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Multiple sclerosis
1. MULTIPLE SCLEROSIS AND OTHER
INFLAMMATORY DEMYELINATING
DISEASES
Dr. Muneshwar SAH , MD Resident
,NAMS
2. CLASSIFICATION
I. Multiple sclerosis
II. Neuromyelitis optica (Devic disease, NMO)
and progressive necrotic myelopathy
III. Acute disseminated encephalomyelitis
(ADEM) and acute hemorrhagic encephalitis
(Weston Hurst disease)
IV. Demyelination in association with autoimmune
disease (SLE, Sjögren disease, and related
conditions)
V. Sarcoid-related demyelination
VI. Graft-versus-host disease
3. MULTIPLE SCLEROSIS :
History
In 19th century, described by Carswell,
Cruveilhier and later, Frerichs
Multiple sclerosis was referred to by the
British as disseminated sclerosis and by the
French as sclérose en plaques .
J. M. Charcot : collected 34 cases and set a
foundation for understanding the disease
Cruveilhier (circa 1835), in his original
description of the disease, attributed it to
suppression of sweat.
4. Multiple sclerosis
An autoimmune disease of the central nervous
system (CNS) characterized by chronic
inflammation, demyelination, gliosis (plaques
or scarring), and neuronal loss; the course can
be relapsing or progressive.
MS plaques typically develop at different times
and in different CNS locations (i.e., MS is said
to be disseminated in time and space)
5. PREVALENCE
Possibly No study done in nepal
Low near the equator and increases in the
temperate zones of both hemispheres
Prevalence of MS increased with geographic
latitude in Western Europe, North America,
and Australia/New Zealand
Study from India, (Bharucha etal.,1988). The
age-standardized prevalence-
15/100,000(95%C.I.3.1–43.8) in bombay city.
7. EPIDEMIOLOGY AND RISK
FACTORS
Women > men ( 2.3:1)
mean age of MS onset : 28 - 31 years. RMS
has an earlier onset : 25 to 29 years; SPMS at
a mean age of 40 to 49 years. PPMS has a
mean age of onset of 39 to 41 years
Have Autoimmune disorders : psoariasis ,
thyroid disorders , IBD , uveitis , pamphigoid ,
T1DM.
8. Environmental factors
viral infections : VZV – MS exacerbations .
CMV and early childhood infection – protection
against autoimmunity
geographic latitude :
sunlight exposure and vitamin D levels :
inversely associated with MS
Vaccination : no association
Others : smoking , childhood obesity
9. Genetic susceptibility
Related to MHC : HLA-DRB1 locus
Monozygotic twins (20-40%) > dizygotic =
siblings
A variant in the TNFSF13B gene, encoding B-
cell activating factor (BAFF) – enhanced
humoral immunity – increased risk of MS and
SLE.
Drugs : tumor necrosis factor-alpha inhibitors
may induce or exacerbate MS .
10. Pathogenesis
Inflammation, demyelination, and axonal
degeneration .
Immune-mediated disorder characterized by
autoreactive lymphocytes . Immune hypothesis
supported by
• Inflammatory T cells, B cells and
macrophage seen in MS lesions.
• The presence of immunoglobulin G (IgG) and
immunoglobulin M (IgM) oligoclonal bands in
the cerebrospinal fluid.
11. Pathogenesis continued
• Myelin reactive T cells are found in MS
plaques and in the CSF and the peripheral
circulation.
• T helper 17-type immune activation
• Associated with certain class I and class II
alleles of the major histocompatibility complex
(MHC)
• Immunomodulatory drug – decrease MS
disease activity.
12. Entry of activated T lymphocytes across the
blood–brain barrier recognize myelin-derived
antigens on the surface of the nervous
system’s antigen-presenting cells ( the
microglia ) clonal proliferation releases
cytokines and initiates destruction of the
oligodendrocyte–myelin unit by macrophages.
13. The main physiologic effect of demyelination is
to impede saltatory electrical conduction of
nerve impulses from one node of Ranvier,
where sodium channels are concentrated, to
the next node. The resulting failure of electrical
transmission is thought to underlie most of the
abnormalities of function resulting from
demyelinating diseases of both the central and
peripheral nerves.
14. Pathology
The characteristic feature -presence of focal
demyelinated plaques within the central
nervous system, accompanied by variable
degrees of inflammation and gliosis, with
partial preservation of axons.
These lesions tend to be located in the optic
nerves, spinal cord, brainstem, cerebellum,
and the juxtacortical and periventricular white
matter.
15.
16. Clinical feature
Onset – abrupt or insidious
Symptoms –may severe or minor or asymtomatic.
Symptoms and signs of MS usually evolve over days
or weeks, resolving over weeks or months.
Common presentation :
• Optic neuritis
• Relapsing/remitting sensory symptoms
• Subacute painless spinal cord lesion
• Acute brainstem syndrome
• Subacute loss of function of upper limb (dorsal
column deficit)
• 6th cranial nerve palsy
17.
18. Optic neuritis (ON)
Diminished visual acuity and color perception
in the central field of vision.
mild or may progress to severe visual loss.
generally monocular but may be bilateral.
Periorbital pain (aggravated by eye
movement) often precedes or accompanies
the visual loss
Fundoscopy : normal or optic disc swelling .
Optic atrophy commonly occurs.
19. Sensory symptoms
paraesthesias (e.g., tingling , prickling
sensations, formications, “pins and needles, or
painful burning )
hyperesthesia (e.g., reduced sensation,
numbness, or a “dead” feeling).
Unpleasant sensations (e.g., feelings that
body parts are swollen, wet, raw, or tightly
wrapped)
Pain is a common symptom of MS( >50% of
patients) .Anywhere on the body and can
change locations over time
20. Weakness of the limbs
Exercise-induced weakness is a characteristic
symptom of MS.
loss of strength, speed, or dexterity, as fatigue,
or as a disturbance of gait
The weakness is of the upper motor neuron
type and is usually accompanied by other
pyramidal signs such as spasticity,
hyperreflexia, and Babinski signs.
21. Facial weakness
resemble idiopathic Bell’s palsy (not
associated with ipsilateral loss of taste
sensation or retroauricular pain ) (Vs) Bell’s
palsy.
22. Spasticity
> 30% of patients have moderate to severe
spasticity, especially in the legs.
Painful spasms interfering with ambulation,
work, or self-care.
treatment of spasticity may do more harm than
good.
23. Visual blurring
Due to ON or diplopia
Diplopia may result from internuclear
ophthalmoplegia (INO) or from palsy of the
sixth cranial nerve.
An INO consists of impaired adduction of one
eye due to a lesion in the ipsilateral medial
longitudinal fasciculus .
Prominent nystagmus is often observed in
the abducting eye, along with a small skew
deviation.
A bilateral INO is particularly suggestive of
MS..
25. Other common gaze disturbances :
(1) a horizontal gaze palsy,
(2) a “one and a half” syndrome (horizontal
gaze palsy plus an INO),
(3) acquired pendular nystagmus
Ataxia - manifests as cerebellar tremors
,cerebellar dysarthria (scanning speech).
Vertigo – due to brainstem lesion, resemble
acute labyrinthitis .
26. Ancillary symptoms
Lhermitte’s symptom is an electric shock–like
sensation (typically induced by flexion or other
movements of the neck) that radiates down the
back into the legs.
self-limited .
Also present in Cervical spinal cord (e.g.,
cervical spondylosis).
27. Heat sensitivity
Neurologic symptoms produced by an
elevation of the body’s core temperature.
Unilateral visual blurring may occur during a
hot shower or with physical exercise (Uhthoff’s
symptom). Probably due to transient
conduction block
28. Bladder dysfunction
>90% of MS patients
Detrusor hyperreflexia (impairment of
suprasegmental Inhibition) - urinary frequency,
urgency, nocturia, and uncontrolled bladder
emptying.
Detrusor sphincter dyssynergia ( loss of
synchronization between detrusor and
sphincter muscle ) - hesitancy, urinary
retention, overflow incontinence, and recurrent
infection.
29. Constipation - >30% of patients
Sexual dysfunction - decreased libido,
impaired genital sensation, impotence in men,
and diminished vaginal lubrication or adductor
spasms in women
Depression – 50 % of patients . Can be
reactive, endogenous, or part of the illness
itself and can contribute to fatigue.
30. Fatigue - 90% of patients , exacerbated by
elevated temperatures, depression, sleep
disturbances (e.g., from frequent nocturnal
awakenings to urinate).
Cognitive dysfunction - memory loss; impaired
attention; difficulties in executive functioning,
memory, and problem solving; slowed information
processing; and problems shifting between
cognitive tasks
Trigeminal neuralgia, hemifacial spasm, and
glossopharyngeal neuralgia - Uncommon
31. DISEASE COURSE
1. Relapsing or bout
onset MS (RMS) : 90 % ,
characterized by discrete
attacks of neurological
dysfunction that generally
evolve over days to weeks
which substantialy or
completely recover over
the weeks to months.
Between attacks, patients
are neurologically stable.
32. 2.Secondary progressive MS
(SPMS)
Always begins as RMS
At some poin , the clinical
course changes and produces
a greater amount of fixed
neurologic disability
the risk of developing SPMS
is ~2% each year. represent a
late stage RMS.
33. 3.Primary progressive MS
(PPMS)
~10% of cases
Sex distribution - more
even
mean age ~40 years
disability develops
faster (relative to the
onset of the first clinical
symptom).
35. CLINICAL
PRESENTATION
ADDITIONAL DATA NEEDED FOR MS
DIAGNOSIS
2 or more
attacks;
objective
clinical
evidence
of 1 lesion
Dissemination in space,
demonstrated by
• ≥1 T2 lesion on MRI in at least
2 out of 4 MS-typical regions of
the CNS (periventricular,
juxtacortical, infratentorial, or
spinal cord)
OR
• Await a further clinical attack
implicating a different CNS site
36. CLINICAL
PRESENTATION
ADDITIONAL DATA NEEDED FOR MS DIAGNOSIS
1 attack;
objective
clinical
evidence of 2
or more
lesions
Dissemination in time, demonstrated by
• Simultaneous presence of
asymptomatic
gadolinium-enhancing and
nonenhancing
lesions at any time
OR
• A new T2 and/or gadolinium-
enhancing
lesion(s) on follow-up MRI, irrespective
of its
timing with reference to a baseline scan
37. CLINICAL
PRESENTATI
ON
ADDITIONAL DATA NEEDED FOR MS DIAGNOSIS
1 attack;
objective
clinical
evidence of
1
lesion
(clinically
isolated
syndrome
Dissemination in space and time, demonstrated by:
For dissemination in space
• ≥1 T2 lesion in at least 2 out of 4 MS-typical regions of
the CNS (periventricular, juxtacortical, infratentorial, or
spinal cord)
OR
• Await a second clinical attack implicating a different
CNS site
AND
For dissemination in time
• Simultaneous presence of asymptomatic gadolinium-
enhancing and nonenhancing lesions at any time
OR
• A new T2 and/or gadolinium-enhancing lesion(s) on
follow-up MRI, irrespective of its timing with reference to
a baseline scan
OR
• Await a second clinical attack
38. CLINICAL
PRESENTATION
ADDITIONAL DATA NEEDED FOR MS DIAGNOSIS
Insidious
neurologic
progression
suggestive of
MS (PPMS)
1 year of disease progression
(retrospectively or prospectively
determined)
PLUS
2 out of the 3 following criteria
•Evidence for dissemination in space in
the brain based on ≥1 T2+ lesions in the
MS-characteristic periventricular,
juxtacortical, or infratentorial regions
•Evidence for dissemination in space in
the spinal cord based on ≥2 T2+ lesions
in the cord
•Positive CSF (isoelectric focusing
evidence of
39. Diagnostic test
Magnetic Resonance Imaging (MRI) :
characteristic abnormalities in >95% of
patients.
Dawson’s fingers - Lesions are frequently
oriented perpendicular to the ventricular
surface, corresponding to the pathologic
pattern of perivenous demyelination
Lesions are multifocal and >6 mm located in
the corpus callosum, periventricular white
matter, brainstem, cerebellum, or spinal cord.
40. 1 .T2-weighted sequence demonstrates multiple bright signal abnormalities in white matter, typical for MS
2 . Sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) image in which the high signal of cerebrospinal
fluid (CSF) has been suppressed.
41. Sagittal T1-weighted image after the intravenous administration of
gadolinium DTPA reveals focal areas of blood-brain barrier disruption
42.
43. Cerebrospinal Fluid ( CSF )
mononuclear cell pleocytosis (>5 cells/μL in ~25%
MS )
CSF protein – normal or mildly elevated
Increased level of intrathecally synthesized IgG
CSF IgG index CSF IgG/Serum IgG <0.7
CSF serum Albumin index
CSF serum Albumin index : CSF Albumin (mg/dL)
If < 9 = intact BBB Serum Albumin (g/dL)
The measurement of OCBs by agarose gel
electrophoresis in the CSF
44. MS less likely If CSF analysis --
A pleocytosis of >75 cells/μL
the presence of polymorphonuclear
leukocytes
protein concentration >1 g/L (>100 mg/dL) in
CSF
45. Evoked Potentials test : assesses function in
afferent (visual,auditory, and somatosensory)
or efferent (motor) CNS pathways
EP abnormalities are not specific to MS. A
marked delay in the latency of a specific EP
component (as opposed to a reduced
amplitude or distorted wave-shape) is
suggestive of demyelination.
Abnormalities on one or more EP modalities
occur in 80–90% of MS patients.
46. To exclude alternative diagnosis- Erythrocyte
sedimentation rate, serum B12 level, anti-
nuclear antibodies, and treponemal antibody
The possibility of an alternative diagnosis should
always be considered
symptoms are localized exclusively to the
posterior fossa, craniocervical junction, or spinal
cord;
the patient is <15 or >60 years of age;
the clinical course is progressive From onset.
47. the patient has never experienced visual,
sensory, or bladder symptoms;
laboratory findings (e.g., MRI, CSF, or
EPs) are atypical.
uncommon or rare symptoms in MS (e.g.,
aphasia, parkinsonism, chorea, isolated
dementia, severe muscular atrophy,
peripheral neuropathy, episodic loss of
consciousness, fever, headache, seizures,
or coma)
49. Human immunodeficiency virus (HIV) infection
Ischemic optic neuropathy (arteritic and
nonarteritic)
Lyme disease
Mitochondrial encephalopathy with lactic
acidosis and stroke (MELAS)
Neoplasms (e.g., lymphoma, glioma,
meningioma)
Sarcoid , Neurosyphilis
Sjogren’s syndrome
50. Stroke and ischemic cerebrovascular disease
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
51. TREATMENT
A. Treatment of acute attacks:
1. Glucocorticoid – IV methylprednisolone, 500–
1000 mg/d for 3–5 days, either without a taper or
by a course of oral prednisone 60–80 mg/d and
gradually tapered over 2 weeks.
(not useful in“pseudoexacerbation” resulting from an
increase in ambient temperature, fever, or an infection )
2. Plasma exchange (five to seven exchanges: 40–
60 mL/kg per exchange, every other day for 14
days)
If unresponsive to glucocorticoids ,Cost is high,
and lack efficacy.
52. B. DISEASE-MODIFYING THERAPIES FOR RELAPSING
FORMS OF
MS (RMS, SPMS WITH EXACERBATIONS)
1. Interferon ß : Modestly Effective
HOW IT WORKS ?
Downregulating expression of MHC
molecules on antigen-presenting cells
Reducing proinflammatory and increasing
regulatory cytokine levels
Inhibiting T-cell proliferation,
Limiting the trafficking of inflammatory cells in
the CNS.
53. WHAT IS DOSE ?
IFN-β-1a (Avonex) - 30 μg IM qWK
IFN-β-1a (Rebif) - 44 μg SC tiW
IFN-β-1b (Betaseron or Extavia), 250 μg SC
qOD (every other day)
Pegylated IFN-β-1a (Plegridy), 125 μg, SC
Q2wk
Pegylated IFN-β-1a - reduced clearance
allowing less frequent administration.
54. What is side effects ?
flulike symptoms (e.g., fevers, chills, and
myalgias)
elevated liver function tests or lymphopenia
pain, redness, induration, or, rarely, skin
necrosis at injection site ( Rx – NSAID)
Develop neutralizing antibodies ,Disappear
over time – does not affect treatment
55. 2. Glatiramer Acetate (Modestly Effective)
HOW IT WORKS ?
induction of antigen-specific suppressorT cells
binding to MHC molecules, thereby displacing
bound MBP
altering the balance between proinflammatory and
regulatory cytokines
DOSE ?
20 mg every day (FDA approved) or 40 mg thrice
weekly SC
56. 3. Fingolimod (Moderately Effective) - sphingosine-1-
phosphate (S1P) inhibitor
HOW IT WORKS ?
Prevents secretion of lymphocytes from lymph nodes
and spleent
sequestration of lymphocytes in the periphery
DOSE ?
Fingolimod, 0.5 mg, is administered orally each day
SIDE EFFECTS ?
elevated liver function tests or lymphopenia
First- and second-degree heart block and bradycardia
, prolong QT interval
57. 3.Dimethyl Fumarate (DMF) (Moderately Effective):
HOW IT WORKS ?
Modulate the expression of proinflammatory and anti-
inflammatory cytokines
Induces the transcription of several antioxidant proteins
DOSE ?
240 mg, per oral twice a day ( BD ) – poor compliance
SIDE EFFECTS ?
Gastrointestinal side effects (abdominal discomfort,
nausea, vomiting, flushing,and diarrhea)
Flushing , lymphopenia , neutropenia , elevated liver
enzyme
58. NOTE
Case of PML reported in patients receiving DMF who were
lymphopenic (follow up lymphocyte count 6 monthly )
Lymphocyte count <500 cells/mL) - alternate treatments.
4. Natalizumab (Highly Effective) – Humanized
monoclonal antibody
HOW IT WORKS ?
Act against the α4 subunit of α4β1 integrin (a cellular
adhesion molecule expressed on the surface of
lymphocytes) - prevents lymphocytes from binding to
endothelial cells - prevent lymphocytes from penetrating
the BBB and entering the CNS
59. DOSE ?
300 mg, IV infusion each month (qmo) – compliance
good
SIDE EFFECTS ?
Hypersensitivity (10 %)
Neutralizing antibody ( 6 %)
PML ( 0.4 % ) - recommended mainly in JC antibody–
negative patients
in JC antibody positive patient - Risk (1.1-2 %) of
seronegative MS seroconvert annually
Asses JC antibody status – 6 monthly in all patients
60. 5. Ocrelizumab (Highly Effective)
HOW IT WORKS ?
Act against the CD20 molecule present on the
surface of mature B cells -- depletes
circulating B cells through antibody-dependent
cellular toxicity and complement-dependent
cytotoxicity -- interruption in trafficking of B
cells from the periphery to the CNS
61. DOSE ?
Ocrelizumab 600 mg is IV every 24 weeks
(administered as two 300-mg infusions spaced
2 weeks apart for the first dose, and as a
single 600-mg infusion thereafter);
inj. methylprednisolone 100 mg IV before
infusion
62. Less commonly used agents for RMS
Teriflunomide (Modestly Effective)
Alemtuzumab (Highly Effective )
Mitoxantrone Hydrochloride (Highly Effective)-
Rarely used due to cardiotoxicity.
63. Active MS - clinical relapses or the
development of new focal MRI white matter
lesions.
Mild Initial Course In the case of recent
onset, normal examination or minimal
impairment (EDSS ≤2.5 or less), or low
disease activity, either an injectable (IFN-β or
glatiramer acetate) or an oral (DMF,
fingolimod, or teriflunomide)
64. Moderate or Severe Initial Course In highly
active disease or moderate impairment (EDSS
>2.5), either a highly effective oral agent (DMF
or fingolimod) or ocrelizumab or, if the patient
is JC virus antibody seronegative, infusion
therapy with natalizumab is recommended.
vitamin D deficiency - vitamin D3 4000–5000
IU PO daily
65.
66. DISEASE-MODIFYING THERAPIES FOR
PROGRESSIVE MS
SPMS -High-dose IFN-β in SPMS with active
disease
mitoxantrone in progressive MS
PPMS – Ocrelizumab
OFF-LABEL TREATMENT OPTIONS FOR RMS
AND SPMS -Azathioprine ,cyclophosphamide
, methotrexate
antiviral agents or antibiotics is not
recommended.
Several unproven tratment should avoid
69. Detrusor/sphincter dyssynergia :
phenoxybenzamine
(10–20 mg/d) or terazosin hydrochloride (1–20
mg/d).
Cognitive problems - lisdexamfetamine(40
mg/d).
Heat sensitivity : heat avoidance, air-
conditioning, or cooling garments.
Sexual dysfunction : genital stimulation and
sexual arousal. Drugs : Sildenafil (50–100
mg), tadalafil (5–20 mg), or vardenafil (5–20
70. CLINICAL VARIANTS OF MS
Acute MS (Marburg’s variant) : fulminant
demyelinating process
Balo’s concentric sclerosis : characterized by
concentric brain or spinal cord lesions with
alternating spheres of demyelination and
remyelination
71. ACUTE DISSEMINATED
ENCEPHALOMYELITIS (ADEM)
monophasic course Vs (MS – Multiphagic )
common in children than adults
Associated with an antecedent infection
(postinfectious encephalomyelitis) - varicella
(chickenpox) rubella, mumps, influenza,
parainfluenza, EBV, HHV-6, HIV, dengue, Zika,
other viruses, and Mycoplasma pneumoniae
~5% cases follow immunization (postvaccinal
encephalomyelitis)- measles , smallpox (5 cases
per million), the Semple rabies and Japanese
encephalitis
72. presence of widely scattered foci of perivenular
inflammation and demyelination that can involve
both white matter and grey matter structure. Vs
(MS - white matter lesions )
The simultaneous onset of disseminated
symptoms and signs is common Vs ( rare in MS )
Fever , headache, meningismus, and lethargy ,
coma , Seizures. - common ( Vs MS)
Signs - hemiparesis or quadriparesis, extensor
plantar responses, lost or hyperactive tendon
reflexes, sensory loss, and brainstem involvement
73. CSF - protein elevated (0.5–1.5 g/L [50–150
mg/dL]) , Lymphocytic pleocytosis, generally
≥200 cells/µl , OGB + Vs (MS)
MRI - extensive and relatively symmetric white
matter abnormalities, basal ganglia or cortical
gray matter lesions, and Gd enhancement of
all abnormal areas.
74. Neuromyelitis Optica(NMO),
Devic’s disease
women : men (>3:1)
typically begins in adulthood
Early presentation Vs (MS).
Attacks of ON can be bilateral and produce
severe visual loss (uncommon in MS); myelitis
can be severe and transverse (rare in MS) and
is typically longitudinally extensive involving
three or more contiguous vertebral segments.
Progressive symptoms typically do not occur
in NMO Vs ( MS )
75. MRI
Large MRI lesions in the cerebral hemispheres
can be asymptomatic, sometimes have a
“cloud-like” appearance and are often not
destructive, resolve completely. ( Vs MS )
Spinal cord MRI lesions typically consist of
focal enhancing areas of swelling and tissue
destruction, extending over three or more
spinal cord segments.
76. CSF :
Pleocytosis > ( MS ) with neutrophils and
eosinophils
OCBs are uncommon ( < 20 % )
Diagnosis – Anti AQP4 Ab
Pathology :
distinctive astrocytopathy with inflammation,
loss of astrocytes, and an absence of staining of
the water channel protein AQP4 by
immunohistochemistry, plus thickened blood
vessel walls, demyelination, and deposition of
antibody and complement.
77. When MS affects individuals of African or
Asian ancestry, there is a propensity for
demyelinating lesions to involve predominantly
the optic nerve and spinal cord, an MS
subtype termed opticospinal MS.
Acute attacks - methylprednisolone 1 g/d for
5–10 days followed by a prednisone taper ,
Plasma exchange.
Prophylaxis -mycophenolate mofetil (1000 mg
bid); rituximab (2 g IV Q 6 months);
glucocorticoid + azathiprine
78. references
Harrison’s principle of internal medicine-20th
Edition
UP TO DATE- 2021
Davidson Principles and Practice of Medicine
– 23rd Edition
Adams and Victor's Principles of Neurology,
11th edition