multiple sclerosis : principles,& treatment presented by: mehran homam

Multiple Sclerosis:Multiple Sclerosis:

Principles,& treatment

Presented By:

Mehran Homam

1-Overreview1-Overreview

Multiple Sclerosis OverviewMultiple Sclerosis Overview

- Chronic, inflammatory, demyelinating disease its not common

- Affects the myelin sheath and axons of the Central Nervous System (CNS)

- Progressive clinical or subclinical course

- Common cause of disability in young adults

MS Overview

What is Multiple Sclerosis (MS)?What is Multiple Sclerosis (MS)?

MS causes nerve damage over time Ms is not a common disease

MS is not considered fatal, but it affects everyone differently

You’re not alone Worldwide, 2.5 million people have MS

MS currently affects 400,000 Americans

Incidence & prevalence in iran is not clear

Every week, 200 new people are diagnosedin the US

Piere Marie Charcot Piere Marie Charcot

This disease without his name is meaningless

His descriptions about disease is very precise

2-Ethiology2-Ethiology

Is MS a Hereditary Disease?Is MS a Hereditary Disease?

Genetic factors First- and second-degree relatives are at

increased risk

Risk is higher in siblings

– Nontwin siblings (2%)– Monozygotic twins (30%)– Dizygotic twins (2.3%)

Susceptibility gene Major histocompatibility

complex (MHC) on chromosome 6

Source: http://www.msfacts.org/info/info_faq.html, http://www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm#54263215 and http://www.nationalmssociety.org/Sourcebook-Epidemiology.asp. Accessed May 17, 2006

MS plaques contain MS plaques contain

- Complement

- Immunoglobulins

- (These indicate disruption of BBB and local production of Ig)

-TFN(gamma) TNF, IL-2

There is strong evidences that it has immunological base1-CSF changes (cells;oligoclonal bands) 2-Response to immunomodulators3-Specific HLA

1. Research into the Causes of MS1. Research into the Causes of MS

Geneticfactors

Immunologicalfactors

Environmentalfactors

MS

3-The Biology of MS3-The Biology of MS

The Biology of MSWhat does the central

nervous system do?What does the central nervous system do?

The central nervous system (CNS) consists of the:1

Brain

Spinal cord

Optic nerves

The CNS is the body’s command center. It interprets sensory information and sends commands to muscles3

Spinal Spinal cordcord

BrainBrain

The Biology of MS

How does the CNS work?How does the CNS work?

Messages travel to and from the CNS through nerve cells3

Myelin surrounds the nerve fibers, protecting them like the coating of a wire1

Nerve Cell

Nerve fibers (or axon)

MyelinNerve fibers (or axon)

Cell body

Myelin

How could autoimmune responses cause MS?How could autoimmune responses cause MS?

The Biology of MS

How does MS affect the CNS?How does MS affect the CNS?

In MS, cells of the immune system attack myelin and can cause permanent damage3

Areas where myelin has been damaged interrupt communication

Exposed nerve fibers are severed, causing permanent damageNerve Cell

Axonal Transection in Acute MS LesionsAxonal Transection in Acute MS Lesions

Reprinted from Trapp BD et al. N Engl J Med. 1998;338:278-285. Copyright 1998 Massachusetts Medical Society. .

The Biology of MS

How is MS monitored?How is MS monitored?Magnetic Resonance Imaging (MRI) detects areas of inflammation (active lesions) and areas of permanent damage in the brain1

MRI showing no signs of damage

MRI showing an active lesion*

MRI showing permanent damage

Active lesion

Permanent damage

These images may also help detect “silent” damage (lesions detected by MRI that do not result in symptoms)1

The impact of this damage depends on the destructiveness of the lesion and where itis located

*The exact relationship between MRI findings and the clinical status of patients is unknown.

4-Pathophysiology4-Pathophysiology

NORMAL CONDUCTIONNORMAL CONDUCTION

ABNORMAL CONDUCTION

mechanismmechanism

Inflammation and Axonal TransectionInflammation and Axonal Transection

DiseaseStage

Main Component

Main Clinical Outcome

Early Inflammation and demyelination Relapses

Late Atrophy, axonal loss, and Disability increasing tissue destruction(less Gd-defined inflammation,

demyelination ongoing)

MSpathophysiology

What does the effect in central nervous system What does the effect in central nervous system

1-All the symptoms are upper motor

2-Dissamination in time & space

2-Conduction block is cause of fatigue

3-Agrravation with heat

4-remyelination is not perfect

5-plaques could be in silent areas

Immunological pathological physiologic clinical

Treatment GoalsTreatment Goals

Reduce (control) relapses

Delay disease progression

Delay disability

Alleviate symptoms

Early TreatmentEarly Treatment

The National MS Society recommends:

“Initiation of therapy with an immunomodulator is advised as soon as possible following a definite diagnosis of MS with a relapsing course, and may be considered for selected patients with a first attack who are at high risk for MS.”

Source: Recommendation of the Executive Committee of the Medical Advisory Board of the Nat’l MS Society www.nationalmssociety.org/Sourcebook-Early.asp. Accessed May 17, 2006.

Current Therapies: Immunosuppressants and ImmunomodulatorsCurrent Therapies: Immunosuppressants and Immunomodulators

Corticosteroids

Interferons : Betaseron (interferon -1b)

Avonex (interferon -1a)

Rebif (interferon -1a)

Immunosuppressants and immunomodulators: Copaxone (glatiramer acetate)

Novantrone (mitoxantrone)

Symptomatic management

CorticosteroidsCorticosteroids

Symptomatic management

Used in moderate-to-severe exacerbations

IV methylprednisolone 500 mg/day for five days followed by oral prednisone (optional)

Hasten clinical recovery

Delay recurrence of neurologic events

Does not alter the course of MS

Interferon BetaMechanism of ActionInterferon BetaMechanism of Action

Reduce the production of the TNFa , known to induce damage to myelin

Reduce inflammation by: Switching cytokine production from type 1 (pro-

inflammatory) to type 2 (anti-inflammatory) cells

Decrease antigen presentation, to reduce the attack on myelin

Reduce the ability of immune cells to cross the blood-brain barrier,

Interferons : Avonex (Interferon -1a)Interferons : Avonex (Interferon -1a)

Indication: relapsing forms of MS

Dose: 30 mcg IM once weekly

Reduces rate of clinical relapse

Reduces the development of new lesions

May delay progression of disability

Avonex-lyo-vial

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Interferons : RebifInterferons : Rebif

Interferon -1a

Indication: relapsing/remitting forms of MS

Dose: 22 or 44 mcg SC 3 times per week

Decreases frequency of relapse

Delays the increase in the volume of lesions

May delay progression of disability

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Interferons : Betaseron (interferon beta-1b)Interferons : Betaseron (interferon beta-1b)

Indication: Relapsing forms of MS

Dose: 8 million IU SC every other day

Reduces rate of clinical relapse

Reduces the development of new lesions

Delays the increase in the volume of lesions

This page contains prescription brand drugs that are registered or registered trademarks of pharmaceutical manufacturers that are not affiliated with Caremark.

Side Effects of InterferonsSide Effects of Interferons

Common:

Flu-like symptoms

Chills

Fever

Muscle aches

Asthenia (weakness)

Betaseron and Rebif have injection site reactions

Uncommon:

Severe depression

Suicide

Seizures

Cardiac effects

Anemia

Elevated liver enzymes

Severe hepatic injury, including cases of hepatic failure, has been reported in patients taking Avonex

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Noninterferons: Copaxone (glatiramer acetate) PFSNoninterferons: Copaxone (glatiramer acetate) PFS

Indication: Reduction of frequency of relapses in patients with RRMS

Dose: 20 mcg SC once daily

Reduces the frequency of exacerbations

Moderately reduces the development of new lesions

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Copaxone Mechanism of ActionCopaxone Mechanism of Action

Synthetic chain of four amino acids

Structurally resembles the myelin basic protein molecule

Believed to block the immune system from attacking myelin

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Auto InjectorsAuto Injectors

autoject® 2 for glass syringeDispenses Copaxone

Rebiject®

Dispenses Rebif

autoject® 2.25Dispenses Betaseron

All provided free from manufacturer. Rebiject and Copaxone need a prescription.This page contains prescription brand drugs that are registered or registered trademarks of pharmaceutical manufacturers that are not affiliated with Caremark.

Antineoplastics:Nonantrone Antineoplastics:Nonantrone

Indication: Reduction of relapse rate and clinical disability in patients with SPMS, PRMS or worsening RRMS

Dose: 12 mg/m2 as short IV infusion (five minutes to 15 minutes every three months)

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Antineoplastics: Novantrone (cont.)

Antineoplastics: Novantrone (cont.)

Reduces exacerbation rate

Prolongs time to first treated relapse

Improves EDSS scores versus baseline

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NovantroneMechanism of ActionNovantroneMechanism of Action

Inhibits or prevents the development of any uncontrolled new or abnormal growth, such as a neoplasm or tumor

Suppresses B-cell and T-cell immunity

This page contains prescription brand drugs that are registered or registered trademarks of pharmaceutical manufacturers that are not affiliated with Caremark.

NovantroneSide EffectsNovantroneSide Effects

Moderate to severe Bone marrow suppression

– Neutropenia (decreased WBC and ANC)– Thrombocytopenia (decreased platelets)– Acute myelogenous leukemia

Cardiac toxicity

– Congestive heart failure (CHF)– Decreased left ventricular ejection fraction (LVEF) – Maximum cumulative dose 140 mg/m2

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NovantroneSide EffectsNovantroneSide Effects

Moderate to severe Teratogenic effects

– Fetal growth retardation in rats– Shortened gestation period– Excreted in breast milk

Mild to moderate Increased liver enzymes

Nausea

Alopecia (hair loss - transient)

This page contains prescription brand drugs that are registered or registered trademarks of pharmaceutical manufacturers that are not affiliated with Caremark.

NovantroneContraindicationsNovantroneContraindications

LVEF < 50%

CHF

Baseline neutrophil count < 1500 cells/mm3

Pre-existing myelosuppression

Abnormal LFT

Pregnancy, breastfeeding

Cumulative lifetime dose 140 mg/m2

This page contains prescription brand drugs that are registered or registered trademarks of pharmaceutical manufacturers that are not affiliated with Caremark.

ImmunosuppressantsImmunosuppressants

Show only slight evidence of benefit in MS

Used only for progressive MS

Associated with serious side effects Thiopurines (Imuran)

Methotrexate

Alkylating agents (Cytoxan)

Cyclosporine

This page contains prescription brand drugs that are registered or trademarks of pharmaceutical manufacturers that are not affiliated with Caremark.

Symptomatic TreatmentsSymptomatic Treatments

Problem Symptoms Management

Spasticity Painful spasms in the lower and upper limbs

Remove irritating factors Physical therapy, baclofen, diazepam, dantrolene

Paroxysmal phenomena Trigeminal neuralgia, pain, tonic seizures

carbamazepine, Neurontin, phenytoin

Fatigue Feeling tired (morning or early afternoon)

Energy conservation, amantidine

Depression Common, occurs in high percentage of patients

Anti-depressants

Sexual dysfunction Inability to produce/ sustain an erection

Behavioral therapy Viagra, Muse

Urinary dysfunction Urgency, frequency and retention

Detrol, Ditropan, Botox

ConclusionConclusion

Early treatment may delay disability and enhance recovery from relapses

Treatment must be a cooperative effort between multidisciplinary team of healthcare providers

Medications are not a cure for MS

ChallengesChallenges

Challenges for the person with MS Physical difficulties

Financial concerns

Social issues

Emotional issues

Resources and LinksResources and Links

Support/Information National MS Society (NMSS) 1-800-FIGHT-MS

Consortium of MS Centers 1-201-837-0727

MS Foundation 1-800-441-7055

MS Association of America 1-800-833-4MSA

5-Summary5-Summary

ConclusionConclusionConclusion

1-Multiple sclerosis is not a common Disease

2-It’s the result of Different mechanisms

3-the most probable mechanism is immunological

Its clear that effective treatments depends on better undrestanding of mechanisms