58

Clinical Red Flags

• Optic neuritis: Absence of pain, retinal exudates or hemorrhages, severe disc

swelling, bilateral involvement, no visual recovery after 1 month, uveitis.

• Brainstem syndrome: Hyperacute onset, vascular territory distribution (e.g. lateral

medullary syndrome), age >50 years, isolated trigeminal neuralgia, fluctuating

ocular/bulbar weakness, non-remitting symptoms, fever, meningismus, complete

external ophthalmoplegia, third nerve palsy, focal dystonia or torticollis.

• Marked LMN signs: Areflexia, proximal weakness, bilateral LMN facial palsy, cauda

equina lesion.

• Spinal cord syndrome: Hyperacute onset or insidiously progressive, complete

transverse myelitis, sharp sensory level, Radicular pain, failure to remit, anterior

spinal artery distribution (sparing posterior columns only), complete Brown-Sequard

syndrome.

• Cerebral hemisphere: obtundation, confusion, cortical blindness, dementia,

aphasia,

Clinical Red Flags

Outline

The Red Flags

59

• Clinical

• Lab

• Imaging

Outline

The Red Flags

60

• Clinical

• Lab

• Imaging

61

Laboratory

Red Flags

Laboratory Red Flags

62

• CBC: Marked cell count abnormality

• High ESR

• +ve ANA

• Elevated lactate

Laboratory Red Flags

CSF

63

• Cell count: >50 White blood cells

• Cell differential: Neutrophilic predominance

• Protein: Significant elevation(>100 mg/dl)

• Glucose: Low glucose(<2/3 serum glucose)

Outline

The Red Flags

64

• Clinical

• Lab

• Imaging

Outline

The Red Flags

65

• Clinical

• Lab

• Imaging

66

Imaging Red

Flags

67

“The most common reason for

falsely attributing a patient’s

symptoms to multiple sclerosis

is faulty interpretation of the

magnetic resonance imaging.”

Famous Dictum

Loren A. Rolak 2007

WMLs differential diagnosis

70

D.D. OF M.S. IN MRI

71

1. Age-related changes

2. Acute disseminated encephalomyelitis

3. CNS vasculitis

4. Behçet disease

5. Sjögren syndrome

6. Sarcoidosis

7. Metastatic neoplasm

8. CADASIL (cerebral autosomal dominant arteriopathy with

subcortical infarcts and leukoencephalopathy)

9. Binswanger disease

10. Migrainous ischemia

D.D. OF M.S. IN MRI

72

11. Cerebrovascular disease

12. Progressive multifocal leukoencephalopathy

13. Inherited white matter diseases

14. Effects of radiation therapy or drugs

15. CNS lymphoma

16. Lyme disease

17. HTLV-1 infection

18. CNS lupus

19. Mitochondrial encephalopathies

20. Antiphospholipid antibody syndrome

MRI Red Flags (Major)

73

Cerebral venous sinus

thrombosis

Cortical infarcts

Hemorrhages/microhe

morrhages

Meningeal

enhancement

Calcifications on CT

scans

Selective involvement of

the anterior temporal

and inferior frontal lobe

Lacunar infarcts

Persistent Gd-

enhancement and

continued enlargement

of lesions

Simultaneous

enhancement of all

lesions

T2-hyperintensity in the

dentate nuclei

T1-hyperintensity of the

pulvinar

Large and infiltrating

brainstem lesions

Predominance of lesions

at the

cortical/subcortical

junction

MRI Red Flags (Intermediate)

74

Hydrocephalus

Punctiform parenchymal enhancement

T2-hyperintensities of U-fibers at the

vertex, external capsule and insular

regions

Regional atrophy of the brainstem

Diffuse lactate increase on brain MRS

Marked hippocampal and amygdala

atrophy

Symmetrically distributed lesions

T2-hyperintensities of the basal

ganglia, thalamus and hypothalamus

Predominant brainstem and cerebellar

lesions

Lesions in the center of CC, sparing

the periphery

Diffuse abnormalities in the posterior

columns of the cord

MRI Red Flags (Intermediate)

75

Lesions across GM/WM boundaries

T2-hyperintensities of the temporal

pole

Complete ring enhancement

Central brainstem lesions

Dilation of the Virchow-Robin spaces

Cortical/subcortical lesions crossing

vascular territories

Large lesions with absent or rare mass

effect and enhancement

No “occult” changes in the NAWM

No enhancement

No optic nerve lesions

No spinal cord lesions

Large lesions

No T1 hypointense lesions (black

holes)

Marked asymmetry of WM lesions

Mental map for diagnosis of MS

76

Clinical/Paraclinical/Imaging

Typical for MS Fulfills Criteria

Atypical for MS Red Flags Present

Work Up for Alternative Diagnoses


Alternative Diagnosis Established

Further clinical/imaging typical for MS

MS Diagnosis

Typical for MS not Fulfilling Criteria


77

Outcome of MS?

HETEROGENEITY

Pathological

subtypes

Clinical

presentation

Rates of

progression

Resonse to

DMT

78

Timing of the therapy key to preventing disability

Time (Years)

Relapsing Remitting Multiple sclerosis Transitional Secondary Progressive MS CIS Pre- Clinical

Demyelination

Remission State of no disease activity, the period

during which diminution of

symptoms occurs due to the

cessation of inflammatory processes and

some degree of reparative

remyelination of affected axons

Relapses Acute

Inflammation Demyelination

First Clinical Attack

Axonal loss

Inflammation

Brain Volume

MRI Activity

Disability progression Reflects reactive

astrogliosis, Axonal Loss and Brain

volume loss.

Starts Reversible (remyelination) and ends in permanent

disability

Time window

for early

treatment

Mark S. Freedman: Induction vs. escalation of therapy for relapsing Multiple Sclerosis: the evidence, Neurol Sci (2008) 29:S250–S252

80

A Biomarkers for Multiple Sclerosis:WHY ?

BIOMARKERS

81

Biomarkers

82

GENETIC/IMMUNOGENETIC:

• Biomarkers specified via genomics and immunogenetic

techniques.

LABORATORY:

• All other biomarkers that can be measured in body

fluids.

IMAGING:

• Biomarkers provided by imaging techniques.

BIOMARKERS

83

A. GENETIC AND IMMUNOGENETIC

BIOMARKERS

BIOMARKERS

HLA TOB-1 Apo lipoprotein-E

84

B. LABORATORY BIOMARKERS

BIOMARKERS

85

I. Biomarkers of Immunological Activation

II. Biomarkers of Neuroprotection

III. Biomarkers of BBB disruption

IV. Biomarkers of demyelination

V. Biomarkers of Oxidative Stress

VI. Biomarkers of Axonal Damage

VII. Biomarkers of Glial Activation Dysfunction

VIII. Biomarkers of Remyelination Repair

IX. Biomarkers of Therapeutic Response

X. Prognostic Biomarkers

XI. Emering biomarkers

B. Laboratory Biomarkers

86

IV

VI

VII

VIII

III

I

BIOMARKERS

CLINICAL OCB MRI

88

Prediction of prognosis

89

GOOD EPIDEIOLOGICAL FACTORS

BAD

Female Sex Male

< 40 y Age > 40 y

90

GOOD RELAPSES BAD

Mild, monofocal 1st relapse Severe , multifocal

Sensory, ON Clinical presentation Motor, cerebellar

Full recovery Response to ttt Residual

Long Time to 2nd relapse Short

Low Relapse rate High


91

GOOD DISABILITY BAD

Long Time to EDSS 4-5 Short

GOOD MRI BAD

Low Lesion load High

Absent CEL Present


MRI brain and cervical cord (1) with Gd

Abnormal [conversion rate 80%] (2)

Wait till CDMS

DMT

Normal [conversion rate 20%] (2)

Follow up

94

Conversion of CIS to CDMS

95

Treatment options

Relapsing remitting multiple sclerosis

(R.R.M.S.)

96

• Treatment of a

relapse

• Disease modifying

therapy (DMT)

• Symptomatic ttt

• Non

pharmacological

97

• Worsening of present symptoms or appearance of new

symptoms

• At least 24 h

Relapse

• 1 month from last attack.

• Not during steroid withdrawal or infection.

• ↑ EDSS ≥ 0.5

Definition of a relapse

Symptomatic ttt

DMT

99

Existing & Emerging MS therapies

Modified from P. Vermersch

Phase I

Phase II

Phase III

Marketed

Interferons

Antiproliferative agents

Cytolytic mAbs

Symptomatic Tx Vaccine, tolerization

Lymphocyte trafficking

Immune regulation

Other

Idebenone

BIIB033

Fingolimod

Firategrast

Siponimod

ONO-4641

CS-0777

ELND-002

Tysabri

Daclizumab

Laquinimod BG12

NI-0801

AZD5904

GRC4039

CCX-140

AIN457

Cladribine

Nerispirdine Ofatumumab

Belimumab

Ampyra

Ocrelizumab

Sativex

Alemtuzumab

Copaxone

IPX-056

RPI-78M

LY-2127399

Novantrone

Rebif Betaferon

Pixantrone

Peg IFNb

(BIIB017)

ATX-MS-1467

PI2301

RTL1000

Copaxone generics x2

Azathioprine

Teriflunomide

LV Copaxone

Avonex

= Oral administration

= Injectable

Extavia

Ponesimod

10

1

Treatment optimization

BMT

Cyclophosphamide

Mycophenolate mofieil

Mitoxantrone - Fingolimod – Natalizumab Mitoxantrone

Β Interferons – Glatirmar Acetate

Teriflunomide – Dimethyl fumarate - Leflunomide – Azathioprine – Methotrexate – Fingolimod*

Treatment failure

DMDs Strategy

• Rio score is adopted to determine failure of

ttt or non responding patient in order to

escalate. Escalation options include:

– Up shifting (e.g. shifting from 1st line agent to

2nd line agent)

– Lateral Shifting (shifting to another

therapeutic agent classified within same line)

– Combination with monthly methyl

prednisolone.

Escalation Vs Induction

10

8

Induction therapy: • Patients with poor prognostic factors (next

slide) may be optioned to start on a second line agent or a more potent agent within the same line and then

either to • Continue on such agent

or

• Shift to a first line option according to patient’s response.

DMDs Strategy

THANK YOU

practical issues in multiple sclerosis

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