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“Living Well With MS” Problem-oriented MS treatment with a positive spin Charles S. Yanofsky, MD www.susqneuro.com The Best Revenge is Living Well Tasks • • • • Pick your doctor Build Support System Plan for treatment Find Help For your symptoms • Pay Attention to General Health • Read and ask questions “You” to neurologist What are “you” going to Do?? Doctor • Good working knowledge about MS – Neurologist – Exp’c with MS patients • • • • Competence/qualifications Compassion ? Word of mouth You get along with him/her. Mutual understanding • Let doctor sweat the technical stuff and don’t drive yourself crazy about Don’t Squander your Doctor Visits • • • • Focus on 1-2 issues Have your own agenda Know what you want Work Collaboratively – Doctor is ally not adversary • “I’m having a problem with such and such. What can I do about it?” How Am I Doing?? Supports • • • • • Spouse/sign. Other Family Friends Coworkers Never lose sight of what is important to you. – What gives you pleasure/excites you. Supports • • • • Who to tell What to say What are your expectations of others? Self? Be sure you don’t ask for what they can’t provide To Tell or Not? • Once you tell someone e.g. your boss you can’t undo it. • Consider this Carefully • ¾ of pts who are disabled file on their own • ¾ of unemployed MS’ers say they’d like to work • 60-70% disclose their MS to their employers? But When?? Deciding on Therapy • Suppressing the Disease - the four or five alternatives. • What your Doctor recommends • Preferences? – Stage/severity of disease – Lifestyle effects – Past experience Interferons • Low Dose – Avonex – more convenient, less neutralizing antibodies • Hi Dose – Betaseron, Rebif: Possibly more effective. Increased effect on liver and neutralizing antibodies Interferons • • • • • • Betaseron, Avonex, Rebif Cut attacks by about one third Flu-like side effect Liver effect ?Depression Hold in pregnancy Copaxone • • • • • • • Novel Mechanism of action Every day sq injection Very well-tolerated ? As much MRI effect Effect on important MRI black holes ? Effect on Disability Good long term efficacy – longest experience. Novantrone • • • • 12 mg/M2/q 3 months Chemotherapy agent Cumulative dose 100 mg/M2 Monitor heart EF New Agents Being Looked At • Rituxan (Rituximab) binds to b-lymphocyte CD-20 surface (non-Hodgkins) • Inosine (Incr uric acid, decr inflamm) • Zenapax (daclizumab): binds to activated lymphocyte IL-2 (Kidney transplants) • Lipitor/Zocor Symptom Management • • • • • • • • • Fatigue Pain Gait disturbance Visual problems Spasticity Urology/Sexual Depression Cognitive problems Relationships General Health • Diet and Weight • Exercise • What’s Important to you? Divide and Conquer Problems, Problems, More Problems!! Problems have solutions • Optimism • Collaboration between patient and physician Experience Proves: Optimism wins out over pessimism Optimism vs. Pessimism • Optimistic Persons do better clinically – are they optimistic because they feel better or do they feel better because they are optimistic?? • Optimists are willing to explore possibilities – – – – Keep trying Don’t reject therapies that may help Work with their professionals bring up issues pertinent to quality of life Optimism: Rationale • It works better • More effective treatments than before • New effective treatments on Horizon Demise of Tysabri • Forces us to look at Options • Novantrone • NRABC Be not Afraid • New Breakthroughs • New Strategies MS Issues • • • • • • Neuromuscular function Gait Vision Nutrition Bladder Function Sexual Function MS Issues (cont’d) • • • • • • Pain/Paresthesia Energy Spousal/ Social/Relationships Psychiatric Cognition Spiritual Needs Sex • Complex Issue • Psychiatric aspects – Anxiety – Performance – Relational • Physical Issues – Motor dysfunction – Sensory Loss – Ass’d with bladder/ spinal cord Sex (Sol’s) • Drugs – Newer agents – Stopping certain drugs • Relational (counseling) • Techniques – Methods to get around specific problems • Openness!! Psychiatric • Reaction to chronic disease • Reaction to other person’s reaction – spouse – employer – other • Direct effect of MS on brain • Effect of other meds especially interferons psychiatric • • • • • Talk it out support groups avoid whipping yourself help with medication Developing outlets – pleasures – hobbies – “purpose” Spiritual Needs • Developing a personal context • Creating a “network” of acquaintances or one empathic person • Refuse to be defined by your illness • Taking charge Cognition: More common than previously realized • • • • • • • • Attention Concentration Short-term memory Information Processing Executive Function/Organization Perception Speech 50 up to 67% of patients Cognition • • • • Decreased speed of transmission Slowness of processing Problem with multitasking Everpresent fatigue Cognition: What’s going on?? • Connections between patches of brain cortex are frayed. • Fatigue may play a role • Speed of communication between patches or brain “Lesion Burden” More lesions = Greater Effect Less lesion burden Cognition - solutions • Problems with thought don’t make you less of a person • Just like a limp or problem with vision you have to get around it • Efficient working when you’re at your best Cognition: Sol’s 2 • Aids: – – – – – – – Notes Organizers Alarms Keyboards Personal Assistants Cell phone External brain Cognition- sol’s 3 :Let people know... • You are not goofing off • You still care about your work • Slowness of decision making does not make you indecisive • If you are distractible it is not because you don’t care Medical Solutions • Drugs for fatigue • Alzheimer type drugs seem to be effective – Aricept • Stimulants and drugs for fatigue – Provigil, Caffeine, amantadine • Anxiety is the enemy of recall • Immunomodulators/suppressants? Long term prognosis? IF supported by MRI NM/ Fatigue • Causes more Weakness • ?Due to prolonged inflammation – ?similar to prolonged viral illness (cold) • Something in the blood causes fatigue • Damage to nerve fibers is not as important • ? Does more fatigue mean more inflammation • Does fatigue affect prognosis? NM/Fatigue/Sol’ns • Drugs: – Amantadine – Activating antidepressants • Prozac, Wellbutrin – Stimulants • Ritalin, Cylert, – 4-Aminopyridine – Bupropion (Wellbutrin) NM/Fatigue/Sol’ns • Exercise – Preemptive - Goal to increase Stamina • Budgeting Energy – Energy-Saving Strategies Energy: • Chronic effect of inflammation • ?Viral Illness? Energy (Solutions) • • • • • • Exercise (Incr. Stamina) Amantadine Activating Antidepressants Stimulants anti-inflammatories 4-AP Neuromuscular Function/prob’s • • • • Weakness Fatigue Spasticity Incoordination – tremor – Ataxia – Dyscontrol NM Fxn/ Weakness/sol’ns • Attack: Treat Inflammation – Steroids, longer acting agents • Physical Therapies – Increase strength, endurance – Movement Strategies – Assistive Devices • Occup. Therapy: increase function NM/Spasticity/Why? • Nervous system: Control through INHIBITION • Brain connection to spinal cord inhibits reflexes • Connections are broken • Reflexes are dis-inhibited (liberated from higher control • Reflexes are increased • Spasticity=Resistance to Motion: Tightness NM/Spasticity/Sol’ns • Physical/occup Therapies • Be sure there are no exacerbating bladder/bowel problems • “Limbering” loosening up • Drugs: – – – – Baclofen Tizanidine (Zanaflex) Valium Dantrium MS interrupts pathways “Attack” = inflammation Series of MRI scans in one patient LHermitte Phenomenon Spinal Cord INO Inflamed Optic Nerve Inflammation • MS “attack” = Area of inflammation • One or more Areas in the Nervous system is inflamed Problem: Reducing inflammation • Acute attack • Preventing attack Acute Attack • Steroids – Solu-Medrol intravenous – Decdron, Prednisone others Preventing attack/progression • Interferons – Betaseron – Avonex – Rebif • Copaxone • Novantrone • Immune-suppressing drugs – Methotrexate, Imuran, Cell-Cept (mycophenolate), Baclofen Baclofen Pump NM/incoord./problem • Disconnection of: – Cerebellum – Other motor areas • Tremor – Postural: trunk and head – in arms and legs • Disorganization of Movement NM/Incoor/Sol’s • Physical Therapy – Mov’t Strategies and Synergies – Assistive Devices • Drugs – Tremor – Coordination – anti-spastic NM/Tremor/Surgery • Thalamotomy/Pallidotomy • Tremor pacing device Activa tremor implant tremor device • placed in the VIM of thalamus Gait/Problems • • • • • Weakness lowers affected more than uppers Control Loss of Balance Ataxia Gait/Weakness • Therapy • Exercise for muscle strengthening • Stretches and Drugs for Spasticity Gait/Balance • • • • • Usually temporary Balance Exercises cane /walker vestibular medications attention to incoordination Vision • • • • Loss of Vision in one eye (optic Neuritis) Double Vision Problems in coordinating moving eyes Complex visual perceptive problems Vision • Fortunately most problems are temporary Nutrition • • • • Regular well-balanced diet recommended Low saturated fats Vitamin Supplement Avoid Obesity Bladder • Spastic Bladder • Flaccid Bladder • “Dyssynergia” Bladder/Spastic • • • • • Bladder is small and tight urgency, frequency many voids with small volumes Goes with spasticity in legs Ditropan (XL), Detrol Bladder Control Bladder/flaccid • • • • Late in disease and less frequent Bladder is large and empties poorly Chronic change Intermittent Catheter usually recommeded Bladder dyssynergia • Sphincter and bladder contract together • Trouble pushing urine out against a closed sphincter • Training and medication that affects contraction of both elements Bladder • Spastic – Oxytrol patch, Ditropan, Detrol • Outlet obstruction – Flomax, Cardura, Hytrin • Decrease Output – Desmopressin • Botox in bladder wall • Urecholine: For flaccid bladder/urine retention Paresthesias • Discomfort to severe pain • “Painful tonic spasms” • Anticonvulsants – Tegretol, Dilantin, Neurontin • Antidepressants Recent Advances New Treatments • • • • • Immunomodulators Antibody Therapies Pumps New Drugs Devices Rebif study • Positive results were reported from a large clinical trial in Europe, Canada and Australia of interferon beta-1a (Rebif®) in relapsing-remitting MS. The drug reduced relapse rate, slowed progression of disability and reduced MRI-detected brain lesions. Reduced chance of time to first exacerbation compared with Avonex. Betaseron in progressive MS • A large European clinical trial of interferon beta-1b (Betaseron®) in over 700 people with secondary-progressive MS was stopped early because the study showed the drug can slow the progression of disability. The U.S. FDA is reviewing study findings for possible approval of Betaseron for this new use Monoclonal Antibodies • Researchers across the U.S. continued or began separate clinical trials of two monoclonal antibodies (LeukArrest, by ICOS Corp. and Tysabri (Antegren) by Athena Neurosciences) aimed at reducing the severity and duration of MS attacks by blocking the entry of destructive immune cells into the brain and spinal cord. Antegren (Tysabri) • Elan drug teamed up with Biogen Idec • monoclonal antibody • attaches to alpha 4 Integrin – protein on lymphocyte – protein is lymphocyte attachment to blood vessels Tysabri • 2 cases of PML – fatal disease – Both patients using Avonex • Is drug dead? • Will this tell us something more about MS? LeukArrest (monoclonal Ab) Prevents White cells from invading brain Red areas = myelin breakdown Oral interferon • Researchers at the University of Texas Health Science Center began a small-scale clinical trial of an oral form of interferon alpha for relapsing-remitting disease, based on positive findings in rodents with MS-like disease TCR (t-Cell receptor) peptide (Connetics) • vaccine against t-cells Growth Factors • Insulin-like growth factor • Increase myelin • When and where to implant Stem Cell Transplants • May be more effective for diseases that kill neurons or brain cells • One day may be effective for treating certain persons with MS Herpes 6 • Roseola in toddlers – erythema subitum – rash – neurologic symptoms – mononucleosis like in adults • can invade CNS HHV-6 • Demyelinating when invades CNS • Detected high levels in MS CNS (Challoner) • Detected in bloodstream in MS patients • Also seen in chronic fatigue HHV-6 Treatment • Similar to Cytomegalovirus • Ganciclorir and Foscarnet – Gan can affect WBC’s – Fos can affect Kidneys anemia, lytes • ?How long to treat? HHV-6 tests • Peripheral blood test • “Shell vial Culture” • HerpesVirus Diagnostics Inc – c/o Federal Express, 11101 W. Plank Court, Wauwatosa, WI 55226 • $270.00 Disability • If you have little disability over a long time you are more likely to have mild MS • Followed patients mild v. not mild for 10 years. Milder patients progressed less. EDSS of 2 or less 93% chance of little disability. Small study • Didn’t everybody know that? • Unfortunately you can’t predict how things will be early in the disease. • Pittock et al Annals of Neurology (2004;56:303306). Genetic Risk of MS • Risk of MS is 1 per 750 in the United States • Risk increases to 2-5 per 1000 if first degree relative has the disease – 1/40 for parent • Risk 30-50% for identical twin • “Multiplex” families with >1 members important • Implication: MS is genetic with environmental influence. “Polygenic” Black v White • Black: MS about half as common • Rare in Africa • Worse disease: More frequent progress to cane 16 v. 22 years Kurtzke 6 on average • Neurology 63[11]:2039-45 Dec 14, ‘04 • Black NH residents much more cognitively and physically impaired and on fewer meds, younger Hygeine hypothesis • Exposure to a younger sib decrease risk of MS • Sunlight effect • MS patients are more sheltered? – Less exposure to pathogens in early life • JAMA 1005;293:463-469 Infectious Agents tied to MS • • • • • • • • • Canine dystemper virus Chlamidia pneumoniae Epstein-Barr (mononucleosis virus) HHV-6 HTLV l Measles PML? (JC virus, SV40 papovaviruses) ? Lyme Sarcoid Neuromyelitis Optica IgG • May be different disease with different immune determinant • NMO-IgG to the Mayo Clinic • The Lancet 2004, Dec 11; 364[9451]:210612 Lennon et al Hep B vaccine and MS • MS patients compared to controls had a threefold increased chance of having gotten the Hep B vaccine in the past three years. • 11 of 164 MS patients received at least one Hep B shot within 3 years compared with 36 of 1604 control patients. • What does it mean? Nothing. • 2nd study found no relationship Statins • EAE in mice can be partly reversed with statin • MS patients WBC response becomes more normal after treatement with statin • Human MS trials underway • Small study with Zocor 30 patients encouraging • Recommendation: If your cholesterol is high, use statins. Otherwise the jury is still out. Sun Exposure • MS more common in higher latitudes • Tasmania study van der Mei et al More sun exposure more skin damage associated with less MS British Medical Journal (2003;327:316). • UVR radiation more common in tropics • ? Effect of vitamin D which has some immunomodulatory effect Clinical Trials • Avonex Plus – Mtx, azathiatprine, Tysabri • Copaxone plus • Betaseron plus • Rituxan (Rituximab) binds to b-lymphocyte CD20 surface • Inosine • Zenapax (daclizumab): binds to activated lymphocyte IL-2 • ABT-874 immunosuppressor • Lipitor