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 June 2, 2016 DISCLOSURES Research Support: Biogen Idec; Department of Veterans Affairs (CDA2) Career Development Grant Off-label treatment discussion: None

2 LEARNING OBJECTIVES Discuss the diagnostic approach to MS, and the reasoning behind the diagnostic criteria Describe the various clinical courses of MS and their relationship to pathophysiology Review the known risk factors for MS Discuss the natural history of MS and how it relates to prognosis CASE HISTORY: EMILY 40 y/o WF and 3 rd grade teacher, who developed a blurry spot in the central vision of her right eye over 2-3 days.

3 CASE HISTORY: EMILY 40 y/o WF and 3 rd grade teacher, who developed a blurry spot in the central vision of her right eye over 2-3 days. + Photosensitivity 3-4 days later saw ophthalmologist who found no cause of her vision loss but declared her legally blind out of the right eye Vision recovered spontaneously after 2 weeks VISUAL EVOKED POTENTIAL Normal absolute P100 latencies bilaterally Relative P100 delay on right >15 msec

4 DIAGNOSIS? Optic neuritis WHAT MAKES FOR A TYPICAL DEMYELINATING EVENT? Characteristic symptoms Timing of onset, trajectory of stabilization and recovery Characteristics of the patient

5 CONCERN FOR POSSIBLE MS? PRINCIPLES OF MS DIAGNOSIS Symptoms should be explainable as typical demyelinating events Dissemination in space Dissemination in time Exclusion of alternative causes (rule-out MS mimics) 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 Sensory loss & paresthesias Bladder and bowel dysfunction

6 WHAT ABOUT OTHER COMMON MS SYMPTOMS? Fatigue Memory loss/cognitive difficulties Depression, anxiety, irritability Pain Constipation Bladder urgency, frequency, retention DISSEMINATION IN SPACE?

7 NEUROLOGICAL EXAM Red desaturation OD Strength 5/5 throughout except 4/5 R psoas R knee jerk 3+ Diminished vibratory sensation bilaterally in the toes

8 CSF PROFILE Protein: 22 mg/dl Glucose: 50 mg/dl WBC: 7 RBC: 1 IgG index: 0.85 (ULN <0.7) Oligoclonal bands (CSF-unique): present

9 CSF PROFILE Protein: 22 mg/dl Glucose: 50 mg/dl WBC: 7 RBC: 1 IgG index: 0.85 (ULN <0.7) Oligoclonal bands (CSF-unique): present DISSEMINATION IN TIME?

10 RULE OUT MS MIMICS?

11 COMMON CONSIDERATIONS IN THE DIFFERENTIAL DIAGNOSIS OF MS Systemic or other autoimmune Lupus Sjogren s disease Behcet s disease NMO Susac s syndrome Infectious HIV Syphilis Malignant CNS Lymphoma Paraneoplastic syndromes Nutritional/Metabolic B12 deficiency Copper deficiency Genetic/Inherited CADASIL Leukodystrophy Hereditary spastic paraparesis 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)

12 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

13 Primary Progressive Relapsing-Remitting Progressive Relapsing Secondary Progressive Lublin FD et al. Neurology 1996;46: Time

14 From Compston A and Coles A. Lancet 2002; 359: Lublin et al. Neurology 2014

15 Lublin et al. Neurology 2014 Lublin et al. Neurology 2014

16 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 WHAT IS MS? Is it a neurological disease? Or is it an immunological disease?

17 GROSS PATHOLOGY HISTOPATHOLOGY

18 MYELIN AND AXONAL DAMAGE Trapp BD, et al. NEJM 1998; 338: 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

19 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

20 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)

21 STEPS TO DEFINITE MS Presymptomatic phase Genetic predisposition: HLA-DRB1, biological sex Early life exposures: Geography, sun exposure Late adolescent/early adult exposures: Smoking, infections Early symptomatic phase Initial symptomatic demyelinating event: Clinically isolated syndrome Initiating autoimmune event: EBV exposure? Other infectious illness? Non-infectious event? Radiologically isolated syndrome Diagnosis Multiple Sclerosis PROGNOSIS

22 MEASURING DISABILITY/ NEUROLOGICAL IMPAIRMENT The (Expanded) Disability Status Scale RELATIONSHIP BETWEEN RELAPSES AND PROGRESSION MS Onset to DSS 4 DSS 4 to DSS 6 Confavreux C, et al. NEJM 2000;343:

23 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: 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