diagnosis of multiple sclerosis in adults 2

8/18/2019 Diagnosis of Multiple Sclerosis in Adults 2

1/21

INTRODUCTION

Multiple sclerosis (MS) is the most common immune-mediated inflammatorydemyelinatin disease of the central ner!ous system" Multiple sclerosis is

characteri#ed patholoically $y multifocal areas of demyelination %ith loss of oliodendrocytes and astrolial scarrin" &'onal inury is increasinly reconi#edas a prominent patholoic feature of Multiple sclerosis" Certain clinical features aretypical of multiple sclerosis $ut the disease has a hihly !aria$le pace and manyatypical forms"

The dianosis differential dianosis and unusual presentations of multiplesclerosis are re!ie%ed here" Other aspects of MS are discussed separately*

DI&+NOSIS , Multiple sclerosis is primarily dianosed clinically" The corereuirement for the dianosis is the demonstration of central ner!ous system lesion

dissemination in time and space $ased upon either clinical findins alone or acom$ination of clinical and MRI findins" The history and physical e'amination aremost important for dianostic purposes" MRI is the test of choice to support theclinical dianosis of multiple sclerosis" The McDonald dianostic criteria includespecific MRI criteria for the demonstration of lesions dissemination in time andspace" (See .McDonald criteria. $elo%")

The dianosis of multiple sclerosis is relati!ely straihtfor%ard for patients %hopresent %ith symptoms and MRI neuroimain findins that are typical for Multiplesclerosis and ha!e a relapsin-remittin course" The typical patient presents as ayoun adult %ith one or more clinically distinct episodes of central ner!ous systemdysfunction such as optic neuritis lon tract symptoms sins a $rainstemsyndrome or a spinal cord syndrome follo%ed $y at least partial resolution"Symptoms usually de!elop o!er the course of hours to days and then raduallyremit o!er the ensuin %ee/s to months thouh remission may not $e complete"0resentin symptoms and sins may $e either monofocal (consistent %ith a sinlelesion) or multifocal (consistent %ith more than one lesion)" 1hile there are noclinical findins that are uniue to MS (see 2Clinical features of multiple sclerosis inadults2 section on .Clinical symptoms and sins.) some are hihly characteristic(ta$le 3)" Common presentin symptoms of MS are listed in the ta$le (ta$le 4)"

Dianostic difficulties arise in patients %ho ha!e atypical presentationsmonophasic episodes or proressi!e illness from onset (see .Differential dianosis.$elo%)" In these cases in!estiati!e studies in addition to MRI such as e!o/edpotentials and cere$rospinal fluid analysis (ta$le 5) are often needed to confirm thedianosis and e'clude other possi$ilities" &dditionally some indi!iduals ha!echaracteristic MRI lesions %ithout symptoms often disco!ered in the dianostic%or/up for other conditions (ie headaches)" These cases termed radioraphicallyisolated syndrome present an additional dianostic difficulty"


2/21

Dianostic criteria for Multiple sclerosis de!eloped in the early 3678s (the 0oser criteria) considered clinical characteristics and a num$er of la$oratory studiesincludin cere$rospinal fluid analysis e!o/ed potentials and neuroimain" Thesefindins %ere then used to place patients in cateories ranin from clinicallydefinite to la$oratory supported definite to clinically pro$a$le to la$oratory

supported pro$a$le MS" The 0oser criteria %ere de!eloped primarily to ensure thatonly MS patients %ere included in research studies" They ha!e $een supplanted $ythe McDonald criteria %hich %ere de!eloped in 4883 and su$seuently re!ised in4889 and 4838" :uture re!isions are li/ely"

McDonald criteria , The McDonald criteria first de!eloped in 4883 and re!ised in4889 %ere re!ised aain in 4838 in order to incorporate ne%er e!idence and tosimplify the use of neuroimain %hile preser!in the sensiti!ity and specificity of the criteria" The core reuirement of the dianosis is the o$ecti!e demonstration of dissemination of central ner!ous system lesions in $oth space and time $asedupon either clinical findins alone or a com$ination of clinical and MRI findins"

(See .Manetic resonance imain. $elo%")

;Dissemination in space is demonstrated %ith MRI $y one or more T4 lesions inat least t%o of four Multiple sclerosis -typical reions of the central ner!ous system(peri!entricular u'tacortical infratentorial or spinal cord) or $y the de!elopment of a further clinical attac/ implicatin a different central ner!ous system site" :or patients %ith $rainstem or spinal cord syndromes symptomatic MRI lesions aree'cluded from the criteria and do not contri$ute to lesion count"

;Dissemination in time is demonstrated %ith MRI $y the simultaneous presenceof asymptomatic adolinium-enhancin and non enhancin lesions at any time or a ne% T4 and


3/21

;:or patients %ith one attac/ %ho ha!e o$ecti!e clinical e!idence of t%o or morelesions the criteria reuire e!idence of dissemination in time"

;:or patients %ith one attac/ %ho ha!e o$ecti!e clinical e!idence of one lesion (iea clinically isolated syndrome =CIS?) the criteria reuire e!idence of dissemination

in space and time"

;:or patients %ho present %ith insidious neuroloical proression suesti!e of primary proressi!e Multiple sclerosis the criteria reuire e!idence of the one year of disease proression (retrospecti!ely or prospecti!ely determined) plus t%o of thethree follo%in criteria (for patients %ith $rainstem or spinal cord syndromessymptomatic MRI lesions are e'cluded from the criteria and do not contri$ute tolesion count)*

ADissemination in space in the $rain $ased upon one or more T4 lesions in at leastone area characteristic for Multiple sclerosis (peri!entricular u'tacortical or

infratentorial)

ADissemination in space in the spinal cord $ased upon t%o or more T4 lesions inthe cord

A0ositi!e cere$rospinal fluid findins %ith isoelectric focusin e!idence of olioclonal $ands and


4/21

;The dianosis of 2 Multiple sclerosis 2 is i!en if the criteria are fulfilled and thereis no $etter e'planation for the clinical presentation

;The dianosis of 2possi$le Multiple sclerosis 2 is i!en if MS is suspected $ut thecriteria are not completely met

;The dianosis of 2not Multiple sclerosis 2 is i!en if another dianosis $etter e'plains the clinical presentation

It is not clear %hether the McDonald criteria are sufficiently accurate in patients%ith a clinically isolated syndrome to ma/e decisions reardin disease modifyintherapy" This issue is discussed separately" (See 2Clinically isolated syndromessuesti!e of multiple sclerosis2 section on .McDonald dianostic criteria.")

Manetic resonance imain , MRI is the test of choice to support the clinicaldianosis of Multiple sclerosis" The McDonald dianostic criteria for multiple

sclerosis include specific MRI criteria for the demonstration of lesion disseminationin time and space as discussed a$o!e"

esion characteristics , The characteristic lesion demonstrated on MRI is thecere$ral or spinal plaue"

0atholoically plaues consist of a discrete reion of demyelination %ith relati!epreser!ation of a'ons" @o%e!er mountin e!idence suests that a'onal inury isa prominent patholoic feature of MS and that a'onal loss may occur either aspart of the demyelinatin process or as an independent process" @istoloicale'amination of acti!e plaues re!eals peri!ascular infiltration of lymphocytes

(predominantly T cells) and macrophaes %ith occasional plasma cells"0eri!ascular and interstitial edema may $e prominent"

0laues suesti!e of multiple sclerosis are typically found on MRI in theperi!entricular reion corpus callosum centrum semio!ale and to a lesser e'tentdeep %hite matter structures and $asal anlia (imae 3 and imae 4)" Multiplesclerosis plaues usually ha!e an o!oid appearance and lesions are arraned atriht anles to the corpus callosum as if radiatin from this area" 1hen !ie%ed onsaittal imaes they are referred to as Da%son finers" The plaues appear hyperintense on proton density and T4-%eihted studies and they are hypointense(if !isi$le at all) on T3-%eihted imaes"

Con!entional T4-%eihted MRI techniues may underestimate Multiple sclerosisplaue si#e and thus o!erall plaue $urden particularly for cortical lesions"

&d!anced MRI techniues such as diffusion tensor imain and maneticresonance spectroscopy freuently re!eal in!ol!ement of normal appearin %hitematter in patients %ith MS" (See .&d!ances in MRI techniues. $elo%")


5/21

Dianostic utility

MRI detects many more Multiple sclerosis lesions than CT and it is a$le to detectplaues in reions that are rarely a$normal on CT such as the $rainstemcere$ellum and spinal cord (imae 4)" Most lesions seen on MRI correlate %ith

patholoic lesions" @o%e!er some lesions that are e'tensi!e on MRI sho% onlysmall plaues on patholoical e'amination suestin that much of the a$normalMRI sinal may $e a result of increased %ater content of the $rain around suchplaues due to presumed disruption of the $lood-$rain $arrier"

0atients %ith clinically definite Multiple sclerosis ha!e typical %hite matter lesionson MRI in nearly all cases" @o%e!er central ner!ous system lesions due to other disorders (e ischemia systemic lupus erythematosus ehEet.s syndrome other !asculitides @TF-I sarcoidosis) may appear similar to multiple sclerosis lesionson MRI" This is particularly true for ischemic lesions %hich ma/e MRI criteria lessrelia$le for the dianosis of multiple sclerosis in patients o!er the ae of 98"

The sensiti!ity and specificity of MRI for the dianosis of Multiple sclerosis !aries%idely in different studies and the !ariation is pro$a$ly due to differences amonthe studies in MRI criteria and patient populations" In one early study of 3988 $rainMRI scans that included 35B scans of patients %ith a clinical dianosis of Multiplesclerosis usin the criteria of three or four areas of increased sinal intensityresulted in a hih sensiti!ity for the dianosis of MS (68 and 7G percentrespecti!ely) $ut a lo% specificity (G3 and GB percent respecti!ely)" &ccuracy %asimpro!ed $y usin criteria that included at least three areas of increased sinalintensity plus t%o of the follo%in features* lesions a$uttin $ody of lateral!entriclesH infratentorial lesion locationH and si#e 9 mm" Usin these criteriasensiti!ity decreased slihtly to 73 percent %hile specificity impro!ed to 6> percent"In a later study e!aluatin MRI dianostic criteria that %ere e!entually incorporatedinto the re!ised 4838 McDonald criteria the sensiti!ity and specificity %ereappro'imately 95 and 7G percent respecti!ely"

MRI scannin is more sensiti!e and specific for predictin e!olution to clinicallydefinite multiple sclerosis than other studies such as CT scans cere$rospinal fluidparameters or e!o/ed potentials" This %as illustrated in a t%o-year follo%-up of 488 patients referred for suspected MS that found 58 percent (98 percent of thoseunder ae 98 years) had de!eloped clinically definite multiple sclerosis of %hom7B percent had initial MRI scans that %ere stronly suesti!e of multiple sclerosis"In contrast the proportion of patients %ho had cere$rospinal fluid olioclonal$ands a$normal !isual e!o/ed potentials or an a$normal CT %hen initially studied%as >6 >6 and 57 percent respecti!ely" In a second fi!e-year study of 76patients proression to clinically definite multiple sclerosis occurred in 5G out of 9G(>9 percent) %ith an initially a$normal MRI and only 3 of 54 (5 percent) %ith anormal MRI" &ain MRI %as a $etter predictor of proression to clinically definiteMS than cere$rospinal fluid analysis"


6/21

Spinal cord MRI

Spinal cord MRI lesions are nearly as common as $rain lesions in patients %ithMS thouh they are less li/ely to $e clinically silent than $rain lesions" In contrastthe freuency of a$normal sinals on spinal cord MRI in normal indi!iduals is only

5 percent since the non-MS-related hyperintense sinal seen in older patients oncranial MRI does not occur in the spinal cord" :urthermore spinal cord atrophy inpatients %ith MS correlates %ith clinical disa$ility"

Spinal cord MRI may increase the li/elihood of findin dissemination of MS lesionsin space and impro!e dianostic sensiti!ity compared %ith $rain MRI alone" Thepotential utility of spinal MRI in MS is illustrated $y a study of 38B patients %ithearly stae MS and lo% disa$ility" The dianosis of MS %as made $y the 3674criteria of 0oser et al" &$normal cord MRI lesions %ere found in 75 percent andthese lesions %ere typically focalH focal cord lesions %ere usually multiple (median5) small (median 8"7 !erte$ral sements) and located most often in the cer!ical

cord (9> percent)" Diffuse lesions %ere found in 35 percent usually in conunction%ith focal lesions" In this cohort of patients the addition of spinal cord to $rain MRIlesions compared %ith $rain MRI alone increased the dianostic sensiti!ity of theoriinal 4883 McDonald criteria from >> to 79 percent"

Spinal cord lesions typical of MS are associated %ith the follo%in MRIcharacteristics*

;ittle or no cord s%ellin

;Uneui!ocal hyperintensity on T4-%eihted seuences and !isi$le in t%o planes(e a'ial and saittal)

;Si#e at least 5 mm $ut less than t%o !erte$ral sements in lenth

;Occupy only part of the cord in cross-section

;:ocal (ie clearly delineated and circumscri$ed on T4-%eihted seuences)

onitudinally e'tensi!e spinal cord lesions particularly those that e'ceed threespinal sements and mainly in!ol!e the central cord on a'ial MRI sections aresuesti!e of neuromyelitis optica" (See .Neuromyelitis optica. $elo%")


7/21

&cti!e !ersus chronic lesions"

&cute Multiple sclerosis lesions tend to $e larer than chronic lesions on MRI %ithsome%hat ill-defined marins"

&s resolution occurs they $ecome smaller %ith sharper marins" This presuma$lyreflects reduction of edema and inflammation present at the time of acute plaueformation lea!in only residual areas of demyelination liosis and enlarede'tracellular space %ith remission" The MRI appearance of primary proressi!eMultiple sclerosis sho%s a smaller total disease $urden a reater preponderanceof small lesions fe%er adolinium enhancin ne% lesions and acuisition of fe%er lesions per unit time than the secondary proressi!e form of MS"

+adolinium-DT0& a paramanetic contrast aent that can cross only disrupted$lood-$rain $arriers has $een used to assess plaue acti!ity"

+adolinium increases sinal intensity on T3-%eihted imaes" It is not completelyclear if inflammation is the trierin e!ent that causes demyelination and a'onaldeeneration $ut adolinium enhancement diminishes or disappears after treatment %ith lucocorticoids a therapy thouht to restore interity of the $lood-$rain $arrier"

+adolinium (+d) enhancin lesions on T3-%eihted MRI often correspond to areasof hih sinal on T4-%eihted and lo% sinal intensity on unenhanced T3-%eihtedimaes pro$a$ly due to edema (imae 3)"

The importance of +adolinium-enhancin lesions in MS is related to the follo%in

o$ser!ations*

;The accumulation of adolinium in plaues is associated %ith ne% or ne%ly acti!eplaues and %ith patholoically confirmed acute inflammation in MS"

;The maority of adolinium-enhancin plaues are clinically asymptomaticalthouh the presence of onoin enhancement suests continuin diseaseacti!ity that li/ely contri$utes to cumulati!e pathophysioloy"

;&ppro'imately 38 to 48 percent of lesions on T4-%eihted MRI %ill sho% contrastenhancement at some point if follo%ed o!er time"

;+adolinium enhancement is a transient phenomenon in MS and usuallydisappears after 58 to B8 days $ut it may rarely persist for up to eiht %ee/s inacute plaues" 0roloned persistence of enhancement should caution aainst thedianosis of MS"

;onitudinal studies ha!e demonstrated that the presence of acti!e lesions onserial MRI scans carries a hih ris/ of continuous disease acti!ity"


8/21

;& meta-analysis demonstrated that adolinium enhancement predicts theoccurrence of relapses $ut it is not a stron predictor of the de!elopment of cumulati!e impairment or disa$ility"

There are se!eral methods that can $e used to increase the sensiti!ity of

adolinium-enhanced MRI for the detection of acti!e MS lesions such as usinhiher doses of adolinium" In particular triple-dose adolinium is more sensiti!ethan sinle-dose adolinium (8"3 mmol?"

+adolinium enhancement patterns may pro!ide some clues to the underlyinpatholoy of lesions" Concentric rin-enhancin lesions %ith central contrast pallor arise in pre!iously damaed areas or in areas of accelerated local inflammation"They are larer and of loner duration than homoeneously-enhancin lesions"

Moreo!er rin-enhancin lesions %ea/ly predict the de!elopment of persistinhypointense lesions on T3 MRI"

Therefore rin-enhancin lesions are thouht to $e related to accelerated diseaseacti!ity and e'tensi!e tissue damae and may mar/ a type of inflammationcharacteristic of more aressi!e forms of disease"

Rin enhancement may also occur in an incomplete (open) rin pattern %hich issome%hat more specific for MS than infections or neoplastic diseases"

lac/ holes , Most MS lesions are isointense to %hite matter on T3-%eihtedMRI $ut some are hypointense or appear as 2$lac/ holes2 particularly in thesupratentorial reion (imae 3)" These hypointense lesions are nonspecific at ai!en time point as nearly half %ill re!ert to normal in a fe% months" Thedisappearance of a $lac/ hole is most li/ely due to remyelination and resolution of edema"

&lthouh the e!idence is limited persistent $lac/ holes are thouht to $e mar/ersof se!ere demyelination and a'onal loss" The patholoical su$strate for theaccumulation of persistin $lac/ holes appears to $e predominantly a'onaldamae as sho%n in a postmortem histopatholoy-MRI correlation study" Suchfocal a'onal loss most li/ely contri$utes to 1allerian deeneration" In contrast tothis e!idence another study suested that $lac/ holes %ere associated %ithremyelination"

The correlation $et%een $lac/ hole !olume and clinical disa$ility as measured $ythe J'panded Disa$ility Status Scale (JDSS) suests that these $lac/ holes may$e clinically rele!ant for measurin disease proression"

&trophy"

http://www.uptodate.com/contents/diagnosis-of-multiple-sclerosis-in-adults/abstract/36http://www.uptodate.com/contents/diagnosis-of-multiple-sclerosis-in-adults/abstract/36


9/21

rain atrophy can $e a feature of early MS and atrophy of specific areas such asthe thalamus can predict proression to clinically definite MS in patients %ho ha!ehad a sinle attac/"

&d!ances in MRI techniues"

It is difficult to distinuish the edema of an acute plaue from the liosis anddemyelination of a chronic plaue %ith con!entional MRI technoloy" In additioncon!entional MRI techniues do not distinuish other manifestations of MSpatholoy such as demyelination remyelination a'onal loss and liosis"

0hosphorus manetic resonance spectroscopy (MRS) can pro!ide information onphospholipid meta$olism and proton MRS can enerate information a$out other meta$olic components such as N-acetyl aspartate (N&& an e'clusi!ely neuronalmar/er) creatine phosphate (Cr an enery mar/er) choline containincompounds (mem$rane components) and lactic acid (&)" Chronic MS is

associated %ith a reduction of N&& in comparison %ith choline and Cr %ithin the$rain" & reduced N&&


10/21

demyelination and a'onal disruption at the periphery of a centrifually e'pandinplaue is less se!ere than at the centerH the peripheral inury is sufficient to causereduced anisotropy $ut not sufficient to cause increased T4 sinal" &nother possi$ility is that the periphery is underoin reression and repair"

&lthouh MS predominately affects %hite matter in!ol!ement of cortical raymatter is common" Con!entional T4-%eihted MRI seuences may underestimateMS plaue si#e and thus o!erall plaue $urden particularly for cortical lesions"Fisuali#ation of ray matter lesions may $e impro!ed %ith the use of MRItechniues includin se!en-Tesla MRI t%o and three-dimensional fluid-attenuatedin!ersion reco!ery imain dou$le in!ersion reco!ery imain phase-sensiti!ein!ersion reco!ery T3-%eihted seuences and diffusion tensor imain"

Cere$rospinal fluid analysis , & lum$ar puncture is not a reuirement for thedianosis of MS in patients %ith classic MS symptoms and $rain MRI appearance$ut it can $e used to help rule out the dianosis in eui!ocal cases" Kualitati!e

assessment of cere$rospinal fluid (CS:) for olioclonal I+ $ands (OCs) usinisoelectric focusin is the most important dianostic CS: study %hen determinin adianosis of MS in such cases" Jle!ation of the CS: immunolo$ulin le!el relati!eto other protein components is a common findin in patients %ith MS and suestsintrathecal synthesis" The immunolo$ulin increase is predominantly I+ althouhthe synthesis of IM and I& is also increased"

The 4838 McDonald criteria note that positi!e CS: findins can pro!ide supporti!ee!idence that the underlyin disorder is inflammatory demyelinatin andincorporate them into the criteria for primary proressi!e MS" @o%e!er in contrastto the earlier 4883 and 4889 McDonald criteria the CS: findinsare not incorporated into the 4838 criteria for dissemination in space"

& positi!e CS: is $ased upon the findin of either OCs different from any such$ands in serum or $y an increased I+ inde'"

The I+ le!el may $e e'pressed as a percentae of total protein (normal L33percent) as a percentae of al$umin (normal L4G percent) $y use of the I+ inde'(normal !alue L8">> to L8"6 dependin upon the indi!idual la$oratory) or $y useof a formula for intrathecal fluid synthesis of I+" &n a$normality of CS: I+production as measured $y the I+ inde' or I+ synthesis rate is found in 68percent of clinically definite MS patients"

The CS: appearance and pressure are rossly normal in MS" The total leu/ocytecount is normal in t%o-thirds of patients e'ceeds 39 cells


11/21

The techniue for performin a lum$ar puncture in adults is discussed separately"(See 2um$ar puncture* Techniue indications contraindications andcomplications in adults2 and 2Cere$rospinal fluid* 0hysioloy and utility of ane'amination in disease states2 section on .Composition of the CS:.")

Olioclonal $ands , OCs are found in up to 69 percent of patients %ith clinicallydefinite MS (ta$le 5)" OCs represent limited classes of anti$odies that aredepicted as discrete $ands on aarose el" Up to 7 percent of CS: samples frompatients %ithout MS also contain OCsH most are the result of chronic centralner!ous system infections !iral syndromes and neuropathies"

The presence of OCs in monosymptomatic patients predicts a sinificantly hiher rate of proression to MS than the a$sence of $ands* 49 !ersus 6 percent at threeyears follo%-up in one report" @o%e!er uantification of OCs is an insensiti!epronostic indicator" In addition the presence of OCs is not eui!alent to adianosis of MS i!en the num$er of false positi!es that can occur and the

!aria$ility in techniue and interpretation in different la$oratories"

Repeatin the lum$ar puncture and CS: analysis is suested if clinical suspicionfor MS is hih $ut results are eui!ocal neati!e or sho% only a sinle $and onisoelectric focusin"

J!o/ed potentials"

J!o/ed potentials are the electrical e!ents enerated in the central ner!ous system$y peripheral stimulation of a sensory oran" J!o/ed potentials are used to detectsu$clinical a$normal central ner!ous system function" Detection of a su$clinicallesion in a site remote from the reion of clinical dysfunction supports a dianosisof multifocal MS" J!o/ed potentials also may help define the anatomical site of thelesion in tracts not easily !isuali#ed $y imain (e optic ner!es dorsal columns)"

The three most freuently used e!o/ed potentials are somatosensory e!o/edpotentials (SSJ0) !isual e!o/ed responses (FJR) and $rainstem auditory e!o/edpotentials (&J0)" 0atients %ith clinically definite MS ha!e a$normal FJRs in 98 to68 percent of cases (ta$le 5)" The FJR is particularly useful in patients %ho lac/clear clinical e!idence of dysfunction a$o!e the le!el of the foramen manum suchas those %ith a chronic proressi!e myelopathy" Ocular or retinal disorders must$e e'cluded $efore attri$utin a$normal FJRs to demyelination in the opticpath%ays"

&ntimyelin anti$odies

Initial studies suested that anti$odies to myelin oliodendrocyte lycoprotein(MO+) and myelin $asic protein (M0) %ere potential mar/ers of MS diseaseacti!ity and predictors of proression from a clinically isolated syndrome to MS"@o%e!er su$seuent e!idence suests that these anti$odies are not associated%ith an increased ris/ of proression to MS or %ith MS disease acti!ity"


12/21

Se!eral factors may contri$ute to the discrepant findins such as differences intechniue used in MO+ preparation" In addition autoanti$odies to many myelinconstituents in patients %ith MS includin anti-MO+ may simply represent part of a enerali#ed 2nonsense2 anti$ody response reflectin an increased immuneresponse due to MS rather than to a specific root cause of MS"

UNUSU& CINIC& 0RJSJNT&TIONS

Se!eral inflammatory demyelinatin disorders may $e !ariants of MS thouh their precise relationship to MS is uncertain" These include isolated optic neuritisproressi!e myelopathy associated %ith a sinle demyelinatin lesion andtumefacti!e MS"

Isolated optic neuritis

Some patients ha!e their entire clinical illness confined to the optic ner!es" One

optic ner!e may $e affected seuentially after another or there can $esimultaneous $ilateral !isual loss a state that is uncommon in classic MS" In someinstances $rain MRI %ill sho% scattered intracere$ral lesions in addition to lesionsof the optic ner!es or cere$rospinal fluid e'amination %ill sho% olioclonal $andsattestin to some deree of dissemination of the lesions"

Children and preadolescent patients are more li/ely than adults to ha!e recurrentor simultaneous optic neuropathy" The distinction from an MS !ariant can $echallenin" Sarcoidosis is commonly a dianostic consideration in patients %ith$ilateral optic neuritis" Other potential causes of recurrent optic neuritis in thedifferential include lupus chronic relapsin inflammatory optic neuropathy(CRION) and paraneoplastic optic neuropathy (serum CRM0-9


13/21

no ne% lesions %ere found in the three patients %ho had serial MRI scans of the$rain and spinal cord" Olioclonal $ands %ere present in four of the si' patientstested" There %as no e!idence suestin another etioloy for proressi!emyelopathy such as neuromyelitis optica"

In addition to MS the differential dianosis of proressi!e myelopathy includesinflammatory infectious paraneoplastic meta$olic and enetic disorders" Motor neuron disease may $e the cause if there are no sensory sins or symptoms(primary lateral sclerosis)" @TF-I infection 34 deficiency and @IF infection canall $e e'cluded $y appropriate testin" Spinal dural arterio!enous malformation cancause a steadily or step%ise proressi!e myelopathy usually in the lo%er spinalsements and usually in older patients" &drenomyeloneuropathy also should $econsidered" (See 2Disorders affectin the spinal cord2 and 2Dianosis of amyotrophic lateral sclerosis and other forms of motor neuron disease2 and2@uman T-lymphotropic !irus type I* Disease associations dianosis andtreatment2 and 2Dianosis and treatment of !itamin 34 and folate deficiency2 and

2&cute and early @IF infection* Treatment2 and 2Disorders affectin the spinalcord2 section on .Fascular malformations. and 2&drenoleu/odystrophy2 section on.&drenomyeloneuropathy.")

J!entually there remains a roup of patients %ho do not fit into these cateoriesand %hose spinal MRI scans are repeatedly neati!e" Fisual e!o/ed responsescere$rospinal fluid olioclonal $ands and $rain MRI scan sho% no sin of demyelination else%here thouh MRI may sho% nonspecific %hite matter a$normalities" These patients do not ha!e MS" Compression of the cer!ical cord $yinter!erte$ral disc disease is often an issue in middle-aed patients since amaority has some deree of disc disease" There is little dou$t that somelaminectomies ha!e $een carried out for cer!ical spondylosis %here MS %as thefinal correct dianosis" &lternati!ely there are patients %ho ha!e $een dianosed%ith MS %hen cer!ical spondylosis %as the cause of their symptoms"

Tumefacti!e MS"

Tumefacti!e MS is an acute tumor-li/e MS !ariant in %hich some patients %ithdemyelinatin disease present %ith lare (4 cm) acute lesions often associated%ith edema or rin enhancement" There may $e mass effect %ith compression of the lateral !entricle and shift across the midline" &lthouh there is no consensusreardin nomenclature this type of inflammatory demyelinatin disease has $eentermed tumefacti!e multiple sclerosis Mar$ur disease or !ariant and aloconcentric sclerosis"

The clinical a$normalities in such patients are !aria$leH they may $e !ery slihte!en in a patient %ith a massi!e lesion %hile confusion hemiparesis or nelectsyndrome can $e seen in another patient %ith a lesion that appears no different"Typically much of the T4-$riht lesion !olume on $rain MRI is due to edema andmay $e rapidly responsi!e to lucocorticoid treatment" @o%e!er radioloicimpro!ement %ith lucocorticoids can also occur %ith lioma or %ith central


14/21

ner!ous system lymphoma and is therefore not a useful dianostic criterion" iopsyis often reuired"

In the larest series 3>7 patients %ith $iopsy-confirmed tumor-li/e inflammatorydemyelinatin disease %ere analy#ed retrospecti!ely" The follo%in o$ser!ations

%ere reported*

;The median ae at onset %as 5G years (rane 7 to >6)"

;Clinical presentations %ere typically polysymptomatic" Motor coniti!e sensoryand cere$ellar symptoms %ere the most freuent"

;esions on $rain MRI %ere often multifocal and the median si#e of the larest T4lesion %as B cm" +adolinium enhancement on $rain MRI %as o$ser!ed in morethan half of the lesionsH rin heteroeneous and homoeneous patterns %ere themost common"

;The clinical course at last follo%-up %as relapsin-remittin in appro'imately one-half of the patients and monophasic in a$out one-uarter" The final dianosis %asdefinite or pro$a$le multiple sclerosis in G6 percent and an isolated demyelinatinsyndrome in 3B percent"

DI::JRJNTI& DI&+NOSIS

The differential dianosis of MS includes a num$er of inflammatory !ascular

infectious enetic ranulomatous and other demyelinatin disorders (ta$le B) $utdepends on the clinical settin" The differential is limited in the settin of a younadult %ho has had t%o or more clinically distinct episodes of central ner!oussystem dysfunction %ith at least partial resolution" Dianostic difficulties arise inpatients %ho ha!e atypical presentations monophasic episodes or proressi!eillness"

;The unusual nature of some sensory symptoms and the difficulty patientse'perience in descri$in such symptoms may result in a misdianosis of hysteria"

;& monophasic illness %ith symptoms attri$uta$le to one site in the central ner!oussystem creates a lare differential that includes neoplasms !ascular e!ents or infections"

;The larest dianostic difficulty arises %ith proressi!e central ner!ous systemdysfunctionH reat care must $e ta/en in these patients to e'clude other treata$leetioloies such as compressi!e myelopathies arterio!enous malformationca!ernous anioma &rnold-Chiari malformation and human immunodeficiency!irus" Other potential causes ha!e no pro!en treatment such as human T-


15/21

lymphotropic !irus type I and a num$er of hereditary conditions includin adultmetachromatic leu/odystrophy adrenoleu/odystrophy and spinocere$ellar disorders"

& common error is to o!er-interpret multiple hyperintense lesions on MRI as

eui!alent to MS in the a$sence of clinical symptoms consistent %ith the dianosis(ta$le 4)" Some central ner!ous system inflammatory or infectious diseases mayproduce multifocal lesions %ith or %ithout a relapsin-remittin course includinthe follo%in*

;Systemic lupus erythematosus %hich can present as a recurrent neuroloicsyndrome $efore the systemic manifestations appear (see 2Neuroloicmanifestations of systemic lupus erythematosus2)

;Sren.s syndrome (see 2Clinical manifestations of Sren.s syndrome*J'tralandular disease2 section on .Central ner!ous system.)

;0olyarteritis nodosa (see 2Clinical manifestations and dianosis of polyarteritisnodosa in adults2 section on .Neuroloic disease.)

;ehEet.s syndrome (see 2Clinical manifestations and dianosis of ehEetssyndrome2 section on .Neuroloic disease.)

;Syphilis (see 2Neurosyphilis2)

;Retro!iral diseases (see 2&pproach to @IF-infected patients %ith central ner!oussystem lesions2 and 2@uman T-lymphotropic !irus type I* Disease associations

dianosis and treatment2 section on .@TF-I-associated myelopathy


16/21

;0rominent $ac/ pain that persists

;Symptoms and sins that can $e attri$uted to one anatomical site

;0atients %ho are o!er >8 years of ae or less than 39 years at the onset of

disease

;Rapidly proressi!e disease

;Symptoms of systemic disease such as %eiht loss fe!er etc

None of these features e'cludes the dianosis of MS" @o%e!er one shoulde'plore the possi$ility of other etioloies $efore acceptin the dianosis of MSparticularly in patients %ho ha!e atypical clinical syndromes" This point is illustrated$y the findins from a study of 473 ne% patient referrals to an outpatient uni!ersity-$ased MS center for a first or second opinion as to %hether the patient had MS"

0ro$a$le or possi$le MS %as confirmed in only 55 percent of the patients andnone of those %ith confirmed MS had atypical manifestations of demyelination" &%ide !ariety of alternati!e dianoses %ere made includin other neuroloicdiseases possi$le psychiatric disease and no clear dianosis (54 45 and 35percent respecti!ely)" The retrospecti!e nature of this study limits the strenth of its findins"

Clinically isolated syndromes , Clinically isolated syndromes are sinlemonosymptomatic attac/s compati$le %ith MS (e optic neuritis $rainstemsyndromes spinal cord syndromes) that do not fulfill dianostic criteria for MS $utmay $e the first attac/ of MS" :or patients %ith one attac/ %ho ha!e o$ecti!e

clinical e!idence of one lesion (ie a clinically isolated syndrome) MS criteriareuire e!idence of lesion dissemination in space and time (see .McDonald criteria.a$o!e)" This topic is discussed separately" (See 2Clinically isolated syndromessuesti!e of multiple sclerosis2")

&cute disseminated encephalomyelitis , &cute disseminated encephalomyelitis(&DJM) is autoimmune demyelinatin disease of the central ner!ous system thattypically follo%s an immuni#ation or !accination (post!accinationencephalomyelitis) or systemic !iral infection (parainfectious encephalomyelitis)"0atholoically there is peri!ascular inflammation edema and demyelination %ithinthe central ner!ous system" Clinically patients %ith &DJM present %ith the rapidde!elopment of focal or multifocal neuroloic dysfunction includin motor sensorycranial ner!e and $rainstem deficits as %ell as nonspecific symptoms such asheadache malaise and altered mental status" (See 2&cute disseminatedencephalomyelitis in adults2")

Certain clinical features may $e helpful in supportin the dianosis of &DJM or MS"@o%e!er there is su$stantial o!erlap (see 2&cute disseminated encephalomyelitisin adults2 section on .Clinical features.)*


17/21

;&DJM typically follo%s a prodromal !iral illness %hile MS may or may not

;&DJM may present %ith fe!er and stiff nec/ %hich is unusual in MS

;&DJM usually produces a %idespread central ner!ous system distur$ance often

%ith impaired consciousness and


18/21

;Trans!erse myelitis may $e seen in patients %ith acute disseminatedencephalomyelitis" (See 2&cute disseminated encephalomyelitis in adults2")

Clinical and imain e!idence of multifocal in!ol!ement %ithin the central ner!oussystem suest that trans!erse myelitis not idiopathic $ut rather is associated %ith

MS neuromyelitis optica or acute disseminated encephalomyelitis"

Of note patients presentin %ith acute complete idiopathic trans!erse myelitis(complete or near complete clinical deficits $elo% the lesion) ha!e a lo% ris/ of de!elopin MS" @o%e!er partial or incomplete myelitis %ith mild or rosslyasymmetric spinal cord dysfunction is a more common clinical entity %ith a hiher ris/ of proression to MS as discussed separately" (See 2Trans!erse myelitis2section on .0roression to multiple sclerosis.")

Neuromyelitis optica , Neuromyelitis optica (NMO sometimes called De!icdisease) is re!ie%ed here $riefly and discussed in detail else%here" (See

2Neuromyelitis optica spectrum disorders2")

NMO is an inflammatory disorder of the central ner!ous system characteri#ed $yse!ere immune-mediated demyelination and a'onal damae predominantlytaretin the optic ner!es and spinal cord" Once considered a !ariant of multiplesclerosis NMO is no% reconi#ed as a distinct clinical entity $ased upon thepresence of the disease-specific anti-auaporin-B (&K0B) anti$ody %hich plays adirect role in the pathoenesis of NMO" (See 2Neuromyelitis optica spectrumdisorders2 section on .ac/round. and 2Neuromyelitis optica spectrum disorders2section on .0athoenesis.")

The incidence of NMO in %omen is up to 38 times hiher than in men" NMO ismuch more common in people of &sian @ispanic and &frican descent %hich is notthe case %ith MS" @allmar/ features of NMO include acute attac/s of $ilateral or rapidly seuential optic neuritis (leadin to !isual loss) and trans!erse myelitis(often causin lim$ %ea/ness and $ladder dysfunction) %ith a typically relapsincourse" Central ner!ous system in!ol!ement outside of the optic ner!es and spinalcord is also reconi#ed in NMO and NMO spectrum disorders" Other suesti!esymptoms include episodes of intracta$le !omitin or hiccouhs e'cessi!edaytime somnolence or narcolepsy re!ersi$le posterior leu/oencephalopathysyndrome neuroendocrine disorders and (in children) sei#ures" 1hile no clinicalfeatures are disease-specific some are hihly characteristic" NMO has a relapsincourse in 68 percent or more of cases" (See 2Neuromyelitis optica spectrumdisorders2 section on .Jpidemioloy. and 2Neuromyelitis optica spectrumdisorders2 section on .Clinical features.")

The dianosis of NMO is $ased on clinical imain and la$oratory data" Se!ereattac/s of myelitis or optic neuritis should raise suspicion for NMO" Dianosticcriteria for NMO reuire the presence of optic neuritis myelitis and at least t%o of three supporti!e criteria (see 2Neuromyelitis optica spectrum disorders2 section on.J!aluation and dianosis.)*


19/21

;& contiuous spinal cord lesion on MRI e'tendin three or more sements

;Initial $rain MRI not meetin usual dianostic criteria for MS

;Seropositi!ity for NMO-I+ (ie anti-auaporin-B anti$ody)

Se!eral features appear to distinuish NMO from classical relapsin-remittin MS(see 2Neuromyelitis optica spectrum disorders2 section on .Differential dianosis.)*

;rain MRI is often normal in patients %ith NMO particularly at onset and spinalcord MRI $y definition e'hi$its e'tensi!e lesions spannin three or more !erte$ralsements" @o%e!er clinical or MRI e!idence of $rain in!ol!ement particularly inthe $rainstem occurs in a su$stantial proportion of patients %ith NMO" :indins on$rain MRI that suest the dianosis of multiple sclerosis rather than NMO includeT4-%eihted lesions in one or more of the follo%in locations*

Aesion adacent to lateral !entricle

AInferior temporal lo$e %hite matter lesion

AO!oid (ie 2Da%son finer2) peri!entricular lesion

AU-fi$er u'tacortical lesion

;Durin acute attac/s of NMO the cere$rospinal fluid may e'hi$it a neutrophilicpleocytosis $ut it is usually neati!e for olioclonal $ands"

;The detection of &K0B anti$ody positi!ity is specific for NMO and NMO spectrumdisorders" (See 2Neuromyelitis optica spectrum disorders2 section on .&K0Bautoanti$ody.")

;The myelopathy %ith NMO tends to $e more se!ere than %ith MS %ith lessli/elihood of reco!ery" Unli/e MS there does not appear to $e a proressi!e phaseindependent from relapses"

Chronic lymphocytic inflammation %ith pontine peri!ascular enhancementresponsi!e to steroids , Chronic lymphocytic inflammation %ith pontineperi!ascular enhancement responsi!e to steroids (CI00JRS) is a type of

encephalomyelitis that predominantly in!ol!es the pons" The clinical featuresinclude a relapsin-remittin pattern of diplopia ait ata'ia dysarthria and facialparesthesia alon %ith characteristic radioloic appearance of punctate cur!ilinear adolinium-enhancin lesions on MRI scattered throuhout the pons %ith !aria$lein!ol!ement of the medulla $rachium pontis cere$ellum mid$rain and spinal cord(imae B)" Neuropatholoy of the $rainstem and cere$ellar lesions demonstrates apredominantly T cell lymphocytic infiltrate in the peri!ascular %hite matter" Some


20/21

patients ha!e olioclonal $ands in the cere$rospinal fluid" CI00JRS is enerallyresponsi!e to lon-term lucocorticoid therapy"

SUMM&RP &ND RJCOMMJND&TIONS

;Multiple sclerosis (MS) is a clinical dianosis" The core reuirement for thedianosis is the demonstration of central ner!ous system lesion dissemination intime and space $ased upon either clinical findins alone or a com$ination of clinical and MRI findins" There are no clinical findins that are uniue to thisdisorder $ut some are hihly characteristic (ta$le 3)" Common symptoms of MSare listed in the ta$le (ta$le 4)" (See .Dianosis. a$o!e")

;MRI is the test of choice to support the clinical dianosis of MS" The McDonalddianostic criteria include specific clinical and MRI findins needed for thedemonstration of lesion dissemination in time and space (see .McDonald criteria.a$o!e and .Manetic resonance imain. a$o!e)*

ADissemination in space is demonstrated on MRI $y one or more T4 lesions in atleast t%o of four MS-typical reions of the central ner!ous system (peri!entricular

u'tacortical infratentorial or spinal cord) or $y the de!elopment of a further clinical attac/ implicatin a different central ner!ous system site" :or patients %ith$rainstem or spinal cord syndromes symptomatic MRI lesions are e'cluded fromthe criteria and do not contri$ute to lesion count" (See .McDonald criteria. a$o!e")

ADissemination in time is demonstrated on MRI $y the simultaneous presence of asymptomatic adolinium-enhancin and nonenhancin lesions at any time or ane% T4 and


21/21

A:or patients %ith one attac/ %ho ha!e o$ecti!e clinical e!idence of one lesion (iea clinically isolated syndrome =CIS?) the criteria reuire e!idence of disseminationin space and time

;:or patients %ho present %ith insidious neuroloical proression suesti!e of

primary proressi!e MS the McDonald criteria reuire e!idence of the one year of disease proression plus t%o of the three follo%in criteria (note that symptomaticMRI lesions are e'cluded from the criteria and do not contri$ute to lesion count for patients %ith $rainstem or spinal cord syndromes) (see .McDonald criteria. a$o!e)*

ADissemination in space in the brain $ased upon one or more T4 lesions in atleast t%o of four MS-typical reions of the central ner!ous system (peri!entricular

u'tacortical infratentorial or spinal cord)

ADissemination in space in the spinal cord $ased upon t%o or more T4 lesions inthe cord

A0ositi!e cere$rospinal fluid findins %ith isoelectric focusin e!idence of olioclonal $ands and

diagnosis of multiple sclerosis in adults 2

Documents