Acute Fulminant Demyelinating Disease a Descriptive Study of 60 Patients

Home , Demyelinating disease, McDonald criteria

ORIGINAL CONTRIBUTION Acute Fulminant Demyelinating Disease A Descriptive Study of 60 Patients

Je´roˆme de Seze, MD; Marc Debouverie, MD; He´lène Zephir, MD; Christine Lebrun, MD; Fre´de´ric Blanc, MD; Ve´ronique Bourg, MD; Sandrine Wiertlewski, MD; Sophie Pittion, MD; David Laplaud, MD; Emmanuelle Le Page, MD; Romain Deschamps, MD; Philippe Cabre, MD; Jean Pelletier, MD; Irina Malikova, MD; Pierre Clavelou, MD; Vale´rie Jaillon, MD; Gilles Defer, MD; Pierre Labauge, MD; Olivier Gout, MD; Clotilde Boulay, MD; Gilles Edan, MD; Patrick Vermersch, MD

Background: Acute demyelinating encephalomyelitis netic resonance imaging, and follow-up data were evalu- (ADEM) is characterized by a severe inflammatory attack, ated for each group. frequently secondary to infectious events or vaccinations. To date, no clear criteria exist for ADEM, and the Results: Patients in the ADEM group more frequently had risk of subsequent evolution to multiple sclerosis (MS) atypical symptoms of MS (26 of 35 [74%]) than patients remains unknown. with MS (8 of 19 [42%]) (P=.02). Oligoclonal bands were more frequently observed in the MS group (16 of 19 [84%]) Objective: To evaluate the risk of evolution to MS af- than in the ADEM group (7 of 35 [20%]) (P Ͻ.001). Pa- ter a first episode of ADEM. tients in the ADEM group more frequently had gray matter involvement (21 of 35 [60%]) than those in the MS group Design: Observational, retrospective case study. (2 of 19 [11%]) (P Ͻ.001). On the basis of these results, we consider that the presence of any 2 of the following 3 Setting: Thirteen French MS centers. criteria could be used to differentiate patients with ADEM from those with MS in our cohort: atypical clinical symp- Patients: We retrospectively studied 60 patients with toms for MS, absence of oligoclonal bands, and gray mat- ADEM who were older than 15 years with no history sug- ter involvement. On this basis, 29 of the 35 patients in the gestive of an inflammatory event who presented to MS ADEM group (83%) and 18 of the 19 patients in the MS centers from January 1, 1995, through December 31, 2005. group (95%) were classified in the appropriate category. We excluded 6 patients with multiphasic ADEM because this is a rare condition and somewhat difficult to Conclusions: Our study found some differences con- classify. After a mean follow-up of 3.1 years (range, 1-10 cerning the risk of evolution to clinically definite MS af- years), the remaining 54 patients were then classified into ter a first demyelinating episode suggestive of ADEM. 2 groups: monophasic ADEM (ADEM group) (n=35) and These findings led us to propose criteria that should now clinically definite MS (MS group) (n=19). be tested in a larger, prospective cohort study.

Main Outcome Measures: Clinical, laboratory, mag- Arch Neurol. 2007;64(10):1426-1432

RADITIONALLY, ACUTE to represent part of the same acute mono- demyelinating encepha- phasic immune process, including symp- lomyelitis (ADEM) is toms similar to those in the first episode, characterized by a severe the term multiphasic disseminated encepha- inflammatory attack, fre- lomyelitis (MDEM) can be used.6 In ap- quently secondary to infectious events or proximately 30% of cases, a first episode T1,2 vaccinations. Although the pathophysi- of ADEM subsequently evolves to typical ologic mechanism of ADEM remains un- multiple sclerosis (MS), with a clear dis- known, an autoimmune response to my- semination in time and space.6,7 The abil- elin basic protein triggered by infection or ity to determine which patients with immunization is considered to be a pos- ADEM will subsequently develop MS af- sible etiologic factor.3,4 In most cases ter a single clinical episode has prognos- ADEM is monophasic, but in some pa- tic and therapeutic implications because tients it may be recurrent and relapses may early treatment of MS may be advanta- Author Affiliations are listed at occur immediately after the onset of the geous.8,9 The recently proposed criteria for the end of this article. disease.5,6 If these relapses are considered MS include dissemination in time, de-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 fined as new brain lesions observed on magnetic reso- ments during the follow-up. Finally, we noted the Expanded nance imaging (MRI) performed during the months af- Disability Status Scale score at the final visit. ter the first demyelinating episode.10,11 Furthermore, previous studies1,6,7 reported that new gadolinium- BRAIN AND SPINAL CORD MRI enhanced lesions could appear several months after a first episode of ADEM in adults without any new clinical re- All patients underwent brain MRI during the first clinical epi- lapse. This fact could be a limitation for the application sode. The MRIs were performed on a 1.0- or 1.5-T unit with at of the new criteria for MS in cases of ADEM. least the following sequences: sagittal and axial T1-weighted Only a few studies on ADEM have been performed, images before and after gadolinium infusion and axial T2 or fluid attenuation inversion recovery sequences. Spinal cord MRI mostly involving children. To our knowledge, only 1 large 6 was performed in 38 of the 54 patients. All patients had a fol- study has focused on ADEM in adults. The results of low-up brain MRI with a mean±SD delay of 5.7±1.9 months that study were clearly different from those of pediat- (range, 3-8 months). The MRIs were reviewed by a neurora- ric series,5,12,13 especially in terms of clinical and MRI diologist blinded to clinical diagnosis and were classified ac- presentation and the possible evolution to MS. In cording to the following data: number of T2-weighted lesions, pediatric series, the following were found to be risk number of gadolinium-enhanced lesions, and presence of edema. factors for monophasic ADEM compared with MS: Because the MRIs were not all performed with the same pro- previous infection or vaccination, polysymptomatic tocol and were analyzed retrospectively, an evaluation of the manifestations, lack of periventricular lesions, and the T2-lesion load was not possible. We also noted the localiza- absence of oligoclonal bands (OCB) in the cerebrospi- tion of lesions that affected the brainstem, periventricular, corpus callosum, basal ganglia, or cortical regions. We nal fluid (CSF).5,12-15 In contrast, in the adult cohort 6 included as gray matter involvement both basal ganglia and study, patients with ADEM were older, had more fre- cortical lesions. For the spinal cord MRI, we noted the size quent brainstem involvement, and had similar peri- of the lesions (Ͻ2 vertebral segments or Ն2 vertebral seg- ventricular lesions compared with those patients who ments in the sagittal plane), gadolinium enhancement, and subsequently developed MS. A finding of OCB in the whether the spinal cord was swollen. For the follow-up CSF was also a risk factor for MS in this cohort.6 Cur- brain MRI, we noted patients with an overall regression of rently, no clear criteria are available that predict the lesions, patients with a brain MRI similar to that observed at evolution after a first demyelinating episode corre- baseline, and patients with new T2- and T1-weighted sponding to ADEM. The aim of our study was to gadolinium-enhanced lesions. define the spectrum of ADEM in a large, multicenter, adult cohort and look for possible predictive criteria BIOLOGICAL ANALYSIS for evolution to clinically definite MS. All patients underwent biological and immunological tests, including measurement of complete blood cell count, erythrocyte METHODS sedimentation rate, serum cryoglobulins, total serum gamma- globulins, serum protein immunoelectrophoresis, C-reactive In a large, collaborative, multicenter study, we retrospectively protein, complement factors, antinuclear antibodies, antinative studied patients identified as having ADEM in a European da- DNA, anticardiolipin antibodies, rheumatoid factor, and anti- tabase on MS.16 In this database, patients with a differential di- prothrombinase and serologic testing for human immunodefi- agnosis of MS, such as neuromyelitis optica or ADEM, are spe- ciency virus, herpes simplex virus, varicella-zoster virus, hepa- cifically identified. In the database, ADEM is defined as a first titis C and B, cytomegalovirus, and Epstein-Barr virus. acute fulminant demyelinating episode without any previous All patients underwent a CSF analysis with blood cell count, neurologic history. Patients who presented with acute neuro- protein level, and OGB evaluation by isoelectrofocusing meth- logic symptoms and multiple supratentorial and/or infraten- ods. They did not undergo a CSF follow-up analysis. Four pa- torial demyelinating lesions on MRI that were suggestive of a tients had brain biopsies performed in stereotactic conditions. first and severe acute inflammatory process, as usually de- In all cases the result was nonspecific demyelinating lesions. scribed in ADEM, were included in our study.6,7 The lesions included widespread, multifocal, or extensive white matter le- FINAL CLASSIFICATION sions. We excluded patients younger than 16 years (pediatric cases), patients with a history suggestive of an inflammatory We first analyzed clinical, CSF, and MRI data for the entire study event, and patients with transverse myelitis or optic neuritis population. All patients were followed up at least 1 time per as the only neurologic deficit. We also excluded patients with year by the same neurologist. After a mean follow-up of 3.1 years central nervous system infection, vasculitis, or other autoim- (range, 1-10 years), patients were classified into 3 groups: the mune diseases. From January 1, 1995, through December 31, MDEM group (n=6), when the patients had recurrent epi- 2005, a total of 60 patients from 13 French MS centers were sodes similar to the first one; the ADEM group (monophasic identified as having presented with ADEM. ADEM) (n=35), when patients did not have any new neurologic manifestations; and the MS group (n=19), when a sec- CLINICAL AND DEMOGRAPHIC DATA ond relapse was observed with new symptoms in new clinical territories at least 1 month after the first episode to define clini- We noted age, sex, date of onset, previous infectious diseases cal space and time dissemination. We subsequently excluded or vaccinations, and clinical presentation. Clinical presenta- patients with MDEM from the comparative study because this tion was considered atypical for MS in cases of consciousness was a rare condition and difficult to classify. alteration, hypersomnia, aphasia, hemiplegia, paraplegia, tet- We analyzed the clinical, MRI, and CSF data for all groups. raplegia, seizure, vomiting, bilateral optic neuritis, or confu- We then sought to identify clinical, MRI, and CSF data that could sion. We also recorded the occurrence of new relapses and the help to predict the evolution of the disease in an individual pa- number of relapses, treatments during the acute phase, and treat- tient after a first episode of ADEM.

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Variable All (N = 54) ADEM (n = 35) MS (n = 19) P Valueb Female/male 34/20 20/15 14/5 .24 Age, mean ± SD, y 32.7 ± 13.2 35.9 ± 15.4 27.1 ± 8.2 .04 White race 47 (87) 29 (83) 18 (95) .20 Infections or vaccinations 26/10 (67) 19/7 (74) 7/3 (53) .12 Delay after infection or vaccination episode, 23.3±26 26±37 18±15 .18 mean ± SD, d Symptoms Polysymptomatic 38 (70) 21 (60) 17(89) .06 Atypical for MS 34 (63) 26 (74) 8 (42) .002 Sensory 10 (19) 4 (11) 6 (32) .07 Motor 26 (48) 18 (51) 8 (42) .49 Paralysis 3 (6) 3 (9) .80 Paresis 23 (43) 15 (43) 8 (42) .80 Optic neuritis 7 (13) 4 (11) 3 (16) .68 Bilateral 2 (4) 2 (6) .80 Unilateral 5 (9) 2 (6) 3 (16) .80 Intracranial hypertension 13 (24) 11 (31) 2 (11) .08 Brainstem 13 (24) 8 (23) 5 (26) .80 Cerebellar 12 (22) 7 (20) 5 (26) .60 Urinary 6 (11) 5 (14) 1 (5) .31 Aphasia 8 (15) 6 (17) 2 (11) .53 Seizure 3 (6) 3 (9) 0 .60 Hemianopia 2 (4) 2 (6) 0 .60

Abbreviations: ADEM, acute demyelinating encephalomyelitis; MS, multiple sclerosis. a Patients could have 1 or more clinical symptoms. Data are presented as number (percentage) of patients unless otherwise indicated. b Comparison between the ADEM and the MS groups.

STATISTICAL ANALYSIS (n=2), hepatitis A (n=1), influenza (n=1), yellow fever (n=1), rubella (n=1), and poliomyelitis (n=1). Where appropriate, results are presented as mean±SD. For In the MS group, vaccinations were against poliomy- the statistical comparison between the ADEM group and elitis (n=2) and hepatitis B (n=1). ␹2 the MS group, we used or Fisher exact tests for qualitative Clinical symptoms were not different between the 2 variables, depending on the number of patients, and groups when we considered each symptom separately. an unpaired Mann-Whitney test for quantitative variables. The proposed criteria for ADEM were evaluated using Furthermore, although patients in the MS group were sensitivity, specificity, positive-negative predictive value, more frequently polysymptomatic (17 of 19 [89%] and accuracy. compared with 21 of 35 [60%] in the ADEM group), the difference did not reach statistical significance. The only statistically significant difference we found RESULTS concerning clinical symptoms was with regard to atypical features for MS (consciousness alteration, DEMOGRAPHIC AND CLINICAL DATA hypersomnia, aphasia, hemiplegia, paraplegia, tetraplegia, seizure, vomiting, bilateral optic neuritis, or We did not find many differences in terms of demo- confusion), which were more frequent in the ADEM graphic data between the groups (Table 1). Patients group (26 of 35 [74%]) than in the MS group (8 of 19 in the ADEM group were older (P=.04). Infectious [42%]) (P=.02). episodes or vaccinations before the neurologic episode were reported in 26 of the 35 patients in the ADEM group (74%) compared with 10 of the 19 patients in MRI FINDINGS the MS group (53%), but the difference was not statistically significant. The first clinical symptoms were Gray matter involvement (basal ganglia or cortical observed after a mean±SD delay of 28±40 days after lesions) was more frequent in the ADEM group (21 of vaccinations or infectious episodes, without any sig- 35 [60%]) than in the MS group (2 of 19 [11%]) nificant difference between the ADEM group and the (PϽ .001) (Table 2). In contrast, corpus callosum MS group. In the ADEM group, infectious episodes involvement was less frequent in the ADEM group (8 included diarrhea (n=7), pharyngeal symptoms of 35 [23%]) than in the MS group (15 of 19 [79%]) (n=7), pulmonary symptoms (n=2), urinary symp- (PϽ .001). We did not find any differences in terms of toms (n=1), and cat-scratch disease (n=1). In the MS the number of T2 lesions, gadolinium enhancement, group, infectious episodes consisted of pharyngeal edema, or periventricular or brainstem lesions. The symptoms (n=6) and urinary symptoms (n=1). In the Barkhof criteria (included in the criteria of McDonald ADEM group, vaccinations were against hepatitis B et al10) were not discriminant between the 2 groups.

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Variable All (n = 54) ADEM (n = 35) MS (n = 19) P Valueb Brain MRI No. of T2 lesions, mean ± SD 13.2 ± 7.8 12.2 ± 7.4 15.3 ± 8 .68 Barkhof criteriac met 43 (80) 26 (74) 17 (89) .20 Edema 26 (48) 17 (49) 9 (47) .80 Gadolinium-enhanced lesions 41 (76) 23 (66) 18 (95) .06 Periventricular lesions 49 (91) 30 (86) 19 (100) .24 Corpus callosum lesions 23 (43) 8 (23) 15 (79) Ͻ.001 Cerebellar lesions 25 (46) 15 (43) 10 (53) .52 Brainstem lesions 27 (50) 16 (46) 11 (58) .52 Gray matter (basal ganglia or cortical) lesions 23 (43) 21 (60) 2 (11) Ͻ.001 Basal ganglia lesions 17 (31) 15 (43) 1 (5) .004 Cortical lesions 21 (39) 11 (31) 1 (5) .003 Spinal cord MRId Spinal cord lesions 25 (66) 15 (68) 10 (63) .49 Swollen spinal cord 2 (5) 2 (6) 0 .80 Gadolinium-enhanced lesions 8 (22) 5 (23) 3 (19) .70 Large lesion (Ն2 vertebral levels) 9 (24) 7 (32) 2 (13) .37

Abbreviations: ADEM, acute demyelinating encephalomyelitis; MRI, magnetic resonance imaging; MS, multiple sclerosis. a Data are presented as number (percentage) of patients unless otherwise indicated. b Comparison between the ADEM and the MS groups. c Included in the criteria of McDonald et al.10 d The sample sizes for these entries are 38 for all patients, 22 for the ADEM group, and 16 for the MS group.

Table 3. Biological Dataa

Variable All (N = 54) ADEM (n = 35) MS (n = 19) P Valueb Cerebrospinal fluid White blood cells/µL, mean ± SD 41.7 ± 102.5 49.2 ± 134.1 28.2 ± 35.6 .09 Ͼ30/µL 13 (24) 8 (23) 5 (26) .80 Proteins, mean ± SD, g/dL 0.58 ± 0.3 0.63 ± 0.3 0.5 ± 0.3 .70 Ͼ1 g/dL 7 (13) 5 (14) 2 (11) .80 Oligoclonal bands 34 (42) 7 (20) 16 (84) Ͻ.001 Antinuclear antibodies 3 (6) 1 (3) 2 (11) .28

Abbreviations: ADEM, acute demyelinating encephalomyelitis; MS, multiple sclerosis. a Data are presented as number (percentage) of patients unless otherwise indicated. b Comparison between the ADEM and the MS groups.

CSF AND BIOLOGICAL DATA CLINICAL AND MRI FOLLOW-UP

The inflammatory reaction in the CSF was more severe During a mean±SD follow-up of 3.4±2.9 years (range, in the ADEM group (mean±SD white blood cell count, 1-8 years), patients in the MS group had 2.3±1.3 re- 49.2±134.1/µL; to convert white blood cell count to ϫ109 lapses, corresponding to a mean of 0.68 relapse per year per liter, multiply by 0.001) than in the MS group (Table 4). The last Expanded Disability Status Scale (28.2±35.6/µL), but the difference was not statistically evaluation was higher in the MS group (2.9±1.3) than significant (Table 3). The protein level was not differ- in the ADEM group (1.9±1.9), but the difference did not ent between the 2 groups. Similarly, if we considered the reach statistical significance (P=.08). frequency of atypical CSF features for MS (protein level The control brain MRI showed a complete regression higher than 1 g/dL [to convert protein to grams per li- of lesions in 2 patients in the ADEM group. New gado- ter, multiply by 10.0] or white blood cell count higher linium-enhanced lesions were observed in 3 patients in than 30/µL), we did not observe any difference between the ADEM group (9%) and in 9 patients in the MS group the 2 groups. In contrast, OCB were more frequently ob- (47%) (PϽ .001). New T2-weighted lesions were observed in the MS group (16 of 19 [84%]) than in the served in only 1 patient in the ADEM group (3%) and in ADEM group (7 of 35 [20%]) (PϽ .001). We did not find 11 patients in the MS group (58%) (PϽ .001). In the any differences between the 2 groups in terms of bio- ADEM group, 4 patients (11%) met the MRI criteria (ie, logical data, including dose of autoantibodies (anti- dissemination in time defined by MRI follow-up) for MS.10 nuclear, anticardiolipin antibodies). In these 4 patients, follow-up brain MRIs were per-

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Variable All (N = 54) ADEM (n = 35) MS (n = 19) P Valuea Clinical data, mean ± SD Follow-up, y 3.1 ± 3.4 2.9 ± 3.6 3.4 ± 2.9 .17 No. of relapses 0.87 ± 1.1 0 2.3 ± 1.3 NA Last EDSS score 2.2 ± 1.7 1.9 ± 1.9 2.9 ± 1.3 .28 Control brain MRI, No. (%) Normalized 2 (4) 2 (6) 0 .80 New gadolinium-enhanced lesions 12 (22) 3 (9) 9 (47) Ͻ.001 New T2 lesions 12 (22) 1 (3) 11 (58) Ͻ.001 McDonald criteria10 met 23 (43) 4 (11) 19 (100) Ͻ.001

Abbreviations: ADEM, acute demyelinating encephalomyelitis; EDSS, Expanded Disability Status Scale; MRI, magnetic resonance imaging; MS, multiple sclerosis; NA, not applicable. a Comparison between the ADEM and the MS groups.

feron beta and 1 with glatiramer acetate). Because of the Table 5. Proposed Criteria for Differentiation retrospective aspect of our study and the lack of ran- Between MS and ADEM domization, we did not look for any correlation between treatment and clinical outcome. ADEM corresponds to patients with at least 2 of the following 3 criteria: Clinical atypical symptoms of MS. One or more of the following: consciousness alteration, hypersomnia, seizures, cognitive PROPOSED CRITERIA FOR DIFFERENTIATION impairment, hemiplegia, tetraplegia, aphasia, or bilateral optic BETWEEN ADEM AND MS neuritis; Absence of oligoclonal bands in the cerebrospinal fluid; Gray matter involvement (basal ganglia or cortical lesions). On the basis of the results of clinical, MRI, and CSF data, Twenty-nine of the 35 patients with ADEM (82.9%) at the end of the we propose that ADEM could correspond to patients with follow-up had 2 or more of these criteria and would therefore have at least 2 of the following 3 criteria: (1) clinical symp- been correctly classified, and 18 of the 19 patients with MS (94.7%) toms atypical for MS, including 1 or more of the follow- had no criteria or only 1 criterion and would also have been correctly ing: consciousness alteration, hypersomnia, seizures, cog- classified. Statistical data concerning the criteria for ADEM: nitive impairment, hemiplegia, tetraplegia, aphasia, or Sensitivity = 82.9% bilateral optic neuritis; (2) absence of OCB in CSF; and Specificity = 94.7% (3) gray matter involvement (basal ganglia or cortical le- Positive predictive value = 96.7% sions) (Table 5). We also observed marked differences Negative predictive value = 75.0% concerning corpus callosum involvement, but we did not Accuracy = 87.0% include this in our proposed differential diagnostic criteria because it did not increase the discrimination be- Abbreviations: ADEM, acute demyelinating encephalomyelitis; MS, multiple sclerosis. tween the 2 groups. According to these criteria, 29 of the 35 patients with ADEM at the end of the follow-up (83%) were classified in the correct category; 18 of the 19 patients with MS (95%) formed between 3 and 6 months after the clinical event. had none or only 1 of the criteria and were classified in the These 4 patients did not differ from the other patients in correct category. On the basis of these results, the criteria the ADEM group in any other respect. Furthermore, if have a sensitivity of 83%, a specificity of 95%, a positive we omitted these 4 patients, the results were similar (data predictive value of 97%, a negative predictive value of 75%, not shown). and an accuracy of 87%. When we considered only those patients with a minimum follow-up of 3 years, the results TREATMENT were similar (data not shown). All patients were treated with intravenous corticosteroids (3-10 g per patient). Oral substitution was per- COMMENT formed in 14 cases at a dosage of 1 mg/d during 1 month. We did not observe any differences between patients with Our study of 60 adults with an initial feature of ADEM and without oral substitution, including with regard to showed a 32% rate of conversion to clinically definite MS the risk of relapse. Fourteen patients (9 [26%] in the after a mean follow-up of 37 months. This result con- ADEM group and 5 [26%] in the MS group) were treated firms the first and only other study,6 to our knowledge, with immunosuppressive drugs: 7 with mitoxantrone, 4 on ADEM in adults, which found a 35% rate of conver- with cyclophosphamide, 2 with methotrexate, and 1 with sion to MS after a mean follow-up of 38 months. This azathioprine. Three patients (all in the ADEM group) were rate in adults is higher than that reported in pediatric stud- treated with intravenous immunoglobulin and 1 with ies,5,12-15 which found a rate of conversion to MS of ap- plasma exchange. Nine patients (all in the MS group) were proximately 15%. This difference might, however, be treated with immunomodulatory drugs (8 with inter- largely dependent on the length of follow-up. Patients

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 with isolated events of demyelination often do not One possible explanation for the differentiation be- experience a second event until 10 to 20 years later. It tween MS and ADEM may be that high-affinity auto- seems likely, therefore, that a longer follow-up in our antibodies could be present in a subset of patients with cohort would have increased the number of conver- ADEM and not in those with MS. Unfortunately, be- sions to MS. cause we evaluated antinuclear antibodies but not high- Adult and pediatric ADEM cohorts are also slightly affinity antibodies in our study, we are not yet in a po- different in terms of age risk for MS, MRI data, and sition to resolve this issue. outcome.5,6,12-15 However, the diagnostic criteria for The CSF results remain important for the differentia- ADEM proposed in the pediatric literature are similar tion between MS and ADEM, especially the presence or to those we propose in the present study, including absence of OCB, which is highly discriminant. Surpris- clinical presentation, OCB in CSF, and gray matter ingly, the white blood cell count was not discriminant. involvement.5,6,12-15 Twenty-five percent of our patients with MS had a white Although no specific diagnostic criteria for ADEM are blood cell count of more than 30/µL, a finding consid- available in the literature, an analysis of the different pro- ered to be a red flag for MS.17 This result could be re- files of the patients confirms a consistency between the lated to the high level of inflammation observed in this various MS centers in the way that ADEM is diagnosed. particular subtype of patients. This finding raises the ques- The clinical presentation of ADEM described in our study tion of whether these patients represent a different bio- is in accordance with the only previous large study6 in logical process than that of patients with more classic MS. adults for most of the data, including age, sex ratio, and Multiple sclerosis may have been underdiagnosed in symptoms. The authors found a significant difference be- patients without OCB in the CSF, since reports have been tween ADEM and MS in terms of brainstem symptoms. made of early MS cases in which OCB appeared with time. In contrast, we did not find any differences between our It would therefore be interesting to perform a CSF fol- 2 groups with regard to clinical symptoms, except for what low-up in all patients with ADEM; OCB tend to disap- we refer to as symptoms atypical for MS, which were more pear in ADEM and other fulminant demyelinating dis- frequently found in the ADEM group than in the MS eases, such as neuromyelitis optica, but may appear group. In our study, the ADEM definition is based on a subsequently in MS.18,19 clinicoradiologic pattern, which could explain the rela- At the end of our study, we suggest criteria that could tively low percentage of patients with atypical clinical pre- be highly predictive of conversion from ADEM to MS. sentation for MS. The presence of at least 2 of the 3 criteria, namely, atypi- With regard to MRI data, the most important finding cal clinical symptoms, absence of OCB in the CSF, and for the differentiation between ADEM and MS was the the existence of gray matter involvement on brain MRI gray matter involvement in patients in the ADEM group. (basal ganglia or cortical lesions), appears to be highly This variable was not clearly evaluated in the previous suggestive of ADEM because this was the case in 29 of cohort of adult patients with ADEM, but similar find- 35 patients with ADEM (83%), whereas only 1 of the 19 ings have been reported in pediatric ADEM co- patients diagnosed as having MS (5%) had the criteria horts.5,12-15 We also found a higher proportion of pa- for monophasic ADEM. This result could well be tients with MS than patients with ADEM with corpus modified after a longer follow-up, which would likely callosum involvement, but we did not include this in our reveal new relapses among the patients classified as proposed differential diagnostic criteria because it did not having ADEM in this study. Furthermore, the validity increase the discrimination between the 2 groups. It would of these criteria in terms of their sensitivity and speci- be surprising if T2 lesions did not help to differentiate ficity will need to be verified in a new, more robust between ADEM and MS, but because of the multicenter prospective cohort. and retrospective approach of our study, we were not able Our patients were not randomized for the therapeu- to evaluate the lesion load precisely. The main problem tic approach, and the various treatments were chosen em- with MRI in ADEM, especially since the advent of new pirically. It is therefore not possible to draw any conclu- diagnostic criteria for MS, is the possible occurrence of sions regarding efficacy. Many proposals have been put several waves of hypersignals during the months after the forward for the treatment of ADEM, including plasma ex- initial episode.17 Such events were observed in 4 of our change, intravenous immunoglobulin, a high dose of in- patients classified in the ADEM group because they did travenous corticosteroids, and immunosuppression.20-23 not present a new clinical relapse. All 4 of these patients Multicenter randomized studies are necessary to deter- underwent their control brain MRI between 3 and 6 mine the efficacy of these therapeutic strategies. Fur- months after the first clinical event. A recent article on thermore, to enable disease-modifying drugs to be used ADEM7 suggested that the interval between the initial and early in MS, it is absolutely essential to define the risk of the control brain MRI should not be shorter than 6 developing MS. months. The mean follow-up of only 3 years in our co- In conclusion, our study confirms the wide spectrum hort may also be a limitation because we cannot be sure of the disease currently referred to as ADEM, including that patients classified as having ADEM will not subse- patients with a monophasic disease (ADEM) and a few quently have new clinical relapses. A longer follow-up with similar, recurrent episodes (MDEM), and an over- of these patients is the only way to confirm that they do all risk of subsequently developing MS of approxi- not eventually develop MS. However, when we ana- mately 30%. Our study found some differences concern- lyzed the data for patients with a minimum follow-up of ing the risk of an evolution to clinically definite MS after 3 years, the results were no different. a first demyelinating episode suggestive of ADEM. These

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 findings led us to propose criteria that should now be 3. Pohl-Koppe A, Burchett SK, Thiele EA, Hafler DA. Myelin basic protein reactive tested in a larger, prospective cohort. Th2 T cells are found in acute disseminated encephalomyelitis. J Neuroimmunol. 1998;91(1-2):19-27. 4. Jorens PG, VanderBorght A, Ceulemans B, et al. Encephalomyelitis-associated Accepted for Publication: December 12, 2006. antimyelin autoreactivity induced by streptococcal exotoxins. Neurology. 2000; Author Affiliations: Departments of Neurology, Univer- 54(7):1433-1441. sity of Strasbourg, Strasbourg (Drs de Seze and Blanc), 5. Dale RC, de Sousa C, Chong WK, Cox TCS, Harding B, Neville BGR. Acute dis- University of Nancy, Nancy (Drs Debouverie and Pit- seminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain. 2000;123(pt 12):2407-2422. tion), University of Lille, Lille (Drs Zephir and Ver- 6. Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-Hagenlocher B. Acute dis- mersch), University of Nice, Nice (Drs Lebrun and Bourg), seminated encephalomyelitis: a follow-up study of 40 adult patients. Neurology. University of Nantes, Nantes (Drs Wiertlewski and 2001;56(10):1313-1318. Laplaud), University of Rennes, Rennes (Drs Le Page and 7. Menge T, Hemmer B, Nessler S, et al. Acute disseminated encephalomyelitis: an Edan), Fondation Rothschild-Paris Hospital, Paris update. Arch Neurol. 2005;62(11):1673-1680. (Drs Deschamps and Gout), Fort de France-Martinique 8. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357 Hospital, Fort de France, Martinique (Dr Cabre), Uni- (9268):1576-1582. versity of Marseille, Marseille (Drs Pelletier and Mali- 9. Beck RW, Chandler DL, Cole SR, et al. Interferon beta-1a for early multiple scle- kova), University of Clermont-Ferrand, Clermont- rosis: CHAMPS trial subgroup analyses. Ann Neurol. 2002;51(4):481-490. Ferrand (Dr Clavelou), University of Caen, Caen 10. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for (Drs Jaillon and Defer), University of Nıˆmes, Nıˆmes multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol. 2001;50(1):121-127. (Dr Labauge), and Mulhouse Hospital, Mulhouse 11. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclero- (Dr Boulay), France. sis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005;58(6):840- Correspondence: Je´roˆme de Seze, MD, Departement de 846. Neurologie, Hoˆpital Civil, 1 Place de l’Hoˆpital, BP 426, 12. Hynson JL, Kornberg AJ, Coleman LT, Shield L, Harvey AS, Kean MJ. Clinical 67091 Strasbourg CEDEX, France (jerome.de.seze and neurologic features of acute disseminated encephalomyelitis in children. @chru-strasbourg.fr). Neurology. 2001;56(10):1308-1312. 13. Mikaeloff Y, Adamsbaum C, Husson B, et al. MRI prognostic factors for relapse Author Contributions: Study concept and design: de Seze, after acute CNS inflammatory demyelination in childhood. Brain. 2004;127 Debouverie, Pelletier, Malikova, and Vermersch. Acqui- (pt 9):1942-1947. sition of data: de Seze, Debouverie, Zephir, Lebrun, Blanc, 14. Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyeli- Bourg, Wiertlewski, Pittion, Laplaud, Le Page, De- tis: a long-term follow-up study of 84 pediatric patients. Neurology. 2002;59 schamps, Cabre, Pelletier, Malikova, Jaillon, Defer, Gout, (8):1224-1231. 15. Leake JA, Albani S, Kao AS, et al. Acute disseminated encephalomyelitis in child- Boulay, Edan, and Vermersch. Analysis and interpreta- hood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J. 2004; tion of data: de Seze, Debouverie, Lebrun, Pelletier, 23(8):756-764. Clavelou, Labauge, and Vermersch. Drafting of the manu- 16. Confavreux C, Compston DA, Hommes OR, McDonald WI, Thompson AJ. EDMUS, script: de Seze, Debouverie, Zephir, Pelletier, Malikova, and a European database for multiple sclerosis. J Neurol Neurosurg Psychiatry. 1992; Boulay. Critical revision of the manuscript for important in- 55(8):671-676. 17. Sellebjerg F, Christiansen M, Nielsen PM, Frederiksen JL. Cerebrospinal fluid mea- tellectual content: de Seze, Debouverie, Lebrun, Blanc, Bourg, sures of disease activity in patients with multiple sclerosis. Mult Scler. 1998; Wiertlewski, Pittion, Laplaud, Le Page, Deschamps, 4(6):475-479. Cabre, Pelletier, Clavelou, Jaillon, Defer, Labauge, Gout, 18. Sandberg-Wollheim M, Vandvik B, Nadj C, Norrby E. The intrathecal immune re- Edan, and Vermersch. Statistical analysis: Debouverie and sponse in the early stage of multiple sclerosis. J Neurol Sci. 1987;81(1):45- Pelletier. Obtained funding: Debouverie, Lebrun, Bourg, and 53. 19. Bergamaschi R, Tonietti S, Franciotta D. Oligoclonal bands in Devic’s neuromy- Labauge. Administrative, technical, and material support: elitis optica and multiple sclerosis: differences in repeated cerebrospinal fluid Debouverie, Lebrun, Bourg, and Vermersch. Study super- examinations. Mult Scler. 2004;10(1):2-4. vision: Malikova, Edan, and Vermersch. 20. Rodriguez M, Karnes WE, Bartleson JD, Pineda AA. Plasmapheresis in acute epi- Financial Disclosure: None reported. sodes of fulminant CNS inflammatory demyelination. Neurology. 1993;43(6): 1100-1104. 21. Markus R, Brew BJ. Successful outcome with aggressive treatment of acute haem- REFERENCES orrhagic leukoencephalitis. J Neurol Neurosurg Psychiatry. 1997;63(4):551- 552. 1. Kesselring J, Miller DH, Robb SA, et al. Acute disseminated encephalomyelitis: 22. Pradhan S, Gupta RP, Shashank S, Pandley N. Intravenous immunoglobulin therapy MRI findings and the distinction from multiple sclerosis. Brain. 1990;113:291- in acute disseminated encephalomyelitis. J Neurol Sci. 1999;165(1):56-61. 302. 23. Sahlas DJ, Miller SP, Guerin M, Veilleux M, Francis G. Treatment of acute dis- 2. Singh S, Alexander M, Korah IP. Acute disseminated encephalomyelitis: MR imaging seminated encephalomyelitis with intravenous immunoglobulin. Neurology. 2000; features. AJR Am J Roentgenol. 1999;173(4):1101-1107. 54(6):1370-1372.

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