Demyelination of central

nervous system
!Multiple sclerosis (MS)
!ADEM ACUTE DISSEMINATED ENCEPHALOMYELITIS
!ANHEM acute necrotizing hemorrhagic encephalomyelitis (Weston-Hurst syndrome)
‫د‬.‫ﺣﺳـﻧﯾن‬ ‫أﻟﺧـﺎﻟـدي ﻋﺑﺎس‬
‫اﻟﺑورد ﺷﮭﺎدة‬ (‫واﻷﻋص اﻟدﻣﺎغ طب ) اﻟدﻛﺗوراه‬
‫اب‬
‫ﻛﻠﯾﺔ‬ ‫ اﻟطب‬/ ‫اﻟﻛوﻓﺔ ﺟﺎﻣﻌﺔ‬
 Objectives
!Pathophysiology of MS.

!Clinical presentation of MS.

!Diagnosis of MS.

!Management of MS.

!The difference between MS and ADEM.

 Multiple sclerosis
(disseminated sclerosis)
" It is chronic inflammation ,demyelination and gliosis (scar) involving
central WM in disseminated fashion in time and place.
" With exception to trauma, it is common cause of N disability.
PNS is spared.
" Incidence :5/100 000 prevalence :80/100 000

" There is increasing evidence that MS also has a neurodegenerative

component which appears to be the major cause of disability of MS
patients.

" There is increasing evidence from morphological studies that axonal

pathology such as axonal transections or acute axonal damage
occurs early in MS lesions but also in areas that are described as
normal appearing white matter.
Etiology
" Exactly unknown most accepted one is an multifactorial

" More accepted theory is an autoimmune mediated

process triggered by environmental factors in genetically
susceptible host which have been supported by
following evidence:

# The incidence is low in equatorial areas and higher in

‫معتدل املناخ‬
temperate zone supporting an environmental factors.
" Genetic influence is suggested by many evidence:

# 10 fold increase in risk of 1st degree relative and higher

concordance rate in monozygotic versus dizygotic twin.

# HLA system study found high incidence of HLA haplo

type A3,B7, DW2 and DR2 (In UK)

" Immunological mechanism is suggested by increase

level of activated T-lymphocyte and Ig in CSF.

" Infection role: is suggested by detection of AB titer to

some viruses including measles, EPV, -------which
suggest an epiphenomenon mechanism.
Pathology
" An attack of CNS infl. starts with entry of T- lymphocyte
through BBB which recognize myelin derived IG on
surface of NS antigen presenting cells and microglia and
undergo clonal proliferation .
" The resulting inflammatory cascade release cytokines and
initiate destruction of oligodendrocytes -myelin unit by
macrophage.
" There is evidence now that MS injure neuronal axons as
the disease progress resulting in brain atrophy and
permanent damage.
= It may be an autoimmune disease with inflammatory features that affect the CNS.
= It should be recalled that oligodendrocytes (not Schwann cells) provide myelination in the CNS.
= The body erroneously directs antibodies against proteins in the myelin sheath in the CNS.
= Thus, demyelination occurs in the axons of the CNS, whereas demyelination of axons in the peripheral nerves
occurs in Guillain-Barré syndrome
= Viral infection or other inciting factors may promote the entry of T cells and antibodies into the central nervous
system by disrupting the blood–brain barrier.
= This leads to increased expression of cell-adhesion molecules, matrix metalloproteinases, and
proinflammatory cytokines.
= These molecules work in concert to attract additional immune cells, break down the extracellular matrix to aid
their migration, and activate autoimmune responses against several antigens (eg, myelin basic protein, myelin-
associated glycoprotein, myelin oligodendrocyte glycoprotein, proteolipid protein, α B-crystallin,
phosphodiesterases, and S-100).
= Binding of these target antigens by antigen-presenting cells triggers an autoimmune response that may
involve cytokines, macrophages, and complement.
= Immune attack on myelin denudes axons, which slows nerve conduction.
= Together with loss of axons and nerve cell bodies, this leads to progressive neurologic symptoms.

= A scar (sclerosis) develops on the nerve fibers, which delays or blocks nerve impulses.
= Finally, nerve fibers degenerate.
Histopathology
In pathologic specimens, the demyelinating lesions of MS, called plaques (see the image below), appear
as indurated areas—hence the term sclerosis.

$ As a result of inflammation and demyelination there is

plaque formation mainly seen in Para ventricular area
(wm), optic N. ,and spinal cord .

$The no. of lesions is not parallel with clinical finding,

microscopically there is circumscribed area of disintegration
of m. sheath accompanied by infiltration with activated
lymphocyte and macrophages in perivascular fashion .
At the microscopic level, one usually sees multiple areas of perivenular inflammatory
cell infiltrates with extravasation into the surrounding tissue parenchyma.
$After acute inflammation and as sequel there is gliosis
(Astrocytes proliferation) leaving shrunken grey scars
(sclerosis) with decrease in no. of oligodendrocytes.
With time, gliosis develops, and plaques reach a burned-out stage consisting of
demyelinated axons traversing glial scar tissue (inactive plaque).
Pathophysiology
" In acute clinical deficit result from the effect of acute
phase reactants upon neuronal impulse transmission
rather than str. damage or disruption of myelin.

" This explain rapid recovery of deficits and probably the

efficacy of steroid in ameliorating the acute deficit.
" Myelin loss from an attack ----conduction defect leading
to decrease or loss of function (negative phenomenon)

" Axonal loss in established MS secondary to inflammatory

mediators which is released during acute attack including
nitrous oxide this will result in what is called cross talk
phenomenon between axons (positive phenomenon) ex:
Lhermitte's signs , paraesthesia , -----

" 4- amino pyridine ----------------can block these ectopic

impulses and improve conduction
= During relapses, MS patients lose partial or totally some type of physiological functions, traduced by a variety of
negative symptoms, as, for instance, paresis, hyposthesia, visual impairment, diplopia or ataxia. As daily testified in MS
Clinics, the variability in the clinical manifestations is high among patients, as well as in different phases of the disease
in each patient. The symptomatic expression depends not only on the location of MS lesions but also on the variety of
conduction properties displayed by affected axons.

= The main cause of relapse is the failure of axonal conduction at the site of a lesion, which is due to axonal changes,
related both to acute inflammation and demyelination, which possibly act in sequential phases and ultimately proceed
each other in a complex way.

= The impairment in the axonal transmission may be mainly functional due to inflammation, oedema and toxic action of
products released in the MS plaques, which happens in the earlier acute phases of a relapse, or entirely structural, in
later phases, when axon is exposed by myelin damage in internodal segments and also by direct axonal injury in the
nodal and perinodal regions
Inflammation

= Inflammation may be sufficient to provoke significant clinical deficits without demyelination.

= Some substances released upon the formation of a new lesion have been pointed out to mediate the biophysical consequences of
inflammation, leading to transient impairment or block of nerve conduction, such as cytokines, nitric oxid (NO) and antibodies against
ion channels.
= Moreover, proinflammatory cytokines - tumor necrosis factor (TNF)-alpha and interferon gama - may stimulate the formation of
inducible form of the enzyme nitric oxide syntetase with further liberation of NO, that is a mediator of axonal block, particularly in
axons affected by demyelination.
Demyelination

= The myelin damage in MS is characteristically segmental, resulting in the loss of whole internode of myelin, and
occurs in the typical lesions of the white matter, as well as in cortical lesions.
= In segmental demyelination, conduction specifically fails at the site of the lesion, whereas the unaffected parts of the
axon on either side of the lesion continue to conduct normally.
= Since the damage of myelin, sheath eliminates the insulator of the internodal segments, the axonal current flow is
locally interrupted and short-circuited through the uncovered portions of the axon; however, as the density of sodium
channels in the axolemma beneath the internodal myelin sheath is low, the impulse propagation is inhibited, leading to
a much slower current flow or to its interruption
= Further propagation of the action potential is blocked due to the exposition of voltage-gated potassium channels
normally restricted to the internodes.
 Clinical features
" it is twice more common in female than males .
" Age incidence : pediatric MS ? Adult ?
" initial S. : sensory s., motor(weakness),visual blurring ,
diplopia and ataxia, the weakness?
" Can reflex be lost or absent? Inflammation of root entry
zone .
" Sensory s., Optic neuritis?

" device’s diseases or Japanese MS ( now not considered

to be a type of MS..
" Cerebellar involvement ?
Ataxia of gait or limbs , in advanced cases dysartheria is
common.
" Urinary bladder problems? Early
Urgency and hesitancy ,incontinence and incomplete
emptying of bladder is common in MS at presentation.
" Fecal incontinence , or constipation and urgency is common
Late
in advanced MS.
" V nerve : might be affected at level of brain stem lead to sever
V neuralgia which is tend to occur in young ,with constant
pain ,bilateral with focal N. signs.
 Diplopia ?
can result from lesion affecting the nuclei of 3rd ,4th and or 6th
cranial nerves or it can be due to INO due to lesion affecting
MLF in which there is failure of adduction of one eye with jerky
nystagmus in abducting eye.

Facial nerve?
#Bell’s like picture, often bilateral and recurrent ,
usually with no change in sensation.
#Chronic flickering movement: facial myokymia is common
which is due to affection of Corticobulbar tract and
deafferentation of facial nucleus.
vertigo
" Sudden or in dramatic fashion with unsteadiness and
vomiting resemble acute labyrinthitis central rather than
peripheral type is supported by presence of other brainstem
signs .

" Hearing loss is unusual.

#Bulbar and or pseudo bulbar palsy due to affection of 9th

and 10th cranial nerves.
" Cognitive function affection?
$ It is common in advanced MS but can be seen at time of
presentation in form of

$ Impaired concentration and attention-----memory

disturbance or impaired judgment and reasoning
$ Emotional liability in pseudo-bulbar palsy
$ Euphoria
$ Depression is common
% Ancillary symptoms? Including

$ lehermitt’s signs:
$ Heat insensitivity: including Uthoff’s phenomenon
=visual blurring up on exercise or increase in
temperature.
$ Fatigue? After noon with without increase in motor
weakness in form of mental fatigue, lassitude, and
sleepiness.
$ Paroxysmal symptoms: in form tonic or and clonic
movement or sensory S. Any where in the body persist for
seconds.
Signs and symptoms

Investigations
 DIAGNOSIS? CNS INVOLVEMENT IN?
DISSEMINATIN IN TIME . DISSEMINATIN IN
SPCACE
" No diagnostic test for MS but we depend upon
clinical and Para clinical criteria with exclusion of
other.
" There are McDonald’s, Schumacher and poser’s
criteria. All depends on no. of attack (N deficit which
is lasted at least 24 hours and resolved within 1
month).
" Clinical evidence, Para clinical evidence and
CSF oligoclonal band /IgG.

" McDonald criteria were developed for MS

diagnosis by panels of expert depending on
extensive scientific clinical studies focusing on
sensitivity and specificity of MRI criteria.
Diagnosis

= The diagnosis of multiple sclerosis requires evidence that at least two different regions of the central white matter have been
affected at different times.
= Multiple sclerosis can be diagnosed straightaway in patients with at least two typical attacks and two MRI lesions.
= Typical attacks are characterized clinically by symptoms or signs typical of an acute inflammatory demyelinating event in the CNS,
lasting at least 24 hours and occurring in the absence of fever or infection.
= If imaging has been performed in patients with typical attacks but shows no abnormality, the diagnosis of multiple sclerosis should
be made only when other possibilities have been excluded.

= If only one clinical attack has occurred, the MRI findings may be used to provide evidence of dissemination.
= To fulfill the criterion of dissemination in space, MRI should demonstrate at least one T2 lesion in at least two of four characteristic
locations (juxtacortical, periventricular, infratentorial, and spinal cord); in patients with brainstem or spinal cord syndromes, lesions
within the symptomatic region are excluded.
= To show dissemination in time in a patient with only one attack, the simultaneous presence on MRI of asymptomatic gadolinium-
enhancing and non-enhancing lesions at any time is sufficient; alternatively, it is necessary to await development of a new T2 or
gadolinium-enhancing lesion on follow-up MRI or a second clinical attack.

= Diagnosis of primary progressive disease requires at least one year of progressive disease plus two of the following: (1) at least
one typical T2 brain lesion, (2) at least two spinal T2 lesions, and (3) positive CSF oligoclonal bands, increased IgG index, or both.

= In patients with only a single clinical event and who do not satisfy criteria for multiple sclerosis, a clinically isolated syndrome (CIS)
is diagnosed.
= These patients are at increased risk for developing multiple sclerosis and are sometimes offered treatment as if they had the
disease in the hope of delaying progression to clinically definite disease.
= Follow-up MRI should be considered 6 to 12 months later to determine whether any new lesions have occurred.
Diagnosis? CNS
involvement in……

Dissemination in time

Dissemination in space
 Disease course
" Relapsing–remitting (80-85%) in which progression does not occur
between attacks

" primary progressive (10% of cases), marked by gradual progression

of disability from clinical onset

" secondary progressive characterized by a gradually progressive course

after an initial relapsing-remitting pattern

" progressive relapsing wherein acute relapses occur during a primary

progressive course, is rare.

" benign form???

Radiologically
isolated syndrome
= No need for treat
 Management
Concept for early treatment of MS ?
CIS stage….
" The time you lose never return back
" The deficit you have can not be reversed.
" Time therapeutic window is critical
" How we can sure that with CIS presentation is MS? Ataxia ,
optic neuritis, INO, weakness or sensory deficit??
!Case of ON?
$ MRI will label the pt. as a high risk pt. or not? High risk
patient with CIS.
$ Criteria? no. ,size and site.
Treatment
! Team work management.

$ Treatment of acute relapse.

(pulse therapy /plasma exchange)

$ disease modifying therapy.

$ Symptomatic treatments.

$ Prognosis.
 Relapsing-remitting disease

Treatment of acute relapse

MP pulse therapy /plasma exchange

 Approved DMA used in treatment of MS
Drug dosage Comments
Interferon 30Mg IM wkly For long In CIS ,less aggressive presentation Flue like illness
beta1a(avonex) duration Monitor CBC&LFT ,low risk NABs
reduces the
Interferon relapse 22-44MG sc/3/wk Used in aggressive presentation with 2 or more relapses,
rate. polysymptomatic, multiple enhancing lesions in MRI
Beta1a (rebif) .monitor CBC ,LFT .moderate risk of NABs
Flue like illness, local pain, local injection site
IF beta 8milionIU SC every other Used in aggressive presentation----same as above or if Rebif shots is
day painful
1b(betaferon)
Flue like illness, injection site reaction, monitor CBC
&LFT ,high risk of NABs.
Glatirameracetat 20mg SC every other day Non-aggressive course, early course of RRMS, depressed patient ,IF
Delayed response breakthrough? ,no blood monitor
(copaxone) Injection site reaction, rare systemic reaction
May have protective
Category B
Mitoxantrone 5-12MG/m2 IV every 3 Worsening RRMS ,early SPMS
months* Mild chemotherapy SE ,cardiac toxicity (may be asymptomatic EF should
*cyclophosphamide be assessed) , Risk of leukemia is small
New treatments in MS?
" Monoclonal antibody (FDA approval)

" Oral therapy in MS (Fingolimod ,Teriflunamide dimethyl

fumarate BG12)

" Stem cell transplantation

" Use of vitamin D3 in MS?

" Use of statins?

Monoclonal antibody
(FDA approval 2004-2017)
" DACLIZUMAB (target IL2 receptor,CD25) = zenapax
" NATALiZUMAB (antegren) target WBC adhesion molecule . Now in use
even in surroundings area
$ Problem is---?JC virus /2005---- PML
" RITUXIMAB (CD20).
" ALEMTUZUMAB (CD52): very promising, SE (autoimmune diseases)
" OCRELIZUMAB (CD20) : FDA approved in 2017 for relapsing or
primary progressive MS
Symptomatic treatments
" Spasticity.

" pain

" paroxysmal symptoms.

" bladder Dysfunction : urodynamic assessment is

required.

" Fatigue
" emotional liability ..we can use tryptizole or Prozac=
fluoxetine.
" physiotherapy ,occupational ,and family support and
psychological support .

" pregnancy : does not increase n. disability ,tend to have

less frequent attacks but high rate of attacks in 1st 3
months after delivery may be related to increase in level
of PL and sustained level due to breast feeding ,this not
constant observation .

$ child bearing and family size depend on situation ,

disability and family support.
 Prognosis
good prognostic signs are
---early onset ,relapsing remitting ,female ,optic neuritis alone
presenting feature& minimal deficit 5 years after the onset .
bad signs :
---late onset, progressive , sever action tremor, and truncal ataxia

They found that ; 15 years after the onset ---

" 20% have no functional limitation
" 70% have no ability to perform major activity .
" 75% are not employed.

" Optic neuritis ---50% -60% will have ms within 5 years if they
have positive MRI finding of ms during initial attack and 5% if
MRI is negative.
 Neuromyelitis Optica

MS (OSMS) VS NMO
NMO is distinct from MS
Clinical, laboratory, neuroimaging, and prognostic characteristics
characteristics

Department of Neurology, www.meduni-graz.at/neurologie Franz Fazekas

ADEM?acute disseminated encephalomyelitis

" Monophasic acute D. event

" Post vaccination , post viral

" Patient is in toxic condition, seizure and
disturbed consciousness and wide CNS
involvement
" Treatment steroid and prognosis is good