1. MULTIPLE SCLEROSIS -
Recent perspectives:
Prof. A.V. SRINIVASAN
Dr.S.Arunan,Dr.C.T.Suresh,Dr.G.Mugundhan,Dr.G.Vikramraj.
INSTITUTE OF NEUROLOGY
MADRAS MEDICAL COLLEGE, CHENNAI-3
24th MAY 2008

2. LAND MARKS IN MS:
 Top Ten Events...Thus Far
 1868: MS described by Jean-Martin Charcot.
 1878: Myelin discovered by Louis Ranvier.
 1916: Detailed microscopic description made
by James Dawson revealed the basic damage
done in MS.
 1935: An animal form of NIS (EAE) developed
by Thomas Rivers, ultimately suggesting an
autoimmune basis for the disease.
 1946: National Multiple Sclerosis Society
founded by Sylvia Lawry.

3.  1948: Under an early NMSS grant, oligoclonal bands
discovered in the spinal fluid by Elvin Kabat and
others, provided a diagnostic test suggestive of MS
and linking MS to immune system problems.
 1965: Definite criteria for MS diagnosis developed by
NMSS expert committee.
 1969-1970: ACTH used to treat MS exacerbations. This
was the first controlled trial of a successful treatment
for MS: it used newly standardized diagnostic criteria
and rating scales to evaluate the efficacy of treatment.
Success is a prize to be won. Action is the road to it.
Chance is what may lurk in the shadows at the road side.
- O. Henry

4.  1981: MRI first used to examine a person
with MS. MRI revolutionized diagnosis
and provided evidence that MS is a
constantly active disease even when
symptoms abate.
 1993: Beta-interferon 1b (Betaseron)
approved as the first drug to alter the
course of MS.
 2001:Macdonald’s criteria.
Discipline Weighs Ounces Regret Weighs Tons

5. THE MAGNITUDE:
 Most common nontraumatic neurologic
cause of disability.
 400000 persons in USA affected.
 USA spends 7 billion per annum(whetten-
goldstein etal 1998).
 If extrapolated to current economic
environment MS society – burden of 20
billion dollars.
"There is dignity in suffering; nobility in pain; but failure is a salted
wound, that burns and burns again!"

8. MS epidemics:

10. EPIDEMIOLOGY:
 The peak onset of MS occurs in the late
30s. It has been suggested that pubertal
and sex hormone factors play a role.
 MS clusters - in TIME- favored an
environmental agent – kutzke etal,1995 and
other investigators- unable to identify agent.
 North-south gradient- in northern
hemisphere and south-north gradient in
southern hemisphere.
The power to believe in yourself, is the power to change fate

11.  VITAMIN D-PROBABLE PROTECTIVE ROLE.
(Islam et al 2007,Van der Mei 2003) - also
protective for animal model of EAE.
 Smoking – increased risk - odds ratio 1.81(Riise et
al – Norwegian study) Hawkes et al 2007 – 1.22 –
1.51 odds ratio – increased risk of MS.
 EBV – Increased risk – 99% of MS patients have
evidence of EBV while 90% of non MS patients
have evidence of EBV. Brain infiltrating B and
plasma cells – 100%evidence of EBV (Serfani etal
2007) – incidental association or causation?
Memory, the daughter of attention ,
is the teeming mother of knowledge - Martin Tupper

12. Migration:

13. Unidentified gene – hunt still on:

15.  If migration occurs before 15 years – adopted
country prevelance.(gale and martyn 1995)
 Samples – SMALL.
 Increased incidence - in monozygotic and
dizygotic twins – Genetic predisposition ?
 Though in northern Europeans -HLA 2 association
linked-other studies inconclusive (Ebers etal).
 Two loci in IL2 and IL7 – increased risk for
MS(International MS genetics con 2007;gregory
etal 2007)
Our greatest glory is not in never failing, but in rising up every time we fail

16. MS IN INDIA:
 1.33/100000 – Singhal etal.
 2.54% of total neurology admissions between
January'93 to March'98 -Syal,Khandelwal N, PGI
Chandigarh.
 In the Parsi - a prevalence of 26/100,000 – Wadia
etal.
 Optico spinal form more common than west
-Pandit et al.
 Class II HLA association in 23 MS - non Parsi
origin DRB1*1501 (50%) similar to western
studies.11
Resistance drains energy
Acceptance saves it
Cheerfulness sustains it -- Anonymous

17. Where are We:
 The hunt continues.
 Handful of genes might be operative –
ELUSIVE.
 An environmental agent – STILL
UNIDENTIFIED.
 IS IT AN INTERPLAY BETWEEN BOTH – A
PROBABLE YES.
We do not know one millionth of one percent about anything –
Thomas Edison

18. IMMUNO PATHOGENESIS:

19.  Initiating cause unknown.
 T cells activated – APC - TCR &MHC/ANTIGEN
COMPLEX – Trimolecular complex – differentiates
–CD4 and CD8
 T h 1- pro inflammatory -TGF beta + IL 6
stimulates – CD4 – Th17.
 Treg cells – a subset of CD4 – expresses high
level ofCD25 and transcription factor Foxp3 (Rose
and Carlson 2007)
 Migration of Th1 to receptive CNS.
“ Many Ideas grow better when transplanted into another mind than in the
one where they sprang up” - O.W. Holmes

20.  Reactivation by auto antigens.
 Release of inflammatory cytokines.
 At this level there is significant contribution
from by B cells.
 Result- axonal loss and demyelination.
Success is a prize to be won. Action is the road to it.
Chance is what may lurk in the shadows at the road side.

21. An active lesion:

22. LUCCHINETTI CATEGORISATION:
 Type 1- demyelination and macrophages
relate products.
 Type 2-presence of immunoglobulin and
complement.
 Type 3-lacks immunoglobulin and
complement,early loss of myelin associate
glycoprotein-oligodendrocyte dysfunction.
 Type 4-apoptosis of oligodendrocytes-DNA
fragmentation.
Every discovery contains an irrational element or 4 creative intuition

23. Current concepts:
 Axonal damage and demyelination.
 Remyelination does occur – transient – shadow
plaque.
 MBP EXON 2 might be responsible – can be
upregulated.
 Jagged notch pathway –active lesions-can be
down regulated for remyelination.
 Chemockine ligand 1 can be targeted to prevent
recruitment of T cells to Breach the BB barrier.
Motivation is the Spark that lights the Fire of Knowledge and fuels the
engine of Accomplishment”

24. Clinical course:

25. Clinical severity:
 BENIGN AND MALIGNANT MS:
 RELAPSING SUBTYPE.
 FEMALE SEX & AGE LESS THAN 40.
 PROLONGED REMISSION AFTER FIRST
ATTACK( MORE THAN 1 YEAR)
 INFREQUENT AND MILD RELAPSES WITH
GOOD RECOVERY.
 MILD DISABILTY OVER 25 YEARS AND LOW
LESION LOAD IN MRI WITH LITTLE CORTICAL
ATROPHY.
Marriage and Private Practice are the two extinguishers of science

26. CLINICAL FEATURES:
 MOTOR.
 SOMATOSENSORY.
 VISUAL-ANTERIOR PATHWAY
INVOLVED,UNILATERAL,CENTRAL SCOTOMA
WITH PAIN-CHRACTERISTIC-IMPROVES BY 6
MONTHS.
 OTHER CARNIAL NERVES AND BRAIN STEM
SYMPTOMS- INO,MONOCULAR
NYSTAGMUS,OLFACTORY DISTURBANCE
,FACIAL WEAKNESS ETC.
Expert is one who think to his chosen mode of ignorance

27.  COGNITIVE AND PSYCHIATRY
DISTURBANCES – PREDOMINANTLY
SUBCORTICAL(Kotterba etal
2003,Schltheis et al 2001)
 CORTICAL VARIANT DO OCCUR(Zerei
and colleagues 2003)
 Depression – 75% suicide 15% of adult
deaths(Feinstein 2002)
“ By Nature All Men/ Women are alike but
by Education widely different”

28.  FATIGUE-SYSTEMIC AND HANDICAP FATIGUE.
 PAIN – FREQUENT PRIMARY PAIN
SYNDROMES- NEURALGIC PAIN(5TH
NERVE,DYSESTHETIC PAIN OF
LEGS,RADICULAR PAIN,TONIC
SEIZURES,SPASTIC PAIN,OPTIC NEURITIS
PAIN.
 SECONDARY PAIN SYNDROMES LIKE LOW
BACK ACHE AND OSTEPOROSIS WITH
FRACTURES.
“ Medical School can be a tool of torture or
an Instrument of Inspiration”

29. Paroxysmal symptoms:
 Trigeminal neuralgia.
 Tonic seizures.
 Paroxysmal dysarthria.
 Hemifacial spasm.
 Paroxysmal itching.
 Abrupt loss of muscle tone.
 Paroxysmal aphasia.
 Paroxysmal kinesogenic choreoathetosis.
 Lhermitte’s sign.

30. Favorable indicators:
 Early age of onset.
 Female sex.
 Optic neuritis as presenting episode.
 Sensory symptoms as presenting episode.
 Acute onset.
 Little residual disabilty.
 Long inter exacerbation period.
 Small lesion load.

31. Unfavorable indicators:
 Later age of onset.
 Progressive course.
 Male sex.
 Frequent exacerbations.
 Poor recovery.
 Involvement of cerebellar and or motor functions.
 More disease load in MRI.
 Positive oligoclonal bands.

32. DIAGNOSIS OF MULTIPLE
SCLEROSIS

33. Schumacher Diagnostic Criteria
(Schumacher G, et al. Ann NY Acad Sci 1965)
 The following 6 criteria are essential for a
diagnosis of “definite MS”:
– Age between 10-50 yrs
– Objective abnormalities on exam
– Two or more separate lesions in the CNS
– CNS disease must reflect white matter involvement
– Consistent time course
 Attacks last > 24 hrs; spaced 1 mo apart
 Slow/stepwise progression > 6 mo
– No better explanation by a physician competent in clinical
neurology

34. Poser Diagnostic Criteria
(Poser C, et al Ann Neurol, 1983)

35. McDonald Diagnostic Criteria
Primary Progressive MS
 Insidious course with steady progression of
clinical deficits with paraclinical evidence:
– DIS by MRI in combination with VER & positive
CSF
– DIT by MRI or continued progression for 1 yr
Thought is the labour of the intellect; Reverie is its pleasure

36. McDonald Diagnostic Criteria
MRI-High Specificity & Sensitivity for MS
 Typical MS demyelinating lesions meeting
at least 3 of the following 4 criteria:
– At least 1 Gd lesion or at least 9 T2 lesions
– At least one infratentorial lesion
– At least one juxtacortical lesion
– At least 3 periventricular lesions

37. McDonald Diagnostic Criteria
MRI-Dissemination in Space
 Stringent MRI Criteria
– At least 3 of the 4 criteria must be met:
 1 Gd enhancing lesion or 9 T2 lesions
 > 1 Infratentorial lesion
 > 1 Juxtacortical lesion
 > 3 Periventricular lesions
 MRI + CSF Criteria
– Both of the following must be met:
 > 2 lesions consistent with MS
 CSF showing OCB or increased IgG index

38. McDonald Diagnostic Criteria
MRI-Dissemination in Time
 If the first MRI is performed 3 months after the clinical
event, 1 of the 2 below must be found:
– > 1 Gd lesion not at site of original attack; or
– MRI 3 months later showing a new T2 or Gd lesion
 If the first MRI is performed < 3 months after the clinical
event, then a second MRI done 3 months after the attack
provides evidence for DIT if 1 of the 2 below must be
found:
– New Gd lesion on the second MRI
– Later MRI showing new T2 or Gd lesion

40.  MRI Evidence Of Dissemination In Space is when
three out of four criteria are seen:
 1 Gd-enhancing or 9 T2 hyperintense lesions if no
Gd-enhancing lesion
 1 or more infratentorial lesions
 1 or more juxtacortical lesions
 3 or more periventricular lesions (1 spinal cord
lesion can replace a missing infratentorial lesion
and contribute to the 9 T2-lesions)
It is a great misfortune not to posses sufficient wit to speak well nor
sufficient judgement to keep silent.
La Broyers Charactor

41.  The revised MRI criteria for dissemination in
time are detection of gadolinium enhancement at
least three months after the onset of the first clinical
event or detection of a new T2 lesion appearing at any
time compared with a reference scan done at least 30
days after the onset of the initial clinical event .
 Positive CSF is oligoclonal IgG bands in CSF (and not
serum) or elevated IgG index.
 Positive visual evoked potentials (VEP) is delayed but
well-preserved wave form
Material Gains Soul Losses

42.  An Attack is defined as:
 Neurological disturbance of kind seen in MS
 Subjective report or objective observation
 24 hours duration, minimum
 Excludes pseudo attacks, single paroxysmal
episodes.
 Time Between Attacks is defined as 30 days
between onset of event 1 and onset of event 2.

43. New Queensquare’s criteria
 In 2007, new criteria were proposed in
which DIS requires at least one T2 lesion in
at least two of four locations (juxtacortical,
periventricular, infratentorial, and spinal-
cord) and DIT requires a new T2 lesion on a
follow-up scan
“ Back pain – prize human beings pay
for their UPRIGHT POSTURE”

44.  The specificity of all criteria for CDMS was
high (2001 McDonald, 91%; 2005
McDonald, 88%; new, 87%). Sensitivity of
the new (72%) and 2005 McDonald (60%)
criteria were higher than the 2001
McDonald criteria (47%).
“ You have got to be before you can do
and do before you can have”

45.  The new criteria are simpler than the
McDonald criteria without compromising
specificity and accuracy.
 The presence of both DIS and DIT from two
MRI scans has a higher specificity and risk
for CDMS than either DIS or DIT alone.
A true commitment is a heart felt promise to yourself
from which you will not back down - D. Mcnally

48. McDonald Diagnostic Criteria
Correct Application
 Clinical & lab findings typical of MS
 No better explanation of patient’s findings
 Unusual cases require close follow-up
 Criteria may be applied flexibly but not
casually
 Revisions to criteria may be needed in
future

49. McDonald Diagnostic Criteria
Prospective Performance
(Dalton, et al Ann Neurol 2002)
 Diagnosis of MS by McDonald Diagnostic
Criteria in CIS patients at one year after
presentation compared to reanalysis of
these patients by Poser criteria at three
years:
– Sensitivity: 83%
– Specificity: 83%
– PPV: 75%
– NPV: 89%

50. Focused Neurologic Exam
(Adapted from Whitney D, Int J MS Care, 2001)
 MMSE: Attention, psychomotor slowing
 CN: VA, fundoscopic exam, VFs, swinging
flashlight, EOM evaluating for paresis (INO) &
nystagmus
 Reflexes: asymmetries, Babinski sign
 Motor: spasticity, pyramidal pattern of weakness
 Sensory: Thoracic or cervical level
 Gait: integrates many functions, 25’ timed walk
 Bladder: PVR (if symptomatic)

51. Imaging & Lab Work-up for MS
(Modified from Fleming J, MS & Its Masquerades, AAN-2003)
 Brain MRI with Gd
 VERs
 CBC, Chem 7, Liver enzymes
 Lyme serology (based on exposure history)
 ANA, RPR, ESR
 B12
 TSH
 HIV
 CSF (based on clinical and MRI)
 C & T Spine MRI (if Brain MRI nl or indicated clinically)
 CXR

52. MRI: FLAIR & T1 with Gadolinium
(Noseworthy J, et al NEJM, 2000)

53. MRI: T1 “Black Holes”

54. MRI: Sagittal Views

55. MRI: Spinal Imaging

56. NON CONVENTIONAL MRI:
 MTI :
 Using MTI with gadolinium to improve lesion detection
 Distinguishing lesions of differing severity;
 Studying MTR in brain tissues that appear normal on
conventional MRI. T1-hypointense lesions ("black holes")
have a lower MTR than T1 iso intense lesions- Axonal
damage.
 MTR values fall considerably when gadolinium
enhancement occurs in lesions, with recovery of MTR over
months, although not usually back to normal

57.  Diffusion tensor imaging:
 Chronic lesion : increased ADC and MD with
decreased FA in chronic T1 hypo intense lesions -
extensive tissue loss.
 Acute lesion : FA is lower in acute, gadolinium
enhancing lesions - extracellular oedema - alters
the anisotropic diffusion. ADC and MD values are
raised, but the extent may depend upon the lesion
age.
 ADC – Apparent diffusion co effecient. MD- mean
diffusion. FA- fractional anisotrophy.
Many Ideas grow better when transplanted into another mind than in
the one where they sprang UP O.W. Holmos

58. Visual Evoked Potentials
(Baker’s Clin Neurol 2003)

59. Oligoclonal Bands:
Baker's Clinical Neurology, CDROM-2003

60. MS Variants:
 Balo’s concentric sclerosis.
 Neuromyeltis optica.
 Marburg Disease.
 Myelinoclastic Diffuse sclerosis.
 Tumefactive multiple sclerosis.
 Clinically isolated syndromes.
“ Healthy Mind and Healthy expression of Emotion
Go hand in Hand”

61. Balos concentric sclerosis:
 Pathologic diagnosis- rare acute variant-large concentric
bands of demyelination separated by intact myelin –
Leukoencephalitis periaxialis concentrica(Karaarslan
etal2001.
 More common in Phillipines and China.
 Acute,monophasic,20-50 yrs,features of raised
ICT,seizures,aphasia,decreased level of consiousness.
 CSF similar to MS.
 Differs from MS in clinical presentation,type of lesion & no
involvement of Brainstem,optic nerve,spinal cord.
 Post mortem diagnosis

62. No Caption Found
IANNUCCI, G. et al. J Neurol Neurosurg Psychiatry 2000;69:399-400
Copyright ©2000 BMJ Publishing Group Ltd.

63. Neuro myelitis optica:

64.  NMO is considered - longitiduinally extensive
myelitis.(more than 3vertebral segments)
- optic neuritis.
- Normal MRI or atypical
brain lesions.
Different from MS- clinically,readiologically and
pathologically.
Can be monophasic or relapsing.
NMOIgG antibody - targets aquaphorin 4 water
channel – 73%sensitive & 91%specific (Lennon
&coworkers mayo clinic)

65.  NMO SPECTRUM DISORDER:
Idiopathic relasping myelitis
optic neuropathy.
Asian optico spinal MS.
These patients – histopathologically similar
to NMO & Positive for NMO IgG.
“Fools Admire but of men of sense approve”

66.  Eugene Devic (1858-
1930)- raised two
questions- Why such a
peculiar localisation?
 What is the intimate
nature of the disease?
 Both the questions
largely unanswered.
Eugène Devic (1858–1930).

67. TUMEFACTIVE MS:

68.  MARBURG – ACUTE FULMINANT,DEATH BY 1
YEAR – DUE TO BRINSTEM INVOLVEMENT-
FEW CASES- MATURE MYELIN CONVERTED
TO CITRULLINATED AND IMMATURE FORM
(WOOD etal 1996)
 TUMEFACTIVE MS – LARGE PLAQUES > 2CM
WITH MASS EFFECT AND RING
ENHANCEMENT – MIMICKING A TUMOR – NO
CONSISTENT CLINICAL COURSE KNOWN.
“ Social Isolation is in itself a pathogenic
Factor for disease production”
- Dr. Elsen Borg

69.  Concentric lacunar leukoencephalopathy –
pathological diagnosis –rare disorder with
extensive axonal damage and
demyelination &features of cavitation
separated with band of gliosis.
 Disseminated subpial demyelination – two
cases are described – focal neurological
deficits with mental status changes.
“ My Opinions are founded on knowledge but modified by experience”

70.  Schilder’s disease:
Handful of cases –
childhood MS-rare condition.
Bilateral symmetric
hemispherical demyelinating lesions
U fibers involved (Kotil etal
2002)

71. Monophasic syndromes within the
spectrum of ADEM:
 Normal MRI and CSF – low risk for
conversion into MS.
 MRI lesions & Positive CSF- High risk.
(Fillipi etal 1994,Brex etal 2002)
 Optic neuritis – 12 - 85% conversion to MS.
 Complete transverse myelopathy – low risk
(2 - 8%)
 Incomplete myelopathy (72 - 80%)

72. Factors related to risk of
development of MS after Acute ON:
 High Risk – Young adult(26-40 Yrs).
Venous sheathing.
Recurrent optic neuritis.
Female sex.
History of minor neurological
symptoms.
Brain MRI lesions.
CSF oligoclonal bands or intrathecal
IgG production.

73.  Lower risk: Age <10yrs.
Macular star/exudates.
Retinal or disc hemorrhage.
Severe disc edema.
No Brain MRI lesions.
Normal CSF

74. Figure 4 Approach to the diagnosis of multiple sclerosis (MS) in a patient with a typical
presentation of a clinically isolated syndrome (CIS). CSF, cerebrospinal fluid; MRI, magnetic
resonance imaging.
Trip, S A et al. J Neurol Neurosurg Psychiatry 2005;76:iii11-iii18
Copyright ©2005 BMJ Publishing Group Ltd.

75. Three Categories of Treatment
 Treatment of disease activity.
 Treatment of exacerbations.
 Treatment of symptoms.
A open foe may prove a curse ; but
a pretended friend is worse

76. Rationale for disease modifying
treatments in MS
Relapsing remitting Secondary & primary
MS progressive MS
Prevent new inflammatory Prevent loss of nerve fibres:
lesions: (neuroprotection)
β-interferon ?lamotrigine
Copaxone ?cannabinoids
Mitoxantrone
Prevent development of Remyelination:
secondary progressive MS: ?stem cells
?possible with existing
treatments

77. Treatment of Underlying
Disease
Interferons vs. Glatiramer Acetate
Glatirmer acetate is a substitute antigen that mimics myelin
basic protein. It inhibits the CNS immune reactions that are
responsible for tissue damage.
Given subcutaneously daily injection
Reduces number of attacks and brain lesions seen on
MRI patients
No flu-like side effects associated with interferons

78. Interferons :
 Discovered in 1957
 Significant antiviral agents
 phenomenon where one
infection with one virus interferes
with a subsequent infection with
another virus
The Truth is fear and immorality are two of the greatest inhibitors
of Performance too progress

79. What are they??
A protein substance naturally produced in the
body and believed to function to modulate the
immune system. Interferons interact with
receptors on non-infected cells to promote the
synthesis of antiviral proteins that prevent
further infection. They belong to Cytokines,
which are hormones of the immune system.

80. Beta Interferon
Beta interferon-1a
 Avonex – administered weekly by an
intramuscularly injection (2003)
 Rebif – administered subcutaneously three
times a week (2002)
Beta interferon-1b
 Betaseron – administered subcutaneously
every other day (1993)

81.  Early and aggressive treatment with
immune stimulating interferons can
delay diseae progression.
Prevents crippling symptoms of MS
“ Men of Genius Admired: Men of Wealth envied:
women of power feared: But only women of character are trusted”
-A- Friedman

82. Common Side
Effects…
 Typical Flu-like symptoms
 headache, nausea, and fever
 muscle aches
Chills
Irritation at the injection site
Alcohol and exposure to sunlight may irritate side effects

83. TRIALS:
CHAMPIONS: Avonex altered long-term course MS in patients
who began treatment immediately after initial attack
35% decrease in the rate of developing second attack
42% reduction in new or enlarging T2 hyper intense lesions
Avonex associated with fewer neutralizing
antibodies. Binding antibodies decrease the
medications efficacy. They hasten the drugs
removal from the bloodstream.
10 0
80
Avonex
60
40
Rebif
20 Betaseron
0

84. June 18th 2003
EVIDENCE: Showed that patients on Avonex who converted to
Rebif showed signs of relapse reduction
 Patients taking Rebif had fewer active lesions per MRI
scan for all studied activity
July 21st 2003
QUASIMS: Higher doses and frequencies of interferon beta are
not necessarily better with comparable disease progression
 Annual Relapse rates
Avonex - .52
Rebif - .69

85. Tysabri targets α4-Integrin (VLA4)
adhesion molecule on white blood cells
White blood cells White blood cells use
Chemoattractant signal adhesion molecules
VLA4 and VCAM1 to
α 4 (VLA-4) cross the blood-brain
barrier and enter the
Blood Vessel Lumen brain and cause new
Endothelial Cells inflammatory MS
lesions
Brain VCAM-1
Tysabri block the
White blood cells VLA4 adhesion
Chemoattractant Signal
molecule on white
blood cells so
α 4 (VLA-4) should stop them
Tysabri from getting in to the
Blood Vessel Lumen
brain and causing
Endothelial Cells new MS lesions
Brain VCAM-1

86. Other trials:
 AFFIRM STUDY- NATALIZUMAB MONOTHERAPY
MORE EFFECTIVE THAN INTERFERONS IN TREATING
RRMS.
 BEYOND TRIAL-DOUBLE DOSE INTERFERON
BETA1B – NO ADVANTAGE OVER CONEVENTIONAL
DOSAGE.
 REGARD TRIAL - THRICE WEEKLY INTERFERON
SHOWED NO ADVANTAGE OVER GLATIRMER
ACETATE.
 ETOMS TRIAL- EARLY TREATMENT WITH
INTERFERONS REDUCED SECOND ATTACK BY 24%

87. COMBINATION THERAPY:
 NATALIZUMAB WITH IM BETA 1A OVER INTERFERON
AND PLACEBO – FORMER WAS BETTER – REDUCED
MRI LOAD AND RELAPSES (RUDICK ETAL 2006)
 PML WAS A DREADED SIDE EFFECT IN TWO
PATIENTS.
 COMBINATION OF MINOCYCLINE AND GLATIRMER
ACETATE IS UNDER WAY NOW.
 BETA1A COMBINATION WITH GA (TULLMAN AND
LUBLIN) WAS SUCCESSFUL AND NOW A PHASE 3
TRIAL IS ONGOING – RESULTS EXPECTED IN 2011
“ Maintaining the right attitude is easier than regaining the
right mental attitude”

88. Other drugs:
 MITOXANTRONE:
Worsening forms of MS –SP,PRMS,RRMS
WITH ACCUMULATING DISABILITY.
Cytotoxic anthracenedione
Multicenter observer blinded placebo controlled
trial,5mg/m2 or12mg/m2 IV every 3 months for 2 years
(Hartung etal 2002) – patients receiving 12mg/m 2 did
better.
Another European trial combining mitoxantrone
with methyly prednisone – 86%reduction in new disease
activity when compared with methyl pred group alone.
Important cumulative dose dependent cardio
toxic effect, kept below 140mg/m 2

89.  CYCLOPHOSPHAMIDE - No consistent benefit
(canadian cooperative study group 1991).
 AZOTHIOPRINE - Modest effect on relapses.no
convincing effect on relapses.commonest drug in
progressive MS-cytostatic agent – More so due to
lack of effective therapy(british and dutch MS AZT
trial group1988:Ellison etal 1989:Goodkin etal
1991).
 METHOTHREXATE - A small trial in Prog MS at
7.5 mg orally modertae benefit in upper extremity
function- no effect on ambulation.
 CLADIRIBINE - A large trial in PPMS,SPMS,- no
benefit after 1 year but gadolinium enhancing
lesions reduced(Rice etal 2000)

90.  Cyclosporine – in progressive MS modest
effect with significant renal toxicity(MS atudy
group 1990)
 Repetitive course of steroids- one study
showed no benefit (goodkin etal 1998)while
another study showed lessened
accumulation of black holes,atrophy and
disability (Zivadinov etal 2001)
Success in life is a matter not so much of talent and opportunity
as of concentration and perseverance
- C.W. Wendte

91.  IVig – A double blind placebo controlled study in Austria
(Fazekas etal 1997)-59%reduction in relapses.
A study in denmark – reduction in Gad Enhancing
lesions.relapse rate was not significantly reduced.
(Sorenson etal)
A study conducted in Israel- relapses
decreased,number of exacerbation free periods decreased.
A recently concluded European trial- no activity on
disease activity.
Mind is the great level of all things; Human thought is the process by
which, Human ends are ultimately answered

92. WHOM TO START AND WHEN TO
TREAT:
 When to start DMD- as early as possible.
 Interferons,glatirmer acetate- RRMS.
 IFN beta – relapsing form of SPMS (goodin
etal 2002).
 MITOXONTRONE - Relaping MS
(RR,SP,PROG.RELAPSING).
 NO SUCCESFUL TRIALS FOR PPMS.

93. UNANSWERED QUESTIONS:
 DOSE vs DOSING FREQUENCY.
 DOES TIME ON THERAPY MATTER.
 WHEN TO START NATALIZUMAB.
 HIGH DOSE IFN vs NATALIZUMAB.
“ Peace Rules the day where reason Rules the mind”
- Colling

94. Symptomatic therapy:
 Spasticity – baclofen 5mg bd (max dose80
mg in three divided doses).
-Tizanidine 2mg(max dose 36
mg). Intrathecal baclofen and botulinium
toxin are also used now.
 Weakness - 4 amino pyridine K channel
opener – improves conduction in
demyelinated nerve fibers- phase three trial
is on.
Truth comes out of error sooner than that of confusion

95.  Psychitaric manifestations:depression is
commonest ,SSRI –
citalopram,escitalopram,fluoxetine,sertaralin
 Norepinephrine and dopa reuptake
inhibitors- bupropion .
 Bipolar disorder-lithium or valproic acid.
 Psychotherapy.
Opinion is ultimately determined by the feelings
and not by the intellect

96.  Fatigue -Psychotherapy.
Amantadine.
Acetyl L carnitine
Pemoline – hepatotoxic.
Acetly L carnitine more effective
than amantadine in a recent double
blinded trial(Tomassini etal)
Experience can be defined as yesterday’s answer to today’s problems

97. Sexual Dysfunction:
 90% have sexual dysfunction and more common
in RRMS.
 Drugs used for treatment,might be a reason.
 Loss of libido &difficulty in attaining orgasm-
bupropion 150mg-400mg –seizure side
effect(crenshaw etal 1987).
 Erectile dysfunction:Sildenafil,vardenafil,tadalafil.
Vardenafil faster onset while
tadalafil longer duration of action.

98.  Eros therapy – USFDA appproved vacum
device-increases blood flow and
engorgement when placed on clitoris.
 Topical esterogen creams & lubricants to
enhance sexual desire.
Memory, Pity & Beauty are short lived in life,
Tinged with emotions persist in life

99.  Cognitive dysfunction:donezipil- increases
verbal memory(krupp etal 2004,small
double lind placebo controlled trial)
 Bladder dysfunction-
Detrusor hyopreflexia – rule out infection –
intermittent self catherisation.
detrusor hyperreflexia – anticholinergics,
oral,extended release,transdermal patch.
Being ignorant is not so much a shame as being unwilling to learn

100.  Detrusor sphincter dyssynergia- alpha adrenergic
antagonists-
Doxazosin,prazosin,tamsulosin,terazosin along
with anticholinergics are used.alpha blockers
prone to cause postural hypotension – if so
intermittent self catherisation advised.
 Urologic evaluation – if symptoms suggestive of
dterusor hyper reflexia an voiding
dysfunction(continum of AAN 2007)
Dual action of brain is reflected in the duality of god;
Each is in-separable but has individual existence

101.  Bowel dysfunction –
 Constipation and fecal incontinence both are
problems.
 bulk formers-methylcellulose,psyllium.
 Stool softener-docussate sodium.
 Stimulant laxatives-Senna,Bisacodyl.
 Osmotic laxatives-lactulose.
 High fiber diets-fecal impaction and overflow
incontinence.

102. TREMOR:
 35% HAVE TREMOR AND 25% are
disabling.
 Carbamazepine,clonazepam,gabapentin,glu
tethmide,INH,leviteracetam,primidone,propr
anolol.
 DBS- not approved – Hooper etal
2002,showed improved function in 15
patients.
“Give us the GRACE to accept with serenity the things that cannot be changed;
T COURAGE to change the things that should be changed and;
he
T W
he ISDOM to know the difference”

103. CONCLUSIONS:
 SIGNIFICANT ADVANCES HAVE BEEN MADE,IN
IMMUNOPATHOLOGY,CATEGORISATION OF
SEVERITY,DISEASE MODIFYING DRUGS AND THEIR
USAGE.
 CRIPPLING DISABLTY CAN BE LIMITED,EARLIER
DIAGNOSIS AND BETTER SYMPTOMATIC THERAPY
ARE AVAILABLE NOW.
 RESEARCH IS STILL ON IN FINDING THE ELUSIVE
GENE OR AN ENVIRONMENTAL AGENT OR BOTH.
 DESPITE ALL THESE ADVANCES TWO THINGS ARE
STILL UNANSWERED – CURATIVE THERAPY & THE
EXACT CAUSE FOR MS.
 OVER 140 YEARS MS REMAINS AN UNSOLVED
PUZZLE AND AN ENIGMA.

104. Take home advances in MS:
 Queen square criteria – Earlier diagnosis of
MS.
 DIS & DIT – Predicts conversion rate to
Definite MS even in CIS.
 NMO & NMO spectrum disorder – distinct
disorder from MS?
 In terms of Biological difference thin line
separates PPMS & SPMS.

105.  TH 17 a Subset of CD4 and Treg
cells(expressing CD25 & transcription factor
Fox p 3) – pro inflammatory – a significant
advance in immunopathogenesis.
 Two new gene loci IL2 and IL 7 -
IDENTIFIED – needs substantiation.
 EBV, SMOKING – INCREASES RISK OF
MS WHILE Vitamin D – Decreases risk of
MS.

106.  Negative prognosticators are, bladder
symtoms as presentation, incomplete
recovery from an attack, shorter interval
between first and second attack and early
accumulation of disability.
 Benign MS – percentage of cases less –
they eventually progress – not ACTUALLY
BENIGN.

107.  A MAGIC PILL – BASED ON
PHRMACOGENETICS(DNA LEVEL) AND
PHRAMACOGENOMICS(RNA LEVEL)OF
AN INDIVIDUAL.PROTEOMICS INFCAT
RESEARCH BEYOND RNA LEVEL –
FUTURE HOLDS PROMISE .

108. Dedicated to my family
for making everything worthwhile

110. READ not to contradict or confute
Nor to Believe and Take for Granted
but TO WEIGH AND CONSIDER
THANK YOU
My sincere thanks to
DrC.T.SURESH,Dr.G.MUGUNTHAN,DR.G.VIKRAMRAJ
Dr.S.ARUNAN.
Institute of Neurology,
Chennai-03