This document provides an overview of demyelinating diseases of the central nervous system, with a focus on multiple sclerosis. It discusses the etiology, pathogenesis, clinical features, diagnosis, treatment and management of multiple sclerosis. Key points include: MS results from an autoimmune attack on the myelin sheath surrounding nerves in the brain and spinal cord; diagnosis involves evidence of lesions disseminated in space and time via MRI or other tests; and treatments include steroids for acute attacks and disease-modifying drugs such as interferons to reduce relapse rates long-term.

1. Demylinating diseases of
CNS
 Multiple sclerosis
 NMO ( devics disease)
 ADEM
Dr. Sunil Bobade
Dept. of Medicine
Gmc latur

2.  Brief Overview of disease condition
 History of MS
 Epidemiology and world wide distribution
 Types of MS
 Signs and Symptoms
 Factors causing Disease
 Diagnosis
 Treatments
 Research Themes
 Conclusion
 References

5.  ETIOPATHOGENESIS :The exact cause of multiple
sclerosis is unknown, but it is believed to be some
combination of immunologic, environmental,
infectious, or genetic factors
 Multiple sclerosis (MS) is an autoimmune disease in
which the body's immune system attacks its own
central nervous system (the brain and spinal cord).
 In MS, the immune system attacks and damages or
destroys the myelin, a substance that surrounds and
insulates the nerves.
 The myelin destruction causes a distortion or
interruption in nerve impulses traveling to and from
the brain.

6.  New MS lesion begins with perivenular cuffing by
inflammatory mononuclear cells predominantly T
cells and macrophages
 BBB is disrupted but unlike vaculitis vessel wall is
preserved
 Small no. of B cells also infiltrate nervous system ,
myelin specific auto antibodies are present on
degenerating myelin sheaths
 Demyelination is the hallmark of pathology

9.  Auto reactive T lymphocytes
 T cells play key role in activating & maintaining
autoimmune response
 TNF-α & IFN-γ can directly injure oligodendrocytes &
myelin membrane
T cells
TH1 –IL2,TNF-
α,IFN-γ
TH17-IL-17

10.  Humoral autoimmunity
 B cell activation is also necessary to full development
of demyelinating lesions
 Myelin specific autoantibodies
Extracellular myelin myelin
protein oligodendrocyte
gycoprotein (MOG)

11.  Increased levels of locally synthesized Ig & oligoclonal
Ab derived from clonally restricted CNS B cells &
plasma cells are characteristics of MS

12.  Inflammation
 Demyelination
Astrocytes oligodendrocytes

 Gliosis
 remylination

13. Prevalence and incidence:
 MS 3 times more common in women
 Age of onset typically 20 to 40
 10 % can begin before 18 yrs of age
 Geographical variability is found in MS
 Highest prevalance is 250/1lac in orkney islands
Risk factors : vit. D def
exposure to EBV
cigarette smoking

15. Whites are at high risk
MS is polygenic
Pt. with HLA-DRB 1 gene in class 2 MHC accounts for 10
% of cases
Risk is 1 in 3 if identical twin has MS

17. It is mc type 85 %
Characterized by discrete attacks that generally evolve over days to week
s
Between attacks pt is neurologically stable

21. 15% PPMS
85% RRMS
50% SPMS and
50% need support
90% SPMS
11-15 years
26 years
from onset
50% need
support
5 years
Natural History of RRMS and PPMS
30 years
from onset
83% need cane
~ 34% bed bound
22 years
from onset
50% bed bound

23.  Clinical features
 Weakness of limbs- exercise induced weakness is a
characteristic of MS –UMN type
pyramidal signs such as spasticity, hyperreflexia,
babinski sign
 Optic neuritis - visual acuity , dimness, decreased
color vision,(desaturation) generally monocular may be
biocular
periorbital pain often precedes or accompanies visual
loss
papillitis, optic atrophy
diplopia may be due to INO or 6 th N. palsy

25.  b/l INO is s/o of MS
 Other gaze disturbances
1 horizontal gaze palsy
2 one and half syndrome (horizonatal gaze palsy plus INO
)
3 acquired pendular nystagmus
Uveitis is uncommon should raise the possibility of
alternative diagnosis such as sarcoid or lymhoma
Sensory symptoms – parasthesias (tingling , prickling
,formications ) hypoesthesia , reduced sensations(dead
felling), unpleasant sensations
Ataxia as cerebellar tremors , cerebellar dysarthria(scanning
speech)

26. Cognitive dysfunction –memory loss , impaired attention ,
Depression , sexual dysfunction ,facial weakness, vertigo
Bladder dysfunction –
occurs in > 90 % of pts
detrusor hyperreflexia – increased frequency , urgency,
nocturia ,(UMN bladder)
detrusor sphincture dyssynergia –hesitancy, retention ,
overflow incontinence
 constipation in 30 % of cases and bowel incontinence in
< 15 % of cases

27. Ancillary symptoms
 Heat sensitivity –uthoffs symptoms
 Lhermittes symptom- also in cervical spondylsis
 Paroxysmal symptoms – brief duration 10 s to 2 min,
high frequency 5 to 40 /day
may be ppted by hyperventilation or movements
It iclude s leermittes symptom , tonic contraction of
limb ,facr or trunk (Tonic seizures) dysartheia ataxia
E/o –probably result from spontaneous discharge arising
at the edges of demyelinating plaque & spreading to
adjacent white matter

28.  Trigeminal neuralgia , hemifacial spasm, glasophyringeal
neuralgia can occur
 Facial myokymia – consist of either rapid flickering
contractions of facial musculature or contraction that
slowly spreads across the face
it is due to lesion of the corticobulbar tract or brainstem
course of facial nerve

29. tests to Confirm a Multiple Sclerosis Diagnosis
 MRI
 Electrophysiological test
 Cerebrospinal fluid exam (spinal tap, lumbar
puncture)
 Evoked potential (EP) tests

35.  Diagnostic criteria ( McDonalds criteria )
clinical additional data
A. 2 or more attacks +
Objective evidance of 2 or more none
Lesions OR
obj. evidance of 1 lesion with
resonable history of prior attack
B. 2 or more attacks + DIS
Obj. clinical evidance of >1 T2 lesion on MRI in
1 lesion at least 2 out of 4 MS
t typical regions

36. C. 1 attack + additional data required
objective clinical Evidence
of 2 or more lesions
is DIT
Simultaneous presence of
asymptomatic Gd enhancing
& non enhancing lesion at
any time
OR
New T2 &/or
Gd enhancing lesion on
follow up MRI

37. D. 1 attack + obj. clinical evidence of 1 lesion
Additional data required is both DIS & DIT
DIS
>1 T2 lesion in 2 0ut of 4
MS specific regions
DIT
Simultaneous presence of asymptomatic Gd enhancing
& non enhancing lesion at any time
OR
New T2 &/or Gd enhancing lesion on follow up MRI

38. E. Insidious onset neurologically progressive MS ie
PPMS
Additional data required is
1 yr of disease progression + 2 out of 3 following
1) Evidence of DIS in brain based on >1 T2 lesion in 2/4
2) Evidence of DIS in spinal cord >2 T2 lesion in cord
3) +ve CSF for oligoclonal band & or increased IgG
index

41. August
November
DIS
DIT

42. 1. Dissemination in space: Objective
evidence of neurological deficits
localized to two separate parts of
the CNS
2. Dissemination in Time:
Onset of neurological deficits
separated by at least one month
3. Rule out other explanations!
August
November

43. MS specific areas
 Periventricular
 Infratentorial
 Juxtacortical lesion
 Spinal cord
MRI - Dissemination in Space

44. T2
> 1 month
Gd
> 3 months
Polman, 2005
Gd
T2

45.  Elevated IgG Index >0.7
 Increased CNS IgG synthesis, with
normal serum IgG consistent with
MS
 Oligoclonal Bands
 Presence of 2 distinct bands
in CSF is consistent with MS
• Most helpful for suggesting an alternative Dx
-high protein, marked pleocytosis, PMNs

46.  Lupus 25%
 Sarcoidosis 51%
 Behcet’s dz 8%
 Syphilis
 CJD
 Whipple’s disease
 Lyme disease
 Vasculitidies
 Devic’s disease
 Healthy siblings of MS
patients

47. Therapy of MS can be divided into
 1 . Treatment of acute attacks
 2 treatment with disease modifying agents
 3 . Symptomatic treatment

48.  Treatments for MS attacks
 Corticosteroids, such as oral prednisone and
intravenous methylprednisolone, are prescribed to
reduce nerve inflammation.
 IV MPS 500- 1000mg /d for 3-5 days f/b oral
prednisone beginning with dose 60- 80 mg /d
gradually tapered over 2 wks
Side effects may include insomnia, increased blood
pressure, mood swings and fluid retention, wt gain,
acne , K loss ,

50.  s/e of corticosteroid can be treated or minimize as
low salt potassium rich diet
Avoidance of potassium wasting diuretics
Lithium carbonate 300mg bd for emotional liability
PUD can be t/t with PPI

51.  Plasma exchange (plasmapheresis). The liquid
portion of part of your blood (plasma) is removed and
separated from your blood cells.
 The blood cells are then mixed with a protein solution
(albumin) and put back into your body.
 Plasma exchange may be used if your symptoms are
new, severe and haven't responded to steroids.
 Effective in fulminant attacks of demyenation

 5-7 exchanges 40-60 ml/kg every other day for 14 days

52. Mild intial course : recent onset , normal exam ,
minimal ipairment (EDSS < 2.5 )
or low disease activity
either inj. IFN BETA OR glatrimer acetate
oral ; DMF, fingolimod , teriflunamide
Mod or severe intial course : ie highely active disease
or moderate imairment (EDSS > 2.5 )
highly effective oral agent DMF OR Fingolimod
If pt is sreonegative gor JV virus Natlizumab van be used
Finally vit . D def should be corrected in all pts with vit D3
4000 to 5000 IU daily

53. Treatments to modify disease progression
 For relapsing-remitting MS, several disease-modifying
therapies are available.
 Treatment options for relapsing-remitting MS include:
1. IFN Beta 1a , 1b
2. Glatrimer acetate
3. Natalizumab
4. Fingolimod
5. Dimethyl fumarate
6. Teriflunamide
7. Mitoxantrone
8. Alemtuzumab

54. Beta interferons.
 Originally Identified as antiviral property
 MOA
1. Down regulate expression of MHC molecule on APC
2. Reducing proinflamatory and increasing regulatory
cytokine levels
3. Inhibiting T cell proliferation
4. Limiting trafficking of inflammatory cells in CNS


55.  IFN –β 1a (Avonex ) 30 μg IM once a week
 IFN –β 1a ( Rebif ) 44 μg sc t IFN –β 1a three /wk
 IFN –β 1b ( betaseron or extavia ) 250 μg sc every othre
day
Side effects
 include flu-like symptoms and injection-site
reactions.
 You'll need blood tests to monitor your liver enzymes
because liver damage is a possible side effect of
interferon use.
 People taking interferons may develop neutralizing
antibodies that can reduce drug effectiveness which
disapper over time

56. Glatiramer acetate (Copaxone).
it is polypeptide of 4 AA Glutamic acid , lysine .
Alanine , tyrosine
MOA:
1. Induction of ag specific supressor T cells
2. Binding to MHC molecule , thereby displacing
bound MBP
3. Aletring the balance between proinflamattory and
regulatory cytokine
Dose 20 mg every day or 40 mg thrice wkly
S/E injection site reaction , flushing ,chest tightness,
dyspnea , palpitations , anxiety , lipoatrophy

57. Fingolimod . This once-daily oral medication reduces
relapse rate. 0.5 mg daily
 MOA- prevents egress of lyphocytes from secondary
lyphoid organs
 It reduces attack rate
You'll need to have your heart rate monitored for six
hours after the first dose because your heartbeat may
be slowed. 1st degree heart block
Other side effects include headache, high blood pressure
and blurred vision.

58. Mitoxantrone : dose 12 mg/m2 every 3 months
 Indicated for SPMS & PRMS
 It is cardio toxic
 >40 % women experience amenorrhea
 It should not be used first line agent in RRMS
 Only selected pts with progressive course:;;
Alemtuzunab : anti CD 52 expressed on both
monocytes and lyphocytes
It causes lyphocyte depletion of both (B & T cells )
Toxicities : autoimmune diseases ( thyroididtis, graves ,
ITP
Malignancies: thyroid cancer, melanoma , breast ca
Serious infections and infusion reaction

59. Teriflunamide: it inhibits denove pyrimidine synthesis
 It exerts its anti-inflammatory action by limiting thr
proliferation by rapidly dividing T & B cells
 Dose 7 or 14 mg orally each day
 S/E mild hair thinning , g I symptoms ,
 It is teratogenic
 Remain in blood for 2 yrs
 Pt who wants conceive receive cholestyarmine or
activate charcoal to eliminate it
 DMF

60. DMF : MOA modulation of proinflamatory and anti-
inflammatory cytokines
 Dose 240 mg twice daily oral
Natalizumab : monoclonal Ab against α4 subunit of
α4β1 intigrin expressed on lymphocytes
 Dose 300 mg iv infusion each month
 S/E : PML
 Risk is low in 1st yr regardless Ab status so can be used
safely for 12 months

61.  DISORDERS THAT CAN MIMIC MULTIPLE SCLEROSIS
(MS)
 Acute disseminated encephalomyelitis (ADEM)
 Antiphospholipid antibody syndrome
 Behçet’s disease
 CADASIL
 Congenital leukodystrophies (e.g., adrenoleukodystrophy,
metachromatic
 leukodystrophy)
 HIV infection
 Ischemic optic neuropathy (arteritic and nonarteritic)
 Lyme disease
 MELAS
 Abbreviations: AV, arteriovenous; CADASIL, cerebral
autosomal

62.  Neoplasms (e.g., lymphoma, glioma, meningioma)
 Sarcoid
 Sjögren’s syndrome
 Stroke and ischemic cerebrovascular disease
 Syphilis
 Systemic lupus erythematosus and related collagen
vascular disorders
 Tropical spastic paraparesis (HTLV-1/2 infection)
 Vascular malformations (especially spinal dural AV
fistulas)
 Vasculitis (primary CNS or other)
 Vitamin B12 deficiency

63.  ANA
 ACE
 Lyme
 Anticardiolipin ab
 ESR
 HIV
 Syphilis IgG
 SSA, SSB
 Neuromyelitis optica antibody(AQP4 ab)

64.  Treatments for MS signs and symptoms
 Physical therapy session
 Physical therapy. A physical or occupational therapist can
teach you stretching and strengthening exercises and show
you how to use devices to make it easier to perform daily
tasks.
 Physical therapy along with the use of a mobility aid when
necessary can also help manage leg weakness and other
gait problems often associated with MS.
 Muscle relaxants. You may experience painful or
uncontrollable muscle stiffness or spasms, particularly in
your legs. Muscle relaxants such as baclofen (Lioresal) and
tizanidine (Zanaflex) may help.
 Medications to reduce fatigue.
 Other medications. Medications also may be prescribed
for depression, pain, sexual dysfunction, and bladder or
bowel control problems that are associated with MS.

65. Dysesthesia may respond to carbamazepine (100–1000
mg/d in divided doses),
 phenytoin (300–600 mg/d), gabapentin (300–3600 mg/d),
pregabalin (50–300mg/d), or amitriptyline (25–150 mg/d).
•
Treatment of bladder symptoms is based on the underlying
pathophysiology
 investigated with urodynamic testing: bladder
hyperreflexia is treated with
 evening fluid restriction and frequent voiding; if this fails,
anticholinergics such as oxybutynin (5–15 mg/d) may be
tried;
 hyporeflexia is treated with the cholinergic drug
bethanechol (30–150 mg a day),
 and dyssynergia due to loss of coordination between
bladder wall and sphincter muscles is treated with
anticholinergics and intermittent catheterization.
 • Depression should be treated aggressively withSSRI

66.  Exercise (avoid overheating)
 Physical / occupational therapy
 Nutrition (avoid extremes of weight)
 Avoid excess heat exposure or elevated core
temperature
 Prompt tx of fever with antipyretics
 Cool environment / cool bath

67. AGENT MECHANISM ROUTE PHASE
Rituximab Anti CD20 IV (2 x year) Phase II
Campath Anti CD52 IV (1 x year) Phase II
Daclizumab Anti CD25 IV or SC (q mo) Phase II
Anti IL-12 Anti IL-12 SC (qw or qow) Phase II
Statins immunomodulator oral Phase II
Teriflunomide immunomodulator oral Phase III
Anti VLA-4 SAM inhibitor oral Phase III
FTY 720 immunomodulator oral Phase III
Oral Cladribine immunosuppressan
t
oral Phase III
Minocycline immunomodulator oral Phase II
Estriol immunomodulator oral Phase II
MBP 8292 immunomodulator IV (q month) Phase III
Therapeutic Agents Under Investigation

70. Effect of pregnancy
 Pregnant MS pt experience fever attack than expected
during gestation ( especially in the last three months )
 But more attacks than expected in the first 3 months
of postpartum
 Overall disease course is unaffected
Decision about childbearing should be made on
1. Mothers physical state
2. Her ability to care for the child
3. Availability of social support

71.  Harrisons principle of internal
medicine 19th edition
 All About MS @ http://www.mult-
sclerosis.org/
 Multiple Sclerosis Society
@ http://www.mssociety.org.uk/
 The National Multiple Sclerosis Society
@ http://www.nationalmssociety.org

72. Thank you