Differentiation of Neuromyelitis Optica

8/13/2019 Differentiation of Neuromyelitis Optica

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International Journal of MS Care209

From the Departments of Neurology (SL, MK, RH), Radiology (MK,BS, JG), and Geriatrics and Biostatistics (AP), University of Mis-sissippi Medical Center, Jackson, MS, USA; and Department ofNeurology, Louisiana State University, New Orleans, LA, USA

(SL).Correspondence: Saurabh Lalan, MBBS, MD, Department ofNeurology, Louisiana State University, 1542 Tulane Ave., NewOrleans, LA 70112; e-mail: [email protected].

Differentiation of Neuromyelitis Opticafrom Multiple Sclerosis on Spinal

Magnetic Resonance Imaging Saurabh Lalan, MBBS, MD; Majid Khan, MD; Bruce Schlakman, MD;

Alan Penman, MD, PhD, MPH, MSc; Joseph Gatlin, MD; Robert Herndon, MD

In order to examine the accuracy of magnetic resonance imaging (MRI)based diagnosis of neuromy-elitis optica (NMO) versus multiple sclerosis (MS), we performed a retrospective, rater-blinded reviewof 29 cases of NMO and 30 cases of MS using the criteria of long (more than three vertebral levels),continuous lesions with a central cord location for NMO and more peripheral and patchy lesions for

MS. Using these criteria, two raters were able to distinguish the two conditions with a good degreeof condence, particularly when the imaging was performed at the time of an acute cord attack. Thesensitivity and specicity for diagnosis of NMO were 86.2% and 93.3%, respectively, for Rater A and

96.4% and 78.6%, respectively, for Rater B, with a kappa value of 0.72. Thus there are signicantdifferences in lesion characteristics that allow the distinction on spinal cord imaging between MS and

NMO with a moderately high degree of condence. The location of the lesion as evident on MRI of thespine can be regarded as a distinguishing diagnostic feature between MS and NMO. Int J MS Care .2012;14:209214.

Neuromyelitis optica (NMO) is a demyelin-

ating disease of the central nervous system(CNS) that meets all formal criteria for an

autoimmune etiology,1 with clinical manifestationsresembling those of multiple sclerosis (MS).2-4 Theadvent of NMO antibody has permitted clearer differ-entiation between NMO and MS. It has increased theaccuracy of diagnosis, allowing differentiation of the twodisorders in many cases where it was not previously pos-sible.5,6 New diagnostic criteria have been developed forNMO, which have extended our understanding of thedisease and its characteristics. Before the introduction ofNMO antibody, the presence of cerebral lesions wouldchange a diagnosis of NMO to MS. It is now knownthat the presence of cerebral demyelinating lesions onmagnetic resonance imaging (MRI) does not rule out

NMO. Since the introduction of NMO antibody, some

patients followed for long periods with a diagnosis ofMS have been found to have NMO. The differentiationof the two diseases has become increasingly important,as some treatments for MS are totally ineffective inNMO, and evidence has emerged that beta-interferonscan actually make NMO worse.7

Background, Clinical Features, andDiagnostic Criteria of NMO

The coexistence of optic nerve and spinal cord dys-

function was rst described by Albutt in the late 19thcentury. In 1894, Gault used the term neuromyliteoptique aigu(acute optic neuromyelitis) to describe 17cases collected from the literature and personal experi-ence by his mentor, Eugne Devic. From then on, thedisorder was also known as Devic disease or Devic syn-drome.8,9 The disorder consists of one or more clinicalepisodes of optic neuritis (ON) in combination withmyelitis. These clinical events also occur commonly intypical MS; however, in NMO they are usually more

acute (sometimes fulminant) and severe, raising initialdiagnostic suspicion of NMO. Paraclinical measures,such as MRI of the brain and spinal cord and cerebrospi-


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in recent case series consisting predominantly of patients with a relapsing course. The incidence and prevalence ofNMO are unknown. The disorder appears to be morecommon in nonwhites including African Americans, Japanese, and other Pacific Islanders. Demyelinatingdisease in Asia and India is often restricted to the optic

nerves and spinal cord. Reports exist of identical twinsor siblings with NMO. Despite these clues, the role ofgenetic factors in NMO is not known.

Materials and MethodsThis was a retrospective case-control study designed

to examine the accuracy of MRI-based diagnosis ofNMO versus MS. A list of NMO and MS patients wasgenerated from hospital discharge codes over a 10-yearperiod; medical records were reviewed to determine

whether the patient had received a diagnosis of NMOand whether he or she had myelopathy. The records ofabout 70 randomly selected MS patients were reviewedfor the presence of spinal cord symptoms and at leastone cord lesion on spinal MRI. All MS patients selectedmet McDonald criteria for the diagnosis. Of the 70 MSpatients, 30 were randomly selected for the study basedmainly on the availability of spinal MRI scans. Amongthe NMO patients, some of the antibody-negative cases were diagnosed clinically by other physicians, and we

were not able to denitively determine whether they met Wingerchuk criteria for NMO. Although not all of theMS patients had NMO antibody testing, of those who were tested, nearly half (14 of 30) were antibody-nega-tive. Neuromyelitis optica antibody status was recordedfor those who had undergone antibody testing. Thisstudy was approved by the institutional review board atthe University of Mississippi Medical Center.

All records were checked for the availability ofspinal cord imaging. Images for review were initially

selected in a blinded fashion; however, because some ofthe images selected were remote from the time of theattack, the procedure was revised to provide the avail-able image closest to the spinal cord attack. This revision was necessary because changes over time obscure someof the imaging ndings present immediately after anacute attack. One NMO patient who had symptomsof myelopathy was rejected because there was no visiblelesion in the available cord images. Another NMO anti-bodypositive patients MR images could not be used

because the patient did not have radiologic abnormalityin the spinal cord despite some symptoms attributableto cord involvement. The scans were obtained on 1.5-T

nal uid (CSF) examination, also frequently reveal nd-ings that differ from those in typical MS. In retrospectiveand small prospective series, most patients with NMOhave been found to have no or very few nonspecific white matter lesions on brain MRI. Spinal cord MRIalso shows distinctive ndings: a majority of patients

have longitudinally extensive lesions covering three ormore vertebral segments. Furthermore, NMO patientsfrequently have CSF pleocytosis of more than 50 leuko-cytes, with or without the presence of neutrophils.10

Revised diagnostic criteria for NMO proposed by Wingerchuk et al.10 are shown in Table 1. The disordermay follow either a monophasic or a relapsing course.2 In monophasic NMO, patients experience both unilat-eral or bilateral ON and a single episode of myelitis, typ-ically within a very short interval. In contrast, patients

with a relapsing course continue to have discrete exac-erbations of ON and/or myelitis after they meet NMOdiagnostic criteria.

Epidemiology Neuromyelitis optica affects young adults, as does

MS, but has been reported from infancy through theninth decade. The reported mean age of onset, especiallyfor the relapsing type, may be greater than for typicalMS. The mean onset ages were 35 and 47 years in two

series of patients with relapsing NMO.11,12

Wingerchuket al.2 reported a mean age of onset of 29 years (range,154 years) for monophasic patients and 39 years(range, 672 years) for relapsing patients. The ratio of women to men may differ according to disease course.Most reports suggest a ratio of approximately 1.4:1 to1.8:1; rates of 83% to 100% women have been reported

Table 1. Proposed diagnostic criteria forneuromyelitis opticaNote: Diagnosis requires absolute criteria plus at least 2 of the 3supportive criteria.Absolute criteria

1. Optic neuritis

2. Acute myelitis

Supportive criteria 1. Negative brain MRI at disease onset

2. Spinal cord MRI with contiguous T2-weighted signalabnormality extending over 3 or more vertebral segments

3. NMO-IgG seropositive status

Source: Data from Wingerchuk et al. 10 Abbreviations: MRI, magnetic resonance imaging; NMO-IgG, neu-romyelitis opticaimmunoglobulin G.


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Neuromyelitis Optica vs. Multiple Sclerosis on MRI

pared with the actual clinical diagnosis. The results werethen statistically evaluated by a statistician. Sensitiv-ity was calculated as the percentage of true NMO casesdiagnosed as NMO by Rater A (or B); specicity wascalculated as the percentage of true MS cases diagnosedas MS by Rater A (or B). Interrater agreement was mea-

sured using Cohens kappa statistic.13

ResultsThe ndings of Rater A are as follows: A total of 13

of 29 NMO patients had central lesions, 4 had periph-eral lesions, and the remaining 12 had both centraland peripheral lesions, with a propensity toward thecentral location. Meanwhile, 25 of 30 MS patients hadperipheral lesions, 2 had central lesions, and the remain-ing 3 had both central and peripheral lesions, with a

propensity toward the peripheral location. The ndingsfor Rater B are as follows: A total of 21 of 29 NMOpatients had central lesions, none had peripheral lesions,and the remaining 8 had both central and peripherallesions, with a propensity toward the central location.Meanwhile, 7 of 30 MS patients had peripheral lesions,3 had central lesions, and the remaining 20 had bothcentral and peripheral lesions, with a propensity towardthe peripheral location.

The blinded diagnosis of NMO or MS given bythe raters was based on the length of the spinal lesion(number of vertebral segments) and, most importantly,the centricity or the peripheral nature of the lesion. Thestatistical results are published in Tables 3A and 3B andTable 4. As shown in Table 3A, the sensitivity and speci-city for diagnosis of NMO were 86.2% and 93.3%,respectively, for Rater A and 96.4% and 78.6%, respec-tively, for Rater B. The two raters agreed on 48 of 56readings, yielding a kappa value of 0.72, which is goodbut not excellent agreement (Table 3B).

GE and Siemens MR Magnets with scan parameters ofthe relevant T2-weighted images as shown in Table 2.

The nal participants in the study were 29 patientsdiagnosed with NMO and 30 patients diagnosed withMS with spinal cord involvement. The spinal cordlesions were independently reviewed in a blinded fashionby two CAQ (certicate of added qualication)certiedneuroradiologists at our institution who were asked totry to determine whether the patient had MS or NMObased on imaging alone. The two raters made commentson the location, cross-sectional area of involvement,length of cord abnormality corresponding to number ofvertebral bodies involved, whether continuous or discon-tinuous segments were involved, type of cord (cervical,thoracic, or lumbar) involvement with or without con-trast enhancement, and the sequence best demonstratingthe abnormality. They were then asked to make a blind-ed diagnosis based mainly on the criteria of centricity ofthe lesions and length of the segments involved. RaterB did not comment on three of the cases because he feltthere was insufcient information on the MRI scans tosupport any diagnosis. The data were then collected andcompiled, and the raters blinded diagnosis was com-

Table 2. Imaging parameters used for spinalmagnetic resonance imaging

ParameterT2TSE

T2MEDIC

T1 TSESagittal

T1 TSEAxial

Sequence type TSE MEDIC TSE TSEFOV, mm 165 180 220 165

Slices (brain/body) 30 30 13 30

Slice thickness, mm 3 3 4 3

Slice gap, % 17 17 25 17

TR, ms 3750 571 450 450

TE, ms 111 17 11 13

Averages 2 1 2 2IPAT 2 2 2 2

Flip angle, 180 25 180 180

Fat suppression No No Yes No

Base resolution 256 256 256 156

Phase resolution 192 192 224 192

Receiver bandwidth,Hz/pixel

155 150 161 132

Acquisition time, min:s 2:54 2:56 2:46 3:11

Abbreviations: FOV, eld of view; IPAT, integrated parallel acquisi-tion technique; MEDIC, multiple-echo data image combination; TE,echo delay time; TR, repetition time; TSE, turbo spin echo.

Table 3A. Radiologic diagnosis versus clinicaldiagnosis for each rater

Blind diagnosis

True diagnosis

TotalNMO MS

Rater ANMO 25 2 27MS 4 28 32Total 29 30 59

Rater BNMO 27 6 33MS 1 22 23Total 28 28 56

Abbreviations: MS, multiple sclerosis; NMO, neuromyelitis optica.


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promote NMO progression and increase relapses.14,15

Therefore, it is necessary to differentiate between thetwo diagnosticallyspecically, between antibody-nega-tive NMO with brain lesions and MS.

This study has several limitations indicating that theoverall accuracy gures should be considered a lower

limit for the accuracy of radiologic diagnosis of NMOusing the criteria of longitudinal extension and centrallocation of the cord lesion. First, the clinical diagnosisof both MS and NMO almost certainly includes someerrors for both the NMO antibodynegative patientsand the MS patients who had not undergone antibodytesting. In several cases diagnosed as MS before NMOantibody became available, diagnosis was based on ear-lier criteria in which any evidence of the presence ofintracerebral involvement led to a diagnosis of MS. Neu-

romyelitis optica antibody was available in only 33 of 59cases. It is now known that intracerebral lesions are fairlycommon in NMO; thus some of the cases diagnosed asMS may in fact be NMO. Also, in some of these casesthe initial diagnosis was made at another institution, andrecords to verify the diagnosis were not available.

In the NMO antibodypositive cases, when there wasa disagreement between the two raters (in one instance),the MRI was performed 8 years after the occurrenceof the patients acute transverse myelitis. No MRI per-

formed close to the time of the myelitis was available.Because the changes that occur in MRI after the acutephase of the illness often obscure the initial changes, we would expect better accuracy with MRI performed dur-ing or immediately after the attack.

Long-segment linear T2-hyperintense lesions inthe spinal cord have been shown to be characteristicof NMO myelopathy.16,17 Additionally, in our experi-ence the typical lesions are symmetrical and centrallylocated in the cord (Figures 1 and 2). Those seen in MS

myelopathies are usually less extensive on cross-sectionalimaging and are typically asymmetrical and located at ornear the periphery of the cord (Figure 3).

The central localization of the lesions in NMO andthe peripheral localization of the vast majority of thelesions in MS have some interesting implications relatedto disease mechanism. In MS, the peripheral localizationalong with the recent emphasis on cortical lesions thatare present early in the disease course suggests that theCSF is somehow involved in initiating the peripheral

lesions. On the other hand, the central localization inNMO and the preferential localization of lesions withinthe spinal cord suggest possible differences in blood

If we restrict the results to NMO antibodypositivepatients as shown in Table 4, the accuracy rates are 12 of14 for Rater A and 13 of 14 for Rater B. In these NMOcases, 12 of 14 NMO antibodypositive cases were readas having central lesions in the cord by Rater A, whereas

13 of 14 NMO antibodypositive cases were read ashaving central lesions in the cord by Rater B. In the casein which there was agreement between the two raters onnoncentricity of the lesion, the interval between myelop-athy and imaging was 8 years.

Discussion Although NMO and MS were once thought to be

different manifestations of a single autoimmune diseaseentity, we now know that they are different entities inmany respects, and must be treated with different thera-pies. For instance, some authors have suggested that astandard therapy for MS (interferon beta) may actually

Table 3B. Raters diagnosis and judgment oflocation of lesions within the cordRater A Rater B Total

DiagnosisDiagnosis NMO MSNMO 26 1 27

MS 7 22 29Total 33 23 56Kappa: 0.72 (95% CI: 0.54-0.89)

LocationLocation Central Peripheral

Central 29 1 30

Peripheral 19 7 26Total 48 8 56Kappa: 0.25 (95% CI: 0.05-0.44)

Abbreviations: CI, condence interval; MS, multiple sclerosis; NMO,

neuromyelitis optica.

Table 4. Lesion location in antibody-positiveand antibody-negative NMO

Blinded lesionlocation

NMO antibody

TotalPositive Negative

Rater A

Central 12 12 24Peripheral 2 2 4Total 14 14 28

Rater B

Central 13 14 27Peripheral 1 0 1Total 14 14 28

Abbreviation: NMO, neuromyelitis optica.


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Neuromyelitis Optica vs. Multiple Sclerosis on MRI

ConclusionSignificantly different lesion parameters allow the

distinction on spinal cord imaging between MS andNMO with a moderately high degree of condence. The

location of the lesion as evident on MRI of the spine cannow be considered a distinguishing diagnostic featurebetween the two disorders. Certainly, MRI examination

ow, in the concentration of aquaporin-4 around theblood vessels, or in the blood-brain barrier in the cord.

While NMO antibody has helped us to dene thedisease and distinguish it from MS, it is clear that thereare many antibody-negative cases that are otherwisetypical both clinically and in terms of imaging charac-teristics. Whether another, as yet unidentied antibody

is involved or a different immunologic mechanism isinvolved remains to be determined. However, we believethat the clinical picture and the imaging characteristicsdiscussed in this article are sufcient to identify the con-dition as distinct from MS, and experience suggests thatthe antibody-negative cases respond better to the immu-nosuppressive approach used in antibody-positive NMOthan to typical MS medications. We believe that theimaging features characteristic of NMO and discussedin this article may be sufcient to dene the disease andthus call for a treatment program different from thattypical for MS.

Figure 1. Axial T2 fast spin echo (A) and axial T2gradient (B) images of the cervical cord showing central T2hyperintensity (arrows) in neuromyelitis optica involvingcentral portions of the spinal cord with signal changesinvolving more than 50% of the cross-sectional area

A

B

Figure 2. Sagittal T2 fast spin echo images of the cervical(A, B) and thoracic (C) spine showing continuous long-segment linear T2 signal hyperintensity (arrows) involving thespinal cord extending from the cervicomedullary junction tothe T8-9 level with predominantly central involvement of thecord in a patient with neuromyelitis optica

A

B

C


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Financial Disclosures: The authors have no conicts of interest todisclose.

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performed as we have described seems to be specic andsensitive for an NMO diagnosis. When MRI is per-formed acutely, the characteristics we have describedmay have even better interrater reliability for the diag-nosis of NMO than we found in this retrospective series.

Larger-scale studies in patients who are NMO antibodypositive or NMO antibodynegative may reveal greatersensitivity and specicity.o

Figure 3. Axial T2 fast spin echo (A, B) and sagittalshort tau inversion recovery (STIR) (C) sequences showingthe typical peripheral signal changes on axial images (A, B)and discontinuous high T2 signal (arrows) involving shortsegments of the spinal cord (C) in a patient with multiplesclerosis

A

B

C

Practice Points On spinal magnetic resonance imaging, neuro -

myelitis optica (NMO) is strongly suggested byacute continuous longitudinal lesions coveringthree or more vertebral levels, while MS is sug-gested by patchy lesions that are rarely continu-ous over more than one vertebral segment.

In NMO, spinal cord lesions tend to be centrallylocated, rarely extending to the surface of thecord, whereas in MS such lesions are usuallylocated peripherally.

Chronic cord lesions in NMO often change overtime, becoming patchier in appearance, makingthese distinguishing criteria less applicable toolder lesions.

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Differentiation of Neuromyelitis Optica