Dr. Anzil Mani Singh Maharjan
Resident Phase- B
Department of Neurology
BSMMU

Myelin
 Myelin forms a
layer, the myelin
sheath around
the axon of
a neuron
 It is an outgrowth
of a type of glia
cell

Myelin composition
 Cholesterol is an essential constituent of myelin
 Myelinated axons appear white, hence the the
term "white matter" of the brain
 Some of the proteins are myelin basic
protein, myelin oligodendrocyte glycoprotein,
and proteolipid protein
 The intertwining hydrocarbon chains
of sphingomyelin serve to strengthen the myelin
sheath

Myelination
 The production of the myelin sheath is called
myelination
 In humans, myelination begins in the 14th week of
fetal development
 During infancy, myelination occurs quickly and
continues through the adolescent stages of life
 Schwann cells supply the myelin for peripheral
neurons
 Oligodendrocytes myelinate the axons of the CNS
neurons

Myelin Function
 Propagate nerve
impulses rapidly in a
saltatory fashion
 Voltage-gated Na+
channels found at the
nodes of Ranvier
 Na+ influx
 Current cannot flow
outward in myelinated
internodal segments
• Provides insulation

Myelin Diseases
 Demyelination is the
process of damage to the
myelin or oligodendroglial
cell
◦ Autoimmune- MS
◦ Infectious- PML
◦ Toxic and metabolic
◦ Vascular processes –
Binswanger
 Dysmyelination - a primary
biochemical abnormality of
myelin formation exists
◦ Hereditary disorders-
Leukodystrophies

Classification of the Inflammatory
Demyelinative Diseases
I. Multiple sclerosis
Chronic relapsing encephalomyelopathic form
Acute multiple sclerosis (Marburg disease)
Primary and secondary progressive types
Diffuse cerebral sclerosis (Schilder disease
and concentric sclerosis of Balo

Classification of the Inflammatory
Demyelinative Diseases
IV. Acute and subacute necrotizing
hemorrhagic encephalitis
A. Acute encephalopathic form
B. Subacute encephalitis
III. Neuromyelitis optica (Devic disease)
II.Acute disseminated encephalomyelitis
A.Postinfectious: Following measles, chickenpox, smallpox,
mumps, rubella, influenza,Mycoplasma
B.Postvaccinal : Following rabies or smallpox

Introduction
 British as “disseminated sclerosis”
 French as “sclérose en plaques”
 MS is a chronic condition characterized clinically
by episodes of focal disorders of the:
◦ Optic nerves
◦ Spinal cord
◦ Brain
 remit to a varying extent and recur over a period of
many years

Pathology

Pathology
 Hallmark of MS is the cerebral or spinal
plaque, which consists of a discrete region
of demyelination
 Relative preservation of axons
 Atrophy and ventricular dilatation
 Disruption of BBB but vessel wall is
preserved

Pathology (Gross)
 Active plaques appear whitish
yellow or pink with somewhat indistinct borders
 Older plaques appear translucent with a blue-gray
discoloration and sharply demarcated margins
 Plaques are small (1-2 cm) but may become confluent,
generating large plaques
 Develop in a perivenular distribution
 Most frequently in the periventricular white matter,
brainstem, and spinal cord

Pathology (Gross)
Brain - Coronal Section Spinal Cord

Histopathology
 Active plaques reveals
perivascular infiltration of
lymphocytes
(predominantly T cells)
and macrophages, with
occasional plasma cells
 In the plaque, myelin is
disrupted, resulting in
myelin debris found in
clumps or within lipid-
laden macrophages
 Reactive astrocytes are
prominent in plaques
Venule
Demyelination
area

EPIDEMIOLOGY

Epidemiology
 Age of Onset
◦ Mean and median age of
onset in relapsing forms of
MS is age 29 to 32
◦ Primary progressive MS
(PPMS) has a mean age
of onset of 35 to 39
◦ Can occur as late as the
seventh decade
◦ 5% of cases of MS have
their onset before age 18
 Sex Distribution
◦ F>M
◦ 2 : 1

Epidemiology
Geographical Distribution
 MS is a location-related
illness with a latitude
gradient
 High-frequency areas with
prevalence of 60 -100 per
100,000 or more, include
◦ All of Europe (including
Russia)
◦ Southern Canada
◦ Northern United States
◦ New Zealand
◦ SE portion of Australia
 The highest reported rate of
300 per 100,000 occurring
in the Orkney Islands

Epidemiology
Race
 Determinant of MS risk
 White extraction, especially from Northern Europe are
the most susceptible
 People of Asian, African, or Amerindian origin have the
lowest risk
 Other groups are variably intermediate
 Migration after puberty no increased risk
 Migration before childhood increased risk

Pathogenesis

Pathogenesis
 The cause of MS remains undetermined
 Possible Etiologies include
◦ Infection
◦ Enviromental factors
◦ Autoimmunity
◦ Genetic Susceptibility

Pathogenesis
Infection
 Little direct evidence supports the concept of a
role for viral infection
 Human T-cell lymphotropic virus type 1 [HTLV1]
 Human herpesvirus 6 (HHV6)
 Epstein-Barr virus (EBV)
 Chlamydia pneumoniae
Environmental Factors
 Sunlight exposure during growth
 Vitamin D
 Epidemiological data supportive

Pathogenesis
Autoimmunity
 Break down of tolerance (unresponsiveness of the
immune system)
 By means of molecular mimicry between self-
antigens and foreign antigens
 Myelin basic protein (MBP), the target for
autoimmune attack
 T cells that respond to MBP are found in the
peripheral blood possibly at higher levels in MS
patients with active disease

Pathogenesis
Genetic susceptibility
 The risk of familial recurrence in MS is 15%
 Highest risk in first-degree relatives (age-adjusted risk):
4–5% for siblings and
2–3% for parents or offspring
 Monozygotic twins have a concordance rate of 30%
 The genes that predispose to MS are incompletely defined
 Inheritance appears to be polygenic, with influences from
◦ Genes for human leucocyte antigen (HLA) typing
◦ Interleukin receptors
◦ CLEC16A (C-type lectin domain family 16 member A)
◦ CD226 genes

CLINICAL
PRESENTATION

Clinical Manifestations
 Multiple sclerosis is classically described as a relapsing
remitting disorder
 MS may display marked clinical heterogeneity. This
variability includes
◦ age of onset
◦ mode of initial manifestation
◦ frequency
◦ severity
◦ sequelae of relapses
◦ extent of progression
◦ Cumulative deficit over time
 High degree of variability and the difficulty in predicting
the course and severity make MS one of the most
puzzling CNS disease

Clinical Manifestations
Early symtoms
and signs
Symptoms and Signs in the
Established Stage of the
Disease
Disability

Clinical Manifestations
Early Symptoms
 Onset over hours or days
 Motor or sensory system involvement in 50 % of
patients
 Symptoms of tingling of the extremities and tight band-
like sensations around the trunk
 Dragging or poor control of one or both legs to a spastic
or ataxic paraparesis
Early Signs
 The tendon reflexes are retained and later become
hyperactive
 Extensor plantar reflexes
 Disappearance of the abdominal reflexes
 Varying degrees of deep and superficial sensory loss
may be associated

Clinical Manifestations
 The patient will complain of weakness,
incoordination, or numbness and tingling in one
lower limb
 But the examination will reveal
◦ Bilateral Babinski signs
◦ Bilateral corticospinal tract signs
◦ Posterior column disease

Clinical Manifestations
Several syndromes typical of MS and may
be the initial manifestation :
(1) Optic neuritis
(2) Transverse myelitis
(3) Cerebellar ataxia - nystagmus and ataxia
(4) Various brainstem syndromes (vertigo, facial
pain or numbness, dysarthria, diplopia)
◦ These syndromes may pose a diagnostic
dilemma as these do occur in other diseases
too

Clinical Manifestations
 Paresthesia or numbness of an entire arm or leg
 Facial pain often simulating tic douloureux
 Disorders of micturition
 Cervical myelopathy- slowly progressive with
weakness and ataxia

Clinical Manifestations
Diplopia
◦ Medial longitudinal fasciculi
◦ Internuclear ophthalmoplegia
◦ Paresis of the medial rectus on attempted lateral
gaze, with a coarse nystagmus in the abducting
eye
◦ Usually bilateral
The presence of bilateral internuclear
ophthalmoplegia in a young adult is
virtually diagnostic of MS

Clinical Manifestations
 Myokymia or paralysis of facial muscles
 Deafness, tinnitus, unformed auditory hallucinations
(because of involvement of cochlear connections)
 Vomiting (vestibular connections), and, rarely, stupor
and coma
 Vertigo of central type
 Dull, aching low back pain
 Sharp, burning, poorly localized, or lancinating radicular
pain, localized to a limb or discrete part of the trunk

Clinical Manifestations
Lhermitte sign
 Flexion of the neck may
induce a tingling, electric
shock like feeling down
the shoulders and back
 Frequent occurrence of
this phenomenon in MS
 Due to an increased
sensitivity of
demyelinated axons to
the stretch or pressure
on the spinal cord
induced by neck flexion

Clinical Manifestations
Uhthoff phenomenon
 Transient worsening of function with
increased body temperature
 Due to a drop below the safety threshold for
conduction because of physiological
changes involving the partially
demyelinated axon

Clinical Manifestations
Established Stage of the Disease
 50 % will manifest a clinical picture of mixed or
generalized type with signs pointing to involvement of
the optic nerves, brainstem, cerebellum, and spinal cord
 30 to 40 % will exhibit only varying degrees of spastic
ataxia and deep sensory changes in the extremities,
i.e., essentially a spinal form of the disease
 5 % have a predominantly cerebellar or brainstem–
cerebellar form occurs

Clinical Manifestations
Cognitive impairment
 Progressive decline, is present in perhaps one-
half of patients with long-standing MS
 Reduced attention
 Diminished processing speed and executive
skills
 Memory decline
 Language skills and other intellectual functions
are preserved

Clinical Manifestations
 The most characteristic clinical course of MS
is the occurrence of relapses
 Relapses can be defined as
◦ acute or subacute onset of clinical dysfunction
◦ that usually reaches its peak from days to
several weeks,
◦ followed by a remission during which the
symptoms and signs usually resolve partially or
completely
 The minimum duration for a relapse has been
arbitrarily established at 24 hours

Clinical Manifestations (Course)
1. Relapsing-remitting (RRMS):
Clearly defined relapses with full recovery or with sequelae and
residual deficit on recovery
The periods between disease relapses are characterized by a
lack of disease progression
2. Secondary progressive (SPMS):
Initial relapsing remitting disease course followed by progression
with or without occasional relapses, minor remissions, and plateaus
3. Primary progressive (PPMS):
Disease progression from onset, with occasional plateaus and
temporary minor improvements allowed
4. Progressive relapsing (PRMS):
Progressive disease from onset, with clear acute relapses with or
without full recovery
The periods between relapses are characterized by continuing
progression

Clinical Manifestations

Disease progression

INVESTIGATIONS

CSF ANALYSIS
Cytology
 In 1/3 of with an acute onset or
an exacerbation, there may be a
slight to moderate mononuclear
pleocytosis (6 to 20 or less than
50 cells/mm3)
 In rapidly severe demyelinating
disease of the brainstem, the
total cell count may reach or
exceed 100, and rarely 1,000,
cells/mm3
 In the hyperacute cases, the
greater proportion of these may
be polymorphonuclear
leukocytes

CSF ANALYSIS
Protein
 40 % of patients, the total protein content of the
CSF is increased slightly
 Not more than 100 mg/dL
 In two-thirds of patients, the proportion of gamma
globulin (mainly IgG) is increased (greater than
12 percent of the total protein)
 IgG index obtained by measuring albumin and
gamma globulin in both the serum and CSF

CSF ANALYSIS
Oligoclonal bands
 Gamma globulin proteins in the CSF of
patients with MS are synthesized in the
CNS
 They migrate in agarose electrophoresis
as abnormal discrete populations, so-
called oligoclonal bands
 The most widely used CSF test for the
confirmation of the diagnosis
 Show several bands in the CSF in more
than 90 percent of cases of MS
 But they are not always found with the
first attack or even in the later stages of
the disease

Magnetic Resonance Imaging
 MRI is the most helpful ancillary examination
in the diagnosis of MS
 Reveal asymptomatic plaques in the
cerebrum, brainstem, optic nerves, and spinal
cord
 T2-weighted images show :
◦ Hyperintense well-demarcated lesions
◦ Multiple and asymmetrical
◦ Periventricular surface in location

Magnetic Resonance Imaging
Axial images showing multiple hyperintense lesions
in the white matter

Magnetic Resonance Imaging
 The presence
lesions in the
corpus callosum is
diagnostically
useful
 This structure is
spared in many
other disorders
Midsagittal FLAIR image

Magnetic Resonance Imaging
 In sagittal images
extension of the lesion
outward from the
corpus callosum in a
fimbriated pattern and
have been termed
“Dawson fingers”
 These areas may
extend into the
centrum semiovale
and may reach the
convolutional white
matter
Sagittal FLAIR image

Magnetic Resonance Imaging
Sagittal fat-suppressed
image
Sagittal T1-weighted
postcontrast image

Newer Imaging Tecniques
 MAGNETIC RESONANCE SPECTROSCOPY
◦ a tool that derives MRI signal from
multiple metabolites
◦ A high choline (Cho) peak is indicative of
an increase in membrane turnover, as can
be seen in demyelination and
remyelination
 DIFFUSION TENSOR IMAGING
 HIGH-FIELD-STRENGTH MRI

Evoked Potentials
 EPs are CNS electrical events
generated by peripheral stimulation of a
sensory organ
 Are useful
◦ To determine abnormal function that may
be clinically unapparent
◦ When the clinical data point to only one
lesion in the CNS mainly in the early
stages of the disease or in the spinal form
Commonly used EPs are
1. Visual Evoked response (VEPs)
2. Somatosensory evoked potentials (SSEPs)
3. Brainstem auditory-evoked responses (BAER)

Comparison of Sensitivity of
Laboratory Testing
Investigations Sensitivity
VER 80%-85%
BAER 50%-65%
SSEP 65%-80%
OCB 85%-95%
MRI 90%-97%

Revised McDonald et al. (2005)
Diagnostic Criteria for MS

McDonald (2011) Diagnostic
Criteria for MS

Differential diagnosis
 The differential diagnosis of MS in the setting
of a young adult with two or more clinically
distinct episodes of CNS dysfunction with at
least partial resolution is limited
 Problems arise with
◦ Atypical presentations
◦ Monophasic episodes
◦ Progressive illness
◦ The unusual nature of some sensory symptoms
may result in a misdiagnosis of conversion
disorder

Differential diagnosis
Inflammatory Diseases
 Granulomatous angiitis, SLE,
Sjogren disease, Behcet
disease,PAN
 Paraneoplastic
encephalomyelopathies
 ADEM, postinfectious
encephalomyelitis
Infectious Diseases
 Lyme neuroborreliosis,
 HTLV, HIV
 PML
 Neurosyphilis
Granulomatous Diseases
• Sarcoidosis
• Wegener granulomatosis
• Lymphomatoid
granulomatosis
Diseases of Myelin
• MLD (juvenile and adult)
•Adrenomyeloleukodystrophy
Miscellaneous
• Spinocerebellar disorders
• Arnold-Chiari malformation

TREATMENT

Treatment
Treatment of the MS patient should be directed toward these
basic goals:
 Relief or modification of symptoms
 Shortening the duration or limiting the residual effects of an
acute relapse
 Reducing the frequency of relapses
 Preventing disability progression or slowing its pace
 Supporting family and patient, alleviating social and economic
effects, and advocating for the disabled or handicapped

Symptomatic Treatment
Spasticity
 Baclofen a GABA agonist Daily divided doses of 20 to 120 mg and
occasionally .Intrathecal baclofen via an implanted pump
 Tizanidine a centrally active α2-noradrenergic agonist, gradually
increased starting with 2 mg at bedtime
 Benzodiazepines
 Dantrolene sodium rarely
 4-Aminopyridine and 3,4-diaminopyridine (3,4-DAP) block
potassium channels in the axolemma
 Botulinum toxin type A (Botox) injections into spastic or
contracted muscles may also be effective in selective cases

Symptomatic Treatment
Tremor
 Weighted wrist bracelets and specially adapted utensils are
nonpharmaceutical options
 Most attempts at pharmacological amelioration of tremor fail
 Isoniazid
 Primidone
 Carbamazepine
 Gabapentin
 Topiramate
 Clonazepam
 Propranolol
 Ondansetron

Symptomatic Treatment
Fatigue
 Amantadine 100 mg twice a day
 Modafinil - a wakefulness promoting agent
 Methylphenidate 10 to 60 mg/day in 2 to 3 divided dose
 SSRIs
 Fluoxetine 10 to 20 mg once twice daily
 Bupropion

Symptomatic Treatment
Bladder Dysfunction
 Initial steps in managing bladder dysfunction include
◦ fluid management,
◦ timed voiding
◦ use of a bedside commode
 Hyperreflexic bladder without outlet obstruction
◦ Oxybutynin,Tolterodine,Trospium,Darifenacin,solifenacin,
Desmopressin
 Imipramine for enuresis
 Detrusor hyperreflexia with outlet obstruction may respond
Credé maneuvers terazosin hydrochloride
 Intermittent catheterization
 Chronic indwelling catheterization may be required
 Surgical correction-augmentation of bladder capacity with an
exteriorized loop of bowel

Symptomatic Treatment
Depression
 SSRIs are the medications of choice
 Fluoxetine
 Amitriptyline, 25 to 100 mg daily
Sexual Dysfunction
 Sildenafil 25 to 100 mg 1 hour before sexual
intercourse for erectile dysfunction

Symptomatic Treatment
Cognitive Impairment
 Interferon beta-1a SC
 L-amphetamine
 Modafinil
 Donepezil
 Cognitive-behavioral therapy
 Family and individual counseling
 Strategies to improve day-to-day function
 Job modifications and accommodations

Treatment of Acute Attacks
 Acute attacks are typically treated with corticosteroids
 Indications for treatment of a relapse include
functionally disabling symptoms with objective evidence
of neurological impairment
 Short courses of IV methylprednisolone – 500 to 1000
mg daily for 3 to 5 days
◦ With or without a short prednisone
 S/Es include psychiatric changes, predilection for
infections,GI disturbances,anaphylactoid reactions,
Increased incidence of fracture

Disease-Modifying Treatments
 INTERFERONS
◦ A recombinant interferon beta-1b SC
◦ interferon beta-1a IM injections
 SYNTHETIC POLYMER
◦ Glatiramer acetate (GA) - a synthetic
polypeptide SC
 MONOCLONAL ANTIBODY
◦ Natalizumab
◦ Fingolimod (FTY720)

Disease-Modifying Treatments
Emerging Therapies
 Laquinimod
Orally active synthetic immunoregulator
 Oral fumarate/BG-12
Induces apotosis of activated T cells
 Teriflunomide
Is a metabolite of leflunomide
 Alemtuzumab
Humanized monoclonal anti-body against CD52 antigen expressed in all
lymphocytes
 Rituximab
A chimeri murine-human monoclonal antibody directed against CD30
antigen on B lymphocytes

Treatment-Rehabilitation
 Referral to
physical,occupational and
speech therapists
1.Physical therapy
 Evaluate and train the patient
in appropriate exercise
programs to :
◦ decrease spasticity
◦ maintain range of motion
◦ strengthen muscles
◦ improve coordination
 Mechanical aids, such as
ankle-foot orthoses, also can
be useful in spasticity
management.

Treatment-Rehabilitation
3.Occupational therapy
• Assessment of the patient's
functional abilities in completing
activities of daily living
•Evaluate for adaptive equipment
and assistive technology needs
2. Speech therapy

Treatment Strategies

Prognosis
Prognostic indicators:
 MS appears to follow a more benign course in women than in men
 Onset at an early age is a favorable factor, whereas onset at a later
age carries a less favorable prognosis
RRMS is more common in younger patients, and PPMS and SPMS
are more common in the older age group
 Relapsing form of the disease is associated with a better prognosis
than progressive disease
 Among initial symptoms, impairment of sensory pathways or ON has
a favorable prognostic feature
 Pyramidal and particularly brainstem and cerebellar symptoms carry
a poor prognosis
 Devic disease, Baló concentric sclerosis, and particularly Marburg
disease are more fulminant variants of MS, with early disability and
even death