Post on 25-Dec-2015
Multiple Multiple SclerosisSclerosis
Prepared by:Prepared by:
Dr. Sarwer Jamal BajalanDr. Sarwer Jamal BajalanM.B.Ch.B, F.I.B.M.S(Neurology)M.B.Ch.B, F.I.B.M.S(Neurology)
Multiple SclerosisMultiple Sclerosis
I.I. DefinitionDefinition
II.II. EpidemiologyEpidemiology
III.III. PathogenesisPathogenesis
IV.IV. Clinical featuresClinical features
V.V. Diagnostic Criteria & Diagnostic Criteria & EvaluationEvaluation
VI.VI. Differential Diagnosis Differential Diagnosis
VII.VII. Management Management
Definition of Multiple Definition of Multiple SclerosisSclerosis An inflammatory demyelinating An inflammatory demyelinating
disease of the CNS where there disease of the CNS where there is:is:– Dissemination in spaceDissemination in space– Dissemination in timeDissemination in time– No alternative neurologic diseaseNo alternative neurologic disease
MS is a clinical diagnosisMS is a clinical diagnosis
An immune-mediated [autoimmunity], An immune-mediated [autoimmunity], with secondary, significant axonal loss with secondary, significant axonal loss & cerebral atrophy& cerebral atrophy
Occurs in genetically susceptible Occurs in genetically susceptible individuals who are exposed to an individuals who are exposed to an environmental agent at a young ageenvironmental agent at a young age
Highly variable clinical courseHighly variable clinical course
EpidemiologyEpidemiology
The most common progressive neurologic disease of The most common progressive neurologic disease of young adultsyoung adults
Affects 350,000 persons in the USAAffects 350,000 persons in the USA
Most cases strike between ages 15 and 45Most cases strike between ages 15 and 45
Women outnumber men by as much as 2 to 3:1Women outnumber men by as much as 2 to 3:1
Risk Factors: Risk Factors: Female gender Female gender White raceWhite race Northern latitude (USA)Northern latitude (USA) High socioeconomic statusHigh socioeconomic status Scandinavian ancestryScandinavian ancestry
PathogenesisPathogenesis
MS involves genetic, environmental, and MS involves genetic, environmental, and immune factorsimmune factors
MS has inflammatory, demyelinating, and MS has inflammatory, demyelinating, and axonal damage componentsaxonal damage components
Pathogenesis is not clearly understoodPathogenesis is not clearly understood
Immune modulation is most successful Immune modulation is most successful therapeutic approach supporting immune therapeutic approach supporting immune role in pathogenesisrole in pathogenesis
Optic nerveMonocular visual lossScotoma
Spinal cordLimb weaknessSpasticity and hyper-reflexiaLhermitte’s signUrinary urgency and incontinence
Signs and Symptoms of MS by Lesion Location
BrainstemBrainstem Diplopia (double vision)Diplopia (double vision)
Pain (acute versus chronic)Pain (acute versus chronic)– Trigeminal neuralgia, tic-like Trigeminal neuralgia, tic-like
extremity painextremity pain
– Aching back pain, burning Aching back pain, burning sensation, leg spasmssensation, leg spasms
Numbness of face and tongueNumbness of face and tongue
Vertigo (Vertigo (sensation of moving around sensation of moving around
in spacein space))
Nystagmus (Nystagmus (involuntary eye involuntary eye
movementsmovements))
INO (INO (Inter Nuclear Inter Nuclear
OphthalmoplegiaOphthalmoplegia))
Bilateral Internuclear ophthalmoplegia (INO) - YouTube.MP4
CerebrumCerebrum– Impairment of Impairment of
concentration or concentration or memorymemory
– Hemiparesis Hemiparesis Hemisensory lossHemisensory loss
– Visual field defectVisual field defect
CerebellumCerebellum– Incoordination of limbsIncoordination of limbs– Ataxic gateAtaxic gate
Severe fatigueSevere fatigue Experienced by 75% to 95% of MS Experienced by 75% to 95% of MS
suffererssufferers
Heat sensitivityHeat sensitivity
DepressionDepression Etiology can be a: Etiology can be a:
– SymptomSymptom– Secondary complicationSecondary complication– Side effect of medications Side effect of medications
Secondary Secondary ComplicationsComplications DepressionDepression Urinary tract infectionUrinary tract infection Accelerated lumbar spondylosisAccelerated lumbar spondylosis Aspiration pneumoniaAspiration pneumonia Pulmonary thromboembolismPulmonary thromboembolism Pressure soresPressure sores Limb contractures Limb contractures Gastroparesis Gastroparesis
MS SubtypesMS Subtypes
AsymptomaticAsymptomatic SymptomaticSymptomatic
– Relapsing-remitting (85% at onset)Relapsing-remitting (85% at onset)– Primary progressive (10%)Primary progressive (10%)– Secondary Progressive (transitional Secondary Progressive (transitional
form ~50% of RR)form ~50% of RR)– Progressive Relapsing (5%)Progressive Relapsing (5%)
Multiple Sclerosis SubtypesMultiple Sclerosis Subtypes
DiagnosisDiagnosis
Clinical findingsClinical findings
– HistoryHistory– Neurologic examNeurologic exam– Clinical pictureClinical picture
Laboratory Laboratory evaluations evaluations
– Magnetic resonance Magnetic resonance imaging (MRI)imaging (MRI)
– Evoked potentialsEvoked potentials– Cerebrospinal fluid Cerebrospinal fluid
(CSF) analysis(CSF) analysis
McDonald Diagnostic Criteria-McDonald Diagnostic Criteria-11[Relapsing Remiting MS][Relapsing Remiting MS]
Lesions disseminated in time(DIT) and space(DIS)
Time: More than one attack separated by at least one month
Space: CNS involvement of more than one area
Exclusion of other possible causes
McDonald Diagnostic Criteria - 2McDonald Diagnostic Criteria - 2 [[Primary Progressive MS]Primary Progressive MS]
Insidious course with steady Insidious course with steady progression of clinical deficits with progression of clinical deficits with paraclinicalparaclinical evidence of: evidence of:
– DISDIS by MRI in combination with VER & by MRI in combination with VER & positive CSFpositive CSF
– DIT DIT by MRI or continued progression for 1 by MRI or continued progression for 1 yryr
Imaging & Lab Work-up for Imaging & Lab Work-up for MSMS(Modified from Fleming J, MS & Its Masquerades, AAN-2003)(Modified from Fleming J, MS & Its Masquerades, AAN-2003)
Brain MRI with GdBrain MRI with Gd Evoked Responses [VER(VEP), BAER, SSER]Evoked Responses [VER(VEP), BAER, SSER] CBC, Chem 7, Liver enz, UACBC, Chem 7, Liver enz, UA Lyme serology (based on exposure history)Lyme serology (based on exposure history) ANA, VDRL, ESRANA, VDRL, ESR B12B12 T3, T4, TSHT3, T4, TSH HIVHIV CSF (based on clinical and MRI)CSF (based on clinical and MRI) C & T Spine MRI (if Brain MRI nl or indicated clinically)C & T Spine MRI (if Brain MRI nl or indicated clinically) CXR CXR
MRI: FLAIR & T1 with MRI: FLAIR & T1 with GadoliniumGadolinium
MRI: T1 MRI: T1 ““Black HolesBlack Holes””
MRI: Sagittal ViewsMRI: Sagittal Views
MRI: Spinal ImagingMRI: Spinal Imaging
MRIMRI: T2, T2, FLAIR, T1-Gd: T2, T2, FLAIR, T1-Gd
Visual Evoked PotentialsVisual Evoked Potentials
CSF StudiesCSF Studies Glucose:Glucose: NormalNormal
Protein:Protein: Normal to Mild ElevationNormal to Mild Elevation
WBC:WBC: Normal to Mild Mononuclear Normal to Mild Mononuclear PleocytosisPleocytosis
Intrathecal Antibody Production:Intrathecal Antibody Production:
Increased Increased IgG Synthesis RateIgG Synthesis Rate,,
Oligoclonal BandsOligoclonal Bands
Oligoclonal BandsOligoclonal Bands
Differential Diagnosis of Differential Diagnosis of MSMS
MANGEMENT OFMANGEMENT OF
MULTIPLE SCLEROSISMULTIPLE SCLEROSIS
Treatment GoalsTreatment Goals
Reduce (control) relapsesReduce (control) relapses
Delay disease progression & Delay disease progression & disability disability
Alleviate symptomsAlleviate symptoms
CorticosteroidsCorticosteroids
Symptomatic management for acute relapses Symptomatic management for acute relapses
Used in moderate-to-severe exacerbations Used in moderate-to-severe exacerbations
IV methylprednisolone 500-1000 mg/day for 3-5 days IV methylprednisolone 500-1000 mg/day for 3-5 days followed by oral prednisone (followed by oral prednisone (optionaloptional))
Hasten clinical recoveryHasten clinical recovery
Delay recurrence of neurologic eventsDelay recurrence of neurologic events
Does not alter the course of MSDoes not alter the course of MS
Disease Modifying AgentsDisease Modifying Agents
(Parentral(Parentral)) BetaseronBetaseron (interferon (interferon -1b)-1b) AvonexAvonex (interferon (interferon -1a)-1a) RebifRebif (interferon (interferon -1a)-1a) CopaxoneCopaxone (glatiramer acetate) (glatiramer acetate)
NovantroneNovantrone (mitoxantrone) (mitoxantrone) 12 mg/m2 as short IV infusion12 mg/m2 as short IV infusion Cumulative lifetime dose Cumulative lifetime dose 140 mg/m2 140 mg/m2
TysabriTysabri (Natalizumab) (Natalizumab) 300mg IV infusion over 1hr q 4 wks300mg IV infusion over 1hr q 4 wks
Disease Modifying AgentsDisease Modifying Agents(Oral)(Oral)
Gilenya (Fingolimod)Gilenya (Fingolimod) available since 2011available since 2011 0.5 mg/day0.5 mg/day S/E:S/E: Transitory slow heart rate Transitory slow heart rate macular edemamacular edema Herpes infection: 2 patients have died from itHerpes infection: 2 patients have died from it
Aubagio (Terflunamide)Aubagio (Terflunamide) 30% reduction in relapse frequency30% reduction in relapse frequency S/E: diarrhea, nausea, hair loss and abnormal S/E: diarrhea, nausea, hair loss and abnormal
hepatic biochemistryhepatic biochemistry
FumarateFumarate used in Germany for 10 years to treat psoriasis used in Germany for 10 years to treat psoriasis
(Fumaderm)(Fumaderm)
Laquinimod Laquinimod One dose: 0.6 mg/dayOne dose: 0.6 mg/day Modest effect: 25% reduction in relapse frequencyModest effect: 25% reduction in relapse frequency
Interferon BetaInterferon BetaMechanism of ActionMechanism of Action
Reduce the production of the Reduce the production of the TNFaTNFa (tumor necrosis factor (tumor necrosis factor alpha) and T-cells, known to induce damage to myelinalpha) and T-cells, known to induce damage to myelin
Reduce inflammation by:Reduce inflammation by:– Switching Switching cytokinecytokine production from type 1 ( production from type 1 (pro-inflammatorypro-inflammatory) )
to type 2 (to type 2 (anti-inflammatoryanti-inflammatory) cells ) cells
– Increasing levels of interleuken 10 (Increasing levels of interleuken 10 (IL-10IL-10))
Decrease antigen presentation, to reduce the attack on myelinDecrease antigen presentation, to reduce the attack on myelin
Reduce the ability of immune cells to cross the blood-brain Reduce the ability of immune cells to cross the blood-brain barrier, by affecting barrier, by affecting adhesion molecules, chemokines, and adhesion molecules, chemokines, and proteasesproteases
Betaseron (interferon beta-Betaseron (interferon beta-1b)1b)(Betaferon)(Betaferon) Indication:Indication: Relapsing forms of MS Relapsing forms of MS
Dose:Dose: 8 million IU (250 8 million IU (250 mcgmcg) SC every other ) SC every other dayday
Reduces rate of clinical relapseReduces rate of clinical relapse Reduces the development of Reduces the development of
new lesionsnew lesions Delays the increase in the Delays the increase in the
volume of lesionsvolume of lesions
Immunomodulating AgentsImmunomodulating Agents
Type Recombinant Recombinant RecombinantPolypeptide
protein protein protein mixture
Use Slow Reduce ReduceReduce
accumulation frequency frequencyfrequency
of disability of relapses of relapses of relapses
Injection IM SC SCSC
Administration Weekly 3 /week Every other day Daily
Dosage 30 g 22 g 0.25 mg (8 MIU) 20 mg
44 g
IFN -1a(Avonex®)
IFN -1a(Rebif®)
IFN -1b(Betaseron
®)
Glatiramer Acetate
(Copaxone®)
IFNs
Symptomatic TreatmentsSymptomatic Treatments
Problem Management
Spasticity Remove irritating factors, Physical therapy, baclofen, diazepam, dantrolene
Paroxysmal phenomena carbamazepine, gabapentin, phenytoin
Fatigue Energy conservation, amantidine ,Modafinil ,Dalfampridine (Ampyra)
Depression Anti-depressants
Sexual dysfunction Behavioral therapy, Viagra(sildenafil), Muse(alprostadil)
Urinary dysfunction Tolterodine(Detrol), Oxybutynin(Ditropan), Bethanicol, Botox
PrognosisPrognosis
FavorableFavorable
Low attack rateLow attack rate Long interval to 2nd attackLong interval to 2nd attack Complete recovery from 1st attackComplete recovery from 1st attack Younger age at onsetYounger age at onset Female sexFemale sex Low disability at 2 and 5 yearsLow disability at 2 and 5 years
yearsO
2
4
6
8
201000
Multiple sclerosis- Disease progression (EDSS) -
What’s NewWhat’s New??
The Therapy The Therapy Pyramid in 2013Pyramid in 2013
ReferencesReferences
1. Multiple Sclerosis: Making the Diagnosis 1. Multiple Sclerosis: Making the Diagnosis M. Wallin, MD, MPH M. Wallin, MD, MPH Neurology Service VAMC, Washington, DCNeurology Service VAMC, Washington, DC
2. 2. Wallin M, et al Baker Clin Neurol CD-2003Wallin M, et al Baker Clin Neurol CD-2003
3. 3. David H. Snyder, M.D.: Multiple Sclerosis: Clinical Aspects David H. Snyder, M.D.: Multiple Sclerosis: Clinical Aspects 2005 2005 dsnyder@nynapc.com 212.794.2281212.794.2281
4. Multiple Sclerosis: Janet Toth, MS, RPh Branch Manager, 4. Multiple Sclerosis: Janet Toth, MS, RPh Branch Manager, Specialty Pharmacy July 15, 2006Specialty Pharmacy July 15, 2006
5. Harrison’ principles of internal medicine; MS5. Harrison’ principles of internal medicine; MS
6. Continuum multiple sclerosis. 20116. Continuum multiple sclerosis. 2011
7. 7. Clinical Neurology, Michael J. Aminoff, etal
8. Neurology 8. Neurology
9. NEJM9. NEJM