République Algérienne Démocratique et Populaire

Ministère de l’Enseignement Supérieur et de la Recherche Scientifique

UNIVERSITE MOULOUD MAMMERI DE TIZI-OUZOU

Centre Hospitalo-universitaire de Tizi-Ouzou
Service de Neurologie

Neurology internship report :

Multiple Sclerosis

- Supervised by : Dr H. SI AHMED

- Realised by :
 Chayer Tin-hinan
 Senane Idris
 Slimani Damya

Period from February 15th to June 30th 2019

 TABLE OF CONTENTS
LIST OF TABLES AND FIGURES……………………….3
ACKNOWLEDGEMENTS………………………………...4
REVIEW OF THE LITTERATURE………………………5
I. Introduction……………………………………………...5
II. Epidemiology of MS…………………………………….6
III. Anatomical overview of the CNS……………………...10
IV. Pathogenesis and neuropathology of MS……………...12
V. Diagnosis of MS……………………………………….17
VI. Predicting Prognosis in MS……………………………26
VII. Management of MS……………………………...…….29
EXPERIMENTAL STUDY………………………………34
I. Aims of the study………………………………………34
II. Subjects and methods………………………………….34
III. Results and analysis……………………………………36
IV. Discussion……………………………………………...56
CONCLUSION……………………………………………58
REFERENCES…………………………………………….59

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 LIST OF TABLES AND FIGURES
Table 1 : 2010 McDonald crtieria for multiple sclerosis.................... 19
Table 2 : Expanded Disability Status Scale (EDSS) .......................... 27
Table 3 : Different DMT's used in MS and their various action
mechanisms ....................................................................................... 29

Figure 1 : Age at Onset of symptoms of MS ....................................... 6

Figure 2 : Age-standardised MS prevalence in 2016 ...................... 8
Figure 3 : Main divisions of the Nervous System .............................. 10
Figure 4 : Myelin sheath on a nerve cell ............................................ 11
Figure 5 : Myelin sheath in normal neurone and in a damaged one. .. 12
Figure 6 : Activation of immune cells in MS .................................... 14
Figure 7 : Summary of pathogenetic mechanisme of formation of
actively demyelinating lesions .......................................................... 16
Figure 8 : Example of MRI lesions found in patients with MS.......... 20
Figure 9 : Sagittal intermediate and T2-weighted dual echo fast-spin
echo images of the spinal cord in a patient with multiple sclerosis.... 21
Figure 10 : Brain MRI scan showing white lesions associated with MS
.......................................................................................................... 21
Figure 11 : Clinical types of Mltiple sclerosis ................................... 22
Figure 12 : Progression of disability in patients with MS .................. 28

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 ACKNOWLEDGEMENTS
The completion and final outcome of this report required a lot of guidance and
assistance from many people and we would like to address our acknowledgements:

To the head of the Neurology unit of the Tizi Ouzou hospital, Pr. S. DAOUDI,
thank you for providing us with the opportunity to work and complete our internship in
your department, being alongside such a diligent, passionate and conscientious
neurologist/person has inspired us for our own future careers. It was truly an honor.

To Dr. H. SI AHMED, our project guide who took keen interest in our report,
your careful and precisous guidance, assistance and suggestions were extremely
valuable for our study both theoretically and practically. Thank you for allowing us to
encroach upon your precious time from the beggining till the completion of this work.

Also, we would not forget to remember all the Neurology Balloua Unit medical
staff including the assistant professors and the residents, we are sincerely grateful for
your encouragements and more over for your daily support during our period in
Balloua.

More than just learning about neurology and medical conditions, working with
all of you permited us to witness kindness, compassion and consciousness, those
human qualities which are indispensible to the medical practice.

Finally, we would like to extend our sincere esteems to the all the staff working
in the unit.

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 REVIEW OF THE LITTERATURE
I. Introduction :
Multiple sclerosis (MS) is an acquired chronic immune-mediated inflammatory
condition of the central nervous system (CNS), affecting both the brain and spinal
cord, It is the commonest cause of serious physical disability in adults of working age.

The cause of MS is still not clearly known. It is believed that an abnormal

immune response to environmental triggers in people who are genetically predisposed,
results in immune-mediated acute, and then chronic inflammation. The initial phase of
inflammation is followed by a phase of progressive degeneration of the affected cells
in the nervous system. MS is a potentially highly disabling disorder with considerable
personal, social and economic consequences. People with MS live for many years after
diagnosis with significant impact on their ability to work, as well as an adverse and
often highly debilitating effect on their quality of life and that of their families.

There are 2,500,000 people in the world with multiple sclerosis and 350,000 people
in the U.S. have multiple sclerosis. Women are affected by multiple sclerosis 50%
more often than men are: the ratio of women to men suffers of multiple sclerosis is 3
to 2.

The most definitive tool for diagnosing multiple sclerosis (MS) is magnetic
resonance imaging (MRI) and a new MR technique called "Turbo FLAIR" in
particular. There are no drugs or treatments which can cure multiple sclerosis, but
treatments are now available which can modify the course of the disease. Life span is
not significantly affected by multiple sclerosis, but the unpredictable physical and
emotional effects of multiple sclerosis can be life

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 II. Epidemiology :
 Age of Onset :

Most studies agree that the mean and median age of onset in relapsing forms of MS is
age 29 to 32. The peak age of onset is approximately 5 years earlier for women than
for men. Primary progressive MS (PPMS) has a mean age of onset of 35 to 39 years. It
is well recognized that the onset of MS can occur well outside of the mean age of
onset. Perhaps as many as 5% of cases of MS have their onset before age 18. Most of
these cases occur in adolescence, but a small percentage begins in the first decade of
life. Patients may also present with first symptoms after age 50, in 3%–12% of
incident cases

Figure 1 : Age at Onset of symptoms of MS

 Sex distribution :

Similar to most other autoimmune conditions, MS affects more women than men.
During the twentieth century the female : male ratio of incident relapsing MS cases has
increased in most geographic locations for unknown reasons, though changes in
childbearing patterns, epigenetic and environmental factors may play a role (Miller et
al., 2014). The female: male ratio in relapsing-remitting MS is 2–3: 1, although
interestingly it has remained steady at 1: 1 in primary progressive MS.

 Geographical and racial distribution:

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More than 250 prevalence surveys have been carried out; serving as the basis for the
delineation of geographical risk for MS. High-frequency areas of the world, include all
of Europe (including Russia), southern Canada, the northern United States, New
Zealand, and the southeastern portion of Australia. In many of these areas, the
prevalence is more than 100 per 100,000, with the highest reported rate of 300 per
100,000 occurring in the Orkney Islands. The number of cases of MS in the United
States was estimated by the National MS Society in 2002 to be approximately 400,000
persons. Several studies suggest that the prevalence is increasing beyond what might
occur because of enhanced recognition and better-appreciated diagnostic techniques.
One possible conclusion is that MS is a location-related illness with a latitude gradient.
However, notable exceptions then have to be explained. Japan, situated at the same
latitude as areas of high prevalence in Europe, is a low-risk area. Second-generation
Japanese in the United States retain their parents’ low risk of MS. The white
population of South Africa, with medium prevalence of MS, is surrounded by a black
population in whom the disease is very uncommon. Native North Americans,
especially of pure Amerindian background, have a very low prevalence but are
surrounded by a white population with a medium or high risk for MS. Thus, race may
be one determinant of MS risk, with populations of white extraction, especially from
Northern Europe, being most susceptible. People of Asian, African, or Amerindian
origin have the lowest risk. Migration data have often been used to support the view
that an environmental agent is involved in the pathogenesis of MS. The data indicate
that persons migrating from an area of high risk to an area of low risk after the age of
puberty carry their former high risk with them. With migration during childhood, the
risk seems to be that of the new area to which the person has migrated.

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Figure 2 : Age-standardized MS prevalence in 2016
  Mortality

Most studies of MS and mortality have shown that MS shortens lifespan, on

average, by a period of 7–14 years. Death due to a catastrophic MS relapse is
exceedingly rare. Although MS is listed as the primary cause of death on an MS
patient’s death certificate approximately 50% of the time, more typically an infection
or other complication of progressive MS is the actual cause. Cardiovascular disease,
accidents, and suicide seem to be represented in a higher proportion in the MS
population.

The evidence suggests that the increased rate of death in patients with MS does
seem to be declining out of proportion to that of the general population. In Denmark,
an exceptionally complete survey of the country found the median survival after
diagnosis for men was 28 years and for women 33 years, compared with matched
population death rates of 37 and 42 years, respectively. The 10-year excess mortality
was reduced by 50% in recent decades, even before the introduction of disease-
modifying therapies (DMTs) this trend seems to have continued in the post-DMT era.
In another important study, a 21-year follow-up that included 98.4% of the patients
enrolled in the pivotal IFNβ-1b trial, the risk for death in patients initially randomized
to IFNβ-1b 250 μg was found to be decreased, with a hazard ratio (HR) of 0.53 versus
those initially on placebo thus suggesting that early initiation of DMT might further
alter mortality outcomes.
III. Anatomical overview of CNS :
The Nervous System is divided into Two Main Divisions: Central Nervous
System (CNS) and the Peripheral Nervous System (PNS)

Figure 3 : Main divisions of the Nervous System

In this report we’re going to detail only the CNS’s anatomy, because it’s the
component in MS.

Some General Terminology for CNS: gray matter = thin myelin; mostly cell
bodies dendrites & synapses -outer layer of brain = cortex -inner layer of spinal cord -
nuclei: small areas of gray matter deeper inside the brain White matter = thick
insulation; mostly axons -inner layers of brain: nerve tracts = bundles of axons that
interconnect various parts of the brain -outer layer of spinal cord.

The brain and the spinal cord are the central nervous system, and they represent
the main organs of the nervous system. The spinal cord is a single structure, whereas
the adult brain is described in terms of four major regions: the cerebrum, the
diencephalon, the brain stem, and the cerebellum. A person’s conscious experiences
are based on neural activity in the brain. The regulation of homeostasis is governed by
a specialized region in the brain. The coordination of reflexes depends on the
integration of sensory and motor pathways in the spinal cord.

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Overview about the myelin sheath:
The myelin sheath is a fatty insulating later that surrounds the nerve cells of
jawed vertebrates, or gnathostomes. All extant members of the Gnathostomata, from
fish to humans, have a myelin sheath on the axon of their nerve cells.

Myelin sheath is produced in a process called myelination, in which can be seen

in the image above. The myelin sheath of nerve cells is typically produced early in
development. Special cells called oligodendrocytes or Schwann cells create and store
large amounts of myelin. The oligodendrocytes then wrap themselves around the axon
of a nerve cell. Many oligodendrocytes are needed to cover the long axons in
mammals, which can be up to a meter long. By itself, myelin is a fatty substance that
appears white. In parts of the brain and nervous system called white matter there is an
excess of myelin sheath. In grey matter, more cell bodies are present. Myelin is
chemically composed of various lipids and proteins, which also absorb some water.

Figure 4 : Myelin sheath on a nerve cell

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IV. Pathogenesis and neuropathology:

1. Neuropathology of multiple sclerosis:

Pathologically MS is characterized by the presence of large, multifocal,

demyelinated CNS lesions in multiple areas leading to scar tissue called sclerosis. This
demyelination process is accompanied by autoimmune inflammatory reactions that are
mediated mainly by T cells, B cells and macrophages. Primary targets are the myelin
sheaths and oligodendrocytes, but axons, nerve cells and astrocytes are also affected.

Figure 5 : Myelin sheath in normal neuron and in a damaged one.

The lesions observed in the CNS of MS patients are typically characterized by a

demyelinated core separated by a very sharp border from normally myelinated
surrounding tissue, many white matter lesions are detected in certain predilection sites,
notably around the ventricles. Other predilection sites include the optic nerve and
spinal cord. Moreover, lesions may also occur in the deep white matter far from
ventricles as well as grey matter. The white matter lesions can be characterized
broadly as chronic and active lesions:
 In chronic lesions there are less mononuclear cells, almost complete
demyelination and even astrogliosis.
 Active lesions are defined by ongoing destruction of myelin and are heavily
infiltrated by macrophages and microglial cells.

Clinical and MRI data suggest that inflammation and formation of new white
matter lesions are the substrate for RRMS. In the progressive phase the new
inflammatory demyelinating lesions are rare, but diffuse atrophy of the grey and white
matter and changes in the normal-appearing white matter (NAWM) are more
predominant. Although MS is considered to be inflammatory demyelinating disease,
axonal injury and loss also occurs in the MS lesions and is associated with the
development of permanent disability in MS patients.

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 Normal appearing white matter may consider highly abnormal in MS patients,
especially in patients in the progressive stage of the disease. Changes in the NAWM
consist of a diffuse inflammatory process; inflammatory infiltrates are present in the
perivascular space and are also dispersed throughout the tissue. Inflammation is
associated with profound microglia activation. This microglia activation is associated
with diffuse axonal injury and loss ,the mechanisms that lead to diffuse injury of the
NAWM are so far poorly understood It is suggested that free radical mediated
mitochondrial injury may be an important factor driving progressive axonal
dysfunction and loss in MS .

Grey matter: MS lesion can also be located in the grey matter, especially in the
cerebral cortex; cortical lesions have been observed 80% of patients with PPMS.
The histopathological characteristics of these cortical lesions differ substantially from
white matter lesions. Three types of cortical lesions have been reported, two of these
lesions may appear in continuity with subcortical white matter plaques (type I) or as
small intracortical perivascular lesions (type II). The most abundant form of cortical
demyelination is subpial demyelination, which appears as large band-like lesions
extending from the outer surface of the cortex into its deeper layer (type III).
Although cortical lesions are characterized by substantial loss of oligodendrocytes and
axons, they differ markedly from white matter lesions in terms of the degree and type
of inflammation. Pure intracortical lesions typically have a very low degree of
inflammation.

2. Immunopathogenesis of multiple sclerosis

 Activation of immune cells :

The cause of MS is still unknown and its pathogenetic pathways are not fully
understood. Studies of experimental autoimmune encephalomyelitis (EAE), an animal
model for MS, have indicated the role of myelin specific CD4+ Th1 and Th17 as the
driving force in the autoimmune processes, but other cell types that contribute to the
pathogenesis of MS, such as CD8+, B cells, or NK cells have also been investigated.

The initial step in immune cell activation is to activate dendritic cells (DC) via
toll like receptors, which recognize very specific microbial products. After ligation, the
DCs are activated and these cells start to produce type I IFNs. Once activated, CD4+ T
cells interact with DC through the HLA class II molecule that recognizes the T-cell
receptor (TCR) on the T cells (signal 1) in the secondary lymphoid organ. However,
activation of T cells also requires additional signals. Interaction with HLA and TCR
induces activation of CD40 ligand (CD154) on the surface of T cells, which binds to
its receptor CD40 on the DC. This interaction induces up regulation of CD80 (B7-1)
and CD86 (B7-2) on the surface of DC that interacts with CD28 and cytotoxic T-
lymphocyte antigen-4 (CTLA4) on the surface of the T cells (Signal 2). CD28 is
associated with the activation of T cells, whereas CTLA4 (CD158) is more regulatory.
After signal 2, DC start to produce important cytokines, which binds to receptors on
the cell surface of T cells and drive them to secrete different cytokines. For example,

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secretion of IL-10, IL-12, IL-4 or combination of Interleukin (IL)-6/IL-1/IL-23
promotes differentiation to Th3, Th1, Th2, and Th17, respectively.

Figure 6 : Activation of immune cells in MS

 Transmigration of immune cells to the central nervous system :

Peripherally activated T cells enter distinct CNS microenvironments via the
blood brain barrier (BBB) within the CNS parenchyma and by blood-CSF barrier
(BCB) within choroid plexus. Tight junctions between endothelial cells of the 28 BBB
and the epithelial cells of the BCB limit immune cells access to the CNS. However,
activated and memory T cells can transmigrate into the CNS, because they express
adhesion molecules, chemokine receptors and integrins that enable these cells to
readily cross these barriers (Engelhardt et al., 1998; Engelhardt, 2008). The migration
of leukocytes from blood into the CNS includes chronological leukocyte-endothelial
interactions. Tethering and rolling of the leukocytes on the vascular endothelial surface
initiate this process that is mediated by selectins and carbohydrate counter receptors.

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During the rolling, leukocytes also interact with the chemokines, which are produced
on the endothelial surface. Chemokine stimulation induces up regulation of adhesion
molecules of the integrin family on the leukocyte surface and leads to firm adhesion of
leukocytes to the vascular endothelium by binding to cell adhesion molecules or the
extracellular matrix component. This process ultimately leads to leukocyte
transmigration to the CNS (Prendergast and Anderton, 2009).

 Mechanisms of neural tissue damage :

In the CNS, CD4+ T cells are reactivated and then mediate activation of
macrophages/microglia, B cells and cytotoxic CD8+ T cells (Figure 5). Tissue damage
in the inflammatory lesion of the brain and spinal cord may be induced by numerous
mechanisms, such as cell-, cytokine, antibody- and radicals-mediated mechanisms
(Lassmann, 2010).
Macrophage/microglia-mediated damage: Activated macrophages and microglia
have an important role in the CNS lesion development. They produce a large array of
toxic molecules, such as proteo- and lipolytic enzymes, cytotoxic cytokines,
excitotoxins and reactive oxygen species or nitric oxide (NO) intermediates, which are
potential inducers of axonal damage. For axonal injury, oxygen and NO radicals seem
to be of particular importance.
T cells are also central to MS lesion development. Both CD4+ and CD8+ T cells
can express ligands for death receptors. Among them, TNF-related apoptosis inducing
ligand (TRAIL), Fas ligand (FasL), tumor necrosis factor (TNF)-􀁄 have been
described to mediate neuronal and oligodendrocytes damage (Aktas et al., 2006).
CD8+ T cells are more prevalent in the MS lesions than the CD4+ T cells, and CD8+
cells can recognize antigen presented on HLA class I on neurons and oligodendrocytes
and kill the target cells (Hauser et al., 1986; Friese and Fugger, 2009).
B cells and antibodies, B cell derived plasma cells and antibodies are found in the
CNS of MS patients (Baranzini et al., 1999). The target antigens of the humoral
immune response in MS are still largely unknown, but it is suggested that the primary
targets of the antibodies are the proteins of the myelin sheath, such as MBP, myelin
oligodendrocytes glycoprotein (MOG) and proteolipid protein (PLP). Possible
mechanisms are the antibody-mediated complement activation and antibody-
dependent cellular cytotoxicity via Fc-receptors (Franciotta et al., 2008; Weber et al.,
2011).
Pathological analyses of actively demyelinating lesions have revealed four
different structural and immunological features. Separate pattern of demyelination
were homogenous in multiple lesions of the same patients, but different between the
patients (Lucchinetti et al., 2000) (Figure 6). In these lesions, activated macrophages
or microglia, cytotoxic cytokines, reactive oxygen and nitrogen species or specific
demyelinating antibodies and activated complement component could be found.
Although all actively demyelinating lesions were associated with an
inflammatory infiltrates composed mainly of T lymphocytes and macrophages, they
segregated into the four different patterns (Pattern I-IV) based on the distribution of
myelin protein loss, the plaque geography and extension, pattern of oligodendrocyte
destruction and the immunological evidence of immunoglobulins and activated
complement deposit. Demyelination may be induced by macrophages and their toxic

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products (pattern I), by specific demyelinating antibodies and complement (pattern II),
by degenerative changes in distal processes, in particular periaxonal oligodendrocytes
followed by apoptosis (pattern III) or by primary degeneration of oligodendrocytes
followed by myelin destruction (pattern IV).

Figure 7 : Summary of pathogenetic mechanism of formation of actively demyelinating lesions

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 V. Diagnosis of MS:

1. McDonald criteria :
The diagnosis of multiple sclerosis requires objective evidence of CNS lesions
disseminated in time and space, and also importantly that there is no better explanation
for the clinical presentation and that alternative diagnoses are considered and
excluded. Historically, dissemination in time and space has been based on clinical
findings alone, requiring two separate attacks with signs of two or more lesions.

Using the McDonald 2010 criteria , a diagnosis of multiple sclerosis can still be
made on clinical grounds alone; however, MRI is used to provide evidence for
dissemination in time and space, including in patients with clinically isolated
syndrome.1 For relapsing-remitting multiple sclerosis, MRI evidence of dissemination
in space requires at least one T2 lesion in at least two of four sites, periventricular,
juxtacortical, and infratentorial regions and the spinal cord (figure), with symptomatic
lesions in the brainstem and spinal cord excluded.

Dissemination in time requires either asymptomatic gadolinium-enhancing and

non-enhancing lesions on the same MRI scan or a new lesion on a follow-up scan.
Using the McDonald 2010 criteria, a diagnosis of relapsing-remitting multiple
sclerosis can be made in up to a third of patients with clinically isolated syndrome with
a single MRI scan.

The McDonald criteria provide separate recommendations for the diagnosis of

primary progressive multiple sclerosis, which includes testing for CSF abnormalities
in addition to MRI. Brain T2 lesion load tends to be lower in primary progressive
multiple sclerosis and the combination of MRI and CSF findings provides a higher
sensitivity than MRI alone.

Dissemination in space in suspected primary progressive multiple sclerosis

requires two or more of the following: at least one T2 brain lesion in at least one of
three sites typically affected in multiple sclerosis (periventricular, juxtacortical, and
infratentorial); at least two T2 spinal cord lesions; and positive CSF (at least two
oligoclonal bands not present in serum, raised IgG index, or both). Progressive
worsening over a period of at least 12 months provides evidence of dissemination in
time.

The McDonald 2010 criteria are easily applied in a clinical setting and allow for
an earlier diagnosis of multiple sclerosis. However, there are important caveats when
using MRI criteria. The criteria are intended for diagnosis of patients in whom
multiple sclerosis is clinically suspected, rather than to differentiate multiple sclerosis

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from other neurological disorders. MRI in patients with small vessel cerebrovascular
disease, other inflammatory disorders, and non-inflammatory disorders affecting white
matter , and even in healthy people (especially in older age groups), might show brain
lesions that fulfil MRI criteria for multiple sclerosis.

The McDonald MRI criteria were developed and tested after a clinically isolated
syndrome in patients with symptoms typical of multiple sclerosis (ex. unilateral optic
neuritis) and they should not be applied to patients with non-specific neurological
symptoms such as paraesthesia, dizziness, or headache, in whom the diagnosis is much
less likely, additionally, MRI criteria were tested and validated in European
populations with a high incidence of multiple sclerosis, although studies investigating
the McDonald 2010 criteria in cohorts with clinically isolated syndrome in Latin
America and Asia have reported a similarly good performance. Finally, the diagnosis
of multiple sclerosis should be made only by a neurologist taking into account the
clinical picture, MRI findings, and the results of any other investigations.

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 Table 1 : 2010 McDonald criteria for multiple sclerosis

Mc Donald criteria for multiple sclerosis

Attacks Lesions Additional criteria for diagnosis

02 or more 02 or more None, clinical evidence alone will
suffice.

02 or more 01 lesion Dissemination in space on MRI

(Or await further clinical attack
implicating a different CNS site).

01 attack 02 lesions Dissemination in time on MRI (or

await further clinical attack
implicating a different CNS site).on
in time on MRI

01 attack 01 lesion Dissemination in space and time on

MRI (or await further clinical attack
implicating a different CNS site).

0 attack One year of disease progression

Progression (retrospective or prospective), and at
from onset least 2 out of 3 criteria:
*Dissemination in space in the brain.
*Dissemination in space in the spinal
cord based on 02 or more T2 lesions.
*Positive CSF.

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Figure 8 : Example of MRI lesions found in patients with MS

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Figure 9 : Sagital intermediate and T2-weighted dual echo fast-spin echo images of the spinal cord in a
patient with multiple sclerosis.

Figure 10 : Brain MRI scan showing white lesions associated with MS

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 2. Clinical types of MS:
MS is commonly described as one of several clinically defined types, which describe
the course of the disease. However, it is not necessarily a natural progression from one
to the next, and often a clear classification of type of MS cannot be made.

a) Relapsing-remitting MS: is the most common (80% of people at onset),

manifesting in a relapse of symptoms followed by periods of remission.
b) Secondary progressive MS: describes cases where fewer periods of remission
occur and neurological deficits progressively worsen. About 50% of people
diagnosed with relapsing remitting MS develop the secondary progressive form
within 10 years.
c) Primary progressive MS: is the least common (10-15% of people at onset) in
this form neurological deficits progressively worsen from the onset. Primary
progressive MS may differ to other types of MS in the underlying damage
within the immune system. Whereby milder inflammatory damage occurs
overtime, with the accumulation of disability being ultimately more
progressive, rather than the clear relapsing pattern more commonly seen.
However some people with more progressive MS may also experience
occasional relapses, and thus a subsidiary form of Primary progressive MS,
which has no clear definition, is Progressive relapsing MS, whereby relapse
occurs alongside progression of the disease, and subsequent disability .

Another form of MS, when there has been no change in any neurological systems
for 15 years or more is known as benign MS (Lublin and Reingold 1996).
The pattern of clinical symptoms and descriptors is complex, variable and
unpredictable; however, the types are displayed in Figure below.

Figure 11 : Clinical types of Multiple sclerosis

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 3. Overview of the RIS and CIS:

 The radiologically isolated syndrome (RIS):

The widespread use of MRI means incidental findings suggestive of multiple
sclerosis are sometimes identified in people who have no clinical symptoms, referred
to as a “radiologically isolated syndrome”. The typical demyelinating lesions that
characterize radiologically isolated syndrome need to be carefully differentiated from
small vessel cerebrovascular disease and non-specific white matter lesions (the latter
being common in people with migraine.
A third of patients with “radiologically isolated syndrome” will develop clinical
symptoms of multiple sclerosis in 5 years of follow-up (either a relapse or progressive
symptoms). Younger age, male sex, and gadolinium-enhancing, cortical, or spinal cord
lesions might be associated with an increased risk of developing multiple sclerosis,
there are no accepted diagnostic criteria for radiologically isolated syndrome, but the
Okuda 2009 criteria have been used in research studies and can also be applied in a
clinical setting. These criteria consider only dissemination in space and are more
stringent than the McDonald criteria, taking into account lesion size and morphology,
as well as location, to differentiate asymptomatic demyelinating lesions from other
white matter lesions. A diagnosis of multiple sclerosis should only be made in a
patient who has symptoms suggestive of demyelination.2 However, patients with
radiologically isolated syndrome are at risk of developing multiple sclerosis and
should be counseled and offered follow-up as appropriate.

 The clinically isolated syndrome (CIS):

Clinically isolated syndrome (CIS) is a term that describes a first clinical episode
of a disease that shows characteristics of inflammatory demyelination that could be
MS but has yet to fulfill criteria of dissemination in time (Lublin et al., 2014). It
usually occurs in young adults and affects optic nerves, the brainstem, or the spinal
cord. Although patients usually recover from their presenting episode, CIS is often the
first manifestation of MS.

The most common CIS presentations and risk factors for Clinically Definite MS
(Brownlee and Miller, 2014) include:

Optic Neuritis

 Unilateral reduced visual acuity

 Orbital pain particularly with eye movement
 Reduced color vision
 Afferent pupillary defect

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  Retrobulbar or mild disc swelling
Brainstem

 Bilateral internuclear ophthalmoplegia

 Ataxia and gaze evoked nystagmus
 6th nerve palsy
 Multi-focal symptoms
 Facial sensory loss
 Vertigo
 Ataxia
 Dysarthria
Spinal cord

 Incomplete transverse myelitis

 Positive Lhermitte’s sign
 Sphincter symptoms
 Asymmetric limb weakness
 Symptom progression between 4 hours and 21 days.
The important risk factors for the conversion to clinically definite MS (CDMS) are:

 Polysymptomatic presentation (Cinar et al., 2018)

 > 2 T2 MRI lesions (Kuhle et al., 2018; Cinar et al., 2018)
 Oligoclonal bands present in CSF, not in serum (Kuhle et al., 2018)
Red flags for other diagnoses:
 Normal MRI
 No abnormal findings on neurological exam
 Bilateral vision loss
 Peripheral neuropathy
 Rigidity; sustained dystonia
 Seizures
 Headache
 Early dementia
 Abrupt onset of symptoms
 Cortical deficits (aphasia, apraxia, alexia, neglect)
 Intractable hiccups

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 Onset before age 10 or after age 50.

4. Differential diagnosis (MS mimics)

- Autoimmune/inflammatory conditions :
 Neuromyelitis optica spectrum disorder (NMOSD)

 Acute disseminated encephalomyelitis (ADEM)

 Myelin Oligodendrocyte Glycoprotein (MOG)-related demyelination
 Sjogren’s Syndrome
 CNS lupus
 Sarcoidosis
 Behçet’s disease
 CNS vasculitis
- CNS infections :
 CNS Syphilis

 Lyme disease
 Human T lymphotropic virus (HTLV)
 HIV
- Metabolic conditions :
 Vitamin B12 deficiency
 Copper deficiency
 Mitochondrial disease
 Leukodystrophies
- Vascular conditions :
 Small vessel disease

 Stroke
 Susac syndrome
 CADASIL
 Antiphospholipid antibody syndrome (APLAS)
- Other :
 CNS lymphoma

 Paraneoplastic myelopathy

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VI. Predicting prognosis
1. EDSS score
The Expanded Disability Status Scale (EDSS) (Kurtzke 1983) is the most widely
used measure of disability for MS. It describes both neurological and functional
aspects of the disease. The scale quantifies neurological impairments, in each of eight
neurological functional systems (FS); pyramidal, cerebellar, brainstem, sensory, bowel
and bladder, visual, cerebral and other. These are combined with ambulation
ability/mobility and give a measure of disability on a scale from 0 (normal) to 10
(death due to MS) (See Appendix 9.1). In general, as the number of symptoms
increases so will the EDSS level. The EDSS has, for many years attracted criticism
(despite this it is still a commonly used tool clinically and in research allowing for
comparison between study populations. Authors have noted a poor response to change
(Sharrack et al 1999) and that scores are clustered around 3/4 and 5/6 (Whitaker et al
1995; Jacobs et al 1999). Grades above three are heavily reliant on mobility, thus at
the higher end of the scale a newly acquired FS problem may not necessarily modify
the EDSS score.

The definitions of mild, moderate and severe MS are often linked with the EDSS,
however the original author (Kurtzke 1983) did not use these definitions. Moderate
MS, defined in the present study as 5 (ambulatory without aid or rest for about 200 m)
to 6.5 (constant bilateral assistance required to walk about 20m and without resting)
was the description used by Freeman et al (1997) and Hammond et al (2000). However
there is a discrepancy in the literature as moderate MS has been described by others as
an EDSS score of 5-7 (Filipi et al 2011), 4-6 (Craig et al 2003) or 3-4 (Goldman et al
2008). Higher levels of disability have been associated with a poorer prognosis, and
faster disease progression (Cottrell et al 1999). A prevalence study showed that
persons with milder MS (EDSS 0-3) at initial disease diagnosis have a much better
prognosis than those with moderate or severe MS (EDSS 4-9) (Hammond et al 2000).
These authors also found that an increased number of multiple symptoms at disease
onset had a negative effect on prognosis. Brain imaging (MRI) is also increasingly
used to predict prognosis. It has been shown in a 20 year follow-up study that more
damage to the brain at baseline (number of T2 lesions) is associated with a higher
disability score after 20 years (Fisniku et al 2008). However brain imaging is not
utilized within this thesis and thus will not be explored in any depth.

26
 Table 2 : Expanded Disability Status Scale (EDSS)

Score Description
0.0 No disability
1.0 No disability, minimal signs in one FS
1.5 No disability, minimal signs in more than one FS
2.0 Minimal disability in one FS
2.5 Mild disability in one FS or minimal disability in two FS
3.0 Moderate disability in one FS, or mild disability in three or four FS. No
impairment to walking.
3.5 Moderate disability in one FS and more than minimal disability in
several others. No impairment to walking.
4.0 Significant disability but self-sufficient and up and about some 12 hours
a day. Able to walk without aid or rest for 500m.
4.5 Significant disability but up and about much of the day, able to work a
full day, may otherwise have some limitation of full activity or require
minimal assistance. Able to walk without aid or rest for 300m.
5.0 Disability severe enough to impair full daily activities and ability to work
a full day without special provisions. Able to walk without aid or rest for
200m.
5.5 Disability severe enough to preclude full daily activities. Able to walk
without aid or rest for 100m.
6.0 Requires a walking aid - cane, crutch, etc. - to walk about 100m with or
without resting.
6.5 Requires two walking aids - pair of canes, crutches, etc. - to walk about
20m without resting.
7.0 Unable to walk beyond approximately 5m even with aid. Essentially
restricted to wheelchair; though wheels self in standard wheelchair and
transfers alone. Up and about in wheelchair some 12 hours a day.
7.5 Unable to take more than a few steps. Restricted to wheelchair and may
need aid in transferring. Can wheel self but cannot carry on in standard
wheelchair for a full day and may require a motorized wheelchair.
8.0 Essentially restricted to bed or chair or pushed in wheelchair. May be out
of bed itself much of the day. Retains many self-care functions.
Generally has effective use of arms
8.5 Essentially restricted to bed much of day. Has some effective use of arms
retains some self-care functions.
9.0 Confined to bed. Can still communicate and eat.
9.5 Confined to bed and totally dependent. Unable to communicate
effectively or eat/swallow
10.0 Death due to MS

27
Figure 12 : Progression of disability in patients with MS

28
VII. Management of multiple sclerosis :
As has been discussed MS symptoms and prognoses vary widely, and thus there
is no one specific treatment, although many options are available. These will be
discussed in brief and taken from the National Institute for Health Clinical Excellence
(2003) guidelines of acute exacerbations and long-term management in MS, with
updates to these guidelines acknowledged as appropriate.

1. Disease-modifying therapies of multiple sclerosis:

A number of disease-modifying therapies (DMT) with partial efficacy for
patients with RRMS became available during the past 20 years. All of these drugs
mainly target the inflammatory component of the diseases (Table 1). All the DMTs
have shown to be effective in the RRMS type, but not in the PPMS. The most
commonly used therapies that are approved for RRMS include the type-1 beta IFNs
and GA (Table 1) (Barten et al., 2010). Several follow-up studies have evaluated the
efficacy of DMTs in MS, and it has been shown that treatments decrease the relapse
rate and reduce the number of MRI lesions (The IFNB Multiple Sclerosis Study
Group, 1993; Johnson et al., 1995; Jacobs et al., 1996; PRISMS Study Group, 1998).
Also DMTs over a long period of time improves outcome by delaying the time to
significant disease progression (Freedman, 2011).

Table 3 : Different DMT's used in MS and their various action mechanisms

Therapy Mechanism of action

First-line therapy
Interferon beta Inhibit T-cell activation
and reduce
blood-brain barrier (BBB)
permeability to
inflammatory cells.

Glatiramer acetate Immune modulator and it

is thought to shift the
immune responses from T
helper (Th) 1 to Th2 type.

Second-line therapies
Natalizumab Blocks very late antigen-4
(VLA-4) on the surface of
lymphocytes and therefore
reduce the transmigration
of inflammatory
lymphocytes via BBB into
the CNS.

29
Mitoxantrone Immunosuppressive
cytotoxic agent
that inhibits B-cell, T-cell,
and macrophage
proliferation and impairs
antigen presentation and
production of
proinflammatory
cytokines.
Fingolimod Blocks sphingosine-1
phosphates receptors in T
cells that results in an
inhibition of T-cell
migration from lymphoid
tissue into the peripheral
circulation and CNS.
Promising new drugs
Cladribine Purine nucleoside analog
that produces selective
lymphocyte depletion
through the inhibition of
cellular DNA synthesis and
repair.
Laquinimod Immunomodulatory
molecule that favors
Th2/Th3 cytokine
production and inhibits
immune cell transmigration
into the CNS.
Teriflunomide Inhibitor of dihydroorotate
dehydrogenase, which is an
integral membrane protein
for pyrimidine synthesis.
Inhibition of the enzyme
prevents the clonal
expansion of B and T cells
and antibody production.
Dimethyl fumarate Anti-inflammatory and
neuroprotective Effects
Alemtuzumab Humanized monoclonal
antibody directed against
CD52 antigen on T cells and
B lymphocytes, monocytes,
macrophages, natural killer
cells.

30
 Rituximab First generation monoclonal
antibody against the CD70
antigen on B cells that
effectively depletes B cells
via complement-dependent
cell lysis and antibody
dependent cellular toxicity

Ocrelizumab Humanized monoclonal

antibody against CD70.
Ofatumumab Fully human monoclonal
antibody against CD70
antigen.
Daclizumab Monoclonal antibody
directed against subunit of
interleukin-2 receptor
(CD25) on activated T cells,
which limits T-cell
activation.

IFNs are the cytokines that are normally released from the lymphocytes in
response to pathogens. There are three types of interferons: IFN-alpha, -beta and -
gamm. IFN beta is approved for the treatments of MS. Its mechanism of action is not
fully understood, but it has been shown to inhibit T-cell proliferation, reduce T-cell
migration from the periphery to the CNS, and alter the T cell cytokine secretion
toward anti-inflammatory responses (Markowitz, 2007). In clinical practice three
different IFN brta preparations are available, in which dose and frequency of
administration differ.
GA is a synthetic polypeptide (40-100 amino acids) composed of random
sequences of four amino acids (tyrosine, glutamate, alanine, and lysine), which are
common in myelin basic protein (MBP). GA clinical efficacy has been explained by a
shift of proinflammatory responses towards anti-inflammatory responses (Farina et al.,
2005; Johnson, 2010).

2. Management of acute exacerbations :

When a severe exacerbation or attack of symptoms occurs medical treatment
such as corticosteroids are often administered, and hospitalisation may be necessary
dependent on the severity of the exacerbation. Corticosteroids will often be
administered (intravenous or high dose oral methylprednisolone) for 3-5 days.
Rehabilitation will target the sudden increase in disability, with referral to the
appropriate specialist within the rehabilitation service. Long-term management Where
relapses are the predominant feature of the disease, as in Relapsing-remitting MS,

31
National Institute for Health and Clinical Excellence (2003) guidelines suggest that
patients are offered disease modifying therapy (DMT), either interferon beta or
glatiramer acetate under the guidance of their neurologist. Other medical treatments
which include azathioprine, mitoxantrone, intravenous immunoglobulin, plasma
exchange and intermittent methyprednisolone should be prescribed judiciously if
appropriate. Updates to these guidelines suggest that natalizumab be prescribed to
rapidly evolving cases of severe relapsing remitting MS (National Institute for Health
and Clinical Excellence 2007) .Whilst fingolimod has recently been recommended for
those with highly active relapse-remitting MS (National Institute for Health and
Clinical Excellence 2012).

Maintaining functional activities and social participation is important and can be

managed through rehabilitation. Assessment and access to a multidisciplinary
neurological rehabilitation service is important. This will offer early intervention of
any change in symptoms, whilst offering disease management to minimize the impact
of disease progression. It is advised by National Institute for Health and Clinical
Excellence (2003) that as a minimum the following specialists are involved in a
multidisciplinary neurological rehabilitation service:

 Doctors
 Nurses
 Physiotherapists
 Occupational Therapists
 Clinical Psychologists
 Social workers

These services will aim to maintain the person with MS in their chosen
vocational activity, encourage leisure and social interaction, maintain mobility,
maintain activities of daily living and help manage symptoms.

3. Symptom management in Multiple Sclerosis :

Khan et al (2008) provides a comprehensive review of the common

multidisciplinary therapy approaches to management in MS, finding that
multidisciplinary approaches are effective in managing MS, although no
recommendations on optimum dose or type of therapy to guide best practice emerged.
Thompson et al (2010) provides a good source of reference for multidisciplinary
therapy approaches (including occupational therapy and physiotherapy),
pharmacological and surgical treatments in MS to address symptoms such as;
spasticity, ataxia, impaired mobility, bladder/bowel and sexual dysfunction, fatigue,
cognitive problems, mood disturbance, visual and brainstem symptoms. The authors
conclude that a diverse range of management options are available and should be
utilized when appropriate. They acknowledge that although there are promising

32
treatments on the horizon, improvement in study design is required before
recommendations in clinical practice can be made.
Freedman et al (2002) provide a consensus statement on the use of DMTs in MS,
with other authors updating these guidelines (Wiendl et al 2008; Goodin 2008). The
recommended DMTs for MS are interferon beta, glatiramer acetate, mitoxantrone,
natalizumab and fingolimod (National Institute for Health and Clinical Excellence
2003; National Institute for Health and Clinical Excellence 2007; National Institute for
Health and Clinical Excellence 2012). These treatments can positively influence the
signs and symptoms of the disease, reduce the frequency and severity of relapse rates
and minimize accumulation of brain lesions, as evidenced through MRI. Each
medication does however have known side effects, which must be considered.

However there is a consensus in all of the above works that a multimodal

approach is taken towards management in MS, combining medical, pharmacological
and therapeutic intervention.

33
 EXPERIMENTAL STUDY
1. Aims of our study :
The aim of this study is to establish a comparison between patients with initial
medullar or cerebellar events (infra tentorial lesions), and others with another onset
(supra tentorial or optical), and the prognosis after 05 years of disease evolution, by
referring to EDSS scale.

2. Subjects and methods :

- Type, location, duration and population of the study:

This is a retrospective study using files of patients hospitalized and diagnosed with
multiple sclerosis in its Relapsing-Remitting form, according to Mc Donald 2010
criteria (see Table 1 p.19), in the department of neurology in Tizi Ouzou’s Hospital
Center (Balloua Unit) during the time period ranging from February 2013 to February
2014, and followed for a duration of 05 years after the diagnosis onset (Respectively
February 2018 and February 2019).

- Data collection :

The data collected in this study were generated from the patient’s medical records
(medical history ,clinical examination, neuroradiological reports, EDSS scale at the
beginning and after 05 years of disease evolution, MRI lesions, immunological tests
results and neurological consultation folders.)

3. Results :
During the time period ranging from February 2013 to February 2014, 69 cases
of Multiple Sclerosis were hospitalized and diagnosed in the Neurology department of
TIZI OUZOU’s Hospital center:

- 40 patients were included according to our parameters.

4. Statistical parameters :

 Demographic parameters : Age (at diagnosis onset), gender, dominant

cerebral hemisphere
 Clinical parameters : early clinical symptoms, EDSS score at diagnosis onset,
type of early clinical event
 Biological parameters : Immunological cerebrospinal fluid tests results

34
 Radiological parameters : Sites/location of demyelination lesions, number of
demyelination lesions (less than three, three to nine, superior to nine), volume
of demyelination lesions (superior to 1cm, less than 1cm), existence/absence of
contrast-enhanced lesions (after Gadolinium injection), existence/absence of
cortical atrophy.
 Evolution/therapeutic parameters: type of long-term treatment initiated,
time duration between the diagnosis onset and the initiation of the long-term
treatment, number of corticosteroid therapies received in the five years of
disease evolution, EDSS score 5 years after the diagnosis of the disease.

35
 5. Results and analysis :

A. Epidemiologic profile :
 Age :
Table 4 : Representation of MS cases according to the age at onset

Age (years) [0-16[ [16-36[ [36-46[ More than Total

46
Number of cases 0 22 8 10 40,0
Percentage (%) 0,0 55,0 20,0 25,0 100,0

MS cases according to age at Onset

25

20

15

Number of cases
10

0
[0-16[ [16-36[ [36-46[ More than 46

Figure 13: Graphical representation of MS cases according to the age at diagnosis onset

In this series, the average age for MS diagnosis is: 35.85 years.

55% of patients in this series were diagnosed between 16 and 36 years.

The youngest patient was aged of 16 years; the older diagnosed one was aged of 71.

25% (10 patients) were above 46 years and 20% were ranged between 36-46 years at
the diagnosis of the disease.

36
 Gender :
Table 5: Representation of MS cases according to gender

Gender Female Male Total

Number of cases 26 14 40

Percentage (%) 65,0 35,0 100,0

MS patient's gender

35,0%
Female
Male
65.0%

Figure 14 : Graphical representation of MS cases according to gender

In this series, MS is diagnosed predominantly in women with 65%, comparing to

35% for men.

 Dominant hemisphere :

Table 6 : Distribution of MS cases according to the dominant cerebral hemisphere

Dominant Hemisphere Right Left Total

Number of cases 4 36 40

Percentage (%) 10,0 90,0 100,0

37
 Dominant cerebral hemisphere
10.0%

Right
Left

90,0%

Figure 15 : Pie chart representing the distribution of MS cases according to the dominant
cerebral hemisphere

90% of cases collected in our study have left dominant hemisphere. Only 10% were
left-handed.

38
 B. Clinical profile :

 Clinical findings at onset :

Table 7 : Distribution of MS cases depending on the different clinical findings at diagnosis onset

Clinical findings Pyramidal Cerebellar Visual Sensitivity

syndrome syndrome impairment/visual disorders
disorders
Number of cases 23 12 8 5

Percentage( %) 57,5 30,0 20,0 12,5

Clinical findings at Onset

12,5% Pyramidal syndrome

Cerebellar syndrome
20,0%
57,50%
Visual impairment/Visual
disorders
30,0% Sensitivity disorders

Figure 16 : Distribution of MS cases depending on the clinical findings at onset

In this series the predominant initial clinical findings of multiple sclerosis is the
pyramidal syndrome with 57.5% of cases, represented mainly with motor deficiency in
lower/upper limb or the right/left hemibody, followed up with static and kinetic
cerebellar syndrome (30%), at the last position visual disorders with 20% of cases,
disorders of objective sensitivity (associated with other neurological syndrome) were
found in 12.5% of cases.

39
 Types of early clinical event of MS:
Table 8 : Representation of MS cases according to types of early clinical event

Types of early clinical Supratentorial/optic Infratentorial event Medullar Total

event event (Cerebellum and event
brainstem)
Number of cases 11 13 16 40

Percentage (%) 27,5 32,5 40,0 100,0

Types of early clinical event

Supratentorial/optic
27.5%
40.0%
Infratentorial
(Cerebellum/brainstem)
Medulla
32.5%

Figure 17: Graphical representation of MS cases according to the types of early clinical events

40% of patients (16cases/40) of our series have presented at diagnosis onset

clinical symptoms of medullary involvement, 32.5% had cinical symptoms of infra
tentorial involvement and at last 27% had supra tentorial or optic locations.

 EDSS scale at diagnosis onset :

Table 9: Distribution of MS cases according to EDSS score at diagnosis onset

EDSS score Inferior to 3 3 to 6 Superior to 6 Total

at diagnosis
onset
Number of 34 6 0 40
cases
Percentage 85,0 15,0 - 100,0
(%)

40
 EDSS scale at onset
40
35
30
25
20
Number of cases
15
10
5
0
inferior to 3 3 to 6 Superior to 6

Figure 18 : Diagram representation of EDSS score at diagnosis onset

In our serie , 85% of patients had an EDSS scale lower than 3 at the diagnosis
onset of MS (before starting the treatment of the first episode), 15% had an EDSS
scale ranging between 3 and 6, the highest EDSS scale found at diagnosis onset was 04
(found in 02 cases), and the lowest one was 0.
Table 10 : EDSS scale at diagnosis onset according to the type of early clinical event

EDSS at Onset Inferior to 3 3 to 6 Superior to Total

6
Number of cases with 10 1 0 11
supratentorial/optical event

Number of cases with infratentorial 10 3 0 13

event

Number of cases with medullar event 14 2 0 16

Total 34 6 0 40

About the patients who have presented a first episode evoquing a supra tentorial
lesion, or an optic one, we notice that 91% had an initial EDSS scale below 3, 9% had
their EDSS located between 3 and 6, none of them was above 6 at diagnosis onset of
multiple sclerosis

41
 For whom with an initial supra tentorial event, 77% had an EDSS lower than 3,
23% between 3 and 6.

At last, for the patients with a first clinical medullary event 87.5% had an initial
EDSS below 3, 12.5% only had an EDSS between 3 and 6.

In these three groups the highest EDSS scale encountered was 04.

42
 C. Biological profile :
 CSF Tests results and analysis:
Table 11 : Distribution of MS cases according to the CSF test results and analysis

CSF test results Presence of Absence of Unavailable Total

oligoclonal bands oligoclonal bands results

Number of cases 32 4 4 40

Percentage (%) 80,0 10,0 10,0 100,0

CSF immunological tests

35
30
25
20
15 Number of cases
10
5
0
Presence of Absence of Unavailable
oligoclonal oligoclonal results
bands bands

Figure 19 : CSF test results in MS patients

The results of CSF tests were found in 90% of patients, in 80% of cases the
immunological analysis has found intrathecal synthesis of immunoglobulins with the presence
of oligoclonal bands. For 10% (04 cases) no oligoclonal bands were found in the CSF
analysis.

43
 D. Radiological profile :

 MRI topography of lesions at onset:

Table 12 : Distribution of MS cases according to the topography of MRI demyelination lesions at
onset

Infratentorial lesions
Topography of MRI lesions Medullar lesions (cerebellum, Supratentorial
at onset brainstem) lesions

Number of cases 20 26 39

Percentage (%) 50,0 65,0 97,5

50% of patients in our serie had medullar demyelination lesions (symptomatic or not) at the
diagnosisonset of MS.

65% had infratentorial lesions (posterior cerebral fossa), and 97,5% have presented
radiological supra tentorial lesions (periventricular and juxtacortical).

Table 13 : Répartition des cas de SEP selon la topographie IRM des lésions initiales

Topography of Supra+infratentorial Medullar + Supratentorial Medullar + Medullar + Total

MRI lesions at supra and supratentorial infratentorial
onset infratentorial
Number of 13 12 7 7 1 40
cases
Percentage(%) 32,5 30,0 17,5 17,5 2,5 100,0

MRI topography of lesions

12.5%
Supra + infratentorial

Medullar + supra and

17.5% infratentorial
32.5%
Supratentorial
17.5%
Medullar + supratentorial

30.0% Medullar + infratentorial

Figure 20 : Pie chart of the different MRI topographies of lesions found in MS patients at onset

44
 In this serie, the most frequent location found was an association between infra
tentorial and supra tentorial lesions on cerebral MRI (32.5% of cases), followed by the
association of the both cited above (supra and infra tentorial) with medullary lesions in
30% of cases.

Only one case was found of medullary lesions with infratentorial ones (without a
cerebral topography).

The exclusive supra tentorial involvement was noticed in 17.5% of cases (in 07
patients).

 Size of MRI lesions:

Table 14 : Distribution of MS cases according to size of MRI lesions

Size Infracentimetric Supracentimetric Total

Number of cases 35 5 40

Percentage (%) 87,5 12,5 100,0

Size of MRI lesions

40
35
30
25
20
Number of cases
15
10
5
0
Infracentimetric Supracentimetric

Figure 21 : Size of MRI lesions in patients with MS

In our study, the size of MRI demyelinating lesions wasn’t exceeding 01 cm

(infracentimetric lesions) for 35 patients (85.7%) and only 12.5% (5 patients) had
lesions exceeding 01 cm (up to 1.7 cm).

45
  Number of MRI lesions :

Table 15 : Representation of MS cases according to the number of demyelination lesions found

in MRI at onset

Number of lesions Inferior to 3 3 to 9 Superior to 9 Total

Number of cases 0 15 25 40

Percentage (%) 0,0 37,5 62,5 100,0

Number of demyelinating lesions

37.5%
Inferior to 3
62,50%
3 to 9
Superior to 9

Figure 22 : Graphical representation of the number of lesions found in MRI

In 62.5% cases of this study, cerebral /medullary MRI done for these patients
during the diagnosis onset of MS has found more than 09 demyelinating lesions,
37.5% of them (25 cases) had 3 to 6 lesions. None of them had less than 03 lesions.

 Existence of gadolinium-enhanced T1 lesions :

Table 16 : MS cases according to existence/absence of gadolinium enhanced lesions

GADO enhanced lesions + - Total

Number of cases 17 23 40

Percentage (%) 42,5 57,5 100,0

46
 Gadolinium enhanced lesions
25

20

15

Number of cases
10

0
+ -

Figure 23 : Existence/absence of T1 Gadolinium enhanced lesions in patients with MS

The existance of active lesions on cerebral /medullary T1 MRI (showed by

enhancing-gadolinium T1) was found in 17 patients, in 57.5% of cases there was no
enhanced-godolinium lesions (meaning that lesions found at diagnosis onset were not
active).

 The existence of cortical atrophy :

Table 17 : Distribution of MS cases depending on presence/absence of cortical atrophy in MRI

Presence/absence of cortical atrophy + - Total

Number of cases 5 35 40

Percentage (%) 12,5 87,5 100,0

47
 Cortical atrophy in MRI

12,50%

Presence of cortical
atrophy
Absence of cortical atrophy

87,50%

Figure 24 : Presence or absence of cortical atrophy in patients with MS

Cortical atrophy was only found in 12.5% of cases (05 cases/40), associated with
an older age (42, 64, 71 years), however we found the presence of cortical atrophy in
one patient aged of 29.

87.5% of patients hadn’t cortical atrophy at the diagnosis of multiple sclerosis.

48
 E. Evolutive profile:
 Type of long-term therapy :
Table 18 : Distribution of patients with MS according to the type of long-terme therapy received
initially

Type of long term therapy Imurel Rebif Avonex Tysabri Total

(initially)
Number of cases 2 24 13 1 40

Percentage (%) 5,0 60,0 32,5 2,5 100,0

Long term therapies 5%

2.5%

Imurel
32.5% Rebif
Avonex
60.0% Tysabri

Figure 25 : Different types of long term treatments received by patients with MS

92.5% of patients had received Interferon-beta-1a (60% treated by Rebif and

32.5% treated by Avonex).

Only 02 patients were initially treated with immunosuppressors: Azathioprin

(Imurel) and one patient in this serie has received a monoclonal antiboby initially:
Natalizumab (Tysabri).

It is to be noticed that the treatment was modified for 10 patients during these 05
years of evolution, 05 of them received Natalizumab,3 were treated by Rituximab , one
with Mycophenolate Mofetil (Cellcept) and the last one with azathioprin( imurel)

49
  Type of DMT instaured according to the clinical type:
Table 19 : Distribution of cases of MS according to the type of long term treatment and the type
of initial clinical event

Long-term treatment Imurel Rebif Avonex Tysabri Total

Supratentorial/optic event 1 7 3 0 11

Infratentorial event 0 9 3 1 13

Medullar event 1 8 7 0 16

Total 2 24 13 1 40

We notice that independently from initial clincal event (supratentorial, optic,

medullary or infratentorial), the most used long-term first line therapy in our serie is
Rebif ®.

We notice also that for 44% of patients with initial medullary involvement , a
long-term treatment by Avonex® was used , however it was used only for 27% and
23% of patients with other locations (supra and infra tentorial respectively)

Treatment by Tysabri was initially given to one patient , with initial infra
tentorial involvement .

 Interval for DMT initiation:

Table 20 : Interval for DMT initiation in patients with MS

Interval for DMT [0-2[ [2-4[ [4-6[ [6-8[ [8-10[ [10-12[ 12 ou Total
initiation (months) more

Number of cases 4 9 7 7 0 5 8 40
Percentage (%) 10,0 22,5 17,5 17,5 0,0 12,5 20,0 100,0

50
 Interval of DMT initiation
9
8
7
6
5
4 Number of cases
3
2
1
0
[0-2[ [2-4[ [4-6[ [6-8[ [8-10[ [10-12[ 12 or
more

Figure 26 : Interval of DMT initiation in patients with MS

In 40 patients diagnosed with multiple sclerosis included in our study, the

middle term for long-term therapy initiation is 07 months and 15 days.

22.5% of patients have received their long-term treatment between 2 and 4

months after the diagnosis of the disease, 20% of them have received it after 12
months (until 36 months) of the diagnosis of MS.

4 patients have received their long-term treatment just after 2 months from the
diagnosis onset.

 Number of relapses during 05 years of disease evolution (number of

corticosteroid therapies instaured at every relapse) :
Table 21 : Distribution of MS cases according to the number of corticosteroid therapies
instaured in 05 years

Nombre of corticosteroid 0 [1-3[ [3-5[ 5 or more Total

therapies
Number of cases 2 20 15 3 40

Percentage (%) 5,0 50,0 37,5 7,5 100,0

51
 Number of corticoisteroid therapies
25

20

15

Number of cases
10

0
0 [1-3[ [3-5[ 5 or more

Figure 27: Number of corticosteroid therapies received by patients with MS in 05 years of

disease evolution

The most representative number of relapses (number of corticosteroid therapies)

in this serie is 3.50% of our patients have received 1 to 2 corticosteriod therapies
during 05 years of disease evolution, 02 of them didn’t receive any corticosteroid
pulse after the diagnosis, and 05 have received more than 05 pulses (until 9 pulses)

 Number of corticosteriod pulses received during 05 years of disease

evolution related to the initial clinical type event :
Table 22 : Distribution of MS cases according to the numbre of corticosteroid therapies received
in 05 years and the initial clinical type event

Number of pulses Inferior to 3 3 to 5 Superior to Total

5
Supratentorial/optic event 7 2 2 11

Infratentorial event 7 6 0 13

Medullar event 8 7 1 16

Total 22 15 3 40

43.7% of patients with medullary lesions have received between 3 and 5 corticosteriod
pulses (3-5 relapses) during 05 years of disease evolution, 50% of them have presented less
than 06 relapses, however onr patient have presented more than 05 relapses.

In patients with supra tentorial lesions, 63.6% of them have just presented 02 relapses
(or none) during these 05 years of disease evolution.

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  EDSS scale after 05 years of MS diagnosis :

Table 23 : Distribution of MS cases according to the EDSS score 05 years after diagnosis onset

EDSS scale Inferior to 3 to 6 Superior to 6 Total

3
Number of 21 17 2 40
cases
Percentage (%) 52,5 42,5 5,0 100,0

EDSS scale 05 years after diagnosis

onset
25

20

15
Number of cases
10

0
Inferior to 3 3 to 6 Superior to 6

Figure 28 : EDSS scale in patients with MS 05 years after diagnosis onset

05 years after the diagnosis, 52.5% of patients in our serie have an EDSS lower
than 3, 42.5% with an EDSS between 3 and 6, 5% have more than 6.

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  Relationship between the initial clinical event and the EDSS scale after 05
years of disease evolution :
Table 24 : Distribution of MS cases according to the initial clinical event and the EDSS scale
after 05 years of disease evolution

EDSS Scale Inferior to 3 3 to 6 Superior to 6 Total

Supratentorial/optic 10 1 0 11
event

Infratentorial event 6 7 0 13

Medullar event 5 9 2 16

Total 21 17 2 40

An EDSS scale lower than 3 was found after 05 years of disease evolution in 21
cases ( 52.5%), in this population 47.6% have presented initially a supra tentorial or
optic clinical event, 28% an infra tentorial event and 23.6% a medullary clinical event

An EDSS scale ranged between 3 and 6 was found in 17 patients, 52.9 and
41.2% presented a medullary and infra tentorial lesions respectively, and only one case
had a supra tentorial lesion.

An EDSS below 6 was found in 02 patients diagnosed with MS with initial

clinical medullary event, none of them have an initial supra or infra tentorial clinical
event .

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  Relationship between EDSS scale 05 years after disease evolution and
topography of MRI lesions at diagnosis onset:

Table 25 : Distribution of MS cases according to EDSS scale 05 years after diagnosis and initial
MRI topography of lesion

EDSS Scale Inferior to 3 3 to 6 Superior to 6 Total

With Medullar MRI lesions 10 8 2 20

Without Medullar MRI lesions 12 8 0 20

Total 22 16 2 40

Table 26 : Representation of EDSS statistical modes (initial and actual) according to the initial
topography of MRI multiple sclerosis lesions

With Medullar lesions With supra/infratentorial

Topography lesions

Initial EDSS mode 1 1

05 years EDSS mode 3 1

The two tables above show that EDSS scale after 05 years of disease evolution is
higher in patients who had medullary demyelinating lesions on T2 at the diagnosis
onset (50% of these cases have an EDSS of 3 or more, comparing to 40% with no
medullary lesions on MRI)

The mode of EDSS 05 years after disease evolution is the highest (03) in patients
with initially medullary lesions comparing with the others.

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 6. Discussion :
In this studied population, composed of 40 cases diagnosed with multiple
sclerosis in neurology unit at Tizi Ouzou’s hospital center(Balloua unit), during the
time period ranging from February 2013 anf February 2014, we have gathered the
following findings:

- About the epidemiological profile :

The average age of MS diagnosis in this population is 35.85years, more than the
half of these patients were diagnosed between 16 and 36 years, these results agree
fully with what have been said in literature, MS is a disease affecting mostly young
people, and the diagnosis is generally made between 29 and 36 years.

In our serie MS is diagnosed predominantly in women with 65%, comparing to

35% for men, this confirms that multiple sclerosis is affecting more women than men.

90% of these patients use their right hands and 10% the left ones.

About the clinical profile:

In this serie the predominant initial symptoms of multiple sclerosis is the

pyramidal syndrome with 57.5% of cases,represented mainly by motor deficiency,
followed up with cerebellar syndrome, this confirms also what is said in literature
about the predominance of pyramidal syndrome in multiple sclerosis.

85% of our patients had initially an EDSS scale lower than 3, and 15% between 3
and 6.

For the biological profile:

In 80% of cases CSF test has found an intrathecal synthesis of immunoglobulins

with oligoclonal bands.

For the radiological profile:

Demyeliniting medullary lesions were observed in 50% cases, assotiated in most

cases with supra and infra tentorial lesions (32.5%).

87.5% of patients had more than 9 infracentimetric demyelinating lesions on

MRI, in 42.5% of cases gadolinium-enhancing T1 was observed.

Cortical atrophy was initially found in just 12.5% of patients.

About the evolutive profile :

56
 92.5% of our patients were initially treated by interferon beta-1a (60% by Rebif
and 32.5 % by Avonex), patients with initially medullary lesions were treated by
Avonex comaring to oher categories of patients.

The average duration for Starting the long-term therapy was 7months and 15
days.

After 05 years of disease evolution,the patients who presented initially a

medullary event or infra tentorial one have highest EDSS scale comparing to those
with an initial supra tentorial or optic event.

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 CONCLUSION
Multiple sclerosis is the most common neurological disease causing an
irreversible neurological disability in young adults. Recognized as a chronic
inflammatory disease of the central nervous system (CNS) causing demyelination and
axonal loss, it is characterized by a variable clinical course, heterogeneous and
complex pathology and pathogenesis.

Current diagnostic criteria for multiple sclerosis integrate clinical and MRI
findings and enable an earlier and more reliable diagnosis than with clinical findings
alone, and lead to a better and ealier management of the disease.

The initial locations of MS lesions can predict the prognosis of disease, like
shown in this study (link between initial medullary events and higher EDSS scale
years after evolution).

The choice of long -term thrapy is important for the evolution of this pathology
and if is correctly choosen and administered at the beginning of the disease, this will
lead to better evolution of the patients with multiple sclerosis.

58
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