Practical Controversies in MS Lucas McCarthy, MD, MSc Neurologist, Director MS Center Practical Controversies How to approach common questions in the gray-zone of evidence- based practice? © 2016 Virginia Mason Medical Center The Evidence Free Zone © 2016 Virginia Mason Medical Center Poll Everywhere – Audience Participation Open cell phone or laptop to following link to participate in live questions https://pollev.com/MSsummit © 2016 Virginia Mason Medical Center Practical Controversies in MS • Misdiagnosis of MS • Vitamin D testing / supplementation • Use of complimentary / experimental treatments • Treatment of Progressive MS © 2016 Virginia Mason Medical Center Misdiagnosis of Multiple Sclerosis Misdiagnosis of MS Updated 2017 McDonald MS Diagnostic Criteria Easier to diagnosis = Easier to misdiagnose? © 2016 Virginia Mason Medical Center RRMS Diagnosis – 2017 Updated Criteria Lesions: ≥ 2 characteristic lesions (≥3mm) in ≥ 2 different locations Symptoms: objective clinical evidence of at least 1 lesion Relapse: ≥ 1 characteristic clinical attack Changes over Time: ≥2 CSF Oligoclonal bands or >1 attack over time or new lesions over time (including enhancing and non-enhancing) *No other reasonable diagnosis © 2016 Virginia Mason Medical Center MS Diagnosis – 2017 Updated Criteria Using 2017 Criteria compared with 2010 MS Criteria: 23-27% more patients diagnosed with MS at first attack Previously needed to wait until MRI change or second attack Can make MS diagnosis easier now with 1st Attack and 1st MRI Earlier Diagnosis, Earlier Treatment, Lower Future Disability © 2016 Virginia Mason Medical Center ECTRIMS 2018. Abstracts 139-142, presented October 11, 2018. Multiple Sclerosis Differential Diagnosis ExcludeAutoimmune Others:Infectious DiseasesGenetic that Mimic OtherMS Neurologic: HIV CADASIL Neoplasm (Glioma, Lymphoma) - Multiple Sclerosis Lyme MELAS Vitamin B12 or Copper deficiency - Neuromyelitis Optica Syphilis Neurofibromatosis Thiamine (B1) Deficiency - Autoimmune Encephalitis PML Porphyria Vascular Malformations - ADEM Tuberculosis Friedrich’s Ataxia Medication Effects (TNF-alpha) - Susac’s Syndrome Neuro-cysticercosis SCA Migraine Headache - Hashimoto’s Encephalitis Coccidiomycosis ALS / Motor Neuron Disease - CLIPPERS Cryptococcus Adult Onset Leukodystrophy: Compressive Myelopathy - CRION Brucellosis - Adreno-Leukodystrophy SSPE - Metachromatic Vascular: Systemic: HHV6 - Alexander’s Disease - Stroke - SLE (Lupus) Whipple’s Disease - Krabbe’s Disease - Amyloid Angiopathy - APS - Granulomatous Vasculitis - Sjogren’s - Primary CNS Angiitis - Sarcoidosis - Moya-Moya Disease - Behcet disease - Celiac disease Infiltrative: - Paraneoplastic - Langerhan’s Cell Histiocytosis - Lymphomatoid Granulomatosis - Erdheim-Chester Disease - HLH © 2016 Virginia Mason Medical Center MS Mis-diagnosis Caution on Overdiagnosis for the sake of giving an answer: “My radiologist said it could be MS” “My symptoms fit perfectly with MS” ”I just want an answer…” © 2016 Virginia Mason Medical Center Alternative Diagnosis in an MS Specialty Clinic 754 consecutive patients referred to an MS Center in the Netherlands: 67 % - MS or Probable MS (52% Definite, 15% Probable MS) 23 % - No Certain Diagnosis 7.7 % - Other Neurologic Disease • 2.2 % Ischemic Cerebrovascular Disease • 0.5 % Vasculitis • 0.4 % Multi-System Atrophy 1.3% - Other Demyelinating Disease © 2016 Virginia Mason Medical Center Nielsen et al. Ann Neurol 2005 MS Misdiagnosis 18% Misdiagnosed with MS on second opinion Previously diagnosed MS patients did not fit criteria for MS when seen for second opinion at an MS specialty center (UCLA / Cedars- Sinai) Other Diagnosis: 1. Migraine headache (most common) 2. Radiologically Isolated Syndrome (RIS) 3. Cervical spinal stenosis 4. Peripheral Neuropathy 5. Optic Neuropathy © 2016 Virginia Mason Medical Center Kaisey et al. ECTRIMS 2018 MS Conference Vitamin D and Multiple Sclerosis Vitamin D and MS Cohort Evidence Low Vitamin D serum levels associates with increased prevalence of MS, MRI lesions and relapses in RRMS “Correlation does not equal Causation” Just because something is associated, does not make it causal. Low Vitamin D levels also correlate with risk for: • Colon cancer, Breast cancer, Prostate cancer, Type 1+2 Diabetes; Cardiovascular Disease; Dementia; Osteoperosis; Depression; Schizophrenia; Rheumatoid Arthritis © 2016 Virginia Mason Medical Center Low Vit D levels (<20ng/ml) increased risk of transition from CIS→ definite RRMS Normal Vit D 50 nmol/L = Low Vit D 20ng/mL BENEFIT trial. early or delayed start of interferon beta-1b. © 2016 Virginia Mason Medical Center Taylor et al. Eur Neurol Rev. 2015 Low Vit D associated with New MRI Lesions Each 10 ng/mL higher Vit D level was associated ~32% reduced risk of a subsequent contrast-enhancing lesion over 5 years (IRR=0.68, 95% CI [0.54, 0.86], p=0.001) EPIC is a 5-year longitudinal MS cohort study at the University of California at San Francisco, USA. Participants (N = 469) © 2016 Virginia Mason Medical Center Why Vitamin D and MS? Vitamin D has anti-inflammatory actions in vitro1 - enhanced Th2 and decreased Th1 cytokine production - dendritic cell effects - enhanced macrophage phagocytosis In experimental autoimmune encephalitis (EAE)2 • pre-induction treatment prevents disease development • Post-induction treatment ameliorates disease activity Genetic association of SNPs with Vitamin D and MS 1Smolders et al. Neuroimmunol 2008 2Vieth R. Am J Clin Nutr 1999 © 2016 Virginia Mason Medical Center High Dose Vitamin D Supplements in MS Prior lower dose trials did not show significant benefits Larger trials have been and are being done Lets look at some – trend toward benefit, low risk for harm © 2016 Virginia Mason Medical Center High Dose Vitamin D Supplements Largest high dose Vitamin D trial to date: SOLAR trial: Smolders et al. “Efficacy of vitamin D3 as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon β-1a”. ECTRIMS 2016 229 MS patients Taking Interferon β-1a sc already Age 18 - 55 Vitamin D levels < 150nmol/ml (60ng/ml) Randomized to 14,000IU D3 (VigantOL Oil) vs. placebo 48 Weeks duration *reported but unpublished © 2016 Virginia Mason Medical Center data SOLAR Trial Results 14,000IU D3 vs. PBO Poor recruitment – reduced study duration from 96 to 48 week *Primary Endpoint: % Disease Activity Free (NEDA) No relapses, no EDSS progression, no new or enhancing lesions Vitamin D3 Placebo Endpoint 14,000 Difference P Value (n = 116) (n = 113) *Disease 37.2 35.3 1.9% 0.912 Activity Free (%) Relapse Free (%) 78.8 75.0 3.8% Annualized 0.28 0.41 31.7% 0.165 Relapse Rate New/Active MRI 1.09 1.49 32% 0.0005 Lesions (mean) Results Reported : https://clinicaltrials.gov/ct2/show/results/NCT01285401 © 2016 Virginia Mason Medical Center Presented: Ectrims 2016 Vitamin D Supplementation Trials Camu et al. Cholecalciferol supplementation in relapsing multiple sclerosis patients treated with subcutaneous interferon beta-1a: a randomized, controlled trial. ECTRIMS 2016. Abstract P750 129 pts, randomized placebo controlled trial; 2 year duration 100,000IU D3 q2 weeks (7,143IU / day) + IFNB-1a No significant benefit for Relapses (ARR 0.34 vs. 0.45, p = 0.38) Subgroup analysis: per protocol, completers (90 out of 129): - ARR reduction – RR 0.40, p = 0.011 - New T2 lesions – RR 0.23, p < 0.001 *reported but unpublished - New T1 lesions – RR 0.22, p = 0.001 © 2016 Virginia Mason Medical Center data Vitamin D Supplementation Trials Koduah et al. Vitamin D supplementation in multiple sclerosis: primary efficacy endpoint and safety of a randomized, controlled, double-blind phase II trial (EVIDIMS). ECTRIMS 2018. EVIDIMS trial - German multicenter RCT Patients: 53 pts with CIS or MS on IFNB-1b Intervention: equivalent to 10,200 IU vs. 200 IU D3 Daily x 18mo Primary Outcome: New T2 lesions – no significant difference *reported but unpublished © 2016 Virginia Mason Medical Center data Evidence © 2016 Virginia Mason Medical Center Systematic Review – Vit D and MS Jagannath VA et al. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev. 2018 Sep 24 12 RCTs including 933 subjects in years 2010 – 2017 *included SOLAR trial 464 in vitamin D group, 469 in comparison groups © 2016 Virginia Mason Medical Center Systematic Review – Vit D and MS No Significant Differences: Annualized Relapse Rate (ARR) - difference = -0.05 (-0.17 to 0.07) from five trials; 417 participants EDSS – mean difference = -0.25, (-0.61 to 0.10) from five trials; 221 participants MRI Gad enhancing lesions – difference = 0.02, (-0.45 to 0.48) two trials; 256 participants © 2016 Virginia Mason Medical Center Multiple Systematic Reviews – Vit D + MS 1. Jagannath VA et al. Cochrane Database Syst Rev. 2018 Sep 24 “evidence suggests no benefit of vitamin D for patient‐important outcomes among people with MS” 2. McLaughlin et al. J Neurol. 2018 “No statistically significant difference was seen for any of the outcome measures. There were non-significant trends in favour of vitamin D for all outcome measures” 3. Zheng et al. Mult Scler Relat Disord. 2018 Jul “Our findings suggest that vitamin D appeared to have no therapeutic effect on EDSS score or ARR in the patients with MS.” © 2016 Virginia Mason Medical Center Vitamin D Supplementation – Risks Meta-analysis Serious Adverse Events – difference = 1%, (-3% to 4%) Minor Adverse Effects – difference = 2%, (-2% to 6%) Cost of Testing: Vit D-25(OH)- $96 (range $33 – $231)1 IOM Report 2011: • >4000IU D3 daily supplement