MULTIPLE SCLEROSIS MULTIPLE SCLEROSIS (MS)(MS)

CASE STUDY CASE STUDY

• 30 year old white female presents to family physician 30 year old white female presents to family physician with acute loss of vision in left eyewith acute loss of vision in left eye

• Referred to neurologistReferred to neurologist> Diagnosis of optic neuritisDiagnosis of optic neuritis> Treated with IV corticosteroids for 5 daysTreated with IV corticosteroids for 5 days

– Normal vision over next 3 weeksNormal vision over next 3 weeks> Family history (mother)Family history (mother)> Magnetic resonance imaging (MRI) Magnetic resonance imaging (MRI)

– Multiple lesions in white matter of brain under cortex and Multiple lesions in white matter of brain under cortex and around ventriclesaround ventricles

CASE STUDY CASE STUDY

• 3 years later3 years later> Muscle weakness on left side of face and fatigueMuscle weakness on left side of face and fatigue> Radiology (MRI with gadolinium)Radiology (MRI with gadolinium)

– New lesions in left middle cerebellar peduncle and ponsNew lesions in left middle cerebellar peduncle and pons> Laboratory (CSF from lumbar puncture)Laboratory (CSF from lumbar puncture)

– 12 lymphocytes/uL12 lymphocytes/uL– IgG index of 1.2IgG index of 1.2– Oligoclonal bands (high resolution protein electrophoresis) Oligoclonal bands (high resolution protein electrophoresis)

• 2 bands in gamma region of CSF and no bands in gamma region of serum2 bands in gamma region of CSF and no bands in gamma region of serum

> Diagnosis of MSDiagnosis of MS> Treatment with 5 day course of IV methylprednisolone and Treatment with 5 day course of IV methylprednisolone and

weekly IM interferon-beta (Avonex)weekly IM interferon-beta (Avonex)

CASE STUDY CASE STUDY

• 3 years later3 years later> Clinical symptomsClinical symptoms

– Weakness in left hand and left legWeakness in left hand and left leg– Slurred speech, nystagmus, ataxia and fatigueSlurred speech, nystagmus, ataxia and fatigue

> LaboratoryLaboratory– Myelin basic protein (serum)Myelin basic protein (serum)

• 3.4 ng/mL [< 1.5 ng/mL]3.4 ng/mL [< 1.5 ng/mL]

> TreatmentTreatment– 5 day course of IV methylprednisolone5 day course of IV methylprednisolone– Weekly IM interferon-beta (Avonex) continuedWeekly IM interferon-beta (Avonex) continued

CASE STUDY CASE STUDY

• Eight months laterEight months later> Clinical symptoms recurredClinical symptoms recurred> LaboratoryLaboratory

– Myelin basic protein (serum)Myelin basic protein (serum)• 4.1 ng/mL [< 1.5 ng/mL]4.1 ng/mL [< 1.5 ng/mL]

> TreatmentTreatment– IFN-beta (Avonex) stoppedIFN-beta (Avonex) stopped– High dose IV methylprednisolone and cyclophosphamide (Cytoxan) High dose IV methylprednisolone and cyclophosphamide (Cytoxan)

monthly for 3 months then quarterlymonthly for 3 months then quarterly> Following 9 months therapyFollowing 9 months therapy

– Asymptomatic Asymptomatic – No new lesions on gadolinium MRINo new lesions on gadolinium MRI

MULTIPLE SCLEROSIS (MS)MULTIPLE SCLEROSIS (MS)

• Chronic unpredictable disease of CNSChronic unpredictable disease of CNS> Tends to follow certain patterns (clinical courses)Tends to follow certain patterns (clinical courses)> Initial symptoms 20 to 40 yearsInitial symptoms 20 to 40 years> Not contagiousNot contagious> Rarely fatalRarely fatal

• Autoimmune diseaseAutoimmune disease

• Characterized by patches (plaques) of demyelination Characterized by patches (plaques) of demyelination and inflammation of myelin sheath of axons and and inflammation of myelin sheath of axons and degeneration of axons in white matter of CNSdegeneration of axons in white matter of CNS

ETIOLOGY OF MULTIPLE ETIOLOGY OF MULTIPLE SCLEROSIS (MS)SCLEROSIS (MS)

• Complex with multiple causal factorsComplex with multiple causal factors• Environmental agentsEnvironmental agents

• Chemicals (organic solvents)Chemicals (organic solvents)• UV lightUV light

• Infectious agentsInfectious agents• VirusesViruses

• EBV, HH-6, measles virus, CDV, HERVEBV, HH-6, measles virus, CDV, HERV• BacteriaBacteria

• Chlamydophila pneumoniaeChlamydophila pneumoniae• Genetic predispositionGenetic predisposition

• HLA-DR2HLA-DR2• IL-2R and IL-7 receptor mutationsIL-2R and IL-7 receptor mutations

EPIDEMIOLOGY OF MULTIPLE EPIDEMIOLOGY OF MULTIPLE SCLEROSISSCLEROSIS

• Female to male ratio of 2:1Female to male ratio of 2:1

• Prevalence of 1 case per 750/1000 populationPrevalence of 1 case per 750/1000 population> Northern EuropeNorthern Europe> Continental North AmericaContinental North America

– 350,000 to 400,000 in US350,000 to 400,000 in US> Australia (SE) and New ZealandAustralia (SE) and New Zealand

• Incidence in US of 200 to 300 cases/weekIncidence in US of 200 to 300 cases/week

• Disease prevalenceDisease prevalence> Caucasians > African Americans > AsiansCaucasians > African Americans > Asians

EPIDEMIOLOGY OF MULTIPLE EPIDEMIOLOGY OF MULTIPLE SCLEROSIS (MS)SCLEROSIS (MS)

• Hemisphere gradients for prevalenceHemisphere gradients for prevalence> North to south in northern hemisphereNorth to south in northern hemisphere> South to north in southern hemisphereSouth to north in southern hemisphere

• Prevalence gradients in Northern HemispherePrevalence gradients in Northern Hemisphere> North of 37North of 37thth parallel (125 cases/100,000 population) parallel (125 cases/100,000 population)> South of 37South of 37thth parallel (70 cases/100,000 population) parallel (70 cases/100,000 population)

• Migration riskMigration risk> Geographic move and risk for developing diseaseGeographic move and risk for developing disease

• Disease rare or not seen in Disease rare or not seen in > Inuit, Lapps, American Indians, Aborigines, MaorisInuit, Lapps, American Indians, Aborigines, Maoris

RISK OF MULTIPLE RISK OF MULTIPLE SCLEROSIS (MSSCLEROSIS (MS))

• A 12 year old femaleA 12 year old female> Moves from Rochester, Minnesota to Moves from Rochester, Minnesota to

Miami, FloridaMiami, Florida

Risk for MS is: Increased Decreased SameRisk for MS is: Increased Decreased Same

• An 18 year old female An 18 year old female > Moves from Rochester, Minnesota to Moves from Rochester, Minnesota to

Miami, FloridaMiami, Florida

Risk for MS is: Increased Decreased SameRisk for MS is: Increased Decreased Same

PATHOPHYSIOLOGY OF PATHOPHYSIOLOGY OF MULTIPLE SCLEROSISMULTIPLE SCLEROSIS

• Destruction of Destruction of > Myelin, oligodendrocytes, nerve axonsMyelin, oligodendrocytes, nerve axons

• Hypothesis of molecular mimicryHypothesis of molecular mimicry

• AntigensAntigens> Myelin basic protein (MBP)Myelin basic protein (MBP)> Myelin oligodendrocyte glycoprotein (MOG)Myelin oligodendrocyte glycoprotein (MOG)> Proteolipid protein (PLP)Proteolipid protein (PLP)> Myelin associated glycoprotein (MAG)Myelin associated glycoprotein (MAG)

PATHOPHYSIOLOGY OF PATHOPHYSIOLOGY OF MULTIPLE SCLEROSISMULTIPLE SCLEROSIS

• CellsCells> CD4 TH1, CD4 TH2 and CD8 T cellsCD4 TH1, CD4 TH2 and CD8 T cells> Macrophages and microglial cellsMacrophages and microglial cells> Mast cellsMast cells> B cellsB cells

• Cytokines, chemokines and adhesion molecules Cytokines, chemokines and adhesion molecules – IL-12IL-12– IFN-gammaIFN-gamma– ALCAM (Activated leukocyte cell adhesion molecule)ALCAM (Activated leukocyte cell adhesion molecule)

DIAGNOSIS OF MULTIPLE DIAGNOSIS OF MULTIPLE SCLEROSIS (MS)SCLEROSIS (MS)

• McDonald Criteria (2005 Revision)McDonald Criteria (2005 Revision)

> History and clinical symptomsHistory and clinical symptoms

> RadiologyRadiology– Magnetic resonance imaging (MRI) with and without gadolinium Magnetic resonance imaging (MRI) with and without gadolinium

enhancementenhancement• Head and spinal columnHead and spinal column

> LaboratoryLaboratory– MS panelMS panel

CLINICAL SYMPTOMS OF CLINICAL SYMPTOMS OF MULTIPLE SCLEROSIS (MS)MULTIPLE SCLEROSIS (MS)

• FatigueFatigue• Visual disturbancesVisual disturbances

> Blurred vision, diplopia, nystagmus, red-green color dissociationBlurred vision, diplopia, nystagmus, red-green color dissociation• MotorMotor

> Spasticity, paresis, dysarthria, spasms, ataxia, muscle weaknessSpasticity, paresis, dysarthria, spasms, ataxia, muscle weakness• Sensory changesSensory changes

> Paraesthesia, neuralgia Paraesthesia, neuralgia • Cognitive deficitsCognitive deficits

> Memory lossMemory loss• Bladder / bowel urgency and incontinenceBladder / bowel urgency and incontinence

CLINICAL CONDITIONS CLINICAL CONDITIONS ASSOCIATED WITH MSASSOCIATED WITH MS

• Optic neuritisOptic neuritis> Inflammation of optic nerveInflammation of optic nerve

• Internuclear ophthalmoplegiaInternuclear ophthalmoplegia> Paraylsis of ocular musclesParaylsis of ocular muscles

• Transverse myelitisTransverse myelitis> Inflammation of spinal cordInflammation of spinal cord

PATTERNS (CLINICAL COURSES) PATTERNS (CLINICAL COURSES) OF MULTIPLE SCLEROSISOF MULTIPLE SCLEROSIS

• Relapsing-Remitting (85%)Relapsing-Remitting (85%)> Relaspes (attacks, exacerbations) followed by Relaspes (attacks, exacerbations) followed by

remission (rest periods)remission (rest periods)> Attack symptoms (old may flare, new may appear)Attack symptoms (old may flare, new may appear)

• Secondary Progressive (50%)Secondary Progressive (50%)

• Primary Progressive (10%)Primary Progressive (10%)

• Progressive-Relapsing (5%)Progressive-Relapsing (5%)

RADIOLOGY DIAGNOSIS OF RADIOLOGY DIAGNOSIS OF MULTIPLE SCLEROSIS (MS)MULTIPLE SCLEROSIS (MS)

• McDonald CriteriaMcDonald Criteria> 3 of 4 criteria for “positive MRI”3 of 4 criteria for “positive MRI”

– 1 gadolinium (Gd) enhancing lesion or 9 T2 1 gadolinium (Gd) enhancing lesion or 9 T2 hyperintense non-Gd enhancing lesions hyperintense non-Gd enhancing lesions

– 1 or more infratentorial lesions1 or more infratentorial lesions– 1 or more juxtacortical lesions1 or more juxtacortical lesions– 3 or more periventricular lesions3 or more periventricular lesions

• 1 brain lesion = 1 spinal cord lesion1 brain lesion = 1 spinal cord lesion

LABORATORY DIAGNOSIS OF LABORATORY DIAGNOSIS OF MULTIPLE SCLEROSIS (MS)MULTIPLE SCLEROSIS (MS)

• Oligoclonal bandsOligoclonal bands

• CSF IgG IndexCSF IgG Index

• Myelin basic protein (MBP)Myelin basic protein (MBP)> Serum reference range of < 1.5 ng/mLSerum reference range of < 1.5 ng/mL

• Anti-myelin associated glycoprotein (Anti-MAG)Anti-myelin associated glycoprotein (Anti-MAG)> IgM by IFA of < 1:10IgM by IFA of < 1:10

LABORATORY DIAGNOSIS OF MS LABORATORY DIAGNOSIS OF MS (OLIGOCLONAL BANDS)(OLIGOCLONAL BANDS)

• Marker for intrathecal antibody synthesisMarker for intrathecal antibody synthesis

• Associated withAssociated with> MS, Sjogrens syndrome, SLEMS, Sjogrens syndrome, SLE> AIDS, Creutzfeldt-Jakob disease (CJD), AIDS, Creutzfeldt-Jakob disease (CJD),

Lyme disease, SyphilisLyme disease, Syphilis> Subacute sclerosing panencephalitis (SSPE)Subacute sclerosing panencephalitis (SSPE)> Guillain-Barre syndrome (GBS)Guillain-Barre syndrome (GBS)> NeoplasmsNeoplasms

LABORATORY DIAGNOSIS OF MS LABORATORY DIAGNOSIS OF MS (OLIGOCLONAL BANDS)(OLIGOCLONAL BANDS)

• SpecimensSpecimens> CSF and serumCSF and serum

• MethodMethod> High resolution protein electrophoresisHigh resolution protein electrophoresis

– Concentration of CSF (80-100 X)Concentration of CSF (80-100 X)– Agarose gelAgarose gel– 250 V for 20 minutes250 V for 20 minutes– Coomassie brilliant blue stainCoomassie brilliant blue stain

• InterpretationInterpretation> 2 or more bands in gamma region of CSF and no bands in gamma 2 or more bands in gamma region of CSF and no bands in gamma

region of serumregion of serum

LABORATORY DIAGNOSIS OF LABORATORY DIAGNOSIS OF MS (CSF IgG INDEX)MS (CSF IgG INDEX)

• CSF IgG to CSF albumin ratio compared to CSF IgG to CSF albumin ratio compared to serum IgG to serum albumin ratioserum IgG to serum albumin ratio

CSF IgG / CSF albuminCSF IgG / CSF albuminserum IgG / serum albuminserum IgG / serum albumin

• Reference valueReference value> << 0.85 0.85

TREATMENT OF MULTIPLE TREATMENT OF MULTIPLE SCLEROSISSCLEROSIS

• Two categoriesTwo categories> Symptom management agentsSymptom management agents> Disease modifying agentsDisease modifying agents

• Symptom management agentsSymptom management agents> CorticosteroidsCorticosteroids

– Prednisone, methylprednisolone, dexamethasonePrednisone, methylprednisolone, dexamethasone– Indicated for acute exacerbationsIndicated for acute exacerbations

TREATMENT OF MULTIPLE TREATMENT OF MULTIPLE SCLEROSISSCLEROSIS

• Disease modifying agentsDisease modifying agents> ImmunomodulatingImmunomodulating

– Interferon beta-1b (Betaseron)Interferon beta-1b (Betaseron)– Interferon beta-1a (Avonex)Interferon beta-1a (Avonex)– Interferon beta-1a (Rebif)Interferon beta-1a (Rebif)– Glatiramer acetate (Copaxone)Glatiramer acetate (Copaxone)– Natalizumab (Tysabri)Natalizumab (Tysabri)

> ImmunosuppressantImmunosuppressant– Mitoxantrone (Novantrone)Mitoxantrone (Novantrone)

NATALIZUMAB (TYSABRI)NATALIZUMAB (TYSABRI)

• Chimeric IgG4 monoclonal antibodyChimeric IgG4 monoclonal antibody

• Indicated for relapsing forms of MSIndicated for relapsing forms of MS> MonotherapyMonotherapy

• MOAMOA> Binds to alpha4 family of integrins on leukocytes (except Binds to alpha4 family of integrins on leukocytes (except

neutrophils)neutrophils)> Prevents leukocytes from leaving bloodPrevents leukocytes from leaving blood> Receptors for alpha 4 familyReceptors for alpha 4 family

– VCAM-1VCAM-1– MadCAM-1MadCAM-1

NATALIZUMAB (TYSABRI)NATALIZUMAB (TYSABRI)

• FDA approval in November, 2004FDA approval in November, 2004

• Manufacturer withdrawal in February, 2005Manufacturer withdrawal in February, 2005

• Adverse event (Boxed Warning)Adverse event (Boxed Warning)> Increased risk ofIncreased risk of

– Progressive multifocal leukoencephalopathy (PML)Progressive multifocal leukoencephalopathy (PML)

• PMLPML> Viral encephalitis caused by JC virusViral encephalitis caused by JC virus

• FDA reapproval in March, 2006FDA reapproval in March, 2006

INTERFERON BETA-1b INTERFERON BETA-1b (BETASERON)(BETASERON)

• Protein from human interferon beta-1b gene on plasmid in Protein from human interferon beta-1b gene on plasmid in Escherichia coliEscherichia coli> Serine for cysteine at 17Serine for cysteine at 17

• IndicationsIndications> Relapsing forms Relapsing forms > Initial clinical episode with MRIInitial clinical episode with MRI

• Mechanism of action is unknownMechanism of action is unknown

• AdministrationAdministration> Subcutaneous injection every other daySubcutaneous injection every other day

INTERFERON BETA – 1a INTERFERON BETA – 1a (AVONEX)(AVONEX)

• Glycoprotein from human interferon beta-1a gene in Chinese Glycoprotein from human interferon beta-1a gene in Chinese Hamster Ovary CellsHamster Ovary Cells

• IndicationsIndications> Relapsing formsRelapsing forms

• Mechanism of action is unknownMechanism of action is unknown> Beta 2 microglobulin Beta 2 microglobulin > NeopterinNeopterin

• Dose and administrationDose and administration> 30 mcg IM / week30 mcg IM / week

INTERFERON BETA – 1a INTERFERON BETA – 1a (REBIF)(REBIF)

• Glycoprotein from human interferon beta-1a gene in Chinese Hamster Glycoprotein from human interferon beta-1a gene in Chinese Hamster Ovary CellsOvary Cells

• IndicationsIndications> Relapsing formsRelapsing forms

• Mechanism of action is unknownMechanism of action is unknown> Beta 2 microglobulinBeta 2 microglobulin> NeopterinNeopterin

• Dose and administrationDose and administration> 22 mcg or 44 mcg SC 3x /week22 mcg or 44 mcg SC 3x /week

DIFFERENCE BETWEEN DIFFERENCE BETWEEN AVONEX AND REBIFAVONEX AND REBIF

% Patients% Patients Avonex RebifAvonex Rebif

Relapse free (24 w) Relapse free (24 w) 63 75 63 75

Relapse free (48 w) Relapse free (48 w) 52 62 52 62

Injection site reactions Injection site reactions 33 85 33 85