multiple scl aam
TRANSCRIPT
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Multiple Sclerosis ( MS)
Dr Shanthi Viswanathan
MBBS,MRCP ( Ire),Fellow ship inNeurology ( Malaysia)
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Outline
• What is “Multiple Sclerosis
•
What is “Neuromyelitis Optica”
• Treatment ( Summary)
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DIAGNOSIS
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Post Gadoenhancement
Cavitation
On T1 post
Gad
Conventional MS
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What is Multiple Sclerosis?
• Idiopathic Inflammatory demyelinating
disease of the central nervous system, with
typical lesions disseminated in time and space
• Space : diff regions of CNS ,
• Time: new lesions dev with passage of time
• “Multiple Sclerosis” Scleros Greek word
“Scars”
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What is Demyelination?Inflammatory T cell
Mediated attack ,? Trigger/BBB
breached
Myelin attacked
Failure of conduction of impulses
( conduction block)
Symptoms produced
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MS pathology
• Perivenous inflamm’n
• Multifocal plaque like
demyelination
• Reactive glial scar
formation
Devoid of myelin stain
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M, T-cells activation, B-cells
BBB disruption (MRI: T1-Gd)
Inflammation
(MRI: T1-Gd, T2 active lesion, i.e. new+enlarging)
demyelination, axonal damage
axonal transection
disability
M clean up,gliosis occurs (MRI:T2 chronic lesions
Wallerian degeneration in normal
appearing white matter
recovery Repair
mechanisms
YES
NO
sv09 8
PATHOPHYSIOLOGY OF AN ACUTE RELAPSE & CHRONIC
PROGRESSION
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Inflammation and Axonal
Degeneration in MS
Clinical symptoms
Subclinical degeneration
Time (years)
+
-
THERAPY A
x o n a l d a m a g e
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Doinikow, 1915 Trapp, 1998
Terminal Axonal Bulbs:Evidence of Transected Axons
Doinikow B. D Zeitschr Nervenheilkunde 1915;26:233–47
Trapp BD. NEJM 1998;338:278–85
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Epidemiology• Median age of onset 23 yrs ( 15 – 50yrs)
• Female: male= 1.77: 1
• Very rare in children and > 60 yrs
• In Malaysia : F: M 6.6:1, Age of onset : 31 yrs
Chong Tan Tin Neuro J SEA,97
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Epidemiology
• Incidence
– 1 in a million in low risk area
– 10 in 100,000 in high risk area
– High risk area: Europe, northern US, NZ, SE
Australia
–
Migration before age of 15 alters the riskaccording to the risk of adopted area
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Aetiology
• Unknown
• Genetic
– 20-30% monozygotic concordance
–
Whites, HLA-DR2• Environmental
– ?viral ( HHV-6, mumps ,Epstein Barr Virus (EBV)
– ?autoimmune
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Short segment lesion in cord of
patients with MS
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Clinical features: Optic Neuritis
• Optic neuritis
• Loss of vision
• Eye pain
• Dyschromatopsia impaired color vision
• Movement & sound induced phosphenes
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Fat Sat Axial MRI post Gad
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Clinical features: motor
• Weakness (80% West ,80% East)
• Paraparesis ( myelitis),Hemiparesis
/monoparesis ( subcortical leisons)
• Spasticity/Tonic spasms /flexor spasms
• Feeling of feebleness aft exercise /
heat exposure
( Uthoffs phenomenon)**
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Clinical features: sensory
• Numbness, tingling, pins and needles, tightness,coldness, swelling, intense itching ( 84% in West ,
77% East)
• Lhermitte’s phenomenon : flexion of neck
tingling in spine & limbs
• Clumsy/useless hand : ‘oppenheim hand’ ( plaquein dorsal column cervical cord)
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Brain stem & Cerebellar inv
Neurocognitive Issues,Sphincter
problems• Internuclear ophthalmoplegia (INO)• Vertigo (in 30-50% of patients)• Gait /trunkal ataxia
• Tremor
• Cognitive & psychiatric issueseg poor memory,attention probsDepression & anxiety.
• Bowel/bladder issues• Sexual problems, Fatigue
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Clinical evidence
• Attack - An episode of neurological disturbance
lasting at least 24H
• Objective clinical evidence- objectively determinedclinical signs separated in time and space
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Diagnosis: CLINICAL,CLINICAL, CLinical
• Must demonstrate dissemination in time & space of CNSlesions clinically & paraclinical evidence aided by MRIbrain, CSF analysis & EP’s
• Diagnosis of exclusion (inflammatory, infectious / postinfectious, granulomatous etc)
• In RRMS :- neurological dysfxn separated in time & space with
good recovery & minor disability in between attacks
• In Progressive MS: prog course > than 6/12
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Relapsing-Remitting
Secondary-Progressive
Primary-
Progressive
Progressive-Relapsing
ProgressiveOnset
Exacerbating-Remitting
Onset
15 %
85 %
58 %
27 %
9 %
6 %
MS can be classified according to frequency and severity of
neurological symptoms, the ability of the CNS to recover, and
the accumulation of damage.
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CLINICALLY ISOLATED
DEMYELINATING SYNDROME
• Clinically isolated Syndrome :
• Acute /subacute neurological event
First ever expression of a CNS demyelinating event, occurs in
1/> sites ( WARNING OF MS/NMO)
Typical presentations
•
Optic neuritis• myelitis
• Cerebellar /Brainstem syndromes
85% of
individuals
Miller et al Lancet
Neurology 0530 to 70% of these pts with CIS will convert to
CDMS
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Risk of MS after monosymptomatic
episode
• Optic neuritis
– 5 years cumulative risk
• 16% ( normal MRI brain)
• 51% ( 3 or more lesions on MRI brain)
• Acute transverse myelitis
– Complete: 5-10%
– Partial: 57-72%
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Poser Diagnostic Criteria
DIAGNOSTIC CRITERIA FOR MULTIPLE SCLEROSIS
(Poser C, et al Ann Neurol, 1983
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enen
Revised 2001,2005 & 2010
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Mc Donald criteria (2001/05)
• Incorporating the use of MRI for the early
diagnosis to
• Demonstrate dissemination in time
• &
•
Dissemination in space
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DIS
DIT
DIT &DIS
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Lesion should be at least 3mm
Original 2010
criteria
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Ovoid
Perpendicular to the ventricles
Involve the corpus callosum
Callosalpericallosal
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Callosal
/Pericallosal
lesions:Dawsons
fingers
Juxtacortical/
cortical lesionsPeriventricular lesions
ChronicMS
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flair
PostGado
T2 blackhole
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MRI cervicothoracic spine July 2002
Sagittal T2W
1 spinal cord lesion= 1
brain infratentorial (
posterior fossa) lesion
An enhancing spinal
cord lesion= an
enhancing brain lesion
Indvd spinal cord
lesions = can be
counted into No of T2
brain lesions
< 2 vs
,posterolateral
Paraclinical Investigations: What is a positive
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Paraclinical Investigations: What is a positive
CSF?
• CSF
• :OCB Ig G -85- 90% ,
• Ig G index > 0.7 in 90%
• Protein : raised 30%
• Cell count < 50 lymphocytes/mm3
Isoelectric focusing: the presence of bands in
the FSC different from any such bands in
serum and or the presence of an elevated Ig G
index
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Paraclinical Evidence : What is a positive VEP?
LEFT (P100-130)
Evoked potential testing(visual, auditory, orsomatosensory) is helpfulin
*detecting clinically silentlesions, and
The most sensitive are the
VEPs (50-90% sensitivity)and SSEPs (50-70%sensitivity).
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Investigation to exclude other diagnoses
• ESR• P-ANCA, c-ANCA
• ANA, Rheumatoid factor
• Lupus anticoagulant, anticardiolipin antibodies
•Anti-Ro, anti-La
• HTLV-1 (CSF)
• HIV serology
• VDRL, TPHA
• CXR, serum and CSF ACE level
• Vit B12
• Lyme’s serology
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Differential diagnosis
• SLE
• Sjorgens Synd
• Behchets
• Sarcoidosis
• CVA : thromboembolic
• ADEM
• NMO
• CADASIL,SCA’s,Leukodystrophies,SACD
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Neuromyelitis optica
• Devic described it 19th century
• Historical definition : severe ON & myelitis ,close asscn.
• NOW WIDER : Relapsing forms
• Recurrent optic neuritis• Recurrent transverse myelitis
• Brain inv ( Not MS like)
• #Recently : AB to aquaporin-4 water channel said to be
sensitive & specfic for NMO
• 75% & 90% sensitive & specific for NMO
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Neurology 2006
Mcdonalds 2010
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Neuromyelitis Optica (NMO)Epidem: gender, age, race M=F, childhood-adult
Symptomatology
Severity
ON, TM or both
More severe, one/2 episodes of
ON & very quickly patient is
left with visual disability
CSF
Anti aquaporin 4 AB
Pleocytosis , > 50 WBC
OCB: 15-35%
60-90%
Natural Hx Monophasic: acute fulminant
Polyphasic: RR
Association Systemic ds (secondary NMO)Brain involvement
Spinal cord
May be atypical from
conventional MS
Length of lesion >= 3 vs
Necrosis,atrophy
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Imaging
• Long segment cord (> 3segments) :
white and grey matter; cavitation
• Brain: usually normal; or atypical of MS
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When to suspect NMO in the brain?
• Lesions involving corticospinal tract
• Extensive hemispheric lesions
• Periaqueductal lesions around the 3rd /4th ventricle
• Periependymal lesion around lateral ventricles
• Medullary with extensive spinal cord lesion
• Non specific brain disease
• In the absence of vasculitis, malignancy, infection
and stroke Suspect NMO
• Vasogenic Edema
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Neuromyelitis Optica
Recurrent Optic neuritis with myelitis, Anti aquaporin status positive,
CSF OCB -ve , EDSS 3,steroids & azathioprine, severe tonic spasms,
better with tegretol
LESCLOwls nest
appearance
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NMO MS
• AQP4 pos
• Worse outcome ( CNS destruction)
• Left with disability
• > 3 segments cord
• CSF: pleocytosis, OCB less
• Has relapsing & monophasic forms
• Can have brain involvement
• Pathology of the 2 conditions is also
different.
• AQP4 neg
• Better outcome
• Recovers quickly
• Cord: < 2 segments
• CSF: no pleocytosis; OCB
• Has relapsing forms
• Brain involvement present
Lancet Neurology
2007
Acute relapses with Steroids/PE
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Acute relapses with Steroids/PE
Preventive, Maintenance therapy:
Immunosuppressants
Treatment of MS: Acute Rx/Preventive
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Treatment of MS: Acute Rx/Preventive
Rx : Non curative
2 relapses within 2
yrs/CIS with MRI CDMS
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Acute Relapse
• IV Methylprednisolone
closure of BBB
suppression of inflammation
Reduces duration of attack – no long term benefit
• Dose 500-1000 mg/day X 3-5 days Beck et al 99NEJM
• ONTT trial in ON – use of IV steroids to hasten recovery, no effect onvisual improvement ( NEJM 92)
• Refractory relapses
Further - IVMP after 4-8/52
Consider plasma exchange
- 46% of refractory relapses at 8 wk improved with plasma
exchange(Ann Neuro 99)
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Prevent/ slow progression
• Disease Modifying Drugs
• B-interferon
• Oral drugs : Fingolimod
• Natazulimab ( Tysabri)
• Immunosuppressants
• Mitoxantrone
• # not talking about Rituximab,Alemtuzumab, IV
Immunoglobulin
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PRISMS, OWIMS , BENEFIT, EVIDENCE Drug Administration No of pts % Reduction in
relapse rate (ARR)
Avonex 30g IM wkly 251 18%
Betaferon 1.6 MU 372 8%
Betaferon 8 MU 372 34%
Rebif 22 22g 3X/wk 540 29%
Rebif 44 44g 3X/wk 540 33%
Copaxone 20 mg od 251 29%
2 Conclusions : Interferons reduced relapse rates, severity of relapses
Dose –frequency relationship : High dose,more
more frequent dosing associated with less ARR
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Fingolimod Natazulimab Mitoxantrone
Sphingosine 1
Phosphate inhibitor
Traps T-cells in the
lymph nodes
Acts on the alpha 4
integrin adhesion
molecule Px T cells
penetrating BBB
Targets proliferating
cells & prod
apoptosis of T/B
cells
Mode oral IV-monthly IV -3 monthly
Relapse rate
reduction
50-60% 60-80% 60-80%
MRI T2 lesion load 60-70% 70-80% 80%
Side effects First dose
bradycardia,macula
edema,LFT
increases,infections
Allergic reactions,
risk of PML (1:1000)
Cardiotoxicity
Acute leukemias
PML: infection with Jamestown cameron virus – producing
Progressive multifocal leukoencephalopathy
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Algorithm for Treatment Failure
ESCALATION THERAPY
Fingolimod
Fingolimod
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MultidisciplinaryApproach
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Conclusion
• Get the Diagnosis correct : MS vs NMO
• Treat : Relapses Interferons 2nd line
drugs
• Treat the symptoms : spasticity,
pain,depression