Multiple Sclerosis Overview for Nurse Practitioners Defining Multiple

Multiple Sclerosis: Overview for Nurse Practitioners

Defining Multiple Sclerosis • An immune-mediated disease of the central nervous system – Immune cells are made throughout the body except in the brain and spinal cord • • • Tonsils Thymus Bone Marrow Spleen Lymphoid tissue of the gut

The Body’s Immune System

Trafficking Is a Multistep Process Requiring Many Molecules Resting State Inflammatory Stimulus Leukocyte Inactive Integrin Selection Counterceptor Vessel Lumen Rolling Adhesion Activated Integrin Firm Adhesion Transendothelial Migration Selectin Expression Endothelial Cell Subendothelial Matrix Papadaki HA. Haema 1992; 2: 180 -191 Vascular cell adhesion molecule Chemokines

Balancing the Mediators of the Immune System Proinflammatory and Neurotoxic Factors TH 1 and TH 17 cytokines TNF IL-1 osteopontin leukotrienes MMP plasminogen activators nitric oxide reactive oxygen species glutamate antibody + complement cell-mediated cytotoxicity neurotrophins via p 75 NTR? Destruction The balance between the protective and destructive response determines the net effect of the inflammatory response Kerschsteiner M et al. Ann Neurol 2003; 53: 292 -304 Anti-inflammatory and Neuroprotective Factors TH 2 cytokines TGF-beta soluble TNF receptor soluble IL-1 receptor antagonist some prostaglandins lipoxins TIMP antithrombin BDNF NGF NT 3 neurotrophic NT 4/5 factors GDNF LIF Protection

Defining Multiple Sclerosis • An immune-mediated disease of the central nervous system • A disease of myelin and axons

Nerve Damage and Myelin Loss A B C D E A. Normally, axons have a protective myelin coating that is necessary for normal conduction of electrical impulses B. In MS, the immune system destroys myelin, resulting in slowed conduction and exposure of axons C. Exposed axons may then be severed… D. …leading to permanent loss of the axon E. The result is permanent loss of nerve function Adapted from Trapp BD, et al. The Neuroscientist. 1999; 5: 48 -57.

Myelin in Chronic Multiple Sclerosis Lesions • In a demyelinated area, a remyelinating oligodendrocyte extends its processes to myelin internodes Arrowheads = oligodendrocyte processes; White arrow = oligodendrocyte; Yellow arrows = myelin internodes; Human brain; Green = immunostained for nonphosphorylated neurofilament; Red = immunostained for proteolipid protein; Bar = 20 m. Chang A et al. N Engl J Med. 2002; 346: 165 -173.

Active Inflammatory Demyelination and Axonal Transection • It has been shown that active inflammation results in both demyelination and axonal transection Arrowheads = areas of active demyelination; Arrow = terminal axon ovoid; Human brain; Red = immunostained for myelin basic protein; Green = immunostained for nonphosphorylated neurofilament; Bar = 45 m. Trapp BD et al. N Engl J Med. 1998; 338: 278 -285. Peterson JW et al. Neurol Clin. 2005; 23: 107 -129.

Multiple Sclerosis • An immune-mediated disease of the central nervous system • A disease of myelin and axons • A disease of people

Who gets MS? • Usually diagnosed between 20 and 50 – Occasionally diagnosed in young children and older adults • More common in women than men (>2 -3: 1) • Most common in those of Northern European ancestry – More common in Caucasians than Hispanics or African Americans; rare among Asians • More common in temperate areas of the world – Environmental factor(s)? – Genetic factor? – Lower vitamin D exposure? – Combination?

The genetic factor in MS • The risk of getting MS is approximately: – 1/750 for the general population (0. 1%) – 1/40 for those with first-degree relative with MS (3%) – 1/4 for an identical twin (25%) • 20% of people with MS have a blood relative with MS The risk is higher in any family in which there are several family members with the disease (multiplex families)

Diagnosing MS • MS is a clinical diagnosis – Signs and symptoms – Medical history • Paraclinical tests provide support – Magnetic resonance imaging – Spinal fluid – Evoked potentials • Diagnostic criteria: – Dissemination in time and space: evidence that damage has occurred in at least two separate areas of the CNS at different points in time – There must be no other explanation

Conventional MRI in MS Clinical Practice FLAIR T 2 BOD* T 1 precontrast T 1 Gd postcontrast Disease Activity† Black Holes† The strongest correlation with progression of disability *Reprinted with permission from Miller DH et al. Magnetic Resonance in Multiple Sclerosis. Cambridge: Cambridge University Press; 1997. †Reprinted with permission from Noseworthy JH et al. N Engl J Med. 2000; 343: 938 -952. Copyright © 2003 Massachusetts Medical Society. All rights reserved.

Evoked Potential Testing

Lumbar Puncture

Oligoclonal Banding

Disease Types • Clinically isolated syndrome (CIS) • Relapsing-remitting MS (RRMS) – About 85% of people are diagnosed with RRMS • Primary progressive MS (PPMS) – About 15% of people experience this course • Secondary progressive – Most people diagnosed with RRMS will eventually transition to SPMS Lublin et al, 2014

Clinically Isolated Syndrome (CIS) • A first neurologic event suggestive of demyelination • Individuals with CIS are at high risk for developing clinically definite MS if the neurologic event is accompanied by multiple, clinically silent (asymptomatic) lesions on MRI typical of MS

Lublin et al, 2014

Lublin et al, 2014

Lublin et al, 2014

Lublin et al, 2014

Managing Multiple Sclerosis • A complex disease requiring a multi-pronged approach that involves many clinical disciplines: – Disease Management – Relapse Management – Symptom Management – Rehabilitation – Psychosocial Support

Patient-Physician Communication: Autonomy preferences among 168 MS patients Active roles “I prefer to make the decision” (Pure autonomy) “I prefer to make the final decision after consideration my doctor’s opinion” (informed choice) “I prefer that my doctor and I share responsibility” (shared decision making) Passive roles – “I prefer that my doctor makes the final decision” (Professional-asagents) – “I prefer to leave all decisions to my doctor” (paternalistic) Heesen C et al. Multiple Sclerosis 2004

Proposed MS Health-Care Standards Key issues - Certain, clear diagnosis - Appropriate support at diagnosis - Access to information - Continuing education Key issues - Continuity in service provision - Access to support and informed advice - Access to appropriate treatment/management options aimed at keeping people with MS healthy 3. Moderate disability Key issues - Responsiveness of services - Access/location - Expertise - Communication/co-ordination - Empowerment 4. Severe disability Key issues 1. Diagnostic phase 2. Experiencing minimal impairment Freeman et al. 2002, www. mssociety. org. uk - Provision of respite care - Appropriate long-term care - Access to information - Expertise - Communication/co-ordination - Adequate community care - Community mobility

Management of Multiple Sclerosis The MS “Treatment Team”: • • Neurologist Urologist Nurse Primary care physician Physiatrist Physical therapist Occupational therapist Speech/language pathologist • • Psychiatrist Psychotherapist Neuropsychologist Social worker/Care manager • Pharmacist

FDA-Approved Disease-Modifying Drugs Drug Origin Dosage Freq Route Glatiramer acetate Random polypeptides 20 mg Every day SC IFNb-1 b Recombinant protein 0. 25 mg Every other day SC IFNb-1 a IM Recombinant protein 30 mcg 1 x/wk IM IFNb-1 a SC Recombinant protein 22 mcg 44 mcg 125 mg 3 x/wk IFNb-1 a SC SC 2 x/mo Dimethyl fumarate Oral formulation of dimethyl fumarate rapidly hydrolyzed to monomethyl fumarate 24 o mg Twice daily Oral Fingolimod Sphingosine 1 -phosphate receptor modulator 0. 5 mg Every day Oral Teriflunomide De novo pyrimidine synthesis inhibitor of the DHO-DH enzyme 7 mg or 14 mg Daily Oral Alemtuzumab CD 52 -directed cytolytic Mab 12 mg/day 5 consecutive days 3 consecutive days 12 mos. later IV infusion Mitoxantrone Chemotherapy 12 mg/m 2 (cumulative lifetime dose < 140 mg/m 2) Every 3 months IV infusion

Deciding Which Immunomodulating Agent Should Be Used—and When • A medical decision taking into account several factors: – Patient’s disease course and prognostic indicators – Benefits vs. risks of each medication – Cost vs. benefits for each patient – Patient’s lifestyle and preferences – Patient readiness

Lifestyle and Personal Preferences • • Patient readiness to treat their MS Preconceptions/attitudes about medications Comfort with needles and self-injection Medication side effects Lifestyle Depression, anxiety Cognitive status

Negative Prognostic Indicators • • Frequent, multifocal attacks Heavy MRI burden on initial scans Pyramidal involvement Ataxia Cognitive difficulties 5 year accumulation of disability Spinal progression (primary progressive MS)

The Concept of “Benign” MS Maybe it should be called: “Mild MS”

Managing Progressive MS • Azathiorpine (Imuran) • Methotrexate • Mitoxantrone (Novantrone) • Monthly administration of methylprednisolone • IVIg • Cladribine • Cytoxan • Bone marrow transplantation

Relapse Management • Relapse = new symptom or sudden worsening of old symptom lasting at least 24 hours, and usually accompanied by an objective change in neurologi findings • Treatment with corticosteroids recommended if relapse significantly interferes with everyday functioning – 3 -5 day course of high-dose intravenous methylprednisolone with or without oral taper – High-dose oral steroids may also be used • Rehabilitation can help restore function following a relapse

MS Symptom Management • MS symptoms are variable and unpredictable - Fatigue (most common) - Loss of sensation - Decreased visual acuity, diplopia - Bladder and/or bowel dysfunction - Pain - Sexual dysfunction - Paresthesias (tingling, (numbness, burning) - Emotional disturbances (depression, mood swings) - Cognitive difficulties (memory, attention, processing) - Heat sensitivity - Spasticity - Gait, balance, and coordination problems - Speech/swallowing problems - Tremor - Weakness

Treating MS Fatigue • Deconditioning – Exercise • Impaired mobility requiring extra exertion – Mobility aids; dalfampridine • Depression – Diagnosis and treatment • Sleep disruption – Symptom management • Medication side effects – Adjustment of dosage/timing • MS Lassitude – Amantidine, SSRI, modafinil, armodafinil

Treating Spasticity Step 1: Eliminate sources of pain in the body Step 2: Reduce the spasticity if it interferes with comfort or function

Treating Spasticity, cont’d • Exercises and Therapy – Stretching – Range of motion – Weight bearing – Cryotherapy – Inhibitory casting – Pool therapy – Aerobic exercise – EMG biofeedback – Electrical stimulation

Treating Spasticity, cont’d • Medications – Baclofen (Lioresal) – oral; intrathecal – Tizanidine (Zanaflex) – Clonazapam (Klonopin) – Gabapentin (Neurontin) – Cyproheptidine (Periactin) – Dantrolene (Dantrium) – Dopaminergic agonists

Treating Spasticity, cont’d • Procedures – Botulinum toxin (Botox) – Baclofen pump – Cryotherapy (cooling and stretching) – Tendonotomy – Rhizotomy – Myelotomy – Motor point blocks

Baclofen Injection: Intrathecal Delivery

Adjusting the Baclofen Dose

Before Treatment with ITB

After Treatment with ITB

Managing Weakness • Exercise – The role of progressive resistive exercise • Pharmacological treatment – Dalfampridine • Mobility aids

Mobility vs. Ambulation • The goal of treatment is to promote function, comfort, and independence • Mobility aids conserve energy, enhance safety, and allow people to remain active and involved – – – – Cane Crutches Walker Ankle foot orthosis Manual wheelchairs Motorized scooters Electric wheelchairs • Dalfampridine (Ampyra™) was approved in 2010 to improve walking speed in MS.

A Word about Temperature Sensitivity • Heat sensitivity is common in MS • Sensitivity to cold can also occur • Even a slight elevation in core body temperature can cause temporary worsening of symptoms (called a pseudoexacerbation) • Cooling strategies are beneficial during: – Hot, humid weather – Exercise – Cooking

Treating Bladder Dysfunction • The small (failure to store) bladder – Oxybutynin in various forms – Tolteridine – Trospium chloride – Others • The large (failure to empty) bladder – Stimulating medication – Intermittent self-catheterization

Treating Bladder Dysfunction, cont’d • Dysynergic bladder – Alpha adrenergic agonists • dibenzyline, terazosin (Hytrin), Cardura – Intermittent self-catheterization • Nocturia – DDAVP-desmopressin

Managing Bowel Dysfunction • • Regular bowel regimen High fiber diet; sufficient liquids Bulk formers Stool softeners Mini enemas Suppositories Enemas

Managing Pain • Dysesthesia, paresthesia – Pharmacological: gabapentin (Neurontin), lamotrigine (Lamictal), carbamazepine (Tegretol), amitriptyline (Elavil), pregabalin (Lyrica), others – Mechanical: gloves, counter-irritant – Other: accupuncture, biofeedback • Orthopedic, mechanical

Depression in MS: Diagnosis and Treatment • Symptoms of depression can be confused with symptoms of MS difficult to diagnose. • Depression is under-diagnosed and under-treated MS. • Best treatment for depression: Psychotherapy + Medication (+ Exercise) in

Depression in MS: What Do We Know? • Depression differs from normal grieving. • People with MS are at increased risk; depression is one of the most common symptoms of MS • 50+% of people will experience a major depressive episode at some point over the course of the disease. • Suicide is 7. 5 x more common in MS than in general population (Sadovnick et al. , 1991). • Depression in MS is under diagnosed and under treated. Feinstein, A. (2007). The clinical neuropsychiatry of multiple sclerosis (2 nd ed. ). Cambridge and New York: Cambridge University Press.

Depression: The Implications People who are depressed: • Carry an additional, painful burden • Can’t participate actively in their own care • Can’t plan/problem-solve effectively • Are difficult to live with Note: Depression is one of the most treatable symptoms of MS

A Word about Stress and MS • Stress worsens the symptoms of any neurological disease. • Data concerning the role of stress in the onset or progression of MS is conflicting. • Patients need effective strategies to manage the unavoidable stresses of everyday life Mohr D. Talking about Stress. National MS Society, 2009.

Common Misconceptions about MS and Cognition • Cognitive impairment (CI) is rare in MS. • CI only occurs in late stage MS or severe MS. • MS is a white-matter disease and does not affect: 1) brain volume, 2) gray matter, 3) the cerebral cortex. • If an MS patient can pass a brief mental status exam, everything is OK. • Memory problems reported by MS patients are usually caused by stress, anxiety, and/or depression. • Discussing CI will upset MS patients/families.

Cognitive Symptoms

Cognition and Other Disease Characteristics • Cognitive function correlates with lesion load and brain atrophy. • Cognitive dysfunction can occur at any time (even as a first symptom) but is more common later on. • Cognitive dysfunction can occur with any disease course, but is more likely in progressive MS. • Being in an exacerbation is a risk factor for cognitive dysfunction. • Depression can worsen cognition, particularly executive functions (Arnett et al. , 1999). La. Rocca N, Kalb R. Multiple Sclerosis: Understanding the Cognitive Challenges. New York: Demos Medical Publishing, 2006.

The Impact of Cognitive Dysfunction in Daily Life Work status P<0. 01 Social activity P<0. 05 Personal assistance P<0. 01 Community services Financial status Cognitively intact (n=52) Transportation Cognitively impaired (n=48) Personal residence 0 1 2 Mean scale score Rao et al. Neurology. 1991; 41: 692. Worsening 3

Cognitive Functions Affected in MS • • • Memory - acquisition and retrieval Attention & concentration - working memory Speed of information processing Executive Functioning Visual/spatial organization Verbal fluency - word finding De. Luca, J. What we know about cognitive changes in multiple sclerosis. In La. Rocca, N & Kalb, R (eds. ) Multiple sclerosis: understanding the cognitive challenges. New York: Demos Medical Publishing, 2006.

When Cognitive Evaluation is Appropriate • • • To establish a baseline There are reported changes in ability There is a potentially treatable condition Person is being started on a new treatment When considering an application for SSDI or vocational rehabilitation • When there is a need to know Note: The standard mental status examination used in the neurologic exam will miss 50% of cognitively impaired patients (Peyser J. , 1980)

Cognitive Dysfunction: Guidelines for Treatment • Symptomatic Treatments – slow progress - As of 2012, no agents have been shown to be effective in controlled clinical trials. - Disease Modifying Agents – may be most important - Modest results so far, but if they can slow or halt accumulation of cerebral lesions. . . • Cognitive Rehabilitation – common-sense help - Disappointing thus far but common-sense points to compensatory measures as best strategy

MS-Related Stresses for Patients and Families • MS is a chronic disease that many will live with for decades. • The unpredictability from day to day and year to year is difficult for patients and families to handle • MS is a disease characterized by change and loss. • Treatment costs and loss of income threaten patient and family well-being. • With more options available and choices to make, patients and families worry about making “wrong” choices.

Where do we go from here?

Current Treatment Priorities • Better understanding of MS pathogenesis and heterogeneity to guide development of better therapies and monitoring methods • Additional treatment options for relapsing-remitting MS(RRMS) that are more effective, convenient, and/or tolerable • Effective therapies for purely progressive MS • Neuroprotective and repair strategies • More effective treatments for common symptoms such as fatigue, pain, tremor, and cognitive impairment • More effective psychosocial support Cohen J. Arch Neurol. 2009; 66(7): 821 -828

National MS Society Resources for Your Patients • National network of chapters around the country • Web site (www. national. MSsociety. org) • Access to reliable information and referrals (1 -800 -344 -4867) • Educational programs (in-person, online) • Support programs (self-help groups, peer and professional counseling, friendly visitors) • Consultation (legal, employment, insurance, long-term care) • Financial assistance

National MS Society Resources for You • Professional Resource Center www. national. MSsociety. org/PRC; healthprof_info@nmss. org – Clinical consultations with MS specialists – Literature search services – Professional publications (Clinical Bulletins; Expert Opinion Papers; Talking with Your MS Patients about Difficult Topics; Pamela Cavallo Education Series for nurses, rehab professionals, mental health professionals, and pharmacists – Professional Education Programs (Nursing, Rehab, Mental Health) – Consultation on insurance and long-term care issues