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“Multiple Sclerosis Overview” January 17, 2008 Khurram Bashir, MD, MPH Associate Professor of Neurology Director, Multiple Sclerosis Center. Optic Neuritis. MS History – Saint Lidwina (1421). 1794-1848 » Sir Augustus d'Esté. Grand-son of George III - PowerPoint PPT Presentation
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““Multiple Sclerosis Overview”Multiple Sclerosis Overview”January 17, 2008January 17, 2008
Khurram Bashir, MD, MPHAssociate Professor of NeurologyDirector, Multiple Sclerosis Center
Optic NeuritisOptic Neuritis
MS History – Saint Lidwina (1421)MS History – Saint Lidwina (1421)
1794-1848 » Sir Augustus d'Esté
Grand-son of George III
The Regent did not approve of the marriage of his son, Prince Augustus Frederick, to Lady Augusta Murray, and had the marriage annulled
Although later given a knighthood, Augustus was made illegitimate
1868 1868 » First First detailed clinicopathological description of MS
Charcot became the Professor of Neurology at the University of Paris and is often referred to as the "Father of Modern Neurology".
Multiple SclerosisMultiple Sclerosis
Immune-mediated, demyelinating Immune-mediated, demyelinating disease of thedisease of the central nervous system central nervous system white matter white matter characterized bycharacterized by neurologic dysfunction neurologic dysfunction separated in separated in time and spacetime and space
Multiple SclerosisMultiple Sclerosis
Immune-mediated Immune-mediated and and neurodegenerativeneurodegenerative, demyelinating , demyelinating with with axonal lossaxonal loss disease of thedisease of the central central nervous system white nervous system white and grayand gray matter matter characterized bycharacterized by neurologic dysfunction neurologic dysfunction separated in time and spaceseparated in time and space
CHALLENGES FOR THE CHALLENGES FOR THE HEALTHCARE PROVIDERHEALTHCARE PROVIDER
• Difficult diagnosis
• No single specific test
• No two cases of MS are alike
• No proven cause
• No known cure
• MS is unpredictable
• Partially effect treatments
Epidemiology of Multiple SclerosisEpidemiology of Multiple Sclerosis
Age:Age: 20-40 yrs (mean 30 yrs)20-40 yrs (mean 30 yrs) F:M ratio:F:M ratio: 1.5-2.0 : 11.5-2.0 : 1 Race:Race: W > B > Other racial groupsW > B > Other racial groups IncidenceIncidence
• WorldwideWorldwide 2.5 million2.5 million• USUS 365,000 – 400,000365,000 – 400,000
Clusters/”Epidemics”:Clusters/”Epidemics”: Faroe Islands, IcelandFaroe Islands, Iceland Effect of migration:Effect of migration: Exposure at < 15 yrs of Exposure at < 15 yrs of
age is importantage is important
Epidemiology of Multiple SclerosisEpidemiology of Multiple Sclerosis Geographical Geographical Increases with increasing Increases with increasing
Association:Association: and decreasing latitudeand decreasing latitude
Epidemiology of Multiple SclerosisEpidemiology of Multiple Sclerosis
Duration of diseaseDuration of disease > 30 years> 30 years
Severely disabledSeverely disabled 30% (w/o Rx)30% (w/o Rx)
UnemployedUnemployed 70%70%
Average care costAverage care cost $30,000/year $30,000/year (1998 $)(1998 $)
US economy cost US economy cost $9.6 billion/year$9.6 billion/year (1998 $)(1998 $)
Pathophysiology of Multiple SclerosisPathophysiology of Multiple Sclerosis
Genetic FactorsGenetic Factors PolygenicPolygenic Monozygotic twin concordance rate of ~25-Monozygotic twin concordance rate of ~25-
30% compared to dizygotic twin concordance 30% compared to dizygotic twin concordance rate of ~4-5%rate of ~4-5%
MS is more common in CaucasiansMS is more common in Caucasians Minor influence of HLA Minor influence of HLA (on chromosome 6) (on chromosome 6) in in
familial cases and Caucasian patients with RR familial cases and Caucasian patients with RR MSMS
Several areas of interest - Several areas of interest - 17q11, 17q11, 6p216p21, 5q11, , 5q11, 17q22, 16p13, 3p21, 12p13, and 6qtel. 17q22, 16p13, 3p21, 12p13, and 6qtel.
Pathophysiology of Multiple SclerosisPathophysiology of Multiple Sclerosis
Environmental FactorsEnvironmental Factors Infectious ?Infectious ? Toxins ?Toxins ? UnknownUnknown
No increased risk of MS in adopteesNo increased risk of MS in adoptees No increased risk in spousesNo increased risk in spouses
Abnormal immunologic response
Genetic predisposition
Infectious agent?
Pathophysiology of Multiple SclerosisPathophysiology of Multiple Sclerosis
MS
Environmental factors
Noseworthy J., Progress in determining the causes and treatment of multiple sclerosis. Nature. June 1999: A40-A47.
Activation of Immune System in MSActivation of Immune System in MS
Inflammation and the CNS in MSInflammation and the CNS in MS
Axonal Damage and Lesion Formation Axonal Damage and Lesion Formation in MSin MS
Multiple Sclerosis – Gross PathologyMultiple Sclerosis – Gross Pathology
Multiple Sclerosis PathologyMultiple Sclerosis Pathology
Demyelination
Inflammation
Axonal Loss
Remyelinating OligodendrocyteRemyelinating Oligodendrocyte
Adapted with kind permission from Dr. W. Brück.
Multiple Sclerosis : Severe Myelin, Multiple Sclerosis : Severe Myelin, Axonal, and Neuronal LossAxonal, and Neuronal Loss
Normal White Matter Plaque
Myelin
Axons
Astrocytes
NeuronsLymphocytes
Macrophages
Peterson JW et al. Neurol Clin. 2005;23:107-129.
Affects subcortical and white matter and cortex
Restricted to the cortex, small in size, circular intracortical lesions, often centered on vessels
Extend from the pial surface into the cortex, often involve multiple gyri
Patients often experience neurologic symptoms that do not correlate with white matter pathology
Gray Matter Lesion PatternsGray Matter Lesion Patterns
Symptoms at Onset of MSSymptoms at Onset of MS
SymptomSymptom Percentage of Percentage of PatientsPatients
Sensory symptoms in arms/legsSensory symptoms in arms/legs 3333
Unilateral vision lossUnilateral vision loss 1616
Polysymptomatic onsetPolysymptomatic onset 1414
Slowly progressive motor deficitSlowly progressive motor deficit 99
Acute motor deficitAcute motor deficit 5 5
DiplopiaDiplopia 77
OtherOther 1616
Paty. In: Multiple sclerosis, diagnosis, medical management, and rehabilitation. 2000.
MS: Common SymptomsMS: Common Symptoms
Symptom Symptom Prevalence, %Prevalence, %
Bladder symptomsBladder symptoms 97.197.1
FatigueFatigue 89.889.8
SpasticitySpasticity 70.270.2
Sexual dysfunctionSexual dysfunction 64.264.2
PainPain 61.961.9
Cognitive dysfunctionCognitive dysfunction 61.961.9
Bowel dysfunctionBowel dysfunction 47.847.8
DepressionDepression 41.641.6
Goodin et al. Mult Scler. 1999;5:78-88.
Forms of MSForms of MS
Relapses
Incr
easi
ng
dis
abili
ty
Time
Relapsing-remitting
55%
Relapses with Disability
Some of the available therapies can slow disability progression in relapsing forms of MS.
TimeIncr
easi
ng
dis
abili
ty
Primaryprogressive
5%-10%
Disability ProgressionNo Distinct Relapses
Incr
easi
ng
dis
abili
tyTime
Secondaryprogressive
30%
Increasing Disability
SPECTRUM OF MS DISEASE ACTIVITYSPECTRUM OF MS DISEASE ACTIVITY
Genetic SusceptibilityGenetic Susceptibility Environmental FactorsEnvironmental Factors
Immune System Activation in the CNSImmune System Activation in the CNS
Demyelination ± Axonal LossDemyelination ± Axonal Loss
Multiple SclerosisMultiple Sclerosis
Benign RR SP Transitional PP PR MalignantBenign RR SP Transitional PP PR Malignant
Minimal DisabilityMinimal Disability Severe DisabilitySevere Disability
Laboratory and Imaging StudiesLaboratory and Imaging Studies
MRIMRI BrainBrain Spinal cordSpinal cord
CSFCSF Evoked Potential StudiesEvoked Potential Studies
VisualVisual Brainstem auditoryBrainstem auditory SomatosensorySomatosensory
Multiple Sclerosis: Cranial MRIMultiple Sclerosis: Cranial MRI
Gdenhancement
T2 lesion
T1 “black hole”
Brain atrophy
Spinal cord lesion
Multiple Sclerosis : Serial MRI FindingsMultiple Sclerosis : Serial MRI Findings
Visual Evoked PotentialsVisual Evoked Potentials
Common CSF AbnormalitiesCommon CSF Abnormalities
MS ProfileMS ProfileMBPMBP ElevatedElevated
IgG IndexIgG Index ElevatedElevated
IgG Synthesis RateIgG Synthesis Rate ElevatedElevated
OCBOCB PresentPresent
Revised MacDonald Diagnostic CriteriaRevised MacDonald Diagnostic Criteria
Relapse DefinitionRelapse Definition• Neurological disturbance consistent with MSNeurological disturbance consistent with MS• Subjective report or objective observationSubjective report or objective observation• 24 hour duration, minimum24 hour duration, minimum• Excludes psudorelapses, single paroxysmal Excludes psudorelapses, single paroxysmal
episodesepisodes• At least 30 days between onset of event 1 and At least 30 days between onset of event 1 and
event 2event 2
Revised MacDonald Diagnostic CriteriaRevised MacDonald Diagnostic CriteriaClinical PresentationClinical Presentation Additional data needed for MS diagnosisAdditional data needed for MS diagnosis
11 ≥ ≥ 2 relapses;2 relapses; Objective clinical evidence Objective clinical evidence of ≥ 2 lesionsof ≥ 2 lesions
NoneNone
22 ≥ ≥ 2 relapses2 relapses Objective clinical evidence Objective clinical evidence of 1 lesionsof 1 lesions
Dissemination in space, demonstrated Dissemination in space, demonstrated by:by:
- MRI, - MRI, OROR
- ≥ 2 MRI lesions + positive CSF, - ≥ 2 MRI lesions + positive CSF, OROR
- 2- 2ndnd clinical relapse disseminated in clinical relapse disseminated in spacespace
33 1 relaspe1 relaspe Objective clinical evidence Objective clinical evidence of ≥ 2 lesionsof ≥ 2 lesions
Dissemination in time, demonstrated Dissemination in time, demonstrated by:by:
- MRI, - MRI, OROR
- 2- 2ndnd clinical relapse clinical relapse
Revised MacDonald Diagnostic CriteriaRevised MacDonald Diagnostic CriteriaClinical PresentationClinical Presentation Additional data needed for MS diagnosisAdditional data needed for MS diagnosis
44 1 relapse1 relapse Objective clinical evidence of 1 Objective clinical evidence of 1 lesionlesion
Dissemination in space, demonstrated by:Dissemination in space, demonstrated by:
- MRI, - MRI, OROR
- ≥ 2 MRI lesions + positive CSF, - ≥ 2 MRI lesions + positive CSF,
ANDAND Dissemination in time, demonstrated by:Dissemination in time, demonstrated by:
- MRI, - MRI, OROR
- 2- 2ndnd clinical relapse clinical relapse
55 Insidious neurological Insidious neurological progression suggestive of MSprogression suggestive of MS
1 year of disease progression 1 year of disease progression (retrospectively or prospectively determined)(retrospectively or prospectively determined)
ANDAND 2 out of 3 of the following:2 out of 3 of the following:
- Positive bran MRI (9 T2 lesions - Positive bran MRI (9 T2 lesions OROR ≥ 4 T2 ≥ 4 T2 MRI lesions and positive VEPMRI lesions and positive VEP
- Positive spinal cord MRI (≥ 2 T2 lesions)- Positive spinal cord MRI (≥ 2 T2 lesions)
- Positive CSF- Positive CSF
Revised MacDonald Diagnostic CriteriaRevised MacDonald Diagnostic Criteria
CaveatCaveat• No Better ExplanationNo Better Explanation
• Need to rule out other potential etiologies that Need to rule out other potential etiologies that might explain clinical or imaging might explain clinical or imaging abnormalitiesabnormalities
Clinical Stages in Relapsing MSClinical Stages in Relapsing MS
Gd + lesions Clinical Relapse
T2W lesion burdenAccumulateddisability
Pre-Symptomatic
Early RR MS Late RR MSSP MS
BPF
WM NAA
Multiple Sclerosis TreatmentMultiple Sclerosis Treatment
Treatment of Relapse (“Exacerbation”)Treatment of Relapse (“Exacerbation”) Treatment of Underlying DiseaseTreatment of Underlying Disease Treatment of SymptomsTreatment of Symptoms Psychosocial SupportPsychosocial Support Patient EducationPatient Education
Acute RelapseAcute Relapse
Pre-Symptomatic
Early RR MS Late RR MSSP MS
Treatment of an Acute RelapseTreatment of an Acute Relapse
Standard Treatment(s):Standard Treatment(s):
• IV MethylprednisoloneIV Methylprednisolone• Oral PrednisoneOral Prednisone• ACTH injectionsACTH injections• Therapeutic Plasma Exchange Therapeutic Plasma Exchange (for steroid (for steroid
unresponsive severe demylinating relapses)unresponsive severe demylinating relapses)
Relapsing MSRelapsing MS
Pre-Symptomatic
Early RR MS Late RR MSSP MS
Treatment for Relapsing MSTreatment for Relapsing MS
Interferon AgentsInterferon Agents• IFN IFN -1b (Betaseron)-1b (Betaseron)• IFN IFN -1a intramuscular (Avonex)-1a intramuscular (Avonex)• IFN IFN -1a subcutaneous (Rebif)-1a subcutaneous (Rebif)
Non-Interferon AgentsNon-Interferon Agents• Synthetic Polymer Synthetic Polymer
Glatiramer acetate (Copaxone)Glatiramer acetate (Copaxone)
• Selective Adhesion Molecule (SAM) InhibitorSelective Adhesion Molecule (SAM) Inhibitor Natilzumab (Tysabri)Natilzumab (Tysabri)
SP MSSP MS
Pre-Symptomatic
Early RR MS Late RR MSSP MS
Treatment for SP MSTreatment for SP MS
Interferon AgentsInterferon Agents• IFN IFN -1b (Betaseron)*-1b (Betaseron)*• IFN IFN -1a (Avonex, Rebif)**-1a (Avonex, Rebif)**• Natalizumab (Tysabri)**Natalizumab (Tysabri)**
Non-Interferon AgentsNon-Interferon Agents• Anthracenedione DerivativeAnthracenedione Derivative
Mitoxantrone (Novantrone)***Mitoxantrone (Novantrone)***
* Approved therapy for SP MS in Europe and Canada* Approved therapy for SP MS in Europe and Canada* And ** Appropriate for use in relapsing SP MS* And ** Appropriate for use in relapsing SP MS
*** Only FDA-approved therapy for SP MS in the US*** Only FDA-approved therapy for SP MS in the US
Goals of Treatment of MSGoals of Treatment of MS
Therapeutic Effects of Current Therapies:Therapeutic Effects of Current Therapies:
• Reduction inReduction in
Relapse rateRelapse rate Progression of disabilityProgression of disability MRI MRI
• Total burden of diseaseTotal burden of disease• Gad enhancing lesions on MRIGad enhancing lesions on MRI• Brain atrophyBrain atrophy
PP MSPP MS
Treatment for PP MSTreatment for PP MS
Currently no treatments proven to slow or Currently no treatments proven to slow or stop progression of diseasestop progression of disease
Management focused on:Management focused on:• Treating symptomsTreating symptoms• Maximizing functionMaximizing function• Improving quality of lifeImproving quality of life
MS symptom and side effect management
SYMPTOMS PHARMACOLOGIC TREATMENT OPTIONSSpasticity Baclofen, Diazepam, Gabapentin, Tizanidine, Dantrium
Urinary Dysfunction Propantheline Bromide, Oxybutynin,
Hyoscyamine Sulfate, Tolterodine Tartrate
Fatigue Amantadine, Pemoline, Fluoxetine,
Methylphenidate, Modafinil
Depression SSRIs:Fluoxetine, Sertraline
Tricyclics: Amitriptyline, Nortriptyline, Desipramine
Venlafaxine
Pain Anticonvulsants: Carbamazepine, DPH, Gabapentin
Antidepressants: Amitriptyline, Nortriptyline,
Desipramine, Venlafaxine
Sexual Dysfunction Sildenafil, Vardenafil, Tidalafil
Ataxia Ondansetron, Clonazepam, Propranolol, Levetiracetam
Aug2000
Other Demyelinating DiseasesOther Demyelinating Diseases
Acute Disseminated EncephalomyelitisAcute Disseminated Encephalomyelitis Hyper-acute, severe, monophasic, multifocal, Hyper-acute, severe, monophasic, multifocal,
paraifectious/paravaccination, demylinating paraifectious/paravaccination, demylinating Devic’s Diseases (Neuromyelitis Optica, NMO)Devic’s Diseases (Neuromyelitis Optica, NMO)
Severe, necrotizing, relapsing/rapidly progressive, Severe, necrotizing, relapsing/rapidly progressive, demyelinating, associated with NMO IgG, involving optic demyelinating, associated with NMO IgG, involving optic nerves and spinal cordnerves and spinal cord
Balo’s Concentric SclerosisBalo’s Concentric Sclerosis MS variant, acute, large, demyelinating lesions, with MS variant, acute, large, demyelinating lesions, with
concentric rings of demyelination and remyelination concentric rings of demyelination and remyelination Marburg VariantMarburg Variant
MS variant, severe, rapidly progressive, involves large MS variant, severe, rapidly progressive, involves large area of CNS white matter, death usually within monthsarea of CNS white matter, death usually within months
Questions ?Questions ?
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