THE NATURAL HISTORY OF MS: DIAGNOSIS, CLINICAL COURSE, AND EPIDEMIOLOGY

Transcription

1 THE NATURAL HISTORY OF MS: DIAGNOSIS, CLINICAL COURSE, AND EPIDEMIOLOGY John R. Rinker II, MD University of Alabama at Birmingham Birmingham VA Medical Center May 29, 2014 DISCLOSURES Salary/Research: Department of Veterans Affairs (CDA2) Career Development Grant Research Support: Biogen Idec Off-label treatment discussion: None 1

2 LEARNING OBJECTIVES Discuss how MS is diagnosed, and the reasoning behind the diagnostic criteria Describe the various clinical courses which MS may take Review the known risk factors for MS Discuss the natural history of MS and how it relates to prognosis CASE HISTORY: REGINA 33 y/o WF who was referred by neurosurgery out of concern for possible MS. Symptoms began 1 year earlier with horizontal diplopia developing over days, attributed to an inner ear infection. After antibiotics and steroids her symptoms resolved within 1 month. Five weeks before consultation, she developed low-grade vertigo; simultaneously she also developed retro-orbital headaches and diminished visual acuity on the right. Primary care MD ordered an MRI brain to evaluate her symptoms. 2

3 ARACHNOID CYST 3

4 CASE HISTORY, CONTINUED Additional symptoms since the MRI: Two weeks of numbness in the interior of her mouth on the right side One week of numbness in hands, first on the right, then on the left. Showering makes the numbness worse Numbness on the right anterior torso below the bra line Over the last two weeks, she has experienced uncomfortable shock-like sensations in her back when she flexes her neck Increased fatigue, irritability, and constipation for the past several weeks REGINA: ADDITIONAL BACKGROUND PMH: None significant FH: No MS, neurological, or autoimmune disease in the family SH: Married with two children; grew up in northern Michigan Denies tobacco, alcohol, recreational drugs Homemaker; husband works in manufacturing Medications: OCP, cetirizine (for seasonal allergies) 4

5 REGINA: NEUROLOGICAL EXAM Cognition: normal to bedside testing Vision: VA 20/30 OD, 20/20 OS. Red desaturation OD. R APD Brainstem: pain with EOM but no nystagmus, diplopia, or facial numbness or weakness Motor: 4+/5 weakness R deltoid, bilateral psoas muscles Sensory: R chest wall decreased pinprick; diminished vibration (mild) all 4 extremities Coordination: Normal except slowed alternating movements on the right Reflexes: Brisk L patella; otherwise normal. Toes downgoing. Gait: Normal HOW IS MS DIAGNOSED? MS is a clinical diagnosis MS is not diagnosed based on MRI MS is not diagnosed by a lab test Patients must experience one or more typical demyelinating events Time course and localization must both be considered 5

6 WHAT ARE TYPICAL DEMYELINATING EVENTS? Optic neuritis Visual scotomas Changes in acuity, color and contrast perception Ocular/orbital pain Brainstem syndrome(s) Oculomotor problems (e.g., INO) Facial weakness, numbness, trigeminal neuralgia Cerebellar/ataxic syndromes (Partial) transverse myelitis Weakness Numbness & paresthesias Bladder and bowel dysfunction WHAT ABOUT THE OTHER MS SYMPTOMS I VE HEARD ABOUT? Fatigue Memory loss/cognitive difficulties Depression, anxiety, irritability Pain Constipation Bladder urgency, frequency, retention 6

7 HOW IS MS DIAGNOSED? MS is a clinical diagnosis MS is not diagnosed based on MRI MS is not diagnosed by a lab test Patients must experience one or more typical demyelinating events Time course and localization must both be considered Demyelinating events must localize to multiple CNS regions at multiple points in time WHAT ABOUT REGINA? Does she have dissemination in space? Horizontal diplopia & vertigo brainstem Right eye vision loss optic nerve Right-sided sensory changes and Lhermitte s spinal cord Does she have dissemination in time? Horizontal diplopia one year ago Vision & sensory symptoms currently present Are there other ways to demonstrate dissemination in time? 7

8 TRAVIS 24 y/o WM who reported several months of balance problems Presented to university hospital after sustaining repeated falls Simultaneous with his balance difficulties, he has lost the ability to drive, type without errors, or play bass guitar He denies any additional, prior neurological events 8

9 HOW IS MS DIAGNOSED? MS is a clinical diagnosis MS is not diagnosed based on MRI MS is not diagnosed by a lab test Patients must experience one or more typical demyelinating events Time course and localization must both be considered Demyelinating events must localize to multiple CNS regions at multiple points in time MS must be the best possible explanation for the neurological signs and symptoms (alternative causes should be considered) 9

10 WHAT ABOUT REGINA? Does she have dissemination in space? Horizontal diplopia & vertigo brainstem Right eye vision loss optic nerve Right-sided sensory changes and Lhermitte s spinal cord Does she have dissemination in time? Horizontal diplopia one year ago Vision & sensory symptoms currently present Have we ruled out alternative causes? CONSIDERING MS MIMICS Autoimmune/inflammatory mimics Lupus, Sjogren s, Behcet s, Sarcoidosis NMO Vasculitis Infectious mimics HIV, syphilis, HTLV Toxic/metabolic mimcs B12 deficiency, Cu deficiency, Thyroid disease Neurodegenerative/genetic mimics CADASIL, inherited ataxias 10

11 WHAT ABOUT REGINA? Does she have dissemination in space? Horizontal diplopia & vertigo brainstem Right eye vision loss optic nerve Right-sided sensory changes and Lhermitte s spinal cord Does she have dissemination in time? Horizontal diplopia one year ago Vision & sensory symptoms currently present Have we ruled out alternative causes? REGINA: FOLLOW-UP VISIT Can we make the diagnosis of multiple sclerosis? Dissemination in space? YES Dissemination in time? YES Rule-out alternative causes? YES* 11

12 ADDITIONAL TESTING Spinal cord imaging Short segment, lateralized lesions are most typical of MS Cerebrospinal fluid Useful in situations of unclear diagnosis or concern about certain MS mimics Presence of oligoclonal bands or elevated IgG index establishes dissemination in space Very high protein or WBC counts may suggest an alternative diagnosis Evoked potential testing VEPs, BAEPs, SSEPs Establish dissemination in time through demonstration of a conduction delay along CNS pathways 12

13 EVOLUTION OF DIAGNOSTIC CRITERIA Mild Disease severity Severe Charcot Clinicalhistological era Marburg Allison and Millar Broman First consensus clinical definitions CSF as diagnostic study Schumacher McAlpine, etc. Poser MRI era McDonald: 2001, 2005, 2010 Complete affected population 1860s 1950s 1960s 1980s 2000s Diagnostic criteria (over time) 13

14 CLINICALLY ISOLATED SYNDROME (CIS) Single typical demyelinating event (optic neuritis, brainstem syndrome, partial transverse myelitis) MRI not meeting criteria for dissemination in time Patients can be grouped as low-risk or high-risk for transition to definite MS Treatment indicated for those at highest risk of later MS RADIOLOGICALLY ISOLATED SYNDROME (RIS) MRI abnormalities typical of CNS demyelination, in the ABSENCE of clinical symptoms or exam findings suggestive of demyelinating events No formal guidelines or approved indication for use of MS drugs for these patients Treatment/diagnosis made on case-by-case basis TYPES OF MULTIPLE SCLEROSIS IMPORTANT DEFINITIONS: Relapses (attacks, exacerbations, flare-ups) Progression THE FOUR MS SUBTYPES DESCRIBE THE RELATIONSHIP OF THESE TWO TYPES OF MS WORSENING TO THE PASSAGE OF TIME Benign MS is not a well-defined MS subtype, and should only be used in hindsight, if at all, not as a predictor of future disability 14

15 Primary Progressive Relapsing-Remitting Progressive Relapsing Secondary Progressive Lublin FD et al. Neurology 1996;46: Time CASE HISTORY: CHERYL 60 y/o WF presented with chief complaint of worsening gait One year prior (~2006), she awoke one morning with vertigo, left-sided weakness, and left facial paresthesias Symptoms eventually improved but her left sided weakness persisted and worsened over subsequent months By the time of evaluation, she could not walk >30 minutes at a time In retrospect, she identified subtle problems with gait dating to around 2001, which worsened in gradual fashion 15

16 CHERYL: EXAM Vision: 20/20 bilaterally, no scotomas, no red desaturation Brainstem: Normal Motor: Increased tone LLE; 4/5 strength L deltoid, triceps, hamstring, TA; bilateral psoas; bilateral ankle clonus Sensory: decreased pinprick LLE Cerebellar: No ataxia Cognitive: Subjective increase in forgetfulness Bladder & Bowel: Normal CHERYL: MRI 16

17 What type of MS does Cheryl have? PROGRESSIVE-RELAPSING WHAT IS MS? Is it a neurological disease? Or is it an immunological disease? 17

18 GROSS PATHOLOGY HISTOPATHOLOGY 18

19 MYELIN AND AXONAL DAMAGE Trapp BD, et al. NEJM 1998; 338: From Compston A and Coles A. Lancet 2002; 359:

20 THE CONVERSATION AFTER THE DIAGNOSIS Why did this happen to me? How common is MS? What are the risk factors for developing MS? Is there anything I could have done to prevent it? Is my family at risk now that I am diagnosed? EPIDEMIOLOGY FACTS Prevalence: 2.5 million worldwide (350,000 U.S.) 0.9/1000 individuals (U.S.) Sex: Female prevalence: 1:750 Male: 1:1500 Age of Onset: (majority); Range from childhood to late adulthood Ethnicity: Most common in whites, persons with northern European ancestry Geography: Prevalence increases with latitude 20

21 EPIDEMIOLOGY Milo R, et al. Autoimm Reviews 2010; 9:A WHAT DOES GEOGRAPHY HAVE TO DO WITH MS RISK? Latitude (UV-radiation/Vitamin D) Infectious illnesses (EBV?) Migration patterns 21

22 FAMILIAL RISK AND ETHNIC BACKGROUND 1 st degree family are times more likely to develop MS (1-2%) Why? Common environments Common genetics Twin studies Immune system-related genes (HLA-DR2) MODIFIABLE RISK FACTORS? Vitamin D deficiency Smoking increases risk of MS, may also increase risk of progressive disease Obesity (in girls) 22

23 WHAT DOES THE FUTURE HOLD? MEASURING DISABILITY/ NEUROLOGICAL IMPAIRMENT The (Expanded) Disability Status Scale 23

24 RELATIONSHIP BETWEEN RELAPSES AND PROGRESSION MS Onset to DSS 4 DSS 4 to DSS 6 Confavreux C, et al. NEJM 2000;343: MS AND LIFE EXPECTANCY MS is not considered a fatal disease; however Mean life expectancy is years below general population Time to Death 1 Affected by disease subtype, comorbidity, degree of disability, and treatment with disease modifying drugs General approximations of time from dx to death: PPMS: 33 years SPMS: >33 years RRMS: 40 years Approx ½ of deaths attributed to MS 1. Degenhardt et al. Nat Rev Neurol 2009;5:

25 CONCLUSIONS MS is a disabling condition caused by accumulating immunemediated damage within the CNS Diagnosis is established by demonstrating dissemination in space and time of demyelinating events MS can be clinically divided into relapsing and progressive subtypes Epidemiological clues have only partially answered the questions of MS causation Onset of progressive disease is the strongest determinant of future disability 25