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Multiple Sclerosis: A Diagnosis and Treatment Update Case Manager Society of America Natasha Frost, MD 5/26/2016 Objectives Define Multiple Sclerosis (MS) Forms of MS Diagnostic Criteria MS Treatment Disease modifying Symptomatic MS symptomatic issues important to therapy professions Multiple Sclerosis An immune-mediated disease of the central nervous system A disease of myelin and axons A disease of people and behaves differently in everyone Huge spectrum of severity and disability from the same disease Balancing the Mediators of the Immune System Proinflammatory and Neurotoxic Factors TH1 and TH17 cytokines TNF IL-1 osteopontin leukotrienes MMP plasminogen activators nitric oxide reactive oxygen species glutamate antibody + complement cell-mediated cytotoxicity neurotrophins via p75NTR? Destruction Anti-inflammatory and Neuroprotective Factors TH2 cytokines TGF-beta soluble TNF receptor soluble IL-1 receptor IL-1 receptor antagonist some prostaglandins lipoxins TIMP antithrombin BDNF NGF NT3 neurotrophic NT4/5 factors GDNF LIF 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 Protection 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. Who gets MS and why? Usually diagnosed between 20 and 50 Occasionally diagnosed in young children and older adults More common in women than men (>2-3:1) More common in smokers and children of smokers 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? What are the typical signs? Classically Optic neuritis Transverse myelitis Brainstem syndrome (diplopia) Other Numbness, weakness, vertigo etc. More non specific but probably just as common as classic presentation. Differential Diagnosis of MS (not all inclusive) Infection - Lyme, syphilis, PML, HIV, HTLV1, Herpes viruses Inflammatory - CTD, vasculitis, sarcoid, Behcet’s, Susac’s, celiac disease, NMO/Devic’s Genetic/metabolic - B12, Copper, lysosomal, ALD, mitochondrial, CADASIL, other genetic Neoplastic - CNS lymphoma Spine disease - vascular malformations, tumor, degenerative/compressive spine disease Psychiatric – psychosomatic, depression, etc.. Diagnosing MS MS is a clinical diagnosis Signs and symptoms 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 T2 BOD* T1 precontrast T1 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. MRI in MS: typical features vs non specific Peri-ventricular Sub-cortical Perpendicular to ventricle more specific for MS Deep white matter Anterior/ posterior horns non-specific for MS Clinical Patterns of MS Relapsing-remitting Secondary progressive Primary progressive Progressive relapsing Time Adapted from Lublin et al. Neurology. 1996;46:907-911. 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 Several MS medications are approved in CIS at risk for MS Radiographically isolated syndrome A MRI that looks “like MS” No signs or symptoms of MS 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) ?Males, older age at first symptoms, race Relapse Management Relapse = NEW symptom lasting at least 24 hours, and usually accompanied by an objective change in neurologic findings. Rarely “old symptom” that is worse. “pseudo relapses” are common and should not be treated with steroids Treatment with corticosteroids recommended if relapse significantly interferes with functioning 3-5 day course of high-dose intravenous methylprednisolone with or without oral taper If very mild sensory symptoms or intermittent it can be allowed to just run its course. Other options – ACTH, IVIG or plasma exchange. Rehabilitation can help restore function following a relapse Disease modifying therapies (DMT) Medication Dose Route Frequency Side effects and monitoring Inteferon betas (Avonex, Betaseron, Rebif, Extavia, Plegridy) varies Self injection IM or SQ Every other day to every 2 weeks Flu like and injection site reactions CBC, LFT, TSH monitoring Glatiramer Acetate (Copaxone) 20-40 mg Self injection SQ Daily to 3 times per week Site reactions, lipoatrophy, and post injection reaction Fingolimod (Gilenya) 0.5 mg Oral Daily Cardiac, macular edema, and infections 6 hour monitoring during first dose. Labs and OCT afterwards Teriflunomide (Aubagio) 14 mg Oral Daily Liver toxicity, hair loss, nausea, Stays in system 2 years without chelation Pregnancy Category X Monthly LFTs for 6 months Dimethyl fumarate (Tecfidera) 240 mg Oral Twice a day Flushing, GI side effects, rare infection LFT and CBC monitoring Natalizumab (Tysabri) 300 mg IV Once a month Rare infusion reaction and PML Close clinical and imaging monitoring Alemtuzumab (Lemtrada) 12 mg/day IV Once a year, 5 day course x2 Other serious autoimmune (thyroid, TTP, kidney), infection, malignancy, infusion reactions. Monthly labs 4 years. Mitoxantrone (Novantrone) 12 mg/m2 IV Every 3 months Leukemia and cardiac toxicity, chemotherapy side effects Frequent labs during treatment and life long follow up. Why treat? Goal is to reduce Relapses Disability progression At 10 years w/o 50% need gait assistance 10% wheelchair Progression of cognitive difficulties 45-65% cross sectional. Development of MRI lesions Progression of brain atrophy None are perfect Early treatment important 7 years of imaging in a patient with relapsing MS – courtesy of R. Fox The Future of Treatment Stem cells Autologus versus donor Intravenous versus intrathecal Neuroprotection Remyelinating agents Medications for primary and secondary progressive MS Ocrelizumab Improved symptomatic management Improved rehabilitation and devices MS Symptomatic Treatment- so many things to talk about and often too many medications Symptoms Fatigue, spasticity, pain, depression, cognitive dysfunction, balance, neurogenic bladder/bowel, tremor, weakness, paresthesias, numbness, gait disorder, falls, constipation, vision loss, and others. MS is commonly blamed for all complaints. Especially those that are not easily explained. PT, OT, rehab and exercise are often the best place to start. If these do not help we have many medications at our disposal but caution as polypharmacy and medications side effects are very common. Depression in MS Depression is common in MS Lifetime prevalence 50% or more. 12 mo. prevalence 15-25%. 4.75x rate of antidepressant use as age matched controls and 3.21 those with OA. Depression correlates with gender, marital status, insurance, fatigue and DMT use. Also, increased rate of suicide IF they contact someone for depression it is usually PCP. Responds to combination of therapy and medications (SSRIs etc…) Worsens many other symptoms and makes them harder to treat. (Kessing, International Clinical Pharmacology, 2008)(Cetin, MS, 2007) Anxiety Disorder (25% prevalence in MS) Etiology: reactive or biologic? Debated Very common at time of diagnosis especially if some anxiety disorder prior Anxiety in partners of MS patients is equal to that of MS patients Patient education, reassurance (e.g., at first diagnosis: “life isn’t over; disease is mild in many patients, now many treatments”), and psychotherapy are effective. Counseling first and pharmacotherapy, if indicated: benzodiazepines (note cognitive risk in MS) or SSRIs Janssens ACJW. Acta Neurol Scand 2003;108:389 Cognitive problems in MS Cognitive Disorder – subtle changes are common (65+%) severe dementia is uncommon rare isolated first presentation neuropsychological testing may be helpful most studies to not indicate a benefit in MS from anti-Alzheimer’s meds behavioral strategies help look for other fixable coexisting causes Vitamin deficiencies Thyroid problems Depression Medication side effects Common and “fixable.” Fatigue (lack of energy, lassitude) Mild fatigue is almost universal in MS Severe fatigue may be disabling in ≈ 5+% of MS patients Fatigue may be associated with or due to depression, anxiety, sleep disturbance, pain, heat sensitivity, diminished physical or mental reserve, co-morbidities First, assess/treat relevant medical (e.g., anemia, hypothyroidism) or psychiatric co-morbidities Second, non-pharmacologic therapy: exercise, behavioral therapy, energy conservation (prioritize, naps, cooling), smoking cessation Third, pharmacologic treatment: amantadine, modafinil/armodafinil, methylphenidate, amphetamine Krupp LB, Serafin DJ. Ch. 56 in JJA Cohe, RA Rudick. Multiple Sclerosis Therapeutics, 2012 Temperature sensitivity Heat sensitivity is very common in MS Sometimes cold reported as well (spasticity) Brings back any old symptom when core temperature is up Some studies suggest as little as ¼ degree Not new damage, but decompensation under stress Environment, exercise, illness, fever Treat with NSAIDs/Tylenol when ill Cooling vests and other aides Cold drinks, exercising in cool area/fan etc.. Cool down and wait it out Gait Disorder Figure out of MS related or other (such as joint disease) Referral to therapy and increased activity Treat spasticity Evaluate for assistive devices Cane, walker, chairs AFO, walkaide/bioness Money available for assistance NMSS/MSAA as not FDA approved for MS. Hip assist device Medication for walking Dalfampridine SR (Ampyra) Dalfampridine SR (Ampyra) Dalfampridine SR (Ampyra) – potassium channel blocker, “axonal stabilizer” Approved to improve walking speed in any form of MS 10 mg every 12 hours Renal clearance (no kidney disease, increased dose increased risk seizure) In pivotal clinical trial Improvement in timed 25 foot walk Subset works and others does not Subjectively other symptoms may improve but only has approval for walking and often must prove effective Ampyra • • • Average change in walking speed from baseline in double blind placebo controlled study. More patients had a 10-30% improvement in timed 25 foot walk on Ampyra. In both trials, 34-42% of patients responded versus 8-9% of placebo. (Figure taken from Ampyra prescribing guide). Spasticity Therapy and home stretching Aerobic activity program for any able limbs Antispasticity medications Lioresal (Baclofen) Tizanidine (Zanaflex) Sometimes benzodiazepines or others Botox Works best for single limb or targeted function Baclofen pumps Trial needed Can be very effective for severe or more wide spread spasticity with fewer systemic side effects. Rarely infectious or malfunction complications Neuropathic pain Can be one of the hardest symptoms to treat Again, make sure consistent with MS and nerve pain Everything we use for this is used off label Medications Gabapentin, pregabalin, carbamazepine, phenytoin, lamotrigine, duloxetine, tricyclic antidepressants etc. NSAIDS Narcotics pain referral with procedures Infusions, injections, morphine/baclofen pump neurosurgery or radiation oncology referral Radiofrequency ablation for trigeminal neuralgia or other destruction of pain fibers. Other overlooked symptoms Balance Fall prevention and home safety Therapy, exercise, Tai Chi and Yoga Coordination and ataxia Therapy and adaptations Tremor Medications – beta blockers, topiramate, benzos etc. Weighted utensils, pens, and other adaptations Diplopia- prisms Speech Speech therapy and aspiration prevention Very rarely feeding tubes Other overlooked symptoms Neurogenic bladder Fluids and treating constipation Evaluating caffeine intake Urinary tract infections Medications for overactive versus atonic bladder Catheterization if needed Neurogenic bowel Fiber and fluids Then, pro motility agents if needed Sexual dysfunction (men and women) Treat pain, mobility, and counseling Medications for erectile dysfunction Devices for erection or stimulation This is the hardest for patients to bring up Resources National MS society (nmss.org) WI chapter with support resources and patient information. Clinical trials by state (also clinicaltrials.gov) Multiple Sclerosis Association of America (MSAA.org) UW MS Center Myself, Dr. Luzzio, Dr. Fleming, and Jocelyn Wilke, NP. Appointments – 608-262-0546 [email protected] Thank you and questions