1. CasePerspectives: Illuminating Dark Pathways in Complex MS Cases Program Highlights Stephen Krieger, MD Associate Professor of Neurology Corinne Goldsmith Dickinson Center for MS Director, Neurology Residency Program Icahn School of Medicine at Mount Sinai New York, New York

2. AAN MS Quality Measurement Set A multidisciplinary AAN working group identified areas for improvement in the diagnosis and management of patients with MS −The need for improvement is related to the high cost of treatment and broad range of symptoms that affect patients with MS The AAN working group has recommended 13 areas for the quality measurement set This program focuses on the guidelines that support the quality measures related to MS diagnosis and treatment, but the full set also addresses MS symptom management American Academy of Neurology Multiple Sclerosis Quality Measurement Set Draft 2014. Available at http://tools.aan.com/practice/measures/measures/MS-All.pdf.

3. Draft AAN MS Quality Measurement Set Emphasizes Using 2010 McDonald Diagnostic Criteria Diagnostic errors are common in MS—reducing misdiagnosis would ensure that DMT is provided only to patients who need it 2010 criteria rely primarily on validated MRI features to confirm the MS diagnosis DIS and DIT, in the absence of an alternative diagnosis, remain the foundation for establishing an MS diagnosis 2010 revisions simplify and streamline diagnosis, and in cases where the clinical picture is consistent with MS, are sensitive and specific for MS Using the 2010 criteria can lead to an earlier diagnosis, with fewer diagnostic tests, than previous versions of the diagnostic criteria Polman CH, et al. Ann Neurol. 2011:69:292-302. American Academy of Neurology Multiple Sclerosis Quality Measurement Set Draft 2014. Available at http://tools.aan.com/practice/measures/measures/MS-All.pdf.

4. Summary of the 2010 McDonald Diagnostic Criteria for Relapsing-Remitting MS Polman CH, et al. Ann Neurol. 2011:69:292-302. Clinical Attacks Clinical Presentation Additional Data for MS Diagnosis ≥2 attacks Objective clinical evidence of ≥2 lesions or Clinical evidence of 1 lesion with historical evidence of a prior attack None Objective clinical evidence of 1 lesion Dissemination in time 1 attack Objective clinical evidence of ≥2 lesions Dissemination in space Objective clinical evidence of 1 lesion Both dissemination in time and space

5. Summary of 2010 McDonald Diagnostic Criteria Requirements for DIS and DIT Polman CH, et al. Ann Neurol. 2011:69:292-302. Dissemination in Space (DIS) ≥1 T2 lesion in 2 of the following 4 regions Periventricular Juxtacortical Infratentorial Spinal cord* Another clinical attack at a distinct CNS site *For patients with brainstem or spinal lesion, symptomatic lesions are excluded Dissemination in Time (DIT) A new T2 lesion and/or gadolinium-enhancing lesion on follow-up MRI* Simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions A second clinical attack *Compared to a baseline MRI, irrespective of its timing

6. Summary of 2010 McDonald Diagnostic Criteria for PPMS DIT and DIS, with other possible diagnoses excluded, remain the principle for diagnosing PPMS Abnormal MRI features in the brain, combined with lesions in the spinal cord, are sufficient to diagnose PPMS even in the absence of abnormal cerebrospinal fluid (CSF) MRI of the cervical spine is recommended for all patients during the initial workup for MS Polman CH, et al. Ann Neurol. 2011:69:292-302. Giovannoni G. ANCR. 2012;12:8-11. Rice CM, et al. J Neurol Neurosurg Psychiatry. 2013;84:1100-1106. Consortium of Multiple Sclerosis Centers. 2015 Revised MRI Protocol and Guidelines. Available at http://www.mscare.org/?page=MRI_protocol. 2010 McDonald Diagnostic Criteria for PPMS One year of disease progression At least 2 of the following 3 criteria Dissemination in space based on ≥1 T2 lesion in the periventricular, juxtacortical, or infratentorial regions Dissemination in space in the spinal cord based on ≥2 T2 lesions in the cord Positive CSF (oligoclonal bands and/or elevated immunoglobulin G index) Symptomatic lesions are excluded if the patient has a brainstem or spinal cord syndrome; gadolinium-enhancing lesions are not required.

7. Draft AAN MS Quality Measurement Set Aligns with CMSC MRI Protocol for Monitoring Patients Monitoring schedule recommended in the draft AAN MS Quality Measurement Set is based on the 2015 Consortium of Multiple Sclerosis Centers (CMSC) MRI Protocol Patients should have an MRI every 1-2 years to evaluate subclinical disease activity More frequent MRI would be appropriate to investigate clinical deterioration or other clinical signs of disease activity Patient-related factors such as claustrophobia or inability to lie still for the MRI could affect the frequency American Academy of Neurology Multiple Sclerosis Quality Measurement Set Draft 2014. Available at http://tools.aan.com/practice/measures/measures/MS-All.pdf. Consortium of Multiple Sclerosis Centers. 2015 Revised MRI Protocol and Guidelines. Available at http://www.mscare.org/?page=MRI_protocol.

8. Summary of CMSC Guidelines for MRI Monitoring of Patients with an Established Diagnosis of MS Consortium of Multiple Sclerosis Centers. 2015 Revised MRI Protocol and Guidelines. Available at http://www.mscare.org/?page=MRI_protocol. Timing of core brain MRI protocol with gadolinium for patients with an established diagnosis of MS 1 No recent prior imaging available Postpartum to establish a new baseline Prior to starting or switching DMT Approximately 6 months after switching DMT to establish a new baseline on the new therapy Every 1-2 years while on DMT to assess for subclinical disease activity Unexpected clinical deterioration or reassessment of original diagnosis Progressive multifocal leukoencephalopathy (PML) surveillance 2 : Every 12 months for serum JC virus (JCV) antibody-negative patients Every 3-6 months for serum JCV antibody-positive patients and ≥18 months on natalizumab 1 Routine spinal cord follow-up is not required unless syndrome is predominately recurrent transverse myelitis. 2 The core brain MRI protocol for monitoring patients on DMT includes the PML surveillance protocol sequences.

9. Draft AAN MS Quality Measurement Set Recommends an Annual Disability Assessment An annual assessment of disability using a validated MS disability scale is recommended to provide a quantitative measure of patient’s disease progression −The Kurtzke EDSS is the most commonly used scale −When administration of the formal EDSS is impractical, consider estimating EDSS, using a focused neurologic exam, or utilizing an alternative, such as the timed 25-foot walk Polman CH, et al. Ann Neurol. 2011:69:292-302. American Academy of Neurology Multiple Sclerosis Quality Measurement Set Draft 2014. Available at http://tools.aan.com/practice/measures/measures/MS-All.pdf.

10. Frequent Quantitative Monitoring Allows Timely Intervention Regular monitoring using MRI and formal neurologic assessments, in addition to monitoring clinical signs of disease activity, allow early identification of a suboptimal response to treatment The CMSC Consensus Conference for Therapeutic Decision Making in MS has proposed algorithms for treating RRMS, CIS, aggressive-onset MS, and for identifying suboptimal responses Ford CF, et al. Int J MS Care. 2014;16(suppl 6): 23-28. Available at http://ijmsc.org/doi/pdf/10.7224/1537-2073-16.S6.1.

11. CMSC Consensus Conference on Therapeutic Decision Making in MS: Proposed Criteria for Switching DMT Ford CF, et al. Int J MS Care. 2014;16(suppl 6): 23-28. Available at http://ijmsc.org/doi/pdf/10.7224/1537-2073-16.S6.1. Criteria Proposed by the CMSC for Switching DMT >1 relapses within 12 months while on treatment ≥1 significant relapse and poor recovery with permanent disability Disease activity on MRI ≥1 gadolinium-enhancing lesion ≥2 new T2 lesions in 1 year MRI activity on consecutive MRIs 3-12 months apart Sustained, objective disability worsening on the Kurtzke EDSS, 25-foot timed walk, or cognitive testing

12. New and Select Emerging Treatments for MS* CompoundMechanismStatusIndication AlemtuzumabCD52 inhibitorApprovedRRMS Dimethyl fumarateAnti-inflammatoryApprovedRRMS Pegylated IFNβ-1aImmunomodulatorApprovedRRMS Teriflunomide Dihydroorotate dehydrogenase inhibitor ApprovedRRMS DaclizumabHumanized anti-CD25Phase 3RRMS LaquinimodImmunomodulatorPhase 3RRMS, progressive MS MasitinibTyrosine kinase inhibitorPhase 3Progressive MS MinocyclinePhase 3RRMS OcrelizumabHumanized anti-CD20Phase 3RRMS, PPMS SiponimodSphingosine-1-phosphate receptorPhase 3PPMS RPC1063Sphingosine-1-phosphate receptorPhase 3RRMS *Therapies approved since 2012, or compounds with completed phase 3 trials for MS.

13. Select Pipeline Treatments* CompoundTarget Amiloride Acid-sensing ion channel 1 Anti-LINGO1Myelin ATX-MS-1467Immune system Epigallocatechin- gallate Oxidative damage FirategrastVLA-4 IbudilastPhosphodiesterases IdebenoneCoenzyme Q10 Imilecleucel-TT cells Laquinimod Quinoline-3 carboxamide Lipoic acidcAMP signaling MIS416Immune system CompoundTarget MT-1303S1P1 ObinutuzumabCD-20 OcaratuzumabCD-20 OfatumumabCD-20 ONO-4641 Sphingosine-1- phosphate receptor OxcarbazepineSodium channels Pones imod Sphingosine-1- phosphate receptor rHIgM22Myelin RiluzoleGlutamate receptors SBI-087CD-20 SecukinumabIL17 VatelizumabVLA-2 VeltuzumabCD-20 *Compounds with active phase1 or phase 2 trials, or no active phase 3 trials.