fulminant demyelinating encephalomyelitis · neurol neuroimmunol neuroinflamm 2015;2:e175; doi:...

Franziska Di Pauli MDRomana Houmlftberger MDMarkus Reindl PhDRonny Beer MDPaul Rhomberg MDKathrin Schanda MScDouglas Sato MDKazuo Fujihara MDHans Lassmann MDErich Schmutzhard MDThomas Berger MD

Correspondence toDr Bergerthomasbergeri-medacat

Fulminant demyelinatingencephalomyelitisInsights from antibody studies and neuropathology

ABSTRACT

Objectives Antibodies to myelin oligodendrocyte glycoprotein (MOG) are detectable in inflamma-tory demyelinating CNS diseases and MOG antibodyndashassociated diseases seem to have a betterprognosis despite occasionally severe presentations

Methods We report the case of a 71-year-old patient with acute visual and gait disturbance that dra-matically worsened to bilateral amaurosis tetraplegia and respiratory insufficiencywithin a fewdays

Results MRI showed multiple progressive cerebral and spinal lesions with diffusion restriction (includ-ing both optic nerves) andmarginal contrast enhancement Routine blood andCSFmeasures includingoligoclonal bands were normal At disease onset MOG immunoglobulin G was detected (serum titer11280 corresponding CSF titer was 120) and remained positive in patient serum Aquaporin-4antibodieswere absent at disease onset but seroconverted to positive at week 9 In addition CSF glialfibrillary acid protein and myelin basic protein levels were very high at onset but decreased during dis-ease course After 4months the patient died despite immunomodulatory treatment Postmortem neu-ropathologic examination revealed an acute multiple sclerosis (MS) defined by multiple demyelinatinglesions with a pronounced destructive component and loss of astrocytes Lesion pattern of optic chi-asm met MS pattern II characterized by antibody and complement-mediated demyelination

Conclusion The case with the clinical presentation of an acute demyelinating encephalomyelitiswith predominant optic and spinal involvement absent oligoclonal bands a histopathology of acuteMS pattern II and development of aquaporin-4 antibodies extends the spectrum of MOG antibodyndashassociated encephalomyelitis Although MOG antibodies are suspected to indicate a favorableprognosis fulminant disease courses are possible and warrant an aggressive immunotherapyNeurol Neuroimmunol Neuroinflamm 20152e175 doi 101212NXI0000000000000175

GLOSSARYADEM 5 acute disseminated encephalomyelitis AQP4 5 aquaporin-4 GFAP 5 glial fibrillary acid protein Ig 5 immuno-globulin MBP 5 myelin basic protein MOG 5 myelin oligodendrocyte glycoprotein MS 5 multiple sclerosis NMO 5 neuro-myelitis optica

Acute inflammatory demyelinating syndromes of the CNS comprise heterogeneous diseasessuch as multiple sclerosis (MS) neuromyelitis optica (NMO) and acute disseminated enceph-alomyelitis (ADEM) with different pathogenesis severity prognosis disease course and treat-ment options1 Diagnosis based on clinical examination neuroimaging as well as CSFexamination2 might be challenging and reliable biomarkers aremdashexcept for NMO3mdashstill miss-ing Although biopsy is only rarely performed to exclude other treatable differential diagnosesneuropathologic characteristics of different MS patterns ADEM and NMO are well known4

and facilitate the diagnosis of different demyelinating CNS diseases5 However since the initialclinical assessment does not always correlate with the final diagnosis less invasive markers arenecessary to identify different diseases or disease patterns

From the Clinical Department of Neurology (FDP MR RB KS ES TB) and Department of Neuroradiology (PR) Medical Universityof Innsbruck Institute of Neurology (RH) and Center for Brain Research (HL) Medical University of Vienna Austria and Departments ofNeurology and Multiple Sclerosis Therapeutics (DS KF) Tohoku University Graduate School of Medicine Sendai Japan

Funding information and disclosures are provided at the end of the article Go to Neurologyorgnn for full disclosure forms The Article ProcessingCharge was paid by authors

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CCBY-NC-ND) which permits downloading and sharing the work provided it is properly cited The work cannot be changed in any way or usedcommercially

Neurologyorgnn copy 2015 American Academy of Neurology 1

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

In addition to antibodies to aquaporin-4(AQP4) in NMO myelin oligodendrocyte gly-coprotein (MOG) a cell surface protein of mye-lin sheaths and oligodendrocytes in the CNS isan important and extensively studied targetstructure of immunoreactivity in CNS demye-linating diseases6 Measured by cell-based assayMOG antibodies are predominately found inchildren with CNS demyelinating diseases7ndash11

However MOG antibodies have also beendescribed in adults with ADEM in anti-AQP4 antibodyndashnegative NMO cases1213 andin patients with anti-NMDA receptor enceph-alitis with demyelination14

Herein we report the postmortem neuro-pathologic examination of a patient with anacute demyelinating fatal CNS disease andantibodies against MOG

CASE REPORT Clinical course A 71-year-old malepatient with a current history of bronchial asthmaand arterial hypertension complained of acutebilateral vision and gait disturbance in August 2013Initial assessment performed at an external hospital

included cerebral MRI and lumbar puncture CSFanalysis including oligoclonal bands was normalCerebral and spinal MRI showed multiple supra-and infratentorial lesions with marked diffusionrestriction only slight hyperintensity on T2-weightedimages (figures 1A 2 A and D) and intramedullarylesions (figure 2B) Lesions marginally enhancedcontrast (figure 2C) After admission the patientrsquoscondition worsened dramatically to bilateral amaurosiswithin 2 days and tetraplegia within 5 days

Subsequently the patient was referred to our neu-rologic intensive care unit for further diagnostics andtreatment Within 1 day the patientrsquos condition dete-riorated again and acute respiratory insufficiencynecessitated mechanical ventilation

The cerebral and spinal MRI showed progressivemultiple cerebral supra- and infratentorial and spinallesions The lesions were now clearly hyperintense onT2-weighted images and were predominantly local-ized periventricular in the brainstem and intramedul-lary The MRI also demonstrated a restricteddiffusion of both optic nerves (figure 2A) Therewas no evidence of any vascular pathology Incidentalfindings were a frontotemporal meningioma and ver-tebrostenosis due to degenerative changes of spinalcolumn (figure 2 B and C)

Figure 1 Cerebral MRI during the disease course

Cerebral MRI with multiple cerebral supratentorial lesions during the disease course periventricular lesions with diffusionrestriction only slight hyperintensity on T2-weighted images (A) Progressive diffusion restriction and now clearly hyperin-tense lesions on T2-weighted images 2 weeks after disease onset (B) and 4 weeks after disease onset (C) ADC5 apparentdiffusion coefficient

2 Neurology Neuroimmunology amp Neuroinflammation


A second CSF sample taken 1 week after diseaseonset now revealed inflammation with pleocytosiscomposed of lymphocytes and neutrophilic granulo-cytes and increased permeability of the bloodndashbrainbarrier Oligoclonal bands were absent Routine lab-oratory findings including cell count of peripheralblood and inflammatory measures were normal Fur-ther detailed laboratory investigations such as sero-logic analyses for potential infectious agents(including culture and PCR in blood and CSF) andseveral autoantibodies (such as anti-ganglioside andonconeural antibodies thyroid antibodies PR3 andMPO antineutrophil cytoplasmic antibodies anti-phospholipid antibodies) were negative Howeverimmunoglobulin G (IgG) MOG antibodies were pos-itive in serum with a titer of 11280 (IgG1 only witha titer of 1640) and in CSF (titer 120) whereasAQP4 antibodies were absent at disease onset (figure3) MOG and AQP4 antibodies were measured usinga recombinant live cell-based immunofluorescenceassay and an optimized tissue-based immunohisto-chemistry antibody assay as described before1213

An empiric antimicrobial combination therapywas initiated because of the differential diagnostic sus-picion of an infectious cause However no treatmentresponse was observed and another cerebral MRIshowed progressive findings 2 weeks after diseaseonset (figure 1B) Simultaneously an immunomod-ulatory therapy with corticosteroids and IV immuno-globulins was started Because the patient did notrespond to the immune treatment as evidenced by

repeated neuroimaging a brain biopsy was per-formed Corticosteroids were discontinued 3 weeksbefore biopsy Histopathology showed small frag-ments of an actively demyelinating lesion withinflammatory infiltrates consisting of macrophagesand CD3- and CD8-positive T cells (figure 4AndashC) There was no evidence of CD20-positive Bcells (data not shown) One vessel in the periplaquewhite matter revealed perivascular complement depo-sition (figure 4D)

The diagnostic findings suggested an acute demyelin-ating encephalomyelitis with predominantly optic andspinal involvement associated with MOG antibodies

In the following 3 months of continuous hospital-ization repeated MRI CSF and laboratory analyseswere performed All MRI controls (from Septemberto December 2013) showed a stable lesion load with-out any contrast enhancement (MRI 4 weeks afterdisease onset figure 1C) CSF cell counts continu-ously decreased to normal ranges in December 2013Serial serumMOG antibody testing was conducted atweeks 1 4 6 8 9 and 14 after disease onset At 4weeks serum MOG antibody titer had decreased to1640 and at 14 weeks to 180 (figure 3) CSF MOGantibodies (available at disease onset and at weeks 14 9 and 14) were detectable at onset with a titer of120 at week 1 (120) and week 4 (14) and werenegative at weeks 9 and 14 Subclass analyses of IgG1ndash4 revealed that the antibodies belonged to the IgG1subgroup Furthermore only at disease onset IgMMOG antibodies were present at a titer of 1160

Figure 2 Cerebral and spinal MRI

(A) Restricted diffusion of both optic nerves (arrows) on diffusion-weighted and apparent diffusion coefficient imaging (B)Intramedullary lesions (C) Marginal contrast enhancement at disease onset (arrows) (D) Brainstem lesions (arrows)

Neurology Neuroimmunology amp Neuroinflammation 3


Serum AQP4 antibodies were absent at disease onsetbut seroconverted to low-titer positive at week 9 (titer140 IgG1 subclass only figure 3) by cell-basedimmunofluorescence assay and were negative usingtissue immunohistochemistry CSF AQP4 antibodieswere negative at all time points The patient was neg-ative for AQP1 antibodies at all time points

CSF glial fibrillary acid protein (GFAP) and mye-lin basic protein (MBP) levels were retrospectivelyanalyzed by Sato and colleagues at disease onset week4 and week 9 as described before15 Initial levels ofGFAP and MBP were very high at 152492 and3709 ngmL respectively CSF GFAP levelsdecreased in week 4 to 709 ngmL whereas CSFMBP levels firstly increased to 7224 ngmL In week9 both CSF GFAP and MBP levels clearly declinedto 12 and 291 ngmL respectively

Apart from stable or even improved laboratory andimaging findings the clinical condition of the patientwith amaurosis and tetraplegia was unchanged andrequired continuous mechanical ventilation Becauseof the prolonged clinical course without any func-tional improvements treatment was switched to com-fort therapy according to the patientrsquos living will Thepatient died at the end of December 2013 and anautopsy was performed

Neuropathology Postmortem examination of the brainrevealed multiple demyelinating lesions in opticchiasm cerebrum and brainstem The cerebrumshowed multiple confluent chronic inactive demyeli-nated plaques with well-demarcated lesion borders

(figure 4 EndashG) and relatively better preserved axons(data not shown) The plaques were characterized byan absence of myelin in the Luxol fast blue anti-PLP(data not shown) and anti-MBP staining (figure 4H)but contained abundant large preoligodendrocytes thatstrongly labeled for CNPase (figure 4I) while MOGwas almost negative (figure 4J) Cortical plaques werenot visible The inflammatory infiltrates mainlycontained CD3- and CD8-positive T cells (figure 4K and L) and perivascular CD20- and CD79a-positive B cells (figure 4M) The optic chiasmshowed demyelination with residual lesion activitywith perivascular complement deposition (figure 4N)and was characterized by destructive tissue injury withtissue rarefaction and severe loss of astrocytes in theanti-AQP4 AQP1 and GFAP staining (figure 4OndashQ) One plaque in the medulla oblongata wascharacterized by selective loss of AQP4 (figure 4R)while AQP1 and GFAP were still preserved (figure 4SndashT) The astrocytes in this lesion showedclasmatodendrosis with beading or loss of cellularprocesses resulting in rounded astrocytes (figure 4Tmagnified sections) Activated complement depositionwas not found in these areas

DISCUSSION We report the case of an acute fatalCNS demyelinating disease with MOG antibodiesand postmortem neuropathologic examination Thecase shared clinical imaging and laboratory featuresof different demyelinating diseases Clinically thepatient had an acute inflammatory demyelinating dis-ease with predominant involvement of optic nervesand spinal cord The older age of the patient isunusual However several cases with acute CNSdemyelinating diseases in this age group weredescribed before1617 Cerebral and spinal MRIshowed lesions of both optic nerves and a longitudi-nally extensive transverse myelitis compatible withthe diagnosis of NMO However since there wereadditional multiple brain lesions with gadoliniumenhancement and a negative AQP4 antibody statusat disease onset the 2013 criteria as well as the newrecently published diagnostic criteria of NMO werenot met1819 Other potential differential diagnoses ofour case were ADEM andMS In children diagnosticcriteria for ADEM require a demyelinating polyfocalCNS event accompanied by encephalopathy and typ-ical MRI alterations20 whereas widely acceptedADEM diagnostic criteria in adults are lacking21 Inour case the presence of periventricular T1 hypoin-tense lesions which are useful to distinguish ADEMfrom MS2223 argued against diagnosis of ADEM

Fulminant clinical course imaging findings andabsence of oligoclonal bands are also not typical forMS and current diagnostic criteria of a relapsingremitting or primary progressive MS were not met2

Figure 3 Antibody titers during the disease course

Temporal dynamic of MOG and AQP4 antibodies and time points of MRI and CSF samplingAQP4 5 aquaporin-4 MOG 5 myelin oligodendrocyte glycoprotein



Figure 4 Neuropathology of MOG and AQP4 antibodyndashassociated demyelinating lesions in the brain

The biopsy specimen revealed a small actively demyelinating lesion (A arrow in the magnified section indicates macrophages containing LFB-positive myelindegradation products) and inflammatory infiltrates composed of CD68-positive macrophages (B) and CD8-positive T cells (C) One vessel showed perivas-cular deposits of activated complement complex C9neo (D arrows) The autopsy tissue showed confluent demyelinating lesions in the brain that were im-munohistochemically characterized by loss of MBP (E rectangle enlarged in H) but contained large preoligodendrocytes that strongly labeled for CNPase(F rectangle enlarged in I) while MOG was almost negative (G rectangle enlarged in J lesion borders highlighted with dotted lines) The inflammatory infil-trates mainly contained CD3-positive (K) and CD8-positive (L) T cells and perivascular CD79a-positive B cells (M) The lesion in the optic chiasm showedperivascular deposits of activated complement complex C9neo (N arrows) and was characterized by a destructive tissue injury with loss of astrocytesin the anti-AQP4 (O) AQP1 (P) and GFAP staining (Q) One plaque in the medulla oblongata showed a selective loss of AQP4 (R lesion border highlightedwith dotted lines) while AQP1 (S) and GFAP (T) were still preserved The astrocytes in this lesion showed clasmatodendrosis with beading or loss of processesresulting in rounded astrocytes (T magnified sections) Magnification EndashG 340 A and OndashT 3100 BndashD 2003 HndashN and magnified section in T 4003magnified section in A 6003 AQP5 aquaporin CNPase5 2rsquo3rsquo-cyclic-nucleotide 3rsquo-phosphodiesterase GFAP5 glial fibrillary acid protein LFB5 Luxol fastblue MBP 5 myelin basic protein MOG 5 myelin oligodendrocyte glycoprotein



However neuropathology revealed features ofacute MS characterized by destructive lesions withtypical hallmarks of pattern II demyelination24well-demarcated demyelinating lesions were charac-terized by T cellndashmediated inflammation absenceof myelin preserved axons and complement depos-its Similar to our case the clinical presentation maylead to the misdiagnosis of ADEM as it has beenshown that 9 of patients with a clinical diagnosisof ADEM had in contrast to ADEM with typicalperivenous demyelination confluent demyelinationin histopathology and revealed clinically definiteMS in the follow-up25

In our case inflammatory infiltrates were composedof CD68-positive macrophages and CD3- and CD8-positive T cells in accordance with pattern II demyelina-tion24 In contrast to pattern I the presence of immu-noglobulins and complement is a typical finding andindicates the important role of the humoral immuneresponse The diagnosis of the case presented here wascomplicated by the fact that both early MOG and lateAQP4 antibodies were detected MOG antibodies wererecently shown to be present in a subgroup of AQP4antibodyndashnegative NMO cases1226 In addition theyhave been found in different CNS demyelinating dis-eases such as ADEM7112728 optic neuritis transversemyelitis recurrent optic neuritis2930 and a subgroupof anti-NMDA receptor encephalitis with signs ofdemyelination14 In MOG antibodyndashpositive ADEMcases NMO typical sites of demyelination (such as lon-gitudinally extensive transverse myelitisrecurrent opticneuritis) seem to be involved more often than in MOGantibodyndashnegative cases3132 The disease course of thispatient was fulminant without any signs of improve-ment and finally fatal In other studies MOG antibod-ies were associated with a more favorable diseaseoutcome132633 although patients with antibodies occa-sionally have severe acute presentations9 Because of thepossible differential diagnosis of an infectious diseasestart of immunomodulatory treatment was delayedand no treatment escalation was induced These factorsin combination with the older age of the patient mayhave been relevant for the poor outcome

MOG antibodyndashpositive patients with demyelin-ating diseases in whom histopathologic results of abiopsy were available are rare3435 and in accordancewith our case pathology showed MS findings of pat-tern II Furthermore in the present case and anothercase34 antibodies mainly belong to the IgG1 subclasswith the capability to bind complement Since MOGwas identified as a potential target of antibodies in MSand experimental autoimmune encephalomyelitis36 aMOG-specific immunoreactivity in the group ofMOG antibodyndashassociated encephalomyelitis seemslikely Although bystander activation cannot be com-pletely excluded the high immunoreactivity at

disease onset and histopathologic evidence of anantibody-mediated disease mechanism supports thehypothesis of a primary involvement of MOG anti-bodies in disease pathogenesis

Besides MOG antibodies our patient also devel-oped AQP4 antibodies and lesions with complementactivation and AQP4 loss indicating AQP4-mediatedNMO pathology37 Coexistence of AQP4 and MOGantibodies is very rare only single cases are describedin literature12133338 The temporal dynamics of anti-bodies to AQP4 (first detectable after 9 weeks) andMOG (high titer at disease onset) might indicate thatthe immune response to AQP4 developed secondaryto the release of a new antigen(s) However severeloss of astrocytes in optic chiasm and selective loss ofAQP4 in one brainstem lesion suggests in addition tothe loss of myelin per se a pathogenic relevant immu-noreaction against astrocytes although typical patho-logic findings of NMO were missing Furthermorethe initial elevation of GFAP as well as MBP levelsmarkers for astrocyte and myelin damage respec-tively supports a coexisting injury of myelin and as-trocytes early at disease onset A possible explanationfor the high GFAP levels at disease onset instead ofnegative AQP4 antibodies is that AQP4 antibodieswere bound to sites of inflammation and not detect-able in serum as described in a patient with very largeand fulminant NMO lesions in whom serum AQP4antibody titers decreased and accumulated in the cor-responding CNS lesion39 Finally it is also possiblethat 2 different pathogenic processes associated withMOG and AQP4 antibodies overlapped in a singlepatient as has been demonstrated in a subgroup ofpatients with anti-NMDA receptor encephalitis anddemyelinating syndromes with MOG or AQP4 anti-bodies14 or the co-occurrence of antibodies to MOGand the glycine receptor a1 subunit in patients withisolated optic neuritis40

In different clinical presentations MOG antibod-ies are detectable and MOG antibodyndashassociateddiseases seem to be related to an MS pattern II pathol-ogy These findings elucidate the upcoming spectrumof MOG antibodyndashassociated diseases and impor-tantly contribute to the understanding of their patho-genic mechanism

AUTHOR CONTRIBUTIONSCase analysis FDP RB ES TB Neuropathology RH HL Anti-

body analysis MR KS MRI PR GFAP and MBP measurements

DS KF Wrote the manuscript FDP MR

STUDY FUNDINGThis study was supported by a research grant from the Austrian Federal

Ministry of Science and Economy (grant BIG WIG MS)

DISCLOSUREF Di Pauli received travel funding andor speaker honoraria from Biogen

Idec and Genzyme R Houmlftberger reports no disclosures M Reindl is an



academic editor for PLOS ONE is on the editorial board for Current

Medicinal Chemistry and Autoimmune Diseases and received research sup-

port from the Austrian Federal Ministry of Science and Economy The

University Hospital and Medical University of Innsbruck receive pay-

ments for antibody assays (NMDA receptor AQP4 and other autoanti-

bodies) and for AQP4 antibody validation experiments organized by

Euroimmun R Beer received research support from Austrian Science

Fund P Rhomberg and K Schanda report no disclosures D Sato

received speaker honoraria from Novartis is an associate editor for

Arquivos de Neuropsiquiatria and received research support from the

Ministry of Education Culture Sports Science amp Technology in Japan

Japanese Government Scholarship Program Japan Society for the Pro-

motion of Science and CAPESBrasil K Fujihara is on the scientific

advisory board for Bayer Schering Pharma Biogen Idec Mitsubishi

Tanabe Pharma Corporation Novartis Chugai Pharmaceutical Ono

Pharmaceutical Nihon Pharmaceutical Merck Serono Alexion Pharma-

ceuticals MedImmune and Medical Review received travel funding and

speaker honoraria from Bayer Schering Pharma Biogen Idec Eisai Inc

Mitsubishi Tanabe Pharma Corporation Novartis Astellas Pharma Inc

Takeda Pharmaceutical Company Limited Asahi Kasei Medical Co

Daiichi Sankyo and Nihon Pharmaceutical is on the editorial board

for Clinical and Experimental Neuroimmunology is on the advisory board

for Sri Lanka Journal of Neurology received research support from Bayer

Schering Pharma Biogen Idec Japan Asahi Kasei Medical The Chemo-

Sero-Therapeutic Research Institute Teva Pharmaceutical Mitsubishi

Tanabe Pharma Teijin Pharma Chugai Pharmaceutical Ono Pharma-

ceutical Nihon Pharmaceutical Genzyme Japan Ministry of Education

Science and Technology of Japan and the Ministry of Health Welfare

and Labor of Japan H Lassmann has received speaker honoraria and

travel funding from Biogen Idec Novartis and Teva is on the editorial

board for several journals in the fields of neurology and neuroscience has

consulted for Biogen Idec and AMGEN and received research support

from the Austrian Science Fund and the European Union E Schmutz-

hard received speaker honoraria from UCB and ZOLL Medical

T Berger reports no disclosures Go to Neurologyorgnn for full disclo-

sure forms

Received July 28 2015 Accepted in final form September 18 2015

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J Autoimmun 201448ndash49134ndash142

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3 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

4 Popescu BF Lucchinetti CF Pathology of demyelinating

diseases Annu Rev Pathol 20127185ndash217

5 Kuhlmann T Lassmann H Bruck W Diagnosis of

inflammatory demyelination in biopsy specimens a prac-

tical approach Acta Neuropathol 2008115275ndash287

6 Berger T Reindl M Antibody biomarkers in CNS demy-

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2015221162ndash1168

7 OrsquoConnor KC McLaughlin KA De Jager PL et al Self-

antigen tetramers discriminate between myelin autoanti-

bodies to native or denatured protein Nat Med 200713

211ndash217

8 Probstel AK Rudolf G Dornmair K et al Anti-MOG

antibodies are present in a subgroup of patients with a

neuromyelitis optica phenotype J Neuroinflamm 2015

1246

9 Ketelslegers IA Van Pelt DE Bryde S et al Anti-MOG

antibodies plead against MS diagnosis in an acquired

demyelinating syndromes cohort Mult Scler 201521

1513ndash1520

10 Di Pauli F Mader S Rostasy K et al Temporal dynamics

of anti-MOG antibodies in CNS demyelinating diseases

Clin Immunol 2011138247ndash254

11 McLaughlin KA Chitnis T Newcombe J et al Age-

dependent B cell autoimmunity to a myelin surface anti-

gen in pediatric multiple sclerosis J Immunol 2009183

4067ndash4076

12 Mader S Gredler V Schanda K et al Complement

activating antibodies to myelin oligodendrocyte glycopro-

tein in neuromyelitis optica and related disorders

J Neuroinflamm 20118184

13 Hoftberger R Sepulveda M Armangue T et al Antibod-

ies to MOG and AQP4 in adults with neuromyelitis optica

and suspected limited forms of the disease Mult Scler

201521866ndash874

14 Titulaer MJ Hoftberger R Iizuka T et al Overlapping

demyelinating syndromes and anti-N-methyl-D-aspartate

receptor encephalitis Ann Neurol 201475411ndash428

15 Takano R Misu T Takahashi T Sato S Fujihara K

Itoyama Y Astrocytic damage is far more severe than

demyelination in NMO a clinical CSF biomarker study

Neurology 201075208ndash216

16 Krumbholz M Hofstadt-van Oy U Angstwurm K et al

Very late-onset neuromyelitis optica spectrum disorder

beyond the age of 75 J Neurol 20152621379ndash1384

17 Collongues N Marignier R Jacob A et al Characteriza-

tion of neuromyelitis optica and neuromyelitis optica spec-

trum disorder patients with a late onset Mult Scler 2013

201086ndash1094

18 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

19 Wingerchuk DM Banwell B Bennett JL et al Interna-

tional consensus diagnostic criteria for neuromyelitis opti-

ca spectrum disorders Neurology 201585177ndash189

20 Krupp LB Tardieu M Amato MP et al International

Pediatric Multiple Sclerosis Study Group criteria for pedi-

atric multiple sclerosis and immune-mediated central ner-

vous system demyelinating disorders revisions to the 2007

definitions Mult Scler 2013191261ndash1267

21 Koelman DL Mateen FJ Acute disseminated encephalo-

myelitis current controversies in diagnosis and outcome

J Neurol 20152622013ndash2024

22 Callen DJ Shroff MM Branson HM et al MRI in the

diagnosis of pediatric multiple sclerosis Neurology 2009

72961ndash967

23 Verhey LH Branson HM Shroff MM et al MRI param-

eters for prediction of multiple sclerosis diagnosis in children

with acute CNS demyelination a prospective national

cohort study Lancet Neurol 2011101065ndash1073

24 Lucchinetti C Bruck W Parisi J Scheithauer B

Rodriguez M Lassmann H Heterogeneity of multiple

sclerosis lesions implications for the pathogenesis of

demyelination Ann Neurol 200047707ndash717

25 Young NP Weinshenker BG Parisi JE et al Perivenous

demyelination association with clinically defined acute

disseminated encephalomyelitis and comparison with

pathologically confirmed multiple sclerosis Brain 2010

133333ndash348

26 Kitley J Woodhall M Waters P et al Myelin-oligoden-

drocyte glycoprotein antibodies in adults with a neuromy-

elitis optica phenotype Neurology 2012791273ndash1277



27 Reindl M Rostasy K MOG antibody-associated diseases

Neurol Neuroimmunol Neuroinflamm 20152e60

28 Brilot F Dale RC Selter RC et al Antibodies to native

myelin oligodendrocyte glycoprotein in children with

inflammatory demyelinating central nervous system dis-

ease Ann Neurol 200966833ndash842

29 Waters P Woodhall M OrsquoConnor KC et al MOG cell-

based assay detects non-MS patients with inflammatory

neurologic disease Neurol Neuroimmunol Neuroinflamm

20152e89

30 Rostasy K Mader S Schanda K et al Anti-myelin oligo-

dendrocyte glycoprotein antibodies in pediatric patients

with optic neuritis Arch Neurol 201269752ndash756

31 Baumann M Sahin K Lechner C et al Clinical and

neuroradiological differences of paediatric acute dissemi-

nating encephalomyelitis with and without antibodies to

the myelin oligodendrocyte glycoprotein J Neurol Neuro-

surg Psychiatry 201586265ndash272

32 Huppke P Rostasy K Karenfort M et al Acute dissem-

inated encephalomyelitis followed by recurrent or mono-

phasic optic neuritis in pediatric patients Mult Scler 2013

19941ndash946

33 Kitley J Waters P Woodhall M et al Neuromyelitis

optica spectrum disorders with aquaporin-4 and myelin-

oligodendrocyte glycoprotein antibodies a comparative

study JAMA Neurol 201471276ndash283

34 Spadaro M Gerdes LA Mayer MC et al Histopathology

and clinical course of MOG-antibody-associated encepha-

lomyelitis Ann Clin Transl Neurol 20152295ndash301

35 Konig FB Wildemann B Nessler S et al Persistence of

immunopathological and radiological traits in multiple

sclerosis Arch Neurol 2008651527ndash1532

36 Genain CP Cannella B Hauser SL Raine CS Identifica-

tion of autoantibodies associated with myelin damage in

multiple sclerosis Nat Med 19995170ndash175

37 Misu T Hoftberger R Fujihara K et al Presence of six

different lesion types suggests diverse mechanisms of tissue

injury in neuromyelitis optica Acta Neuropathol 2013

125815ndash827

38 Kezuka T Usui Y Yamakawa N et al Relationship

between NMO-antibody and anti-MOG antibody in

optic neuritis J Neuroophthalmol 201232107ndash110

39 Aboulenein-Djamshidian F Hoftberger R Waters P et al

Reduction in serum aquaporin-4 antibody titers during

development of a tumor-like brain lesion in a patient with

neuromyelitis optica a serum antibody-consuming effect

J Neuropathol Exp Neurol 201574194ndash197

40 Martinez-Hernandez E Sepulveda M Rostasy K et al

Antibodies to aquaporin 4 myelin-oligodendrocyte glyco-

protein and the glycine receptor alpha1 subunit in pa-

tients with isolated optic neuritis JAMA Neurol 2015

72187ndash193



DOI 101212NXI000000000000017520152 Neurol Neuroimmunol Neuroinflamm

Franziska Di Pauli Romana Houmlftberger Markus Reindl et al neuropathology

Fulminant demyelinating encephalomyelitis Insights from antibody studies and

This information is current as of November 4 2015

2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy

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In addition to antibodies to aquaporin-4(AQP4) in NMO myelin oligodendrocyte gly-coprotein (MOG) a cell surface protein of mye-lin sheaths and oligodendrocytes in the CNS isan important and extensively studied targetstructure of immunoreactivity in CNS demye-linating diseases6 Measured by cell-based assayMOG antibodies are predominately found inchildren with CNS demyelinating diseases7ndash11

However MOG antibodies have also beendescribed in adults with ADEM in anti-AQP4 antibodyndashnegative NMO cases1213 andin patients with anti-NMDA receptor enceph-alitis with demyelination14

Herein we report the postmortem neuro-pathologic examination of a patient with anacute demyelinating fatal CNS disease andantibodies against MOG

CASE REPORT Clinical course A 71-year-old malepatient with a current history of bronchial asthmaand arterial hypertension complained of acutebilateral vision and gait disturbance in August 2013Initial assessment performed at an external hospital

included cerebral MRI and lumbar puncture CSFanalysis including oligoclonal bands was normalCerebral and spinal MRI showed multiple supra-and infratentorial lesions with marked diffusionrestriction only slight hyperintensity on T2-weightedimages (figures 1A 2 A and D) and intramedullarylesions (figure 2B) Lesions marginally enhancedcontrast (figure 2C) After admission the patientrsquoscondition worsened dramatically to bilateral amaurosiswithin 2 days and tetraplegia within 5 days

Subsequently the patient was referred to our neu-rologic intensive care unit for further diagnostics andtreatment Within 1 day the patientrsquos condition dete-riorated again and acute respiratory insufficiencynecessitated mechanical ventilation

The cerebral and spinal MRI showed progressivemultiple cerebral supra- and infratentorial and spinallesions The lesions were now clearly hyperintense onT2-weighted images and were predominantly local-ized periventricular in the brainstem and intramedul-lary The MRI also demonstrated a restricteddiffusion of both optic nerves (figure 2A) Therewas no evidence of any vascular pathology Incidentalfindings were a frontotemporal meningioma and ver-tebrostenosis due to degenerative changes of spinalcolumn (figure 2 B and C)

Figure 1 Cerebral MRI during the disease course

Cerebral MRI with multiple cerebral supratentorial lesions during the disease course periventricular lesions with diffusionrestriction only slight hyperintensity on T2-weighted images (A) Progressive diffusion restriction and now clearly hyperin-tense lesions on T2-weighted images 2 weeks after disease onset (B) and 4 weeks after disease onset (C) ADC5 apparentdiffusion coefficient













































































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sure forms


REFERENCES

















2015221162ndash1168




211ndash217




1246




1513ndash1520







4067ndash4076








201521866ndash874














201086ndash1094

















72961ndash967













133333ndash348















20152e89












19941ndash946

















125815ndash827













72187ndash193























Reprints













20152e89












19941ndash946

















125815ndash827













72187ndash193























Reprints
























Reprints




fulminant demyelinating encephalomyelitis · neurol neuroimmunol neuroinflamm 2015;2:e175; doi:...

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