MULTIPLE SCLEROSIS (MS)

CASE STUDY

• 30 year old white female presents to family physician with acute loss of vision in left eye • Referred to neurologist > Diagnosis of optic neuritis > Treated with IV corticosteroids for 5 days – Normal vision over next 3 weeks > Family history (mother) > Magnetic resonance imaging (MRI) – Multiple lesions in white matter of brain under cortex and around ventricles

CASE STUDY

• 3 years later > > > > > Muscle weakness on left side of face and fatigue Radiology (MRI with gadolinium) – New lesions in left middle cerebellar peduncle and pons Laboratory (CSF from lumbar puncture) – 12 lymphocytes/uL – – IgG index of 1.2

Oligoclonal bands (high resolution protein electrophoresis) • 2 bands in gamma region of CSF and no bands in gamma region of serum Diagnosis of MS Treatment with 5 day course of IV methylprednisolone and weekly IM interferon-beta (Avonex)

CASE STUDY

• 3 years later > Clinical symptoms – Weakness in left hand and left leg – Slurred speech, nystagmus, ataxia and fatigue > Laboratory – Myelin basic protein (CSF) • 3.4 ng/mL [< 1.5 ng/mL] > Treatment – 5 day course of IV methylprednisolone – Weekly IM interferon-beta (Avonex) continued

CASE STUDY

• Eight months later > > > > Clinical symptoms recurred Laboratory – Myelin basic protein (CSF) • 4.1 ng/mL [< 1.5 ng/mL] Treatment – IFN-beta (Avonex) stopped – High dose IV methylprednisolone and cyclophosphamide (Cytoxan) monthly for 3 months then quarterly Following 9 months therapy – Asymptomatic – No new lesions on gadolinium MRI

MULTIPLE SCLEROSIS (MS)

• Chronic unpredictable disease of CNS > > > Tends to follow certain patterns (clinical courses) Initial symptoms 20 to 40 years Not contagious > Rarely fatal • Autoimmune disease • Characterized by patches (plaques) of demyelination and inflammation of myelin sheath of axons and degeneration of axons in white matter of CNS

ETIOLOGY OF MULTIPLE SCLEROSIS (MS)

• Complex with multiple causal factors > > > Environmental agents – Chemicals (organic solvents) – UV light Infectious agents – Viruses • EBV, HHV-6, measles virus, CDV, HERV – Bacteria • Chlamydophila pneumoniae Genetic predisposition – HLA-DR2 – IL-2R and IL-7 receptor mutations

EPIDEMIOLOGY OF MULTIPLE SCLEROSIS

• Female to male ratio of 2:1 • Prevalence of 1 case per 750/1000 population > > > Northern Europe Continental North America – 350,000 to 400,000 in US Australia (SE) and New Zealand • Incidence in US of 200 to 300 cases/week • Disease prevalence > Caucasians > African Americans > Asians

EPIDEMIOLOGY OF MULTIPLE SCLEROSIS (MS)

• Hemisphere gradients for prevalence > > North to south in northern hemisphere South to north in southern hemisphere • Prevalence gradients in Northern Hemisphere > > North of 37 th parallel (125 cases/100,000 population) South of 37 th parallel (70 cases/100,000 population) • Migration risk > Geographic move and risk for developing disease • Disease rare or not seen in > Inuit, Lapps, American Indians, Aborigines, Maoris

RISK OF MULTIPLE SCLEROSIS (MS

) • A 12 year old female > Moves from Rochester, Minnesota to Miami, Florida Risk for MS is: Increased Decreased Same • An 18 year old female > Moves from Rochester, Minnesota to Miami, Florida Risk for MS is: Increased Decreased Same

PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS

• Destruction of > Myelin, oligodendrocytes, nerve axons • Hypothesis of molecular mimicry • Antigens > Myelin basic protein (MBP) > > > Myelin oligodendrocyte glycoprotein (MOG) Proteolipid protein (PLP) Myelin associated glycoprotein (MAG)

PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS

• Cells > > > CD4 TH1, CD4 TH2 and CD8 T cells Macrophages and microglial cells Mast cells > B cells • Cytokines, chemokines and adhesion molecules – IL-12 – – IFN-gamma ALCAM (Activated leukocyte cell adhesion molecule)

DIAGNOSIS OF MULTIPLE SCLEROSIS (MS) • McDonald Criteria (2005 Revision) > History and clinical symptoms > Radiology – Magnetic resonance imaging (MRI) with and without gadolinium enhancement • Head and spinal column > Laboratory – MS panel

CLINICAL SYMPTOMS OF MULTIPLE SCLEROSIS (MS) • • • • • • Fatigue Visual disturbances > Blurred vision, diplopia, nystagmus, red-green color desaturation Motor > Spasticity, paresis, dysarthria, spasms, ataxia, muscle weakness Sensory changes > Paraesthesia, neuralgia Cognitive deficits > Memory loss Bladder / bowel urgency and incontinence

CLINICAL CONDITIONS ASSOCIATED WITH MS • Optic neuritis > Inflammation of optic nerve • Internuclear ophthalmoplegia > Paraylsis of ocular muscles • Transverse myelitis > Inflammation of spinal cord

PATTERNS (CLINICAL COURSES) OF MULTIPLE SCLEROSIS • Relapsing-Remitting (85%) > > Relaspes (attacks, exacerbations) followed by remission (rest periods) Attack symptoms (old may flare, new may appear) • Secondary Progressive (50%) • Primary Progressive (10%) • Progressive-Relapsing (5%)

RADIOLOGY DIAGNOSIS OF MULTIPLE SCLEROSIS (MS) • McDonald Criteria > 3 of 4 criteria for “positive MRI” – 1 gadolinium (Gd) enhancing lesion or 9 T2 hyperintense non-Gd enhancing lesions – 1 or more infratentorial lesions – 1 or more juxtacortical lesions – 3 or more periventricular lesions • 1 brain lesion = 1 spinal cord lesion

LABORATORY DIAGNOSIS OF MULTIPLE SCLEROSIS (MS)

• Oligoclonal bands > High resolution protein electrophoresis > Isoelectric focusing (IEF) • CSF IgG Index • Myelin basic protein (MBP) > Primary protein component (30%) of myelin > Elevated level indicates active demyelination > CSF reference range of < 1.5 ng/mL

LABORATORY DIAGNOSIS OF MS (OLIGOCLONAL BANDS) • Marker for intrathecal antibody synthesis • Associated with > MS, Sjogrens syndrome, SLE > AIDS, Creutzfeldt-Jakob disease (CJD), Lyme disease, Syphilis > Subacute sclerosing panencephalitis (SSPE) > Guillain-Barre syndrome (GBS) > Neoplasms

LABORATORY DIAGNOSIS OF MS (OLIGOCLONAL BANDS) • Specimens > CSF and serum • Method > High resolution protein electrophoresis – Concentration of CSF (80-100 X) – – – Agarose gel 250 V for 20 minutes Coomassie brilliant blue stain • Interpretation > 2 or more bands in gamma region of CSF and no bands in gamma region of serum

LABORATORY DIAGNOSIS OF MS (CSF IgG INDEX)

• CSF IgG to CSF albumin ratio compared to serum IgG to serum albumin ratio CSF IgG / CSF albumin serum IgG / serum albumin • Reference value > < 0.85

TREATMENT OF MULTIPLE SCLEROSIS

• Two categories > Symptom management agents > Disease modifying agents • Symptom management agents > Corticosteroids – Prednisone, methylprednisolone, dexamethasone – Indicated for acute exacerbations

TREATMENT OF MULTIPLE SCLEROSIS

• Disease modifying agents > Immunomodulating – Interferon beta-1b (Betaseron) – Interferon beta-1a (Avonex) – – – Interferon beta-1a (Rebif) Glatiramer acetate (Copaxone) Natalizumab (Tysabri) > Immunosuppressant – Mitoxantrone (Novantrone)

NATALIZUMAB (TYSABRI)

• Chimeric IgG4 monoclonal antibody • Indicated for relapsing forms of MS > Monotherapy • MOA > Binds to alpha4 family of integrins on leukocytes (except neutrophils) > > Prevents leukocytes from leaving blood Receptors for alpha 4 family – VCAM-1 – MadCAM-1

NATALIZUMAB (TYSABRI)

• FDA approval in November, 2004 • Manufacturer withdrawal in February, 2005 • Adverse event (Boxed Warning) > Increased risk of – Progressive multifocal leukoencephalopathy (PML) • PML > Viral encephalitis caused by JC virus • FDA reapproval in March, 2006

INTERFERON BETA-1b (BETASERON)

• Protein from human interferon beta-1b gene on plasmid in Escherichia coli > Serine for cysteine at 17 • Indications > > Relapsing forms Initial clinical episode with MRI • Mechanism of action is unknown • Administration > Subcutaneous injection every other day

INTERFERON BETA – 1a (AVONEX)

• Glycoprotein from human interferon beta-1a gene in Chinese Hamster Ovary Cells • Indications > Relapsing forms • Mechanism of action is unknown > > Beta 2 microglobulin Neopterin • Dose and administration > 30 mcg IM / week

INTERFERON BETA – 1a (REBIF)

• Glycoprotein from human interferon beta-1a gene in Chinese Hamster Ovary Cells • Indications > Relapsing forms • Mechanism of action is unknown > > Beta 2 microglobulin Neopterin • Dose and administration > 22 mcg or 44 mcg SC 3x /week

DIFFERENCE BETWEEN AVONEX AND REBIF

% Patients Avonex Rebif Relapse free (24 w) 63 75 Relapse free (48 w) Injection site reactions 52 62 33 85