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GENERAL PART

INTRODUCTION
Demyelinating diseases, though well-known phenomena in the
medical milieu are still subject to a lot of research. Due to their
varied prevalence among various units of a populace, and
within sub-units of any given population, with sub-types
affecting people of different ages, races, and both genders,
demyelinating diseases remain a relevant topic of research and
study.
This paper shall attempt to discuss the medical imaging of
such disorders, with eventual emphasis on multiple sclerosis, it
being the most common autoimmune disorder of the central
nervous system.
Emphasis will obviously be put upon the incidence and
imaging thereof, among patients in Constanta, Romania.

CHAPTER 1
1.1 Definition
A demyelinating disease is any disease affecting the
central nervous system, which results in damage to the myelin
sheath of neurons. This damage impairs the conduction of
signals in the affected nerves. In turn, the reduction in
conduction ability causes deficiency in sensation, movement,
cognition, or other functions depending on which nerves are
involved (1).
Some demyelinating diseases are caused by genetics, some
by infectious agents, others by autoimmune reactions, and a
few by unknown factors and agents. Organophosphates, a class
of chemicals which are the active ingredients in commercial
insecticides such as sheep dip, weed-killers, and flea treatment
preparations for pets, etc., will also demyelinate nerves.
Neuroleptics can also cause demyelination(2).
Lysophosphatidylcholine causes demyelination and is in
unnaturally high amounts in foods with lecithin treated with the
enzyme phospholipase (enzyme-modified foods) and as
lysolecithin in products such as make up and personal care
products.

1.2 Classification
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Demyelinating diseases are traditionally classified in two


kinds: demyelinating myelinoclastic diseases and
demyelinating leukodystrophic diseases. In the first group a
normal and healthy myelin is destroyed by a toxic, chemical or
autoimmune substance. In the second group, myelin is
abnormal and degenerates. The second group was termed
denominated demyelinating diseases according to the Poser
criteria.

1.3 Pathophysiology
In the most known example, Multiple Sclerosis (MS), there
is good evidence that the body's own immune system is at
least partially responsible. Acquired immune system cells called
T-cells are known to be present at the site of lesions. Other
immune system cells called Macrophages (and possibly Mast
cells as well) also contribute to the damage.
Some demyelinating diseases are caused by genetics, some
by infectious agents, some by autoimmune reactions, some by
exposure to chemical agents, and some by unknown factors.
The role of prolonged cortical myelination in human evolution
has been implicated as a contributing factor in some cases of
demyelinating disease. Unlike other primates, humans exhibit a
unique pattern of post pubertal myelination, which may
contribute to the development of psychiatric disorders and
neurodegenerative diseases that present in early adulthood
and beyond. The extended period of cortical myelination in
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humans may allow greater opportunity for disruption in


myelination, resulting in the onset of demyelinating disease.
Furthermore, it has been noted that humans have significantly
greater prefrontal white matter volume than other primate
species, which implies greater myelin density. Increased myelin
density in humans as a result of a prolonged myelination may
therefore structure risk for myelin degeneration and
dysfunction.
Evolutionary considerations for the role of prolonged cortical
myelination as a risk factor for demyelinating disease are
particularly pertinent given that genetics and autoimmune
deficiency hypotheses fail to explain many cases of
demyelinating disease. As has been argued, diseases such as
multiple sclerosis cannot be accounted for by autoimmune
deficiency alone, but strongly imply the influence of flawed
developmental processes in disease pathogenesis.
Therefore, the role of the human-specific prolonged period of
cortical myelination is an important evolutionary consideration
in the pathogenesis of demyelinating disease.

1.4 Incidence of Demyelinating Diseases


This varies from disorder to disorder. Some conditions, such as
Tabes Dorsalis appear predominantly in males and begin in
mid-life. Optic neuritis on the other hand, occurs preferentially
in females typically between the ages of 30 and 35. Other
conditions such as multiple sclerosis vary in prevalence
depending on the country and population. This condition can
appear in children as well as adults.
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Demyelinating diseases can be divided in those affecting the


central nervous system and those presents in the peripheral
nervous system, presenting different demyelination conditions.

1.5 Symptoms
That present in demyelinating diseases are different for each
condition. Below is a list of symptoms that can present in a
person with a demyelinating disease:

Blurred double vision

Ataxia

Clonus

Dysarthria

Fatigue

Clumsiness

Hand paralysis

Hemiparesis

Genital anaesthesia

Incoordination

Paraesthesia

Ocular paralysis

Impaired muscle coordination

Weakness (muscle)

Loss of sensation

Impaired vision

Neurological symptoms

Unsteady gait

Spasticity

Incontinence

Hearing problems

Speech problems

1.6 Diagnostic Methods


Exclusion of other conditions that have overlapping symptoms
is important, seeing as a number of conditions could mimic
various demyelinating disorders.
Below are various methods/techniques used to diagnose
demyelinating diseases:
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Magnetic Resonance Imaging (MRI) is a medical imaging


technique used in radiology to visualize internal structures of
the body in detail. MRI makes use of the property of nuclear
magnetic resonance (NMR) to image nuclei of atoms inside the
body.

1.7 Laboratory Markers


A test that is sometimes used to confirm or rule out a
diagnosis of MS is a lumbar puncture. A lumbar puncture
involves removing and analysing a sample of cerebrospinal fluid
(CSF), the fluid that surrounds the brain and spinal cord within
the skull and backbone. Specific markers in the cerebrospinal
fluid can indicate MS activity. Studies have investigated
whether analysis of cerebrospinal fluid can help predict the
likelihood of developing MS after a clinically isolated syndrome.
One of these studies was based on the data of 40 people who
presented with a clinically isolated syndrome and underwent
MRI scanning and cerebrospinal fluid analysis within the
following two months. Of the15 people who subsequently
developed MS, 14 had abnormalities on MRI and 13 tested
positive for markers of disease activity in their cerebrospinal
fluid. The risk of developing MS was significantly higher in
people who tested positive in cerebrospinal fluid analysis and
had abnormalities on their first MRI scan compared to people
who were negative for both or one of the tests. However,
because it is less useful as a predictive tool than MRI, a lumbar
puncture is not routinely recommended in cases of clinically
isolated syndrome.
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To evaluate for the potential for other conditions, it would be


appropriate to consider several blood tests in the initial
evaluation of the patient with suspected MS. As mentioned
earlier, these tests include; complete blood count (CBC),
antinuclear antibodies (ANA), serum test for syphilis (RPR,
VDRL, etc.).
There may also be an increase in CSF myelin basic protein
levels, which is evidence of actual damage to myelin. Evidence
of subclinical demyelinated lesions can be provided by MRI,
visual, somatosensory, or brain stem auditory evoked
responses.
Evoked potential is an electrical potential recorded from the
nervous system following the presentation of a stimulus as
detected by electroencephalography (EEG), electromyography
(EMG), or other electrophysiological recording method.
Cerebrospinal fluid analysis (CSF) can be extremely beneficial
in the diagnosis of central nervous system infections. A CSF
Culture examination may yield the Microorganism that caused
the infection.
However, the medical imaging of demyelinating diseases, with
emphasis on multiple sclerosis in the area of Constanta,
Romania, shall now be stressed upon.

1.8 The Role of MRI in MS


Magnetic resonance imaging (MRI) has been shown to be
highly sensitive in detecting clinically silent MS plaques.
Consequently, findings of this imaging modality are included in
diagnostic criteria that have been proposed by one set of
investigators.
The major advantage of the proposed criteria is that an early
diagnosis of MS can be made if an MRI scan performed three
months after a clinically isolated attack demonstrates formation
of a new lesion. The proposed diagnostic criteria also define
MRI lesion characteristics that increase the likelihood of MS,
including number of lesions (nine or more), location of lesions
(position abutting the ventricles; juxtacortical, infratentorial, or
spinal position), and lesion enhancement with the use of
contrast medium.
As observed in various patients, MRI lesion characteristics
suggestive of Multiple Sclerosis, once again include:
- Brain lesions
- High signal on T2-weighted and FLAIR MRI sequences
(more than nine lesions)
- When actively inflammed, often enhanced with
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gadolinium contrast
Position abutting ventricles (often perpendicular)
Juxtacortical position (gray-white junction)
Involvement of brainstem, cerebellum, or corpus callosum
Spinal cord lesions
One or two vertebral segments in length

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- Incomplete cross-sectional involvement (dorsolateral


common)
- Less likely to enhance with gadolinium contrast
- No cord swelling
- Better seen with STIR MRI sequences.
A brain MRI scan is indeed the most useful test for confirming
the diagnosis of MS. MS lesions appear as areas of high signal,
predominantly in the cerebral white matter or spinal cord, on
T2-weighted images.
MRI scanning is useful for detecting structural pathology in
regions that can be difficult to image by computed tomography,
such as the posterior fossa, craniocervical junction, and cervical
cord.2 A brain MRI scan performed with a high-field magnet
(1.5 tesla or greater) is abnormal in almost all patients who
have clinically definite MS.
Fluid attenuation inversion recovery (FLAIR) sequence image
of certain transverse sections from the brain of patients with
multiple sclerosis (MS). Certain images showed multiple highsignal periventricular and white-matter lesions. Although the
FLAIR sequence is the most sensitive sequence for detecting
MS lesions, it is not specific for demyelination.
In MRI scans of the spinal cord in certain patients with MS,
sagittal images using the Short Tau Inversion Recovery (STIR)
protocol tend to reveal multiple high-signal lesions within the
spinal cord, consistent with demyelination. These lesions, which
also can be seen on the transverse cuts, often are situated
dorsolaterally, and are usually less than one vertebral body in
length. The lesions rarely cause cord swelling.
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As we therefore see from all the above, widespread use of MRI


has indeed revolutionized the ability to diagnose multiple
sclerosis. Disease-related changes in the brain or spinal cord
are detected by MRI in more than 90% of people suspected of
having MS.

Advantages And Disadvantages of MRI Usage


Reasons why MRI is best for this include the facts that MRI can
often detect damaged areas in the brain or spinal cord that
would be missed by other imaging techniques such as a CAT
scan, MRI is considered the best test to help diagnose MS.
However, 5% of people with MS do not have abnormalities
detected on MRI; thus, a "negative" scan does not completely
rule out MS. In addition, some common changes of aging may
look like MS on a MRI.
Although they aren't widely needed, people with MS may get
repeat scans to determine the status of their disease and how
well their medications are working.
The MRI exam poses no risk to the average person if
appropriate safety guidelines are followed. Many people who
have had heart surgery and people with the following medical
devices can be safely examined with MRI (the metals used in
these surgeries are not "magnetic" and the person can be
safely placed in the MRI machine:

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Artificial joints
Staples
Many cardiac valve replacements (check with physician)
Disconnected medication pumps
Vena cava filters
Brain shunt tubes for hydrocephalus

Some conditions may make an MRI exam a bad idea.


Consultation with the doctor in charge is necessary with the
following situations/conditions:
- Heart pacemaker
- Cerebral aneurysm clip (metal clip on a blood vessel in the
brain)
- Implanted insulin pump (for treatment of diabetes),
narcotics pump (for pain medication), or implanted spinal
cord stimulators for chronic pain
- Metal in the eye or eye socket
- Cochlear (ear) implant for hearing impairment
- Implanted spine stabilization rods (newer titanium rods
and plates are fine)
- Severe lung disease (such as tracheomalacia or
bronchopulmonary dysplasia)
- Heartburn
- Obesity (weighing more than 300 pounds (approx. 130
Kg) may limit which machine can be used)
- Not able to lie on your back for 30 to 60 minutes
- Claustrophobia (which can be handled with sedation)
Certain possible risks worth discussing include the
following:

Projectile risk
The extremely high strength of the magnetic field can
cause projectile effect (or "missile-effect") accidents. This

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is when ferromagnetic objects are attracted to the center


of the magnet (3).

Heating caused by absorption of waves


An MRI scanner has a powerful radio transmitter to
generate the electromagnetic field which excites the
spins. When the body absorbs the energy, heating occurs.
For this reason, the transmitter rate at which energy is
absorbed by the body has to be controlled and limited,
lest it results in potential burns (4).

Peripheral nerve stimulation (PNS)


The rapid switching on and off of the magnetic field
gradients is capable of causing nerve stimulation,
particularly in the extremities (5) .The reason the
peripheral nerves are stimulated is that the changing field
increases with distance from the center of the gradient
coils (which more or less coincides with the center of the
magnet). Although PNS was not a problem for the slow,
weak gradients used in the early days of MRI, the strong,
rapidly switched gradients used in techniques such as EPI,
fMRI, diffusion MRI, etc. are capable of inducing PNS.
Cryogens
The Physics of Magnetic Resonance Imaging, describes
many MRI scanners as relying on cryogenic liquids to
enable the superconducting capabilities of the
electromagnetic coils within. Though the cryogenic liquids
used are non-toxic, their physical properties present
specific hazards.
An unintentional shut-down of a superconducting
electromagnet, an event known as "quench", involves the
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rapid boiling of liquid helium from the device. If the rapidly


expanding helium cannot be dissipated through an
external vent, it may be released into the scanner room
where it may cause displacement of the oxygen and
present a risk of asphyxiation (6).

Pregnancy
No effects of MRI on the foetus have been proven. MRI
avoids the use of ionizing radiation, to which the foetus is
particularly sensitive. However, as a precaution, current
guidelines recommend that pregnant women undergo MRI
only when essential. This is particularly the case during
the first trimester of pregnancy, as organogenesis takes
place during this period. The concerns in pregnancy are
the same as for MRI in general, but the foetus may be
more sensitive to the effectsparticularly to heating and
to noise.
Despite these concerns, MRI is rapidly growing in
importance as a way of diagnosing and monitoring
congenital defects of the foetus because it can provide
more diagnostic information than ultrasound and it lacks
the ionizing radiation of CT (7).

MRI vs CT
MRI and computed tomography (CT) are complementary
imaging technologies and each has advantages and
limitations for particular applications. A concern is the
potential for CT to contribute to radiation-induced cancer
and in 2007 it was estimated that 0.4% of current cancers
in the United States were due to CTs performed in the

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past, and that in the future this figure may rise to 1.52%
based on historical rates of CT usage.
An advantage of MRI is that no ionizing radiation is used
and so it is recommended over CT when either approach
could yield the same diagnostic information.
However, though MRI cost has fallen, thus making it
more competitive with CT, there are not many common
imaging scenarios in which MRI can simply replace CT,
although this substitution has been suggested for the
imaging of hepatic disorders.
The effect of low doses of radiation on carcinogenesis is
also disputed. Although MRI is associated with certain
biological effects, these have not been proven to cause
significant and measurable harm (8).
Regardless of the benefts of CT, let us note that it has no
bearing upon the diagnosis of MS.
MRI remains the absolute imaging method for the positive
diagnosis of the disease.

Practical Guidelines
Simple practical guidelines/applications for the MRI procedure
include:
- Allowing two hours for the MRI exam. In most cases, the
procedure takes 40 to 80 minutes; during that time,
several dozen images may be taken.
- Personal items such as watches, wallets (including credit
cards with magnetic strips that can be erased by the
magnet), and jewelery should be removed prior to the MRI
scan.

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- The patient may be advised to wear a hospital gown


during the MRI scan.
As the MRI scan begins, the patient will hear the equipment
making a variety of different sounds, including a muffled
thumping sound or banging sound that will last for several
minutes at a time. Other than that sound, one aught experience
no unusual sensations during the scanning.
Certain MRI exams require an injection of a contrast material,
as we saw from the general patients, and from the specific
patients from Constanta, Romania.
This helps identify abnormalities in certain parts of the body
on the scan images.
Quantitative proton magnetic resonance spectroscopy (MRS)
is a non-invasive analytical technique that has been used to
study metabolic changes in brain tumors, strokes, seizure
disorders, Alzheimer's disease, depression and other diseases
affecting the brain. It has also been used to study the
metabolism of other organs such as muscles.
Diagnostic Criteria refers to a specific combination of signs,
symptoms, and test results that the clinician uses in an attempt
to determine the correct diagnosis.

1.9 Treatment
Typically involves improving the patient's quality of life. This is
accomplished through the management of symptoms or
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slowing the rate of demyelination. Treatment can include


medication, lifestyle changes (i.e. quit smoking, adjusting daily
schedules to include rest periods and dietary changes),
counselling, relaxation, physical exercise, patient education
and, in some cases, deep brain thalamic stimulation (in the
case of tremors).
The progressive phase of MS appears to driven by the innate
immune system, which will directly contribute to the
neurodegenerative changes that occur in progressive MS. Until
now, there are no therapies that specifically target innate
immune cells in MS. As the role of innate immunity in MS
becomes better defined, it may be possible to better treat MS
by targeting the innate immune system. Treatments are
patient-specific and depend on the symptoms that present with
the disorder, as well as the progression of the condition.

1.9.1 Prognosis
This depends on the condition itself. Some conditions such as
multiple sclerosis depend on the subtype of the disease and
various attributes of the patient such as age, sex, initial
symptoms and the degree of disability the patient experiences.
Life expectancy in Multiple sclerosis patients is 5 to 10 years
lower than unaffected people. MS is an inflammatory
demyelinating disease of the central nervous system (CNS) that
develops in genetically susceptible individuals after exposure to
unknown environmental trigger(s).The bases for MS are

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unknown but are strongly suspected to involve immune


reactions against autoantigens, particularly myelin proteins.
The most accepted hypothesis is that dialogue between T-cell
receptors and myelin antigens leads to an immune attack on
the myelin-oligodendrocyte complex. These interactions
between active T cells and myelin antigens provoke a massive
destructive inflammatory response and promotes continuing
proliferation of T- and B-cells and macrophage activation, which
sustains secretion of inflammatory mediators.
Other conditions such as central pontine myelinolysis have
about a third of patients recover and the other two thirds
experience varying degrees of disability. There are cases, such
as transverse myelitis where the patient can begin recovery as
early as 2 to 12 weeks after the onset of the condition.

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CHAPTER 2
2.1 Various Demyelinating disorders of the
Central Nervous System
The demyelinating disorders of the CNS include:
- Myelinoclastic disorders, in which myelin is attacked by
external substances.
- Standard Multiple sclerosis, Devic's disease and other
disorders with immune system involvement called
inflammatory demyelinating diseases.
- Leukodystrophic disorders, in which myelin is not properly
produced:
- CNS Neuropathies like those produced by Vitamin B12
deficiency.
- Central pontine myelinolysis.
- Myelopathies like Tabes dorsalis (syphilitic Myelopathy).
- Leukoencephalopathies like Progressive multifocal
leukoencephalopathy.
- Leukodystrophies.
These disorders are normally associated also with the
conditions Optic neuritis and Transverse myelitis, which are
inflammatory conditions, because inflammation and
demyelination are frequently associated. Some of them are

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idiopatic and for some others the cause has been found, like
some cases of neuromyelitis optica.

2.2 Various Demyelinating diseases of the Peripheral


Nervous System
The demyelinating diseases of the peripheral nervous system
include:
- Guillain-Barr syndrome, and its chronic counterpart,
chronic inflammatory demyelinating polyneuropathy.
- Anti-MAG peripheral neuropathy.
- Charcot-Marie-Tooth Disease.
- Copper deficiency associated conditions (peripheral
neuropathy, myelopathy, and rarely optic neuropathy.
- Progressive inflammatory neuropathy.

2.3 Worldwide Research


Research is being conducted in a variety of very specific
areas. The focus of this research is aimed at gaining more
insight into how demyelinating disorders affect the central
nervous system and peripheral nervous system, how they
develop and how these disorders are affected by various
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external inputs. Much of the research is targeted towards


learning about the mechanisms by which these disorders
function in an attempt to develop therapies and treatments for
individuals affected by these conditions.
Currently it is believed that N-cadherin plays a role in the
myelination process. Experimentation has shown that Ncadherin plays an important role in producing a remyelinationfacilitating environment. It has been shown in animal models
that there is a direct correlation between the amount of myelin
debris present and the degree of Inflammation observed.
Experimentation has shown that manipulating the levels of
thyroid hormone can be considered as a strategy to promote
remyelination and prevent irreversible damage in Multiple
sclerosis patients. N-cadherin agonists have been identified and
observed to stimulate neurite growth and cell migration, key
aspects of promoting axon growth and remyelination after
injury or disease. It has been shown that intranasal
administration of aTf (apotransferrin) can protect myelin and
induce remyelination (9).
Demyelinating diseases/disorders have been found worldwide
in various animals. Some of these animals include mice, pigs,
cattle, hamsters, rats, sheep, Siamese kittens, and a number of
dog breeds (including Chow Chow, Springer Spaniel, Dalmatian,
Samoyed, Golden Retriever, Lurcher, Bernese Mountain Dog,
Vizsla, Weimaraner, Australian Silky Terrier, and mixed breeds).
Another notable animal found able to contract a
demyelinating disease is the Northern Fur Seal. Ziggy Star, a
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Northern Fur Seal, has been a patient at The Marine Mammal


Center for the past several months and has been noted as the
first case of such disease in a marine mammal. She will be
transported to Mystic Aquarium & Institute for Exploration for
lifelong care as an ambassador to the public (10).

CHAPTER 3
3.1 Definition of Multiple Sclerosis
Multiple sclerosis (MS), also known as disseminated
sclerosis or encephalomyelitis disseminata, is an
inflammatory disease in which the insulating covers of nerve
cells in the brain and spinal cord are damaged. This damage
disrupts the ability of parts of the nervous system to
communicate, resulting in a wide range of signs and symptoms,
including physical, mental, and sometimes psychiatric
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problems. MS takes several forms, with new symptoms either


occurring in isolated attacks (relapsing forms) or building up
over time (progressive forms). Between attacks, symptoms may
disappear completely; however, permanent neurological
problems often occur, especially as the disease advances (11).

Fig.1 Sagittal View of MS patient, T2-Scan. Note sclerae around


the Corpus Callosum (Arrows).

3.2 Causes Of Multiple Sclerosis


While the cause is not clear, the underlying mechanism is
thought to be either destruction by the immune system or
failure of the myelin-producing cells. Proposed causes for this
include genetics and environmental factors such as infections.
MS is usually diagnosed based on the presenting signs and
symptoms and the results of supporting medical tests (12).
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There is no known cure for multiple sclerosis. Treatments


attempt to improve function after an attack and prevent new
attacks. Medications used to treat MS while modestly effective
can have adverse effects and be poorly tolerated. Many people
pursue alternative treatments, despite a lack of evidence. The
long-term outcome is difficult to predict, with good outcomes
more often seen in women, those who develop the disease
early in life, those with a relapsing course, and those who
initially experienced few attacks. Life expectancy is on average
5 to 10 years lower than that of an unaffected population.
Multiple sclerosis is the most common autoimmune disorder
affecting the central nervous system. As of 2008, between 2
and 2.5 million people are affected globally with rates varying
widely in different regions of the world and among different
populations. In 2013, 20,000 people died from MS, up from
12,000 in 1990. The disease usually begins between the ages
of 20 and 50 and is twice as common in women as in men. The
name multiple sclerosis refers to scars (scleraebetter known
as plaques or lesions) in particular in the white matter of the
brain and spinal cord. MS was first described in 1868 by JeanMartin Charcot. A number of new treatments and diagnostic
methods are under development.

3.3 Pathophysiology

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The three main characteristics of MS are the formation of


lesions in the central nervous system (also called plaques),
inflammation, and the destruction of myelin sheaths of
neurons. These features interact in a complex and not yet fully
understood manner to produce the breakdown of nerve tissue
and in turn the signs and symptoms of the disease.
Additionally, MS is believed to be an immune-mediated disorder
that develops from an interaction of the individual's genetics
and as yet unidentified environmental causes. Damage is
believed to be caused, at least in part, by attack on the nervous
system by a person's own immune system.

Fig. 2 Spine of MS patient. Note the inflammatory plaques


along the spinal cord.
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The name multiple sclerosis refers to the scars (sclerae


better known as plaques or lesions) that form in the nervous
system. These lesions most commonly affect the white matter
in the optic nerve, brain stem, basal ganglia, and spinal cord, or
white matter tracts close to the lateral ventricles.The function
of white matter cells is to carry signals between grey matter
areas, where the processing is done, and the rest of the body.
The peripheral nervous system is rarely involved.
To be specific, MS involves the loss of oligodendrocytes, the
cells responsible for creating and maintaining a fatty layer
known as the myelin sheathwhich helps the neurons carry
electrical signals (action potentials).This results in a thinning or
complete loss of myelin and, as the disease advances, the
breakdown of the axons of neurons. When the myelin is lost, a
neuron can no longer effectively conduct electrical signals.
A repair process, called remyelination, takes place in early
phases of the disease, but the oligodendrocytes are unable to
completely rebuild the cell's myelin sheath. Repeated attacks
lead to successively less effective remyelinations, until a scarlike plaque is built up around the damaged axons. These scars
are the origin of the symptoms and during an attack magnetic
resonance imaging (MRI) often shows more than ten new
plaques. This could indicate that there are a number of lesions
below which the brain is capable of repairing itself without
producing noticeable consequences.

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Fig. 3 Remyelination process, histopathological overview.

Another process involved in the creation of lesions is an


abnormal increase in the number of astrocytes due to the
destruction of nearby neurons. A number of lesion patterns
have been described.
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Apart from demyelination, the other sign of the disease is


inflammation. Fitting with an immunological explanation, the
inflammatory process is caused by T-cells, a kind of lymphocyte
that plays an important role in the body's defences. T- cells gain
entry into the brain via disruptions in the bloodbrain barrier.
The T-cells recognize myelin as foreign and attack it, explaining
why these cells are also called "autoreactive lymphocytes".
The attack of myelin starts inflammatory processes, which
triggers other immune cells and the release of soluble factors
like cytokines and antibodies. Further breakdown of the blood
brain barrier, in turn cause a number of other damaging effects
such as swelling, activation of macrophages, and more
activation of cytokines and other destructive proteins.
Inflammation can potentially reduce transmission of
information between neurons in at least three ways. The
soluble factors released might stop neurotransmission by intact
neurons. These factors could lead to or enhance the loss of
myelin, or they may cause the axon to break down completely.
The bloodbrain barrier is a part of the capillary system that
prevents the entry of T cells into the central nervous system. It
may become permeable to these types of cells secondary to an
infection by a virus or bacteria. After it repairs itself, typically
once the infection has cleared, T cells may remain trapped
inside the brain. Gadolinium cannot cross a normal BBB and,
therefore, Gadolinium-enhanced MRI is used to show BBB
breakdowns.

3.4 Epidemiology
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Prevalence wise, MS is more common in people who live


farther from the equator, although exceptions exist. These
exceptions include ethnic groups that are at low risk far from
the equator such as the Samis, Amerindians, Canadian
Hutterites, New Zealand Mori, and Canadas Inuit, as well as
groups that have a relatively high risk close to the equator such
as Sardinians, inland Sicilians, Palestinians and Parsis. The
cause of this geographical pattern is not clear. While the northsouth gradient of incidence is decreasing, as of 2010 it is still
present.
MS is more common in regions with northern European
populations and the geographic variation may simply reflect
the global distribution of these high-risk populations. Decreased
sunlight exposure resulting in decreased vitamin D production
has also been put forward as an explanation. A relationship
between season of birth and MS lends support to this idea, with
fewer people born in the northern hemisphere in November as
compared to May being affected later in life. Environmental
factors may play a role during childhood, with several studies
finding that people who move to a different region of the world
before the age of 15 acquire the new regions risk to MS. If
migration takes place after age 15, however, the person retains
the risk of his home country. There is some evidence that the
effect of moving may still apply to people older than 15.

3.5 Risk Factors


a) Genetic

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MS is not considered a hereditary disease; however, a number


of genetic variations have been shown to increase the risk. The
probability is higher in relatives of an affected person, with a
greater risk among those more closely related. In identical
twins both are affected about 30% of the time, while around 5%
for non-identical twins and 2.5% of siblings are affected with a
lower percentage of half-siblings. If both parents are affected
the risk in their children is 10 times that of the general
population. MS is also more common in some ethnic groups
than others.

b) Pathogenic
Many pathogens, infectious agents and microbes have been
proposed as triggers of MS, but none have been confirmed.
Evidence for a virus as a cause include: the presence of
oligoclonal bands in the brain and cerebrospinal fluid of most
people with MS, the association of several viruses with human
demyelination encephalomyelitis, and the occurrence of
demyelination in animals caused by some viral infection.
Human herpes viruses are a candidate group of viruses.
Individuals having never been infected by the Epstein-Barr virus
are at a reduced risk of getting MS, whereas those infected as
young adults are at a greater risk than those having had it at a
younger age. Although some consider that this goes against the
hygiene hypothesis, since the non-infected have probably
31

experienced a more hygienic upbringing, others believe that


there is no contradiction, since it is a first encounter with the
causative virus relatively late in life that is the trigger for the
disease. Other diseases that may be related include measles,
mumps and rubella.
c) Smoking
This has been shown to be an independent risk factor for MS.
Stress may be a risk factor although the evidence to support
this is weak. Association with occupational exposures and
toxinsmainly solventshas been evaluated, but no clear
conclusions have been reached. Vaccinations were studied as
causal factors; however, most studies show no association.
Several other possible risk factors, such as diet and hormone
intake, have been looked at; however, evidence on their
relation with the disease is "sparse and unpersuasive". Gout
occurs less than would be expected and lower levels of uric
acid have been found in people with MS. This has led to the
theory that uric acid is protective; although its exact
importance remains unknown.
Prognosis for complete recovery is generally poor.

32

3.6 Signs and Symptoms


Multiple sclerosis can cause a variety of signs and symptoms:
Changes in sensation (hypoesthesia), muscle weakness,
abnormal muscle spasms, or difficulty moving; difficulties with
coordination and balance; problems in speech (dysarthria) or
swallowing (dysphagia), visual problems (nystagmus, optic
neuritis, phosphenes or diplopia), fatigue and acute or chronic
pain syndromes, bladder and bowel difficulties, cognitive
impairment, or emotional symptomatology (mainly major
depression). The main clinical measure in progression of the
disability and severity of the symptoms is the Expanded
Disability Status Scale or EDSS.
The initial attacks are often transient, mild (or asymptomatic),
and self-limited. They often do not prompt a health care visit
and sometimes are only identified in retrospect once the
diagnosis has been made after further attacks. The most
common initial symptoms reported are: changes in sensation in
the arms, legs or face (33%), complete or partial vision loss
(optic neuritis) (20%), weakness (13%), double vision (7%),
unsteadiness when walking (5%), and balance problems (3%);
but many rare initial symptoms have been reported such as
aphasia or psychosis. Fifteen percent of individuals have
multiple symptoms when they first seek medical attention.
a) Bladder problems appear in 7080% of people with
multiple sclerosis (MS) and they have an important effect
both on hygiene habits and social activity. Bladder

33

problems are usually related with high levels of disability


and pyramidal signs in lower limbs.
The most common problems are an increase in frequency and
urgency (incontinence) but difficulties to begin urination,
hesitation, leaking, sensation of incomplete urination, and
retention also appear. When retention occurs secondary urinary
infections are common.
There are many cortical and subcortical structures implicated
in urination and MS lesions in various central nervous system
structures can cause these kinds of symptoms.
Treatment objectives are the alleviation of symptoms of
urinary dysfunction, treatment of urinary infections, reduction
of complicating factors and the preservation of renal function.
Treatments can be classified in two main subtypes:
pharmacological and non-pharmacological. Pharmacological
treatments vary greatly depending on the origin or type of
dysfunction and some examples of the medications used are:
alfuzosin for retention, trospium and flavoxate for urgency and
incontinency, and desmopressin for nocturia. Non
pharmacological treatments involve the use of pelvic floor
muscle training, stimulation, biofeedback, pessaries, bladder
retraining, and sometimes intermittent catheterization.
b) Bowel problems affect around 70% of the patients, with
around 50% of the patients suffering from constipation
and up to 30% from fecal incontinence. Cause of bowel
impairments in MS patients is usually either a reduced gut
motility or an impairment in neurological control of
34

defecation. The former is commonly related to immobility


or secondary effects from drugs used in the treatment of
the disease. Pain or problems with defecation can be
helped with a diet change which includes among other
changes an increased fluid intake, oral laxatives or
suppositories and enemas when habit changes and oral
measures are not enough to control the problems.
c) Cognitively, some of the most common deficits affect
recent memory, attention, processing speed, visual-spatial
abilities and executive function. Symptoms related to
cognition include emotional instability and fatigue
including neurological fatigue. Commonly a form of
cognitive disarray is experienced, where specific cognitive
processes may remain unaffected, but cognitive processes
as a whole are impaired. Cognitive deficits are
independent of physical disability and can occur in the
absence of neurological dysfunction. Severe impairment is
a major predictor of a low quality of life, unemployment,
caregiver distress, and difficulty in driving; limitations in a
patient's social and work activities are also correlated with
the extent of impairment.
Cognitive impairments occur in about 40 to 60 percent of
patients with multiple sclerosis, with the lowest percentages
usually from community-based studies and the highest ones
from hospital-based. Impairments may present at the beginning
of the disease. Probable multiple sclerosis sufferers, meaning
after a first attack but before a secondary confirmatory one,

35

have up to 50 percent of patients with impairment at onset.


Dementia is rare and occurs in only five percent of patients.
Measures of tissue atrophy are well correlated with, and
predict, cognitive dysfunction. Neuropsychological outcomes
are highly correlated with linear measures of sub-cortical
atrophy. Cognitive impairment is the result of not only tissue
damage, but tissue repair and adaptive functional
reorganization. Neuropsychological testing is important for
determining the extent of cognitive deficits. Neuropsychological
rehabilitation may help to reverse or decrease the cognitive
deficits although studies on the issue have been of low quality.
Acetylcholinesterase inhibitors are commonly used to treat
Alzheimer's disease related dementia and so are thought to
have potential in treating the cognitive deficits in multiple
sclerosis. They have been found to be effective in preliminary
clinical trials.

d) Emotional symptoms are also common and are thought


to be both a normal response to having a debilitating
disease and the result of damage to specific areas of the
central nervous system that generate and control
emotions.
Clinical depression is the most common neuropsychiatric
condition: lifetime depression prevalence rates of 4050% and
12-month prevalence rates around 20% have been typically
36

reported for samples of people with MS; these figures are


considerably higher than those for the general population or for
people with other chronic illnesses. Brain imaging studies have
tried to relate depression to lesions in certain regions of the
brain have met with variable success. On balance the evidence
seems to favour an association with neuropathology in the left
anterior temporal/parietal regions.
Other feelings such as anger, anxiety, frustration, and
hopelessness also appear frequently and suicide is a very real
threat since it results in 15% of deaths in MS sufferers. Rarely
psychosis may also be featured.
e) Fatigue is very common and disabling in MS with a close
relationship to depressive symptomatology. When
depression is reduced fatigue also tends to reduce and it is
recommended that patients should be evaluated for
depression before other therapeutic approaches are used.
In a similar way other factors such as disturbed sleep,
chronic pain, poor nutrition, or even some medications can
all contribute to fatigue and medical professionals are
encouraged to identify and modify them. There are also
different medications used to treat fatigue; such as
amantadine, or pemoline; as well as psychological
interventions of energy conservation; but their effects are
small and for these reasons fatigue is a difficult symptom
to manage. Fatigue has also been related to specific brain
areas in MS, using magnetic resonance imaging.

37

f) Internuclear ophthalmoplegia is a disorder of


conjugate lateral gaze. The affected eye shows
impairment of adduction. The partner eye diverges from
the affected eye during abduction, producing diplopia;
during extreme abduction, compensatory nystagmus can
be seen in the partner eye. Diplopia means double vision
while nystagmus is involuntary eye movement
characterized by alternating smooth pursuit in one
direction and a saccadic movement in the other direction.
Internuclear ophthalmoplegia occurs when MS affects a
part of the brain stem called the medial longitudinal
fasciculus, which is responsible for communication
between the two eyes by connecting the abducens
nucleus of one side to the oculomotor nucleus of the
opposite side. This results in the failure of the medial
rectus muscle to contract appropriately, so that the eyes
do not move equally (called disconjugate gaze).
Different drugs as well as optic compensatory systems and
prisms can be used to improve these symptoms. Surgery can
also be used in some cases for this problem.
g) Restrictions in mobility (walking, transfers, bed mobility
etc.) are common in individuals suffering from multiple
sclerosis. Within 10 years after the onset of MS one-third
of patients reach a score of 6 on the Expanded Disability
Status Scale (EDSS), requiring the use of a unilateral
walking aid, and by 30 years the proportion increases to
83%. Within five years of onset the EDSS is six in 50% of
those with the progressive form of MS.
38

A wide range of impairments may exist in MS sufferers which


can act either alone or in combination to impact directly on a
person's balance, function and mobility. Such impairments
include fatigue, weakness, hypertonicity, low exercise
tolerance, impaired balance, ataxia and tremor.
Interventions may be aimed at the individual impairments that
reduce mobility or at the level of disability. This second level
intervention includes provision, education, and instruction in
the use of equipment such as walking aids, wheelchairs,
motorized scooters and car adaptations as well as instruction
on compensatory strategies to accomplish an activity for
example undertaking safe transfers by pivoting in a flexed
posture rather than standing up and stepping around.
Up to 50% of patients with MS will develop an episode of
optic neuritis and 20% of the time optic neuritis is the
presenting sign of MS. The presence of demyelinating white
matter lesions on brain MRIs at the time of presentation for
optic neuritis is the strongest predictor in developing clinical
diagnosis of MS. Almost half the patients with optic neuritis
have white matter lesions consistent with multiple sclerosis.
At five year follow-ups the overall risk of developing MS is
30%, with or without MRI lesions. Patients with a normal MRI
still develop MS (16%), but at a lower rate compared to those
patients with three or more MRI lesions (51%).

From the
39

other perspective, however, 44% of patients with any


demyelinating lesions on MRI at presentation will not have
developed MS ten years later.
Individuals experience rapid onset of pain in one eye followed
by blurry vision in part or all its visual field. Flashes of light
(phosphenes) may also be present. Inflammation of the optic
nerve causes loss of vision most usually by the swelling and
destruction of the myelin sheath covering the optic nerve.
The blurred vision usually resolves within 10 weeks but
individuals are often left with less vivid colour vision, especially
red, in the affected eye. A systemic intravenous treatment with
corticosteroids may quicken the healing of the optic nerve,
prevent complete loss of vision and delay the onset of other
symptoms.
h) Pain is a common symptom in MS. A recent study
systematically pooling results from 28 studies (7101
patients) estimates that pain affects 63% of people with
MS. These 28 studies described pain in a large range of
different people with MS. The authors found no evidence
that pain was more common in people with progressive
types of MS, in females compared to males, in people with
different levels of disability, or in people who had had MS
for different periods of time.
Pain can be severe and debilitating, and can have a profound
effect on the quality of life and mental health of the sufferer.
Certain types of pain are thought to sometimes appear after a
lesion to the ascending or descending tracts that control the
40

transmission of painful stimulus, such as the anterolateral


system, but many other causes are also possible. The most
prevalent types of pain are thought to be headaches (43%),
dysesthetic limb pain (26%), back pain (20%), painful spasms
(15%), painful Lhermitte's phenomenon (16%) and Trigeminal
Neuralgia (3%). These authors did not however find enough
data to quantify the prevalence of painful optic neuritis.
Acute pain is mainly due to optic neuritis, trigeminal
neuralgia, Lhermitte's sign or dysesthesias. Subacute pain is
usually secondary to the disease and can be a consequence of
spending too much time in the same position, urinary retention,
or infected skin ulcers. Chronic pain is common and harder to
treat.

i) Trigeminal neuralgia (or "tic douloureux") is a disorder


of the trigeminal nerve that causes episodes of intense
pain in the eyes, lips, nose, scalp, forehead, and jaw,
affecting 2-4% of MS patients.The episodes of pain occur
paroxysmally (suddenly) and the patients describe it as
trigger area on the face, so sensitive that touching or even
air currents can bring an episode of pain. Usually it is
successfully treated with anticonvulsants such as
carbamazepine, or phenytoin although others such as
gabapentin can be used. When drugs are not effective,
surgery may be recommended. Glycerol rhizotomy
(surgical injection of glycerol into a nerve) has been
41

studied although the beneficial effects and risks in MS


patients of the procedures that relieve pressure on the
nerve are still under discussion.
j) Lhermitte's sign is an electrical sensation that runs
down the back and into the limbs and is produced by
bending the neck forwards. The sign suggests a lesion of
the dorsal columns of the cervical cord or of the caudal
medulla, correlating significantly with cervical MRI
abnormalities. Between 25 and 40% of MS patients report
having Lhermitte's sign during the course of their illness. It
is not always experienced as painful, but about 16% of
people with MS will experience painful Lhermitte's sign.
k) Dysesthesias are disagreeable sensations produced by
ordinary stimuli. The abnormal sensations are caused by
lesions of the peripheral or central sensory pathways, and
are described as painful feelings such as burning, wetness,
itching, electric shock or pins and needles. Both
Lhermitte's sign and painful dysesthesias usually respond
well to treatment with carbamazepine, clonazepam or
amitriptyline. A related symptom is a pleasant, yet
unsettling sensation which has no normal explanation
(such as sensation of gentle warmth arising from touch by
clothing).
l) Sexual dysfunction (SD) is one of many symptoms
affecting persons with a diagnosis of MS. SD in men
encompasses both erectile and ejaculatory disorder. The
prevalence of SD in men with MS ranges from 75 to 91%.
Erectile dysfunction appears to be the most common form
of SD documented in MS. SD may be due to alteration of
42

the ejaculatory reflex which can be affected by


neurological conditions such as MS. Sexual dysfunction is
also prevalent in female MS patients, typically lack of
orgasm, probably related to disordered genital sensation.
m)
Spasticity is characterised by increased stiffness
and slowness in limb movement, the development of
certain postures, an association with weakness of
voluntary muscle power, and with involuntary and
sometimes painful spasms of limbs. Painful spasms affect
about 15% of people with MS overall. A physiotherapist
can help to reduce spasticity and avoid the development
of contractures with techniques such as passive
stretching. There is evidence, albeit limited, of the clinical
effectiveness of THC and CBD extracts, baclofen,
dantrolene, diazepam, and tizanidine. In the most
complicated cases intrathecal injections of baclofen can
be used. There are also palliative measures like castings,
splints or customised seatings.
n) Speech problems include slurred speech, low tone of
voice (dysphonia), decreased talking speed, and problems
with articulation of sounds (dysarthria). A related problem,
since it involves similar anatomical structures, is
swallowing difficulties (dysphagia)
Some MS patients develop rapid onset of numbness,
weakness, bowel or bladder dysfunction, and/or loss of muscle
function, typically in the lower half of the body. This is the result
of MS attacking the spinal cord. The symptoms and signs
depend upon the nerve cords involved and the extent of the
involvement.
43

o) Tremor is an unintentional, somewhat rhythmic, muscle


movement involving to-and-fro movements (oscillations)
of one or more parts of the body. It is the most common of
all involuntary movements and can affect the hands,
arms, head, face, vocal cords, trunk, and legs. Ataxia is an
unsteady and clumsy motion of the limbs or torso due to a
failure of the gross coordination of muscle movements.
People with ataxia experience a failure of muscle control in
their arms and legs, resulting in a lack of balance and
coordination or a disturbance of gait.
Tremor and ataxia are frequent in MS and present in 25 to
60% of patients. They can be very disabling and embarrassing,
and are difficult to manage. The origin of tremor in MS is
difficult to identify but it can be due to a mixture of different
factors such as damage to the cerebellar connections,
weakness, spasticity, etc.
Many medications have been proposed to treat tremor;
however their efficacy is very limited. Medications that have
been reported to provide some relief are isoniazid,
carbamazepine, propranolol and gluthetimide but published
evidence of effectiveness is limited. Physical therapy is not
indicated as a treatment for tremor or ataxia although the use
of orthese devices can help. An example is the use of wrist
bandages with weights, which can be useful to increase the
inertia of movement and therefore reduce tremor. Daily use
objects are also adapted so they are easier to grab and use.

44

If all these measures fail patients are candidates for thalamus


surgery. This kind of surgery can be both a thalamotomy or the
implantation of a thalamic stimulator. Complications are
frequent (30% in thalamotomy and 10% in deep brain
stimulation) and include a worsening of ataxia, dysarthria and
hemiparesis. Thalamotomy is a more efficacious surgical
treatment for intractable MS tremor though the higher
incidence of persistent neurological deficits in patients
receiving lesional surgery supports the use of deep brain
stimulation as the preferred surgical strategy.
The cause of MS is unknown; however, it is believed to occur
as a result of some combination of genetic and environmental
factors such as infectious agents. Theories try to combine the
data into likely explanations, but none has proved definitive.
While there are a number of environmental risk factors and
although some are partly modifiable, further research is needed
to determine whether their elimination can prevent MS.

3.7 Diagnostic Criteria


Multiple sclerosis is typically diagnosed based on the
presenting signs and symptoms, in combination with supporting
medical imaging and laboratory testing. It can be difficult
to confirm, especially early on, since the signs and symptoms
may be similar to those of other medical problems. The
McDonalds criteria, which focus on clinical, laboratory, and
radiologic evidence of lesions at different times and in different
areas, is the most commonly used method of diagnosis with the
Schumacher and Poser criteria being of mostly historical
45

significance. While the above criteria allow for a non-invasive


diagnosis, some state that the only definitive proof is an
autopsy or biopsy where lesions typical of MS are detected
(13).
Clinical data alone may be sufficient for a diagnosis of MS if an
individual has had separate episodes of neurologic symptoms
characteristic of the disease. In those who seek medical
attention after only one attack, other testing is needed for the
diagnosis. The most commonly used diagnostic tools are
neuroimaging, analysis of cerebrospinal fluid and evoked
potentials. Magnetic resonance imaging of the brain and spine
may show areas of demyelination (lesions or plaques).
Gadolinium can be administered intravenously as a contrast
agent to highlight active plaques and, by elimination,
demonstrate the existence of historical lesions not associated
with symptoms at the moment of the evaluation. Testing of
cerebrospinal fluid obtained from a lumbar puncture can
provide evidence of chronic inflammation in the central nervous
system.
The cerebrospinal fluid is tested for oligoclonal bands of IgG
on electrophoresis, which are inflammation markers found in
7585% of people with MS.The nervous system in MS may
respond less actively to stimulation of the optic nerve and
sensory nerves due to demyelination of such pathways. These
brain responses can be examined using visual- and sensoryevoked potentials.

46

To evaluate for the potential for other conditions, it would be


appropriate to consider several blood tests in the initial
evaluation of the patient with suspected MS. These tests
include complete blood count (CBC), antinuclear antibodies
(ANA), serum test for syphilis (RPR, VDRL, etc.), fluorescent
treponemal antibody test (FTA), Lyme titer, ESR and, possibly,
angiotensin converting enzyme level (a test for sarcoidosis).
Imaging (MRI preferably) should be performed to rule out
alternative diagnoses and because MRI can provide information
about dissemination of disease. Over 90% of patients with MS
have abnormalities on the MRI scan. Multifocal white matter
disease of MS is easily observed but not easily differentiated
from vascular lesions, gliotic scars or other forms of
inflammation.
As yet, there are no entirely pathognomonic criteria for MS on
an MRI scan, but McDonalds criteria are used in research
studies.
These are MRI criteria used in the diagnosis of multiple
sclerosis, first introduced in 2001, revised in 2005 and again
recently in 2010. This latest revision improves sensitivity from
46% to 77% with a slight trade-off in specificity (slight
deterioration from 94% to 92%), with an overall accuracy of
86%.
As before the diagnosis of multiple sclerosis requires
establishing disease dissemination in both space and time.
Dissemination in space:

47

Dissemination in space requires 1 T2 bright lesions in two or


more of the following locations;

Periventricular
juxtacortical
infratentorial
spinal cord

If a patient has a brainstem / spinal cord syndrome, the


symptomatic lesion(s) are excluded from the criteria, not
contributing to the lesion count.
Dissemination in time:
Dissemination in time can be established in one of few ways;
A new lesion when compared to a previous scan
(irrespective of timing).
T2 bright lesion and/or gadolinium enhancing.
Presence of asymptomatic enhancing lesion and a nonenhancing T2 bright lesion on any one scan.
Primary progressive multiple sclerosis (PPMS)
In addition to the above criteria, the diagnosis of primary
progressive multiple sclerosis has also been revised. The
diagnosis now requires:
1 year of disease progression (this can be determined either
prospectively or retrospectively) plus two of the following three
criteria ;
- Brain dissemination in space ( 1 T2 bright lesions in 1
of juxtacortical, periventricular, infratentorial areas)
- Spinal cord dissemination in space (2 T2 bright lesions)
48

- Positive CSF (oligoclonal bands and/or elevated IgG index


Signs pertaining to the McDonalds Criteria include:
a) Dawson's fingers ;
These are a radiographic feature depicting demyelinating
plaques through the corpus callosum, arranged at right angles
along medullary veins (callososeptal location). They are a
relatively specific sign for multiple sclerosis (MS), which
presents as T2 hyperintensities (14).

Fig. 4 Dawsons Fingers clearly visible intra-axially.

b) Open ring enhancement


The open ring sign is a relatively specific sign for
demyelination, most commonly multiple sclerosis (MS), and is
helpful in distinguishing between ring enhancing lesions.
Interestingly open ring enhancement is not seen in
neuromyelitis optica (NMO). The enhancing component is
49

thought to represent advancing front of demyelination and thus


favours the white matter side of the lesion. The open part of
the ring will therefore usually point towards the grey matter
(15).
c) T1 black holes
As neurodegeneration in MS ensues, the formation and
evolution of persistent Tl-hypointense lesions (black
holes) have been used as markers of axonal loss and
neuronal destruction to measure disease activity. Despite
the use of various detection methods, including advanced
imaging techniques such as magnetization transfer
imaging and magnetic resonance spectroscopy,
correlation of persistent black holes with clinical outcomes
in patients with MS remains uncertain. Furthermore,
although axonal loss and neuronal tissue destruction are
known to contribute to irreversible disability in patients
with MS, there is limited data on the effect of therapy in
Tl-hypointense lesion volume.

Variants pertaining to the McDonalds Criteria include;


-

Tumefactive multiple sclerosis


Acute malignant Marburg type
Schilder type (diffuse cerebral sclerosis)
Balo concentric sclerosis (BCS)
Opticospinal multiple sclerosis (OSMS)
Neuromyelitis optica (NMO) (Devic disease)[+]
Acute disseminated encephalomyelitis (ADEM) and acute

haemorrhagic -encephalomyelitis (AHEM)


- Tumefactive demyelinating lesions
- Transverse myelitis
50

- Chronic inflammatory demyelinating polyneuropathy


(CIDP)
- Guillain-Barre Syndrome (GBS) (16).

3.8 Progression Pattern


Several phenotypes (commonly named types), or patterns of
progression, have been described. Phenotypes use the past
course of the disease in an attempt to predict the future course.
They are important not only for prognosis but also for treatment
decisions. In 1996, the United States National Multiple Sclerosis
Society described four clinical courses. This set of courses was
later reviewed by an international panel in 2013, adding
clinically isolated syndrome (CIS) and radiologically isolated
syndrome (RIS) as phenotypes, but leaving the main structure
untouched (17). They are:
1. Relapsing-remitting.
2. Secondary progressive (SPMS).
3. Primary progressive (PPMS).
4. Progressive relapsing.
1. The relapsing-remitting subtype is characterized by
unpredictable relapses followed by periods of months to
years of relative quiet (remission) with no new signs of
disease activity. Deficits that occur during attacks may
either resolve or leave problems, the latter in about 40%
of attacks and being more common the longer a person
has had the disease. This describes the initial course of
80% of individuals with MS.
51

When deficits always resolve between attacks, this is


sometimes referred to as benign MS, although people will
still build up some degree of disability in the long term. On
the other hand, the term malignant multiple sclerosis is
used to describe people with MS having reached
significant level of disability in a short period. The
relapsing-remitting subtype usually begins with a clinically
isolated syndrome (CIS). In CIS, a person has an attack
suggestive of demyelination, but does not fulfill the
criteria for multiple sclerosis. 30 to 70% of persons
experiencing CIS later develop MS.
2. Secondary progressive MS occurs in around 65% of
those with initial relapsing-remitting MS, who eventually
have progressive neurologic decline between acute
attacks without any definite periods of remission.
Occasional relapses and minor remissions may appear.
The most common length of time between disease onset
and conversion from relapsing-remitting to secondary
progressive MS is 19 years.
3. The primary progressive subtype occurs in
approximately 1020% of individuals, with no remission
after the initial symptoms. It is characterized by
progression of disability from onset, with no, or only
occasional and minor, remissions and improvements. The
usual age of onset for the primary progressive subtype is
later than of the relapsing-remitting subtype. It is similar
to the age that secondary progressive usually begins in
relapsing-remitting MS, around 40 years of age.
52

4. Progressive relapsing MS describes those individuals


who, from onset, have a steady neurologic decline but also
have clear superimposed attacks. This is the least
common of all subtypes.

Fig.5 Relapsing and Progressive MS, juxtaposed with healthy


control specimen
Unusual types of MS have been described; these include
Devic's disease, Balo concentric sclerosis, Schilder's diffuse
sclerosis, and Marburg multiple sclerosis. There is debate on
whether they are MS variants or different diseases. Multiple
sclerosis behaves differently in children, taking more time to
reach the progressive stage. Nevertheless, they still reach it at
a lower average age than adults usually do.

3.9 Therapy and Management


Although there is no known cure for multiple sclerosis, several
therapies have proven helpful. The primary aims of therapy are
53

returning function after an attack, preventing new attacks, and


preventing disability. As with any medical treatment,
medications used in the management of MS have several
adverse effects. Alternative treatments are pursued by some
people, despite the shortage of supporting evidence.
No treatment has been shown to change the course of
primary progressive MS, and as of 2011 only one
medication, mitoxantrone, has been approved for secondary
progressive MS. In this population tentative evidence supports
mitoxantrone moderately slowing the progression of the
disease and decreasing rates of relapses over two years (18).
The prognosis of the disease depends on the subtype of the
disease; the individual's sex, age, and initial symptoms; and the
degree of disability the person has. Female sex, relapsingremitting subtype, optic neuritis or sensory symptoms at onset,
few attacks in the initial years and especially early age at
onset, are associated with a better course.

The average life expectancy is 30 years from the start of the


disease, which is 5 to 10 years less than that of unaffected
people. Almost 40% of people with MS reach the seventh
decade of life. Nevertheless, two-thirds of the deaths are
directly related to the consequences of the disease.

54

Fig. 6 MS progression as seen over 4 years. Note the


disseminations in time and space.
As far as epidemiology is concerned, MS is the most
common autoimmune disorder of the central nervous system.
As of 2010, the number of people with MS was 22.5 million
(approximately 30 per 100,000) globally, with rates varying
widely in different regions. It is estimated to have resulted in
55

18,000 deaths that year. In Africa rates are less than 0.5 per
100,000, while they are 2.8 per 100,000 in South East Asia, 8.3
per 100,000 in the Americas, and 80 per 100,000 in Europe.
Rates surpass 200 per 100,000 in certain populations of
Northern European descent. The number of new cases that
develop per year is about 2.5 per 100,000 (19).
Rates of MS appear to be increasing; this, however, may be
explained simply by better diagnosis. Studies on populational
and geographical patterns have been common and have led to
a number of theories about the cause.

3.9.1 Multiple Sclerosis Research


Treatments under investigation for multiple sclerosis may
improve function, curtail attacks, or limit the progression of the
underlying disease. Many treatments already in clinical trials
involve drugs that are used in other diseases or medications
that have not been designed specifically for multiple sclerosis.
There are also trials involving the combination of drugs that are
already in use for multiple sclerosis. Finally, there are also
many basic investigations that try to understand better the
disease and in the future may help to find new treatments.
Advancements during the last decades have led to the recent
approval of several oral drugs. These drugs are expected to
gain in popularity and frequency of use at the expense of
previously existing therapies.
Finally, regarding neuroprotective and specially regenerative
treatments such as stem cell therapy, while their research is
56

considered of high importance at the moment they are only a


promise of future therapeutic approaches.
Likewise, there are not any effective treatments for the
progressive variants of the disease. Many of the newest drugs
as well as those under development are probably going to be
evaluated as therapies for PPMS or SPMS, and their improved
effectiveness when compared with previously existing drugs
may eventually lead to a positive result in these groups of
patients.
Improvement in neuroimaging techniques such as positron
emission tomography (PET) or magnetic resonance imaging
(MRI) carry a promise for better diagnosis and prognosis
predictions, although the effect of such improvements in daily
medical practice may take several decades. Regarding MRI,
there are several techniques that have already shown some
usefulness in research settings and could be introduced into
clinical practice, such as double-inversion recovery
sequences, magnetization transfer, diffusion tensor, and
functional magnetic resonance imaging. These techniques
are more specific for the disease than existing ones, but still
lack some standardization of acquisition protocols and the
creation of normative values.
In the medical imaging of demyelinating diseases, there can
however exist some unusual findings. For instance, with regards
to chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP).

57

Chronic inflammatory demyelinating polyradiculoneuropathy


(CIDP) is clinically defined as a 'chronically progressive,
stepwise or recurrent proximal and distal weakness and sensory
dysfunction of all extremities, developing over at least 2
months, with absent or reduced tendon reflexes in all limbs and
sometimes with cranial nerve involvement'.

Sensory dysfunction is frequently present, most usually


affecting joint position and vibration submodalities. Wasting is
not prominent early in the disease. There are atypical forms,
such as multifocal acquired demyelinating sensory and motor
neuropathy (MADSAM, or LewisSumner syndrome), pure
sensory or pure motor CIDP and focal or distal forms (distal
acquired demyelinating sensory polyneuropathy (DADS).
However, the medical imaging of demyelinating diseases, with
emphasis on multiple sclerosis in the area of Constanta,
Romania, shall now be stressed upon.

58

SPECIAL PART

59

CHAPTER 4
An understanding of what is seen in medical imaging of
demyelination, with emphasis on Multiple Sclerosis, is
necessary to be understood, before embarking upon specific
patient files.

4.1 Magnetic Resonance Imaging (MRI)


This is a medical imaging technique used in radiology to
investigate the anatomy and physiology of the body in both
health and disease. MRI scanners use magnetic fields and radio
waves to form images of the body. The technique is widely used

60

in hospitals for medical diagnosis, staging of disease and


follow-up without exposure to ionizing radiation.
This is is the diagnostic tool that currently offers the most
sensitive non-invasive way of imaging the brain, spinal cord, or
other areas of the body. It is the preferred imaging method to
help establish a diagnosis of MS and to monitor the course of
the disease. MRI has made it possible to visualize and
understand much more about the underlying pathology of the
disease.
MRI is the investigative tool of choice for various disorders
such as conditions of the central nervous system including
demyelinating diseases, dementia, cerebrovascular disease,
infectious diseases and epilepsy (20), as it is more sensitive
than CT for small tumours and offers better visualization of the
posterior fossa. The contrast provided between grey and white
matter makes it the optimal choice.

61

Fig. 7 Standard MRI equipment.

How it works:
Unlike a computed tomography (CT) scan or conventional Xray, MRI does not use radiation. MRI measures the water
content in tissues both normal tissue and abnormal. MRI
uses a powerful magnetic field that:
- Makes the hydrogen protons in water molecules line up in
the direction of the magnetic field.
- Once the hydrogen protons have been lined up, radio
waves are used to knock them out of line.
- When the radio waves are stopped, the protons relax back
into line. As they relax, the protons release resonance
signals that are transmitted to a computer.

Types:
The various types of MRI scans that are used (most commonly
the T1 and T2) measure this relaxation time in different ways.
Computer programs translate these data into cross-sectional
pictures of the water in human tissue.
Because the layer of myelin that protects nerve cell fibers is
fatty, it repels water. In the areas where the myelin has been
damaged by MS, the fat is stripped away. With the fat gone, the
area holds more water, and shows up on an MRI scan as either
62

a bright white spot or a darkened area depending on the type


of scan that is used.

4.2 Use In Diagnosis of MS


Because MRI is particularly useful in detecting central nervous
system demyelination, it is a powerful tool in helping to
establish the diagnosis of MS. However, approximately 5
percent of people with clinically-definite MS do not initially show
lesions on MRI at the time of diagnosis. If repeat MRIs continue
to show no lesions, the diagnosis of MS should be questioned.
Since many lesions seen on MRI may be in so-called "silent"
areas of the brain that dont produce symptoms, it is not always
possible to make a specific correlation between what is seen on
the MRI scan and the person's clinical signs and symptoms.
In addition, with advancing age (probably over age 50), there
are often small areas seen on MRI in healthy people that
resemble MS but are actually related to the aging process.

Clinically Isolated Syndrome (CIS):


In diagnosing a clinically isolated syndrome it is important to
rule out other potential causes. An individual's medical history
might be used alongside a clinical examination and blood tests
63

to identify or rule out any other potential causes for the attack
or symptom(s).
The type and number of assessments that may be used in the
diagnosis of a clinically isolated syndrome may vary but the
main test that is used is an MRI scan. An MRI scan will show any
areas of scarring or demyelination in the central nervous
system.
The sites of scarred tissue (areas often referred to as lesions)
vary in clinically isolated syndrome and may determine the
type of symptoms experienced. The areas where this damage is
most frequently seen include:

The spinal cord - where the medical description for it is


transverse myelitis
The optic nerve - where the medical description for it is
optic neuritis
The brainstem - where the medical description for it is
brainstem syndrome
Where damage is seen in more than one of the above areas it
is often referred to as 'multifocal abnormalities'.
MRI is particularly helpful in patients who have had a single
demyelinating attack that is suggestive of MS, also called a
clinically isolated syndrome (CIS).

The number of lesions on an initial MRI of the brain (or spinal


cord) can help the physician assess the persons risk of
64

developing a second attack (and therefore clinically-definite


MS) in the future. Some of the treatments for MS have been
shown to delay the occurrence of a second episode of
symptomatic demyelination in people who have had only one.
The MRI can also be used to identify a second neurological
event in a person who has no additional symptoms thereby
helping to confirm a diagnosis of MS as early as possible.
Once a diagnosis of MS has been clearly established,
subsequent MRI scans are useful in tracking the progress of the
disease and making treatment decisions. For example, a
neurologist may consider disease activity on MRI as well as a
person's clinical symptoms and relapses in order to determine
whether the current treatment is effective or a change in
treatment needs to be considered.
Healthcare professionals differ in their opinion about how
often an MRI should be done for MS, but most now recommend
it on an annual basis. When possible, follow-up MRIs should be
obtained on the same scanner as this will help the radiologist
and the patients healthcare provider, to make a comparison
between one MRI and the next.

65

4.3 Different Sequences Provide Different


Information:
These areas of inflammation appear as active lesions, meaning
that they are new or getting bigger.
T1-sequences also show dark areas (hypointensities) that are
thought to indicate areas of permanent nerve damage.
T2- sequences provide information about disease burden or
lesion load (meaning the total amount of lesion area, both old
and new).
FLAIR (fluid attenuated inversion recovery) images are used to
better identify brain lesions associated with MS.
Spinal cord imaging can identify pathology in the cord. It can
also help establish the diagnosis of MS by demonstrating that
damage has occurred in different parts of the central nervous
system (dissemination in space) at different points in time
(dissemination in time).

A T1-sequence, enhanced with gadolinium (injected


intravenously to further enhance scan sensitivity), supplies
information about current disease activity by highlighting areas
of active inflammation.
Because gadolinium is a large molecule, it normally cannot
pass through the blood-brain barrier (a cell layer around blood
66

vessels in the brain and spinal cord that prevents substances


from passing from the blood stream into the central nervous
system). However, when there is active inflammation, the blood
brain barrier is disrupted and gadolinium can enter and
highlight the inflamed areas.

Although other types of scans are used for research purposes,


these are the ones most commonly used in clinical care.

4.4 Different Magnetic Strengths Provide


Different Information:
The strength of the magnet used in the MRI machine is
important to the quality of the images. Magnet strength is
measured in Tesla (T).
Most conventional MRI machines are 1.5T or 3.0T. Open MRIs
are usually less than 1.5T and do not provide the best images
for detecting MS activity, although they may be used when
someone has difficulty tolerating a closed MRI machine.
MRI machines used for research purposes have much higher T.

4.5 Differential Diagnosis Using MRI


A brain MRI scan at the time a person presents with initial
symptoms of a clinically isolated syndrome is thought to be the
most useful predictive tool. A normal MRI scan showing no
67

lesions is associated with a lower risk of developing MS


whereas a brain scan that shows a high number or volume of
lesions is associated with a higher risk of developing MS.
The diagnosis of MS is strongly suggested when a person in
the appropriate age range has evidence of lesions of white
matter separated in space and time. There are several
conditions that should at least be considered before making the
diagnosis. Multiple emboli and vasculitis can result in small
infarcts that can appear as white matter damage on MRI scans.
Central nervous system sarcoidosis (an idiopathic, steroidresponsive inflammatory condition) can produce reversible
optic neuritis and other CNS signs. Whipple disease also has a
tendency to result in inflammatory lesions, along with unusual
eye movements due to midbrain involvement.
Vitamin B12 deficiency is suggested by dementia, spasticity,
and posterior column findings. Meningovascular syphilis, a rare
but reemerging entity, can give rise to multifocal CNS damage
due to multifocal meningeal vascular inflammation. CNS Lyme
disease can also produce multifocal disease, probably due to
vasculitis. An additional concern is that single lesions (by
definition, not MS) can affect several different neurological
systems.
For example, a patient may have cerebellar ataxia and spastic
paraparesis that could both result from a single lesion
compressing the rostral spinal cord and the cerebellum at the
level of the foramen magnum. Fortunately, magnetic resonance
imaging, is particularly good at detecting such lesions
68

(although they were difficult to see with older technology, such


as the CT scan). On the other hand, if that person also had
optic neuritis or hemiparesis involving the face, one lesion
could no longer explain the findings. A history of remissions and
exacerbations also helps in the diagnosis of MS, but it must be
remembered that the symptoms of neoplasms commonly
fluctuate to some degree.

CHAPTER 5
5.1 Research Study Subjects
Five (5) patients in the Constanta area, in Romania, were
examined. Two male, ages 35 and 26 (Born 1980 and 1989,
respectively), and three female, ages 47, 43, and 38. (Born
1968, 1972, and 1977, respectively). They were diagnosed with

69

multiple sclerosis within the past year and a half, from the time
of this study.
The age range of the patients was on point with the general
age range of multiple sclerosis affected patients (20-50) given
that the youngest of the 5 was 26 (male), and the oldest was
47 (female).
The gender distribution was also in accordance with general
statistics, with slightly more women being affected than men.

5.2 Study Method


For diagnostic purposes at the begining investigations were
done with and without gadolinium enhancement. T1 and T2
sequences were used to diagnose and appreciate disease
activitiy. T1 is with regards to hypointensities and T2 with
hyperintensities.
Gadolinium does not normally cross the blood-brain barrier
unless there are active lesions, and generalised inflammation,
as is the case with these 5 subjects.

70

Fig.8 Sagittal plane image, highlighting hyperintense lesions,


visible in spinal area, in 47 year old female patient.

71

Fig.9 T2 axial plane image, showing white matter lesions, in 35 year


old male patient. Note the visible presence of Dawsons Fingers.

Disseminated lesions are observed, both dissemination in


space (various places in the CNS; brain and spinal cord) and
dissemination in time (various time periods). The
dissemination was particularly visible from the axial plane.

72

Fig.10 Visible diffusion, in 26 year old male patient.

For the further enhanced identification of lesions, FLAIR was


used (Fluid Attenuated Inversion Recovery), visible in the
sagittal, coronal, and axial planes.

73

Fig.11 Sagittal FLAIR in 43 year old female patient, highlighting


white hyperintense lesions near corpus callosum.

Fig.12 Coronal FLAIR in same 43 year old female patient, showing


same lesion pattern.
74

Fig.13 Continued with same 43 year old female patient. Note


the lesions visible in axial FLAIR.

5.3 Study Results And Analysis


In all the patients, there were massive lesions and plaques,
clear demyelination, inflammation, within the actual cerebral
parenchyma, as well as on the cerebral fringes, and along the
spinal cord.
Specifically, in all the five patients, to varying degrees, we
could observe:
- Sagittal T2-sequences, depicting multiple hyperintense
lesions around the corpus callosum; this finding is
characteristic of multiple sclerosis.
75

Fig.14 43 year old female patient with pericalossal


hyperintensities.

76

Fig.15 47 year old female patient. Calossal lesions.

- Coronal fluid-attenuated inversion recovery (FLAIR), with


obvious multiple sclerosis demonstrating periventricular
77

highsignal intensity lesions, which exhibit a typical


distribution for multiple sclerosis. As mentioned before,
FLAIR MRI is a highly sensitive sequence for lesion
detection, particularly supratentorially.
-

Fig.16 Coronal FLAIR. Lesions in 47 year old patient.

78

Fig.17 Coronal FLAIR highlighting lesions in 43 year old


patient.

- Axial T2-sequences, with clear multiple sclerosis,


demonstrating numerous white matter plaques in a
callosal and pericallosal white matter distribution.

79

Fig.18 38 year old patient with visible axial T2


hyperintensities

Fig.19 Visible lesions near calossum, 43 year old .

80

Fig.20 47 year old patient with visible axial T2 lesions

Fig.21 38 year old female patient, with visible white matter


lesions in and around calossal area.

81

- Axial diffusion-sequence with multiple sclerosis, showing


several hyperintense lesions, an obvious feature of
inflammatory disease activity.

Fig.22 Multiple hyperintensities, characteristic of general


inflammation. Diffusion. 38 year old female.

On all the patients, the presence of corpus callosum white


matter lesions was observable, cortical lesions, as well as
lesions on brainstem, u-fibers, and on the 43 year old female
patient, temporal lobe involvement, suggesting early stages.
The general distribution for all 5 of the white matter lesions,
was symmetric and diffuse.
This as opposed to other kinds of, say, vascular
inflammations, where the distribution is often asymmetric and

82

the lesions are not in the aforementioned areas. Thus the MRI
images would look quite different.
All patients examined showed juxtacortical lesions, meaning
lesions adjacent to and touching the cortex.
All 5 patients also showed manifestations of multiple lesions,
adjacent to the ventricles, as well as ovoid lesions,
perpendicular to the ventricles. These ovoid lesions, known as
Dawsons Fingers, represent areas of demyelination along the
small cerebral veins that run perpendicular to the ventricles
(see Fig.9).
There were also multiple lesions on the spinal cords. This is
another typical feature of MS. Typical spinal cord lesions in MS
are relatively small and peripherally located. They are most
often found in the cervical cord and are usually less than 2
vertebral segments in length.

A spinal cord lesion together with a lesion in the cerebellum or


brainstem is very suggestive of MS. Spinal cord lesions are
uncommon in most other CNS diseases, with the exception of
ADEM, sarcoidosis, Lyme disease and SLE. Three of the five
patients studied showed more advanced spinal cord
involvement; the 47, and 43 year old females, and the 35 year
old male.

83

Fig.23 35 year old male in question. Note spinal hyperintense


lesions.

In the 26 year old male and the 38 year old female, especially
on the T2 axial plane, we could readily observe signs of
multiple enhancing lesions.

84

Many of these lesions 'touch the cortex' and must be located


in the U-fibers.

These enhancing lesions all are new lesions, since Gadolinium


enhancement is only visible for about 1 month.

Fig.24 Multiple enhancing lesions in 26 year old male.

So this finding is proof of dissemination in time.

85

In the 38 year old female, we also observed general


inflammation activity on the FLAIR axial plane, as well as the
diffusion axial plane.

Fig.25 38 year old female, showcasing lesions in generalised


white and grey matter. Diffusion Axial Plane.

According to the McDonald's criteria, we notice the


following on these five patients:
Dissemination in space:
Dissemination in space requires 1 T2 bright lesions in two or
more of the following locations:

Periventricular
Juxtacortical
Infratentorial
Spinal cord
86

NOTE: If, however, a patient has a brainstem / spinal cord


syndrome, the symptomatic lesion(s) are excluded from the
criteria, not contributing to the lesion count!

Therefore, all five patients examined had dissemination


in space.
Dissemination in time:
Dissemination in time can be established in one of a number
of ways:
- A new lesion when compared to a previous scan
(irrespective of timing)
- T2 bright lesion and/or gadolinium enhancing.
- Presence of asymptomatic enhancing lesion and a nonenhancing T2 bright lesion on any one scan.

Therefore, though all also had dissemination in space, it was


more observable in the 26 year old male, and the 38 year old
female.

87

Fig.26 35 year old patient with dissemination in space. Coronal


view

88

Fig.27 Dissemination in space in 43 year old patient

Fig.28 38 year old patient showing visible dissemination in


space

89

Fig.29 Multifocal hyperintensities in 47 year old visible in both


hemispheres

From the MRI scan images, we notice that, even on a single


scan, some features are helpful in predicting relapsingremitting vs. progressive disease. Features favouring
progressive disease include:
- Large numerous plaques.
- Hyperintense lesions.

90

According to this, the 35 year old male, as well as the 43 and


47 year old females have the progressive disease; while the 26
year old male and the 38 year old female have the relapsingremitting version of the disease.
Obviously, emboli, vasculitis, sarcoidosis, etc, had all been
ruled out by;
Lumbar puncture, CSF examination, CBC, ANA, serum for
syphilis, ACE level for sarcoidosis.
Generally, this is typical from the images of the patients
examined, since 90% of MS patients do have MRI scan
abnormalities, and 14 out of 15 patients generally suspected
tend to show white matter lesions in the brain and spinal cord.

5.4 Treatment and Prognosis


As far as these 5 patients are concerned, therapeutic treatment
and management would have a twofold aim:
- To curtail progression (disease modifying agents), and
- Symptomatic relief.
Steroids, interferon, monoclonal antibodies are all used.
Discussion of individual agents is beyond the scope of this
segment, and have already been mentioned earlier.
It is important to remember from an imaging perspective that
the use of steroids can make an active lesion reduce in size and
reduce enhancement.

91

Prognosis is variable and depends on the pattern of disease


(primary progressive carries a worse prognosis than relapsingremitting).
Therefore, from the images, the 26 year old male, and 38 year
old female have a better prognosis than the other three
patients.
However, generally, patients with relapsing-remitting MS will
progress to the secondary progressive type of the disease in 10
years, and will require ambulatory aids (e.g.
cane/wheelchair/frame) within another 5 to 15 years.
As we therefore notice from the above specific patients, the
general manifestations in the MRI scans of MS patients present
with, in at least 95% of cases, periventricular lesions and over
90% show discrete white matter abnormalities. Areas of focal
demyelination can also be seen as plaques in the optic nerve,
brainstem and spinal cord. By using a contrast agent, active
inflammatory plaques can be distinguished from inactive ones.
The number and size of lesions do not correlate well with
disease activity or progress. It also excludes other lesions
producing the symptoms.
Cerebrospinal fluid: rise in total protein with increase in
immunoglobulin concentration with presence of oligoclonal
cases.

92

CHAPTER 6
CONCLUSION
Getting an MS diagnosis can be a lengthy process. When some
patients finally learn they have the condition after months or
even years of symptoms, for some it might be something of a
relief. For others, it can be shocking. Either way, it is lifechanging. It is important to remember that MS affects

93

everyone differently, so what one person with the condition


feels/experiences is hardly the general and standard rule.
As observed with patients all over the world, and the
Constanta, Romania patients, it can be a challenge for doctors
to diagnose multiple sclerosis. There is no single test that can
definitely show if someone is affected. And there are many
conditions with symptoms that can seem like MS.
But a neurologist (in conjunction with a diagnostic
radiologist, primary physician, etc...) who specializes in treating
the disease should be able to look into if the symptoms are
positively MS or another problem.
As we have seen from general treatments, and procedures,
and from the patients involved in this research from Constanta,
the treating doctor investigates the medical history and
symptoms. Also, a few tests are done to see if the brain and
spinal cord are working as they should. These include:
- Imaging tests, like an MRI, to take a closer look at the
brain
- Spinal taps, also called lumbar punctures, to check the
fluid that runs through the spinal column
- Electrical tests, called evoked potentials, to see if MS has
affected the nerve pathways
- Blood tests
In the case of a spinal tap, when physicians do this test, they
are looking closely at the fluid in your spine, called
cerebrospinal fluid, for higher levels of proteins and other
substances that are signs of the disease. These can be helpful
94

in diagnosing MS, but they are not absolute proof of the


condition.
Keeping in mind that this research paper is about the project
of medically imaging demyelinating diseases (especially with
MRI scanning), with emphasis on MS, particularly in patients in
Constanta, it must be reiterated that MRI scans are still, as of
now, the best way for doctors to see any brain changes caused
by multiple sclerosis. It can show clear signs of inflammation in
the deep parts of the brain or spinal cord that are red flags for
the condition.
However, let us bear in mind that older patients, or patients
with hypertension, and diabetes, may also have the same kinds
of spots on a brain MRI scan image. So, the treating physician
will therefore have to consider other information and variables,
including a myriad symptoms (along with the scan results),
before making a conclusive and definitive diagnosis.
In addition, it is imperative to remember that an MRI result
that says things are normal does not absolutely rule out MS.
Approximately 5% of people with multiple sclerosis do not have
lesions in the brain that show up on the test. They may have
them in places the scan cannot highlight, yet.
As we saw from the general, as well as the special part with the
Constanta patients, MRI was the only certain way to ascertain
the presence of MS, confirmed in conjunction with various
aforementioned tests, and markers, due to the visibility of white
matter lesions, Dawsons fingers, and the progression of the
disease and dissemination in time and space, among others.
95

REFERENCES
1 "Demyelinating Disease" at Dorland's Medical Dictionary
2 Jump up ^ Konopaske GT; Dorph-Petersen KA; Sweet RA
et al. (April 2008). "Effect of chronic antipsychotic exposure
on astrocyte and oligodendrocyte numbers in macaque
96

monkeys". Biol. Psychiatry 63 (8): 75965.


doi:10.1016/j.biopsych.2007.08.018. PMC 2386415. PMID
17945195.
3 "Safety in the MR Environment: Ferromagnetic Projectile
Objects in the MRI Scanner Room". Pa Patient Saf Advis
(Pennsylvania Patient Safety Authority) 6 (2): 5662. 2009-06.
Retrieved 4 February 2015.
4 James R. Ross, MD; Matthew J. Matava, MD. "TattooInduced Skin Burn During Magnetic Resonance Imaging in a
Professional Football Player"
5 Budinger TF, Fischer H, Hentschel D, Reinfelder HE,
Schmitt F (1991). "Physiological effects of fast oscillating
magnetic field gradients".
6 Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley
WG, Froelich JW, Gilk T, Gimbel JR, Gosbee J, KuhniKaminski E, Lester JW, Nyenhuis J, Parag Y, Schaefer
DJ, Sebek-Scoumis EA, Weinreb J, Zaremba LA, Wilcox
P, Lucey L, Sass N (2007). "ACR guidance document for
safe MR practices: 2007". AJR Am J Roentgenol 188 (6): 1447
74.
7 Alorainy IA, Albadr FB, Abujamea AH (2006). "Attitude
towards MRI safety during pregnancy". Ann Saudi Med 26 (4):
3069.
8 "MRI procedure". Royal College of Radiologists. Retrieved
17 November 2013.
9 Jump up "Johnson RT. DEMYELINATING DISEASES. In:
Institute of Medicine (US) Forum on Microbial Threats; Knobler
SL, O'Connor S, Lemon SM, et al., editors. The Infectious
Etiology of Chronic Diseases: Defining the Relationship,
Enhancing the Research, and Mitigating the Effects:
Workshop Summary. Washington (DC): National Academies
Press (US)". NCBI. 2004. Retrieved 2012-10-30.

97

10 Jump up "Ziggy Star has a Neurologic Condition". The Marine


Mammal Center. Retrieved 2 February 2014.
11 Compston A, Coles A (April 2002). "Multiple sclerosis".
Lancet 359 (9313): 122131.
12 Marrie RA (December 2004). "Environmental risk factors in
multiple sclerosis aetiology". Lancet Neurol 3 (12)
13 Polman CH, Reingold SC, Banwell B, et al; Diagnostic
criteria for multiple sclerosis: 2010 revisions to the McDonald
criteria. Ann Neurol. 2011 Feb;69(2):292-302. doi:
10.1002/ana.22366.
14 Sahraian M, Rad E. MRI Atlas of MS Lesions. Springer
Science & Business Media. (2007) ISBN:3540713727.
15 Given CA, Stevens BS, Lee C. The MRI appearance of
tumefactive demyelinating lesions. AJR Am J Roentgenol.
2004;182 (1): 195-9. AJR Am J Roentgenol
16 Swanton JK, Fernando K, Dalton CM et-al. Modification of
MRI criteria for multiple sclerosis in patients with clinically
isolated syndromes. J. Neurol. Neurosurg. Psychiatr. 2006;77
(7): 830-3.
17 Fred D. Lublin et al. (Jul 15, 2014). "Defining the clinical
course of multiple sclerosis, The 2013 revisions". Neurology.
83(3): 278286.
18 Compston A, Coles A (October 2008). "Multiple sclerosis".
Lancet 372 (9648): 150217.
19 Milo R, Kahana E (March 2010). "Multiple sclerosis:
geoepidemiology, genetics and the environment".
Autoimmun Rev 9 (5): A38794.
20 American Society of Neuroradiology (2013).ACR-ASNR
Practice Guideline for the Performance and Interpretation of
Magnetic Resonance Imaging (MRI) of the Brain

98

99