Bertha C. Fonseca, MDNSC Multiple Sclerosis Center, Coral Gables, FL
Multiple Sclerosis Is an autoimmune chronic neurological conditionwhere the myelin (protective covering) surroundingnerve fibers in the brain, optic nerves, and spinal cordis damaged or destroyed. These lesions can cause interruption in the electricalimpulses which are transmitted to and from the brainresulting in the symptoms of MS.
Multiple Sclerosis The exact cause is unknown, but it is believe to bemulti-factorial. Usually develops between the 20-40. There are approximately 400,000 patients diagnosedwith MS. There are different types of MS: RRMS, PPMS, SPMS,and PRMS.
Common Symptoms in MS Loss of function/sensation in limbs Disturbance of walking/balance Disturbance of vision Bowel/bladder dysfunction * Fatigue * Pain Cognitive changes * Sexual dysfunction
Cognitive Impairment Cognition is the process of thought It can be seen in 45-65% of MS patients, usually mildto moderate Only 5-10% have severe dysfunction Disability and disease duration are not good predictorsof cognitive dysfunction
Cognitive Impairment There are certain areas of cognition that are moreaffected in MS Recent memory (short term memory) Verbal fluency Abstract reasoning Sustained attention (specifically with multiple tasks) Concentration
Etiology of Cognitive Impairment Extent and location of lesions Greater burden of disease T2 lesions Locations such as the frontal lobe Degree or extent of brain atrophy T1 “Black holes” lesion volume
Etiology of Cognitive Impairment Other causes which need to be evaluated: Depression (common cause of pseudodementia) Stress Fatigue (affects concentration and performance ofintellectual tasks) Medications (Baclofen, Neurontin, Clonazepam, etc) Sleep disturbances
Assessment of CognitiveImpairment Screening Neuropsychological test batteries have beendeveloped specifically for MS patients Performed by Neuropsychologists mainly.
Treatment of Cognitive Impairment Multiple medications have been studied and theyhave failed to show benefit in the treatment of MSrelated cognitive impairment. The most important factor is to be on an approvedtreatment for MS Like in the case of RRMS one of the many FDA approvedoptions that we have now (9).
Treatment of Cognitive Impairment Cognitive Rehab Restorative – to restore and strengthen impairedfunctions through drills and exercises Compensatory – to train the patient to function anduse strategies that can be helpful (ex., organizers,notes, etc)
Treatment of Cognitive Impairment Cognitive strategies: Write everything down Have a designated space for everything Repeat things that need to be remembered Take your time If you find cognitive problems happen at a particulartime reorganize activities so you have the moredemanding things done before that time. Focus on thing at a time.
Treatment of Cognitive Impairment Most importantly, discuss all your symptoms,including cognitive impairment or memory loss, withyou physician immediately so that he or she canevaluate you and treat you accordingly.
Fatigue One of the most disabling and common symptoms inMS patients (80%). Consists of lack of energy, tiredness and/orgeneralized weakness. Could be more pronounced in patients with atrophy incertain parts of the brain (parietal lobes). Other causes must be excluded including: depression,insomnia, OSA, thyroid dysfunction, medications,vitamin deficiencies, anemia, etc.16
Treatment of Fatigue Depending on cause it would need specific treatment. If fatigue is caused my MS, there are several un-approved treatments for it: Amantadine Provigil Nuvigil17
Treatment of Fatigue Non-pharmacological treatments of fatigue: Conserve energy. Take naps during the day. Arrange activities to be done in the part of the day withmost energy. Stay away from the heat. Stay hydrated and eat healthy. Exercise regularly, if your physician approves.18
Bladder dysfunction Some patients with MS might experience problemswith their bladder. There are several types of bladderproblems: Bladder with failure to store (spastic) Bladder with failure to empty Conflicting bladder20
Bladder dysfunction There are several symptoms that can be seen: Frequency and/or urgency of urination. Hesitancy of urination. Inability to completely empty bladder. Inability to hold urine. Frequent nighttime urination. Discuss with your HCP if you are experiencing thesesymptoms, so that further tests such as post-voidalresidual, urodynamics, ultrasound, and Urologyevaluation can be ordered.21
Bladder dysfunction Some tips that can help with bladder issues: Stay hydrated. Avoid caffeine. Don’t sip water and liquids all day long. Take bathroom breaks. Also, there are approved medications for the treatmentof overactive bladder that can be of help for those thatcan take them.22
Bowel dysfunction Some patients with MS might experience twoproblems with bowel: Accidental loss of stool (incontinence) Constipation which might be caused by lack of properhydration, lack of physical exercise or by medication.23
Bowel dysfunction Some tips that could help some patients with boweldysfunction would be: Stay well hydrated. Changes in diet, by increasing fiber intake. Stool softeners. Bowel program. In some cases, medication.24
Bertha C. Fonseca, MDNSC Multiple Sclerosis Center, Coral Gables, FL
Vitamin D Vitamin D is a fat soluble vitamin that is responsiblefor the absorption of calcium and phosphate. It is mainly obtained from our diet and alsosynthesized by exposure to sunlight. Low vitamin D levels are associated to cardiovasculardisease, osteoporosis, and certain cancers (ex. colon). It is also believed to have a positive effect on ourimmune system.26
Vitamin D Low levels of vitamin D are associated with MultipleSclerosis. Several studies have shown that maintaining adequatelevels of Vit D have protective effect and lower the riskof developing MS. Another study from the Netherlands suggest that forMS patients, vitamin D may lessen the frequency andthe severity of their symptoms.27
Vitamin D The connection between MS and vitamin D is linkedto the association of sunlight and the risk of MS. The father away a person lives from the Equator, thehigher the risk of MS. Your HCP needs to check the level of Vitamin D-25with a simple blood test and based on that give specificrecommendations on dosing to prevent toxicity.28
Smoking In a study in Norway, published in Neurology, the riskof MS was significantly higher among smokers whencompared to those who had never smoked. Another paper published in Brain supported the linkbetween smoking and the risk of developing MS, andalso suggested that smoking may be a risk factor fortransforming a relapsing-remitting clinical course intoa secondary-progressive course. (NMSS)29
Smoking Another study in Buffalo demonstrated thatindividuals that smoked had lower brain volumes. Also, another study suggested that MS patients thatsmoked had accumulated disability faster than non-smokers. Discuss with your HCP your desire to stop smoking sothat he/she can provide recommendations that canhelp you quit smoking.30
Salt Recently, studies evaluated a possible link of high saltdiets and the increment in the cases of autoimmunedisease, such as MS. A study published in the journal Nature, showed thathigh salt diets increased levels of a type of immunecells , Th17 (that promote inflammation), linked withautoimmune diseases. In this study, mice that were genetically engineered todevelop MS got much worse when they ate high saltdiets when compared to those that ate a moremoderate salt intake.31
Salt These studies could suggest that high salt intake couldplay a role in triggering autoimmune disease, such asMS and DM, in individuals who are geneticallypredisposed. The effect of high salt intake on MS now needs to bestudies in humans. Reducing the dietary salt might be a good idea forthose that can, since it has also been linked for manyyears to hypertension and cardiovascular disease.32
Bertha C. Fonseca, MDNSC Multiple Sclerosis Center, Coral Gables, FL
Treatments for MS There are several FDA approved treatments for RelapsingRemitting Multiple Sclerosis: Betaseron Avonex Copaxone Novantrone Rebif Tysabri Extavia Gilenya Aubagio Tecfidera
The changing treatment landscape1-181. Multiple Sclerosis Treatments. Avonex Web site. 2. Company news; F.D.A. approves a multiple sclerosis drug. 3. Biotechnology medications move closer to the market.4. Seronos rebif(R) receives FDA approval. 5. Immunex gets FDA OK. 6. Multiple sclerosis (relapsing-remitting): emerging therapies that offer improved convenience will not unseatcurrent drugs. Decision Base 2009. 7. Novartis media release. 8. Merck Serono news release. 9. Giovannoni G, et al. N Engl J Med. 2010; 362(5):416-426. 10. Cohen JA, et al.N Engl J Med. 2010;362(5):402-415. 11. Kappos L, et al. N Engl J Med. 2010;362(5):387-401. 12. Study results: multiple sclerosis patients have significant and sustained reductionin disability and risk of relapse on alemtuzumab versus approved therapy. 13. ALLEGRO study. Clinicaltrials.gov Web site. 14. BRAVO study. Clinicaltrials.gov Web site.15. Biogen Idec showcases more than 70 data presentations at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis [news release].16. Study of teriflunomide in reducing the frequency of relapses and accumulation of disability in patients with multiple sclerosis (TEMSO). 17. Novantrone®. National MultipleSclerosis Society Web site. 18. Tysabri® prescribing information. Biogen Idec Inc.Under FDA review Currently not submittedFDA-approved therapies1995 2000 2005 2009 2010 2011CladribineFingolimodAlemtuzumabFumarate(BG-12)TeriflunomideExtavia®(IFNβ-1b)Tysabri® (natalizumab)Betaseron®(IFNβ-1b)COPAXONE®(glatiramer acetate injection)Avonex®(IFNβ-1a)Rebif®(IFNβ-1a)Novantrone®(mitoxantrone)LaquinimodApproval date Estimated launch date35
Emerging therapies for MS Copaxone Approved for the treatment of RRMS since 1996. Believed to cause a shift from Th1 cells (inflammatory)to Th2 (anti-inflammatory cells). GALA Study Copaxone was given to patients at 40 milligrams three timesa week, rather than 20 mg daily sub cut. Awaiting for approval currently.36
Emerging therapies for MS Tecfidera (formerly known as BG-12) Dimethyl fumarate Approved by FDA on March 2013 for RRMS. Exact mechanism not understood, but it is believed havean antiinflammatory effect and also inhibits an enzymethat accumulates leukocytes at sites of inflammation. It is believed to reduce the oxidative stress, whichreleases free radicals. Similar component has been used for treatment ofPsoriasis for 30 years in Europe.
Emerging therapies for MS Tecfidera In the DEFINE (Determination of the Efficacy and safetyof oral Fumarate IN Relapsing Remitting MS) showed53% reduction in ARR and 90% reduction in the meannumber of new or enlarging lesions at 2 years whencompared to placebo (NEJM, Fox et al) Most common side effects: Flushing, headache, nausea,diarrhea, and abdominal pain.
Emerging therapies for MS Tecfidera It is started 120 mg po bid with food for 1 week and thenincreased to 240 mg po bid, unless recommendedotherwise by the HCP. It has been shown that when taken with food it reducesthe risks of the side effects. It is recommended to monitor liver enzymes and WBCand lymphocytes. Labs must be done before startingmedication and followed up according to the HCP.39
Emerging therapies for MS Teriflunomide Oral agent Approved as Aubagio Inhibits rapidly dividing cells. Suppresses proinflammatoryfactors and limits proliferation of T and B cells Used for Rheumatoid Arthritis In the studies it has shown decreased ARR by 30% Patients also showed fewer gadolinium-enhancing lesions perT1-weighted scan than those in the placebo group . Most common side effects: hair loss, nausea, and diarrhea.Infections have been reported. It is teratogenic (for men andwomen) and hepatotoxic, therefore it has two black boxwarnings.
Emerging therapies for MS Teriflunomide (Aubagio) Other warnings and precautions: May decrease WBC count (TB testing and not recommendedfor patients with immunodeficiencies). Acute renal failure. Skin reactions Peripheral neuropathy Increase in blood pressure Could interact with other medications (propanolol,acetaminophen, diazepam, etc)41
Emerging therapies for MS Alemtuzumab Intravenous infusion Monoclonal antibody Currently used for treatment of chronic lymphocyticleukemia and T-cell lymphoma Causes lymphocyte depletion Within an hour of receiving dose, lymphocytes andmonocytes are no longer detectable in circulation.
Emerging therapies for MS Alemtuzumab The cumulative number of relapses over time was reduced by74%, and the time to sustained accumulation of disability(SAD) was reduced by 71% with alemtuzumab, comparedwith interferon. Side effects: autoimmune thyroid dysfunction, mild tomoderate infections (respiratory, UTI, herpes), infusionreactions, etc. In the CAMMS223 trial there were 3 cases of cancer, 3 cases ofserious infusion reactions and 1 death related to cardiacdisease Needs monitoring with monthly CBC, quarterly TSH,Acyclovir for 1 month as prevention, and needs monitoringfor 4 years after last dose.
Emerging therapies for MS Rituximab Intravenous infusion Monoclonal antibody Approved for non-Hodgkin lymphoma and refractoryRA. Causes rapid depletion of B cells for 4-12 months Reduction of contrast enhancing lesions in MRI andrelapse rate Side effects: infusion reactions, nausea, infections, andthere have been cases of PML described.
Emerging therapies for MS Ocrelizumab Intravenous infusion Phase II trial Monoclonal antibody Targets mature B lymphocytes, hence it has animmunosuppressive effect. Trials have shown significant MRI activity decrease anddecrease ARR by 80% Deaths have been reported in the RA trial and wassuspended for SLE as well due to opportunisticinfections.
Emerging therapies for MS Laquinimod Induces anti-inflammatory cytokines and reducesproinflammatory cytokines production by monocytes. Targets cells in the CNS and peripheral immune cellsthat then lead to demyelination and neuronal loss. It penetrates the blood-brain barrier. Probably will be available, if approved by the FDA, in theyear 2017.46
Emerging therapies for MS Laquinimod In the ALLEGRO study, Laquinimod showed: 23% reduction in the annualized relapse rate. 36% decrease in the risk of disability progression whencompared to placebo. 33% reduction in progression of brain volume loss vs. placebo The most common side effects seen in the study were: Abdominal pain, elevated liver enzymes, back pain, andcough. Also a higher rate of appendicitis was reported in theLaquinimod group.47
Other medications for MS Ampyra “The walking pill” Only approved for use by MS patients Believed to send the nerve impulses faster towards thelegs, therefore could give patient the ability to walkfaster. Contraindicated in patients with seizures or kidneydysfunction Some of the side effects are: UTI, dizziness, imbalance,gastrointestinal issues, etc.49
Other medications for MS ACTHAR gel ACTH which is a hormone that helps the body producenatural steroid hormones to reduce inflammation. Recommended to treat MS exacerbations for patientsthat have developed side effects to Solumedrol, havepoor venous access or have not responded well toSolumedrol treatment during a flare-up. Given daily in subcutaneous form for the amount of daysnecessary to treat relapse (average of 5 days).50
Conclusions There are currently several trials in the process toprovide us with treatment options, oral andintravenous, for MS patients. Many of them show promising results, proving to benot only effective but also safe.