Rev. Bras. Reumatol. vol.56 número3

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rev bras reumatol.2016;56(3):240–251

ww w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Original

article

Myelopathy

in

systemic

lupus

erythematosus:

clinical,

laboratory,

radiological

and

progression

findings

in

a

cohort

of

1,193

patients

Beatriz

Lavras

Costallat

a

_,

_Daniel

_Miranda

_Ferreira

b

_,

_Lilian

_Tereza

_Lavras

_Costallat

a

_,

Simone

Appenzeller

a,∗

a_Faculdade_de_Ciências_Médicas_(FCM),_Universidade_Estadual_de_Campinas_(UNICAMP),_Campinas,_SP,_Brazil

b_Hospital_das_Clínicas,_Faculdade_de_Ciências_Médicas_(FCM),_Universidade_Estadual_de_Campinas_(UNICAMP),_Campinas,_SP,_Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received14September2015

Accepted8December2015

Availableonline14April2016

Keywords:

Systemiclupuserythematosus

Myelopathy

Transversemyelitis

Magneticresonance

a

b

s

t

r

a

c

t

Objective:To describeclinical,laboratory, radiological andprogression characteristicsof

myelopathyinsystemiclupuserythematosus(SLE).

Patientsandmethods:Aretrospectiveanalysiswasperformedonacohortof1193patients

withSLE(ACRcriteria)inordertoidentifypatientswithmyelopathy(neuropsychiatricACR).

DiseaseactivitywasassessedbytheSLEactivityindex(SLEDAI)onthedateoftheeventand

functionalcapacitywasassessedbytheExpandedDisabilityStatusScale(EDSS)atthelast

visit.

Results:Weidentified14(1.2%)patientswithmyelopathy.Allwerewomenwithamean

ageof30±11.5years.MyelopathyoccurredatthediagnosisofSLEinfour(28%)patients;

andnine(64%)patientshadanothertypeofneuropsychiatricmanifestationassociated.

Neurologicalrecurrencewasobservedinone(7%)patient.Diseaseactivitywasobservedin

2(14%)patients.Cerebrospinalfluidpresentedpleocytosison7(53%)patients;

antiphos-pholipidantibodieswerepositivein5(45%).Magneticresonanceimaging(MRI)showedT2

hyperintensitywithapredominanceoflongitudinalinvolvementin6(86%)patients.Most

weretreatedwithintravenouscorticosteroidsandcyclophosphamide.Nopatienthadfull

recoveryandfour(36%)hadhighEDSSscores.Three(21%)patientsdiedfromsepsisearly

inthecourseoftheirmyelopathy,duringorafterimmunosuppressivetherapy.

Conclusions:Myelopathyoccurredin14(1.2%)ofthepatientsinourcohortandthismaybe

thefirstmanifestationofthediseaseoccurringindependentlyofsystemicdiseaseactivity.

Althoughrare,myelopathyshowsgreatmorbidityandmortality,canberecurrentandMRI

iscriticalfordiagnosis.

BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗ _{Corresponding}_author_.

E-mail:appenzellersimone@yahoo.com(S.Appenzeller).

http://dx.doi.org/10.1016/j.rbre.2016.03.006

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rev bras reumatol.2016;56(3):240–251

241 Mielopatia

no

lúpus

eritematoso

sistêmico:

achados

clínicos,

laboratoriais,

radiológicos

e

evolutivos

em

uma

coorte

de

1.193 pacientes

Palavras-chave:

Lúpuseritematososistêmico

Mielopatia

Mielitetransversa

Ressonânciamagnética

r

e

s

u

m

o

Objetivo: Descrever características clínicas, laboratoriais, radiológicas e evolutivas de

mielopatianolúpuseritematososistêmico(LES).

Pacientesemétodos:Foirealizadaanáliseretrospectivadeumacoortede1193pacientescom

LES(critériosACR),paraidentificarospacientescommielopatia(ACRneuropsiquiátrico).

Aatividadededoenc¸afoianalisadapeloÍndicedeAtividadedoLES(SLEDAI)nadatado

eventoeacapacidadefuncionalpelaEscalaExpandidadoEstadodeIncapacidade(EDSS)

naúltimaconsulta.

Resultados: Foramidentificados14(1,2%)pacientescommielopatia.Todaserammulheres

commédiadeidadede30anos(DP±11,5anos).AmielopatiaocorreunodiagnósticodoLES

emquatro(28%)eemnove(64%)haviaoutrotipodemanifestac¸ãoneuropsiquiátrica

asso-ciada.Recorrênciadoquadroneurológicofoiobservadoemuma(7%)paciente.Atividade

dedoenc¸afoiobservadaem2(14%)pacientes.Olíquidocefalorraquidianoapresentava

pleocitoseem7(53%)pacientesanticorposantifosfolípideserampositivosem5(45%).A

ressonânciamagnética(RM)demonstrouhipersinalemT2compredomíniodo

comprome-timentolongitudinalem6(86%)pacientes.Amaioriafoitratadacomcorticosteroidese

ciclofosfamidaendovenosos.Nenhumapacientetevecompletarecuperac¸ãoequatro(36%)

tinhamescoresaltosdaEDSS.Óbitofoiobservadoem3(21%)duranteepisódiodemielopatia,

porsepticemiaduranteouapósterapiaimunossupressora.

Conclusões: Amielopatiaocorreuem14(1,2%)dospacientesdanossacoorteepodesera

primeiramanifestac¸ãodadoenc¸aocorrendoindependentementedeatividadesistêmicada

doenc¸a.Emborarara,édegrandemorbimortalidade,podeserrecorrenteeaRMé

funda-mentalparaodiagnóstico.

deCCBY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Neuropsychiatricmanifestations in systemic lupus

erythe-matosus(SLE)haveanimportantimpactontheprognosisof

thediseasebytheirfrequencyandseverity.1_Myelopathy_is_a

manifestationofthecentralnervoussystem(CNS)thatoccurs

onlyrarelyinSLE,affectingabout1–2%ofpatients.1–3

In 1999, the American College of Rheumatology (ACR)

establishedthecriteriaofneuropsychiatricmanifestationsin

SLE,includingmyelopathy.Thispossibilityshouldbe

consid-eredifthepatientshowsarapidprogression(hoursordays)of

oneormoreofthefollowingsigns/symptoms:bilateral

mus-cleweakness in lower limbs,with or without involvement

upperlimbs;asensorydisorder withsimilarlevelofmotor

impairment,withorwithoutbowelorbladderinvolvement.

Expansiveinjurycausingspinalcordcompressionandcauda

equinainjuryshouldberuledout.4

In2002,theTransverseMyelitisConsortiumWorkingGroup

proposeddiagnosticcriteriaforidiopathictransverse

myeli-tis,definedwiththeclinicalmanifestationsdescribedabove,

associatedwithinflammationwithinthespinalcord

demon-strated bycerebrospinal (CSF) pleocytosis or increasedIgG

index or gadolinium enhancement in magnetic resonance

imaging(MRI).5

Myelopathymaypresentasatransversemyelopathywith

sectionalinvolvementofonelevelofthespinalcord,orasa

longitudinalmyelopathyinwhichmorethanthreesegments

areaffected,continuouslyornot.6

The term myelitis is still used by many authors;

how-ever,myelopathyismoresuitabletocharacterizespinalcord

changesassociatedwithinflammatorydiseasessuchasSLE,

thisbeingthenomenclaturerecommendedbyACR.4

Thecause of myelopathy inSLEisnot well understood

and the participation of both thrombosis and vasculitis

have been implicatedin this process.3 _Some _authors

sug-gest that there is a relationshipbetween antiphospholipid

antibodiesand myelopathy,whichwouldaugmentthe

pos-sibilityofthrombosis;butotherstudiesdonotconfirmthis

association.7–10

Although rare, thanks to its importance this condition

wasrecentlyincludedinthenewclassificationcriteriaofthe

disease.11_The_literature_only_presents_case_reports,_with_the

publicationofcaseseriesonlybyafewauthors.8,10,12–19

Theaimofthisstudyistodescribecasesofmyelopathyin

SLE,fromacohortofasingleuniversityhospital,describing

theirclinicalpicture,laboratoryresults,imagingfindingson

MRIofthespinalcord,treatmentandoutcome.

Patients

and

methods

Medicalrecordsofacohortof1193patientswithSLE,20

fol-lowedattheRheumatologyoutpatientclinicoftheHospital

dasClínicas,UniversidadeEstadualdeCampinas(UNICAMP)

wereanalyzedretrospectively.

Patientswithmyelopathywereidentifiedbythepresence

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242

injury,andofsensoryandmotorchanges,sphincter

dysfunc-tion,or acombination ofthese,and changes consistentat

theneurologicalexamination.4,5_Patients_with_other_causes_of

myelopathysuchascompression,trauma,malignanciesand

infectionswereexcluded.Informationondemographics,

clin-icaldataofSLEdiseasedurationofthemyelopathyepisode,

adjuvant tests, including imaging studies, auto-antibodies

and cerebrospinal fluid screening were collected. Disease

activitywasanalyzedbytheSystemicLupusErythematosus

DiseaseActivity Index –SLEDAI21 _on _the _day_of_the _event,

whendataforapplicationwereavailable,consideringdisease

activityifSLEDAI≥6,discreteactivitywhenSLEDAI<6,and

inactivitywhenSLEDAI=zero.

Informationaboutprescribedtreatmentandprogressionof

thesepatientswerealsocollected.Toevaluatethefunctional

capacity after myelopathy, the Expanded Disability Status

Scale(EDSS)ofKurtzke,appliedinthelastfollow-upvisit,was

used.22_This_is_a_method_used_to_quantify_disability_occurring

duringprogressionandovertime.

Ethicalaspects

AuthorizationoftheResearchEthicsCommittee–FCM

UNI-CAMPwasobtainedforuse ofdatafrom patients’ medical

records(OpinionoftheEthicsCommitteeofFCM-UNICAMP:

NO920/2007).

Results

Fourteen of 1193 (1.2%) SLE patients with myelopathy, all

femalesandCaucasian,withameanageattheonsetof

myelo-pathyof30±11.5yearsandmeandiseasedurationatthetime

ofmyelopathyof4±5.2years(Table1)wereidentified.

Table1showsthecumulativeclinicalmanifestationsofSLE

untilthetimeofthestudy.Infourof14(28%)patients,

myelo-pathywastheinitialmanifestation.Inone(7%)patient,the

diagnosisofSLEwasconfirmedonlytwoyearsand3months

afterthespinalcordmanifestation.

Theinitialsymptomsof these14 patientsincluded

uri-nary retention in 10 (71%), paraplegia in 7 (50%), fever in

6(42%), paraparesis in3 (21%)and paresthesiain 2(14%).

Nine(64%)patientshadalreadyhadotherneuropsychiatric

symptomsbeforethemyelopathy,three(21%)patientswith

aclinical picture ofpsychosis, two(14%) withseizure, one

(7%)withheadache,andone(7%)withcerebrovascular

dis-ease(stroke).Two(14%)patientsalsohadopticneuritis(ON).

One(7%)ofthesepatientshadsevere bilateraloptic

neuri-tismanyyearsafterherclinicalpictureofmyelopathy,which

wasconfirmedbyvisualevoked potentialchanges,without

evidenceofdemyelinatingdiseaseonbrainMRI,witha

neg-ativeresultforanti-aquaporin4antibody.Theotherpatient

hadrecurrentneuromyelitis optica(NMO)andwaspositive

foranti-aquaporin4antibody;andSLEwasconfirmed3years

andtwomonthslater,whennephritis,lymphopenia,and

pos-itivityforantinuclearantibodyandanti-DNA werenoticed.

Inthesepatientswecouldnotperformotherautoantibodies

suchasanti-MOG and anti-aquaporinI, but demyelinating

causeswereruledout,andtheclinicalpictureofbothofthem

wasattributedtoSLE.

Onlytwo(14%)patientshadnephritis,oneofthem

con-currently with myelopathy. Six patients had some typeof

hematologicalabnormalityduringthecourseofSLE.

Two(14%)patientshaddiseaseactivityduringtheepisode

ofmyelopathy,thatis,SLEDAI≥6;inone(7%)patientSLEDAI

wasnotappliedonthisoccasion,sincethediagnosisofSLE

hadnotbeenconfirmed;inthree(21%)patientstherewasno

dataavailableforthecalculationofSLEDAI.Inanother8(57%)

patientsSLEDAIwas<6,thuswithmilddiseaseactivity.Only

one(7%)patienthadnoactivedisease(Table1).Inthese10

patientsinwhomitwaspossibletoapplytheactivityindex,

aSLEDAIscorewasobtainedbecauseoffeverin3(30%),low

complementlevelsin9(90%),anti-DNApositivityin5(50%),

psychosisin1(10%),nephritisin1(10%),thrombocytopeniain

1(10%)andleukopeniain1(10%).

Table2showstheadditionaltestsperformedduringthe

episode of myelopathy. All patients had positive tests for

antinuclearantibodies(ANA).Anti-DNAandanti-Sm

antibod-ies were positive in 6of 13 (46%) patients who were thus

examined,andantiphospholipidantibodieswerepositivein5

of11(45%)patientssubmittedtothistest.Tenineleven(90%)

patientswhowereexaminedatthetimeofthemyelopathy

haddecreasedcomplementlevels.

Acerebrospinalfluid(CSF)testwasperformedinall(100%)

patients with normal results in seven (53%). In six (46%)

patients, pleocytosis with lymphocyte predominance was

noted. Thecultureswerenegativeinall14(100%) patients.

FulldetailsofCSFofonepatientwerenotavailable,although

thistesthadbeenconducted.

Seven(50%)patientswereexaminedbyMRI.Theother7

patients did notperform the test, and in four (28.5%)MRI

was notconductedduetolackofthis resourceinourUnit

at the time of myelopathy. In these latter patients,

myel-ography was performed in order to rule out other causes,

with normal results in all these women. The other three

(21.5%) patients died without having been able toperform

MRI,becausetherewasnoclinicalstabilityforperformingthis

test.

Uponthe clinicalepisode, allpatientsunderwent spinal

cordMRIinaclosed-fielddevice.In6(86%)cases,patients

hadlongitudinallesionswithhyperintensityinT2fast

spin-echosequences,withextensionto4ormorevertebrallevels

(Fig. 1)and inonlyone (14%) ofthese patients the

exam-ination was performed at 3 levels (Table 2). There was

predominantly thoracic involvement in 6 (85%) of these

cases, in 4 (57%) of them with high thoracic levels. A

spinalcordswelling effectwasnoted in2(28%)cases, and

one(14%)ofthesepatients alsoshowedcontrast

enhance-ment.Asforcontrastuptake,only2(28%)patientsshowed

enhancement at the same level of signal exchange in

pre-contrast sequences (Fig. 2). In our cases, it was not

possible to differentiate between white versus gray matter

involvement.

Withregardtotreatment,eight(57%)patientsweretreated

withacombinationofpulsetherapywithmethylprednisolone

(MP) followed by intravenous (IV) cyclophosphamide; four

(28%) patients used onlyMP pulse therapy; and two (14%)

receivedoralcorticosteroidsathighdoses,togetherwith

aza-thioprine.Allpatientsweretreatedwithinthefirsthours,or

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Table1–SLE:demographic,clinical,anddiseaseactivitydataof14patientswithmyelopathy.

Patients(n=14) Race Age(years) Symptoms SLEduration

(years)

PreviousNPSLE Cumulativeclinicalmanifestationsa _SLEDAI

1 Br 31 Urinaryretention/paraparesis 8 Absent Arthritis/photo/leukopenia/APS 4

2 Bl 40 Urinaryretention/paraplegia 2 Absent Arthritis/leukopenia/thrombocytopenia 0

3 W 29 Difficultyinwalking/tactilehypoesthesia 3 Psychosis Arthritis/malarrash/photo 2

4 W 42 Urinaryretention/flaccidtetraparesis 0 Seizure Malarrash/photo/oralulcers 2

5 Br 42 Fever/urinaryretention/paraplegia 2 Psychosis Arthritis/malarrash/photo/leucopenia NA

6 W 19 Urinaryretention/paresthesia 6 Stroke Arthritis/malar

rash/photo/thrombocytopenia

3

7 Br 20 Fever/urinaryretention/paraplegia 9 Absent Arthritis/malarrash/photo/nephritis 17

8 W 18 Paraparesis 1 Absent Arthritis/malar

rash/photo/serositis/lymphopenia

3

9 NA 16 Paresthesia/difficultyinwalking NAp Opticneuritis Nephritis/lymphopenia b

10 W 9 Fever/urinaryretention/paraplegia 1 Opticneuritis Arthritis/malar

rash/photo/pericarditis

3

11 Br 45 Fever/urinaryretention/paraplegia 0 Psychosis,stroke Arthritis/discoid/photo/leucopenia 13

12 W 31 Fever/urinaryretention/paraplegia 0 Headache Arthritis/alopecia NA

13 Br 41 Paraparesis 16 Seizureandplexopathy Arthritis 4

14 W 30 Fever/urinaryretention/paraplegia 13 Absent Malarrash/photo/hemolyticanemia NA

SLE,systemiclupuserythematosus;NPSLE,neuropsychiatricsystemiclupuserythematosus;SLEDAI,SystemicLupusErythematosusDiseaseActivityIndex;APS,antiphospholipidsyndrome;Br, brown;W,white;Bl,black;photo,photosensitivity;NA,notavailable;NAp,notapplicable.

a _Cumulative_until_the_date_of_the_study.

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Table2–LaboratorytestsandimagingfindingsonMRIof14SLEpatientswithmyelopathy.

Patients(n=14) Anti-DNA Complement Anti-phospholipid(LA, aCL,␤2)

Otherantibodies ImagingfindingsonspinalcordMRI (T2FSE)

CSF

1 + ↓ aCL+LA+ − NA Normal

2 − Normal − Anti-Sm+ LongitudinalhyperintensityfromC7to

T9,poorlydefined,predominantlyinGM, mildswelling,withoutcontrast

enhancement

Pleocytosis(lymphocytes)

3 − ↓ − − LongitudinalhyperintensityfromT1to

T6,causingtaperingwithoutcontrast enhancement

Normal

4 − ↓ LA+ Anti-Sm,anti-Roand

anti-LA+

LongitudinalhyperintensityfromC7to T1,focalcontrastenhancementinC7

Normal

5 − NA ND − NA Normal

6 + ↓ LA+ − NA Pleocytosis(lymphocytes)

7 + ↓ − Anti-Sm+ LongitudinalhyperintensityfromC5to

T2,centromedularregion,without contrastenhancement

8 − ↓ ␤2+ − LongitudinalhyperintensityfromT1to

T12andlumbararea,centromedular regionwithoutcontrastenhancement

9 NA ↓ aCL+LA+ Anti-AQP4IgG+ Hyperintensityinthebulb,cerebellar

peduncleandspinalcordthroughC5, affectsWMandGM,w/oswelling,w/o contrastenhancement

NA

10 − ↓ − Anti-Sm+ NA Pleocytosis

11 + ↓ ND Anti-Sm+ NA Pleocytosis(lymphocytes)

12 − NA ND − NA Pleocytosis(lymphocytes)

13 + ↓ − Anti-Sm+andantiRo+ LongitudinalhyperintensityfromT11to

L1withdiscreteswellingeffect,withfocal contrastenhancement

Normal

14 + NA − − NA Normal

a _6/13_(45%) _10/11_(90%) _5/11_(45%) _Anti-Sm_6/13_(46%) _7/7_(100%) _7/13(53%)

SLE,systemiclupuserythematosus;CSF,cerebrospinalfluid;NA,notavailable;ND,notdone;aCL,anticardiolipinantibody;LAlupusanticoagulant;␤2,anti-beta2glycoproteinIantibody,anti-AQP4 IgG,anti-aquaporin4;WM,whitematter;GM,graymatter;MRI,magneticresonanceimaging,T2FSE,T2fastspin-echosequence

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245

Fig.1–SagittalT2-weightedimagesshowinghyperintensityinspinalcord,extendingfromthebulbtoC3inthefirst episode(A)andhyperintensityandincreasedspinalcordvolumeextendingtoC5inthesecondepisode,sevenmonths afterthefirstone(B).

Uponthe applicationofEDSSafterameanfollow-up of

11.5±10.4years,itwasobservedthatall11(78%)patientsin

whichitwaspossibletoapplythisscalehadsomedegreeof

disability,whosescorerangedfrom3to8,i.e.frompatients

abletowalkbutwithsomedegreeofdisability, topatients

withneurogenicbladderrequiringwheelchairuse.Nopatient

obtainedafullrecovery.

Three(21%)deathsoccurredduringthemyelopathy

man-ifestation, caused bya widespread infection that occurred

duringorshortlyaftertheimmunosuppressivetherapy

pre-scribedfortreatmentofmyelopathyinallthreecases.

Table3liststreatment,monitoringandprogressiondata. Table4showstherelevantseriesofcasesofmyelopathyin

SLEwhichhavebeenpublishedinEnglishlanguage,

includ-ing the present series, with information on MRI findings.

Twelvecaseseriesarepresented,withresultsshowing4–22

patientsandtheirdemographic,respectiveclinicaland

labo-ratorycharacteristicsandMRI,treatmentandoutcomedata.

Diseaseactivity,recurrenceofepisodesandthepresenceof

otherneuropsychiatricsymptoms,inadditiontothe

occur-renceofmyelopathyasthefirstmanifestationofthedisease,

arealsohighlightedinthistable,whenevermentionedbytheir

authors.

Table3–Treatment,monitoringandprogressionof14 patientswithSLEandmyelopathy.

Patients Treatment Follow-up EDSS

1 IVMPandIVCYC 6years 5.5

2 IVMPandIVCYC 14years 3

3 CSandAZA 15years 6

4 IVMPandIVCYC 22years 7.5

5 IVMP 3years 6

6 IVMPandIVCYC 2months Death

7 IVMPEIVCYC 4months 3.5

8 IVMPandIVCYC 12months 6

9 IVMP,IVCYC,IVIG andMMF

3years 3

10 IVMP 24years 8

11 IVMP 2months Death

12 CSandAZA 1year 8

13 IVMPandIVCYC 2years 8

14 IVMP 8years Death

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Table4–CaseseriesofmyelopathyinSLE.

Caseseries n Ageatdiagnosisof myelopathy(years)

Gender Race SLEduration Myelopathyasthe

firstmanifestation (n)

ActiveSLE PreviousNPSLE

Salmaggietal.12 ₅ _18–46 _F₍₅₎ _NA _2–5_yearsa ₂ ₀ _Absent

Provenzaleetal.13 ₄ _33–47 _F₍₄₎ _NA _NA ₁ _NA _Absent

Harisdangkuletal.14 ₇ _16–52 _F₍₇₎ _NA ₃_months_to₄_years ₄ ₂ _Absent

Kovacs10 ₁₄ _23–77 _F₍₁₂₎_M₍₂₎ _NA _0–21_years ₆ _NA _{D(2)/ON(3)/OS(1)}

Telles-Zenteno15 ₆ _23–37 _F₍₆₎ _NA ₇_months-16_years ₀ ₃ _NA

D’Cruz8 ₁₅ _21–68 _F₍₁₅₎ _NA ₀_yearsa ₁₅ ₁₅ _Absent

Lu23 ₁₄ _15–45 _F₍₁₂₎_M₍₂₎ _A(14) ₂_months_to₂₀_years ₁ ₁₄ _ON(3)/ICH(1)

E(1)/OS(1)/HL(1)

Birnbaun16 ₂₂ _15.5–48.1_(GM)_and

16.6–70.5(WM)

F(20)M(2) AA(8)/W(9)/other (5)

5.4–6.5years 6 11(GM)and6

(WM)

ON(6)

Espinosa17 ₂₂ _12–53 _F₍₁₇₎_M₍₅₎ _NA _0–17_years ₅ _NA _{CHO(3)/CE(1)/AM(1)}

Schultz18 ₁₅ _22–78 _F₍₁₄₎_M₍₁₎ _AA(8)/W(7) _NA ₁₅ _NA _ON₍₂₎

Saison19 ₂₀ _22.9–67.3 _F₍₁₇₎_M₍₃₎ _W

(12)/AA(2)/A(3)/NA(3)

0–36yearsa ₈ ₂₀ _ON(4)/SE(1)

Costallatetal.(2015) 14 9–42 F(14) W(7)/AA(2)/Br(5) 0–16yearsa ₄ ₈ _{ON(2)/SE(2)/OS}

(3)c_/CVA

(1)/HE(1)/PLE(1)b

Complement↓(%) APL+(%) CSFfindings SpinalcordMRI(T2FSE) Treatment Recurrence(%) Progression

40 20 Oligoclonal

bands(1)

Longitudinal hypersignal(2)/N (3)

IVMP(4)/1CS(1) 60 CR(3)/PR(2)

NA NA NA Hypersignal(4) IVMP(4)/IVCYC

(2)

75 NA

NA NA NA Longitudinal

hypersig-nal(3)/ND(4)

IVMP(4)/CS(3) 43 CR(2)/ND(2)/DEATH(4)

50 54 NA(8)/N

(2)/↑protein(4)

Changed(9)/N(5) IVCYC(9)/P(4) NA CR(3)/PR(2)/UR(9)

50 66 ↑protein(2) Longitudinal

hypersignal(6)

IVMP(6)/IVCYC (5)

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Table4–(Continued)

Complement↓(%) APL+(%) CSFfindings SpinalcordMRI(T2FSE) Treatment Recurrence(%) Progression

NA 73 Pleocytosis(2)/N

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Changed(11)/N (2)/ND(1)

IVMP(7)/CS (6)/AZA(6)

6 CR(6)/PR(9)

28 11 Pleocytosis(6) Longitudinal

hypersignal(6) focal(5)/N(1)/ND(2)

CS(14)/IVCYC (2)/P(1)

7 R(4)

NA 54 Pleocytosis(GM) Longitudinal

hypersignal92% (GM)and74% (WM)

GMgroup,more aggressive therapy

9(GM)and 73(WM)

GMgroup,moredisability (meanofEDSS>inGM group)

74 50 Predominanceof

pleocytosis

Longitudinal hypersignal(22)

IVMP(22)/IVCYC (13)/IV

IG(4)/P(4)/RTX(2)

18 CR(3)/PR(13)/w/oR(6)

87 11 ↑protein Predominanceof

focallesion

IVMP(14)/IVCYC (2)/P(1)

NA NA

87 45 Pleocytosis(5) Longitudinal

hypersignal(9)/N (3)

IVMP(18)/IV CYC(11)/IV IG(2)/P(3)/RTX(3)

50 CR(5)/PR(12)/w/oR(1)/O(1)

90 45 Pleocytosis(7)/N

(6)

Longitudinal hypersignal(7)

IVMP(12)/CS (2)/IVCYC (10)/AZA(1)

7 CR(0)/PR(7)/w/oR(4)/DEATH(3)

SLE,systemiclupuserythematosus;NPSLE,neuropsychiatricsystemiclupuserythematosus;APL,antiphospholipidantibody;CSF,cerebrospinalfluid;FSET2,T2fastspin-echosequence;F,female;M, male;AA,AfricanAmerican;Br,brown,;A,Asian;W,white;NA,notavailable;ND,notdone;N,Normal;GM,graymatter;WM,whitematter;CHO,chorea;CE,cerebritis;HE,headache;SE,seizure;AM, asepticmeningitis;ICH,intracranialhemorrhage;HL,hearingloss;PSpsychosis;PLE,plexopathy;E,epilepsy;ON,opticneuritis;D,depression;CVA,stroke;IVMP,intravenousmethylprednisolone; IVCYC,intravenouscyclophosphamide;AZA,azathioprine;IVIG,intravenousimmunoglobulin;CS,corticosteroids;P,plasmapheresis;RTX,Rituximab;CR,completeremission;PR,partialremission; R,remission;w/oRwithoutremission.

a _With_cases_of_myelopathy_preceding_SLE.

b _With_seizure.

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248

Fig.2–SagittalT2-weightedimage,showinghyperintensityandmildenlargementofspinalcordvolume,extendingfrom T11tothemedullarycone.B,T1-weightedsagittalimageaftercontrastinjection,withfociofmedullaryenhancement (arrow)extendingfromT11toL1.C,AxialT2-weightedimagesdemonstratingthespinalcordwithanormalsignal obtainedattheT10level(1)andspinalcordwithhyperintensityobtainedatthelevelofT12(2).

Discussion

Myelopathyisoneofthemostrareneuropsychiatric

mani-festationsinSLE,affectingabout1–2%ofpatients,but this

conditionisveryrelevant,thankstoitshighmorbidityand

mortalityandhasbeenincludedinthenewSLEcriteria.11

Our 14 patients represented 1.2%of the cohort of 1193

patientswithSLE,apercentagesimilartothat observedin

previousstudies.1,2

All patients were female, as noted by all authors and

in line with the gender profile of this disease.8,10,12–19,23

Myelopathycan affect individuals ofall ages; ourpatients

had a mean age of 30 years – a lower mean than that

observed by other authors,8,10,12,13,15,17–19,23 _and _similar _to

those described in two series.14,15 _As _for _the _race, _there

is no reference to a higher prevalence of this

mani-festation in any ethnic group, and many authors have

not highlighted this demographic characteristic. However,

Schutz et al., in a comparison of myelopathy in SLE

ver-susidiopathic myelopathy,commentthe highestfrequency

ofAfrican–AmericanwomenwithSLE, butthis factcan be

attributed to the prevalence of the disease itself in that

area.18

Initialsymptomsarenonspecificandmayincludeashort

viralprodrome:fever,photophobia,nausea,vomiting,

dizzi-ness and nuchal pain. Subsequently, sensory and motor

changesandsphincterdysfunctioncanoccur,anditsonset

cantakehours,daysorevenweeks.Ourmyelopathypatients

presentedwithurinary retentionand fever,whichwas

ini-tially confused,insomecases,withurinarytractinfection.

Thespinalcordinjuryclueswereparesthesia,walking

difficul-ties,paraplegiaandsphincterdysfunction,withsuddenonset

withinhoursordays.

Inasystematicreviewof22casesreportedinthe

litera-turebyEspinosaetal.,theauthorsobservedin23%ofcases

a prodromal picture offever, cough,flu and constitutional

symptomsafewdaysbeforetheonsetofmyelopathy,17_which

wasobservedalsobyHarisdangkuletal.11_The_presence_of

feverandurinaryretentionwasassociatedwithanirreversible

paraplegia,accordingtoBirnbaumetal.16

MyelopathymaybetheinitialmanifestationofSLE,as

hap-penedwithfourofourpatients;andthisfactwasnotedbyall

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249

etal.15 _Some_authors_consider_that_when_myelopathy_occur

inSLE,this canbeaninitialmanifestationinup to39%of

patientswithinthefirstfiveyears.10_By_analyzing_the_series

ofreportedcases(Table4),andtakingintoaccountthetime

pointwherethemyelopathymayariseduringtheprogression

ofSLE,wecanobservetheoccurrenceofavariable

percent-age forthe duration of SLE,and there are cases inwhich

thepatientalreadyhadSLEfor36yearsbeforetheonsetof

myelopathy.19_It_is_also_possible_that_myelopathy_arises_before

SLE;this happenedinonecaseinourseries, inwhichthe

patientpresentedwithspinalcordmanifestations2yearsand

3monthsbeforeherdiagnosisofSLE.All15casesdescribed

byD’Cruzetal.8 _were_affected_by_myelopathy_as_the_initial

manifestationofSLE,and only4(26%)met ACRcriteriafor

SLEattheonsetofmyelopathy.OfthefivecasesofSalmaggi

etal.,12 _in_two_patients _myelopathy _preceded_SLE,_and _the

sameoccurredwith4(20%)of20casesofaFrench

multicen-terstudy.InthisFrenchstudy,twocaseshadmyelopathyfor

morethan10yearsbeforetheestablishmentofadiagnosisof

SLE.19_Salmaggi_et_al.12_concluded_that_in_women_with

myelo-pathyofunknownetiology,exhaustiveclinicalandlaboratory

assessmentsarecriticaltotrytodefineSLE.

AlthoughmyelopathyinSLEcanberecurrent,6,10 _in_our

series13(93%)patientshadasingleepisodeofthiscondition;

andonlyone(7%)patientexperiencedrecurrence.Recurrence

wasobservedinmanycaseseries,insomeofthemwithhigh

frequency(50–75%)asemphasizedinTable4.8,10,12–19,23_This

significantpossibilityofrecurrenceimposestheneedforthe

implementationofamaintenanceimmunosuppressive

treat-ment for these patients, in an attempt to prevent further

crises.

Other neuropsychiatric manifestationshavebeen

corre-latedtothepresenceofmyelopathyinSLE10_;_in_our_series_such

eventsoccurredinnine(64%)patients. Inmostcases,

neu-ropsychiatricinvolvementwasanintegralpartoftheclinical

historyofthedisease,butwithoutasimultaneousoccurrence,

with the exception of one ofthe patients who had major

manifestationofpsychosis concomitantly withspinal cord

symptoms, and this patientdied after immunosuppressive

therapy.Two (14%)patientshadoptic neuritis.Optic

neuri-tisisaneuropsychiatricmanifestationoftenassociatedwith

myelopathy,also known as Devic disease or neuromyelitis

optica(NMO),andthisconditionwasreportedinsomeofthe

seriesofcasespresentedinTable4. Forsomeauthors,the

associationwithopticneuritismaybepresentin21–48%of

casesofmyelitisinSLE.10,16,23_{Neuromyelitis}_optica_recurrence

hasbeen describedinpatients positivefor

anti-aquaporin-4 antibody (anti-AQP4 IgG).24 _One _of _our _patients _showed

NMOassociatedwithpositivityforanti-aquaporin4antibody,

beingtheonlycasewitharecurrentpictureofmyelopathy.

Another patientwithNMO developedbilateral optic

neuri-tismanyyearsaftermyelitis,whichwasconfirmedbyvisual

evokedpotentialtest,althoughantiaquaporin-4antibodywas

negative,whichcanoccurinNMOcases.Inbothcases,the

possibilityofdemyelinatingdiseasewasruledout,andthese

manifestationshavebeenattributedtoSLE.

Theoccurrenceofmyelopathymaybeassociatedwith

dis-easeactivity.Inourseries,twopatientshadactivedisease(one

withnephritisandtheotherwithpsychosis)andonepatient

showedinactivedisease;theremainingcasesexhibitedmild

diseaseactivity.Somepatientshadnoclinicalandlaboratory

datatoallowcalculationofthisindex;andSLEDAIwasnot

appliedinonepatientbecauseatthetimeofemergenceof

myelopathythediagnosisofSLEhadnotyetbeenconfirmed.

Some authors highlight thefact that inone thirdofcases

myelopathycanoccurinascenarioofinactivedisease.25_That

isimportant,becauseinthefaceofarelevantclinicalpicture,

one should always consider myelopathy, regardless ofSLE

activity.Asfortheotherauthorsofthecaseseriespresented

inTable4,noteveryonerecordeddataondiseaseactivity.

Withrespecttoothertests,complementwasreducedin

10(90%)patientsofourcases,insomecasesaccompaniedby

otherlaboratorychanges,andinthreecasesthiswastheonly

punctuationonSLEDAIscore.

Antiphospholipid antibodies have been associated with

myelopathyinSLE7,10_;_in_our_series,_we_found_these

antibod-iesin5(45%)ofcases,justasobservedbySaisonetal.17_But

onlyone(7%) ofour patientsfulfilled theantiphospholipid

syndrome(APS) criteria.Other authors havefoundvariable

percentages, between 11% and 73% of cases, as shown in

Table4.AccordingtoBirnbaumetal.,16_{antiphospholipid}

anti-bodiescanbeimportantinthepathogenesisofneuromyelitis

optica. In anextensive systematicreviewbyKatsiari et al.

ontheoccurrenceoftheseantibodiesincasesoftransverse

myelitis and the use ofanticoagulation inthe presenceof

myelopathy,these authorsconcludedthat, while

antiphos-pholipidantibodies mayhavearoleinthe pathogenesisof

myelopathy,themerepresenceoftheseantibodiesisnot

suf-ficienttoindicatetheanticoagulationtherapy.26

Thefindingsofthecerebrospinalfluidanalysisare

non-specific. Someauthorsfoundincreasedcellularity andalso

proteinorrhachia,18,23_but_often_the_CSF_is_normal_in_patients

withmyelopathy.7,10,27_In_our_series,_CSF_was_collected_in_all

(100%)patients,andthemostfrequentchangewaspleocytosis

(53%),withlymphocytepredominance.

Magneticresonanceimagingisthemostsensitive

imag-ingtoolintheevaluationofspinalcordinjuries,includingin

myelopathyassociatedwithSLE.Theexaminationprotocolfor

MRIimagesshouldcoverthelevelcorrespondingto

neurologi-caldamageobservedonclinicalexamination,butitisstrongly

recommendedtostudytheentirecord.Theimagingfindings

mayvary,withanemphasisontheT2hyperintensesignalon

spinalcord,theeffectofswellingincasesofspinalcordedema,

andalsothecontrastuptake.Amongthesefindings,themost

common isthesignal change,aswas alsoobservedinour

study.Wemustbearinmindthatinsomecases,MRImaybe

normal,especiallyintheearlystages.8,10,12_In_cases_where_the

MRIimagingwithcontrastisnormal,itisrecommendedthat

thetestberepeated2–7daysaftertheinitialmanifestation.5

It is importantto note that CT should not beused for

diagnosis ofmyelopathybecause ofitslowsensitivity.This

technologyshouldbeusedincaseswheretheMRIis

unavail-able, andonlytoexcludecompressivecauses ofthespinal

cord.5

The thoracic region is the most frequently affected

part, which alsooccurred inourpatients.10,23 _This_may _be

attributed to the type of blood supply that nourishes the

region, withemphasisforthe branches ofthelongitudinal

arteriesthatarelesslargeinthethoracicregionwhen

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250

in the vascular supply, as concluded by Kovacset al.10 _In

recentyears,withtheimprovementinthequalityofimages

andequipment,anincreaseintheidentificationof

longitu-dinalspinalcordinjurieswasnotedincasesofmyelopathy

inSLEexaminedbyMRI–afactalsoobservedinmostofour

patients.15,18

Birnbaum et al. compared patients with lesions in

spinalcordwhitematter(spasticityandhyperreflexia)versus

patientswithlesionsinthegraymatter(flaccidityand

hypore-flexia).Theseauthorsconcludedthatthelesionsinthegray

matterareassociatedwithirreversibleparaplegiaandgreater

diseaseactivity.16_We_could_not_make_this_distinction_in_our

patients.

While being very important for the diagnosis of these

patients,MRIdoesnotseemtohavemuchusefortheir

follow-up,becausethereisnoclinicalcorrelationaftertreatmentin

theinitialstages.18_As_for_the_prognosis,_there_seems_to_be_a

worseprognosisinpatientswithchangesinMRIinthe

begin-ningoftheprocess,whencomparedtopatientswithnormal

MRI,10 _especially_in_those_cases_with_presence_of_extensive

lesions.15

Thetreatmentofmyelopathyshouldbeinstituted

imme-diatelyafterthediagnosis,asthismanifestationhasapoor

prognosis,withhighmorbidityinupto50%ofcases10,23_and

with high mortality. Delayed institution of an appropriate

treatmentwastheunfavorable outcomefactor notedbyall

authorsselected.Thecombinationofintravenouspulsesof

methylprednisoloneandcyclophosphamideisconsideredthe

treatmentofchoiceforsuchpatients.6,27_According_to_Saison

et al.,19 _the _use _of_{hydroxychloroquine} _decreased_the

neu-rologicalflaresincasesofmyelopathyinSLE,althoughthis

findingwasnotstatisticallysignificant.Insomecasesitis

nec-essarytouse intravenousimmunoglobulin,plasmapheresis

andrituximab,28_especially_in_unresponsive_or_recurrent_cases;

buttheresponsevary.Twelve(85%)ofourpatientsreceived

pulseMPand10(71%)receivedIVcyclophosphamidewithin

onemonth ofthe onset ofsymptoms. Ourunique caseof

recurrencewastreated,alongthediseaseprogression,with

IVimmunoglobulinandmycophenolatemofetil(MMF).None

ofourpatientsachievedfullrecovery.Theevaluationofthese

patientsbyEDSSresultedinscoresof7.5–8infourofthem,

thatis, patientswithwalking difficultiesand requiringthe

use ofa wheelchair,besidesaneurogenicbladder.All four

(28%)patientsusedMP pulseathigh doses,andtwo (14%)

ofthemwerealsomedicatedwithIVcyclophosphamide;but

eventhentheoutcome wasnotfavorable,perhapsbecause

notallofthemhaveusedbothmedicationswithintwoweeks

aftertheonsetofthemanifestation.Inourgroup,three(21%)

deathsoccurred,allcausedbyaninfectionduringorshortly

after immunosuppressive therapy for treatment of

myelo-pathy.Thisreinforcestheseriousnessofthismanifestation.

Theprognosticfactorsofmyelopathyarenotfullyknown,

butsphincterdysfunction,16,23_MRI_changes,10,16_involvement

ofgraymatter(flaccidityandhyporeflexia),16_and_initial

sever-ity with paraplegia19 _are _cited _as _poor _prognostic _factors.

Musclestrength≥grade3atthetimeofhospitalizationand

anaggressivetherapyinstitutednolaterthantwoweeksafter

theepisodeofmyelopathyarebetterprognosticfactors.23_In

summary,myelopathyinSLEisveryrare,butalsovery

seri-ous.Itoccurredin14(1.2%)ofourpatients.Myelopathymay

bethefirstmanifestationofthedisease,canoccuraftermany

years ofaninstalledSLE,ormay evenprecedethe disease.

Althoughrare,myelopathyhashighmorbidityandmortality

andmaybepresent,regardlessofdiseaseactivity.Moreover,

itcanberecurrentandthereforeitisrecommendeda

mainte-nanceimmunosuppressivetherapysothatnewepisodesare

prevented.MRIisessentialfordiagnosis,butthisexamination

maybenormalinveryearlystages.

Funding

Capes (Master’s scholarship) and CNPq (302205/2012-8,

466715/2014-5).

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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