ASN MS Update 2015 Annual Meeting Carefree, AZ Guy Buckle, MD, MPH Director of Neuroimaging Research Andrew C. Carlos MS Institute at Shepherd Center Atlanta, GA

Learning Objectives Discuss how new information on the immunopathology of MS affects understanding of the disease process Employ current information on the use of MRI to improve diagnosis, treatment, and monitoring of patients with MS

Overview MS History and Epidemiology MS Presentation and Diagnostic Criteria Emerging Prognostic Tools

St. Lidwina of Schiedam (1380-1433) St Lidwina’s disease began soon after a fall while skating, at the age of 16. From that time onwards, she developed walking difficulties, headaches and violent pains in her teeth. By the age of 19, both her legs were paralyzed and her vision was disturbed. Over the next 34 years, Lidwina's condition slowly deteriorated, although with apparent periods of remission, until eventually she died at the age of 53.

Robert Carswell (1793-1857) "a peculiar diseased state of the chord and pons Varolii, accompanied with atrophy of the discoloured portions"

Jean Cruveilhier (1791 – 1874) "had been ill six years without cause … she noticed that the left leg resisted her will to such a degree that she fell in the street"

DR. JEAN MARTIN CHARCOT (1825-1893)

Nikola Tesla (1856-1943) “The operator’s body, in this experiment, is charged to a high potential by means of a coil responsive to the waves transmitted to it from a distant oscillator.” Electrical Review, March 29,1899

First MRI in MS Ian R Young "[MRI] scanning promises to be of value in patients presenting with symptoms and signs referable to the brain and ... spinal cord ." Reproduced with permission from Nuclear magnetic resonance imaging of the brain in Multiple Sclerosis, IR Young et al., The Lancet, Nov 14, 1981, p1063-5 Copyright The Lancet Ltd, 1981

Gadolinium (Gd) enhancement Robert Grossman Introduction of Gd as a contrast agent. Robert Grossman, a radiologist working in Philadelphia, found that when using the enhancing agent gadolinium-DPTA, some MRI lesions enhance while others do not. Grossman recognized that the Gd enhancement identified breakdown of the blood-brain barrier, indicating areas of active inflammation.

Epidemiology of MS The most common chronic disabling disease affecting the CNS in young adults MS strikes individuals between the ages 20-50 ~400,000 cases in the US (1:1000) ~2 million cases worldwide Risk factors First degree relative with MS (25% with identical twin) Distance from the equator Caucasian Women (~ 2.5:1) HLA-DR*1501 (OR = 3.2) According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < .0001 and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359:1221-1231. Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72:871-878. The National MS Society Information Sourcebook. Available at: www.nationalmssociety.org/sourcebook.asp. Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-gets-ms/index.aspx. Accessed October, 2013. 11 11

Pathogenesis of MS MS Abnormal Immunologic Response Infectious Agent Genetic Predisposition Environmental Factors MS is believed to result from of an abnormal immunologic response to an infectious agent and/or unknown environmental factors in people who have a genetic predisposition to MS.1 Besides geography, researchers have concentrated on two other broad areas of inquiry: genetics and infectious agents (bacteria and viruses). Genetics: Numerous studies show that genetics play a role in the development of MS, but are not the sole cause of the disease. Roughly 1%-4% of MS patients will have a first-degree relative, a parent, a sibling, or an aunt or uncle, who also has MS.2 The identical twin of a person with MS has a 1 in 3 chance of developing MS.2 Although these facts are not considered conclusive proof of familial inheritance of MS, they do tell doctors that genetic factors definitely contribute to the risk of developing MS. Infectious agents: There is the possibility that a single germ or combination of germs may increase a person’s risk of developing MS. The viruses that cause measles and herpes, and chlamydia have been considered possible culprits; however, to date, no specific agent has ever been conclusively proven to be the sole cause of MS.2 Miller, et al. Immunopathogenesis. In: Continuum: Lifelong Learning in Neurology. Multiple Sclerosis (Part A). 1999. What is MS? Available at: http;//mscenter.ucsf.edu/fag.htm. Accessed 12-22-03. Abnormal Immunologic Response MS O'Gorman C, et al. Int J Mol Sci. 2012;13(9):11718-11752. 12 12

Immune Pathways Nat Rev Rheumatol. 2011 Aug 9;7(9):537-50. Pharmacogenetics: implications for therapy in rheumatic diseases. Davila L, Ranganathan P. DMARDs not only improve the joint pain and swelling associated with rheumatoid arthritis (RA), but also slow down the joint damage associated with the disease. The efficacy of biologic therapies, introduced in the past decade for the treatment of RA, has been unequivocally established. Similarly, in addition to traditional drugs such as hydroxychloroquine, new biologic agents such as rituximab have been introduced for systemic lupus erythematosus in recent years. However, considerable variability occurs in the responses of patients to these therapies. Pharmacogenetics, the study of variations in genes encoding drug transporters, drug-metabolizing enzymes and drug targets, and their translation to differential responses to drugs, is a rapidly progressing field in rheumatology. Pharmacogenetic applications, particularly to the old vanguard DMARD, methotrexate, and the newer, more expensive biologic agents, might make personalized therapy in rheumatic diseases possible. The pharmacogenetics of commonly used DMARDs and of biologic therapies are described in this Review. Linker RA, et al. Trends Pharmacol Sci. 2008;29(11):558-565. Claussen MC, Korn T. Clin Immunol. 2012;142(1):49-56. Davila L, et al. Nat Rev Rheumatol. 2011;7(9):537-550.

MS: Prevalence

Average World UV Index http://www.temis.nl/uvradiation/UVindex.html. Accessed October 2013.

Vitamin D Status is Associated With New Brain MRI Activity Magnetic resonance imaging outcomes associated with quintiles of vitamin D. CI = confidence interval. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party. Mowry EM, et al. Ann Neurol. 2012;72(2):234-240. 16

Secondary-Progressive Natural History of MS Measures of brain volume Secondary-Progressive Relapses and impairment MRI burden of disease MRI activity Preclinical (RIS) CIS RRMS The purpose of this slide is to illustrate progression of disease without treatment. Time Comi. Opin Neurol. 2000;13:235; Munschauer. Clin Ther. 1997;19:868; Weinshenker. Brain. 1989;112:1422. 17

Multiple Sclerosis: Diagnosis and Monitoring RIS: Definition and natural history CIS: Early Findings and predictive value CDMS and RRMS: Diagnostic Criteria Effect of DMTs on MRI 18

RIS Criteria Okuda D T et al. Neurology 2009;72:800-805

RIS: Typical Findings Figure 1 Cross-sectional and longitudinal MR images from select RIS cases (A) Axial 3.0 T proton density image demonstrating a juxtacortical and multiple, ovoid, periventricular foci of T2 prolongation (arrows). Figure 1 Cross-sectional and longitudinal MR images from select RIS cases (A) Axial 3.0 T proton density image demonstrating a juxtacortical and multiple, ovoid, periventricular foci of T2 prolongation (arrows). (B) Axial 3.0 T T2-weighted image 1 year later revealing new areas of T2 prolongation (arrowheads) involving the deep white matter and midbrain. A total of four new foci of T2 prolongation (>3 mm) were identified (all new lesions not shown). (C) Axial 3.0 T proton density image demonstrating multiple regions of T2 prolongation involving the periventricular and deep white matter (arrows). Chiari Type I malformation identified following clinical presentation along with incidental white matter changes. (D) Repeat axial 3.0 T proton density MR image at 1.5 years demonstrating a new focus (>3 mm) of T2 prolongation (arrowhead). (E) Sagittal 1.5 T T1-weighted image revealing two regions of T1 hypointensity adjacent to the corpus callosum. A reduction in total brain volume, outside the upper limits of normal for age, is seen. (F) Sagittal 1.5 T FLAIR image demonstrating multiple areas of hyperintensity extending in a Dawson’s finger pattern. Despite the high lesion load, the patient currently remains asymptomatic and exhibits a normal neurologic examination. (G) Axial 1.5 T, post contrast T1-weighted image (H) from the same patient with a periventricular gadolinium-enhancing lesion in the left hemisphere. A total of three contrast-enhancing lesions (all not shown) were present in this study and discordant with clinical symptomatology. T = Tesla; FLAIR = fluid-attenuated inversion recovery. Okuda D T et al. Neurology 2009;72:800-805 © 2013 American Academy of Neurology

RIS: Natural History Figure 2 Kaplan-Meier curves for clinical and radiologic endpoints Kaplan-Meier curves for patients with endpoints including (A) tie to first clinical event and (B) time to first new T2-weighted focus on subsequent brain MRI studies. Figure 2 Kaplan-Meier curves for clinical and radiologic endpoints Kaplan-Meier curves for patients with endpoints including (A) time to first clinical event and (B) time to first new T2-weighted focus on subsequent brain MRI studies. The presence of contrast-enhancing lesions on the initial MRI was associated with an increased risk of dissemination in time on repeat imaging of the brain (C) (HR = 3.4, 95% CI [1.3, 8.7], p = 0.01). Okuda D T et al. Neurology 2009;72:800-805 © 2013 American Academy of Neurology

RIS: Predictive Value of Spinal Cord Imaging Asymptomatic cervical spinal cord lesion in a subject with radiologically isolated syndrome (A) Sagittal T2-weighted MRI of the cervical spine demonstrating a focus of high signal abnormality at C2. (B) Postcontrast T1-weighted image acquired during the same evaluation revealing an area of enhancement and parenchymal swelling at C2. (C) Axial T2-weighted MRI of the same lesion revealing a posterolateral predominance. Asymptomatic cervical spinal cord lesion in a subject with radiologically isolated syndrome (A) Sagittal T2-weighted MRI of the cervical spine demonstrating a focus of high signal abnormality at C2. Okuda D et al. Neurology 2011;76:686-692 © 2013 American Academy of Neurology

3 Cases

26 y/o Woman w/ numbness, tingling and HA: Neurologic Exam, LP, EPs, S 26 y/o Woman w/ numbness, tingling and HA: Neurologic Exam, LP, EPs, S.C. imaging all WNL

Clinically Isolated Syndrome: Optic Neuritis 26 year-old woman with acute onset of monocular visual loss O.S. with pain on eye movement. Examination: Mild papilledema; Acuity of 20/200 w/ red desat. central scotoma and RAPD. Remainder of exam is normal. A woman, 26 years of age, presented with an acute onset of visual loss in her right eye. Results of the ophthalmologic examination was consistent with optic neuritis. The patient was treated with methylprednisolone, 1 gram intravenous (IV) per day for 3 days, after which her symptoms resolved completely. 25

Clinically Isolated Syndrome 2: Initial Findings on FLAIR MRI The patient’s brain fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans were unremarkable. FLAIR = fluid-attenuated inversion recovery 26

Clinically Isolated Syndrome 2: Transverse Myelitis 23-year-old woman with gradual onset of tingling and numbness in her feet that ascends to the umbilicus over the next 4 days. Exam shows a T8 sensory level to LT and temp. and reduced vibratory sensation with hyper-reflexia in the LE’s. The remainder of the neurological examination is normal. T2 T1 + Gd 27

Clinically Isolated Syndrome 2: Initial Findings on Proton Density MRI T1 w/Gd Proton Density

Medical History Patient is active and appears to be in good health. No personal history of previous neurological disease. There is no family history of neurological or autoimmune disease. Patient does not report any other symptoms.

Basic Differential Diagnosis TM Metabolic — B12 Copper deficiency Infectious — Lyme, syphilis, HIV, HTLV-1 Vascular — arteriovenous malformation (AVM) Malignancy — intramedullary or extrinsic tumor Inflammatory/autoimmune — SLE, Sjögren's, sarcoidosis, APLS, NMO Structural — cervical spondylosis Sources: MD Consult National MS Society Sourcebook 30

Clinically Isolated Syndrome: Discussion Points Which patient has multiple sclerosis (MS)? Would you recommend treatment for this patient? If yes, what type of treatment should be offered? If no, how should this patient be followed? Most clinicians would not recommend treatment for patients who present with clinically isolate syndrome (CIS) and normal findings on MRI scans. Some clinicians would recommend that the patient be followed with serial MRI scans, initially every 3 to 6 months and then annually. This would identify the 22% of patients who will develop clinically definite (CD) multiple sclerosis (MS).

Clinically Isolated Syndrome (CIS) Patients who present with clinically isolated syndrome (CIS) should be managed based on their risk of progression to MS: In the Optic Neuritis Trial, risk at 10 years was: 56% for patients with ≥1 lesion 22% for patients with no lesions In patients with CIS and no lesions, risk of MS at 14 years was: 19% for clinically definite (CD) MS Patients who present with CIS must be evaluated and managed based on the risk of progression to CDMS. In the Optic Neuritis Trial involving 388 patients with acute optic neuritis, the 10-year risk of developing MS was 56% in patients with 1 or more lesions on MRI at baseline compared with 22% for patients with no lesions at baseline. In patients with CISs, Brex and colleagues determined that the 14-year risk of developing CDMS was 19% compared with 5% for developing clinically probable MS. References: Brex PA, Ciccarelli O, O’Riordan I, et al. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med. 2002;346:158-164. Optic Neuritis Study Group. High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis. Arch Ophthalmol. 2003;121:944-949. Brex et al. N Engl J Med. 2002;346:158-164. Optic Neuritis Study Group. Arch Ophthalmol. 2003;121:944-949. 32

Number and Volume of T2 Lesions at Presentation Predict Disability 7 6 6 5 4 4 Median EDSS Score at Year 14 3 2 1.75 2 1 This slide demonstrates that, within the natural history of RRMS, what we measure by MRI is predictive of future disability. The rationale for treatment is that if you can prevent these lesions from building up, you can prevent disability progression in many patients. These data come from a study entitled, “A Longitudinal Study of Abnormalities on MRI and Disability from Multiple Sclerosis.” This study explored the association between early T2 lesion number/volume and later progressive disease. Twenty-eight patients with clinically probable or definite multiple sclerosis were followed for 14 years after first onset of symptoms. T2 lesion loads were estimated soon after symptom onset and 14 years later. Patients with a higher T2 lesion number/volume at presentation tended to have a worse EDSS score 14 years later. (0 cm3) 1 to 3 (0.6 cm3) 4 to 10 (0.9 cm3) >10 (5.6 cm3) Number (Median Volume) of T2 Weighted Lesions at Presentation Brex. N Engl J Med. 2002;346:158. 33

Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:808-817. 34

Evolution of Diagnostic Criteria Multiple Sclerosis: Evolution of Diagnostic Criteria 35

Poser Criteria Define MS as “Clinically Definite” or “Probable” 8 Poser Criteria Define MS as “Clinically Definite” or “Probable” Clinically definite MS A1: 2 attacks + 2 lesions A2: 2 attacks + 1 lesion + 1 paraclinical lesion Laboratory-supported definite MS B1: 2 attacks + 1 lesion or 1 paraclinical lesion + abnormal CSF B2: 1 attack + 2 lesions + abnormal CSF B3: 1 attack + 1 lesion + 1 paraclinical lesion + abnormal CSF Poser criteria also includes 2 additional categories Clinically probable MS Laboratory-supported probable MS The Poser criteria (introduced in 1983) separate patients into “clinically definite” MS and “probable” MS Clinically definite patients have 2 attacks and 2 lesions (A1), or 2 attacks, 1 lesion, and 1 paraclinical lesion (A2) Another category is “laboratory-supported definite” MS 2 attacks and 1 lesion or 1 paraclinical lesion and abnormal CSF (B1) 1 attack, 2 lesions, and abnormal CSF (B2) 1 attack, 1 lesion, 1 paraclinical lesion, and abnormal CSF (B3) Probable MS is divided into “clinically probable” and “laboratory-supported probable” MS Poser CM et al. Ann Neurol. 1983;13(3):227-231. 36

Diagnosis of Multiple Sclerosis: McDonald Criteria Objective evidence of dissemination in space (DIS) and dissemination in time (DIT) is essential. Alternative diagnostic considerations must be excluded (no better explanation). Clinical evidence must be based on objective clinical signs (not solely on pt’s provided history). MRI, CSF, and visual evoked potentials may be helpful for diagnosis when clinical presentation is not diagnostic (SSEPs and BAERs discarded). Following evaluation, diagnosis will be: MS, not MS, or possible MS (no laboratory-supported, clinically probable MS, etc.). In the 20 years since the Poser criteria were published, advances in MRI technology and a growing body of information about the natural course and pathology of MS have occurred. Thus, the International Panel on the Diagnosis of Multiple Sclerosis stressed the importance of using the existing criteria as a foundation on which to build. Based on consensus, the International Panel concluded: As in the past, obtaining objective evidence of dissemination in time and space of lesions is essential for diagnosis. All other, better explanations for clinical signs and symptoms must be systematically excluded. Objective clinical evidence of lesions separated in time and space must be obtained; patient accounts of previous episodes may increase suspicion of MS but cannot be used for diagnosis. When the clinical presentation is not sufficient for diagnosis, tests, including MRI, analysis of CSF, and visual evoked potentials (VEPs), must be performed. If after evaluation all criteria are met, the diagnosis of MS can be made. If criteria are not met, the diagnosis must be “not MS.” If clinical presentation is suggestive of MS, but not all criteria are met, the diagnosis of “possible MS” can be made. However, the clinical course of these patients should be followed to see if the criteria of 2 attacks and clinical evidence of at least 2 separate lesions are met. The criteria developed by the International Panel are applicable to individuals between 10 and 59 years of age with a clinical presentation that is suggestive of MS. Reference: McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol. 2001;50:121-127. McDonald WI, et al. Ann Neurol. 2001;50:121-127. 37

McDonald Criteria 2001 2 or more 1 1 mono- symptomatic 0 (progression CLINICAL (ATTACKS) OBJECTIVE LESIONS ADDITIONAL REQUIREMENTS TO MAKE DIAGNOSIS 2 or more None; clinical evidence will suffice (additional evidence desirable but must be consistent with MS) 1 Dissemination in space by MRI or positive CSF and 2 or more MRI lesions consistent with MS or further clinical attack involving different site Dissemination in time by MRI or second clinical attack 1 mono- symptomatic Dissemination in space by MRI or positive CSF and 2 or more MRI lesions consistent with MS AND 0 (progression from onset) Positive CSF AND Dissemination in space by MRI evidence of 9 or more T2 brain lesions or 2 or more cord lesions or 4–8 brain and 1 cord lesion or positive VEP with 4–8 MRI lesions or positive VEP with less than 4 brain lesions plus 1 cord lesion AND Dissemination in time by MRI or continued progression for 1 year 38

McDonald Criteria: Dissemination in Space MRI evidence of dissemination in space Three of the following: One Gd-enhancing lesion or 9 T2-hyperintense lesions At least 1 infratentorial lesion At least 1 juxtacortical lesion At least 3 periventricular lesions Note: 1 spinal cord lesion can be substituted for 1 brain lesion. Magnetic resonance imaging can be used to provide evidence that lesions are disseminated in space. Three of the 4 criteria are required for diagnosis of MS: One Gd-enhancing lesion or, if there is no enhancing lesion, 9 T2-hyperintense lesions At least 1 infratentorial lesion At least 1 juxtacortical lesion (ie, involving the subcortical U-fibers) At least 3 periventricular lesions. A lesion in the spinal cord can be substituted for 1 brain lesion. Lesions will usually be larger than 3 mm in cross section. Reference: McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol. 2001;50:121-127. McDonald WI, et al. Ann Neurol. 2001;50:121-127. 39

2005 Criteria for Demonstration of Dissemination in Space (DIS) ORIGINAL MCDONALD Three out of four of the following: 1. One Gd-enhancing lesion or nine T2 hyperintense lesions if there is no Gd-enhancing lesion 2. At least one infratentorial lesion 3. At least one juxtacortical lesion 4. At least three periventricular lesions NOTE: One spinal cord lesion can substitute for one brain lesion THE 2005 REVISIONS Three out of four of the following: 1. One Gd-enhancing lesion or nine T2 hyperintense lesions if there is no Gd-enhancing lesion 2. At least one infratentorial lesion 3. At least one juxtacortical lesion 4. At least three periventricular lesions NOTE: A spinal cord lesion can be considered equivalent to a brain infratentorial lesion: an enhancing spinal cord lesion is considered to be equivalent to an enhancing brain lesion, and individual spinal cord lesions can contribute along with individual brain lesions to reach the required number of T2 lesions.

Table 1 - MRI Criteria for Dissemination of Lesions in Time (DIT) ORIGINAL 2001 MCDONALD CRITERION If a first scan occurs 3 months or more after the onset of the clinical event, the presence of a Gd-enhancing lesion is sufficient to demonstrate dissemination in time, provided that it is not at the site implicated in the original clinical event. If there is no enhancing lesion at this time, a follow-up scan is required. The timing of this follow-up scan is not crucial but 3 months is recommended. A new T2- or Gd-enhancing lesion at this time then fulfills the criterion for dissemination in time. If the first scan is performed less than 3 months after the onset of the clinical event, a second scan done 3 months or more after the clinical event showing a new Gd-enhancing lesion provides sufficient evidence for dissemination in time. However, if no enhancing lesion is seen at this second scan, a further scan not less than 3 months after the first scan that shows a new T2 lesion or an enhancing lesion will suffice.

MRI Criteria for Dissemination of Lesions in Time (DIT) THE 2005 REVISIONS 1. Detecting Gd enhancement at least 3 months after the onset of the initial clinical event, if not at the site corresponding to the initial event. 2. Detecting a NEW T2 lesion if it appears at any time compared to a reference scan done at least 30 days after the onset of the initial clinical event.

≥ 1 lesion in each of ≥ 2 characteristic locations McDonald 20011,2 McDonald 20051,3 McDonald 2010 Dissemination in Space (on Either Baselines or Follow-Up Magnetic Resonance Imaging [MRI]) ≥ 3 of: ≥ 1 lesion in each of ≥ 2 characteristic locations ≥ 9 T2 lesions or ≥ 1 gadolinium-enhancing lesion ≥ 9 T2 lesions or ≥ 1 gadolinium-enhancing lesion Periventricular ≥ 3 periventricular lesions Juxtacortical ≥ 1 juxtacortical lesion Posterior fossa ≥ 1 posterior fossa lesion Spinal cord 1 cord lesion can replace 1 brain lesion Any number of lesions can be included in lesion count All lesions in symptomatic regions excluded in brain stem and spinal cord syndromes Dissemination in Time ≥ 1 gadolinium-enhancing lesion ≥ 3 months after CIS onset (if not related to CIS) Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time A new T2 lesion with reference to a prior scan obtained ≥ 3 months after CIS A new T2 lesion with reference to a prior scan obtained ≥ 30 days after CIS A new T2 and/or gadolinium-enhancing lesion on follow-up MRI irrespective of timing of baseline scan This slide is meant to demonstrate the contribution of MRI in diagnosing multiple sclerosis, particularly in those patients who have had only one episode. The traditional criteria of McDonald in 2001 and then revised in 2005 are the Gold Standard. More recently, the European MRI research group in MS known as MAGNIMS, made another proposal with the major difference that, based on one MRI scan, fulfillment of all criteria in this column gives the same degree of sensitivity and specificity in diagnosing MS as McDonald’s MRI criteria. 43

Patient Meets Criteria for MS Using the MAGNIMS 2010 Criteria A 32-year-old woman with left heminumbness and left leg weakness. No prior medical history. Examination demonstrates diminished sensation in the left upper and lower extremities; mild weakness of the left leg with extensor plantar response and asymmetrically hyperreflexic. Brain MRI shows: Patient Meets Criteria for MS Using the MAGNIMS 2010 Criteria Posterior fossa lesion Asymptomatic gadolinium-enhancing lesion Here we’ll discuss a brief case as it applies to the aforementioned diagnostic criteria: A 32-year-old woman with left heminumbness and left leg weakness. No prior medical history. Examination demonstrates diminished sensation in the left upper and lower extremities; mild weakness of the left leg with extensor plantar response and asymmetrically hyperreflexic. Her brain MRI shows: The MRI obtained at a single time point in this patient as shown meets all the criteria, meaning it has 1 or more lesions in at least 2 or more of the classic locations. In this case, the patient has 3 or more classic locations in which 1 or more lesions are seen: juxtacortical, posterior fossa, and periventricular. In addition to dissemination in space, it also fulfills the criteria for dissemination in time by demonstrating at least 1 asymptomatic T2 lesion and at least 1 asymptomatic gadolinium-enhancing lesion. The point is: In this case do you really need to repeat another scan to show a new lesion or more dissemination in time or space or is this sufficient? Juxtacortical lesion Periventricular lesion Asymptomatic T2 lesion Images courtesy of Omar Khan, MD. 44

Predicting Conversion From CIS to CDMS Criteria Specificity (95% CI) Sensitivity Positive Predictive Value McDonald (2001) 91.1% (85-95) 47.1% (36-58) 78.4% (65-89) McDonald (2005) 87.8% (81-93) 60.0% (49-70) 77.3% (65-87) MAGNIMS 2010 87.0% (80-92) 71.8% (61-81) 79.2% (68-88) CDMS: clinically defined MS Montalban X, et al. Neurology. 2010;74:427-434. 45

Importance of New MAGNIMS/ McDonald MRI Criteria User-friendly Clinically oriented Lead to earlier diagnosis Sensitivity and specificity are comparable to existing diagnostic criteria May reduce repeat MRI scans Caution: consider other possibilities in the differential diagnosis. Careful interpretation of the MRI scans will be critical

Why Treat Early? Relapses and impairment parallel the MRI burden of disease.1-3 Axonal damage occurs early and may cause permanent neurological dysfunction.4 Number of MRI lesions are predictive of future disability.5   Preventing development of lesions may prevent progression of disability in patients.6 Preventing early relapses may prevent long-term disability in patients.3 1. Comi. Curr Opin Neurol. 2000;13:235; 2. Munschauer. Clin Ther. 1997;19:868; 3. Weinshenker. Brain. 1989;112:1422; 4. Trapp. N Engl J Med. 1998;338:278; 5. Brex. N Engl J Med. 2002;346:158; 6. O’Riordan. Brain. 1998;121:495. 1. Jacobs et al. N Engl J Med. 2000;343:898-904. 2. Comi et al. Lancet. 2001;357:1576-1582. 47

Early Relapses Affect Long-Term Disability 100 Low (0―1 attacks in 2 years) Intermediate (2―4 attacks in 2 years) High (>5 in 2 years) 80 60 Patients (%) 40 20 10 20 30 40 50 Time From Onset of MS (years) Actuarial analysis of disability: percentage of patients not having reached EDSS 6: difference between the groups significant (P<0.0001). Weinshenker. Brain. 1989;112:1422. 48

Axons Are Transected in MS Plaques and in NAWM SMI-32 (non-phosphorylated neurofilament) Trapp. N Engl J Med. 1998;338:278. 49

Number of Transected Axons Increases with Level of Activity in MS Lesions (NAWM: normal-appearing white matter) Trapp BD, et al. N Engl J Med. 1998;338:278-285. 50

Prognosis Summary High volume and high number of T2 brain lesions at presentation predicts a worse future course Early relapse rate and disability accumulation is correlated with a worse future disease course Serum and CSF biomarkers may refine disease course prediction, but to date none have been validated other than presence of OCBs in CSF. MRI is our “Biomarker” in MS.

MRI Lesions at 12 Month F/U Scan Indicate Treatment Failure MRI Lesions at 12 Months 394 patients Mean follow-up 4.8 years 30.4% poor responders Eur J Neurol. 2009 Nov;16(11):1202-9. One-year MRI scan predicts clinical response to interferon beta in multiple sclerosis. Prosperini L, Gallo V, Petsas N, Borriello G, Pozzilli C. Multiple Sclerosis Centre, Department of Neurological Sciences, S. Andrea Hospital, La Sapienza University, Rome, Italy. BACKGROUND AND PURPOSE: To define the predictive value of clinical and magnetic resonance imaging (MRI) characteristics in identifying relapsing-remitting multiple sclerosis (RR-MS) patients with sustained disability progression during interferon beta (IFNB) treatment. METHODS: All patients receiving treatment with one of the available IFNB formulations for at least 1 year were included in this single-centre, prospective and post-marketing study. Demographic, clinical and MRI data were collected at IFNB start and at 1 year of therapy; patients were followed-up at least yearly. Poor clinical response was defined as the occurrence of a sustained disability progression of > or =1 point in the Expanded Disability Status Scale (EDSS) during the follow-up period. RESULTS: Out of 454 RR-MS patients starting IFNB therapy, data coming from 394 patients with a mean follow-up of 4.8 (2.4) years were analysed. Sixty patients were excluded because of too short follow-up. Less than 1/3 (30.4%) of the patients satisfied the criterion of 'poor responders'. Patients presenting new lesions on T2-weighted MRI scan after 1 year of therapy (compared with baseline) had a higher risk of being poor responder to treatment with IFNB during the follow-up period (HR 16.8, 95% CI 7.6-37.1, P < 0.001). An augmented risk increasing the number of lesions was observed, with a 10-fold increase for each new lesion. CONCLUSIONS: Developing new T2-hyperintense lesions during IFNB treatment was the best predictor of long-term poor response to therapy. MRI scans performed after 1 year of IFNB treatment may be useful in contributing to early identification of poor responders. Studies using more robust analyses are even more robust: See Liquori et al. J Neurol Neurosurg Psych 2011; 82:1125-31 Responders Poor responders (sustained progression ≥ 1 point on EDSS) Prosperini L, et al. Eur J Neurol. 2009;16:1202-1209.

Multiple Sclerosis: Effects of DMTs on MRI 53

MRI Defined Burden of Disease Traditionally defined as total volume of hyperintense lesion on T2-weighted images. Also defined as sum of T2 hyperintense and T1 hypointense lesion volume. Number of new gad-enhancing lesions Number of new T2 or enlarging and/or gad- enhancing lesions (Combined unique lesions) Brain volume (atrophy) Personal communication from Dr. Bakshi.

IFN Beta-1b SC (Betaseron): T2 Burden of Disease Figure from: IFNB MS Study Group/pg 1282/Table 7 p=0.0363 p=0.0002 p=0.0055 p=0.0015 Median % Change from Baseline p=0.0012 n=75 n=72 n=62 n=77 n=72 n=61 n=73 n=70 n=59 n=73 n=72 n=61 n=14 n=16 n=19 aTreatment administered every other day IFNB=interferon beta; MIU=million international units; SC=subcutaneous IFNB MS Study Group et al. Neurology 1995;45:1277-85.

Interferon Beta-1b (Betaseron): Gd-enhancing Lesions Pretreatment (n=27) IFNB-1b 8 MIU sq QOD 160 Right figure: pg 866/Figure 2 Left figure: pg 864/Table 1 P value: pg 864/col2/para 1/last 4 lines 140 120 100 Mean New Contrast-enhancing Lesion Frequency Total Contrast-enhancing Lesions 80 60 40 91.4% reduction p<0.0001 20 1 2 3 4 5 6 7 8 9 10 11 12 Month Stone LA et al. Neurology 1997;49:862-69.

Glatiramer Acetate (CopaxoneTM): T2 Burden of Disease European/Canadian MRI Trial Glatiramer Acetate (CopaxoneTM): T2 Burden of Disease Comi/pg 294/col1/lines 32-36. N numbes: pg 291/Table 1 40.3% reduction p=0.001 Median % Change in T2 Lesion Volume (Baseline to 9 Months) n=120 n=119 Comi G et al. Ann Neurol 2001;49:290-97.

Glatiramer Acetate (Copaxone): Gd-enhancing Lesions Over 9 months European/Canadian Trial Cumulative monthly change from baseline in Gd-enhancing lesion volume showed a significant treatment effect in favor of glatiramer acetate compared with placebo Comi pg 294/Fig 3 3.0 Placebo (n=120) 2.5 Glatiramer acetate (n=119) 2.0 p<0.05 Cumulative Median Enhancing Lesion Volume (mL) 1.5 p<0.05 1.0 0.5 1 2 3 4 5 6 7 8 9 Month Comi G et al. Ann Neurol 2001;49:290-97.

Natalizumab (Tysabri): T2 Lesion Counts over 2 Years AFFIRM Trial Natalizumab (Tysabri): T2 Lesion Counts over 2 Years Placebo (n=315) Natalizumab (n=627) Miller/pg 1392/col2/para 3/lines 1-3 83% reduction p<0.001 Median No. of New or Enlarging T2 Lesions This slide shows the mean number of new or enlarging T2-hyperintense lesions over 2 years in the AFFIRM trial. natalizumab significantly reduced the number of new or enlarging T2-hyperintense lesions by 83% compared with placebo (P<0.001). Over the 2-year study period, a mean of 1.9 new or enlarging T2-hyperintense lesions had accumulated in the natalizumab group compared with 11 lesions in the placebo group. The number of new or enlarging T2-hyperintense lesions on brain MRI scans over 2 years measures the accumulation of MS lesions since baseline, and reflects the change in the overall burden of disease during that time period. As such, demonstration of a treatment effect on this measure provides objective evidence in support of the primary endpoints. Miller DH et al. Neurology 2007;68:1390-401.

Natalizumab (Tysabri): T2 Lesion Load over 2 Years AFFIRM Trial Natalizumab (Tysabri): T2 Lesion Load over 2 Years Placebo (n=315) Natalizumab (n=627) Miller/pg 1395/ Table 3 Mean Change in T2 Hyperintense Lesion Volume (mm3) p<0.001 Miller DH et al. Neurology 2007;68:1390-401.

Natalizumab (Tysabri): Gd-enhancing Lesions AFFIRM Trial Natalizumab (Tysabri): Gd-enhancing Lesions Miller/pg 1394/Table 2 Mean No. of Gd-enhancing Lesions 92.3% reduction (p<0.001) 91.6% reduction (p<0.001) Miller DH et al. Neurology 2007;68:1390-401.

Natalizumab: Mechanism of Action Prescribing information for natalizumab (Tysabri®). Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm 62

Tysabri clinical efficacy 67% relative reduction in relapses at 2 yrs (P <0.001) ®

Natalizumab: Risk Management Infusion-related reactions Neutralizing antibodies Hepatotoxicity Opportunistic infections Progressive Multifocal Leukoencephalopathy (PML) Polman CH, et al. N Eng J Med. 2006;354(9):899-910. 64

Factors that Increase PML Risk JCV exposure indicated by anti-JCV antibody positive status Receiving an immunosuppressant prior to receiving natalizumab Natalizumab treatment duration (especially >2 years) JCV = John Cunningham virus Prescribing information for natalizumab (Tysabri®). Available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm Soelberg Sorensen P, et al. Mult Scler. 2012;18(2):143-152. Fox RJ. Rudick RA. Neurology. 2012;78(6):436-437. Bloomgren G, et al. New Eng J Med. 2012;366:1870-1880. 65

Natalizumab-Associated PML: Updated Incidence by Treatment Epoch The clinical trial incidence of 1.0 per 1000 treated patients (95% CI: 0.2 to 2.8 per 1000) previously reported was based upon an average natalizumab exposure of 17.9 months among the natalizumab- treated patients that were evaluated for PML. As a result, the clinical trial rate of PML is no longer directly comparable to the post-marketing rate as duration of natalizumab treatment is an identified risk factor for natalizumab-associated PML. As of 12/31/12, ~112,200 patients have received natalizumab in the post-marketing setting worldwide As of 5/13/13, there have been 347 confirmed cases of PML worldwide Biogen Idec. Data on file. List of PML diseases under Tysabri. Available at: http://chefarztfrau.de/?page_id=716. 66

Current Stratification of Natalizumab-Associated PML Risk Anti-JCV Antibody Status Negative Positive Prior IS Use NTZ Exposure NO YES 1–24 months 0.6/1,000 patients (95% CI 0.4–0.9) 1.8/1,000 patients (95% CI 1.1–2.8) > 24 months 5.2/1,000 patients 95% CI 4.3–6.2) 10.6/1,000 patients (95% CI 8.1–13.8) 0.07/1,000 95% CI 0–0.38 JCV = John Cunningham virus; IS = immunosuppressant. Dong-Si T, et al. Presented at AAN; March 16–23, 2013; San Diego, CA. Abstract P04.271. Foley J. Presented at AAN; March 16–23, 2013; San Diego, CA. Abstract S30.002. <<Note: Dong-Si abstract not available.>> [S30.002] Natalizumab Related PML: An Evolving Risk Stratification Paradigm John Foley, Salt Lake City, UT OBJECTIVE: To further characterize natalizumab related PML risk factors and present the case for ameliorating risk via dosing interval prolongation. BACKGROUND: PML remains an important issue when considering natalizumab as an MS therapy. Our group has analyzed many demographic factors and potential biomarkers to reduce PML risk. We have identified patient body mass as a novel potential predictor of PML susceptibility. Dose interval extension has been suggested as a possible PML risk mitigation tactic. We present data providing insight on the pharmacokinetic/pharmacodynamic effects of dose extension. DESIGN/METHODS: Primary demographic and clinical data was collected in a cohort of 301 natalizumab-infusing patients at a single clinic. This data set was compared to an aggregate of natalizumab-infusing patients worldwide, including a cohort of natalizumab-related PML cases. RESULTS: Mean natalizumab plasma concentrations rose from approximately 16 to 32 ug/ml over the first two years of therapy. Patients with a body mass of <= 75 kg have higher mean natalizumab concentrations and VLA-4 lymphocyte saturations. Initial data analysis of 29 PML cases revealed a body mass of <= 75 kg in 83% and was statistically different from the single site comparative population (n=301). We will present additional PML cases, reference populations, and the relationship of natalizumab concentration to dosing interval extension. CONCLUSIONS: Patients with high natalizumab concentrations, resulting from a low body mass and/or natalizumab exposure duration, may be at a higher risk for PML. We hypothesize that high natalizumab plasma concentrations reduce immunosurveillance of the JC virus in the brain, allowing for the development of PML. Increasing the interval between natalizumab infusions may be an effective method for reducing plasma natalizumab concentrations and may decrease PML risk. Further research confirming this hypothesis is warranted. Supported by: Biogen, Idec., Elan Pharmaceuticals. 67

Newer Therapies for MS Oral Medications fingolimod (Gilenya) teriflunimide (Aubagio) dimethyl fumarate (Tecfidera) Monoclonal Antibodies alemtuzumab (Lemtrada)

Fingolimod: Mechanism of Action S1P Activation Proliferation and differentiation Lymphatic sinus Afferent lymphatic vessel Sinus-lining endothelium Activated T cells Naïve T cell S1P1 receptor Efferent lymphatic vessel Lymph node S1P1 downregulation Sinus-lining endothelial cell barrier enhancement Causes internalization of the S1P1 receptor on lymphocytes Rapid but reversible inhibition of lymphocyte egress from the secondary lymphatic organs Reduced recirculation of pro-inflammatory T cells to the periphery Prevents autoreactive T cells from reaching sites of inflammation Reduced T cell egress Fingolimod S1P = sphingosine-1 phosphate Horga A, Montalban X. Expert Rev Neurother. 2008;8:699-714. 69 69

Fingolimod (Gilenya): T2 Lesions at 24 Months FREEDOMS Trial Fingolimod (Gilenya): T2 Lesions at 24 Months Kappos/pg 394/Table 2 Mean No. of New or Enlarging T2 Lesions -74% p<0.001 -74% p<0.001 Kappos L et al. N Engl J Med 2010;362:387-401.

Fingolimod (Gilenya): Gd-enhancing Lesions over 24 Months FREEDOMS Trial Fingolimod (Gilenya): Gd-enhancing Lesions over 24 Months Kappos/ pg 393/Table 2 82% reduction (p<0.001) Mean No. of Gd-enhancing Lesions Kappos L et al. N Engl J Med 2010;362:387-401.

Teriflunomide (Aubagio) Phase 2 Study: Primary Efficacy Endpoint Significant reduction in number of combined unique active lesions Teriflunomide (7 or 14 mg/day) was generally well tolerated and reduced MRI activity vs. placebo1 These findings led to the initiation of the phase 3 program Patients completing this study were eligible for entry into a long-term open-label extension; 8-year follow-up available2,3 RR: 61.3% RR: 61.1% Mean No. of Unique Active Lesions per Scan * † MS.US.P01028.1112 – Aubagio Managed Care deck Teriflunomide *p<0.03 placebo vs. 7 mg †p<0.01 placebo vs. 14 mg RR=relative reduction 1. O'Connor PW et al. Neurology 2006;66(6):894-900; 2. Li D et al. ECTRIMS 2010; 3. Confavreux C et al. Mult Scler 2012;18(9):1278-89. 72

Teriflunomide (Aubagio): Gd-enhancing Lesions TEMSO Trial Teriflunomide (Aubagio): Gd-enhancing Lesions Mean No. of T1 Gd-enhancing Lesions per Scan Proportion of Patients Free from T1 Gd-enhancing Lesions (%) Mean No. of Lesions Per Scan 1.4 1.2 1.0 0.8 0.6 0.2 Placebo Teriflunomide 7 mg 14 mg RRR: 80.4%a (p<0.001) 0.4 1.33 0.57 0.26 RRR: 57.2%a (p<0.001) Proportion of Patients (%) 70 60 50 40 30 10 Placebo Teriflunomide 7 mg 14 mg 20 39 51.4 64.1 p<0.001 (n=363) (n=358) (n=365) (n=363) (n=365) MS.US.PO.1626.0413 – South (Nashville) regional advisory board presentation (n=358) (n=363) (n=365) (n=358) (n=363) (n=365) (n=358) aDerived from a Poisson regression model with robust error variance; the model included treatment, EDSS strata, region, and baseline number of unique active lesions as covariates and log-transformed number of scans as an offset variable. Data presented for the modified intent-to-treat population. O’Connor P et al. N Engl J Med 2011;365:1293-303. 73

Dimethyl Fumarate (BG-12/Tecfidera): T2 Lesions at 2 Years DEFINE1 (Secondary efficacy endpoint) CONFIRM2 (Secondary efficacy endpoint) 85% p<0.001 71% p<0.001 73% p<0.001 54% p<0.001 74% p<0.001 New/Newly Enlarging T2 Lesions Adjusted Mean No. of New/Newly Enlarging T2 Lesions Adjusted Mean No. of Placebo BG-12 240 mg BID BG-12 240 mg TID Glatiramer acetate n=165 n=152 n=152 n=139 n=140 n=140 n=153 1. Gold R et al. N Engl J Med 2012;367:1098-107; 2. Fox RJ et al. N Engl J Med 2012;367:1087-97.

Dimethyl Fumarate (BG-12/Tecfidera): Gd-enhancing Lesions at 2 Years DEFINE1 (Secondary efficacy endpoint) CONFIRM2 (Tertiary efficacy endpoint) Gold 2012; Pg 1103, table 2 (MRI assessment) Fox 2012; Supplementary/pg 16/ Fig S6. 74% p<0.001 65% p<0.001 61% p=0.002 90% p<0.001 73% p<0.001 Mean No. of Gd+ Lesions Mean No. of Gd+ Lesions n=165 n=152 n=152 n=139 n=140 n=140 n=153 Compared with placebo, BG-12 BID and TID significantly reduced the mean number of new Gd+ lesions at 2 years in both DEFINE and CONFIRM trials 1. Gold R et al. N Engl J Med 20y12;367:1098-107; 2. Fox RJ et al. N Engl J Med 2012;367:1087-97.

Median % Change in T2 Lesion Load Alemtuzumab (Lemtrada): Phase 2 CAMMS223: T2 Burden of Disease Over 36 Months Coles Pg 1793 /Table 2 Median % Change in T2 Lesion Load p=0.03 p=0.01 Coles J et al. N Engl J Med 2008;359:1786-801.

Alemtuzumab (Lemtrada): Gd-enhancing Lesions CARE-MS I1 CARE-MS II2 Arnold ECTRIMS/ Fig 2 Arnold AAN/ slide 10 p=0.17 p=0.009 p=0.77 p=0.51 52% reduction p=0.02 SC IFNB-1a (n=187) Alemtuzumab 12 mg (n=376) SC IFNB-1a (n=202) Alemtuzumab 12 mg (n=426) 1. Arnold DL et al. AAN 2012, S11.006; 2. Arnold DL et al. ECTRIMS 2012, P877.

Alemtuzumab CAMMS223 Study: Safety Principal AEs associated with alemtuzumab included: Infusion reactions Mild-to-moderate infections Autoimmunity Immune thrombocytopenia (ITP approx. 1%) Thyroid disorders (28% vs 3% for IFNβ-1a) Glomerulonephropathy (Goodpasture syndrome). Coles A. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, 2009. Poster # 890.

Ocrelizumab: T2 Hyperintense Lesions at 24 Weeks KapposPg 1783/ Table 2 p=0.5 Mean change in volume of T2 lesions from baseline to Week 24 Total number of new or enlarging T2 lesions at Week 24 p<0.0001 p<0.0001 p=0.2 p=0.2 OCR=ocrelizumab Kappos L et al. Lancet 2011;378;1779-87.

Ocrelizumab: Gd-enhancing lesions over 24 weeks All citations from Kappos Lancet 2011: Figure: p. 1783, Table 2, “MRI,” “Total no. of gadolinium enhancing…” AND p.1784, Results, first para, lines 8-10 (for reductions vs. placebo) 25 *p<0.0001 vs. placebo 20 15 Mean (SD) Gd-enhancing Lesions 10 89% reduction vs. placebo 96% reduction vs. placebo 6.9 5 5.5 * 0.6 * 0.2 Median 1.6 Placebo (n=54) 0.0 OCR 600 mg (n=55) 0.0 OCR 2000 mg (n=55) 1.0 IFNB-1a IM (n=54) At Weeks 12, 16, 20 and 24 (ITT): average imputation Van Elteren test is stratified by geographical region and baseline presence of Gd-enhancing lesions (absent or present) IFNB-1a arm was open-label; all efficacy comparisons were exploratory OCR=ocrelizumab Kappos L et al. Lancet 2011;378:1779-87.

Risk-Benefit Assessment Risk-Benefit assessments should include: The benefits of therapies The risks of those therapies The risks of not treating or under-treating the disease itself Quality of life Long-term outcomes Patient’s history of disease and disease activity Costs When one considers the benefit:risk ratio associated with the use of a medication, one must consider the risks of the underlying disease itself (especially if it is under-treated or incompletely controlled), as well as the positive impact (benefit) the medication may have on the disease and the risks associated with the use of the medication. Risk-Benefit information should be communicated to patients!

One More Experimental Symptomatic Therapy…

Conclusions MRI is a powerful and sensitive tool for diagnosing MS but lacks pathological specificity. MRI is a valuable surrogate marker of biological disease activity and severity. The continuing worsening of MRI findings, even if clinically silent, significantly impacts on long term clinical outcomes. Conventional MRI measures (T2 lesions and Gad. Enhancement) represent only the “tip of the iceberg,” in terms of disease activity. Newer techniques hold greater promise for following both inflammation and neurodegeneration throughout all stages of the disease process.

Thank you for your attention Any Questions?