Program Highlights. A multidisciplinary AAN working group identified areas for improvement in the diagnosis and management of patients with MS

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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 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 Available at 1

2 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: American Academy of Neurology Multiple Sclerosis Quality Measurement Set Draft Available at Summary of the 2010 McDonald Diagnostic Criteria for Relapsing-Remitting MS Clinical Attacks Clinical Presentation Additional Data for MS Diagnosis 2 attacks of 2 lesions or Clinical evidence of 1 lesion with historical evidence of a prior attack None 1 attack of 1 lesion of 2 lesions of 1 lesion Dissemination in time Dissemination in space Both dissemination in time and space Polman CH, et al. Ann Neurol. 2011:69:

3 Summary of 2010 McDonald Diagnostic Criteria Requirements for DIS and DIT Polman CH, et al. Ann Neurol. 2011:69: 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 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 2010 McDonald Diagnos0c Criteria for PPMS One year of disease progression At least 2 of the following 3 criteria Dissemina:on in space based on 1 T2 lesion in the periventricular, juxtacor:cal, or infratentorial regions Dissemina:on in space in the spinal cord based on 2 T2 lesions in the cord Posi:ve CSF (oligoclonal bands and/or elevated immunoglobulin G index) Symptoma(c lesions are excluded if the pa(ent has a brainstem or spinal cord syndrome; gadolinium-enhancing lesions are not required. Polman CH, et al. Ann Neurol. 2011:69: Giovannoni G. ANCR. 2012;12:8-11. Rice CM, et al. J Neurol Neurosurg Psychiatry. 2013;84: Consortium of Multiple Sclerosis Centers Revised MRI Protocol and Guidelines. Available at 3

4 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 Available at measures/ms-all.pdf. Consortium of Multiple Sclerosis Centers Revised MRI Protocol and Guidelines. Available at Summary of CMSC Guidelines for MRI Monitoring of Patients with an Established Diagnosis of MS 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. Consortium of Multiple Sclerosis Centers Revised MRI Protocol and Guidelines. Available at 4

5 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: American Academy of Neurology Multiple Sclerosis Quality Measurement Set Draft Available at 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): Available at 5

6 CMSC Consensus Conference on Therapeutic Decision Making in MS: Proposed Criteria for Switching DMT 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 Ford CF, et al. Int J MS Care. 2014;16(suppl 6): Available at New and Select Emerging Treatments for MS* Compound Mechanism Status Indication Alemtuzumab CD52 inhibitor Approved RRMS Dimethyl fumarate Anti-inflammatory Approved RRMS Pegylated IFNβ-1a Immunomodulator Approved RRMS Teriflunomide Dihydroorotate dehydrogenase inhibitor Approved RRMS Daclizumab Humanized anti-cd25 Phase 3 RRMS Laquinimod Immunomodulator Phase 3 RRMS, progressive MS Masitinib Tyrosine kinase inhibitor Phase 3 Progressive MS Minocycline Phase 3 RRMS Ocrelizumab Humanized anti-cd20 Phase 3 RRMS, PPMS Siponimod Sphingosine-1-phosphate receptor Phase 3 PPMS RPC1063 Sphingosine-1-phosphate receptor Phase 3 RRMS *Therapies approved since 2012, or compounds with completed phase 3 trials for MS. 6

7 Select Pipeline Treatments* Compound Amiloride Anti-LINGO1 ATX-MS-1467 Firategrast Ibudilast Idebenone Imilecleucel-T Laquinimod Lipoic acid MIS416 Target Acid-sensing ion channel 1 Myelin Immune system Oxidative damage VLA-4 Phosphodiesterases Coenzyme Q10 T cells Quinoline-3 carboxamide camp signaling Immune system *Compounds with active phase1 or phase 2 trials, or no active phase 3 trials. Compound MT-1303 Obinutuzumab Ocaratuzumab Ofatumumab ONO-4641 Oxcarbazepine Pones imod rhigm22 Riluzole SBI-087 Secukinumab Vatelizumab Veltuzumab Target S1P1 Epigallocatechingallate Sphingosine-1- phosphate receptor Sodium channels Sphingosine-1- phosphate receptor Myelin Glutamate receptors IL17 VLA-2 7