medical imaging of demyelinating diseases; with emphasis on multiple sclerosis

8/17/2019 Medical Imaging of Demyelinating Diseases; With Emphasis On Multiple Sclerosis

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GENERAL PART

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INTRODUCTION

Demyelinating diseases, though well-known phenomena in themedical 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

aecting people of dierent 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.

mphasis will obviously be put upon the incidence and

imaging thereof, among patients in !onstanta, "omania.

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CHAPTER 1

1.1 Defnition

$ demyelinating disease is any disease aecting the

central nervous system, which results in damage to the myelin

sheath of neurons. This damage impairs the conduction of

signals in the aected nerves. %n turn, the reduction in

conduction ability causes de&ciency in sensation, movement,

cognition, or other functions depending on which nerves are

involved '1(.

)ome demyelinating diseases are caused by genetics, someby infectious agents, others by autoimmune reactions, and a

few by unknown factors and agents. *rganophosphates, a class

of chemicals which are the active ingredients in commercial

insecticides such as sheep dip, weed-killers, and +ea treatment

preparations for pets, etc., will also demyelinate nerves.

euroleptics can also cause demyelination'#(.

Lysophosphatidylcholine causes demyelination and is in

unnaturally high amounts in foods with lecithin treated with the

enyme phospholipase 'enyme-modi&ed foods( and as

lysolecithin in products such as make up and personal care

products.

1.2 Classifcation


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Demyelinating diseases are traditionally classi&ed in two

kinds/ demyelinating myelinoclastic diseases and

demyelinating le!odyst"o#$ic diseases. %n the &rst group a

normal and healthy myelin is destroyed by a to0ic, chemical or

autoimmune substance. %n the second group, myelin is

abnormal and degenerates. The second group was termed

denominated demyelinating diseases according to the oser

criteria.

1.% Pat$o#$ysiology

%n the most known e0ample, Multiple Sclerosis (MS), there

is good evidence that the body2s own immune system is at

least partially responsible. $c3uired immune system cells called

T-cells are known to be present at the site of lesions. *ther

immune system cells called 4acrophages 'and possibly 4ast

cells as well( also contribute to the damage.

)ome demyelinating diseases are caused by genetics, some

by infectious agents, some by autoimmune reactions, some by

e0posure 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. 5nlike other primates, humans e0hibit a

uni3ue 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 e0tended 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.

7urthermore, it has been noted that humans have signi&cantly

greater prefrontal white matter volume than other primate

species, which implies greater myelin density. %ncreased myelin

density in humans as a result of a prolonged myelination may

therefore structure risk for myelin degeneration and

dysfunction.

volutionary considerations for the role of prolonged cortical

myelination as a risk factor for demyelinating disease are

particularly pertinent given that genetics and autoimmune

de&ciency hypotheses fail to e0plain many cases of

demyelinating disease. $s has been argued, diseases such as

multiple sclerosis cannot be accounted for by autoimmune

de&ciency alone, but strongly imply the in+uence of +awed

developmental processes in disease pathogenesis.

Therefore, the role of the human-speci&c prolonged period of

cortical myelination is an important evolutionary consideration

in the pathogenesis of demyelinating disease.

1.& Incidence o' Demyelinating Diseases

This varies from disorder to disorder. )ome conditions, such as

Tabes Dorsalis appear predominantly in males and begin in

mid-life. *ptic neuritis on the other hand, occurs preferentially

in females typically between the ages of 8 and 9. *ther

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 aecting the

central nervous system and those presents in the peripheral

nervous system, presenting dierent demyelination conditions.

1.( )ym#toms

That present in demyelinating diseases are dierent for each

condition. :elow 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

• ncoordination

• !araesthesia

• "cular paralysis

• mpaired muscle coordination


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• #ea$ness %muscle&

• Loss o' sensation

• mpaired vision

• (eurological symptoms

• )nsteady gait

• *pasticity

• ncontinence

• Hearing problems

• *peech problems

1.* Diagnostic +et$ods

0clusion of other conditions that have overlapping symptoms

is important, seeing as a number of conditions could mimic

various demyelinating disorders.

:elow are various methods=techni3ues used to diagnose

demyelinating diseases/

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+agnetic esonance maging %+& is a medical imaging

techni3ue used in radiology to visualie internal structures of

the body in detail. 4"% makes use of the property of nuclear

magnetic resonance '4"( to image nuclei of atoms inside the

body.

1., La-o"ato"y +a"!e"s

$ test that is sometimes used to con&rm or rule out a

diagnosis of 4) is a lumbar puncture. $ lumbar puncture

involves removing and analysing a sample of cerebrospinal +uid

'!)7(, the +uid that surrounds the brain and spinal cord within

the skull and backbone. )peci&c markers in the cerebrospinal

+uid can indicate 4) activity. )tudies have investigated

whether analysis of cerebrospinal +uid can help predict the

likelihood of developing 4) after a clinically isolated syndrome.

*ne of these studies was based on the data of 68 people who

presented with a clinically isolated syndrome and underwent

4"% scanning and cerebrospinal +uid analysis within the

following two months. *f the19 people who subse3uently

developed 4), 16 had abnormalities on 4"% and 1 tested

positive for markers of disease activity in their cerebrospinal

+uid. The risk of developing 4) was signi&cantly higher in

people who tested positive in cerebrospinal +uid analysis and

had abnormalities on their &rst 4"% scan compared to people

who were negative for both or one of the tests. ?owever,

because it is less useful as a predictive tool than 4"%, 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 4). $s mentioned

earlier, these tests includeA complete blood count '!:!(,

antinuclear antibodies '$$(, serum test for syphilis '"",

BD"C, etc.(.

There may also be an increase in !)7 myelin basic protein

levels, which is evidence of actual damage to myelin. vidence

of subclinical demyelinated lesions can be provided by 4"%,

visual, somatosensory, or brain stem auditory evoked

responses.

-vo$ed potential is an electrical potential recorded from the

nervous system following the presentation of a stimulus as

detected by electroencephalography '(, electromyography

'4(, or other electrophysiological recording method.

Cerebrospinal .uid analysis %C*F& can be e0tremely bene&cial

in the diagnosis of central nervous system infections. $ !)7

!ulture e0amination may yield the 4icroorganism that caused

the infection.

?owever, the medical imaging of demyelinating diseases, with

emphasis on multiple sclerosis in the area of !onstanta,

"omania, shall now be stressed upon.

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1. T$e Role o' +RI in +)

4agnetic resonance imaging '4"%( has been shown to be

highly sensitive in detecting clinically silent 4) pla3ues.

!onse3uently, &ndings 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 4) can be made if an 4"% scan performed three

months after a clinically isolated attack demonstrates formation

of a new lesion. The proposed diagnostic criteria also de&ne

4"% lesion characteristics that increase the likelihood of 4),

including number of lesions 'nine or more(, location of lesions

'position abutting the ventriclesA ju0tacortical, infratentorial, or

spinal position(, and lesion enhancement with the use of

contrast medium.

$s observed in various patients, 4"% lesion characteristics

suggestive of 4ultiple )clerosis, once again include/

- Brain lesions

-High signal on /012eighted and FLA + se3uences%more than nine lesions&

- #hen actively in.ammed, o'ten enhanced 2ith

gadolinium contrast - !osition abutting ventricles %o'ten perpendicular&- 4uxtacortical position %gray12hite 5unction&- nvolvement o' brainstem, cerebellum, or corpus callosum- *pinal cord lesions-

"ne or t2o vertebral segments in length

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- ncomplete cross1sectional involvement %dorsolateral

common&- Less li$ely to enhance 2ith gadolinium contrast - (o cord s2elling

-Better seen 2ith */ + se3uences6

$ brain 4"% scan is indeed the most useful test for con&rming

the diagnosis of 4). 4) lesions appear as areas of high signal,

predominantly in the cerebral white matter or spinal cord, on

T#-weighted images.

4"% scanning is useful for detecting structural pathology in

regions that can be diFcult to image by computed tomography,

such as the posterior fossa, craniocervical junction, and cervical

cord.# $ brain 4"% scan performed with a high-&eld magnet

'1.9 tesla or greater( is abnormal in almost all patients who

have clinically de&nite 4).

7luid attenuation inversion recovery '7C$%"( se3uence image

of certain transverse sections from the brain of patients with

multiple sclerosis '4)(. !ertain images showed multiple high-

signal periventricular and white-matter lesions. $lthough the

7C$%" se3uence is the most sensitive se3uence for detecting

4) lesions, it is not speci&c for demyelination.

%n 4"% scans of the spinal cord in certain patients with 4),

sagittal images using the )hort Tau %nversion "ecovery ')T%"(

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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$s we therefore see from all the above, widespread use of 4"%

has indeed revolutionied the ability to diagnose multiple

sclerosis. Disease-related changes in the brain or spinal cord

are detected by 4"% in more than E8G of people suspected of

having 4).

Advantages And Disadvantages of MRI sage

"easons why 4"% is best for this include the facts that 4"% can

often detect damaged areas in the brain or spinal cord that

would be missed by other imaging techni3ues such as a !$T

scan, 4"% is considered the best test to help diagnose 4).

?owever, 9G of people with 4) do not have abnormalities

detected on 4"%A thus, a HnegativeH scan does not completely

rule out 4). %n addition, some common changes of aging may

look like 4) on a 4"%.

$lthough they aren2t widely needed, people with 4) may get

repeat scans to determine the status of their disease and how

well their medications are working.

The 4"% e0am poses no risk to the average person if

appropriate safety guidelines are followed. 4any people who

have had heart surgery and people with the following medical

devices can be safely e0amined with 4"% 'the metals used in

these surgeries are not HmagneticH and the person can be

safely placed in the 4"% machine/

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- Arti7cial 5oints- *taples- +any cardiac valve replacements %chec$ 2ith physician&- Disconnected medication pumps

-8ena cava 7lters

- Brain shunt tubes 'or hydrocephalus

)ome conditions may make an 4"% e0am a bad idea.

!onsultation with the doctor in charge is necessary with the

following situations=conditions/

- Heart pacema$er

-Cerebral aneurysm clip %metal clip on a blood vessel in thebrain&

- mplanted insulin pump %'or treatment o' diabetes&,

narcotics pump %'or pain medication&, or implanted spinal

cord stimulators 'or chronic pain- +etal in the eye or eye soc$et - Cochlear %ear& implant 'or hearing impairment - mplanted spine stabili9ation rods %ne2er titanium rods

and plates are 7ne&- *evere lung disease %such as tracheomalacia or

bronchopulmonary dysplasia&- Heartburn- "besity %2eighing more than :;; pounds % appro!" 1#$

%g & may limit 2hich machine can be used&- (ot able to lie on your bac$ 'or :; to


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is when ferromagnetic objects are attracted to the center

of the magnet %:&6

Heating caused asorption of *aves

$n 4"% scanner has a powerful radio transmitter to

generate the electromagnetic &eld which e0cites the

spins. Ihen the body absorbs the energy, heating occurs.

7or 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 %=&6

Perip+eral nerve sti,ulation (P-S)

The rapid switching on and o of the magnetic &eld

gradients is capable of causing nerve stimulation,

particularly in the e0tremities %>& 6 The reason the

peripheral nerves are stimulated is that the changing &eld

increases with distance from the center of the gradientcoils 'which more or less coincides with the center of the

magnet(. $lthough ) was not a problem for the slow,

weak gradients used in the early days of 4"%, the strong,

rapidly switched gradients used in techni3ues such as %,

f4"%, diusion 4"%, etc. are capable of inducing ).Crogens

The !hysics o' +agnetic esonance maging, describes

many 4"% scanners as relying on cryogenic li3uids to

enable the superconducting capabilities of the

electromagnetic coils within. Though the cryogenic li3uids

used are non-to0ic, their physical properties present

speci&c haards.

$n unintentional shut-down of a superconductingelectromagnet, an event known as H3uenchH, involves the

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rapid boiling of li3uid helium from the device. %f the rapidly

e0panding helium cannot be dissipated through an

e0ternal vent, it may be released into the scanner room

where it may cause displacement of the o0ygen and

present a risk of asphy0iation %


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past, and that in the future this &gure may rise to 1.9K#G

based on historical rates of !T usage. $n advantage of 4"% is that no ioniing radiation is used

and so it is recommended over !T when either approachcould yield the same diagnostic information. ?owever, though 4"% cost has fallen, thus making it

more competitive with !T, there are not many common

imaging scenarios in which 4"% can simply replace !T,

although this substitution has been suggested for the

imaging of hepatic disorders.

The eect of low doses of radiation on carcinogenesis is

also disputed. $lthough 4"% is associated with certain

biological eects, these have not been proven to cause

signi&cant and measurable harm %@&6"egardless of the benefLts of !T, let us note that it has no

bearing upon the diagnosis of 4).4"% remains the absolute imaging method for the positive

diagnosis of the disease.

Practical .uidelines

)imple practical guidelines=applications for the 4"% procedure

include/

- $llowing two hours for the 4"% e0am. %n most cases, the

procedure takes 68 to @8 minutesA during that time,

several doen images may be taken.- ersonal 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 4"%

scan.

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- The patient may be advised to wear a hospital gown

during the 4"% scan.

$s the 4"% scan begins, the patient will hear the e3uipment

making a variety of dierent sounds, including a muMed

thumping sound or banging sound that will last for several

minutes at a time. *ther than that sound, one aught e0perience

no unusual sensations during the scanning.

!ertain 4"% e0ams re3uire an injection of a contrast material,

as we saw from the general patients, and from the speci&c

patients from !onstanta, "omania.

This helps identify abnormalities in certain parts of the body

on the scan images.

uantitative proton magnetic resonance spectroscopy %+*&

is a non-invasive analytical techni3ue that has been used tostudy metabolic changes in brain tumors, strokes, seiure

disorders, $lheimer2s disease, depression and other diseases

aecting the brain. %t has also been used to study the

metabolism of other organs such as muscles.

Diagnostic Criteria refers to a speci&c combination of signs,

symptoms, and test results that the clinician uses in an attempt

to determine the correct diagnosis.

1. T"eatment

Typically involves improving the patient2s 3uality 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. 3uit smoking, adjusting daily

schedules to include rest periods and dietary changes(,

counselling, rela0ation, physical e0ercise, patient education

and, in some cases, deep brain thalamic stimulation 'in the

case of tremors(.

The progressive phase of 4) appears to driven by the innate

immune system, which will directly contribute to the

neurodegenerative changes that occur in progressive 4). 5ntil

now, there are no therapies that speci&cally target innate

immune cells in 4). $s the role of innate immunity in 4)

becomes better de&ned, it may be possible to better treat 4)

by targeting the innate immune system. Treatments are

patient-speci&c and depend on the symptoms that present with

the disorder, as well as the progression of the condition.

1..1 P"ognosis

This depends on the condition itself. )ome conditions such as

multiple sclerosis depend on the subtype of the disease and

various attributes of the patient such as age, se0, initialsymptoms and the degree of disability the patient e0periences.

Cife e0pectancy in 4ultiple sclerosis patients is 9 to 18 years

lower than unaected people. 4) is an in+ammatory

demyelinating disease of the central nervous system '!)( that

develops in genetically susceptible individuals after e0posure to

unknown environmental trigger's(.The bases for 4) 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 comple0. These interactions

between active T cells and myelin antigens provoke a massive

destructive in+ammatory response and promotes continuing

proliferation of T- and :-cells and macrophage activation, which

sustains secretion of in+ammatory mediators.

*ther conditions such as central pontine myelinolysis have

about a third of patients recover and the other two thirds

e0perience varying degrees of disability. There are cases, such

as transverse myelitis where the patient can begin recovery as

early as # to 1# weeks after the onset of the condition.

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CHAPTER /

2.1 a"ios Demyelinating diso"de"s o' t$e

Cent"al Ne"3os )ystem

The demyelinating disorders of the !) include/

- +yelinoclastic disorders, in which myelin is attacked by

e0ternal substances.- *tandard +ultiple sclerosis, Devic2s disease and other

disorders with immune system involvement called

in+ammatory demyelinating diseases.

-Leu$odystrophic disorders, in which myelin is not properly

produced/- C(* (europathies like those produced by Bitamin :1#

de&ciency.- Central pontine myelinolysis.- +yelopathies like Tabes dorsalis 'syphilitic 4yelopathy(.- Leu$oencephalopathies like rogressive multifocal

leukoencephalopathy.- Leu$odystrophies6

These disorders are normally associated also with the

conditions *ptic neuritis and Transverse myelitis, which are

in+ammatory conditions, because in+ammation and

demyelination are fre3uently associated. )ome 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 a"ios Demyelinating diseases o' t$e Pe"i#$e"al

Ne"3os )ystem

The demyelinating diseases of the peripheral nervous system

include/

- Guillain1Barr syndrome, and its chronic counterpart,

chronic in+ammatory demyelinating polyneuropathy.- Anti1+AG peripheral neuropathy.- Charcot1+arie1/ooth Disease6- Copper de7ciency associated conditions 'peripheral

neuropathy, myelopathy, and rarely optic neuropathy.- !rogressive in.ammatory neuropathy6

2.% 4o"ld/ide Resea"c$

"esearch is being conducted in a variety of very speci&c

areas. The focus of this research is aimed at gaining more

insight into how demyelinating disorders aect the central

nervous system and peripheral nervous system, how they

develop and how these disorders are aected by various

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e0ternal inputs. 4uch 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 aected by these conditions.

!urrently it is believed that -cadherin plays a role in the

myelination process. 0perimentation has shown that -

cadherin plays an important role in producing a remyelination-

facilitating environment. %t has been shown in animal models

that there is a direct correlation between the amount of myelin

debris present and the degree of %n+ammation observed.

0perimentation has shown that manipulating the levels of

thyroid hormone can be considered as a strategy to promote

remyelination and prevent irreversible damage in 4ultiple

sclerosis patients. -cadherin agonists have been identi&ed and

observed to stimulate neurite growth and cell migration, keyaspects of promoting a0on growth and remyelination after

injury or disease. %t has been shown that intranasal

administration of a/' 'apotransferrin( can protect myelin and

induce remyelination %&6

Demyelinating diseases=disorders have been found worldwide

in various animals. )ome of these animals include mice, pigs,

cattle, hamsters, rats, sheep, )iamese kittens, and a number of

dog breeds 'including !how !how, )pringer )paniel, Dalmatian,

)amoyed, olden "etriever, Curcher, :ernese 4ountain Dog,

Bisla, Ieimaraner, $ustralian )ilky Terrier, and mi0ed breeds(.

$nother notable animal found able to contract a

demyelinating disease is the orthern 7ur )eal. Niggy )tar, a

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orthern 7ur )eal, has been a patient at The 4arine 4ammal

!enter for the past several months and has been noted as the

&rst case of such disease in a marine mammal. )he will be

transported to 4ystic $3uarium O %nstitute for 0ploration for

lifelong care as an ambassador to the public %;&6

CHAPTER #

%.1 Defnition o' +lti#le )cle"osis

+lti#le scle"osis 5+)6, also known as disse,inated

sclerosis or encep+alo,elitis disse,inata, is an

in+ammatory 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. 4) takes several forms, with new symptoms either

occurring in isolated attacks 'relapsing forms( or building up

over time 'progressive forms(. :etween attacks, symptoms may

disappear completelyA however, permanent neurological

problems often occur, especially as the disease advances %&6

7ig.1 )agittal Biew of 4) patient, T#-)can. ote sclerae around

the !orpus !allosum '$rrows(.

%.2 Cases O' +lti#le )cle"osis

Ihile 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. roposed causes for this

include genetics and environmental factors such as infections.

4) is usually diagnosed based on the presenting signs and

symptoms and the results of supporting medical tests %0&6

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There is no known cure for multiple sclerosis. Treatments

attempt to improve function after an attack and prevent new

attacks. 4edications used to treat 4) while modestly eective

can have adverse eects and be poorly tolerated. 4any people

pursue alternative treatments, despite a lack of evidence. The

long-term outcome is diFcult 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 e0perienced few attacks. Cife e0pectancy is on average

9 to 18 years lower than that of an unaected population.

4ultiple sclerosis is the most common autoimmune disorder

aecting the central nervous system. $s of #88@, between #

and #.9 million people are aected globally with rates varying

widely in dierent regions of the world and among dierent

populations. %n #81, #8,888 people died from 4), up from

1#,888 in 1EE8. The disease usually begins between the ages

of #8 and 98 and is twice as common in women as in men. The

name multiple sclerosis refers to scars 'scleraeJbetter known

as pla3ues or lesions( in particular in the white matter of the

brain and spinal cord. 4) was &rst described in 1@


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The three main characteristics of 4) are the formation of

lesions in the central nervous system 'also called pla3ues(,

in+ammation, and the destruction of myelin sheaths of

neurons. These features interact in a comple0 and not yet fully

understood manner to produce the breakdown of nerve tissue

and in turn the signs and symptoms of the disease.

$dditionally, 4) is believed to be an immune-mediated disorder

that develops from an interaction of the individual2s genetics

and as yet unidenti&ed environmental causes. Damage is

believed to be caused, at least in part, by attack on the nervous

system by a person2s own immune system.

0ig" / )pine of 4) patient. ote the in+ammatory pla3ues

along the spinal cord.

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The name multiple sclerosis refers to the scars 'sclerae K

better known as pla3ues or lesions( that form in the nervous

system. These lesions most commonly aect 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 speci&c, 4) involves the loss of oligodendrocytes, the

cells responsible for creating and maintaining a fatty layerJ

known as the myelin sheathJwhich 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 a0ons of neurons. Ihen the myelin is lost, aneuron can no longer eectively conduct electrical signals.

$ repair process, called remyelination, takes place in early

phases of the disease, but the oligodendrocytes are unable to

completely rebuild the cell2s myelin sheath. "epeated attacks

lead to successively less eective remyelinations, until a scar-

like pla3ue is built up around the damaged a0ons. These scars

are the origin of the symptoms and during an attack magnetic

resonance imaging '4"%( often shows more than ten new

pla3ues. This could indicate that there are a number of lesions

below which the brain is capable of repairing itself without

producing noticeable conse3uences.

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0ig" # "emyelination process, histopathological overview.

$nother process involved in the creation of lesions is an

abnormal increase in the number of astrocytes due to the

destruction of nearby neurons. $ number of lesion patternshave been described.

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$part from demyelination, the other sign of the disease is

in+ammation. 7itting with an immunological e0planation, the

in+ammatory process is caused by T-cells, a kind of lymphocyte

that plays an important role in the body2s defences. T- cells gain

entry into the brain via disruptions in the bloodKbrain barrier.

The T-cells recognie myelin as foreign and attack it, e0plaining

why these cells are also called Hautoreactive lymphocytesH.

The attack of myelin starts in+ammatory processes, which

triggers other immune cells and the release of soluble factors

like cytokines and antibodies. 7urther breakdown of the bloodK

brain barrier, in turn cause a number of other damaging eects

such as swelling, activation of macrophages, and more

activation of cytokines and other destructive proteins.

%n+ammation 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 a0on to break down completely.

The bloodKbrain barrier is a part of the capillary system that

prevents the entry of T cells into the central nervous system. %t

may become permeable to these types of cells secondary to aninfection by a virus or bacteria. $fter it repairs itself, typically

once the infection has cleared, T cells may remain trapped

inside the brain. adolinium cannot cross a normal ::: and,

therefore, adolinium-enhanced 4"% is used to show :::

breakdowns.

%.& E#idemiology

#E


30/99

revalence wise, 4) is more common in people who live

farther from the e3uator, although e0ceptions e0ist. These

e0ceptions include ethnic groups that are at low risk far from

the e3uator such as the )amis, $merindians, !anadian

?utterites, ew Nealand 4Qori, and !anadaRs %nuit, as well as

groups that have a relatively high risk close to the e3uator such

as )ardinians, inland )icilians, alestinians and arsis. The

cause of this geographical pattern is not clear. Ihile the north-

south gradient of incidence is decreasing, as of #818 it is still

present.

4) is more common in regions with northern uropean

populations and the geographic variation may simply re+ect

the global distribution of these high-risk populations. Decreased

sunlight e0posure resulting in decreased vitamin D production

has also been put forward as an e0planation. $ relationship

between season of birth and 4) lends support to this idea, with

fewer people born in the northern hemisphere in ovember as

compared to 4ay being aected later in life. nvironmental

factors may play a role during childhood, with several studies

&nding that people who move to a dierent region of the world

before the age of 19 ac3uire the new regionRs risk to 4). %f

migration takes place after age 19, however, the person retains

the risk of his home country. There is some evidence that the

eect of moving may still apply to people older than 19.

%.( Ris! 7acto"s

a) .enetic

8


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4) is not considered a hereditary diseaseA however, a number

of genetic variations have been shown to increase the risk. The

probability is higher in relatives of an aected person, with a

greater risk among those more closely related. %n identical

twins both are aected about 8G of the time, while around 9G

for non-identical twins and #.9G of siblings are aected with a

lower percentage of half-siblings. %f both parents are aected

the risk in their children is 18 times that of the general

population. 4) is also more common in some ethnic groups

than others.

) Pat+ogenic

4any pathogens, in'ectious agents and microbes have beenproposed as triggers of 4), but none have been con&rmed.

vidence for a virus as a cause include/ the presence of

oligoclonal bands in the brain and cerebrospinal +uid of most

people with 4), the association of several viruses with human

demyelination encephalomyelitis, and the occurrence of

demyelination in animals caused by some viral infection.

?uman herpes viruses are a candidate group of viruses.

%ndividuals having never been infected by the pstein-:arr virus

are at a reduced risk of getting 4), whereas those infected as

young adults are at a greater risk than those having had it at a

younger age. $lthough some consider that this goes against the

hygiene hypothesis, since the non-infected have probably

1


32/99

e0perienced a more hygienic upbringing, others believe that

there is no contradiction, since it is a &rst encounter with the

causative virus relatively late in life that is the trigger for the

disease. *ther diseases that may be related include measles,

mumps and rubella.

c) S,o'ing

This has been shown to be an independent risk factor for 4).

*tress may be a risk factor although the evidence to support

this is weak. $ssociation with occupational e0posures and

to0insJmainly solventsJhas been evaluated, but no clear

conclusions have been reached. Baccinations were studied as

causal factorsA however, most studies show no association.

)everal other possible risk factors, such as diet and +or,one

inta'e, have been looked atA however, evidence on their

relation with the disease is Hsparse and unpersuasiveH. Gout occurs less than would be e0pected and lower levels of uric

acid have been found in people with 4). This has led to the

theory that uric acid is protectiveA although itRs e0act

importance remains unknown.

!rognosis for complete recovery is generally poor.

#


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%.* )igns and )ym#toms

4ultiple sclerosis can cause a variety of signs and symptoms/

!hanges in sensation 'hypoesthesia(, muscle weakness,abnormal muscle spasms, or diFculty movingA diFculties with

coordination and balanceA 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 diFculties, cognitive

impairment, or emotional symptomatology 'mainly major

depression(. The main clinical measure in progression of the

disability and severity of the symptoms is the 0panded

Disability )tatus )cale or D)).

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 identi&ed 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 'G(, complete or partial vision loss

'optic neuritis( '#8G(, weakness '1G(, double vision '>G(,

unsteadiness when walking '9G(, and balance problems 'G(A

but many rare initial symptoms have been reported such as

aphasia or psychosis. 7ifteen percent of individuals have

multiple symptoms when they &rst seek medical attention.

a)ladder problems appear in >8K@8G of people with

multiple sclerosis '4)( and they have an important eect

both on hygiene habits and social activity. :ladder


34/99

problems are usually related with high levels of disability

and pyramidal signs in lower limbs.

The most common problems are an increase in fre3uency and

urgency 'incontinence( but diFculties to begin urination,

hesitation, leaking, sensation of incomplete urination, and

retention also appear. Ihen retention occurs secondary urinary

infections are common.

There are many cortical and subcortical structures implicated

in urination and 4) 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 classi&ed in two main subtypes/

pharmacological and non-pharmacological. harmacological

treatments vary greatly depending on the origin or type of

dysfunction and some e0amples of the medications used are/

alfuosin for retention, trospium and +avo0ate for urgency and

incontinency, and desmopressin for nocturia. on

pharmacological treatments involve the use of pelvic +oor

muscle training, stimulation, biofeedback, pessaries, bladder

retraining, and sometimes intermittent catheteriation.

)o*el problems aect around >8G of the patients, with

around 98G of the patients suering from constipation

and up to 8G from fecal incontinence. !ause of bowel

impairments in 4) patients is usually either a reduced gut

motility or an impairment in neurological control of

6


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defecation. The former is commonly related to immobility

or secondary eects from drugs used in the treatment of

the disease. ain or problems with defecation can be

helped with a diet change which includes among other

changes an increased +uid intake, oral la0atives or

suppositories and enemas when habit changes and oral

measures are not enough to control the problems.c) Cognitivel2 some of the most common de&cits aect

recent memory, attention, processing speed, visual-spatial

abilities and e0ecutive function. )ymptoms related tocognition include emotional instability and fatigue

including neurological fatigue. !ommonly a form of

cognitive disarray is e0perienced, where speci&c cognitive

processes may remain unaected, but cognitive processes

as a whole are impaired. !ognitive de&cits are

independent of physical disability and can occur in theabsence of neurological dysfunction. )evere impairment is

a major predictor of a low 3uality of life, unemployment,

caregiver distress, and diFculty in drivingA limitations in a

patient2s social and work activities are also correlated with

the e0tent of impairment.

!ognitive impairments occur in about 68 to


36/99

have up to 98 percent of patients with impairment at onset.

Dementia is rare and occurs in only &ve percent of patients.

4easures of tissue atrophy are well correlated with, and

predict, cognitive dysfunction. europsychological outcomes

are highly correlated with linear measures of sub-cortical

atrophy. !ognitive impairment is the result of not only tissue

damage, but tissue repair and adaptive functional

reorganiation. europsychological testing is important for

determining the e0tent of cognitive de&cits. europsychological

rehabilitation may help to reverse or decrease the cognitive

de&cits although studies on the issue have been of low 3uality.

$cetylcholinesterase inhibitors are commonly used to treat

$lheimer2s disease related dementia and so are thought to

have potential in treating the cognitive de&cits in multiple

sclerosis. They have been found to be eective in preliminary

clinical trials.

d)E,otional symptoms are also common and are thought

to be both a normal response to having a debilitating

disease and the result of damage to speci&c areas of the

central nervous system that generate and control

emotions.

!linical depression is the most common neuropsychiatric

condition/ lifetime depression prevalence rates of 68K98G and

1#-month prevalence rates around #8G have been typically


37/99

reported for samples of people with 4)A these &gures are

considerably higher than those for the general population or for

people with other chronic illnesses. :rain imaging studies have

tried to relate depression to lesions in certain regions of the

brain have met with variable success. *n balance the evidence

seems to favour an association with neuropathology in the left

anterior temporal=parietal regions.

*ther feelings such as anger, an0iety, frustration, and

hopelessness also appear fre3uently and suicide is a very real

threat since it results in 19G of deaths in 4) suerers. "arely

psychosis may also be featured.

e)0atigue is very common and disabling in 4) with a close

relationship to depressive symptomatology. Ihen

depression is reduced fatigue also tends to reduce and it is

recommended that patients should be evaluated fordepression before other therapeutic approaches are used.

%n 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

dierent medications used to treat fatigueA such asamantadine, or pemolineA as well as psychological

interventions of energy conservationA but their eects are

small and for these reasons fatigue is a diFcult symptom

to manage. 7atigue has also been related to speci&c brain

areas in 4), using magnetic resonance imaging.

>


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f) Internuclear op+t+al,oplegia is a disorder of

conjugate lateral gae. The aected eye shows

impairment of adduction. The partner eye diverges from

the aected eye during abduction, producing diplopiaA

during e0treme abduction, compensatory nystagmus can

be seen in the partner eye. Diplopia means double vision

while nystagmus is involuntary eye movement

characteried by alternating smooth pursuit in one

direction and a saccadic movement in the other direction.

%nternuclear ophthalmoplegia occurs when 4) aects 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 e3ually 'called disconjugate gae(.

Dierent drugs as well as optic compensatory systems and

prisms can be used to improve these symptoms. )urgery can

also be used in some cases for this problem.

g)Restrictions in ,oilit 'walking, transfers, bed mobilityetc.( are common in individuals suering from multiple

sclerosis. Iithin 18 years after the onset of 4) one-third

of patients reach a score of < on the 0panded Disability

)tatus )cale 'D))(, re3uiring the use of a unilateral

walking aid, and by 8 years the proportion increases to

@G. Iithin &ve years of onset the D)) is si0 in 98G ofthose with the progressive form of 4).

@


39/99

$ wide range of impairments may e0ist in 4) suerers which

can act either alone or in combination to impact directly on a

person2s balance, function and mobility. )uch impairments

include fatigue, weakness, hypertonicity, low e0ercise

tolerance, impaired balance, ata0ia and tremor.

%nterventions 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 e3uipment such as walking aids, wheelchairs,

motoried scooters and car adaptations as well as instruction

on compensatory strategies to accomplish an activity J for

e0ample undertaking safe transfers by pivoting in a +e0ed

posture rather than standing up and stepping around.

5p to 98G of patients with 4) will develop an episode of

optic neuritis and #8G of the time optic neuritis is the

presenting sign of 4). The presence of demyelinating white

matter lesions on brain 4"%s at the time of presentation for

optic neuritis is the strongest predictor in developing clinical

diagnosis of 4). $lmost half the patients with optic neuritis

have white matter lesions consistent with multiple sclerosis.

$t &ve year follow-ups the overall risk of developing 4) is

8G, with or without 4"% lesions. atients with a normal 4"%

still develop 4) '1


40/99

other perspective, however, 66G of patients with any

demyelinating lesions on 4"% at presentation will not have

developed 4) ten years later.

%ndividuals e0perience rapid onset of pain in one eye followed

by lurr vision in part or all its visual &eld. 7lashes of light

' phosphenes( may also be present. %n+ammation 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 18 weeks but

individuals are often left with less vivid colour vision, especially

red, in the aected eye. $ systemic intravenous treatment with

corticosteroids may 3uicken the healing of the optic nerve,

prevent complete loss of vision and delay the onset of other

symptoms.

+)Pain is a common symptom in 4). $ recent study

systematically pooling results from #@ studies '>181

patients( estimates that pain aects


41/99

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 '6G(,

dysesthetic limb pain '#


42/99

studied although the bene&cial eects and risks in 4)

patients of the procedures that relieve pressure on the

nerve are still under discussion.

&) 3+er,itte4s sign is an electrical sensation that runsdown 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 signi&cantly with cervical 4"%

abnormalities. :etween #9 and 68G of 4) patients report

having Chermitte2s sign during the course of their illness. %tis not always e0perienced as painful, but about 19 to E1G.

rectile dysfunction appears to be the most common form

of )D documented in 4). )D may be due to alteration of

6#


43/99

the ejaculatory re+e0 which can be aected by

neurological conditions such as 4). )e0ual dysfunction is

also prevalent in female 4) patients, typically lack of

orgasm, probably related to disordered genital sensation.,) Spasticit is characterised by increased stiness

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. ainful spasms aect

about 19G of people with 4) overall. $ physiotherapistcan help to reduce spasticity and avoid the development

of contractures with techni3ues such as passive

stretching. There is evidence, albeit limited, of the clinical

eectiveness of T?! and !:D e0tracts, baclofen,

dantrolene, diaepam, and tianidine. %n the most

complicated cases intrathecal injections of baclofen canbe used. There are also palliative measures like castings,

splints or customised seatings.n)Speec+ prole,s include slurred speech, low tone of

voice 'dysphonia(, decreased talking speed, and problems

with articulation of sounds 'dysarthria(. $ related problem,

since it involves similar anatomical structures, is

swallowing diFculties 'dysphagia(

)ome 4) 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 4) attacking the spinal cord. The symptoms and signs

depend upon the nerve cords involved and the e0tent of the

involvement.

6


44/99

o)Tre,or is an unintentional, somewhat rhythmic, muscle

movement involving to-and-fro movements 'oscillations(

of one or more parts of the body. %t is the most common of

all involuntary movements and can aect the hands,

arms, head, face, vocal cords, trunk, and legs. $ta0ia is an

unsteady and clumsy motion of the limbs or torso due to a

failure of the gross coordination of muscle movements.

eople with ata0ia e0perience 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 fre3uent in 4) and present in #9 to


45/99

%f 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. !omplications are

fre3uent '8G in thalamotomy and 18G in deep brain

stimulation( and include a worsening of ata0ia, dysarthria and

hemiparesis. Thalamotomy is a more eFcacious surgical

treatment for intractable 4) tremor though the higher

incidence of persistent neurological de&cits in patients

receiving lesional surgery supports the use of deep brain

stimulation as the preferred surgical strategy.

The cause of 4) is unknownA 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 e0planations, but none has proved de&nitive.

Ihile there are a number of environmental risk factors and

although some are partly modi&able, further research is needed

to determine whether their elimination can prevent 4).

%., Diagnostic C"ite"ia

4ultiple sclerosis is typically diagnosed based on the

presenting signs and symptoms, in combination with supporting

medical imaging and la-o"ato"y testing. %t can be diFcult

to con&rm, especially early on, since the signs and symptoms

may be similar to those of other medical problems. The

+cDonaldEs criteria, which focus on clinical, laboratory, and

radiologic evidence of lesions at dierent times and in dierent

areas, is the most commonly used method of diagnosis with the

*chumacher and !oser criteria being of mostly historical

69


46/99

signi&cance. Ihile the above criteria allow for a non-invasive

diagnosis, some state that the only de&nitive proof is an

autopsy or biopsy where lesions typical of 4) are detected

%:&6

!linical data alone may be suFcient for a diagnosis of 4) if an

individual has had separate episodes of neurologic symptoms

characteristic of the disease. %n 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 +uid and evoked

potentials. 4agnetic resonance imaging of the brain and spine

may show areas of demyelination 'lesions or pla3ues(.

adolinium can be administered intravenously as a contrast

agent to highlight active pla3ues and, by elimination,

demonstrate the e0istence of historical lesions not associated

with symptoms at the moment of the evaluation. Testing of

cerebrospinal +uid obtained from a lumbar puncture can

provide evidence of chronic in+ammation in the central nervous

system.

The cerebrospinal +uid is tested for oligoclonal bands of %g

on electrophoresis, which are in+ammation markers found in>9K@9G of people with 4).The nervous system in 4) may

respond less actively to stimulation of the optic nerve and

sensory nerves due to demyelination of such pathways. These

brain responses can be e0amined using visual- and sensory-

evoked potentials.

6


47/99

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

appropriate to consider several lood tests in the initial

evaluation of the patient with suspected 4). These tests

include complete blood count '!:!(, antinuclear antibodies

'$$(, serum test for syphilis '"", BD"C, etc.(, +uorescent

treponemal antibody test '7T$(, Cyme titer, )" and, possibly,

angiotensin converting enyme level 'a test for sarcoidosis(.

%maging '4"% preferably( should be performed to rule out

alternative diagnoses and because 4"% can provide information

about dissemination of disease. *ver E8G of patients with 4)

have abnormalities on the 4"% scan. 4ultifocal white matter

disease of 4) is easily observed but not easily dierentiated

from vascular lesions, gliotic scars or other forms of

in+ammation.

$s yet, there are no entirely pathognomonic criteria for 4) on

an 4"% scan, but +cDonald8s c"ite"ia are used in research

studies.

These are 4"% criteria used in the diagnosis of multiple

sclerosis, first introduced in #881, revised in #889 and again

recently in #818. This latest revision improves sensitivity from

6>G with a slight trade-o in speci&city 'slightdeterioration from E6G to E#G(, with an overall accuracy of

@


48/99

Dissemination in space re3uires S1 T# bright lesions in two or

more of the following locationsA

eriventricular

ju0tacortical

infratentorial

spinal cord

%f a patient has a brainstem = spinal cord syndrome, the

symptomatic lesion's( are e0cluded from the criteria, not

contributing to the lesion count.

Disse,ination in ti,e5

Dissemination in time can be established in one of few waysA

$ new lesion when compared to a previous scan

'irrespective of timing(. T# bright lesion and=or gadolinium enhancing.

resence of asymptomatic enhancing lesion and a non-enhancing T# bright lesion on any one scan.

Pri,ar progressive ,ultiple sclerosis (PPMS)

%n addition to the above criteria, the diagnosis of primary

progressive multiple sclerosis has also been revised. The

diagnosis now re3uires/

S1 year of disease progression 'this can be determined either

prospectively or retrospectively( plus two of the following three

criteria A

- :rain dissemination in space ' S1 T# bright lesions in S1

of ju0tacortical, periventricular, infratentorial areas(- )pinal cord dissemination in space 'S# T# bright lesions(

6@


49/99

- ositive !)7 'oligoclonal bands and=or elevated %g inde0

Signs pertaining to t+e McDonald6s Criteria include5

a)Da2sons 7ngers

These are a radiographic feature depicting demyelinating

pla3ues through the corpus callosum, arranged at right angles

along medullary veins 'callososeptal location(. They are a

relatively speci&c sign for multiple sclerosis '4)(, which

presents as T# hyperintensities '=(.

0ig" 7 DawsonRs 7ingers clearly visible intra-a0ially.

)"pen ring enhancement

The open ring sign is a relatively speci&c sign for

demyelination, most commonly multiple sclerosis '4)(, and is

helpful in distinguishing between ring enhancing lesions.

%nterestingly open ring enhancement is not seen in

neuromyelitis optica 'N+O(. The enhancing component is

6E


50/99

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

'>&6

c) / blac$ holes$s neurodegeneration in 4) ensues, the formation and

evolution of persistent Tl-hypointense lesions 'black

holes( have been used as markers of a0onal loss and

neuronal destruction to measure disease activity. Despite

the use of various detection methods, including advanced

imaging techni3ues such as magnetiation transfer

imaging and magnetic resonance spectroscopy,

correlation of persistent black holes with clinical outcomes

in patients with 4) remains uncertain. 7urthermore,

although a0onal loss and neuronal tissue destruction are

known to contribute to irreversible disability in patients

with 4), there is limited data on the eect of therapy in

Tl-hypointense lesion volume.

a"iants pertaining to the 4cDonaldRs !riteria includeA

-/ume'active multiple sclerosis

- Acute malignant +arburg type- *childer type %diuse cerebral sclerosis&- Balo concentric sclerosis %BC*&- "pticospinal multiple sclerosis %"*+*&- (euromyelitis optica %(+"& %Devic disease&IJK- Acute disseminated encephalomyelitis %AD-+& and acute

haemorrhagic 1encephalomyelitis %AH-+&

-/ume'active demyelinating lesions

- /ransverse myelitis

98


51/99

- Chronic in.ammatory demyelinating polyneuropathy

%CD!&- Guillain1Barre *yndrome %GB*( %


52/99

Ihen de&cits always resolve between attacks, this is

sometimes referred to as benign 4), although people will

still build up some degree of disability in the long term. *n

the other hand, the term malignant multiple sclerosis is

used to describe people with 4) having reached

signi&cant level of disability in a short period. The

relapsing-remitting subtype usually begins with a clinically

isolated syndrome '!%)(. %n !%), a person has an attack

suggestive of demyelination, but does not ful&ll the

criteria for multiple sclerosis. 8 to >8G of persons

e0periencing !%) later develop 4).

/" Secondar progressive +* occurs in around


53/99

7" Progressive relapsing +* 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.

0ig"9 "elapsing and rogressive 4), ju0taposed with healthy

control specimen

5nusual types of 4) have been describedA these include

Devic2s disease, :alo concentric sclerosis, )childer2s diuse

sclerosis, and 4arburg multiple sclerosis. There is debate on

whether they are 4) variants or dierent diseases. 4ultiple

sclerosis behaves dierently in children, taking more time to

reach the progressive stage. evertheless, they still reach it at

a lower average age than adults usually do.

%. T$e"a#y and +anagement

$lthough there is no known cure for multiple sclerosis, several

therapies have proven helpful. The primary aims of therapy are

9


54/99

returning function after an attack, preventing new attacks, and

preventing disability. $s with any medical treatment,

medications used in the management of 4) have several

adverse eects. $lternative treatments are pursued by some

people, despite the shortage of supporting evidence.

-o treat,ent +as een s+o*n to c+ange t+e course of

pri,ar progressive +), and as of #811 only one

medication, mitoxantrone9 has been approved for secondary

progressive 4). %n this population tentative evidence supports

mito0antrone moderately slowing the progression of the

disease and decreasing rates of relapses over two years %@&6

The prognosis of the disease depends on the subtype of the

diseaseA the individual2s se0, age, and initial symptomsA and the

degree of disability the person has. 7emale se0, relapsing-

remitting 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 e0pectancy is 8 years from the start of the

disease, which is 9 to 18 years less than that of unaected

people. $lmost 68G of people with 4) reach the seventh

decade of life. evertheless, two-thirds of the deaths are

directly related to the conse3uences of the disease.

96


55/99

7ig. * 4) progression as seen over 6 years. ote the

disseminations in time and space.

$s far as epide,iolog is concerned, 4) is the most

common autoimmune disorder of the central nervous system.

$s of #818, the number of people with 4) was #K#.9 million

'appro0imately 8 per 188,888( globally, with rates varying

widely in dierent regions. %t is estimated to have resulted in

99


56/99

1@,888 deaths that year. %n $frica rates are less than 8.9 per

188,888, while they are #.@ per 188,888 in )outh ast $sia, @.

per 188,888 in the $mericas, and @8 per 188,888 in urope.

"ates surpass #88 per 188,888 in certain populations of

orthern uropean descent. The number of new cases that

develop per year is about #.9 per 188,888 %&6

"ates of 4) appear to be increasingA this, however, may be

e0plained simply by better diagnosis. )tudies on populational

and geographical patterns have been common and have led to

a number of theories about the cause.

%..1 +lti#le )cle"osis Resea"c$

Treatments under investigation for multiple sclerosis may

improve function, curtail attacks, or limit the progression of the

underlying disease. 4any treatments already in clinical trials

involve drugs that are used in other diseases or medications

that have not been designed speci&cally for multiple sclerosis.

There are also trials involving the combination of drugs that are

already in use for multiple sclerosis. 7inally, there are also

many basic investigations that try to understand better the

disease and in the future may help to &nd new treatments.

$dvancements during the last decades have led to the recent

approval of several oral drugs. These drugs are e0pected to

gain in popularity and fre3uency of use at the e0pense of

previously e0isting therapies.

7inally, regarding neuroprotective and specially regenerative

treatments such as stem cell therapy, while their research is

9


57/99

considered of high importance at the moment they are only a

promise of future therapeutic approaches.

Cikewise, there are not any eective treatments for the

progressive variants of the disease. 4any of the newest drugs

as well as those under development are probably going to be

evaluated as therapies for 4) or )4), and their improved

eectiveness when compared with previously e0isting drugs

may eventually lead to a positive result in these groups of

patients.

%mprovement in ne"oimaging tec$ni:es such as positron

emission tomography %!-/ ( or magnetic resonance imaging

%+( carry a promise for better diagnosis and prognosis

predictions, although the eect of such improvements in daily

medical practice may take several decades. "egarding 4"%,

there are several techni3ues that have already shown someusefulness in research settings and could be introduced into

clinical practice, such as do-le;in3e"sion "eco3e"y

se:ences9 magneti


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!hronic in+ammatory demyelinating polyradiculoneuropathy

'!%D( is clinically de&ned as a >8chronically progressive,

stepwise or recurrent pro0imal and distal weakness and sensory

dysfunction of all e0tremities, developing over at least #

months, with absent or reduced tendon re+e0es in all limbs and

sometimes with cranial nerve involvement8>.

)ensory dysfunction is fre3uently present, most usually

aecting joint position and vibration submodalities. Iasting is

not prominent early in the disease. There are atypical forms,

such as multifocal ac3uired demyelinating sensory and motor

neuropathy '4$D)$4, or CewisK)umner syndrome(, pure

sensory or pure motor !%D and focal or distal forms 'distal

ac3uired demyelinating sensory polyneuropathy 'D$D)(.

?owever, the medical imaging of demyelinating diseases, with

emphasis on multiple sclerosis in the area of !onstanta,

"omania, shall now be stressed upon.

9@


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)PECIAL PART

9E


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CHAPTER 7

$n understanding of what is seen in medical imaging of

demyelination, with emphasis on 4ultiple )clerosis, is

necessary to be understood, before embarking upon speci&c

patient &les.

&.1 +agnetic Resonance Imaging 5+RI6

This is a medical imaging techni3ue used in radiology to

investigate the anatomy and physiology of the body in both

health and disease. 4"% scanners use magnetic &elds and radio

waves to form images of the body. The techni3ue is widely used


61/99

in hospitals for medical diagnosis, staging of disease and

follow-up without e0posure to ioniing radiation.

This is is the diagnostic tool that currently oers the most

sensitive non-invasive way of imaging the brain, spinal cord, or

other areas of the body. %t is the preferred imaging method to

help establish a diagnosis of 4) and to monitor the course of

the disease. 4"% has made it possible to visualie and

understand much more about the underlying pathology of the

disease.

4"% 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 '#8(, as it is more sensitive

than !T for small tumours and oers better visualiation of the

posterior fossa. The contrast provided between grey and whitematter makes it the optimal choice.


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7ig. , )tandard 4"% e3uipment.

Ho* it *or's/

5nlike a computed tomography '!T( scan or conventional -

ray, 4"% does not use radiation. 4"% measures the water

content in tissues J both normal tissue and abnormal. 4"%

uses a powerful magnetic &eld that/

-

4akes the hydrogen protons in water molecules line up inthe direction of the magnetic &eld.

- *nce the hydrogen protons have been lined up, radio

waves are used to knock them out of line.- Ihen the radio waves are stopped, the protons rela0 back

into line. $s they rela0, the protons release resonance

signals that are transmitted to a computer.

Tpes5

The various types of 4"% scans that are used 'most commonly

the T1 and T#( measure this rela0ation time in dierent ways.

!omputer programs translate these data into cross-sectional

pictures of the water in human tissue.

:ecause the layer of myelin that protects nerve cell &bers is

fatty, it repels water. %n the areas where the myelin has been

damaged by 4), the fat is stripped away. Iith the fat gone, the

area holds more water, and shows up on an 4"% scan as either


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

of scan that is used.

&.2 Use In Diagnosis o' +)

:ecause 4"% is particularly useful in detecting central nervous

system demyelination, it is a powerful tool in helping to

establish the diagnosis of 4). ?owever, appro0imately 9

percent of people with clinically-de&nite 4) do not initially show

lesions on 4"% at the time of diagnosis. %f repeat 4"%s continue

to show no lesions, the diagnosis of 4) should be 3uestioned.

)ince many lesions seen on 4"% may be in so-called HsilentH

areas of the brain that donRt produce symptoms, it is not always

possible to make a speci&c correlation between what is seen on

the 4"% scan and the person2s clinical signs and symptoms.

%n addition, with advancing age 'probably over age 98(, thereare often small areas seen on 4"% in healthy people that

resemble 4) but are actually related to the aging process.

Clinicall Isolated Sndro,e (CIS)5

%n diagnosing a clinically isolated syndrome it is important to

rule out other potential causes. $n individual2s medical history

might be used alongside a clinical e0amination and blood tests


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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 4"% scan. $n 4"% 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 e0perienced. The areas where this damage is

most fre3uently seen include/

/he spinal cord - where the medical description for it is

transverse myelitis /he optic nerve - where the medical description for it is

optic neuritis /he brainstem - where the medical description for it is

brainstem syndrome

Ihere damage is seen in more than one of the above areas it

is often referred to as >mlti'ocal a-no"malities2.

4"% is particularly helpful in patients who have had a single

demyelinating attack that is suggestive of 4), also called a

clinically isolated syndrome '!%)(.

The number of lesions on an initial 4"% of the brain 'or spinal

cord( can help the physician assess the personRs risk of


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developing a second attack 'and therefore Uclinically-de&nite

4)V( in the future. )ome of the treatments for 4) have been

shown to delay the occurrence of a second episode of

symptomatic demyelination in people who have had only one.

The 4"% can also be used to identify a second neurological

event in a person who has no additional symptoms J thereby

helping to con&rm a diagnosis of 4) as early as possible.

*nce a diagnosis of 4) has been clearly established,

subse3uent 4"% scans are useful in tracking the progress of the

disease and making treatment decisions. 7or e0ample, a

neurologist may consider disease activity on 4"% as well as a

person2s clinical symptoms and relapses in order to determine

whether the current treatment is eective or a change in

treatment needs to be considered.

?ealthcare professionals dier in their opinion about how

often an 4"% should be done for 4), but most now recommend

it on an annual basis. Ihen possible, follow-up 4"%s should be

obtained on the same scanner as this will help the radiologist

and the patientRs healthcare provider, to make a comparison

between one 4"% and the ne0t.


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&.% Di=e"ent )e:ences P"o3ide Di=e"ent

In'o"mation0

These areas of in+ammation appear as active lesions, meaning

that they are new or getting bigger.

/1se3uences also show dark areas 'hypointensities( that are

thought to indicate areas of permanent nerve damage.

/01 se3uences provide information about disease burden or

lesion load 'meaning the total amount of lesion area, both old

and new(.

FLA %.uid attenuated inversion recovery& images are used to

better identify brain lesions associated with 4).

)pinal cord imaging can identify pathology in the cord. %t can

also help establish the diagnosis of 4) by demonstrating that

damage has occurred in dierent parts of the central nervous

system 'dissemination in space( at dierent points in time

'dissemination in time(.

$ T1-se3uence, enhanced with gadolinium 'injected

intravenously to further enhance scan sensitivity(, supplies

information about current disease activity by highlighting areas

of active in+ammation.

:ecause gadolinium is a large molecule, it normally cannot

pass through the blood-brain barrier 'a cell layer around blood


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vessels in the brain and spinal cord that prevents substances

from passing from the blood stream into the central nervous

system(. ?owever, when there is active in+ammation, the blood

brain barrier is disrupted and gadolinium can enter and

highlight the in+amed areas.

$lthough other types of scans are used for research purposes,

these are the ones most commonly used in clinical care.

&.& Di=e"ent +agnetic )t"engt$s P"o3ide

Di=e"ent In'o"mation0

The strength of the magnet used in the 4"% machine is

important to the 3uality of the images. 4agnet strength is

measured in Tesla 'T(.

4ost conventional 4"% machines are 1.9T or .8T. *pen 4"%Rs

are usually less than 1.9T and do not provide the best images

for detecting 4) activity, although they may be used when

someone has diFculty tolerating a closed 4"% machine.

4"% machines used for research purposes have much higher T.

&.( Di=e"ential Diagnosis Using +RI

$ brain 4"% scan at the time a person presents with initial

symptoms of a clinically isolated syndrome is thought to be the

most useful predictive tool. $ normal 4"% scan showing no


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lesions is associated with a lower risk of developing 4)

whereas a brain scan that shows a high number or volume of

lesions is associated with a higher risk of developing 4).

The diagnosis of 4) 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. 4ultiple emboli and vasculitis can result in small

infarcts that can appear as white matter damage on 4"% scans.

!entral nervous system sarcoidosis 'an idiopathic, steroid-

responsive in+ammatory condition( can produce reversible

optic neuritis and other !) signs. Ihipple disease also has a

tendency to result in in+ammatory lesions, along with unusual

eye movements due to midbrain involvement.

Bitamin :1# de&ciency is suggested by dementia, spasticity,and posterior column &ndings. 4eningovascular syphilis, a rare

but reemerging entity, can give rise to multifocal !) damage

due to multifocal meningeal vascular in+ammation. !) Cyme

disease can also produce multifocal disease, probably due to

vasculitis. $n additional concern is that single lesions 'by

de&nition, not 4)( can aect several dierent neurologicalsystems.

7or e0ample, a patient may have cerebellar ata0ia 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. 7ortunately, magnetic resonance

imaging, is particularly good at detecting such lesions


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'although they were diFcult to see with older technology, such

as the !T scan(. *n the other hand, if that person also had

optic neuritis or hemiparesis involving the face, one lesion

could no longer e0plain the &ndings. $ history of remissions and

e0acerbations also helps in the diagnosis of 4), but it must be

remembered that the symptoms of neoplasms commonly

+uctuate to some degree.

CHAPTER 9

(.1 Resea"c$ )tdy )-?ects

7ive '9( patients in the Constanta area, in "omania, were

e0amined. Two male, ages 9 and #< ':orn 1E@8 and 1E@E,

respectively(, and three female, ages 6>, 6, and @. ':orn

1E#, and 1E>>, respectively(. They were diagnosed with


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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 aected patients '#8-98( given

that the youngest of the 9 was #< 'male(, and the oldest was

6> 'female(.

The gender distribution was also in accordance with general

statistics, with slightly more women being aected than men.

(.2 )tdy +et$od

7or diagnostic purposes at the begining investigations were

done with and without gadolinium enhancement. T1 and T#

se3uences were used to diagnose and appreciate disease

activitiy. T1 is with regards to $y#ointensities and T# with

$y#e"intensities.

adolinium does not normally cross the blood-brain barrier

unless there are active lesions, and generalised in+ammation,

as is the case with these 9 subjects.

>8


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0ig": )agittal plane image, highlighting hyperintense lesions,

visible in spinal area, in 6> year o

medical imaging of demyelinating diseases; with emphasis on multiple sclerosis

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