1、“Multiple”- multiple areas of lost myelin“Sclerosis”- ScarringMS is a chronic autoimmune inflammatory diseaseAffects Central Nervous System (brain, spinal chord and optic nerves)Multiple SclerosisInternational Journal of MS CareMultiple SclerosisMultiple SclerosisA chronic, autoimmune disease Affect
2、s central nervous system the myelin sheath covering of nerve fibers in the brain and spinal cordImpairs the nerves ability to send electrical impulsesMS StatisticsApproximately 400,000 Americans are diagnosed with MS Affects 2.5 million people worldwideSymptom onset and diagnosis occur typically bet
3、ween the ages of 20-502.5:1 women:man ratioPeople of Northern European descent are afflicted most commonlyMore common above 40 latitude in areas like western New York.Women are 2 times more likely to get the disease (i.e. 2 women for every 1 men)More common in Northern European descendants than any
4、other raceFound in people who live in temperate climatesOnset occurs between ages of 20 and 40http:/ of MSMuscle weaknessVisual symptomsBlurry visionDouble visionUnsteady gait/balance issuesPain/ParesthesiasEmotional/Cognitive disturbancesShort term memory lossInability to concentrateFatigueSexual D
5、ysfunctionSpeechSwallowingAbnormal sensationsTinglingNumbnessSensitivity to heatBladder and bowel problemsFrequencyLoss of controlMultiple Sclerosis Kurtzke disability status scale1 No disability & minimal neurologic sign2 Minimal disability - slight weakness or stiffness, mild disturbance of gait o
6、r mild visual disturbance3 Moderate disability - monoparesis (partial or incomplete paralysis affecting one or part of one extremity) mild hemiparesis (slight paralysis affecting one side of body) moderate ataxia, disturbing sensory loss, prominent urinary or eye symptom, or a combination of lesser
7、dysfunction4 Relatively severe disability, but fully ambulatory without aid, self sufficient and able to be up and about 12 hours a day, does not prevent the ability to work or carry on normal living activities, excluding sexual dysfunction5 Disability is severe enough to preclude working, maximal m
8、otor function involves walking unaided up to 500 meters6 Needs assistance walking, for example a cane, crutches, or braces7 Essentially restricted to a wheelchair but able to wheel oneself and enter and leave the chair without assistance8 Essentially restricted to bed or a chair, retains many self c
9、are functions and has effective use of arms9 Helpless and bedridden10 Death due to MS - results from respiratory paralysis, coma of uncertain origin, or following repeated or prolonged epileptic seizuresDiagnosing MSA diagnosis by exclusion eliminate other disease states that may explain symptoms be
10、fore suggesting MSPatients undergo clinical, laboratory (hematology and CSF panels), and imaging studies to confirm diagnosisDiagnosis by Poser Criteria Clinically definite MS 2 attacks and clinical evidence of 2 separate lesions Laboratory supported Definite MS 2 attacks, either clinical or paracli
11、nical evidence of 1 lesion, and CSF immunologic abnormalities 1 attack, clinical evidence of 2 separate lesions & CSF abnormalities 1 attack, clinical evidence of 1 and paraclinical evidence of another separate lesion, & CSF abnormalities MRI MRI findings that strongly suggestive of MS 4 or more whi
12、te matter lesions (each 3mm) 3 white matter lesions, 1 periventricular Lesions 6 mm diameter or greater Ovoid lesions, oriented perpendicular to ventricles Corpus callosum lesions Brainstem lesions Open ring appearance of gadolinium enhancementThe axial T2WI shows peri-ventricular flame-shaped hyper
13、intense areas MRI ImagingNormal BrainPatient with MSMS Lesions “Dawsons Fingers”MS Lesions in SpineCerebral Spinal Fluid Studies Strongly suggestive of MS Normal Red Blood Cells and glucose Normal or mildly elevated protein 5-20 mononuclear cells/ul Intrathecal IgG synthesis Increased IgG index or 2
14、4 hour synthesis rate Increased free kappa light chains Oligoclonal bandsRelapsing-Remitting MS (RRMS)Most common, affecting 85% of patients.Patients experience worsening of pre-existing symptoms or onset of new symptoms for periods of greater than 48 hours without concomitant fever, known as relaps
15、es, flare-ups, or exacerbations, of MS. Contrasted by symptom-free periods, known as remissions, where the patients symptoms partially or completely disappear.Secondary-Progressive MS (SPMS)A progression of RRMSMore common before advent of disease-modifying medicationsApproximately 50% of patients p
16、rogressed to SPMS after 10-15 years with RRMSIncidence has since decreasedThis disease course is steadily progressing.Can present with or without clear-cut relapses. Primary-Progressive MS (PPMS)Relatively rare, affecting 10% of patients.Disease course is characterized by steady decline, without cle
17、ar-cut relapses. Medications are generally not effective at treating this type of disease.Progressive-Relapsing MS (PRMS)Relatively rare, affecting 5% of patients.Steady disease progression, in addition to clear-cut periods of exacerbations of MS.Patients can be treated for relapses with steroids, h
18、owever disease will progress regardless of therapy.TreatmentNot a known cureTreatment aimed at controlling symptoms and maintaining functionDisease modifying therapyTreatment of RelapsesMedications depending on the symptomsPhysical therapySpeech therapyPlanned exercise programs in early course of di
19、sease Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability.Methylprednisone (Solumedrol): 1 gram iv infusion per day x 3 to 5 days - may be followed by oral Prednisone taper 60 mg qd x 7 days, then 60 mg qod x 7 days, the
20、n 40 mg qod x 7 days, then 20 mg qod x 7 days, then stop H2 blocker/PPI for ulcer prophylaxis Monitor blood glucose Watch for infectionAdrenocorticotropic hormone stimulates the adrenal cortex to secrete adrenal steroids (including cortisol), weakly androgenic substances, and aldosteroneIntramuscula
21、r or Subcutaneously: 80 to 120 units/day for 2 to 3 weeksCurrently Available Disease Modifying TreatmentsKM. Gawronski et al. Treatment Options for Multiple Sclerosis: Current and Emerging TherapiesPharmacotherapy. 2010;30(9):916-927.Dipiro et al. Pharmacotherapy: A Pathophysiologic Approach 7th ed.
22、 Interferon betaMechanism of Action = Specific interferon-induced proteins and mechanisms by which interferon beta exerts its effects in MS have not been fully defined. It may augment suppressor T-cell function; may decrease interferon gamma secretion by activated lymphocytes; may decrease macrophag
23、e activating effect; may down-regulate expression of major histocompatibility complex gene production on antigen presenting glial cells.May also suppress T cell proliferation and decrease blood brain barrier permeabilityIntramuscular injection given once weeklyDose: 30 mcgPregnancy Category CSubcuta
24、neous injection given three times a weekDose: 22 or 44 mcg Pregnancy Category CInterferon beta-1bSubcutaneous injection given every other dayDose: 250 mcg achieved over a 6 week titrationPregnancy Category CBetaseronRebifAvonexInterferon beta-1aAvailable in three forms:Interferon beta Side EffectsFL
25、U LIKE SYMPTOMS! Up to 60% of patients.Pre-medicate before injection and the day following with Ibuprofen or Acetaminophen to decrease these symptoms.Will dissipate with continued use.Generally worse in females and those with lower body weight.FeverChillsHeadacheChest painInjection site reactionsEry
26、themaInflammationPainSkin discoloration/swellingDepressionMyalgiaArthralgiaAstheniaMalaiseDiaphoresisMyastheniaAbdominal painGlatiramer acetate Mechanism of Action = Not fully known, thought to be related to alteration of T-cell activation and differentiation.Studies in animals and in vitro systems
27、suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery.May mimic antigenic properties of myelin basic protein; May bind to Major histocompatibility complex class II receptors and inhibit binding of myelin basic protein peptides
28、 to T cell receptor complexes; May induce Th2 antiinflammatory lymphocytes and decrease inflammation, demyelination, and axon damage. Available as CopaxoneSubcutaneous injection given once dailyDose = 20 mgPregnancy Category BGlatiramer acetate Side EffectsINJECTION SITE REACTION!Indurations, masses
29、, and welts from injections may last for days after administration.PainErythemaInflammationUrticariaTransient flushingVasodilitationChest tightness and/or chest painAstheniaNausea/vomitingPainArthralgiaAnxietyPalpitationsDyspneaConstriction of the throatNatalizumabMechanism of Action = Antagonizes 4
30、-integrin of the adhesion molecule very late activating antigen (VLA)-4 on leukocytes.binds to the 4-subunit of 41 and 47 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the 4-mediated adhesion of leukocytes to their counter-receptor(s). prevents transmigration
31、of leukocytes across the endothelium into inflamed parenchymal tissueAvailable as TysabriA humanized monoclonal antibody.Intravenous infusion given once every 4 weeksDose = 300 mgPregnancy Category CTysabriIn multiple sclerosis, lesions are believed to occur when activated inflammatory cells, includ
32、ing T lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and their counter-receptors present on endothelial cells of the vessel wall. The clinical effect of natalizumab in multiple sclerosis may b
33、e secondary to blockade of the molecular interaction of 41-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells, and with connecting segment 1 and/or osteopontin expressed by parenchymal cells in the brain. Data from an experimental autoimmune encephalitis animal model
34、of multiple sclerosis demonstrate reduction of leukocyte migration into brain parenchyma and reduction of plaque formation, detected by MRI following repeated administration of natalizumab. Natalizumab PMLProgressive Multifocal Leukoencephalopathy (PML) is a sometimes fatal viral opportunistic infec
35、tion that has been observed in patients receiving natalizumab. Results from activation of the latent John Cunningham polyomavirus in immunocompromised patients.PML is a demyelinating disease similar to MS, causing impairment of the transmission of nerve impulses, however once myelin is lost in PML,
36、it cannot be regained.Due to PML, there is a TOUCH Prescribing Program where patients, prescribers, and infusion centers must be registered to monitor for the development of this condition.Note: PML has now also been seen in patients treated with Fingolimod and Dimethyl FumarateNatalizumab Side Effe
37、ctsInfusion reaction including hypersensitivity reactionsRespiratory tract infectionUrinary tract infectionDepressionHeadacheFatigueDiarrheaCholelithiasisArthralgiaPMLMitoxantroneMechanism of Action = Intercalates with DNA strands causing breaks, and inhibits DNA repair through topoisomerase II. Aff
38、ects rapidly dividing cells secondary effects on the immune systemAntigen presentationPro-inflammatory cytokine expressionDecreased leukocyte migrationAvailable as NovantroneAn immunosuppressive agent chemically related to doxorubicin and daunorubicin Intravenous infusion given once every 3 monthsDo
39、se = 12 mg/m2 Cumulative lifetime dose of 100 mg/m2Pregnancy Category DMitoxantrone Side EffectsCardiotoxicityBone marrow suppressionHemoglobin levels, white blood cell count, and platelet counts must be measured before each infusionStomatitis, esophagitis, oral ulcerationNausea/vomitingAlopeciaHead
40、acheFatigueHepatic dysfunctionFingolimod (Gilenya)Mechanism of Action = Acts on the sphingosine-1-phosphate (S1P) receptors S1P1 and S1P3-5 on the surface of lymphocytesDepletes both CD4+ and CD8+ T lymphocytes in the blood stream, up to 75% below baseline.CD4+ cells are decreased to a greater exten
41、t than CD8+ cells. Inhibits lymphocyte release from lymphatic organs decreasing overall numbers in circulationFingolimodFingolimod has been assessed as an oral therapy for RRMS and SPMSDose = 0. 5 mg QDsignificantly reduced gadolinium-enhancing lesions, relapse rate compared to both placebo and Avon
42、ex, and demonstrated significantly less loss in brain volume35Clinical Pharmacology800 patients in Pharmacology studies using 0.125 to 40 mg doseHigh oral bioavailability with no food effectMetabolized by cytochrome CyP450-4F2; no DDI; no toxic metabolitesT1/2 of 6-9 days No dose adjustment (renal,
43、hepatic dysfunction; age, gender, race)Reduced lymphocyte count: 70% reduction at 0.5 mg steady stateHeart rate decrease on day 1, attenuates over timeMild-moderate decrease in FEV1 at high dose (5.0 mg)First Dose MonitoringECG needed before initiatingMonitor hourly for 6 hrs post 1st dose for brady
44、cardiatake HR and BPContinue observing if bpm placebo:Asthenia, balance discorder, dizziness, HA, insomnia, Paresthesia, nasopharygitis, pharyngolaryneal pain, constipation, dyspepsia, nausea, back pain, UTI Not a known cureTreatment aimed at controlling symptoms and maintaining functionDisease modifying therapyTreatment of RelapsesMedications depending on the symptomsMS tends to be less active during pregnancy; careful planning for pregnancy should be considered.
