SCLEROSIS - كلية الطب · 2019-03-06 · Slide 18 of 26 Clinically Isolated Syndrome (CIS)...

of 26

SCLEROSIS

DR.Sadik AL-Ghazzwi

Consultant Neurologist

MRCP,FRCP UK

1396: Earliest Recorded Case of MS

• 1868—Jean-Martin Charcot describes the disease and finds MS plaques (scars) on autopsy.

• 1878—Louis Ranvier describes the myelin sheath (the primary target of MS in the central nervous system).

“Multiple sclerosis is often one of the most difficult problems in clinical medicine.” (Charcot, 1894)

“When more is known of the causes and…pathology of the disease… more rational methods may brighten the therapeutic

prospect.” (Gowers, 1898)

• 1981—1st MRI image of MS is published.

HISTORY

of 26

What is Multiple Sclerosis (MS)?

• CHRONIC Autoimmune demyelination

disease of

CNS:

- brain

-optic nerve

- and spinal cord

• Affects 2.3 million people in the world

of 26

What is the epidemiology of MS?

• Geographic distribution

of 26

What are the possible risk factors?

• Infections : viral ,bacterial, fungal.

• Age: 15yr.-45yr.

• Gender :female: male 3:1

• Genetic Factors

– DR15 haplotype

• Autoimmune diseases

• Race

• Climate

of 26

What are the possible triggers of MS?

• Epstein-Barr Virus

• Smoking

• Vitamin-D deficiency

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)

of 26

What RISKS OF MS?

Genetic

Predisposition

Environmental

Trigger

Autoimmunity

Loss of myelin

& nerve fiber

of 26

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

of 26

How are myelin autoreactive T-cells activated?

• Myelin-reactive T-cells

– Myelin basic protein (MBP)

• T-cell activation

– Autoantigens

– Molecular mimicry

• Immune cell recruitment

– CD8+ cells

– B cells

– Granulocytes

– Monocytes

– Mast cells

of 26

What happens once across the BBB?

• Reactivation of CD4+ cells

– Proinflammatory cytokines

• Microglial and astrocyte activation

– Myelin phagocytosis

• Humoral response

• B cell co-stimulation

• Demyelination

– Type II hypersensitivity

https://michellepetersen76.files.wordpress.com/2015

/05/discovery-of-a-treatment-to-block-the-

progression-of-multiple-sclerosis-

neuroinnovations.jpg

of 26

What causes neuronal degeneration?

• MS lesions

– Active lesions

– Inactive, chronic lesions

• Demyelination

• Immune mechanisms cause:

– Oligodendrocyte damage

– Injury and loss of axon

– Gliosis

of 26Lublin et al, 2014

Relapsing-Remitting MS

• Subacute repeated onset of CNS dysfunction with

resolution ( sometimes incomplete , over days to

weeks)

• Revised McDonald criteria

• MRI: Periventricular, brainstem, juxtacortical

prominent T2, often Gad enhancing lesions, T1

hypointense (black holes)

Secondary Progressive MS

• Majority of RRMS many years following onset

• Progressive impairment (spastic gait disturbance) between or in

absence of attacks

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 1 year and accompanied by a combination of brain spinal abnormalities and/or CSF abnormalities consistent with MS

• Lack of clinical attacks/ relative paucity of MRI lesions

of 26

Clinically Isolated Syndrome (CIS)

• A first neurologic event suggestive of demyelination

• 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

18

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

of 26

What are the symptoms of MS?

• Early symptoms

• Daily effects

• Age range

• Characteristics of symptoms

of 26

Cycle of MS Symptoms:Related and Interdependent

Sleep

Fatigue

Depression

Bladder

& Bowel

problems

Sexuality

issues

Spasticity

Constipation

Cognitive

function

Features Consistent With MS

• Relapses and remissions

• Age Onset between ages 15 and 50

• Optic neuritis

• Lhermitte's sign

• Internuclear ophthalmoplegia (INO)

• Fatigue

• Uhthoff's phenomenon

of 26

How is MS diagnosed?

• MS is a clinical diagnosis

– Medical history

– SIGNS And symptoms

– Laboratory tests

• Requires dissemination in time and space:

– Space: Evidence of scarring (plaques) in at least two separate areas of the CNS (space)

– Time: Evidence that the plaques occurred at different points in time

• There must be no other explanation

of 26

Diagnosis of MS

• No single test for diagnosing MS

• Usually diagnosed when all other possibilities ruled out

• Many tests

– Medical history

– Nervous system functioning

– MRI McDonald criteria

– Evoked potential tests, spinal tap

of 26

INITIAL SYMPTOMS

• ascending numbness

starting in the feet;-

bilateral hand numbness;-

hemiparesthesia;-

dysesthesia in one of the

above distributions;-

generalized heat

intolerance

of 26

• Sensory systems:

• -Lhermitte's sign-

dysesthetic pain-

paresthesia-

numbness-dorsal

column signs

(i.e.,. severe

decrease or loss

of vibratory sense

and

proprioception,

of 26

• Ongoing Symptoms and Signs

•

Motor system:-

• weakness (variable severity mono- and

paraparesis, hemiparesis, quadriparesis)-

• increased spasticity resulting in spastic gait

• -pathologic signs (Babinski's, , Hoffmann,, etc.)

-dysarthria

of 26

• Cerebellar signs

• incoordination (dysdiadochokinesia,

problems with heel-to-shin test)-slowing

• of rapid repeating movements-cerebellar

ataxia (ataxic gait)

of 26

Expanded Disability Status Scale

of 26

What tests may be used to help confirm the diagnosis?

• Magnetic resonance imaging

(MRI)

• Visual evoked potentials (VEP)

• Lumbar puncture

of 26

McDonald Diagnostic CriteriaMRI-High Specificity & Sensitivity for MS

• Typical MS demyelinating lesions meeting at least 3 of the

following 4 criteria:

– At least 1 Gd lesion or at least 9 T2 lesions

– At least one infratentorial lesion

– At least one juxtacortical lesion

– At least 3 periventricular lesions

of 26

McDonald Diagnostic CriteriaMRI-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 Gd lesion

of 2633

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 1 of the 2 below must be found:

New Gd lesion on the second MRILater MRI showing new T2 or Gd lesion

of 26

Case : MRI Brain

of 26

Case 2: MRI Spine

of 26

Case 1: Fundoscopy

© 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

Case : CSF Oligoclonal bands



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



Infections

HIV, Lyme disease, syphilis

Human T-lymphotropic virus

Vascular disorders

Sporadic and genetic stroke syndromes

CNS vasculitis

Dural arteriovenous fistula

Migraine

Neoplasia (i.e., primary CNS neoplasm (glioma or lymphoma)

or metastatic disease)

Paraneoplastic syndromes

of 26

An Overview of Treatment Strategies

of 26

How is MS treated?

• There is no cure for MS

• Treatments FOR:

– MS attacks or acute relapse.

– Immune Modify agents

to prevent progression and reduce activity

Of the disease.

• Treatment of symptoms

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

of 26

Disease-Modifying Drugs for RRMS

• All reduce attack frequency and severity, reduce lesions

on MRI, and probably slow disease progression.

• These medications are not designed to:

– Cure the disease

– Make people feel better

– Alleviate symptoms

of 26

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.]

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

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

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”

of 26

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 Fingolim

od

0.5 mg gd

Teriflun

PO qd

Laquin

PO

Daclizum

ab

SC

BG-12

PO

bid

Alemtu

z

IV

The Changing Landscape of MS Disease Modifying Treatment

Of Approved and Emerging Therapies

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

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

of 26

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 with an

average molar fraction of 0.141, 0.427, 0.095, and 0.338,

respectively. The average molecular weight of glatiramer

acetate is 5,000 – 9,000 daltons. Glatiramer acetate is

identified by specific antibodies.

of 26

COPAXON

• COPAXONE 20 mg per mL: administer once per day

• or

• COPAXONE 40 mg per mL: administer three times per

week

of 26

Rituximab• Mechanism of action

– Chimeric human/murine mAb to CD20

– Depletes circulating B-cells

• Dosing

– 2 doses given 2 weeks apart IV: 1 g on days 1 and 151

• Side effects

– Infusion reactions, infections, hepatitis B reactivation, cases of progressive multifocal leukoencephalopathy in systemic lupus erythematosus/cancer population

Approved by FDA for lymphomas, rheumatoid arthritis

• HERMES phase II study for RRMS1

• Randomized, 48 weeks, 104 patients with RRMS

– Rituximab 1 g IV vs placebo on days 1 and 15

– 91% decrease in mean total Gd+ lesions

Rituximab 0.5 ± 2.0; placebo 5.5 ± 15 (P <.0001)

– Relapses at 24 weeks

Rituximab 14.5% vs placebo 34.3% (P = .02)

• Neuromyelitis optica/Devic’s open-label study2

• OLYMPUS trial phase II/III in PPMS – ineffective3

1. Hauser S, et al. N Engl J Med. 2008;358:676-688.

2. Cree BA, et al. Neurology. 2005;64:1270-1272.

3. Hawker KS, et al. Mult Scler. 2008;14:S299. Abstr 78.

of 26

Alemtuzumab• Mechanism of action

– Anti-CD52 mAb to receptor on surface of T- and B-cells

FDA approved for chronic lymphocytic leukemia

– Given 12mg\day IV for 5days (60mg) followed by 12mg\day for 3days 12monthes later.

• Alemtuzumab CAMSS223 Phase II trial 1

– 334 early RRMS patients randomized to alemtuzumab vs interferon beta-1a

2-year follow-up results

– Alemtuzumab group: 75% reduction in relapse rate vs interferon beta-1a

– Significant reduction of risk of sustained disability

3-year follow-up

– Maintained 71% and 74% reduction in risk of sustained disability and relapse rate, respectively, vs interferon beta-1a

2 phase III trials (CARE-MS, CARE-MS2) now enrolling

• Serious adverse events

– Infusion reactions

– Idiopathic thrombocytopenic purpura (3%): total of 6 cases – 1st case was fatal

– Grave’s disease – autoimmune thyroiditis (20%)

of 26

Daclizumab• Mechanism of action

– Anti-CD25 mAb targeting α chain of IL-2 receptor (IL-2Rα)

– Blocks the IL-2 “proinflammatory, ie, bad” cytokine receptor

– Prevents activation of sensitized T-cells

• Dosing

– IV infusion every 2 weeks (high dose) or every 4 weeks (low dose)

Side effects – infections, cutaneous reactions

• FDA approved for graft versus host disease/kidney transplant rejection

– CHOICE Trial – phase II results1

Randomized double-blind controlled trial

Add-on to interferon in 230 patients with RRMS

3 arms: 2 doses of daclizumab and placebo added to interferon

– Results

Decrease in new MRI lesions with higher dose vs interferon alone

No significant difference in relapse rate

5.2% with significant infections, none life-threatening

– SELECT: phase II trial of daclizumab monotherapy – Ongoing

1. Montalban X, et al. Mult Scler. 2007;13:S7-S273. Abstr 50.

of 26

Teriflunomide( Aubagio)

• Mechanism of action

– Inhibits pyrimidine (DNA) synthesis in T-cells resulting in destruction of immune cells

• Dosing

– Once-daily 7mg or 14mg\day

• Side effects: alopecia,diarrhea,flu,liver injury,renal failure

• Results of phase II trial1: 36 weeks in 179 patients

– Teriflunomide (high dose and low dose) vs placebo

– Significant (>61%) decrease in new MRI lesions in both doses

– Decrease in disease progression (in high dose)

– Trend towards lower relapse rate in high-dose group

.

of 26

FINGOLIMOD

Sphingosine-1-Phosphate (S1P) Receptor

Agonist

of 26

LN

T-cell FTY720-P

Prevents T-cell

invasion of central

nervous system

S1P receptor

Sphingosine-1-phosphate (S1P) receptor modulator

Internalises S1P1, blocks

lymphocyte egress from lymph

node (LN) while sparing

immune surveillance by

peripheral memory T-cells

FTY720 traps

circulating

lymphocytes in

peripheral lymph

nodes

Multiple sclerosis

FTY720

Fingolimod: Mechanism of Action

of 26

Fingolimod

• Treatment with fingolimod 0.5 mg:

– Significant benefits on relapse-related

outcomes within first 3 months and on volume

loss over 6 months compared with PBO in

FREEDOMS and FREEDOMS II studies;

concordant results from 2 large phase 3 trials,

along with phase 2 data, allow better definition

of expectations regarding time lag between

initiation and effects of fingolimod treatment

of 26

Injectable therapiesOral therapies

Consider side

effects

BG 12

Fingolimod0,5mg\

day

DIMETHYL

FUMARATE

Terflunomide

Natalizumab 300MG

I.V inj.\month

Glatirame

r

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

of 26

Dimethyl Fumarate

(TECFIDERA)(sclera)

: A New Small Molecule Disease-

Modifying Drug for Multiple Sclerosis

120 mg PO BID initially; after 7 days,

increase to maintenance dose of

240 mg BID

of 26

Dimethyl fumarate (TECFIDERA) is

an orally administered fumarate ester FDA

approved for first-line monotherapy of multiple

sclerosis in 2013. Because it is rapidly and

completely hydrolyzed by esterases before

reaching the systemic circulation, the

pharmacologic activity of dimethyl fumarate is due

to its active metabolite, monomethyl fumarate

of 26

Although the precise mechanism of action is

incompletely characterized, monomethyl

fumarate is thought to exert neuroprotective

effects in patients with multiple sclerosis by

activating the nuclear erythroid 2-related factor

2 (nuclear factor erythroid-derived 2-like

2; Nrf2) transcriptional pathway. Using a model

of endogenous neuronal oxidative stress

http://www.ncbi.nlm.nih.gov/gene/4780

of 26

Proposed Mechanism of Action of Dimethyl Fumarate.

Abbreviations used: ARE, antioxidant response element;

GCLC, glutamate-cysteine ligase; GSH, glutathione;

GstA2, glutathione S-transferase A2; HO-1, heme-

oxygenase-1; Nqo1, NADPH quinone oxidoreductase 1;

MMF, monomethyl fumarate; Nrf2, nuclear factor

erythroid-derived 2-related factor 2.

Comments

of 26

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

of 26

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

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

of 26

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

• Early diagnosis and treatment are important

– Significant, irreversible damage can occur early on

– Available treatments reduce the number of relapses and may slow

progression

• Treatment includes: attack management, symptom management,

disease modification, rehab, emotional support

of 26

•QUESTIONS

of 26

THANK YOU

SCLEROSIS - كلية الطب · 2019-03-06 · Slide 18 of 26 Clinically Isolated Syndrome (CIS)...

Documents

Transcript of SCLEROSIS - كلية الطب · 2019-03-06 · Slide 18 of 26 Clinically Isolated Syndrome (CIS)...