Harmel et al. BMC Neurology (2014) 14:247
DOI 10.1186/s12883-014-0247-3

CASE REPORT

Open Access

Interferon-β-related tumefactive brain lesion in a
Caucasian patient with neuromyelitis optica and
clinical stabilization with tocilizumab
Jens Harmel1, Marius Ringelstein1, Jens Ingwersen1, Christian Mathys2, Norbert Goebels1, Hans-Peter Hartung1,
Sven Jarius3 and Orhan Aktas1*

Abstract
Background: Neuromyelitis optica (NMO) is a severely disabling inflammatory disorder of the central nervous
system and is often misdiagnosed as multiple sclerosis (MS). There is increasing evidence that treatment options
shown to be beneficial in MS, including interferon-β (IFN-β), are detrimental in NMO.
Case presentation: We here report the first Caucasian patient with aquaporin 4 (AQP4) antibody (NMO-IgG)seropositive NMO presenting with a tumefactive brain lesion on treatment with IFN-β. Disease started with
relapsing optic neuritis and an episode of longitudinally extensive transverse myelitis (LETM) in the absence of any
brain MRI lesions or cerebrospinal fluid-restricted oligoclonal bands. After initial misdiagnosis of multiple sclerosis
(MS) the patient received subcutaneous IFN-β1b and, subsequently, subcutaneous IFN-β1a therapy for several years.
Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of
subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain
hemisphere and a smaller T2 lesion on the right side. Despite rituximab therapy two further LETM episodes occurred,
resulting in severe neurological deficits. Therapeutic blockade of the interleukin (IL)-6 signalling pathway by
tocilizumab was initiated, followed by clinical and radiological stabilization.
Conclusion: Our case (i) illustrates the relevance of correctly distinguishing NMO and MS since these disorders
differ markedly in their responsiveness to immunomodulatory and -suppressive therapies; (ii) confirms and extends
a previous report describing the development of tumefactive brain lesions under IFN-β therapy in two Asian NMO
patients; and (iii) suggests tocilizumab as a promising therapeutic alternative in highly active NMO disease courses.
Keywords: Neuromyelitis optica, Aquaporin-4 antibodies (NMO-IgG), Interferon-beta, Tocilizumab, Interleukin-6,
Rituximab, Azathioprine, Methylprednisolone, Tumefactive brain lesions, Multiple sclerosis

Background
Interferon-β (IFN-β) is one of the established first-line
therapies for patients with relapsing-remitting multiple
sclerosis (MS). While the efficacy of IFN-β in MS is
widely accepted, the possible benefit in non-classical
MS variants has been disputed. This is the case for neuromyelitis optica (NMO/Devic’s syndrome), considered
an MS subtype until the discovery of the anti-aquaporin 4
(AQP4) antibodies (AQP4-Ab) [1,2]. In both Asian and

European NMO patients, IFN-β failed to show therapeutic
efficacy [3-5]. Of note, Shimizu and colleagues recently reported two Asian patients with NMO spectrum disease
(NMOSD) who developed extensive brain lesions following IFN-β therapy [6]. Here we report the case of an
AQP4 Ab-seropositive NMO patient of Caucasian descent presenting with a tumefactive lesion on IFN-β
treatment. Of note, our patient did not respond to B cell
depletion by the monoclonal anti-CD20 antibody rituximab but improved upon blockade of the interleukin (IL)-6
pathway using tocilizumab.

* Correspondence: orhan.aktas@hhu.de
1
Department of Neurology, Medical Faculty, Heinrich-Heine-University,
Moorenstr. 5, 40225 Düsseldorf, Germany
Full list of author information is available at the end of the article
© 2014 Harmel et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.

Harmel et al. BMC Neurology (2014) 14:247

Page 2 of 5

Case Presentation
A 47-year old Caucasian female patient had been diagnosed with MS in 1995 in an external hospital after
four episodes of optic neuritis (ON) since 1989 and an
episode of longitudinally extensive transverse myelitis
(LETM) in 1995 (Figure 1). Cerebrospinal fluid (CSF)restricted oligoclonal bands (OCBs) were repeatedly
negative and brain MRI scans did not show any

abnormalities (e.g. MRI performed in 2001, Figure 1).
After an initial two months azathioprine treatment in
1995, which had to be discontinued because of side effects, repeated monthly intravenous (iv) steroid pulse
treatments with 250 mg methylprednisolone (MP) were
initiated and continued until April 2013. In 2001, after
three further episodes of ON, subcutaneous IFN-β1b
medication was added to the ongoing steroid pulse

FLAIR

T2

Brain MRI
normal

normal

normal
AQP4+

MS diagnosis

1989

1993

1997

2001

2005

2009

2013 2014

Relapses
MP 1000mg iv
Tocilizumab 8mg/kg 1/m
Rituximab 1000mg
IFN- 1a s.c
IFN- 1b s.c.
MP 250mg iv 1/m
AZA
Figure 1 Disease course, MRI scans and therapy in a patient with AQP4-Ab-positive NMO. The figure depicts clinical relapses (diamonds),
MRI findings (T2, FLAIR), and therapy data (methyl prednisolone (MP) 1000 mg i.v. 3–5 daily infusions; tocilizumab 8 mg/kg bodyweight once a
month; rituximab 1000 mg i.v. (single infusion), IFN (interferon)-β1a 44 μg s.c. three times a week (Rebif®); IFN-β1b s.c. daily (Betaferon®, Betaseron®);
methylpredisolone 250 mg i.v. once per month; azathioprine (AZA)). No relapses have occurred during therapy with tocilizumab (follow-up: 12 months).
AQP: aquaporin, AZA: azathioprine, FLAIR: fluid attenuated inversion recovery, IFN: interferon, MP: methyl prednisolone, MRI: magnetic resonance
imaging, MS: multiple sclerosis, NMO: neuromyelitis optica.

Harmel et al. BMC Neurology (2014) 14:247

treatment. In 2005, subcutaneous IFN-β1b was switched
to subcutaneous IFN-β1a (3 × 44 μg/week). During
IFN-β therapy the patient still suffered from further relapses, most of them occurring between the years 2001
and 2005 (July 2002, February 2005, and April 2005).
She recovered only partially from the relapses and accumulated fixed neurological deficits such as amaurosis of
the right eye and impaired walking with an expanded
disability status scale (EDSS) score of 4.0 in January
2012. Of note, there was no chronic progression between the relapses. In 2011 persisting disease activity
prompted testing for serum AQP4 antibodies (by a cellbased assay; CBA [7]) which were found positive and
confirmed the diagnosis of seropositive NMO. Following the patient’s wishes and in light of the reduced
relapse rate since 2005 therapy with subcutaneous IFNβ1a was continued, together with the regular monthly
steroid therapy (250 mg MP each) established since
1995. In January 2012, she suffered from a subacute
aphasia and right sided hemiparesis and presented to
our department. MRI imaging showed a large T2 hyperintensive, tumefactive lesion in the prefrontal white
matter of the superior and middle frontal gyrus of the
left hemisphere and smaller T2 lesions on the right
side without clear evidence of a disturbed blood brain
barrier (Figure 1). MR spectroscopy showed an unchanged
choline peak and thus did not give a hint to a malignant
process. Analysis of CSF was unremarkable with still
no quantitative evidence for intrathecal immunoglobulin (Ig) synthesis or OCBs and a normal CSF white cell
count. AQP4-Ab serum titre was 1:1000 (CBA). Furthermore, a time-of-flight MR-angiography showed no
signs of vasculitis, and laboratory work-up revealed no
clinical or serological evidence for connective tissue
diseases. The patient received a high-dose methylprednisolone iv pulse and clinically improved. The follow-up
MRI one month later showed a mild regression of the
large T2 hyperintense lesion. We stopped IFN-β therapy
and continued the already existing monthly steroid pulses
(250 mg MP each) as the patient declined any additional
medication at that time. However, two attacks of myelitis
occurred in March 2013 and April 2013. Follow-up
AQP4-Ab testing in April 2013 confirmed seropositivity
(1:1000; CBA). The patient was treated with high-dose
steroid iv pulse therapy and rescue plasmapheresis. Thereafter our patient agreed to an adaptation of therapy and
the monthly steroid infusions were discontinued without
tapering.
We initiated treatment with rituximab (single intravenous infusion of 1000 mg) in May 2013 and transferred our patient to a rehabilitation centre. However,
further severe LETM attacks occurred shortly thereafter
in June and August 2013. The patient was re-admitted
to our department in September 2013 and showed

Page 3 of 5

persistently increased AQP4-Ab titres (1:3200, CBA).
Absolute B cell counts were normal (68/μl) while relative proportion was decreased (3% of all lymphocytes;
reference value 5-24%). This relapse was associated with
a urinary tract infection (without systemic signs of inflammation, i.e. without leucocytosis, fever or elevated C-reactive protein (CRP) levels) which we successfully treated
according to local guidelines. In light of the patient’s severe clinical deficits (EDSS of 9.0) we applied another iv
steroid pulse and decided to switch to tocilizumab, a humanized monoclonal anti-IL-6-receptor antibody. Monthly
infusions of tocilizumab with 8 mg/kg bodyweight were
followed by clinical stabilization as no further relapses occurred for the following 12 months (see clinical and MRI
follow-up after withdrawal of IFN-β in Figure 1). We also
observed a slight clinical improvement, as reflected by an
EDSS of 8.0. Of note, serum AQP4 antibodies were still detectable at high titre at last follow-up in October 2014
(1:3200, CBA).

Conclusions
To our knowledge, we here present the first Caucasian
NMO patient who developed a tumefactive brain lesion
on long-term IFN-β treatment. Our case confirms and
extends similar findings in two Asian NMOSD patients
recently reported by Shimizu and colleagues [6]. Obviously the development of a tumefactive brain lesion
during IFN-β therapy of NMO is not linked to a specific
ethnicity. Moreover, in line with results obtained previously in other cohorts, our patient experienced numerous relapses under IFN-β therapy. Why NMO patients
fail to respond to IFN-β remains so far unclear. Possible
explanations consider the complex immunomodulatory
effects of IFN-β, including the upregulation of proinflammatory cytokines observed in MS [8]. Since in
NMOSD higher CNS levels of IL-17 are observed than
in MS [9], it may be speculated that IL-17 biology may
play a role in NMO unresponsiveness to IFN-β. Moreover, a recent study in NMO patients could link serum
levels of IFN-α, a type I interferon closely related to
IFN-β, with clinical disease activity and severity [10]. Independent experimental work demonstrated that NMOIgG-mediated astrocyte damage is reduced in the CNS of
type I interferon receptor deficient mice, suggesting that
type I interferon signalling contributes to the pathogenesis
of neuromyelitis optica [11].
Of note, administration of a single intravenous infusion of 1000 mg rituximab was followed by further relapses just one and three months later. While CD19
counts were not determined directly after rituximab
application, an investigation four months after rituximab dosing showed normal absolute B cell counts and
persistently increased AQP4-Ab levels. We may speculate that our patient belongs to individuals characterized

Harmel et al. BMC Neurology (2014) 14:247

by an early repopulation of the B cell compartment following rituximab therapy [12].
Our case adds preliminary evidence in favour of a
possible beneficial effect of tocilizumab in NMO, even
following treatment with rituximab [13-15]. However,
considering that NMO is often characterized by very
long periods free of any relapses, the suggested success
of tocilizumab in our patient needs to be followed up.
Moreover, more studies, in particular independent controlled trials, are required to confirm the efficacy of
tocilizumab in NMO suggested by this case report and
previous ones [13-16]. The demonstration of significantly increased levels of IL-6 in comparison to MS in
the CSF and serum of patients with NMO [17,18], particularly in AQP4 Ab-seropositive patients with severe
disease activity [18], provides a rationale for the use of
this drug in NMO. In an ex vivo experimental model of
NMO spinal cord slice cultures exposed to NMO-IgG and
complement showed a marked loss of AQP4 and myelin
which was enhanced by adding IL-6 [19]. Moreover,
Chihara and colleagues described a specific IL-6-dependent
B lymphocyte subpopulation in the peripheral blood
and CSF of NMO patients: these CD19+ CD27+ CD38+
CD180+ B cells were found to produce AQP4 antibodies
and showed enhanced survival as well as AQP4 antibody secretion in the presence of IL-6, whereas blockage
of the IL-6 receptor signalling by an anti-IL-6R antibody
shortened their survival in vitro [20].
Our report illustrates the importance of correctly
diagnosing NMO and MS to avoid mistreatment with
potentially severe or even fatal consequences. Two recent studies have revealed that up to 30% of patients
with NMO were falsely diagnosed with MS [21,22] and,
in consequence, often treated with drugs not effective
in NMO. While AQP4-IgG serum testing is certainly the
most important differential diagnostic measure, other investigations such as lumbar puncture or brain and spinal
cord MRI are important as well. In the present case,
the diagnosis of MS was made in the absence of CSFrestricted OCBs. OCB negativity is extremely rare in
MS (~2-5%) and should prompt physicians to question
that diagnosis; by contrast, around 70% of patients with
AQP4-IgG-positive NMOSD lack OCBs [22-24]. Normal CSF/serum concentration quotient values of IgG
(QIgG) in NMOSD are especially common during periods of clinical remission [23]. Similarly, a persistently
normal brain MRI as observed in our patient should
warn against the diagnosis of MS [25]. Brain lesions
are absent in most patients with NMO at disease onset,
but may occur later in the disease and may even meet
MRI criteria for MS [23,26]. Of note, for Asian NMO
patients, independent case reports described the occurrence of hemispheric brain lesions even without
association to IFN-β therapy [27-29], while we are not

Page 4 of 5

aware of such observations for NMO patients of other
ethnic background. Finally, predominantly central, longitudinally extensive spinal cord lesions extending over
more than three vertebral segments are extremely rare
in MS while their presence is highly suggestive of
NMOSD [30].
Our case supports the conclusion that the development of tumefactive brain lesions under IFN-β therapy
for suspected MS should prompt considering NMOSD
as the underlying disease, obviously not only in Asian but
also in Caucasian patients. Moreover, our report underlines – in accordance with previous reports and recommendations [31] – the need to treat MS and NMO, two
conditions with substantial differences in pathogenesis
[32,33] differentially and, in particular, to avoid treatment
with IFN-β in patients with NMO. Our report adds to previous evidence indicating a potential treatment effect of
tocilizumab, an IL-6 signalling pathway blocker in
NMO therapy.

Consent
Written informed consent was obtained from the patient
for publication of this case report and any accompanying
images. A copy of the written consent is available for
review by the Editor of this journal.
Competing interests
J.H. received speaker honoraria from Novartis and travel expenses from
Merck Serono
M.R. received speaker honoraria from Novartis and travel reimbursement
from Bayer Schering and Biogen Idec.
J.I. reports no conflicts of interest.
C.M. reports no conflicts of interest.
N.G. reports no conflicts of interest.
H.P.H. reports having received honoraria for consulting and speaking at
symposia funded by Bayer Healthcare, Biogen Idec, GeNeuro, Genzyme,
MedImmune, Merck Serono, Novartis, Roche, Teva, and Sanofi-Aventis, with
approval by the Rector of Heinrich Heine University.
S.J. received travel compensation from the Guthy Jackson Charitable
Foundation. The work of S.J. was directly supported by a research grant from
the European Committee for Treatment and Research in Multiple Sclerosis
(ECTRIMS) and indirectly by research grants from the Dietmar Hopp Stiftung,
from Merck Serono and from Bayer Healthcare to the Division of Molecular
Neuroimmunology, University of Heidelberg.
O.A. reports having received honoraria for consulting and speaking from
Bayer HealthCare, Biogen Idec, Genzyme, Merck Serono, Novartis, Teva,
Sanofi-Aventis, as well as research funding from the German Research Council
(DFG), the Hertie Foundation and the Eugène Devic European Network
(BMBF/EU-FP7).

Authors’ contributions
JH. acquired the data, drafted the manuscript and created the figure. MR.
acquired the data and helped to draft the manuscript. JI. revised the
manuscript for important intellectual content and helped creating the figure.
CM. revised the manuscript for important intellectual content and helped
creating the figure. NG revised the manuscript for important intellectual
content. HPH revised the manuscript for important intellectual content. SJ
revised the manuscript for important intellectual content. OA helped to draft
the manuscript, revised the manuscript for important intellectual content
and updated the figure. All authors read and approved the final manuscript.

Harmel et al. BMC Neurology (2014) 14:247

Acknowledgements
We thank the patient for giving her consent to publishing this case report.
We thank the Walter-und-Ilse-Rose-Stiftung for supporting the Multiple
Sclerosis Center at the Department of Neurology, Heinrich-Heine University,
Düsseldorf, Germany. S.J. thanks the Dietmar Hopp Foundation and Merck
Serono for supporting research at the Department of Neurology, University
of Heidelberg, Heidelberg, Germany. This work was supported by the Eugène
Devic European Network (EDEN, BMBF 01GM1203A; EU-FP7).
Author details
1
Department of Neurology, Medical Faculty, Heinrich-Heine-University,
Moorenstr. 5, 40225 Düsseldorf, Germany. 2Department of Diagnostic and
Interventional Radiology, Medical Faculty, Heinrich-Heine-University
Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. 3Molecular
Neuroimmunology, Department of Neurology, University of Heidelberg, Otto
Meyerhof Center, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.

Page 5 of 5

16.

17.

18.

19.

20.

Received: 27 July 2014 Accepted: 11 December 2014
21.
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