Multiple Sclerosis 2011 Update - Cleveland Clinic · Multiple Sclerosis (MS) Updates • Definition...

Oxtober 20101Confidential

Multiple Sclerosis2011 Update

Marie Namey, RN, MSN, MSCNMellen CenterNeurological InstituteCleveland ClinicCleveland , Ohio

© Cleveland Clinic 20111 DOS CNE Course 2011

Mellen Center• Opened February 8,1985

• One of the largest and most comprehensive programs for Multiple Sclerosis care and research worldwide.

• Focus on addressing physical, emotional, cognitive and rehabilitation needs of the MS patient and their families

• Provide consultative services for neurologists and patients world-wide and ongoing care for approximately 8,000 MS patients annually, including approximately 1,600 new patient/consult visits.

• Emphasis on neurorehabilitation, imaging, therapeutics and clinical research.

2 DOS CNE Course 2011

Multiple Sclerosis (MS) Updates• Definition

• Epidemiology

• Pathophysiology

• Diagnosis

• Treatments

• Monitoring Disease Activity

• Research


• Multiple sclerosis is a chronic, often disabling disease that attacks the central nervous system (CNS), which is made up of the brain, spinal cord, and optic nerves.

• Symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision.

• The progress, severity, and specific symptoms of MS are unpredictable and vary from one person to another.

• Today, new treatments and advances in research are giving new hope to people affected by the disease.

Multiple Sclerosis (MS)


MS Triggers

• Gender

• Geography

• Virus

• Trauma

• Infection

• Genetics


Epidemiology of MS

• Most common disease of CNS in young adults

• Patient characteristics – 20 to 50 years of age1

– 70% are women2 -- More women than men (ratio of 3:1)

• Incidence: 8,500 to 10,000 per year in US3

• Prevalence: 400,000 in US

• Not directly hereditary, although genetic susceptibility plays part in development

1. NMSS. National Multiple Sclerosis Society Information Sourcebook: Epidemiology. Available at: http://www.nationalmssociety.org/sourcebook.asp. Accessed March 31, 2006. 2. Anderson DW et al. Ann Neurol. 1992;31:333-336.3. Jacobsen DL et al. Clin Immunol Immunopathol. 1997;84:223-243.


World Prevalence of MS

Alonso A et al. Neurol. 2008 Jul 8 ; 71 ( 8): 129-35


Ethnicity and MS

• African Americans with MS have more severe disease course, older age at onset, more likely to have opticospinal symtoms, cerebellar dysfunction, more rapid accumulation of disabilities, than whites with MS

• Asians with MS: characteristic findings- few brain lesions but extensive spinal cord lesions, severe optic nerve disease, associated with higher female; male ratio, frequent relapses, severe disability, absent oligoconal bands in CSF, different T cell responses in relapses and remission


Paradigm Shift in View of MS

• MS is a continuous process

• Involving inflammatory myelin destruction

• Recognition of axonal destruction

• Recognition of activity of oligodendrocytes

• Monitored by MRI


Multiple SclerosisMultiple Sclerosis

• Disease that affects the central nervous system (CNS)1

• Occurs when myelin, the fatty tissue surrounding and protecting neurons, is destroyed by the body’s immune system1

• Destruction of myelin results in formation of plaques and lesions (inflammation and sclerosis)1

• MS is characterized by periodic loss of neurologic function and often progressive disability2

1. Noseworthy JH et al. N Engl J Med. 2000;343:938-952.2. Compston A et al. Lancet. 2008;372:1502-1517.


Classifications of MSRadiologically isolated syndrome (RIS)

Clinically isolated syndrome (CIS)

Clinically definite MS (CDMS)

Four established clinical courses differ by the time course of relapse and progression

Relapsing-remitting MS (RRMS) Secondary progressive MS (SPMS) Primary progressive MS (PPMS) Progressive relapsing MS (PRMS)

Goodin DS, et al. Neurology. 2002;58(2):169‐178.

Craig J, et al. J Neurol Neurosurg Psychiatry. 2003;74(9):1225‐1230.


Radiologically Isolated Syndrome (RIS)

Absence of MS symptoms

MRI taken for reasons other than MS

MRI findings highly suggestive of MS based on location and morphology in CNS

Okuda study of 44 patients with RIS over 5 years10 patients developed a CIS or CDMS; 59% showed radiologic progression over time

Question: When to treat?

Emotional/ psychological repercussions for the patient of living with a radiological diagnosis, but not a clinical diagnosis; risk of patient developing fear of the clinical disease?

Okuda DT, et al. Neurology. 2009;72(9):800‐805.


CIS = clinically isolated syndrome; MRI = magnetic resonance imaging.Frohman EM, et al. Neurology. 2003;61:602‐611. Hogancamp WE, et al. Mayo Clin Proc. 1997;72(9):871‐878. Orton SM, et al. Lancet Neurol. 2006;5(11):932‐936.

Clinically Isolated Syndrome (CIS)• Episode of neurological symptom(s) consistent with inflammation and

demyelination in the CNS

– Characterized by MRI and lab data

– Patient may or may not develop clinically definite MS

• Features of CIS suggestive of a first MS attack include

– Appropriate age; female gender

– Abnormal brain MRI

– Optic neuritis

– Brainstem/cerebellar dysfunction

– Myelitis


Lublin FD et al. Neurology. 1996;46:907-911.

Relapsing-remitting

Primary-progressive

Dis

abili

ty

Time

Time

Dis

abili

ty

Secondary-progressive

Progressive-relapsing

Time

Time

Dis

abili

tyD

isab

ility

Disease Courses


Therapeutic Interventions

•Relapse management

•Disease modifying agents

•Symptoms and symptom management

•Psychosocial issues


Philosophy of MS Care

•Acute, symptomatic and rehabilitative care remain the mainstays of care

•A wellness approach incorporates other systems of care (primary services, preventive measures, focus on education)

•The MS team may be found in centers, community practices, and in centers without walls


Sensory symptoms,Lhermitte’sPainProprioception

Optic neuritis

Diplopia, VertigoDysarthriaINO

Tremor,Ataxia

Cognitive loss

Emotional disinhibition

Bladder dysfunction

Sources of MS SymptomsSources of MS Symptoms

© 2004 Serono, Inc. All rights reserved.

Symptoms vary widely in incidence and severity.


Signs and Symptoms• Generalized weakness• Visual changes• Focal muscle weakness• Fatigue• Depression• Bowel/bladder/sexual

dysfunction• Gait problems/spasticity• Paresthesias• Heat intolerance

• Dysarthria, scanning speech, dysphagia

• Lhermitte’s phenomenon*

• Neuritic pain

• Vertigo/ataxia

• Cognitive dysfunction

• Tremor/incoordination

• Sexual dysfunction

• Depression

• Pain*Electric shock-like sensation down the spinal chord when flexing the neck


Pathology of MS

• An immune-mediated disease in genetically susceptible individuals

• Dual nature: inflammatory and neurodegenerative

• Demyelination leads to slower nerve conduction• Axonal injury and destruction are associated with

permanent neurological dysfunction• Lesions occur in optic nerves, periventricular

white matter, cerebral cortex, brainstem, cerebellum, and spinal cord


MS Triggers• Initial target is myelin

and the cells that make myelin

• Myelin is comprised of fat and protein

• Individual nerve fibers are wrapped in numerous layers of myelin


• MS is thought to be an autoimmune disease

• The breakdown of the BBB permits entry of autoreactive T cells into the CNS

• Once within CNS, T cells activate the release of multiple cytokines which directly attack the myelin, oligodendrocytes, and neuron

• This attack on the myelin creates what is known as the MS lesion

MS and the Central Nervous System (CNS)

FPO((Logo to be deleted))

Immune cells pass through blood-brain

barrier

Immune cells may reactivate and produce

cytokines

Immune cells stimulate

autoimmune attack against

myelin

1. Frohman EM et al. Arch Neurol. 2005;62:1345‐1356.


Waxman SG. N Engl J Med. 1998;338(5):323-325. Copyright © 2004 Massachusetts Medical Society. All rights reserved

NormalMyelinated

Axon

AcutelyDemyelinated

Axon

ChronicallyDemyelinated

Axon

DegeneratedAxon

Conduction restored byIncrease in density of

sodium channels

Postsynapticneuron

Sodiumchannels

Action potential

End oftransected

axon

Myelinsheath

Postsynapticneuron

Action potential

DemyelinationAxon

A

B

C

D

Overview of Demyelination


Axonal Loss in MS• Axons may be or are transected during inflammatory

demyelination

• Cortical demyelination causes axonal or dendritic transection which leads to neuronal death

• Chronic demyelination results in axonal degeneration


Axonal Damage in MS

• 50-80% axonal loss in chronic lesions (Lovas et al 2000)• Immune-mediated inflammation is continuous, even during

periods of apparent remission

Trapp, et al. N Engl J Med. 1998;338:278-285.

Transection of axons (arrows) Demyelination (arrowheads)

64 µm 45 µm


What Causes Demyelinationand Axonal Loss in MS

• Activation of T cells in the periphery

• Migration of T cells into the CNS

• Reactivation by autoantigens in the CNSReactivation by autoantigens in the CNS [myelin proteins: myelin oligodendrocyte glycoprotein (MOG), Myelin associated glycoprotein (MAG), myelinbasic protein (MBP), proteolipid protein (PLP)]

• Release of inflammatory cytokines & other effectors (eg, nitric oxide, glutamate, matrix metalloprotease) in the CNS

• B cells & other leukocytes

• Pathology

•Yong VW. Continuum: Lifelong Learning in Neurology. 2004;10(6):11-27.


Cytokine Imbalance

Normal MS

InflammatoryIFN γIL-12TNF

InflammatoryIFN- γIL-12TNF

Anti-inflammatory

IL-4IL-10TGF β

Anti-inflammatory

IL-4IL-10TGF β

Th1 Th2Th1

Th2

Prineas JW. In: Handbook of Multiple Sclerosis. 2001:289‐324.

IFN=interferon; IL=interleukin; TNF=tumor necrosis factor; TGF=transforming growth factor


Th2/Th3

MO

IL-4IL-5IL-6IL-13TGFβ

B

HistamineProteasesTNFαNAA, ATPNOO25-HT

Mast Cell

HistamineTryptase5-HTTNFα

IL-12

APCThp

CD4 CD40LCD40

IL-4 & IL-10

CD4APC

ThpCD28B7

IL-10TGFβ

Th2/Th3

CD40L

CD28B7

CD40MicTh1

B

Glutamate

γδT CD8

MMP-2/9VCAM-1ICAM-1 VCAM-1

IFNγTNFα

MCP-1MIP-1αΙP-10RANTES

Astrocyte

Ab+C

Mast Cell

γδT

Granutocyte

Complement

Monocyte

CD8

Pl

IFNγTNFα

NOOiTNFaMMP

Oligo

BBB

LFA-1 VLA-4Th1

Disease modification—understanding pathogenesis

Courtesy of Suhayl Dhib-Jalbut, MD,. 2005.

Immunopathogenesis of MSImmunopathogenesis of MS

Inflammatory Processes Occurring Early in MS Leadto Demyelination and Axonal Loss

Compston A et al. Lancet. 2008;372:1502‐1517; Kuhlmann T et al. Brain. 2002;125:2202‐2212; Paolilo A et al. J Neurol. 2004;251:432‐439; Trapp BD et al. Curr Opin Neurol. 1999;12:295‐302.

Inflammation

Regeneration

TimeOnset of Disease

Inflammation Demyelination Axonal loss


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

Natural History: Untreated MS Natural History: Untreated MS

Compston A et al. Lancet. 2008;372:1502‐1517; Noseworthy JH et al. N Engl J Med. 2000;343:938‐952;Weinshenker BG et al. Brain. 1989;112:1419‐1428; Trapp BD et al. Curr Opin Neurol. 1999;12:295‐302.

Silent Phase Relapsing-Remitting Secondary Progressive

Invisible

MRI Activity

Visible

Progressionand axonal loss


Theoretical Changes: Treated MSTheoretical Changes: Treated MS

Noseworthy JH et al. N Engl J Med. 2000;343:938‐952; Trapp BD et al. Curr Opin Neurol. 1999;12:295‐302.

Progression and axonal loss

Visible

DMT

MRI Activity

Silent Phase Relapsing-Remitting

Invisible


MS: Principles of Management• Delay progression to disability

– Cognitive and physical disability

• Reduce frequency and severity of relapses

• Treat relapses when they occur

• Manage symptoms

• Maintain functional independence

• Improve and facilitate an acceptable quality of life and promote hope


National MS Society: CIS. http://www.nationalmssociety.org/about‐multiple‐sclerosis/diagnosing‐ms/cis/index.aspx. April 8, 2009.

• Relapse is a defining clinical feature of MS

• Synonyms: – Attack – Exacerbation – Flare

• Definition:– Sudden worsening of any MS symptom or the appearance of new

symptom– Last at least 24 hours – Separated from a previous exacerbation by at least 1 month– Occur in absence of environmental, metabolic, or infectious

processes

Relapses in MS


Treatment of Relapses

• High-dose steroids

– IV methylprednisolone Various treatment regimens

– Often 1 g/day for 3–5 days with /without oral prednisone taper

– Canadian protocol: 1250 mg qod 5 doses


Burden of Disease• Physical disability

– Median time to requiring cane/crutch: 9 years1

– Median time to wheelchair confinement: 12 years1

– During relapsing-remitting stage, unresolved relapses are major contributor2

• Cognitive dysfunction – Prevalence: 43% to 65%3

– Affects employment, activities of daily living, family, and social contacts3

• Life shortening– 5- to 7-year decrease in life expectancy4,5

– 2- to 7-fold increase in suicide risk6

– ~50% of MS patients die of disease-related causes6

1. Jacobs L et al. Mult Scler. 1999;5:369‐376. 2. Confavreux C et al. Brain. 2003;126:770‐782. 3. Rao SM et al. Neurology. 1991;41:692‐696. 4. Sadovnick AD et al. Neurology. 1992;42:991‐994.5. Ebers GC. J Neurol Neurosurg Psychiatry. 2001;71(suppl 11):ii16‐ii19. 6. Sadovnick AD et al. Neurology. 1991;41:1193‐1196.


Positive Negative• Younger age at onset• Female sex• Normal MRI at

presentation• Complete recovery from

first relapse• Low relapse rate• Long interval to second

relapse• Low disability at 2 and 4

years

• Older age at onset• Male sex• High lesion load on MRI at

presentation• Lack of recovery from first

relapse• High relapse rate• Early cerebellar involvement• Short interval to second

relapse• Early development of mild

disability• Insidious motor onset

Prognostic Indicators for MS


Diagnosis—Basic Principles• Ultimately a clinical diagnosis; no definitive laboratory test

• Clinical profile

• Laboratory evaluation

• Evidence of dissemination of lesions in space and time

• Exclusion of other diagnoses


Diagnosis—History• Most important component of diagnostic process

– Suggestive of previous symptoms to establish dissemination in time

– Suggests differential diagnosis list

• Basics: Two episodes of neurological symptoms referable to the CNS separated in space and time and are not due to any other diagnosis


Assessments—Medical History• Chief complaint, obtained in patient's own words

• Chronological narrative of present illness

• Childhood or adult illnesses, psychiatric illness, injuries, surgeries, and hospitalizations

• Medications, allergies, immunizations, abnormal test results, and exposure to environmental hazards

• Exercise/leisure activities, including sleep patterns, diet, tobacco, alcohol and other substance use

• Family health

• Psychosocial situation


• Cranial nerves

• Sensory system

• Motor system and reflexes

• Cognition– Self awareness– Executive function– Verbal skills– Memory/learning

• Functional status– Ambulation– Upper extremity function

Diagnosis—Neurological Examination


Diagnosis—DifferentialInflammatory

conditionsInfections Metabolic

and geneticOther

• Systemic lupus erythematosus

• Neuromyelitis optica

• Sjøgren syndrome

• Vasculitis

• Behcet’s disease

• Sarcoidosis• Acute

disseminated encephalomyelitis

• Lyme disease

• Syphilis

• Progresive Multifocal Leukoencephalopathy (PML)

• HTLV-1b

• Herpes zoster

• Vitamin-B deficiency

• Wilson Disease

• Lysosomal disorders

• Adrenoleuko-dystrophy

• Mitochondrial disorders

• CADASILc

• Inherited ataxias

• CNS lymphoma

• Spinal diseases

• Radiation therapy

Trojano M, Paolicelli D. Neurol Sci. 2001;22:S98-S201.


• Evoked potentials (measure response of brain and/or spinal cord to stimuli)

• CSF examination (to detect presence of cellular and chemical abnormalities)

• Blood count, Lyme Titer, HIV, tests for vasculitis, heavy metal testing in urine and hair, and tests for syphilis are used to rule out other potential diagnoses

Diagnosis—Other tests


Poser CM, et al. Ann Neurol. 1983;13:227-231.McDonald WI, et al. Ann Neurol. 2001;50:121-127.Polman CH, et al. Ann Neurol. 2005;58:840-846.

• Poser criteria published in 1983– Required clinical evidence of 2 attacks occurring disseminated in

time and space

• McDonald criteria published in 2001– Reaffirms importance of diagnosis based on clinical findings– Expands role of MRI findings as an alternate method of meeting

time or space criteria

• McDonald criteria revised in 2005– Diagnosis can still be made per clinical findings– Earlier diagnosis facilitated with expanded role of MRI findings

(particularly spinal MRI findings) to meet dissemination in time or space criteria, when available

Diagnosing MS: Diagnostic Criteria


Diagnosing MS: McDonald Criteria (2005)

2005 revisions focused on 2 main areas:

Spinal cord lesionsMRI evidence of spinal cord lesions are more liberally accepted as evidence of dissemination in space

Dissemination of lesions in timeNew T2, as well as contrast-enhancing, lesions can qualify after only 1 month instead of 3 months

McDonald WI, et al. Ann Neurol. 2001;50:121-127.

These changes allow for diagnosis earlier in the course of disease with the intent of optimizing patient management and outcomes.

The ability to diagnose per clinical criteria remains unchanged.


Focus on Early Treatment• Results of CHAMPS/ETOMS studies

- autoimmune component of the disease may be more amenable to treatment during this early phase

• Secondary Progressive trials - the effect of immunomodulatory therapy is greater earlier in the disease


Risk for a Person with Clinically Isolated Syndrome Developing MS

• High Risk: When the CIS is accompanied by MRI-detected brain lesions that are similar to those seen in MS, the person has a high risk of a second neurologic event, and therefore a diagnosis of clinically definite MS, within several years.

• Lower Risk: When the CIS is not accompanied by MRI-detected lesions, the person has a lower risk of developing MS over the same time period.


Treatment for CIS

• Interferon Beta 1 a Avonex®The CHAMPS (Controlled High-Risk Subjects Avonex® MS Prevention Study) study

• Intereferon B 1 b Betaseron®The BENEFIT (Betaseron® in Newly Emerging MS For Initial Treatment) study.

• Glatiramer acetate (Copaxone ® ) PreCISe study

• Interferon beta 1 a (Rebif ®) The ETOMS (Early Treatment of MS )European study (not approved in US for CIS treatment)


• MRI demonstrates approximately 90%–95% of white matter lesions in brain

• MRI demonstrates 50%–75% lesions in spinal cord

• Looks for new or recent lesions in CNS myelin• Based upon the new criteria, MRI can be utilized to

facilitate a definitive diagnosis of MS in the absence of clinical symptom, if the following criteria are met:─A Gd-enhancing lesion demonstrated in a scan

done at least 3 months following onset of clinical attack at a site different from attack

─In absence of Gd-enhancing lesions at 3 mo scan, follow-up scan after an additional 3 months showing Gd-lesion or new T-2 lesion

Diagnosis—MRI


Gd-enhancing lesions:

BBB breakdown & InflammationTransient

T2-hyperintenselesions:

Global lesion load

Pathologicallynon-specific

T1-hypointenseT 1 Hypointense

Reversible (oedema and demyelination)

Irreversible (axonal loss)

Gd-Enhancing, T2, and T1-Hypointense Lesions

Diagnosis—Typical MRI lesions


Case Study: Katherine

– 21-year-old college senior (majoring in biology) – New onset visual loss

–Began yesterday upon awakening after a long night studying for a midterm examination

–Describes right eye pain when moving eyes–Notes reduced field of vision superiorly and “diluted”

color perception–No prior neurologic or medical history except for

intermittent fatigue


Katherine: Clinical findings

– 20/70 vision OD, 20/20 OS– Right relative afferent pupillary defect (RAPD)– Reduced color vision on the right– Fundus examination normal– Exam is otherwise normal except for brisk reflexes– Laboratory studies are all negative


Katherine: MRI

A B

Coronal fat suppressed T1 MRI with Gad (A). Note enhancement (arrow).Also note periventricular plaques on axial FLAIR MRI (B).


Every Life Deserves World Class Care

Katherine: Discussion

What is your diagnosis?


Katherine: Diagnosis and Treatment

–Diagnosis–Treatment

–Corticosteroids for the optic neuritis–Recommend a disease-modifying therapy–Adherence–Surveillance strategy (clinical, labs, MRI, ADLs)


Katherine: Outcome at 2 years

–After 2 years on injectable medication

–Katherine has been attack free–Independent for all activities of daily living and feels

well–MRI assessed yearly has been stable except for 1

small new lesion in 2 years–Neurologic exam is normal except for some right

optic disc pallor


Goals of MS Disease Management

• Treat/manage relapses

• Modify the course of disease–Relapses, disability

• Manage symptoms

• Improve QoL


Trapp BD, et al. N Engl J Med. 1998;338(5):278-285. Ruiz-Peňa JL, et al. BMC Neurol. 2004;4:8. Losseff NA, et al. J Neurol. 2001;248(6):517-521. De Stefano N, et al. Arch Neurol. 2001;58(1):65-70. Ferguson B, et al. Brain.1997;120(Pt 3):393-399. Filippi M, et al. Brain. 2003;126(Pt 2):433-437. Coyle PK, et al. Mult Scler. 2002;8(1):2-9. Narayanan S, et al. J Neurol. 2001;248(11):979-986.

The Importance of Early Effective Treatment

• MS may be active in the brain and spinal cord in the absence of clinical symptoms

• Lesions may occur early and may be associated with irreversible damage

• Evidence suggests that degenerative changes can occur in normal-appearing white matter

• Damage can lead to permanent disability

• Starting effective treatment early may help slow the accumulation of damage


Currently Approved Therapies for MS• Interferon (IFN)

– IFNβ-1b (Betaseron,Extavia)– IFNβ-1a IM (Avonex)– IFNβ-1a SC (Rebif)

• Glatiramer acetate (GA) (Copaxone)

• Mitoxantrone (Novantrone)

• Natalizumab (Tysabri)

• Gilenya (Fingolimod)


Disease Modification—Injectable Agents

IFN β-1b(Betaseron®)(Extavia ®)

• Relapsing-remitting MS

• SC every other day

• Reconstitution

• Prefilled syringe

• Autoinjector

IFN β-1a(Avonex®)


• IM once weekly

• Reconstitution

• Premixed syringe

Glatiramer acetate

(Copaxone®)• Relapsing-

remitting MS

• SC every day

• Reconstitution

• Prefilled syringe

• Autoinjector

IFN β-1a(Rebif®)


• SC TIW

• Reconstitution


• Autoinjector

IFN=interferon

SC=subcutaneous

IM=intramuscular

TIW=three times weekly)


Disease Modification—Side EffectsIFN β-1b

(Betaseron®)

• Flu-like symptoms

• Injection site reactions

• Allergic reactions*

• Depression*

• ↑ Liver enzymes*

• ↓ WBC*

IFN β-1a(Avonex ®)


• Depression*

• Mild anemia*


• ↑ Liver enzymes*


Glatiramer acetate

(Copaxone ® )


• Post-injection reaction†*

• Vasodilation*

IFN β-1a(Rebif®)



• Liver abnormalities*

• Depression*


• Low RBC/WBC**Rare †Includes anxiety, chest pain, palpitations, shortness of breath, and flushing

WBC=white blood cell count; RBC=red blood cell count


Mechanism of Action of DMTs—Interferons• Anti-proliferative effect

• Down-regulation of HLA-class II

• Apoptosis of autoreactive T-cells

• IFN-gamma antagonism

• Induction of cytokine shifts (Increased IL-10, Decreased IFN-gamma and IL-12)

• Decreased VLA-4 on T-cells and increase in sVCAM

• Inhibition of MMPs

• Possible anti-viral effect

Dhib-Jalbut, S.. Neurology 2002;58(8 Suppl 4): S3-S9.Graber J, Zhan M, Ford D, et al. J Neuroimmunol 2005;161(1-2): 169-176.


Mechanism of Action of DMTs—Glatiramer acetate

• Binds to human leukocyte antigen (HLA) Class II molecules on an antigen-presenting cell and recognition by the T-cell receptor1

• Systemic effects include:2

− Competition with myelin antigens binging to the HLAclass II molecules

− T-cell receptor modulation− Induction of anergey in myelin reactive T-cells

• Results in the expansion of the pool of anti-inflammatory Th2 cells.

1. Dhib-Jalbut, S. Neurology 58(8 Suppl 4): S3-S9. 2. Gran B, et al. Neurology, 2000, 55:1704-1714.


Hartung HP, et al. Lancet. 2002;360(9350):2018-2025. Physicians’ Desk Reference. 62nd ed. Montvale, NJ: Thomson PDR; 2008.

Mitoxantrone: FDA-Approved for Worsening RRMS, SPMS, and PRMS

• Synthetic anthreacenedione derivative, originally used inthe treatment of malignant diseases

• Approved for SPMS and worsening relapsing MS

• Reduces exacerbations, disability progression, and MRI activity

• Given IV 12 mg/m2

every 3 months

• Lifetime dose: 140 mg/m2

• Cardiotoxicity limits lifetime dosing

• Other risks: infections, sterility, secondary leukemia

• Side effects: nausea, vomiting, alopecia


.

Natalizumab

Natalizumab (Tysabri®) -- monoclonal antibody that selectively inhibits an adhesion molecule, alpha4beta1 integrin1,2

-Inhibits adhesion of activated lymphocytes to blood vessel endothelium– Restricts trafficking of lymphocytes into the CNS– Approved initially in 2004 for RRMS; however, two deaths in

clinical trial participants due to PML led to the voluntary withdrawal from marketing and distribution3

• Decreases exacerbations, disability progression, and MRI activity

• Given IV q4w

1. Tubridy NP, Behan, O, et al. Neurology 1999;53(3): 466-472.2. Elices, MJ. Current Opinion in Investigational Drugs. 2003; 4:1354-1362.3. Engelhardt B, Briskin Eur J Immunol. 2005;35(8):2268-2273.4. Tysabri® (natalizumab) Prescribing Information. Biogen Idec Inc.

Polman CH, et al. N Engl J Med. 2006;354(9):899-910


Slide courtesy of Heidi Maloni PhD, ANP. Hughes SC. Anesth Clin N Am. 2004;22(3):379-404.

PML

• Rare, progressive, demyelinating disease of CNS (1:200,000 in the United States)

• Lytic infection of oligodendrocytes by JC virus, a human polyomavirus

• Often fatal within 6 months of diagnosis

• Reactivates in settings of profound immunosuppression

• Primarily affects immunocompromised (HIV, transplant, hematologic malignancy)


MRI

Slide courtesy of Heidi Maloni, PhD, ANP.

PML MS


Fingolimod (GilenyaTM)Sphingosine-1P (S-1P) receptor modulator

Blocks lympocyte egress and migration from nodes

Approved for RRMS 9/10.

Key Safety Issues– Hepatic enzyme elevation– Hypertension– Cardiac abnormalities (eg, bradycardia, AV block)– Malignancies– Herpes viral infections– Macular edema


Nursing tasks

Universal MS-specific• Therapeutic

relationship

• Comprehensive assessment

• Collaborative treatment plan

• Full knowledge of disease

• Empowerment

• Advocacy


Disease Modifying Therapy—Selection

• Factors that influence choice of therapy– Clinical subtype– Disease duration– Prognostic profile– Clinical disease severity (relapse rate, type of relapse, extent of

recovery, disability)– MRI disease severity– Comorbidity– Lifestyle preferences– Ability to self-inject– Compliance– Lifestyle


Making Treatment DecisionsMaking Treatment DecisionsConsidering the Benefits and RisksConsidering the Benefits and Risks

Evidence based

approach

MOA

Response

Physician experience

Patient preference Cost

Pregnancy issues

Monitoring

Convenience

TolerabilitySafety

Treatmentdecisions


How to MeasureProgression of Disease in MSWell-defined methods

• Relapses

• Disability Rating ScalesExpanded Disability Status Scale (EDSS )Multiple Sclerosis Functional Composite (MSFC)

• MRI changesGadolinium-enhancing lesions (T1-weighted)Measurement of brain atrophy (using visual analysis of MRI data to estimate brain

atrophy)

Other methods under development– Optical coherence tomography (a structural biomarker)– Visual evoked potentials – Biologic markers


Disease Modification— Assessing Outcomes: Relapses

Relapses

Notable Worrisome Actionable

Frequency/severity 1 mild 1 moderate/year >6 mo after start of therapy

>1 moderate or 1 severe/year >6 mo after start of therapy

Recovery Rapid following prompt steroid Rx

Slow following prompt steroid Rx

Incomplete recovery

Bashir K, Buchwald L, Coyle PK, et al. Int J MS Care. 2002; 4(suppl), 1-7.


Disease Modification— Assessing Outcomes: Progression

Progression


EDSS <3.5 <2 point change

2 point change >2 point change

EDSS >4 <1 point change

1 point change >1 point change

Clinically documented progression

No motor; minor sensory

Some motor, cognitive, or more pronounced sensory

Pronounced motor, cognitive, sensory

Bashir K, Buchwald L, Coyle PK, et al. Int J MS Care. 2002;4 (suppl), 1-7.


7 8 9 10

m=metersKurtzke JF. Neurology. 1983;33(11):1444‐1452.

Increasing Disease Burden

0 1 2 3 4 5 6

Normalneurologicexam

No disability

Minimaldisability

Moderate disability

Fully ambulatory; severe disability

Ambulatory without aid 200 m

Ambulatory with unilateral assistance 100 m

Wheelchair

Bedridden

Helpless

Death due to MS

EDSS Score

Level o

f Disab

ility

Expanded Disability Status Scale (EDSS)


Cutter GR, et al. Brain. 1999;122(Pt 5):871‐882.

Multiple Sclerosis Functional Composite

Clinical Dimension Test Name Measurement MetricArm 9-hole peg test Mean of right and left

arm scoresTime to insert and remove 9 pegs

Leg Timed walk A walk of 25 ft Time taken in seconds

Cognitive PASAT Paced auditory serial addition test, 3 min version

Number correct


MS Functional Composite

• Developed for use in clinical trials

• Individual components used in clinical practice:– Timed 25-Foot Walk

–Quantitative mobility and leg function performance test

– 9 Hole Peg Test–Quantitative test of upper

extremity function– Paced auditory serial addition

test (PASAT)– Measure of cognitive

function

1. Cutter GR, Baier ML, Rudick RA, et al. Brain. 1999 May;122 ( Pt 5):871-882.2. National Multiple Sclerosis Society. http://www.nationalmssociety.org/MUCS_25foot.asp. Last updated SeptembeAccessed

September 1, 2005.


Disease Modification—Assessing Outcomes: MRI

MRI


New Gd-enhancing lesions

New T2 lesions

Enlarging T2 (burden of disease)

Change in 2 categories

Change in 3 categories Change in >3 categories

New T1 hypointense lesions

Enlarging T1 hypointense lesions

Increased atrophy

Bashir K, Buchwald L, Coyle PK, et al. Int J MS Care. 2002; 4(suppl), 1-7.


Freedman MS, et al. Can J Neurol Sci. 2004;31:157-168.

Suboptimal Response to DMTs

• Response to DMTs is highly variable

• DMTs may become ineffective as the disease progresses; why?

• MS is a heterogeneous disease with great variability in clinical presentation and underlying pathology

• 1 DMT might work while others may not


Freedman MS, et al. Can J Neurol Sci. 2004;31:157-168. Freedman MS, et al. Mult Scler. 2008;14(9):1234-1241.

Signs of Worsening MS

• Increasing disability without relapses

• Increasing relapses without return to baseline

• Decreased cognitive function

• Increasing MRI activity

• Increased use of MS-related medicines to control symptoms

• Decline in activities of daily living and Quality of Life


Motl RW, et al. Int J MS Care. 2008;10:(Suppl 1):26. Harris C, et al. Int J MS Care. 2003;5(3):67-78.

Addressing QoL

• Individualized care is critical to treating the inter-relatedness of:

– Neurological symptoms

– Side effects of therapies

– Adherence to therapies

• DMTs must be part of the treatment plan as they can alter the course of MS

• Symptoms need to be aggressively managed as they negatively impact QoL

• Care must be comprehensive and culturally sensitive


On the Horizon

New Imaging TechniquesNew Treatments


DTI = diffusion tensor imaging ; fMRI = functional MRI.

New Imaging Techniques

• MR spectroscopy

• DTI

• High-field strength MRI

• fMRI


NAA = N-acetylaspartate.Giacomini PS, et al. Curr Opin Neurol. 2008;21(3):272-277. Tedeschi G, et al. Neuroradiology. 2002;44:37-42.

MR Spectroscopy

• Looks at various CNS metabolites

• NAA is a marker of neuronal and axonal integrity

• NAA is decreased in MS, especially in progressive MS

• Potential use in MS treatment trials to measure neuroprotection

NAA

Glx Cre

Cre Cho GlxGABA Lac

m-Ino

4.0 3.0 2.0 1.0 0.0

(Ppm)


Slide courtesy of Peter Calabresi, MD.

DTI- Diffusion Tensor Imaging

• Measures the diffusion of water molecules in tissues

• Enables diffusion to be measured in multiple directions and the fractional anisotropy in each direction to be calculated

• With this technique, areas of neural degeneration and demyelination can be visualized and quantified

• Allows for visualization of very early changes caused by MS


Wattjes MP, et al. Neuroradiology. 2009;51(5):279-292.

High-Field-Strength MRI

• High strength magnet 3-8 Tesla

• Ability to visualize more MS pathology

• Ability to visualize gray matter pathology


Rocca MA, et al. Neuroimaging. 2007;17(Suppl 1):36S-41S. Rocca MA, et al. Neuroimag. 2004;18:847-855. Pantano P, et al. Brain. 2005;128(9):2146-2153.

fMRI

• fMRI provides information about brain plasticity, which follows MS inflammation and damage

• Demonstrates areas of brain activation

• fMRI demonstates the recruitment of regions, which are not typically activated in healthy controls for a given task

Control CIS Patient

Right Upper Ext Motor Task


Ampyra™ (dalfampridine) Prescribing Information, Acorda Therapeutics, Inc. Montalban X, et al. Mult Scler. 2008;14(Suppl 1):S29. O’Connor P, et al. Mult Scler. 2008;14(Suppl 1):S29. Wegner C, et al. Mult Scler. 2008;14(Suppl 1):S29. Gold R, et al. Mult Scler. 2008;14(Suppl 1):S29. Kuckert S, et al. Mult Scler. 2008;14(Suppl 1):S29. Noismith R, et al. Mult Scler.. 2008;14(Suppl 1):S29. Neyer L, et al. Mult Scler. 2008;14(Suppl 1):S29. Guarnaccia JB, et al. Mult Scler. 2008;14(Suppl 1):S29.

New Treatments for MS

Symptomatic Therapy• 4-aminopyridine

– FDA-approved January 2010

– Symptomatic treatment– Oral treatment to

improve walking in patients with MS

Disease Modification• Fingolimod (oral)approved 9/10

• Cladribine (oral)

• Laquinimod (oral)

• BG-12 (oral)

• Alemtuzumab (IV)

• Rituximab (IV)

• Daclizumab (IV)


AGENTAGENT MECHANISMMECHANISM ROUTEROUTE PHASEPHASE

RituxanRituxan Anti CD20Anti CD20 IV (2 x year)IV (2 x year) Phase II/IIIPhase II/III

CampathCampath Anti CD52Anti CD52 IV (1 x year)IV (1 x year) Phase II/IIIPhase II/III

DaclizumabDaclizumab Anti CD25Anti CD25 IV or SC (q month)IV or SC (q month) Phase IIPhase II

TeriflunomideTeriflunomide immunomodulatorimmunomodulator oraloral Phase IIIPhase III

Statins Statins immunomodulatorimmunomodulator oraloral Phase IIPhase II

TeriflunomideTeriflunomide immunomodulatorimmunomodulator oraloral Phase IIIPhase III

FingolimodFingolimod immunomodulatorimmunomodulator oraloral Phase IIIPhase III

CladribineCladribine immunosuppressantimmunosuppressant oraloral Phase III competedPhase III competed

LaquinomodLaquinomod immunomodulatorimmunomodulator oraloral Phase IIIPhase III

EstriolEstriol immunomodulatorimmunomodulator oraloral Phase IIPhase II

FumarateFumarate immunomodulaorimmunomodulaor oraloral Phase IIIPhase III

MBP 8292MBP 8292 immunomodulatorimmunomodulator IV (q month)IV (q month) Phase IIIPhase III

Therapeutic Agents Under InvestigationTherapeutic Agents Under Investigation


MS PipelineDifferent therapeutic approaches

CURE

Preclinical

Phase I

Phase II

Phase III

Market

TysabriIFNßs

Glatirmer acetate T cell vaccine

Protein-based therapeutics

AntimetabolitesOral treatments

AlemtuzumabRituximab

IFN tauAnti-IL12/23

Anti-CCR2Anti-CD52

Anti-Cholinergic peptides

MBP8298

Anti-IL12

CladribineToposimeraseinhibitor

Laquinimod

Fumaric esters

FTY-720Teriflunomide

K+ Channel blocker

JNK inhib MMP12 inhib

BIRT258B4XX

CCR2 antag CCR1 antag

mTOR inhibAMPA blocker

After Pr. G. Comi

tetracyclines

Mitoxantrone

Other

Stem cell therapies


MS Treatment Pipeline

IFNβ-1b

1993

BG-12

Laquinimod

Alemtuzumab

>2012

Fingolimod

2011

Fampridine

Cladribine

2010

GA

IFNβ-1a IM

1996

Mitoxantrone

2000

IFNβ-1a SC

2002

Natalizumab

2006

IFNβ-1b(Extavia®)

2009


Summary

• MS is a complex disease of the CNS

• Early treatment is important for long-term outcomes

• Many DMTs are currently available, with several promising treatments in late-stage development

• Nurses play a unique role in comprehensive management– Assessment, education, counseling, symptom management– Improvement in QoL


Thank you for your attention……


Multiple Sclerosis 2011 Update - Cleveland Clinic · Multiple Sclerosis (MS) Updates • Definition...

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