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 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 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 Misdiagnosis of Multiple Sclerosis Misdiagnosis of MS Updated 2017 McDonald MS Diagnostic Criteria Easier to diagnosis = Easier to misdiagnose? © 2016 Virginia Mason Medical Center MS 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 – Evolving Diagnostic Criteria MS Diagnostic Criteria Comments 1965 - Schumacher Criteria 2 attacks of neurologic symptoms > 24 hours in duration, separated by at least one month. No MRI yet 1983 - Poser Criteria Added cerebrospinal fluid (CSF) markers and Evoked Potentials to diagnostic criteria. No MRI yet 2001 - McDonald Criteria Added MRI (commonly use since early 1990’s) Classifications: "MS", "possible MS", or "not MS“ 2005 –McDonald Criteria updated Added more MRI considerations; attention to enhancing lesions and primary progressive MS (PPMS) 2010 – McDonald Criteria updated Added - Asymptomatic contrast enhancing lesion and non- enhancing lesion = DIT Earlier diagnosis possible 2017 - McDonald Criteria updated Added - +CSF and non-enhancing lesions = DIT; Enhancing lesions do not have to be asymptomatic (except optic neuritis) Even earlier diagnosis possible © 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 © 2016 Virginia Mason Medical Center Haselink. Top Mag Reson Imaging. 2006 © 2016 Virginia Mason Medical Center Haselink. Top Mag Reson Imaging. 2006 MS Mis-diagnosis Caution on Overdiagnosis for the sake of naming “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 Experimental Diagnostic Testing Iquity RNA testing Machine Learning Discrimination Analysis of serum RNA © 2016 Virginia Mason Medical Center Experimental Diagnostic Testing Iquity RNA testing RNA expression levels of 30 genes in blood 199 subjects with MS, 203 subjects with other neurologic disorders, 114 healthy control subjects Used to train machine learning algorithms. © 2016 Virginia Mason Medical Center Journal of Clinical Bioinformatics 2013 Experimental Diagnostic Testing Iquity RNA testing © 2016 Virginia Mason Medical Center 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 Vitamin D © 2016 Virginia Mason Medical Center Ascherio A, Munger KL, Simon KC. “Vitamin D and Multiple Sclerosis”. Lancet Neurol. 2010 Vitamin D (25 – 60 ng/mL) © 2016 Virginia Mason Medical Center Ascherio A, Munger KL, Simon KC. “Vitamin D and Multiple Sclerosis”. Lancet Neurol. 2010 Low Vit D associated with New MRI Lesions Each 10 ng/mL higher vitamin D level was associated ~32% reduced risk of a subsequent contrast-enhancing lesion (IRR=0.68, 95% CI [0.54, 0.86], p=0.001) © 2016 Virginia Mason Medical Center 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 Institute of Medicine (IOM) Recommendations "a considerable overestimation of the levels of vitamin D deficiency" exists in North America © 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 Seemingly safe at high doses (~10,000IU D3 daily) in RCTs Burten, JM et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 2010. 25 treated patients (49 total) spent 36+ weeks on doses of 10,000 IU/day D3 or greater. No significant side effects. Sotirchos et al. Safety and immunologic effects of high vs low dose cholecalciferol in multiple sclerosis. Neurology 2016 20 treated patients (40 total) - 10,400IU vs. 800IU D3 in with RRMS x 6 months. No significant safety concerns. 1 Relapse in each group. Reductions in IL17 seen in treated group. © 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 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 Results: No benefit for MS relapse (ARR 0.34 vs. 0.45, p = 0.38)