Multiple Sclerosis Doug Symptom Presentation and Course What Causes MS? Clues from epidemiology Autoimmune response or idiopathic degeneration? Neurobehavioral Manifestations Cognitive profile The role of fatigue Psychiatric symptoms

Doug 35 y.o. married software engineer Age 20 – 1st episode unexplained symptoms Bilateral lower extremity numbness, tingling, weakness, lack of coordination Resolved spontaneously at 3 mos. Played hockey senior year of college Age 26 – 2nd episode Visual blurring, diagnosed as optic neuritis MRI showed plaques characteristic of MS Ages 26-33 – 3 exacerbations with full recovery Age 33 – exacerbation followed by persisting BLE weakness, fatigue & cognitive changes

Doug Functional limitations Current complaints severe difficulty concentrating, easily distracted poor memory for recent events severe fatigue Functional limitations left work 2 years ago limited multitasking (no complex recipes) extensive use of lists/cellphone 1-2 household chores/day sleeps 12-16 hours/day, fewer with Adderal

Multiple Sclerosis An immune-mediated process in which an abnormal response of the body’s immune system is directed against the central nervous system (brain, spinal cord and optic nerves). Immune system attacks the myelin and nerve fibers nerve impulses traveling to and from the brain and spinal cord are distorted or interrupted, producing a wide variety of symptoms.

Most Common Presenting Symptoms Frequency Sensory disturbance – limbs 30.7 Visual loss 15.9 Motor disturbance (gradual onset) 8.9 Double vision 6.8 Gait disturbance 4.8 Motor disturbance (sudden onset) 4.3 Balance problem 2.9 Sensory disturbance - face 2.8 Bobholz & Gremley, 2011

Multiple Sclerosis Diagnostic Criteria Establish dissemination of 2+ lesions in space and time Rule out other diagnoses Polman , 2011

Progression of MS Lesions on MRI www.radiologyassistant.nl

Signs and Symptoms Compston, 2008

Epidemiology 80-90/100,000 in US ~400,000 in US/ 2.5 million worldwide Female:Male ratio = 2.6:1 Onset - 20-50 (5% < 18 years) Slow course

Subtypes by Course SYMPTOMS TIME Progressive Relapsing (~5-10%) Secondary Progressive ( ~ 65%) SYMPTOMS Primary Progressive ( ~10%) Relapsing Remitting( ~15%) TIME Bobholz & Gremley, 2011

Epidemiology Increased risk with affected family member linkage to gene for immune molecule higher latitude of residence in childhood Ohio = 112.4/100,000 Texas = 42.8/100,000 later infection with Measles, Epstein-Barr virus

Compston, 2008

Compston, 2008

Risk of MS by UV exposure and Gender Orton, 2011

Effect of Month of Birth and Latitude on MS Risk All Samples Dobson, 2013

Effect of Month of Birth and Latitude on MS Risk All Samples Samples Living > 52° Latitude Dobson, 2012

Effect of Month of Birth and Latitude on MS Risk HI LO Pre-natal UV Exposure All Samples Samples Living > 52° Latitude Dobson, 2012

Effect of Month of Birth and Latitude on MS Risk Dobson, 2012

Pathogenesis of MS Blood-brain barrier: abnormally activated lymphocytes disrupt BBB Autoimmune: lymphocytes enter brain, activate local immune response Inflammation: T- cell attacks on myelin triggers inflammatory processes

Waxman, 1998

Gray Matter Loss 1 year after 1st MS Episode Raz, 2010

Cognitive Function in MS Common (40-50%) Predict vocational status Affect daily function Heterogeneous Emerge early in disease Deficits in verbal fluency, information processing, working memory, encoding and retrieval

adapted from Benedict, 2011

Effect of Exertion in MS Claros-Salinas, 2012

Effect of Exertion in MS Claros-Salinas, 2012

Prevalence of Neuropsychiatric Comorbidities Condition Prevalence in MS* Major Depression 25-50% Anxiety Disorders 36% Pseudo-bulbar Affect 10% Euphoria Sclerotica 9% Bipolar Disorder 2% Psychosis 2.5-4% * all elevated compared to control population Feinstein, 2012; Korostil, 2007;Patten, 2005

Doug’s Test Results WAIS-III SS Similarities 11 Premorbid IQ (HART) Comprehension 13 Trail Making A 8 Matrix Reasoning 15 Trail Making B 1 Symbol Search 6 Phonemic Fluency Letter-Num Seq. Category Fluency Digit Span 5 Grooved Pegboard 10 WMS-III Imm. Memory Finger Tapping Delayed Memory CVLT Initial Learning 7 Intrusions – Cued Recall

Self-reported Psychiatric Symptoms Clinically Significant